Organic compounds -- part of the class 532-570 series – Organic compounds – Azides
Reexamination Certificate
2001-05-21
2002-05-21
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Azides
C549S034000
Reexamination Certificate
active
06392067
ABSTRACT:
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
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. Methods for preparing nelfinavir mesylate from nelfinavir free base are disclosed in U.S. Pat. No. 5,484,926, as well as U.S. patent appln. Ser. No. 08/708,411 of inventors M. Deason and K. Whitten, entitled “Intermediates for Making HIV-Protease Inhibitors and Methods of Making HIV-Protease Inhibitors”, filed on Sep. 5, 1996, which application is entirely incorporated herein by reference.
SUMMARY OF THE INVENTION
The present invention relates to the novel compounds illustrated below. These compounds are useful as intermediates and starting materials for the preparation of nelfinavir free base and nelfinavir mesylate.
A first compound according to this invention is a compound of formula 6, as follows:
wherein each R
3
is independently an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A second compound according to this invention is a compound of formula 6a:
wherein each X is independently a halogen; or a pharmaceutically acceptable salt or solvate thereof.
A third compound according to this invention is a compound of formula 7:
wherein each R
3
is independently an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A fourth compound according to this invention is a compound of formula 8:
wherein each R
3
is independently an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A fifth compound according to the invention is a compound of formula 9:
wherein each R
3
is independently an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A sixth compound according to this invention is a compound of formula 10:
wherein R
3
is an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A seventh compound according to this invention is a compound of formula 7a:
wherein each R
3
is independently an aryl group or an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
An eighth compound according to this invention is a compound of formula 8a:
wherein R
4
is an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A ninth compound according to this invention is a compound of formula 9a:
wherein R
4
is an alkyl group; or a pharmaceutically acceptable salt or solvate thereof.
A tenth compound according to this invention is a compound of formula 10a:
or a pharmaceutically acceptable salt or solvate thereof.
This invention further relates to processes for making and using the compounds and intermediates described above. For example, these compounds can be used to prepare nelfinavir free base and nelfinavir mesylate.
A first method according to the invention relates to a method of making a compound of formula 6:
wherein each R
3
is independently an aryl group or an alkyl group, by converting, under sufficient conditions, a compound of formula 5:
wherein each R
3
independently an aryl group or an alkyl group, to the compound of formula 6 shown above.
In a second method according to this invention, a compound of formula 6a is produced:
wherein each X is independently a halogen. In this method, the compound according to formula 5 (illustrated above) is converted, under sufficient conditions, to the compound of formula 6a.
This invention further relates to methods of making a compound of formula 7:
wherein each R
3
is independently an aryl group or an alkyl group. In one method, a compound of formula 6:
wherein each R
3
is independently an aryl group or an alkyl group, is converted, under sufficient conditions, to the compound of formula 7. In another method, a compound according to formula 6a:
wherein each X is independently a halogen, is converted, under sufficient conditions, to the compound of formula 7.
Another method according to this invention relates to a method of making a compound of formula 8:
wherein each R
3
is independently an aryl group or an alkyl group. The compound according to formula 8 is produced by converting, under sufficient conditions, a compound of formula 7:
wherein each R
3
is independently an aryl group or an alkyl group, to the compound of formula 8.
In another method according to this invention, a compound according to formula 8 (illustrated above), can be converted, under sufficient conditions, to a compound of formula 9:
wherein each R
3
is independently an aryl group or an alkyl group.
Yet another method according to this invention relates to a method of making a compound of formula 10:
wherein R
3
is an aryl group or an alkyl group. In this method, a compound of formula 9:
wherein each R
3
is independently an aryl group or an alkyl group, is converted, under sufficient conditions, to a compound of formula 10.
This invention also relates to a method of making a compound of formula 11:
by converting, under sufficient conditions, a compound of formula 10:
wherein R
3
is an aryl group or an alkyl group, to a compound of formula 11.
As mentioned above, another compound or intermediate according to this invention is a compound of formula 7a:
wherein each R
3
is independently an aryl group or an alkyl group. This material can be made, in accordance with another method of this invention, by converting, under sufficient conditions, a compound of formula 6:
wherein each R
3
is independently an aryl group or an alkyl group, to the compound of formula 7a. In an alternative method according to this invention, the compound according to formula 7a (shown above) can be produced by converting, under sufficient conditions, a compound of formula 6a:
wherein each X is independently a halogen, to the compound of formula 7a.
Another method according to this invention relates to a method of making a compound of formula 8a:
wherein R
4
is an alkyl group. This compound is produced by converting, under sufficient conditions, a compound of formula 7a:
wherein each R
3
is independently an aryl group or an alkyl group, to the compound of formula 8a.
In another method according to the invention, a compound of formula 9a:
wherein R
4
is an alkyl group, can be produced by converting, under sufficient conditions, a compound of formula 8a:
wherein R
4
is an alkyl group, to the compound of formula 9a.
Yet another method according to this invention relates to a method of making a compound of formula 10a:
by converting, under sufficient conditions, a compound of formula 9a:
wherein R
4
is an alkyl group, to the compound of formula 10a.
The compound according to formula 10a (shown above) can be used in another method of this invention to produce a compound of formula 11a:
wherein Y
−
is a suitable salt anion. In this method, the compound of formula 10a is converted, under sufficient conditions, to the compound of formula 11a.
The compounds and intermediates according to the invention advantageously can be used to produce nelfinavir mesylate:
In one method, a compound of formula 10:
wherein R
3
is an aryl group or an alkyl group, is converted, under sufficient conditions, to a compound of formula 11:
The compound according to formula 11 then is converted, under sufficient conditions, to a compound of formula 12:
The compound according to formula 12 is then converted to nelfinavir mesylate.
A second method according to the invention for making nelfinavir mesylate (illust
Albizati Kim F.
Babu Srinivasan
Borer Bennett C.
Busse Juliette K.
Remarchuk Travis P.
Agouron Pharmaceuticals , Inc.
Davis Zinna Northington
Fitzpatrick ,Cella, Harper & Scinto
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