Aromatic derivatives with HIV integrase inhibitory properties

Details Aromatic derivatives with HIV integrase inhibitory properties Aromatic derivatives with HIV integrase inhibitory properties

2001-09-26

2003-03-04

Seaman, D. Margaret (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C562S448000, C562S451000, C562S455000, C564S153000, C564S157000, C564S158000, C514S019300, C514S020800, C514S400000, C514S419000, C514S423000

Reexamination Certificate

active

06528655

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention relates to hydroxylated aromatic and heteroaromatic derivatives which have HIV integrase inhibitory properties that have been characterized by specific structural and physicochemical features. This inhibitory property may be advantageously used, for example, to provide medicinals (e.g. compositions) with antiviral properties against HIV viruses, including the HIV-1 and HIV-2 viruses, i.e. the hydroxyphenyl 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 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
Thus, the present invention relates to a compound of formula I′
and pharmaceutically acceptable derivatives thereof including, for example, where applicable or appropriate pharmaceutically acceptable salts thereof. Ar may, for example, be R
1
which is referred to below; Ar′ may, for example, be R
2
which is also referred to below.
A compound in accordance with the present invention may, for example, take the form of a compound of formula II′, III′ or IV′ below:
In accordance with the present invention, n may be 1, 2 or 3; Hal may represent a halogen atom (e.g. Cl, Br, F or I); p may be 0, 1 or 2; X and X′ may each independently represent a single bond, a saturated straight or branched hydrocarbon group of 1 to 4 carbon atoms, or a straight or branched hydrocarbon group of 2 to 4 carbon atoms comprising a carbon to carbon double bond; and W may represent an amino acid residue or fragment (in particular alpha-amino acid residues) such as for example a residue based on tyrosine, DOPA, hydroxyproline, serine, threonine, histidine, valine, phenylalanine, lysine, alanine, glycine, glutamic acid, aspartic acid, arginine, asparagine, glutamine, leucine, lysine, isoleucine, proline, tryptophan, methionine, cysteine, cystine, thyroxine, meta-tyrosine, sarcosine, other alpha-methyl amino acids such as alpha-methyl DOPA, as well as other 3-substituted tyrosines, and the like.
Z
a
may, for example, be a substituent selected from H, NO
2
, NH
2
, alkyloxy, cycloalkyloxy, aryloxy (e.g. benzyloxy), SH, thioalkyl, thioaryl, NHCO-alkyl, NHCO-aryl, etc. Z
a
may, for example, be referred to hereinafter interchangeably with respect to particular radicals, groups or moieties, etc. as R
7
, R
9
, R
10
, R
11
, R
12
, R
13
, R
14
, R
15
, R
16
, R
17
, R
18
, R
19
, ect.
In accordance with the present invention an alkyl radical, group or moiety may signifiy an unsubstituted straight-chained (or branched alkyl group) with 1 to 8 carbon atoms; a cycloalkyloxy radical group or moiety may comprise 3 to 8 carbon atoms; an aryl radical, group or moiety may signify a phenyl (or benzyl) group which may be substituted by one or more (e.g. one to three), same or different, substituents such as for example OH, OCH
3
, SH, SCH
3
, NO
2
, NH
2
, F, Cl, and Br, etc.
Y and Y′ may, for example, each independently be C or N.
Ar and Ar′ may, for example, each independently represent an aromatic radical, group or moiety which is incorporated into a compound of formula I′ by using an appropriate amine, benzoyl hydrazide or carboxylic acid selected, for example, from the following commercially available or synthetic molecules; dopamine, benzylamine, 2,5-dimethoxyaniline, 3-hydroxy-4-methoxyaniline, thiazole-2-amine, 2-(2′-thiophenyl)ethylamine, benzoyl hydrazide, salicylic hydrazide, caffeic acid, dihydrocaffeic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxynaphthalene-2-carboxylic acid, 4,8-dihydroxyquinoline-2-carboxyl

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