Intermediates for making HIV-protease inhibitors and methods...

Details Intermediates for making HIV-protease inhibitors and methods... Intermediates for making HIV-protease inhibitors and methods...

2002-04-02

2003-01-28

Davis, Zinna Northington (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S056000, C560S061000

Reexamination Certificate

active

06512135

ABSTRACT:

RELATED APPLICATION DATA
This application relates to the following U.S. patent applications:
U.S. Pat. Appln. No.
Filing Date
08/133,543
October 7, 1993, abandoned;
08/133,696
October 7, 1993, abandoned;
08/190,764
February 2, 1994,
now U.S Pat. No. 5,484,926;
08/481,833
June 7, 1995,
now U.S. Pat. No. 5,846,993; and
08/708,411
September 5, 1996, abandoned.
Each of these U.S. patents and applications also is entirely incorporated herein by reference.
INTRODUCTION
Treatment of HIV-infected individuals is one of the most pressing biomedical problems of recent times. A promising new therapy has emerged as an important method for preventing or inhibiting the rapid proliferation of the virus in human tissue. HIV-protease inhibitors block a key enzymatic pathway in the virus resulting in substantially decreased viral loads, which slows the steady decay of the immune system and its resulting deleterious effects on human health. The HIV-protease inhibitor nelfinavir mesylate of formula 7
has been shown to be an effective treatment for HIV-infected individuals. Nelfinavir mesylate is disclosed in U.S. Pat. No. 5,484,926, issued Jan. 16, 1996. This patent is entirely incorporated by reference into this patent application.
The present inventors have discovered useful intermediate compounds that can be used in several reaction schemes to make nelfinavir mesylate. The present inventors also have discovered new methods for making nelfinavir mesylate from the free base nelfinavir of formula 4:
The nelfinavir free base also is disclosed in U.S. Pat. No. 5,484,926.
SUMMARY OF THE INVENTION
It is an object of this invention to provide compounds and intermediates useful for making HIV-protease inhibitors and methods of making HIV-protease inhibitors. Such inhibitors are useful for treating HIV-infected individuals.
In a first aspect, the invention relates to compounds of formula 3:
wherein R
1
is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
 wherein R
2
is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R
6
, wherein R
6
is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R
1
is a group of formula 9
 wherein each R
3
is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R
1
is a group of formula 10
 wherein R
4
and each R
5
independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR
7
, wherein R
7
is alkyl or aryl; halogen; pseudohalogen; OSO
2
R
8
, wherein R
8
is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with the proviso that when R
1
is —CH
3
, X cannot be —OCH
3
or —OH, and when R
1
is CH
3
C(O)—, X cannot be —OH;
or a pharmaceutically acceptable salt or solvate thereof.
In various preferred embodiments of the invention, R
1
is —C(O)CH
3
and/or X is a halogen, preferably, Cl.
In another aspect, the invention relates to compounds of formula 2:
 wherein R
1
is a C
2
to C
8
alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula 8
 wherein R
2
is a C
2
to C
8
alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R
6
, wherein R
6
is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R
1
is a group of formula 9
 wherein each R
3
independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R
1
is a group of formula 10
 wherein R
4
and each R
5
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.
This invention further relates to methods for making the compounds of formulae 2 and 3. In a method for making a compound of formula 2:
a compound according to formula 1, shown below,
is reacted under suitable and sufficient conditions to add an R
1
protecting group and form a compound of formula 2. In this instance,
R
1
is a C
2
to C
8
alkyl group; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; or a group of formula 8
 wherein R
2
is a C
2
to C
8
alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R
6
, wherein R
6
is an alkyl group, an aralkyl group, or an aryl group;
or R
1
is a group of formula 9
 wherein each R
3
is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or R
1
is a group of formula 10
 wherein R
4
and each R
5
independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.
This invention includes a method of making a compound according to formula 3
This method includes adding, under suitable and sufficient conditions, a suitable protecting group R
1
and a leaving group X to a compound of formula 1
In this instance,
R
1
is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
 wherein R
2
is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R
6
, wherein R
6
is an alkyl group, an aralkyl group, or an aryl group;
or R
1
is a group of formula 9
 wherein each R
3
is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R
1
is a group of formula 10
 wherein R
4
and each R
5
independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR
7
, wherein R
7
is alkyl or aryl; halogen; pseudohalogen; OSO
2
R
8
, wherein R
8
is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with the proviso that when R
1
is —CH
3
, X cannot be —OCH
3
or —OH, and when R
1
is CH
3
C(O)—, X cannot be —OH. As noted above, in certain embodiments, R
1
is —C(O)CH
3
and/or X is a halogen, preferably, Cl.
A compound according to formula 3, as defined above, also can be made from a compound of formula 2. The reaction proceeds by adding a suitable leaving group X to the compound of formula 2. In this instance, formula 2 is as defined below:
wherein R
1
is alkyl; cycloalkyl, heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
 wherein R
2
is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R
6
, wherein R
6
is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R
1
is a group of formula 9
 wherein each R
3
is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R
1
is a group of formula 10
 wherein R
4
and each R
5
independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group. Additionally, in this instance, X is defined as OH; OR
7
, wherein R
7
is alkyl or aryl; halogen; pseudohalogen; OSO
2
R
8
, wherein R
8
is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen. In this method, when R
1
is —CH
3
, X cannot be —OCH
3
or —OH, and when R
1
is CH
3
C(O)—, X cannot be —OH.
This invention further relates to methods for making HIV-protease inhibitors. One HIV-protease inhibitor produced by a method according to this invention is a compound of formula 4, illustrated below:
In this method, a compound of formula 3
wherein R
1
is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8
 wherein R
2
is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or O—R
6
, wherein R
6
is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R
1
is a group of formula 9
 wherein each R
3
independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl

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