Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-07
2003-09-16
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S461000, C514S465000, C549S200000, C549S429000, C549S462000, C549S468000, C549S469000, C549S483000, C549S498000
Reexamination Certificate
active
06620841
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a novel compound having an antiviral activity, in detail heteroaromatic derivatives having an inhibitory activity against HIV integrase, a pharmaceutical composition containing the same, especially an anti-HIV agent and a process for preparing the same.
BACKGROUND ART
Among viruses, human immunodeficiency virus (HIV), a kind of retrovirus, is known to cause acquired immunodeficiency syndrome (AIDS). The therapeutic agent for AIDS is mainly selected from the group of reverse transcriptase inhibitors (e.g., AZT, 3TC, and the like) and protease inhibitors (e.g., Indinavir and the like), but they are proved to be accompanied by side effects such as nephropathy and the emergence of resistant viruses. Thus, the development of anti-HIV agents having the other mechanism of action has been desired.
On the other hand, a combination therapy is reported to be efficient in treatment for acquired immunodeficiency syndrome because of the frequent emergence of the resistant mutant in Balzarini, J. et al, Proc. Natl. Acad. Sci. USA 1996, 93, p13152-13157. Reverse transcriptase inhibitors and protease inhibitors are clinically used as an anti-HIV agent but agents having the same mechanism of action often exhibit cross resistance or only an additional activity. Therefore, anti-HIV agents having the other mechanism of action are desired.
Under the above circumstance, the research has been focused on integrase, which is an enzyme relating to the site-specific recombination or insertion of viral DNA into chromosomes in animal cells, and the research for anti-HIV agents based on the enzyme inhibitory activity has been performed; (1) KOURILSKY P et al., Proc. Natl. Acad. Sci. USA 61 (3), 1013-1020 (1968); (2) F Barin et al., J. VIROL. METHODS (NETHERLANDS), 17/1-2(55-61) (1987); (3) Fesen. M R, Proc. Natl. Acad. Sci. USA 90:2399, (199:3); (4) DeNoon, D J, CDC AIDS Weekly Pagination:P2 (1990).
On the other hand, a gene therapy has been applied to thirteen hereditary diseases such as adenosine deaminase deficiency, familial hypercholesterolemia, haemophilia and the like, and recently extended to rheumatics, cancer, infectious diseases such as HIV and the like. Namely, the number of diseases as an object of a gene therapy is increasing year by year. The gene therapies have been applied on more than three thousands patients in the world, especially in the U.S.A. Several methods for transfections of genes have been developed such as a lipofectin method and a transfection with an adenovirus vector, an adeno-associated virus vector, and the like. Over fifty percents of the gene therapies are performed by using a retrovirus vector prepared from MLV (Moloney murine leukemia virus, Mo-MLV, MMLV). Though each method has merits and demerits, a retrovirus vector is expected to stably express the gene for a long term without disappearance of the gene by cell divisions because it is inserted into host cells. However, the clinically used retrovirus vector derived from MLV can infect only proliferating cells because it is not able to actively transfer to the nucleus. Therefore, the retrovirus vector derived from HIV can overcome the above problem, which is being researched.
The problems accompanied by these retrovirus vectors include 1) the emergence of self-replicating viruses by mutation or transformation with endogenous virus, 2) cytotoxicity, 3) oncogenicity and the like. Therefore, it is important to solve the problems accompanied by these retrovirus vectors and various types of the improved vectors are studied. (Takashi Yoshida, The Japanese Association of Gene, Handbook of the development of the gene therapy, N.T.S., 1999).
Some integrase inhibitors have recently been reported, for example, peptide derivatives described in U.S. Pat. No. 5,578,573, tetrahydronaphthyl derivatives described in GB 2306476A, and acrydone derivatives described in WO 97/38999.
Additionally, in Khim. Geterotsikl. Soedin. 1973, (11), 1519, the following 2-hydroxy-4-oxo-2-butenoic acid derivatives substituted with indolyl at the 4-position are described without showing any therapeutic activity.
Gardner, T. S. reported, in J. Org. Chem. 1961, (26), 1514, the following 2-hydroxy-4-oxo-2-butenoic acid esters substituted with heteroaryl at the 4-position, but their therapeutic activity is not described therein.
It is described in JP-A 61-134346 that the following 2-hydroxy-4-oxo-2-butenoic acid derivatives substituted with heteroaryl at the 4-position are useful as an antiulcer agent.
Ferles, M. Collect. Czech. Chem. Commun., 1990, 55, p1228-1233 and Barluenga, J. Synthesis 1996, 1, p133-140 disclose the following heteroaromatic derivatives having 1-hydroxy-3-oxo-propenylene group are described without any therapeutic activity.
Moreover, in U.S. Pat. No. 5,475,109, dioxobutanoic acid derivatives substituted with non-aromatic heterocycles are described to be useful as an anti influenza viral agent, whose mechanism of the action is the inhibition of cap-dependent endonuclease.
1-(5-Phenylaminotriazol-3-yl)-3-hydroxy-(thiophen-2-yl)-propenone, 1-[5-(4-tolylamino)triazol-3-yl]-3-hydroxy-(thiophen-2-yl)-propenone and the like are described in Indian. Journal of Chemistry Vol. 30B, March 1991, pp. 313-319, but their therapeutic activity is not described.
DISCLOSURE OF INVENTION
Under the above circumstance, the development of a novel integrase inhibitor has been desired. The present inventors have intensively studied to find that a novel heteroaromatic derivative, namely, a compound of the general formula (I) or (II):
wherein X is hydroxy, protected hydroxy or optionally substituted amino; Y is —COOR
A
wherein R
A
is hydrogen or ester residue, —CONR
B
R
C
wherein R
B
and R
C
each is independently hydrogen or amide residue, optionally substituted aryl or optionally substituted heteroaryl; A
1
is optionally substituted heteroaryl; Z
1
and Z
3
each is independently a bond, lower alkylene or lower alkenylene; Z
2
and Z
4
each is independently a bond, lower alkylene, lower alkenylene, —CH(OH)—, —S—, —SO—, —SO
2
—, —SO
2
NR
21
—, —NR
21
SO
2
—, —O—, —NR
21
—, —NR
21
CO—, —CONR
21
—, —C(═O)—O—, —O—C(═O)— or —CO—; R
21
is hydrogen, lower alkyl or lower alkenyl; R
1
is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle; R
2
is optionally substituted lower alkyl, optionally substituted lower alkyloxy, optionally substituted lower alkyloxycarbonyl, optionally substituted aryl, optionally substituted aryloxy, optionally substituted aryloxycarbonyl, carboxy, optionally substituted cycloalkyl, hydroxy, mercapto, optionally substituted amino, nitro or halogen; and p is 0 or 1, (hereinafter referred to as “a compound of the present invention”), a tautomer, a prodrug, a pharmaceutically acceptable salt or a hydrate thereof has an inhibitory activity against integrase and is useful as an antiviral agent, an antiretroviral agent, an anti-HIV agent, an anti-HTLV-1 (Human T cell leukemia virus type 1) agent, an anti-FIV (Feline immunodeficiency virus) agent or an anti-SIV (Simian immunodeficiency virus) agent, especially an anti-HIV agent or an integrase inhibitor, to accomplish the present invention.
Moreover, the present inventors have discovered that the compound of the present invention inhibits not only integrase of HIV, SIV and FIV, but also that of MLV, which is often used in the gene therapy.
In addition, the present inventors have discovered a process for producing the compound of the formula (I) or (II) and a useful intermediate thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention relates to the following compounds and pharmaceutical compositions;
(1) a pharmaceutical composition for inhibition of an integrase which contains as an active ingredient a compound of the formula (I):
wherein X is hydroxy, protected hydroxy or optionally substituted amino; Y is —COOR
A
wherein R
A
is hydrogen or ester residue, —CONR
B
R
C
where
Fujishita Toshio
Sato Akihiko
Yoshinaga Tomokazu
Patel Sudhaker B.
Shionogi & Co. Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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