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  • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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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-Dehvate-Dehvaten 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, but are not limited to, 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 others 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 therefore neurodegenerative 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).
• 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 those there mentioned indications are suitable.
• the compounds should influence norepinephrine and serotonin reuptake.
• the invention therefore provides substituted cyclohexyl-1,4-diamine derivatives of the general formula I
• n 1, 2, 3, 4 or 5
• R ⁇ and R ⁇ independently represent H; C j _5-alkyl in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C .s-Cycloalkyl, in each case monosubstituted or polysubstituted or unsubstituted; or aryl bound via C- ⁇ -alkyl, C. Cycloalkyl or heteroaryl, each singly or multiply substituted or unsubstituted; or the radicals R and R 2 together represent CH 2 CH 2 OCH 2 CH 2 , CH 2 CH 2 NR 10 CH 2 CH 2 or (CH 2 ) 3 .
• R 10 is H; in each case saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; C .s-Cycloalkyl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; or via Ci. alkyl bonded aryl, C .g-cycloalkyl or heteroaryl, each eir ⁇ acrr or polysubstituted or unsubstituted; C (0) phenyl, C (0) heteroaryl, C (O) -C. 5- alkyl, each substituted or unsubstituted;
• _5-alkyl in each case saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted;
• C .g-Cycloalkyl in each case monosubstituted or polysubstituted or unsubstituted;
• Aryl or heteroaryl in each case unsubstituted or monosubstituted or polysubstituted;
• R 4 by- (CR 6 R 7) p R 8 is wherein p is 0, 1, 2, 3 or 4;
• R 6 is H or C ⁇ -5 alkyl, respectively saturated or unsaturated, branched or unbranched, unsubstituted or mono- or polysubstituted,
• R 5 is H or for- (CH 2 ), R 8 , where I is 1, 2 or 3, or together with R 4 for CH 2 CHR 14 OCHR 14 CH 2 , CH 2 CH 2 SCH 2 CH 2 ⁇
• R 11 is H; C j _5-alkyl, respectively saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted; C ⁇ .g-cycloalkyl, each saturated or unsaturated, mono- or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; or aryl, C .g-cycloalkyl or heteroaryl bonded via C 1-4 -alkyl, in each case monosubstituted or polysubstituted or unsubstituted;
• R 12 H; C ⁇ _5-alkyl, in each case saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted; OH; C (O) phenyl, unsubstituted or monosubstituted or polysubstituted; C .g-Cycloalkyl, in each case monosubstituted or polysubstituted or unsubstituted; Aryl or heteroaryl, in each case monosubstituted or polysubstituted or unsubstituted; or aryl, C ⁇ .g-cycloalkyl or heteroaryl bonded via C 1-6 -alkyl, in each case monosubstituted or polysubstituted or unsubstituted; and R 13 is H or OH, or together with R 12 via the same C atom (spiro compound) or an adjacent C atom forms a five-membered or six-membered ring
• R 14 is H or C ⁇ -3 alkyl, in each case saturated or unsaturated, branched or unbranched, mono- or polysubstituted or unsubstituted, group; in the form of the Razemats; 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.
• 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.
• Ci. ⁇ -alkyl in the context of this invention comprise acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chain and unsubstituted or monosubstituted or polysubstituted, having 1, 2, 3, 4, 5 or 6 C atoms or 1, 2, 3, 4 or 5 C atoms or
• Alkynyls at least one C-C triple bond on.
• alkyl from the
• cycloalkyl or "C ⁇ . ⁇ -cycloalkyl” 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 - or may be substituted several times. With respect to cycloalkyl, the term 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_s-cycloalkyl from the group which contains cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, but also tetrahydropyranyl, dioxanyl, dioxolanyl, morpholinyl, piperidinyl, piperazinyl, pyrazolinonyl and pyrrolidinyl.
• 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, i.a. Phenyle, 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 may be in any desired 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.
• heteroaryl moiety is selected from the group consisting of pyrrolyl, indolyl, furyl (furanyl), benzofuranyl, thienyl (thiophenyl), benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotazolyl, 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 attachment to the compounds of
• 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 of the active ingredient with other molecules and ions in particular complexes that are complexed via ionic interactions.
• they include (and this is also a preferred embodiment of this invention) physiologically acceptable salts, especially 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 acceptable 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.
• 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 tolerated salts of certain acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid,
• Particularly preferred is the hydrochloride 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.
• the substituted cyclohexyl-1, 4-diamine derivatives according to the invention, the following applies:
• R ⁇ and R 2 are independently H; C 1-6 alkyl, 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 mean, where saturated or unsaturated, branched or unbranched, monosubstituted or polysubstituted or unsubstituted, means.
• R 1 and R 2 independently of one another are CH 3 or H, where R 1 and R 2 are not simultaneously H, or R 1 and R 2 are CH 2 CH 2 OCH 2 CH 2 or (CH 2 ) 6 stand.
• R 1 represents cyclopentyl, cyclohexyl, phenyl, benzyl, naphthyl, anthracenyl, thiophenyl, benzothiophenyl, furyl, benzofuranyl, benzodioxolanyl, indolyl, indanyl, benzodioxanyl, pyrrolyl, pyridyl, Pyrimidyl or pyrazinyl, each unsubstituted or monosubstituted or polysubstituted; over a saturated, unbranched C
• 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 substituted; over a saturated, unbranched C ⁇
• R 3 is phenyl, thiophenyl, pyridyl or benzyl, in each case substituted or unsubstituted, particularly preferably 4-methylbenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3 Methylbenzyl, benzyl, phenyl, thiophenyl and 3-fluorophenyl.
• substituted cyclohexyl-1, 4-diamine derivatives wherein R 4 is - (CR 6 R 7 ) P R 8 and R 5 is H.
• substituted cyclohexyl-1,4-diamine derivatives wherein R 4 is (CH 2 ) P R 8 and R 5 is - (CH 2 ) ⁇ R 8 .
• R 6 is H and R 7 is H, CH 3 , benzyl, unsubstituted or monosubstituted or polysubstituted, or COOR 9 or R 6 and R 7 are a ring ( CH 2 ) k CHR 8 (CH 2 ) m .
• R 8 C- ⁇ - 6 alkyl in each case saturated or unsaturated, branched or unbranched, unsubstituted or monosubstituted or polysubstituted; Pyrrolidinyl, morpholinyl, tetrahydrofuryl, tetrahydronaphthyl, dihydroindolyl, pyridyl, thienyl, piperazinyl, naphthyl, indanyl, quinolinyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, furyl, benzofuryl, phenyl or indolyl, in each case unsubstituted or monosubstituted or polysubstituted, means.
• substituted cyclohexyl-1,4-diamine derivatives from the group consisting of N- [1- (2,6-dichlorobenzyl) -pyrrolidin-3-yl] -N '- [4-dimethylamino-4- ( 4-methyl-benzyl) -cyclohexyl-succinamide N- [4- (3-chloro-benzyl) -4-dimethylamino-cyclohexyl] -N '- (2-oxo-tetrahydro-furan-3-yl) -succinamide N- [4- (4-Chloro-benzyl) -4-dimethylamino-cyclohexyl] -N '- (3,3-diphenyl-propyl) -succinamide N- [4-dimethylamino-4- (4-methyl-benzyl) -cyclohexyl ] -4- [4- (7-
• 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, as semi-solid dosage forms in the form of granules, tablets, pellets, patches,
• Capsules, patches / spray patches or aerosols are administered.
• the choice of excipients etc. as well as the amounts to be used depend on whether the drug is oral, peroral, parenteral, intravenous, intraperitoneal, intradermal, intramuscular, intranasal, buccal, rectal or topical, for example on the skin, mucous membranes or in the eyes, to 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, easily reconstitutable dry preparations and sprays.
• 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 skin penetration promoting agents, are suitable percutaneous administration preparations. Orally or percutaneously applicable formulations 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 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 cyclohexyl-1, 4-diamine derivative according to the invention are applied.
• the drug in addition to at least one substituted cyclohexyl 1, 4-diamine derivative, also a further active substance, in particular an opioid, preferably a strong opioid, in particular morphine, or an anesthetic, preferably hexobarbital or halothane.
• an opioid preferably a strong opioid, in particular morphine, or an anesthetic, preferably 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 prepared for the preparation a drug for the treatment of pain, especially acute, neuropathic or chronic pain.
• Another object of the invention is therefore the use of a substituted cyclohexyl-1, 4-diamine 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 cyclohexyl-1, 4-diamine derivative of the invention for the manufacture of a medicament for the treatment of anxiety, stress and stress associated syndromes, depression, epilepsy, Alzheimer's 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, impaired food intake, anorexia, obesity, locomotor disorders, diarrhea, cachexia, urinary incontinence or as muscle relaxant, anticonvulsant or anesthetic or for coadministration with treatment with an opioid analgesic or with an anesthetic, for diuresis or antinatriuresis, anxiolysis, modulation of locomotor activity, modulation of neurotransmitter release and treatment of associated neurodegenerative diseases, treatment of withdrawal symptoms and / or reduction of the addictive potential of opioids.
• 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.
• a further subject 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 or a treatment of pain, especially chronic pain, by administering a therapeutically significant dose of a substituted cyclohexyl-1,4-diamine derivative of the invention, or a pharmaceutical composition of the invention.
• Another object of the invention is a process for preparing the substituted cyclohexyl-1,4-diamine derivatives of the invention as set forth in the following description and examples.
• radicals R 1 and R 2 have the meanings given for the compounds according to the invention of formula I for R 1 and R 2 and may additionally be independently of one another a protective group.
• the remaining radicals have the meaning given in formula I:
• the various methods known to those skilled in the art are generally suitable for the preparation of amides.
• the process according to the invention is based on linking substituted cyclohexane-1,4-diamines (WO 02090317) via anhydrides, open-chain dicarboxylic acids or preferably their activated analogs, in particular their acid halides, with further primary or secondary amines and thus converting them into compounds according to the invention.
• dehydrating agents with a complementary primary or secondary amines or a cyclohexane-1, 4-diamine to diamide becomes.
• the reactions with anhydrides preferably take place in polar or nonpolar aprotic solvents such as DMF, DMSO, diethyl ether, diisopropyl ether, THF, toluene, dichloromethane or acetonitrile at temperatures between -20 and + 110 ° C., preferably -10 and + 40 ° C.
• polar or nonpolar aprotic solvents such as DMF, DMSO, diethyl ether, diisopropyl ether, THF, toluene, dichloromethane or acetonitrile
• polar or non-polar aprotic solvents are likewise used, to which an organic or inorganic auxiliary base, preferably tertiary amines, such as triethylamine, diisopropylethylamine or DMAP, has been added.
• an organic or inorganic auxiliary base preferably tertiary amines, such as triethylamine, diisopropylethylamine or DMAP
• pyridine is also suitable as base and as solvent.
• acid chlorides are reacted with amines at -10 and + 40 ° C in dichloromethane or chloroform in the presence of triethylamine or pyridine and optionally catalytic amounts of DMAP.
• ether means diethyl ether
• EE is ethyl acetate
• DCM dichloromethane
• Equivalents means equivalent molar 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.
• the stationary phase used for the column chromatography was silica gel 60 (0.040-0.063 mm) from E. Merck, Darmstadt.
• Table 1 lists the amines used for the last step for the examples.
• Table 1 List of examples and illustration of the amine used in the last step of the synthesis.
• Example 341 N- [4- (3-Chlorobenzyl) -4-dimethylaminocyclohexyl] -N'-furan-2-yl-methylsuccinic acid amide hydrochloride, more nonpolar diastereoisomer
• Example 342 N- [4- (3-Chlorobenzyl) -4-dimethylaminocyclohexyl] -N'-furan-2-yl-methylsuccinamide hydrochloride, more polar diastereoisomer
• Example 341 there were also obtained 357 mg of the more polar diastereoisomer of N- [4- (3-chlorobenzyl) -4-dimethylaminocyclohexyl] -N'-furan-2-yl-methyl-succinic acid amide dissolved in 25 ml of 2-butanone adding 14.4 ⁇ l of water and 100 ⁇ l of chlorotrimethylsilane were converted into the corresponding hydrochloride (230 mg of white solid, mp 186-188 ° C.).
• Example 341 As described for Example 341, 0.95 mg of 4- [2- (2-fluorophenyl) ethylcarbamoyl] butyric acid and 0.87 g of 1-benzyl-N, N-dimethylcyclohexane-1,4-diamine in 5 ml of DMF in the presence of 0.59 ml of N, N-diisopropylcarbodiimide and 0.50 g of 1-hydroxybenzotriazole were reacted and the crude product (1.65 g of yellow solid) was isolated analogously.
• Example 343 260 mg of the more polar diastereoisomer of glutaric acid (4-benzyl-4-dimethylaminocyclohexyl) amide were also dissolved in 5 ml of 2-butanone and 45 ml of ethyl acetate by adding 10 ⁇ l of water and 71 ⁇ l of chlorotrimethylsilane to the corresponding Hydrochloride (110 mg of glassy solid).
• Example 34 As described for Example 341, 0.96 mg of N- [2- (4-chlorophenyl) ethyl] succinic acid and 1.0 g of 4- (3-chlorobenzyl) -4-dimethylaminocyclohexanone in 5 ml of DMF in the presence of 0, Reacted 59 ml of N, N-diisopropylcarbodiimide and 0.5 g of 1-hydroxybenzotriazole and the crude product (2.23 g yellow solid) isolated analogously.
• Example 347 Glutaric acid (4-benzyl-4-dimethylaminocyclohexyl) amide [2- (4-chlorophenyl) ethyl] amide hydrochloride, more nonpolar diastereoisomer
• Example 341 As described for Example 341, 0.87 mg of 4- [2- (4-chlorophenyl) ethylcarbamoyl] butyric acid and 1.0 g of 4-benzyl-4-dimethylaminocyclohexanone in 5 ml of DMF were added in the presence of 0.59 ml of N, N- DiisopropyIcarbodiimid and 0.5 g of 1-hydroxybenzotriazole reacted and the crude product (1.80 g) isolated analogously.
• Example 348 Glutaric acid (4-benzyl-4-dimethylaminocyclohexyl) amide [2- (4-chlorophenyl) ethyl] amide hydrochloride, more polar diastereoisomer
• the cyclohexane derivatives of the general formula I were investigated in a receptor binding assay with ⁇ H-nociceptin / orphanin FQ with membranes from 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 in these experiments was 0.5 nM.
• 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 determined using 1 mg each of WGA-SPA beads (Amersham-Pharmacia, Freiburg), incubation of the mixture at RT for one hour and subsequent measurement in the scintillation counter Trilux (Wallac, Finland).
• the receptor affinity for the human ⁇ -opiate receptor was determined in a homogeneous batch in microtiter plates. For this purpose, serial dilutions of each substituted substituted cyclohexyl-1,4-diamine derivative 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 one
• 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 the ninety-minute incubation period, the microtiter plates were centrifuged off for 20 minutes at 1000 g and the radioactivity was measured in a ⁇ -counter (Microbeta-Trilux, PerkinElmer Wallac, Freiburg, Germany). The percentage displacement of the radioactive ligand from its binding to the human ⁇ -opiate receptor was determined at a concentration of the test substances of 1 ⁇ mol / l and as a percentage inhibition

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