Carbocyclic HIV protease inhibitors

Details Carbocyclic HIV protease inhibitors Carbocyclic HIV protease inhibitors

2002-09-24

2003-10-14

O'Sullivan, Peter (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S605000, C546S172000, C564S099000

Reexamination Certificate

active

06632826

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention is concerned with novel HIV protease inhibitors, a process for their manufacture, pharmaceutical compositions and the use of such compounds in medicine. In particular, the compounds are peptide 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.
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
In one aspect of the present invention, there are provided novel compounds which are potent inhibitors of the HIV aspartyl protease and which accordingly show a potential to be efficacious in the treatment of HIV related diseases. Compounds of the invention may also therefore show the potential to inhibit the replication of virus that is resistant to commonly used protease inhibitors.
The compounds of the present invention may be characterized by the following formula I
as individual isomers, racemates, non-racemic mixtures or mixtures of diastereoisomers; wherein n, R
1
and R
4
are as described below.
The present invention is also directed to pharmaceutical compositions containing compounds of formula I and the use of the compounds of formula I in the treatment or therapy of HIV mediated diseases.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to, inter alia, a compound of formula I,
wherein n is 0, 1 or 2;
R
1
is naphthyl, quinolinyl or phenyl, optionally substituted by halogen;
R
4
is (C
1
-C
7
)-alkyl;
A is a group
 wherein
R
2
is hydrogen or (C
1
-C
7
) lower alkoxy; and
R
3
is (C
1
-C
7
)-alkyl;
or pharmaceutically acceptable salts thereof.
The term (C
1
-C
7
)-alkyl defines an optionally substituted straight or branched alkyl chain carrying 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. Alkyl preferably stands for methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl.
The term (C
1
-C
7
)-alkoxy defines an optionally substituted straight or branched alkoxy chain carrying 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms. Alkoxy preferably stands for methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy and t-butoxy.
The term halogen stands for fluorine, chlorine, bromine and iodine.
The term “racemate” defines a mixture of 50:50 of pure dextrorotatory and levorotatory enantiomers. The term “non racemic” defines mixtures containing pure dextrorotatory and levorotatory enantiomer at ratios different from 50:50 and varying between 1:99 and 99:1.
Compounds of formula (I) which are acidic can form pharmaceutically acceptable salts with bases such as alkali metal hydroxides, e.g. sodium hydroxide, potassium hydroxide and the like; alkaline earth metal hydroxides, e.g. calcium hydroxide, barium hydroxide, magnesium hydroxide and the like; with organic bases e.g. N-ethyl piperidine, dibenzylamine and the like. Those compounds of formula (I) which are basic can form pharmaceutically acceptable salts with inorganic acids, e.g. hydrohalic acids such as hydrochloric acid and hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid and the like; and with organic acids, e.g. acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulphonic acid, p-toluene sulphonic acid and the like. The formation and isolation of such salts can be carried out according to methods known in the art.
Preferred compounds of formula I include the following cyclopentanecarboxylic acid tert-butylamides:
2-{2-Hydroxy-3-[2-methanesulfonylamino-3-(naphthalen-2-ylsulfanyl)-propionylamino]-4-phenyl-butyl}-4-methyl-cyclopentanecarboxylic acid tert-butylamide;
2-{2-Hydroxy-3-[2-methanesulfonylamino-3-(quinolin-8-ylsulfanyl)-propionylamino]-4-phenyl-butyl}-4-methyl-cyclopentanecarboxylic acid tert-butylamide;
2-{2-Hydroxy-3-[2-methanesulfonylamino-3-(naphthalen-2-ylsulfanyl)-propionylamino]-4-phenyl-butyl}-4-methyl-cyclopentanecarboxylic acid tert-butylamide;
2-{3-[3-(4-Fluoro-phenylsulfanyl)-2-methanesulfonylamino-propionylamino]-2-hydroxy-4-phenyl-butyl}-4-methyl-cyclopentanecarboxylic acid tert-butylamide;
2-{3-[3-(4-Fluoro-phenylsulfanyl)-2-methanesulfonylamino-propionylamino]-2-hydroxy-4-phenyl-butyl}-4-methyl-cyclopentanecarboxylic acid tert-butylamide;
2-{2-Hydroxy-3-[2-methanesulfonylamino-3-(naphthalene-2-sulfinyl)-propionylamino]-4-phenyl-butyl}-4-methyl-cyclopentanecarboxylic acid tert-butylamide;
2-{2-Hydroxy-3-[2-methanesulfonylamino-3-(naphthalene-2-sulfonyl)-propionylamino]-4-phenyl-butyl}-4-methyl-cyclopentanecarboxylic acid tert-butylamide;
2-{2-Hydroxy-3-[2-methanesulfonylamino-3-(naphthalene-2-sulfonyl)-propionylamino]-4-phenyl-butyl}-4-methyl-cyclopentanecarboxylic acid tert-butylamide;
2-{2-Hydroxy-3-[2-methanesulfonylamino-3-(quinoline-8-sulfonyl)-propionylamino]-4-phenyl-butyl}-4-methyl-cyclopentanecarboxylic acid tert-butylamide;
2-{3-[3-(4-Fluoro-benzenesulfonyl)-2-methanesulfonylamino-propionylamino]-2-hydroxy-4-phenyl-butyl}-4-methyl-cyclopentanecarboxylic acid tert-butylamide.
Further preferred compounds of formula I include the following cyclohexanecarboxylic acid tert-butylamides:
2-{2-Hydroxy-3-[2-methanesulfonylamino-3-(naphthalen-1-ylsulfanyl)-propionylamino]-4-phenyl-butyl}-4-methoxy-cyclohexanecarboxylic acid tert-butylamide;
N-tert-Butyl-2-[2-hydroxy-3-[[N2-(methanesulfonyl)-S-(2-naphthyl)-D-cysteinyl]amino]-4-phenylbutyl]-4-methoxy-1-cyclohexanecarboxamide;
2-{3-[3-(4-Fluoro-phenylsulfanyl)-2-methanesulfonylamino-propionylamino]-2-hyd

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