Substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine

• US 20030225116A1
• Filed: 03/07/2003
• Published: 12/04/2003
• Est. Priority Date: 09/08/2000
• Status: Active Grant

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Hinze, Claudia, Sundermann, Bernd, Chizh, Boris, Sattlegger, Michael, Henn, Gisela, Kerwer-Thomas, Angelika
• Granted Patent: US 7,034,041 B2
• Time in Patent Office: Days
• US Class Current: 514/277
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 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
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 211/70 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Abstract

Substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine (compounds), methods for the production thereof, pharmaceutical compositions containing said compounds, and methods of treatment of pain and other diseases using the pharmaceutical compositions.

Claims

1. A substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine compound of formula I,

2. A compound according to claim 1, wherein R¹ denotes methyl, chlorine other than in the 4-position, fluorine, methoxy or methylsulfanyl.

3. A compound according to claim 1, which is:

4-(2-fluorophenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine,

4-(3-fluorophenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine,

4-(4-fluorophenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine

4-(2-methoxyphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine,

4-(3-methoxyphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine,

4-(4-methoxyphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine,

4-(2-methylphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine,

4-(3-methylphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine,

4-(4-methylphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine,

4-(2-methylsulfanylphenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine,

4-(2-chlorophenyl)-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine, or

a corresponding hydrochloride thereof.

4. A process for the production of a substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine of formula I according to claim 1, wherein the process comprises

(1) reacting a cyclohexanone of formula II with a 1,4-dioxa-8-aza-spiro[4,5]decane of formula III in the presence of titanium tetrachloride to form an enamine of formula IV,

(2) reacting the enamine of formula IV with a phenylmagnesium halide of formula V in the presence of trimethyl-chlorosilane to form an amine of formula VI,

(3) hydrolyzing and precipitating the amine of formula VI as a hydrochloride of formula VII with concentrated hydrochloric acid

(4) converting the hydrochloride into a free base of formula VIII,

(5) reacting the free base with a Grignard reagent of formula IX to form a compound of formula X,

(6) precipitating the compound of formula X as hydrochloride of formula XI, and

(7) reacting the hydrochloride of compound XI with formic acid to form a compound of formula I:

5. A process according to claim 4, further comprising purifying the compound of formula I.

6. A method according to claim 4, further comprising reacting the compound of formula I with a physiologically acceptable acid to form a physiologically acceptable salt.

7. A process for the production of a substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrahydropyridine of formula I according to claim 1, wherein the process comprises

(1) reacting a cyclohexanone of formula II with a 1,4-dioxa-8-aza-spiro[4,5]decane of formula III in the presence of titanium tetrachloride to form an enamine of formula IV,

(2) introducing ethereal HCl to the enamine of formula IV, and reacting the enamine with a phenylmagnesium halide of formula V in the presence of ethereal HCl to form an amine of formula VI,

(3) hydrolyzing and precipitating the amine of formula VI as a hydrochloride of formula VII with concentrated hydrochloric acid,

(4) converting the hydrochloride into a free base of formula VIII,

(5) reacting the free base with a Grignard reagent of formula IX to form a compound of X:

(6) precipitating the compound of formula X as a hydrochloride of formula XI, and

(7) reacting the hydrochloride of formula XI with formic acid to form a compound of formula I.

8. A process according to claim 7, further comprising purifying the compound of formula I.

9. A method according to claim 7, further comprising reacting the compound of formula I with a physiologically acceptable acid to form a physiologically acceptable salt.

17. A pharmaceutical composition comprising at least one compound according to claim 1, and a pharmaceutically acceptable carrier.

10. A process for the production of a compound of formula I, wherein the process comprises

(1) reacting a cyclohexanone of formula II with a 1,4-dioxa-8-aza-spiro[4,5]decane of formula III in the presence of potassium cyanide and hydrochloric acid to form an aminonitrile of formula XII,

(2) reacting the aminonitrile of formula XII with a phenyl Grignard reagent to form an amine of formula VI,

(3) hydrolyzing and precipitating the amine of formula VI as a hydrochloride of formula VII with concentrated hydrochloric acid,

(4) converting the hydrochloride into a free base of formula VIII,

(5) reacting the free base with a Grignard reagent of formula IX to form a compound of formula X:

(6) precipitating the compound of formula X as a hydrochloride of formula XI, and

(7) reacting the hydrochloride of formula XI with formic acid to form a compound of formula I.

11. A process according to claim 10, further comprising purifying the compound of formula I.

12. A method according to claim 10, further comprising reacting the compound of formula I with a physiologically acceptable acid to form a physiologically acceptable salt.

13. A process for the production of a substituted 4-phenyl-1-(1-phenylcyclohexyl)-1,2,3,6-tetrapyridine of formula I, wherein the process comprises

(1) reacting an N-tert.-butyloxycarbonyl-4-piperidone of formula XIII with a Grignard reagent of formula IX to form a compound of formula XIV:

(2) removing the tert.-butyloxycarbonyl protective group from the compound of formula XIV with an acid, to obtain a compound of formula XV as a HCl salt,

(3) reacting the HCl salt with titanium(IV) chloride and a cyclohexanone of formula II to form an enamine of formula XVI,

(4) reacting the enamine of formula XVI with a phenylmagnesium halide in the presence of trimethylchlorosilane or ethereal HCl,

wherein a HCl salt of the compound of formula I is precipitated.

14. A process according to claim 13, further comprising purifying the compound of formula I.

15. A process according to claim 13, further comprising converting the HCl salt of formula I to a free base and reacting the free base to a physiologically acceptable acid.

16. A process according to claim 13, wherein the acid in step (2) is HCl, HBr, or formic acid, or a mixture of HBr and glacial acetic acid.

18. A method for relieving pain, comprising administering a pharmaceutical composition of claim 16 to a patient in need thereof.

19. A method for the treatment of at least one disease selected from the group consisting of epilepsy, schizophrenia, a neurodegenerative disease, cerebral ischaemia, cerebral infarct, psychosis due to raised amino acid level, brain swelling, a deficiency state of the central nervous system, AIDS dementia, encephalomyelitis, Tourette'"'"'s syndrome, perinatal asphyxia, and tinnitus, or for the prophylaxis of stroke, comprising administering a pharmaceutical composition of claim 16 to a patient in need thereof.