US20040229872A1

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

Info

Publication number: US20040229872A1
Application number: US10/704,524
Authority: US
Inventors: Elmar Friderichs; Bernd Sundermann; Claudia Hinze; Babette-Yvonne Koegel
Original assignee: Gruenenthal GmbH
Current assignee: Gruenenthal GmbH
Priority date: 2001-05-09
Filing date: 2003-11-10
Publication date: 2004-11-18
Also published as: NO328600B1; US7276518B2; MXPA03010201A; HUP0400888A2; ATE359260T1; KR20040017214A; NO20034930L; KR20040002943A; BR0209580A; AU2007202033B2; PE20021094A1; NO20034931L; IL158782A0; DE50209929D1; WO2002090317A1; EP1385493A1; DK1385825T3; HUP0400888A3; RU2003134145A; ES2284876T3

Abstract

The use of substituted cyclohexan-1,4-diamine compounds in pharmaceutical compositions and for the treatment of diarrhea or irritable bowel diseases or as immunotherapeutic agents or peripheral analgesics, especially for treating burn pains, peripheral operation pains, pains generated by inflammation of soft tissues or inflammatory arthropathies, especially rheumatisms.

Description

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of international patent application no. PCT/EP02/05122, filed May 9, 2002, designating the United States of America, and published in German as WO 02/089783, the entire disclosure of which is incorporated herein by reference. Priority is claimed based on Federal Republic of Germany patent application no. DE 101 23 163.6, filed May 9, 2001.[0001]

BACKGROUND OF THE INVENTION

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 μ-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”. μ-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. Progress in the use of opioids in the treatment of diarrhea was provided by the drug loperamide, in which the opioid properties affecting the central nervous system are absent and which therefore has no potential for addiction and dependence and which is no longer subject to legislation governing the use of narcotics. A decisive factor is that the action is transmitted peripherally and not via the central nervous system.

In addition to their use as antidiarrhea agents and in other gastrointestinal disorders substances with a high affinity for the μ-receptor may be used as peripherally active analgesics. According to recent investigations, in particular in the team led by Stein, it was found that, in addition to the opiate receptors in the central nervous system, opiate receptors in the periphery are also involved in suppressing pain. These 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.

In many in vitro and in vivo models μ-opioids exhibit immunomodulating properties. Generally an immunosuppressive effect is seen, which is transmitted via peripheral opioid systems and which could be used for therapeutic purposes.

SUMMARY OF THE INVENTION

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. In particular the compounds used for this purpose are peripherally active μ-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

wherein

R ¹and R²independently 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 R¹and R²may not both be H, or the radicals R¹and R²together form a ring and denote CH₂CH₂OCH₂CH₂, CH₂CH₂NR⁶CH₂CH₂or (CH₂)_3-6,

where R ⁶is 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 ³is 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 ⁴is selected from H, C_1-8-alkyl, saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted, or C(X)R⁷, C(X)NR⁷R⁸, C(X)OR⁹, C(X)SR⁹, S(O₂)R⁹

where X=O or S,

where R ⁷is 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;

where R ⁸is selected from H, C_1-4-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted, or

the radicals R ⁷and R⁸together form a ring and denote CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹⁰CH₂CH₂or (CH₂)_3-6,

where R ¹⁰is 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;

where R ⁹is 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 ⁵is selected from C_3-8-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹², —CHR¹¹—CH₂—CH₂—CH₂R¹², —C(Y)R¹², —C(Y)—CH₂R¹², —C(Y)—CH₂—CH₂R¹²or —C(Y)—CH₂—CH₂—CH₂R¹²

where Y=O, S or H ₂,

where R ¹¹is 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;

and where R ¹²is selected from

H; C _3-8-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted,

or R ⁴and R⁵together 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,

optionally in the form of their racemates, their pure stereoisomers, in particular enantiomers or diastereomers, or in the form of mixtures of the stereoisomers, in particular of the enantiomers or diastereomers, in an arbitrary mixture ratio;

in the prepared form or in the form of their acids or bases or in the form of their salts, in particular of the physiologically compatible salts, or salts of physiologically compatible acids or cations; or in the form of their solvates, in particular the hydrates; for the production of a medicament 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, pain in inflammation of soft tissues, peripheral operation pain or inflammatory joint diseases, in particular rheumatism.

The compounds used are outstanding peripherally active μ-agonists without any effect on the central nervous system.

Preferably 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.

Within the context of the present invention 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. In this connection 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-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9- or C10-alkyl and C_1-18-alkyl denotes C1-, C2-, C3-, C4-, C5-, C6-, C7-, C8-, C9-, C10-, C11-, C12-, C13-, C14-, C15-, C16-, C17- or C18-alkyl. Furthermore 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- or C7-cycloalkyl, C_5-6-cycloalkyl denotes C5- or C6-cycloalkyl and C_5-7-cycloalkyl denotes C5-, C6- or C7-cycloalkyl. With regard to cycloalkyl, the term also includes saturated cycloalkyls in which 1 or 2 carbon atoms are replaced by a heteroatom, i.e. S, N or O. The term 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. Preferably 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, CHF₂, CF₃or CH₂OH as well as pyrazolinone, oxopyrazolinone, [1,4]dioxane or dioxolane.

In connection with alkyl and cycloalkyl—unless specifically defined otherwise—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 CF₃, or at different positions as in the case of —CH(OH)—CH═CH—CHCl₂. Particularly preferred substituents in this connection are F, Cl and OH. With regard to cycloalkyl, 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, CF₃, methoxy or ethoxy.

The term (CH ₂)_3-6is understood to denote —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—, the term (CH₂)_1-4is understood to denote —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—, and (CH₂)_4-5is understood to denote —CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂—, 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. By way of example there may be mentioned from the group of heteroaryls, furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine, benzo[1,2,5]thiadiazole, benzothiazole, indole, benzotriazole, benzodioxolane, benzodioxane, carbazole, indole and quinazoline.

In connection with aryl and heteroaryl, the term substituted is understood to denote the substitution of the aryl or heteroaryl with R ²², OR²², a halogen, preferably F and/or Cl, a CF₃, a CN, an NO₂, an NR²³R²⁴, 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.

In this connection the radical R ²²denotes 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 ²³and R²⁴, 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,

or the radical R ²³and R²⁴together denote CH₂CH₂OCH₂CH₂, CH₂CH₂NR²⁵CH₂CH₂or (CH₂)_3-6, and

the radical R ²⁵denotes 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.

The term 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. In particular the term 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.

The term 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. In particular 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. Examples of 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-dihydro1λ 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, α-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid. The hydrochloride salt is particularly preferred.

The term 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. Examples of 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-dihydro1λ 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, α-lipoic acid, acetylglycine, acetylsalicylic acid, hippuric acid and/or aspartic acid.

The term 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.

The term 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. The choice of the 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. For oral application preparations in the form of tablets, sugar-coated pills, capsules, granules, droplets, juices and syrups are suitable, while 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. In principle other 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.

In the uses according to the invention it may be preferred if, in the compound according to formula I that is used, R ¹and R²are not both H.

Likewise and in addition it may be preferred if in formula I

R ¹and R²independently 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;

or the radicals R ¹and R²together form a ring and denote CH₂CH₂OCH₂CH₂, CH₂CH₂NR⁶CH₂CH₂or (CH₂)_3-6,

where R ⁶is selected from H; C_1-8-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted,

preferably

R ¹and R²independently 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;

or the radicals R ¹and R²together form a ring and denote (CH₂)_4-5;

in particular

R ¹and R²independently of one another are selected from methyl or ethyl or the radicals R¹and R²together form a ring and denote (CH₂)₅.

In one of the uses mentioned hereinbefore it may be preferred if in formula I

R ³is 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;

preferably

R ³is 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 C_1-2-alkyl group and in each case unsubstituted or singly or multiply substituted;

in particular

R ³is 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.

In one of the uses mentioned hereinbefore it may be preferred if in formula I R ⁴is H.

Likewise, in one of the uses mentioned hereinbefore it may be preferred if in formula I

R ⁴is selected from H, C(X)R⁷, C(X)NR⁷R⁸, C(X)OR⁹, C(X)SR⁹or S(O₂)R⁹where X=O or S,

preferably

R ⁴is selected from H, C(X)R⁷, C(X)NR⁷R⁸or C(X)OR⁹where X=O,

in particular

R ⁴is selected from H or C(O)R⁷; preferably where R⁷is selected from

H; or C _1-8-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted;

preferably

H; or C _1-3-alkyl that is saturated, unsubstituted, branched or unbranched;

in particular CH ₃.

In one of the uses mentioned hereinbefore it may be preferred if in formula I

R ⁴and R⁵together 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;

wherein the heterocycle formed from R ⁴and R⁵may optionally be condensed with further rings,

preferably with aromatic and/or heteroaromatic rings, wherein these may be condensed with further aromatic and/or heteroaromatic rings,

in particular the heterocycle formed from R ⁴and R⁵is condensed with one or two further rings, preferably the heterocycle formed from R⁴and R⁵is condensed with two further rings in such a way that R⁴and R⁵together denote

In one of the uses mentioned hereinbefore it may be preferred if in formula I

R ⁴is selected from H, C_1-8-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted,

preferably

H, C _1-6-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted,

in particular

H, C _1-3-alkyl that is saturated, unbranched and unsubstituted.

In one of the uses mentioned hereinbefore it may be preferred if in formula I

R ⁵is selected from C_3-8-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted;

preferably

R ⁵is 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, oxopyrazolinonyl, dioxolanyl, adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl, in each case unsubstituted or singly or multiply substituted;

in particular

R ⁵is 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 ⁵is selected from —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹², —CHR¹¹—CH₂—CH₂—CH₂R¹², —C(Y)R¹², —C(Y)—CH₂R¹², —C(Y)—CH₂—CH₂R¹²or —C(Y)—CH₂—CH₂—CH₂R¹²

where Y=O, S or H ₂,

preferably

R ⁵is selected from —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹², —C(Y)R¹², —C(Y)—CH₂R¹²or —C(Y)—CH₂—CH₂R¹²

where Y=O or S,

in particular

R ⁵is selected from —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹², —C(Y)R¹²or —C(Y)—CH₂R¹²

where Y=O.

With regard to the preceding embodiment it is preferred if in the substituted cyclohexane-1,4-diamine compounds according to formula I that are used

R ¹¹is 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;

preferably

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;

in particular

H, CH ₃, C₂H₅and C(O)O—CH₃;

and/or, if in the substituted cyclohexane-1,4-diamine compounds according to formula I that are used

R ¹²is selected from C_3-8-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted;

preferably

R ¹²is 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, oxopyrazolinonyl, dioxolanyl, adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl, in each case unsubstituted or singly or multiply substituted;

in particular

R ¹²is 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.

Furthermore it is particularly preferred to use according to the invention substituted cyclohexane-1,4-diamine compounds selected from the following group:

N′-benzyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer

N′-benzyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine hydrochloride, polar diastereomer

1,N′-dibenzyl-N,N-dimethylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer

1,N′-dibenzyl-N,N-dimethylcyclohexane-1,4-diamine hydrochloride, polar diastereomer

N-(4-benzyl-4-dimethylaminocyclohexyl)-N-propylbenzamide hydrochloride

N,N-dimethyl-1-phenyl-N′-propylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer

N-(4-dimethylamino-4-phenylcyclohexyl)-N-propylbenzamide hydrochloride, non-polar diastereomer

N-(4-dimethylamino-4-phenylcyclohexyl)-N-propylbenzamide hydrochloride, polar diastereomer

1,N′-dibenzyl-N,N,N′-trimethylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer

1,N′-dibenzyl-N,N,N′-trimethylcyclohexane-1,4-diamine hydrochloride, polar diastereomer

N-(4-benzyl-4-dimethylaminocyclohexyl)-N-methylbenzamide hydrochloride, polar diastereomer

N-(4-benzyl-4-dimethylaminocyclohexyl)-N-ethylbenzamide hydrochloride, polar diastereomer

1-benzyl-N′-(1H-indol-3-ylmethyl)-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride

1-benzyl-N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethylcyclohexane-1,4-diamine, cis/trans mixture

1-benzyl-N′-indan-5-yl-N,N-dimethylcyclohexane-1,4-diamine hydrochloride

1-benzyl-N′-indan-1-yl-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride, cis/trans mixture

N′-indan-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine

N′-(1H-indol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine

N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, cis/trans mixture

N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, non-polar diastereomer

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, non-polar diastereomer

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, cis/trans mixture

N′-indan-5-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, non-polar diastereomer

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, non-polar diastereomer

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, cis/trans mixture

N′-[2-(5-benzyloxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, cis/trans mixture

N′-(9H-fluoren-1-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride

N′-indan-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, cis/trans mixture

N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, cis/trans mixture

1-benzyl-N′-(9H-f fluoren-9-yl)-N,N-dimethylcyclohexane-1,4-diamine

1-benzyl-N′-(1H-indol-3-ylmethyl)-N,N-dimethylcyclohexane-1,4-diamine, cis/trans mixture

N,N-dimethyl-N′-(1-methyl-1H-indol-3-ylmethyl)-1-phenylcyclohexane-1,4-diamine, cis/trans mixture

N,N-dimethyl-N′-(1-methyl-1H-indol-3-ylmethyl)-1-phenylcyclohexane-1,4-diamine, polar diastereomer

N′-(2-benzo[b]thiophen-3-yl-ethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, cis/trans mixture

N′-(2-benzo[b]thiophen-3-yl-ethyl)-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride, cis/trans mixture

N′-acenaphthen-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer

N′-acenaphthen-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-benzo[b]thiophen-5-yl-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-benzo[b]thiophen-5-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer

N′-benzothiazol-6-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-benzo[1,2,5]thiadiazol-4-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-adamantan-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride

N′-(9-ethyl-9H-carbazol-3-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-(3H-benzotriazol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer

N′-(3H-benzotriazol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine hydrochloride, polar diastereomer

N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, cis/trans mixture

N′-cyclooctyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride

N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer

N′-benzo[b]thiophen-3-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-benzo[b]thiophen-3-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer

N′-anthracen-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer

N′-benzo[b]thiophen-3-ylmethyl-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-benzo[b]thiophen-3-ylmethyl-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-naphthalen-2-yl-cyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer

Methyl 2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionate dihydrochloride, non-polar diastereomer

Methyl 2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionate dihydrochloride, polar diastereomer

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-naphthalen-2-yl-cyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-benzo[1,3]dioxol-5-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, cis/trans mixture

N′-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer

N′-[2-(1H-indol-3-yl)-ethyl]-N,N,N′-trimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-[2-(1H-indol-3-yl)-ethyl]-N,N,N′-trimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer

N,N-dimethyl-N′-[2-(7-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N,N-dimethyl-N′-[2-(7-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer

N′-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer

N′-acenaphthen-5-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, cis/trans mixture

N′-[2-(7-benzyloxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-cyclooctyl-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-adamantan-2-yl-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

3-[2-(4-dimethylamino-4-phenylcyclohexylamino)-ethyl]-1H-indol-5-ol dihydrochloride, non-polar diastereomer

3-[2-(4-dimethylamino-4-phenylcyclohexylamino)-ethyl]-1H-indol-5-ol dihydrochloride, polar diastereomer

N′-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N′-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer

N,N-dimethyl-N′-[2-(5-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N,N-dimethyl-N′-[2-(5-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer

Dimethyl-[1-phenyl-4-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-cyclohexyl]-amine dihydrochloride

N-(4-dimethylamino-4-phenylcyclohexyl)-N-[2-(4-fluorophenyl)-ethyl]-acetamide hydrochloride, non-polar diastereomer

2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(5-fluoro-1H-indol-3-yl)-propionic acid methyl ester dihydrochloride, non-polar diastereomer

N-(4-dimethylamino-4-phenylcyclohexyl)-N-(3-phenylpropyl)-acetamide hydrochloride, non-polar diastereomer

2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(6-fluoro-1H-indol-3-yl)-propionic acid methyl ester dihydrochloride, non-polar diastereomer

N-(4-dimethylamino-4-phenylcyclohexyl)-2-(1H-indol-3-yl)-acetamide hydrochloride, polar diastereomer

2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid methyl ester dihydrochloride, non-polar diastereomer

N-(4-dimethylamino-4-phenylcyclohexyl)-2-(5-methoxy-1H-indol-3-yl)-acetamide hydrochloride, non-polar diastereomer

N,N-dimethyl-1-phenyl-N′-(2-pyridin-4-yl-ethyl)-cyclohexane-1,4-diamine trihydrochloride,

N,N-dimethyl-1-phenyl-N′-(2-pyridin-2-yl-ethyl)-cyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer

N-(4-dimethylamino-4-pyridin-2-yl-cyclohexyl)-N-[2-(1H-indol-3-yl)-ethyl]-acetamide dihydrochloride, non-polar diastereomer

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexane-1,4-diamine trihydrochloride, non-polar diastereomer

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexane-1,4-diamine trihydrochloride, polar diastereomer

(S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid methyl ester trihydrochloride, non-polar diastereomer

(S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid methyl ester trihydrochloride, polar diastereomer

(S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid dihydrochloride, non-polar diastereomer

in particular

potassium (S)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionate, non-polar diastereomer

potassium rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(5-fluoro-1H-indol-3-yl)-propionate, non-polar diastereomer

potassium rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(6-fluoro-1H-indol-3-yl)-propionate, non-polar diastereomer

potassium (S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionate, non-polar diastereomer

(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid hydrochloride, polar diastereomer

(S)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-phenylpropionic acid hydrochloride, non-polar diastereomer

potassium rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyrate, non-polar diastereomer

rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyric acid hydrochloride, polar diastereomer

(R)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionic acid hydrochloride, non-polar diastereomer

(R)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-phenylpropionic acid hydrochloride, non-polar diastereomer

rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(3-hydroxyphenyl)-propionic acid hydrochloride

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.

In this connection, in one of the uses mentioned hereinbefore it may be preferred if 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 μmolar to sub-μmolar range for the μ-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 α-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 process for the production of the substituted cyclohexane-1,4-diamine compounds as outlined in the following description and examples is also important.

Particularly suitable in this connection is a process, hereinafter termed main process, for the production of a substituted cyclohexane-1,4-diamine compound comprising the following steps:

a) a cyclohexane-1,4-dione according to formula II and protected by the groups S ¹and S²is reacted in the presence of a compound of the formula HNR⁰¹R⁰²with a cyanide, preferably potassium cyanide, to form a protected N-substituted 1-amino-4-oxocyclohexane carbonitrile compound according to formula III;

is then optionally acylated, alkylated or sulfonated in an arbitrary order and optionally repeatedly, and/or in the case of compounds where R ⁰¹and/or R⁰²and/or R⁰⁶denotes 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 R⁰¹and/or R⁰²and/or R⁰⁶are H, a protective group is introduced at least once and optionally acylated, alkylated or sulfonated,

b) the aminonitrile according to formula III is reacted with organometallic reagents, preferably Grignard or organolithium reagents of the formula metal-R ³, so that a compound according to formula IVa is formed;

is then optionally acylated, alkylated or sulfonated in an arbitrary order and optionally repeatedly, and/or in the case of compounds where R ⁰¹and/or R⁰²and/or R⁰⁶denotes 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 R⁰¹and/or R⁰²and/or R⁰⁶denote H, a protective group is introduced at least once and optionally acylated, alkylated or sulfonated,

c) the protective groups S ¹and S²are cleaved from the compound according to the formula IVa so that a 4-substituted 4-aminocyclohexanone compound according to formula IV is formed;

which is then optionally acylated, alkylated or sulfonated in an arbitrary order and optionally repeatedly, and/or in the case of compounds where R ⁰¹and/or R⁰²and/or R⁰⁶denote 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 R⁰¹and/or R⁰²and/or R⁰⁶denote H a protective group is introduced at least once and optionally acylated, alkylated or sulfonated,

d) the 4-substituted 4-aminocyclohexanone compound according to formula IVa is reductively aminated with a compound of the formula HNR ⁰⁴R⁰⁵so that a cyclohexane-1,4-diamine compound according to formula V is formed;

is then optionally acylated, alkylated or sulfonated in an arbitrary order and optionally repeatedly, and/or in the case of compounds where R ⁰¹and/or R⁰²and/or R⁰⁴and/or R⁰⁵and/or R⁰⁶denote 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 R⁰¹and/or R⁰²and/or R⁰⁴and/or R⁰⁵and/or R⁰⁶denote H, a protective group is introduced at least once and optionally acylated, alkylated or sulfonated to form a compound according to formula I,

wherein R ¹, R², R³, R⁴and R⁵have the same meanings as the compounds used according to formula I

and

R ⁰¹and R⁰²independently 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;

or the radicals R ⁰¹and R⁰²together form a ring and denote CH₂CH₂OCH₂CH₂, CH₂CH₂NR⁰⁶CH₂CH₂or (CH₂)_3-6,

where R ⁰⁶is 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 ⁰⁴is 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 ⁰⁵is 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; —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—R¹², —CHR¹¹—CH₂—CH₂—CH₂R¹², —C(Y)R¹², —C(Y)—CH₂R¹², —C(Y)—CH₂—CH₂R¹²or —C(Y)—CH₂—CH₂—CH₂R¹²

where Y=H ₂,

where R ¹¹is selected from

H, C _1-7-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted;

and where R ¹²is selected from

or R ⁰⁴and R⁰⁵together form a heterocycle with between 3 and 8 atoms in the ring, which is saturated or unsaturated, singly or multiply substituted or unsubstituted,

and S ¹and S²independently of one another are selected from protective groups or together denote a protective group, preferably monoacetal.

In this connection alkylation also denotes a reductive amination since it leads to the same result.

Also important is a process, hereinafter termed alternative process, for the production of a substituted cyclohexane-1,4-diamine compound comprising the following steps:

a) a cyclohexane-1,4-dione according to formula II and protected by the groups S ¹and S²is reductively aminated with a compound of the formula HNR⁰⁴R⁰⁵so that a 4-aminocyclohexanone compound according to formula VI is obtained;

is then optionally acylated, alkylated or sulfonated in an arbitrary order and optionally repeatedly, and/or in the case of compounds where R ⁰⁴and/or R⁰⁵denote 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 R⁰⁴and/or R⁰⁵denote H, a protective group is introduced at least once and optionally acylated, alkylated or sulfonated,

b) the 4-aminocyclohexanone compound according to formula VI is reacted in the presence of a compound of the formula HNR ⁰¹R⁰²with a cyanide, preferably potassium cyanide, to form a cyclohexanone nitrile compound of the formula VII,

is then optionally acylated, alkylated or sulfonated in an arbitrary order and optionally repeatedly, and/or in the case of compounds where R ⁰¹and/or R⁰²and/or R⁰⁴and/or R⁰⁵and/or R⁰⁶denote 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 R⁰¹and/or R⁰²and/or R⁰⁴and/or R⁰⁵and/or R⁰⁶denote H, a protective group is introduced at least once and optionally acylated, alkylated or sulfonated,

c) the cyclohexanone nitrile compound of the formula VII is reacted with organometallic reagents, preferably Grignard or organolithium reagents of the formula metal-R ³and the protective groups S¹and S²are then cleaved so that a cyclohexane-1,4-diamine compound according to formula V is formed,

is then optionally acylated, alkylated or sulfonated in an arbitrary order and optionally repeatedly, and/or in the case of compounds where R ⁰¹and/or R⁰²and/or R⁰⁴and/or R⁰⁵and/or R⁰⁶denote 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 R⁰¹and/or R⁰²and/or R⁰⁴and/or R⁰⁵and/or R⁰⁶denote H, a protective group is introduced at least once and optionally acylated, alkylated or sulfonated until a compound according to formula I is formed,

wherein R ¹, R², R³, R⁴and R⁵have the meanings given for the compounds used according to formula I,

and

R ⁰¹and R⁰²independently 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;

where R ⁰⁶is 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 ⁰⁴is 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 ⁰⁵is selected from H provided with a protective group; C_3-8-cycloalkyl, aryl or heteroaryl, in each case unsubstituted or singly or multiply substituted; —CHR¹¹R¹², —CHR¹¹—CH₁₂R¹², —CHR¹¹—CH₂—CH₂R¹², —CHR¹¹—CH₂—CH₂—CH₂R¹², —C(Y)R¹², —C(Y)—CH₂R¹², —C(Y)—CH₂—CH₂R¹²or —C(Y)—CH₂—CH₂—CH₂R¹²

where Y=H ₂,

where R ¹¹is selected from

and where R ¹²is selected from

or R ⁰⁴and R⁰⁵together form a heterocycle with between 3 and 8 atoms in the ring that is saturated or unsaturated; singly or multiply substituted or unsubstituted,

For both processes it is preferred if the protective groups at H in the case of R ⁰¹, R⁰², R⁰⁴, R⁰⁵and/or R⁰⁶are selected from alkyl, benzyl or carbamates, for example FMOC, Z or Boc.

Furthermore, it is preferred for the main process if the reductive amination in step d. takes place in the presence of ammonium formate, ammonium acetate or NaCNBH ₃.

For the main process a particularly advantageous modification is also if, instead of the reductive amination with HNR ⁰⁴R⁰⁵in step d), the compound IV is reacted with hydroxylamine and is reduced after oxime formation.

It is also advantageous for the alternative process if in step b) the radical R ⁰¹in the formula HNR⁰¹R⁰²denotes H, the reaction with the cyanide is carried out with TMSCN, and a protective group is then optionally introduced at R⁰¹.

The invention is illustrated further hereinafter by means of examples, without however being restricted thereto.

EXAMPLES

The following examples serve to illustrate the invention in more detail, without however restricting the general concept of the invention. [0281]
The yields of the prepared compounds are not optimised. [0282]
All temperatures are uncorrected. [0283]
The term “ether” denotes diethyl ether, “EE” denotes ethyl acetate and “DCM” denotes dichloromethane. The term “equivalent” denotes quantitative equivalent, “m.p.” denotes melting point or melting point range, “RT” denotes room temperature, “vol. %” denotes volume percent, “m %” denotes weight percent and “M” denotes the concentration in mole/l. [0284]
Silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt, was used as stationary phase for the column chromatography. [0285]
The thin layer chromatography investigations were carried out with HPTLC precoated plates, silica gel 60 F 254, from E. Merck, Darmstadt. [0286]
The mixture ratios of solvents for chromatographic investigations are always specified in volume/volume. [0287]

Example 1

N′-benzyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer [0288]
200 ml of methanol, 1680 ml of aqueous dimethylamine solution (40 m %), 303 g of dimethylamine hydrochloride and 200 g of potassium cyanide were added to 200 g of 1,4-dioxaspiro[4.5]decan-8-one and stirred for ca. 65 hours. The resultant white suspension was extracted four times with 800 ml of ether each time, the combined extracts were concentrated by evaporation, the residue was taken up in ca. 500 ml of dichloromethane and the phases were separated. The dichloromethane phase was dried over sodium sulfate, filtered and concentrated by evaporation. 265 g of 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile were obtained as a white solid. [0289]
50.0 g of 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile were dissolved in 400 ml of tetrahydrofuran of analysis purity, 216 ml of a commercially obtainable 2 M solution of phenyl magnesium chloride in tetrahydrofuran were added dropwise under a nitrogen atmosphere while cooling in an ice bath, and the whole was stirred overnight while heating to room temperature. The reaction mixture was worked up by adding 200 ml of ice-cold ammonium chloride solution (20 m %) while stirring and cooling in an ice bath, and the phases were separated after 30 minutes. The 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. [0290]
165 ml of hydrochloric acid (32 m %) were diluted with 100 ml of water, 60.0 g of dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)-amine were added to this ca. 6 M hydrochloric acid and the whole was stirred for 24 hours. The reaction mixture was washed three times with 50 ml of diethyl ether each time, adjusted alkaline (pH>10) with 100 ml of sodium hydroxide (32 m %) and extracted three times with 100 ml of dichloromethane each time. The extracts were combined, dried over sodium sulfate, filtered and concentrated by evaporation. 36.1 g of 4-dimethylamino-4-phenylcyclohexanone were obtained. [0291]
2.00 g of 4-dimethylamino-4-phenylcyclohexanone were dissolved in 30 ml of tetrahydrofuran of analysis purity and 986 mg of benzylamine followed by 794 μl of glacial acetic acid were added while stirring and cooling in an ice bath. 2.72 g of sodium triacetoxy boron hydride were then added in portions within 15 minutes and the reaction mixture was stirred for ca. 65 hours. The reaction mixture was worked up by adding 15 ml of 2 M sodium hydroxide dropwise (pH>10) and extracted three times with 25 ml of diethyl ether each time. The combined organic phases were then washed twice with 20 ml of water each time, dried over sodium sulfate, filtered and concentrated by evaporation. The crude product obtained was chromatographed on silica gel with diethyl ether under the addition of 1 volume percent of aqueous ammonia solution (25 m %). 844 mg of the non-polar diastereomer of N′-benzyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained, which were converted, by dissolving in 6.8 ml of 2-butanone and adding 27.1 μl of water followed by 381 μl of chlorotrimethylsilane and stirring overnight, into 843 mg of the corresponding hydrochloride. [0292]

Example 2

N′-benzyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine hydrochloride, polar diastereomer [0293]
As described for Example 1, 1.01 g of the polar diastereomer of N′-benzyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were also obtained, which were converted by dissolving in 8.1 ml of 2-butanone and addition of 32.5 μl of water followed by 457 μl of chlorotrimethylsilane and stirring overnight, into 781 mg of the corresponding hydrochloride. [0294]

Example 3

1,N′-dibenzyl-N,N-dimethylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer [0295]
50.0 g of 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile (see Example 1) were dissolved in 400 ml of tetrahydrofuran of analysis purity, 214 ml of a commercially obtainable 2 M solution of benzyl magnesium chloride in tetrahydrofuran were added dropwise under a nitrogen atmosphere while cooling in an ice bath, and the whole was stirred overnight while heating to room temperature. The reaction mixture was worked up by adding 200 ml of ice-cold ammonium chloride solution (20 m %) while stirring and cooling in an ice bath, and the phases were separated after 30 minutes. The 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. 200 ml of hydrochloric acid (32 m %) were diluted with 120 ml of water, 78.49 of crude (8-benzyl-1,4-dioxa-spiro[4.5]dec-8-yl)-dimethylamine were added to this ca. 6 M hydrochloric acid, and the whole was stirred for 24 hours. The reaction mixture was washed three times with 100 ml of diethyl ether each time, adjusted alkaline (pH>10) with 100 ml of sodium hydroxide (32 m %) while cooling in an ice bath and extracted three times with 100 ml of dichloromethane each time. The extracts were combined, dried over sodium sulfate, filtered and concentrated by evaporation. 50.4 g of 4-benzyl-4-dimethylaminocyclohexanone were obtained. [0296]
2.00 g of 4-benzyl-4-dimethylaminocyclohexanone were dissolved in 30 ml of tetrahydrofuran of analysis purity and 926 mg of benzylamine followed by 746 μl of glacial acetic acid were added while stirring in an ice bath. 2.56 g of sodium triacetoxy boron hydride were then added in portions within 15 minutes and the reaction mixture was stirred for a further ca. 65 hours. The reaction mixture was worked up by adding 15 ml of 2 M sodium hydroxide dropwise (pH>10) and extracted three times with 25 ml of diethyl ether each time. The combined organic phases were then washed twice with 20 ml of water each time, dried over sodium sulfate, filtered and concentrated by evaporation. The crude product obtained was chromatographed on silica gel with diethyl ether under the addition of 1 volume percent of aqueous ammonia solution (25 m %). 774 mg of the non-polar diastereomer of 1,N′-dibenzyl-N,N-dimethylcyclohexane-1,4-diamine were obtained, which were converted by dissolving in 6.2 ml of 2-butanone and adding 23.8 μl of water followed by 334 μl of chlorotrimethylsilane and stirring overnight, into 731 mg of the corresponding hydrochloride. [0297]

Example 4

1,N′-dibenzyl-N,N-dimethylcyclohexane-1,4-diamine hydrochloride, polar diastereomer [0298]
As described for Example 3, 820 mg of the polar diastereomer of 1,N′-dibenzyl-N,N-dimethylcyclohexane-1,4-diamine were also obtained, which were converted by dissolving in 6.6 ml of 2-butanone and addition of 25.2 μl of water followed by 354 μl of chlorotrimethylsilane and stirring overnight, into 793 mg of the corresponding hydrochloride. [0299]

Example 5

N-(4-benzyl-4-dimethylaminocyclohexyl)-N-propylbenzamide hydrochloride [0300]
6.00 g of 4-benzyl-4-dimethylaminocyclohexanone (see Example 3) were dissolved in 90 ml of tetrahydrofuran of analysis purity and 1.53 g of n-propylamine followed by 3.36 ml of glacial acetic acid were added while stirring in an ice bath. 7.68 g of sodium triacetoxy boron hydride were then added in portions within 15 minutes and the reaction mixture was stirred for ca. 65 hours. The reaction mixture was worked up by adding 45 ml of 2 M sodium hydroxide dropwise (pH>10) and extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed twice with 50 ml of water each time, dried over sodium sulfate, filtered and concentrated by evaporation. The crude product obtained (6.43 g) was chromatographed on silica gel with diethyl ether under the addition of 5 volume percent of aqueous ammonia solution (25 m %). 707 mg of the non-polar diastereomer of 1-benzyl-N,N-dimethyl-N′-propylcyclohexane-1,4-diamine were obtained. [0301]
700 mg of the non-polar diastereomer of 1-benzyl-N,N-dimethyl-N′-propylcyclohexane-1,4-diamine were dissolved in 10 ml of dichloromethane and 370 μl of triethylamine and ca. 10 mg of DMAP (4-dimethylaminopyridine) were added. 311 μl of benzoyl chloride were added dropwise while cooling in an ice/methanol bath and the reaction mixture was then stirred overnight while heating to room temperature. The reaction mixture was worked up by adding 10 ml of 5 M KOH solution and 10 ml of water, stirred for 10 minutes, extracted three times with 20 ml of dichloromethane each time, and the combined extracts were dried over magnesium sulfate, filtered and concentrated by evaporation. 909 mg of N-(4-benzyl-4-dimethylaminocyclohexyl)-N-propylbenzamide hydrochloride were prepared from the obtained product (834 mg) using water and chlorotrimethylsilane as described for Example 1. [0302]

Example 6

N,N-dimethyl-1-phenyl-N′-propylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer [0303]
10.0 g of 4-dimethylamino-4-phenylcyclohexanone were dissolved in 160 ml of tetrahydrofuran of analysis purity and 2.72 g of n-propylamine followed by 5.97 ml of glacial acetic acid were added while stirring in an ice bath. 13.6 g of sodium triacetoxy boron hydride were then added in portions within 15 minutes and the reaction mixture was stirred for ca. 65 hours. The reaction mixture was worked up by adding 85 ml of 2 M sodium hydroxide (pH>10) dropwise and extracted three times with 100 ml of diethyl ether each time. The combined organic phases were then washed twice with 100 ml of water each time, dried over sodium sulfate, filtered and concentrated by evaporation. 5.00 g of the crude product obtained (9.79 g) were chromatographed on silica gel with diethyl ether to which 1 volume percent of aqueous ammonia solution (25 m %) was added and with an addition of methanol increasing from 1 volume percent to 40 volume percent. 2.79 g of the non-polar diastereomer and 1.33 g of the polar diastereomer of N,N-dimethyl-1-phenyl-N′-propylcyclohexane-1,4-diamine were obtained. 253 mg of the corresponding hydrochloride were obtained from a sample of 356 mg of the non-polar diastereomer, using water and chlorotrimethylsilane in 2-butanone as described for Example 1. [0304]

Example 7

N-(4-dimethylamino-4-phenylcyclohexyl)-N-propylbenzamide hydrochloride, non-polar diastereomer [0305]
1.00 g of the non-polar diastereomer of N,N-dimethyl-1-phenyl-N′-propylcyclohexane-1,4-diamine (see Example 6) were dissolved in 15 ml of dichloromethane and 560 μl of triethylamine and ca. 10 mg of DMAP were added. 468 μl of benzoyl chloride were added dropwise while cooling in an ice/methanol bath and the reaction mixture was then stirred overnight while heating to room temperature. The 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. [0306]

Example 8

N-(4-dimethylamino-4-phenylcyclohexyl)-N-propylbenzamide hydrochloride, polar diastereomer [0307]
1.00 g of the polar diastereomer of N,N-dimethyl-1-phenyl-N′-propylcyclohexane-1,4-diamine (see Example 6) were dissolved in 15 ml of dichloromethane and 560 μl of triethylamine and ca. 10 mg of DMAP were added. 468 μl of benzoyl chloride were added dropwise while cooling in an ice/methanol bath and the reaction mixture was then stirred overnight while heating to room temperature. The 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. [0308]

Example 9

1,N′-dibenzyl-N,N,N′-trimethylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer [0309]
10.0 g of 4-benzyl-4-dimethylaminocyclohexanone (see Example 3) were dissolved in 150 ml of tetrahydrofuran of analysis purity and 5.24 g of benzylmethylamine followed by 5.60 ml of glacial acetic acid were added while stirring in an ice bath. 12.8 g of sodium triacetoxy boron hydride were then added in portions within 15 minutes and the reaction mixture was stirred overnight. The reaction mixture was worked up by adding 75 ml of 2 M sodium hydroxide (pH>10) dropwise and extracted three times with 100 ml of diethyl ether each time. The combined organic phases were then washed twice with 100 ml of water each time, dried over sodium sulfate, filtered and concentrated by evaporation. The crude product obtained (13.1 g) was chromatographed on silica gel with ethyl acetate and an addition of methanol increasing from 0 volume percent to 100 volume percent. [0310]
In addition to a mixed fraction of 5.23 g, 5.37 g of the non-polar and 1.20 g of the polar diastereomer of N,N-dimethyl-1-phenyl-N′-propylcyclohexane-1,4-diamine were obtained. 5.44 g of the corresponding hydrochloride were obtained from the non-polar diastereomer as described for Example 1 using water and chlorotrimethylsilane in 2-butanone. [0311]

Example 10

1,N′-dibenzyl-N,N,N′-trimethylcyclohexane-1,4-diamine hydrochloride, polar diastereomer [0312]
1.24 g of the corresponding hydrochloride were obtained as described for Example 9 from 1.20 g of the polar diastereomer of 1,N′-dibenzyl-N,N,N′-trimethylcyclohexane-1,4-diamine. [0313]

Example 11

N-(4-benzyl-4-dimethylaminocyclohexyl)-N-methylbenzamide hydrochloride, polar diastereomer [0314]
15.0 g of 4-benzyl-4-dimethylaminocyclohexanone (see Example 3) were dissolved in 225 ml of tetrahydrofuran of analysis purity and 4.38 g of methylamine hydrochloride, 8.9 ml of triethylamine and 8.40 ml of glacial acetic acid were added while stirring in an ice bath. 19.2 g of sodium triacetoxy boron hydride were then added in portions within 15 minutes and the reaction mixture was stirred overnight. The reaction mixture was worked up by adding 110 ml of 2 M sodium hydroxide (pH>10) dropwise and extracted three times with 200 ml of diethyl ether each time. The combined organic phases were washed twice with 200 ml of water each time, dried over sodium sulfate, filtered and concentrated by evaporation. The crude product obtained (15.0 g) was chromatographed on silica gel with methanol with the addition of 1 volume percent of aqueous ammonia solution (25 m %). 11.6 g of the still substantially impure product were obtained, which was chromatographed again on silica gel with ethyl acetate and an addition of methanol increasing from 25 volume percent to 50 volume percent. 6.67 g of 1-benzyl-N,N,N′-trimethylcyclohexane-1,4-diamine were obtained as a cis/trans mixture. [0315]
3.00 g of 1-benzyl-N,N,N′-trimethylcyclohexane-1,4-diamine were dissolved in 50 ml of dichloromethane and 1.78 ml of triethylamine and ca. 10 mg of DMAP were added. 1.41 ml of benzoyl chloride were added dropwise while cooling in an ice/methanol bath and the reaction mixture was then stirred overnight while heating to room temperature. 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 (3.61 g) was chromatographed on silica gel with methanol/ether (1:1). 231 g of the polar diastereomer of N-(4-benzyl-4-dimethylaminocyclohexyl)-N-methylbenzamide were obtained, from which 188 mg of the corresponding hydrochloride were prepared as described for Example 1 using water and chlorotrimethylsilane in 2-butanone. [0316]

Example 12

N-(4-benzyl-4-dimethylaminocyclohexyl)-N-ethylbenzamide hydrochloride, polar diastereomer [0317]
15.0 g of 4-benzyl-4-dimethylaminocyclohexanone (see Example 3) were dissolved in 225 ml of tetrahydrofuran of analysis purity and 2.89 g of ethylamine followed by 8.40 ml of glacial acetic acid were added while stirring in an ice bath. 19.2 g of sodium triacetoxy boron hydride were then added in portions within 15 minutes and the reaction mixture was stirred overnight. The reaction mixture was worked up by adding 110 ml of 2 M sodium hydroxide dropwise (pH>10) and extracted three times with 200 ml of diethyl ether each time. The combined organic phases were washed twice with 200 ml of water each time, dried over sodium sulfate, filtered and concentrated by evaporation. The crude product obtained (15.7 g) was chromatographed on silica gel with methanol with the addition of 1 volume percent of aqueous ammonia solution (25 m %). 14.1 g of the still substantially impure product were obtained, which was chromatographed again on silica gel with methanol with the addition of 1 volume percent of aqueous ammonia solution (25 m %). 12.1 g of 1-benzyl-N′-ethyl-N,N-dimethylcyclohexane-1,4-diamine were obtained as a cis/trans mixture. [0318]
3.00 g of 1-benzyl-N′-ethyl-N,N-dimethylcyclohexane-1,4-diamine were dissolved in 50 ml of dichloromethane and 1.68 ml of triethylamine and ca. 10 mg of DMAP were added. 1.40 ml of benzoyl chloride were added dropwise while cooling in an ice/methanol bath and the reaction mixture was then stirred overnight while heating to room temperature. 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. [0319]

Example 13

1-benzyl-N′-(1H-indol-3-ylmethyl)-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride [0320]
14.5 g of 3-formylindole and 13.9 g of hydroxylamine hydrochloride were boiled for two hours in a mixture of dry pyridine (80 ml) and absolute ethanol (80 ml). The initially yellow reaction mixture turned deep red during this time. The solvent mixture was then distilled off in vacuo. In order to remove the pyridine the residue was evaporated to dryness three times with ethanol (each time 30 ml). Water (100 ml) was then added to the residue and the mixture was vigorously stirred for 30 minutes using a magnetic stirrer. The reaction solution with the pink-coloured solid that had formed was cooled for 2 hours in a cooling cabinet. 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. [0321]
4.8 g of 1H-indole-3-carbaldehyde-(Z)-oxime were suspended (sparingly soluble) in methanol (100 ml) and diluted with 5 M sodium hydroxide (100 ml). The reaction vessel was continuously flushed with a gentle stream of argon. Devarda's alloy (20 g) was added in portions to the mixture. The rate of addition was governed by the intensity of the reaction. The reaction was cooled from time to time with iced water. The addition was completed after 2 hours, following which the mixture was stirred for 30 minutes at RT and then diluted with water (100 ml). The methanol was removed in vacuo and the aqueous solution was extracted with ether (4×50 ml). After drying and distilling off the ether the residue was purified by recrystallisation from toluene (20 ml). 2.2 g of C-(1H-indol-3-yl)-methylamine were obtained as a beige-coloured solid with a melting point of 90°-94° C., which quickly changed colour on exposure to light and RT. The product could be stored for a few days in dark bottles and in a cooling cabinet. [0322]
292 mg of C-(1H-indol-3-yl)-methylamine were partially dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 463 mg of 4-benzyl-4-dimethylaminocyclohexanone (see Example 3), glacial acetic acid (4 mmole) and sodium triacetoxy boron hydride (550 mg) the suspension was stirred for 72 hours at room temperature. The reaction mixture was worked up by adding water (10 ml). The organic phase was separated and the aqueous phase was extracted twice with ether and then made strongly alkaline with sodium hydroxide. The product was re-extracted with ethyl acetate (4×10 ml). A pale precipitate formed from the combined ethyl acetate phases already during the working-up. The precipitate was cooled and then suction filtered, washed twice with cold ethyl acetate and dried. The product thereby obtained (235 mg) was white and solid (m.p. 194°-198° C.). 217 mg were dissolved hot in 2-butanone/ethanol (30 ml+10 ml) and saturated ethanolic hydrochloric acid (1.5 ml; 1.85 M) was added at RT while stirring. After 2 hours a precipitate had still not formed. Also, no hydrochloride had precipitated after reducing the amount of solvent and cooling. Accordingly the mixture was evaporated to dryness at 40° C. in vacuo and excess HCl was expelled. As residue 260 mg of 1-benzyl-N′-(1H-indol-3-ylmethyl)-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride were obtained as a pale pink solid with an m.p. of 170°-174° C. [0323]

Example 14

1-benzyl-N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethylcyclohexane-1,4-diamine, cis/trans mixture [0324]
348 mg of DL-α-methyltryptamine were dissolved in dry 1,2-dichloroethane (10 ml) under argon (clear solution), 463 mg of 4-benzyl-4-dimethylaminocyclohexanone (see Example 3), and glacial acetic acid (229 μl) were added and the mixture was stirred for 1 hour at RT. 550 mg of sodium triacetoxy boron hydride were then added and the suspension was stirred for a further 72 hours at RT. The reaction mixture was worked up by adding water (20 ml), the organic phase was separated and the aqueous phase was extracted once with ether and then made strongly alkaline with sodium hydroxide (pH>10). A gel-like precipitate was formed, which dissolved in ethyl acetate. The aqueous phase was extracted with ethyl acetate (4×10 ml). All the ethyl acetate phases were combined, dried with sodium sulfate and evaporated to dryness. 766 mg of a mixture of cis- and trans-1-benzyl-N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethylcyclohexane-1,4-diamine were obtained as a glass-like solid (m.p. 48°-53° C.). [0325]

Example 15

1-benzyl-N′-indan-5-yl-N,N-dimethylcyclohexane-1,4-diamine hydrochloride [0326]
266 mg of 5-aminoindane and 462 mg of 4-benzyl-4-dimethylaminocyclohexanone (see Example 3) were dissolved in dry 1,2-dichloroethane under argon and stirred with 2 g of sodium sulfate for 24 hours at RT. 600 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 2 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate. 440 mg of 1-benzyl-N′-indan-5-yl-N,N-dimethylcyclohexane-1,4-diamine were obtained as a colourless oil. In order to prepare the hydrochloride the base was dissolved in 2-butanone (8 ml) and 1.85 M ethanolic hydrochloric acid (1.75 ml) was added. The precipitated solid was suction filtered and dried. 280 mg of 1-benzyl-N′-indan-5-yl-N,N-dimethylcyclohexane-1,4-diamine hydrochloride were obtained as a white solid (m.p. 200°-203° C.). [0327]

Example 16

1-benzyl-N′-indan-1-yl-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride, cis/trans mixture [0328]
266 mg of 1-aminoindane and 462 mg of 4-benzyl-4-dimethylaminocyclohexanone (see Example 3) were dissolved in dry 1,2-dichloroethane under argon and stirred with 2 g of sodium sulfate for 24 hours at RT. 600 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 2 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate. 696 mg of 1-benzyl-N′-indan-1-yl-N,N-dimethylcyclohexane-1,4-diamine were obtained as a colourless oil. In order to prepare the hydrochloride the base was dissolved in 2-butanone (10 ml) and 1.85 M ethanolic hydrochloric acid (2.80 ml) was added. The precipitated solid was suction filtered and dried. 540 mg of a mixture of cis- and trans-1-benzyl-N′-indan-1-yl-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride was obtained as a white solid (m.p. 170°-172° C.). [0329]

Example 17

N′-indan-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine [0330]
266 mg of 1-aminoindane and 434 mg of 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry 1,2-dichloroethane (10 ml) and THF (10 ml) under argon. Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg) were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (5×20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 200 mg of N′-indan-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a white solid (m.p. 99°-101° C.). [0331]

Example 18

N′-(1H-indol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine [0332]
264 mg of 5-aminoindane and 434 mg of 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg) were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 315 mg of N′-(1H-indol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a white solid (m.p. 191°-192° C.). [0333]

Example 19

N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, cis/trans mixture [0334]
292 mg of C-(1H-indol-3-yl)methylamine were dissolved in dry 1,2-dichloroethane (15 ml) and THF (5 ml) under argon to form an almost clear solution. After addition of 4-dimethylamino-4-phenylcyclohexanone (435 mg), glacial acetic acid (4 mmole) and sodium triacetoxy boron hydride (550 mg) a suspension formed which was stirred for 72 hours at RT. For working-up water (20 ml) was added to the reaction mixture and stirred vigorously for 1 hour. The organic phase was separated and the aqueous phase was extracted twice with ether (10 ml) and then made strongly alkaline with 5 M sodium hydroxide. The aqueous phase was extracted with ethyl acetate (4×10 ml). A solid thereby precipitated out, which dissolved in ethyl acetate (50 ml) on heating. The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product obtained (382 mg) was recrystallised from a mixture of methanol (1 ml) and ethyl acetate (5 ml). The precipitate was suction filtered and washed with a small amount of cold ethyl acetate. 156 mg of N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a cis/trans mixture. [0335]

Example 20

N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, non-polar diastereomer [0336]
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.). [0337]

Example 21

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, non-polar diastereomer [0338]
Tryptamine (320 mg) was dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 4-dimethylamino-4-phenylcyclohexanone (435 mg), glacial acetic acid (229 μl) and sodium triacetoxy boron hydride (550 mg) the suspension was stirred for 3 days at RT. For working-up water (20 ml) was added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted once with ether and then made strongly alkaline with sodium hydroxide. The aqueous phase was opalescently turbid at pH 10. The aqueous phase was extracted with ethyl acetate (4×10 ml) and the extracts were combined, dried over sodium sulfate, filtered and concentrated by evaporation. The crude product obtained (674 mg) was recrystallised twice from ethyl acetate (5 ml). 22 mg of the non-polar diastereomer of N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained (m.p. 134°-138° C.). [0339]

Example 22

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, cis/trans mixture [0340]
As described for Example 21, 320 mg of N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were also obtained as a mixture of the cis/trans isomers (m.p. 149°-153° C.). [0341]

Example 23

N′-indan-5-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, non-polar diastereomer [0342]
5-aminoindane (266 mg) and 4-dimethylamin-4-phenylocyclohexanone (434 mg) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg) were added and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product obtained was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 270 mg of the non-polar diastereomer of N′-indan-5-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a white solid (m.p. 162°-164° C.). [0343]

Example 24

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, non-polar diastereomer [0344]
DL-α-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 μl) 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 aqueous phase was extracted with ethyl acetate (4×10 ml) and the combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product obtained (723 mg) was recrystallised twice from a mixture of ethyl acetate/cyclohexane (2 ml/6 ml). A fraction of the non-polar diastereomer of N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine was obtained (128 mg, m.p. 155°-162° C.). [0345]

Example 25

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, cis/trans mixture [0346]
As described for Example 24, 375 mg of N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were also obtained as a mixture of the cis/trans isomers (dark yellow oil). [0347]

Example 26

N′-[2-(5-benzyloxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine, cis/trans mixture [0348]
5-benzyloxytryptamine (440 mg, 1.65 mmole) was dissolved in dry 1,2-dichloroethane (14 ml) under argon (slightly turbid solution). After addition of 4-dimethylamino-4-phenylcyclohexanone (359 mg, 1.65 mmole) and glacial acetic acid (189 μl, 3.3 mmole) the mixture was stirred for 2 hours at RT. Sodium triacetoxy boron hydride (462 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 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). 396 mg of N′-[2-(5-benzyloxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a cis/trans mixture (m.p. 130°-134° C.). [0349]

Example 27

N′-(9H-fluoren-1-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride [0350]
1-aminofluorene (181 mg, 1 mmole) and 4-dimethylamino-4-phenylcyclohexanone (217 mg, 1 mmole) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (1 mmole) and sodium triacetoxy boron hydride (300 mg) were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 200 mg of N′-(9H-fluoren-1-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a colourless oil, dissolved in 2-butanone (5 ml) followed by the addition of 1.85 M ethanolic HCl (0.7 ml) for the preparation of the hydrochloride. The N′-(9H-fluoren-1-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride obtained was suction filtered and dried. (220 mg, m.p. 223°-225° C.). [0351]

Example 28

N′-indan-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, cis/trans mixture [0352]
2-aminoindane (266 mg, 2 mmole) and 4-dimethylamin-4-phenylocyclohexanone (434 mg, 2 mmole) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg) were added to this mixture and stirred for 24 hours at RT. For working-up the mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 490 mg of N′-indan-2-yl-N,N-dimethyl-1-phenylcyclo-hexane-1,4-diamine were obtained as a white solid, which for the preparation of the hydrochloride was dissolved in 2-butanone (10 ml) followed by the addition of 1.85 M ethanolic HCl (2 ml). The mixture of cis- and trans-N′-indan-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride that was obtained was suction filtered and dried (540 mg, m.p. 224°-226° C.). [0353]

Example 29

N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, cis/trans mixture [0354]
9-aminofluorene (362 mg, 2 mmole) and 4-dimethylamino-4-phenylcyclohexanone (434 mg, 2 mmole) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg) were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (5×20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 440 mg of N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a white solid, which for the preparation of the hydrochloride was dissolved in 2-butanone (10 ml) followed by the addition of 1.85 M ethanolic HCl (1.55 ml). The mixture of N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride that was obtained was suction filtered and dried (460 mg, m.p. 202°-205° C.). [0355]

Example 30

1-benzyl-N′-(9H-fluoren-9-yl)-N,N-dimethylcyclohexane-1,4-diamine [0356]
1-aminofluorene (181 mg, 1 mmole) and 4-benzyl-4-dimethylaminocyclohexanone (231 mg, 1 mmole) were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (1 mmole) and sodium triacetoxy boron hydride (300 mg) were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 150 mg of 1-benzyl-N′-(9H-fluoren-9-yl)-N,N-dimethylcyclohexane-1,4-diamine were obtained as a white solid (m.p. 123°-125° C.) [0357]

Example 31

1-benzyl-N′-(1H-indol-3-ylmethyl)-N,N-dimethylcyclohexane-1,4-diamine, cis/trans mixture [0358]
292 mg of C-(1H-indol-3-yl)-methylamine were partially dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 463 mg of 4-benzyl-4-dimethylaminocyclohexanone (see Example 3), glacial acetic acid (4 mmole) and sodium triacetoxy boron hydride (550 mg) the suspension was stirred for 72 hours at room temperature. For working-up water (10 ml) was added to the reaction mixture. [0359]
The organic phase was separated and the aqueous phase was extracted twice with ether and then made strongly alkaline with sodium hydroxide. The aqueous phase was re-extracted with ethyl acetate (4×10 ml). A white precipitate formed from the combined ethyl acetate phases during the processing. After cooling this was suction filtered, washed twice with cold ethyl acetate and dried. 235 mg of 1-benzyl-N′-(1H-indol-3-ylmethyl)-N,N-dimethylcyclohexane-1,4-diamine were obtained as a cis/trans mixture (m.p. 194°-198° C.). [0360]

Example 32

N,N-dimethyl-N′-(1-methyl-1H-indol-3-ylmethyl)-1-phenylcyclohexane-1,4-diamine, cis/trans mixture [0361]
450 mg of C-(1H-indol-3-yl)-methylamine were partially dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 609 mg of 4-dimethylamino-4-cyclohexanone, glacial acetic acid (5.6 mmole), sodium sulfate (2 g) and sodium triacetoxy boron hydride (770 mg) the suspension was stirred for 5 days at room temperature. For working-up water (20 ml) was added to the reaction mixture. The organic phase was separated and the aqueous phase was washed twice with ether (5 ml) and then made strongly alkaline with sodium hydroxide. 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. [0362]

Example 33

N,N-dimethyl-N′-(1-methyl-1H-indol-3-ylmethyl)-1-phenylcyclohexane-1,4-diamine, polar diastereomer [0363]
As described for Example 32, 106 mg of the polar diastereomer of N,N-dimethyl-N′-(1-methyl-1H-indol-3-ylmethyl)-1-phenylcyclohexane-1,4-diamine were also obtained. [0364]

Example 34

N′-(2-benzo[b]thiophen-3-yl-ethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, cis/trans mixture [0365]
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. For working-up 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. Treatment with methanolic hydrochloric acid afforded a sticky hydrochloride that was immediately converted into the free base. 794 mg (15%) of benzo[b]thiophen-3-yl-ethylamine were obtained as a yellow oil, which was used for the further synthesis. [0366]
Benzo[b]thiophen-3-yl-ethylamine (289 mg, 1.6 mmole) was dissolved in dry 1,2-dichloroethane (10 ml) under argon and, after the addition of 4-dimethylamino-4-phenylcyclo-hexanone (354 mg, 1.6 mmole) and sodium sulfate (2 g), was stirred for 1 hour at RT. Sodium triacetoxy boron hydride (440 mg, 2.0 mmole) was then added in one portion to the reaction mixture. After 3 days glacial acetic acid (4 mmole) was then added and the mixture was stirred for a further 24 hours at RT. For working-up water (20 ml) was added and the reaction mixture was suction filtered. The solid obtained was dissolved with 2 M sodium carbonate solution and ethyl acetate. The organic phase was separated, dried over sodium sulfate, filtered and concentrated by evaporation. The solid but sticky residue obtained (213 mg) was dissolved in 2-butanone (5 ml) and ethanolic HCl (500 μl, 1.5 mmole) was added at RT. After 2 hours the solution was evaporated to dryness and the residue was suspended in diethyl ether (5 ml), suction filtered and washed with diethyl ether (3×3 ml). A mixture of cis- and trans-N′-(2-benzo [b]thiophen-3-yl-ethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride (217 mg, m.p. 164°-167° C.) was obtained as a beige-brown solid. [0367]

Example 35

N′-(2-benzo[b]thiophen-3-yl-ethyl)-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride, cis/trans mixture [0368]
Benzo[b]thiophen-3-yl-ethylamine (350 mg, 1.9 mmole) was dissolved in dry 1,2-dichloroethane (10 ml) under argon and, after the addition of 4-benzyl-4-dimethylaminocyclo-hexanone (463 mg, 2 mmole), glacial acetic acid (2 mmole) and anhydrous sodium sulfate (2 g) was stirred for 1 hour at RT. Sodium triacetoxy boron hydride (550 mg, 2.5 mmole) was then added in one portion and stirred for 4 days at RT. For working-up 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). 366 mg of the obtained diastereo isomer mixture were dissolved in 2-butanone (30 ml) and ethanolic hydrochloric acid (847 μl, 2.8 mmole) was added at RT. A precipitate formed that rapidly redissolved and then reprecipitated during the post-stirring time (4 days at RT). After a further 30 minutes in a cooling cabinet the precipitate was suction filtered, washed with cold 2-butanone (3×3 ml) and dried. 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.). [0369]

Example 36

N′-acenaphthen-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer [0370]
339 mg of acenaphthen-1-ylamine and 435 mg of 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmole) and 600 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 130 mg of the polar diastereomer of N′-acenaphthen-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were 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) (151 mg: m.p. 214°-216° C.). [0371]

Example 37

N′-acenaphthen-1-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0372]
As described for 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.). [0373]

Example 38

N′-benzo[b]thiophen-5-yl-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0374]
300 mg of 5-aminobenzothiophene and 463 mg of 4-benzyl-4-dimethylaminocyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmole) and 600 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (6×20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 520 mg of the non-polar diastereomer of N′-benzo[b]thiophen-5-yl-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine were obtained as a white solid, from which the corresponding dihydrochloride was precipitated with 1.85 M ethanolic hydrochloric acid (1.93 ml) in 2-butanone (15 ml) (621 mg; m.p. 140°-142° C.). [0375]

Example 39

N′-benzo[b]thiophen-5-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer [0376]
300 mg of 5-aminobenzothiophene and 435 mg of 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmole) and 600 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. 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, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 230 mg of the non-polar diastereomer of N′-benzo[b]thiophen-5-yl-1-benzyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a white solid, from which the corresponding hydrochloride was precipitated with 1.85 M ethanolic hydrochloric acid (0.54 ml) in 2-butanone (8 ml) (243 mg; m.p. 155°-157° C.). [0377]

Example 40

N′-benzothiazol-6-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0378]
300 mg of 6-aminobenzothiazole and 435 mg of 4-dimethyl-amino-4-phenylcyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmole) and 600 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. 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, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 220 mg of the non-polar diastereomer of N′-benzothiazol-6-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a yellow solid, from which the corresponding dihydrochloride was precipitated with 1.85 M ethanolic hydrochloric acid (0.83 ml) in 2-butanone (10 ml) (197 mg; m.p. 144°-147° C.). [0379]

Example 41

N′-benzo[1,2,5]thiadiazol-4-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer [0380]
302 mg of benzo[1,2,5]thiadiazol-4-ylamine and 435 mg of 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmole) and 600 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. 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, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 40 mg of the polar diastereomer of N′-benzo[1,2,5]thiadiazol-4-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a red solid, from which the corresponding dihydrochloride was precipitated with 1.85 M ethanolic hydrochloric acid (0.15 ml) in 2-butanone (2 ml) (35 mg; m.p. 122°-125° C.). [0381]

Example 42

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0382]
DL-α-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. 1.20 g of the non-polar diastereomer of N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained (m.p. 158°-160° C.). The corresponding dihydrochloride was precipitated from 1 g of this compound with chlorotrimethylsilane (840 μl) in 2-butanone/acetone (100 ml/30 ml) (977 mg; m.p. 170°-174° C.). [0383]

Example 43

N′-adamantan-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride [0384]
302 mg of 2-adamantylamine and 434 mg of 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry tetrahydrofuran (15 ml) and 1,2-dichloroethane (5 ml) under argon. 600 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 23 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was extracted with 1 M hydrochloric acid (20 ml) and ether (40 ml). The aqueous phase was washed with ether (2×20 ml), made alkaline with 5 M sodium hydroxide and extracted with ether (3×30 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/methanol (4:1). 130 mg of N′-adamantan-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a beige-coloured solid, from which the corresponding dihydrochloride was precipitated with 3.3 M phenolic hydrochloric acid (0.34 ml) in 2-butanone (6 ml), the dihydrochloride decomposing on heating from 237° C. [0385]

Example 44

N′-(9-ethyl-9H-carbazol-3-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0386]
421 mg of 3-amino-9-ethylcarbazole and 435 mg of 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmole) and 600 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. 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, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 288 mg of the non-polar diastereomer of N′-(9-ethyl-9H-carbazol-3-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a brown solid, from which the corresponding dihydrochloride was precipitated with 1.85 M ethanolic hydrochloric acid (0.95 ml) in 2-butanone (10 ml) (339 mg; m.p. 145°-150° C.). [0387]

Example 45

N′-(3H-benzotriazol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer [0388]
268 mg of 5-aminobenzotriazole and 435 mg of 4-dimethyl-amino-4-phenylcyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmole) and 600 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. 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, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 135 mg of the non-polar diastereomer of N′-(3H-benzotriazol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a white solid, from which the corresponding hydrochloride was precipitated with 1.85 M ethanolic hydrochloride (0.54 ml) in 2-butanone (5 ml) (98 mg; m.p. 168°-173° C.). [0389]

Example 46

N′-(3H-benzotriazol-5-yl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine hydrochloride, polar diastereomer [0390]
As described for 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.). [0391]

Example 47

N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, cis/trans mixture [0392]
2-iodothiophene (22.9 g) was dissolved in THF (80 ml) under argon and 2 M isopropyl magnesium chloride (35.7 ml) in THF was added within 30 minutes at 0° C. After a reaction time of 1 hour at 3°-5° C., 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile (10 g) dissolved in tetrahydrofuran (20 ml) were added and stirred for 20 hours at room temperature. For working-up saturated NH[0393] ₄Cl solution (85 ml) was added, the product was extracted with diethyl ether (3×100 ml) and the combined extracts were washed with water (50 ml) and saturated NaCl solution (50 ml), dried and concentrated by evaporation. The crude product obtained (21.3 g of dark brown oil) was dissolved in 2-butanone (140 ml) and converted with chlorotrimethylsilane (9.1 ml) into the hydrochloride of dimethyl-(8-thiophen-2-yl-1,4-dioxaspiro[4.5]dec-8-yl)-amine (white solid; 8.74 g).
Dimethyl-(8-thiophen-2-yl-1,4-dioxaspiro[4.5]dec-8-yl)-amine hydrochloride (8.68 g) was dissolved in 7.5 M hydrochloric acid (29 ml), stirred for 48 hours at room temperature and then extracted with diethyl ether (2×50 ml). The aqueous phase was adjusted alkaline with 5 M sodium hydroxide while cooling with ice, extracted with dichloromethane (3×50 ml), dried and concentrated by evaporation. 4-dimethylamino-4-thiophen-2-yl-cyclohexanone was thus obtained as a yellow solid (5.66 g; m.p. 108°-110° C.). [0394]
362 mg of 9-aminofluorene and 434 mg of 4-dimethylamino-4-thiophen-2-yl-cyclohexanone were dissolved in dry 1,2-dichloroethane (10 ml) under argon. Glacial acetic acid (2 mmole) and 600 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide. The alkaline phase was diluted with water (10 ml) and extracted with ethyl acetate (5×20 ml). The combined-extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 440 mg of a cis/trans mixture of N′-(9H-fluoren-9-yl)-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine were obtained as a white solid, from which the corresponding dihydrochloride was precipitated with 1.85 M ethanolic HCl (1.55 ml) in 2-butanone (10 ml) (460 mg; m.p. 202°-205° C.). [0395]

Example 48

N′-cyclooctyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride [0396]
254 mg of cyclooctylamine and 434 mg of 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry tetrahydrofuran (15 ml) and 1,2-dichloroethane (5 ml) under argon. Glacial acetic acid (120 mg) and 600 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 18 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was washed with 1 M hydrochloric acid (20 ml) and with ether (2×30 ml). The aqueous phase was adjusted alkaline with 5 M sodium hydroxide and extracted with ether (3×30 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product (515 mg) was chromatographed on silica gel with methanol. 108 mg of N′-cyclooctyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a colourless oil, from which the corresponding dihydrochloride was precipitated with 3.3 M ethanolic HCl (0.25 ml) in 2-butanone (2 ml) (102 mg; m.p. 247°-249° C.). [0397]

Example 49

N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0398]
970 mg of C-(1H-indol-3-yl)-methylamine and 1.44 mg of 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry tetrahydrofuran (15 ml) and 1,2-dichloroethane (50 ml) under argon. Glacial acetic acid (13.2 mmole) and 1.82 g of sodium triacetoxy boron hydride were added to this mixture and stirred for 72 hours at RT. For working-up the reaction mixture was concentrated by evaporation, and water (20 ml) and ether (30 ml) were added to the residue and vigorously stirred. The aqueous phase was separated, washed with ether (2×15 ml), adjusted to pH 11 with 5 M sodium hydroxide and extracted with ethyl acetate (4×25 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product (2.11 g) was chromatographed on silica gel with methanol/triethylamine (199:1). 465 mg of the non-polar diastereomer of N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained (m.p. 182°-184° C.), from which the corresponding dihydrochloride was precipitated with chlorotrimethylsilane (443 μl ) in 2-butanone/acetone (20 ml/50 ml) (498 mg; m.p. 164°-168° C.). [0399]

Example 50

N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer [0400]
As described for Example 49, 360 mg of the polar diastereomer of N′-(1H-indol-3-ylmethyl)-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were also obtained, from which the corresponding dihydrochloride was precipitated with chlorotrimethylsilane (328 μl) in 2-butanone/acetone (10 ml/25 ml) (435 mg; m.p. 185°-188° C.). [0401]

Example 51

N′-benzo[b]thiophen-3-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0402]
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.). [0403]
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). After concentration by evaporation of the organic phase 1.43 g of C-benzo[b]thiophen-3-yl-methylamine remained as a green oil. 3.3 M ethanolic hydrochloric acid (3.6 ml, 12 mmole) was added to a solution of this amine (1.3 g, 8 mmole) in 2-butanone (5 ml), 1.18 g of C-benzo[b]thiophen-3-yl-methylamine hydrochloride precipitating as a white crystalline solid with a melting point of 254°-256° C. [0404]
449 of C-benzo[b]thiophen-3-yl-methylamine and 434 mg of 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry tetrahydrofuran (20 ml) and 1,2-dichloroethane (7 ml) under argon. Glacial acetic acid (165 mg) and 825 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 41 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was washed with 1 M hydrochloric acid (20 ml) and with ether (2×20 ml). 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 yellow, crystalline crude product (787 mg) was dissolved in methanol (7 ml) for chromatographic separation, the non-polar diastereomer then precipitating out. 247 mg of the non-polar diastereomer of N′-benzo[b]thiophen-3-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a white solid (m.p. 138°-140° C.), from which the corresponding dihydrochloride was precipitated with 3.3 M ethanolic hydrochloric acid (0.8 ml) in 2-butanone (25 ml) (187 mg; m.p. 225°-230° C.). [0405]

Example 52

N′-benzo[b]thiophen-3-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer [0406]
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.). [0407]

Example 53

N′-anthracen-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine hydrochloride, non-polar diastereomer [0408]
386 mg 2-aminoanthracene and 434 mg of 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry 1,2-dichloroethane (20 ml) under argon. Glacial acetic acid (2 mmole) and 600 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M sodium hydroxide and extracted with ethyl acetate (4×20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with ethyl acetate/ethanol (1:1). 132 mg of the non-polar diastereomer of N′-anthracen-2-yl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained as a green solid, from which the corresponding hydrochloride was precipitated with 1.85 M ethanolic HCl (0.46 ml) in 2-butanone (5 ml) (104 mg; m.p. 169°-172° C.). [0409]

Example 54

N′-benzo[b]thiophen-3-ylmethyl-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0410]
391 mg of C-benzo[b]thiophen-3-yl-methylamine and 554 mg of 4-dimethylaminocyclohexanone were dissolved in dry tetrahydrofuran (18 ml) and 1,2-dichloroethane (6 ml) under argon. Glacial acetic acid (144 mg) and 720 mg of sodium triacetoxy boron hydride were added to this mixture and stirred for 22 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was taken up in 1 M hydrochloric acid (20 ml) and washed with ether (2×20 ml). 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. 368 mg of the non-polar diastereomer of N′-benzo[b]thiophen-3-ylmethyl-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine were obtained, from which the corresponding dihydrochloride was precipitated with 3.3 M ethanolic hydrochloric acid (0.88 ml) in 2-butanone (25 ml) (364 mg; m.p. 246°-255° C.). [0411]

Example 55

N′-benzo[b]thiophen-3-ylmethyl-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer [0412]
As described for Example 54, 347 mg of the polar diastereomer of N′-benzo[b]thiophen-3-ylmethyl-1-benzyl-N,N-dimethylcyclohexane-1,4-diamine were obtained, from which the corresponding dihydrochloride was precipitated with 3.3 M ethanolic hydrochloric acid (0.83 ml) in 2-butanone (25 ml) (418 mg; m.p. 242°-248° C.). [0413]

Example 56

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-naphthalen-2-yl-cyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0414]
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. After completion of the reaction the mixture was quenched with saturated ammonium chloride solution while cooling with ice, and was extracted with diethyl ether (2×70 ml), dried over sodium sulfate and concentrated by evaporation. For purification the crude product (24.2 g) was dissolved in 2-butanone (130 ml) and Me[0415] ₃SiCl (14.8 ml) was added while cooling with ice. After 6 hours the precipitated dimethyl-(8-naphthalen-2-yl-1,4-dioxaspiro-[4.5]dec-8-yl)-amine was filtered under suction (white solid; 6.09 g).
Dimethyl-(8-naphthalen-2-yl-1,4-dioxaspiro[4.5]dec-8-yl)-amine hydrochloride (6.09 g) was dissolved in 7.5 N hydrochloric acid, stirred for 32 hours at RT and then extracted with diethyl ether (3×30 ml). The aqueous phase was adjusted alkaline with 25% ammonia solution while cooling in ice and extracted with 1,2-dichloroethane (3×30 ml). The combined extracts were dried over sodium sulfate and concentrated by evaporation. 4.48 g of 4-dimethylamino-4-naphthalen-2-yl-cyclohexanone were obtained as a white solid (m.p. 81°-83° C.) [0416]
The dihydrochloride of the non-polar diastereomer of N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-naphthalen-2-yl-cyclohexane-1,4-diamine was obtained similarly to the examples described above by reductive amination of 4-dimethylamino-4-naphthalen-2-yl-cyclohexanone with tryptamine. [0417]

Example 57

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0418]
1.12 g of tryptamine and 1.52 g of 4-dimethylamino-4-phenylcyclohexanone were dissolved in dry tetrahydrofuran (12 ml) and 1,2-dichloroethane (40 ml) under argon. Glacial acetic acid (801 μl) and 1.92 g of sodium triacetoxy boron hydride were added to this mixture and stirred for 4 days at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was taken up in water (20 ml), 2 M hydrochloric acid (5 ml) and ether (35 ml). The aqueous phase was separated, washed with ether (2×15 ml), adjusted to pH 11 with sodium hydroxide and extracted with ethyl acetate (3×20 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated by evaporation. The beige-brown residue that was obtained (2.0 g) was chromatographed on silica gel with methanol containing 0.75 vol. % of triethylamine. 553 mg of the non-polar diastereomer of N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were obtained (m.p. 175°-178° C.), from which the corresponding dihydrochloride was obtained with chlorotrimethylsilane in 2-butanone/acetone (20 ml/50 ml) (600 mg; m.p. 216°-218° C.). [0419]

Example 58

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer [0420]
As described for Example 57, 546 mg of the polar diastereomer of N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were also obtained (m.p. 175°-180° C.), from which the corresponding dihydrochloride was obtained with chlorotrimethylsilane (573 μl) in 2-butanone/acetone (3 ml/30 ml) (520 mg; m.p. 223°-229° C.). [0421]

Example 59

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer [0422]
As described for Example 42, 546 mg of the polar diastereomer of N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were also obtained (m.p. 50°-55° C.), from which the corresponding dihydrochloride was obtained as a pale pink solid with chlorotrimethylsilane (1.0 ml) in 2-butanone (50 ml) (1.1 mg; m.p. 194°-199° C.). [0423]

Example 60

Methyl 2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionate dihydrochloride, non-polar diastereomer [0424]
4-dimethylamino-4-phenylcyclohexanone (435 mg, 2 mmole), glacial acetic acid (57 μl, 1 mmole) and fused sodium sulfate (2 g) were added to L-tryptophan methyl ester (438 mg, 2 mmole) in 1,2-dichloroethane (20 ml). After stirring for 2 hours at RT sodium triacetoxy boron hydride (660 mg, 3 mmole) was added and stirring was continued. After 3 days the reaction mixture was concentrated by evaporation and the residue was suspended in diethyl ether (20 ml) and 1 M NaOH (5 ml). After the extraction of the aqueous phase with dietheyl ether and ethyl acetate (each 3×10 ml) the combined organic phases were then washed twice in a separating funnel with 1 M NaOH (5 ml), dried and concentrated by evaporation. The viscous residue (718 mg) was purified twice by flash chromatography [50 kg silica gel, eluent: ethyl acetate/methanol (3:1) as well as ethyl acetate/MeOH (1:1)] and in this way the diastereomers were separated. 270 mg of the non-polar diastereomer of methyl 2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionate were obtained, from which the corresponding dihydrochloride was obtained as a white solid with chlorotrimethylsilane (244 μl) in 2-butanone/acetone (8 ml/4ml) (291 mg, m.p. 175°-180° C.). [0425]

Example 61

Methyl 2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionate dihydrochloride, polar diastereomer [0426]
As described for Example 60, the polar diastereomer of methyl 2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionate was also obtained (140 mg, m.p. 60°-65° C.), from which the corresponding dihydrochloride was obtained as a white solid with chlorotrimethylsilane (126 μl) in 2-butanone/acetone (7 ml/3 ml) (129 mg; m.p. 180°-185° C.). [0427]

Example 62

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-naphthalen-2-yl-cyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0428]
4-dimethylamino-4-naphthalen-2-yl-cyclohexanone (534 mg) and DL-α-methyltryptamine (348 mg) were dissolved in a mixture of tetrahydrofuran (20 ml) and 1,2-dichloroethane (5 ml) under argon. Glacial acetic acid (120 mg) was added thereto and, after a reaction time of 15 minutes, sodium triacetoxy boron hydride (600 mg) was also added. After 64 hours the reaction mixture was suction filtered. After taking up the white solid obtained in 1 M sodium hydroxide (20 ml), extraction with diethyl ether (3×20 ml) and concentrating by evaporation the dried combined extracts, an oily residue (520 mg) was obtained. The chromatographic separation of the mixture was carried out first of all with methanol, 295 mg (m.p. 68°-70° C.) of the non-polar diastereomer being obtained as a white solid. The non-polar diamine was dissolved in 2-butanone (5 ml) and 3.3 N ethanolic hydrochloric acid (0.52 ml) was added, an oily solid precipitating out. After concentrating by evaporation the reaction mixture and adding diethyl ether the crystalline dihydrochloride of the non-polar diastereomer of N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-naphthalen-2-yl-cyclohexane-1,4-diamine was obtained (319 mg; m.p. 206°-210° C.). [0429]

Example 63

N′-benzo[1,3]dioxol-5-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, cis/trans mixture [0430]
3,4-(methylenedioxy)benzylamine (250 μl) and 4-dimethylamino-4-phenylcyclohexanone (434 mg) were dissolved in dry 1,2-dichloroethane (10 ml) with the exclusion of oxygen. Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg) were added to this mixture. The mixture was then stirred for 24 hours at RT. The mixture was worked up by concentration by evaporation, adjusting to pH 11 with 5 M NaOH, diluting with water (10 ml) and extracting with ethyl acetate (4×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated by evaporation. The colourless oil obtained (795 mg) was dissolved in 2-butanone (13 ml) and the dihydrochloride of N′-benzo[1,3]dioxol-5-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine was obtained as a mixture of the cis/trans isomers with chlorotrimethylsilane (718 μl) (white solid; 790 mg; m.p. 128°-131° C.). [0431]

Example 64

N′-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0432]
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). A white solid (785 mg) precipitated out between the phases and was separated. 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. After stirring for 1 hour at RT the white dihydrochloride of the non-polar diamine of N′-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine was obtained (344 mg; m.p. 190°-195° C.). [0433]

Example 65

N′-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer [0434]
As described for Example 64, 305 mg of the polar diastereomer of N′-[2-(6-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine were also obtained, from which the corresponding dihydrochloride was obtained with 3.3 M ethanolic HCl (0.73 ml) in ethanol (20 ml) (270 mg; m.p. 208°-211° C.). [0435]

Example 66

N′-[2-(1H-indol-3-yl)-ethyl]-N,N,N′-trimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0436]
N-ω-methyltryptamine ([2-(1H-indol-3-yl)-ethyl]methylamine, 348 mg) was dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 4-dimethylamino-4-phenylcyclohexanone (435 mg) and glacial acetic acid (114 μl) 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. A white solid precipitated out, which was suction filtered, washed and dried (174 mg, m.p. 208°-210° C., non-polar diastereomer). The aqueous phase was adjusted to pH 11 with 1 M NaOH and extracted with ethyl acetate (4×25 ml). The extracts were combined, dried over sodium sulfate and concentrated by evaporation in vacuo. The residue (469 mg) was separated by flash chromatography with methanol/triethylamine (99:1). The non-polar diastereomer that was thus obtained (172 mg) was dissolved hot in 2-butanone/acetone (15 ml/15 ml) and the hydrochloride of N′-[2-(1H-indol-3-yl)-ethyl]-N,N,N′-trimethyl-1-phenylcyclohexane-1,4-diamine was precipitated as a white solid at RT with chlorotrimethylsilane (174 μl) (173 mg; m.p. 195°-198° C.). [0437]

Example 67

N′-[2-(1H-indol-3-yl)-ethyl]-N,N,N′-trimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer [0438]
As described for Example 66, 129 mg of the polar diastereomer of N′-[2-(1H-indol-3-yl)-ethyl]-N,N,N′-trimethyl-1-phenylcyclohexane-1,4-diamine were also obtained, which was converted into the corresponding dihydrochloride by heating in 2-butanone/acetone (15 ml/3 ml) with chlorotrimethylsilane (121 μl) (white solid; 141 mg; m.p. 198°-206° C.). [0439]

Example 68

N,N-dimethyl-N′-[2-(7-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0440]
7-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 (2 mmole) and sodium triacetoxy boron hydride (600 mg) were added to this mixture and stirred for 24 hours at RT. For working-up 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[0441] 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 μl) (white solid; 420 mg; m.p. 189°-191° C.).

Example 69

N,N-dimethyl-N′-[2-(7-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer [0442]
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 μl) (white solid; 146 mg; m.p. 244°-246° C.). [0443]

Example 70

N′-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0444]
2-(5-fluoro-1H-indol-3-yl)ethylamine (282 mg) and 4-dimethylamino-4-phenylcyclohexanone (343 mg) were first of all added to a mixture of tetrahydrofuran (12 ml) and 1,2-dichloromethane (4 ml) under argon, following which glacial acetic acid (0.09 ml) was added. After 15 minutes NaBH(OAc)[0445] ₃(474 mg) was added and stirred for 40 hours at RT. The reaction mixture was concentrated by evaporation and the residue was taken up in 1 M hydrochloric acid (20 ml) and extracted with ether (2×30 ml). A white precipitate formed (191 mg), which was separated. The aqueous solution was then adjusted alkaline with 1 M NaOH (28 ml) and extracted with ether (2×30 ml) and ethyl acetate (2×30 ml). The combined organic extracts were dried over sodium sulfate and concentrated by evaporation. The residue (468 mg) consisted, just like the previously separated solid, of two products. The combined products (459 mg) were purified by column chromatography with methanol/ammonia (500:1). The non-polar diastereomer was obtained as a white solid (218 mg; m.p. 191°-192° C.), dissolved in ethanol (15 ml) by heating, following which 3.3 N ethanolic hydrochloric acid (0.47 ml, 1.56 mmole) was added. Since after 90 minutes no solid had yet precipitated, 2-butanone (5 ml) was added. After a short time crystallisation of the hydrochloride then began (184 mg; m.p. 230°-237° C.).

Example 71

N′-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer [0446]
As described for Example 70, 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.). [0447]

Example 72

N′-acenaphthen-5-ylmethyl-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0448]
Acenaphthen-5-ylmethylamine (366 mg) and 4-dimethylamino-4-phenylcyclohexanone (434 mg) were dissolved in dry 1,2-dichloroethane (10 ml) with the exclusion of oxygen. Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg) were added to this mixture and stirred for 24 hours at RT. For working-up the reaction mixture was concentrated by evaporation and the residue was 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 organic phases were dried over sodium sulfate and concentrated by evaporation. The crude product obtained was purified by chromatography with ethyl acetate/EtOH (1:1). The non-polar diastereomer was obtained as a colourless oil (330 mg), dissolved in 2-butanone (10 ml) and converted into the corresponding dihydrochloride with chlorotrimethylsilane (272 μl) (white solid; 393 mg; m.p. 164°-167° C.). [0449]

Example 73

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0450]
DL-α-methyltryptamine (N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine, 348 mg) were dissolved in dry 1,2-dichloroethane (20 ml) under argon. After addition of 4-dimethylamino-4-thiophen-2-yl-cyclohexanone (447 mg) and glacial acetic acid (114 μl) a voluminous precipitate formed. The suspension was stirred for 1 hour at RT. Sodium triacetoxy boron hydride (660 mg) was then added and the reaction mixture was stirred for 2 days at RT. For working-up the mixture was diluted with 1,2-dichloroethane (10 ml) and water (15 ml), the organic phase was separated, and the aqueous phase was extracted once more with 1,2-dichloroethane (2×5 ml), adjusted alkaline with 5 M NaOH and extracted with ethyl acetate (4×15 ml). The combined organic phases were dried, concentrated by evaporation and purified by flash chromatography (50 g silica gel 60, eluent: methanol/NEt[0451] ₃(99:1)). The non-polar diastereomer (202 mg, m.p. 158°-161° C.) was dissolved in 2-butanone (5 ml) and converted into the corresponding dihydrochloride with chlorotrimethylsilane (202 μl) (white solid, 207 mg; m.p. 162°-165° C.).

Example 74

N′-[2-(1H-indol-3-yl)-1-methylethyl]-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, cis/trans mixture [0452]
As described for Example 73, a mixture of the diastereomers (195 mg) was also isolated, dissolved in 2-butanone (4 ml) and converted into the corresponding dihydrochloride with chlorotrimethylsilane (194 μl) (white solid; 232 mg; polar/non-polar=70:30). [0453]

Example 75

N′-[2-(7-benzyloxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0454]
7-benzyloxytryptamine (200 mg) was dissolved in dry 1,2-dichloroethane (10 ml) and THF (10 ml) under argon. After addition of 4-dimethylamino-4-phenylcyclohexanone (180 mg) and glacial acetic acid (43 μl) the mixture was stirred for 1 hour at RT following which sodium triacetoxy boron hydride (248 mg) was added. The reaction mixture was stirred for 3 days at RT. For working-up 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[0455] 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 μl) (white solid, 176 mg; m.p. 162°-166° C.).

Example 76

N′-cyclooctyl-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0456]
4-dimethylamino-4-phenylcyclohexanone (447 mg, 2 mmole) was dissolved in 1,2-dichloroethane (25 ml) under argon, followed by the addition of cyclooctylamine (254 mg) and glacial acetic acid (120 mg). The mixture was stirred for 15 minutes at RT and sodium triacetoxy boron hydride (600 mg) was then added. After 48 hours at RT the reaction mixture was concentrated by evaporation on a rotary evaporator, and the residue was taken up in 1 M HCl (20 ml) and washed with diethyl ether (2×30 ml). The aqueous solution was then adjusted alkaline with 1 M NaOH (28 ml) and extracted with Et[0457] ₂O (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.).

Example 77

N′-adamantan-2-yl-N,N-dimethyl-1-thiophen-2-yl-cyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0458]
2-adamantylamine (302 mg) and 4-dimethylamino-4-phenylcyclohexanone (446 mg) were dissolved under argon in a mixture of THF (15 ml) and 1,2-dichloroethane (5 ml). After 15 minutes sodium triacetoxy boron hydride (600 mg) was added to the mixture and the whole was stirred for 45 hours at room temperature. For working-up 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 washed with diethyl ether (2×30 ml). 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°). [0459]

Example 78

3-[2-(4-dimethylamino-4-phenylcyclohexyl-amino)-ethyl]-1H-indol-5-ol dihydrochloride, non-polar diastereomer [0460]
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 μl) 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. For working-up 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[0461] ₃(99.5:0.5)). 267 mg of the non-polar diastereomer were isolated (m.p. 90°-100° C.), which was dissolved in ethanol/2-butanone (3 ml/15 ml) and converted into the corresponding dihydrochloride with 3.3 M ethanolic HCl (642 μl) (white solid; 304 mg; m.p. 215°-217° C.).

Example 79

3-[2-(4-dimethylamino-4-phenylcyclohexyl-amino)-ethyl]-1H-indol-5-ol dihydrochloride, polar diastereomer [0462]
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 μl) (white solid; 123 mg; m.p. 230°-233° C.). [0463]

Example 80

N′-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0464]
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 μl) 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. The phases were separated, the aqueous phase (pH 3) was washed with diethyl ether (3×10 ml), and then adjusted to pH 11 with 1 M NaOH and extracted with ethyl acetate (5×15 ml). The combined extracts were dried over sodium sulfate and concentrated by evaporation. The remaining residue (1.0 g; m.p. 129°-153° C.) was purified by flash chromatography (eluent: MeOH/NEt[0465] ₃(99.25:0.75)). The non-polar diastereomer (550 mg, m.p. 164°-169° C.) was separated cleanly, dissolved hot in 2-butanone/acetone (15 ml/16 ml) and converted into the corresponding dihydrochloride with chlorotrimethylsilane (533 μl) (white solid; 633 mg; m.p. 165°-175° C.).

Example 81

N′-[2-(5-methoxy-1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer [0466]
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 μl) (white solid; 362 mg; m.p. 206°-210° C.). [0467]

Example 82

N,N-dimethyl-N′-[2-(5-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0468]
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 μl) and sodium triacetoxy boron hydride (600 mg) were added to this mixture and the whole was stirred for 24 hours at RT. For working-up 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[0469] 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 μl) (white solid; 405 mg; m.p. 234°-236° C.).

Example 83

N,N-dimethyl-N′-[2-(5-methyl-1H-indol-3-yl)-ethyl]-1-phenylcyclohexane-1,4-diamine dihydrochloride, polar diastereomer [0470]
As described for Example 82, the polar diastereomer (266 mg) was also obtained, dissolved in 2-butanone (10 ml) and converted into the corresponding dihydrochloride with ME[0471] ₃SiCl (224 μl, 1.76 mmole) (white solid; 272 mg; m.p. 248°-250° C.).

Example 84

Dimethyl-[1-phenyl-4-(1,3,4,9-tetrahydro-b-carbolin-2-yl)-cyclohexyl]-amine dihydrochloride [0472]
2,3,4,9-tetrahydro-1H-β-carboline (345 mg) and 4-dimethylamino-4-phenylcyclohexanone (435 mg) were dissolved in a mixture of THF (10 ml) and 1,2-dichloroethane (15 ml) under argon, followed by the addition of glacial acetic acid (120 mg, 2 mmole). After 15 minutes NaBH(OAc)[0473] ₃(600 mg) was added, the reaction mixture was stirred for 68 hours and concentrated by evaporation, and the residue was taken up in 1 N hydrochloric acid (20 ml) and washed with ether (2×20 ml). The aqueous solution was adjusted alkaline with 1 M NaOH (30 ml) and extracted with ether (3×30 ml). After drying and concentrating by evaporation the combined extracts a semi-solid crude product was obtained, which after column chromatography separation with methanol/NH₃(500:3) yielded the non-polar diastereomer (334 mg, m.p. 147°-150° C.), which was dissolved by heating in 2-butanone (20 ml) and ethanol (10 ml) and converted into the corresponding dihydrochloride with 3.3 M ethanolic hydrochloric acid (0.8 ml) (335 mg; m.p. 264°-269° C.)

Example 85

N-(4-dimethylamino-4-phenylcyclohexyl)-N-[2-(4-fluorophenyl)-ethyl]-acetamide hydrochloride, non-polar diastereomer [0474]
4-(fluorophenyl)ethylamine (1.15 g) and 4-dimethylamino-4-phenylcyclohexanone (1.8 g) were dissolved in dry 1,2-dichloroethane (20 ml) and tetrahydrofuran (60 ml) with the exclusion of oxygen. Glacial acetic acid (8.28 mmole) and sodium triacetoxy boron hydride (2.48 g, 11.59 mmole) were added to this mixture and stirred for 24 hours at RT. For working-up the 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.). [0475]

Example 86

2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(5-fluoro-1H-indol-3-yl)-propionic acid methyl ester dihydrochloride, non-polar diastereomer [0476]
4-dimethylamino-4-phenylcyclohexanone (935 mg), sodium sulfate (4 g) and glacial acetic acid (245 μl, 4.4 mmole) were added to rac-5-fluorotryptophan methyl ester (1030 mg) in 1,2-dichloroethane (ca. 40 ml) under argon. After stirring for 1 hour at RT sodium triacetoxy boron hydride was added (1.4 g, 6.5 mmole). The mixture was stirred for 3 days at RT. For working-up 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. 55°-62° C.) was dissolved in 2-butanone/acetone (7 ml/1 ml) and converted into the corresponding dihydrochloride with chlorotrimethylsilane (174 μl) (beige solid; 135 mg; m.p. 172°-182° C.). [0477]

Example 87

N-(4-dimethylamino-4-phenylcyclohexyl)-N-(3-phenylpropyl)-acetamide hydrochloride, non-polar diastereomer [0478]
3-phenylpropylamine (676 mg) and 4-dimethylamino-4-phenylcyclohexanone (1.086 g) were dissolved in dry 1,2-dichloroethane (5 ml) and tetrahydrofuran (15 ml) with the exclusion of oxygen. Glacial acetic acid (5 mmole) and sodium triacetoxy boron hydride (1.5 g, 7 mmole) were added to this mixture and stirred for 24 hours at RT. For working-up the mixture was concentrated by evaporation, followed by the addition of 1 M HCl (20 ml) and diethyl ether (40 ml). 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. After stirring for 24 hours at RT some ice cubes were added and the mixture was concentrated as far as possible on a rotary evaporator. 1 N NaOH (20 ml) was added to the residue and the latter was extracted with ethyl acetate (3×30 ml). The combined organic extracts were dried over sodium sulfate and concentrated by evaporation. The acetamide obtained (528 mg) was dissolved in 2-butanone (10 ml) and converted into the corresponding hydrochloride with chlorotrimethylsilane (0.353 ml) (white solid; 282 mg; m.p. 206°-211° C.). [0479]

Example 88

2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(6-fluoro-1H-indol-3-yl)-propionic acid methyl ester dihydrochloride, non-polar diastereomer [0480]
4-dimethylamino-4-phenylcyclohexanone (877 mg), sodium sulfate (2 g) and glacial acetic acid (230 μl, 4 mmole) were added under argon to rac-6-fluorotryptophan methyl ester (952 mg) in 1,2-dichloroethane (ca. 30 ml). After stirring for 1 hour at RT sodium triacetoxy boron hydride (1.33 g, 6 mmole) was added and stirred for 2 days at RT. For working-up the mixture was concentrated by evaporation, the residue was dissolved in ethyl acetate (30 ml) and 1 M NaOH (25 ml), the clear phases were separated in a separating funnel, the aqueous phase was extracted three times with ethyl acetate (10 ml each time) and the combined extracts were dried and concentrated by evaporation. The residue obtained (1.72 g) was purified by flash chromatography (eluent: MeOH/EtOAc 1:2, followed by MeOH/EtOAc 1:1 and MeOH/NH[0481] ₃400:1). The non-polar diastereomer (868 mg) was partially dissolved (261 mg) in 2-butanone (7 ml) and the corresponding dihydrochloride was precipitated with chlorotrimethylsilane (227 μl) (white solid; 224 mg; m.p. 164°-169° C.).

Example 89

N-(4-dimethylamino-4-phenylcyclohexyl)-2-(1H-indol-3-yl)-acetamide hydrochloride, polar diastereomer [0482]
4-dimethylamino-4-phenylcyclohexanone (10 mg) and hydroxylamine hydrochloride (4.8 g) were dissolved in absolute ethanol (120 ml), Amberlyst A 21 basic ion exchanger (30.7 g) was added to the solution and the mixture was stirred overnight at RT. The ion exchanger was filtered off and washed with ethanol (3×50 ml) on the frit. The ethanol was removed in vacuo, the residue was adjusted to pH 11 with 5 M NaOH, diluted with water, and extracted with ethyl acetate (4×30 ml). The combined extracts were dried over sodium sulfate and concentrated by evaporation. 11 g of 4-dimethylamino-4-phenylcyclohexanone oxime were obtained. 4-dimethylamino-4-phenylcyclohexanone oxime (11 mg) was dissolved in methanol (200 ml) and diluted with 5 M NaOH (200 ml). Devarda's alloy (30 g) was added in portions to this mixture. The reaction temperature was between 500 and 60° C. 15 minutes after completion of the addition the mixture was diluted with water (150 ml), the methanol was removed in vacuo and the aqueous solution was extracted with ether (5×50 ml). The combined extracts were dried over sodium sulfate and concentrated by evaporation. N,N-dimethyl-1-phenylcyclohexane-1,4-diamine was obtained as a yellow oil (10.0 g). [0483]
N-methylmorpholine (235 μl, 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. For working-up 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 μl) (white solid; 128 mg; m.p. 100°-102° C.). [0484]

Example 90

2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid methyl ester dihydrochloride, non-polar diastereomer [0485]
The hydrochloride of L-tryptophan methyl ester (1.01 g) was vigorously for 15 minutes with 1,2-dichloroethane (20 ml) and saturated NaHCO[0486] ₃solution (20 ml) and the aqueous phase was immediately extracted with 1,2-dichloroethane (2×20 ml). After drying over sodium sulfate the organic phase was concentrated by evaporation to 40 ml and 4-dimethylamino-4-phenylcyclohexanone (893 mg, 4 mmole) was added under argon. Glacial acetic acid (0.228 ml, 4 mmole) 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 4 days at room temperature. For working-up saturated NaHCO₃solution (40 ml) was added 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, a pale brown oil being obtained. Column chromatography purification was carried out with ethyl acetate and methanol. The non-polar diastereomer (918 mg; m.p. 108°-112° C.) was dissolved in 2-butanone (15 ml) and converted into the corresponding dihydrochloride with chlorotrimethylsilane (0.4 ml) (white solid; 326 mg; m.p. 197°-202° C.).

Example 91

N-(4-dimethylamino-4-phenylcyclohexyl)-2-(5-methoxy-1H-indol-3-yl)-acetamide hydrochloride, non-polar diastereomer [0487]
The non-polar diastereomer of N,N-dimethyl-1-phenylcyclohexane-1,4-diamine (387 mg) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (267 mg, 2.0 mmole) were added to a solution of (5-methoxy-1H-indol-3-yl)-acetic acid (364 mg) in absolute methanol (20 ml). The mixture was then stirred for 24 hours at RT. For working-up the mixture was concentrated by evaporation, diluted with water (10 ml), adjusted to pH 11 with 5 M NaOH and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated by evaporation. After column chromatography with MeOH the non-polar amide (154 mg; colourless oil) was dissolved in 2-butanone (5 ml) and converted into the corresponding hydrochloride with chlorotrimethylsilane (72 μl) (white solid; 168 mg; m.p. 143°-145° C.). [0488]

Example 92

N,N-dimethyl-1-phenyl-N′-(2-pyridin-4-yl-ethyl)-cyclohexane-1,4-diamine trihydrochloride [0489]
2-(pyridin-4-yl)ethylamine (484 mg) and 4-dimethylamino-4-phenylcyclohexanone (434 mg) were dissolved in dry 1,2-dichloroethane (10 ml) under the exclusion of oxygen. Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg) were added to this mixture and stirred for 24 hours at RT. For working-up the mixture was concentrated by evaporation 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 organic phases were dried over sodium sulfate, concentrated by evaporation and purified by chromatography with MeOH. The crude product obtained (420 mg) was dissolved in 2-butanone (10 ml) and converted into the trihydrochloride with chlorotrimethylsilane (577 μl) (white solid; 560 mg; m.p. 143°-148° C.). This compound also exhibited inter alia an affinity for the ORL1 receptor, expressed as a K[0490] _ivalue in μm of 0.23.

Example 93

N,N-dimethyl-1-phenyl-N′-(2-pyridin-2-yl-ethyl)-cyclohexane-1,4-diamine dihydrochloride, non-polar diastereomer [0491]
2-(pyridin-2-yl)ethylamine (363 mg) and 4-dimethylamino-4-phenylcyclohexanone (434 mg) were dissolved in dry 1,2-dichloroethane (10 ml) under the exclusion of oxygen. Glacial acetic acid (2 mmole) and sodium triacetoxy boron hydride (600 mg) were added to this mixture. The mixture was then stirred for 24 hours at RT. For working-up the mixture was concentrated by evaporation and the residue was adjusted to pH 11 with 5 M NaOH, diluted with water (10 ml) and extracted with ethyl acetate (4×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated by evaporation. The crude product was purified by chromatography with MeOH. The non-polar diastereomer was obtained as a colourless oil in a yield of 210 mg (33%), dissolved in 2-butanone (5 ml) and converted into the corresponding dihydrochloride with chlorotrimethylsilane (288 μl) (white solid; 285 mg; m.p. 115°-118° C.). This compound also exhibited inter alia an affinity for the ORL1 receptor, expressed as a K[0492] _ivalue in μm of 0.089. In the tail flick test in mice the substance was 100% (1) active as measured by the antinociceptive action compared to the control group according to Example 106.

Example 94

Potassium (S)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionate, non-polar diastereomer [0493]
200 ml of methanol, 1680 ml of aqueous dimethylamine solution (40 m %), 303 g of dimethylamine hydrochloride and 200 g of potassium cyanide were added to 200 g of 1,4-dioxaspiro[4.5]-decan-8-one and stirred for ca. 65 hours. The white suspension obtained was extracted four times with 800 ml of ether each time, the combined extracts were concentrated by evaporation, and the residue was taken up in ca. 500 ml of dichloromethane and the phases were separated. The organic phase was dried over sodium sulfate, filtered and concentrated by evaporation. 265 g of 8-dimethylamino-1,4-dioxaspiro[4.5]-decane-8-carbonitrile were obtained as a white solid. [0494]
50.0 g of 8-dimethylamino-1,4-dioxaspiro[4.5]-decane-8-carbonitrile were dissolved in 400 ml of tetrahydrofuran of analysis purity, 216 ml of a commercially obtainable 2 M solution of phenyl magnesium chloride in tetrahydrofuran were added dropwise under a nitrogen atmosphere while cooling in an ice bath, and the whole was stirred overnight while heating to room temperature. For working-up 200 ml of ice-cold ammonium chloride solution (20 m %) were added while stirring and cooling in an ice bath, and after 30 minutes the phases were separated. The 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. [0495]
165 ml of hydrochloric acid (32 m %) were diluted with 100 ml of water, followed by the addition of ca. 6 M hydrochloric acid and 60.0 g of dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]-dec-8-yl)amine, and the whole was stirred for 24 hours. The reaction mixture was washed three times with 50 ml of diethyl ether each time, adjusted alkaline (pH>10) with 100 ml of sodium hydroxide (32 m %), and extracted three times with 100 ml of dichloromethane each time. The extracts were combined, dried over sodium sulfate, filtered and concentrated by evaporation. 36.1 g of 4-dimethylamino-4-phenylcyclohexanone were obtained. [0496]
In order to release the base, 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. 4-dimethylamino-4-phenylcyclohexanone (435 mg), glacial acetic acid (57 μl) and fused sodium sulfate (2 g) were added to the previously prepared dried solution of tryptophan methyl ester (438 mg) in 1,2-dichloroethane (ca. 20 ml). After stirring for 2 hours at RT sodium triacetoxy boron hydride (660 mg) was added and stirring was continued. After 3 days the solvent was removed in vacuo and the residue was suspended in diethyl ether (20 ml) and 1 M NaOH (5 ml). After the extraction of the aqueous phase with ether and ethyl acetate (each 3×10 ml) the combined organic extracts were washed twice with 1 M NaOH (5 ml), then dried and concentrated by evaporation. The viscous residue (718 mg) was purified twice by flash chromatography (silica gel; eluent: EtOAc/MeOH (3:1) as well as EtOAc/MeOH (1:1)). The non-polar diastereomer (385 mg) was dissolved in ethanol, 1.7 M potassium hydroxide solution (10.8 ml) was added to the clear solution, and the mixture was stirred for 20 hours at RT. For working-up the ethanol was distilled off, water (20 ml) and ethyl acetate (30 ml) were added to the oily residue, and the mixture was stirred vigorously for 1 hour at RT. During this time the potassium salt formed as a white precipitate between the phases. The solid was suction filtered, washed with water (1×3 ml) and EtOAc (3×5 ml) and then dried. The non-polar diastereomer of potassium (S)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionate was thus obtained as a white solid (309 mg; m.p. 190°-196° C.). [0497]

Example 95

Potassium rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(5-fluoro-1H-indol-3-yl)-propionate, non-polar diastereomer [0498]
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. 4-dimethylamino-4-phenylcyclohexanone (935 mg), sodium sulfate (4 g) and glacial acetic acid (245 μl) were added under argon to the solution of rac-5-fluorotryptophan methyl ester (1030 mg) in 1,2-dichloroethane (ca. 40 ml). After stirring for 1 hour at RT sodium triacetoxy boron hydride (1.4 g) was added and the mixture was stirred for 3 days at RT. For working-up the solvent was removed in vacuo and the residue was dissolved in ethyl acetate (40 ml) and 1 M NaOH (35 ml). The clear phases were separated in a separating funnel and the aqueous phase was washed three times with EtOAc (10 ml each time). The combined EtOAc phases were then dried and concentrated by evaporation. The crude product obtained (1.73 g) was separated by flash chromatography (silica gel 60, eluent: 1000 ml MeOH/EtOAc (1:3), 800 ml MeOH/EtOAc (1:1) and 1000 ml MeOH). The non-polar diastereomer (911 mg, m.p. 55°-62° C.) was separated and 673 mg thereof were dissolved in ethanol (60 ml). 1.7 N potassium hydroxide solution (18.1 ml) was added to the clear solution. After stirring for 20 hours at RT the ethanol was distilled off. Water (20 ml) and EtOAc (50 ml) were added to the oily residue and stirred for 1 hour at RT. During this time potassium 2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(5-fluoro-1H-indol-3-yl)-propionate formed as a white precipitate between the phases. The solid was suction filtered, washed with EtOAc (3×5 ml) and dried (white solid; 641 mg; m.p. 175°-180° C.). [0499]

Example 96

Potassium rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(6-fluoro-1H-indol-3-yl)-propionate, non-polar diastereomer [0500]
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. [0501]
4-dimethylamino-4-phenylcyclohexanone (877 mg), sodium sulfate (2 g) and glacial acetic acid (230 μl) were added under argon to the solution of rac-6-fluorotryptophan methyl ester (952 mg) in 1,2-dichloroethane (ca. 30 ml). After stirring for 1 hour at RT sodium triacetoxy boron hydride (1.33 g) was added and the mixture was stirred for 2 days at RT. For working-up the solvent was removed in vacuo and the residue was dissolved in ethyl acetate (30 ml) and 1 M NaOH (25 ml). The clear phases were separated in a separating funnel and the aqueous phase was washed three times with EtOAc (10 ml each time). The combined EtOAc phases were dried and concentrated by evaporation. The residue (1.72 g) was separated by flash chromatography (150 g silica gel 60, eluent: 1000 ml MeOH/EtOAc (1:2), 600 ml MeOH/EtOAc (1:1) and 1500 ml MeOH/NH[0502] ₃(400:1). The non-polar diastereomer (868 mg) was separated cleanly and 613 mg thereof were dissolved in ethanol (60 ml). 1.7 N potassium hydroxide solution (16.5 ml) was added to the clear solution. After stirring for 20 hours at RT the ethanol was distilled off, water (20 ml) and EtOAc (70 ml) were added to the oily residue, and the whole was vigorously stirred for 2 days at RT. During this time potassium 2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(6-fluoro-1H-indol-3-yl)-propionate separated out as a white precipitate between the phases. The solid was suction filtered, washed with EtOAc (3×5 ml) and dried (570 mg; m.p. 207°-212° C.).

Example 97

Potassium (S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionate, non-polar diastereomer [0503]
2-iodothiophene (22.9 g) were dissolved in THF (80 ml) under argon and 2 M isopropyl magnesium chloride (35.7 ml) in THF was added within 30 minutes at 0° C. After a reaction time of 1 hour at 3°-5° C., 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile (10 g) dissolved in tetrahydrofuran (20 ml) was added and stirred for 20 hours at room temperature. For working-up saturated NH[0504] ₄Cl solution was added (85 ml), the product was extracted with diethyl ether (3×100 ml) and the combined extracts were washed with water (50 ml) and saturated NaCl solution (50 ml), dried and concentrated by evaporation. The crude product obtained (21.3 g of dark brown oil) was dissolved in 2-butanone (140 ml) and converted with chlorotrimethylsilane (9.1 ml) into the hydrochloride of dimethyl-(8-thiophen-2-yl-1,4-dioxaspiro[4.5]dec-8-yl)-amine (white solid; 8.74 g).
Dimethyl-(8-thiophen-2-yl-1,4-dioxaspiro[4.5]dec-8-yl)-amine hydrochloride (8.68 g) was dissolved in 7.5 M hydrochloric acid (29 ml), stirred for 48 hours at room temperature and then extracted with diethyl ether (2×50 ml). The aqueous phase was adjusted alkaline with 5 M sodium hydroxide while cooling with ice, extracted with dichloromethane (3×50 ml), dried and concentrated by evaporation. 4-dimethylamino-4-thiophen-2-yl-cyclohexanone was thus obtained as a yellow solid (5.66 g; m.p. 108°-110° C.). [0505]
The hydrochloride of L-tryptophan methyl ester (1.01 g) was vigorously stirred for 15 minutes with 1,2-dichloroethane (20 ml) and saturated NaHCO[0506] ₃solution (20 ml) and the aqueous phase was immediately extracted with 1,2-dichloroethane (2×20 ml). After drying over sodium sulfate the organic phase was concentrated by evaporation to 40 ml and 4-dimethylamino-4-thiophen-2-yl-cyclohexanone (893 mg) was added under argon. Glacial acetic acid (0.228 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 4 days at room temperature. For working-up saturated NaHCO₃solution (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 extracts were dried and concentrated by evaporation, a pale brown oil being obtained. Column chromatography separation of the crude product was carried out with ethyl acetate and methanol. 500 mg of the non-polar diastereomer obtained (918 mg; m.p. 108°-112° C.) were dissolved in ethanol (50 ml). After the addition of 1.7 N KOH (13.8 ml, 23.5 mmole) a slight turbidity occurred, which disappeared during the hydrolysis. After a reaction time of 2.5 days the mixture was concentrated by evaporation, an oil separating out that was soluble in water (30 ml). After the addition of ethyl acetate (20 ml) the mixture was stirred for 30 minutes, potassium (S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionate precipitating out as a white solid (291 mg).

Example 98

(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid hydrochloride, polar diastereomer [0507]
As described for Example 97, 432 mg of the polar diastereomer of 2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid methyl ester were also obtained (m.p. 55°-58° C.). 250 mg were dissolved in ethanol (20 ml) and 1.7 M KOH (6.9 ml). After 2.5 days the mixture was concentrated by evaporation and the remaining yellow oil was dissolved in water (20 ml), washed with ethyl acetate (2×20 ml) followed by the addition of 5.5 N HCl (2.72 ml). Since no hydrochloride had precipitated the aqueous phase was concentrated by evaporation and stirred with ethanol (2×30 ml). The remaining KCl was separated off and the filtrate was concentrated by evaporation. In this way, after treatment with ether, (S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid hydrochloride was obtained as a beige-coloured solid (223 mg, m.p. 196°-199° C.) [0508]

Example 99

(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid hydrochloride, polar diastereomer [0509]
The hydrochloride of L-phenylalanine methyl ester (1.29 g) was vigorously stirred for 15 minutes with 1,2-dichloroethane (40 ml) and saturated NaHCO[0510] ₃solution (40 ml) and the aqueous phase was immediately extracted with 1,2-dichloroethane (2×40 ml). After drying over sodium sulfate the organic phase was concentrated to 40 ml by evaporation and 4-dimethylamino-4-phenylcyclohexanone (1.3 g) was added under argon. Glacial acetic acid (0.345 ml) and sodium sulfate (3 g) were added to the clear solution. After a reaction time of 15 minutes NaBH(OAc)₃(1.8 g) was added to the reaction mixture and stirred for 2 days at room temperature. For working-up saturated NaHCO₃solution (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 extracts were dried and then concentrated by evaporation, a pale brown oil being obtained. Chromatographic separation of the substance mixture on silica gel was carried out with ethyl acetate/methanol (20:1). The non-polar product (1.29 g) was obtained as a beige-coloured compound. 400 mg of this compound were dissolved in ethanol (30 ml) and 1.7 M KOH (12.4 ml). After 1 day the reaction mixture was concentrated by evaporation, an oil separating out that redissolved in water (20 ml). The aqueous solution was washed with ethyl acetate (2×20 ml) and 5.5 N HCl (4.77 ml) was added. Since no hydrochloride had precipitated, the aqueous phase was concentrated by evaporation and the residue was stirred with ethanol (2×20 ml). The remaining KCl was separated and the filtrate was concentrated by evaporation. (S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid hydrochloride was obtained in this way (436 mg, m.p. 205°-207° C.).

Example 100

Potassium rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyrate, non-polar diastereomer [0511]
The hydrochloride of 2-amino-4-phenylbutyric acid methyl ester (1.37 g) was vigorously stirred for 15 minutes with 1,2-dichloroethane (30 ml) and saturated NaHCO[0512] ₃solution (30 ml) and the aqueous phase was immediately extracted with 1,2-dichloroethane (2×30 ml). After drying over sodium sulfate the organic phase was concentrated to 40 ml by evaporation and 4-dimethylamino-4-phenylcyclohexanone (1.3 g) was added under argon. Glacial acetic acid (0.345 ml) and sodium sulfate (3 g) were added to the clear solution. After a reaction time of 15 minutes NaBH(OAc)₃(1.8 g) was added to the reaction mixture and stirred for 4 days at room temperature. For working-up saturated NaHCO₃solution (60 ml) was added to the mixture and stirred for 15 minutes. The aqueous phase was extracted with dichloromethane (2×30 ml). The combined organic extracts 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 (20:1). The non-polar product (1.34 g) was obtained as a beige-coloured compound, 484 mg of which were dissolved in ethanol (25 ml) and 1.7 M KOH (14.4 ml). After a reaction time of 3 days the mixture was concentrated by evaporation, an oil separating out that redissolved in water (20 ml). After the addition of ethyl acetate (20 ml), potassium 2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyrate crystallised out as a white solid (427 mg; m.p. 207°-210° C.).

Example 101

rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyric acid hydrochloride, polar diastereomer [0513]
As described for Example 100, 733 mg of the polar diastereomer of rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyric acid methyl ester were also obtained. [0514]
225 mg were dissolved in ethanol (20 ml) and 1.7 M KOH (6.7 ml). After 3 days the mixture was concentrated by evaporation, the remaining oil was dissolved in water (20 ml), washed with ethyl acetate (2×20 ml) and 5.5 N HCl (2.6 ml) was added. Since no hydrochloride had precipitated out the aqueous phase was concentrated by evaporation and stirred with ethanol (2×30 ml). The remaining KCl was separated off and the filtrate was concentrated by evaporation. The polar diastereomer of rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyric acid hydrochloride was thus obtained (240 mg, m.p. 153°-155° C.). [0515]

Example 102

(R)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionic acid hydrochloride, non-polar diastereomer [0516]
The hydrochloride of D-tryptophan methyl ester (1.49 g) was vigorously stirred for 15 minutes with 1,2-dichloroethane (40 ml) and saturated NaHCO[0517] ₃solution (40 ml) and the aqueous phase was immediately extracted with 1,2-dichloroethane (2×40 ml). After drying over sodium sulfate the organic phase was concentrated to 40 ml by evaporation and 4-dimethylamino-4-phenylcyclohexanone (1.48 g) was added under argon. Glacial acetic acid (0.392 ml) and sodium sulfate (3.4 g) were added to the clear solution. After a reaction time of 15 minutes NaBH(OAc)₃(2.05 g) was added to the reaction mixture and stirred for 2 days at room temperature. For working-up saturated NaHCO₃solution (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 dried and then concentrated by evaporation, a pale brown oil being obtained. Chromatographic separation of the substance mixture on silica gel was carried out with ethyl acetate/methanol (1.5:1). The non-polar product (1.64 g) was obtained as a beige-coloured compound, 640 mg of which were dissolved in ethanol (30 ml) and 1.7 N KOH (17.8 ml). After a reaction time of 2 days the mixture was concentrated by evaporation, an oil separating out that remained undissolved in water (20 ml) and ethyl acetate (20 ml). 5.5 N HCl (6.9 ml) was added to the aqueous phase with the oil. Since no hydrochloride precipitated out, the aqueous phase was concentrated by evaporation and the residue was digested with ethanol (2×20 ml). The remaining KCl was separated and the filtrate was concentrated by evaporation. The hydrochloride of the non-polar diastereomer of (R)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionic acid was thereby obtained (383 mg, m.p. 181°-195° C.).

Example 103

(R)-2-(4-dimethylamino-4-phenylcyclohexyl-amino)-3-phenylpropionic acid hydrochloride, non-polar diastereomer [0518]
The hydrochloride of D-phenylalanine methyl ester (1.29 g) was vigorously stirred for 20 minutes with 1,2-dichloroethane (30 ml) and saturated NaHCO[0519] ₃solution (30 ml) and the aqueous phase was immediately extracted with 1,2-dichloroethane (2×30 ml). The residue (960 mg) obtained after drying with sodium sulfate and concentration by evaporation was dissolved in 1,2-dichloroethane (50 ml) and 4-dimethylamino-4-phenylcyclohexanone (1.16 g) was added under argon. Glacial acetic acid (0.295 ml) and sodium sulfate (2 g) were added to the clear solution. After a reaction time of 15 minutes NaBH(OAc)₃(1.6 g) was added to the reaction mixture and stirred for 2 days at room temperature. Saturated NaHCO₃solution (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). 300 mg of the pale yellow non-polar product (1.16 g; [α]²⁰ _D=−2.79, (c=1.33 in trichloromethane)) were dissolved in ethanol (30 ml) and 1.7 N KOH (9.3 ml). After 2 days at room temperature the mixture was concentrated by evaporation. An oil then separated out which dissolved in water (20 ml). The aqueous phase was washed with ethyl acetate (2×20 ml) and 5.5 N HCl (3.6 ml, 20 mmole) was added. Since no hydrochloride had precipitated out, the aqueous phase was concentrated by evaporation and the residue was digested with ethanol (2×20 ml). The remaining KCl was filtered off and the filtrate was concentrated by evaporation. The hydrochloride of the non-polar acid of (R)-2-(4-dimethyl-amino-4-phenylcyclohexylamino)-3-phenylpropionic acid was thus obtained (230 mg, m.p. 211°-217° C.).

Example 104

rac-2-(4-dimethylamino-4-phenylcyclohexyl-amino)-3-(3-hydroxyphenyl)-propionic acid hydrochloride [0520]
The hydrochloride of 2-amino-3-(3-hydroxyphenyl) propionic acid methyl ester (1.16 g) was stirred for 10 minutes with saturated NaHCO[0521] ₃solution (30 ml). The solution was then evaporated to dryness on a rotary evaporator. The solid white residue was vigorously stirred with ethanol (2×50 ml), each time for 10 minutes, suction filtered, and the combined filtrates were concentrated by evaporation. The 2-amino-3-(3-hydroxyphenyl) propionic acid methyl ester obtained was dissolved in 1,2-dichloroethane (50 ml) under argon and 4-dimethylamino-4-phenylcyclohexanone (869 mg) was added. 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 NaHCO₃solution (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). 219 mg of the crude product obtained (632 mg of a pale brown oil) were dissolved in ethanol (22 ml) and 1.7 N KOH (5.75 ml). After a reaction time of 44 hours the mixture was concentrated by evaporation. An oil then separated out, which dissolved in water (20 ml). The aqueous phase was washed with ethyl acetate (2×20 ml) and 5.5 N HCl (2.12 ml) was added. Since no hydrochloride precipitated out, the aqueous phase was concentrated by evaporation and the residue was digested with ethanol (2×20 ml). The remaining KCl was separated and the filtrate was concentrated by evaporation. The hydrochloride of rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(3-hydroxyphenyl)-propionic acid were thus obtained (593 mg; m.p. 115°-125° C.).

Example 105

N-(4-dimethylamino-4-pyridin-2-yl-cyclohexyl)-N-[2-(1H-indol-3-yl)-ethyl]-acetamide dihydrochloride, non-polar diastereomer [0522]
200 ml of methanol, 1680 ml of aqueous dimethylamine solution (40 m %), 303 g of dimethylamine hydrochloride and 200 g of potassium cyanide were added to 200 g of 1,4-dioxaspiro[4.5]decan-8-one and stirred for ca. 65 hours. The white suspension obtained was extracted four times with 800 ml of ether each time, the combined extracts were concentrated by evaporation, the residue was taken up in ca. 500 ml of dichloromethane and the phases were separated. The organic phase was dried over sodium sulfate, filtered and concentrated by evaporation. 265 g of 8-dimethylamino-1,4-dioxaspiro[4.5]decane-8-carbonitrile were obtained as a white solid. [0523]
A solution of 4.5 g of 8-dimethylamino-1,4-dioxaspiro[4.5]-decane-8-carbonitrile, 50 mg of cyclopentadienyl-cycloocta-1,5-diene cobalt (I) [cpCo(cod)] and 100 ml of toluene was added to the reaction vessel in a countercurrent of protective gas/acetylene. After saturation with acetylene the reaction solution was irradiated 6 hours while stirring vigorously at a temperature of 25° C. The reaction was interrupted by switching off the lamps and air feed and the reaction solution was concentrated by evaporation. The crude product obtained (5.47 g) was taken up in a mixture of water (8.7 ml) and concentrated hydrochloric acid (15 ml) and stirred overnight at RT. For working-up the mixture was washed with diethyl ether (3×100 ml), the phases were separated, the aqueous phase was adjusted alkaline with 32 wt. % sodium hydroxide, extracted with dichloromethane (3×100 ml), and the combined extracts were dried (sodium sulfate), filtered and concentrated by evaporation. 3.72 g of 4-dimethylamino-4-pyridin-2-yl-cyclohexanone were obtained. [0524]
Acetic acid (0.448 ml) was added to a solution of 4-dimethylamino-4-pyridin-2-yl-cyclohexanone (873 mg) and tryptamine (640 mg) in dry tetrahydrofuran (40 ml) and anhydrous 1,2-dichloroethane (10 ml) under argon and stirred for 15 minutes. After the addition of sodium triacetoxy boron hydride (1.2 g) the reaction mixture was stirred for 3 days under argon at room temperature. For working-up the solvent was removed in vacuo, the residue was taken up in 1 N sodium hydroxide (40 ml) and diethyl ether (40 ml), the phases were separated, the aqueous phase was extracted with diethyl ether (2×30 ml), and the organic phases were combined, dried and concentrated by evaporation. The crude product obtained was separated by column chromatography on silica gel with methanol and methanol/ammonia (100:1). The non-polar diastereomer of N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexane-1,4-diamine was obtained as a white solid (617 mg; m.p. 150°-152° C.). [0525]
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). The aqueous phase of the filtrate was extracted with ethyl acetate (2×20 ml). The combined organic extracts were dried and then concentrated by evaporation. The residue thus obtained was identical to the solid obtained previously. Both substances were combined. 219 mg of N-(4-dimethylamino-4-pyridin-2-yl-cyclohexyl)-N-[2-(1H-indol-3-yl)-ethyl]-acetamide were obtained (m.p. 209°-210° C.), 195 mg of which were dissolved in 2-butanone (25 ml) while gently warming to 40° C. and were converted into the corresponding dihydrochloride with chlorotrimethyl-silane (0.303 ml) (white solid; 219 mg; m.p. 244°-247° C.). [0526]

Example 106

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexane-1,4-diamine trihydrochloride, non-polar diastereomer [0527]
The N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexane-1,4-diamine (342 mg) obtained according to Example 105 was dissolved in 2-butanone (20 ml) and converted into the corresponding trihydrochloride (beige-coloured solid; 408 mg) with chlorotrimethylsilane (0.59 ml). [0528]

Example 107

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexane-1,4-diamine trihydrochloride, polar diastereomer [0529]
As described for Example 105, 171 mg of the polar diastereomer of N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexane-1,4-diamine were also obtained, and were dissolved in 2-butanone (20 ml) and converted into the corresponding trihydrochloride with chlorotrimethylsilane (0.297 ml) (171 mg of beige solid, m.p. 225°-230° C.). [0530]

Example 108

N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexane-1,4-diamine trihydrochloride, non-polar diastereomer [0531]
The hydrochloride of L-tryptophan methyl ester (1.01 g) was vigorously stirred for 15 minutes with 1,2-dichloroethane (20 ml) and saturated NaHCO[0532] ₃solution (20 ml) and the aqueous phase was extracted with 1,2-dichloroethane (2×20 ml). After drying over sodium sulfate the organic phase was concentrated by evaporation to 40 ml and 4-dimethyl-amino-4-pyridin-2-yl-cyclohexanone (873 mg) was added under argon. Glacial acetic acid (0.448 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 4 days at room temperature. For working-up saturated NaHCO₃solution (40 ml) was added to the mixture and stirred for 15 minutes. The aqueous phase was extracted with dichloromethane (2×30 ml) and the combined organic phases were 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/methanol (4:1) and methanol. The non-polar product (820 mg of slightly oily compound) was dissolved in 2-butanone (50 ml) and converted with chlorotrimethylsilane (1.22 ml) into the trihydrochloride (719 mg of white hygroscopic solid; [α]_D ²⁰=19.85 (MeOH, c=1.33)).

Example 109

(S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid methyl ester trihydrochloride, polar diastereomer [0533]
As described for Example 108, 284 mg of the polar diastereomer of (S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid methyl ester were also obtained, and were dissolved in 2-butanone (15 ml) and converted into the corresponding trihydrochloride with chlorotrimethylsilane (0.43 ml) (171 mg of white solid, m.p. 170°-175° C.; [α][0534] _D ²⁰=17.61 (MeOH, c=1.45)).

Example 110

(S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid dihydrochloride, non-polar diastereomer [0535]
1.7 N KOH (8.8 ml) was added to a solution of the non-polar diastereomer of N′-[2-(1H-indol-3-yl)-ethyl]-N,N-dimethyl-1-pyridin-2-yl-cyclohexane-1,4-diamine trihydrochloride (378 mg) in ethanol (20 ml) prepared according to Example 108. After 70 hours the reaction mixture was concentrated by evaporation, the remaining yellow oil was dissolved in water (10 ml), the aqueous phase was washed with ethyl acetate (3×20 ml), and 5.5 N HCl (9.0 ml) was added. The aqueous phase was concentrated by evaporation and the residue was digested with ethanol (2×20 ml). The remaining KCl was separated and the filtrate was concentrated by evaporation and washed with ether. The dihydrochloride of (S)-2-(4-dimethylamino-4-pyridin-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid dihydrochloride (non-polar diastereomer) was thereby obtained (307 mg; [α][0536] _D ²⁰=20.69 (MeOH, c=1.213)).

Example 111

μ-Binding [0537]
The affinity of the compounds for the μ-opioid receptor was determined by known methods, in particular by a radioactive displacement assay, and is expressed as Ki value in μM. [0538]

TABLE 1

μ-Opioid Receptor

Example K_i(μM)

94 0.0011

95 0.0012

96 0.0091

97 0.0021

98 0.079

99 0.014

100 0.0008

101 0.140

102 0.0210

103 91% (1 μM)*

104 97% (1 μM)*
The investigated compounds all exhibited a pronounced μ-binding, which clearly points to an analgesic action and action according to the invention since the peripheral μ-receptors are, as discussed in the introduction, involved in irritable bowel disease as well as in diarrhea and also in peripheeral analgesia and immunomodulation. [0539]

Example 112

Analgesia Testing in the Tail Flick Test in Mice [0540]
The 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. [0541]
The solutions of the compound of the general formula I as well as the comparison solutions were then administered intravenously. The pain measurement was carried out in each case 10, 20, 40 and 60 minutes after the intravenous administration. The analgesic action was determined as the increase in the pain latency (percent of the maximum possible antinociceptive effect according to the following formula:[0542]
[(T₁-T₀)/(T₂-T₀)]×100
Here the time T[0543] ₀is the latency time before the application, the time T₁is the latency time after the application of the active substances combination, and the time T₂is the maximum exposure time (12 seconds).
The ED[0544] ₅₀was 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.

The results of the selected investigations are summarised in the following table.

TABLE 2


Example
No.	CNS Analgesia

94	1.0-4.64 = ineff.
	10.0 = 70-80% MPE
95	1.0-31.6 = ineff.
96	10.0 = ineff.
97	10.0-21.5 = ineff.
98	10.0 = ineff.
99	10.0 = 48% MPE (5/10)
100	10.0 = ineff.
101	10.0 = ineff.
102	10.0 = ineff.
103	10.0 = ineff.

The prepared investigated compounds showed despite a clear μ-binding (see above; Example 111), which is clear evidence of an analgesic effect according to the invention, no analgesic effect in this model, which should be regarded as a pattern for the CNS analgesic effect. If therefore these compounds bind strongly to the μ-receptor but do not exhibit any CNS pain inhibition, this can only mean that they bind to and act on the peripheral μ-receptor—for example analgesically—and more specifically without exhibiting CNS side effects. [0546]

Example 113

Diarrhea Suppression [0547]
Mice were investigated in the standard model of PGE[0548] 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[0549] ₅₀value was determined from several concentration-dependent measurements.

Example 114

Comparison of the Anti-diarrhea Action of Examples 94, 97, 96 and 98 with Loperamide: [0550]
The substance loperamide is a peripheral opioid—acknowledged not to have any peripheral side effects—which is used as an antidiarrhetic. [0551]
The ED[0552] ₅₀values with i.v. administration in the known model of PGE2-induced diarrhea are given as mg/kg.

TABLE 4

Example ED₅₀Value

No. (mg/kg) i.v.

Loperamide 0.41

95 0.23

94 0.53

97 0.78

96 2.77

98 3.88

Example 115

Comparison of the (Anti-diarrhea) Action of Example 95 with Loperamide: [0553]

In direct comparison between Example 95 and loperamide the following result was found:

TABLE 5


Experiment	Example 95	Loperamide

Analgesia, tail flick	ineffective up	ED₅₀> 0.562
test in mice, i.v.	to 31.6	toxic from 0.464
According to Example 112
PGE₂-diarrhea, mice [μM]	ED₅₀i.v. = 0.23	ED₅₀i.v. = 0.41
	ED₅₀p.o. = 12.6	ED₅₀p.o. = 9.34
Carbon passage, mice	ED₅₀i.v. = 0.32	ED₅₀i.v. = n.m.
[μM]	ED₅₀p.o. = n.m.	ED₅₀p.o. = ˜15

The PGE[0555] ₂diarrhea test as well as the carbon passage are known standard test systems for diarrhea. The ED₅₀was 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[0556] ₂diarrhea test, which is also confirmed by the carbon passage measurement.

Example 116

Parenteral Solution of a Substituted cyclohexane-1,4-diamine Compound [0557]
38 g of one of the substituted cyclohexane-1,4-diamine compounds according to the invention, here according to Example 95, is dissolved in 1 l of water for injection purposes at room temperature and is then adjusted to isotonic conditions by addition of anhydrous glucose for injection purposes. [0558]
The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Since modifications of the described embodiments incorporating the spirit and substance of the invention may occur to persons skilled in the art, the invention should be construed broadly to include all variations within the scope of the appended claims and equivalents thereof. [0559]

Claims

1. A method of treating diarrhea or irritable bowel disease or administering immunotherapeutic treatment to a patient, said method comprising administering to said patient a pharmaceutically effective amount of a substituted cyclohexane-1,4-diamine compound corresponding to formula I

wherein

R¹and R²are independently selected from the group consisting of H; C_1-8-alkyl and C_3-8-cycloalkyl, each saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl and heteroaryl, each singly or multiply substituted or unsubstituted; and aryl, C_3-8-cycloalkyl and heteroaryl each bound via C_1-3-alkylene and each singly or multiply substituted or unsubstituted; or

R¹and R²together form a ring and denote CH₂CH₂OCH₂CH₂, CH₂CH₂NR⁶CH₂CH₂or (CH₂)_3-6, where

R⁶is selected from the group consisting of H; C_1-8-alkyl and C_3-8-cycloalkyl, each saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl and heteroaryl, each singly or multiply substituted or unsubstituted; and aryl, C_3-8-cycloalkyl and heteroaryl, each bound via C_1-3-alkylene and each singly or multiply substituted or unsubstituted;

R³is selected from the group consisting of C_1-8-alkyl and C_3-8-cycloalkyl, each saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl and heteroaryl, each unsubstituted or singly or multiply substituted; and aryl, C_3-8-cycloalkyl and heteroaryl, each bound via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C_1-4-alkylene group and each unsubstituted or singly or multiply substituted;

R⁴is selected from the group consisting of H; C_1-8-alkyl, saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; C(X)R⁷; C(X)NR⁷R⁸; C(X)OR⁹; C(X)SR⁹, and S(O₂) R⁹, where

X=O or S;

R⁷is selected from the group consisting of H; C_1-8-alkyl and C_3-8-cycloalkyl, each saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl and heteroaryl, each unsubstituted or singly or multiply substituted; and aryl, C_3-8-cycloalkyl and heteroaryl, each bound via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C_1-4-alkylene group and each unsubstituted or singly or multiply substituted; and

R⁸is selected from the group consisting of H and C_1-4-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; or

R⁷and R⁸together form a ring and denote CH₂CH₂OCH₂CH₂, CH₂CH₂NR¹⁰CH₂CH₂or (CH₂)_3-6, where

R¹⁰is selected from the group consisting of H; C_1-8-alkyl or C_3-8-cycloalkyl, each saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl and heteroaryl, each singly or multiply substituted or unsubstituted; and aryl, C_3-8-cycloalkyl and heteroaryl, each bound via C_1-3-alkylene and each singly or multiply substituted or unsubstituted; and

R⁹is selected from the group consisting of C_1-8-alkyl and C_3-8-cycloalkyl, each saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; aryl and heteroaryl, each unsubstituted or singly or multiply substituted; and aryl, C_3-8-cycloalkyl and heteroaryl, each bound via a saturated or unsaturated, branched or unbranched, substituted or unsubstituted C_1-4-alkylene group and each unsubstituted or singly or multiply substituted; and

R⁵is selected from the group consisting of C_3-8-cycloalkyl, aryl and heteroaryl, each unsubstituted or singly or multiply substituted; —CHR¹¹R¹²; —CHR¹¹—CH₂R¹²; —CHR¹¹—CH₂—CH₂R¹²; —CHR¹¹—CH₂—CH₂—CH₂R¹²; —C(Y)R¹²; —C(Y)—CH₂R¹²; —C(Y)—CH₂—CH₂R ¹², and —C(Y)—CH₂—CH₂—CH₂R¹², where

Y=O, S or H₂;

R¹¹ is selected from the group consisting of H; C_1-7-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; and C(O)O—C_1-6-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; and

R¹²is selected from the group consisting of H; C_3-8-cycloalkyl, aryl or heteroaryl, each unsubstituted or singly or multiply substituted; or

R⁴and R⁵together form a heterocycle with from 3 to 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,

or a salt thereof with a physiologically acceptable acid or base.

2. A method according to claim 1, wherein said compound is in the form of a racemate.

3. A method according to claim 1, wherein said compound is in the form of a pure stereoisomer.

4. A method according to claim 3, wherein said stereoisomer is in the form of a pure enantiomer.

5. A method according to claim 3, wherein said stereoisomer is in the form of a pure diastereomer.

6. A method according to claim 1, wherein said compound is the the form of mixture of stereoisomers in an arbitrary mixing ratio.

7. A method according to claim 1, wherein said compound is in the form of a free base.

8. A method according to claim 1, wherein said compound is in the form of a salt with a physiologically compatible acid.

9. A method according to claim 1, wherein said compound is in the form of a solvate.

10. (canceled)

11. A method according to claim 1, wherein in said compound R¹and R²are not both H.

12. A method according to claim 1, wherein R¹and R²in said compound are independently selected from the group consisting of H, and C_1-8-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted, with the proviso that R¹and R²are not both H, or R¹and R²together form a ring and denote CH₂CH₂OCH₂CH₂, CH₂CH₂NR⁶CH₂CH₂or (CH₂)_3-6, where R⁶is selected from the group consisting of H and C_1-8-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted.

13. A method according to claim 12, wherein R¹and R²are independently selected from the group consisting of H, and C_1-4-alkyl which is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted, with the proviso that R¹and R²are not both H, or wherein R¹and R²together form a ring and denote (CH₂)_4-5.

14. (cancelled)

15. A method according to claim 1, wherein R³in said compound is selected from the group consisting of C_3-8-cycloalkyl, aryl and heteroaryl, each unsubstituted or singly or multiply substituted; and aryl, C_3-8-cycloalkyl and heteroaryl, each bound via a saturated or unsaturated, unbranched, substituted or unsubstituted C_1-2-alkylene group and each unsubstituted or singly or multiply substituted.

16. A method according to claim 15, wherein R³in said compound is selected from the group consisting of C_5-6-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl, and pyrazinyl, each unsubstituted or singly or multiply substituted; and C_5-6-cycloalkyl, phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl and pyrazinyl, each bound via a saturated, unbranched C_1-2-alkylene group and each unsubstituted or singly or multiply substituted.

17. A method according to claim 15, wherein R³in said compound is selected from the group consisting of phenyl, furyl, thiophenyl, cyclohexanyl, naphthyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyrrolyl, pyridyl, pyrazinyl and benzothiophenyl, each unsubstituted or singly or multiply substituted; and phenyl, furyl and thiophenyl, each bound via a saturated, unbranched C_1-2-alkylene group and each unsubstituted or singly or multiply substituted.

18. A method according to claim 1, wherein R⁴in said compound is H.

19. A method according to claim 1, wherein R⁴in said compound is selected from the group consisting of H, C(X)R⁷, C(X)NR⁷R⁸, C(X)OR⁹, C(X)SR⁹and S(O₂)R⁹, where X=O or S.

20. A method according to claim 19, wherein R⁴in said compound is selected from the group consisting of H, C(X)R⁷, C(X)NR⁷R⁸and C(X)OR⁹, where X=O.

21. A method according to claim 19, wherein R⁴in said compound is H or C(O)R⁷, where R⁷is H or C_1-8-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted.

22. (canceled)

23. (canceled)

24. A method according to claim 1, wherein in said compound R⁴and R⁵together with the N-atom to which they are bound form a heterocyclic ring containing from 3 to 8 atoms, which is saturated or unsaturated; singly or multiply substituted or unsubstituted.

25. A method according to claim 24, wherein said heterocyclic ring contains from 5 to 7 atoms and in addition to the N-atom to which R4 and R5 are bound contains 0 to 1 heteroatom selected from the group consisting of N, S and O.

26. A method according to claim 24, wherein the heterocyclic ring formed by R⁴and R⁵is condensed with at least one further ring.

27. (canceled)

28. (canceled)

29. A method according to claim 26, wherein the heterocyclic ring formed by R⁴and R⁵is condensed with two further rings to produce

30. A method according to claim 1, wherein R⁴in said compound is selected from the group consisting of H, and C_1-8-alkyl that is saturated or unsaturated, branched or unbranched, and singly or multiply substituted or unsubstituted.

31. A method according to claim 30, wherein R⁴in said compound is selected from the group consisting of H, and C_1-6-alkyl that is saturated or unsaturated, branched or unbranched, and singly or multiply substituted or unsubstituted.

32. (canceled)

33. A method according to claim 1, wherein R⁵in said compound is selected from the group consisting of C_1-8-cycloalkyl, aryl and heteroaryl, each unsubstituted or singly or multiply substituted.

34. A method according to claim 33, wherein R⁵in said compound is selected from the group consisting of cyclobutyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, anthracenyl, indolyl, naphthyl, benzofuranyl, benzothiophenyl, indanyl, benzodioxanyl, benzodioxolanyl, acenaphthyl, carbazolyl, phenyl, thiophenyl, furyl, pyridyl, pyrrolyl, pyrazinyl, pyrimidyl, fluorenyl, fluoranthenyl, benzothiazolyl, benzotriazolyl, benzo[1,2,5]thiazolyl, 1,2-dihydroacenaphthenyl, pyridinyl, furanyl, benzofuranyl, pyrazolinonyl, oxopyrazolinonyl, dioxolanyl, adamantyl, pyrimidinyl, quinolinyl, isoquinolinyl, phthalazinyl and quinazolinyl, each unsubstituted or singly or multiply substituted.

35. (canceled)

36. A method according to claim 1, wherein R⁵in said compound is selected from the group consisting of —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂CH₂R¹², —CHR¹¹—CH₂—CH₂—CH₂R¹², —C(Y)R¹², —C(Y)—CH₂R¹², —C(Y)—CH₂—CH₂R¹², and —C(Y)—CH₂—CH₂—CH₂R¹², where Y=O, S or H₂.

37. A method according to claim 36, wherein R⁵in said compound is selected from the group consisting of —CHR¹¹R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹², —C(Y)R¹², —C(Y)—CH₂R¹², and —C(Y)—CH₂—CH₂R¹², where Y=O or S.

38. (canceled)

39. A method according to claim 36, wherein R¹¹in said compound is selected from the group consisting of H; C_1-4-alkyl that is saturated or unsaturated, branched or unbranched, and singly or multiply substituted or unsubstituted; and

C(O)O—C_1-4-alkyl that is saturated or unsaturated, branched or unbranched, and singly or multiply substituted or unsubstituted.

40. (canceled)

41. (canceled)

42. A method according to claim 36, wherein R¹²in said compound is selected from the group consisting of C_3-8-cycloalkyl, aryl and heteroaryl, each unsubstituted or singly or multiply substituted.

43. (canceled)

44. (canceled)

45. A method according to claim 1, wherein said compound is selected from the group consisting of:

potassium (S)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionate, non-polar diastereomer;

potassium rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(5-fluoro-1H-indol-3-yl)-propionate, non-polar diastereomer;

potassium rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(6-fluoro-1H-indol-3-yl)-propionate, non-polar diastereomer;

potassium (S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionate, non-polar diastereomer;

(S)-2-(4-dimethylamino-4-thiophen-2-yl-cyclohexylamino)-3-(1H-indol-3-yl)-propionic acid hydrochloride, polar diastereomer;

(S)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-phenylpropionic acid hydrochloride, non-polar diastereomer;

potassium rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyrate, non-polar diastereomer;

rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-4-phenylbutyric acid hydrochloride, polar diastereomer;

(R)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(1H-indol-3-yl)-propionic acid hydrochloride, non-polar diastereomer;

(R)-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-phenylpropionic acid hydrochloride, non-polar diastereomer, and

rac-2-(4-dimethylamino-4-phenylcyclohexylamino)-3-(3-hydroxyphenyl)-propionic acid hydrochloride.

46. A method of treating peripheral pain in a patient, said method comprising administering to said patient an effective peripheral analgesically effective amount of a substituted cyclohexane-1,4-diamine compound corresponding to formula I

wherein

R⁴is selected from the group consisting of H; C(X)R⁷; C(X)NR⁷R⁸; C(X)OR⁹; C(X)SR⁹, and S(O₂)R⁹, where

X=O or S;

R⁵is selected from the group consisting of C_3-8-cycloalkyl, aryl and heteroaryl, each unsubstituted or singly or multiply substituted; —CHR¹¹R¹²; —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹², —CHR¹¹—CH₂—CH₂—CH₂R¹²; —C(Y)R¹²; —C(Y)—CH₂R¹², —C(Y)—CH₂—CH₂R¹², and —C(Y)—CH₂—CH₂—CH₂R¹², where

Y=O, S or H₂;

R¹¹is selected from the group consisting of H; C_1-7-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; and C(O)O—C_1-6-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted; and

R¹²is selected from the group consisting of H; C_3-8-cycloalkyl, aryl or heteroaryl, each unsubstituted or singly or multiply substituted;

or a salt thereof with a physiologically acceptable acid or base.

47. (canceled)

48. A method according to claim 46, wherein said compound is in the form of a pure stereoisomer.

49. (canceled)

50. (canceled)

51. (canceled)

52. (canceled)

53. (canceled)

54. A method according to claim 46, wherein said compound is in the form of a solvate.

55. (canceled)

56. (canceled)

57. A method according to claim 46, wherein R¹and R²in said compound are independently selected from the group consisting of H, and C_1-8-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted, with the proviso that R¹and R²are not both H, or R¹and R²together form a ring and denote CH₂CH₂OCH₂CH₂, CH₂CH₂NR⁶CH₂CH₂or (CH₂)_3-6, where R⁶is selected from the group consisting of H and C_1-8-alkyl that is saturated or unsaturated, branched or unbranched, singly or multiply substituted or unsubstituted.

58. (canceled)

59. (canceled)

60. A method according to claim 46, wherein R³in said compound is selected from the group consisting of C_3-8-cycloalkyl, aryl and heteroaryl, each unsubstituted or singly or multiply substituted; and aryl, C_3-8-cycloalkyl and heteroaryl, each bound via a saturated or unsaturated, unbranched, substituted or unsubstituted C_1-2-alkylene group and each unsubstituted or singly or multiply substituted.

61. (canceled)

62. (canceled)

63. (canceled)

64. A method according to claim 46, wherein R⁴in said compound is selected from the group consisting of H, C(X)R⁷, C(X)NR⁷R⁸and C(X)OR⁹, where X=O.

65. (canceled)

66. (canceled)

67. (canceled)

68. A method according to claim 46, wherein R⁵in said compound is selected from the group consisting of C_3-8-cycloalkyl, aryl and heteroaryl, each unsubstituted or singly or multiply substituted.

69. (canceled)

70. (canceled)

71. A method according to claim 46, wherein R⁵in said compound is selected from the group consisting of —CHR¹¹—R¹², —CHR¹¹—CH₂R¹², —CHR¹¹—CH₂—CH₂R¹², —CHR¹¹—CH₂—CH₂—CH₂R¹², —C(Y)R¹², —C(Y)—CH₂R₁₂, —C(Y)—CH₂—CH₂R¹², and —C(Y)—CH₂—CH₂—CH₂R¹²,

where

Y=O, S or H₂.

72. (canceled)

73. (canceled)

74. (canceled)

75. (canceled)

76. (canceled)

77. (canceled)

78. (canceled)

79. (canceled)

80. A method according to claim 46, wherein said compound is selected from the group consisting of:

81. A method according to claim 46, wherein said peripheral pain is selected from the group consisting of burn pains, pain in inflammation of soft tissues, peripheral operation pain and inflammatory joint disease pain.

82. (canceled)