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WO2007009697A1 - Quaternary ammonium salts of substituted pyrazoline compounds, their preparation and use as medicaments - Google Patents

Quaternary ammonium salts of substituted pyrazoline compounds, their preparation and use as medicaments Download PDF

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Publication number
WO2007009697A1
WO2007009697A1 PCT/EP2006/006971 EP2006006971W WO2007009697A1 WO 2007009697 A1 WO2007009697 A1 WO 2007009697A1 EP 2006006971 W EP2006006971 W EP 2006006971W WO 2007009697 A1 WO2007009697 A1 WO 2007009697A1
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substituted
mono
group
unsubstituted
methyl
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PCT/EP2006/006971
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French (fr)
Inventor
Antonio Torrens Jover
Jose Mas Prio
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Esteve Pharmaceuticals SA
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Laboratorios del Dr Esteve SA
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Priority claimed from EP05384026A external-priority patent/EP1749821A1/en
Priority claimed from EP05384025A external-priority patent/EP1749820A1/en
Application filed by Laboratorios del Dr Esteve SA filed Critical Laboratorios del Dr Esteve SA
Publication of WO2007009697A1 publication Critical patent/WO2007009697A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • Quaternary ammonium salts of substituted pyrazoline compounds their preparation and use as medicaments
  • the present invention relates to quaternary ammonium salts of substituted pyrazoline compounds, methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans and animals.
  • Cannabinoids are compounds, which are derived from the cannabis sativa plant which is commonly known as marijuana.
  • the most active chemical compound of the naturally occurring cannabinoids is tetrahydrocannabinol (THC), particularly ⁇ 9 -THC.
  • cannabinoids as well as their synthetic analogues promote their physiological effects via binding to specific G-coupled receptors, the so-called cannabinoid-receptors.
  • CBi and CB 2 are involved in a variety of physiological or pathophysiological processes in humans and animals, e. g. processes related to the central nervous system, immune system, cardiovascular system, endocrinous system, respiratory system, the gastrointestinal tract or to reproduction, as described for example, in Hollister, Pharm. Rev. 38, 1986, 1-20; Reny and Singha, Prog. Drug. Res., 36, 71-114, 1991 ; Consroe and Sandyk, in Marijuana/Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds., CRC Press, 1992.
  • the CB r receptor is involved in many different food-intake related disorders such as bulimia or obesity, including obesity associated with type Il diabetes (non-insulin-dependent diabetes) and thus, compounds suitable for regulating this receptor may be used in the prophylaxis and/or treatment of these disorders.
  • these compounds have a high affinity for cannabinoid receptors, particularly for the CB r receptor, and that they act as modulators e. g. antagonists, inverse agonists or agonists on these receptors. They are therefore suitable for the prophylaxis and/or treatment of various disorders related to the central nervous system, the immune system, the cardiovascular system, the endocrinous system, the respiratory system, the gastrointestinal tract or reproduction in humans and/or animals, preferably humans including infants, children and grown- ups.
  • the present invention relates to quaternary ammonium salts of substituted pyrazoline compounds of general formula I,
  • X is O or S
  • A represents a hydrogen atom or an unsubstituted or at least mono-substituted alkyl radical
  • R 1 and R 2 independently of one another, in each case represent an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
  • an unsubstituted or at least mono-substituted aryl or heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an optionally at least mono-substituted alkylene group, alkenylene group or alkinylene group; a -O-R 7 moiety; a -S-R 8 moiety; a -NH-R 9 moiety or a -NR 10 R 11 moiety;
  • R 5 and R 6 independently of one another, in each case represent a hydrogen atom
  • R 5 and R 6 together with the bridging nitrogen form an unsubstituted or at least mono-substituted, saturated or unsaturated heterocyclic ring which may contain at least one further heteroatom as a ring member and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems;
  • R 7 , R 8 , R 9 , R 10 and R 11 independently of one another, in each case represent a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
  • an unsubstituted or at least mono-substituted aryl or heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group;
  • B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo- glutarate, formate, acetate, propionate, lactate, gluconate, unsubstituted or at least mono-substituted benzoate or naphthoate, pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
  • R 12 and R 13 independently of one another, in each case, represent a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • residues R 1 to R 13 and B represents or comprises an aryl, heteroaryl, benzoate or naphthoate radical, which may be substituted, unless defined otherwise, preferably said aryl, heteroaryl, benzoate or naphthoate radical may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -Ci- 6 -perfluoralkyl, -d- 6 -alkyl substituted with one or more methoxy and/or ethoxy groups, -Ci.
  • cyclic moieties cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl, thiophenyl, phenoxy and benzyl can optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -OH, -CF 3 , -CN, -NO 2 , -d. 6 -alkyl, -0-Ci -6 - alkyl, -O-CF 3 and -S-CF 3 and
  • R A , R B , R E and R F independently of one another, represent hydrogen or -Ci- 6 -alkyl or R A and R B in each case together with the bridging nitrogen atom form a radical selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, azepanyl and diazepanyl which may be at least mono-substituted with one or more identical or different C h alky! radicals
  • said aryl and heteroaryl radicals may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF 3 , - C 2 F 5 , -C 3 F 7 , -C 4 F 9 , -CH 2 CI, -CHCI 2 , -C 2 H 4 CI, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -CH 2 -OH, -CH 2 -CH 2 -OH, -CH 2 -CH 2 -CH 2 -OH, -0-CH 2 -O-CH 3 , -0-CH 2 -CH 2 -O-CH 3 , -0-CH 2 -O-C 2 H 5 , - C(OCH 3 )(
  • Preferred aryl radicals which are optionally at least mono-substituted are phenyl and naphthyl (1- and 2-naphthyl).
  • heteroatoms which are present as ring members in the heteroaryl radical may, unless defined otherwise, independently be selected from the group consisting of nitrogen, oxygen and sulfur. More preferably a heteroaryl radical is 5- to 14-membered and may comprise 1 , 2, 3 or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
  • Preferred heteroaryl radicals which are unsubstituted or at least mono-substituted are pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]-benzoxadiazolyl, [1 ,2,3]-benzoxadiazolyl, benzox
  • Preferred aryl and heteroaryl radicals which are condensed with a mono- or polycyclic ring system are [1 ,3]-benzodioxolyl, [1 ,4]-benzodioxanyl, [1 ,2,3,4]- tetrahydronaphthyl, (2,3)-dihydro-1 H-cyclopenta[b]indolyl, [1 ,2,3,4]- tetrahydroquinolinyl, [1 ,2,3,4]-tetrahydroisoquinolinyl, [1 ,2,3,4]-tetrahydroquinazolinyl and [3,4]-dihydro-2H-benzo[1 ,4]oxazinyl.
  • residues R 1 to R 13 and B represents or comprises a saturated or unsaturated, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, preferably a C3.-i 8 cycloaliphat.ic radical, a heterocyclic ring, preferably a 4- to 10-membered heterocyclic ring, a C 3- i 6 cycloalkyl radical, a C 4-16 cycloalkenyl radical, a C 4-I6 heterocycloalkyl radical, or a C 5- - I6 heterocycloalkenyl radical, which may be substituted, unless defined otherwise, preferably said cycloaliphatic radical, heterocyclic ring, C 3 -i 6 cycloalkyl radical, C 4-I6 cycloalkenyl radical, C 4-I6 heterocycloalkyl radical, or C 5-I6 heterocycloalkenyl radical, may in each case optionally be substituted with 1 , 2, 3, 4 or 5 substituent(
  • 6 -alkyl substituted with one or more chlorine atoms -Ci. 6 -alkyl substituted with one or more methoxy and/or ethoxy groups, -O-Ci. 6 -alkyl, -O-Ci.
  • R A , R B , R E and R F independently of one another, represent hydrogen or -Ci- 6 -alkyl or R A and R B in each case together with the bridging nitrogen atom form a radical selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, azepanyl and diazepanyl which may be at least mono-substituted with one or more identical or different C- ⁇ - 6 alkyl radicals
  • residues R 1 to R 13 and B represents or comprises a cycloaliphatic radical, preferably a C 3 .i 6 cycloaliphatic radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of nitrogen, oxygen and sulfur. More preferably a cycloaliphatic group may optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of N, O and S as ring members.
  • Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing cycloaliphatic radicals may preferably be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl
  • Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing cycloaliphatic radicals which are condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system may preferably be selected from the group consisting of indolinyl, isoindolinyl, decahydronaphthyl, (1 ,2,3,4)- tetrahydroquinolinyl, (1 ,2,3,4)-tetrahydroisoquinolinyl, (1 ,2,3,4)-tetrahydronaphthyl, octahydro-cyclopenta[c]pyrrolyl, (1 ,3,4,7,9a)-hexahydro-2H-quinolizinyl, (1 ,2,3,5,6,8a)-hexahydro-indolizinyl, decahydroquinolinyl, dodecahydro-carbazolyl, 9H-carbazolyl
  • a cycloaliphatic radical, a C 3 -i 6 cycloalkyl radical, a C/ M ⁇ cycloalkenyl radical, a C-ne heterocycloalkyl radical or a C 5-I6 heterocycloalkenyl radical may be bridged by 1 , 2 or 3 unsubstituted or at least mono-substituted alkylene group(s).
  • Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing cycloaliphatic radicals which are bridged by at least one unsubstituted or at least mono-substituted alkylene group may preferably be selected from the group consisting of adamantyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, norbornenyl and 8- aza-bicyclo[3.2.1]octyl.
  • a mono- or polycyclic ring system according to the present invention - if not defined otherwise - means a mono- or polycyclic hydrocarbon ring system, preferably a mono- or bicyclic ring system, that may be saturated, unsaturated or aromatic. Each of its different rings may show a different degree of saturation, i.e. they may be saturated, unsaturated or aromatic.
  • each of the rings of the mono- or bicyclic ring system may contain one or more, preferably 1 , 2 or 3, heteroatom(s) as ring member(s), which may be identical or different and which can preferably be selected from the group consisting of nitrogen, oxygen and sulfur.
  • the rings of the mono- or bicyclic ring system are preferably 5-, 6- or 7-membered.
  • condensed means that a ring or ring system is attached to another ring or ring system, whereby the terms “annulated” or “annelated” are also used by those skilled in the art to designate this kind of attachment.
  • cyclic moieties cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl, thiophenyl, phenoxy and benzyl can optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -OH, -CF 3 , -CN, -NO 2 , -d -6 -alkyl, -0-Ci -6 - alkyl, -0-CF 3 and -S-CF 3 and
  • R A , R B , R E and R F independently of one another, represent hydrogen or -Ci- 6 -alkyl or R A and R B in each case together with the bridging nitrogen atom form a radical selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, azepanyl and diazepanyl which may be at least mono-substituted with one or more identical or different d- ⁇ alkyl radicals
  • residues R 3 to R 13 , A and B represent or comprise a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical, preferably a Ci- 16 aliphatic radical, said aliphatic radical may be linear or branched.
  • Ci-i 6 alkyl radicals, C 2 -i 6 alkenyl radical and C 2 .i 6 alkinyl radicals may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently selected from the group consisting of -OH, F, Cl, Br, I, -O-Ci- 6 -alkyl, -OCF 3 , -0-C 2 F 5 , -0-C 3 F 7 , -0-C 4 F 9 , -CF 3 , -C 2 F 5 , -C 3 F 7 , -C 4 F 9 , - NH 2 , -NH-d- ⁇ -alkyl, -N(Ci.
  • Suitable alkyl radicals are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)- heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7-methyl)-octyl, 2-(6-methyl)-octyl, 2-(6-methyl)-oc
  • Suitable at least mono-substituted alkyl radicals are selected from the group consisting of -CF 3 , -CH 2 F, -CF 2 H, -CH 2 -O-CH 3 , -C 2 F 5 , -CH 2 -CH 2 -F, -CH 2 -CN, -CH 2 - OH, -CH 2 -CH 2 -CN, -CH 2 -CH 2 -OH, -CH 2 -CH 2 -OCH 3 , -CH 2 -CH 2 -CH 2 -CN, -CH 2 -CH 2 - CH 2 -OH, -CH 2 -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -CH 2 -CH 2 -O-CH 31 -CH 2 -NH 2 , -CH 2 - N(CH 3 ) 2 , -CH 2 -N(C 2 Hs) 2 , -CH 2 -CH-NH
  • An alkenyl radical according to the present invention comprises at least one carbon- carbon double bond.
  • Suitable alkenyl radicals preferably C 2- i 6 alkenyl radicals, are selected from the group consisting of vinyl, n-propenyl, n-butenyl, n-pentenyl, n- hexenyl, n-heptenyl, n-octenyl, n-nonenyl, n-decenyl, n-undecenyl, n-dodecenyl, n- tridecenyl, n-tetradecenyl, n-pentadecenyl and n-hexadecenyl.
  • An alkinyl radical comprises at least one carbon-carbon triple bond.
  • Suitable alkinyl radicals preferably C 2- -I 6 alkinyl radicals, are selected from the group consisting of ethinyl, propinyl, n-butinyl, n-pentinyl, n-hexinyl, n-octinyl, n-noninyl, n-decinyl, n- undecinyl, n-dodecinyl, n-tridecinyl, n-tetradecinyl, n-pentadecinyl and n-hexadecinyl.
  • any of the substituents represents an alkylene group, an alkenylene group or an alkinylene group, which may be substituted, said alkylene group, alkenylene group or alkinylene group may - if not defined otherwise - be unsubstituted or substituted by one or more substituents, preferably unsubstituted or substituted with 1 , 2 or 3 substituent(s).
  • Said substituent(s) may preferably be selected independently from the group consisting of -O-Ci-e-alkyl, -S-Ci -6 -alkyl, -F, Cl, Br, I 1 -CN, -CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -SO 3 H, -NH 2 , -NH(C 1-6 -alkyl), -N(C 1-6 -alkyl) 2 and phenyl.
  • said substituent(s) may be selected from the group consisting of -F, Cl, Br, I, -CN, - CF 3 , -OCF 3 , -SCF 3 , -OH, -SH, -SO 3 H, -NH 2 , -NH-CH 3 , -N(CH 3 ) 2 , -0-CH 3 and -O- C 2 H 5 .
  • An alkenylene group comprises at least one carbon-carbon double bond
  • an alkinylene group comprises at least one carbon-carbon triple bond.
  • X is O or S
  • A represents a hydrogen atom or an unsubstituted or at least mono-substituted Ci-- I0 alkyl radical
  • R 1 and R 2 independently of one another, in each case represent an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
  • an unsubstituted or at least mono-substituted C 3-I e cycloalkyl radical or C 4- - I6 cycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci -5 alkylene group;
  • an unsubstituted or at least mono-substituted C 3- I 6 cycloalkyl radical or C4- 16 cycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C 1 . 5 alkylene group, C 2 - 5 alkenylene group or C 2 - 5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci -5 alkylene group;
  • an unsubstituted or at least mono-substituted C4-1 6 heterocycloalkyl radical or C 5- i 6 heterocycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C 1 - 5 alkylene group, C 2-5 alkenylene group or C 2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci -5 alkylene group;
  • an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted Ci- 5 alkylene group, C 2-5 alkenylene group or C 2-5 alkinylene group;
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci -5 alkylene group, C 2-5 alkenylene group or C 2-5 alkinylene group;
  • a -O-R 7 moiety a -S-R 8 moiety; a -NH-R 9 moiety or a -NR 10 R 11 moiety;
  • R 5 and R 6 independently of one another, in each case represent a hydrogen atom
  • Ci -16 alkyl radical an unsubstituted or at least mono-substituted Ci -16 alkyl radical, C 2 -i 6 alkenyl radical or C 2 -i ⁇ alkinyl radical;
  • R 5 and R 6 together with the bridging nitrogen form an unsubstituted or at least mono- substituted, saturated or unsaturated 4- to 10-membered heterocyclic ring which may optionally contain 1 , 2 or 3 additional heteroatom(s) selected from the group consisting of sulfur, nitrogen and oxygen as ring member(s) and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems;
  • R 7 , R 8 , R 9 , R 10 and R 11 independently of one another, in each case represent
  • cycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci -5 alkylene group, C 2 - 5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci -5 alkylene group;
  • an unsubstituted or at least mono-substituted C 4-16 heterocycloalkyl radical or C 5-I6 heterocycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C 1 .
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci -5 alkylene group, C 2 - 5 alkenylene group or C 2-5 alkinylene group;
  • B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo- glutarate, formate, acetate, propionate, lactate, gluconate, unsubstituted or at least mono-substituted benzoate or naphthoate, pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
  • Ci-i 6 alkyl radical an unsubstituted or at least mono-substituted Ci-i 6 alkyl radical, C 2 -i 6 alkenyl radical or C 2- i 6 alkinyl radical;
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be bonded via an unsubstituted or at least mono-substituted Ci -5 alkylene group, C2- 5 alkenylene group or C2 -5 alkinylene group; an unsubstituted or at least mono-substituted C 3 -i 6 cycloalkyl radical or C 4- i 6 cycloalkenyl radical, which in each case may be bonded via an unsubstituted or at least mono-substituted C-1. 5 alkylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci -5 alkylene group;
  • the rings of the aforementioned ring system are in each case independently of one another 5- 6- or 7-membered and may in each case independently of one another optionally contain 1 , 2 or 3 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur;
  • heteroaryl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
  • heterocycloalkyl radicals and heterocycloalkenyl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2- hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl and 4- octyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -0-CH 3 , -0-C 2 H 5 , -0-CH 2
  • R 1 to R 13 , X and B have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • R 1 and R 2 independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]- benzothiadia
  • R 3 to R 13 , X, A and B have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • R 3 and R 4 independently of one another, in each case represent H; F; Cl; Br; I; -CN; -NO 2 ; -NC; -OH; -NH 2 ; -SH; -C(O)-H; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl and 4- oc
  • a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH 2 )-, -(CH 2 HCH 2 )-, -(CH 2 )-(CH 2 )-(CH 2 )- or -CH CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF 3 , methyl, ethyl, n-propyl, isopropyl, n-but
  • a -O-R 7 moiety a -S-R 8 moiety, a -NH-R 9 moiety or a -NR 10 R 11 moiety;
  • R 1 , R 2 , R 5 to R 13 , X, A and B have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above wherein R 5 and R 6 , independently of one another, in each case represent a hydrogen atom;
  • R 1 to R 4 , R 7 to R 13 , X, A and B have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • R 1 to R 4 , R 7 to R 13 , X, A and B have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • R 7 , R 8 , R 9 , R 10 and R 11 independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4- heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5- methyl)-he
  • a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH 2 )-, -(CH 2 HCH 2 )-, -(CH 2 )-(CH 2 )-(CH 2 )- or -CH CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF 3 , methyl, ethyl, n-propyl, isopropyl, n-CF
  • R 1 to R 6 , R 12 , R 13 , X, A and B have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • quaternary ammonium salts of substituted pyrazoline compounds of general formula I wherein B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo-glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate which may be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, -OH, -0-CH 3 and -0-C 2 H 5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
  • R 1 to R 13 , X and A have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • R 12 and R 13 independently of one another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2- octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2- (4-methyl)-hex
  • R 1 to R 11 , X 1 B and A have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • X is O or S:
  • A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4- heptyl, n-octyl, 2-octyl, 3-octyl and 4-octyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -O- CH 3 , -0-C 2 H 5 , -0-CH 2 -CH 2 -CH 3 , -O-CH(CH 3 ) 2 , -0-CH 2
  • R 1 and R 2 independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl
  • cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, diazepanyl, azocan
  • a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH 2 )-, -(CH 2 HCH 2 )-, -(CH 2 )-(CH 2 )-(CH 2 )- or -CH CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF 3 , methyl, ethyl, n-propyl, isopropyl, n-but
  • a -O-R 7 moiety a -S-R 8 moiety, a -NH-R 9 moiety or a -NR 10 R 11 moiety;
  • R 5 and R 6 independently of one another, in each case represent a hydrogen atom
  • R 5 and R 6 together with the bridging nitrogen atom form a moiety selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, azepanyl, diazepanyl, azocanyl, (2,5)-dihydro-1 H-pyrrolyl, (2,3)-dihydro-1 H-pyrrolyl, (1 ,2,3,6)- tetrahydropyridinyl, (1 ,2,3,4)-tetrahydropyridinyl, (1 ,2,5,6)-tetrahydropyridinyl, [1 ,3]- oxazinanyl, hexahydropyrimidinyl, (5,6)-dihydro-4H-pyrimidinyl, (5,6)-d
  • R 7 , R 8 , R 9 , R 10 and R 11 independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2- hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7- methyl)-octyl;
  • a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH 2 )-, -(CH 2 )-(CH 2 )-, -(CH 2 )-(CH 2 )-(CH 2 )- or -CH CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF 3 , methyl, ethyl, n-propyl, isopropyl,
  • B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo- glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate which may be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, -OH, -0-CH 3 and -0-C 2 H 5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate, R i2 -sor and R 13 -NH-S ⁇ 3 ;
  • R 12 and R 13 independently of one another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n- heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)- heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7-methyl)-octyl; 2-(6-methyl)-octyl
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • X is O or S
  • A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl;
  • R 1 and R 2 independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]-benzoxadiazolyl, [1 ,2,3]- be
  • a -O-R 7 moiety a -S-R 8 moiety, a -NH-R 9 moiety or a -NR 10 R 11 moiety;
  • R 4 represents H or an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl;
  • R 7 , R 8 , R 9 , R 10 and R 11 independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl; R 5 and R 6 together with the bridging nitrogen atom form a moiety selected from the group consisting of
  • B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo-glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate which may be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, -OH, -O- CH 3 and -0-C 2 H 5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
  • R 12 and R 13 independently of one another, in each case represent a radical selected from the group consisting Of -CF 3 , -C 2 F 5 , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2- hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7- methyl )-oct
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl and n-propyl;
  • R 1 represents a radical selected from the group consisting of phenyl and thienyl (thiophenyl), which may optionally be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -0-CH 3 and -O-C 2 H 5 ;
  • R 2 represents a phenyl radical, which may be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br and I;
  • R 4 represents H or a radical selected from the group consisting of methyl, ethyl, n- propyl, iso-propyl and n-butyl;
  • R 5 and R 6 together with the bridging nitrogen atom form a moiety selected from the group consisting of
  • R 7 represents a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl;
  • B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, methanesulfonate, ethanesulfonate, toluenesulfonate, benzenesulfonate, (2,5)-dihydroxy-benzenesulfonate, naphthalene-2-sulfonate, 5- sulfo-napthalene-1 -sulfonate, cyclamate, dodecane-1 -sulfonate and (7,7)-dimethyl-2- oxo-bicyclo[2.2.1]-hept-1-yl-methanesulfonate;
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • trans-1 [27] trans-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [28] trans-1 -[[5-(4-Bromo-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [29] trans-1 -[[5-(4-Fluoro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [30] c
  • trans-1 [32] trans-1 -[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-pyrrolidinium iodide [33] trans-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-azepanium iodide [34] cis-2-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-2-methyl-octahydrocyclopenta[c]pyrrolium iodide [
  • 4,5-dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • the present invention provides a N-oxide of general formula Ia,
  • X a is O or S
  • R 1a and R 2a independently of one another, in each case represent an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
  • an unsubstituted or at least mono-substituted aryl or heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an optionally at least mono-substituted alkylene group, alkenylene group or alkinylene group;
  • R 5a and R 6 * 1 independently of one another, in each case represent a hydrogen atom
  • R 5a and R 68 together with the bridging nitrogen form an unsubstituted or at least mono-substituted, saturated or unsaturated heterocyclic ring which may contain at least one further heteroatom as a ring member and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems;
  • R 7a , R 8a , R 9a , R 1Oa and R 11a independently of one another, in each case represent a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
  • an unsubstituted or at least mono-substituted aryl or heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group;
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • X a is O or S
  • R 1a and R 2a independently of one another, in each case represent an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
  • Ci-i 6 alkyl radical C 2-16 alkenyl radical or C 2-16 alkinyl radical;
  • an unsubstituted or at least mono-substituted C 3-16 cycloalkyl radical or C- M6 cycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C 1 - S alkylene group, C 2-5 alkenylene group or C 2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted C 1-5 alkylene group;
  • an unsubstituted or at least mono-substituted C-J -16 heterocycloalkyl radical or C 5 .i 6 heterocycloalkenyl radical which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C 1-5 alkylene group, C 2-5 alkenylene group or C 2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted C 1-5 alkylene group;
  • an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted Ci- 5 alkylene group, C 2-5 alkenylene group or C 2 .
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C 2 . 5 alkenylene group or C 2 - 5 alkinylene group;
  • a -O-R 7a moiety a moiety; a -S-R 83 moiety; a -NH-R 9a moiety or a -NR 1Oa R 11a moiety;
  • R 5a and R 68 independently of one another, in each case represent a hydrogen atom
  • Ci.i 6 alkyl radical an unsubstituted or at least mono-substituted Ci.i 6 alkyl radical, C 2- i 6 alkenyl radical or C 2 -i 6 alkinyl radical;
  • R 5a and R 68 together with the bridging nitrogen form an unsubstituted or at least mono-substituted, saturated or unsaturated 4- to 10-membered heterocyclic ring which may optionally contain 1 , 2 or 3 additional heteroatom(s) selected from the group consisting of sulfur, nitrogen and oxygen as ring member(s) and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems;
  • R 7a , R 83 , R 9a , R 1Oa and R 11a independently of one another, in each case represent
  • an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted C1-5 alkylene group, C2- 5 alkenylene group or C 2-5 alkinylene group;
  • an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci -5 alkylene group, C 2 - 5 alkenylene group or C 2-S alkinylene group;
  • the rings of the aforementioned ring system are in each case independently of one another 5- 6- or 7-membered and may in each case independently of one another optionally contain 1 , 2 or 3 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur;
  • heteroaryl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
  • heterocycloalkyl radicals and heterocycloalkenyl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s); optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • N-oxides of general formula Ia given above More particularly preferred are N-oxides of general formula Ia given above, wherein
  • X a is O or S
  • R 1a and R 2a independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]-benzoxadiazolyl, [1 ,2,3]
  • R 4a represents H or an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl;
  • R 7a , R 8a , R 9a , R 1Oa and R 11a independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl;
  • R 5a and R 68 together with the bridging nitrogen atom form a moiety selected from the group consisting of
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • X a is O
  • R 1a represents a radical selected from the group consisting of phenyl and thienyl (thiophenyl), which may optionally be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -0-CH 3 and -0-C 2 H 5 ;
  • R 2a represents a phenyl radical, which may be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br and I;
  • R 4a represents H or a radical selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl and n-butyl;
  • R 5a and R 68 together with the bridging nitrogen atom form a moiety selected from the group consisting of
  • R 7a represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl;
  • stereoisomers optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
  • R 3 and X have the meaning given above and R' represents a linear or branched Ci -6 -alkyl radical, a potassium cation or a sodium cation, in a reaction medium, optionally in an inert atmosphere, optionally in the presence of at least one base, to yield at least one compound of general formula IV,
  • R 1 , X and R 3 have the meaning given above, which is optionally purified and/or isolated,
  • R 1 , X, R 2 and R 3 have the meaning given above, which is optionally isolated and/or purified,
  • R 1 , X, R 2 and R 3 have the meaning given above and LG represents a leaving group, which is optionally purified and/or isolated, and at least one compound of general formula VII is reacted with at least one compound of general formula NH 2 -NR 5 R 6 , wherein R 5 and R 6 have the meaning given above, in a reaction medium, optionally in an inert atmosphere, optionally in the presence of at least one base selected from the group consisting of diisopropylethylamine, triethylamine, pyridine, dimethylaminopyridine and N- methylmorpholine, to yield at least one compound of general formula VIII,
  • R 1 , R 2 , R 3 , X, R 5 and R 6 have the meaning given above, which is optionally purified and/or isolated;
  • At least one compound of general formula Vl is reacted with at least one compound of general formula NH 2 -NR 5 R 6 , wherein R 5 and R 6 have the meaning given above, in a reaction medium, in the presence of at least one coupling agent, optionally in the presence of at least one base, to yield at least one compound of general VIII, which is optionally purified and/or isolated;
  • R 4 represents hydrogen, which is optionally purified and/or isolated.
  • a compound of general formula Il is reacted with a compound of general formula III in a protic reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n- butanol, water and mixtures thereof, in the presence of at least one base, preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide, as described, for example, in Synthetic Communications, 26(11 ), 2229-33, (1996).
  • Reaction temperature as well as the duration of the reaction may vary over a broad range. Preferred reaction temperatures range from -10 0 C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
  • reaction between a compound of general formula Il and a compound of general formula III can also be carried out under acid catalysed conditions, more preferably by refluxing the above mentioned compounds in dichloromethane in the presence of copper(ll)trifluoromethanesulfonate as described, for example, in Synlett, (1 ), 147-149, 2001.
  • acid catalysed conditions more preferably by refluxing the above mentioned compounds in dichloromethane in the presence of copper(ll)trifluoromethanesulfonate as described, for example, in Synlett, (1 ), 147-149, 2001.
  • the respective description is hereby incorporated by reference and forms part of the disclosure.
  • step 2 a compound of general formula IV is reacted with a compound of general formula V in a reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n- butanol, dieethylether, tert-butyl-methylether, dioxane, tetrahydrofuran or mixtures of at least two of these afore mentioned reaction media.
  • said reaction may be carried out in the presence of an acid, whereby the acid may be organic such as acetic acid and/or inorganic such as hydrochloric acid.
  • reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide or mixtures of at least two of these bases.
  • a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide or mixtures of at least two of these bases.
  • Reaction temperature as well as the duration of the reaction may vary over a broad range. Suitable reaction temperatures range from room temperature, i.e. approximately 25 0 C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
  • the carboxylic group of the compound of general formula Vl may be activated for further reactions by the introduction of a suitable leaving group according to conventional methods well known to those skilled in the art.
  • a suitable leaving group Preferably the compounds of general formula Vl are transferred into an acid chloride, an acid anhydride, a mixed anhydride, a Ci- 4 alkyl ester or an activated ester such as p- nitrophenylester.
  • Suitable activating agent therefore are selected from the group consisting of thionyl chloride, oxalyl chloride and ethylchloroformiate.
  • said activated compound of general formula VII is an acid chloride, wherein LG represents a chlorine atom
  • that compound is preferably prepared by the reaction of the corresponding acid of general formula Vl with thionyl chloride or oxalyl chloride, whereby said chlorinating agent is also used as the reaction medium, in the presence of at least one base, preferably in the presence of a base selected from the group consisting of triethylamine, N-methylmorpholine, pyridine, dimethylaminopyridine and diisopropylethylamine.
  • a base selected from the group consisting of triethylamine, N-methylmorpholine, pyridine, dimethylaminopyridine and diisopropylethylamine.
  • an additional reaction medium may be used.
  • Suitable reaction media include hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane or dimethylformamide and mixtures thereof. More preferably toluene in the presence of a catalytic amount of dimethylformamide is used as reaction medium.
  • Preferred reaction temperature range from 0° C to the boiling point of the solvent and reaction times vary from several minutes to several hours.
  • said anhydride may preferably be prepared, for example, by reaction of the corresponding acid of general formula Vl with ethylchloroformiate in the presence of a base such as triethylamine, pyridine or diisopropylethylamine, in a suitable solvent such as dichloromethane, optionally in an inert atmosphere, at a temperature between -50 0 C and 50 0 C.
  • step 4 the reaction between a compound of general formula VII with a compound of general formula NHb-NR 5 R 6 to yield a compound of general formula VIII is preferably carried out in the presence of a base such as triethylamine in a reaction medium such as methylenchloride.
  • a base such as triethylamine
  • a reaction medium such as methylenchloride.
  • the temperature is preferably in the range from 0 0 C to the boiling point of the reaction medium.
  • the reaction time may vary over a broad range, e.g. from several hours to several days.
  • a compound of general formula Vl is reacted with a compound of general formula NHk-NR 5 R 6 in a reaction medium, preferably in a reaction medium selected from the group consisting of diethylether, tetrahydrofuran, acetonitrile, methanol, ethanol, (1 ,2)-dichlorethane, dimethylformamide, dichlormethane and mixtures thereof, in the presence of at least one coupling agent, preferably in the presence of at least one coupling agent selected from the group consisting of 1 -benzotriazolyloxy- tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI) 1 diisoproylcarbodiimide, 1 ,1'-carbonyl-diimidazole (CDI
  • reaction is carried out in the presence of EDCI and HOBt, optionally in the presence of N-methylmorpholine or triethylamine, in an aprotic reaction medium such as dimethylformamide or tetrahydrofuran, at a temperature between 20 °C and 30 0 C for 15 to 24 hours as described in Tetrahedron Lett. 2004, 45, 4977.
  • aprotic reaction medium such as dimethylformamide or tetrahydrofuran
  • reaction can be carried out by using HBTU in the presence of a base such as diisopropylethylamine in an aprotic solvent, such as acetonitrile, preferably at a temperature between 20 and 30 0 C for 15 to 24 hours.
  • a base such as diisopropylethylamine
  • an aprotic solvent such as acetonitrile
  • A represents an unsubstituted or at least mono-substituted alkyl radical, preferably an unsubstituted C 1-I0 alkyl radical and B represents an anion selected from the group consisting of fluoride, chloride, bromide and iodide, in a reaction medium, preferably in a reaction medium selected from the group consisting of chloroform, acetone, acetonitrile, dichloromethane, carbon tetrachloride, toluene and mixtures of the afore mentioned reaction media, at a temperature between 0 0 C to 120 °C, preferably at a temperature between 20 0 C to 100 0 C, to afford a salt of general formula I.
  • the duration of the reaction may vary over a broad range. Suitable reaction times may vary for example
  • A represents a hydrogen atom
  • B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo- glutarate, formate, acetate, propionate, lactate, gluconate, unsubstituted or at least mono-substituted benzoate or naphthoate, pyruvate, ascorbate, glycolate, nicotinate, phenylacetate, R 1 -SO-f and R 1 -NH-SO 3 ; wherein R 12 and R 13 have the meaning given above; in a reaction medium, preferably in a reaction medium selected from the group consisting of
  • Suitable acids include hydrochloric, hydrofluoric, hydroiodic or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; thiocyanic acid; cyanic acid; cyclamic acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g.
  • Suitable acids also include 3-amino-1-propanesulfonic acid, aniline-2-sulfonic acid, 3- pyridinesulfonic acid, 4-amino-3-hydroxy-1 -naphthalenesulfonic acid, 2-amino-1 ,5- naphthalenedisulfonic acid, aminomethanesulfonic acid, 2-mesitylenesulfonic acid, 7- amino-1 ,3-naphthalenedisulfonic acid, (2,5)-diaminobenzenesulfonic acid, trifluormethanesulfonic acid, 1 -naphthalenesulfonic acid, 6-amino-m-toluenesulfonic acid, 2-phenylbenzimidazole-5-sulfonic acid, 1-amino-benzimidazole-2-sulfonic acid, I H-benzimidazole-2-sulfonic acid, 1-methylbenzimidazole-2-sulfonic acid, 5- isoquinolinesulfonic
  • Hydrochloric acid is preferably used as a methanolic, ethanolic, ethereal or aqueous solution.
  • hydrogen chloride gas can be used for the preparation of the salts of general formula I given above.
  • a compound of general formula IMb is reacted with a compound of general formula Il in a reaction medium , preferably in a protic reaction medium, more preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, water and mixtures thereof, in the presence of at least one base, preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide or in the presence of lithium diisopropylamide in an aprotic solvent, preferably in tetrahydrofuran.
  • a reaction medium preferably in a protic reaction medium, more preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, water and mixtures thereof, in the presence of at least one base, preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or
  • step 2 a compound of general formula Xl is transformed into a compound of general formula XII which contains a good living group LG, preferably a leaving group selected from the group consisting of mesyl and tosyl, using conventional methods known to those skilled in the art.
  • LG preferably a leaving group selected from the group consisting of mesyl and tosyl
  • step 3 a compound of general formula XII is reacted with a compound of general formula V in a reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n- butanol, dieethylether, tert-butyl-methylether, dioxane, tetrahydrofuran or mixtures of at least two of these afore mentioned reaction media.
  • said reaction may be carried out in the presence of an acid, whereby the acid may be organic such as acetic acid and/or inorganic such as hydrochloric acid.
  • reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide or mixtures of at least two of these bases.
  • a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide or mixtures of at least two of these bases.
  • Reaction temperature as well as the duration of the reaction may vary over a broad range. Suitable reaction temperatures range from room temperature, i.e. approximately 25 0 C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
  • Step 4 can be carried out as described for step 3, scheme I; step 5 can be carried out as described for step 5, scheme I, step 6 can be carried out as described for step 4, scheme 1 and step 7 can be carried out as described for step 6, scheme I.
  • the afore mentioned reactions involving the synthesis of the 4,5-dihydro-pyrazole ring or the reaction of a compound comprising said ring are preferably carried out under an inert atmosphere, preferably under a nitrogen or argon atmosphere, to avoid oxidation of the ring-system.
  • an inert atmosphere preferably under a nitrogen or argon atmosphere
  • the protection of sensitive or reactive groups may be necessary and/or desirable. This can be performed by using conventional protective groups like those described in Protective groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; T.W. Greene & P.G.M. Wuts and Protective Groups in Organic Chemistry, John Wiley & sons, 1991.
  • the respective parts of the description is hereby incorporated by reference and forms part of the disclosure.
  • the protective groups may be eliminated when convenient by means well-known to those skilled in the art.
  • substituted pyrazoline compounds and/or the quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or crystallization with chiral reagents. It is also possible to obtain pure stereoisomers via stereoselective synthesis.
  • Solvates preferably hydrates, of the quaternary ammonium salts of substituted pyrazoline compounds, of corresponding stereoisomers or of corresponding diastereomers thereof may also be obtained by standard procedures known to those skilled in the art.
  • the purification and isolation of the substituted pyrazoline compounds and/or of quaternary ammonium salts of substituted pyrazoline compounds, of a corresponding stereoisomer, or diastereomer or solvate or any intermediate thereof may, if required, be carried out by conventional methods known to those skilled in the art, e.g. chromatographic methods or recrystallization.
  • the quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above may also act as prodrugs, i.e. they represent a drug precursor, which following administration to a patient releases a drug in vivo via some kind of chemical and/or physiological process (e.g., a prodrug on being brought to a physiological pH and/or through an enzyme action is converted to a desired drug form; see, e.g., R. B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chp. 8).
  • the compounds of general formula I give rise to a compound of general formula XIII,
  • Prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically enter the reactive site of the protease) or the pharmacokinetics for a particular compound.
  • a hydroxyl group can be esterified, e.g., with a carboxylic acid group to yield an ester.
  • the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively or hydrolytically, to reveal the hydroxyl group.
  • quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above have a high affinity to cannabinoid receptors, particularly cannabinoid 1 (CBi)-receptors, i.e. they are selective ligands for the (CBi)-receptor and act as modulators, e.g. antagonists, inverse agonists or agonists, on these receptors.
  • cannabinoid 1 (CBi)-receptors particularly cannabinoid 1 (CBi)-receptors, i.e. they are selective ligands for the (CBi)-receptor and act as modulators, e.g. antagonists, inverse agonists or agonists, on these receptors.
  • these quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above show little or no development of tolerance during treatment, particularly with respect to food intake, i.e.
  • the inventively used quaternary ammonium salts of substituted pyrazoline compounds will again show the desired effect.
  • the positive influence on the body weight is found to continue.
  • inventively used quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above are distinguished by a broad spectrum of beneficial effects, while at the same time showing relatively little undesired effects, i.e. effects which do not positively contribute to or even interfere with the well being of the patient.
  • an other aspect of the present invention relates to a medicament comprising at least quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally at least one physiologically acceptable auxiliary agent.
  • said medicament is suitable for the modulation (regulation) of cannabinoid-receptors, preferably cannabinoid 1 (CBi) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
  • cannabinoid-receptors preferably cannabinoid 1 (CBi) receptors
  • Particularly preferably said medicament is suitable for the prophylaxis and/or treatment of psychosis.
  • said medicament is suitable for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity and/or type Il diabetus mellitus (non-insuline dependent diabetes mellitus), more preferably obesity.
  • the inventive medicament also seems to be active in the prophylaxis and/or treatment of appetency disorders, e.g. the quaternary ammonium salts of substituted pyrazoline compounds also reduce the desire for sweets.
  • pyrazoline compounds as defined herein and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the treatment of metabolic syndrome.
  • the metabolic syndrome and definitions thereof are described in detail by Eckel et al., The Lancet, Vol. 365 (2005), 1415-1428, included herewith by reference.
  • One of the respective definitions was established by the WHO in 1998 (as described in Alberti et al., Diabet. Med. 1998, 15, pages 539-53, the respective description thereof is herewith incorporated by reference and forms part of the present disclosure).
  • the other, more widely accepted, definition of the metabolic syndrome was established by the Adult Treatment Panel (ATP III) of the US National Cholesterol Education Program (NCEP) in 2001 , as described in JAMA 2001 ; 285; 2486-97, the respective description thereof is herewith incorporated by reference and forms part of the present disclosure.
  • the metabolic syndrome is characterized by an interaction of several physiological parameters such as triglycerides, lipids, blood pressure, glucose levels and insuline levels.
  • Another aspect of the invention is the use of one or more pyrazoline compounds as defined herein for the manufacture of a medicament for improvement of cardiovascular and/or metabolic risk factors, such as one or more of the following factors:
  • Elevated triglycerides whereby elevated levels of triglycerides are preferably understood as being > 150 mg/dl,
  • Low HDL cholesterol whereby low levels of HDL cholesterol are preferably understood as being ⁇ 40 mg/dl in men and ⁇ 50 mg/dl in women,
  • Hypertension whereby hypertension is preferably understood as being > 130/85 mm Hg,
  • Impaired fasting glucose whereby impaired fasting glucose levels are preferably understood as being > 110 mg/dl,
  • Another aspect of the invention is the use of one or more pyrazoline compounds as defined herein for the manufacture of a medicament for the treatment of the weight independent aspects of metabolic syndrome.
  • Another aspect of the invention is a method for improving cardiovascular and/or metabolic risk factors, such as one or more of the following factors:
  • Elevated triglycerides whereby elevated levels of triglycerides are preferably understood as being > 150 mg/dl,
  • Low HDL cholesterol whereby low levels of HDL cholesterol are preferably understood as being ⁇ 40 mg/dl in men and ⁇ 50 mg/dl in women,
  • Hypertension whereby hypertension is preferably understood as being > 130/85 mm Hg, Impaired fasting glucose, whereby impaired fasting glucose levels are preferably understood as being > 110 mg/dl,
  • a subject preferably a human.
  • Another aspect of the invention is a method for treating of the weight independent aspects of metabolic syndrome.
  • said medicament is suitable for the prophylaxis and/or treatment of cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, bowel cancer and prostate cancer, more preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer.
  • cancer preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer.
  • Particularly preferably said medicament is suitable for the prophylaxis and/or treatment of alcohol abuse and/or alcohol addiction, nicotine abuse and/or nicotine addiction, drug abuse and/or drug addiction and/or medicament abuse and/or medicament addiction, preferably drug abuse and/or drug addiction and/or nicotine abuse and/or nicotine addiction.
  • the inventive medicament is active in the treatment of abstinence, craving reduction and relapse prevention of alcohol intake.
  • the inventive medicament can also be used in the prophylaxis and/or treatment of smoking addiction, cessation and/or dependence including treatment for craving reduction and relapse prevention of tobacco smoking.
  • Medicaments and/or drugs, which are frequently the subject of misuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.
  • the medicament is also suitable for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of bone disorders, preferably osteoporosis (e.g. osteoporosis associated with a genetic predisposition, sex hormone deficiency, or ageing), cancer-associated bone disease or Paget's disease of bone; schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebella disorders, spinocerebella disorders, cognitive disorders, cranial trauma, head trauma, stroke, panic attacks, peripheric neuropathy, inflammation, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, medicament-induced movement disorders, dystonia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunologic disorders, sclerotic plaques, vomiting, diarrho
  • the medicament is also suitable for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of dementia and related disorders, preferably for the prophylaxis and/or treatment of one or more types of dementia selected from the group consisting of memory loss, vascular dementia, mild cognitive impairment, frontotemporal dementia and Pick's disease; binge eating disorders; juvenile obesity; drug induced obesity; atypical depression; behavioural addictions; attention deficit disorders; Tourette's syndrome; suppression of reward-related behaviours; e. g.
  • conditioned place avoidance such as suppression of cocaine- and morphine induced conditioned place preference; impulsivity; sexual dysfunction; preferably for the prophylaxis and/or treatment of one or more types of sexual dysfunction selected from the group consisting of erectile difficulty and female sexual dysfunction; seizure disorders; nausea; emesis; neuroinflammatory disease, preferably for the prophylaxis and/or treatment of one or more types of neuroinflammatory diseases selected from the group consisting of multiple sclerosis, demyelinisation related disorders, Guillan-Barre syndrome, viral encephalitis and cerebrovascular accidents; neurological disorders; muscle spasticity; traumatic brain injury; spinal cord injury; inflammation and immunomodulatory disorders, preferably for the treatment and/or prophylaxis of one or more types of inflammation and immunomodulatory disorders selected from the group consisting of cutaneous T-cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus, sepsis, sarcoidosis, idiopathic pulmonary
  • Another aspect of the present invention is the use of at least one quaternary ammonium salt of general formula I given above as suitable active substances, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the modulation of cannabinoid-receptors, preferably cannabinoid 1 (CBi) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
  • cannabinoid-receptors preferably cannabinoid 1 (CBi) receptors
  • At least one of the respective quaternary ammonium salts of general formula I given above optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of psychosis.
  • a medicament for the prophylaxis and/or treatment of food intake disorders preferably bulimia, anorexia, cachexia, obesity and/or type Il diabetus mellitus (non-insuline dependent diabetes mellitus), more preferably obesity.
  • a medicament for the prophylaxis and/or treatment of cancer preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, bowel cancer and prostate cancer, more preferably for the prophylaxis and/or treatment of one or more types of cancer selected
  • At least one quaternary ammonium salt of substituted pyrazoline compounds of general formula I given above optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of alcohol abuse and/or alcohol addiction, nicotine abuse and/or nicotine addiction, drug abuse and/or drug addiction and/or medicament abuse and/or medicament addiction, preferably drug abuse and/or drug addiction and/or nicotine abuse and/or nicotine addiction.
  • Medicaments/drugs which are frequently the subject of misuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.
  • At least one of the respective quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of bone disorders, preferably osteoporosis (e.g.
  • At least one of the respective quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of dementia and related disorders, preferably for the prophylaxis and/or treatment of one or more types of dementia selected from the group consisting of memory loss, vascular dementia, mild cognitive impairment, frontotemporal dementia and Pick's disease; binge eating disorders; juvenile obesity; drug induced obesity; atypical depression; behavioural addictions; attention deficit disorders; Tourette's syndrome; suppression of reward-related behaviours
  • conditioned place avoidance such as suppression of cocaine- and morphine induced conditioned place preference; impulsivity; sexual dysfunction; preferably for the prophylaxis and/or treatment of one or more types of sexual dysfunction selected from the group consisting of erectile difficulty and female sexual dysfunction; seizure disorders; nausea; emesis; neuroinflammatory disease, preferably for the prophylaxis and/or treatment of one or more types of neuroinflammatory diseases selected from the group consisting of multiple sclerosis, demyelinisation related disorders, Guillan-Barre syndrome, viral encephalitis and cerebrovascular accidents; neurological disorders; muscle spasticity; traumatic brain injury; spinal cord injury; inflammation and immunomodulatory disorders, preferably for the treatment and/or prophylaxis of one or more types of inflammation and immunomodulatory disorders selected from the group consisting of cutaneous T-cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus, sepsis, sarcoidosis, idiopathic
  • Dementia is a disease characterized by the progressive deterioration in cognitive and social adaptive functions that can eventually interfere with the patient's ability to live independently. Dementia also constitutes of impairment in short- and long-term memory plus additional symptoms, such as problems with abstract thinking, judgment, or personality. An estimated 18 million patients suffer from dementia worldwide. The most common forms of dementia include Alzheimer's disease and vascular dementia. Other forms are frontotemporal dementia and Pick's disease.
  • Vascular dementia is considered to be the second most common dementia of late life, affecting approximately 10-15% of all cases. AD and vascular dementia can exist in isolation or together (mixed dementia). In vascular dementia, atherosclerotic changes in cerebral vessels can lead to reduced local blood flow that results in multiple small strokes (multi-infarct dementia). Vascular dementia is pharmacologically treated by stroke prophylaxis, and by treatment of the cognitive deficit.
  • AD Alzheimer's disease
  • AD the most common and important form of dementia
  • cognitive functions such as abstract reasoning and memory.
  • AD is a neurodegenerative disorder that is characterized by progressive impairment of cognitive functions, such as abstract reasoning and memory.
  • AD is one of the most prevalent illnesses in the elderly.
  • the majority of AD patients are in their sixties or older. More than 5% of all persons over the age of 70 have significant memory loss due to AD.
  • AD is mainly characterized through a gradual development of forgetfulness. In further advanced disease stages, other failures in cerebral function become increasingly apparent. This includes impairment of speech, writing, and arithmetic skills.
  • Visiospacial orientation such as parking the car, dressing properly, and giving and understanding directions to a location, can become defective or impaired.
  • patients forget how to use common objects and tools while retaining necessary motor power and co-ordination for these activities.
  • Schizophrenia is characterized by profound disruption in cognition and emotion, affecting the most fundamental human attributes: language, thought, perception, affect, and sense of self.
  • Positive symptoms include psychotic manifestations, such as hearing internal voices or experiencing other sensations not connected to an obvious source (hallucinations) and assigning unusual significance or meaning to normal events or holding fixed false personal beliefs (delusions).
  • Negative symptoms are characterized by affective flattening and lack of initiative or goals (avolition), loss of usual interests or pleasures (anhedonia), disturbances of sleep and eating, dysphoric mood (depressed, anxious, irritable, or angry mood) and difficulty concentrating or focusing attention.
  • Major depression is a multifaceted disorder characterized by primarily by dysphoric mood and loss of interest or pleasure in activities that were once enjoyable. Other physical and psychological symptoms include inability to concentrate, motor disturbances (psychomotor retardation or agitation), feelings of worthlessness, inappropriate guilt, thoughts of suicide, and disturbances in appetite and sleep.
  • Anxiety disorders are a group of syndromes that include generalized anxiety disorder, panic disorder, phobias, obsessive-compulsive disorder, and post traumatic stress disorder. Although each disorder has its own distinct features, all share common symptoms of excessive worrying, intense fears and dread, hypervigilance and/or somatic symptoms, in the absence of a dangerous situation.
  • Normal sexual function requires, among others, the ability to achieve and maintain penile erection.
  • Major anatomic structures of the penis that are involved in erectile function include the corpus cavernosum, corpus spinosum, and the tunica albuginea (a collagenous sheath that surrounds each corpus).
  • Thecorpora are composed of a mass of smooth muscle (trabecule) which contains a network of endothelial-lined vessels (lacunar spaces). Penile tumescence and erection is caused by relaxation of the arteries and corporal smooth muscles, while closing emissary veins, leading to increased blood flow into the lacunar network. Central and peripheral innervation contributes to regulation of the erectile response.
  • Erectile dysfunction may result from failure to initiate, fill, or store adequate blood volume within the lacunar network of the penis.
  • ED may be vasculogenic, neurogenic, endocrinologic, diabetic, psychogenic, or medication-related.
  • ED affects 10-25% of middle-aged and elderly men, and has a profound impact on the well-being of affected men. It is currently treated using PDE5 inhibitors such as vardenafil, tadalifil, and sildenafil, lntraurethral alpostadil (prostaglandin El) may be used in patients that fail on oral agents.
  • PDE5 inhibitors such as vardenafil, tadalifil, and sildenafil, lntraurethral alpostadil (prostaglandin El) may be used in patients that fail on oral agents.
  • VCD vacuum constriction devices
  • FSD Female sexual dysfunction
  • FSD denotes a range of medical problems and is categorized according to disorders of (1) desire, (2) arousal, (3) orgasm and (4) sexual pain, and symptoms include diminished vaginal lubrication, pain and discomfort with intercourse, decreased arousal, and difficulty achieveing orgasm.
  • VIP vasoactive intestinal peptide
  • NO nitic oxide
  • sex hormones such as estrogens and androgens
  • Current treatment approaches include estrogen replacement therapy, methyl testosterone, PDE5 inhibitors such as sildenafil, the NO-donor L- arginine, prostaglandin El, phentolamine, and the dopamine agonists apomorphine.
  • the medicament according to the present invention may be in any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults and can be produced by standard procedures known to those skilled in the art.
  • the medicament can be produced by standard procedures known to those skilled in the art, e.g. from the table of contents of "Pharmaceutics: The Science of Dosage Forms", Second Edition, Aulton, M.E. (ED. Churchill Livingstone, Edinburgh (2002); “Encyclopedia of Pharmaceutical Technology", Second Edition, Swarbrick, J. and Boylan J.C. (Eds.), Marcel Dekker, Inc. New York (2002); "Modern Pharmaceutics", Fourth Edition, Banker G.S. and Rhodes CT.
  • composition of the medicament may vary depending on the route of administration.
  • the medicament of the present invention may for example be administered parentally in combination with conventional injectable liquid carriers, such as water or suitable alcohols.
  • conventional pharmaceutical excipients for injection such as stabilising agents, solubilizing agents, and buffers, may be included in such injectable compositions.
  • These medicaments may for example be injected intramuscularly, intraperitoneally, or intravenously.
  • Medicaments according to the present invention may also be formulated into orally administrable compositions containing one or more physiologically compatible carriers or excipients, in solid or liquid form.
  • These compositions may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents.
  • the compositions may take any convenient form, such as tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or retarded release.
  • the multiparticulate forms, such as pellets or granules may e.g. be filled into a capsule, compressed into tablets or suspended in a suitable liquid.
  • Suitable controlled release formulations, materials and methods for their preparation are known from the prior art, e.g. from the table of contents of "Modified-Release Drug Delivery Technology", Rathbone, M.J. Hadgraft, J. and Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); "Handbook of Pharmaceutical Controlled Release Technology”, Wise, D.L. (Ed.), Marcel Dekker, Inc. New York, (2000);
  • Medicaments according to the present invention may also comprise an enteric coating, so that their dissolution is dependent on pH-value. Due to said coating the medicament can pass the stomach undissolved and the respective quaternary ammonium salt of general formula I is liberated in the intestinal tract.
  • the enteric coating is soluble at a pH value of 5 to 7.5. Suitable materials and methods for the preparation are known from the prior art.
  • the medicaments according to the present invention may contain 1-60 % by weight of one or more quaternary ammonium salts of substituted pyrazoline compounds as defined herein and 40-99 % by weight of one or more auxiliary substances (additives).
  • liquid oral forms for administration may also contain certain additives such as sweeteners, flavoring, preservatives, and emulsifying agents.
  • Non-aqueous liquid compositions for oral administration may also be formulated, containing edible oils. Such liquid compositions may be conveniently encapsulated in e.g., gelatin capsules in a unit dosage amount.
  • compositions of the present invention may also be administered topically or via a suppository.
  • the daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth.
  • the daily dosage for humans may preferably be in the range from 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000, even more preferably 1 to 150 milligrams of active substance to be administered during one or several intakes per day.
  • Binding affinity to CB1 receptor was evaluated according to a modification of the method described by Govaerts et al., Eur J Pharmac Sci 23, 233-243 (2004). The respective parts of the description is hereby incorporated by reference and forms part of the present disclosure.
  • cerebellum from male wistar rats 250-30Og were carefully dissected on ice and homogenates were prepared with Potter-Helveheim in a cold 50 mM Tris-HCI solution containing 5 mM MgCI 2 , 1 mM EDTA and 0.25 M sucrose, pH 7.4. The suspension was centrifuged at 1 ,000 x g for 5 minutes. The supernatants were collected and centrifuged 50,000 x g for 15 minutes. The resulting pellets were then resuspended in Tris-HCI buffer without sucrose, homogenized and incubated for 15 min at 37 0 C in an orbital shaker bath and centrifuged again at 50,000 x g for 15 min.
  • Pellets were weighted, resuspended in Tris-HCI buffer without sucrose, homogenized with Ultraturrax at 13,500 rpm for 3 x 5 seconds and alicuoted in 0.9 ml volumes in Eppendorf tubes. Alicuotes were centrifuged at 20,800 x g for 5 minutes, supernatants discarded and pellets were frozen at -8O 0 C until use. Total protein concentration was determined using the Bio-Rad Lowry method based kit.
  • Binding data were analyzed by non-linear regression with the software GraphPad Prism Version 3.03.
  • Substances with affinity for cannabinoid receptors are known to produce a wide range of pharmacological effects. It is also known that intravenous administration of a substance with affinity for cannabinoid receptors in mice produces analgesia , hypothermia, sedation and catalepsy. Individually, none of these effects can be considered as proof that a tested substance has affinity for cannabinoid-receptors, since all of these effects are common for various classes of centrally active agents. However, substances, which show all of these effects, i.e. substances that are active in this so-called tetrad model are considered to have affinity for the cannabinoid receptors. It has further been shown that cannabinoid receptor antagonists are highly effective in blocking the effects of a cannabinoid agonist in the mouse tetrad model.
  • mice with a weight of 20-30 g Male NMRI mice with a weight of 20-30 g (Harlan, Barcelona, Spain) are used in all of the following experiments.
  • mice are acclimatised to the experimental setting.
  • Pre-treatment control values are determined for analgesia hot plate latency (in seconds), rectal temperature, sedation and catalepsy.
  • mice In order to determine the agonistic activity of the substance to be tested, the mice are injected intravenously with the substance to be tested or the vehicle alone. 15 minutes after injection, latency in hot plate analgesia is measured. Rectal temperature, sedation and catalepsy are measured 20 minutes after injection.
  • the hot plate analgesia is determined according to the method described in Woolfe D. et al. ,,The evaluation of analgesic action of pethidine hydrochloride (Demerol)", J. Pharmacol. Exp. Ther. 80, 300-307,1944. The respective description is hereby incorporated by reference and forms part of the present disclosure.
  • mice are placed on a hot plate (Harvard Analgesimeter) at 55 ⁇ 0.5 0 C until they show a painful sensation by licking their paws or jumping and the time for these sensations to occur is recorded. This reading is considered the basal value (B).
  • B basal value
  • PC cut-off time
  • mice Fifteen minutes after the administration of the substance to be tested, the mice are again placed on the hot plate and the afore described procedure is repeated. This period is called the post-treatment reading (PT).
  • PT post-treatment reading
  • the degree of analgesia is calculated from the formula :
  • % MPE of Analgesia ( PT- B) / (PC-B) x 100
  • Sedation and ataxia is determined according to the method described in Desmet L. K. C. et al. ..Anticonvulsive properties of Cinarizine and Flunarizine in Rats and Mice", Arzneim. -Forsch. (Frug Res) 25, 9, 1975.
  • the respective description is hereby incorporated by reference and forms part of the present disclosure.
  • the chosen scoring system is
  • the percentage of sedation is determined according to the formula:
  • % of sedation arithmetic mean / 3 X 100 Hypothermia:
  • the base-line rectal temperatures are determined with a thermometer (YeIIo Springs Instruments Co., Panlabs) and a thermistor probe inserted to 25mm before the administration of the substance to be tested. Rectal temperature is again measured 20 minutes after the administration of the substances to be tested. The temperature difference is calculated for each animal, whereby differences of ⁇ -2 0 C are considered to represent activity.
  • Catalepsy is determined according to the method described in Alpermann H. G. et al. ..Pharmacological effets of Hoe 249: A new potential antidepressant", Drugs Dev. Res. 25, 267-282. 1992. The respective description is hereby incorporated by reference and forms part of the present disclosure.
  • the cataleptic effect of the substance to be tested is evaluated according to the duration of catalepsy, whereby the animals are placed head downwards with their kinlegs upon the top of the wooden block.
  • the chosen scoring system is:
  • the percentage of catalepsy is determined according ot the following formula:
  • % Catalepsy arithmetic mean / 6 X 100
  • CB1 Chinese hamster ovary (CHO) cells stably expressing recombinant human cannabinoid 1 receptor (CB1) were cultured in nutrient mixture Ham's F 12 supplemented with 10 % heat-inactivated fetal bovine serum, 2 mM L-glutamine, 50 U/ml penicillin, 50 U/ml streptomycin and 0.5 mg/ml geneticin.
  • culture flasks were washed twice with phosphate buffered saline and scraped. Then, cells were collected by centrifugation (200 x g, 10 min) and stored dry at -8O 0 C.
  • Cells were homogenized in ice-cold 20 mM HEPES, 10 mM EDTA (pH 7.5) and centrifuged at 40,000 x g for 15 min at 4 0 C. The pellet was resuspended in 20 mM HEPES, 0.1 mM EDTA (pH 7.5) and centrifuged for 15 min at 4 0 C. The final pellet was resuspended in 20 mM HEPES, 0.1 mM EDTA (pH 7.5), and divided in aliquots and stored at -8O 0 C until use.
  • the reaction was performed in 96-well plates. Membranes (15 ⁇ g protein/well) were incubated for 60 min at 30 0 C in buffer (50 mM HEPES, 100 mM KCI, 5 mM MgCI 2 ,1 mM EDTA, 0.1 % wt/vol bovine serum albumin, 5 ⁇ M GDP, saponin (10 ⁇ g/ml), 0.5 nM [ 35 S]GTPyS, pH 7.4) with compound at 1 ⁇ M final concentration in either the absence or presence of dose response curve of agonist WIN 55,212-2 between 3 nM and 3 ⁇ M.
  • buffer 50 mM HEPES, 100 mM KCI, 5 mM MgCI 2 ,1 mM EDTA, 0.1 % wt/vol bovine serum albumin, 5 ⁇ M GDP, saponin (10 ⁇ g/ml), 0.5 nM [ 35 S]GTPyS, pH 7.4
  • P alcohol preferring
  • the following protocol may be used to evaluate the effects of alcohol intake in alcohol preferring (P) female rats (e.g. bred at Indiana University) with an extensive drinking history.
  • P rats Lumeng, L, et al..”Different sensitivities to ethanol in alcohol-preferring and- nonpreferring rats,"Pharmacol, Biochem Behav., 16, 125-130 (1982).
  • mice Female rats are given 2 hours of access to alcohol (10% v/v and water, 2-bottle choice) daily at the onset of the dark cycle. The rats are maintained on a reverse cycle to facilitate experimenter interactions. The animals are initially assigned to four groups equated for alcohol intakes: Group 1 -vehicle; Group 2-positive control (e. g. 5.6 mg/kg AM251 ; Group3-low dose test compound; and Group 4-high dose of test compound. Test compounds are generally mixed into a vehicle of 30% (w/v) - cyclodextrin in distilled water at a volume of 1-2 ml/kg. Vehicle injections are given to all groups for the first two days of the experiment.
  • mice upon arrival mice are individually housed and given unlimited access to powdered rat chow, water and a 10 % (w/v) alcohol solution. After 2-3 weeks of unlimited access, water is restricted for 20 hours and alcohol is restricted to only 2 hours access daily. This is done in a manner that the access period was the last 2 hours of the dark part of the light cycle.
  • mice are considered stable when the average alcohol consumption for 3 days is 20% of the average for all 3 days.
  • Day 1 of test consists of all mice receiving vehicle injection (sc or ip). Thirty to 120 minutes post injection access is given to alcohol and water. Alcohol consumption for that day is calculated (g/kg) and groups are assigned so that all groups have equivocal alcohol intake.
  • day 2 and 3 mice are injected with vehicle or drug and the same protocol as the previous day is followed.
  • Day 4 iss wash out and no injections are given. Data is analyzed using repeated measures ANOVA. Change in water or alcohol consumption is compared back to vehicle for each day of the test. Positive results would be interpreted as a compound that was able to significantly reduce alcohol consumption while having no effect on water
  • the chambers are opened and the animals are administered a single dose of compound (the usual dose range is 0.001 to 10 mg/kg) by oral gavage (or other route of administration as specified, i. e. , sc, ip, iv).
  • Drugs are prepared in methylcellulose, water or other specified vehicle (examples include PEG400, 30% beta-cyclo dextran and propylene glycol).
  • Oxygen consumption and ambulatory activity are measured every 10 minutes for an additional 1-6 hours post-dosing.
  • the Oxymax calorimeter software calculates the oxygen consumption (ml/kg/h) based on the flow rate of air through the chambers and difference in oxygen content at inlet and output ports.
  • the activity monitors have 15 infrared light beams spaced one inch apart on each axis, ambulatory activity is recorded when two consecutive beams are broken and the results are recorded as counts.
  • An intravenous nicotine self-administration model or place preference model may be used to assess the effects of a test compound on nicotine dependence (see, e.g., Vastola, et al. Physiol. Behav. 77:107-114, 2002; Brower, et al., Brain Res. 930:12- 20, 2002).
  • Sprague-Dawley rats are used in this study (Vastola, et al., 2002). Animals are housed in a temperature-controlled, 12h/12h illumination cycle with ad libitum access to food and water. Conditioning and testing are conducted in a chamber divided into two compartments with a door separating the two compartments. Behavior of the animals is recorded by video camera. Animals are habituated to the injection procedure for several days. The animals are then placed into the test chamber and given free access to both compartments. The initial preference for a particular compartment is determined. For the conditioning trials, animals are injected with nicotine and restricted to the nonpreferred compartment, or the animals are injected with saline and restricted to the preferred compartment. On test day, the door separating the compartments is removed, the animal is placed in the center of the chamber and allowed to move freely between compartments. Time spent in each compartment is scored. Preferential occupancy of the nicotine compartment follows from the conditioned reinforcing effects of nicotine.
  • Self-administration in animals is a predictor of a compound's abuse potential in humans. Modifications to this procedure may also be used to identify compounds that prevent or block the reinforcing properties of drags that have abuse potential. A compound that extinguishes the self- administration of a drag may prevent that drag's abuse or its dependence.
  • Sprague-Dawley rats are used in this study. Initially, animals are housed in a temperature-controlled, 12h/12h illumination cycle with ad libitum access to food and water. The animals are then implanted with jugular catheters which exit through the animal's back, and each animal is placed in an individual operant chamber (Brower, et al., 2002). The catheters are connected to a computer-driven syringe pump which is located outside of the chamber. The chamber contains two levers with a green light located above each lever. The light is illuminated when nicotine is available.
  • a self-administration test animals are placed in the operant chambers and the levers are randomly designated as an active and inactive lever. Each response on the active lever produces an infusion of nicotine. Presses on the inactive lever have no effect, but are also recorded. Animals are then trained to self -administer nicotine over a set period of time by having drag access during each daily session. Illumination of the chamber house light signals the beginning of the session and the availability of nicotine. When the session ends, the house light is turned off. Initially, a nicotine infusion occurs with every press of the active lever. Once lever-pressing behavior has been established, the number of presses to produce a nicotine infusion is increased. After stable nicotine self-administration is obtained, the effect of a test compound on the nicotine- reinforced behavior may be evaluated. Administration of this test compound prior to the session can either potentiate, extinguish, or produce no change to the self-administrating behavior. Tests are conducted every two days, and the order of the administration of the test compound doses is controlled.
  • the Morris water maze is a behavioral in vivo test to measure spatial orientation learning and memory through a complex learning task. It is highly suitable for testing compounds that enhance learning and memory.
  • a circular water tank or pool (diameter 2 m, height 0.7 m) is filled with water, and a 10 cm2 platform is placed 1- 1.5 cm below the water surface at a defined location within the pool. The escape platform is not visible for an animal swimming in the water tank. For the experiment, a rat or mouse is placed into the pool to swim freely.
  • the animals have the task to localize the submerged platform, and the time and distance required for successful retrieval is measured.
  • Multiple extra-maze cues are provided by the furniture in the room, including desks, computer equipment, a second water tank, the presence of the experimenter, and by a radio on a shelf that is playing softly.
  • test compounds are administered orally or intraperitoneally on the day of the experiment at a defined time (e.g., 30 minutes before the first swim test). Control animals are dosed with the corresponding vehicle not containing test compound. Active compounds yield shorter times and distances to localize the platform (i.e., the better the animal remembers the location of the platform, the shorter the distance covered and the faster the platform is reached).
  • the test can also be carried out using transgenic or cognitively impaired animals. Cognitive impairment is induced either by old age or experimentally through brain lesions, such as bilateral lesions of the entorhinal cortex in rats. Such lesions can be induced by intracerebral injections of the excitotoxin ibotenic acid.
  • the object recognition task is used to assess the effects of compounds on the cognitive performance of rodents.
  • a rat is placed in an open field, in which two identical objects are located. The rats inspects both objects during the initial trial of the test. After a certain retention interval (e.g., 24 hours), a second trial is carried out.
  • a certain retention interval e.g. 24 hours
  • a second trial is carried out.
  • one of the two objects used in the first trial (the "familiar 1 object) and a novel object are placed in the open field, and the inspection time at each of the objects is measured. Good retention is reflected by higher exploration times towards the novel compared with the 'familiar' object.
  • Administration of the putative cognition enhancer prior to the first trial predominantly allows assessment of the effects on acquisition, and on the consolidation processes.
  • Administration of the test compound after the first trial allows to assess the effects on consolidation processes, whereas administration before the second trial allows to measure effects on retrieval processes.
  • the passive avoidance task assesses memory performance in rats and mice.
  • the inhibitory avoidance uses an apparatus consisting of a box with two compartments separated by a guillotine door that can be operated by the experimenter. One compartment is illuminated with bright light, and the other compartment is dark. A threshold of 2 cm separates the two compartments when the guillotine door is 15 raised. When the door is open, the illumination in the dark compartment is about 2 lux. The light intensity is about 500 lux at the center of the floor of the light compartment.
  • Two habituation sessions, one shock session, and a retention session are given, separated by inter-session intervals of 24 hours. During the habituation sessions and the retention session, the rat is allowed to explore the apparatus for 300 seconds.
  • the rat is placed in the light compartment, facing the wall opposite to the guillotine door. After an accommodation period of 15 seconds, the guillotine door is opened so that all parts of the apparatus can be visited freely. Rats normally avoid brightly lit areas and will enter the dark compartment within a few seconds.
  • the guillotine door between the compartments is lowered as soon as the rat has entered the dark compartment with all paws, and a scrambled 1 mA footshock is administered for 2 seconds. Then the rat is removed from the apparatus and returned into its home cage. The procedure during the retention session is identical to that of the habituation sessions.
  • the step-through latency that is, the first latency of entering the dark compartment (in seconds) during the retention session is an index of the memory performance of the animal: a better retention is assumed if the latency to enter the dark compartment is longer.
  • a test compound is given 30 minutes before the shock session, together with 1 mg/kg scopolamine. Scopolamine impairs the memory performance during the retention session 24 hours later. If the test compound increases the enter latency compared with the scopolamine-treated controls, it is considered to possess cognition enhancing activity.
  • the T-maze spontaneous alternation task assesses the spatial memory performance in mice.
  • the start arm and the two goal arms of the T-maze are provided with guillotine doors that can be operated manually by the experimenter.
  • a mouse is put into the start arm at the beginning of training.
  • either the left or right goal arm is blocked by lowering the respective guillotine door (forced trial).
  • the mouse After the mouse has been released from the start arm, it will explore the maze, eventually entering the open goal arm, and return to the start position, where it will be confined for 5 seconds, by lowering the guillotine door. Then, the animal can choose freely between the left and right goal arm (all guillotine-doors opened) during 14 additional trials (free choice trials). As soon as a mouse has entered one goal arm, the other arm is closed. The mouse eventually returns to the start arm and is free to visit whichever arm it wants after having been confined to the start arm for 5 seconds. After completion of 14 free choice trials in one session, the animal is removed from the maze.
  • a forced swim or tail suspension model may be used to assess the efficacy of antidepressant compounds (see , e.g., Porsolt, et al., Nature 266:730-732, 1977; Stem, et al., Psychopharmacology 85:367-370, 1985).
  • Rats or mice are placed in a cylinder filled with water 23-25 0 C from which no escape is possible. Initially, animals struggle and try to escape, but eventually adopt a characteristic immobile posture and make no further attempts to escape except for small movements needed their head above water. Animals are dosed with a compound and the activity (swimming or climbing) or immobility is measured by an observer. The immobility is considered by some to reflect a 'behavioral despair 1 in which animals cease to struggle to escape the aversive situation.
  • TCAs clinically used antidepressants
  • MAOIs MAOIs
  • SSRIs atypicals
  • At least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, whereas drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. There are false positives (psychostimulants) but relatively few false negatives ([beta]-adrenergic agonists).
  • test is sensitive to muscle-relaxant (benzodiazepines) and sedative (neuroleptics) effects, leading to enhanced immobility. False positives and false negatives can often be screened by measuring if the compound produces locomotor stimulation or sedation.
  • mice When suspended by the tail, mice will initially struggle and try to escape and then alternate between active escape attempts and immobililty. In this test, animals are dosed with a compound and the immobility is measured by an observer for 6 min. Porsolt describes the immobile behavior as 'behavioral despair' which animals cease to struggle to escape the aversive situation.
  • a large variety of clinically antidepressants tricyclics, MAOIs, SSRIs, and atypicals reduce immobility in this model. The test has a good predictive validity for antidepressant activity and works for most antidepressant classes including but has some false positives (psychostimulants).
  • the test is sensitive to muscle-relaxant (benzodiazepines) and sedative (neuroleptics) effects, which lead to enhanced immobility. False positives and false negatives can often be screened by measuring if the compound produces locomotor stimulation or sedation. Strain differences in the tail suspension test have been found in mice. The tail suspension test has some face validity but its construct validity is rather weak.
  • a prepulse inhibition model may be used to assess the efficacy of antipsychotic compounds (see Swerdlow and Geyer, Schizophrenia Bulletin 24: 285-301 , 1998).
  • Prepulse inhibition is the process whereby a relatively mild stimulus, the prepulse, suppresses the response to a strong, startle-eliciting stimulus when the prepulse precedes the startle stimulus by a brief duration (about 10 to 500 milliseconds).
  • Prepulse inhibition is a cross-species phenomenon (ie, it is present in mammals ranging from mice to humans), yet it is relatively absent among schizophrenic patients.
  • the deficit in PPI in schizophrenic patients is thought to reflect the loss of sensorimotor gating that may lead to sensory flooding and cognitive fragmentation.
  • mice or rats are administered compounds and individually placed into a holder on a transducer platform to measure whole body startle.
  • the holder is housed in a startle chamber with background white noise. Following a brief habituation period, animals are given multiple trials of a weak auditory prepulse stimululs, followed by a strong auditory startle stimulus. Four types of trials are given: prepulse plus startle, prepulse alone, startle alone, and no stimulation. PPI is measured as the amount of inhibition of startle following the prepulse and is expressed as the percentage of basic startle. As a control, measurements are taken in the no stimulation and prepulse alone trials. PPI is considered a test with good predictive, face and construct validity for schizophrenia. Putative antipsychotics can be tested alone to determine if they enhance PPI.
  • antipsychotics can be screened to determine if they block various agents that disrupt PPI (apomorphine, d- amphetamine, PCP, ketamine, DOI).
  • PPI apomorphine, d- amphetamine, PCP, ketamine, DOI.
  • mutant mice with or without drugs can be screened using the PPI procedure.
  • An elevated plus maze model may be used to assess the efficacy of anxiolytic compounds (see Pellow and File, Pharm. Biochem. Behav. 24, 525-529, 1986).
  • the elevated plus maze is widely used as an anxiety paradigm that examines the conflict between the drive to explore and the aversiveness of heights and open spaces of rats or mice.
  • the maze is a cross made up of two open and two closed arms that is raised above the ground. The combination of light, the open arms, and the height is thought to produce unconditioned fear or anxiety responses in mice or rats.
  • the test apparatus is an open top maze constructed of opaque plastic with alternating open and enclosed arms. For rats, each arm is 45-55 cm long and 8-12 cm wide, with the sides of the enclosed arms 35-45 cm high, the juncture approximately 10 x 10 cm, and the maze is elevated 45-55 cm above the floor.
  • the mouse elevated plus maze consists of two closed arms (15 x 6 x 30 cm) and two open arms (1 x 6 x 30 cm) forming a cross, with a quadrangular center (6 x 6cm).
  • the maze is placed 50 cm above the floor. Testing is performed in a room free of noise and distraction. On test days animals are administered drug or vehicle. If a pretreatment period is necessary, the animals are returned to the home cage for the duration of the pretreatment time; otherwise, the animals are placed in a clear plastic holding chamber singly or with cage mates for 1-10 minutes prior to test time. Rats are then placed in the center of the maze always oriented in the same direction, either consistently facing an open arm or an enclosed arm.
  • Drugs affecting erectile function may be tested by measuring the effect on apomorphine- evoked increases in intracavernous pressure in the awake rat as described by Andersson, et al., (J. Urol. 161 : 1707-17 ] 2, 1999).
  • One end of a polyethylene tubing is implanted into the cavernosal space of the penis of male Sprague-Dawley rats. After recovery from the surgery, intracavernous pressure is recorded using a pressure transducer connected to a multichannel pen-recorder. Erections are induced by administration of apomorphine (100-250 ug/kg s.c.) with or without test compound, and the results are compared for the treated group and the non-treated group.
  • Female Sexual Dysfunction is induced by administration of apomorphine (100-250 ug/kg s.c.) with or without test compound, and the results are compared for the treated group and the non-treated group.
  • Systems to test compounds for the treatment of female sexual dysfunction include in vitro and in situ models using vaginal or clitoral smooth muscle preparations, histological evaluation, and vaginal blood flow assessments.
  • In vivo studies of sexual responses focus on behavioral paradigms involving lordotic posturing and receptivity, as well as indices of motivation using a dual chamber pacing method (see, e.g., Hale, et al., Int. J. Impot. Res. 15 Suppl 5: S75-79, 2003).
  • Example 1 1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H- pyrazole-S-carbonylJ-arninol-i-methyl-piperidinium iodide
  • Example 51 N-oxide of N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)- 4,5-dihydropyrazole-3-carboxamide
  • N-piperidinyl-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide (0.15 g, 0.33 mmol) was dissolved in 7 mL of dichloromethane. The resulting solution was ice-cooled to 0 0 C and m-chloroperbenzoic acid (0.204 g, 0.83 mmol) was added in several portions. After stirring for 15 minutes a control via thin layer chromatography showed that no starting material was present. A saturated solution of sodium bicarbonate was then slowly added, the organic phase separated, washed with water, dried over sodium sulfate and filtered.

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Abstract

The present invention relates to quaternary ammonium salts of substituted pyrazoline compounds, methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans and animals.

Description

Quaternary ammonium salts of substituted pyrazoline compounds, their preparation and use as medicaments
The present invention relates to quaternary ammonium salts of substituted pyrazoline compounds, methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans and animals.
Cannabinoids are compounds, which are derived from the cannabis sativa plant which is commonly known as marijuana. The most active chemical compound of the naturally occurring cannabinoids is tetrahydrocannabinol (THC), particularly Δ9-THC.
These naturally occurring cannabinoids as well as their synthetic analogues promote their physiological effects via binding to specific G-coupled receptors, the so-called cannabinoid-receptors.
At present, two distinct types of receptors that bind both the naturally occurring and synthetic cannabinoids have been identified and cloned. These receptors, which are designated CBi and CB2 are involved in a variety of physiological or pathophysiological processes in humans and animals, e. g. processes related to the central nervous system, immune system, cardiovascular system, endocrinous system, respiratory system, the gastrointestinal tract or to reproduction, as described for example, in Hollister, Pharm. Rev. 38, 1986, 1-20; Reny and Singha, Prog. Drug. Res., 36, 71-114, 1991 ; Consroe and Sandyk, in Marijuana/Cannabinoids, Neurobiology and Neurophysiology, 459, Murphy L. and Barthe A. Eds., CRC Press, 1992.
Therefore, compounds, which have a high binding affinity for these cannabinoid receptors and which are suitable for modulating these receptors are useful in the prevention and/or treatment of cannabinoid-receptor related disorders.
In particular, the CBrreceptor is involved in many different food-intake related disorders such as bulimia or obesity, including obesity associated with type Il diabetes (non-insulin-dependent diabetes) and thus, compounds suitable for regulating this receptor may be used in the prophylaxis and/or treatment of these disorders.
Thus, it was an object of the present invention to provide novel compounds for use as active substances in medicaments. In particular, these active substances should be suitable for the modulation of cannabinoid receptors, more particularly for the modulation of cannabinoid 1 (CBi) receptors.
Said object was achieved by providing the quaternary ammonium salts of substituted pyrazoline compounds of general formula I given below, their stereoisomers, corresponding salts and corresponding solvates thereof.
It has been found that these compounds have a high affinity for cannabinoid receptors, particularly for the CBrreceptor, and that they act as modulators e. g. antagonists, inverse agonists or agonists on these receptors. They are therefore suitable for the prophylaxis and/or treatment of various disorders related to the central nervous system, the immune system, the cardiovascular system, the endocrinous system, the respiratory system, the gastrointestinal tract or reproduction in humans and/or animals, preferably humans including infants, children and grown- ups.
Thus, in one of its aspects the present invention relates to quaternary ammonium salts of substituted pyrazoline compounds of general formula I,
Figure imgf000003_0001
wherein X is O or S;
A represents a hydrogen atom or an unsubstituted or at least mono-substituted alkyl radical;
R1 and R2, independently of one another, in each case represent an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
or a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted alkylene group;
R3 and R4, independently of one another, in each case represent H; F; Cl; Br; I; -CN; -NO2; -NC; -OH; -NH2; -SH; -C(=O)-H;
a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted alkylene group;
an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an optionally at least mono-substituted alkylene group, alkenylene group or alkinylene group; a -O-R7 moiety; a -S-R8 moiety; a -NH-R9 moiety or a -NR10R11 moiety;
R5 and R6, independently of one another, in each case represent a hydrogen atom;
a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
or
R5 and R6 together with the bridging nitrogen form an unsubstituted or at least mono-substituted, saturated or unsaturated heterocyclic ring which may contain at least one further heteroatom as a ring member and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems;
R7, R8, R9, R10 and R11, independently of one another, in each case represent a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted alkylene group;
or an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group;
B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo- glutarate, formate, acetate, propionate, lactate, gluconate, unsubstituted or at least mono-substituted benzoate or naphthoate, pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
Figure imgf000006_0001
and
R12 and R13, independently of one another, in each case, represent a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
an unsubstituted or at least mono-substituted aryl or heteroaryl radical which may be bonded via an unsubstituted or at least mono-substituted alkylene group
or a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be bridged by at least one unsubstituted or at least mono-substituted alkylene group and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group;
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
If one or more of the residues R1 to R13 and B represents or comprises an aryl, heteroaryl, benzoate or naphthoate radical, which may be substituted, unless defined otherwise, preferably said aryl, heteroaryl, benzoate or naphthoate radical may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -Ci-6-perfluoralkyl, -d-6-alkyl substituted with one or more methoxy and/or ethoxy groups,
Figure imgf000006_0002
-Ci.6-alkyl substituted with one or more hydroxy groups, -Ci-6-alkyl substituted with one or more chlorine atoms, -O-Ci- 6-alkyl, -O-Ci_6-alkyl substituted with one or more methoxy and/or ethoxy groups, -S-
Figure imgf000006_0003
F, Cl, Br, I1 -CN, - OCF3, -0-C2F5, -0-C3F7, -0-C4F9, -SCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -SO3H, -NH-C(=O)-Ci-6-alkyl, -N(C1-6-alkyl)-C(=O)-C1-6-alkyl, -NO2, -CHO, -C(=O)-C1.6-alkyl, - C(=O)-C1-6-perfluoroalkyl, -C(=S)-NH-Ci.6-alkyl, -CF2H, -CFH2, -C(=O)-NRARB, - C(=O)-NH-NRCRD, -S(=O)-C1-6-alkyl, -S(=O)2-C1-6-alkyl, -S(=O)2-phenyl, -(C1-5- alkylene)-S-C1.6-alkyl, -(C1-5-alkylene)-S(=O)-Ci-6-alkyl, -(C1-5-alkylene)-S(=O)2-Ci-6- alkyl, -NRERF, -(C1-5-alkylene)-NRERF, -S(=O)-NH2, -S(=O)2-NH-Ci-6-alkyl, -S(=O)2- NH-phenyl, -NH-S(=O)2-Ci-6-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl, thiophenyl, phenoxy and benzyl;
whereby in each case the cyclic moieties cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl, thiophenyl, phenoxy and benzyl can optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -OH, -CF3, -CN, -NO2, -d.6-alkyl, -0-Ci-6- alkyl, -O-CF3 and -S-CF3 and
whereby RA, RB, RE and RF, independently of one another, represent hydrogen or -Ci- 6-alkyl or RA and RB in each case together with the bridging nitrogen atom form a radical selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, azepanyl and diazepanyl which may be at least mono-substituted with one or more identical or different Chalky! radicals
and whereby Rc and RD, independently of one another, represent hydrogen, -Ci-6- alkyl, -C(=O)-O-C1-6-alkyl, C3.8-cycloalkyl, -(Ci-5-alkylene)-C3-8-cycloalkyl, -(d.6- alkylene)-O-Ci-6-alkyl or -d-β-alkyl substituted with one or more hydroxy groups or Rc and RD in each case together with the bridging nitrogen atom form a radical selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, azepanyl and diazepanyl which may be at least mono-substituted with one or more substituents independently selected from the group consisting -Ci-6-alkyl, -C(=O)-Ci-6-alkyl, -C(=O)-O-Ci-6-alkyl, -C(=O)-NH-d. 6-alkyl, -C(=S)-NH-Ci-6-alkyl, oxo (=O), -Ci-6-alkyl substituted with one or more hydroxy groups, -(Ci-6-alkylene)-O-Ci-6-alkyl and -C(=O)-NH2.
More preferably said aryl and heteroaryl radicals may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF3, - C2F5, -C3F7, -C4F9, -CH2CI, -CHCI2, -C2H4CI, methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -CH2-OH, -CH2-CH2-OH, -CH2-CH2-CH2-OH, -0-CH2-O-CH3, -0-CH2-CH2-O-CH3, -0-CH2-O-C2H5, - C(OCH3)(C2Hs)2, -C(OCH3)(CH3)2, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3. -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CHs)3, -C(=O)-OH, -C(=O)-O-CH3, -C(=O)-O-C2H5, - C(=O)-O-C3H7l -C(=O)-O-C(CH3)3, -O-C(=O)-CH3, -O-C(=O)-C2H5, -0-C(O)-
CH(CH3)2, -O-C(=O)-CH2-CH2-CH3, -O-C(=O)-C(CH3)3, F, Cl, Br, I, -CN1 -OCF3, -O- C2F5, -0-C3F7, -0-C4F9, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -SO3H, -NH-C(=O)-CH3, -NH-C(=O)-C2H5, -NH-C(=O)-C(CH3)3, -NO2, -CHO, -C(O)-CH3, -C(=O)-C2H5, - C(=O)-C(CH3)3, -C(=O)-CF3, -C(=O)-C2F5, -C(=O)-C3F7, -C(=S)-NH-CH3, -C(=S)-NH- C2H5, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3l -C(=O)-NH-C2H5, -C(O)-NH- C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -C(=O)-NH-NH-CH3l -C(=O)-NH-NH-C2H5, - C(O)-NH-NH2, -C(O)-NH-N(CH3)2, -S(O)-CH3, -S(O)-C2H5, -S(O)-C3H7, - S(O)2-CH3, -S(O)2-C2H5, -S(O)2-C3H7, -S(O)2-phenyl, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2, -N(C2Hs)2, -CH2-N(CHs)2, -(CH2)-morpholinyl, -(CH2)-piperidinyl, -(CH2)- piperazinyl, -(CH2)-N(C2H5)2, -CH2-N(C3H7)2, -CH2-N(C4Hg)2, -CH2-N(CH3)(C2H5), - S(O)-NH2, -S(O)2-NH-CH3, -S(O)2-NH-phenyl, -NH-S(O)2-CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl, thiophenyl, phenoxy and benzyl, whereby said thiophenyl radical can be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, methyl, ethyl and n-propyl.
Preferred aryl radicals which are optionally at least mono-substituted are phenyl and naphthyl (1- and 2-naphthyl).
Preferably the heteroatoms which are present as ring members in the heteroaryl radical may, unless defined otherwise, independently be selected from the group consisting of nitrogen, oxygen and sulfur. More preferably a heteroaryl radical is 5- to 14-membered and may comprise 1 , 2, 3 or 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur.
Preferred heteroaryl radicals which are unsubstituted or at least mono-substituted are pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]- benzoxadiazolyl, [1 ,2,3]-benzoxadiazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl, imidazo[2,1-b]thiazolyl, 2H-chromenyl, pyranyl, indazolyl, benzimidazolyl and quinazolinyl.
Preferred aryl and heteroaryl radicals which are condensed with a mono- or polycyclic ring system are [1 ,3]-benzodioxolyl, [1 ,4]-benzodioxanyl, [1 ,2,3,4]- tetrahydronaphthyl, (2,3)-dihydro-1 H-cyclopenta[b]indolyl, [1 ,2,3,4]- tetrahydroquinolinyl, [1 ,2,3,4]-tetrahydroisoquinolinyl, [1 ,2,3,4]-tetrahydroquinazolinyl and [3,4]-dihydro-2H-benzo[1 ,4]oxazinyl.
If one or more of the residues R1 to R13 and B represents or comprises a saturated or unsaturated, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, preferably a C3.-i8 cycloaliphat.ic radical, a heterocyclic ring, preferably a 4- to 10-membered heterocyclic ring, a C3-i6cycloalkyl radical, a C4-16 cycloalkenyl radical, a C4-I6 heterocycloalkyl radical, or a C5--I6 heterocycloalkenyl radical, which may be substituted, unless defined otherwise, preferably said cycloaliphatic radical, heterocyclic ring, C3-i6cycloalkyl radical, C4-I6 cycloalkenyl radical, C4-I6 heterocycloalkyl radical, or C5-I6 heterocycloalkenyl radical, may in each case optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -Ci-β-perfluoralkyl, -Ci-6- alkyl, -d-β-alkyl substituted with one or more hydroxy groups, -Ci.6-alkyl substituted with one or more chlorine atoms, -Ci.6-alkyl substituted with one or more methoxy and/or ethoxy groups, -O-Ci.6-alkyl, -O-Ci.6-alkyl substituted with one or more methoxy and/or ethoxy groups, -S-C1-6-alkyl, -C(=O)-OH, -C(=O)-O-Ci-6-alkyl, -O- C(=O)-C1-6-alkyl, F, Cl, Br1 11 -CN, -OCF3, -0-C2F5, -0-C3F7, -0-C4F9, -SCF3, -SCF2H1 -SCFH2, -OH, -SH, -SO3H, -NH-C(=O)-C1-6-alkyl, -N(C1-6-alkyl)-C(=O)-Ci-6-alkyl, - NO2, -CHO, -C(=O)-Ci-6-alkyl, -C(=O)-Ci-6-perfluoroalkyl, -C(=S)-NH-Ci.6-alkyl, - CF2H, -CFH2, -C(=O)-NRARB, -C(=O)-NH-NRCRD, -S(=O)-C1-6-alkyl, -S(=O)2-d.6- alkyl, -S(=O)2-phenyl, -(Ci-5-alkylene)-S-Ci-6-alkyl, -(Ci-5-alkylene)-S(=O)-Ci-6-alkyl, - (Ci-s-alkyleneJ-S^Ofe-CLe-alkyl, -NRERF, -(Ci.5-alkylene)-NRERF, -S(=O)-NH2, - S(=O)2-NH-Ci.6-alkyl, -S(=O)2-NH-phenyl, -NH-S(=O)2-Ci.6-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl, thiophenyl, phenoxy and benzyl; whereby in each case the cyclic moieties cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl, thiophenyl, phenoxy and benzyl can optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I1 -OH, -CF3, -CN, -NO2, -Ci-6-alkyl, -0-Ci-6- alkyl, -0-CF3 and -S-CF3 and
whereby RA, RB, RE and RF, independently of one another, represent hydrogen or -Ci- 6-alkyl or RA and RB in each case together with the bridging nitrogen atom form a radical selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, azepanyl and diazepanyl which may be at least mono-substituted with one or more identical or different C-ι-6 alkyl radicals
and whereby Rc and RD, independently of one another, represent hydrogen, -Ci-β- alkyl, -C(=O)-O-Ci-6-alkyl, C3-8-cycloalkyl, -(Ci.5-alkylene)-C3-8-cycloalkyl, -(Ci.6- alkylene)-O-Ci.6-alkyl or -Ci.6-alkyl substituted with one or more hydroxy groups or Rc and RD in each case together with the bridging nitrogen atom form a radical selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, azepanyl and diazepanyl which may be at least mono-substituted with one or more substituents independently selected from the group consisting -C1-6-alkyl, -C(=O)-Ci-6-alkyl, -C(=O)-O-Ci-6-alkyl, -Cf=O)-NH-C1. 6-alkyl, -C(=S)-NH-Ci.6-alkyl, oxo (=O), -Ci-6-alkyl substituted with one or more hydroxy groups, -(Ci.6-alkylene)-O-Ci-6-alkyl and -C(=O)-NH2.
More preferably said cycloaliphatic radicals, heterocyclic rings, C3-i6cycloalkyl radicals, C-nβcycloalkenyl radicals, C4-16 heterocycloalkyl radicals, or C5.i6 heterocycloalkenyl radicals may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=O), thioxo (=S), -CF3, -C2F5, -C3F7, -C4F9, -CH2CI, -CHCI2, -C2H4CI, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -CH2-OH, - CH2-CH2-OH, -CH2-CH2-CH2-OH, -0-CH2-O-CH3, -0-CH2-CH2-O-CH3, -0-CH2-O- C2H5, -C(OCH3)(C2Hs)2, -C(OCH3)(CH3)2, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, - S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, -C(=O)-OH, -C(=O)-O-CH3, -C(=O)- 0-C2H5, -C(=O)-O-C3H7, -C(=O)-O-C(CH3)3, -O-C(=O)-CH3, -O-C(=O)-C2H5, -O- C(=O)-CH(CH3)2, -O-C(=O)-CH2-CH2-CH3, -O-C(=O)-C(CH3)3, F, Cl, Br, I1 -CN, - OCF3, -0-C2F5, -0-C3F7, -O-C4F9, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -SO3H, -NH- C(=O)-CH3, -NH-C(=O)-C2H5, -NH-C(=O)-C(CH3)3> -NO2, -CHO, -C(=O)-CH3, -C(O)- C2H5, -C(=O)-C(CH3)3, -C(O)-CF3, -C(O)-C2F5, -C(O)-C3F7, -C(=S)-NH-CH3, - C(=S)-NH-C2H5l -CF2H, -CFH2, -C(O)-NH2, -C(O)-NH-CH3, -C(O)-NH-C2H5, - C(O)-NH-C3H7, -C(O)-N(CH3)2, -C(O)-N(C2H5)2l -C(O)-NH-NH-CH3, -C(O)-NH- NH-C2H5, -C(O)-NH-NH2, -C(O)-NH-N(CH3)2, -S(O)-CH3, -S(O)-C2H5, -S(O)- C3H7, -S(O)2-CH3, -S(O)2-C2H5, -S(O)2-C3H7, -S(O)2-phenyl, -NH2, -NH-CH3, - NH-C2H5, -N(CH3)2, -N(C2Hs)2, -CH2-N(CH3)2, -(CH2)-morpholinyl, -(CH2)-piperidinyl, - (CH2)-piperazinyl, -(CH2)-N(C2H5)2) -CH2-N(C3H7J2, -CH2-N(C4Hg)2, -CH2- N(CH3)(C2H5), -S(O)-NH2, -S(O)2-NH-CH3, -S(O)2-NH-phenyl, -NH-S(O)2-CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl, thiophenyl, phenoxy and benzyl, whereby said thiophenyl radical can be substituted with 1 , 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, methyl, ethyl and n-propyl.
If one or more of the residues R1 to R13 and B represents or comprises a cycloaliphatic radical, preferably a C3.i6cycloaliphatic radical, which contains one or more heteroatoms as ring members, unless defined otherwise, each of these heteroatoms may preferably be selected from the group consisting of nitrogen, oxygen and sulfur. More preferably a cycloaliphatic group may optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of N, O and S as ring members.
Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing cycloaliphatic radicals may preferably be selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, diazepanyl, azocanyl, (2,5)-dihydrofuranyl, (2,5)-dihydrothiophenyl, (2,3)- dihydrofuranyl, (2,3)-dihydrofuranyl, (2,5)-dihydro-1 H-pyrrolyl, (2,3)-dihydro-1 H- pyrrolyl, tetrahydrothiopyranyl, tetrahydropyranyl, (3,4)-dihydro-2H-pyranyl, (3,4)- dihydro-2H-thiopyranyl, (1 ,2,3,6)-tetrahydropyridinyl, (1 ,2,3,4)-tetrahydropyridinyl, (1 ,2,5,6)-tetrahydropyridinyl, [1 ,3]-oxazinanyl, hexahydropyrimidinyl, (5,6)-dihydro- 4H-pyrimidinyl, oxazolidinyl, (1 ,3)-dioxanyl, (1 ,4)-dioxanyl and (1 ,3)-dioxolanyl.
Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing cycloaliphatic radicals which are condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system may preferably be selected from the group consisting of indolinyl, isoindolinyl, decahydronaphthyl, (1 ,2,3,4)- tetrahydroquinolinyl, (1 ,2,3,4)-tetrahydroisoquinolinyl, (1 ,2,3,4)-tetrahydronaphthyl, octahydro-cyclopenta[c]pyrrolyl, (1 ,3,4,7,9a)-hexahydro-2H-quinolizinyl, (1 ,2,3,5,6,8a)-hexahydro-indolizinyl, decahydroquinolinyl, dodecahydro-carbazolyl, 9H-carbazolyl, decahydroisoquinolinyl, (6,7)-dihydro-4H-thieno[3,2-c]pyridinyl, (2,3)- dihydro-1 H-benzo[de]isoquinolinyl and (1 ,2,3,4)-tetrahydroquinoxazlinyl.
Preferably a cycloaliphatic radical, a C3-i6cycloalkyl radical, a C/Mβcycloalkenyl radical, a C-ne heterocycloalkyl radical or a C5-I6 heterocycloalkenyl radical may be bridged by 1 , 2 or 3 unsubstituted or at least mono-substituted alkylene group(s).
Suitable saturated or unsaturated, optionally at least one heteroatom as ring member containing cycloaliphatic radicals which are bridged by at least one unsubstituted or at least mono-substituted alkylene group may preferably be selected from the group consisting of adamantyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, norbornenyl and 8- aza-bicyclo[3.2.1]octyl.
A mono- or polycyclic ring system according to the present invention - if not defined otherwise - means a mono- or polycyclic hydrocarbon ring system, preferably a mono- or bicyclic ring system, that may be saturated, unsaturated or aromatic. Each of its different rings may show a different degree of saturation, i.e. they may be saturated, unsaturated or aromatic. Optionally each of the rings of the mono- or bicyclic ring system may contain one or more, preferably 1 , 2 or 3, heteroatom(s) as ring member(s), which may be identical or different and which can preferably be selected from the group consisting of nitrogen, oxygen and sulfur. The rings of the mono- or bicyclic ring system are preferably 5-, 6- or 7-membered. The term "condensed" according to the present invention means that a ring or ring system is attached to another ring or ring system, whereby the terms "annulated" or "annelated" are also used by those skilled in the art to designate this kind of attachment.
If one or more of the residues R1 to R11 comprises a mono- or polycyclic ring system, which may be substituted, unless defined otherwise, preferably said mono- or polycyclic ring system may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -Ci-6- perfluoralkyl, -Ci.6-alkyl, -Ci.6-alkyl substituted with one or more hydroxy groups, -Ci- 6-alkyl substituted with one or more chlorine atoms, -C-ι.6-alkyl substituted with one or more methoxy and/or ethoxy groups, -O-C-ι-6-alkyl, -O-Ci-6-alkyl substituted with one or more methoxy and/or ethoxy groups, -S-Ci-6-alkyl, -C(=O)-OH, -C(=O)-O-Ci.6- alkyl, -O-C(=O)-C1-6-alkyl, F, Cl, Br, I, -CN, -OCF3, -0-C2F5, -0-C3F7, -0-C4F9, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -SO3H1 -NH-C(=O)-C1.6-alkyl, -N(C1-6-alkyl)-C(=O)-C1-6- alkyl, -NO2, -CHO, -C(=O)-Ci.6-alkyl, -C(=O)-C1-6-perfluoroalkyl, -C(=S)-NH-C1.6-alkyl, -CF2H, -CFH2, -C(=O)-NRARB, -C(=O)-NH-NRCRD, -S(=O)-Ci-6-alkyl, -S(=O)2-C1-6- alkyl, -S(=O)2-phenyl, -(Ci-5-alkylene)-S-Ci-6-alkyl, -(C1.5-alkylene)-S(=O)-C1-6-alkyl, - (Ci-5-alkylene)-S(=O)2-C1.6-alkyl, -NRERF, -(C1-5-alkylene)-NRERF, -S(=O)-NH2l - S(=O)2-NH-Ci.6-alkyl, -S(=O)2-NH-phenyl, -NH-S(=O)2-C1-6-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl, thiophenyl, phenoxy and benzyl;
whereby in each case the cyclic moieties cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl, thiophenyl, phenoxy and benzyl can optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -OH, -CF3, -CN, -NO2, -d-6-alkyl, -0-Ci-6- alkyl, -0-CF3 and -S-CF3 and
whereby RA, RB, RE and RF, independently of one another, represent hydrogen or -Ci- 6-alkyl or RA and RB in each case together with the bridging nitrogen atom form a radical selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, azepanyl and diazepanyl which may be at least mono-substituted with one or more identical or different d-βalkyl radicals
and whereby Rc and RD, independently of one another, represent hydrogen, -Ci-6- alkyl, -C(=O)-O-C1-6-alkyl, C3-8-cycloalkyl, -(Ci.5-alkylene)-C3-8-cycloalkyl, -(C1-6- alkylene)-O-Ci-6-alkyl or -Ci-6-alkyl substituted with one or more hydroxy groups or Rc and RD in each case together with the bridging nitrogen atom form a radical selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperazinyl, piperidinyl, thiomorpholinyl, morpholinyl, azepanyl and diazepanyl which may be at least mono-substituted with one or more substituents independently selected from the group consisting -Ci-e-alkyl, -C(=O)-C1.6-alkyl, -C(=O)-O-Ci-6-alkyl, -C(O)-NH-C1- 6-alkyl, -C(=S)-NH-C1-6-alkyl, oxo (=O), -C1-6-alkyl substituted with one or more hydroxy groups, -(Ci-6-alkylene)-O-Ci-6-alkyl and -C(=O)-NH2.
More preferably said mono- or polycyclic ring system may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=O), thioxo (=S), -CF3, -C2F5, -C3F7, -C4F9, -CH2CI, -CHCI2, -C2H4CI, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n- hexyl, -CH2-OH, -CH2-CH2-OH, -CH2-CH2-CH2-OH, -0-CH2-O-CH3, -0-CH2-CH2-O- CH3, -0-CH2-O-C2H5, -C(OCH3)(C2Hs)2, -C(OCH3)(CH3)2, -0-CH3, -0-C2H5, -0-CH2- CH2-CH3, -O-CH(CH3)2> -0-CH2-CH2-CH2-CH3, -O-C(CH3)3. -S-CH3, -S-C2H5, -S- CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, -C(=O)-OH, -C(O)- 0-CH3, -C(=O)-O-C2H5l -C(=O)-O-C3H7, -C(=O)-O-C(CH3)3, -O-C(=O)-CH3, -O- C(=O)-C2H5, -O-C(=O)-CH(CH3)2) -O-C(=O)-CH2-CH2-CH3, -O-C(=O)-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -0-C2F5, -0-C3F7, -0-C4F9, -SCF3, -SCF2H, -SCFH2, -OH, -SH, - SO3H, -NH-C(=O)-CH3, -NH-C(=O)-C2H5, -NH-C(=O)-C(CH3)3, -NO2, -CHO, -C(O)- CH3, -C(=O)-C2H5, -C(=O)-C(CH3)3) -C(=O)-CF3, -C(=O)-C2F5, -C(=O)-C3F7, -C(=S)- NH-CH3, -C(=S)-NH-C2H5, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(O)-NH- C2H5, -C(=O)-NH-C3H7, -C(=O)-N(CH3)2l -C(=O)-N(C2H5)2, -C(=O)-NH-NH-CH3, - C(O)-NH-NH-C2H5, -C(O)-NH-NH2, -C(O)-NH-N(CH3)2) -S(O)-CH3, -S(O)- C2H5, -S(O)-C3H7, -S(O)2-CH3, -S(O)2-C2H5, -S(O)-C3H7, -S(O)2-phenyl, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2, -N(C2Hg)2, -CH2-N(CH3)2, -(CH2)-morpholinyl, -(CH2)- piperidinyl, -(CH2)-piperazinyl, -(CH2)-N(C2H5)2, -CH2-N(C3H7J2, -CH2-N(C4Hg)2, -CH2- N(CH3)(C2H5), -S(O)-NH2, -S(O)2-NH-CH3, -S(O)2-NH-phenyl, -NH-S(O)2-CH3, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, phenyl, thiophenyl, phenoxy and benzyl, whereby said thiophenyl radical can be substituted with 1 , 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, methyl, ethyl and n-propyl.
If one or more of the residues R3 to R13, A and B represent or comprise a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical, preferably a Ci-16 aliphatic radical, said aliphatic radical may be linear or branched.
Preferably aliphatic radicals, Ci-i6alkyl radicals, C2-i6alkenyl radical and C2.i6alkinyl radicals, unless defined otherwise, may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently selected from the group consisting of -OH, F, Cl, Br, I, -O-Ci-6-alkyl, -OCF3, -0-C2F5, -0-C3F7, -0-C4F9, -CF3, -C2F5, -C3F7, -C4F9, - NH2, -NH-d-β-alkyl, -N(Ci.6-alkyl)2, -C(O)-OH, -qO^O-d-e-alkyl, -C(=O)-NH2, - C(=O)-NH-Ci.6-alkyl, -C(=O)-N(C1.6-alkyl)2, -CN1 -NO2, -S(=O)-NH2, -CHO, -C(O)- Ci-6-alkyl, -S(=O)-d.6-alkyl, -S(=O)2-Ci.6-alkyl, -NH-S(=O)-Ci.6-alkyl, -NH-C(O)-O- Ci-6-alkyl and -NH-C(=O)-d-6-alkyl.
More preferably aliphatic radicals, Ci-i6alkyl radicals, C2-i6alkenyl radical and C2.i6 alkinyl radicals, may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituents independently selected from the group consisting of -OH, F, Cl, Br, I, -O- CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, - NH2, -NH-CH3, -NH-C2H5, -N(CH3)2i -N(C2H5)2, -CN, -NO2, -NH-C(=O)-CH3, -NH- C(=O)-C2H5, -NH-C(=O)-C(CH3)3, -NH-C(=O)-O-CH3l -NH-C(O)-O-C2H5, -NH- C(O)-O-C(CHa)3, -C(O)-NH-CH3, -C(O)-NH-C2H5, -C(O)-NH-C(CH3)3, -C(O)- N(CH3)2, -C(O)-N(C2Hs)2, -C(O)-OH, -C(O)-O-CH3, -C(O)-O-C2H5, -C(O)-O- C(CH3)3, -C(O)-CH3, -C(O)-C2H5 and -C(O)-C(CH3J3.
Suitable alkyl radicals, preferably CM6 alkyl radicals, are selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)- heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7-methyl)-octyl, 2-(6-methyl)-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecycl and n- hexadecyl.
Suitable at least mono-substituted alkyl radicals are selected from the group consisting of -CF3, -CH2F, -CF2H, -CH2-O-CH3, -C2F5, -CH2-CH2-F, -CH2-CN, -CH2- OH, -CH2-CH2-CN, -CH2-CH2-OH, -CH2-CH2-OCH3, -CH2-CH2-CH2-CN, -CH2-CH2- CH2-OH, -CH2-CH2-CH2-O-CH3, -CH2-CH2-CH2-CH2-O-CH31 -CH2-NH2, -CH2- N(CH3)2, -CH2-N(C2Hs)2, -CH2-CH-NH2, -CH2-CH2-N(CH3)2, -CH2-CH2-N(C2Hs)2, - CH2-CH2-CH2-NH2, -CH2-CH2-CH2-N(CHs)2 and -CH2-CH2-CH2-N(C2Hs)2.
An alkenyl radical according to the present invention comprises at least one carbon- carbon double bond. Suitable alkenyl radicals, preferably C2-i6 alkenyl radicals, are selected from the group consisting of vinyl, n-propenyl, n-butenyl, n-pentenyl, n- hexenyl, n-heptenyl, n-octenyl, n-nonenyl, n-decenyl, n-undecenyl, n-dodecenyl, n- tridecenyl, n-tetradecenyl, n-pentadecenyl and n-hexadecenyl.
An alkinyl radical comprises at least one carbon-carbon triple bond. Suitable alkinyl radicals, preferably C2--I6 alkinyl radicals, are selected from the group consisting of ethinyl, propinyl, n-butinyl, n-pentinyl, n-hexinyl, n-octinyl, n-noninyl, n-decinyl, n- undecinyl, n-dodecinyl, n-tridecinyl, n-tetradecinyl, n-pentadecinyl and n-hexadecinyl.
If any of the substituents represents an alkylene group, an alkenylene group or an alkinylene group, which may be substituted, said alkylene group, alkenylene group or alkinylene group may - if not defined otherwise - be unsubstituted or substituted by one or more substituents, preferably unsubstituted or substituted with 1 , 2 or 3 substituent(s). Said substituent(s) may preferably be selected independently from the group consisting of -O-Ci-e-alkyl, -S-Ci-6-alkyl, -F, Cl, Br, I1 -CN, -CF3, -OCF3, -SCF3, -OH, -SH, -SO3H, -NH2, -NH(C1-6-alkyl), -N(C1-6-alkyl)2 and phenyl. More preferably said substituent(s) may be selected from the group consisting of -F, Cl, Br, I, -CN, - CF3, -OCF3, -SCF3, -OH, -SH, -SO3H, -NH2, -NH-CH3, -N(CH3)2, -0-CH3 and -O- C2H5. An alkenylene group comprises at least one carbon-carbon double bond, an alkinylene group comprises at least one carbon-carbon triple bond. Suitable alkylene groups, preferably Ci-5-alkylene groups, include -(CH2)-, -CH(CH3)-, -CH(phenyl), -(CH2J2-, -(CH2)3-,-(CH2)4-,-(CH2)5 and -(CH2J6-, suitable alkenylene groups, preferably C2-5-alkenylene groups, include -CH=CH-, -CH2-CH=CH- and - CH=CH-CH2- and suitable alkinylene groups, preferably C2-5-alkinylene groups, include -C≡C- , -CH2-C≡C- and -C≡C-CH2-.
Preferred are quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, wherein
X is O or S;
A represents a hydrogen atom or an unsubstituted or at least mono-substituted Ci--I0 alkyl radical;
R1 and R2, independently of one another, in each case represent an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
an unsubstituted or at least mono-substituted C3-Ie cycloalkyl radical or C4--I6 cycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
or an unsubstituted or at least mono-substituted C4-I6 heterocycloalkyl radical or C5-I6 heterocycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group; R3 and R4, independently of one another, in each case represent H; F; Cl; Br; I; -CN; -NO2; -NC; -OH; -NH2; -SH; -C(=O)-H;
an unsubstituted or at least mono-substituted Chalky! radical, C2-i6 alkenyl radical or C2-i6 alkinyl radical;
an unsubstituted or at least mono-substituted C3-I6 cycloalkyl radical or C4-16 cycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C1.5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
an unsubstituted or at least mono-substituted C4-16 heterocycloalkyl radical or C5-i6 heterocycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C1-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted Ci-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group;
an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group;
a -O-R7 moiety; a -S-R8 moiety; a -NH-R9 moiety or a -NR10R11 moiety;
R5 and R6, independently of one another, in each case represent a hydrogen atom;
an unsubstituted or at least mono-substituted Ci-16 alkyl radical, C2-i6alkenyl radical or C2-iβalkinyl radical;
or
R5 and R6 together with the bridging nitrogen form an unsubstituted or at least mono- substituted, saturated or unsaturated 4- to 10-membered heterocyclic ring which may optionally contain 1 , 2 or 3 additional heteroatom(s) selected from the group consisting of sulfur, nitrogen and oxygen as ring member(s) and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems;
R7, R8, R9, R10 and R11, independently of one another, in each case represent
an unsubstituted or at least mono-substituted C-M6 alkyl radical, C2-i6 alkenyl radical or C2-i6alkinyl radical;
an unsubstituted or at least mono-substituted C3-i6cycloalkyl radical or C4.16 cycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
an unsubstituted or at least mono-substituted C4-16 heterocycloalkyl radical or C5-I6 heterocycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C1.5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group; an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted Ci.5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group;
or an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group;
B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo- glutarate, formate, acetate, propionate, lactate, gluconate, unsubstituted or at least mono-substituted benzoate or naphthoate, pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
R12-Sθf and R13-NH-Sθ3 ;
and
R )12 D R13 , independently of one another, in each case, represent
an unsubstituted or at least mono-substituted Ci-i6alkyl radical, C2-i6alkenyl radical or C2-i6alkinyl radical;
an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group;
an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group; an unsubstituted or at least mono-substituted C3-i6cycloalkyl radical or C4-i6 cycloalkenyl radical, which in each case may be bonded via an unsubstituted or at least mono-substituted C-1.5 alkylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
or an unsubstituted or at least mono-substituted C4-i6 heterocycloalkyl radical or C5-I6 heterocycloalkenyl radical, which in each case may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
whereby
the rings of the aforementioned ring system are in each case independently of one another 5- 6- or 7-membered and may in each case independently of one another optionally contain 1 , 2 or 3 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur;
the aforementioned heteroaryl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
the aforementioned heterocycloalkyl radicals and heterocycloalkenyl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Preference is also given to quaternary ammonium salts of substituted pyrazoline compounds of general formula I, wherein A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2- hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl and 4- octyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -0-CH3, -0-C2H5, -0-CH2-CH2- CH3, -0-CH(CH3)Z, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5. -S-CH2- CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3l -CN and -NO2;
and R1 to R13, X and B have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Also preferred are quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, wherein R1 and R2, independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]- benzothiadiazolyl, [2,1 ,3]-benzoxadiazolyl, [1 ,2,3]-benzoxadiazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and imidazo[2,1-b]thiazolyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF3, -CH2-CI, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -O- C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, - S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2) -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I1 -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)- C2H5, -C(=O)-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH- C2H5, -C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, - N(CH3)2, -N(C2H5)2, phenoxy and thiophenyl, whereby the thiophenyl radical can be substituted with 1 , 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, methyl, ethyl and n-propyl; or a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, diazepanyl, azocanyl, (2,5)- dihydrofuranyl, (2,5)-dihydrothiophenyl, (2,3)-dihydrofuranyl, (2,3)-dihydrofuranyl, (2,5)-dihydro-1 H-pyrrolyl, (2,3)-dihydro-1 H-pyrrolyl, tetrahydrothiopyranyl, tetrahydropyranyl, (3,4)-dihydro-2H-pyranyl, (3,4)-dihydro-2H-thiopyranyl, (1 ,2,3,6)- tetrahydropyridinyl, (1 ,2,3,4)-tetrahydropyridinyl, (1 ,2,5,6)-tetrahydropyridinyl, [1 ,3]- oxazinanyl, hexahydropyrimidinyl, (5,6)-dihydro-4H-pyrimidinyl, (5,6)-dihydro-4H- pyrimidinyl, oxazolidinyl, (1 ,3)-dioxanyl, (1 ,4)-dioxanyl, (1 ,3)-dioxolanyl, decahydronaphthyl, octahydro-cyclopenta[c]pyrrolyl, decahydroquinolinyl and dodecahydro-carbazolyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -O- CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, - S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I1 -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(O)- CH3, -C(=O)-C2H5, -C(=O)-C(CH3)3l -CF2H1 -CFH2, -C(O)-NH2, -C(O)-NH-CH3, - C(O)-NH-C2H5, -C(O)-NH-C3H7, -C(O)-N(CH3)2, -C(O)-N(C2Hs)2, -S(O)-CH3, - S(O)-C2H5, -S(O)-C3H7, -S(O)2-CH3, -S(O)2-C2H5, -S(O)2-C3H7, -NH2, -NH- CH3, -NH-C2H5, -N(CH3J2 and -N(C2Hs)2;
and R3 to R13, X, A and B have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Preference is also given to quaternary ammonium salts of substituted pyrazoline compounds of general formula I, wherein R3 and R4, independently of one another, in each case represent H; F; Cl; Br; I; -CN; -NO2; -NC; -OH; -NH2; -SH; -C(O)-H; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl and 4- octyl, which may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituent(s) independently selected from the group consisting of -OH, F, Cl, Br, I, -O-CH3, -O- C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -O-CH2-CH2-CH2-CH3, -O-C(CH3)3, -NH2, - NH-CH3, -NH-C2H5, -N(CH3)2, -N(C2H5J2, -CN and -NO2;
a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH2)-, -(CH2HCH2)-, -(CH2)-(CH2)-(CH2)- or -CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -O- C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, - S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(O)-CH3, -C(O)- C2H5, -C(=O)-C(CH3)3, -CF2H, -CFH2, -C(O)-NH2, -C(O)-NH-CH3, -C(O)-NH- C2H5, -C(O)-NH-C3H7, -C(O)-N(CH3)2, -C(O)-N(C2Hs)2, -S(O)-CH3, -S(O)-C2H5, -S(O)-C3H7, -S(O)2-CH3, -S(O)2-C2H5, -S(O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, - N(CH3)2 and -N(C2Hs)2;
a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl and diazepanyl, which may be bonded via a -(CH2)-, -(CH2)-(CH2)-, -(CH2)-(CH2)-(CH2)- or -CH=CH- group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (O), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2- pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2- CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2- CH3, -S-C(CH3)3, F1 Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, - CHO, -C(=O)-CH3, -C(=O)-C2H5, -C(=O)-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, - C(O)-NH-CH3, -C(=O)-NH-C2H5, -C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)- N(C2Hs)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2-CH3, -S(=O)2-C2H5, - S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2 and -N(C2Hs)2;
a -O-R7 moiety; a -S-R8 moiety, a -NH-R9 moiety or a -NR10R11 moiety;
and R1, R2, R5 to R13, X, A and B have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Also preferred are quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, wherein R5 and R6, independently of one another, in each case represent a hydrogen atom;
or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl and 4- octyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -0-CH3, -0-C2H5, -0-CH2-CH2- CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3) -S-CH3, -S-C2H5, -S-CH2- CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, -CN and -NO2;
and R1 to R4, R7 to R13, X, A and B have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Preference is also given to quaternary ammonium salts of substituted pyrazoline compounds of general formula I, wherein R5 and R6 together with the bridging nitrogen atom form a moiety selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, azepanyl, diazepanyl, azocanyl, (2,5)- dihydro-1 H-pyrrolyl, (2,3)-dihydro-1 H-pyrrolyl, (1 ,2,3,6)-tetrahydropyridinyl, (1 ,2,3,4)- tetrahydropyridinyl, (1 ,2,5,6)-tetrahydropyridinyl, [1 ,3]-oxazinanyl, hexahydropyrimidinyl, (5,6)-dihydro-4H-pyrimidinyl, (5,6)-dihydro-4H-pyrimidinyl, oxazolidinyl, indolinyl, isoindolinyl, (1 ,2,3,4)-tetrahydroquinolinyl, (1 ,2,3,4)- tetrahydroisoquinolinyl, octahydro-cyclopenta[c]pyrrolyl, (1 ,3,4,7,9a)-hexahydro-2H- quinolizinyl, (1 ,2,3,5,6,8a)-hexahydro-indolizinyl, decahydroquinolinyl, dodecahydro- carbazolyl, 9H-carbazolyl, decahydroisoquinolinyl, (6,7)-dihydro-4H-thieno[3,2- c]pyridinyl, (2,3)-dihydro-1 H-benzo[de]isoquinolinyl and (1 ,2,3,4)- tetrahydroquinoxazlinyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=O), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n- pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2- CH2-CH2-CH3, -O-C(CH3)3, -0-CH2-O-CH3, -0-CH2-CH2-O-CH3, -0-CH2-O-C2H5, - C(OCH3)(C2Hs)2, -C(OCH3)(CHs)2, -CH2-O-CH3, -CH2-O-C2H5, -S-CH3, -S-C2H5, -S- CH2-CH2-CH3, -S-CH(CHa)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I1 -CN, - OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)-C2H5, - C(=O)-C(CH3)3, -C(=O)-OH, -C(=O)-O-CH3, -C(=O)-O-C2H5, -C(=O)-O-C(CH3)3, - CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH-C2H5, -C(=O)-NH-C3H7, - C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2- CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2, -N(C2Hs)2, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl;
and R1 to R4, R7 to R13, X, A and B have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Also preferred are quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, wherein R7, R8, R9, R10 and R11, independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4- heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5- methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7-methyl)-octyl; 2-(6-methyl)-octyl, vinyl, n- propenyl, n-butenyl, n-pentenyl, n-hexenyl, ethinyl, propinyl, n-butinyl, n-pentinyl and n-hexinyl, which may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituent(s) independently selected from the group consisting of -OH, F, Cl, Br, I, - 0-CH3, -0-C2H5. -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2, -N(C2Hs)2, -CN and -NO2;
a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, 8-aza- bicyclo[3.2.1]octyl and diazepanyl, which may be bonded via a -(CH2)-, -(CH2HCH2)- , -(CH2)-(CH2)-(CH2)- or -CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, - S-CH(CH3)2l -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, - SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)-C2H5, -C(=O)-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3) -C(=O)-NH-C2H5, -C(=O)-NH-C3H7, - C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2- CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2 and - N(C2Hs)2;
or a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH2)-, -(CH2HCH2)-, -(CH2)-(CH2)-(CH2)- or -CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -O- C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, - S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I1 -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)- C2H5, -C(=O)-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH- C2H5, -C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, - N(CH3)2 and -N(C2Hs)2;
and R1 to R6, R12, R13, X, A and B have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Preference is also given to quaternary ammonium salts of substituted pyrazoline compounds of general formula I, wherein B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo-glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate which may be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, -OH, -0-CH3 and -0-C2H5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
R12-Sθ3 and R13-NH-Sθf;
and R1 to R13, X and A have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Also preferred are quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, wherein R12 and R13, independently of one another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2- octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2- (4-methyl)-hexyl, 2-(7-methyl)-octyl; 2-(6-methyl)-octyl, n-nonyl, n-decyl, n-undecyl, n- dodecyl, n-tridecyl, n-tetradecyl, vinyl, n-propenyl, n-butenyl, n-pentenyl, n-hexenyl, ethinyl, propinyl, n-butinyl, n-pentinyl and n-hexinyl; which may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituent(s) independently selected from the group consisting of F, Cl, Br, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2 and -N(C2Hs)2;
a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, benzimidazolyl, isoquinolinyl and pyrazolyl, which may be bonded via a -(CH2)-, - (CH2HCH2)- or -(CH2)-(CH2)-(CH2)-group and/or may be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n- hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O- C(CH3J3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S- C(CHs)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, - C(=O)-CH3, -C(O)-C2H5, -C(=O)-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(O)-NH- CH3, -C(=O)-NH-C2H5, -C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(O)- CH3, -S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2-CH3) -S(=O)2-C2H5, -S(O)2-C3H7, -SO3H, - NH2, -NH-CH3, -NH-C2H5, -N(CH3)2, -N(C2Hg)2 and phenyl;
or a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and bicyclo[2.2.1]heptyl, which may be bonded via a - (CH2)-, -(CH2HCH2)-, -(CH2)-(CH2)-(CH2)-group and/or may optionally be substituted with 1, 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2- butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -0-CH2-O-CH3, -0-CH2-CH2-O-CH3, - 0-CH2-O-C2H5, -C(OCH3)(C2Hs)2, -C(OCH3)(CH3)2, -CH2-O-CH3, -CH2-O-C2H5, -S- CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(O)-CH3, - C(O)-C2H5, -C(O)-C(CH3)3, -C(O)-OH, -C(O)-O-CH3, -C(O)-O-C2H5, -C(O)-O- C(CHs)3, -CF2H, -CFH2, -C(O)-NH2, -C(O)-NH-CH3, -C(O)-NH-C2H5, -C(O)-NH- C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, - S(=O)2-CH3, -S(=O)2-C2H5l -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2 and - N(C2Hs)2;
and R1 to R11, X1 B and A have the meaning given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Preference is also given to quaternary ammonium salts of substituted pyrazoline compounds of general formula I, wherein
X is O or S:
A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4- heptyl, n-octyl, 2-octyl, 3-octyl and 4-octyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -O- CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, - S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, - CN and -NO2;
R1 and R2, independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl
(thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]-benzoxadiazolyl, [1 ,2,3]- benzoxadiazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and imidazo[2,1-b]thiazolyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF3, -CH2-CI, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2- pentyl, n-hexyl, -O-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2- CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2- CH3, -S-C(CH3)3, F, Cl, Br, I1 -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, - CHO, -C(=O)-CH3, -C(=O)-C2H5, -C(=O)-C(CH3)3, -CF2H, -CFH2, -Cf=O)-NH2, - C(=O)-NH-CH3, -C(=O)-NH-C2H5, -Cf=O)-NH-C3H7, -C(=O)-N(CH3)2, -Cf=O)- N(C2Hs)2, -Sf=O)-CH3, -Sf=O)-C2H5, -Sf=O)-C3H7, -Sf=O)2-CH3, -Sf=O)2-C2H5, - Sf=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2, -N(C2Hg)2, phenoxy and thiophenyl, whereby the thiophenyl radical can be substituted with 1 , 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, methyl, ethyl and n-propyl;
or a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, diazepanyl, azocanyl, (2,5)- dihydrofuranyl, (2,5)-dihydrothiophenyl, (2,3)-dihydrofuranyl, (2,3)-dihydrofuranyl, (2,5)-dihydro-1 H-pyrrolyl, (2,3)-dihydro-1 H-pyrrolyl, tetrahydrothiopyranyl, tetrahydropyranyl, (3,4)-dihydro-2H-pyranyl, (3,4)-dihydro-2H-thiopyranyl, (1 ,2,3,6)- tetrahydropyridinyl, (1 ,2,3,4)-tetrahydropyridinyl, (1 ,2,5,6)-tetrahydropyridinyl, [1 ,3]- oxazinanyl, hexahydropyrimidinyl, (5,6)-dihydro-4H-pyrimidinyl, (5,6)-dihydro-4H- pyrimidinyl, oxazolidinyl, (1 ,3)-dioxanyl, (1 ,4)-dioxanyl, (1 ,3)-dioxolanyl, decahydronaphthyl, octahydro-cyclopenta[c]pyrrolyl, decahydroquinolinyl and dodecahydro-carbazolyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituentfs) independently selected from the group consisting of oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -O- CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, - S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -Cf=O)- CH3, -Cf=O)-C2H5, -Cf=O)-C(CHs)3, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, - C(=O)-NH-C2H5, -C(=O)-NH-C3H7l -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, - S(=O)-C2Hs, -S(=O)-C3H7, -S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH- CH3, -NH-C2H5, -N(CH3)2 and -N(C2Hs)2; R3 and R4, independently of one another, in each case represent H; F; Cl; Br; I; -CN; - NO2; -NC; -OH; -NH2; -SH; -C(=O)-H;
a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl and 4- octyl, which may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituent(s) independently selected from the group consisting of -OH, F, Cl, Br, I, -O-CH3, -O- C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -NH2, - NH-CH3, -NH-C2H5, -N(CH3)2ι -N(C2Hs)2, -CN and -NO2;
a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH2)-, -(CH2HCH2)-, -(CH2)-(CH2)-(CH2)- or -CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -O- C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, - S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN1 -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)- C2H5, -C(=O)-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH- C2H5, -C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, - N(CH3), and -N(C2Hs)2;
a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl and diazepanyl, which may be bonded via a -(CH2)-, -(CH2)-(CH2)-, -(CH2)-(CH2)-(CH2)- or -CH=CH- group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2- pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2l -0-CH2-CH2-CH2- CH3, -O-C(CH3)3, -S-CH3, -S-C2Hs, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2- CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, - CHO, -C(=O)-CH3, -C(O)-C2H5, -C(=O)-C(CH3)3, -CF2H1 -CFH2, -C(=O)-NH2, - C(=O)-NH-CH3, -C(=O)-NH-C2H5, -C(=O)-NH-C3H7) -C(=O)-N(CH3)2, -C(=O)- N(C2Hs)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2-CH3, -S(=O)2-C2H5, - S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2 and -N(C2Hs)2;
a -O-R7 moiety; a -S-R8 moiety, a -NH-R9 moiety or a -NR10R11 moiety;
R5 and R6, independently of one another, in each case represent a hydrogen atom;
or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl and 4- octyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -0-CH3, -0-C2H5, -0-CH2-CH2- CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2- CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, -CN and -NO2;
or
R5 and R6 together with the bridging nitrogen atom form a moiety selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, azepanyl, diazepanyl, azocanyl, (2,5)-dihydro-1 H-pyrrolyl, (2,3)-dihydro-1 H-pyrrolyl, (1 ,2,3,6)- tetrahydropyridinyl, (1 ,2,3,4)-tetrahydropyridinyl, (1 ,2,5,6)-tetrahydropyridinyl, [1 ,3]- oxazinanyl, hexahydropyrimidinyl, (5,6)-dihydro-4H-pyrimidinyl, (5,6)-dihydro-4H- pyrimidinyl, oxazolidinyl, indolinyl, isoindolinyl, (I ^.SΛHetrahydroquinolinyl, (1 ,2,3,4)-tetrahydroisoquinolinyl, octahydro-cyclopenta[c]pyrrolyl, (1 ,3,4,7,9a)- hexahydro-2H-quinolizinyl, (1 ,2,3,5,6,8a)-hexahydro-indolizinyl, decahydroquinolinyl, dodecahydro-carbazolyl, 9H-carbazolyl, decahydroisoquinolinyl, (6,7)-dihydro-4H- thieno[3,2-c]pyridinyl, (2,3)-dihydro-1 H-benzo[de]isoquinolinyl and (1 ,2,3,4)- tetrahydroquinoxazlinyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=O), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n- pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2- CH2-CH2-CH3, -O-C(CH3)3) -0-CH2-O-CH3, -0-CH2-CH2-O-CH3, -0-CH2-O-C2H5, - C(OCH3)(C2Hs)2, -C(OCH3)(CHs)2, -CH2-O-CH3, -CH2-O-C2H5, -S-CH3, -S-C2H5, -S- CH2-CH2-CH3, -S-CH(CHs)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, - OCF3, -SCF3, -SCF2H, -SCFH2, -OH1 -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)-C2H5, - C(=O)-C(CH3)3l -C(=O)-OH, -C(=O)-O-CH3, -C(=O)-O-C2H5, -C(=O)-O-C(CH3)3, - CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH-C2H5| -C(=O)-NH-C3H7, - C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2- CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2, -N(C2H5J2, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl;
R7, R8, R9, R10 and R11, independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2- hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7- methyl)-octyl; 2-(6-methyl)-octyl, vinyl, n-propenyl, n-butenyl, n-pentenyl, n-hexenyl, ethinyl, propinyl, n-butinyl, n-pentinyl and n-hexinyl, which may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituent(s) independently selected from the group consisting of -OH, F, Cl, Br, I, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3J2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2) - N(C2Hs)2, -CN and -NO2;
a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, moφholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, 8-aza- bicyclo[3.2.1]octyl and diazepanyl, which may be bonded via a -(CH2)-, -(CH2HCH2)- , -(CH2)-(CH2)-(CH2)- or -CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3J2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, - S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, - SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)-C2H5, -C(=O)-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2| -C(=O)-NH-CH3, -C(=O)-NH-C2H5, -C(=O)-NH-C3H7, - C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2- CH3, -S(O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2 and - N(C2H5)2;
or a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH2)-, -(CH2)-(CH2)-, -(CH2)-(CH2)-(CH2)- or -CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -O- C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, - S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)- C2H5, -C(=O)-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH- C2H5, -C(=O)-NH-C3H7, -C(=O)-N(CH3)2l -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7l -NH2, -NH-CH3, -NH-C2H5, - N(CH3J2 and -N(C2Hs)2;
B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo- glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate which may be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, -OH, -0-CH3 and -0-C2H5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate, Ri2-sor and R13-NH-Sθ3 ;
and
R12 and R13, independently of one another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n- heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)- heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7-methyl)-octyl; 2-(6-methyl)-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, vinyl, n-propenyl, n-butenyl, n-pentenyl, n-hexenyl, ethinyl, propinyl, n-butinyl, n- pentinyl and n-hexinyl; which may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituent(s) independently selected from the group consisting of F, Cl, Br, - NH2, -NH-CH3, -NH-C2H5, -N(CH3)2 and -N(C2Hs)2;
a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, benzimidazolyl, isoquinolinyl and pyrazolyl, which may be bonded via a -(CH2)-, - (CH2HCH2)- or -(CH2)-(CH2)-(CH2)-group and/or may be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n- hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O- C(CH3J3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S- C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, - C(=O)-CH3, -C(=O)-C2H5, -C(=O)-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(O)-NH- CH3, -C(=O)-NH-C2H5, -C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(O)- CH3, -S(=O)-C2H5, -S(=O)-C3H7l -S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -SO3H, - NH2, -NH-CH3, -NH-C2H5, -N(CH3)2, -N(C2Hs)2 and phenyl;
or a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and bicyclo[2.2.1]heptyl, which may be bonded via a - (CH2)-, -(CH2HCH2)-, -(CH2)-(CH2)-(CH2)-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2- butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3) -0-CH2-O-CH3, -0-CH2-CH2-O-CH3, - 0-CH2-O-C2H5, -C(OCH3)(C2Hs)2, -C(OCH3)(CH3)2, -CH2-O-CH3, -CH2-O-C2H5, -S- CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I1 -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, - C(=O)-C2H5, -C(=O)-C(CH3)3, -C(O)-OH1 -C(=O)-O-CH3, -C(=O)-O-C2H5, -C(=O)-O- C(CHa)3, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH-C2H5, -C(=O)-NH- C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, - S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2 and - N(C2Hs)2.
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Particularly preferred are quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, wherein
X is O or S;
A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl;
R1 and R2, independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]-benzoxadiazolyl, [1 ,2,3]- benzoxadiazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and imidazo[2,1-b]thiazolyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF3, -CH2-CI, -O- CH3, -O-C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -O-CH2-CH2-CH2-CH3, -O-C(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2- pentyl, n-hexyl, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, - CHO, -CF2H, -CFH2, phenoxy and thiophenyl, whereby the thiophenyl radical can be substituted with 1 , 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, methyl, ethyl and n-propyl;
R3 represents H; F; Cl; Br; I; -CN; -NO2; -NC; -OH; -NH2; -SH; -C(=O)-H;
a radical selected from the group consisting of methyl, -CF3, -CH2F, -CF2H, -C2F5, ethyl, -CH2-CN, -CH2-OH, n-propyl, isopropyl, -CH2-CH2-CN, -CH2-CH2-OH, n-butyl, - CH2-CH2-CH2-CN1 -CH2-CH2-CH2-OH, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl;
a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl) and pyrrolyl, which may be bonded via a -(CH2)-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, F, Cl and Br;
a -O-R7 moiety; a -S-R8 moiety, a -NH-R9 moiety or a -NR10R11 moiety;
R4 represents H or an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl;
R7, R8, R9, R10 and R11, independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl; R5 and R6 together with the bridging nitrogen atom form a moiety selected from the group consisting of
Figure imgf000039_0001
Figure imgf000039_0002
and B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo-glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate which may be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, -OH, -O- CH3 and -0-C2H5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
Figure imgf000040_0001
and
R12 and R13, independently of one another, in each case represent a radical selected from the group consisting Of -CF3, -C2F5, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2- hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7- methyl )-octyl; 2-(6-methyl)-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl and n-tetradecyl;
a radical selected from the group consisting of phenyl, pyridinyl, pyrazolyl, benzimidazolyl, isoquinolinyl and naphthyl, which may be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n- hexyl, -O-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O- C(CH3)3, -OH, -NO2, -NH2, phenyl and -SO3H;
a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and bicyclo[2.2.1]heptyl, which may be bonded via a - (CH2)-, -(CH2HCH2)-, -(CH2)-(CH2)-(CH2)-group;
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
More particularly preferred are quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, wherein X is O;
A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl and n-propyl;
R1 represents a radical selected from the group consisting of phenyl and thienyl (thiophenyl), which may optionally be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -0-CH3 and -O-C2H5;
R2 represents a phenyl radical, which may be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br and I;
R3 represents H; F; Cl; Br; I; -OH, -CN; -C(=O)-H;
a radical selected from the group consisting of methyl, -CF3, -CH2F, -CF2H, -C2F5, ethyl, -CH2-CN, -CH2-OH, n-propyl, isopropyl, -CH2-CH2-CN, -CH2-CH2-OH, n-butyl, - CH2-CH2-CH2-CN, -CH2-CH2-CH2-OH, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl;
a benzyl radical or a -O-R7 moiety;
R4 represents H or a radical selected from the group consisting of methyl, ethyl, n- propyl, iso-propyl and n-butyl;
R5 and R6 together with the bridging nitrogen atom form a moiety selected from the group consisting of
Figure imgf000042_0001
Figure imgf000042_0002
R7 represents a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl;
B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, methanesulfonate, ethanesulfonate, toluenesulfonate, benzenesulfonate, (2,5)-dihydroxy-benzenesulfonate, naphthalene-2-sulfonate, 5- sulfo-napthalene-1 -sulfonate, cyclamate, dodecane-1 -sulfonate and (7,7)-dimethyl-2- oxo-bicyclo[2.2.1]-hept-1-yl-methanesulfonate;
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Most particularly preferred are quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above selected from the group consisting of
[1 ] 1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [2] 1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-4-methyl-morpholin-4-ium iodide [3] 1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-azepanium iodide [4] 1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-2-methyl-octahydro-cyclopenta[c]pyrrolium iodide
[5] 1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-pyrrolidinium iodide [6] (R)-1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [7] (S)-1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [8] 1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -ethyl-piperidinium iodide [9] (R)-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -ethyl-piperidinium iodide
[10] (S)-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -ethyl-piperidinium iodide [11] 1-[[5-(4-Bromo-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [12] 1-[[2,4-Dichloro-phenyl)-5-(4-iodo-phenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-amino]-1 -methyl-piperidinium iodide [13] 1-[[2,4-Dichloro-phenyl)-5-(4-fluoro-phenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-amino]-1 -methyl-piperidinium iodide
[14] i-fPΛ-Dichloro-phenyO-S^-methoxy-phenyO^.δ-dihydro-I H-pyrazole-S- carbonyl]-amino]-1 -methyl-piperidinium iodide
[15] 1 -[[2,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-amino]-1 -methyl-azepanium iodide [16] 1 -[[2,4-Dichloro-phenyl)-5-(4-fluoro-phenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-amino]-1 -methyl-azepanium iodide [17] 1 -[[2,4-Dichloro-phenyl)-5-(4-iodo-phenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-amino]-1 -methyl-azepanium iodide [18] 1-[[5-(4-Bromo-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H- pyrazole-3-carbonyl]-amino]-1 -methyl-azepanium iodide [19] 1-[[5-(4-Bromo-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1-methyl-pyrrolidinium iodide [20] 1 -[[2,4-Dichloro-phenyl)-5-(4-fluoro-phenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-amino]-1 -methyl-pyrrolidinium iodide
[21] 1-[[2,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-amino]-1 -methyl-pyrrolidinium iodide
[22] cis-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [23] cis-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [24] cis-1 -[[5-(4-Bromo-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [25] cis-1 -[[5-(4-Fluoro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide
[26] trans-1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide
[27] trans-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [28] trans-1 -[[5-(4-Bromo-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [29] trans-1 -[[5-(4-Fluoro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [30] cis-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-azepanium iodide
[31] cis-1 -[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-pyrrolidinium iodide
[32] trans-1 -[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-pyrrolidinium iodide [33] trans-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-azepanium iodide [34] cis-2-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-2-methyl-octahydrocyclopenta[c]pyrrolium iodide [35] trans-2-[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-2-methyl-octahydrocyclopenta[c]pyrrolium iodide [36] 2-[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,4-dimethyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-2-methyl-octahydrocyclopenta[c]pyrrolium iodide [37] 2-[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,4-dimethyl-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [38] cis-1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-trifluormethyl-4,5-dihydro-
1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [39] cis-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methoxy-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide
[40] cis-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-cyano-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide
[41] 1-[[5-(5-Chloro-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-
3-carbonyl]-amino]-1 -methyl-piperidinium iodide [42] 1-[[5-(5-Bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-
3-carbonyl]-amino]-1 -methyl-piperidinium iodide [43] 1-[[5-(4-Bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H-pyrazole-
3-carbonyl]-amino]-1 -methyl-piperidinium iodide [44] cis-1 -[[5-(5-Chloro-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-
1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [45] trans-1 -[[5-(5-Chloro-thiophen-2-yl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide
[46] cis-1 -[[5-(5-Bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-
1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [47] trans-1 -[[5-(5-Bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [48] cis-1 -[[5-(4-Bromo-thiophen-2-yl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-
1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [49] trans-1 -[[5-(4-Bromo-thiophen-2-yl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide and [50] cis-1 -[[5-(4-Bromo-thiophen-2-yl)-1 -(2,4-dichloro-phenyl)-4-hydroxy-4-methyl-
4,5-dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
In another aspect the present invention provides a N-oxide of general formula Ia,
Figure imgf000046_0001
Ia
wherein
Xa is O or S;
R1a and R2a, independently of one another, in each case represent an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
or a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted alkylene group; R3a and R4a, independently of one another, in each case represent H; F; Cl; Br; I; - CN; -NO2; -NC; -OH; -NH2; -SH; -C(=O)-H;
a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted alkylene group;
an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an optionally at least mono-substituted alkylene group, alkenylene group or alkinylene group;
a -O-R7a moiety; a -S-R8a moiety; a -NH-R9a moiety or a -NR103R11a moiety;
R5a and R6*1, independently of one another, in each case represent a hydrogen atom;
a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
or
R5a and R68 together with the bridging nitrogen form an unsubstituted or at least mono-substituted, saturated or unsaturated heterocyclic ring which may contain at least one further heteroatom as a ring member and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems; R7a, R8a, R9a, R1Oa and R11a, independently of one another, in each case represent a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted alkylene group;
or an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group;
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Particularly preferred are N-oxides of general formula Ia given above, wherein
Xa is O or S;
R1a and R2a, independently of one another, in each case represent an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
an unsubstituted or at least mono-substituted C3.i6cycloalkyl radical or C4-16 cycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted C1.5 alkylene group;
or an unsubstituted or at least mono-substituted C4-16 heterocycloalkyl radical or C5.i6 heterocycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted C1-5 alkylene group;
R3a and R4a, independently of one another, in each case represent H; F; Cl; Br; I; - CN; -NO2; -NC; -OH; -NH2; -SH; -C(=O)-H;
an unsubstituted or at least mono-substituted Ci-i6alkyl radical, C2-16 alkenyl radical or C2-16 alkinyl radical;
an unsubstituted or at least mono-substituted C3-16cycloalkyl radical or C-M6 cycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C1-S alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted C1-5 alkylene group;
an unsubstituted or at least mono-substituted C-J-16 heterocycloalkyl radical or C5.i6 heterocycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C1-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted C1-5 alkylene group;
an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted Ci-5 alkylene group, C2-5 alkenylene group or C2.5 alkinylene group; an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C2.5 alkenylene group or C2-5 alkinylene group;
a -O-R7a moiety; a -S-R83 moiety; a -NH-R9a moiety or a -NR1OaR11a moiety;
R5a and R68, independently of one another, in each case represent a hydrogen atom;
an unsubstituted or at least mono-substituted Ci.i6alkyl radical, C2-i6alkenyl radical or C2-i6alkinyl radical;
or
R5a and R68 together with the bridging nitrogen form an unsubstituted or at least mono-substituted, saturated or unsaturated 4- to 10-membered heterocyclic ring which may optionally contain 1 , 2 or 3 additional heteroatom(s) selected from the group consisting of sulfur, nitrogen and oxygen as ring member(s) and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems;
R7a, R83, R9a, R1Oa and R11a, independently of one another, in each case represent
an unsubstituted or at least mono-substituted C1-I6 alkyl radical, C2-i6alkenyl radical or C2-i6alkinyl radical;
an unsubstituted or at least mono-substituted 03.16 cycloalkyl radical or 04.16 cycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C1.5 alkylene group, C2-S alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group; an unsubstituted or at least mono-substituted C-M6 heterocycloalkyl radical or C5-i6 heterocycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted C1-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group;
or an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C2-5 alkenylene group or C2-S alkinylene group;
whereby
the rings of the aforementioned ring system are in each case independently of one another 5- 6- or 7-membered and may in each case independently of one another optionally contain 1 , 2 or 3 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur;
the aforementioned heteroaryl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
the aforementioned heterocycloalkyl radicals and heterocycloalkenyl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s); optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
More particularly preferred are N-oxides of general formula Ia given above, wherein
Xa is O or S;
R1a and R2a, independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]-benzoxadiazolyl, [1 ,2,3]- benzoxadiazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and imidazo[2,1-b]thiazolyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF3, -CH2-CI, -O- CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2- pentyl, n-hexyl, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, - CHO, -CF2H, -CFH2, phenoxy and thiophenyl, whereby the thiophenyl radical can be substituted with 1 , 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, methyl, ethyl and n-propyl;
R3a represents H; F; Cl; Br; I; -CN; -NO2; -NC; -OH; -NH2; -SH; -C(=O)-H;
a radical selected from the group consisting of methyl, -CF3, -CH2F, -CF2H, -C2F5, ethyl, -CH2-CN, -CH2-OH, n-propyl, isopropyl, -CH2-CH2-CN, -CH2-CH2-OH, n-butyl, - CH2-CH2-CH2-CN, -CH2-CH2-CH2-OH, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl;
a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl) and pyrrolyl, which may be bonded via a -(CH2)-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, F, Cl and Br;
a -O-R7a moiety; a -S-R83 moiety, a -NH-R9a moiety or a -NR103R11a moiety;
R4a represents H or an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl;
R7a, R8a, R9a, R1Oa and R11a, independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl;
R5a and R68 together with the bridging nitrogen atom form a moiety selected from the group consisting of
Figure imgf000053_0001
Figure imgf000054_0001
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Even more particularly preferred are N-oxides of general formula Ia given above, wherein
Xa is O;
R1a represents a radical selected from the group consisting of phenyl and thienyl (thiophenyl), which may optionally be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -0-CH3 and -0-C2H5;
R2a represents a phenyl radical, which may be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br and I;
R3a represents H; F; Cl; Br; I; -OH, -CN; -C(=O)-H; a radical selected from the group consisting of methyl, -CF3, -CH2F, -CF2H, -C2F5, ethyl, -CH2-CN, -CH2-OH, n-propyl, isopropyl, -CH2-CH2-CN, -CH2-CH2-OH, n-butyl, - CH2-CH2-CH2-CN, -CH2-CH2-CH2-OH, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl;
a benzyl radical or a -O-R7a moiety;
R4a represents H or a radical selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl and n-butyl;
R5a and R68 together with the bridging nitrogen atom form a moiety selected from the group consisting of
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000055_0003
and R7a represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl;
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof. Most particularly preferred is the compound
[51] N-oxide of 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
Compounds of general formula Ia may be obtained by methods well known to those skilled in the art.
In another aspect the present invention also provides a process for the preparation of a salt of general formula I given above, wherein R4 represents hydrogen, according to which at least one compound of general formula R1-C(=O)-H (general formula II), wherein R1has the meaning given above, is reacted with at least one compound of general formula III,
Figure imgf000056_0001
wherein R3 and X have the meaning given above and R' represents a linear or branched Ci-6-alkyl radical, a potassium cation or a sodium cation, in a reaction medium, optionally in an inert atmosphere, optionally in the presence of at least one base, to yield at least one compound of general formula IV,
Figure imgf000056_0002
wherein R1, X and R3 have the meaning given above, which is optionally purified and/or isolated,
and at least one compound of general formula IV is reacted with at least one compound of general formula V,
Figure imgf000057_0001
V, or a corresponding salt thereof, wherein R2 has the meaning given above, in a reaction medium, optionally in an inert atmosphere, optionally in the presence of at least one acid, to yield at least one compound of general formula Vl,
Figure imgf000057_0002
wherein R1, X, R2 and R3 have the meaning given above, which is optionally isolated and/or purified,
and at least one compound of general formula Vl is reacted with an activating agent in a reaction medium, optionally in an inert atmosphere, to yield at least one compound of general formula VII,
Figure imgf000057_0003
VII wherein R1, X, R2 and R3 have the meaning given above and LG represents a leaving group, which is optionally purified and/or isolated, and at least one compound of general formula VII is reacted with at least one compound of general formula NH2-NR5R6, wherein R5 and R6 have the meaning given above, in a reaction medium, optionally in an inert atmosphere, optionally in the presence of at least one base selected from the group consisting of diisopropylethylamine, triethylamine, pyridine, dimethylaminopyridine and N- methylmorpholine, to yield at least one compound of general formula VIII,
Figure imgf000058_0001
VIII wherein R1, R2, R3, X, R5 and R6 have the meaning given above, which is optionally purified and/or isolated;
or at least one compound of general formula Vl is reacted with at least one compound of general formula NH2-NR5R6, wherein R5 and R6 have the meaning given above, in a reaction medium, in the presence of at least one coupling agent, optionally in the presence of at least one base, to yield at least one compound of general VIII, which is optionally purified and/or isolated;
and at least one compound of general formula VIII is reacted with at least one compound of general formula A-B, wherein A and B have the meaning given above, in a reaction medium, to yield at least one salt of general formula I,
B
Figure imgf000058_0002
I wherein A, B1 R1, R2, R3, X, R5 and R6 have the meaning given above and R4 represents hydrogen, which is optionally purified and/or isolated.
The inventive process is also illustrated in scheme I given below:
Figure imgf000059_0001
IV
Figure imgf000059_0002
Vl VII VIII
H9N-NR5R6
Figure imgf000059_0003
Scheme I
In step 1 a compound of general formula Il is reacted with a compound of general formula III in a protic reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n- butanol, water and mixtures thereof, in the presence of at least one base, preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide, as described, for example, in Synthetic Communications, 26(11 ), 2229-33, (1996). The respective description is hereby incorporated by reference and forms part of the disclosure. Reaction temperature as well as the duration of the reaction may vary over a broad range. Preferred reaction temperatures range from -10 0C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
Preferably the reaction between a compound of general formula Il and a compound of general formula III can also be carried out under acid catalysed conditions, more preferably by refluxing the above mentioned compounds in dichloromethane in the presence of copper(ll)trifluoromethanesulfonate as described, for example, in Synlett, (1 ), 147-149, 2001. The respective description is hereby incorporated by reference and forms part of the disclosure.
In step 2 a compound of general formula IV is reacted with a compound of general formula V in a reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n- butanol, dieethylether, tert-butyl-methylether, dioxane, tetrahydrofuran or mixtures of at least two of these afore mentioned reaction media. Also preferably, said reaction may be carried out in the presence of an acid, whereby the acid may be organic such as acetic acid and/or inorganic such as hydrochloric acid. Alternatively the reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide or mixtures of at least two of these bases. Reaction temperature as well as the duration of the reaction may vary over a broad range. Suitable reaction temperatures range from room temperature, i.e. approximately 25 0C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
The carboxylic group of the compound of general formula Vl may be activated for further reactions by the introduction of a suitable leaving group according to conventional methods well known to those skilled in the art. Preferably the compounds of general formula Vl are transferred into an acid chloride, an acid anhydride, a mixed anhydride, a Ci-4 alkyl ester or an activated ester such as p- nitrophenylester. Suitable activating agent therefore are selected from the group consisting of thionyl chloride, oxalyl chloride and ethylchloroformiate.
If said activated compound of general formula VII is an acid chloride, wherein LG represents a chlorine atom, that compound is preferably prepared by the reaction of the corresponding acid of general formula Vl with thionyl chloride or oxalyl chloride, whereby said chlorinating agent is also used as the reaction medium, in the presence of at least one base, preferably in the presence of a base selected from the group consisting of triethylamine, N-methylmorpholine, pyridine, dimethylaminopyridine and diisopropylethylamine. Also preferably an additional reaction medium may be used. Suitable reaction media include hydrocarbons such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform or carbon tetrachloride, ethers such as diethyl ether, dioxane, tetrahydrofuran or dimethoxyethane or dimethylformamide and mixtures thereof. More preferably toluene in the presence of a catalytic amount of dimethylformamide is used as reaction medium. Preferred reaction temperature range from 0° C to the boiling point of the solvent and reaction times vary from several minutes to several hours.
If said activated compound of general formula VII is a mixed anhydride, wherein LG represents -O-C(=O)-O-C2H5, said anhydride may preferably be prepared, for example, by reaction of the corresponding acid of general formula Vl with ethylchloroformiate in the presence of a base such as triethylamine, pyridine or diisopropylethylamine, in a suitable solvent such as dichloromethane, optionally in an inert atmosphere, at a temperature between -50 0C and 50 0C.
In step 4 the reaction between a compound of general formula VII with a compound of general formula NHb-NR5R6 to yield a compound of general formula VIII is preferably carried out in the presence of a base such as triethylamine in a reaction medium such as methylenchloride. The temperature is preferably in the range from 0 0C to the boiling point of the reaction medium. The reaction time may vary over a broad range, e.g. from several hours to several days. In step 5 a compound of general formula Vl is reacted with a compound of general formula NHk-NR5R6 in a reaction medium, preferably in a reaction medium selected from the group consisting of diethylether, tetrahydrofuran, acetonitrile, methanol, ethanol, (1 ,2)-dichlorethane, dimethylformamide, dichlormethane and mixtures thereof, in the presence of at least one coupling agent, preferably in the presence of at least one coupling agent selected from the group consisting of 1 -benzotriazolyloxy- tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), dicyclohexylcarbodiimide (DCC), N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDCI)1 diisoproylcarbodiimide, 1 ,1'-carbonyl-diimidazole (CDI), N-[(dimethyamino)- 1 H-1 , 2, 3-triazolo[4, 5-b]pyridino-1-ylmethylen]-N-methylmethanaminium hexafluorophosphate N-oxid (HATU), O-(benzotriazol-1-yl)-N,N,N',N'- tetramethyluroniom hexafluorophosphate (HBTU), O-(benzotriazol-1-yl)-N,N,N',N'- tetramethyluronium-tetrafluoroborate (TBTU), 1-hydroxy-benzotriazole (HOBt) and 1- hydroxy-7-azabenzotriazol (HOAt), optionally in the presence of a base, preferably in the presence of at least one base selected from the group consisting of pyridine, dimethylaminopyridine, N-methylmorpholine, triethylamine and diisopropylethylamine to yield a compound of general formula I.
Preferably said reaction is carried out in the presence of EDCI and HOBt, optionally in the presence of N-methylmorpholine or triethylamine, in an aprotic reaction medium such as dimethylformamide or tetrahydrofuran, at a temperature between 20 °C and 30 0C for 15 to 24 hours as described in Tetrahedron Lett. 2004, 45, 4977. The respective description is hereby incorporated by reference and forms part of the disclosure. Polymer-supported EDCI (P-EDCI) can also suitably be used for this process instead of EDCI as described in Tetrahedron Lett. 1998, 39, 1487 and Tetrahedron Lett. 2002, 43, 7685. The respective descriptions are hereby incorporated by reference and form part of the disclosure.
Alternatively said reaction can be carried out by using HBTU in the presence of a base such as diisopropylethylamine in an aprotic solvent, such as acetonitrile, preferably at a temperature between 20 and 30 0C for 15 to 24 hours. In step 6 a compound of general formula VIII or a compound of general formula IX,
Figure imgf000063_0001
IX wherein R1, R2, R3, R4, R5, R6 and X have the meaning given above, is reacted with a compound of general formula A-B, wherein A represents an unsubstituted or at least mono-substituted alkyl radical, preferably an unsubstituted C1-I0 alkyl radical and B represents an anion selected from the group consisting of fluoride, chloride, bromide and iodide, in a reaction medium, preferably in a reaction medium selected from the group consisting of chloroform, acetone, acetonitrile, dichloromethane, carbon tetrachloride, toluene and mixtures of the afore mentioned reaction media, at a temperature between 0 0C to 120 °C, preferably at a temperature between 20 0C to 100 0C, to afford a salt of general formula I. The duration of the reaction may vary over a broad range. Suitable reaction times may vary for example from several minutes to several hours.
Alternatively, a compound of general formula VIII or IX given above is reacted with an acid of general formula A-B, wherein A represents a hydrogen atom, and B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo- glutarate, formate, acetate, propionate, lactate, gluconate, unsubstituted or at least mono-substituted benzoate or naphthoate, pyruvate, ascorbate, glycolate, nicotinate, phenylacetate, R1 -SO-f and R1 -NH-SO3 ; wherein R12 and R13 have the meaning given above; in a reaction medium, preferably in a reaction medium selected from the group consisting of ethyl acetate, chloroform, acetone, acetonitrile, dichloromethane, carbon tetrachloride, toluene, methanol, ethanol, 2-propanol, (1 ,4)-dioxane, tetrahydrofuran and mixtures of the afore mentioned reaction media, at a temperature between 0 °C and 50 0C, preferably at a temperature between 5 0C and 40 0C, for less than an hour, preferably for less than 30 minutes, more preferably for less than 10 minutes, to afford a salt of general formula I.
Suitable acids include hydrochloric, hydrofluoric, hydroiodic or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; thiocyanic acid; cyanic acid; cyclamic acid; aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid, ascorbic acid, maleic acid, fumaric acid, pyruvic acid, phenylacetic acid, benzoic acid, 4-aminobenzoic acid, anthranilic acid, 4- hydroxybenzoic acid, salicylic acid, 4-aminosalicylic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethane-1 ,2- disulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalene-2-sulfonic acid, hydroquinonesulfonic acid, camphersulfonic acid, naphthalene-1 ,5-disulfonic acid, n-dodecyl-sulfonic acid, sulfanilic acid or cyclohexylsulfamic acid.
Suitable acids also include 3-amino-1-propanesulfonic acid, aniline-2-sulfonic acid, 3- pyridinesulfonic acid, 4-amino-3-hydroxy-1 -naphthalenesulfonic acid, 2-amino-1 ,5- naphthalenedisulfonic acid, aminomethanesulfonic acid, 2-mesitylenesulfonic acid, 7- amino-1 ,3-naphthalenedisulfonic acid, (2,5)-diaminobenzenesulfonic acid, trifluormethanesulfonic acid, 1 -naphthalenesulfonic acid, 6-amino-m-toluenesulfonic acid, 2-phenylbenzimidazole-5-sulfonic acid, 1-amino-benzimidazole-2-sulfonic acid, I H-benzimidazole-2-sulfonic acid, 1-methylbenzimidazole-2-sulfonic acid, 5- isoquinolinesulfonic acid, 3-amino-4-chlorobenzenesulfonic acid, 3-amino-4- methoxybenzenesulfonic acid, 2-amino-5-methoxy-benzenesulfonic acid, 2,4- diamino-benzenesulfonic acid, (3,5)-diamino-2,4,6-trimethylbenzenesulfonic acid, (2,5)-disulfoaniline, 2-aminopropyl-sulfonic acid, 4-amino-i-naphthalenesulfonic acid, 8-amino-1-naphthol-5-sulfonic acid, metanilic acid, 5-chloro-1 ,3-dimethyl-1 H- pyrazole-4-sulfonic acid, 8-chloronaphthalene-i -sulfonic acid, (2,5)-dihydroxy- benzenesulfonic acid and 4-amino-3-nitrobenzene-1 -sulfonic acid.
Hydrochloric acid is preferably used as a methanolic, ethanolic, ethereal or aqueous solution. Alternatively, hydrogen chloride gas can be used for the preparation of the salts of general formula I given above.
In case R4 is unlike hydrogen the reaction sequence given in Scheme I is adapted as follows.
Figure imgf000065_0001
1Mb Xl XII
Figure imgf000065_0002
VIb VIIb
Figure imgf000065_0003
IX
Scheme
In step 1 a compound of general formula IMb is reacted with a compound of general formula Il in a reaction medium , preferably in a protic reaction medium, more preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, water and mixtures thereof, in the presence of at least one base, preferably in the presence of an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide or an alkali metal methoxide such as sodium methoxide or in the presence of lithium diisopropylamide in an aprotic solvent, preferably in tetrahydrofuran.
In step 2 a compound of general formula Xl is transformed into a compound of general formula XII which contains a good living group LG, preferably a leaving group selected from the group consisting of mesyl and tosyl, using conventional methods known to those skilled in the art.
In step 3 a compound of general formula XII is reacted with a compound of general formula V in a reaction medium, preferably in a reaction medium selected from the group consisting of methanol, ethanol, isopropanol, n- butanol, dieethylether, tert-butyl-methylether, dioxane, tetrahydrofuran or mixtures of at least two of these afore mentioned reaction media. Also preferably, said reaction may be carried out in the presence of an acid, whereby the acid may be organic such as acetic acid and/or inorganic such as hydrochloric acid. Alternatively the reaction may also be carried out in the presence of a base such as piperidine, piperazine, sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide or mixtures of at least two of these bases. Reaction temperature as well as the duration of the reaction may vary over a broad range. Suitable reaction temperatures range from room temperature, i.e. approximately 25 0C to the boiling point of the reaction medium. Suitable reaction times may vary for example from several minutes to several hours.
Step 4 can be carried out as described for step 3, scheme I; step 5 can be carried out as described for step 5, scheme I, step 6 can be carried out as described for step 4, scheme 1 and step 7 can be carried out as described for step 6, scheme I.
The afore mentioned reactions involving the synthesis of the 4,5-dihydro-pyrazole ring or the reaction of a compound comprising said ring are preferably carried out under an inert atmosphere, preferably under a nitrogen or argon atmosphere, to avoid oxidation of the ring-system. During some synthetic reactions described above the protection of sensitive or reactive groups may be necessary and/or desirable. This can be performed by using conventional protective groups like those described in Protective groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; T.W. Greene & P.G.M. Wuts and Protective Groups in Organic Chemistry, John Wiley & sons, 1991. The respective parts of the description is hereby incorporated by reference and forms part of the disclosure. The protective groups may be eliminated when convenient by means well-known to those skilled in the art.
If the substituted pyrazoline compounds and/or the quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above are obtained in form of a mixture of stereoisomers, particularly enantiomers or diastereomers, said mixtures may be separated by standard procedures known to those skilled in the art, e.g. chromatographic methods or crystallization with chiral reagents. It is also possible to obtain pure stereoisomers via stereoselective synthesis.
Solvates, preferably hydrates, of the quaternary ammonium salts of substituted pyrazoline compounds, of corresponding stereoisomers or of corresponding diastereomers thereof may also be obtained by standard procedures known to those skilled in the art.
The purification and isolation of the substituted pyrazoline compounds and/or of quaternary ammonium salts of substituted pyrazoline compounds, of a corresponding stereoisomer, or diastereomer or solvate or any intermediate thereof may, if required, be carried out by conventional methods known to those skilled in the art, e.g. chromatographic methods or recrystallization.
The quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above may also act as prodrugs, i.e. they represent a drug precursor, which following administration to a patient releases a drug in vivo via some kind of chemical and/or physiological process (e.g., a prodrug on being brought to a physiological pH and/or through an enzyme action is converted to a desired drug form; see, e.g., R. B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chp. 8). In particular, the compounds of general formula I give rise to a compound of general formula XIII,
Figure imgf000068_0001
XIII wherein R1, R2, R3, R4 and X have the meaning given above, upon administration to a patient.
Prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically enter the reactive site of the protease) or the pharmacokinetics for a particular compound. For example, a hydroxyl group, can be esterified, e.g., with a carboxylic acid group to yield an ester. When the ester is administered to a subject, the ester is cleaved, enzymatically or non-enzymatically, reductively or hydrolytically, to reveal the hydroxyl group.
The quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, their stereoisomers, their diastereomers and corresponding solvates are toxicologically acceptable and are therefore suitable as pharmaceutical active substances for the preparation of medicaments.
It has been found that quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, stereoisomers thereof, diastereomers thereof and corresponding solvates have a high affinity to cannabinoid receptors, particularly cannabinoid 1 (CBi)-receptors, i.e. they are selective ligands for the (CBi)-receptor and act as modulators, e.g. antagonists, inverse agonists or agonists, on these receptors. In particular, these quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above show little or no development of tolerance during treatment, particularly with respect to food intake, i.e. if the treatment is interrupted for a given period of time and then continued afterwards, the inventively used quaternary ammonium salts of substituted pyrazoline compounds will again show the desired effect. After ending the treatment with the quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above the positive influence on the body weight is found to continue.
Furthermore, these quaternary ammonium salts of substituted pyrazoline compounds show relatively weak Herg channel affinity, thus a low risk of prolongation of the QT- interval is to be expected for these compounds.
In summary, the inventively used quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above are distinguished by a broad spectrum of beneficial effects, while at the same time showing relatively little undesired effects, i.e. effects which do not positively contribute to or even interfere with the well being of the patient.
Thus, an other aspect of the present invention relates to a medicament comprising at least quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally at least one physiologically acceptable auxiliary agent.
Preferably said medicament is suitable for the modulation (regulation) of cannabinoid-receptors, preferably cannabinoid 1 (CBi) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
Particularly preferably said medicament is suitable for the prophylaxis and/or treatment of psychosis.
Also particularly preferably said medicament is suitable for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity and/or type Il diabetus mellitus (non-insuline dependent diabetes mellitus), more preferably obesity. The inventive medicament also seems to be active in the prophylaxis and/or treatment of appetency disorders, e.g. the quaternary ammonium salts of substituted pyrazoline compounds also reduce the desire for sweets.
Also particularly preferred is the use of at least one of the pyrazoline compounds as defined herein and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the treatment of metabolic syndrome.
The metabolic syndrome and definitions thereof are described in detail by Eckel et al., The Lancet, Vol. 365 (2005), 1415-1428, included herewith by reference. One of the respective definitions was established by the WHO in 1998 (as described in Alberti et al., Diabet. Med. 1998, 15, pages 539-53, the respective description thereof is herewith incorporated by reference and forms part of the present disclosure). The other, more widely accepted, definition of the metabolic syndrome was established by the Adult Treatment Panel (ATP III) of the US National Cholesterol Education Program (NCEP) in 2001 , as described in JAMA 2001 ; 285; 2486-97, the respective description thereof is herewith incorporated by reference and forms part of the present disclosure.
The metabolic syndrome is characterized by an interaction of several physiological parameters such as triglycerides, lipids, blood pressure, glucose levels and insuline levels.
Even though obesity may play a critical role in the development of metabolic syndrome, many of its aspects are weight independent, especially some lipid parameters. Especially the positive influence on the weight independent aspects of the metabolic syndrome (see e.g. Pagotto and Pasquali, The Lancet, Vol. 365 (2005), 1363, 1364, included herewith by reference) like some blood parameters, especially lipid parameters is one of the major and surprising advantages of the inventively used substituted pyrazoline compounds.
Another aspect of the invention is the use of one or more pyrazoline compounds as defined herein for the manufacture of a medicament for improvement of cardiovascular and/or metabolic risk factors, such as one or more of the following factors:
Elevated triglycerides, whereby elevated levels of triglycerides are preferably understood as being > 150 mg/dl,
Low HDL cholesterol, whereby low levels of HDL cholesterol are preferably understood as being < 40 mg/dl in men and < 50 mg/dl in women,
Hypertension, whereby hypertension is preferably understood as being > 130/85 mm Hg,
Impaired fasting glucose, whereby impaired fasting glucose levels are preferably understood as being > 110 mg/dl,
Insulin resistance
Dyslipidemia.
Another aspect of the invention is the use of one or more pyrazoline compounds as defined herein for the manufacture of a medicament for the treatment of the weight independent aspects of metabolic syndrome.
Another aspect of the invention is a method for improving cardiovascular and/or metabolic risk factors, such as one or more of the following factors:
Elevated triglycerides, whereby elevated levels of triglycerides are preferably understood as being > 150 mg/dl,
Low HDL cholesterol, whereby low levels of HDL cholesterol are preferably understood as being < 40 mg/dl in men and < 50 mg/dl in women,
Hypertension, whereby hypertension is preferably understood as being > 130/85 mm Hg, Impaired fasting glucose, whereby impaired fasting glucose levels are preferably understood as being > 110 mg/dl,
Insulin resistance
Dyslipidemia,
in a subject, preferably a human.
Another aspect of the invention is a method for treating of the weight independent aspects of metabolic syndrome.
Also particularly preferably said medicament is suitable for the prophylaxis and/or treatment of cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, bowel cancer and prostate cancer, more preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer.
Particularly preferably said medicament is suitable for the prophylaxis and/or treatment of alcohol abuse and/or alcohol addiction, nicotine abuse and/or nicotine addiction, drug abuse and/or drug addiction and/or medicament abuse and/or medicament addiction, preferably drug abuse and/or drug addiction and/or nicotine abuse and/or nicotine addiction.
Thus, the inventive medicament is active in the treatment of abstinence, craving reduction and relapse prevention of alcohol intake. The inventive medicament can also be used in the prophylaxis and/or treatment of smoking addiction, cessation and/or dependence including treatment for craving reduction and relapse prevention of tobacco smoking. Medicaments and/or drugs, which are frequently the subject of misuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.
The medicament is also suitable for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of bone disorders, preferably osteoporosis (e.g. osteoporosis associated with a genetic predisposition, sex hormone deficiency, or ageing), cancer-associated bone disease or Paget's disease of bone; schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebella disorders, spinocerebella disorders, cognitive disorders, cranial trauma, head trauma, stroke, panic attacks, peripheric neuropathy, inflammation, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, medicament-induced movement disorders, dystonia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunologic disorders, sclerotic plaques, vomiting, diarrhoea, asthma, memory disorders, pruritus, pain, or for potentiation of the analgesic effect of narcotic and non-narcotic analgesics, or for influencing intestinal transit.
The medicament is also suitable for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of dementia and related disorders, preferably for the prophylaxis and/or treatment of one or more types of dementia selected from the group consisting of memory loss, vascular dementia, mild cognitive impairment, frontotemporal dementia and Pick's disease; binge eating disorders; juvenile obesity; drug induced obesity; atypical depression; behavioural addictions; attention deficit disorders; Tourette's syndrome; suppression of reward-related behaviours; e. g. conditioned place avoidance such as suppression of cocaine- and morphine induced conditioned place preference; impulsivity; sexual dysfunction; preferably for the prophylaxis and/or treatment of one or more types of sexual dysfunction selected from the group consisting of erectile difficulty and female sexual dysfunction; seizure disorders; nausea; emesis; neuroinflammatory disease, preferably for the prophylaxis and/or treatment of one or more types of neuroinflammatory diseases selected from the group consisting of multiple sclerosis, demyelinisation related disorders, Guillan-Barre syndrome, viral encephalitis and cerebrovascular accidents; neurological disorders; muscle spasticity; traumatic brain injury; spinal cord injury; inflammation and immunomodulatory disorders, preferably for the treatment and/or prophylaxis of one or more types of inflammation and immunomodulatory disorders selected from the group consisting of cutaneous T-cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus, sepsis, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, renal ischemia, mycocardial infarction, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, Crohn's disease, inflammatory bowel disease, reversible airway obstruction, adult respiratory distress syndrome, chronic obstructive pulmonary disease and bronchitis; cerebral apoplexy; craniocerebral trauma; neuropathic pain disorders; gastric ulcers; atheriosclerosis and liver cirrhosis.
Another aspect of the present invention is the use of at least one quaternary ammonium salt of general formula I given above as suitable active substances, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the modulation of cannabinoid-receptors, preferably cannabinoid 1 (CBi) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
Particularly preferred is the use of at least one of the respective quaternary ammonium salts of general formula I given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of psychosis. Also particularly preferred is the use of at least one of the respective quaternary ammonium salts of general formula I given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity and/or type Il diabetus mellitus (non-insuline dependent diabetes mellitus), more preferably obesity.
Also particularly preferred is the use of at least one of the respective quaternary ammonium salts of general formula I given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, bowel cancer and prostate cancer, more preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer.
Also particularly preferred is the use of at least one quaternary ammonium salt of substituted pyrazoline compounds of general formula I given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of alcohol abuse and/or alcohol addiction, nicotine abuse and/or nicotine addiction, drug abuse and/or drug addiction and/or medicament abuse and/or medicament addiction, preferably drug abuse and/or drug addiction and/or nicotine abuse and/or nicotine addiction.
Medicaments/drugs, which are frequently the subject of misuse include opioids, barbiturates, cannabis, cocaine, amphetamines, phencyclidine, hallucinogens and benzodiazepines.
Also particularly preferred is the use of at least one of the respective quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of bone disorders, preferably osteoporosis (e.g. osteoporosis associated with a genetic predisposition, sex hormone deficiency, or ageing), cancer-associated bone disease or Paget* s disease of bone; schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebellar disorders, spinocerebellar disorders, cognitive disorders, cranial trauma, head trauma, stroke, panic attacks, peripheric neuropathy, inflammation, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, medicament-induced movement disorders, dystonia, endotoxemic shock, hemorragic shock, hypotension, insomnia, immunologic disorders, sclerotic plaques, vomiting, diarrhoea, asthma, memory disorders, pruritus, pain, or for potentiation of the analgesic effect of narcotic and non-narcotic analgesics, or for influencing intestinal transit.
Also particularly preferred is the use of at least one of the respective quaternary ammonium salts of substituted pyrazoline compounds of general formula I given above, optionally in form of one of the stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of the stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof, and optionally one or more pharmaceutically acceptable excipients, for the preparation of a medicament for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of dementia and related disorders, preferably for the prophylaxis and/or treatment of one or more types of dementia selected from the group consisting of memory loss, vascular dementia, mild cognitive impairment, frontotemporal dementia and Pick's disease; binge eating disorders; juvenile obesity; drug induced obesity; atypical depression; behavioural addictions; attention deficit disorders; Tourette's syndrome; suppression of reward-related behaviours; e. g. conditioned place avoidance such as suppression of cocaine- and morphine induced conditioned place preference; impulsivity; sexual dysfunction; preferably for the prophylaxis and/or treatment of one or more types of sexual dysfunction selected from the group consisting of erectile difficulty and female sexual dysfunction; seizure disorders; nausea; emesis; neuroinflammatory disease, preferably for the prophylaxis and/or treatment of one or more types of neuroinflammatory diseases selected from the group consisting of multiple sclerosis, demyelinisation related disorders, Guillan-Barre syndrome, viral encephalitis and cerebrovascular accidents; neurological disorders; muscle spasticity; traumatic brain injury; spinal cord injury; inflammation and immunomodulatory disorders, preferably for the treatment and/or prophylaxis of one or more types of inflammation and immunomodulatory disorders selected from the group consisting of cutaneous T-cell lymphoma, rheumatoid arthritis, systemic lupus erythematosus, sepsis, sarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia, retinal disease, scleroderma, renal ischemia, mycocardial infarction, cerebral ischemia, nephritis, hepatitis, glomerulonephritis, cryptogenic fibrosing aveolitis, psoriasis, transplant rejection, atopic dermatitis, vasculitis, allergy, seasonal allergic rhinitis, Crohn's disease, inflammatory bowel disease, reversible airway obstruction, adult respiratory distress syndrome, chronic obstructive pulmonary disease and bronchitis; cerebral apoplexy; craniocerebral trauma; neuropathic pain disorders; gastric ulcers; atheriosclerosis and liver cirrhosis.
Dementia is a disease characterized by the progressive deterioration in cognitive and social adaptive functions that can eventually interfere with the patient's ability to live independently. Dementia also constitutes of impairment in short- and long-term memory plus additional symptoms, such as problems with abstract thinking, judgment, or personality. An estimated 18 million patients suffer from dementia worldwide. The most common forms of dementia include Alzheimer's disease and vascular dementia. Other forms are frontotemporal dementia and Pick's disease.
Dementia can also be of vascular origin. Vascular dementia (atherosclerotic cerebrovascular disease) is considered to be the second most common dementia of late life, affecting approximately 10-15% of all cases. AD and vascular dementia can exist in isolation or together (mixed dementia). In vascular dementia, atherosclerotic changes in cerebral vessels can lead to reduced local blood flow that results in multiple small strokes (multi-infarct dementia). Vascular dementia is pharmacologically treated by stroke prophylaxis, and by treatment of the cognitive deficit.
Alzheimer's disease (AD), the most common and important form of dementia, is a neurodegenerative disorder that is characterized by progressive impairment of cognitive functions, such as abstract reasoning and memory. Currently, an estimated 2 million people in the United States and 12 million worldwide are afflicted by this disease. Due to increasing life expectancy, it is predicted that there will be over 100 million AD patients worldwide by the year 2050. AD is one of the most prevalent illnesses in the elderly. The majority of AD patients are in their sixties or older. More than 5% of all persons over the age of 70 have significant memory loss due to AD.
AD is mainly characterized through a gradual development of forgetfulness. In further advanced disease stages, other failures in cerebral function become increasingly apparent. This includes impairment of speech, writing, and arithmetic skills.
Visiospacial orientation, such as parking the car, dressing properly, and giving and understanding directions to a location, can become defective or impaired. In late stage disease, patients forget how to use common objects and tools while retaining necessary motor power and co-ordination for these activities.
Schizophrenia is characterized by profound disruption in cognition and emotion, affecting the most fundamental human attributes: language, thought, perception, affect, and sense of self. Positive symptoms include psychotic manifestations, such as hearing internal voices or experiencing other sensations not connected to an obvious source (hallucinations) and assigning unusual significance or meaning to normal events or holding fixed false personal beliefs (delusions). Negative symptoms are characterized by affective flattening and lack of initiative or goals (avolition), loss of usual interests or pleasures (anhedonia), disturbances of sleep and eating, dysphoric mood (depressed, anxious, irritable, or angry mood) and difficulty concentrating or focusing attention.
Major depression is a multifaceted disorder characterized by primarily by dysphoric mood and loss of interest or pleasure in activities that were once enjoyable. Other physical and psychological symptoms include inability to concentrate, motor disturbances (psychomotor retardation or agitation), feelings of worthlessness, inappropriate guilt, thoughts of suicide, and disturbances in appetite and sleep.
Anxiety disorders are a group of syndromes that include generalized anxiety disorder, panic disorder, phobias, obsessive-compulsive disorder, and post traumatic stress disorder. Although each disorder has its own distinct features, all share common symptoms of excessive worrying, intense fears and dread, hypervigilance and/or somatic symptoms, in the absence of a dangerous situation.
Normal sexual function requires, among others, the ability to achieve and maintain penile erection. Major anatomic structures of the penis that are involved in erectile function include the corpus cavernosum, corpus spinosum, and the tunica albuginea (a collagenous sheath that surrounds each corpus). Thecorpora are composed of a mass of smooth muscle (trabecule) which contains a network of endothelial-lined vessels (lacunar spaces). Penile tumescence and erection is caused by relaxation of the arteries and corporal smooth muscles, while closing emissary veins, leading to increased blood flow into the lacunar network. Central and peripheral innervation contributes to regulation of the erectile response.
Erectile dysfunction (ED) may result from failure to initiate, fill, or store adequate blood volume within the lacunar network of the penis. Depending on the underlying dysfunction, ED may be vasculogenic, neurogenic, endocrinologic, diabetic, psychogenic, or medication-related. ED affects 10-25% of middle-aged and elderly men, and has a profound impact on the well-being of affected men. It is currently treated using PDE5 inhibitors such as vardenafil, tadalifil, and sildenafil, lntraurethral alpostadil (prostaglandin El) may be used in patients that fail on oral agents. In addition, vacuum constriction devices (VCD) are a well-established, noninvasive therapy.
Female sexual dysfunction (FSD) is highly prevalent, age-related, and progressive. It affects 30 to 50% of women. FSD denotes a range of medical problems and is categorized according to disorders of (1) desire, (2) arousal, (3) orgasm and (4) sexual pain, and symptoms include diminished vaginal lubrication, pain and discomfort with intercourse, decreased arousal, and difficulty achieveing orgasm. On a molecular level, vasoactive intestinal peptide (VIP), nitic oxide (NO), and sex hormones such as estrogens and androgens have been suggested to be important in female sexual function. Current treatment approaches include estrogen replacement therapy, methyl testosterone, PDE5 inhibitors such as sildenafil, the NO-donor L- arginine, prostaglandin El, phentolamine, and the dopamine agonists apomorphine.
The medicament according to the present invention may be in any form suitable for the application to humans and/or animals, preferably humans including infants, children and adults and can be produced by standard procedures known to those skilled in the art. The medicament can be produced by standard procedures known to those skilled in the art, e.g. from the table of contents of "Pharmaceutics: The Science of Dosage Forms", Second Edition, Aulton, M.E. (ED. Churchill Livingstone, Edinburgh (2002); "Encyclopedia of Pharmaceutical Technology", Second Edition, Swarbrick, J. and Boylan J.C. (Eds.), Marcel Dekker, Inc. New York (2002); "Modern Pharmaceutics", Fourth Edition, Banker G.S. and Rhodes CT. (Eds.) Marcel Dekker, Inc. New York 2002 y "The Theory and Practice of Industrial Pharmacy", Lachman L., Lieberman H. And Kanig J. (Eds.), Lea & Febiger, Philadelphia (1986). The respective descriptions are hereby incorporated by reference and form part of the disclosure. The composition of the medicament may vary depending on the route of administration.
The medicament of the present invention may for example be administered parentally in combination with conventional injectable liquid carriers, such as water or suitable alcohols. Conventional pharmaceutical excipients for injection, such as stabilising agents, solubilizing agents, and buffers, may be included in such injectable compositions. These medicaments may for example be injected intramuscularly, intraperitoneally, or intravenously.
Medicaments according to the present invention may also be formulated into orally administrable compositions containing one or more physiologically compatible carriers or excipients, in solid or liquid form. These compositions may contain conventional ingredients such as binding agents, fillers, lubricants, and acceptable wetting agents. The compositions may take any convenient form, such as tablets, pellets, granules, capsules, lozenges, aqueous or oily solutions, suspensions, emulsions, or dry powdered forms suitable for reconstitution with water or other suitable liquid medium before use, for immediate or retarded release. The multiparticulate forms, such as pellets or granules, may e.g. be filled into a capsule, compressed into tablets or suspended in a suitable liquid.
Suitable controlled release formulations, materials and methods for their preparation are known from the prior art, e.g. from the table of contents of "Modified-Release Drug Delivery Technology", Rathbone, M.J. Hadgraft, J. and Roberts, M.S. (Eds.), Marcel Dekker, Inc., New York (2002); "Handbook of Pharmaceutical Controlled Release Technology", Wise, D.L. (Ed.), Marcel Dekker, Inc. New York, (2000);
"Controlled Drug Delivery", VoI, I, Basic Concepts, Bruck, S. D. (Ed.), CRD Press Inc., Boca Raton (1983) y de Takada, K. and Yoshikawa, H., "Oral Drug Delivery", Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 728-742; Fix, J., "Oral drug delivery, small intestine and colon", Encyclopedia of Controlled Drug Delivery, Mathiowitz, E. (Ed.), John Wiley & Sons, Inc., New York (1999), Vol. 2, 698-728. The respective descriptions are hereby incorporated by reference and form part of the disclosure.
Medicaments according to the present invention may also comprise an enteric coating, so that their dissolution is dependent on pH-value. Due to said coating the medicament can pass the stomach undissolved and the respective quaternary ammonium salt of general formula I is liberated in the intestinal tract. Preferably the enteric coating is soluble at a pH value of 5 to 7.5. Suitable materials and methods for the preparation are known from the prior art.
Typically, the medicaments according to the present invention may contain 1-60 % by weight of one or more quaternary ammonium salts of substituted pyrazoline compounds as defined herein and 40-99 % by weight of one or more auxiliary substances (additives).
The liquid oral forms for administration may also contain certain additives such as sweeteners, flavoring, preservatives, and emulsifying agents. Non-aqueous liquid compositions for oral administration may also be formulated, containing edible oils. Such liquid compositions may be conveniently encapsulated in e.g., gelatin capsules in a unit dosage amount.
The compositions of the present invention may also be administered topically or via a suppository.
The daily dosage for humans and animals may vary depending on factors that have their basis in the respective species or other factors, such as age, sex, weight or degree of illness and so forth. The daily dosage for humans may preferably be in the range from 1 to 2000, preferably 1 to 1500, more preferably 1 to 1000, even more preferably 1 to 150 milligrams of active substance to be administered during one or several intakes per day.
Pharmacological Methods
I. In-vitro determination of affinity to CB1/CB2-Receptors
a)
The in-vitro determination of the affinity of the inventive quaternary ammonium salts of substituted pyrazoline compounds to CBi/CB2-Rezeptors is carried out as described in the publication of Ruth A. Ross, Heather C. Brockie et al., "Agonist-inverse agonist characterisation at CBi and CB2 cannabinoid receptors of L-759633, L759656 and AM630", British Journal of Pharmacology, 126, 665-672, (1999), whereby the transfected human CB1 and CB2 receptors of Receptor Biology, Inc. are used. The radioligand used for both receptors is [3H]-CP55940. The respective parts of the description is hereby incorporated by reference and forms part of the present disclosure.
b)
Rat cerebellum CB1 binding
Binding affinity to CB1 receptor was evaluated according to a modification of the method described by Govaerts et al., Eur J Pharmac Sci 23, 233-243 (2004). The respective parts of the description is hereby incorporated by reference and forms part of the present disclosure.
Briefly, cerebellum from male wistar rats (250-30Og) were carefully dissected on ice and homogenates were prepared with Potter-Helveheim in a cold 50 mM Tris-HCI solution containing 5 mM MgCI2, 1 mM EDTA and 0.25 M sucrose, pH 7.4. The suspension was centrifuged at 1 ,000 x g for 5 minutes. The supernatants were collected and centrifuged 50,000 x g for 15 minutes. The resulting pellets were then resuspended in Tris-HCI buffer without sucrose, homogenized and incubated for 15 min at 370C in an orbital shaker bath and centrifuged again at 50,000 x g for 15 min. Pellets were weighted, resuspended in Tris-HCI buffer without sucrose, homogenized with Ultraturrax at 13,500 rpm for 3 x 5 seconds and alicuoted in 0.9 ml volumes in Eppendorf tubes. Alicuotes were centrifuged at 20,800 x g for 5 minutes, supernatants discarded and pellets were frozen at -8O0C until use. Total protein concentration was determined using the Bio-Rad Lowry method based kit. Competitive binding experiments were performed in presence of 1 nM [3H]-CP 55,940 in siliconized glass tubes containing 100 μg protein/tube resuspended in 1 ml final volume of 50 mM Tris-HCI, 5 mM MgCb , 1 mM EDTA, 0.5% (w/v) bovine serum albumin, pH 7.4. Compounds were present at various concentrations and the non specific binding was determined in the presence of 10 μM HU-210. After 1 hour incubation at 3O0C, the suspension was rapidly filtered through 0.5% PEI pre-treated GF/B fiber filters on a 96-well harvester and washed 3 times with 3 ml ice-cold binding buffer without bovine serum albumin. Radioactivity on filters was measured with Wallac Winspectral 1414 counter by liquid scintillation in 6 ml Ecoscint H (National Diagnostics, U.K.). Assays were made in triplicates.
Binding data were analyzed by non-linear regression with the software GraphPad Prism Version 3.03.
II. In-vivo bioassay system for determination of cannabinoid activity
Mouse tetrad model
Substances with affinity for cannabinoid receptors are known to produce a wide range of pharmacological effects. It is also known that intravenous administration of a substance with affinity for cannabinoid receptors in mice produces analgesia , hypothermia, sedation and catalepsy. Individually, none of these effects can be considered as proof that a tested substance has affinity for cannabinoid-receptors, since all of these effects are common for various classes of centrally active agents. However, substances, which show all of these effects, i.e. substances that are active in this so-called tetrad model are considered to have affinity for the cannabinoid receptors. It has further been shown that cannabinoid receptor antagonists are highly effective in blocking the effects of a cannabinoid agonist in the mouse tetrad model.
The tetrad model is described, for example, in the publication of A. C. Howlett et al, International Union of Pharmacology XXVII. Classification of Cannabinoid Receptors, Pharmacol Rev 54, 161-202 , 2002 and David R. Compton et al., Jn-vivo Characterisation of a Specific Cannabinoid Receptor Antagonist (SR141716A) Inhibition of Tetrahydrocannbinol- induced Responses and Apparent Agonist Activity", J. Pharmacol. Exp. Ther. 277 , 2, 586-594, 1996. The corresponding parts of the description are hereby incorporated by reference.
Material and Methods
Male NMRI mice with a weight of 20-30 g (Harlan, Barcelona, Spain) are used in all of the following experiments.
Before testing in the behavioural procedures given below, mice are acclimatised to the experimental setting. Pre-treatment control values are determined for analgesia hot plate latency (in seconds), rectal temperature, sedation and catalepsy.
In order to determine the agonistic activity of the substance to be tested, the mice are injected intravenously with the substance to be tested or the vehicle alone. 15 minutes after injection, latency in hot plate analgesia is measured. Rectal temperature, sedation and catalepsy are measured 20 minutes after injection.
In order to determine the antagonistic activity the identical procedure is used as for the determination of the agonistic effects, but with the difference that the substance to be evaluated for its antagonistic activity is injected 5 minutes before the intravenous injection of 1.25 mg/kg Win-55,212 a known cannabinoid-receptor agonist.
Hot plate analgesia
The hot plate analgesia is determined according to the method described in Woolfe D. et al. ,,The evaluation of analgesic action of pethidine hydrochloride (Demerol)", J. Pharmacol. Exp. Ther. 80, 300-307,1944. The respective description is hereby incorporated by reference and forms part of the present disclosure.
The mice are placed on a hot plate (Harvard Analgesimeter) at 55 ± 0.5 0C until they show a painful sensation by licking their paws or jumping and the time for these sensations to occur is recorded. This reading is considered the basal value (B). The maximum time limit the mice are allowed to remain on the hot plate in absence of any painful response is 40 seconds in order to prevent skin damage. This period is called the cut-off time (PC).
Fifteen minutes after the administration of the substance to be tested, the mice are again placed on the hot plate and the afore described procedure is repeated. This period is called the post-treatment reading (PT).
The degree of analgesia is calculated from the formula :
% MPE of Analgesia = ( PT- B) / (PC-B) x 100
MPE = Maximum possible effect.
Determination of sedation and ataxia
Sedation and ataxia is determined according to the method described in Desmet L. K. C. et al. ..Anticonvulsive properties of Cinarizine and Flunarizine in Rats and Mice", Arzneim. -Forsch. (Frug Res) 25, 9, 1975. The respective description is hereby incorporated by reference and forms part of the present disclosure.
The chosen scoring system is
0: no ataxia; 1: doubtful;
2: obvious calmness and quiet; 3 pronounced ataxia;
prior to as well as after treatment.
The percentage of sedation is determined according to the formula:
% of sedation = arithmetic mean / 3 X 100 Hypothermia:
Hypothermia is determined according to the method described in David R. Compton et al. Jn-vivo Characterisation of a Specific Cannabinoid Receptor Antagonist (SR141716A) Inhibition of Tetrahydrocannbinol- induced Responses and Apparent Agonist Activity", J. Pharmacol Exp Ther. 277 , 2, 586-594, 1996. The respective description is hereby incorporated by reference and forms part of the present disclosure.
The base-line rectal temperatures are determined with a thermometer (YeIIo Springs Instruments Co., Panlabs) and a thermistor probe inserted to 25mm before the administration of the substance to be tested. Rectal temperature is again measured 20 minutes after the administration of the substances to be tested. The temperature difference is calculated for each animal, whereby differences of ≥ -2 0C are considered to represent activity.
Catalepsy:
Catalepsy is determined according to the method described in Alpermann H. G. et al. ..Pharmacological effets of Hoe 249: A new potential antidepressant", Drugs Dev. Res. 25, 267-282. 1992. The respective description is hereby incorporated by reference and forms part of the present disclosure.
The cataleptic effect of the substance to be tested is evaluated according to the duration of catalepsy, whereby the animals are placed head downwards with their kinlegs upon the top of the wooden block.
The chosen scoring system is:
Catalepsy for: more than 60 seconds = 6; 50 -60 seconds = 5, 40-50 seconds = 4, 30-40 seconds =
3, 20-30 seconds = 2, 5-10 seconds = 1 , and less than 5 seconds =0. The percentage of catalepsy is determined according ot the following formula:
% Catalepsy = arithmetic mean / 6 X 100
III. In vivo testing for antiobesic activity
a) Accute Treatment
Normally handled rats were habituated to a reversed cycle 12/12h, and the tested compound as well as saline was acutely orally administered. After administration the cumulated food intake (g) was measured at 6 h and 24 h. Following that the difference in body weight between control and compound treated animals was measured. This is a variation of the test according to Colombo et al. as described below.
b) Long-term Treatment
The in-vivo testing for antiobesic activity of the inventive pyrazoline compounds is carried out as described in the publication of G. Colombo et al., ..Appetite Suppression and Weight Loss after the Cannabinoid Antagonist SR 141716"; Life Sciences, 63 (8), 113-117, (1998). The respective part of the description is hereby incorporated by reference and forms part of the present disclosure.
IV. In vivo testing for antidepressant activity
The in-vivo testing for antidepressant activity of the inventive pyrazoline compounds in the water despair test is carried out as described in the publication of ET. Tzavara et al., ,,The CB1 receptor antagonist SR141716A selectively increases monoaminergic neurotransmission in the medial prefrontal cortex: implications for therapeutic actions"; Br. J. Pharmacol. 2003, 138(4):544:53. The respective part of the description is hereby incorporated by reference and forms part of the present disclosure. V. In vitro determination of antagonism to CB1 -receptor
Membrane preparation:
Chinese hamster ovary (CHO) cells stably expressing recombinant human cannabinoid 1 receptor (CB1) were cultured in nutrient mixture Ham's F 12 supplemented with 10 % heat-inactivated fetal bovine serum, 2 mM L-glutamine, 50 U/ml penicillin, 50 U/ml streptomycin and 0.5 mg/ml geneticin. In order to obtain cells, culture flasks were washed twice with phosphate buffered saline and scraped. Then, cells were collected by centrifugation (200 x g, 10 min) and stored dry at -8O0C. Cells were homogenized in ice-cold 20 mM HEPES, 10 mM EDTA (pH 7.5) and centrifuged at 40,000 x g for 15 min at 40C. The pellet was resuspended in 20 mM HEPES, 0.1 mM EDTA (pH 7.5) and centrifuged for 15 min at 40C. The final pellet was resuspended in 20 mM HEPES, 0.1 mM EDTA (pH 7.5), and divided in aliquots and stored at -8O0C until use.
[35S]GTPyS binding assay:
The reaction was performed in 96-well plates. Membranes (15 μg protein/well) were incubated for 60 min at 30 0C in buffer (50 mM HEPES, 100 mM KCI, 5 mM MgCI2,1 mM EDTA, 0.1 % wt/vol bovine serum albumin, 5 μM GDP, saponin (10 μg/ml), 0.5 nM [35S]GTPyS, pH 7.4) with compound at 1 μM final concentration in either the absence or presence of dose response curve of agonist WIN 55,212-2 between 3 nM and 3 μM. The incubation was terminated by rapid filtration through Millipore Multiscreen glass fiber FB, and rinsed two-times with ice-cold assay buffer. Filter plates were dried and 30 μl of scintillation liquid was added. Radioactivity was determined using Wallac Microbeta Trilux. Each experiment was performed at least in duplicate. A WIN 55,212-2 dose-response either alone or in the presence of Rimonabant (1 μM) was systematically performed.
Calculations: The average of basal [35S]GTPyS binding was subtracted from all binding data. In order to compare the antagonism results from one screening campaign to another one, the difference between the maximal agonist effect of WIN 55,212-2 alone, and the maximal antagonism effect due to WIN 55,212-2 plus Rimonabant (1 μM) was defined as 100 %. Further methods:
Alcohol Intake
The following protocol may be used to evaluate the effects of alcohol intake in alcohol preferring (P) female rats (e.g. bred at Indiana University) with an extensive drinking history. The following reference provides detailed a description of P rats: Lumeng, L, et al.."Different sensitivities to ethanol in alcohol-preferring and- nonpreferring rats,"Pharmacol, Biochem Behav., 16, 125-130 (1982).
Female rats are given 2 hours of access to alcohol (10% v/v and water, 2-bottle choice) daily at the onset of the dark cycle. The rats are maintained on a reverse cycle to facilitate experimenter interactions. The animals are initially assigned to four groups equated for alcohol intakes: Group 1 -vehicle; Group 2-positive control (e. g. 5.6 mg/kg AM251 ; Group3-low dose test compound; and Group 4-high dose of test compound. Test compounds are generally mixed into a vehicle of 30% (w/v) - cyclodextrin in distilled water at a volume of 1-2 ml/kg. Vehicle injections are given to all groups for the first two days of the experiment. This is followed by 2 days of drug injections (to the appropriate groups) and a final day of vehicle injections. On the drug injection days, drugs are given sc 30 minutes prior to a 2-hour alcohol access period. Alcohol intake for all animals is measured during the test period and a comparison is made between drug and vehicle-treated animals to determine effects of the compounds on alcohol drinking behavior.
Additional drinking studies can be done utilizing female C57BI/6 mice (Charles River). Several studies have shown that this strain of mice will readily consume alcohol with little to no manipulation required (Middaugh et al., "Ethanol Consumption by C57BU6 Mice : Influence of Gender and Procedural Variables" Alcohol, 17 (3),175-183, 1999; Le et al.,"Alcohol Consumption by C57BL/6, BALA/c, and DBA/2 Mice in a Limited AccessParadigm" PharmacologyBiochemistry and Behavior,47, 375-378,1994).
For example, upon arrival mice are individually housed and given unlimited access to powdered rat chow, water and a 10 % (w/v) alcohol solution. After 2-3 weeks of unlimited access, water is restricted for 20 hours and alcohol is restricted to only 2 hours access daily. This is done in a manner that the access period was the last 2 hours of the dark part of the light cycle.
Once drinking behavior is stabilized, testing can commence. Mice are considered stable when the average alcohol consumption for 3 days is 20% of the average for all 3 days. Day 1 of test consists of all mice receiving vehicle injection (sc or ip). Thirty to 120 minutes post injection access is given to alcohol and water. Alcohol consumption for that day is calculated (g/kg) and groups are assigned so that all groups have equivocal alcohol intake. On day 2 and 3, mice are injected with vehicle or drug and the same protocol as the previous day is followed. Day 4 iss wash out and no injections are given. Data is analyzed using repeated measures ANOVA. Change in water or alcohol consumption is compared back to vehicle for each day of the test. Positive results would be interpreted as a compound that was able to significantly reduce alcohol consumption while having no effect on water
Oxygen Consumption Methods:
Whole body oxygen consumption is measured using an indirect calorimeter (Oxymax from Columbus Instruments, Columbus, OH) in male Sprague Dawley rats (if another rat strain or female rats are used, it will be specified). Rats (e.g. 300-380 g body weight) are placed in the calorimeter chambers and the chambers are placed in activity monitors. These studies are done during the light cycle. Prior to the measurement of oxygen consumption, the rats are fed standard chow ad libitum. During the measurement of oxygen consumption, food is not available. Basal pre- dose oxygen consumption and ambulatory activity are measured every 10 minutes for 2.5 to 3 hours. At the end of the basal pre-dosing period, the chambers are opened and the animals are administered a single dose of compound (the usual dose range is 0.001 to 10 mg/kg) by oral gavage (or other route of administration as specified, i. e. , sc, ip, iv). Drugs are prepared in methylcellulose, water or other specified vehicle (examples include PEG400, 30% beta-cyclo dextran and propylene glycol). Oxygen consumption and ambulatory activity are measured every 10 minutes for an additional 1-6 hours post-dosing. The Oxymax calorimeter software calculates the oxygen consumption (ml/kg/h) based on the flow rate of air through the chambers and difference in oxygen content at inlet and output ports. The activity monitors have 15 infrared light beams spaced one inch apart on each axis, ambulatory activity is recorded when two consecutive beams are broken and the results are recorded as counts.
Resting oxygen consumption, during pre-and post-dosing, is calculated by averaging the 10-min02 consumption values, excluding periods of high ambulatory activity (ambulatory activity count > 100) and excluding the first 5 values of the pre-dose period and the first value from the post-dose period. Change in oxygen consumption is reported as percent and is calculated by dividing the post-dosing resting oxygen consumption by the pre-dose oxygen consumption *100. Experiments will typically be done with n = 4-6 rats and results reported are mean +/-SEM.
Interpretation :
An increase in oxygen consumption of > 10% is considered a positive result. Historically, vehicle-treated rats have no change in oxygen consumption from pre- dose basal.
Nicotine Dependence
An intravenous nicotine self-administration model or place preference model may be used to assess the effects of a test compound on nicotine dependence (see, e.g., Vastola, et al. Physiol. Behav. 77:107-114, 2002; Brower, et al., Brain Res. 930:12- 20, 2002).
Place Preference
Sprague-Dawley rats are used in this study (Vastola, et al., 2002). Animals are housed in a temperature-controlled, 12h/12h illumination cycle with ad libitum access to food and water. Conditioning and testing are conducted in a chamber divided into two compartments with a door separating the two compartments. Behavior of the animals is recorded by video camera. Animals are habituated to the injection procedure for several days. The animals are then placed into the test chamber and given free access to both compartments. The initial preference for a particular compartment is determined. For the conditioning trials, animals are injected with nicotine and restricted to the nonpreferred compartment, or the animals are injected with saline and restricted to the preferred compartment. On test day, the door separating the compartments is removed, the animal is placed in the center of the chamber and allowed to move freely between compartments. Time spent in each compartment is scored. Preferential occupancy of the nicotine compartment follows from the conditioned reinforcing effects of nicotine.
Self-administration
Self-administration in animals is a predictor of a compound's abuse potential in humans. Modifications to this procedure may also be used to identify compounds that prevent or block the reinforcing properties of drags that have abuse potential. A compound that extinguishes the self- administration of a drag may prevent that drag's abuse or its dependence.
Sprague-Dawley rats are used in this study. Initially, animals are housed in a temperature- controlled, 12h/12h illumination cycle with ad libitum access to food and water. The animals are then implanted with jugular catheters which exit through the animal's back, and each animal is placed in an individual operant chamber (Brower, et al., 2002). The catheters are connected to a computer-driven syringe pump which is located outside of the chamber. The chamber contains two levers with a green light located above each lever. The light is illuminated when nicotine is available.
In a self-administration test, animals are placed in the operant chambers and the levers are randomly designated as an active and inactive lever. Each response on the active lever produces an infusion of nicotine. Presses on the inactive lever have no effect, but are also recorded. Animals are then trained to self -administer nicotine over a set period of time by having drag access during each daily session. Illumination of the chamber house light signals the beginning of the session and the availability of nicotine. When the session ends, the house light is turned off. Initially, a nicotine infusion occurs with every press of the active lever. Once lever-pressing behavior has been established, the number of presses to produce a nicotine infusion is increased. After stable nicotine self-administration is obtained, the effect of a test compound on the nicotine- reinforced behavior may be evaluated. Administration of this test compound prior to the session can either potentiate, extinguish, or produce no change to the self-administrating behavior. Tests are conducted every two days, and the order of the administration of the test compound doses is controlled.
ALZHEIMER/DEMENTIA EXPERIMENTS
Morris Water Maze Task
The Morris water maze is a behavioral in vivo test to measure spatial orientation learning and memory through a complex learning task. It is highly suitable for testing compounds that enhance learning and memory. A circular water tank or pool (diameter 2 m, height 0.7 m) is filled with water, and a 10 cm2 platform is placed 1- 1.5 cm below the water surface at a defined location within the pool. The escape platform is not visible for an animal swimming in the water tank. For the experiment, a rat or mouse is placed into the pool to swim freely.
The animals have the task to localize the submerged platform, and the time and distance required for successful retrieval is measured. Multiple extra-maze cues are provided by the furniture in the room, including desks, computer equipment, a second water tank, the presence of the experimenter, and by a radio on a shelf that is playing softly.
Before administration of the test compound, animals are usually trained in the task 4 times a day for 5 days. Test compounds are administered orally or intraperitoneally on the day of the experiment at a defined time (e.g., 30 minutes before the first swim test). Control animals are dosed with the corresponding vehicle not containing test compound. Active compounds yield shorter times and distances to localize the platform (i.e., the better the animal remembers the location of the platform, the shorter the distance covered and the faster the platform is reached). The test can also be carried out using transgenic or cognitively impaired animals. Cognitive impairment is induced either by old age or experimentally through brain lesions, such as bilateral lesions of the entorhinal cortex in rats. Such lesions can be induced by intracerebral injections of the excitotoxin ibotenic acid.
Object Recognition Task
The object recognition task is used to assess the effects of compounds on the cognitive performance of rodents. A rat is placed in an open field, in which two identical objects are located. The rats inspects both objects during the initial trial of the test. After a certain retention interval (e.g., 24 hours), a second trial is carried out. Here, one of the two objects used in the first trial (the "familiar1 object) and a novel object are placed in the open field, and the inspection time at each of the objects is measured. Good retention is reflected by higher exploration times towards the novel compared with the 'familiar' object.
Administration of the putative cognition enhancer prior to the first trial predominantly allows assessment of the effects on acquisition, and on the consolidation processes. Administration of the test compound after the first trial allows to assess the effects on consolidation processes, whereas administration before the second trial allows to measure effects on retrieval processes.
Passive Avoidance Task
The passive avoidance task assesses memory performance in rats and mice. The inhibitory avoidance uses an apparatus consisting of a box with two compartments separated by a guillotine door that can be operated by the experimenter. One compartment is illuminated with bright light, and the other compartment is dark. A threshold of 2 cm separates the two compartments when the guillotine door is 15 raised. When the door is open, the illumination in the dark compartment is about 2 lux. The light intensity is about 500 lux at the center of the floor of the light compartment. Two habituation sessions, one shock session, and a retention session are given, separated by inter-session intervals of 24 hours. During the habituation sessions and the retention session, the rat is allowed to explore the apparatus for 300 seconds. The rat is placed in the light compartment, facing the wall opposite to the guillotine door. After an accommodation period of 15 seconds, the guillotine door is opened so that all parts of the apparatus can be visited freely. Rats normally avoid brightly lit areas and will enter the dark compartment within a few seconds.
In the shock session, the guillotine door between the compartments is lowered as soon as the rat has entered the dark compartment with all paws, and a scrambled 1 mA footshock is administered for 2 seconds. Then the rat is removed from the apparatus and returned into its home cage. The procedure during the retention session is identical to that of the habituation sessions.
The step-through latency, that is, the first latency of entering the dark compartment (in seconds) during the retention session is an index of the memory performance of the animal: a better retention is assumed if the latency to enter the dark compartment is longer. A test compound is given 30 minutes before the shock session, together with 1 mg/kg scopolamine. Scopolamine impairs the memory performance during the retention session 24 hours later. If the test compound increases the enter latency compared with the scopolamine-treated controls, it is considered to possess cognition enhancing activity. T-maze Spontaneous Alternation Task
The T-maze spontaneous alternation task (TeMCAT) assesses the spatial memory performance in mice. The start arm and the two goal arms of the T-maze are provided with guillotine doors that can be operated manually by the experimenter. A mouse is put into the start arm at the beginning of training. In the first trial, either the left or right goal arm is blocked by lowering the respective guillotine door (forced trial).
After the mouse has been released from the start arm, it will explore the maze, eventually entering the open goal arm, and return to the start position, where it will be confined for 5 seconds, by lowering the guillotine door. Then, the animal can choose freely between the left and right goal arm (all guillotine-doors opened) during 14 additional trials (free choice trials). As soon as a mouse has entered one goal arm, the other arm is closed. The mouse eventually returns to the start arm and is free to visit whichever arm it wants after having been confined to the start arm for 5 seconds. After completion of 14 free choice trials in one session, the animal is removed from the maze.
Out of the 14 trials the alternations in percent are calculated. This percentage and the total time needed to complete the first forced trial and the subsequent 14 free choice trials (in seconds) is analyzed. In addition, cognitive deficits can be induced by injection of scopolamine 30 minutes before the start of the training session. A cognition enhancer, administered before the training session, will at least partially, antagonize the scopolamine-induced reduction in the spontaneous alternation rate.
Depression Model
A forced swim or tail suspension model may be used to assess the efficacy of antidepressant compounds (see , e.g., Porsolt, et al., Nature 266:730-732, 1977; Stem, et al., Psychopharmacology 85:367-370, 1985).
Forced Swim Test
Rats or mice are placed in a cylinder filled with water 23-25 0C from which no escape is possible. Initially, animals struggle and try to escape, but eventually adopt a characteristic immobile posture and make no further attempts to escape except for small movements needed their head above water. Animals are dosed with a compound and the activity (swimming or climbing) or immobility is measured by an observer. The immobility is considered by some to reflect a 'behavioral despair1 in which animals cease to struggle to escape the aversive situation. A wide variety of clinically used antidepressants (TCAs, MAOIs, SSRIs, atypicals) decrease immobility in this test and has a good predictive validity in that it detects antidepressants with different mechanisms of action but its construct validity is weak. At least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, whereas drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. There are false positives (psychostimulants) but relatively few false negatives ([beta]-adrenergic agonists). The test is sensitive to muscle-relaxant (benzodiazepines) and sedative (neuroleptics) effects, leading to enhanced immobility. False positives and false negatives can often be screened by measuring if the compound produces locomotor stimulation or sedation.
Tail Suspension Test
When suspended by the tail, mice will initially struggle and try to escape and then alternate between active escape attempts and immobililty. In this test, animals are dosed with a compound and the immobility is measured by an observer for 6 min. Porsolt describes the immobile behavior as 'behavioral despair' which animals cease to struggle to escape the aversive situation. A large variety of clinically antidepressants (tricyclics, MAOIs, SSRIs, and atypicals) reduce immobility in this model. The test has a good predictive validity for antidepressant activity and works for most antidepressant classes including but has some false positives (psychostimulants). The test is sensitive to muscle-relaxant (benzodiazepines) and sedative (neuroleptics) effects, which lead to enhanced immobility. False positives and false negatives can often be screened by measuring if the compound produces locomotor stimulation or sedation. Strain differences in the tail suspension test have been found in mice. The tail suspension test has some face validity but its construct validity is rather weak.
Schizophrenia Model
A prepulse inhibition model may be used to assess the efficacy of antipsychotic compounds (see Swerdlow and Geyer, Schizophrenia Bulletin 24: 285-301 , 1998).
Prepulse Inhibition
Prepulse inhibition is the process whereby a relatively mild stimulus, the prepulse, suppresses the response to a strong, startle-eliciting stimulus when the prepulse precedes the startle stimulus by a brief duration (about 10 to 500 milliseconds). Prepulse inhibition is a cross-species phenomenon (ie, it is present in mammals ranging from mice to humans), yet it is relatively absent among schizophrenic patients. The deficit in PPI in schizophrenic patients is thought to reflect the loss of sensorimotor gating that may lead to sensory flooding and cognitive fragmentation. In this test, mice or rats are administered compounds and individually placed into a holder on a transducer platform to measure whole body startle. The holder is housed in a startle chamber with background white noise. Following a brief habituation period, animals are given multiple trials of a weak auditory prepulse stimululs, followed by a strong auditory startle stimulus. Four types of trials are given: prepulse plus startle, prepulse alone, startle alone, and no stimulation. PPI is measured as the amount of inhibition of startle following the prepulse and is expressed as the percentage of basic startle. As a control, measurements are taken in the no stimulation and prepulse alone trials. PPI is considered a test with good predictive, face and construct validity for schizophrenia. Putative antipsychotics can be tested alone to determine if they enhance PPI. Alternately, antipsychotics can be screened to determine if they block various agents that disrupt PPI (apomorphine, d- amphetamine, PCP, ketamine, DOI). Finally, mutant mice with or without drugs can be screened using the PPI procedure.
Anxiety Model
An elevated plus maze model may be used to assess the efficacy of anxiolytic compounds (see Pellow and File, Pharm. Biochem. Behav. 24, 525-529, 1986).
Elevated Plus Maze
The elevated plus maze is widely used as an anxiety paradigm that examines the conflict between the drive to explore and the aversiveness of heights and open spaces of rats or mice. The maze is a cross made up of two open and two closed arms that is raised above the ground. The combination of light, the open arms, and the height is thought to produce unconditioned fear or anxiety responses in mice or rats. The test apparatus is an open top maze constructed of opaque plastic with alternating open and enclosed arms. For rats, each arm is 45-55 cm long and 8-12 cm wide, with the sides of the enclosed arms 35-45 cm high, the juncture approximately 10 x 10 cm, and the maze is elevated 45-55 cm above the floor. The mouse elevated plus maze consists of two closed arms (15 x 6 x 30 cm) and two open arms (1 x 6 x 30 cm) forming a cross, with a quadrangular center (6 x 6cm). The maze is placed 50 cm above the floor. Testing is performed in a room free of noise and distraction. On test days animals are administered drug or vehicle. If a pretreatment period is necessary, the animals are returned to the home cage for the duration of the pretreatment time; otherwise, the animals are placed in a clear plastic holding chamber singly or with cage mates for 1-10 minutes prior to test time. Rats are then placed in the center of the maze always oriented in the same direction, either consistently facing an open arm or an enclosed arm. For 5-10 minutes, entries into each arm and the time spent in each arm are recorded by the observers) or by videotape or a computer receiving input from a video camera mounted above the maze. To count as an entry, all four paws must be inside the arm. If necessary, additional measures of anxiety-related behaviors will be recorded, i.e., time spent motionless, time spent in the center, time spent grooming, and the number of rears, stretching postures or feces produced. Following testing the animals are returned to the home cages. When animals are placed in the center of the maze, they spend most of their time in the closed arms, avoiding the open arms. Anxiolytic drugs, such as benzodiazepines, will increase the amount of time animals spend in the open arms. The test is also sensitive to anxiogenic drugs, which lends strong support for its predictive validity.
Erectile Dysfunction
Drugs affecting erectile function may be tested by measuring the effect on apomorphine- evoked increases in intracavernous pressure in the awake rat as described by Andersson, et al., (J. Urol. 161 : 1707-17 ] 2, 1999). One end of a polyethylene tubing is implanted into the cavernosal space of the penis of male Sprague-Dawley rats. After recovery from the surgery, intracavernous pressure is recorded using a pressure transducer connected to a multichannel pen-recorder. Erections are induced by administration of apomorphine (100-250 ug/kg s.c.) with or without test compound, and the results are compared for the treated group and the non-treated group. Female Sexual Dysfunction
Systems to test compounds for the treatment of female sexual dysfunction include in vitro and in situ models using vaginal or clitoral smooth muscle preparations, histological evaluation, and vaginal blood flow assessments. In vivo studies of sexual responses focus on behavioral paradigms involving lordotic posturing and receptivity, as well as indices of motivation using a dual chamber pacing method (see, e.g., Hale, et al., Int. J. Impot. Res. 15 Suppl 5: S75-79, 2003).
The present invention is illustrated below with the aid of examples. These illustrations are given solely by way of example and do not limit the general spirit of the present invention.
Examples
Example 1: 1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H- pyrazole-S-carbonylJ-arninol-i-methyl-piperidinium iodide
Figure imgf000102_0001
1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1H-pyrazole-3-carboxylic acid piperidin-1-y-amide (1 mmol) was dissolved in chloroform (20 ml_) and methyl iodide (3 mmol) was slowly added. The mixture was heated to reflux for 72 hours, excess methyl iodide was evaporated and the crude residue was crystallized in ethanol (5 mL) and a small amount of diethylether to afford the title compound as a yellow solid.
m.p. 174 - 176 X
FTIR ( KBr, cm1) 3448, 2948, 1675, 1480, 1248, 1116, 824
1H NMR (400 MHz, METHANOL-^) δ ppm 1.66 (m, 1 H) 1.91 (m, 3 H) 2.05 (m, 2 H) 3.26 (dd, J=17.98, 6.64 Hz, 1 H) 3.67 (m, 2 H) 3.70 (s, 3 H) 3.74 (dd, J=17.98, 12.50 Hz11 H) 4.45 (d, J=12.90 Hz, 1 H) 4.57 (d, J=12.50 Hz, 1 H) 5.94 (dd, J=12.50, 6.64 Hz, 1 H) 7.22 (m, 5 H) 7.36 (d, J=2.34 Hz, 1 H) 7.41 (d, J=8.79 Hz, 1 H)
The following Examples 2 to 50 were prepared or can be prepared according to the process described for the synthesis of Example 1. Those skilled in the art are familiar with the starting materials that are needed to obtain said compounds. Example 51: N-oxide of N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)- 4,5-dihydropyrazole-3-carboxamide
Under nitrogen gas as an inert atmosphere N-piperidinyl-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4,5-dihydropyrazole-3-carboxamide (0.15 g, 0.33 mmol) was dissolved in 7 mL of dichloromethane. The resulting solution was ice-cooled to 0 0C and m-chloroperbenzoic acid (0.204 g, 0.83 mmol) was added in several portions. After stirring for 15 minutes a control via thin layer chromatography showed that no starting material was present. A saturated solution of sodium bicarbonate was then slowly added, the organic phase separated, washed with water, dried over sodium sulfate and filtered. The filtered solution was evaporated to dryness and the crude product was purified via column chromatography yielding 78 mg (50 % of theoretical yield) of the N-oxide of N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5- dihydropyrazole-3-carboxamide in form of a white solid having a melting point of 115- 120 0C.
IR(KBr, cm1): 3202, 1678, 1654, 1474, 1309, 1107.
1H-NMR (CDCI3, D): 1.6 (m, 2H), 1.8-2.0 (m, 4H), 2.55 (m, 2H), 3.3 (dd, J = 6.3 Hz and 18.2 Hz, 1H), 3.7 (m, 3H), 5.8 (dd, J = 6.3 Hz and 12.5 Hz, 1H), 7.0-7.3 (m, 7H), 8.5 (s, 1H.)
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
-
Figure imgf000108_0001
O
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
(
Figure imgf000114_0001
Figure imgf000115_0001
C
Figure imgf000116_0001
Pharmacological data
The binding data for some of the inventive compounds was obtained as described above in the section pharmacological methods, part I, and is given in the following table (table 1).
Table 1.
Compound according to IC50 [nM] Inhibition [%], 10"' Inhibition [%], example M 10-8 M
146 71.2 -12.8

Claims

Claims:
1. A quaternary ammonium salt of general formula I,
Figure imgf000118_0001
wherein
X is O or S;
A represents a hydrogen atom or an unsubstituted or at least mono- substituted alkyl radical;
R1 and R2, independently of one another, in each case represent an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono- substituted mono- or polycyclic ring system;
or a saturated or unsaturated, unsubstituted or at least mono- substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted alkylene group;
R3 and R4, independently of one another, in each case represent H; F; Cl; Br; I; -CN; -NO2; -NC; -OH; -NH2; -SH; -C(=O)-H; a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted alkylene group;
an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono- substituted mono- or polycyclic ring system and/or may be bonded via an optionally at least mono-substituted alkylene group, alkenylene group or alkinylene group;
a -O-R7 moiety; a -S-R8 moiety; a -NH-R9 moiety or a -NR10R11 moiety;
R5 and R6, independently of one another, in each case represent a hydrogen atom;
a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
or
R5 and R6 together with the bridging nitrogen form an unsubstituted or at least mono-substituted, saturated or unsaturated heterocyclic ring which may contain at least one further heteroatom as a ring member and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems; R7, R8, R9, R10 and R11, independently of one another, in each case represent a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted alkylene group;
or an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group;
B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo-glutarate, formate, acetate, propionate, lactate, gluconate, unsubstituted or at least mono-substituted benzoate or naphthoate, pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
Figure imgf000120_0001
and
R12 and R13, independently of one another, in each case, represent a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
an unsubstituted or at least mono-substituted aryl or heteroaryl radical which may be bonded via an unsubstituted or at least mono-substituted alkylene group
or a saturated or unsaturated, unsubstituted or at least mono- substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be bridged by at least one unsubstituted or at least mono-substituted alkylene group and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group;
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
2. A salt according to claim 1 , characterized in that
X is O or S;
A represents a hydrogen atom or an unsubstituted or at least mono- substituted Ci--IO alkyl radical;
R1 and R2, independently of one another, in each case represent an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
an unsubstituted or at least mono-substituted C3-i6cycloalkyl radical or C-Mβcycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
or an unsubstituted or at least mono-substituted C4--i6 heterocycloalkyl radical or C5-i6 heterocycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
R3 and R4, independently of one another, in each case represent H; F; Cl; Br; I; -CN; -NO2; -NC; -OH; -NH2; -SH; -C(=O)-H;
an unsubstituted or at least mono-substituted CM6 alkyl radical, C2-I6 alkenyl radical or C2-I6 alkinyl radical;
an unsubstituted or at least mono-substituted C3-16 cycloalkyl radical or C4-i6cycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted Ci-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
an unsubstituted or at least mono-substituted C4-I6 heterocycloalkyl radical or C5-i6 heterocycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-s alkylene group, C2-5 alkenylene group or C2-5 alkinylene group;
an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-s alkylene group, C2-5 alkenylene group or C2-5 alkinylene group;
a -O-R7 moiety; a -S-R8 moiety; a -NH-R9 moiety or a -NR10R11 moiety;
R5 and R6, independently of one another, in each case represent a hydrogen atom;
an unsubstituted or at least mono-substituted Ci-i6alkyl radical, C2-i6 alkenyl radical or
Figure imgf000123_0001
radical;
or
R5 and R6 together with the bridging nitrogen form an unsubstituted or at least mono-substituted, saturated or unsaturated 4- to 10-membered heterocyclic ring which may optionally contain 1 , 2 or 3 additional heteroatom(s) selected from the group consisting of sulfur, nitrogen and oxygen as ring member(s) and/or which may be condensed with one or two optionally at least mono- substituted mono- or polycyclic ring systems;
R7, R8, R9, R10 and R11, independently of one another, in each case represent
an unsubstituted or at least mono-substituted C1-16 alkyl radical, C2-i6alkenyl radical or C2-16 alkinyl radical;
an unsubstituted or at least mono-substituted C3-16cycloalkyl radical or C-Mβcycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted C1-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted C1-5 alkylene group;
an unsubstituted or at least mono-substituted C/MΘ heterocycloalkyl radical or C5-i6 heterocycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C1-5 alkylene group, C2-5 alkenylene group or C2-S alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group;
or an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci.5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group;
B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo-glutarate, formate, acetate, propionate, lactate, gluconate, unsubstituted or at least mono-substituted benzoate or naphthoate, pyruvate, ascorbate, glycolate, nicotinate, phenylacetate, R12-Sθf and R13-NH-Sθ3 ;
and
R12 and R13, independently of one another, in each case, represent
an unsubstituted or at least mono-substituted CMβalkyl radical, C2-i6 alkenyl radical or C2-i6alkinyl radical;
an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be bonded via an unsubstituted or at least mono- substituted C1-5 alkylene group;
an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be bonded via an unsubstituted or at least mono-substituted C1.5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group;
an unsubstituted or at least mono-substituted C3--i6cycloalkyl radical or C4-i6cycloalkenyl radical, which in each case may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group and/or may be bridged by at least one unsubstituted or at least mono- substituted C1.5 alkylene group;
or an unsubstituted or at least mono-substituted C4-i6 heterocycloalkyl radical or C5.16 heterocycloalkenyl radical, which in each case may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted C1.5 alkylene group;
whereby
the rings of the aforementioned ring system are in each case independently of one another 5- 6- or 7-membered and may in each case independently of one another optionally contain 1 , 2 or 3 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur;
the aforementioned heteroaryl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
the aforementioned heterocycloalkyl radicals and heterocycloalkenyl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
3. A salt according to claim 1 or 2, characterized in that A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n- octyl, 2-octyl, 3-octyl and 4-octyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -O- CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3. -O- C(CHs)3, -S-CH3, -S-C2Hs, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2- CH3, -S-C(CH3)3, -CN and -NO2.
4. A salt according to one or more of claims 1 to 3, characterized in that R1 and R2, independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]- benzoxadiazolyl, [1 ,2,3]-benzoxadiazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and imidazo[2,1-b]thiazolyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF3, -CH2-CI, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -O- CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O- C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2) -S-CH2-CH2-CH2- CH3, -S-C(CH3)3, F, Cl, Br, I1 -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, ■ NO2, -CHO, -C(O)-CH3, -C(O)-C2H5, -C(O)-C(CH3)3, -CF2H, -CFH2, - C(O)-NH2, -C(O)-NH-CH3, -C(O)-NH-C2H5, -C(O)-NH-C3H7, -C(O)- N(CH3)2, -C(O)-N(C2Hs)2, -S(O)-CH3, -S(O)-C2H5, -S(O)-C3H7, -S(O)2- CH3, -S(O)2-C2H5, -S(O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2, - N(C2H5J2, phenoxy and thiophenyl, whereby the thiophenyl radical can be substituted with 1 , 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, methyl, ethyl and n-propyl;
or a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomoφholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, diazepanyl, azocanyl, (2,5)-dihydrofuranyl, (2,5)-dihydrothiophenyl, (2,3)-dihydrofuranyl, (2,3)-dihydrofuranyl, (2,5)-dihydro-1H-pyrrolyl, (2,3)- dihydro-1 H-pyrrolyl, tetrahydrothiopyranyl, tetrahydropyranyl, (3,4)-dihydro-2H- pyranyl, (3,4)-dihydro-2H-thiopyranyl, (1 ,2,3,6)-tetrahydropyridinyl, (1 ,2,3,4)- tetrahydropyridinyl, (1 ,2,5,6)-tetrahydropyridinyl, [1 ,3]-oxazinanyl, hexahydropyrimidinyl, (5,6)-dihydro-4H-pyrimidinyl, (5,6)-dihydro-4H- pyrimidinyl, oxazolidinyl, (1 ,3)-dioxanyl, (1 ,4)-dioxanyl, (1 ,3)-dioxolanyl, decahydronaphthyl, octahydro-cyclopenta[c]pyrrolyl, decahydroquinolinyl and dodecahydro-carbazolyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (O), thioxo (=S), - CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n- pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, - 0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S- CH(CH3)2, -S-CH2-CH2-CH2-CHs, -S-C(CHS)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, - SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(O)-CH3, -C(=O)-C2H5, -C(O)- C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH-C2H5, - C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2-CH3l -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH- C2H5, -N(CH3)2 and -N(C2Hg)2.
5. A salt according to one or more of claims 1 to 4, characterized in that R3 and R4, independently of one another, in each case represent H; F; Cl; Br; I; -CN; - NO2; -NC; -OH; -NH2; -SH; -C(=O)-H;
a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n- octyl, 2-octyl, 3-octyl and 4-octyl, which may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituent(s) independently selected from the group consisting of -OH, F, Cl, Br, I, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3J2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -NH2, -NH-CH3, -NH-C2H5, - N(CH3)2l -N(C2Hs)2, -CN and -NO2;
a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH2)-, -(CH2)-(CH2)-, - (CH2)-(CH2)-(CH2)- or -CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2- CH3, -S-CH(CHs)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(O)-C2H5, - C(=O)-C(CH3)3, -CF2H, -CFH2, -C(O)-NH2, -C(O)-NH-CH3, -C(O)-NH-C2H5, -C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3l -S(O)- C2H5, -S(=O)-C3H7, -S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2 and -N(C2Hg)2;
a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl and diazepanyl, which may be bonded via a - (CH2)-, -(CH2HCH2)-, -(CH2HCH2HCH2)- or -CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2- CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2- CH2-CH2-CH3, -S-C(CHa)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, - OH, -SH, -NO2, -CHO, -C(O)-CH3, -C(=O)-C2H5, -C(=O)-C(CH3)3, -CF2H1 - CFH2, -C(O)-NH2, -C(O)-NH-CH3, -C(O)-NH-C2H5, -C(O)-NH-C3H7, - C(O)-N(CH3J2, -C(O)-N(C2Hs)2, -S(O)-CH3, -S(O)-C2H5, -S(O)-C3H7, - S(O)2-CH3, -S(O)2-C2H5, -S(O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2 and -N(C2Hs)2;
a -O-R7 moiety; a -S-R8 moiety, a -NH-R9 moiety or a -NR10R11 moiety.
6. A salt according to one or more of claims 1 to 5, characterized in that R5 and R6, independently of one another, in each case represent a hydrogen atom;
or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n- octyl, 2-octyl, 3-octyl and 4-octyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -O- CH3, -Q-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O- C(CHs)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2- CH3, -S-C(CHs)3, -CN and -NO2.
7. A salt according to one or more of claims 1 to 5, characterized in that R5 and R6 together with the bridging nitrogen atom form a moiety selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, azepanyl, diazepanyl, azocanyl, (2,5)-dihydro-1 H-pyrrolyl, (2,3)-dihydro-1 H- pyrrolyl, (1 ,2,3,6)-tetrahydropyridinyl, (1 ,2,3,4)-tetrahydropyridinyl, (1 ,2,5,6)- tetrahydropyridinyl, [1 ,3]-oxazinanyl, hexahydropyrimidinyl, (5,6)-dihydro-4H- pyrimidinyl, (5,6)-dihydro-4H-pyrimidinyl, oxazolidinyl, indolinyl, isoindolinyl,
(1 ,2,3,4)-tetrahydroquinolinyl, (1 ,2,3,4)-tetrahydroisoquinolinyl, octahydro- cyclopenta[c]pyrrolyl, (1 ,3,4,7,9a)-hexahydro-2H-quinolizinyl, (1 ,2,3,5,6,8a)- hexahydro-indolizinyl, decahydroquinolinyl, dodecahydro-carbazolyl, 9H- carbazolyl, decahydroisoquinolinyl, (6,7)-dihydro-4H-thieno[3,2-c]pyridinyl, (2,3)-dihydro-1 H-benzo[de]isoquinolinyl and (1 ,2,3,4)-tetrahydroquinoxazlinyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=O), thioxo (=S), - CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n- pentyl, 2-pentyl, n-hexyl, -O-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, - 0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -0-CH2-O-CH3, -0-CH2-CH2-O-CH3, -O- CH2-O-C2H5, -C(OCH3)(C2Hs)2, -C(OCH3)(CH3)2, -CH2-O-CH3, -CH2-O-C2H5, - S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S- C(CH3)3, F, Cl, Br, I1 -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, - CHO, -C(=O)-CH3, -C(O)-C2H5, -C(=O)-C(CH3)3l -C(=O)-OH, -C(=O)-O-CH3, -C(=O)-O-C2H5> -C(=O)-O-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(O)-NH- CH3, -C(O)-NH-C2H5, -C(O)-NH-C3H7, -C(O)-N(CH3)2, -C(O)-N(C2H5)2, - S(O)-CH3, -S(O)-C2H5, -S(O)-C3H7, -S(O)2-CH3, -S(O)2-C2H5, -S(O)2- C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2, -N(C2H5)2, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl.
8. A salt according to one or more of claims 1 to 7, characterized in that
R7, R8, R9, R10 and R11, independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2- (4-methyl)-hexyl, 2-(7-methyl)-octyl; 2-(6-methyl)-octyl, vinyl, n-propenyl, n- butenyl, n-pentenyl, n-hexenyl, ethinyl, propinyl, n-butinyl, n-pentinyl and n- hexinyl, which may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituent(s) independently selected from the group consisting of -OH, F, Cl, Br, I1 -0-CH3, -O-C2H5, -O-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2, -N(C2Hs)2, -CN and -NO2;
a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, 8-aza-bicyclo[3.2.1]octyl and diazepanyl, which may be bonded via a -(CH2)-, -(CH2HCH2)-, -(CH2MCH2MCH2)- or - CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2- CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)-C2H5, - C(=O)-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH-C2H5, -C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(O)-CH3, -S(=O)- C2H5, -S(=O)-C3H7, -S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3J2 and -N(C2Hg)2;
or a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH2)-, -(CH2)-(CH2)-, - (CH2HCH2HCH2)- or -CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3) -S-CH3, -S-C2H5, -S-CH2-CH2- CH3, -S-CH(CH3)2l -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H1 -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)-C2H5, - C(=O)-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH-C2H5> -C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)- C2H5, -S(=O)-C3H7, -S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CHa)2 and -N(C2Hs)2.
9. A salt according to one or more of claims 1 to 8, characterized in that B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo-glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate which may be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, - OH, -0-CH3 and -0-C2H5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
Figure imgf000132_0001
10. A salt according to one or more of claims 1 to 9, characterized in that R12 and R13, independently of one another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7-methyl)-octyl; 2-(6-methyl)-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, vinyl, n-propenyl, n-butenyl, n-pentenyl, n-hexenyl, ethinyl, propinyl, n-butinyl, n-pentinyl and n-hexinyl; which may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituent(s) independently selected from the group consisting of F, Cl, Br, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2 and
Figure imgf000133_0001
a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, benzimidazolyl, isoquinolinyl and pyrazolyl, which may be bonded via a -(CH2)- , -(CH2HCH2)- or -(CH2)-(CH2)-(CH2)-group and/or may be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of - CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n- pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, - 0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5. -S-CH2-CH2-CH3, -S- CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3J3, F, Cl, Br, I, -CN, -OCF3, -SCF3, - SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)-C2H5, -C(O)- C(CH3)3, -CF2H, -CFH2, -C(O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH-C2H5, - C(=O)-NH-C3H7, -C(=O)-N(CH3)2l -C(=O)-N(C2H5)2, -S(O)-CH3, -S(O)-C2H5, -S(O)-C3H7, -S(O)2-CH3, -S(O)2-C2H5, -S(O)2-C3H7, -SO3H, -NH2, -NH- CH3, -NH-C2H5, -N(CH3J2, -N(C2H5J2 and phenyl;
or a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and bicyclo[2.2.1]heptyl, which may be bonded via a -(CH2)-, -(CH2)-(CH2)-, -(CH2)-(CH2)-(CH2)-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (O), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2- CH3, -O-C(CH3)3, -0-CH2-O-CH3, -0-CH2-CH2-O-CH3, -0-CH2-O-C2H5, - C(OCH3)(C2Hs)2, -C(OCH3)(CHa)2, -CH2-O-CH3, -CH2-O-C2H5, -S-CH3, -S- C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(O)- CH3, -C(O)-C2H5, -C(O)-C(CH3)3, -C(O)-OH, -C(O)-O-CH3, -C(O)-O- C2H5, -C(O)-O-C(CHa)3, -CF2H, -CFH2, -C(O)-NH2, -C(O)-NH-CH3, -C(O)- NH-C2H5, -C(O)-NH-C3H7, -C(O)-N(CH3)2, -C(O)-N(C2H5)2, -S(O)-CH3, - S(=O)-C2H5, -Sf=O)-C3H7, -Sf=O)2-CH3, -Sf=O)2-C2H5, -Sf=O)2-C3H7, -NH2, - NH-CH3, -NH-C2H5, -N(CH3)2 and -N(C2H5J2.
11. A salt according to one or more of claims 1 to 10, characterized in that
X is O or S:
A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2- heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl and 4-octyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituentfs) independently selected from the group consisting of -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3)2l -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2- CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, -CN and -NO2;
R1 and R2, independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]- benzoxadiazolyl, [1 ,2,3]-benzoxadiazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and imidazo[2,1-b]thiazolyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituentfs) independently selected from the group consisting Of -CF3, -CH2-CI, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -O- CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O- C(CHa)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2- CH3, -S-C(CH3J3, F, Cl1 Br, I1 -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, - NO2, -CHO, -C(=O)-CH3, -C(O)-C2H5, -C(=O)-C(CH3)3, -CF2H, -CFH2, - C(=O)-NH2, -C(=O)-NH-CH3, -C(O)-NH-C2H5, -C(O)-NH-C3H7, -C(O)- N(CH3)2, -C(O)-N(C2Hs)2, -S(O)-CH3, -S(O)-C2H5, -Sf=O)-C3H7, -Sf=O)2- CH3, -Sf=O)2-C2H5, -Sf=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -NfCHa)2, - N(C2H5)2, phenoxy and thiophenyl, whereby the thiophenyl radical can be substituted with 1 , 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, methyl, ethyl and n-propyl;
or a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, diazepanyl, azocanyl, (2,5)-dihydrofuranyl, (2,5)-dihydrothiophenyl, (2,3)-dihydrofuranyl, (2,3)-dihydrofuranyl, (2,5)-dihydro-1 H-pyrrolyl, (2,3)- dihydro-1 H-pyrrolyl, tetrahydrothiopyranyl, tetrahydropyranyl, (3,4)-dihydro-2H- pyranyl, (3,4)-dihydro-2H-thiopyranyl, (1 ,2,3,6)-tetrahydropyridinyl, (1 ,2,3,4)- tetrahydropyridinyl, (1 ,2,5,6)-tetrahydropyridinyl, [1 ,3]-oxazinanyl, hexahydropyrimidinyl, (5,6)-dihydro-4H-pyrimidinyl, (5,6)-dihydro-4H- pyrimidinyl, oxazolidinyl, (1 ,3)-dioxanyl, (1 ,4)-dioxanyl, (1 ,3)-dioxolanyl, decahydronaphthyl, octahydro-cyclopenta[c]pyrrolyl, decahydroquinolinyl and dodecahydro-carbazolyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), - CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n- pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, - 0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3. -S- CH(CH3)2l -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I1 -CN, -OCF3, -SCF3, - SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)-C2H5, -C(=O)- C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH-C2H5, - C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH- C2H5, -N(CH3J2 and -N(C2Hg)2;
R3 and R4, independently of one another, in each case represent H; F; Cl; Br; I; -CN; -NO2; -NC; -OH; -NH2; -SH; -C(=O)-H; a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n- octyl, 2-octyl, 3-octyl and 4-octyl, which may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituent(s) independently selected from the group consisting of -OH, F, Cl, Br1 11 -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -NH2, -NH-CH3, -NH-C2H5, - N(CHs)2, -N(C2Hs)2, -CN and -NO2;
a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH2)-, -(CH2)-(CH2)-, - (CH2)-(CH2)-(CH2)- or -CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CHs)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2- CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br1 I, -CN1 -OCF3, -SCF3, -SCF2H, -SCFH2, -OH1 -SH1 -NO2, -CHO1 -C(=O)-CH3, -C(=O)-C2H5, - C(=O)-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH-C2H5, -C(=O)-NH-C3H7, -C(=O)-N(CH3)2l -C(=O)-N(C2H5)2l -S(=O)-CH3l -S(=O)- C2H5, -S(=O)-C3H7l -S(=O)2-CHs, -S(=O)2-C2H5, -S(=O)2-C3H7l -NH2, -NH-CH3, -NH-C2H5, -N(CH3J2 and -N(C2H5J2;
a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl and diazepanyl, which may be bonded via a - (CH2)-, -(CH2HCH2)-, -(CH2HCH2HCH2)- or -CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2- CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2- CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I1 -CN, -OCF3, -SCF3, -SCF2H1 -SCFH2, - OH, -SH, -NO2, -CHO, -C(=O)-CH3, -Cf=O)-C2H5, -C(=O)-C(CH3)3, -CF2H, - CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH-C2H5, -C(=O)-NH-C3H7, - C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -S(=O)-C3H7, - S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2 and -N(C2Hs)2;
a -O-R7 moiety; a -S-R8 moiety, a -NH-R9 moiety or a -NR10R11 moiety;
R5 and R6, independently of one another, in each case represent a hydrogen atom;
or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n- octyl, 2-octyl, 3-octyl and 4-octyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -O- CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O- C(CH3J3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2- CH3, -S-C(CH3)3, -CN and -NO2;
or
R5 and R6 together with the bridging nitrogen atom form a moiety selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, azepanyl, diazepanyl, azocanyl, (2,5)-dihydro- 1 H-pyrrolyl, (2,3)-dihydro-1 H-pyrrolyl, (1 ,2,3,6)-tetrahydropyridinyl, (1 ,2,3,4)- tetrahydropyridinyl, (1 ,2,5,6)-tetrahydropyridinyl, [1 ,3]-oxazinanyl, hexahydropyrimidinyl, (5,6)-dihydro-4H-pyrimidinyl, (5,6)-dihydro-4H- pyrimidinyl, oxazolidinyl, indolinyl, isoindolinyl, (1 ,2,3,4)-tetrahydroquinolinyl, (1 ,2,3,4)-tetrahydroisoquinolinyl, octahydro-cyclopenta[c]pyrrolyl, (1 ,3,4,7,9a)- hexahydro-2H-quinolizinyl, (1 ,2,3,5,6,8a)-hexahydro-indolizinyl, decahydroquinolinyl, dodecahydro-carbazolyl, 9H-carbazolyl, decahydroisoquinolinyl, (6,7)-dihydro-4H-thieno[3,2-c]pyridinyl, (2,3)-dihydro- 1 H-benzo[de]isoquinolinyl and (1 ,2,3,4)-tetrahydroquinoxazlinyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2- CH3, -O-C(CH3)3l -0-CH2-O-CH3, -0-CH2-CH2-O-CH3, -0-CH2-O-C2H5, - C(OCH3)(C2Hs)2, -C(OCH3)(CH3)2, -CH2-O-CH3, -CH2-O-C2H5, -S-CH3, -S- C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH1 -SH, -NO2, -CHO, -C(=O)- CH3, -C(=O)-C2H5, -C(=O)-C(CH3)3, -C(=O)-OH, -C(=O)-O-CH3, -C(=O)-O- C2H5, -C(=O)-O-C(CH3)3, -CF2H, -CFH2, -C(O)-NH2, -C(=O)-NH-CH3, -C(=O)- NH-C2H5, -C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, - S(=O)-C2H5, -S(=O)-C3H7, -S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, - NH-CH3, -NH-C2H5, -N(CH3)2, -N(C2H5)2, cyclopentyl, cyclohexyl, pyrrolidinyl and piperidinyl;
R7, R8, R9, R10 and R11, independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2- (4-methyl)-hexyl, 2-(7-methyl)-octyl; 2-(6-methyl)-octyl, vinyl, n-propenyl, n- butenyl, n-pentenyl, n-hexenyl, ethinyl, propinyl, n-butinyl, n-pentinyl and n- hexinyl, which may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituent(s) independently selected from the group consisting of -OH, F, Cl, Br, I, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2, -N(C2Hg)2, -CN and -NO2;
a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, morpholinyl, aziridinyl, azetidinyl, imidazolidinyl, thiomorpholinyl, pyrazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, 8-aza-bicyclo[3.2.1]octyl and diazepanyl, which may be bonded via a -(CH2)-, -(CH2HCH2)-, -(CH2)-(CH2)-(CH2)- or - CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3l -S-CH3, -S-C2H5, -S-CH2-CH2- CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F1 Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)-C2H5) - C(=O)-C(CH3)3l -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH-C2H5, -C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3> -S(O)- C2H5, -S(=O)-C3H7, -S(=O)2-CH3, -S(=O)2-C2H5, -S(=O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3J2 and -N(C2H5)2;
or a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl and isoindolyl, which may be bonded via a -(CH2)-, -(CH2)-(CH2)-, - (CH2)-(CH2)-(CH2)- or -CH=CH-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O- CH(CH3J2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2- CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(O)-C2H5, - C(=O)-C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NH-C2H5, -C(O)-NH-C3H7, -C(O)-N(CH3)2l -C(O)-N(C2H5)2, -S(O)-CH3, -S(O)- C2H5, -S(O)-C3H7, -S(O)2-CH3, -S(O)2-C2H5, -S(O)2-C3H7, -NH2, -NH-CH3, -NH-C2H5, -N(CH3)2 and -N(C2H5J2;
B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo-glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate which may be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, - OH, -0-CH3 and -O-C2H5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
Ri2-Sθf and R13-NH-SO;f; and
R12 and R13, independently of one another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n-octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5-methyl)-hexyl, 2-(4- methyl)-hexyl, 2-(7-methyl)-octyl; 2-(6-methyl)-octyl, n-nonyl, n-decyl, n- undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, vinyl, n-propenyl, n-butenyl, n- pentenyl, n-hexenyl, ethinyl, propinyl, n-butinyl, n-pentinyl and n-hexinyl; which may optionally be substituted with 1 , 2, 3, 4, 5, 6, 7, 8 or 9 substituent(s) independently selected from the group consisting of F, Cl, Br, -NH2, -NH-CH3, -NH-C2H5, -N(CHa)2 and -N(C2H5)2;
a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, benzimidazolyl, isoquinolinyl and pyrazolyl, which may be bonded via a -(CH2)- . -(CH2HCH2)- or -(CH2)-(CH2)-(CH2)-group and/or may be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of - CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n- pentyl, 2-pentyl, n-hexyl, -O-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, - 0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -S-CH3, -S-C2H5, -S-CH2-CH2-CH3, -S- CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I, -CN, -OCF3, -SCF3, - SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO, -C(=O)-CH3, -C(=O)-C2H5, -C(=O)- C(CH3)3, -CF2H, -CFH2, -C(=O)-NH2, -C(O)-NH-CH3, -C(=O)-NH-C2H5, - C(=O)-NH-C3H7, -C(=O)-N(CH3)2, -C(=O)-N(C2H5)2, -S(=O)-CH3, -S(=O)-C2H5, -Sf=O)-C3H7, -S(=O)2-CH3> -S(=O)2-C2H5l -SC=O)2-C3H7, -SO3H, -NH2, -NH- CH3, -NH-C2H5, -N(CH3)2, -N(C2H5J2 and phenyl;
or a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and bicyclo[2.2.1]heptyl, which may be bonded via a -(CH2)-, -(CH2)-(CH2)-, -(CH2)-(CH2)-(CH2)-group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of oxo (=0), thioxo (=S), -CF3, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2- CH3, -O-C(CH3)3, -0-CH2-O-CH3, -0-CH2-CH2-O-CH3, -0-CH2-O-C2H5, - C(OCH3)(C2Hs)2, -C(OCH3)(CH3)2, -CH2-O-CH3, -CH2-O-C2H5, -S-CH3, -S- C2H5, -S-CH2-CH2-CH3, -S-CH(CH3)2, -S-CH2-CH2-CH2-CH3, -S-C(CH3)3, F, Cl, Br, I1 -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, -CHO1 -C(O)- CH3, -C(=O)-C2H5, -C(O)-C(CHa)3, -C(O)-OH, -C(O)-O-CH3, -C(O)-O- C2H5, -C(O)-0-C(CH3)3, -CF2H, -CFH2, -C(O)-NH2, -C(O)-NH-CH3, -C(O)- NH-C2H5, -C(O)-NH-C3H7, -C(O)-N(CHs)2, -C(O)-N(C2H5)2, -S(O)-CH3, - S(O)-C2H5, -S(O)-C3H7, -S(O)2-CH3, -S(O)2-C2H5, -S(O)2-C3H7, -NH2, - NH-CH3, -NH-C2H5, -N(CH3)2 and -N(C2Hs)2.
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
12. A salt according to one or more of claims 1 to 11 , characterized in that
X is O or S;
A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl; R1 and R2, independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]- benzoxadiazolyl, [1 ,2,3]-benzoxadiazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and imidazo[2,1-b]thiazolyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF3, -CH2-CI, -0-CH3, -0-C2H5, -0-CH2- CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n- hexyl, F, Cl, Br, I, -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH1 -NO2, - CHO, -CF2H, -CFH2, phenoxy and thiophenyl, whereby the thiophenyl radical can be substituted with 1 , 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, methyl, ethyl and n-propyl;
R3 represents H; F; Cl; Br; I; -CN; -NO2; -NC; -OH; -NH2; -SH; -C(=O)-H;
a radical selected from the group consisting of methyl, -CF3, -CH2F, -CF2H, - C2F5, ethyl, -CH2-CN, -CH2-OH, n-propyl, isopropyl, -CH2-CH2-CN, -CH2-CH2- OH, n-butyl, -CH2-CH2-CH2-CN, -CH2-CH2-CH2-OH, isobutyl, sec-butyl, tert- butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl;
a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl) and pyrrolyl, which may be bonded via a -(CH2)- group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting Of -CF3, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n- hexyl, -0-CH3, -0-C2H5, F, Cl and Br;
a -O-R7 moiety; a -S-R8 moiety, a -NH-R9 moiety or a -NR10R11 moiety; R4 represents H or an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl;
R7, R8, R9, R10 and R11, independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl;
R5 and R6 together with the bridging nitrogen atom form a moiety selected from the group consisting of
Figure imgf000143_0001
B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, fumarate, citrate, glutarate, succinate, maleate, tartrate, phosphate, 2-oxo-glutarate, formate, acetate, propionate, lactate, gluconate, benzoate or naphthoate which may be substituted with 1 , 2, 3, 4 or 5 substituents independently selected from the group consisting of F, Cl, Br, - OH, -0-CH3 and -0-C2H5 , pyruvate, ascorbate, glycolate, nicotinate, phenylacetate,
R »112 -SOf and R 13 -NH-SO3 and
R12 and R13, independently of one another, in each case represent a radical selected from the group consisting Of -CF3, -C2F5, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, n- octyl, 2-octyl, 3-octyl, 4-octyl, 2-(6-methyl)-heptyl, 2-(5-methyl)-heptyl, 2-(5- methyl)-hexyl, 2-(4-methyl)-hexyl, 2-(7-methyl)-octyl; 2-(6-methyl)-octyl, n- nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl and n-tetradecyl;
a radical selected from the group consisting of phenyl, pyridinyl, pyrazolyl, benzimidazolyl, isoquinolinyl and naphthyl, which may be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of F, Cl, Br, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n- pentyl, 2-pentyl, n-hexyl, -0-CH3, -0-C2H5, -0-CH2-CH2-CH3, -O-CH(CH3)2) - 0-CH2-CH2-CH2-CH3, -O-C(CH3)3, -OH, -NO2, -NH2, phenyl and -SO3H;
a radical selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl and bicyclo[2.2.1]heptyl, which may be bonded via a -(CH2)-, -(CH2HCH2)-, -(CH2)-(CH2)-(CH2)-group;
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
13. A salt according to one or more of claims 1 to 12, characterized in that
X is O;
A represents a hydrogen atom or a radical selected from the group consisting of methyl, ethyl and n-propyl;
R1 represents a radical selected from the group consisting of phenyl and thienyl (thiophenyl), which may optionally be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl1 Br, I1 -0-CH3 and -0-C2H5;
R2 represents a phenyl radical, which may be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl1 Br and I;
R3 represents H; F; Cl; Br; I; -OH, -CN; -C(=O)-H;
a radical selected from the group consisting of methyl, -CF3, -CH2F, - CF2H, -C2F5, ethyl, -CH2-CN, -CH2-OH, n-propyl, isopropyl, -CH2-CH2- CN, -CH2-CH2-OH, n-butyl, -CH2-CH2-CH2-CN, -CH2-CH2-CH2-OH, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n- hexyl, 2-hexyl and 3-hexyl;
a benzyl radical or a -O-R7 moiety;
R4 represents H or a radical selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl and n-butyl; R5 and R6 together with the bridging nitrogen atom form a moiety selected from the group consisting of
Figure imgf000146_0001
Figure imgf000146_0002
Figure imgf000146_0003
R7 represents a radical selected from the group consisting of methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl;
B represents an anion selected from the group consisting of chloride, bromide, iodide, fluoride, hydrogensulfate, nitrate, dihydrogenphosphate, thiocyanate, cyanate, acrylate, methanesulfonate, ethanesulfonate, toluenesulfonate, benzenesulfonate, (2,5)-dihydroxy-benzenesulfonate, naphthalene-2- sulfonate, 5-sulfo-napthalene-1 -sulfonate, cyclamate, dodecane-1 -sulfonate and (7,7)-dimethyl-2-oxo-bicyclo[2.2.1]-hept-1-yl-methanesulfonate;
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
14. A salt according to one or more of claims 1 to 13 selected from the group consisting of [I] 1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide
[2] 1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-4-methyl-morpholin-4-ium iodide [3] 1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-azepanium iodide [4] 1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-2-methyl-octahydro-cyclopenta[c]pyrrolium iodide [5] 1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-pyrrolidinium iodide [6] (R)-1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [7] (S)-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [8] 1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -ethyl-piperidinium iodide [9] (R)-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -ethyl-piperidinium iodide [10] (S)-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -ethyl-piperidinium iodide
[I I] 1 -[[5-(4-Bromo-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide
[12] 1 -[[2,4-Dichloro-phenyl)-5-(4-iodo-phenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-amino]-1 -methyl-piperidinium iodide [13] 1-[[2,4-Dichloro-phenyl)-5-(4-fluoro-phenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-amino]-1 -methyl-piperidinium iodide [14] 1 -[[2,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-1 H-pyrazole-
3-carbonyl]-amino]-1 -methyl-piperidinium iodide [15] 1 -[[2,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-1 H-pyrazole-
3-carbonyl]-amino]-1 -methyl-azepanium iodide [16] 1 -[[2,4-Dichloro-phenyl)-5-(4-fluoro-phenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-amino]-1 -methyl-azepanium iodide [17] 1 -[[2,4-Dichloro-phenyl)-5-(4-iodo-phenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-amino]-1 -methyl-azepanium iodide [18] 1 -[[5-(4-Bromo-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-azepanium iodide [19] 1 -[[5-(4-Bromo-phenyl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-pyrrolidinium iodide [20] 1-[[2,4-Dichloro-phenyl)-5-(4-fluoro-phenyl)-4,5-dihydro-1 H-pyrazole-3- carbonyl]-amino]-1 -methyl-pyrrolidinium iodide [21 ] 1 -[[2,4-Dichloro-phenyl)-5-(4-methoxy-phenyl)-4,5-dihydro-1 H-pyrazole-
3-carbonyl]-amino]-1 -methyl-pyrrolidinium iodide [22] cis-1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-
1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [23] cis-1-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-
1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [24] cis-1 -[[5-(4-Bromo-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-
1 H-pyrazole-3-carbonyl]-amino]-1-methyl-piperidinium iodide [25] cis-1 -[[5-(4-Fluoro-phenyl)-1 -(2,4-dichloro-phenyl)-4-ethyl-4,5-dihydro-
1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [26] trans-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [27] trans-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-ethyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [28] trans-1 -[[5-(4-Bromo-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [29] trans-1 -[[5-(4-Fluoro-phenyl)-1 -(2,4-dichloro-phenyl)-4-ethyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [30] cis-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-
1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-azepanium iodide [31 ] cis-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-
1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-pyrrolidinium iodide [32] trans-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-pyrrolidinium iodide [33] trans-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-azepanium iodide [34] cis-2-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5-dihydro-
1 H-pyrazole-3-carbonyl]-amino]-2-methyl- octahydrocyclopenta[c]pyrrolium iodide [35] trans-2-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-methyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-2-methyl- octahydrocyclopenta[c]pyrrolium iodide [36] 2-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,4-dimethyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-2-methyl- octahydrocyclopenta[c]pyrrolium iodide [37] 2-[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,4-dimethyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [38] cis-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-trifluormethyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [39] cis-1 -[[5-(4-Chloro-phenyl)-1 -(2,4-dichloro-phenyl)-4-methoxy-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [40] cis-1 -[[5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4-cyano-4,5-dihydro-
1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [41 ] 1 -[[5-(5-Chloro-thiophen-2-yl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [42] 1 -[[5-(5-Bromo-thiophen-2-yl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [43] 1 -[[5-(4-Bromo-thiophen-2-yl)-1 -(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [44] cis-1 -[[5-(5-Chloro-thiophen-2-yl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [45] trans-1 -[[5-(5-Chloro-thiophen-2-yl)-1 -(2,4-dichloro-phenyl)-4-methyl-
4,5-dihydro-1H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [46] cis-1 -[[5-(5-Bromo-thiophen-2-yl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [47] trans-1 -[[5-(5-Bromo-thiophen-2-yl)-1 -(2,4-dichloro-phenyl)-4-methyl-
4,5-dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide [48] cis-1 -[[5-(4-Bromo-thiophen-2-yl)-1 -(2,4-dichloro-phenyl)-4-methyl-4,5- dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide
[49] trans-1-[[5-(4-Bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl- 4,5-dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl-piperidinium iodide and
[50] cis-1 -[[5-(4-Bromo-thiophen-2-yl)-1-(2,4-dichloro-phenyl)-4-hydroxy-4- methyl-4,5-dihydro-1 H-pyrazole-3-carbonyl]-amino]-1 -methyl- piperidinium iodide
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
15. A N-oxide of general formula Ia,
Figure imgf000150_0001
Ia
wherein
Xa is O or S;
R1a and R2a, independently of one another, in each case represent an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono- substituted mono- or polycyclic ring system;
or a saturated or unsaturated, unsubstituted or at least mono- substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted alkylene group;
R3a and R4a, independently of one another, in each case represent H; F; Cl; Br; I; -CN; -NO2; -NC; -OH; -NH2; -SH; -C(=O)-H;
a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted alkylene group;
an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono- substituted mono- or polycyclic ring system and/or may be bonded via an optionally at least mono-substituted alkylene group, alkenylene group or alkinylene group;
a -O-R7a moiety; a -S-R83 moiety; a -NH-R9a moiety or a -NR103R11a moiety; R5a and R6a, independently of one another, in each case represent a hydrogen atom;
a saturated or unsaturated, unsubstituted or at least mono-substituted aliphatic radical;
or
R5a and R68 together with the bridging nitrogen form an unsubstituted or at least mono-substituted, saturated or unsaturated heterocyclic ring which may contain at least one further heteroatom as a ring member and/or which may be condensed with one or two optionally at least mono- substituted mono- or polycyclic ring systems;
R7a, R8a, R9a, R1Oa and R11a, independently of one another, in each case represent a saturated or unsaturated, unsubstituted or at least mono- substituted aliphatic radical;
a saturated or unsaturated, unsubstituted or at least mono-substituted, optionally at least one heteroatom as a ring member containing cycloaliphatic radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted alkylene group;
or an unsubstituted or at least mono-substituted aryl or heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted alkylene group, alkenylene group or alkinylene group;
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
16. A N-oxide according to claim 15, characterized in that
Xa is O or S;
R1a and R2a, independently of one another, in each case represent an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system;
an unsubstituted or at least mono-substituted C3-i6cycloalkyl radical or C-Mβcycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
or an unsubstituted or at least mono-substituted C4-i6 heterocycloalkyl radical or Cs-iδ heterocycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
R3a and R4a, independently of one another, in each case represent H; F; Cl; Br; I; -CN; -NO2; -NC; -OH; -NH2; -SH; -C(=O)-H;
an unsubstituted or at least mono-substituted Ci-i6alkyl radical, C2-i6alkenyl radical or C2-i6alkinyl radical; an unsubstituted or at least mono-substituted 03.16 cycloalkyl radical or C-nβcycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted C-ι-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
an unsubstituted or at least mono-substituted C-Mδheterocycloalkyl radical or C5-16 heterocycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C2-S alkenylene group or C2-5 alkinylene group;
an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group;
a -O-R7a moiety; a -S-R83 moiety; a -NH-R9a moiety or a -NR103R11a moiety;
R5a and R6a, independently of one another, in each case represent a hydrogen atom; an unsubstituted or at least mono-substituted Ci-i6alkyl radical, C2-i6alkenyl radical or C2-16 alkinyl radical;
or
R5a and R6a together with the bridging nitrogen form an unsubstituted or at least mono-substituted, saturated or unsaturated 4- to 10-membered heterocyclic ring which may optionally contain 1 , 2 or 3 additional heteroatom(s) selected from the group consisting of sulfur, nitrogen and oxygen as ring member(s) and/or which may be condensed with one or two optionally at least mono-substituted mono- or polycyclic ring systems;
R7a, R83, R9a, R1Oa and R11a, independently of one another, in each case represent
an unsubstituted or at least mono-substituted d-iβalkyl radical, C2-iβalkenyl radical or C2-16 alkinyl radical;
an unsubstituted or at least mono-substituted C3.i6cycloalkyl radical or C4-i6cycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono- substituted Ci-5alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group;
an unsubstituted or at least mono-substituted C4-I6 heterocycloalkyl radical or C5.16 heterocycloalkenyl radical, which in each case may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C1.5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group and/or may be bridged by at least one unsubstituted or at least mono-substituted Ci-5 alkylene group; an unsubstituted or at least mono-substituted 6- or 10-membered aryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted C1-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group;
or an unsubstituted or at least mono-substituted 5- to 14-membered heteroaryl radical, which may be condensed with an unsubstituted or at least mono-substituted mono- or polycyclic ring system and/or may be bonded via an unsubstituted or at least mono-substituted Ci-5 alkylene group, C2-5 alkenylene group or C2-5 alkinylene group;
whereby
the rings of the aforementioned ring system are in each case independently of one another 5- 6- or 7-membered and may in each case independently of one another optionally contain 1 , 2 or 3 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur;
the aforementioned heteroaryl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
the aforementioned heterocycloalkyl radicals and heterocycloalkenyl radicals in each case optionally contain 1 , 2, 3 or 4 heteroatom(s) independently selected from the group consisting of nitrogen, oxygen and sulfur as ring member(s);
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
17. A N-oxide according to claim 15 or 16, characterized in that
Xa is O or S;
R1a and R2a, independently of one another, in each case represent a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl), pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridazinyl, indolyl, isoindolyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzo[b]furanyl, benzo[b]thiophenyl, benzo[2,1 ,3]thiadiazolyl, [1 ,2,3]-benzothiadiazolyl, [2,1 ,3]- benzoxadiazolyl, [1 ,2,3]-benzoxadiazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and imidazo[2,1-b]thiazolyl, which may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF3, -CH2-CI, -0-CH3, -0-C2H5, -0-CH2- CH2-CH3, -O-CH(CH3)2, -0-CH2-CH2-CH2-CH3, -O-C(CH3)3, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n- hexyl, F, Cl, Br, I1 -CN, -OCF3, -SCF3, -SCF2H, -SCFH2, -OH, -SH, -NO2, - CHO, -CF2H, -CFH2, phenoxy and thiophenyl, whereby the thiophenyl radical can be substituted with 1 , 2 or 3 substituents independently selected from the group consisting of F, Cl, Br, methyl, ethyl and n-propyl;
R3a represents H; F; Cl; Br; I; -CN; -NO2; -NC; -OH; -NH2; -SH; -C(=O)-H;
a radical selected from the group consisting of methyl, -CF3, -CH2F, -CF2H, - C2F5, ethyl, -CH2-CN, -CH2-OH, n-propyl, isopropyl, -CH2-CH2-CN, -CH2-CH2- OH, n-butyl, -CH2-CH2-CH2-CN, -CH2-CH2-CH2-OH, isobutyl, sec-butyl, tert- butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl, 2-hexyl and 3-hexyl;
a radical selected from the group consisting of phenyl, naphthyl, pyridinyl, furyl (furanyl), thienyl (thiophenyl) and pyrrolyl, which may be bonded via a -(CH2)- group and/or may optionally be substituted with 1 , 2, 3, 4 or 5 substituent(s) independently selected from the group consisting of -CF3, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, 2-butyl, tert-butyl, n-pentyl, 2-pentyl, n- hexyl, -0-CH3, -0-C2H5, F, Cl and Br; a -O-R7a moiety; a -S-R8a moiety, a -NH-R9a moiety or a -NR1OaR11a moiety;
R4a represents H or an alkyl radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl;
R7a, R83, R9a, R1Oa and R11a, independently of another, in each case represent a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl;
R5a and R63 together with the bridging nitrogen atom form a moiety selected from the group consisting of
Figure imgf000158_0001
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
18. A salt according to one or more of claims 15 to 17, characterized in that
Xa is O;
R1a represents a radical selected from the group consisting of phenyl and
Figure imgf000159_0001
thienyl (thiophenyl), which may optionally be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl, Br, I, -0-CH3 and -0-C2H5;
R2a represents a phenyl radical, which may be substituted with 1 , 2 or 3 substituent(s) independently selected from the group consisting of F, Cl1 Br and I;
R3a represents H; F; Cl; Br; I; -OH, -CN; -C(=O)-H; a radical selected from the group consisting of methyl, -CF3, -CH2F, - CF2H, -C2F5, ethyl, -CH2-CN, -CH2-OH, n-propyl, isopropyl, -CH2-CH2- CN, -CH2-CH2-OH, n-butyl, -CH2-CH2-CH2-CN, -CH2-CH2-CH2-OH1 isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n- hexyl, 2-hexyl and 3-hexyl;
a benzyl radical or a -O-R7a moiety;
R4a represents H or a radical selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl and n-butyl;
R5a and R68 together with the bridging nitrogen atom form a moiety selected from the group consisting of
Figure imgf000160_0001
Figure imgf000160_0002
Figure imgf000160_0003
and R7a represents a radical selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl;
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
19. A N-oxide according to one or more of claims 15 to 18 selected from the group consisting of
[51] N-oxide of 5-(4-Chloro-phenyl)-1-(2,4-dichloro-phenyl)-4,5-dihydro-1 H- pyrazole-3-carboxylic acid piperidin-1-ylamide;
optionally in form of one of its stereoisomers, preferably enantiomers or diastereomers, a racemate or in form of a mixture of at least two of its stereoisomers, preferably enantiomers and/or diastereomers, in any mixing ratio, or a corresponding solvate thereof.
20. Process for the preparation of a salt of general formula I according to one or more of claims 1 to 14, wherein R4 represents hydrogen, characterized in that at least one compound of general formula R1-C(=O)-H (general formula II), wherein R1 has the meaning according to one or more of claims 1 to 14, is reacted with at least one compound of general formula III,
Figure imgf000161_0001
wherein R3 and X have the meaning according to one or more of claims 1 to 14 and R' represents a linear or branched d-6-alkyl radical, a potassium cation or a sodium cation, in a reaction medium, optionally in an inert atmosphere, optionally in the presence of at least one base, to yield at least one compound of general formula IV,
Figure imgf000162_0001
IV1 wherein R1, X and R3 have the meaning according to one or more of claims 1 to 14, which is optionally purified and/or isolated,
and at least one compound of general formula IV is reacted with at least one compound of general formula V,
Figure imgf000162_0002
V, or a corresponding salt thereof, wherein R2 has the meaning according to one or more of claims 1 to 14, in a reaction medium, optionally in an inert atmosphere, optionally in the presence of at least one acid, to yield at least one compound of general formula Vl,
Figure imgf000162_0003
wherein R1, X, R2 and R3 have the meaning according to one or more of claims 1 to 14, which is optionally isolated and/or purified,
and at least one compound of general formula Vl is reacted with an activating agent in a reaction medium, optionally in an inert atmosphere, to yield at least one compound of general formula VII,
Figure imgf000163_0001
VII wherein R1, X, R2 and R3 have the meaning according to one or more of claims 1 to 14 and LG represents a leaving group, which is optionally purified and/or isolated,
and at least one compound of general formula VII is reacted with at least one compound of general formula NH2-NR5R6, wherein R5 and R6 have the meaning according to one or more of claims 1 to 14, in a reaction medium, optionally in an inert atmosphere, optionally in the presence of at least one base selected from the group consisting of diisopropylethylamine, triethylamine, pyridine, dimethylaminopyridine and N-methylmorpholine, to yield at least one compound of general formula VIII,
Figure imgf000163_0002
VIII wherein R1, R2, R3, X, R5 and R6 have the meaning according to one or more of claims 1 to 14, which is optionally purified and/or isolated;
or at least one compound of general formula Vl is reacted with at least one compound of general formula NH2-NR5R6, wherein R5 and R6 have the meaning according to one or more of claims 1 to 14, in a reaction medium, in the presence of at least one coupling agent, optionally in the presence of at least one base, to yield at least one compound of general VIII, which is optionally purified and/or isolated;
and at least one compound of general formula VIII is reacted with at least one compound of general formula A-B, wherein A and B have the meaning according to one or more of claims 1 to 14, in a reaction medium, to yield at least one salt of general formula I,
Figure imgf000164_0001
I wherein A, B, R1, R2, R3, X1 R5 and R6 have the meaning according to one or more of claims 1 to 14 and R4 represents hydrogen, which is optionally purified and/or isolated.
21. Medicament comprising at least one salt according to one or more of claims 1 to 19 and optionally at least one physiologically acceptable auxiliary agent.
22. Medicament according to claim 21 for the modulation of cannabinoid- receptors, preferably cannabinoid 1 (CBi) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
23. Medicament according to claim 21 or 22 for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type Il diabetes mellitus (non-insuline dependent diabetes mellitus), more preferably obesity.
24. Medicament according to claim 21 or 22 for the prophylaxis and/or treatment of psychosis.
25. Medicament according to claim 21 or 22 for the prophylaxis and/or treatment of alcohol abuse and/or alcohol addiction, nicotine abuse and/or nicotine addiction, drug abuse and/or drug addiction and/or medicament abuse and/or medicament addiction, preferably drug abuse and/or drug addiction and/or nicotine abuse and/or nicotine addiction.
26. Medicament according to claim 21 or 22 for the prophylaxis and/or treatment of cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, bowel cancer and prostate cancer, more preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer.
27. Medicament according to claim 21 or 22 for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of bone disorders, preferably osteoporosis (e.g. osteoporosis associated with a genetic predisposition, sex hormone deficiency, or ageing), cancer-associated bone disease or Paget's disease of bone; schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebella disorders, spinocerebella disorders, cognitive disorders, cranial trauma, head trauma, stroke, panic attacks, peripheral neuropathy, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymus disorders, tardive dyskinesia, bipolar disorders, medicament-induced movement disorders, dystonia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunologic disorders, sclerotic plaques, vomiting, diarrhoea, asthma, memory disorders, pruritus, pain, or for potentiation of the analgesic effect of narcotic and non-narcotic analgesics, or for influencing intestinal transit.
28. Use of at least one salt according to one or more of claims 1 to 19 for the preparation of a medicament for the modulation of cannabinoid-receptors, preferably cannabinoid 1 (CBi) receptors, for the prophylaxis and/or treatment of disorders of the central nervous system, disorders of the immune system, disorders of the cardiovascular system, disorders of the endocrinous system, disorders of the respiratory system, disorders of the gastrointestinal tract or reproductive disorders.
29. Use of at least one salt according to one or more of claims 1 to 19 for the preparation of a medicament for the prophylaxis and/or treatment of food intake disorders, preferably bulimia, anorexia, cachexia, obesity, type Il diabetes mellitus (non-insuline dependent diabetes mellitus), more preferably obesity.
30. Use of at least one salt according to one or more of claims 1 to 19 for the preparation of a medicament for the prophylaxis and/or treatment of psychosis.
31. Use of at least one salt according to one or more of claims 1 to 19 for the preparation of a medicament for the prophylaxis and/or treatment of alcohol abuse and/or alcohol addiction, nicotine abuse and/or nicotine addiction, drug abuse and/or drug addiction and/or medicament abuse and/or medicament addiction, preferably drug abuse and/or drug addiction and/or nicotine abuse and/or nicotine addiction.
32. Use of at least one salt according to one or more of claims 1 to 19 for the preparation of a medicament for the prophylaxis and/or treatment of cancer, preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of brain cancer, bone cancer, lip cancer, mouth cancer, esophageal cancer, stomach cancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast cancer, skin cancer, colon cancer, bowel cancer and prostate cancer, more preferably for the prophylaxis and/or treatment of one or more types of cancer selected from the group consisting of colon cancer, bowel cancer and prostate cancer.
33. Use of at least one salt according to one or more of claims 1 to 19 for the preparation of a medicament for the prophylaxis and/or treatment of one or more disorders selected from the group consisting of bone disorders, preferably osteoporosis (e.g. osteoporosis associated with a genetic predisposition, sex hormone deficiency, or ageing), cancer-associated bone disease or Paget's disease of bone; schizophrenia, anxiety, depression, epilepsy, neurodegenerative disorders, cerebella disorders, spinocerebella disorders, cognitive disorders, cranial trauma, head trauma, stroke, panic attacks, peripheral neuropathy, glaucoma, migraine, Morbus Parkinson, Morbus Huntington, Morbus Alzheimer, Raynaud's disease, tremblement disorders, compulsive disorders, senile dementia, thymic disorders, tardive dyskinesia, bipolar disorders, medicament-induced movement disorders, dystonia, endotoxemic shock, hemorrhagic shock, hypotension, insomnia, immunologic disorders, sclerotic plaques, vomiting, diarrhoea, asthma, memory disorders, pruritus, pain, or for potentiation of the analgesic effect of narcotic and non-narcotic analgesics, or for influencing intestinal transit.
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