SMALL MOLECULE INHIBITORS OF HIV-1 CAPSID ASSEMBLY
First Claim
Patent Images
1. A pharmaceutical composition for the treatment of an HIV infection comprising an effective amount of a compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutically prodrug thereof, and a pharmaceutically acceptable carrier wherein:
- U is CR1 or N;
V is CR1 or N;
R1 and R2 are independently hydrogen, hydroxyl, halogen, carboxyl, nitro, —
NH2, —
NHR6, —
NR6R7, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxyl group, C3-C7 alkylene forming a substituted or unsubstituted second ring on the ring containing U and V, or C1-C4 amide group forming a substituted or unsubstituted second ring on phenyl ring, an aliphatic or aromatic ring substituent selected from the group consisting of substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C8 cycloalkenyl and aryl wherein said aliphatic or aromatic ring substituent may be substituted with one or more 5- or 6-membered aromatic or aliphatic heterocyclic groups;
l is 1, 2, or 3;
R6 and R7 are independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C4-C6 cycloalkyl, or substituted or unsubstituted C1-C6 alkylene-C4-C6 cycloalkyl;
R3 is hydrogen, hydroxyl, substituted or unsubstituted C1-C6 alkyl, a bond which forms a double bond with X when X is a nitrogen, together with Y and R1 or R2 form a substituted or unsubstituted 5- to 11-membered heterocyclic ring;
or together with Y and R8 form a substituted or unsubstituted 5- to 11-membered heterocyclic ring;
n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
m is 0 or 1;
p is 0 or 1;
X is SO2, C═
O, N, or NH;
Y is NH, N, O, S, NC═
O, or substituted or unsubstituted phenylene;
Z is O, SO2, C═
O, NH, or S(O)2NH;
R4 and R5 are independently H, OH, SH, carboxyl, or together form a substituted or unsubstituted ring system selected from the group consisting of a C3-C11 carbocyclic ring system, a C3-C11 heterocyclic ring system, aryl, and heteroaryl; and
R8 is H, OH, SH, carboxyl, substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted ring system selected from the group consisting of a C3-C11, carbocyclic ring system, a C3-C11 heterocyclic ring system, aryl, and heteroaryl.
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Accused Products
Abstract
The present invention provides novel methods of treating HIV infections employing small molecule inhibitors identified by chemical library (DIVERSet™ library). These small molecule inhibitors may specifically bind to HIV-1 capsid protein thereby interfering with capsid assembly. The small molecule inhibitors of the present invention can be potential drug targets in the treatment of HIV infection.
36 Citations
27 Claims
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1. A pharmaceutical composition for the treatment of an HIV infection comprising an effective amount of a compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutically prodrug thereof, and a pharmaceutically acceptable carrier
wherein: -
U is CR1 or N; V is CR1 or N; R1 and R2 are independently hydrogen, hydroxyl, halogen, carboxyl, nitro, —
NH2, —
NHR6, —
NR6R7, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxyl group, C3-C7 alkylene forming a substituted or unsubstituted second ring on the ring containing U and V, or C1-C4 amide group forming a substituted or unsubstituted second ring on phenyl ring, an aliphatic or aromatic ring substituent selected from the group consisting of substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C8 cycloalkenyl and aryl wherein said aliphatic or aromatic ring substituent may be substituted with one or more 5- or 6-membered aromatic or aliphatic heterocyclic groups;l is 1, 2, or 3; R6 and R7 are independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C4-C6 cycloalkyl, or substituted or unsubstituted C1-C6 alkylene-C4-C6 cycloalkyl; R3 is hydrogen, hydroxyl, substituted or unsubstituted C1-C6 alkyl, a bond which forms a double bond with X when X is a nitrogen, together with Y and R1 or R2 form a substituted or unsubstituted 5- to 11-membered heterocyclic ring;
or together with Y and R8 form a substituted or unsubstituted 5- to 11-membered heterocyclic ring;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; m is 0 or 1; p is 0 or 1; X is SO2, C═
O, N, or NH;Y is NH, N, O, S, NC═
O, or substituted or unsubstituted phenylene;Z is O, SO2, C═
O, NH, or S(O)2NH;R4 and R5 are independently H, OH, SH, carboxyl, or together form a substituted or unsubstituted ring system selected from the group consisting of a C3-C11 carbocyclic ring system, a C3-C11 heterocyclic ring system, aryl, and heteroaryl; and R8 is H, OH, SH, carboxyl, substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted ring system selected from the group consisting of a C3-C11, carbocyclic ring system, a C3-C11 heterocyclic ring system, aryl, and heteroaryl. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8)
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9. A method for inhibiting HIV replication in cells comprising administering to said cells a composition comprising a compound of formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutically prodrug thereof, and a pharmaceutically acceptable carrier
wherein: -
U is CR1 or N; V is CR1, or N; R1 and R2 are independently hydrogen, hydroxyl, halogen, carboxyl, nitro, —
NH2, —
NHR6, —
NR6R7, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxyl group, C3-C7 alkylene forming a substituted or unsubstituted second ring on the ring containing U and V, or C1-C4 amide group forming a substituted or unsubstituted second ring on phenyl ring, an aliphatic or aromatic ring substituent selected from the group consisting of substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C8 cycloalkenyl and aryl wherein said aliphatic or aromatic ring substituent may be substituted with one or more 5- or 6-membered aromatic or aliphatic heterocyclic groups;l is 1, 2, or 3; R6 and R7 are independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C4-C6 cycloalkyl, or substituted or unsubstituted C1-C6 alkylene-C4-C6 cycloalkyl; R3 is hydrogen, hydroxyl, substituted or unsubstituted C1-C6 alkyl, a bond which forms a double bond with X when X is a nitrogen, together with Y and R1 or R2 form a substituted or unsubstituted 5- to 11-membered heterocyclic ring;
or together with Y and R8 form a substituted or unsubstituted 5- to 11-membered heterocyclic ring;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; m is 0 or 1; p is 0 or 1; X is SO2, C═
O, N, or NH;Y is NH, N, O, S, NC═
O, or substituted or unsubstituted phenylene;Z is O, SO2, C═
O, NH, or S(O)2NH;R4 and R5 are independently H, OH, SH, carboxyl, or together form a substituted or unsubstituted ring system selected from the group consisting of a C3-C11 carbocyclic ring system, a C3-C11 heterocyclic ring system, aryl, or heteroaryl; and
R8 is H, OH, SH, carboxyl, substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted ring system selected from the group consisting of a C3-C11 carbocyclic ring system, a C3-C11 heterocyclic ring system, aryl, or heteroaryl. - View Dependent Claims (10, 11, 12)
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13. Use of a compound of formula I to treat an HIV infection, comprising the step of administering to a human in need of such treatment a therapeutically effective amount of a compound of formula I
wherein: -
U is CR1 or N; V is CR1 or N; R1 and R2 are independently hydrogen, hydroxyl, halogen, carboxyl, nitro, —
NH2, —
NHR6, —
NR6R7, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxyl group, C3-C7 alkylene forming a substituted or unsubstituted second ring on the ring containing U and V, or C1-C4 amide group forming a substituted or unsubstituted second ring on phenyl ring, an aliphatic or aromatic ring substituent selected from the group consisting of substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C5-C8 cycloalkenyl and aryl wherein said aliphatic or aromatic ring substituent may be substituted with one or more 5- or 6-membered aromatic or aliphatic heterocyclic groups;l is 1, 2, or 3; R6 and R7 are independently substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C4-C6 cycloalkyl, or substituted or unsubstituted C1-C6 alkylene-C4-C6 cycloalkyl; R3 is hydrogen, hydroxyl, substituted or unsubstituted C1-C6 alkyl, a bond which forms a double bond with X when X is a nitrogen, together with Y and R1 or R2 form a substituted or unsubstituted 5- to 11-membered heterocyclic ring;
or together with Y and R8 form a substituted or unsubstituted 5- to 11-membered heterocyclic ring;n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; m is 0 or 1; p is 0 or 1; X is SO2, C═
O, N, or NH;Y is NH, N, O, S, NC═
O, or substituted or unsubstituted phenylene;Z is O, SO2, C═
O, NH, or S(O)2NH;R4 and R5 are independently H, OH, SH, carboxyl, or together form a substituted or unsubstituted ring system selected from the group consisting of a C3-C11 carbocyclic ring system, a C3-C11 heterocyclic ring system, aryl, and heteroaryl; and R8 is H, OH, SH, carboxyl, substituted or unsubstituted C1-C6 alkyl, or a substituted or unsubstituted ring system selected from the group consisting of a C3-C11 carbocyclic ring system, a C3-C11 heterocyclic ring system, aryl, and heteroaryl.
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14. A pharmaceutical composition for the treatment of an HIV infection comprising an effective amount of a compound of formula II, a pharmaceutically acceptable salt thereof, or a pharmaceutically prodrug thereof, and a pharmaceutically acceptable carrier
wherein: -
Ar is a phenyl group or a pyridinyl group, which bear the substituent R9; R9 is independently a hydrogen, hydroxyl group, halogen, carboxyl, nitro oxide, C1-C6 alkoxyl group, C3-C7 alkylene group forming a second ring on Ar, or C1-C4 amide group forming a second ring on Ar. q is 1, 2, 3, 4, or 5; R10 is independently a hydrogen or a branched or unbranched C1-C5 alkyl group; Q is A is independently hydrogen, hydroxyl, halogen, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, or substituted or unsubstituted C4-C8 alkylene group forming a second ring on Ar; a is 1, 2, 3, 4, or 5; D is a substituted or unsubstituted aromatic or heteroaromatic group selected from the group consisting of phenyl, benzyl, phenylamine, toluidinyl, phenacyl, and benzoic acyl; and W is a substituted or unsubstituted aromatic or heteroaromatic group selected from the group consisting of phenyl, pyrimidinyl, tosyl, and pyridiny. - View Dependent Claims (15)
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16. A method for inhibiting HIV replication in cells comprising administering to said cells a composition comprising a compound of formula II, a pharmaceutically acceptable salt thereof, or a pharmaceutically prodrug thereof and a pharmaceutically acceptable carrier
wherein: -
Ar is a phenyl group or a pyridinyl group, which bear the substituent R9; R9 is independently a hydrogen, hydroxyl group, halogen, carboxyl, nitro oxide, C1-C6 alkoxyl group, C3-C7 alkylene group forming a second ring on Ar, or C1-C4 amide group forming a second ring on Ar. q is 1, 2, 3, 4, or 5; R10 is independently a hydrogen or a branched or unbranched C1-C5 alkyl group; Q is A is independently hydrogen, hydroxyl, halogen, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, or substituted or unsubstituted C4-C8 alkylene group forming a second ring on Ar; a is 1, 2, 3, 4, or 5; D is a substituted or unsubstituted aromatic or heteroaromatic group selected from the group consisting of phenyl, benzyl, phenylamine, toluidinyl, phenacyl, and benzoic acyl; and W is a substituted or unsubstituted aromatic or heteroaromatic group selected from the group consisting of phenyl, pyrimidinyl, tosyl, and pyridinyl.
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17. Use of a compound of formula II to treat an HIV infection comprising the step of administering to a human in need of such treatment a therapeutically effective amount of a compound of formula II
wherein: -
Ar is a phenyl group or a pyridinyl group, which bear the substituent R9; R9 is independently a hydrogen, hydroxyl group, halogen, carboxyl, nitro oxide, C1-C6 alkoxyl group, C3-C7 alkylene group forming a second ring on Ar, or C1-C4 amide group forming a second ring on Ar. q is 1, 2, 3, 4, or 5; R10 is independently a hydrogen or a branched or unbranched C1-C5 alkyl group; Q is A is independently hydrogen, hydroxyl, halogen, substituted or unsubstituted C1-C6 alkyl group, substituted or unsubstituted C1-C6 alkoxy group, or substituted or unsubstituted C4-C8 alkylene group forming a second ring on Ar; a is 1, 2, 3, 4, or 5; D is a substituted or unsubstituted aromatic or heteroaromatic group selected from the group consisting of phenyl, benzyl, phenylamine, toluidinyl, phenacyl, and benzoic acyl; and W is a substituted or unsubstituted aromatic or heteroaromatic group selected from the group consisting of phenyl, pyrimidinyl, tosyl, and pyridinyl.
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18. A pharmaceutical composition for the treatment of an HIV infection comprising an effective amount of a compound of formula III, a pharmaceutically acceptable salt thereof;
- or a pharmaceutically prodrug thereof, and a pharmaceutically acceptable carrier
wherein; R10 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C4-C6 cycloalkyl, or substituted or unsubstituted C1-C6 alkylene-C4-C6 cycloalkyl; r is 1 or 2; t is 0, 1, 2, 3, 4, or 5; and R11 is a C(O)O—
(C1-C6) alkyl ester, R12 is a substituted or unsubstituted ring system selected from the group consisting of a C3-C11 carbocyclic ring system and a C3-C11 heterocyclic ring system;
or R11, and R12 together form a substituted or unsubstituted ring system selected from the group consisting of a C3-C11 carbocyclic ring system and a C3-C11 heterocyclic ring system.- View Dependent Claims (19, 20, 21, 22, 23, 24, 25)
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25. The pharmaceutical composition of claim 18, wherein the compound of formula III is
- or a pharmaceutically prodrug thereof, and a pharmaceutically acceptable carrier
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26. A method for inhibiting HIV replication in cells comprising administering to said cells a composition comprising a compound of formula III, a pharmaceutically acceptable salt thereof, or a pharmaceutically prodrug thereof and a pharmaceutically acceptable carrier,
wherein: -
R10 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C4-C6 cycloalkyl, or substituted or unsubstituted C1-C6 alkylene-C4-C6 cycloalkyl; r is 1 or 2; t is 0, 1, 2, 3, 4, or 5; and R11 is a C(O)O—
(C1-C6) alkyl ester;
R12 is a substituted or unsubstituted ring system selected from the group consisting of a C3-C11 carbocyclic ring system and a C3-C11 heterocyclic ring system;
or R11, and R12 together form a substituted or unsubstituted ring system selected from the group consisting of a C3-C11 carbocyclic ring system and a C3-C11 heterocyclic ring system.
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27. Use of a compound of formula III to treat an HIV infection, comprising the step of administering to a human in need of such treatment a therapeutically effective amount of a compound of formula III
wherein: -
R10 is H, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C4-C6 cycloalkyl, or substituted or unsubstituted C1-C6 alkylene-C4-C6 cycloalkyl; r is 1 or 2; t is 0, 1, 2, 3, 4, or 5; and R11 is a C(O)O—
(C1-C6) alkyl ester;
R12 is a substituted or unsubstituted ring system selected from the group consisting of a C3-C11 carbocyclic ring system and a C3-C11 heterocyclic ring system;
or R11 and R12 together form a substituted or unsubstituted ring system selected from the group consisting of a C3-C11 carbocyclic ring system and a C3-C11 heterocyclic ring system.
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Specification
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Current AssigneeUniversity of Alabama At Birmingham (University of Alabama System)
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Original AssigneeUniversity of Alabama At Birmingham (University of Alabama System)
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InventorsPrevelige, Peter
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Application NumberUS12/090,361Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/231.800CPC Class CodesA61K 31/5375 1,4-Oxazines, e.g. morpholineA61K 31/55 having seven-membered rings...A61P 31/18 for HIVA61P 37/04 ImmunostimulantsA61P 43/00 Drugs for specific purposes...
