1-Amino-alkylcyclohexane NMDA receptor antagonists

• US 6,034,134 A
• Filed: 08/27/1998
• Issued: 03/07/2000
• Est. Priority Date: 06/30/1997
• Status: Expired due to Term

• Current Assignee: Merz Pharma GmbH & Company Kgaa
• Original Assignee: Merz Pharmaceuticals GmbH (Merz Pharma GmbH & Company Kgaa)
• Inventors: Parsons, Christopher Graham Raphael, Kauss, Valerjans, Kalvinsh, Ivars, Danysz, Wojciech, Jirgensons, Aigars, Gold, Markus
• Primary Examiner(s): BARTS, SAMUEL A
• Application Number:
  US09/141,381
• Time in Patent Office: 558 Days
• Field of Search: 564/454, 564/455, 564/462, 514/579, 514/659
• US Class Current: 514/579
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 211/17 containing only non-condensed rings
• CPC Class Codes: C07C 211/35 containing only non-condensed rings
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07D 295/135 with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Certain 1-aminoalkylcyclohexanes are systemically-active uncompetitive NMDA receptor antagonists having rapid blocking/unblocking kinetics and strong voltage-dependency and are therefore useful in the alleviation of conditions resulting from disturbances of glutamatergic transmission giving them a wide range of utility in the treatment of CNS disorders involving the same, as well as in non-NMDA indications, due to their immunomodulatory, antimalarial, anti-Borna virus, and anti-Hepatitis C activities and utilities. Pharmaceutical compositions thereof and a method-of-treating conditions which are alleviated by the employment of an NMDA receptor antagonist, as well as the aforementioned non-NMDA indications, and a method for the preparation of the active 1-aminoalkylcyclohexane compounds involved.

Claims

1. A 1-aminoalkylcyclohexane compound selected from the group consisting of those of the formula ##STR12## wherein R* is --(CH₂)_n --(CR⁶ R⁷)_m --NR⁸ R⁹

wherein n+m=0, 1, or 2

wherein R¹ through R⁷ are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C), at least R¹, R⁴, and R⁵ being lower-alkyl, and wherein R⁸ and R⁹ are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C) or together represent lower-alkylene --(CH₂)_x -- wherein x is 2 to 5, inclusive, and enantiomers, optical isomers, hydrates, and pharmaceutically-acceptable salts thereof.

2. A compound of claim 1 wherein R¹ through R⁵ are methyl.

3. A compound of claim 1 wherein R¹ is ethyl.

4. A compound of claim 1 wherein R² is ethyl.

5. A compound of claim 1 wherein R³ is ethyl.

6. A compound of claim 1 wherein R⁴ is ethyl.

7. A compound of claim 1 wherein R⁵ is ethyl.

8. A compound of claim 1 wherein R⁵ is propyl.

9. A compound of claim 1 wherein R⁶ or R⁷ is methyl.

10. A compound of claim 1 wherein R ⁶ or R⁷ is ethyl.

11. A compound of claim 1 wherein the compound is selected from the group consisting of

1-amino-1,3,5-trimethylcyclohexane,

1-amino-1(trans),3(trans),5-trimethylcyclohexane,

1-amino-1(cis),3(cis),5-trimethylcyclohexane,

1-amino-1,3,3,5-tetramethylcyclohexane,

1-amino-1,3,3,5,5-pentamethylcyclohexane,

1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,

1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,

1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane,

1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane,

1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane,

1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane,

1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,

1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane,

N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,

N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, and N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine, and optical isomers, enantiones, hydrates and pharmaceutically-acceptable salts of any of the foregoing.

12. An NMDA-receptor antagonist pharmaceutical composition comprising an effective NMDA-receptor antagonistic amount, or an effective immunomodulatory, antimalarial, anti-Borna virus, or anti-Hepatitis C amount, of a 1-aminoalkylcyclohexane compound selected from the group consisting of those of the formula ##STR13## wherein R* is --(CH₂)_n --(CR⁶ R⁷)_m --NR⁸ R⁹

wherein n+m=0, 1, or 2

wherein R¹ through R⁷ are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C), at least R¹, R⁴, and R⁵ being lower-alkyl, and wherein R⁸ and R⁹ are independently selected from the group consisting of hydrogen and lower-alkyl (1-6C) or together represent lower-alkylene --(CH₂)_x -- wherein x is 2 to 5, inclusive, and optical isomers, enantiomers, hydrates, and pharmaceutically-acceptable salts thereof, in combination with one or more pharmaceutically-acceptable diluents, excipients, or carriers.

13. A pharmaceutical composition of claim 12 wherein R¹ through R⁵ are methyl.

14. A pharmaceutical composition of claim 12 wherein R¹ is ethyl.

15. A pharmaceutical composition of claim 12 wherein R² is ethyl.

16. A pharmaceutical composition of claim 12 wherein R³ is ethyl.

17. A pharmaceutical composition of claim 12 wherein R⁴ is ethyl.

18. A pharmaceutical composition of claim 12 wherein R⁵ is ethyl.

19. A pharmaceutical composition of claim 12 wherein R⁵ is propyl.

20. A pharmaceutical composition of claim 12 wherein R⁶ or R⁷ is methyl.

21. A pharmaceutical composition of claim 12 wherein R⁶ or R⁷ is ethyl.

22. A pharmaceutical composition of claim 12 wherein the compound is selected from the group consisting of

1-amino-1,3,5-trimethylcyclohexane,

1-amino-1(trans),3(trans),5-trimethylcyclohexane,

1-amino-1(cis),3(cis),5-trimethylcyclohexane,

1-amino-1,3,3,5-tetramethylcyclohexane,

1-amino-1,3,3,5,5-pentamethylcyclohexane,

1-amino-1,3,5,5-tetramethyl-3-ethylcyclohexane,

1-amino-1,5,5-trimethyl-3,3-diethylcyclohexane,

1-amino-1,5,5-trimethyl-cis-3-ethylcyclohexane,

1-amino-(1S,5S)cis-3-ethyl-1,5,5-trimethylcyclohexane,

1-amino-1,5,5-trimethyl-trans-3-ethylcyclohexane,

1-amino-(1R,5S)trans-3-ethyl-1,5,5-trimethylcyclohexane,

1-amino-1-ethyl-3,3,5,5-tetramethylcyclohexane,

1-amino-1-propyl-3,3,5,5-tetramethylcyclohexane,

N-methyl-1-amino-1,3,3,5,5-pentamethylcyclohexane,

N-ethyl-1-amino-1,3,3,5,5-pentamethylcyclohexane, and

N-(1,3,3,5,5-pentamethylcyclohexyl) pyrrolidine, and optical isomers, enantiomers, hydrates and pharmaceutically-acceptable salts of any of the foregoing.