Amide derivatives and nociceptin antagonists

• US 6,410,561 B1
• Filed: 09/22/2000
• Issued: 06/25/2002
• Est. Priority Date: 03/26/1998
• Status: Expired due to Fees

• Current Assignee: Japan Tobacco Inc.
• Original Assignee: Japan Tobacco Inc.
• Inventors: Yamada, Hideki, Shinkai, Hisashi, Ito, Takao
• Primary Examiner(s): Rotman, Alan L.
• Assistant Examiner(s): ROBINSON, BINTA M
• Application Number:
  US09/646,781
• Time in Patent Office: 641 Days
• Field of Search: 514/313, 514/314, 546/162, 546/159, 546/178, 546/171
• US Class Current: 514/313
• 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 method for treating pain, comprising administering to a host an effective amount of 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 quinolyl;

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

X is 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, a heterocyclic group selected from the group consisting of pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, indolyl, benzofuranyl, benzimidazolyl, imidazolidinyl, indolinyl, pyrrolidinyl, carbazolyl and 2,3-dihydrobenzofuranyl, 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 is 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.

2. 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.

3. The amide derivative of claim 2, wherein the ring B is phenyl and R² is lower alkyl, or a pharmaceutically acceptable salt thereof.

4. The amide derivative of claim 3, 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.

5. The amide derivative of claim 4 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}benyloxy]benzoate 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-[(2chloro-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.

6. 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.

7. A pharmaceutical composition comprising an effective amount of the amide derivative of claim 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

8. A method for expressing a nociceptin antagonistic action, comprising administering to a host an effective amount of the amide derivative of claim 7 or a pharmaceutically acceptable salt thereof.

9. A method for treating pain, comprising administering to a host an effective amount of the amide derivative of claim 2 or a pharmaceutically acceptable salt thereof.

10. A method for expressing a nociceptin antagonistic action, comprising administering to a host an effective amount of the amide derivative of the formula [1] of claim 1 or a pharmaceutically acceptable salt thereof.

11. The method of claim 1, wherein ring G is aryl, heterocyclic group selected from the group consisting of benzofuranyl and 2,3-dihydrobenzofuranyl, cycloalkyl, or condensed aryl.

12. The amide derivative of claim 2, wherein ring G is aryl, heterocyclic group selected from the group consisting of benzofuranyl and 2,3-dihydrobenzofuranyl, cycloalkyl, or condensed aryl.