Pyridoxal-5-phosphate derivatives as HIV integrase inhibitors

Details Pyridoxal-5-phosphate derivatives as HIV integrase inhibitors Pyridoxal-5-phosphate derivatives as HIV integrase inhibitors

2002-06-28

2003-10-28

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Acyclic nitrogen double bonded to acyclic nitrogen, acyclic...

C534S771000

Reexamination Certificate

active

06638921

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to a series of novel pyridoxal derivatives which have HIV integrase inhibitory properties that have been characterized by specific structural and physicochemical features. This inhibitory property may be advantageously used to provide compounds with antiviral properties against HIV viruses, including the HIV-1 and HIV-2 viruses. The pyridoxal derivatives including pharmaceutical compositions thereof may be used to inhibit the activity of HIV integrase.
BACKGROUND OF THE INVENTION
The HIV (human immunodeficiency virus) retrovirus is the causative agent for AIDS (acquired immunodeficiency syndrome). Thus the HIV-1 retrovirus primarily uses the CD4 receptor (a 58 kDa transmembrane protein) to gain entry into cells, through high-affinity interactions between the viral envelope glycoprotein (gp 120) and a specific region of the CD4 molecule found in CD4 (+) T-helper lymphocytes and certain other cells (Lasky L. A. et al., Cell vol. 50, p. 975-985 (1987)). HIV infection is characterized by a period immediately following infection called “asymptomatic” which is devoid of clinical manifestations in the patient. Progressive HIV-induced destruction of the immune system then leads to increased susceptibility to opportunistic infections, which eventually produces a syndrome called AIDS-related complex (ARC) characterized by symptoms such as persistent generalized lymphadenopathy, fever, weight loss, followed itself by full blown AIDS. After entry of the retrovirus into a cell, viral RNA is converted into DNA, which is then integrated into the host cell DNA. The reverse transcriptase encoded by the virus genome catalyzes the first of these reactions (Haseltine W. A. FASEB J. vol 5, p. 2349-2360 (1991)). At least three functions have been attributed to the reverse transcriptase: RNA-dependent DNA polymerase activity which catalyzes the synthesis of the minus strand DNA from viral RNA, ribonuclease H (RNase H) activity which cleaves the RNA template from RNA-DNA hybrids and DNA-dependent DNA polymerase activity which catalyzes the synthesis of a second DNA strand from the minus strand DNA template (Goff S. P. J. Acq. Imm. Defic. Syndr. Vol 3, p. 817-831 (1990)). At the end of reverse transcription, the viral genome now in the form of DNA (called provirus) is integrated into host genomic DNA and serves as a template for viral gene expression by the host transcription system, which leads eventually to virus replication (Roth et al.,1989). The preintegration complex consists of integrase, reverse transcriptase, p17 and proviral DNA (Bukrinsky M. I., Proc. Natn. Acad. Sci. USA vol. 89 p.6580-6584 (1992)). The phosphorylated p17 protein plays a key role in targeting the preintegration complex into the nucleus of the host cell (Gallay et al., 1995).
The primary RNA transcripts made from the provirus are synthesized by the host cell RNA polymerase II which is modulated by two virus-encoded proteins called tat and rev. The viral proteins are formed as polyproteins.
Post-translational modifications of viral polyproteins include processing and glycosylation of Env (envelope) proteins, and myristylation of the N-terminal residue of the p17 protein in the Gag and Gag-Pol polyproteins. The viral protease is involved in processing polyproteins Gag and Gag-Pol into mature proteins, an essential step for virus infectivity.
A number of synthetic antiviral agents have been designed to block various stages in the replication cycle of HIV. These agents include compounds which interfere with viral binding to CD4 (+) T-lymphocytes (for example, soluble CD4), compounds which block viral reverse transcriptase (for example, didanosine and zidovudine (AZT)), budding of virion from the cell (interferon), or the viral protease (for example Ritonavir and Indinavir). Some of these agents proved ineffective in clinical tests. Others, targeting primarily early stages of viral replication, have no effect on the production of infectious virions in chronically infected cells. Furthermore, administration of many of these agents in effective therapeutic doses has led to cell-toxicity and unwanted side effects, such as anemia, neurotoxicity and bone marrow suppression. Anti-protease compounds in their present form are typically large and complex molecules of peptidic nature that tend to exhibit poor bioavailability and are not generally consistent with oral administration. These compounds often exhibit side effects such as nausea, diarrhea, liver abnormalities and kidney stones.
None of the known antiviral agents on the market target the HIV integrase. Accordingly, the need exists for compounds that can effectively inhibit the action of this viral enzyme and that can be used for treating HIV infections.
The terms HIV integrase and integrase as used herein are used interchangeably and refer to the integrase enzyme encoded by the human immunodeficiency virus type 1 or 2. In particular this term includes the human immunodeficiency virus type 1 integrase.
SUMMARY OF THE INVENTION
The present invention relates to a class of pyridoxal compounds as well as their pharmaceutically acceptable derivatives (e.g., salts).
Accordingly, the present invention in accordance with one aspect thereof provides a compound of formula I
and pharmaceutically acceptable derivatives thereof including where applicable or appropriate pharmaceutically acceptable salts thereof,
wherein Cx may be selected from the group consisting of —CH═O, —CH═N—OH and —CH(OCH
2
CH
3
)
2
,
wherein R
1
may be selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, F, Cl, Br, I, —CN and —COOH,
wherein R
2
may be selected from the group consisting of —COOH, —SO
2
NR
3
R
4
, —SO
2
R
5
, —CONR
3
R
4
and —COR
5
,
wherein R
3
may be selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, and a branched alkyl group of 3 to 6 carbon atoms,
wherein R
4
may be selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, adamantan-1-yl, —CH
2
CH
2
OH, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1,2,3,4-tetrahydroquinolin-5-yl, isoquinolin-5-yl, isoazol-3-yl, 2-halogeno-phenyl, 3-halogeno-phenyl, 4-halogeno-phenyl (halogeno being F, Cl, Br or I), 1,4,5,6-tetrahydropyrimidin-2-yl, pyrimidin-2-yl, 2,6-dimethylpyrimidin-4-yl, thiazol-2-yl,
and a group of formula,
wherein R
5
may be selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, azocanyl (i.e., the azacycloalkanes, 3 to 8 member ring systems containing at least one nitrogen ring atom) and morpholinyl, with the proviso that the R
5
group is linked to the adjacent sulfur atom at or via a ring nitrogen atom thereof (e.g. R
5
may be selected from among aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, etc.) and
wherein m may be 0, 1, 2 or 3, wherein n may be 0 or 1.
Azepan-1-yl has the following structure:
In a further aspect, the present invention provides, a compound(s) of formula IA
and pharmaceutically acceptable derivatives thereof including where applicable or appropriate pharmaceutically acceptable salts thereof,
wherein R
1
may be H,
wherein R
3
may be selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, and branched alkyl group of 3 to 6 carbon atoms, and
wherein R
4
may be selected from the group consisting of H, a straight alkyl group of 1 to 6 carbon atoms, a branched alkyl group of 3 to 6 carbon atoms, a cycloalkyl group of 3 to 8 carbon atoms, adamantan-1-yl, —CH
2
CH
2
OH, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 1,2,3,4-tetrahydroquinolin-5-yl, isoquinolin-5-yl, isoazol-3-yl, 2-halogeno-phenyl, 3-halogeno-phenyl, 4-halogeno-phenyl (halogeno being F, Cl, Br or I), 1,4,5,6-tetrahydropyrimidin-2-yl, pyrimidin-2-yl, 2,6-dimethylpyrimidin-4-yl, thiazol-2-yl,
and a group of formula,
 

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