HIV protease inhibitors

Details HIV protease inhibitors HIV protease inhibitors

2001-11-20

2002-10-29

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S148000, C546S145000, C544S171000, C544S061000, C544S128000, C544S355000, C544S363000, C544S406000, C514S019300, C514S227800, C514S235200, C514S249000, C514S253030

Reexamination Certificate

active

06472404

ABSTRACT:

BACKGROUND OF THE INVENTION
The human immunodeficiency virus HIV is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease characterised by the destruction of the immune system, particularly of the CD4
+
T-cell, with attendant susceptibility to opportunistic infections. HIV infection is also associated with a precursor AIDs-related complex (ARC), a syndrome characterised by symptoms such as persistent generalised lymphadenopathy, fever and weight loss.
In common with other retroviruses, the HIV genome encodes protein precursors known as gag and gag-pol which are processed by the viral protease to afford the protease, reverse transcriptase (RT), endonuclease/integrase and mature structural proteins of the virus core. Interruption of this processing prevents the production of normally infectious virus. Considerable efforts have been directed towards the control of HIV by inhibition of virally encoded enzymes. In particular, much effort has been directed towards the inhibition of HIV protease and the HIV protease inhibitors (PIs) saquinavir, ritonavir, nelfinavir, indinavir, amprenavir and lopinavir have been approved for treatment of HIV infections. Because of the emergence of resistant virus during monotherapy, current clinical practice is to use such protease inhibitors in combination therapy, typically with RT inhibitors.
The emergence of resistant virus can be attributed to errors introduced by the HIV reverse transcriptase, in conjunction with a high virus replication rate. It is likely that mutations that lead to resistant virus occur spontaneously but remain undetectable until initiation of therapy leads to a selective pressure for the emergence of virus with replicative advantage over the wildtype population. In the context of HIV protease inhibition, accumulation of mutations that lead to a reduction in inhibitor binding while maintaining sufficient substrate turnover can lead to drug resistance. Although the onset of drug resistance can be delayed to some extent by the use of combinations of drugs, there remains a need for more effective HIV protease inhibitors that retain activity against PI-resistant and multi-PI resistant viruses.
SUMMARY OF THE INVENTION
This invention is concerned with novel HIV protease inhibitors or prodrugs thereof, a process for their manufacture, pharmaceutical compositions and the use of such compounds in medicine. In particular, the compounds are hydroxyethylamine tripeptide mimetics which act as inhibitors of the HIV aspartyl protease, an essential enzyme in the replicative life cycle of HIV. Consequently, the compounds of this invention may be advantageously used in the treatment of HIV infection, either alone or in combination with other inhibitors of HIV viral replication or with pharmacoenhancers such as cytochrome P450 inhibitors. This object could be achieved with the novel compounds of the general formula I
DETAILED DESCRIPTION OF THE INVENTION
The present invention comprises novel compounds of general formula I
wherein R
1
is H, hydroxy or NHR
2
wherein R
2
is H, alkyl, alkenyl, alkynyl, arylalkyl, heterocyclylalkyl, cycloalkyl alkyl carbonyl, cycloalkyl carbonyl, aryl carbonyl, heterocyclyl carbonyl, heterocyclyl alkyl carbonyl, aryl alkyl carbonyl, alkyl oxy carbonyl, aryl alkyl oxy carbonyl, heterocyclyl alkyl oxy carbonyl, aryl heterocyclyl sulfonyl, alkyl sulfonyl, aryl sulfonyl, heterocyclyl sulfonyl or a group of the formula
 wherein X is O or S and
R
7
and R
8
independently are H, alkyl, aryl, heterocyclyl, aryl alkyl, heterocyclyl alkyl or R
7
and R
8
together with the nitrogen atom to which they are attached form a saturated ring optionally containing a further hetero atom or a group
 wherein when n=0, Y represents O or S and R
10
is H, alkyl, aryl alkyl, heterocyclyl alkyl, aryl, heterocyclyl or when n=1, Y represents N, R
9
is H or alkyl and R
10
H, alkyl, aryl alkyl, heterocyclyl alkyl, aryl, heterocyclyl or R
9
and R
10
taken together with the heteroatom to which they are attached form a heterocycle, R
11
and R
12
independently are H or alkyl or R
11
and R
12
taken together with the carbon atom to which they are attached form a cycle, R
3
, R
4
independently are alkyl or taken together with the carbon atom to which they are attached form a carbocycle, R
5
is alkyl, aryl alkyl, heterocyclyl alkyl or R
4
and R
5
taken together with the carbon and sulfur atom to which they are attached form a heterocycle and R
6
is alkyl, aryl alkyl, heterocyclyl alkyl, alkyl oxy alkyl, hydroxy alkyl, amino alkyl, fluoro alkyl and R
13
is H or the residue of an inorganic or an organic ester and R
15
is aryl and pharmaceutically acceptable salts thereof, with the proviso that, if R
3
, R
4
and R
5
are methyl, R
6
is tert.-butyl, R
13
is H and if R
15
is phenyl R
2
is not benzyl oxycarbonyl and not 2-quinoline carbonyl.
The term alkyl defines an optionally substituted straight or branched alkyl chain carrying 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
The term alkenyl defines an optionally substituted straight or branched alkenyl chain carrying 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms.
The term alkynyl defines an optionally substituted straight or branched alkynyl chain carrying 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms.
Alkyl accordingly preferably stands for methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and tert.-butyl.
Alkenyl accordingly preferably is vinyl, 1-propenyl, 2-propenyl, i-propenyl, and butenyl and its isomers.
Alkynyl accordingly preferably is ethynyl, propynyl and its isomers, and butynyl and its isomers.
Suitable substituents of alkyl, alkenyl or alkynyl can be selected from one or more of aryl, heterocyclyl, carboxy, cyano, alkoxy, cycloalkyl oxy, aryl oxy, heterocyclyl oxy, hydroxy, alkyl carbonyl, cycloalkyl carbonyl, aryl carbonyl, heterocyclyl carbonyl, alkoxy carbonyl, cycloalkyl oxy carbonyl, aryl oxy carbonyl, heterocyclyl oxy carbonyl, amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, cycloalkyl amino carbonyl, aryl amino carbonyl, heterocyclyl amino carbonyl, amino, alkyl amino, dialkyl amino, alkenyl amino, alkynyl amino, cycloalkyl amino, aryl amino, heterocyclyl amino, alkyl carbonyl amino, dialkyl carbonyl amino, cycloalkyl carbonyl amino, aryl carbonyl amino, heterocyclyl carbonyl amino, alkoxy carbonyl amino, cycloalkyl oxy carbonyl amino, aryloxy carbonyl amino, heterocylyl oxy carbonyl amino, alkyl amino carbonyl amino, dialkyl amino carbonyl amino, cycloalkyl amino carbonyl amino, aryl amino carbonyl amino, heterocyclyl amino carbonyl amino alkyl sulfonyl amino, cycloalkyl sulfonyl amino, aryl sulfonyl amino, heterocyclyl sulfonyl amino, nitro, alkyl sulfonyl, cycloalkyl sulfonyl, aryl sulfonyl, heterocyclyl sulfonyl, thio, alkyl thio, cycloalkyl thio, aryl thio, heterocyclyl thio or halogen.
In all cases above where there are NH groups, the free hydrogen may also be substituted, preferably with lower alkyl.
Cycloalkyl has the meaning of an optionally substituted cycloalkyl group containing 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl or adamantyl which can also be benz-fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle or carbocycle, e.g. to phenyl.
The term aryl denotes optionally substituted phenyl and naphthyl, both optionally benz-fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle or carbocycle e.g. to cyclohexyl or cyclopentyl.
The term heterocyclyl stands for an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle which contains one or more hetero atoms selected from nitrogen, oxygen and sulfur which can also be benz-fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic carbocycle or heterocycle.
Examples of suit

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