Antivirals

Details Antivirals Antivirals

2000-11-13

2002-11-26

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S345000, C514S314000, C546S167000, C546S262000, C546S289000

Reexamination Certificate

active

06486183

ABSTRACT:

TECHNICAL FIELD
This invention relates to the field of antivirals and in particular to HIV reverse transcriptase inhibitors. The invention provides novel compounds, pharmaceutical compositions comprising these compounds and methods for the inhibition of HIV employing them.
BACKGROUND TO THE INVENTION
Of the pharmaceuticals which have shown clinically relevant activity in the inhibition of HIV reverse transcriptase in HIV treatment, most are nucleoside analogues such as AZT, ddI, ddC and D4T. These nucleoside analogues are not as specific as is desirable and thus have to be administered at relatively high dosage levels. At these dosage levels, nucleoside analogues tend to be rather toxic, limiting their long term use.
To overcome these problems of specificity and toxicity a number of non-nucleoside inhibitors of the reverse transcriptase of HIV have been developed. For example TIBO, a reverse transcriptase from Janssen inhibits HIV at nanomolar concentrations and displays no clinically significant toxicity. Both TIBO and the non nucleotide reverse transcriptase inhibitor nevirapine proceeded rapidly to phase II clinical trials in patients. However it soon became apparent that these non-nucleoside inhibitors rapidly select out HIV mutants in vivo which are resistant to the usual dosages of the respective inhibitors. In the case of nevirapine for example, after only four weeks of therapy virus isolated from patient serum was 100 fold less sensitive to the drug compared with virus isolated from untreated patients (Drug Design & Discovery 1992 8 pp 255-263). A similar pattern has emerged for other non-nucleoside RT inhibitors which have entered clinical trials, Merck's L-697661 and Upjohn's delavirdine (U-87201), namely that promising in vitro activity has rapidly produced resistant HIV mutants when administered to patients. Notwithstanding this drawback nevirapine and delavirdine have recently been registered for clinical use, although limited to specific coadministration regimes in an attempt to retard resistance development.
International patent application no WO 95/06034 describes a series of novel urea derivatives which exhibit good in vitro activity against HIV reverse transcriptase and good inhibition of HIV replication in cell culture. However practical deployment of the compounds in WO 95/06034 is hampered by their poor pharmacokinetic performance. Additionally, as with many non-nucleoside reverse transcriptase inhibitors, the compounds presented in WO 95/06034 leave room for improvement in the key parameter of slow resistance development and a favourable pattern of activity against HIV mutants generated by other antiviral regimes.
A poster of Öberg et al at the 1995 ICAR at Santa Fe disclosed inter alia a racemic compound nominally within the abovementioned WO 95/06034 and having the formula:
At the time the above depicted compound was regarded as of less interest than thiourea variants having a methoxy/acetyl bearing phenyl ring. However, we have now discovered that an alternative substitution pattern manifests an improved resistance pattern in comparison to these prior art compounds in conjunction with good pharmacokinetic performance and a prolonged time to virus resistance. The invention thus provides inhibitors which combine the superior specificity of non-nucleoside inhibitors with the clinical practicality missing from all prior art inhibitors.
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the invention there are provided compounds of the formula I
wherein
R
1
is halo;
R
2
is C,-C, alkyl;
R
x
is cyano or bromo;
and pharmaceutically acceptable salts and prodrugs thereof.
The invention further provides pharmaceutical compositions comprising the compounds of formula I and pharmaceutically acceptable carriers or diluents therefor. Additional aspects of the invention provide methods for the inhibition of HIV comprising administering a compound of the formula I to a subject afflicted with HIV. The invention also extends to the use of the compounds of formula I in therapy, such as in the preparation of a medicament for the treatment of HIV infections.
In treating conditions caused by HIV, the compounds of formula I are preferably administered in an amount to achieve a plasma level of around 10 to 1000 nM and more preferably 100 to 500 nM. This corresponds to a dosage rate, depending on the bioavailability of the formulation, of the order 0.01 to 10 mg/kg/day, preferably 0.1 to 2 mg/kg/day. A typical dosage rate for a normal adult will be around 0.05 to 5 g per day, preferably 0.1 to 2 g such as 500-750 mg, in one to four dosage units per day.
A preferred subset of compounds within claim
2
, particularly with regard to pharmacokinetics, has the structure IA:
where R
1
and R
2
are as defined above, including the pharmaceutically acceptable salts and prodrugs thereof.
A further favoured subset of compounds within Formula I, particularly with regard to ease of forming prodrugs, comprise compounds wherein R
x
is bromo.
Preferably R
1
is chloro and more preferably fluoro. Suitable R
2
groups include methyl, isopropyl, n-propyl and preferably ethyl.
As depicted above, the cyclopropyl ring is in the cis configuration, allowing two enantiomers, 1S, 2S and 1R, 2R (respectively and non-conventionally denoted 2R,1S and 2S,1R in SE 980016-7 and SE 9800113-4):
Each of these enantiomers are potent antiretrovirals, although the different enantiomers can display subtle differences in physiological properties. For instance the 1S,2S and 1R,2R enantiomers can show a different pattern of metabolism within the P450 system. The 1S,2S enantiomer of compounds wherein R
x
is cyano is particularly preferred as it appears unique in being able to avoid key components of the P450 system. Other retroviral agents such as the HIV protease inhibitor ritonavir interact extensively with the P450 system, leading to an array of undesirable physiological responses including extensive alteration of the metabolism of other co-administered drugs. This is of particular concern with pharmaceuticals administered for a chronic infection where patients can expect to take a number of pharmaceuticals for years, if not decades.
Suitable prodrugs of the compounds of formula I include those of the formula II:
wherein
R
1
, R
1
and R
x
are as defined above,
R
3
is H, (CH
m
)
n
NR
5
R
6
;
R
4
is H, C
1
-C
3
alkyl, (CH
m
)
n
NR
5
R
6
, (CH
m
)
n
C(═O)R
5
, (CH
m
)
n
OH, OR
7
, halo, CF
3
or CN; or
R
3
, and R
4
together define a 5 or 6 membered fused ring having 0-2 hetero atoms and/or 0-2 unsaturated bonds and/or 0-2 substituents;
R
5
, is H, C
1
-C
3
alkyl, C(═O)R
7
or a peptide of 1 to 4 amino acids;
R
6
is H, C
1
-C
3
alkyl; or
R
5
and R
6
together define a 5 or 6 membered ring having 0 or 1 additional hetero atom and/or 0-2 unsaturated bonds and/or 0-2 substituents;
R
7
is H, C
1
-C
12
alkyl, (CH
m
)
n
NR
5
R
6
;
X and its encompassing circle define a 5 or 6 membered ring having 0 to 3 unsaturated bonds and/or 0 to 3 hetero atoms selected from S, O and N;
m is independently 1 or 2;
n is independently 0, 1 or 2;
and pharmaceutically acceptable salts thereof.
Corresponding prodrugs of compounds wherein R
x
is chloro foam a further aspect of the invention.
The ring structure containing X, hereafter referred to the X-ring, may be saturated or have 1-3 unsaturated bonds, including rings with an aromatic character. Preferred X-rings include a cyclohexanyl or cyclohexenyl ring or more preferably a phenyl ring. Other preferred X-rings include morpholino or more preferably a pyridyl ring. Alternatively, X-ring may define a five membered ring such as pentenyl or pyrrolyl.
Suitable fused ring systems for the X-ring in the event that R
3
and R
4
join to form an optionally hetero-containing ring include napthyl, quinolyl, tetrahydroisoquinolyl, indolyl or benzimidazole ring systems. Suitable substituent rings for the X-ring in the event that R
4
and R
5
join to form a ring include morpholino and piperidino. These fused or substituent rings may be may be optionally substi

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