Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-03-27
2002-03-26
Russel, Jeffrey E. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S020800, C514S400000, C514S419000, C514S423000, C514S563000, C514S616000, C548S338100, C548S491000, C548S537000, C562S448000, C562S451000, C562S455000, C564S153000, C564S157000, C564S158000
Reexamination Certificate
active
06362165
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a hydroxyphenyl 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 T-lymphocytes and CD4 (+) T-helper 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 syndrom 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)). The double stranded DNA produced by reverse transcriptase, now called provirus, is then able to be inserted into host genomic DNA. At the end of reverse transcription, the viral genome now in the form of DNA 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 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 latter two precursors correspond to structural proteins and viral enzymes. The viral protease is involved in processing polyproteins Gag and Gag-Pol into mature proteins, a step essential 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.
Accordingly, the need exists for compounds that can effectively inhibit the action of the third viral enzyme called integrase, for use as agents 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 provides an hydroxyphenyl derivative selected from the group consisting of a compound of formula
and when a compound of formula I comprises a carboxylic acid group pharmaceutically acceptable salts thereof and when a compound of formula I comprises an amino group pharmaceutically acceptable ammonium salts thereof, wherein n is 1, 2 or 3, e is 1, 2 or 3, Hal represents a halogen atom (e.g. Cl, Br, F or I), p is 0, 1 or 2, r is 0, 1 or 2, X and X′ each independently represents 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, R
a
represents H or —CH
3
, and R
aa
represents H or —CH
3
; W, may for example, 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.
W, for the above formula I, may, for example, be derived from natural or unnatural alpha-amino acids. The term unnatural alpha-amino acid refers to alpha-amino acids which do not occur in nature but which can be derived from naturally occurring alpha-amino acids or other chemical reagents by methods known to those skilled in the art.
W may, for example, represent a group of formula
wherein k is 0 or 1, A and A′ each independently represents a group of formula
R
a
represents H or —CH
3
, R
b
represents H or —CH
3
, R
c
represents H or OH, R is selected from the group consisting of H, CH
3
—, (CH
3
)
2
CH—, (CH
3
)
2
CHCH
2
—, CH
3
CH
2
CH(CH
3
)—, C
6
H
5
CH
2
—, CH
3
SCH
2
CH
2
—, HO
2
CCH
2
—, H
2
NC(O)CH
2
—, HO
2
CCH
2
CH
2
—, H
2
NC(O)CH
2
CH
2
—, H
2
NCH
2
CH
2
CH
2
CH
2
—, HOCH
2
—, CH
3
CH(OH)—, HSCH
2
—, HO
2
C—, benzyloxycarbonyl, benzyloxycarbonylmethyl,
wherein Hal is as defined above and f is 0, 1 or 2, g is 0, 1 or 2, and each q is independently 0 or 1.
The group of structure
may in particular for example be a fluoride substituted structure of formula
Similarly, the group of structure
may in particular for example be a fluoride substituted structure of formula
As mentioned, when a compound of formula I comprises a carboxylic acid group the polyhydroxy compounds may be any pharmaceutically acceptable salt thereof and when a compound of formula I comprises an amino group the polyhydroxy compounds may be any pharmaceutically acceptable ammonium salt thereof.
The present invention provides, where appropriate, salts (e.g. der
Sauve Gilles
Yelle Jocelyn
Brouillette Robert
Kosie Ronald S.
Pharmacor Inc.
Russel Jeffrey E.
LandOfFree
Hydroxyphenyl derivatives with HIV integrase inhibitory... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Hydroxyphenyl derivatives with HIV integrase inhibitory..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hydroxyphenyl derivatives with HIV integrase inhibitory... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2886768