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  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
• • C—CHEMISTRY; METALLURGY
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  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
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• • A—HUMAN NECESSITIES
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  • A61P25/00—Drugs for disorders of the nervous system
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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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• • A—HUMAN NECESSITIES
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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/40—Oxygen atoms
  • C07D211/42—Oxygen atoms attached in position 3 or 5
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/40—Oxygen atoms
  • C07D211/44—Oxygen atoms attached in position 4
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4

Definitions

• the present invention relates to novel compounds of the general formula
• R 1 is tetrahydronaphtyl
• n is 0-4 and R 4 is H, lower alkyl, or lower alkoxy;
• R 2 is H, OH, lower alkoxy, lower alkenyloxy or lower alkyl
• R 3 is C5-C7 cycloalkyl or phenyl, optionally substituted by OH, halogen, lower alkoxy, lower alkenyloxy, lower alkyl or -0-(CH2)n-C6H ⁇ wherein n is 0-3;
• the compounds of formula I and their salts are distinguished by valuable therapeutic properties. It has surprisingly been found that the compounds of the present invention are agonist/antagonists of the OFQ receptor.
• psychiatric, neurological and physiological disorders especially, but not limited to, amelioration of symptoms of anxiety and stress disorders, depression, memory loss due to Alzheimer's disease or other dementias such as vascular dementia and AIDS dementia complex, Parkinson's disease, epilepsy and convulsions, acute and/or chronic pain conditions, withdrawal symptoms of addictive drugs and reduction of their abuse/craving, control of water balance, Na + excretion and arterial blood pressure disorders and metabolic disorders such as obesity.
• Orphanin FQ a seventeen amino-acid-long peptide (F-G-G-F-T-G-A-R-K-S-A-R-K-L-A-N-Q), has been isolated from rat brain and is a natural ligand for a G-protein coupled receptor (OFQ-R), found at high levels in brain tissue.
• OFQ exhibits agonistic activity at the OFQ-R both in vitro and in vivo.
• R 1 is C 5 -C 12 cycloalkyl, optionally substituted by lower alkyl, for example the following compounds:
• Objects of the present invention are the novel compounds of formula I per se and pharmaceutically acceptable addition salts thereof, racemic mixtures and their corresponding enantiomers, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture as well as the use of the above-mentioned compounds in the control or prevention of illnesses, especially of illnesses and disorders of the kind referred to earlier.
• lower alkyl denotes a straight- or branched- chain alkyl group containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl.
• the compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example by processes described below, which comprise reductively aminating a compound of formula II
• the amination takes place in two steps wherein an imine is formed as intermediate product which further undergoes reduction in the presence of a reductive agent such as sodium cyanoborohydride, molecular hydrogen or nickel.
• a reductive agent such as sodium cyanoborohydride, molecular hydrogen or nickel.
• the amination agent II can be prepared by known methods, for example from compounds of formula III by means of a hydrogenation reaction:
• R 2 and R 3 are as described above and, in the case R 3 is cycloalkyl or phenyl substituted by a -0-CH 2 -C 6 H 5 , the cleavage of the -CH 2 -C 6 H 5 group takes place during reaction.
• the reaction takes place in the presence of hydrogen and a suitable hydrogenation catalyst such as palladium on activated charcoal.
• a suitable hydrogenation catalyst such as palladium on activated charcoal.
• compounds of formula I can be converted into pharma- ceutically acceptable acid addition salts.
• the salt formation is effected at room temperature with methods which are known per se and which are familiar to any person skilled in the art. Not only salts with inorganic acids, but also salts with organic acids come into consideration. Hydrochlorides, hydrobromides, sulphates, nitrates, citrates, acetates, maleates, succinates, methanesulphonates, p-toluenesulphonates and the like are examples of such salts.
• the compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacodynamic properties. It has been found that the compounds of the present invention are agonist/antagonists of the OFQ receptor and have effects in animal models of memory and attention deficits, psychiatric, neurological and physiological disorders, such as anxiety, stress disorders, depression, memory loss due to Alzheimer's disease or other dementias such as vascular dementia and AIDS dementia complex, Parkinson's disease, epilepsy and convulsions, acute and/or chronic pain conditions, withdrawal symptoms of addictive drugs and reduction of their abuse/craving, control of water balance, Na + excretion, arterial blood pressure disorders and metabolic disorders such as obesity.
• HEK-293 cells adapted to suspension growth (293s) were cultured in HL medium plus 2% FBS.
• the cells were transfected with the rat OFQ receptor cDNA (LC132), FEBS Lett. 347, 284-288, 1994, cloned in the expression vector pCEP4 (Invitrogen, SanDiego, CA, USA) using lipofectin (Life Technologies, Bethesda, MD, USA).
• Transfected cells were selected in the presence of hygromycin (1000 U/ml) (Calbiochem, SanDiego, CA, USA).
• a pool of resistant cells was tested for OFQ-R expression by binding of [ 3 H]-OFQ (Amersham PLC, Buckinghamshire, England). These cells (293s-OFQ-R) were expanded for large scale culture and membrane preparation.
• 293s-OFQ-R cells were harvested by centrifugation, washed 3 times with phosphate buffered saline (PBS) before resuspension in buffer A (50 mM Tris-HCl, pH 7.8, 5 mM MgCl 2 , 1 mM EGTA) and disruption with a tissue homogenizer (30 seconds, setting 4, Pt 20, Kinematica, Kriens-Lucern, Switzerland). A total membrane fraction was obtained by centrifugation at 49,000 x g at 4°C. This procedure was repeated twice and the pellet was resuspended in buffer A. Aliquots were stored at -70°C and protein concentrations were determined using the BCATM Protein Assay Reagent (Pierce, Rockford, IL) following the manufacturer's recommendations.
• PBS phosphate buffered saline
• [ 3 H]-OFQ competition studies were carried out with 77 ⁇ g membrane protein in a final assay volume of 0.5 ml buffer A plus 0.1% BSA and 0.01% bacitracin (Boehringer-Mannheim, Mannheim, Germany) for one hour at room temperature. 50 nM unlabeled OFQ was used to define the non-specific binding. The assays were terminated by filtration through Whatman GF/C filters (Unifilter-96, Canberra Packard S.A., Zurich, Switzerland) pretreated with 0.3% polyethylenimine (Sigma, St. Louis, MO, USA) and 0.1% BSA (Sigma) for 1 hour.
• the filters were washed 6 times with 1 ml of ice bold 50 mM Tris-HCl pH 7.5. The retained radioactivity was counted on a Packard Top-Count microplate scintillation counter after addition of 40 ⁇ l of Microscint 40 (Canberra Packard). The effects of compounds were determined using at least 6 concentrations in triplicate, and determined twice. IC5 0 values were determined by curve fitting and these values were converted to Ki values by the method of Cheng and Prusoff, Biochem. Pharmacol., 22, 3099, 1973.
• the affinity to the OFQ-receptor is in the range of 6,0 to 8,0, for example the pKi for the compounds mentioned below is as follows:
• the compounds of formula I as well as their pharmaceutically usable acid addition salts can be used as medicaments, e.g. in the form of pharmaceutical preparations.
• the pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
• the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.
• the compounds of formula I and their pharmaceutically usable acid addition salts can be processed with pharmaceutically inert, inorganic or organic excipients for the production of tablets, coated tablets, dragees and hard gelatine capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc can be used as such excipients e.g. for tablets, dragees and hard gelatine capsules.
• Suitable excipients for soft gelatine capsules are e.g. vegetable oils, waxes, fats, semi-solid and liquid polyols etc.
• Suitable excipients for the manufacture of solutions and syrups are e.g. water, polyols, saccharose, invert sugar, glucose etc.
• Suitable excipients for injection solutions are e.g. water, alcohols, polyols, glycerol, vegetable oils etc.
• Suitable excipients for suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols etc.
• the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
• the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case.
• a daily dosage of about 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit can also be exceeded when it appears to be indicated.
• the title compound was prepared in comparable yield according to a literature procedure (Juan C. Jean and Lawrence D. Wise, J. Heterocyclic Chem. 1987, 24, 1317 - 1319) in two steps starting from 2-benzyloxybromobenzene instead of 2-bromoanisole.
• the product was obtained as a light brown oil.
• the title compound was prepared in comparable yield according to a literature procedure (Juan C. Jean and Lawrence D. Wise, J. Heterocyclic Chem. 1987, 24, 1317 - 1319) in three steps starting from 2-bromoanisole. The product was obtained as a white powder.
• the aqueous solution was adjusted to pH 10 by addition of solid potassium hydroxide and was extracted with dichloromethane, dried (magnesium sulfate) and evaporated to give 155 mg of an oil.
• the amine was dissolved in 10 ml ether and 1 ml of 2.3 M hydrochloric acid in ether was added dropwise. The precipitate was filtered off, washed with ether and dried in ⁇ acuo to give 150 mg (80%) of the title compound as a white powder.
• the aqueous solution was adjusted to pH 10 by addition of solid potassium hydroxide and was extracted with dichloromethane, dried (magnesium sulfate), evaporated and purified by flash- chromatography to give 100 mg of an oil.
• the amine was dissolved in 10 ml ether and 1 ml of 2.3 M hydrochloric acid in ether was added dropwise. The precipitate was filtered off, washed with ether and dried in ⁇ acuo to give 110 mg (55%) of the title compound as a white powder.
• the title compound was prepared in comparable yield according to a literature procedure (Juan C. Jean and Lawrence D. Wise, J. Heterocyclic Chem. 1987, 24, 1317 - 1319) in three steps starting from 2-bromoisopropylbenzene instead of 2-bromoanisole. The product was obtained as a white solid.
• the title compound was prepared in comparable yield according to a literature procedure (Juan C. Jean and Lawrence D. Wise, J. Heterocyclic Chem. 1987, 24, 1317 - 1319) in two steps starting from l,3-dimethoxyphen-2-ylmagnesium bromide instead of 2-methoxyphenylmagnesium bromide.
• the product was obtained as white needles.
• the filtrate was extracted with ethyl acetate, the organic phase washed with brine, dried (magnesium sulfate) and evaporated.
• the residue was purified by flash-chromatography to give 18 mg of white crystals.
• the amine was dissolved in 10 ml ether and 1 ml of 2.3 M hydrochloric acid in ether was added dropwise. The solution was stirred for 30 min at room temperature and was evaporated. The residue was suspended in ether and was stirred for 1 h. The precipitate was filtered off, washed with ether and dried in ⁇ acuo to give 20 mg (6%) of the title compound as a white powder.
• the title compound was prepared in comparable yield according to a literature procedure (Juan C. Jean and Lawrence D. Wise, J. Heterocyclic Chem. 1987, 24, 1317 - 1319) in three steps starting from l,3-dimethoxyphen-2- ylmagnesium bromide instead of 2-methoxyphenylmagnesium bromide.
• the product was obtained as white crystals.
• the filtrate was extracted with dichloromethane, the organic phase washed with brine, dried (magnesium sulfate) and evaporated.
• the residue was purified by flash-chromatography to give 270 mg of a yellow solid.
• the amine was dissolved in 10 ml ethanol and 1 ml of 2.3 M hydrochloric acid in ethanol was added dropwise. The solution was stirred for 30 min at room temperature and was evaporated. The residue was suspended in ether and was stirred for 1 h. The precipitate was filtered off, washed with ether and dried in ⁇ acuo to give 200 mg (48%) of the title compound as a white powder.
• the filtrate was extracted with dichloromethane, the organic phase washed with brine, dried (magnesium sulfate) and evaporated.
• the residue was purified by flash-chromatography to give 80 mg of a light yellow solid.
• the amine was dissolved in 10 ml ethanol and 1 ml of 2.3 M hydrochloric acid in ethanol was added dropwise. The solution was stirred for 30 min at room temperature and was evaporated. The residue was suspended in ether and was stirred for 1 h. The precipitate was filtered off, washed with ether and dried in ⁇ acuo to give 78 mg (19%) of the title compound as a white powder.

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