Anti-HIV pyrazole derivatives

Details Anti-HIV pyrazole derivatives Anti-HIV pyrazole derivatives

2002-05-24

2003-03-25

Ramsuer, Robert W. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S341000, C544S333000, C546S276100, C548S365700, C548S370100, C548S370400

Reexamination Certificate

active

06538015

ABSTRACT:

BACKGROUND OF THE INVENTION
The disease Acquired Immunodeficiency Syndrome (AIDS) is the end result of infection by the distinct retroviruses, human immunodeficiency virus type-1 (HIV-1) or type-2 (HIV-2). Several critical points in the virus life cycle have been identified as possible targets for therapeutic intervention. Inhibition of one of these, the transcription of viral RNA to viral DNA (controlled by reverse transcriptase, RT), has provided a number of the current therapies used in treating AIDS. Inhibition of reverse transcriptase provided the first form of treatment for HIV infection with 3′-azido-3′-deoxythymidine (AZT). Since then several inhibitors have been launched, broadly forming two classes: nucleoside analogues and non-nucleosides. As an example of the latter it has been found that certain benzoxazinones, e.g. efavirenz, are useful in the inhibition of HIV RT. However, development of strains of the virus resistant to current RT inhibitors is a constant problem. Therefore, development of compounds effective against resistant strains is an important goal.
Pyrazole derivatives have been described in the literature with different uses (e.g. agrochemistry or treatment of stress-relating illness).
EP 0 627 423 describes pyrazole derivatives and their use as agrohorticultural bactericides.
U.S. Pat. No. 6,005,109 describes pyrazole derivatives and their use in the treatment of stress-relating illness.
U.S. Pat. No. 5,786,302 describes pyrazole derivatives and their use as herbicides.
SUMMARY OF THE INVENTION
The present invention provides pyrazole compounds of the general formula
which are potent inhibitors of the human immunodeficiency virus reverse transcriptase enzyme (HIV RT) which is involved in viral replication. Consequently the compounds of this invention can be advantageously used as therapeutic agents for the treatment of diseases mediated by the human immunodeficiency virus (HIV).
DETAILED DESCRIPTION OF THE INVENTION
This object can be achieved with compounds of formula I
wherein
R
1
is alkyl or substituted alkyl;
R
2
is aryl or substituted aryl;
R
3
is hydroxy, amino, azido, hydroxy-C
1-4
-alkyl, C
1-4
-alkyl-sulfonyl-amino or a group of the formula —X—C(═O)—Z,
wherein X represents NR″″, O or a single bond; wherein R″″ is hydrogen or C
1-4
-alkyl, and
wherein Z is C
1-4
-alkyl, C
1-4
-alkoxy or NR″, R′″; wherein R″, R′″ are independently of each other hydrogen or C
1-4
-alkyl;
A signifies alkyl, substituted alkyl, aryl-methyl, substituted aryl-methyl, aryl-methoxy-methyl, substituted aryl-methoxy-methyl, heterocyclyl-methyl, substituted heterocyclyl-methyl, heterocyclyl-methoxy-methyl or substituted heterocyclyl-methoxy-methyl;
with ethers of compounds of formula I as well as with pharmaceutically acceptable salts of the foregoing.
The term “alkyl” as used herein, and if not specified by the number of carbon atoms, denotes an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl including their different isomers. The term “C
1-12
-alkyl” denotes a straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms as defined above. The term “C
1-7
-alkyl” denotes a straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms. The term “C
1-4
-alkyl” denotes a straight or branched chain hydrocarbon residue containing 1 to 4 carbon atoms. Suitable substituents for the alkyl group are 1-6 fluorine substituents or 1-3 hydroxy substituents, preferably 1-3 fluorine substituents or 1-2 hydroxy substituents and most preferably 3 fluorine substituents or 1 hydroxy substituent. In case more than one substituent is attached to the alkyl group, these substituents can be identical or different from each other. Alkyl in R
1
is preferably a straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms as defined above. More preferably the alkyl group in R
1
is a straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms. In another preferred embodiment alkyl in R
1
is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert.-butyl. Most preferred alkyl in R
1
is isopropyl.
Substituted alkyl for R
1
is preferably a straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms as defined above substituted with 1-6 fluorine substituents, most preferably the trifluoromethyl group.
Alkyl for the substituent A is preferably a straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms as defined above. More preferred alkyl groups in R
1
are straight or branched chain hydrocarbon residues containing 1 to 7 carbon atoms. Most preferred alkyl in R
1
is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert.-butyl.
Substituted alkyl for the substituent A is preferably a straight or branched chain hydrocarbon residue containing 1 to 12 carbon atoms as defined above substituted with 1-3 hydroxy groups, most preferably the hydroxy-methyl group.
The term “hydroxy-C
1-4
-alkyl” as used herein denotes a C
1-4
-alkyl, preferably a C
1-2
-alkyl as defined above which is substituted with a hydroxy group. Examples are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl.
The term “C
1-4
-alkyl-sulfonyl-amino” as used herein for the substituent R
3
denotes for example a methanesulfonamide, ethanesulfonamide, propanesulfonamide or butanesulfonamide. The NH-function of C
1-4
-alkyl-sulfonyl-amino can as well be alkylated with C
1-4
-alkyl as defined above, preferably methyl or ethyl.
The term “alkoxy” as used herein, denotes a straight or branched chain alkyl-oxy group wherein the “alkyl” portion is as defined above such as methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert.-butyloxy. More preferred alkoxy groups within the invention are methoxy or ethoxy.
Formula “—X—C(═O)—Z” as used herein denotes a chemical group wherein X represents NR″″, O or a single bond (wherein R″″ is hydrogen or C
1-4
-alkyl); and wherein Z is C
1-4
-alkyl, C
1-4
-alkoxy or NR″R′″ (wherein R′, R′″ are independently of each other hydrogen or C
1-4
-alkyl). Preferably, the formula “—X—C(═O)—Z” as used herein denotes a chemical group wherein X represents NR″″ or O (wherein R″″ is hydrogen or C
1-4
-alkyl); and wherein Z is C
1-4
-alkyl, C
1-4
-alkoxy or NR″R′″ (wherein R″, R′″ are independently of each other hydrogen or C
1-4
-alkyl). More preferred, the formula “—X—C(═O)—Z” as used herein denotes a chemical group wherein X represents NR″″ or O (wherein R″″ is hydrogen or C
1-4
-alkyl); and wherein Z is NR″R′″ (wherein R″, R′″ are independently of each other hydrogen or C
1-4
-alkyl). Most preferred, the formula “—X—C(═O)—Z” as used herein denotes a chemical group wherein X represents O (wherein R″″ is hydrogen or C
1-4
-alkyl); and wherein Z is NR″R′″ (wherein R″, R′″ are independently of each other hydrogen or C
1-4
-alkyl). Examples of the chemical group of formula “—X—C(═O)—Z” are amino-carbonyl-oxy, methyl-amino-carbonyl-oxy, di-methyl-amino-carbonyl-oxy, amino-carbonyl-amino, methyl-amino-carbonyl-amino, di-methyl-amino-carbonyl-amino, amino-carbonyl-(methyl)-amino, methyl-amino-carbonyl-(methyl)-amino, di-methyl-amino-carbonyl-(methyl)-amino, methoxy-carbonyl-amino, methoxy-carbonyl-(methyl)-amino, ethoxy-carbonyl-amino or ethoxy-carbonyl-(methyl)-amino.
The term “aryl” as used herein denotes an optionally substituted phenyl and naphthyl, both optionally benz-fused to an optionally substituted saturated, partially unsatura

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