Amide derivatives and nociceptin antagonists

• US 20060030565A1
• Filed: 06/06/2005
• Published: 02/09/2006
• Est. Priority Date: 03/26/1998
• Status: Abandoned Application

• Current Assignee: Japan Tobacco Inc.
• Original Assignee: Japan Tobacco Inc.
• Inventors: Shinkai, Hisashi, Yamada, Hideki, Ito, Takao
• Application Number:
  US11/145,169
• Publication Number:
  US 20060030565A1
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/47 Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61P 23/00 Anaesthetics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07C 235/42 having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07D 215/38 Nitrogen atoms nitro radicals C07D215/18
• CPC Class Codes: C07D 215/42 attached in position 4
• CPC Class Codes: C07D 217/22 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 carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 219/12 Amino-alkylamino radicals attached in position 9
• CPC Class Codes: C07D 221/16 containing carbocyclic rings other than six-membered
• CPC Class Codes: C07D 235/28 Sulfur atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to a compound of the formula [1′]
wherein R² is lower alkyl optionally substituted by hydroxy, amino and the like, ring B is phenyl, thienyl and the like, E is a single bond, —O—, —S— and the like, ring G is aryl, heterocyclic group and the like, R⁵ is halogen atom, hydroxy, lower alkyl optionally substituted by halogen atom etc., and the like, t is 0 or an integer of 1 to 5, when t is an integer of 2 to 5, each R⁵ may be the same or different, m is 0 or an integer of 1 to 8, and n is 0 or an integer of 1 to 4, and a nociceptin antagonist containing compound [1′] as an active ingredient. The compound [1′] shows, due to nociceptin antagonistic action, analgesic effect against sharp pain such as postoperative pain and the like. The present invention also relates to the use of certain amide derivative inclusive of compound [1′] as a nociceptin antagonist or analgesic.

Claims

1. A nociceptin antagonist containing an amide derivative of the formula [1]

wherein

R¹ and R² are the same or different and each is hydrogen atom, lower alkyl optionally substituted by hydroxy, amino, lower alkylamino or di(lower)alkylamino;

R³ and R⁴ are the same or different and each is hydrogen atom, halogen atom or-lower alkyl;

ring A is aryl or heterocyclic group;

ring B is phenyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl or cyclohexenyl; and

X is hydrogen atom, halogen atom, lower alkyl optionally substituted by lower alkoxy, lower alkenyl, amino, cyano or a group of the formula

wherein E is a single bond, carbonyl, sulfinyl,

—

O—

, —

S—

, —

NHCO—

, —

CH═

CR⁶—

wherein R⁶ is hydrogen atom or aryl or —

NR⁷—

wherein R⁷ is hydrogen atom, lower alkyl or lower alkoxycarbonyl;

ring G is aryl, heterocyclic group, cycloalkyl or condensed aryl;

R⁵ is halogen atom, hydroxy, lower alkyl Optionally substituted by any of halogen atom, hydroxy, lower alkanoyloxy and lower alkoxy optionally substituted by lower alkoxy, lower alkoxy optionally substituted by lower alkoxy, amino, lower alkylamino, di(lower)alkylamino, nitro, cyano, lower alkanoyl, lower alkanoyloxy, carboxy, lower alkoxycarbonyl, lower alkylsulfonyl or phenyl;

t is 0 or an integer of 1 to 5, which indicates the number of substituents on the ring G,

wherein when t is an integer of 2 to 5, each R⁵ may be the same or different;

m is 0 or an integer of 1 to 8; and

n is 0 or an integer of 1 to 4, or a pharmaceutically acceptable salt thereof as an active ingredient.

2. A nociceptin antagonist containing the amide derivative of claim 1, wherein the ring A is quinolyl or a pharmaceutically acceptable salt thereof as an active ingredient.

3. A nociceptin antagonist containing the amide derivative of claim 1, wherein the ring B is phenyl and X is a group of the formula

wherein E, ring G, R⁵, t, m and n are as defined in claim 1, or a pharmaceutically acceptable salt thereof as an active ingredient.

4. A nociceptin antagonist containing the amide derivative of claim 3, wherein the ring A is

wherein R⁸ is lower alkylthio, or a pharmaceutically acceptable salt thereof as an active ingredient.

5. An amide derivative of the formula [1′

]

wherein R², ring B, E, ring G, R⁵, t, m and n as defined in claim 1, or a pharmaceutically acceptable salt thereof.

6. The amide derivative of claim 5, wherein the ring B is phenyl and R² is lower alkyl, or a pharmaceutically acceptable salt thereof.

7. The amide derivative of claim 6, wherein the amino substitutes at the 4-position on a quinoline skeleton, R² is methyl substituting at the 2-position on the quinoline skeleton, E is —

O— and

the ring B of phenyl has a substituent of the formula

wherein ring G, R⁵, t, m and n as defined in claim 1, at the 2-position, or a pharmaceutically acceptable salt thereof.

8. The amide derivative of claim 7 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-ethylphenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(2,4-dichlorophenoxy)-methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-(phenoxymethyl)benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-methoxyphenoxy)-methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(3,5-dimethylphenoxy)-methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(3,4-dimethoxyphenoxy)-methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-nitrophenoxy)methyl]-benzamide,

N-(4-amino-2-methyl-6-quinolyl)-2-[(2,3-dimethoxyphenoxy)-methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(3-methylphenoxy)-methyl]benzamide,

N-(4-amino-2-methyl-6-quinolyl)-2-[(3,5-dimethoxyphenoxy)-methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-chlorophenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-acetylphenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-hydroxyphenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-methoxymethoxyphenoxy)-methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(3-methoxyphenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-cyanophenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-methylphenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-trifluoromethylphenoxy)methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(3-nitrophenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(2-nitrophenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-acetoxyphenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(2-methoxyphenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-aminophenoxy)methyl]-benzamide dihydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[-(3-chlorophenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-fluorophenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(3,4-dichlorophenoxy)-methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(2-chlorophenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-dimethylaminophenoxy)-methyl]benzamide dihydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-tert-butylphenoxy)-methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-(4-biphenylyloxymethyl)-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-isopropylphenoxy)-methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-nitrophenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-bromophenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-propylphenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(3-fluorophenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(3-trifluoromethylphenoxy)methyl]benzamide hydrochloride,

methyl 4-[2-{N-(4-amino-2-methyl-6-quinolyl)carbamoyl}-benzyloxylbenzoate hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-iodophenoxy)methyl]-benzamide,

N-(4-amino-2-methyl-6-quinolyl)-2-(3-pyridyloxymethyl)-benzamide hydrochloride,

4-[2-{(4-amino-2-methyl-6-quinolyl)carbamoyl}benzyloxy]-benzoate hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(3-cyanophenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-mesylphenoxy)methyl]-benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(2-chloro-4-ethylphenoxy)-methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-chloro-3-methylphenoxy)methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(2-chloro-4-methylphenoxy)methyl]benzamide hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-ethylphenoxy)methyl]-benzamide,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-chloro-3-methylphenoxy)methyl]benzamide,

4-[2-{(4-amino-2-methyl-6-quinolyl)carbamoyl}benzyloxy]benzyl acetate hydrochloride,

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-hydroxymethylphenoxy)-methyl]benzamide hydrochloride and

N-(4-amino-2-methyl-6-quinolyl)-2-[(4-ethylphenoxy)methyl]-benzamide hydrochloride monohydrate.

9. An amide derivative of the formula [1″

]

wherein the ring A, R², R⁵ and t are as defined in claim 1, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the amide derivative of any of claims 5 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

11. A nociceptin antagonist containing the amide derivative of any of claims 5 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient.

12. An analgesic containing the amide derivative of any of claims 1 to 9 or a pharmaceutically acceptable salt thereof as an active ingredient.

13. A method for expressing a nociceptin antagonistic action, comprising administering the amide derivative of any of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

14. A method for treating pain, comprising administering the amide derivative of any of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

15. Use of the amide derivative of any of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the production of a nociceptin antagonist.

16. Use of the amide derivative of any of claims 1 to 9 or a pharmaceutically acceptable salt thereof for the production of an analgesic.

17. A pharmaceutical composition for antagonizing nociceptin, which comprises the amide derivative of any of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

18. A commercial package comprising the pharmaceutical composition of claim 17 and a written matter associated therewith, the written matter stating that the pharmaceutical composition can be or should be used for antagonizing nociceptin.

19. A pharmaceutical composition for analgesic use, which comprises the amide derivative of any of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

20. A commercial package comprising the pharmaceutical composition of claim 19 and a written matter associated therewith, the written matter stating that the pharmaceutical composition can be or should be used for analgesia.