	US 7,531,554 B2
	4-oxoquinoline compound and use thereof as HIV integrase inhibitor
Motohide Satoh, Osaka (Japan); Takashi Matsuda, Osaka (Japan); Satoshi Okuda, Osaka (Japan); Hiroshi Kawakami, Osaka (Japan); Hisateru Aramaki, Osaka (Japan); Hisashi Shinkai, Osaka (Japan); Yuji Matsuzaki, Osaka (Japan); Wataru Watanabe, Osaka (Japan); Kazunobu Yamataka, Osaka (Japan); Shinichi Kiyonari, Osaka (Japan); Shuichi Wamaki, Osaka (Japan); Mitsuru Takahashi, Osaka (Japan); Naohito Yamada, Osaka (Japan); and Akemi Nagao, Osaka (Japan)
Assigned to Japan Tobacco Inc., (Japan)
Filed on May 20, 2005, as Appl. No. 11/133,470.
Claims priority of application No. 2004-151034 (JP), filed on May 20, 2004.
Prior Publication US 2006/0019906 A1, Jan. 26, 2006
Int. Cl. C07D 215/04 (2006.01); A61K 31/44 (2006.01)

U.S. Cl. 514—313 [514/314; 546/153; 546/159]

14 Claims

1. A 4-oxoquinoline compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof:

wherein

ring Cy is a group selected from the group consisting of

R is a hydrogen atom or

R¹

{wherein R¹¹is —(C_mH_2m)—OR¹², —(C_mH_2m)—SR¹², —(C_mH_2m)—SO₂R¹²(wherein R¹²is a C_1-4alkyl group and m is an integer of 1 to 4), a saturated heterocyclic group, an isopropyl group or a tert-butyl group}, R³²is a hydrogen atom, an ethyl group, a methoxy group, a hydroxyl group, a 2-hydroxyethoxy group, a 3-hydroxypropoxy group, a 4-hydroxybutyloxy group, a 2,2,2-trifluoroethyloxy group, —O—(CH₂)_p—OR³⁴, —O—(CH₂)—NR³⁵R³⁶, —O—(CH₂)_p—CO₂R³⁵, —O—(CH₂)_p—CONR³⁵R³⁷, —O—(CH₂)_p—SO₂NR³⁵R³⁷(wherein R³⁴is a C_1-4alkyl group, R³⁵and R³⁷are the same or different and each is a hydrogen atom or a C_1-4alkyl group, R³⁶is a hydrogen atom, a C_1-4alkyl group, an acetyl group or a mesyl group, and p is an integer of 1 to 4), a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group (wherein each of the pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group and thiomorpholinyl group is optionally substituted by 1 or 2 substituents selected from the group consisting of a hydroxyl group, a C_1-4alkyl group, an oxo group, —COR³⁸, —NR³⁵R³⁷and —NR³⁵COR³⁸, wherein R³⁵and R³⁷are as defined above and R³⁸is a C_1-4alkyl group), or

(wherein X is —O— or —NH—, ring A is a phenyl group or a heterocyclic group, wherein each of the phenyl group and the heterocyclic group is optionally substituted by at least one group independently selected from a cyano group, a mesyl group, a C_1-4alkyl group, —CO₂R³⁵, —CONR³⁵R³⁷, —SO₂NR³⁵R³⁷and —COR³⁸, wherein R³⁵, R³⁷and R³⁸are as defined above, and q is 0 or an integer of 1 to 4), R³³is a hydrogen atom, a hydroxyl group, —O—(CH₂)_n—OR³⁹, —O—(CH₂)_n—NR³⁹R³¹or —O—(CH₂)_n—Ph (wherein R³⁹and R³¹are the same or different and each is a hydrogen atom or a C_1-4alkyl group and n is an integer of 1 to 4),

R⁷is a hydrogen atom or a hydroxyl group,

R³²and R³³may be linked to form an alkylenedioxy group,

R¹and R³³may be linked to form

(wherein * shows the R³³side and R¹³is a C_1-4alkyl group optionally substituted by hydroxyl group(s)),

provided that the compound represented by the formula [I] satisfies at least one condition of the following (1)-(7):

(1) the compound represented by the formula [I] is a compound represented by

wherein ring Cy is a group selected from the group consisting of

(2) the compound represented by the formula [I] is a compound represented by

wherein R³²is a hydrogen atom or a methoxy group, and R¹is

wherein R¹¹is —(C_mH_2m)—OR¹², —(C_mH_2m)—SR¹², —(C_mH_2m)—SO₂R¹²(wherein R¹²and m are as defined above), or a saturated heterocyclic group;

(3) the compound represented by the formula [I] is a compound represented by

wherein R³³is a hydroxyl group, —O—(CH₂)_n—OR³⁹, —O—(CH₂)_n—NR³⁹R³¹, or —O—(CH₂)_n—Ph (wherein R³¹, R³⁹and n are as defined above);

(4) the compound represented by the formula [I] is a compound represented by

wherein R³²is an ethyl group, a 4-hydroxybutyloxy group, a 2,2,2-trifluoroethyloxy group, —O—(CH₂)_p—OR³⁴, —O—(CH₂)_p—NR³⁵R³⁶, —O—(CH₂)_p—CO₂R³⁵, —O—(CH₂)_pCONR³⁵R³⁷, —O—(CH₂)_p—SO₂NR³⁵R³⁷(wherein R³⁴, R³⁵, R³⁶, R³⁷and p are as defined above), a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, a thiomorpholinyl group (wherein each of the pyrrolidinyl group, piperidinyl group, piperazinyl group, morpholinyl group and thiomorpholinyl group is optionally substituted by 1 or 2 substituents selected from the group consisting of a hydroxyl group, a C_1-4alkyl group, an oxo group, —COR³⁸, —NR³⁵R³⁷and —NR³⁵COR³⁸, wherein R³⁵, R³⁷and R³⁸are as defined above), or

wherein X, ring A and q are as defined above;

(5) the compound represented by the formula [I] is a compound represented by

wherein R¹³is as defined above;

(6) the compound represented by the formula [I] is a compound represented by

wherein R³²and R³³are linked to form an alkylenedioxy group; and

(7) the compound represented by the formula [I] is

6-(2-chloro-6-fluorobenzyl)-1-(1-(hydroxymethyl)-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-(2,3-dichlorobenzyl)-1-(1-(hydroxymethyl)-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-(3-chloro-2-fluorobenzyl)-7-(2-hydroxyethoxy)-1-(1-(hydroxymethyl)-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-(3-chloro-2-fluorobenzyl)-1-(1-(hydroxymethyl)-2-methylpropyl)-7-(3-hydroxypropoxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-(3-chloro-2-fluorobenzyl)-7-hydroxy-1-(1-(hydroxymethyl)-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-(3-chloro-2-fluorobenzyl)-1-(2,2-dimethyl-1-(hydroxymethyl)propyl)-7-(morpholin-4-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,

6-((3-chloro-2-fluorophenyl)-hydroxy-methyl)-1-(1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, or

6-[6-(3-chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonyloxy]-3,4,5-trihydroxytetrahydropyran-2-carboxylic acid.