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  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
  • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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  • C07C2601/14—The ring being saturated

Definitions

• the present invention relates to substituted cyclohexylacetic acid derivatives, processes for their preparation, medicaments containing these compounds and the use of substituted cyclohexylacetic acid derivative derivatives for the preparation of medicaments.
• Classic ⁇ -opioids such as morphine are effective in the treatment of severe to severe pain and of paramount importance for pain therapy.
• other opioid receptors in particular the ORL-1 receptor, are also influenced, since the pure ⁇ -opioids also have undesirable side effects such as constipation and
• opioid receptors ⁇ , K and ORL-1 are also involved in pain (Opioids: Introduction, pp. 127-150, Further Opioid Receptors, 455-476 in: Analgesics - From Chemistry and Pharmacology to Clinical Application, Wiley VCH, 2002 ).
• opioids for example: tramadol, s. Opioids with Clinical Relevance: Tramadol, 228-230 in: Analgesics - From Chemistry and Pharmacology to Clinical Application, Wiley VCH 2002.
• the ORL1 receptor is also involved in the regulation of other physiological and pathophysiological processes. These include, inter alia, learning and memory formation (Manabe et al., Nature, 394, 1997, pp. 577-581), hearing (Nishi et al., EMBO J., 16, 1997, pp. 1858-1864) and numerous further processes.
• learning and memory formation Manabe et al., Nature, 394, 1997, pp. 577-581
• hearing Neishi et al., EMBO J., 16, 1997, pp. 1858-1864
• Glutamate serotonin and dopamine, and thus new rodegenerative diseases; Influence of the cardiovascular system, induction of an erection, diuresis, antinatriuresis, electrolyte balance, arterial blood pressure, water retention diseases, intestinal motility (diarrhea), respiratory relaxant effects, micturition reflex (urinary incontinence). Furthermore, the use of agonists and antagonists as anoretic agents, analgesics (also in co-administration with opioids) or nootropics is discussed.
• the object of the present invention was to provide medicaments which act on the opioid receptor system and thus for medicaments, in particular for the treatment of the various diseases associated with this prior art system or for use in the art indicated there indications are suitable.
• the compounds should influence norepinephrine and serotonin reuptake.
• the invention therefore relates to substituted cyclohexylacetic acid derivatives of the general formula I
• R ⁇ and R 2 independently of one another, denote H; CHO; C - j _ 5 alkyl in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C .g-Cycloalkyl, in each case saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; or via Ci.
• R 1 and R 2 together are CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 or (CH 2 ) 3 _6, where R 1 is H; C j _5-alkyl, respectively saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C .g-Cycloalkyl, in each case saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; or C j .3-alkyl-bound aryl, C .g- cycloalkyl or heteroaryl, respectively singly or multiply substitute
• Cycloalkyl in each case saturated or unsaturated, mono- or polysubstituted or unsubstituted; j over C-. -Alkyl group bonded aryl, heteroaryl or C3_g-cycloalkyl, each unsubstituted or mono- or polysubstituted;
• R 9 is H or C ⁇ - 5 alkyl, saturated or unsaturated, branched or unbranched, unsubstituted or singly or multiply substituted;
• R 5 is H or for- (CH 2 ), R 8 , where I is 1, 2 or 3, odedeerr Zuzussaammmmeen with R 4 for CH 2 CH 2 ⁇ CH 2 CH 2 , CH 2 CH 2 NR 11 CH 2 CH 2 or (CH 2 ) 3 _ 6, where R1 1 is H; C 1-4 alkyl, in each case saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C3_g-cycloalkyl, in each case saturated or unsaturated, monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; or aryl, C 3-8 -cycloalkyl or heteroaryl bonded via C 1-6 -alkyl, in each case monosubstituted or polysubstituted or unsubstituted; in
• the compounds of the invention show good binding to the ⁇ receptor and the ORL-1 receptor, but also to other opioid receptors. Surprisingly, it has been found that the compounds are also good inhibitors of noradrenaline and serotonin reuptake. Thus, they are also suitable for the treatment of depression, and / or bulimia and / or anorexia and / or catalepsy and / or for anxiolysis and / or for vigilance and / or libido enhancement.
• C 1-6 -alkyl and “C 1-4 -alkyl” in the context of this invention include acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chained and unsubstituted or monosubstituted or polysubstituted with 1, 2, 3 , 4 or 5 C atoms or 1, 2 or 3 C atoms, ie: C
• Alkenyls have at least one CC double bond and alkynyls at least one CC triple bond.
• cycloalkyl or "C3_g-cycloalkyr” for the purposes of this invention means cyclic hydrocarbons having 3, 4, 5, 6, 7 or 8 carbon atoms wherein the hydrocarbons are saturated or unsaturated (but not aromatic), unsubstituted or mono- or polysubstituted With respect to
• Cycloalkyl also includes saturated or unsaturated (but not aromatic) cycloalkyls in which one or two carbon atoms are replaced by a heteroatom S, N or O.
• C3_g-cycloalkyl is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
• Tetrahydropyranyl dioxanyl, dioxolanyl, morpholinyl, piperidinyl, piperazinyl,
• (CH 2 ) 3-6 is -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - CH 2 -CH 2 - and CH 2 -CH 2 -CH 2 -CH 2 -CH 2 - to understand.
• aryl in the context of this invention means carbocyclic ring systems having at least one aromatic ring, but without heteroatoms in only one of the rings, including phenyls, naphthyls and phenanthrenyls, fluoranthenyls, fluorenyls, indanyls and tetralinyls.
• the aryl radicals can also be condensed with further saturated, (partially) unsaturated or aromatic ring systems.
• Each aryl radical may be unsubstituted or monosubstituted or polysubstituted, wherein the aryl substituents may be the same or different and in any and possible position of the aryl. Particularly advantageous are phenyl or naphthyl radicals.
• heteroaryl represents a 5-, 6- or 7-membered cyclic aromatic radical containing at least 1, optionally also 2, 3, 4 or 5 heteroatoms, wherein the heteroatoms are the same or different and the heterocycle is unsubstituted or may be monosubstituted or polysubstituted; in the case of substitution on the heterocycle, the substituents may be the same or different and may be in any and possible position of the heteroaryl.
• the heterocycle may also be part of a bi- or polycyclic system. Preferred heteroatoms are nitrogen, oxygen and sulfur.
• the heteroaryl radical is selected from the group consisting of pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzodioxolanyl, benzodioxanyl, phthalazinyl, pyrazolyl, imidazolyl, Thiazolyl, oxazolyl, isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl or oxadiazolyl, wherein the bond to the compounds of general structure
• substituted in the context of "alkyl” means the substitution of one or more hydrogen radicals by F, Cl, Br, I, OO, -CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-cycloalkyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-OH, N (alkyl) 2 , N (alkyl-aryl) 2 , N (alkyl-heteroaryl) 2) N ( Cycloalkyl) 2 , N (alkyl-OH) 2 , NO 2 , SH, S-alkyl, S-aryl, S-heteroaryl, S-alkyl-aryl, S-alkyl-heteroaryl, S-cycloalkyl, S-alkyl-OH , S-alkyl-SH, OH, O-alkyl,
• aryl In the context of this invention, "aryl”, “heteroaryl” and “cycloalkyl” are understood as meaning “monosubstituted or polysubstituted” the one or more, for example two, three, four or five times, substitution of one or more hydrogen atoms of the ring system by F, Cl, Br, I, CN, NH 2 , NH-alkyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-cycloalkyl, NH-alkyl-OH, N (alkyl) 2 , N (alkyl-aryl) 2 , N (alkyl-heteroaryl) 2 , N (cycloalkyl) 2 , N (alkyl-OH) 2 , NO 2 , SH, S-alkyl, S-cycloalkyl, S -Aryl, S-heteroaryl, S-al
• salt means any form of the active ingredient according to the invention in which it assumes an ionic form or is charged and is coupled with a counterion (a cation or anion) or is in solution.
• a counterion a cation or anion
• salts also include complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed via ionic interactions.
• physiologically acceptable salts in particular physiologically acceptable salts with cations or bases and physiologically acceptable salts with anions or acids or else a salt formed with a physiologically acceptable acid or a physiologically compatible cation.
• physiologically acceptable salt with anions or acids is understood as meaning salts of at least one of the compounds according to the invention-usually, for example, nitrogen-protonated-as a cation having at least one anion which is physiologically-in particular when used in humans and / or Mammal - are compatible.
• a physiologically acceptable acid namely salts of the respective active ingredient with inorganic or organic acids, which are physiologically compatible - in particular when used in humans and / or mammals.
• physiologically acceptable salts of certain acids are salts of: 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, saccharic acid, monomethylsebacic acid, 5-oxo-proline , Hexane-1-sulfonic acid, nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, ⁇ -lipoic acid, acetylglycine, phosphoric acid, maleic acid, malonic acid, hippuric acid and / or aspartic acid.
• Particularly preferred is the hydrochloride d-salt, citrate and hemicitrate.
• salt formed with a physiologically acceptable acid means salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals.
• Particularly preferred is the hydrochloride and the citrate.
• physiologically acceptable acids are: 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, saccharic acid, monomethylsebacic acid, 5-oxoproline, hexane-1-sulfonic acid , Nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethylbenzoic acid, ⁇ -lipoic acid, acetylglycine, hippuric acid and / or aspartic acid.
• physiologically compatible salt with cations or bases refers to salts of at least one of the compounds according to the invention-usually a (deprotonated) acid-as an anion having at least one, preferably inorganic, cation which is physiologically-in particular when used in humans and / or mammalian.
• Particularly preferred are the salts of the alkali and alkaline earth metals but also ammonium salts, but especially (mono-) or (di) sodium, (mono-) or (di) potassium, magnesium or calcium salts.
• the term salt formed with a physiologically compatible cation means salts of at least one of the respective compounds as anion with at least one inorganic cation which is physiologically acceptable, in particular when used in humans and / or mammals.
• Particularly preferred are the salts of the alkali and alkaline earth metals but also ammonium salts, but especially (mono-) or (di) sodium, (mono-) or (di) potassium, magnesium or calcium salts.
• R 1 and R 2 are each independently H; saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; or the radicals R 1 and R 2 together form a ring and CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 or (CH 2 ) 3_6, wherein R 1 0 H; C j _5-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, means. Particular preference is given to substituted cyclohexylacetic acid derivatives in which R 1 and R 2 independently of one another are CH 3 or H, where R 1 and R 2 do not simultaneously denote H.
• R 3 is cyclopentyl, cyclohexyl, naphthyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl or pyridyl, each unsubstituted or mono- or polysubstituted; over a saturated, unbranched C
• R 3 is pyridyl, substituted or unsubstituted, or phenyl, 2-fluorophenyl, 3-fluorophenyl or 4-fluorophenyl.
• substituted cyclohexylacetic acid derivatives in which R 5 is H are also preferred.
• R 8 is 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-dihydroacenaphthyl, pyridinyl, furanyl, Benzofuranyl
• R8 is 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 monosubstituted or polysubstituted means.
• R 8 is phenyl or indolyl, in each case monosubstituted or polysubstituted.
• the substances according to the invention act, for example, on the ORL-1 receptor relevant in connection with various diseases, so that they are suitable as a pharmaceutical active substance in a pharmaceutical.
• Another object of the invention are therefore pharmaceutical compositions comprising at least one inventive substituted cyclohexycarboxylic acid derivative, and optionally suitable additives and / or auxiliaries and / or optionally other active ingredients.
• the medicaments according to the invention optionally contain suitable additives and / or adjuvants, such as carrier materials, fillers, solvents, diluents, dyes and / or binders and can be used as liquid dosage forms in the form of injection solutions, drops or juices, be administered as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, patches / spray patches or aerosols.
• suitable additives and / or adjuvants such as carrier materials, fillers, solvents, diluents, dyes and / or binders and can be used as liquid dosage forms in the form of injection solutions, drops or juices, be administered as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, patches / spray patches or aerosols.
• suitable additives and / or adjuvants such as carrier materials, fillers, solvents, diluents, dyes and / or binders
• the amounts to be used depend on whether the drug is administered orally, perorally, parenterally, intravenously, intraperitoneally, intradermally, intramuscularly, intranasally, buccally, rectally or locally, for example, on the skin, the mucous membranes or the eyes, should be applied.
• preparations in the form of tablets, dragees, capsules, granules, drops, juices and syrups are suitable, for parenteral, topical and inhalative administration solutions, suspensions, readily reconstitutable dry preparations and sprays.
• Substituted cyclohexylacetic acid derivatives according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of skin penetration promoting agents, are suitable percutaneous administration preparations. Orally or percutaneously applicable preparation forms can release the substituted cyclohexylacetic acid derivatives according to the invention with a delay.
• the substituted cyclohexylacetic acid derivatives of the invention can also be used in parenteral long-term depot forms such. As implants or implanted pumps are applied. In principle, other active compounds known to the person skilled in the art may be added to the medicaments according to the invention.
• the amount of drug to be administered to the patient varies depending on the weight of the patient, the mode of administration, the indication and the severity of the disease. Usually 0.00005 to 50 mg / kg, preferably 0.01 to 5 mg / kg of at least one substituted cyclohexylacetic acid derivative according to the invention are applied.
• the medicament contains, in addition to at least one substituted cyclohexylacetic acid derivative, another active substance, in particular an opioid, preferably a strong opioid, in particular morphine, or an anesthetic, preferably hexobarbital or halothane.
• another active substance in particular an opioid, preferably a strong opioid, in particular morphine, or an anesthetic, preferably hexobarbital or halothane.
• a substituted substituted cyclohexylacetic acid derivative according to the invention is present as a pure diastereomer and / or
• Enantiomer as a racemate or as a non-equimolar or equimolar mixture of the diastereomers and / or enantiomers.
• the ORL-1 receptor but also the other opioid receptors, have been identified in particular in pain. Accordingly, substituted cyclohexylacetic acid derivatives of the invention can be used for the manufacture of a medicament for the treatment of pain, in particular of acute, neuropathic or chronic pain.
• Another object of the invention is therefore the use of a substituted cyclohexylacetic acid derivative of the invention for the manufacture of a medicament for the treatment of pain, in particular of acute, visceral, neuropathic or chronic pain.
• Another object of the invention is the use of a substituted cyclohexylacetic acid derivative of the invention for the manufacture of a medicament for the treatment of anxiety, stress and stress associated syndromes, depression, epilepsy, Alzheimers disease, senile dementia, catalepsy, general cognitive dysfunctions, learning and Memory disorders (as nootropic agents), withdrawal symptoms, alcohol and / or drug and / or drug abuse and / or dependence, sexual dysfunctions, cardiovascular diseases, hypotension, hypertension, tinnitus, pruritus, migraine, deafness, intestinal motility, disturbed
• Another object of the invention is a method of treatment, in particular in one of the aforementioned indications, of a non-human mammal or human, or the treatment of pain, especially chronic pain, requires by administering a therapeutically effective dose of a substituted cyclohexylacetic acid derivative of the invention , or a medicament according to the invention.
• Another object of the invention are methods for preparing substituted cyclohexylacetic acid derivatives.
• R 01 and R 02 have the meaning of R 1 and R 2 and may additionally assume the meaning of a protective group.
• a phosphonoacetic acid ester preferably trimethyl phosphonoacetate or triethyl phosphonoacetate
• a strong base preferably potassium tert-butylate, sodium hydride or butyllithium
• esters II and III are mixed with a suitable aqueous. basic solution, preferably with potassium hydroxide or lithium hydroxide solution, hydrolyzed at RT or slightly elevated temperature to the corresponding Carbo ⁇ klaren IV or V.
• the carboxylic acids according to formula IV or V are as such or as their corresponding hydrochlorides with a dehydrating reagent, preferably with a carbodiimide, particularly preferably with dicyclohexyl-carbodiimide, in the presence of an activating reagent, preferably with 1-hydroxybenzotriazole, reacted with an amine of the formula R 4 R 5 NH to give the corresponding amide according to the formula Ia.
• the C-C double bond of a cyclohexylidene-acetamide derivative of the formula la is optionally reduced by methods known from literature, preferably by heterogeneous, catalytic hydrogenation on palladium or platinum catalysts or by homogeneously catalysed hydrogenation with rhodium catalysts, in each case at temperatures between RT and 60 ° C and under hydrogen pressures between 1 bar and 6 bar, more preferably at RT under a hydrogen pressure between 2 and 3 bar of palladium on carbon, so that a cyclohexylacetamide derivative according to formula Ib is formed.
• the double bond may possibly also be used at another time
• ester hydrolysis is continued as described above.
• R 4 is an aryl radical and R 5 is H
• the ester can also be reacted in the presence of a strong base, preferably nBuLi, and an aniline directly to the compounds of the formula Ic according to the invention.
• protecting groups on R 01 and R 02 are then cleaved by methods known to those skilled in the art.
• groups S 1 and S 2 which are protecting groups - for example, substituted or unsubstituted alkyl, in particular (CH 2)
• ester VI is hydrolyzed with a suitable aqueous, basic solution, preferably with potassium hydroxide or lithium hydroxide solution, at RT or slightly elevated temperature to give the corresponding carboxylic acid VII.
• the carboxylic acid of formula VII is as such or as its corresponding hydrochloride with a dehydrating reagent, preferably with a carbodiimide, more preferably with dicyclohexyl-carbodiimide, in the presence of an activating reagent, preferably with 1-hydroxybenzotriazole, with an amine of formula R 4 R 5 NH converted to the corresponding amide according to the formula VIII.
• the compound according to formula IX is reacted in the presence of a compound of the formula HNR 01 R 02 with a cyanide, preferably potassium cyanide or TMSCN, to give a 4-substituted 1-amino-1-cyano-cyclohexane derivative according to formula X.
• a cyanide preferably potassium cyanide or TMSCN
• organometallic reagents preferably Grignard or organolithium reagents, of the formula metal R 3 , so that the compounds of the invention according to formula Ia are formed.
• compounds of the general formula Ia can then be reduced to compounds of the general formula Ib.
• the double bond can also be reduced at an earlier point in time, namely compound VIII according to the methods described in the first synthesis method. Subsequently, proceed according to the described method.
• the protecting groups on R 0 and R 02 are then cleaved by methods known to those skilled in the art.
• ether means diethyl ether, "EE” ethyl acetate and “DCM” dichloromethane.
• equivalents means molar equivalents, "mp”.
• the stationary phase used for the column chromatography was silica gel 60 (0.040 g).
• the clear solution was cooled to 0 ° C and treated with dicyclohexylcarbodiimide (278 mg, 1, 35 mmol).
• the reaction mixture was stirred for 3 d at RT.
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which separated has been.
• the obtained filtrate was extracted with ether.
• the aqueous phase was treated with 5M sodium hydroxide solution (2 ml, 10 mmol) and diluted with water (150 ml).
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated. The obtained filtrate was extracted with ether. The organic phase was concentrated to give the crude product as a yellow oil (142 mg).
• the solution was cooled to 0 ° C and dicyclohexylcarbodiimide (417 mg, 2.0 mmol) was added.
• the reaction mixture was stirred for 3 d at RT.
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the obtained filtrate was extracted with ether.
• the workup of the The reaction was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was combined with 5M sodium hydroxide solution (4 mL, 20 mmol), diluted with water (300 mL) and stored at 5 ° C for 3 d.
• N-Benzyl-2- (4-dimethylamino-4-phenylcyclohexylidene) acetamide To a solution of (4-dimethylamino-4-phenylcyclohexylidene) acetic acid hydrochloride (296 mg, 1.0 mmol) in dry dimethylformamide (10 ml) was added under Argon 1-hydroxybenzotriazole (273 mg, 2.0 mmol), benzylamine (0.109 mL, 1.0 mmol) and ⁇ / -methylmorpholine (0.222 mL, 2.0 mmol). The solution was cooled to 0 ° C and dicyclohexylcarbodiimide (417 mg, 2.0 mmol) was added.
• the reaction mixture was stirred for 12 d at RT.
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was combined with 5M sodium hydroxide solution (4 mL, 20 mmol), diluted with water (300 mL) and stored at 5 ° C for 3 d.
• the product precipitated as a colorless solid in a yield of 65% (227 mg) and with a mp of 145-148 ° C from.
• the reaction was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was treated with 5M sodium hydroxide solution (4 mL, 20 mmol), diluted with water (300 mL) and stored at 5 ° C for 16 h.
• the product was obtained in a yield of 75% (294 mg) as a colorless oily compound.
• the solution was cooled to 0 ° C and dicyclohexylcarbodiimide (417 mg, 2.0 mmol) was added.
• the reaction mixture was stirred at RT for 7 d.
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which separated has been.
• the aqueous phase was combined with 5M sodium hydroxide solution (4 mL, 20 mmol), diluted with water (300 mL) and stored at 5 ° C for 3 d.
• the product precipitated as a colorless solid in a yield of 82% (287 mg).
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was mixed with 5M sodium hydroxide solution (4 ml, 20 mmol), with. Water (300 ml) and stored at 5 ° C for 16 h.
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was treated with 5M sodium hydroxide solution (4 mL, 20 mmol), diluted with water (300 mL) and stored at 5 ° C for 16 h.
• the product was obtained in a yield of 66% (252 mg) as a colorless oily compound.
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). This precipitated even more urea, the was separated.
• the aqueous phase was treated with 5M sodium hydroxide solution (4 ml, 20 mmol), diluted with water (300 ml) and stored for 4 d at 5 ° C.
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was combined with 5M sodium hydroxide solution (5 mL, 25 mmol), diluted with water (300 mL) and stored at 5 ° C for 16 h.
• the workup of the approach was carried out by separating the precipitated urea and entering of the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was diluted with water (400 ml), combined with 5M sodium hydroxide solution (5 ml, 25 mmol) and stored at 5 ° C. for 3 days.
• the crude product was purified by chromatography on silica gel (130 g) with EE / cyclohexane (1: 3). The product was obtained as a colorless solid having a mp of 76 ° C in a yield of 77% (4.53 g).
• the aluminum compounds thus obtained were separated by filtration and washed with tetrahydrofuran (3 ⁇ 10 ml). The filtrate was concentrated. After the addition of water (30 ml), the amine was extracted with EA (3 40 ml), the extracts combined and washed with water (40 ml). After drying and concentration of the organic phase, the product was obtained as a colorless solid in a yield of 95% (2.21 g) with a mp of 69-78 ° C.
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was diluted with water (300 ml), combined with 5M sodium hydroxide solution (7 ml, 35 mmol) and stored at 5 ° C. for 3 days.
• the crude product precipitated as a beige solid in a yield of 69% (915 mg).
• EA / methanol (1: 1) and methanol the product was isolated in a yield of 25% as a colorless solid (333 mg) with a mp.
• 6- (1H-Indol-3-yl) -hexanoic acid cyanomethyl 6- (1H-indol-3-yl) -hexanoic acid (6.01g, 26.0mmol) was dissolved in acetone (30ml) and DMF (30 ml) and successively mixed with cesium carbonate (4.23 g, 13.0 mmol), chloroacetonitrile (2.45 ml, 39.0 mmol) and potassium iodide (20 mg). After a reaction time of 9 h at 60 ° C and 60 h at RT, the solid residues were separated by filtration, washed with acetone (2 10 ml) and the filtrate was concentrated.
• 6- (1-W indol-3-yl) hexanoic acid amide A solution of 6- (1H-indol-3-yl) hexanoic acid, cyanomethyl ester (5.72 g, 21.16 mmol) in tetrahydrofuran (160 mL) became a 25 percent Added ammonia solution (125 ml) and stirred at RT for 40 h. The workup of the mixture was carried out by phase separation and extraction of the aqueous phase with THF (2 40 ml). The organic extracts were combined and washed with saturated NaCl solution (50 ml). After drying and concentration of the organic phase, the product was isolated as a colorless solid in a yield of 98% (4.75 g) with a mp of 140-142 ° C.
• Tetrahydrofuran 80 ml was added.
• a solution of 6- (1 / - / - indol-3-yl) -hexanoic acid amide (4.7 g, 20.4 mmol) in abs.
• Tetrahydrofuran 100 ml was added with stirring to the LiAlH 4 suspension at 60 ° C over 40 minutes.
• the batch was admixed with tetrahydrofuran (50 ml).
• water 42 ml
• the aluminum compounds thus obtained were separated by filtration, washed with THF (3 ⁇ 30 ml) and the filtrate was concentrated.
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was diluted with water (300 ml), treated with 5M sodium hydroxide solution (7 ml, 35 mmol) and stored at 5 C for 16 h.
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the filtrate was diluted with water (400 ml), combined with 5M sodium hydroxide solution (5 ml, 25 mmol) and stored at 5 ° C. for 3 days.
• the product was obtained as a beige oily solid in a yield of 45% (570 mg).
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the filtrate was washed with water diluted (400 ml), treated with 5M sodium hydroxide solution (5 ml, 25 mmol) and stored 4 d at 5 ° C.
• Dimethylformamide (50 mL) was added under argon to 1-hydroxybenzotriazole (2.03 g, 15 mmol), DL- ⁇ -methyltryptamine (1.3 g, 7.5 mmol) and ⁇ / -methylmorpholine (1.65 mL, 15 mmol ).
• the solution was cooled to 0 ° C and treated with dicyclohexylcarbodiimide (3.09 g, 15 mmol) and stirred for 6 d at RT.
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml).
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was diluted with water (400 ml), treated with 5M sodium hydroxide solution (7 ml, 35 mmol) and stored at 5 ° C for 16 h.
• the crude product precipitated as a beige solid (313 mg, 37%).
• Chromatography on silica gel (45 g) with EA / methanol (4: 1) gave the product as a beige solid in 25% yield (210 mg).
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was diluted with water (300 ml), combined with 5M sodium hydroxide solution (7 ml, 35 mmol) and stored at 5 ° C. for 16 h.
• the crude product was obtained as a beige oily compound (228 mg, 30%). Chromatography on silica gel (40 g) with EE / methanol (4: 1) gave the amide as a beige oil in 27% yield (203 mg).
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell even more urea, which was separated.
• the aqueous phase was diluted with water (300 ml), combined with 5M sodium hydroxide solution (7 ml, 35 mmol) and stored at 5 ° C. for 16 h.
• the crude product precipitated as a beige solid (1.3 g). After chromatography on silica gel (60 g) with EA / methanol (6: 1), the product was obtained in a yield of 62% (1, 03 g) with a mp. Of 172-176 ° C.
• the work up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was diluted with water (300 ml), combined with 5M sodium hydroxide solution (7 ml, 35 mmol) and stored at 5 ° C. for 20 hours.
• the crude product precipitated out as a yellow solid (1.2 g).
• the product was a mixture of the two diastereoisomeric amides, which was purified by chromatography on silica gel G [100 g; EtOAc / MeOH (10: 1)].
• the precipitated urea was separated and the filtrate was added to a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was diluted with water (300 ml), combined with 5M sodium hydroxide solution (7 ml, 35 mmol) and stored at 5 ° C. for 20 hours.
• the crude product precipitated as a beige solid (2.16 g). After chromatography on silica gel G [100 g; EtOAc / MeOH (10: 1)], the amide was recovered in 29% yield (648.5 mg) with a mp of 129-131 ° C.
• the reaction mixture was stirred at RT for 3 d and worked up by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It was diluted with water, treated with 5M sodium hydroxide solution (4 ml, 20 mmol) and stored at 5 ° C for 16 h. A crude product precipitated as a beige substance (400 mg). After chromatographic purification on silica gel with methanol, the product was obtained as a beige solid in a yield of 35% (144 mg) and with a mp. 194-197 ° C.
• the reaction mixture was stirred at RT for 3 d, the precipitated urea was filtered off with suction and the filtrate was added to a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml).
• the aqueous phase was treated with 5M sodium hydroxide (12 mL, 60 mmol), diluted with water (300 mL) and stored at 5 ° C for 3 d. It fell Product as a colorless compound and could be obtained by filtration, taking up the residue in ethanol and concentration in a yield of 58% (220 mg).
• the precipitated urea was filtered off with suction and the filtrate was added to a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). In this case, further urea in a mixture with the product precipitated (349 mg) and was separated. The resulting filtrate was diluted with water (300 ml), 5M sodium hydroxide solution (8 ml, 40 mmol) added and stored at 5 ° C for 16 h. Additional product precipitated out as a colorless solid (172 mg). After chromatographic purification of the dicyclohexylurea contaminated fraction on silica gel with methanol, additional product (49 mg) was obtained. The product was isolated in total in a yield of 61% (221 mg) with a mp of 182-186 ° C.
• the filtrate was diluted with water (300 ml), 5M sodium hydroxide solution (8 ml, 40 mmol) added and stored at 5 ° C for 16 h.
• the crude product precipitated as a beige substance, which was separated by filtration (222 mg).
• the product was taken up in ethyl methyl ketone (7 ml) and separated by filtration from an insoluble residue.
• the filtrate was concentrated and the clean product was obtained in a yield of 194 mg (49%).
• the reaction mixture was worked up by separating the precipitated solid (1.1 g) from a mixture of dicyclohexylurea and the hydrochloride of Amids existed.
• the filtrate became a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml).
• the filtrate of the mixture was extracted by shaking with dichloromethane (3 * 50 ml) and the organic phase was concentrated after drying. This gave an oily crude product (660 mg), from which the product could be recovered after chromatographic purification on silica gel with EA / methanol (4: 1) (188 mg).
• the substance mixture which precipitated at the beginning of the work-up was taken up in dichloromethane and saturated sodium bicarbonate solution.
• the aqueous phase was extracted with dichloromethane.
• the organic phase was concentrated (517 mg) and separated by chromatography with EA / methanol (4: 1), whereby a further fraction of the amide (357 mg) could be isolated.
• the overall yield of the product was 59% (545 mg).
• the work-up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). This precipitated a mixture of urea and product (482 mg), which was separated.
• the resulting filtrate was diluted with water (300 ml), 5M sodium hydroxide solution (4 ml, 20 mmol) added and stored at 5 ° C for 16 h.
• a crude product precipitated as a beige substance (234 mg), which was separated by filtration.
• EA / methanol (4: 1) and methanol the product was isolated as a beige solid in a yield of 30% (230 mg).
• the reaction was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the crude product precipitated out of the filtrate after 10 minutes and was filtered off.
• the aqueous phase was diluted with water (300 ml), combined with 5M sodium hydroxide solution (7 ml, 35 mmol) and stored at 5 ° C. for 3 days. In this case, more product precipitated as a beige solid in a yield of 9% (82 mg) with a mp. From 152 to 156 ° C.
• the crude product was purified by chromatography on silica gel (40 g) with EE / methanol (4: 1) and (1: 1). The product was isolated in a yield of 58% as a beige compound (534 mg).
• the work-up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was diluted with water (300 ml), combined with 5M sodium hydroxide solution (7 ml, 35 mmol) and stored at 5 ° C. for 16 h.
• reaction mixture was concentrated after 2 h to 2 ml, treated with ether (50 ml) and stirred for 1 h at RT.
• the product was isolated as a colorless solid with a mp. Of 150-155 ° C in a yield of 33% (338 mg).
• the work-up of the batch was carried out by separating the precipitated urea and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO 3 solution (10 ml). It fell out even more urea, which was separated.
• the aqueous phase was diluted with water (300 ml), combined with 5M sodium hydroxide solution (7 ml, 35 mmol) and stored at 5 ° C. for 16 h.
• the crude product was obtained as a beige oily compound (303 mg, 37%).
• the reaction was hydrolyzed with ammonium chloride solution and extracted with DCM. After concentration, the crude product was taken up in ether. This left a solid (less polar diastereoisomer, 1.518 g, 50%); the supernatant was chromatographed on silica gel (eluent: ether, then ether / methanol 4: 1). 142 mg (4.7%) of the more nonpolar and 1.20 g (40%) of the more polar diastereoisomer were obtained.
• the cyclohexane derivatives of the general formula I were investigated in a receptor binding assay with H-nociceptin / orphanin FQ with membranes of recombinant CHO-ORL1 cells.
• This test system was tested according to the method described by Ardati et al. (Mol. Pharmacol., 51, 1997, pp. 816-824).
• the concentration of H-nociceptin / orphanin FQ was 0.5 nM in these experiments.
• the binding assays were carried out with 20 ⁇ g membrane protein per 200 ⁇ l batch in 50 mM Hepes, pH 7.4, 10 mM MgCl 2 and 1 mM EDTA.
• Binding to the ORL1 receptor was carried out using 1 mg of WGA-SPA beads (Amersham-Pharmacia, Freiburg), by incubation of the mixture at RT for one hour and subsequent measurement in the scintillation counter Trilux (Wallac, Finland), certainly.
• the receptor affinity for the human ⁇ -opiate receptor was determined in a homogeneous batch in microtiter plates. For this purpose, serial dilutions of the respective substituted cyclohexylacetic acid derivatives to be tested with a receptor membrane preparation (15-40 ⁇ g protein per 250 ⁇ l incubation mixture) of CHO-K1 cells expressing the human ⁇ -opiate receptor (RB-HOM receptor membrane preparation from NEN , Zaventem, Belgium) in the presence of 1 nmol / l of the radioactive ligand [ 3 H] -naloxone (NET719, NEN, Zaventem, Belgium) and 1 mg of WGA-SPA beads (Wheat germ agglutinin SPA beads from Amersham / Pharmacia, Freiburg, Germany) in a total volume of 250 ⁇ l for 90 minutes at room temperature.
• a receptor membrane preparation 15-40 ⁇ g protein per 250 ⁇ l incubation mixture
• CHO-K1 cells expressing the human ⁇ -opiate receptor RB
• the incubation buffer used was 50 mmol / l Tris-HCl supplemented with 0.05% by weight of sodium azide and with 0.06% by weight of bovine serum albumin. To determine the unspecific binding an additional 25 .mu.mol / l naloxone was added. After completion of the ninety-minute incubation period, the microtiter plates were centrifuged off for 20 minutes at 1000 g and the radioactivity in a ⁇ -counter (Microbeta-Trilux, PerkinElmer Waliac, Freiburg, Germany).
• the percentage displacement of the radioactive ligand from its binding to the human ⁇ -opiate receptor at a concentration of the test substances of 1 .mu.mol / l was determined and expressed as a percentage inhibition (% inhibition) of the specific binding.
• IC 50 inhibitory concentrations were calculated, which cause a 50% displacement of the radioactive ligand.
• Ki values were obtained for the test substances.
• mice were individually placed in a test cage and the tail base the focused heat beam of an electric lamp (Tail-flick type 50/08 / 1.bc,
• mice were pretested twice within five minutes and the mean value of these measurements was calculated as the pretest mean value.
• the solutions of the compound of general formula I according to the invention and the comparative solutions were then administered intravenously.
• the pain measurement was carried out in each case 10, 20, 40 and 60 minutes after the intravenous application.
• the analgesic effect was determined as an increase in pain latency (% of the maximum possible antinociceptive effect) according to the following formula: [(To-To) / (T 2 -T 0 )] x 100
• the time T 0 is the latency before the application, the time Ti the latency after the application of the active substance combination and the time T 2 the maximum exposure duration (12 seconds).

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