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US20040229872A1 - Substituted cyclohexane-1,4-diamine compounds with anti-diarrhea and peripheral analgesic activity - Google Patents

Substituted cyclohexane-1,4-diamine compounds with anti-diarrhea and peripheral analgesic activity Download PDF

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Publication number
US20040229872A1
US20040229872A1 US10/704,524 US70452403A US2004229872A1 US 20040229872 A1 US20040229872 A1 US 20040229872A1 US 70452403 A US70452403 A US 70452403A US 2004229872 A1 US2004229872 A1 US 2004229872A1
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unsubstituted
singly
multiply substituted
group
saturated
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Elmar Friderichs
Bernd Sundermann
Claudia Hinze
Babette-Yvonne Koegel
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Gruenenthal GmbH
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Gruenenthal GmbH
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Definitions

  • the present invention relates to the use of substituted cyclohexane-1,4-diamine compounds for the production of medicaments and for the treatment of diarrhea or irritable bowel diseases or for use as an immunotherapeutic agent or as a peripheral analgesic, in particular for the treatment of burn pains, pains in inflammatory joint diseases, inflammation of soft tissues or peripheral operation pain.
  • Peripheral ⁇ -opiate receptors have for a long time been the subject of various investigations. Suppression of diarrhea in acute and chronic diarrhea and other diseases of the gastrointestinal tract that are associated with a hypersecretion and hypermotility of the intestinal tract are the main therapeutically utilisable effects peripherally transmitted via these receptors. These various diseases are summarised under the generic name “irritable bowel diseases”. ⁇ -opioids are extremely suitable for the treatment of these diseases and have long been therapeutically employed (e.g. opium tincture), though they are subject to a considerable restriction due to their side effects on the central nervous system, in particular due to their potential for addiction and dependence.
  • opium tincture e.g. opium tincture
  • peripheral pain-relevant opiate receptors are in some cases induced only within the context of the underlying disease by immunological reactions or inflammation processes and may then be activated, in addition to the central nervous system opioid receptors, in suppressing pain.
  • Typical types of pain in which peripheral opiate receptors play a role are burn pains, pain in inflammatory joint diseases, inflammation of soft tissues and operation pain in orthopaedic interventions. Rheumatic pains also play a role.
  • the object of the present invention was to provide medicaments that are suitable for the treatment of diarrhea or irritable bowel diseases or for use as an immunotherapeutic agent or as a peripheral analgesic, in particular for the treatment of burn pains, pain in inflammatory joint diseases, inflammation of soft tissues or peripheral operation pain.
  • the compounds used for this purpose are peripherally active ⁇ -agonists without any action on the central nervous system.
  • the present invention accordingly provides for the use of substituted cyclohexane-1,4-diamine compounds according to the general formula I
  • R 1 and R 2 independently of one another are selected from H; C 1-8 -alkyl or C 3-8 -cycloalkyl, in each case saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case singly or multiply substituted or unsubstituted, or aryl, C 3-8 -cycloalkyl or heteroaryl bound via C 1-3 -alkylene, in each case singly or multiply substituted or unsubstituted, wherein R 1 and R 2 may not both be H, or the radicals R 1 and R 2 together form a ring and denote CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 or (CH 2 ) 3-6 ,
  • R 6 is selected from H; C 1-8 -alkyl or C 3-8 -cycloalkyl, in each case saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case singly or multiply substituted or unsubstituted; or aryl, C 3-8 -cycloalkyl or heteroaryl bound via C 1-3 -alkylene, in each case singly or multiply substituted or unsubstituted;
  • R 3 is selected from C 1-8 -alkyl or C 3-8 -cycloalkyl, in each case saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl, heteroaryl, in each case unsubstituted or singly or multiply substituted; aryl, C 3-8 -cycloalkyl or heteroaryl bound via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C 1-4 -alkyl group, and in each case unsubstituted or singly or multiply substituted;
  • R 4 is selected from H, C 1-8 -alkyl, saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted, or C(X)R 7 , C(X)NR 7 R 8 , C(X)OR 9 , C(X)SR 9 , S(O 2 )R 9
  • R 7 is selected from H, C 1-8 -alkyl or C 3-8 -cycloalkyl, in each case saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl, heteroaryl, in each case unsubstituted or singly or multiply substituted; aryl, C 3-8 -cycloalkyl or heteroaryl bound via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C 1-4 -alkyl group, and in each case unsubstituted or singly or multiply substituted;
  • R 8 is selected from H, C 1-4 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted, or
  • radicals R 7 and R 8 together form a ring and denote CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 or (CH 2 ) 3-6 ,
  • R 10 is selected from H; C 1-8 -alkyl or C 3-8 -cycloalkyl, in each case saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case singly or multiply substituted or unsubstituted; or aryl, C 3-8 -cycloalkyl or heteroaryl bound via C 1-3 -alkylene and in each case singly or multiply substituted or unsubstituted;
  • R 9 is selected from C 1-8 -alkyl or C 3-8 -cycloalkyl, in each case saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl, heteroaryl, in each case unsubstituted or singly or multiply substituted; aryl, C 3-8 -cycloalkyl or heteroaryl bound via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C 1-4 -alkyl group and in each case unsubstituted or singly or multiply substituted;
  • R 5 is selected from C 3-8 -cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; —CHR 11 R 12 , —CHR 11 —CH 2 R 12 , —CHR 11 —CH 2 —CH 2 R 12 , —CHR 11 —CH 2 —CH 2 —CH 2 R 12 , —C(Y)R 12 , —C(Y)—CH 2 R 12 , —C(Y)—CH 2 —CH 2 R 12 or —C(Y)—CH 2 —CH 2 —CH 2 R 12
  • R 11 is selected from
  • H C 1-7 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; or C(O)O—C 1-6 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted;
  • R 12 is selected from
  • H C 3-8 -cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted,
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, which is saturated or unsaturated; singly or multiply substituted or unsubstituted, and which may optionally be condensed with further rings,
  • the compounds used are outstanding peripherally active ⁇ -agonists without any effect on the central nervous system.
  • the compounds are not CNS-accessible and thus have the desired peripheral selectivity. They are suitable as antidiarrhea agents as well as for the treatment of other gastrointestinal diseases that are associated with hypermotility and hypersecretion. They may furthermore be employed as peripherally active analgesics that are particularly effective in treating burn pains, inflammation pain and in painful diseases of the joints. Furthermore the substances are suitable as immunotherapeutic agents. Their particular advantage is the lack of any effect on the central nervous system. Accordingly the side effects transmitted via CNS opiate receptors such as euphoria, potential for addiction and dependence (including dependence on the narcotic effect of the substance) and respiratory depression are absent.
  • CNS opiate receptors such as euphoria, potential for addiction and dependence (including dependence on the narcotic effect of the substance) and respiratory depression are absent.
  • alkyl and cycloalkyl radicals are understood to denote saturated and unsaturated (but not aromatic), branched, unbranched and cyclic hydrocarbons, which may be unsubstituted or singly or multiply substituted.
  • C 1-2 -alkyl denotes C1- or C2-alkyl
  • C 1-3 -alkyl denotes C1-, C2- or C3-alkyl
  • C 1-4 -alkyl denotes C1-, C2-, C3- or C4-alkyl
  • C 1-5 -alkyl denotes C1-, C2-, C3-, C4- or C5-alkyl
  • C 1-6 -alkyl denotes C1-, C2-, C3-, C4-, C5- or C6-alkyl
  • C 1-7 -alkyl denotes C1-, C2-, C3-, C4-, C5-, C6- or C7-alkyl
  • C 1-8 -alkyl denotes C1-, C2-, C3-, C4-, C5-, C6-, C7- or C8-alkyl
  • C 1-10 -alkyl denotes C1-, C
  • C 3-4 -cycloalkyl denotes C3- or C4-cycloalkyl
  • C 3-5 -cycloalkyl denotes C3-, C4- or C5-cycloalkyl
  • C 3-6 -cycloalkyl denotes C3-, C4-, C5- or C6-cycloalkyl
  • C 3-7 -cycloalkyl denotes C3-, C4-, C5-, C6- or C7-cycloalkyl
  • C 3-8 -cycloalkyl denotes C3-, C4-, C5-, C6, C7- or C8-cycloalkyl
  • C 4-5 -cycloalkyl denotes C4- or C5-cycloalkyl
  • C 4-6 -cycloalkyl denotes C4-, C5- or C6-cycloalkyl
  • C 4-7 -cycloalkyl denotes C4-, C5-, C6
  • cycloalkyl also includes saturated cycloalkyls in which 1 or 2 carbon atoms are replaced by a heteroatom, i.e. S, N or O.
  • cycloalkyl however also includes in particular singly or multiply, preferably singly, unsaturated cycloalkyls without a heteroatom in the ring provided that the cycloalkyl does not form an aromatic system.
  • the alkyl and cycloalkyl radicals are methyl, ethyl, vinyl (ethenyl), propyl, allyl (2-propenyl), 1-propinyl, methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, cyclopropyl, 2-methylcyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentyl-methyl, cyclohexyl, cycloheptyl, cyclooctyl, but also adamantyl, CHF 2 , CF 3 or CH 2 OH as well as pyrazolinone, oxopyrazolinone, [1,4]diox
  • the term substituted within the context of the present invention denotes the substitution (replacement) of at least one (optionally also several) hydrogen atom(s) by F, Cl, Br, I, NH 2 , SH or OH, in which “multiply substituted” or “substituted” in the case of multiple substitution is understood to mean that the substitution takes place on different atoms as well as on the same atoms multiply with the same or different substituents, for example triply on the same C atom as in the case of CF 3 , or at different positions as in the case of —CH(OH)—CH ⁇ CH—CHCl 2 .
  • substituents in this connection are F, Cl and OH.
  • the hydrogen atom may also be replaced by OC 1-3 -alkyl or C 1-3 -alkyl (in each case singly or multiply substituted or unsubstituted), in particular by methyl, ethyl, n-propyl, i-propyl, CF 3 , methoxy or ethoxy.
  • (CH 2 ) 3-6 is understood to denote —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 — and —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —
  • the term (CH 2 ) 1-4 is understood to denote —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 — and —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —
  • (CH 2 ) 4-5 is understood to denote —CH 2 —CH 2 —CH 2 —CH 2 — and —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —, etc.
  • An aryl radical is understood to denote ring systems with at least one aromatic ring but without heteroatoms in even only one of the rings. Examples include phenyl, naphthyl, fluoranthenyl, fluorenyl, tetralinyl or indanyl, in particular 9H-fluorenyl or anthracenyl radicals, which may be unsubstituted or singly or multiply substituted.
  • a heteroaryl radical is understood to denote heterocyclic ring systems with at least one unsaturated ring, which may contain one or more heteroatoms from the group comprising nitrogen, oxygen and/or sulfur, and may also be singly or multiply substituted.
  • substituted is understood to denote the substitution of the aryl or heteroaryl with R 22 , OR 22 , a halogen, preferably F and/or Cl, a CF 3 , a CN, an NO 2 , an NR 23 R 24 , a C 1-6 -alkyl (saturated), a C 1-6 -alkoxy, a C 3-8 -cycloalkoxy, a C 3-8 -cycloalkyl or a C 2-6 -alkylene.
  • the radical R 22 denotes H, a C 1-10 -alkyl radical, preferably a C 1-6 -alkyl radical, an aryl or heteroaryl radical, or an aryl or heteroaryl radical bound via C 1-3 -alkyl that is saturated or unsaturated, or bound via a C 1-3 -alkylene group, wherein these aryl and heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals,
  • the radicals R 23 and R 24 which are identical or different, denote H, a C 1-10 -alkyl radical, preferably a C 1-6 -alkyl radical, an aryl radical, a heteroaryl radical, or an aryl or heteroaryl radical bound via C 1-3 -alkyl that is saturated or unsaturated, or bound via a C 1-3 -alkylene group, wherein these aryl and heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals,
  • R 23 and R 24 together denote CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 25 CH 2 CH 2 or (CH 2 ) 3-6 , and
  • the radical R 25 denotes H, a C 1-10 -alkyl radical, preferably a C 1-6 -alkyl radical, an aryl or heteroaryl radical, or denotes an aryl or heteroaryl radical bound via C 1-3 -alkyl that is saturated or unsaturated, or bound via a C 1-3 -alkylene group, wherein these aryl and heteroaryl radicals may not themselves be substituted by aryl or heteroaryl radicals.
  • salt is understood to denote any form of the active substance according to the invention in which this adopts an ionic form or is charged and is coupled with a counterion (a cation or anion), or is present in solution.
  • the term is also understood to include complexes of the active substance with other molecules and ions, in particular complexes that are complexed via ionic interactions.
  • salt is understood (and this is also a preferred embodiment of the present invention) to denote physiologically compatible salts, in particular physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids or also a salt formed with a physiologically compatible acid or with a physiologically compatible cation.
  • physiologically compatible salt with anions or acids is understood within the context of the present invention to denote salts of at least one of the compounds according to the invention—generally protonated, for example on the nitrogen atom—as a cation with at least one anion, that are physiologically compatible, especially when used in humans and/or mammals.
  • the term is understood within the context of the present invention to mean the salt formed with a physiologically compatible acid, namely salts of the respective active substance with inorganic or organic acids, which are physiologically compatible, especially when used in humans and/or mammals.
  • physiologically compatible salts of specific acids are salts of the following: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro1 ⁇ 6 -benzo[d]isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.
  • the hydrochloride salt is particularly preferred.
  • salt formed with a physiologically compatible acid is understood within the context of the present invention to denote salts of the respective active substance with inorganic or organic acids that are physiologically compatible, especially when used in humans and/or mammals.
  • the hydrochloride is particularly preferred.
  • physiologically compatible acids include: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, 1,1-dioxo-1,2-dihydro1 ⁇ 6 -benzo[d]isothiazol-3-one (saccharinic acid), monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.
  • physiologically compatible salt with cations or bases is understood within the context of the present invention to denote salts of at least one of the compounds according to the invention—generally a (deprotonated) acid—as anion with at least one, preferably inorganic, cation, which are physiologically compatible, especially when used in humans and/or mammals.
  • Particularly preferred are the salts of alkali and alkaline earth metals, but also NH 4 + , but in particular (mono) or (di) sodium, (mono) or (di) potassium, magnesium or calcium salts.
  • salt formed with a physiologically compatible cation is understood within the context of the present invention to denote salts of at least one of the respective compounds as anion with at least one inorganic cation, which are physiologically compatible, especially when used in humans and/or mammals.
  • Particularly preferred are salts of alkali and alkaline earth metals, but also salts of NH 4 + , and in particular (mono) or (di) sodium, (mono) or (di) potassium, magnesium or calcium salts.
  • the medicaments contain in addition to at least one substituted cyclohexane-1,4-diamine compound, optionally suitable additives and/or auxiliary substances, thus also carrier materials, fillers, solvents, diluents, colourants and/or binders, and may be administered as liquid medicament forms in the form of injection solutions, droplets or juices, as semi-solid medicament forms in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols.
  • suitable additives and/or auxiliary substances thus also carrier materials, fillers, solvents, diluents, colourants and/or binders, and may be administered as liquid medicament forms in the form of injection solutions, droplets or juices, as semi-solid medicament forms in the form of granules, tablets, pellets, patches, capsules, plasters or aerosols.
  • auxiliary substances etc. as well as the amounts thereof to be used depend on whether the medicament is to be administered orally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example to the skin, the mucous membranes or the eyes.
  • parenterally intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or topically, for example to the skin, the mucous membranes or the eyes.
  • parenteral for parenteral, topical and inhalative application solutions, suspensions, readily reconstitutable dry preparations as well as sprays are suitable.
  • Substituted cyclohexane-1,4-diamine compounds according to the invention in a depot form, in dissolved form or in a plaster, optionally with the addition of agents promoting penetration of the skin, are suitable percutaneous application preparations.
  • Orally or percutaneously usable preparation forms may provide for the delayed release of the substituted cyclohexane-1,4-diamine compounds according to the invention.
  • active substances known to the person skilled in the art may be added to the medicaments according to the invention.
  • the amount of active substance to be administered to the patient varies depending on the patient's weight, type of application, medical indication and the severity of the disease. Normally 0.005 to 1000 mg/kg, preferably 0.05 to 5 mg/kg of at least one substituted cyclohexane-1,4-diamine compound are administered.
  • R 1 and R 2 are not both H.
  • R 1 and R 2 independently of one another are selected from H; C 1-8 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted;
  • R 1 and R 2 together form a ring and denote CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 6 CH 2 CH 2 or (CH 2 ) 3-6 ,
  • R 6 is selected from H; C 1-8 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted,
  • R 1 and R 2 independently of one another are selected from H; C 1-4 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted;
  • R 1 and R 2 independently of one another are selected from methyl or ethyl or the radicals R 1 and R 2 together form a ring and denote (CH 2 ) 5 .
  • R 3 is selected from C 3-8 -cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; aryl, C 3-8 -cycloalkyl or heteroaryl bound via a saturated or unsaturated, unbranched, substituted or unsubstituted C 1-2 -alkyl group, and in each case unsubstituted or singly or multiply substituted;
  • R 3 is selected from C 5-6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyridyl, pyrimidyl or pyrazinyl, in each case unsubstituted or singly or multiply substituted; C 5-6 -cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl bound via a saturated, unbranched, un
  • R 3 is selected from phenyl, furyl, thiophenyl, cyclohexanyl, naphthyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyridyl, pyrrolyl, pyrimidyl, pyrazinyl or benzothiophenyl, in each case unsubstituted or singly or multiply substituted; phenyl, furyl or thiophenyl bound via a saturated, unbranched C 1-2 -alkyl group and in each case unsubstituted or singly or multiply substituted.
  • R 4 is H.
  • R 4 is selected from H or C(O)R 7 ; preferably where R 7 is selected from
  • H or C 1-8 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted;
  • H or C 1-3 -alkyl that is saturated, unsubstituted, branched or unbranched;
  • R 4 and R 5 together form a heterocycle with between 3 and 8 atoms in the ring, which is saturated or unsaturated; singly or multiply substituted or unsubstituted, preferably with between 5 and 7 atoms in the ring, of which apart from the obligatory N, 0 to 1 further heteroatoms selected from N, S or O are in the ring;
  • heterocycle formed from R 4 and R 5 may optionally be condensed with further rings
  • the heterocycle formed from R 4 and R 5 is condensed with one or two further rings, preferably the heterocycle formed from R 4 and R 5 is condensed with two further rings in such a way that R 4 and R 5 together denote
  • R 4 is selected from H, C 1-8 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted,
  • H C 1-6 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted
  • H C 1-3 -alkyl that is saturated, unbranched and unsubstituted.
  • R 5 is selected from C 3-8 -cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted;
  • R 5 is selected from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[1,2,5]thiazolyl or 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxo
  • R 5 is selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, in each case unsubstituted or singly or multiply substituted.
  • R 5 is selected from —CHR 11 R 12 , —CHR 11 —CH 2 R 12 , —CHR 11 —CH 2 —CH 2 R 12 , —CHR 11 —CH 2 —CH 2 —CH 2 R 12 , —C(Y)R 12 , —C(Y)—CH 2 R 12 , —C(Y)—CH 2 —CH 2 R 12 or —C(Y)—CH 2 —CH 2 —CH 2 R 12
  • R 5 is selected from —CHR 11 R 12 , —CHR 11 —CH 2 R 12 , —CHR 11 —CH 2 —CH 2 R 12 , —C(Y)R 12 , —C(Y)—CH 2 R 12 or —C(Y)—CH 2 —CH 2 R 12
  • R 5 is selected from —CHR 11 R 12 , —CHR 11 —CH 2 R 12 , —CHR 11 —CH 2 —CH 2 R 12 , —C(Y)R 12 or —C(Y)—CH 2 R 12
  • R 11 is selected from
  • H C 1-4 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; or C(O)O—C 1-4 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted;
  • H C 1-4 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; or C(O)O—C 1-2 -alkyl that is saturated, unbranched, singly or multiply substituted or unsubstituted;
  • R 12 is selected from C 3-8 -cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted;
  • R 12 is selected from cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl or benzo[1,2,5]thiazolyl or 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxo
  • R 12 is selected from cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl or pyrimidyl, in each case unsubstituted or singly or multiply substituted.
  • [0224] optionally also in the form of their racemates, in the form of the aforementioned or other pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular enantiomers or diastereomers, in an arbitrary mixture ratio; optionally also in the form of the acids or bases or in the form of other salts, in particular physiologically compatible salts, or salts of physiologically compatible acids or cations; or in the form of their solvates, in particular hydrates.
  • a substituted cyclohexane-1,4-diamine compound that is employed is present as pure diastereomer and/or enantiomer, as racemate or as a non-equimolar or equimolar mixture of the diastereomers and/or enantiomers.
  • Particularly suitable is the use of compounds that do not have an effect on the central nervous system, in particular those compounds that in a tail flick test in mice (according to Example 106) do not exhibit any analgesic effect at a dose of 10.0 mg/kg, although they have an affinity in the ⁇ molar to sub- ⁇ molar range for the ⁇ -opioid receptor.
  • Suitable compounds may include, for example, those cyclohexyl-1,4-diamine compounds in which both amino groups have basic properties and are thus protonated under physiological conditions, with the exception of ⁇ -aminobutyric acid ester compounds.
  • Suitable compounds also include, for example, those cyclohexyl-1,4-diamine compounds that are unesterified carboxylic acids or that have a free carboxyl group.
  • the invention also provides a process for the treatment, in particular in one of the aforementioned medical indications, of a non-human mammal or human that requires a treatment for diarrhea or irritable bowel diseases or a treatment with an immunotherapeutic agent or peripheral analgesic, in particular for the treatment of burn pains, pain in soft tissue inflammations, peripheral operation pain or pain in inflammatory joint diseases, in particular rheumatism, by administration of a therapeutically active dose of one of the aforementioned substituted cyclohexane-1,4-diamine compounds, or of an aforementioned medicament.
  • a) a cyclohexane-1,4-dione according to formula II and protected by the groups S 1 and S 2 is reacted in the presence of a compound of the formula HNR 01 R 02 with a cyanide, preferably potassium cyanide, to form a protected N-substituted 1-amino-4-oxocyclohexane carbonitrile compound according to formula III;
  • [0233] is then optionally acylated, alkylated or sulfonated in an arbitrary order and optionally repeatedly, and/or in the case of compounds where R 01 and/or R 02 and/or R 06 denotes H protected with a protective group, a protective group is cleaved at least once and optionally acylated, alkylated or sulfonated, and/or in the case of compounds where R 01 and/or R 02 and/or R 06 are H, a protective group is introduced at least once and optionally acylated, alkylated or sulfonated,
  • [0235] is then optionally acylated, alkylated or sulfonated in an arbitrary order and optionally repeatedly, and/or in the case of compounds where R 01 and/or R 02 and/or R 06 denotes H protected by a protective group, a protective group is split off at least once and optionally acylated, alkylated or sulfonated, and/or in the case of compounds where R 01 and/or R 02 and/or R 06 denote H, a protective group is introduced at least once and optionally acylated, alkylated or sulfonated,
  • [0239] is then optionally acylated, alkylated or sulfonated in an arbitrary order and optionally repeatedly, and/or in the case of compounds where R 01 and/or R 02 and/or R 04 and/or R 05 and/or R 06 denote H protected by a protective group, a protective group is cleaved at least once and the product is optionally acylated, alkylated or sulfonated, and/or in the case of compounds where R 01 and/or R 02 and/or R 04 and/or R 05 and/or R 06 denote H, a protective group is introduced at least once and optionally acylated, alkylated or sulfonated to form a compound according to formula I,
  • R 01 and R 02 independently of one another are selected from H; H provided with a protective group; C 1-8 -alkyl or C 3-8 -cycloalkyl, in each case saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case singly or multiply substituted or unsubstituted; or aryl, C 3-8 -cycloalkyl or heteroaryl bound via C 1-3 -alkylene, in each case singly or multiply substituted or unsubstituted;
  • R 01 and R 02 together form a ring and denote CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 06 CH 2 CH 2 or (CH 2 ) 3-6 ,
  • R 06 is selected from H; H provided with a protective group; C 1-8 -alkyl or C 3-8 -cycloalkyl, in each case saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case singly or multiply substituted or unsubstituted; or aryl, C 3-8 -cycloalkyl or heteroaryl bound via C 1-3 -alkylene and in each case singly or multiply substituted or unsubstituted;
  • R 04 is selected from H, H provided with a protective group; C 1-8 -alkyl, saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted;
  • R 05 is selected from H, H provided with a protective group; C 3-8 -cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; —CHR 11 R 12 , —CHR 11 —CH 2 R 12 , —CHR 11 —CH 2 —R 12 , —CHR 11 —CH 2 —CH 2 —CH 2 R 12 , —C(Y)R 12 , —C(Y)—CH 2 R 12 , —C(Y)—CH 2 —CH 2 R 12 or —C(Y)—CH 2 —CH 2 —CH 2 R 12
  • R 11 is selected from
  • H C 1-7 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted;
  • R 12 is selected from
  • H C 3-8 -cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted,
  • R 04 and R 05 together form a heterocycle with between 3 and 8 atoms in the ring, which is saturated or unsaturated, singly or multiply substituted or unsubstituted,
  • S 1 and S 2 independently of one another are selected from protective groups or together denote a protective group, preferably monoacetal.
  • alkylation also denotes a reductive amination since it leads to the same result.
  • [0257] is then optionally acylated, alkylated or sulfonated in an arbitrary order and optionally repeatedly, and/or in the case of compounds where R 04 and/or R 05 denote H protected by a protective group, a protective group is cleaved at least once and optionally acylated, alkylated or sulfonated, and/or in the case of compounds where R 04 and/or R 05 denote H, a protective group is introduced at least once and optionally acylated, alkylated or sulfonated,
  • [0259] is then optionally acylated, alkylated or sulfonated in an arbitrary order and optionally repeatedly, and/or in the case of compounds where R 01 and/or R 02 and/or R 04 and/or R 05 and/or R 06 denote H protected by a protective group, a protective group is cleaved at least once and optionally acylated, alkylated or sulfonated and/or in the case of compounds where R 01 and/or R 02 and/or R 04 and/or R 05 and/or R 06 denote H, a protective group is introduced at least once and optionally acylated, alkylated or sulfonated,
  • [0261] is then optionally acylated, alkylated or sulfonated in an arbitrary order and optionally repeatedly, and/or in the case of compounds where R 01 and/or R 02 and/or R 04 and/or R 05 and/or R 06 denote H protected by a protective group, a protective group is cleaved at least once and optionally acylated, alkylated or sulfonated, and/or in the case of compounds where R 01 and/or R 02 and/or R 04 and/or R 05 and/or R 06 denote H, a protective group is introduced at least once and optionally acylated, alkylated or sulfonated until a compound according to formula I is formed,
  • R 01 and R 02 independently of one another are selected from H; H provided with a protective group; C 1-8 -alkyl or C 1-8 -cycloalkyl, in each case saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case singly or multiply substituted or unsubstituted; or aryl, C 3-8 -cycloalkyl or heteroaryl bound via C 1-3 -alkylene, in each case singly or multiply substituted or unsubstituted;
  • R 01 and R 02 together form a ring and denote CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 06 CH 2 CH 2 or (CH 2 ) 3-6 ,
  • R 06 is selected from H; H provided with a protected group; C 1-8 -alkyl or C 3-8 -cycloalkyl, in each case saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl or heteroaryl, in each case singly or multiply substituted or unsubstituted; or aryl, C 3-8 -cycloalkyl or heteroaryl bound via C 1-3 -alkylene, in each case singly or multiply substituted or unsubstituted;
  • R 04 is selected from H, H provided with a protective group; C 1-8 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted;
  • R 05 is selected from H provided with a protective group; C 3-8 -cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; —CHR 11 R 12 , —CHR 11 —CH 12 R 12 , —CHR 11 —CH 2 —CH 2 R 12 , —CHR 11 —CH 2 —CH 2 —CH 2 R 12 , —C(Y)R 12 , —C(Y)—CH 2 R 12 , —C(Y)—CH 2 —CH 2 R 12 or —C(Y)—CH 2 —CH 2 —CH 2 R 12
  • R 11 is selected from
  • H C 1-7 -alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted;
  • R 12 is selected from
  • H C 3-8 -cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted,
  • R 04 and R 05 together form a heterocycle with between 3 and 8 atoms in the ring that is saturated or unsaturated; singly or multiply substituted or unsubstituted,
  • S 1 and S 2 independently of one another are selected from protective groups or together denote a protective group, preferably monoacetal.
  • the protective groups at H in the case of R 01 , R 02 , R 04 , R 05 and/or R 06 are selected from alkyl, benzyl or carbamates, for example FMOC, Z or Boc.
  • step d. takes place in the presence of ammonium formate, ammonium acetate or NaCNBH 3 .
  • a particularly advantageous modification is also if, instead of the reductive amination with HNR 04 R 05 in step d), the compound IV is reacted with hydroxylamine and is reduced after oxime formation.
  • step b) the radical R 01 in the formula HNR 01 R 02 denotes H, the reaction with the cyanide is carried out with TMSCN, and a protective group is then optionally introduced at R 01 .
  • ether denotes diethyl ether
  • EE denotes ethyl acetate
  • DCM dichloromethane
  • Equivalent denotes quantitative equivalent
  • m.p.” denotes melting point or melting point range
  • RT room temperature
  • vol. % denotes volume percent
  • m % denotes weight percent
  • M denotes the concentration in mole/l.
  • aqueous phase was extracted twice with 250 ml of ether each time, the extracts were combined with the organic phase, washed with 200 ml of water followed by 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation. 60.0 g of dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)-amine were obtained.
  • aqueous phase was extracted twice with 250 ml of ether each time, and the extracts were combined with the organic phase, washed with 200 ml of water followed by 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation. 78.4 g of crude product were obtained, which consisted mainly of (8-benzyl-1,4-dioxa-spiro[4.5]dec-8-yl)-dimethylamine and was converted further without additional purification.
  • reaction mixture was worked up by adding 12 ml of 5 M KOH solution and 12 ml of water, stirred for 10 minutes, extracted three times with 25 ml of dichloromethane each time, and the combined extracts were dried over magnesium sulfate, filtered and concentrated by evaporation.
  • 1.01 g of the non-polar diastereomer of N-(4-benzyl-4-dimethylamino-cyclohexyl)-N-propylbenzamide hydrochloride were prepared from the obtained product (1.31 g) as described for Example 1, using water and chlorotrimethylsilane in 2-butanone.
  • reaction mixture was worked up by adding 12 ml of 5 M KOH solution and 12 ml of water, stirred for 10 minutes, extracted three times with 25 ml of dichloromethane each time, and the combined extracts were dried over magnesium sulfate, filtered and concentrated by evaporation.
  • 752 mg of the polar diastereomer of N-(4-benzyl-4-dimethylamino-cyclohexyl)-N-propylbenzamide hydrochloride were prepared as described for Example 1 using water and chlorotrimethyl-silane in 2-butanone.
  • the reaction mixture was worked up by adding 50 ml of 5 M KOH solution and 50 ml of water, stirred for 10 minutes, extracted three times with 50 ml of dichloromethane each time, and the combined extracts were dried over magnesium sulfate, filtered, and concentrated by evaporation.
  • the crude product obtained (4.05 g) was chromatographed on silica gel with methanol/ether (1:1). 1.09 g of the polar diastereomer of N-(4-benzyl-4-dimethylaminocyclohexyl)-N-ethylbenzamide were obtained, from which 1.01 mg of the corresponding hydrochloride were prepared as described for Example 1 using water and chlorotrimethylsilane in 2-butanone.
  • the oxime obtained was suction filtered, washed with water (3 ⁇ 25 ml) and dried in a desiccator. 15.6 g of 1H-indole-3-carbaldehyde-(Z)-oxime with a melting point of 190°-193° C. were obtained.
  • Example 19 The mother liquor obtained in Example 19 was concentrated by evaporation. 173 mg of the non-polar diastereomer of N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained (m.p. 170°-178° C.).
  • DL- ⁇ -methyltryptamine (348 mg, 2 mmole) was dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 4-dimethylamino-4-phenylcyclohexanone (435 mg) and glacial acetic acid (229 ⁇ l) the mixture was stirred for 1 hour at RT. Sodium triacetoxy boron hydride (550 mg) was then added and the suspension was stirred for 4 days at RT. For working-up water (15 ml) was added to the reaction mixture. The clear phases were separated and the aqueous phase was washed with ether (10 ml) and then made strongly alkaline with sodium hydroxide.
  • the phases were separated and the aqueous phase was washed with ether (20 ml) and then made strongly alkaline with sodium hydroxide.
  • the aqueous phase was extracted with ether (2 ⁇ 10 ml) and ethyl acetate (4 ⁇ 10 ml), and the combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation.
  • the crude product obtained (686 mg) was recrystallised from a mixture of ethyl acetate/cyclohexane (35 ml/5 ml).
  • the aqueous phase was extracted with ether (2 ⁇ 5 ml) and ethyl acetate (4 ⁇ 10 ml), and the combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation.
  • the crude product obtained was chromatographed on silica gel with methanol/triethylamine (100:1). 52 mg of N,N-dimethyl-N′-(1-methyl-1H-indol-3-ylmethyl)-1-phenylcyclohexane-1,4-diamine were obtained as a cis/trans mixture.
  • Lithium aluminium hydride (1.16 g, 30.3 mmole) was suspended in dry diethyl ether (100 ml). Anhydrous aluminium chloride (4.04 g, 30.3 mmole) was added under argon to this suspension. After 5 minutes a solution of benzo[b]thiophene-3-acetonitrile (5.25 g, 30.3 mmole) in dry diethyl ether (70 ml) was added. After completion of the addition the mixture was heated for 4 days under reflux. Further lithium aluminium hydride (930 mg) and aluminium chloride (500 mg) were added to the reaction mixture and the whole was heated under reflux for a further 8 hours.
  • the reaction mixture was neutralised with an aqueous solution of potassium/sodium tartrate (80 ml, 20 m %). After the end of the evolution of gas the phases were separated and the turbid aqueous phase was suction filtered through a glass frit. The residue on the frit was washed with ethyl acetate and the clear aqueous phase was extracted with ethyl acetate (3 ⁇ 50 ml). The organic phases were dried over sodium sulfate, filtered and concentrated by evaporation. Crude benzo[b]thiophen-3-yl-ethylamine (3.7 g) was obtained as a reddish-brown oil.
  • the reaction mixture was diluted with 1,2-dichloroethane (10 ml) and water (15 ml). The remaining precipitate was suction filtered (379 mg, m.p. 225°-233° C.). 353 mg of a yellow oil were obtained by extracting the aqueous phase adjusted to pH 11 with 5 M sodium hydroxide with ethyl acetate.
  • the crude product (438 mg, viscous oil) was isolated from both partial amounts by redissolving in dilute hydrochloric acid, extraction with diethyl ether (2 ⁇ 15 ml) followed by adjusting the aqueous phase to pH 11 with 5 M molar sodium hydroxide as well as extraction with ethyl acetate (3 ⁇ 20 ml).
  • the pale yellow solid that was obtained was a mixture of cis- and trans-N′-(2-benzo[b]thiophen-3-yl-ethyl)-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride (338 mg, m.p. 225°-229° C.).
  • Example 36 250 mg of the non-polar diastereomer of N′-acenaphthen-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were also obtained as a white solid, from which the corresponding dihydrochloride was precipitated with 1.85 M ethanolic hydrochloric acid (0.9 ml) in 2-butanone (10 ml) 300 mg; (m.p. 190°-192° C.).
  • DL- ⁇ -methyltryptamine (3.00 g, 17.2 mmole) was dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 4-dimethylamino-4-phenylcyclohexanone (3.70 g) and glacial acetic acid (1.5 ml) the mixture was stirred for 1 hour at RT. Sodium triacetoxy boron hydride (4.7 g) was then added and the suspension was stirred for 4 days at RT. For working-up 1,2-dichloroethane (20 ml) and water (50 ml) were added to the reaction mixture.
  • the clear phases were separated, and the aqueous phase was washed with ether (2 ⁇ 20 ml) and then made strongly alkaline with 5 M sodium hydroxide.
  • the aqueous phase was extracted with ethyl acetate (5 ⁇ 30 ml) and the combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation.
  • the crude product obtained (5.8 g of beige-brown solid) was first of all coarsely fractionated on silica gel with methanol/triethylamine (199:1) and was then once more finely purified.
  • Example 45 122 mg of the polar diastereomer of N′-(3H-benzotriazol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were also obtained as a white solid, from which the corresponding dihydrochloride was precipitated with 1.85 M ethanolic hydrochloric acid (0.5 ml) in 2-butanone (5 ml) (119 mg; m.p. 185°-189° C.).
  • Benzothiophene-3-carbaldehyde (4.0 g, 24.6 mmole) was dissolved in a mixture of pyridine (25 ml) and ethanol (25 ml). Hydroxylamine hydrochloride (3.4 g, 49.2 mmole) was added while stirring. The mixture was stirred for 30 minutes at RT and then heated under reflux for 8 hours. A reddish-brown solution was formed. For working-up the solution was concentration by evaporation and the residue was freed from remaining pyridine by distillation with ethanol (3 ⁇ 50 ml). Water (50 ml) was added to the oily residue and stirred vigorously overnight. The pink solid that was present was suction filtered, washed with water and dried in vacuo. 4.3 g of benzothiophene-3-carbaldehyde oxime were obtained (m.p. 87°-89° C.).
  • Benzothiophene-3-carbaldehyde oxime (3.96 g, 22.3 mmole) was dissolved in methanol (100 ml) and 5 M sodium hydroxide (100 ml) and Devarda's alloy (14.1 g) was added in portions under argon. This resulted in a heating of the solution and evolution of hydrogen. The solution was stirred for 16 hours. The solution was worked up by slowly adding water (100 ml), a vigorous reaction then occurring once more. The mixture was filtered through celite, the methanol was removed in vacuo and the remaining aqueous phase was extracted with diethyl ether (3 ⁇ 50 ml).
  • Example 51 As described for Example 51, the methanolic solution of the crude product was chromatographed on silica gel with methanol. 113 mg of the polar diastereomer of N′-benzo[b]thiophen-3-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a colourless oil, from which the corresponding dihydrochloride was precipitated as a white solid with 3.3 M ethanolic hydrochloric acid (0.28 ml) in 2-butanone (10 ml) (120 mg; m.p. 252°-254° C.).
  • the aqueous phase was adjusted to pH 8-9 with 1 M sodium hydroxide and extracted with ether (3 ⁇ 20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The pale yellow oil that was obtained (904 mg) was chromatographed on silica gel with methanol.
  • a Grignard solution was prepared from magnesium (2.05 g) and 2-bromonaphthalene (17.7 g) in dry tetrahydrofuran (65 ml). This Grignard solution was stirred for 1 hour at the boiling point. 8-dimethylamino-1,4-dioxaspiro[4.5]-decane-8-carbonitrile (9.0 g) dissolved in dry tetrahydrofuran (70 ml) was then added dropwise at RT and stirred overnight at RT.
  • 6-fluorotryptamine (410 mg) and 4-dimethylamino-4-phenylcyclohexanone (545 mg) were dissolved in THF (18 ml) and 1,2-dichloroethane (6 ml) under argon and glacial acetic acid (138 mg) was added. After 15 minutes sodium triacetoxy boron hydride (600 mg) and THF (5 ml) were added. After 40 hours the reaction mixture was concentrated by evaporation and the residue was taken up in 1 M hydrochloric acid (20 ml) and extracted with ether (2 ⁇ 20 ml). The aqueous phase was adjusted alkaline with 1 M sodium hydroxide (30 ml) and extracted with ether (3 ⁇ 30 ml).
  • the white solid was a mixture of the two diastereomers, which also occurred when concentrating by evaporation the ethereal phase.
  • the mixtures (985 mg) were separated jointly by column chromatography with methanol/conc. ammonia (500:1).
  • the non-polar diastereomer was obtained as a white solid (321 mg, m.p. 185°-187° C.), dissolved in ethanol (20 ml) by heating, following which 3.3 N ethanolic HCl (0.79 ml) was added.
  • N- ⁇ -methyltryptamine [2-(1H-indol-3-yl)-ethyl]methylamine, 348 mg
  • 4-dimethylamino-4-phenylcyclohexanone (435 mg)
  • glacial acetic acid 114 ⁇ l
  • a voluminous precipitate formed.
  • the suspension was stirred for 2 hours at RT before adding sodium triacetoxy boron hydride (660 mg).
  • the reaction mixture was stirred for 2 days at RT, worked up by concentration by evaporation, the residue was dissolved in water (15 ml) and diethyl ether (20 ml) and the organic phase was separated.
  • the aqueous phase was extracted with diethyl ether (2 ⁇ 10 ml) and adjusted to pH 10 with 1 M NaOH.
  • the aqueous phase was adjusted to pH 11 with 1 M NaOH and extracted with ethyl acetate (4 ⁇ 25 ml).
  • the reaction mixture was concentrated by evaporation, 1 M HCl (20 ml) and diethyl ether (40 ml) were added thereto, and the acidic aqueous phase was extracted with diethyl ether (2 ⁇ 20 ml) and adjusted to pH 11 with 5 M NaOH.
  • the alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (3 ⁇ 20 ml). The combined extracts were dried over sodium sulfate, concentrated by evaporation and the crude product obtained was separated on silica gel with EtOH/NH 3 (500:1).
  • the non-polar diastereomer was obtained as a brown oil (321 mg), dissolved in 2-butanone (10 ml) and converted into the dichloride with chlorotrimethyl-silane (270 ⁇ l) (white solid; 420 mg; m.p. 189°-191° C.).
  • Example 68 As described for Example 68, 144 mg of the polar diastereomer were also obtained as a brown oil, dissolved in 2-butanone (5 ml) and converted into the corresponding hydrochloride with chlorotrimethylsilane (121 ⁇ l) (white solid; 146 mg; m.p. 244°-246° C.).
  • the polar diastereomer was also obtained (189 mg; m.p. 200°-201° C.), 159 mg of which were dissolved in ethanol (15 ml) and 2-butanone (5 ml) and converted into the dihydrochloride with 3.3 N ethanolic hydrochloride (0.38 ml) (124 mg; m.p. 262°-265° C.).
  • DL- ⁇ -methyltryptamine N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine, 348 mg
  • DL- ⁇ -methyltryptamine N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine, 348 mg
  • dry 1,2-dichloroethane 20 ml
  • 4-dimethylamino-4-thiophen-2-yl-cyclohexanone 447 mg
  • glacial acetic acid 114 ⁇ l
  • the reaction mixture was concentrated by evaporation, the residue was dissolved in water (15 ml), 2 M HCl (2 ml) and diethyl ether (20 ml), the organic phase was separated, and the aqueous phase was washed with diethyl ether (2 ⁇ 15 ml), adjusted to pH 11 with 1 M NaOH and extracted with ethyl acetate (4 ⁇ 10 ml). The combined ethyl acetate extracts were dried, concentrated by evaporation and the residue obtained (351 mg) was purified by flash chromatography (45 g silica gel 60, eluent: MeOH/NEt 3 (99:1)).
  • the non-polar diastereomer (188 mg) was dissolved hot in 2-butanone/acetone (6 ml/6 ml) and converted into the corresponding dihydrochloride with chlorotrimethylsilane (147 ⁇ l) (white solid, 176 mg; m.p. 162°-166° C.).
  • the aqueous solution was then adjusted alkaline with 1 M NaOH (28 ml) and extracted with Et 2 O (3 ⁇ 30 ml). The combined organic extracts were dried over sodium sulfate and concentrated by evaporation.
  • the oily residue (586 mg) was purified chromatographically with methanol/ammonia (500:1).
  • the non-polar product was a colourless oil (280 mg) and was dissolved in 2-butanone (20 ml) and converted into the corresponding dihydrochloride with 3.3 N ethanolic hydrochloric acid (0.76 ml) (white solid; 273 mg; m.p. 205°-207° C.).
  • the aqueous phase was adjusted alkaline with 5 M sodium hydroxide and extracted with diethyl ether (3 ⁇ 30 ml). After concentrating by evaporation the combined organic extracts the crude product obtained was separated chromatographically with methanol.
  • the non-polar diastereomer (286 mg) was dissolved in 2-butanone (15 ml) and converted into the corresponding dihydrochloride with 3.3 N ethanolic hydrochloric acid (0.606 ml) (white solid; 300 mg; m.p. 266°).
  • Serotonin (405 mg) was dissolved in 1,2-dichloroethane/THF (5 ml/20 ml), followed by the addition of 4-dimethylamino-4-phenylcyclohexanone (500 mg), glacial acetic acid (131 ⁇ l) and fused sodium sulfate (2 g). After stirring for 1 hour at RT sodium triacetoxy boron hydride (759 mg) was added and the mixture was stirred for a further 2 days.
  • the reaction mixture was concentrated by evaporation, the residue was suspended in diethyl ether (15 ml), water (10 ml) and 2 M HCl (1 ml), further diethyl ether (20 ml) was added, and the organic phase was coarsely separated.
  • the aqueous phase was first of all adjusted to pH 9 with 1 M NaOH and extracted with ethyl acetate (3 ⁇ 5 ml), and then adjusted to pH 11 and re-extracted with ethyl acetate (5 ⁇ 10 ml).
  • the organic extracts were dried, concentrated by evaporation and purified by flash chromatography (eluent: MeOH/NEt 3 (99.5:0.5)).
  • Example 78 As described for Example 78, 124 mg of the polar diastereomer were also obtained (m.p. 185°-187° C.), dissolved in ethanol/2-butanone (6 ml/15 ml) and converted into the corresponding dihydrochloride with 3.3 N ethanolic HCl (298 ⁇ l) (white solid; 123 mg; m.p. 230°-233° C.).
  • 6-methoxytryptamine (495 mg) was dissolved in dry 1,2-dichloroethane and THF (5 ml/15 ml) under argon to form a clear solution. After addition of 4-dimethylamino-4-phenylcyclohexanone (565 mg) and glacial acetic acid (148 ⁇ l) the mixture was stirred for 2 hours at RT, before adding sodium triacetoxy boron hydride (858 mg). The reaction mixture was stirred for 2 days at RT. For working-up water (15 ml) and 5.5 M HCl (1.5 ml) were added to the reaction mixture.
  • Example 80 As described for Example 80, the polar diastereomer (320 mg; m.p. 136°-140° C.) was also obtained, dissolved in 2-butanone/acetone (15 ml/3 ml) and converted into the corresponding dihydrochloride with chlorotrimethylsilane (310 ⁇ l) (white solid; 362 mg; m.p. 206°-210° C.).
  • 5-methyltryptamine (348 mg) and 4-dimethylamino-4-phenylcyclohexanone (435 mg) were dissolved in dry 1,2-dichloroethane (5 ml) and tetrahydrofuran (15 ml) with the exclusion of oxygen.
  • Glacial acetic acid (114 ⁇ l) and sodium triacetoxy boron hydride (600 mg) were added to this mixture and the whole was stirred for 24 hours at RT.
  • the reaction mixture was concentrated by evaporation, the residue was taken up in 1 M HCl (20 ml) and diethyl ether (40 ml), the phases were separated, and the aqueous phase was extracted with diethyl ether (2 ⁇ 20 ml) and adjusted to pH 11 with 5 M NaOH.
  • the aqueous phase was diluted with water (10 ml) and extracted with ethyl acetate (3 ⁇ 20 ml).
  • the combined organic extracts were dried over sodium sulfate and concentrated by evaporation.
  • the residue was purified by chromatography with MeOH/NH 3 (500:1).
  • the non-polar diastereomer (brown oil, 379 mg) was dissolved in 2-butanone (10 ml) and converted into the corresponding dihydrochloride by the addition of chlorotrimethylsilane (319 ⁇ l) (white solid; 405 mg; m.p. 234°-236° C.).
  • reaction mixture was concentrated by evaporation followed by the addition of 1 M HCl (20 ml) and diethyl ether (40 ml), the phases were separated, and the aqueous phase was extracted with diethyl ether (2 ⁇ 20 ml) and adjusted to pH 11 with 5 N NaOH.
  • the aqueous phase was diluted with water (10 ml) and extracted with ethyl acetate (3 ⁇ 20 ml).
  • the combined organic extracts were dried over sodium sulfate, concentrated by evaporation, and the residue was purified by chromatography on silica gel with methanol.
  • the non-polar diastereomer (531 mg, 1.55 mmole) was dissolved in anhydrous pyridine (10 ml) and acetic anhydride (1.59 g, 15.59 mmole) was added while stirring. After 24 hours some ice cubes were added to the reaction mixture and the latter was concentrated as far as possible on a rotary evaporator. 1 M NaOH (20 ml) was added to the residue. The aqueous phase was extracted with ethyl acetate (3 ⁇ 30 ml) and the combined organic extracts were dried over sodium sulfate and concentrated by evaporation.
  • the acetamide obtained (545 mg) was dissolved in 2-butanone (10 ml) and converted into the corresponding hydrochloride with chlorotrimethylsilane (0.270 ml) (white solid; 302 mg; m.p. 196°-201° C.).
  • the reaction mixture was concentrated by evaporation, the residue was taken up in ethyl acetate (40 ml) and 1 M NaOH (35 ml), the phases were separated and the aqueous phase was extracted three times with ethyl acetate (10 ml each time). The combined extracts were dried, concentrated by evaporation, and the residue obtained (1.73 g) was purified by flash chromatography (eluent: MeOH/EtOAc 1:3). The non-polar diastereomer obtained (911 mg, m.p.
  • the aqueous phase was washed with diethyl ether (2 ⁇ 20 ml), separated, adjusted to pH 11 with 5 N NaOH, diluted with water (10 ml) and extracted with ethyl acetate (3 ⁇ 20 ml). The combined organic extracts were dried over sodium sulfate and concentrated by evaporation.
  • the crude product obtained was purified by chromatography on silica gel with methanol. 761 g of the non-polar diastereomer were obtained. 453 mg were dissolved in anhydrous pyridine (10 ml) and acetic anhydride (1.374 g) was added while stirring.
  • N-methylmorpholine (235 ⁇ l, 2.1 mmole) and 2-chloro-4,6-dimethoxyl-1,3,5-triazine (371 mg, 2.11 mmole) were added to a solution of indol-3-ylacetic acid (257 mg) in absolute THF (10 ml). The mixture was then stirred for 1 hour at RT. Following this the polar diastereomer of N,N-dimethyl-1-phenylcyclohexane-1,4-diamine (320 mg) was added to the mixture and stirred for 12 hours at RT.
  • the mixture was concentrated by evaporation, adjusted to pH 11 with 5 M NaOH, the phases were separated and the aqueous phase was diluted with water (10 ml) and extracted with ethyl acetate (3 ⁇ 20 ml). The combined organic extracts were dried over sodium sulfate and concentrated by evaporation.
  • the amide obtained was purified by column chromatography with ethyl acetate/ethanol (1:1) and dissolved (120 mg) in 2-butanone (3 ml) and converted into the corresponding hydrochloride with chlorotrimethylsilane (61 ⁇ l) (white solid; 128 mg; m.p. 100°-102° C.).
  • aqueous phase was extracted twice with 250 ml of ether each time, the extracts were combined with the organic phase, washed with 200 ml of water followed by 200 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated by evaporation. 60.0 g of dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)amine were obtained.
  • L-tryptophan methyl ester hydrochloride (509 mg) was suspended in 1,2-dichloroethane (10 ml) and vigorously stirred for 2 minutes with concentrated aqueous ammonia solution (10 ml). The phases were separated and the aqueous phase was extracted with 1,2-dichloroethane (2 ⁇ 10 ml). The combined extracts were dried over sodium sulfate and concentrated to about 20 ml by evaporation on a rotary evaporator.
  • rac-5-fluorotryptophan methyl ester hydrochloride (1.12 g) was suspended in 1,2-dichloroethane (30 ml) and stirred vigorously for 5 minutes with concentrated aqueous ammonia solution (30 ml). The phases were then separated in a separating funnel. The aqueous solution was extracted twice with 1,2-dichloroethane (15 ml each time). The combined extracts were dried over sodium sulfate, the solvent volume was reduced to about 40 ml on a rotary evaporator, and the solution of rac-5-fluorotryptophan methyl ester that was obtained was used for the reductive amination described hereinafter.
  • rac-6-fluorotryptophan methyl ester hydrochloride (1.1 g) was suspended in 1,2-dichloroethane (30 ml) and stirred vigorously for 5 minutes with concentrated aqueous ammonia solution (20 ml). The phases were then separated in a separating funnel. The aqueous solution was extracted twice with 1,2-dichloroethane (15 ml each time). The combined extracts were dried over sodium sulfate and the solvent volume was reduced to about 30 ml on a rotary evaporator. The solution of the rac-6-fluorotryptophan methyl ester obtained was used for the reductive amination.
  • Glacial acetic acid 0.295 ml
  • sodium sulfate (2 g) were added to the clear solution.
  • NaBH(OAc) 3 (1.6 g) was added to the reaction mixture and stirred for 2 days at room temperature.
  • Saturated NaHCO 3 solution 60 ml was added to the mixture and stirred for 15 minutes.
  • the aqueous phase was extracted with dichloromethane (2 ⁇ 40 ml). The combined organic phases were then dried and concentrated by evaporation, a pale brown oil being obtained. Chromatographic separation of the substance mixture on silica gel was carried out with ethyl acetate/cyclohexane (2:1).
  • Glacial acetic acid (0.23 ml) and sodium sulfate (2 g) were added to the clear solution. After a reaction time of 15 minutes NaBH(OAc) 3 (1.2 g) was added to the reaction mixture and stirred for 2 days at room temperature. For working-up saturated NaHCO 3 solution (40 ml) was added to the mixture and stirred for 15 minutes. The aqueous phase was extracted with dichloromethane (2 ⁇ 20 ml). The combined organic phases were dried and then concentrated by evaporation, an oil being obtained. Chromatographic separation of the substance mixture on silica gel was carried out with ethyl acetate/methanol (15:1) and carried out once more with chloroform/methanol (20:1).
  • N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexane-1,4-diamine 250 mg was dissolved in dry pyridine (5 ml), acetic anhydride (0.64 ml) was added and the mixture was stirred for 22 hours at room temperature. Some ice was added to the reaction mixture, which was then concentrated by evaporation. The residue was taken up in 1 M sodium hydroxide (20 ml) and ethyl acetate (20 ml) and stirred. A white solid remained, which could be suction filtered (86 mg).
  • mice were in each case placed individually in a test cage and the base of the tail was exposed to the focussed radiant heat from an electric lamp (tail flick type 50/08/1.bc, Labtec, Dr. Hess). The lamp intensity was adjusted so that the time from switching on the lamp up to the sudden withdrawal movement of the tail (pain latency) was 3 to 5 seconds in untreated mice. Before the i.v. administration of the solutions containing the compound according to the invention or the respective comparison solutions, the mice were pretested twice within 5 minutes and the mean value of these measurements was calculated as a pre-test mean value.
  • an electric lamp tail flick type 50/08/1.bc, Labtec, Dr. Hess
  • the time T 0 is the latency time before the application
  • the time T 1 is the latency time after the application of the active substances combination
  • the time T 2 is the maximum exposure time (12 seconds).
  • the ED 50 was determined from several concentration-dependent measurements. A more detailed investigation of the analgesic effectiveness was carried out in the tail flick test on mice, as described above.
  • mice were investigated in the standard model of PGE 2 -induced diarrhea. It was found that with an i.v.-applied dose of 10 mg/kg (nearly) all animals exhibited a marked diarrhea suppression: TABLE 3 Example Diarrhea Suppression No. 10 mg/kg i.v. 94 10/10 95 10/10 96 9/10 97 10/10 98 10/10 99 10/10 100 10/10 101 10/10 102 10/10 103 10/10
  • the ED 50 value was determined from several concentration-dependent measurements.
  • the substance loperamide is a peripheral opioid—acknowledged not to have any peripheral side effects—which is used as an antidiarrhetic.
  • Example 95 Loperamide Analgesia, tail flick ineffective up ED 50 > 0.562 test in mice, i.v. to 31.6 toxic from 0.464
  • the PGE 2 diarrhea test as well as the carbon passage are known standard test systems for diarrhea.
  • the ED 50 was determined from several concentration-dependent measurements. Administration was performed both i.v. as well as p.o.
  • Example 95 shows many advantages compared to loperamide. On the one hand Example 95 is completely ineffective on the central nervous system, in contrast to loperamide, which always has a measurable action on the central nervous system; this means that significantly fewer side effects can be expected with Example 95 than with loperamide. Example 95 turns out to be just as good or better than loperamide in the PGE 2 diarrhea test, which is also confirmed by the carbon passage measurement.

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US8946296B2 (en) 2009-10-09 2015-02-03 Oryzon Genomics S.A. Substituted heteroaryl- and aryl-cyclopropylamine acetamides and their use
US9186337B2 (en) 2010-02-24 2015-11-17 Oryzon Genomics S.A. Lysine demethylase inhibitors for diseases and disorders associated with Hepadnaviridae
US9616058B2 (en) 2010-02-24 2017-04-11 Oryzon Genomics, S.A. Potent selective LSD1 inhibitors and dual LSD1/MAO-B inhibitors for antiviral use
US10202330B2 (en) 2010-04-19 2019-02-12 Oryzon Genomics, Sa Lysine specific demethylase-1 inhibitors and their use
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US8722743B2 (en) 2010-04-19 2014-05-13 Oryzon Genomics S.A. Lysine specific demethylase-1 inhibitors and their use
US9181198B2 (en) 2010-07-29 2015-11-10 Oryzon Genomics S.A. Arylcyclopropylamine based demethylase inhibitors of LSD1 and their medical use
US10233178B2 (en) 2010-07-29 2019-03-19 Oryzon Genomics, S.A. Arylcyclopropylamine based demethylase inhibitors of LSD1 and their medical use
US9006449B2 (en) 2010-07-29 2015-04-14 Oryzon Genomics, S.A. Cyclopropylamine derivatives useful as LSD1 inhibitors
US9676701B2 (en) 2010-07-29 2017-06-13 Oryzon Genomics, S.A. Cyclopropylamine derivatives useful as LSD1 inhibitors
US9708309B2 (en) 2010-07-29 2017-07-18 Oryzon Genomics, S.A. Arylcyclopropylamine based demethylase inhibitors of LSD1 and their medical use
US9061966B2 (en) 2010-10-08 2015-06-23 Oryzon Genomics S.A. Cyclopropylamine inhibitors of oxidases
US9790196B2 (en) 2010-11-30 2017-10-17 Oryzon Genomics S.A. Lysine demethylase inhibitors for diseases and disorders associated with Flaviviridae
US9908859B2 (en) 2011-02-08 2018-03-06 Oryzon Genomics, S.A. Lysine demethylase inhibitors for myeloproliferative disorders
US9670136B2 (en) 2011-10-20 2017-06-06 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US9944601B2 (en) 2011-10-20 2018-04-17 Oryzon Genomics, S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US9487512B2 (en) 2011-10-20 2016-11-08 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US10214477B2 (en) 2011-10-20 2019-02-26 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US9469597B2 (en) 2011-10-20 2016-10-18 Oryzon Genomics S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors
US10329256B2 (en) 2011-10-20 2019-06-25 Oryzon Genomics, S.A. (Hetero)aryl cyclopropylamine compounds as LSD1 inhibitors

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