Multiple-agents-binding compound, production and use thereof

Details Multiple-agents-binding compound, production and use thereof Multiple-agents-binding compound, production and use thereof

1999-08-09

2002-08-27

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S046000, C514S047000, C514S048000, C514S049000, C514S050000, C514S051000, C514S220000, C514S230500, C514S252010, C514S253030

Reexamination Certificate

active

06440946

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a multiple-agents-binding compound comprising a compound having anti-HIV activity bound together with at least one compound having anti-HIV activity and a pharmaceutical composition comprising said multiple-agents-binding compound.
BACKGROUND OF THE INVENTION
It is known that HIV (human immunodeficiency virus) causes various clinical symptoms such as AIDS (acquired immunological deficient syndrome), AIDS-related syndromes, etc. In order to treat the above-mentioned symptoms, HIV protease inhibitors have recently been developed in addition to HIV reverse transcriptase inhibitors which have been used so far. However, most of these anti-HIV agents and in particular peptide compounds of HIV protease inhibitors have a lot of problems such as water insolubility, instability in vivo, low oral absorption, etc. Moreover, since a large amount of these anti-HIV agents are administered for a long time, development of an anti-HIV agent showing superior bioavailability when oral administration is desired. Furthermore, since known anti-HIV agents have problems such as side effects, the advent of drug-resistant virus, etc., an antagonist of CCR5 which is the second receptor from which macrophage-tropic HIV invades to a target cell and an antagonist of CXCR4 which is the second receptor from which T cell-tropic HIV invades to a target cell are being developed, as new anti-HIV agents having different mechanisms. On the other hand, combination use of HIV reverse transcriptase inhibitors with HIV protease inhibitors provides further progress of the treatment of AIDS. However, said combination use is not sufficient for the eradication of AIDS.
OBJECT OF THE INVENTION
Cocktail therapy such as combination of HIV reverse transcriptase inhibitor and HIV protease inhibitor is known to be effective for the treatment of AIDS. However, side effects caused by administration of these agents in large amounts and for a long time are not reduced. In addition thereto, according to said therapy, there are many problems in administration of these agents such as complexity of administration time or dose, etc. The present invention is to provide an anti-HIV agent which has more potent anti-HIV activity, which is improved in absorption when orally administered, stability, physicochemical properties, etc., ease of treatment and which reduces toxicity according to reduction of dose.
SUMMARY OF THE INVENTION
The present inventors diligently made extensive studies on solving the above-mentioned problems and, as a result, they found that a complex obtained by binding the same or different kind of two or more compounds to each other, said compounds being selected from compounds having anti-HIV activity and having no affinity for cell surface protein such as HIV reverse transcriptase inhibitor, HIV protease inhibitor, CCR5 antagonist, etc., shows superior anti-HIV activity and at the same time it has clinically desirable pharmaceutical effects such as improvement of absorption when orally administered, reduction of side effects according to reduction of dose, etc. Moreover, the compounds of the present invention can be substituted for conventional cocktail therapy and can be used more simply and effectively. Based on these findings, the present invention was accomplished.
More specifically, the present invention relates to
(1) a compound (or complex) comprising a compound having anti-HIV activity and having no affinity for cell surface protein bound together with (or conjugated with) a same or different kind of at least one compound having anti-HIV activity and having no affinity for cell surface protein, or a salt thereof;
(2) a compound obtained by binding two compounds to each other, said compounds being selected from HIV reverse transcriptase inhibitor, HIV protease inhibitor or CCR5 antagonist, or a salt thereof;
(3) a compound of the above (1), wherein the compound having anti-HIV activity is HIV reverse transcriptase inhibitor, HIV protease inhibitor or CCR5 antagonist;
(4) a compound of the above (1), wherein at least one of the compounds having anti-HIV activity is CCR5 antagonist;
(5) a compound of the above (2), wherein the two compounds are HIV reverse transcriptase inhibitor and HIV protease inhibitor;
(6) a compound of the above (2), (3) or (5), wherein the HIV reverse transcriptase inhibitor is nucleoside reverse transcriptase inhibitor having at least one hydroxy group or a derivative thereof;
(7) a compound of the above (2), (3) or (5), wherein the HIV reverse transcriptase inhibitor is zidovudine, didanosine, zalcitabine, lamivudine, stavudine or abacavir;
(8) a compound of the above (2), (3) or (5), wherein the HIV reverse transcriptase inhibitor is zidovudine;
(9) a compound of the above (2), (3) or (5), wherein the HIV protease inhibitor is a compound having at least one hydroxy group, amino group and/or carboxyl group and mimicking transition-state of a substrate of HIV protease;
(10) a compound of the above (2), (3) or (5), wherein the HIV protease inhibitor is saquinavir, ritonavir, indinavir, nelfinavir, a compound of the formula:
wherein R is a C
1-6
alkyl group or an optionally substituted phenyl-C
1-3
alkyl group, R
1
and R
2
are independently a hydrogen atom or a C
1-6
alkyl group, and X is an optionally substituted C
1-6
alkylene group, a compound of the formula:
wherein R is a C
1-6
alkyl group or an optionally substituted phenyl-C
1-3
alkyl group, R
1
and R
2
independently a hydrogen atom or a C
1-6
alkyl group, and the ring A is an optionally substituted benzene ring, or a salt thereof;
(11) a compound of the above (2), (3) or (5), wherein the HIV protease inhibitor is a compound of the formula:
wherein each symbol is as defined in the above (10), a compound of the formula:
wherein each symbol is as the above (10), or a salt thereof;
(12) a compound of the above (1) or (2), wherein the compound having anti-HIV activity and having no affinity for cell surface protein such as HIV reverse transcriptase inhibitor, HIV protease inhibitor, CCR5 antagonist, etc. binds to a same or different kind of at least one compound having anti-HIV activity and having no affinity for cell surface protein, directly or through a spacer;
(13) a compound of the above (12), wherein the spacer has at least two carboxyl groups;
(14) a compound of the above (5), which is a compound of the formula:
wherein each symbol is as defined in the above (10), a compound of the formula:
wherein each symbol is as defined in the above (10), or a salt thereof;
(15) a compound of the above (10), (11) or (14), wherein R is (1) a benzyl group substituted with a C
1-3
alkyl group or (2) a t-butyl group, R
1
and R
2
are independently a hydrogen atom or a methyl group, and X is a group of the formula: —(CH
2
)
m
— (m is an integer of 1-3) in which a methylene at an optional position may be substituted with a methyl group;
(16) a pharmaceutical composition which comprises a compound of the above (1) or (2), or a salt thereof;
(17) a composition of the above (16) which is for oral administration;
(18) a composition of the above (16) which is for the prevention or treatment of infectious disease of HIV;
(19) a composition of the above (16) which is for the prevention or treatment of AIDS; etc.
DETAILED DESCRIPTION OF THE INVENTION
The above-mentioned “anti-HIV activity” means that HIV infection is inhibited, HIV proliferation is inhibited, the number of HIV is reduced, etc.
Examples of the “compound having anti-HIV activity and having no affinity for cell surface protein” include a compound having anti-HIV activity and having no affinity for HIV surface protein gp120 and/or HIV target cell surface protein CD4, for example, HIV reverse transcriptase inhibitor; HIV protease inhibitor; chemokine antagonist such as CCR5 antagonist, CXCR4 antagonist, etc.; APJ receptor ligand (for example, apelin, etc.), AIDS vaccine (for example, HIV-1-gp-120 vaccine, etc.), antimetabolite (metabolic antagonist) (for example, ribavirin, hydroxycarbamide, peldesine, etc.), DNA polymerase

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