Back to results
US 2002/0161236 A1Published application
Intermediates for making HIV-protease inhibitors and methods for making HIV-protease inhibitors
AssigneeAgouron Pharmaceuticals, Inc.
InventorsMichael E. Deason, Kathleen R. Whitten
Life of this patent
Estimating the term…
Abstract
HIV protease inhibitors inhibit or block the biological activity of the HIV protease enzyme, causing the replication of the HIV virus to terminate. These compounds can be prepared by the novel methods of the present invention using the novel inventive compounds and intermediates.
Claims33
A compound of formula 3:
- 76
- wherein R1 is alkyl;
- cycloalkyl;
- heterocycloalkyl;
- aryl;
- heteroaryl;
- or a group of formula 8
- 77
- wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
- or further wherein R1 is a group of formula 9
- 78
- wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- or further wherein R1 is a group of formula 10
- 79
- wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- and
- X is OH;
- OR7, wherein R7 is alkyl or aryl;
- halogen;
- pseudohalogen;
- OSO2R6, wherein R6 is alkyl or aryl;
- heteroaryl bonded through the heteroatom;
- or N-hydroxyheterocyclic bonded through the oxygen, with the proviso that when R1 is —CH3, X cannot be —OCH3 or —OH, and when R1 is CH3C(O)—, X cannot be —OH;
- or a pharmaceutically acceptable salt or solvate thereof.
21 more elements
A compound of formula 2:
- 80
- wherein R1 is a C2 to C8 alkyl group;
- a cycloalkyl group;
- a heterocycloalkyl group;
- an aryl group;
- a heteroaryl group;
- or a group of formula 8
- 81
- wherein R2 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
- or further wherein R1 is a group of formula 9
- 82
- wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- or further wherein R1 is a group of formula 10
- 83
- wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- or a pharmaceutically acceptable salt or solvate thereof.
13 more elements
A method of making a compound of formula 2:
- 84
- comprising:
- adding under sufficient conditions a suitable protecting group R1 to a compound of formula 1
- 85
- wherein R1 is a C2 to C8 alkyl group;
- a cycloalkyl group;
- a heterocycloalkyl group;
- an aryl group;
- a heteroaryl group;
- or a group of formula 8
- 86
- wherein R2 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
- or further wherein R1 is a group of formula 9
- 87
- wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloatkyl group, an aryl group, or a heteroaryl group;
- or further wherein R1 is a group of formula 10
- 88
- wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- to form the compound of formula 2.
16 more elements
A method of making a compound of formula 3
- 89
- comprising:
- adding under sufficient conditions a suitable protecting group R1 and a leaving group X to a compound of formula I
- 90
- wherein R1 is alkyl;
- cycloalkyl;
- heterocycloalkyl;
- aryl;
- heteroaryl;
- or a group of formula 8
- 91
- wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
- or further wherein R1 is a group of formula 9
- 92
- wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- or further wherein R1 is a group of formula 10
- 93
- wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- and
- X is OH;
- OR7, wherein R7 is alkyl or aryl;
- halogen;
- pseudohalogen;
- OSO2R6, wherein R8 is alkyl or aryl;
- heteroaryl bonded through the heteroatom;
- or N-hydroxyheterocyclic bonded through the oxygen, with the proviso that when Rt is —CH3, X cannot be —OCH3 or —OH, and when R1 is CH3C(O)—, X cannot be —OH;
- to form the compound of formula 3.
24 more elements
A method of making a compound of formula 3
- 94
- comprising:
- adding under sufficient conditions a leaving group X to a compound of formula 2
- 95
- wherein R1 is alkyl;
- cycloalkyl;
- heterocycloalkyl;
- aryl;
- heteroaryl;
- or a group of formula 8
- 96
- wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
- or further wherein R1 is a group of formula 9
- 97
- wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- or further wherein R1 is a group of formula 10
- 98
- wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- and
- X is OH;
- OR7, wherein R7 is alkyl or aryl;
- halogen;
- pseudohalogen;
- OSO2R6, wherein R8 is alkyl or aryl;
- heteroaryl bonded through the heteroatom;
- or N-hydroxyheterocyclic bonded through the oxygen, with the proviso that when R1 is —CH3, X cannot be —OCH3 or —OH, and when R1 is CH3C(O)—, X cannot be —OH;
- to form the compound of formula 3.
24 more elements
A method of making a compound of formula 4
- 99
- comprising:
- converting under sufficient conditions a compound of formula 3
- 100
- wherein R1 is alkyl;
- cycloalkyl;
- heterocycloalkyl;
- aryl;
- heteroaryl;
- or a group of formula 8
- 101
- wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
- or further wherein R1 is a group of formula 9
- 102
- wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- or further wherein R1 is a group of formula 10
- 103
- wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- and
- X is OH;
- OR7, wherein R7 is alkyl or aryl;
- halogen;
- pseudohalogen;
- OSO2R8, wherein R8 is alkyl or aryl;
- heteroaryl bonded through the heteroatom;
- or N-hydroxyheterocyclic bonded through the oxygen,
- to the compound of formula 4.
24 more elements
A method of making a compound of formula 4
- 104
- comprising:
- deprotecting a compound of formula 5
- 105
- and adding to the deprotected compound of formula 5, under sufficient conditions, a compound of formula 3:
- 106
- wherein R1 is alkyl;
- cycloalkyl;
- heterocycloalkyl;
- aryl;
- heteroaryl;
- or a group of formula 8
- 107
- wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
- or further wherein R1 is a group of formula 9
- 108
- wherein each R3 independently is an-alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- or further wherein R1 is a group of formula 10
- 109
- wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- and
- X is OH;
- OR7, wherein R7 is alkyl or aryl;
- halogen;
- pseudohalogen;
- OSO2R8, wherein R8 is alkyl or aryl;
- heteroaryl bonded through the heteroatom;
- or N-hydroxyheterocyclic bonded through the oxygen, to form the compound of formula 4.
25 more elements
A method of making a compound of formula 4
- 110
- comprising:
- combining under sufficient conditions a compound of formula 3:
- 111
- wherein R1 is alkyl;
- cycloalkyl;
- heterocycloalkyl;
- aryl;
- heteroaryl;
- or a group of formula 8
- 112
- wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
- or further wherein R1 is a group of formula 9
- 113
- wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- or further wherein R1 is a group of formula 10
- 114
- wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- and
- X is OH;
- OR7, wherein R7 is alkyl or aryl;
- halogen;
- pseudohalogen;
- OSO2R6, wherein R8 is alkyl or aryl;
- heteroaryl bonded through the heteroatom;
- or N-hydroxyheterocyclic bonded through the oxygen,
- with a compound of formula 6
- 115
- to obtain the compound of formula 4.
26 more elements
A method of making a compound of formula 7
- 116
- comprising:
- converting under sufficient conditions a compound of formula 4
- 117
- to the compound of formula 7 by:
- (a) contacting the compound of formula 4 with an organic solvent;
- (b) contacting the compound of formula 4 with methanesulfonic acid under conditions sufficient to form a compound of formula 7;
- and
- (c) spray drying the compound of formula 7.
6 more elements
A method of making a compound of formula 7
- 118
- comprising:
- converting under sufficient conditions a compound of formula 4
- 119
- to the compound of formula 7 by:
- (a) combining the compound of formula 4, a suitable solvent, and methanesulfonic acid to form the compound of formula 7, the compound of formula 7 being dissolved in solution;
- (b) adding a first antisbivent to the solution containing the compound of formula 7;
- (c) agitating the compound of formula 7 and the first antisolvent to form a product having a solid phase and a liquid phase;
- and
- (d) filtering and washing the product with a second antisolvent, the second antisolvent being the same as or different from the first antisolvent, to obtain a solid.
7 more elements
A method of making a compound of formula 4
- 120
- comprising:
- converting under sufficient conditions a compound of formula 2
- 121
- wherein R1 is alkyl;
- cycloalkyl;
- heterocycloalkyl;
- aryl;
- heteroaryl;
- a group of formula 8
- 122
- wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
- or further wherein R1 is a group of formula 9
- 123
- wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- or further wherein R1 is a group of formula 10
- 124
- wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- to the compound of formula 4.
16 more elements
A method of making a compound of formula 7
- 125
- comprising:
- deprotecting a compound of formula 5
- 126
- adding to the deprotected compound of formula 5, under sufficient conditions, a compound of formula 3:
- 127
- wherein R1 is alkyl;
- cycloalkyl;
- heterocycloalkyl;
- aryl;
- heteroaryl;
- or a group of formula 8
- 128
- wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
- or further wherein R1 is a group of formula 9
- 129
- wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- or further wherein R1 is a group of formula 10
- 130
- wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
- and
- X is OH;
- OR7, wherein R7 is alkyl or aryl;
- halogen;
- pseudohalogen;
- OSO2R8, wherein R8 is alkyl or aryl;
- heteroaryl bonded through the heteroatom;
- or N-hydroxyheterocyclic bonded through the oxygen, to form a compound of formula 4:
- 131
- and converting the compound of formula 4 to the compound of formula 7.
27 more elements
Dependencies are inferred from the claim text.