US2003027847A1PendingUtilityA1
HIV integrase inhibitors
Priority: Jun 16, 2000Filed: Jun 18, 2001Published: Feb 6, 2003
Est. expiryJun 16, 2020(expired)· nominal 20-yr term from priority
A61P 31/00C07D 317/58C07C 235/74A61P 31/18C07C 237/42C07C 235/28C07D 213/40C07D 317/46C07D 333/20C07D 307/52C07D 317/34C07D 317/40C07C 311/51C07D 213/30C07C 2601/02C07D 213/38A61P 43/00C07D 407/12C07C 59/90C07D 405/12
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Claims
Abstract
The present invention relates to the inhibition of HIV integrase, and to the treatment of AIDS or ARC by administering compounds of the formula wherein R 1 is C 1 -C 4 alkyl, carbocyclic radical, heterocyclic radical, aryl-C 1 -C 2 alkylene, aryloxy-C 1 -C 2 alkylene, alkoxy-CC(O)—, wherein R 1 is optionally substituted from 1-3 times with halo, C 1 -C 2 alkyl or C 1 -C 2 alkoxy, or R 1 is H; R 2 is H or C 1 -C 4 alkyl; R 3 is H, C 1 -C 4 alkyl or phenyl-C 0 -C 2 alkylene which is optionally substituted with 1-3 R 5 ; R 4a is carbocylic radical, heterocyclic radical, aryloxy, aryl-C 1 -C 4 alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R 4a is optionally substituted with 1-3 R 5 ; and wherein each R 5 is independently selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, R 6 -phenyl, R 6 -phenoxy, R 6 -benzyl, R 6 -benzyloxy, NH 2 C(O)—, alkyl-NHC(O)—, wherein R 6 is H, halo; Z is a bond or a substituted or unsubstituted C 1 -C 4 alkylene group; and B 2 is
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A compound of the formula
wherein:
a) R 1 is C 1 -C 4 alkyl, carbocyclic radical, heterocyclic radical, aryl-C 1 -C 2 alkylene, aryloxy-C 1 -C 2 alkylene, alkoxy-CC(O)—, wherein R 1 is optionally substituted from 1-3 times with halo, C 1 -C 2 alkyl or C 1 -C 2 alkoxy, or R 1 is H;
b) R 2 is H or C 1 -C 4 alkyl;
c) R 3 is H, C 1 -C 4 alkyl or phenyl-C 0 -C 2 alkylene which is optionally substituted with 1-3 R 5 ;
d) R 4 is carbocylic radical, heterocyclic radical, aryloxy, aryl-C 1 -C 4 alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R 4 is optionally substituted with 1-3 R 5 , provided that, when R 1 , R 2 and R 3 are each H, R4 is not unsubstituted phenyl, o-methoxyphenyl or naphthalen-1-yl;
e) each R 5 is independently selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, R 6 -phenyl, R 6 -phenoxy, R 6 -benzyl, R 6 -benzyloxy, NH 2 C(O)—, alkyl-NHC(O)—;
f) R 6 is H, halo;
g) Z is a bond or a substituted or unsubstituted C 1 -C 4 alkylene group;
h) B 1 is selected from the group consisting of
i) R 7 is H or C 1 -C 4 alkyl,
or a pharmaceutically acceptable salt or solvate thereof.
2 . A compound of the formula
wherein:
a) R 1 is C 1 -C 4 alkyl, carbocyclic radical, heterocyclic radical, aryl-C 1 -C 2 alkylene, aryloxy-C 1 -C 2 alkylene, alkoxy-CC(O)—, wherein R 1 is optionally substituted from 1-3 times with halo, C 1 -C 2 alkyl or C 1 -C 2 alkoxy, or R 1 is H;
b) R 2 is H or C 1 -C 4 alkyl;
c) R 3 is H, C 1 -C 4 alkyl or phenyl-C 0 -C 2 alkylene which is optionally substituted with 1-3 R 5 ;
d) R 4 is carbocylic radical, heterocyclic radical, aryloxy, aryl-C 1 -C 4 alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R 4 is optionally substituted with 1-3 R 5 , provided that, when R 1 , R 2 and R 3 are each H, R4 is not unsubstituted phenyl, o-methoxyphenyl or naphthalen-1-yl;
e) each R 5 is independently selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, R 6 -phenyl, R 6 -phenoxy, R 6 -benzyl, R 6 -benzyloxy, NH 2 C(O)—, alkyl-NHC(O)—;
f) R 6 is H, halo;
g) Z is a bond or a substituted or unsubstituted C 1 -C 4 alkylene group;
h) B 1 is selected from the group consisting of
i) R 7 is H or C 1 -C 4 alkyl,
or a pharmaceutically acceptable salt, solvate or prodrug thereof.
3 . A prodrug of claim 2 having the formula
wherein:
a) R 1 is C 1 -C 4 alkyl, carbocyclic radical, heterocyclic radical, aryl-C 1 -C 2 alkylene, aryloxy-C 1 -C 2 alkylene, alkoxy-CC(O)—, wherein R 1 is optionally substituted from 1-3 times with halo, C 1 -C 2 alkyl or C 1 -C 2 alkoxy, or R 1 is H;
b) R 2 is H or C 1 -C 4 alkyl;
c) R 3 is H, C 1 -C 4 alkyl or phenyl-C 0 -C 2 alkylene which is optionally substituted with 1-3 R 5 ;
d) R 4 is carbocylic radical, heterocyclic radical, aryloxy, aryl-C 1 -C 4 alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R 4 is optionally substituted with 1-3 R 5 , provided that, when R 1 , R 2 and R 3 are each H, R4 is not unsubstituted phenyl, o-methoxyphenyl or naphthalen-1-yl;
e) each R 5 is independently selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, R 6 -phenyl, R 6 -phenoxy, R 6 -benzyl, R 6 -benzyloxy, NH 2 C(O)—, alkyl-NHC(O)—;
f) R 6 is H, halo; and
g) Z is a bond or a substituted or unsubstituted C 1 -C 4 alkylene group.
4 . A compound of the formula
wherein:
a) W 1 is a bond or a C 1 -C 4 alkylene group;
b) R 11 is aryl, aryloxy, aryl-cyclopropylene, heteroaryl, heteroaryloxy, wherein R 11 is optionally substituted from 1-3 times with halo, C 1 -C 2 alkyl or C 1 -C 2 alkoxy, or wherein R 11 is H;
c) Y 1 is a bond, C 1 -C 3 alkylene or —O-C 1 -C 2 alkylene;
d) each R 13 is independently selected from H, halo, N 2 O, C 1 -C 4 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, phenyl, phenoxy, benzyl, benzyloxy, p-halophenyl, p-halobenzyl, p-halophenoxy and p-halobenzyloxy; and
e) B 2 is selected from
or a pharmaceutically acceptable salt, solvate or prodrug thereof.
5 . A compound of the formula
wherein:
a) W 1 is C 1 -C 3 alkylene;
b) R 11 is aryl, aryloxy, aryl-cyclopropylene, heteroaryl, heteroaryloxy, wherein R 11 is optionally substituted from 1-3 times with halo, C 1 -C 2 alkyl or C 1 -C 2 alkoxy, or R 11 is H;
c) Y 2 is a bond, C 1 -C 3 alkylene;
d) each R 14 is independently selected from H, halo, C 1 -C 2 alkyl C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl; and
e) B 2 is selected from
or a pharmaceutically acceptable salt, solvate or prodrug thereof.
6 . A compound of the formula
wherein:
a) independently, each Q is a bond or a methylene group;
b) each R 15 is independently selected from H, halo, N 2 O, C 1 -C 4 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl and CONHCH 3 ; R 16 is H or C 1 -C 2 alkyl; and
c) B 2 is selected from
or a pharmaceutically acceptable salt, solvate or prodrug thereof.
7 . A compound of the formula
wherein:
a) R 1 is C 1 -C 4 alkyl, carbocyclic radical, heterocyclic radical, aryl-C 1 -C 2 alkylene, aryloxy-C 1 -C 2 alkylene, alkoxy-CC(O)—, wherein R 1 is optionally substituted from 1-3 times with halo, C 1 -C 2 alkyl or C 1 -C 2 alkoxy, or R 1 is H;
b) R 2 is H or C 1 -C 4 alkyl;
c) R 3 is H, C 1 -C 4 alkyl or phenyl-C 0 -C 2 alkylene which is optionally substituted with 1-3 R 5 ;
d) R 4a is carbocylic radical, heterocyclic radical, aryloxy, aryl-C 1 -C 4 alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R 4a is optionally substituted with 1-3 R 5 ;
e) each R 5 is independently selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, R 6 -phenyl, R 6 -phenoxy, R 6 -benzyl, R 6 -benzyloxy, NH 2 C(O)—, alkyl-NHC(O)—;
f) R 6 is H, halo; and
g) Z is a bond or a substituted or unsubstituted C 1 -C 4 alkylene group.
8 . A pharmaceutical composition, comprising
a) a compound of the formula wherein:
(i) R 1 is C 1 -C 4 alkyl, carbocyclic radical, heterocyclic radical, aryl-C 1 -C 2 alkylene, aryloxy-C 1 -C 2 alkylene, alkoxy-CC(O)—, wherein R 1 is optionally substituted from 1-3 times with halo, C 1 -C 2 alkyl or C 1 -C 2 alkoxy, or R 1 is H;
(ii) R 2 is H or C 1 -C 4 alkyl;
(iii) R 3 is H, C 1 -C 4 alkyl or phenyl-C 0 -C 2 alkylene which is optionally substituted with 1-3 R 5 ;
(iv) R 4a is carbocylic radical, heterocyclic radical, aryloxy, aryl-C 1 -C 4 alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R 4a is optionally substituted with 1-3 R 5 ;
(v) each R 5 is independently selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, R 6 -phenyl, R 6 -phenoxy, R 6 -benzyl, R 6 -benzyloxy, NH 2 C(O)—, alkyl-NHC(O)—;
(vi) R 6 is H, halo;
(vii) Z is a bond or a substituted or unsubstituted C 1 -C 4 alkylene group;
(viii) and B 2 is selected from
or a pharmaceutically acceptable salt, solvate or prodrug thereof; and b) a pharmaceutically acceptable carrier.
9 . The pharmaceutical composition of claim 8 , further comprising a therapeutically effective amount of one or more other HIV treatment agents selected from
(a) an HIV protease inhibitor, (b) a nucleoside reverse transcriptase inhibitor, (c) a non-nucleoside reverse transcriptase inhibitor, (d) an HIV-entry inhibitor, or (e) an immunomodulator, or a combination thereof.
10 . A method of inhibiting HIV integrase which comprises administering to a mammal in need of such treatment a therapeutically effective amount a compound of the formula
wherein:
a) R 1 is C 1 -C 4 alkyl, carbocyclic radical, heterocyclic radical, aryl-C 1 -C 2 alkylene, aryloxy-C 1 -C 2 alkylene, alkoxy-CC(O)—, wherein R 1 is optionally substituted from 1-3 times with halo, C 1 -C 2 alkyl or C 1 -C 2 alkoxy, or R 1 is H;
b) R 2 is H or C 1 -C 4 alkyl;
c) R 3 is H, C 1 -C 4 alkyl or phenyl-C 0 -C 2 alkylene which is optionally substituted with 1-3 R 5 ;
d) R 4a is carbocylic radical, heterocyclic radical, aryloxy, aryl-C 1 -C 4 alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R 4a is optionally substituted with 1-3 R 5 ;
e) each R 5 is independently selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, R 6 -phenyl, R 6 -phenoxy, R 6 -benzyl, R 6 -benzyloxy, NH 2 C(O)—, alkyl-NHC(O)—;
f) R 6 is H, halo;
g) Z is a bond or a substituted or unsubstituted C 1 -C 4 alkylene group; and
h) B 2 is selected from
or a pharmaceutically acceptable salt, solvate or prodrug thereof.
11 . A method of for treating an HIV infection, in a patient in need thereof, comprising the administration to said patient of a therapeutically effective amount a compound of the formula
wherein:
a) R 1 is C 1 -C 4 alkyl, carbocyclic radical, heterocyclic radical, aryl-C 1 -C 2 alkylene, aryloxy-C 1 -C 2 alkylene, alkoxy-CC(O)—, wherein R 1 is optionally substituted from 1-3 times with halo, C 1 -C 2 alkyl or C 1 -C 2 alkoxy, or R 1 is H;
b) R 2 is H or C 1 -C 4 alkyl;
c) R 3 is H, C 1 -C 4 alkyl or phenyl-C 0 -C 2 alkylene which is optionally substituted with 1-3 R 5 ;
d) R 4a is carbocylic radical, heterocyclic radical, aryloxy, aryl-C 1 -C 4 alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R 4a is optionally substituted with 1-3 R 5 ;
e) each R 5 is independently selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, R 6 -phenyl, R 6 -phenoxy, R 6 -benzyl, R 6 -benzyloxy, NH 2 C(O)—, alkyl-NHC(O)—;
f) R 6 is H, halo;
g) Z is a bond or a substituted or unsubstituted C 1 -C 4 alkylene group; and
h) B 2 is selected from
or a pharmaceutically acceptable salt, solvate or prodrug thereof.
12 . A method of prophylactically or therapeutically treating AIDS or ARC, in a patient in need thereof, comprising the administration to said patient of a therapeutically effective amount a compound of the formula
wherein:
a) R 1 is C 1 -C 4 alkyl, carbocyclic radical, heterocyclic radical, aryl-C 1 -C 2 alkylene, aryloxy-C 1 -C 2 alkylene, alkoxy-CC(O)—, wherein R 1 is optionally substituted from 1-3 times with halo, C 1 -C 2 alkyl or C 1 -C 2 alkoxy, or R 1 is H;
b) R 2 is H or C 1 -C 4 alkyl;
c) R 3 is H, C 1 -C 4 alkyl or phenyl-C 0 -C 2 alkylene which is optionally substituted with 1-3 R 5 ;
d) R 4a is carbocylic radical, heterocyclic radical, aryloxy, aryl-C 1 -C 4 alkylene, aryl-cyclopropylene, aryl-NHC(O)—, wherein R 4a is optionally substituted with 1-3 R 5 ;
e) each R 5 is independently selected from H, halo, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, R 6 -phenyl, R 6 -phenoxy, R 6 -benzyl, R 6 -benzyloxy, NH 2 C(O)—, alkyl-NHC(O)—;
f) R 6 is H, halo;
g) Z is a bond or a substituted or unsubstituted C 1 -C 4 alkylene group; and
h) B 2 is selected from
or a pharmaceutically acceptable salt, solvate or prodrug thereof.Join the waitlist — get patent alerts
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