2-oxoquinoline compounds and medicinal uses thereof

• US 6,509,352 B1
• Filed: 08/29/2001
• Issued: 01/21/2003
• Est. Priority Date: 01/08/1999
• Status: Expired due to Fees

• Current Assignee: Japan Tobacco Inc.
• Original Assignee: Japan Tobacco Inc.
• Inventors: Inaba, Takashi, Kaya, Tetsudo, Iwamura, Hiroyuki
• Primary Examiner(s): SEAMAN, D MARGARET M
• Application Number:
  US09/869,895
• Time in Patent Office: 510 Days
• Field of Search: 514/312, 546/154, 546/155, 546/157
• US Class Current: 514/312
• 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: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: C07D 215/227 only one oxygen atom which is attached in position 2
• CPC Class Codes: C07D 215/54 attached in position 3
• 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

Abstract

A 2-oxoquinoline compound or its pharmaceutically acceptable salt of general formula [I]:

 

(wherein each symbol in the formula is as determined in the description), and its pharmaceutical use. The compound [I] of the present invention and its pharmaceutically acceptable salts selectively act on cannabinoid receptors, particularly on peripheral type cannabinoid receptors, and have fewer side effects on the central nervous system, having great immunosuppressive action, anti-inflammatory action or antiallergic action. Therefore, these compounds are useful as cannabinoid receptors (particularly peripheral type cannabinoid receptors) modulator, immunosuppressants, anti-inflammatory agents, and antiallergic agents.

Claims

1. A cannabinoid receptor modulator comprising, as an active ingredient, a 2-oxoquinoline compound represented by the following general formula [I] or its pharmaceutically acceptable salt:

2. A cannabinoid receptor modulator comprising, as an active ingredient, the 2-oxoquinoline compound of claim 1 or its pharmaceutically acceptable salt, wherein W represents —

O—

;

R¹ is hydrogen atom or alkyl (the alkyl is as described above);

R² represents —

OR⁶ (R⁶ is as described above); and

R is aryl, heteroaryl or

3. A 2-oxoquinoline compound as represented by the following general formula [I′

] or its pharmaceutically acceptable salt;

4. The 2-oxoquinoline compound of claim 3 or its pharmaceutically acceptable salt, wherein X′

is —

CONR^c—

(Alk^a)_r—

R.

5. The 2-oxoquinoline compound of claim 3 or its pharmaceutically acceptable salt, wherein X′

is —

(CH₂)_p—

OC(═

Y)—

NR^d—

(Alk^b)_s—

R or —

(CH₂)_q—

NR^e—

C(═

Z)—

(NR^f)_w—

(Alk^e)_v—

R.

6. The 2-oxoquinoline compound of any one of claims 3 to 5 or its pharmaceutically acceptable salt, wherein R is aryl, heteroaryl or

7. The 2-oxoquinoline compound of any one of claims 3 to 5 or its pharmaceutically acceptable salt, wherein R is

8. The 2-oxoquinoline compound of claim 3 or its pharmaceutically acceptable salt, wherein W is —

O— and

R² is —

OR⁶ (where R⁶ is a hydrogen atom or alkyl).

9. The 2-oxoquinoline compound of any claim 3 or its pharmaceutically acceptable salt, wherein the substitution position of WR¹ is position-j of the benzene ring, and the substitution position of R² is position-i of the benzene ring.

10. The 2-oxoquinoline compound of claim 3 and 6 to 9 or its pharmaceutically acceptable salt, wherein Alk^a is alkylene and r=1.

11. The 2-oxoquinoline compound of claim 3 or its pharmaceutically acceptable salt, wherein the 2-oxoquinoline compound is selected from the group consisting of 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-4-ylethyl)amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-aminobenzyl)amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-aminophenyl)ethyl]amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-aminophenyl)amide hydrochloride, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide, 8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-4-ylethyl)amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-hydroxyphenyl)ethyl]amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-pyridylmethyl)amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-piperidinoethyl)amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-morpholinoethyl)amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (3-pyridylmethyl)amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-pyridylmethyl)amide, 8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (2-phenylethyl)amide, 8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide, 8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-4-ylethyl)amide, 8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-4-ylethyl)amide hydrochloride, 8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(2-fluorophenyl)ethyl]amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(3-fluorophenyl)ethyl]amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-hydroxy-3-methoxyphenyl)ethyl]amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-chlorophenyl)ethyl]amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-phenylethyl)amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-methylbenzyl)amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-fluorobenzyl)amide, 7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-4-ylethyl)amide, 7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide, 7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-hydroxyphenyl)ethyl]amide, 7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide, 7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid (2-phenylethyl)amide, 7,8-dimethoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide, 7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide, 7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide, 7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-morpholinoethyl)amide, 8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide, 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide, 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-pyridine-4-ylethyl)amide, 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-morpholinoethyl)amide, 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-pyridylmethyl)amide, 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-fluorobenzyl)amide, 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-hydroxyphenyl)ethyl]amide, 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide, 1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide, 1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (2-morpholinoethyl)amide, 1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide, 7,8-dipentyloxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide, 8-hydroxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide, 7-methoxy-2-oxo-B-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (3,4-dihydroxybenzyl)amide, 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid (4-hydroxy-3-methoxybenzyl)amide, 1-O-{2-hydroxy-5-[(7-methoxy-2-oxo-8-pentyloxy-1,2-dihydro-3-quinolyl)carbonylaminomethyl]phenyl}glucosidouronic acid, 1-O-{2-hydroxy-4-[(7-methoxy-2-oxo-8-pentyloxy-1,2-dihydro-3-quinolyl)carbonylaminomethyl]phenyl}glucosidouronic acid, 5-[7-methoxy-3-{(3,4-methylenedioxybenzyl)carbamoyl}-2-oxo-1,2-dihydro-8-quinolyloxy]pentanoic acid, 5-[7-methoxy-3-{(3-hydroxy-4-methoxybenzyl)carbamoyl}-2-oxo-1,2-dihydro-8-quinolyloxy]pentanoic acid, 8-(5-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxyberzyl)amide, 8-(5-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (4-hydroxy-3-methoxybenzyl)amide, 8-(4-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide, 7-methoxy-2-oxo-8-(4-oxopentyloxy)-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide, 8-(3-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide, 7-methoxy-2-oxo-8-(3-oxopentyloxy)-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide, 8-(2-hydroxypentyloxy)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (3,4-methylenedioxybenzyl)amide, 7,8-dihydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [2-(4-fluorophenyl)ethyl]amide, 8-butoxy-3-hydroxymethyl-7-methoxy-2-oxo-1,2-dihydroquinoline, 8-ethoxy-3-hydroxymethyl-7-methoxy-2-oxo-1,2-dihydroquinoline, N-(4-fluorophenyl)carbamic acid (8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl ester, N-pyridine-4-ylcarbamic acid (8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl ester, 3-dimethylaminomethyl-8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline, 8-butoxy-3-aminomethyl-7-methoxy-2-oxo-1,2-dihydroquinoline, 8-ethoxy-7-methoxy-3-morpholinomethyl-2-oxo-1,2-dihydroquinoline, N-[(8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-N′

-(4-fluorophenyl)urea and N-[(8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinolin-3-yl)methyl]-(4-hydroxyphenyl)acetamide.

15. A pharmaceutical composition comprising, as an active ingredient, the 2-oxoquinoline compound of claim 3 or its pharmaceutically acceptable salt.

16. A method of modulating a cannabinoid receptor in a subject, comprising the step of:

administering to a subject a therapeutically effective amount of a pharmaceutically acceptable composition of claim 15,

wherein said composition modulates a cannabinoid receptor within the subject.

17. A method of modulating a peripheral cannabinoid receptor in a subject, comprising the step of:

administering to a subject a therapeutically effective amount of a pharmaceutically acceptable composition of claim 15,

wherein said composition modulates a peripheral cannabinoid receptor within the subject.

18. A method of treating an autoimmune disease, allergy or inflammation in a subject, comprising the step of:

administering to a subject a therapeutically effective amount of a pharmaceutically acceptable composition of claim 15,

wherein the composition treats the autoimmune disease, allergy or inflammation in the subject.

19. A method of treating inflammation in a subject, comprising the step of:

administering to a subject a therapeutically effective amount of a pharmaceutically acceptable composition of claim 15, wherein the composition treats inflammation in the subject.

12. A 2-oxoquinoline compound or its pharmaceutically acceptable salt, the 2-oxoquinoline compound being selected from the group consisting of 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid methyl ester, 7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid methyl ester, 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid methyl ester and 1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid methyl ester.

13. A 2-oxoquinoline compound or its pharmaceutically acceptable salt, the 2-oxoquinoline compound being selected from the group consisting of 7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid, 8-butoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 8-ethoxy-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid, 7-methoxy-2-oxo-8-propoxy-1,2-dihydroquinoline-3-carboxylic acid, 7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid, 1-methyl-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid and 1-methyl-7-methoxy-2-oxo-6-pentyloxy-1,2-dihydroquinoline-3-carboxylic acid.

14. 7-Methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide or its pharmaceutically acceptable salt.