Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-05-01
2003-10-21
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S321000, C544S060000, C544S123000, C514S272000, C514S235800
Reexamination Certificate
active
06635636
ABSTRACT:
The present invention is concerned with compounds which inhibit the reverse transcriptase encoded by human immunodeficiency virus (HIV) or pharmaceutically acceptable salts thereof and are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). It also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the treatment of AIDS arid viral infection by HIV.
BACKGROUND OF THE INVENTION
A retrovirus designated human immunodeficiency virus (HIV) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.
Currently available drugs for AIDS therapy are divided into two groups: those that prevent infection of target cells [nucleoside (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs)], and those that prevent HIV-1-infected cells from yielding infectious viruses (protease inhibitors). Monotherapy with antiretroviral agents has shown limited effects, very likely due to the interplay of phenomena such as: high viral loads and multiplication rates of HIV, incomplete inhibition of viral replication and emergence of drug resistant mutants. For this reason, combination therapies with two or more drugs have been proposed for a more effective treatment of AIDS. Potent suppression of HIV replication over prolonged periods has been accomplished with regimens including reverse transcriptase and protease inhibitors, although on stopping therapies viraemia has rapidly reappeared. In the attempt to obtain better results, research is now focused on exploiting new targets and enhancing the activity of “old” drugs. Among the latter, NNRTs possibly endowed with better pharmacokinetic profiles, capability to inhibit clinically relevant mutants and, hopefully, to minimize HIV multiplication are being pursued.
Compounds of the present invention are dihydro-alkyloxy-benzyl-oxopyrimidines (DABOs) which potently inhibit HIV multiplication targeting reverse transcriptase without bioactivation.
BRIEF DESCRIPTION OF THE INVENTION
Novel compounds of formula A:
as herein defined, are disclosed. These compounds are useful in the inhibition of HIV reverse transcriptase, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS, either as compounds, pharmaceutically acceptable salts (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS
This invention is concerned with the compounds of formula A described below, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS). The compounds of this invention include those with structural formula A:
wherein:
X is —O, —CH
2
, —CHK (wherein K is —H, —C
1-4
alkyl, —C
3-6
Cycloalkyl), —S, —NK (wherein K is —H, —C
1-4
alkyl, —C
3-6
cycloalkyl), -aryl, -arylalkyl;
R is —H, —C
1-4
alkyl (containing one or more of heteroatoms like O, S, N), —C
3-6
cycloalkyl (containing one or more of heteroatoms like O, S, N), -aryl, -arylakl, heterocycle;
Y is —H, —C
1-4
alkyl, —C
3-6
cycloalkyl;
Z is —H, —C
1-4
alkyl, —C
3-6
cycloalkyl;
R
1
is —H, —C
1-4
alkyl, -halogen, —NO
2
, —OW (wherein W is —H, —CH
3
, aryl), —SW (wherein W is —H, —CH
3
, -aryl);
R
2
is —H, —C
1-4
alkyl, -halogen, —NO
2
, (wherein W is —H, —CH
3
, -aryl); —SW (wherein W is —H, —CH
3
, -aryl);
R
3
is —H, —C
1-4
alkyl, -halogen, —NO
2
, —OW (wherein W is —H, —CH
3
, -aryl); —SW (wherein W is —H, —CH
3
, -aryl)
R
4
is —H, —C
1-4
alkyl, -halogen, —NO
2
, —OW (wherein W is —H, —CH
3
, -aryl); —SW (wherein W is —H, —CH
3
, -aryl)
R
5
is —H, —C
1-4
alkyl, -halogen, —NO
2
, —OW (wherein W is —H, —CH
3
, -aryl), —SW (wherein W is —H, —CH
3
, -aryl);
pharmaceutically acceptable salts or soluble derivatives thereof;
preparation process of derivatives thereof;
a method of preventing infection of HIV, or of treating infection by HIV or of treating AIDS, comprising administering to a mammal an effective amount of compounds claimed;
a pharmaceutical, composition useful for inhibiting HIV reverse transcriptase, comprising an effective amount of compounds claimed, and a pharmaceutically acceptable carrier;
a pharmaceutical composition useful for preventing or treating infection of HIV or for treating AIDS, comprising an effective amount of compounds claimed, and a pharmaceutically acceptable carrier.
The most preferred compounds of this invention are those of table 1.
The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
When any variable occurs more than one time in any constituent or in formula A of this invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein except where noted, “alkyl” is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; “Halogen” or “Hal” as used herein, means fluoro, chloro, bromo and iodo.
As used herein, with exceptions as noted, “aryl” is intended to mean any stable monocyclic, bicyclic or tricyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, biphenyl.
The term heterocycle or heterocyclic, as used herein except where noted represents a stable 5- to 7-membered monocyclic or stable 8- to 11-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S; and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
The pharmaceutically-acceptable salts of the novel compounds of this invention that are capable of salt formation (in the form of water- or oil-soluble or dispersible products) include the conventional non-toxic salts or the quaternary ammonium salts of these compounds, which are formed, e.g.; from inorganic or organic acids or bases.
In preferred embodiments, a compound of the present invention is administered in combination or alternation with AZT, D4T, FTC (2′,3′-dideoxy-3′-thia-5-fluorocytidine); 3TC (Epivir, Glaxo Wellcome, Inc.), AZDU (3′-Azido-2′,3′-dideoxyuridine); 141W94 (amprenavir, GlaxoWellcome, Inc.); Viramune (nevirapine), Rescriptor (delavirdine); or DMP-266 (efavirenz). Other examples of antiviral agents that can be used in combination or alternation with the compounds disclosed herein for HIV therapy include DDI, DDC, Delaviridine, &bgr;-LddA, &bgr;-L-3′-azido-d5FC, carbovir, acyclovir, interferon, stavudine, CS-92 (3′-azido-2′,3′-dideoxy-5-methyl-cytidine), 3′-azido nucleosides, and &bgr;-D-dioxolane nucleosides such as &bgr;-D-dioxolanylguanine (DXG), &bgr;-D-dioxolanyl-2,6-diaminopurine (DAPD), and &bgr;-D-dioxolanyl-6-chloropurine (ACP).
Preferred pr
Artico Marino
La Colla Paolo
Idenix Pharmaceuticals Inc.
King & Spalding LLP
Knowles, Esq. Sherry M.
Liu Hong
Raymond Richard L.
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