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WO2002100842A1 - Sulfonyloxazolamines et leur utilisation comme ligands 5-ht6 - Google Patents

Sulfonyloxazolamines et leur utilisation comme ligands 5-ht6 Download PDF

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Publication number
WO2002100842A1
WO2002100842A1 PCT/EP2002/005394 EP0205394W WO02100842A1 WO 2002100842 A1 WO2002100842 A1 WO 2002100842A1 EP 0205394 W EP0205394 W EP 0205394W WO 02100842 A1 WO02100842 A1 WO 02100842A1
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WIPO (PCT)
Prior art keywords
benzenesulfonyl
formula
oxazol
tolyloxazol
amine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/EP2002/005394
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English (en)
Inventor
Hartmut Greiner
Gerd Bartoszyk
Henning Böttcher
Gerhard Barnickel
Bertram Cezanne
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Merck Patent GmbH
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Merck Patent GmbH
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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
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical

Definitions

  • the invention relates to sulfonyloxazolamines of the general formula I
  • R ⁇ R 2 each independently of one another are H, A, cycloal yl having 3 to 8 C atoms, -(CH 2 ) n -Ar, -(CH 2 ) n -OA, -(CH 2 ) n -NH 2 ,-(CH 2 ) n -NHA, -(CH 2 ) n -NA 2 or alkenyl having 2 to 6 C atoms
  • R 1 and R 2 together are also a mononuclear saturated heterocycle having 1 to 2 N, 0 and/or S atoms, Z, Z 1 or Z 2 in each case independently of one another is H, A, CF 3 , N0 2 , Hal, OH, OA, OCF 3 , SCF 3 , NH 2 , NHA or NA 2
  • A is alkyl having 1 to 6 C atoms
  • Ar is phenyl which is mono-, di- or tri- substituted by Z,
  • Hal is F, Cl, Br or I , n is 1 , 2 , 3 or 4 , or their physiologically acceptable salts or solvates as therapeutic active compounds.
  • the invention furthermore relates to the use of the sulfonyloxazolamines of the general formula I as therapeutic active compounds.
  • the invention also relates to the use of the sulfonyloxazolamines of the general formula I for the production of pharmaceutical preparations in the control of disorders of the central nervous system.
  • the formula I includes known and novel compounds .
  • the invention was based on the object of finding novel useful properties of sulfonyloxazolamines, in particular those which confirm the compounds to be therapeutic active compounds and/or can lead to the use of the sulfonyloxazolamines as therapeutic active compounds and/or to the production of pharmaceutical preparations, and of preparing further novel sulfonyloxazolamines having these properties.
  • 5-HT6 receptors form a subfamily of 5-HT receptors.
  • the neurotransmitter 5-hydroxytryptamine (5-HT) also known as serotonin, is an important regulating neurotransmitter in the brain, whose actions are assisted by a family of receptors which, at the current level of knowledge, contain 13 G protein- coupled receptors and an ion channel .
  • the greatest density of the serotonin 5-HT6 receptors in the brain is found in the olfactory tubercle, in the nucleus accumbens, in the striatum, in the dentate gyrus and in the CA1-3 regions of the hippocampus. These regions are involved to a particular extent in psychiatric disorders such as, for example, schizophrenia or depression.
  • the compounds of the formula I and their physiologically acceptable salts are therefore suitable as therapeutic active compounds for disorders of the central nervous system.
  • the compounds of the formula I and their physiologically acceptable salts or solvates are particularly suitable for the treatment of psychoses, schizophrenia, manic depression (B. L. Roth et al., J “ . Pharmacol . Exp. Ther. 1994, 268, 1403-1410), depression (D. R. Sibley et al . , Mol . Pharmacol . 1993, 43 , 320-327) , neurological disorders (A. Bourson et al., J. Pharmacol . Exp . Ther.
  • the invention relates to the compounds of the formula I or their physiologically acceptable salts or solvates as therapeutic active compounds.
  • the invention relates to the use of compounds of the formula I or their physiologically acceptable salts or solvates as therapeutic active compounds.
  • the invention furthermore relates to the use of compounds of the formula I or their physiologically acceptable salts or solvates as therapeutic active compounds for disorders of the central nervous system.
  • the invention also relates to novel compounds of the formula la or their physiologically acceptable salts or solvates.
  • the invention relates to compounds of the formula lb or their physiologically acceptable salts or solvates, and to a process for their preparation.
  • the invention relates to compounds of the formula Ic or their physiologically acceptable salts or solvates, and to a process for their preparation.
  • the invention relates to compounds of the formula Id or their physiologically acceptable salts or solvates, and to a process for their preparation.
  • the invention relates to compounds of the formula Ie or their physiologically acceptable salts or solvates, and to a process for their preparation.
  • Solvates of the compounds of the formula I are understood as meaning adducts of inert solvent molecules to the compounds of the formula I, which are formed on account of their mutual force of attraction. Solvates are, for example, mono- or dihydrates or alcoholates . For all radicals which occur more than once, such as, for example, Z or A, it holds true that their meanings are independent of one another.
  • radicals and parameters R 1 , R 2 , Z, Z 1 , Z 2 and n have the meanings indicated in the formulae I to VII, if not expressly stated otherwise.
  • A is alkyl, is linear or branched, and has 1 to 6, preferably 1, 2, 3 or 4 , C atoms.
  • A is preferably methyl, furthermore ethyl, isopropyl, propyl, butyl, isobutyl, sec-butyl or tert- butyl , in addition also pentyl , 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2 , 2-dimethylpropyl , 1-ethylpropyl or hexyl .
  • Methyl, ethyl, propyl, isopropyl or tert-butyl is particularly preferred.
  • Alkenyl is preferably allyl, 2- or 3-butenyl, isobutenyl, sec-butenyl, in addition is preferably 4-pentenyl, isopentenyl or 5-hexenyl. Allyl is particularly preferred for alkenyl.
  • Ar is pre erably phenyl which is mono- , di or trisubstituted by Z, where Z can be H, A, CF 3 , N0 2 , Hal, OH, OA, OCF 3 , SCF 3 , NH 2 , NHA or NA 2 .
  • Ar is therefore preferably phenyl, o- , m- or p- methylphenyl , o-, m- or p-ethylphenyl, o-, m- or p- propylphenyl , o-, m- or p-isopropylphenyl, o- , m- or p- tert-butylphenyl, o-, m- or p-aminophenyl, o- , m- or p-
  • Cycloalkyl having 3 to 8 C atoms is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl being particularly preferred.
  • Ar has one of the preferred meanings indicated beforehand, where n can be 1 or 2.
  • A has one of the preferred meanings indicated beforehand, where n can be 1, 2, 3 or 4. Methoxypropyl or methoxyethyl is particularly preferred for -(CH 2 ) n -0A.
  • A has one of the preferred meanings indicated beforehand, where n can be 2 , 3 or 4.
  • Dimethylaminopropyl or dimethylaminoethyl is particularly preferred for - (CH 2 ) n -NA 2 .
  • Hal is preferably fluorine, chlorine, bromine or iodine .
  • Z, Z 1 or Z 2 are, in each case independently of one another, H, A, CF 3 , N0 2 , Hal, OH, OA, 0CF 3 , SCF 3 ,
  • NH 2 , NHA or NA 2 where A and Hal have one of the preferred meanings indicated beforehand.
  • H methyl, trifluoromethyl, fluorine, chlorine, bromine, ethoxy or methoxy is particularly preferred for Z in formula I .
  • Z is H or chlorine.
  • Z 2 is H.
  • n is preferably 1, 2, 3 or 4, particularly preferably 1, 2 or 3.
  • R 1 and R 2 are, independently of one another, H,
  • R 1 and R 2 together are also a mononuclear saturated heterocycle having 1 to 2 N, 0 and/or S atoms .
  • R 1 and R 2 together are preferably tetrahydro-2 - or -3-furyl, 1 , 3-dioxolan-4-yl, tetrahydro-2- or -3- thienyl, 1-, 2- or 3-pyrrolidinyl , tetrahydro-1- , -2- or -4-imidazolyl, tetrahydro-1-, -3- or -4-pyrazolyl , 1-, 2-, 3- or 4-piperidinyl, 1-, 2-, 3- or 4-perhydroazepinyl, 2-, 3- or 4-morpholinyl , tetrahydro-2-, -3- or -4-pyranyl, 1, 4-dioxanyl, 1,3- dioxan-2-, -4- or -5-yl, hexahydro-1- , -3- or -4- pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimi
  • the compounds of the formula I include the following groups: a) compounds of the formula la
  • R ⁇ R 2 each independently of one another are H, A,
  • R 1 and R 2 together are also a mononuclear saturated heterocycle having 1 or 2 N, 0 and/or S atoms, Z is H, A, CF 3 , N0 2 , Hal, OH, OA, NH 2 , NHA or
  • NA 2 , * A is alkyl having 1 to 6 C atoms
  • Ar is phenyl which is mono- or disubstituted by
  • Hal is F, Cl, Br or I, n is 1 or 2, or their physiologically acceptable salts or solvates;
  • Z is H, A, CF 3 , N0 2 , Hal, OH, OA, OCF 3 , SCF 3 ,
  • A is alkyl having 1 to 6 C atoms
  • Ar is phenyl which is mono-, di- or trisubstituted by Z
  • Hal is F, Cl, Br or I
  • n is 1, 2 or 3 or their physiologically acceptable salts or solvates;
  • Z is H , A, CF 3 , N0 2 , Hal , OH , OA, OCF 3 , SCF 3 ,
  • A is alkyl having 1 to 6 C atoms
  • Ar is phenyl which is . mono-, di- or trisubstituted by Z, Hal is F, Cl, Br or I, or their physiologically acceptable salts or solvates;
  • Z is H, A, CF 3 , N0 2 , Hal, OH, OA, OCF 3 , SCF 3 ,
  • A is alkyl having 1 to 6 C atoms
  • Ar is phenyl which is mono-, di- or trisubstituted by Z
  • Hal is F, Cl, Br or I, n is 1, 2, 3 or 4, or their physiologically acceptable salts or solvates; or
  • R X ,R 2 each independently of one another are H, A, cycloalkyl having 3 to 8 C atoms, -(CH 2 ) n -
  • R 1 and R 2 together are also a mononuclear saturated heterocycle having 1 or 2 N, O and/or S atoms, Z or Z 1 in each case independently of one another are
  • A is alkyl having 1 to 6 C atoms
  • Ar is phenyl which is mono-, di- or trisubstituted by Z
  • Hal is F, Cl, Br or I, n is 1, 2, 3 or 4
  • those compounds of the formula I which correspond to the formula la are particularly preferred and in which at least one of the radicals mentioned has one of the preferred or particularly preferred meanings indicated above.
  • Some preferred groups of compounds can be expressed by the following subformulae Iaa to lac, which correspond to the formula la and in which the radicals not described in greater detail have the meaning indicated in the formula la, but in which
  • R 1 and R 2 in each case independently of one another are
  • Z is H, A or Hal; alkenyl is allyl;
  • Ar is phenyl, o- or p-methylphenyl , p-tert- butylphenyl , o- or m-trifluoromethylphenyl , o-, m- or p-trifluoromethoxyphenyl , p-tri- fluoromethylsulfanylphenyl , p-fluorophenyl, o- or p-chlorophenyl, p-bromophenyl , m-iodophenyl , o-, m- or p-methoxyphenyl , o-ethoxyphenyl , 5- fluoro-2-methylphenyl or 2 , 4-dichlorophenyl and -(CH 2 ) n -Ar is benzyl, 4-methoxyphenylethyl , 3-methoxy- phenylethyl , 2- ethoxybenzyl , 3-methoxybenzyl
  • R 1 and R 2 in formula I together are piperidin-1-yl or piperazin-1-yl;
  • Z is H, A or Hal
  • Ar is phenyl, o- or p-methylphenyl, p-tert- butylphenyl, o- or m-trifluoromethylphenyl, o-, m- or p-trifluoromethoxyphenyl, p- trif luoromethyl sulf anylphenyl , p- fluorophenyl , o- or p- chlorophenyl , p-bromophenyl , m- iodophenyl , o - , m- or p-methoxyphenyl , o- ethoxyphenyl , 5 - f luoro-2 -methylphenyl or 2 , 4 - dichlorophenyl or
  • R 1 and R 2 in formula I together are morpholin-4-yl ;
  • Z is H, A or Hal and
  • Ar is phenyl, o- or p-methylphenyl, p-tert- butylphenyl , o- or m-trifluoromethylphenyl, o-, m- or p-trifluoromethoxyphenyl , p-trifluoro- methylsulfanylphenyl, p-fluorophenyl, o- or p- chlorophenyl, p-bromophenyl, m-iodophenyl, o- , m- or p-methoxyphenyl, o-ethoxyphenyl , 5- fluoro-2-methylphenyl or 2 , 4-dichlorophenyl .
  • formula la the following known compounds are particularly preferred for use according to Claim 1:
  • Preferred novel compounds of the formula la are the following compounds whose preparation is described in Examples 1 to 7 :
  • (4-benzenesulfonyl-2 -o-tolyloxazol-5-yl) isopropylamine; (4-benzenesulfonyl-2-o-tolyloxazol-5-yl) - (4- methoxybenzyl) amine ; 1- (4-benzenesulfonyl-2-o-tolyloxazol-5-yl) piperazine;
  • those compounds of the formula lb are particularly preferred which correspond to the formula lb and in which at least one of the radicals mentioned has one of the preferred or particularly preferred meanings indicated above .
  • Z is H, A or Hal
  • Ar is phenyl, o- or p-methylphenyl, p-tert- butylphenyl, o- or m-trifluoromethylphenyl, o-, m- or p-trifluoromethoxyphenyl , p- trifluoromethylsulfanylphenyl , p-fluoro- phenyl , o- or p-chlorophenyl , p-bromophenyl, m-iodophenyl, o-, m- or p-methoxyphenyl, o- ethoxyphenyl , 5-fluoro-2-methylphenyl or 2,4- dichlorophenyl .
  • Preferred compounds of the formula lb are:
  • those compounds of the formula Ic are particularly preferred which correspond to the formula Ic and in which at least one of the radicals mentioned has one of the preferred or particularly preferred meanings indicated above .
  • Some preferred groups of compounds can be expressed by the following subformulae lea and Icb, which correspond to the formula Ic and in which the radicals not designated in greater detail have the meaning indicated in the formula Ic, but in which in lea
  • Z is H, A or Hal
  • Z is H, A or Hal
  • Ar is phenyl, o- or p-methylphenyl, p-tert- butylphenyl, o- or m-trifluoromethylphenyl , o-, m- or p-trifluoromethoxyphenyl , p-trifluoromethylsulfanylphenyl, p-fluorophenyl, o- or p- chlorophenyl , p-bromophenyl, m-iodophenyl, o-, m- or p-methoxyphenyl, o-ethoxyphenyl , 5- fluoro-2-methylphenyl or 2 , 4-dichlorophenyl .
  • Preferred compounds of the formula Ic are:
  • those compounds of the formula Id are particularly preferred which correspond to the formula Id and in which at least one of the radicals mentioned has one of the preferred or particularly preferred meanings indicated above .
  • Ar is phenyl, o- or p-methylphenyl, p-tert- butylphenyl, o- or m-trifluoromethylphenyl , o-, m- or p-trifluoromethoxyphenyl, p- trifluoromethylsulfanylphenyl , p-fluoro- phenyl, o- or p-chlorophenyl , p-bromophenyl, m-iodophenyl, o- , m- or p-methoxyphenyl, o- ethoxyphenyl , 5-fluoro-2-methylphenyl or 2,4- dichlorophenyl .
  • Preferred compounds of the formula Id are: N' - [4- (4-bromobenzenesulfonyl-2-o-tolyloxazol-5-yl] - N,N-dimethylethane-l,2-diamine;
  • those compounds of the formula Ie are particularly preferred which correspond to the formula Ie and in which at least one of the radicals mentioned has one of the preferred or particularly preferred meanings indicated above .
  • H A, cycloalkyl having 3 to 8 C atoms, -(CH 2 ) n -Ar, -(CH 2 ) n -OA, - (CH 2 ) n -NH 2 , r (CH 2 ) n - NHA, or - (CH 2 ) n -NA 2 ;
  • R 1 , R 2 in each case independently of one another are H, A, cycloalkyl having 3 to 8 C atoms, -(CH 2 ) n -Ar, -(CH 2 ) n -0A or -(CH 2 ) n -NA 2 and
  • Ar is phenyl, o- or p-methylphenyl, p-tert- butylphenyl, o- or m-trifluoromethylphenyl, o-, m- or p-trifluoromethoxyphenyl, p- trifluoromethylsulfanylphenyl, p-fluorophenyl, o- or p-chlorophenyl, p-bromophenyl, m-iodophenyl, o-, m- or p-methoxyphenyl, o- ethoxyphenyl , 5-fluoro-2-methylphenyl or 2,4- dichlorophenyl ;
  • R 1 , R 2 in each case independently of one another are H, A, cycloalkyl having 3 to 8 C atoms, -(CH 2 ) n -Ar, -(CH 2 ) n -OA or -(CH 2 ) n -NA 2 , ZjZ 1 in each case are Hal and Ar is phenyl, o- or p-methylphenyl, p-tert- butylphenyl , o- or - (trifluoromethyl) henyl , o-, m- or p- (trifluoromethoxy) phenyl , p- (trifluoromethylsulfanyl) phenyl, p- fluorophenyl , o- or p-chlorophenyl , p- bromophenyl, m-iodophenyl , o-, m- or p- methoxyphenyl , o-
  • the invention furthermore relates to the use of the following compounds, selected from the group a) dimethyl- [2-phenyl-4- (toluene-4 -sulfonyl) oxazol-5- yl] amine, b) [2- (2 , 4-dichlorophenyl) -4- (toluene-4 -sulfonyl) - oxazol-5-yl] dimethylamine, c) benzyl- [4- (4-chlorobenzenesulfonyl) -2- (2- chlorophenyl) oxazol -5 -yl] amine , d) (4-benzenesulfonyl-2-o-tolyloxazol-5-yl) - methylamine, e) benzyl- [2- (2 , 4-dichlorophenyl) -4- (toluene-4- sulfonyl) oxazol -5-yl] amine
  • the compounds of the formula I are in some cases commercially obtainable or can be synthesized according to the following synthesis scheme (for this cf . V. A. Chervonyi et al . , Ukr. Khim . Zh . (Russ. Ed.) 1991, 57 (4) , 415-418 or V. A. Chervonyi et al . , Zh . Org. Khim . 1988, 24 (2) , 453-4 corresponding to V. A. Chervonyi et al . , J " . Org. Chem . USSR (Engl . transl . ) 1988, 24 , 401) . Synthesis scheme
  • the starting material of the formula II is reacted with trichloroacetate to give the compound III.
  • the reaction with thionyl chloride and subsequently with the sodium sulfinate of the formula V generates an aryl vinyl sulfone of the formula VI, which cyclizes to give the sulfonyloxazolamines of the formula I by reaction with an amine of the formula VII.
  • the substituents Ar, Z, R 1 and R 2 of the formula II to VII have preferred or particularly preferred meanings as indicated beforehand.
  • novel compounds of the formulae lb to Ie can be prepared analogously to the previous synthesis scheme .
  • the invention therefore furthermore relates to a process for the preparation of compounds of the formulae lb to Ie, and of their salts and solvates, characterized in that a) for the preparation of the compounds of the formula lb a compound of the formula Via in which Z and Ar have one of the meanings described beforehand in formula lb, is reacted with a compound of the formula VIlb
  • a base of the formula I can be converted into the associated acid addition salt using an acid, for example by reaction of equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequent evaporation.
  • suitable acids are in particular those which yield physiologically acceptable salts .
  • inorganic acids can be used, e.g.
  • sulfuric acid nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulf mic acid, in addition organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, e.g.
  • the substances to be tested were dissolved in DMSO at a concentration of 1 mM and diluted to the desired concentrations (0.1 nM to 10 ⁇ M) using test buffer (20 mM HEPES, 0.1% ascorbic acid, adjusted to pH 7.4 using NaOH) .
  • the filters were washed 3 times with 3 ml of test buffer, transferred to minivials and, after addition of Ultima Gold (Packard, Frankfurt) , the radioactivity was determined in a liquid scintillation counter.
  • the evaluation and IC 50 determination was carried out by means of in-house programs in RSI (BBN Software Corporation) .
  • the compounds of the formula I have a selective affinity for 5-HT6 receptors having an inhibition constant IC 50 of less than 4 ⁇ mol/1.
  • the invention furthermore relates to the use of the compounds of the general formula I for the production of a pharmaceutical preparation for controlling disorders of the central nervous system.
  • the invention furthermore relates to the use of compounds of the general formula I for the production of a pharmaceutical preparation for the treatment of psychoses, schizophrenia, manic depression, depression, neurological disorders, memory disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, bulimia, anorexia nervosa or other eating disorders, compulsive acts or premenstrual syndrome .
  • the invention furthermore relates to pharmaceutical preparations for the control of disorders of the central nervous system, comprising at least one compound of the formula I or one of its physiologically acceptable salts or solvates.
  • preparations can be used as pharmaceuticals in human or veterinary medicine.
  • Possible vehicles are organic or inorganic substances which are suitable for enteral (e.g. oral), or parenteral administration or topical application and do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc or petroleum jelly.
  • Tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, in particular, are used for oral administration, suppositories are used for rectal administration, solutions, preferably oily or aqueous solutions, in addition suspensions, emulsions or implants, are used for parenteral administration, and ointments, creams or powders are used for topical application.
  • the novel compounds can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection preparations.
  • the preparations indicated can be sterilized and/or can contain excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavourings and/or other active compounds, e.g. one or more vitamins.
  • excipients such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffer substances, colorants, flavourings and/or other active compounds, e.g. one or more vitamins.
  • the invention also relates to a process for the production of these pharmaceutical preparations, which is characterized in that a compound of the formula I or one of its physiologically tolerable salts or solvates is brought into a suitable dose form together with at least one solid, liquid or semiliquid vehicle or excipient and, if appropriate, in combination with one or more other active compound.
  • the compounds of the formula I and their physiologically acceptable salts or solvates can be employed for the control of disorders of the central nervous system.
  • the substances according to the invention are as a rule administered here in a dose of preferably between approximately 1 and 500 mg, in particular between 5 and 100 mg, per dose unit.
  • the daily dose is preferably between approximately 0.02 and 10 mg/kg of body weight.
  • the specific dose for each patient depends on all sorts of factors, for example on the efficacy of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, and on the excretion rate, pharmaceutical combination and severity of the particular disorder to which the therapy applies. Oral administration is preferred. Above and below, all temperatures are indicated in °C.
  • customary working- up means: if necessary, water is added, if necessary, depending on the constitution of the final product, the mixture is adjusted to a pH of between 2 and 10 and extracted with ethyl acetate or dichloromethane, the organic phase is separated off, dried over sodium sulfate and evaporated, and the residue is purified by chromatography on silica gel, by preparative HPLC and/or by crystallization. m.p. denotes melting point.
  • 4-fluorobenzamide 0.5 mol of 4-fluorobenzamide is suspended in 100 ml of toluene and, after addition of 0.625 mol (92.2 g) of chloral (trichloroacetaldehyde) , the mixture is heated at 110° for 1 hour. After cooling, the crystalline reaction product, 4-fluoro-N- (2 , 2 , 2- trichloro-l-hydroxyethyl)benzamide is filtered off with suction, washed with cold water and dried in vacuo (m.p. 131-133°).
  • propylamine (4-benzenesulfonyl -2-o-tolyloxazol-5- yl) propylamine
  • Example 2 Analogously to Example 1, the following are obtained by stepwise reaction of 2 -trifluoromethyl- benzamide with chloral, thionyl chloride, sodium benzenesulfinate and
  • Example 2 Analogously to Example 1, the following are obtained by stepwise reaction of 2 -trifluoromethyl- benzamide with chloral, thionyl chloride, sodium (2, 5- dichlorobenzene) sulfinate and
  • Example 11 Analogously to Example 1, the following is obtained by stepwise reaction of 2-methylbenzamide with chloral, thionyl chloride, sodiu (4- bromobenzene) sulfinate and
  • N 1 ,N 1 -dimethylpropane-l, 3-diamine N' - [4-benzenesulfonyl) -2-o-tolyloxazol-5-yl] -N,N- dimethylpropane-1 , 3-diamine .
  • a solution of 100 g of an active compound of the formula I and 5 g of disodium hydrogenphosphate is adjusted to pH 6.5 in 3 1 of double-distilled water using 2N hydrochloric acid, sterile-filtered, filled into injection vials, lyophilized under sterile conditions and aseptically sealed. Each injection vial contains 5 mg of active compound.
  • a mixture of 20 g of an active compound of the formula I is fused with 100 g of soya lecithin and 1400 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 20 mg of active compound.
  • 500 mg of an active compound of the formula 1 are mixed with 99.5 g of petroleum jelly under aseptic conditions .
  • a mixture of 1 kg of active compound of the formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 g of talc and 0.1 kg of magnesium stearate is compressed to give tablets in a customary manner such that each tablet contains 10 mg of active compound.
  • Example E tablets are pressed and are then coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth and colorant .
  • Example G Capsules 2 kg of active compound of the formula I are filled into hard gelatin capsules in a customary manner such that each capsule contains 20 mg of the active compound .
  • a solution of 1 kg of active compound of the formula I in 60 ml of double-distilled water is sterile-filtered, filled into ampoules, lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 10 mg of active compound.

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Abstract

L'invention porte sur des sulfonyloxazolamines de formule générale I comme composés actifs thérapeutiques, sur l'utilisation des sulfonyloxazolamines comme composés actifs thérapeutiques et/ou pour la production de préparations pharmaceutiques permettant de lutter contre les troubles du système nerveux central, sur une préparation pharmaceutique et sur son procédé d'obtention, ainsi que sur des composés nouveaux de formule I.
PCT/EP2002/005394 2001-06-13 2002-05-16 Sulfonyloxazolamines et leur utilisation comme ligands 5-ht6 Ceased WO2002100842A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10129940A DE10129940A1 (de) 2001-06-13 2001-06-13 Sulfonyloxazolamine als therapeutische Wirkstoffe
DE10129940.0 2001-06-13

Publications (1)

Publication Number Publication Date
WO2002100842A1 true WO2002100842A1 (fr) 2002-12-19

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PCT/EP2002/005394 Ceased WO2002100842A1 (fr) 2001-06-13 2002-05-16 Sulfonyloxazolamines et leur utilisation comme ligands 5-ht6

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DE (1) DE10129940A1 (fr)
WO (1) WO2002100842A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008061248A3 (fr) * 2006-11-16 2008-07-17 Alan S Verkman Inhibiteurs à composé sulfoxyoxazole de transporteurs d'urée
JPWO2007010731A1 (ja) * 2005-07-15 2009-01-29 Jsr株式会社 含窒素芳香族化合物およびその製造方法、重合体およびプロトン伝導膜
WO2012087182A3 (fr) * 2010-12-21 2012-09-13 Алла Хем, Ллс Amines de méthyle substituées, antagonistes des récepteurs de sérotonine 5-ht6 et procédés de fabrication et d'utilisation
WO2013148813A1 (fr) * 2012-03-27 2013-10-03 The Regents Of The University Of California Composés inhibiteurs triazolothiénopyrimidines de transporteurs d'urée et procédés d'utilisation des inhibiteurs
WO2019139365A1 (fr) * 2018-01-10 2019-07-18 경북대학교 산학협력단 Nouveau dérivé d'oxazole phénylsulfonyle et son utilisation

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Publication number Priority date Publication date Assignee Title
WO2000037452A1 (fr) * 1998-12-18 2000-06-29 Merck Patent Gmbh Sulfonyloxazolamines en tant que principes actifs therapeutiques
WO2001038316A2 (fr) * 1999-11-25 2001-05-31 Merck Patent Gmbh Nouvelles sulfonyloxazolamines

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037452A1 (fr) * 1998-12-18 2000-06-29 Merck Patent Gmbh Sulfonyloxazolamines en tant que principes actifs therapeutiques
WO2001038316A2 (fr) * 1999-11-25 2001-05-31 Merck Patent Gmbh Nouvelles sulfonyloxazolamines

Non-Patent Citations (2)

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Title
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002214998, Database accession no. 1993:124426 *
UKRAINSKII KHIMICHESKII ZHURNAL, vol. 57, no. 4, 1991, pages 415 - 418 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPWO2007010731A1 (ja) * 2005-07-15 2009-01-29 Jsr株式会社 含窒素芳香族化合物およびその製造方法、重合体およびプロトン伝導膜
US8394788B2 (en) 2006-11-16 2013-03-12 The Regents Of The University Of California Phenylsulfoxyoxazole compound inhibitors of urea transporters
WO2008061248A3 (fr) * 2006-11-16 2008-07-17 Alan S Verkman Inhibiteurs à composé sulfoxyoxazole de transporteurs d'urée
JP2014508729A (ja) * 2010-12-21 2014-04-10 アラ・ケム・エルエルシー 置換されたメチルアミン、セロトニン５−ｈｔ６受容体アンタゴニスト、製造のための方法及びその使用
WO2012087182A3 (fr) * 2010-12-21 2012-09-13 Алла Хем, Ллс Amines de méthyle substituées, antagonistes des récepteurs de sérotonine 5-ht6 et procédés de fabrication et d'utilisation
US9303042B2 (en) 2012-03-27 2016-04-05 The Regents Of The University Of California Triazolothienopyrimidine compound inhibitors of urea transporters and methods of using inhibitors
WO2013148813A1 (fr) * 2012-03-27 2013-10-03 The Regents Of The University Of California Composés inhibiteurs triazolothiénopyrimidines de transporteurs d'urée et procédés d'utilisation des inhibiteurs
WO2019139365A1 (fr) * 2018-01-10 2019-07-18 경북대학교 산학협력단 Nouveau dérivé d'oxazole phénylsulfonyle et son utilisation
KR20190085443A (ko) * 2018-01-10 2019-07-18 경북대학교 산학협력단 신규한 페닐설포닐 옥사졸 유도체 및 이의 용도
CN111868043A (zh) * 2018-01-10 2020-10-30 庆北大学校产学协力团 新型苯磺酰基噁唑衍生物及其用途
US11345671B2 (en) 2018-01-10 2022-05-31 Kyungpook National University Industry-Academic Cooperation Foundation Phenylsulfonyl oxazole derivative and use thereof
KR102533605B1 (ko) * 2018-01-10 2023-05-17 주식회사 라이조테크 신규한 페닐설포닐 옥사졸 유도체 및 이의 용도
CN111868043B (zh) * 2018-01-10 2023-11-14 利索科技股份有限公司 新型苯磺酰基噁唑衍生物及其用途

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