EP1747191A1 - Derives de cyclohexyl-1,4-diamine substitues a extension de chaine - Google Patents

Derives de cyclohexyl-1,4-diamine substitues a extension de chaine

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Publication number
EP1747191A1
EP1747191A1 EP05747800A EP05747800A EP1747191A1 EP 1747191 A1 EP1747191 A1 EP 1747191A1 EP 05747800 A EP05747800 A EP 05747800A EP 05747800 A EP05747800 A EP 05747800A EP 1747191 A1 EP1747191 A1 EP 1747191A1
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EP
European Patent Office
Prior art keywords
dimethylamino
benzyl
cyclohexyl
cyclohexylcarbamoyl
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05747800A
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German (de)
English (en)
Inventor
Corinna Sundermann
Bernd Sundermann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
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Gruenenthal GmbH
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Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Publication of EP1747191A1 publication Critical patent/EP1747191A1/fr
Withdrawn legal-status Critical Current

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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
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    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
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Definitions

  • the present invention relates to substituted cyclohexyl-1,4-diamine derivatives, processes for their preparation, medicaments containing these compounds and the use of substituted cyclohexyl-1,4-diamine derivative derivatives for the production of medicaments.
  • Classic ⁇ -opioids such as morphine are effective in the treatment of severe to severe pain and are of the greatest importance for pain therapy.
  • other opioid receptors in particular the ORL-1 receptor, are also influenced in addition to the ⁇ -opioid receptor, since the pure ⁇ -opioids also have undesirable side effects such as constipation and
  • opioid receptors ⁇ , K and ORL-1 are also involved in the pain process (Opioids: Introduction, pp. 127-150, Further Opioid Receptors, 455-476 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 learning and memory formation (Manabe et al., Nature, 394, 1997, pp. 577-581), hearing ability (Nishi et al., EMBO J., 16, 1997, pp. 1858-1864) and numerous others processes. In a review by Calo et al. (Br.J. Pharmacol., 129, 2000, 1261 - 1283) gives an overview of the indications or biological processes in which the ORL1 receptor plays a role or with high
  • Probability could play include: analgesia, stimulation and regulation of food intake, influence on ⁇ -agonists such as morphine, treatment of withdrawal symptoms, reduction of the addictive potential of opioids, anxiolysis, modulation of movement activity, memory disorders, epilepsy; Modulation of the neurotransmitter release, especially of
  • Glutamate Glutamate, serotonin and dopamine, and thus neurodegenerative diseases; Influencing the cardiovascular system, triggering an erection, diuresis, antinatriuresis, electrolyte balance, arterial blood pressure, water storage diseases, intestinal motility (diarrhea), relaxing effects on the respiratory tract, micturition reflex (urinary incontinence).
  • agonists and antagonists as anoretics, analgesics (also in co-administration with opioids) or nootropics is also discussed.
  • the object of the present invention was to provide medicinal products which act on the opioid receptor system and thus for medicinal products, in particular for the treatment of the various diseases associated with this system according to the prior art or for use there indicated indications are suitable.
  • the compounds should also affect noradrenaline and serotonin reuptake.
  • the invention therefore relates to substituted cyclohexyl-1,4-diamine derivative derivatives of the general formula I,
  • R ⁇ and R 2 independently of one another for H; C- j _5-AI yl each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C3_8-cycloalkyl, in each case mono- or polysubstituted or unsubstituted; or aryl, C.beta.-cycloalkyl or heteroaryl bonded via C- ⁇ -alkyl, in each case mono- or polysubstituted or unsubstituted; or the radicals R 1 and R 2 together represent CH2CH2OCH2CH2, CH 2 CH 2 NR 10 CH2CH2 or (CH 2 ) 3_ 6 , where R 1 ⁇ H; C-
  • R ⁇ j for C _5 alkyl respectively saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C.s-Cycloalkyl, in each case mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, each unsubstituted or mono- or polysubstituted; Aryl, heteroaryl or C bonded via C- ⁇ -alkyl group.
  • ⁇ - cycloalkyl in each case unsubstituted or mono- or polysubstituted;
  • A is NH, ON, in which case the bond between N and R 4 is a double bond, O or S,
  • I 1 or 2;
  • R 5 and R 6 independently represent H, C- ⁇ -5 alkyl in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted;
  • Aryl are each mono- or polysubstituted or unsubstituted,
  • X is not heteroaryl when I is 1 and simultaneously A is O or S, in the form of the racemate; the enantiomers, diastereomers, mixtures of the enantiomers or diastereomers or a single enantiomer or diastereomer; the bases and / or salts of physiologically acceptable acids or cations. If a residue, for example X, can occur twice within a compound, it can also have different meanings.
  • the compounds according to the invention show good binding to the ⁇ receptor and the ORL-1 receptor, but also to other opioid receptors. Surprisingly, it was found that the compounds are also good inhibitors of noradrenaline and serotonin reuptake. They are therefore also suitable for the treatment of depression and / or bulimia and / or anorexia and / or catalepsy and / or for anxiolysis and / or for increasing vigilance and / or libido.
  • C 1-4 alkyl and “C-ß-alkyl” encompass acyclic saturated or unsaturated hydrocarbon radicals which can be branched or straight-chain and unsubstituted or mono- or polysubstituted, with 1, 2, 3, 4 or 5 carbon atoms or 1, 2 or 3 carbon atoms, ie C - ⁇ - alkanyls, C2.5-alkenyls and C2_5-alkynyls or C ⁇ -alkanyls, C2_3-alkenyls and C2_3-alkynyls.
  • Alkenyls have at least one CC double bond and alkynyls have at least one CC triple bond.
  • cycloalkyl or "C3_8-cycloalkyl” for the purposes of this invention means cyclic hydrocarbons having 3, 4, 5, 6, 7 or 8 carbon atoms, the hydrocarbons being saturated or unsaturated (but not aromatic), unsubstituted or mono- or can be substituted several times.
  • cycloalkyl the term also includes saturated or unsaturated (but not aromatic) cycloalkyls in which one or two carbon atoms have been replaced by a heteroatom S, N or O.
  • C3_8-Cycloalkyl is advantageously selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, but also tetrahydropyranyl, dioxanyl, dioxolanyl and morphinylrolidine, piperylrolidoline, piperylrolidine, pyrolynyl piperyl.
  • (CH 2 ) 3 -6 is -CH 2 -CH 2 -CH 2 -, -CH2-CH 2 -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 - CH 2 -CH 2 - and CH2-CH 2 -CH 2 -CH2-CH 2 -CH 2 - to understand.
  • aryl means carbocyclic ring systems with at least one aromatic ring, but without heteroatoms in only one of the rings, i.a. 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 can be unsubstituted or mono- or polysubstituted, and the aryl substituents can be the same or different and can be in any and possible position of the aryl. Phenyl or naphthyl radicals are particularly advantageous.
  • heteroaryl stands for a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1, possibly also 2, 3, 4 or 5 heteroatoms, the heteroatoms being the same or different and the heterocycle being unsubstituted or can be substituted one or more times; in the case of substitution on the heterocycle, the substituents can be identical or different and can be in any and possible position of the heteroaryl.
  • the heterocycle can 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, phthalylazidyl, pyrazolyl, pyrazole Thiazolyl, oxazolyl, isoxazolyl, pyrrolyl, isoxazoyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, indazolyl, purinyl, indolizinyl, quinolinyl, isoquinolinyl, isothiazolyl, imidazolyl, triazolyl, triazinyl, phenazoliazyl, carb
  • the multiple substitution can take place with the same or with different substituents. Possibly. a substituent can in turn be substituted; so includes -Oalkyl including -O-CH 2 -CH2-O-CH2-CH 2 -OH.
  • aryl means one or more, for example two, three, four or five times, substitution of one or more hydrogen atoms 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-alkyl-aryl, S-alkyl
  • salt is to be understood to mean any form of the active substance according to the invention in which it takes on an ionic form or is charged and is coupled to a counterion (a cation or anion) or is in solution.
  • This also includes complexes of the active ingredient with other molecules and ions, in particular complexes that are complexed via ionic interactions.
  • physiologically compatible salts in particular physiologically compatible salts with cations or bases and physiologically compatible salts with anions or acids or else a salt formed with a physiologically compatible acid or a physiologically compatible cation ,
  • physiologically compatible salt with anions or acids is understood to mean salts of at least one of the compounds according to the invention - mostly protonated, for example on nitrogen - as a cation with at least one anion which is physiologically - in particular when used in humans and / or Mammal - are tolerated.
  • this is understood in particular to mean the salt formed with a physiologically compatible 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,
  • the hydrochloride salt, the citrate and the hemicitrate are particularly preferred.
  • the term salt formed with a physiologically compatible acid is understood to mean salts of the respective active ingredient with inorganic or organic acids which are physiologically compatible, in particular when used in humans and / or mammals.
  • hydrochloride and the citrate are particularly preferred.
  • physiologically compatible 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-oxo-1-sulfinic acid , Nicotinic acid, 2-, 3- or 4-aminobenzoic acid, 2,4,6-trimethyl-benzoic acid, ⁇ -lipoic acid, acetylglycine, hippuric acid and / or aspartic acid.
  • physiologically compatible salt with cations or bases is understood to mean salts of at least one of the compounds according to the invention - usually one (deprotonated) acid - as an anion with at least one, preferably inorganic, cation which is physiological, in particular when used in humans and / or mammal - are compatible.
  • the salts of the alkali and alkaline earth metals but also ammonium salts are particularly preferred, 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 to mean salts of at least one of the respective compounds as an anion with at least one inorganic cation which is physiologically compatible, in particular when used in humans and / or mammals.
  • the salts of the alkali and alkaline earth metals but also ammonium salts are particularly preferred, but in particular (mono) or (di) sodium, (mono) or (di) potassium, magnesium or calcium salts.
  • R 1 and R 2 are independently H; C- j saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, are _5 alkyl; or the radicals R ⁇ and R 2 together form a ring and represent CH 2 CH 2 OCH2CH2, CH 2 CH2NR 10 CH 2 CH2 or (CH 2 ) 3_6, where R ⁇ OH; C j _5-alkyl, saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, means.
  • Substituted cyclohexyl-1,4-diamine derivatives in which R ⁇ and R 2 independently represent CH3 or H, where R ⁇ and R 2 do not simultaneously denote H, or R 1 and R 2 represent CH2CH 2 OCH 2 are particularly preferred CH2, (CH) 4, (CH 2 ) s or (CH2) Q.
  • substituted cyclohexyl-1,4-diamine derivatives in which R is cyclopentyl, cyclohexyl, phenyl, benzyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolimylyl, pyrrolimyl, pyrrolyl, pyrrolyl, pyrrolyl, pyrrolyl, pyrrolyl, pyrrolyl, pyrrolyl, pyrrolyl, pyrrolimyl, pyrrolimyl, pyrrolimyl, pyrrolimidyl or pyrazinyl, in each case unsubstituted or mono- or polysubstituted; via a saturated, unbranched C - ⁇ - alkyl group.
  • Cycloalkyl phenyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, pyridyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyrimidyl or pyrazinyl, in each case unsubstituted or mono- or polysubstituted; in particular
  • R 3 is phenyl, furyl, thiophenyl, naphthyl, benzyl, benzofuranyl, indolyl, indanyl, benzodioxanyl, benzodioxolanyl, pyridyl, pyrimidyl, pyrazinyl or benzothiophenyl, in each case unsubstituted or mono- or polysubstituted; over a saturated, unbranched C ⁇
  • Substituted cyclohexyl-1,4-diamine derivatives in which R 3 is phenyl, phenethyl, thiophenyl, pyridyl or benzyl, in each case substituted or unsubstituted, are particularly preferred, particularly preferably phenyl, thiophenyl, 4-chlorobenzyl, benzyl, 3- Chlorobenzyl, 4-methylbenzyl, 2-chlorobenzyl, 4-fluorobenzyl, 3-methylbenzyl, 2-methylbenzyl, 3-fluorobenzyl, 2-fluorobenzyl or phenethyl.
  • substituted cyclohexyl-1, 4-diamine derivatives are preferred in which R 4 for C -5 alkyl, cyclohexyl, cyclopentyl, cyclobutyl, cycloheptyl, cyclooctyl, phenyl, benzyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furanyl, Isothiazolyl, imidazolyl, triazolyl, triazinyl, pyrazolyl, benzofuranyl, benzodioxolanyl, isoquinolinyl, phthalazine, benzo [1, 2.5] thiadiazole, benzothiazole, benzotriazole, quinolinyl, carbazole, isoxazolyl, oxazolyl, benzazidylolyl, indanylolyl, indanylolanyl Pyrrol
  • R 4 for C 5 alkyl, branched or unbranched, saturated or unsaturated, cyclohexyl, cyclopentyl, phenyl, benzyl, naphthyl, thiophenyl, benzothiophenyl, furanyl, pyrazolyl, benzofuranyl, isoquinolinyl, benzothiazole, benzotriazole, quinolinyl, oxazylylol, isoxazolyl , Pyrrolyl, pyridyl, pyrimidyl or pyrazinyl, in each case unsubstituted or mono- or polysubstituted, C (O) phenyl, benzyl or phenethyl, in each case unsubstituted or monosubstituted or polysubstituted.
  • Substituted cyclohexyl-1,4-diamine derivatives in which R 4 is phenyl, C (O) phenyl, C 1 are particularly preferred. 5 -alkyl, branched or unbranched, saturated or unsaturated benzyl, pyridyl, pyrimidinyl or indolyl, in each case unsubstituted or mono- or polysubstituted.
  • Substituted cyclohexyl-1,4-diamine derivatives in which X is (CR 5 R 6 ) n , phenyl, pyridyl, naphthyl, thiophenyl, furyl, pyrimidinyl or indolyl, in each case unsubstituted or mono- or polysubstituted, are also preferred, in each case also is bridged by a C 1-3 alkyl chain, which may be substituted; with n 0, 1, 2, 3, 4
  • R 5 , R 6 independently of one another for H, C ⁇ . 5- alkyl each saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; Phenyl, mono- or polysubstituted or unsubstituted.
  • Substituted cyclohexyl-1,4-diamine derivatives are particularly preferred in which X is vinylbenzyl, d-5-alkyl, branched or unbranched, saturated or unsaturated, phenethyl, phenyl, benzyl or pyridyl, in each case unsubstituted or mono- or polysubstituted, stands.
  • Acetic acid (4-dimethylamino-4-thiophene-2-yl-cyclohexylcarbamoyl) methyl ester 2-benzylsulfanyl-N- [4-dimethylamino-4- (4-methyl-benzyl) cyclohexyl] acetamide N- [4-dimethylamino -4- (4-fluoro-benzyl) cyclohexyl] -2-phenoxy-propionamide N- [4-dimethylamino-4- (2-methyl-benzyl) cyclohexyl] -4-phenoxy-butyramide N- [4- ( 3-chloro-benzyl) -4-dimethylamino-cyclohexyl] -2- (4-methoxy-phenoxy) -5-nitro-benzamide benzoic acid 2- (4-benzyl-4-piperidin-1-yl-cyclohexylcarbamoyl) benzyl ester N-
  • Acetic acid 1 [4-dimethylamino-4- (2-methyl-benzyl) cyclohexylcarbamoyl] ethyl ester N- (4-benzyl-4-pyrrolidin-1-yl-cyclohexyl) -2- (4-chlorophenoxy) -acetamide N- (4-phenyl-4-piperidin-1-yl-cyclohexyl) -2- (5-trifluoromethyl-pyridin-2-ylsulfanyl) -acetamide acetic acid [4-dimethylamino-4- (2-fluoro-benzyl) -cyclohexylcarbamoyl] -phenyl-methyl ester
  • Acetic acid [4-dimethylamino-4- (3-fluoro-benzyl) cyclohexylcarbamoyl] phenyl methyl ester N- (4-dimethylamino-4-phenethylcyclohexyl) -4-phenoxy-butyramide N- [4-dimethylamino-4 - (3-fluoro-benzyl) cyclohexyl] -2-phenoxypropionamide 2-phenoxy-N- (4-phenyl-4-piperidin-1-yl-cyclohexyl) butyramide
  • Acetic acid [4-dimethylamino-4- (4-fluoro-benzyl) cyclohexylcarbamoyl] phenyl methyl ester N- (4-benzyl-4-piperidin-1-yl-cyclohexyl) -4- (4-chloro-2-methyl-phenoxy) -butyramide N- (4-benzyl-4-pyrrolidin-1-yl-cyclohexyl) -2-phenoxy-propionamide N- (4-benzyl-4-piperidin-1-yl-cyclohexyl) -2-phenoxy-acetamide benzoic acid 2- (4-phenyl-4-piperidin-1-yl-cyclohexylcarbamoyl) benzyl ester 4- [4- (3-chloro-benzyl) -4-dimethylamino-cyclohexylcarbamoyl] butyric acid methyl ester
  • Acetic acid 1 [4-dimethylamino-4- (4-methyl-benzyl) cyclohexylcarbamoyl] -1-methyl ethyl ester N- (4-Benzyl-4-piperidin-1-yl-cyclohexyl) -2-methoxy-acetamide N- (4-morpholin-4-yl-4-phenyl-cyclohexyl) succinic acid ethyl ester 5- (2.5 -Dimethyl-phenoxy) -2,2-dimethyl-pimelic acid (4-azepan-1-yl-4-benzyl-cyclohexyl) -amide N- (4-azepan-1-yl-4-benzyl-cyclohexyl) -2- phenoxy-propionamide
  • the substances according to the invention act, for example, on the ⁇ -opioid receptor relevant in connection with various diseases, so that they are suitable as an active pharmaceutical ingredient in a medicament.
  • the invention therefore furthermore relates to medicaments comprising at least one substituted cyclohexycarboxylic acid derivative according to the invention, and, if appropriate, suitable additives and / or auxiliaries and / or if appropriate further active compounds.
  • the medicaments according to the invention optionally contain suitable additives and / or auxiliaries, including also carrier materials, fillers, solvents, diluents, dyes and / or binders, and can be in the form of liquid pharmaceutical forms in the form of Injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters / spray plasters or aerosols.
  • suitable additives and / or auxiliaries including also carrier materials, fillers, solvents, diluents, dyes and / or binders, and can be in the form of liquid pharmaceutical forms in the form of Injection solutions, drops or juices, as semi-solid dosage forms in the form of granules, tablets, pellets, patches, capsules, plasters / spray plasters or aerosols.
  • suitable additives and / or auxiliaries including also carrier materials, fillers, solvents, diluents, dyes and / or binders, and can be
  • the amounts to be used depend on whether the medicinal product is oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or local, for example on the skin, mucous membranes or in the eyes to be applied.
  • Substituted cyclohexyl-1,4-diamine derivatives according to the invention in a depot, in dissolved form or in a plaster, optionally with the addition of agents which promote skin penetration, are suitable percutaneous application preparations.
  • Formulations which can be used orally or percutaneously can release the substituted cyclohexyl-1,4-diamine derivatives according to the invention with a delay.
  • the substituted cyclohexyl-1, 4-diamine derivatives according to the invention can also in parenteral long-term depot forms such.
  • B. implants or implanted pumps can be used.
  • the amount of active ingredient to be administered to the patient varies depending on the weight of the patient, the type of application, 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 cyclohexyl-1,4-diamine derivative according to the invention are applied.
  • the medicament in addition to at least one substituted cyclohexyl-1,4-diamine derivative, the medicament also preferably a further active ingredient, in particular an opioid, preferably a strong opioid, in particular morphine, or an anesthetic Contains hexobarbital or halothane.
  • an opioid preferably a strong opioid, in particular morphine, or an anesthetic Contains hexobarbital or halothane.
  • a substituted cyclohexyl-1,4-diamine 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.
  • substituted cyclohexyl-1,4-diamine derivatives according to the invention can be used for the production of a medicament for the treatment of pain, in particular acute, neuropathic or chronic pain.
  • Another object of the invention is therefore the use of a substituted cyclohexyl-1, 4-diamine derivative according to the invention for the manufacture of a medicament for the treatment of pain, in particular acute, visceral, neuropathic or chronic pain.
  • Another object of the invention is the use of a substituted cyclohexyl-1, 4-diamine derivative according to the invention for the manufacture of a medicament for the treatment of anxiety, stress and stress-related syndromes, depression, epilepsy, Alzheimer's disease, senile dementia, catalepsy, general cognitive dysfunction, learning and memory disorders (as a nootropic), withdrawal symptoms, alcohol and / or drug and / or drug abuse and / or addiction, sexual dysfunction, cardiovascular disease, hypotension, hypertension, tinitus, pruritus, migraine, hearing loss, lack of intestinal motility, impaired food intake, anorexia, obesity, locomotor disorders, diarrhea, cachexia, urinary incontinence or as muscle incontinence , Anticonvulsant or anesthetic or for co-administration in the case of treatment with an opioid analgesic or with an anesthetic, for diuresis or antinatriuresis, anxiolysis, for modulating movement activity, for modulating neurotransmitter release and treating associated neurodegenerative
  • a substituted cyclohexyl-1,4-diamine derivative used 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.
  • Another object of the invention is a method for the treatment, in particular in one of the aforementioned indications, of a non-human mammal or human, which requires treatment of pain, in particular chronic pain, by administering a therapeutically viable dose of a substituted cyclohexyl-1 according to the invention , 4-diamine derivative, or a medicament according to the invention.
  • Another object of the invention is a process for the preparation of the substituted cyclohexyl-1,4-diamine derivatives according to the invention as set out in the following description and examples.
  • radicals R 1 and R 2 have the meaning given for compounds of the formula I according to the invention for R 1 and R 2 and can additionally independently of one another stand for a protective group.
  • the remaining radicals have the meaning given in formula I: 4
  • the method according to the invention is preferably based on substituted ones
  • Linking cyclohexane-1,4-diamines (WO 02090317) with suitable carboxylic acids and / or carboxylic acid derivatives, in particular carboxylic acid chlorides or bromides, and thus converting them into compounds according to the invention.
  • suitable carboxylic acids and / or carboxylic acid derivatives in particular carboxylic acid chlorides or bromides, and thus converting them into compounds according to the invention.
  • polar or non-polar aprotic solvents are used, to which an organic or inorganic auxiliary base, preferably tertiary amines such as triethylamine, diisopropylethylamine or DMAP, has been added.
  • pyridine for example, is also suitable as a base and as a solvent.
  • Acid chlorides are preferably reacted with amines at -30 to +40 ° C.
  • ether means diethyl ether, "EE” ethyl acetate and “DCM” dichloromethane.
  • equivalents means equivalent amounts, "mp.” Melting point or melting range, “decomp.” Decomposition, "RT” room temperature, “abs.” absolute (anhydrous),, “rac.” racemic, “conc.” concentrated, “min” minutes, “h” hours, “d” days, “vol.%” volume percent, “m%” mass percent and “M” is a concentration in mol / l.
  • Table 1 lists the carboxylic acids used for the last step for the examples.
  • Table 1 Names of the example compounds and structures of the carboxylic acids used in the last step
  • Example 2 4-Chloro-N- (2- ⁇ 4- [1- (4-dimethylamino-4-phenylcyclohexylcarbamoyl) -1-methylethoxy] phenyl ⁇ ethyl) benzamide
  • Example 3 o N- (4-dimethylamino-4-thiophene-2-yl- ⁇ f cyclohexyl) -2- (2-methoxy-ethoxy) -acetamide OH '
  • Example 4 acetic acid (4-dimethylamino-4-thiophene-2- yl-cyclohexylcarbamoyl) phenyl methyl ester
  • Example 9 Benzoic acid 2- [4-dimethylamino-4- (3-fluorobenzyl) cyclohexylcarbamoyl] benzyl ester Compound Acid used Name
  • Example 10 Benzoic acid 2- (4-benzyl-4-dimethylamino-cyclohexylcarbamoyl) benzyl ester
  • Example 16 Benzoic acid 2- [4-dimethylamino-4- (4-methyl-benzyl) cyclohexylcarbamoyl] benzyl ester
  • Example 17 2-Benzylsulfanyl-N- (4-dimethylamino-4-thiophene-2-yl-cyclohexyl) acetamide
  • Example 18 Benzoic acid 2- [4-dimethylamino-4- (4-fluorobenzyl) cyclohexylcarbamoyl] benzyl ester
  • Some example compounds were synthesized on a larger scale.
  • Example 235 2- (3-chlorophenoxy) -N- (4-dimethylamino-4-phenylcyclohexyl) acetamide hydrochloride, more polar diastereoisomer
  • a cis / trans mixture of N, N-dimethyl-1-phenylcyclohexane-1,4-diamine (800 mg) was mixed with 540 ⁇ l triethylamine (1.05 molar equivalents) and catalytic amounts of DMAP (approx. 15 mg) in 20 ml Dichloromethane submitted, 790 mg (3-chlorophenoxy) acetyl chloride (1, 05 mol equivalents) added dropwise at -20 ° C and the mixture was stirred overnight while warming to room temperature.
  • the mixture was made alkaline (pH> 10) with one molar sodium hydroxide solution, extracted with diethyl ether (3 ⁇ 20 ml), the combined extracts were dried over sodium sulfate, filtered and evaporated to dryness.
  • the crude product obtained (1.53 g) was on silica gel (3.0 x 17 cm) with 100 ml of diethyl ether followed by 500 ml of diethyl ether / methanol
  • Example 236 2- (3-chlorophenoxy) -N- (4-dimethylamino-4-phenylcyclohexyl) acetamide hydrochloride, non-polar diastereoisomer
  • Example 237 N- (4-Dimethylamino-4-phenylcyclohexyl) -4-phenoxybutyramide
  • Example 237 575 mg of the more non-polar diastereoisomer of N- (4-dimethylamino-4-phenylcyclohexyl) -4-phenoxybutyramide were also obtained, which were dissolved in 5 ml of 2-butanone and 5 ml of ethyl acetate by adding 27.2 ⁇ l of water and 190 ⁇ l of chlorotrimethylsilane were converted into the corresponding hydrochloride (530 mg of white solid, mp. 194-197 ° C.).
  • Binding to the ORL1 receptor was determined using 1 mg WGA-SPA beads (Amersham-Pharmacia, Freiburg), by incubating the mixture at RT for one hour and then measuring in the Trilux scintillation counter (Wallac, Finland).
  • the percentage displacement of the radioactive ligand from its binding to the human ⁇ -opiate receptor at a concentration of the test substances of 1 ⁇ mol / l was determined and indicated as a percentage inhibition (% inhibition) of the specific binding.
  • 50 inhibitory concentrations were calculated based on the percentage displacement by different concentrations of the compounds of the general formula I IC to be tested, which cause a 50 percent displacement of the radioactive ligand.
  • Ki values for the test substances were obtained by conversion using the Cheng-Prusoff relationship. Measurement of serotonin reuptake In order to be able to carry out these in vitro studies, synaptosomes from rat brain areas are freshly isolated. A so-called.

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Abstract

Dérivés de cyclohexyl-1,4-diamine substitués, méthode de production desdits dérivés, médicaments contenant lesdits composés et utilisation de dérivés de cyclohexyl-1,4-diamine substitués pour la production de médicaments.
EP05747800A 2004-05-10 2005-05-06 Derives de cyclohexyl-1,4-diamine substitues a extension de chaine Withdrawn EP1747191A1 (fr)

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DE102004023506A DE102004023506A1 (de) 2004-05-10 2004-05-10 Kettenverlängerte substituierte Cyclohexyl-1,4-diamin-Derivate
PCT/EP2005/004912 WO2005110975A1 (fr) 2004-05-10 2005-05-06 Derives de cyclohexyl-1,4-diamine substitues a extension de chaine

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DE102004023635A1 (de) * 2004-05-10 2006-04-13 Grünenthal GmbH Heteroarylsubstituierte Cyclohexyl-1,4-diamin-Derivate
WO2009118169A1 (fr) 2008-03-27 2009-10-01 Grünenthal GmbH Dérivés de spiro(5.5)undécane
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US20070281954A1 (en) 2007-12-06
WO2005110975A1 (fr) 2005-11-24
CA2566219C (fr) 2012-08-07
CA2566219A1 (fr) 2005-11-24
JP5037336B2 (ja) 2012-09-26
DE102004023506A1 (de) 2005-12-01
JP2007536322A (ja) 2007-12-13
US7786328B2 (en) 2010-08-31

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