Novel 1,2-cyclohexylaminoaryl amides useful as analgesic agents

• US 4,906,655 A
• Filed: 01/24/1989
• Issued: 03/06/1990
• Est. Priority Date: 01/24/1989
• Status: Expired due to Term

• Current Assignee: Warner-Lambert Company (Pfizer Inc.)
• Original Assignee: Warner-Lambert Company (Pfizer Inc.)
• Inventors: Rees, David C., Horwell, David C.
• Primary Examiner(s): Shah, Mukund J.
• Assistant Examiner(s): TSUNG, FREDERICK
• Application Number:
  US07/301,219
• Time in Patent Office: 406 Days
• Field of Search: 548/525, 548/528, 514/422, 514/428
• US Class Current: 514/422
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/10 Antioedematous agents; Diuretics
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07C 2603/20 Acenaphthenes; Hydrogenated acenaphthenes
• 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: C07D 307/79 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 307/88 with one oxygen atom directly attached in position 1 or 3

Abstract

Novel 1,2-cyclohexylaminoaryl amides useful as analgesic agents having very high kappa-opioid affinity and selectivity and potency and useful as analgesics, diuretics, antiinflammatory and psychotherapeutic agents are disclosed. Methods for making the compounds and pharmaceutical compositions containing them are also disclosed.

Claims

1. A compound of formula ##STR13## and the pharmaceutically acceptable acid addition salts thereof wherein R₁, R₂, R₃, R₄ =H;

or

wherein one of R₁, R₂, R₃, R₄ may be =OCH₃ when the rest are all H;

or

wherein R₁ =R₄ =OCH₃, and R₂ =R₃ =H;

Ar is ##STR14## wherein X is hydrogen, fluorine, chlorine, alkyl of from one to six carbon atoms or aryl,

n is an integer from 2 to 4, and

A is oxygen or sulfur.

2. A compound according to claim 1 wherein R¹ R², R³, and R⁴ are hydrogen.

3. A compound according to claim 1 where one of R¹ R², R³, or R⁴ is OCH₃.

4. A compound according to claim 1 where R¹ and R⁴ are both --OCH₃.

5. A compound according to claim 1 wherein Ar is ##STR15##

6. A compound according to claim 1 wherein Ar is ##STR16##

7. A compound according to claim 1 wherein Ar is ##STR17##

8. A compound according to claim 1 wherein Ar is ##STR18## and R₁, R₂, R₃, and R₄ are hydrogen.

9. A compound according to claim 1 selected from the group consisting of:

1,2-dihydro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-1-acenaphthylenecarboxamide, monohydrochloride (isomer I, mixture of (1α

,2β

) and (1β

,2α

) forms),

1,2-dihydro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-1-acenaphthylenecarboxamide, monohydrochloride (isomer II, mixture of (1α

,2β

) and (1β

,2α

) forms),

N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-1,2-dihydro-N-methyl-1-acenaphthylenecarboxamide, monohydrochloride (isomer I, mixture of (1α

,2β

,4β

,5β

) and (1β

,2α

,4α

,5α

) forms),

N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]-1,2-dihydro-N-methyl-1-acenaphthylenecarboxamide, monohydrochloride (isomer II, mixture of (1α

,2β

,4β

,5β

) and (1β

,2α

,4α

,5α

) forms),

11. A compound according to claim 1 selected from the group consisting of:

(±

)-trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-9H-fluorene-9-carboxamide, monohydrochloride.

12. A compound according to claim 1 selected from the group consisting of:

(±

)-trans-1,3-dihydro-N-methyl-1-oxo-N-[2-(1-pyrrolidinyl)cyclohexyl]-4-isobenzofuranacetamide, monohydrochloride,

(±

)-(1α

,2β

,4β

,5β

)-N-[4,5-dimethoxy-2-(1-pyrrolidinyl)cyclohexyl]1,3-dihydro-N-methyl-1-oxo-4-isobenzofuranacetamide.

13. A pharmaceutical composition useful for alleviating pain in a mammal comprising a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier.

14. A method of alleviating pain in a mammal which comprises administering to said mammal a pharmaceutical composition which is a compound in accordance with claim 8 in unit dosage form.

15. A method for increasing urination in a mammal which comprises administering to said mammal a pharmaceutical composition which is a compound in accordance with claim 8 in unit dosage form.

16. A method for treating inflammation in a mammal which comprises administering to said mammal a pharmaceutical composition which is a compound in accordance with claim 8 in unit dosage form.

17. A method for treating psychotherapeutic disorders in a mammal which comprises administering to said mammal a pharmaceutical composition which is a compound in accordance with claim 8 in unit dosage form.

10. 2-dihydro-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-1-acenaphthylenecarboxamide, monohydrochloride (isomers I and II, mixtures of (1α

,2β

,4β

) and (1β

,2α

,4α

) forms),

1,2-dihydro-N-[4-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methyl-1-acenaphthylenecarboxamide, monohydrochloride (isomers I and II, mixtures of (1β

,2α

,4α

) and (1α

,2β

,4β

) forms).