Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-09-20
2004-03-02
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S407000, C546S276100, C548S366100
Reexamination Certificate
active
06699887
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to methods and compounds for the treatment of HIV infection. 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 (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.
No pyrazole derivatives have yet been described in the literature for the treatment of diseases mediated by the human immunodeficiency virus (HIV).
SUMMARY OF THE INVENTION
The invention is concerned with novel and known pyrazole derivatives, a process for their manufacture, pharmaceutical compositions and the use of such compounds in medicine, especially in the treatment of viral diseases. In particular, the compounds are inhibitors of the human immunodeficiency virus reverse transcriptase enzyme which is involved in viral replication. Consequently the compounds of this invention may be advantageously used as therapeutic agents for the treatment of diseases mediated by the human immunodeficiency virus (HIV).
DETAILED DESCRITPTION OF THE INVENTION
The present invention describes the use of compounds of formula I
wherein
R
1
is optionally substituted C
1-12
-alkyl, C
3-8
-cycloalkyl, acyl, C
1-4
-alkylsulfonyl, optionally substituted phenylsulfonyl, aryl, heterocyclyl or C
1-4
-alkyl substituted with optionally substituted phenyl;
R
2
is aryl;
R
3
is C
1-12
-alkyl or C
1-4
-alkoxy-C
1-4
-alkyl;
A is a group selected from CH
2
-(aryl-C
1-4
-alkylamino), CH
2
-(aryl-C
1-4
-alkoxy),
CH
2
-(heterocyclyl-C
1-4
-alkoxy), C
1-4
-alkyl substituted with aryl or with heterocyclyl; or
A is a group of formula CH
2
-U-heterocyclyl,
wherein U is O, S or NR″, wherein R″ is hydrogen or C
1-4
-alkyl; or
A is a group of formula CH(V)Z,
wherein V is OH or F, and
wherein Z is aryl or heterocyclyl; or
A is a group of formula CH═CHW,
wherein W is aryl or heterocyclyl;
X represents S or O;
for the treatment of diseases mediated by the human immunodeficiency virus (HIV) or for the preparation of a medicament for such treatment.
The term “alkyl” as used herein 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, 1-sec-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl including their different isomers. Preferably, “alkyl” optionally substituted straight or branched chain hydrocarbon residue containing 1 to 7 or 1 to 6 carbon atoms. Most preferred, “alkyl” denotes an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 4 carbon atoms.
Suitable substituents for the alkyl chain can be selected from one or more of aryl, heterocyclyl, alkoxy, hydroxy or halogen. The terms “aryl”, “heterocyclyl”, “alkoxy” and “halogen” are defined below. Preferred substituents for the alkyl chain are 1-5 substituents selected from fluorine, chlorine and bromine, more preferred 1-5 fluorine substituents and most preferred 1-3 fluorine substituents.
In case more than one substituent is attached to the alkyl group, these substituents can be identical or different from each other.
Aryl (defined below) as substituent for the alkyl group can also be substituted with 1-5 substituents selected from C
1-4
-alkyl, C
1-4
-alkoxy, hydroxy, fluorine, chlorine or bromine. More preferred, the aryl is substituted with 1-3 substituents selected from methyl, ethyl, methoxy, ethoxy, hydroxy, fluorine, chlorine or bromine.
Heterocyclyl (defined below) as substituent for the alkyl group can also be substituted with 1, 2, 3 or 4 (where chemically possible) substituents selected from C
1-4
-alkyl, C
1-4
-alkoxy, hydroxy, fluorine, chlorine or bromine. More preferred, the heterocyclyl is substituted with 1-2 substituents selected from methyl, ethyl, methoxy, ethoxy, hydroxy, fluorine, chlorine or bromine.
Alkyl in R
1
is preferably an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 7, 1 to 6 or 1 to 4 carbon atoms as defined above. Suitable substituents for the alkyl group are selected from aryl, heterocyclyl or halogen. Preferred substituents for the alkyl chain are 1-5 substituents selected from fluorine, chlorine and bromine, more preferred 1-5 fluorine substituents and most preferred 1-3 fluorine substituents. More preferred alkyl in R
1
is methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-sec-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl including their different isomers, trifluoromethyl or 2,2,2-trifluoro-ethyl. Most preferred alkyl in R
1
is methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-sec-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl.
Alkyl in R
3
is preferably an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms and most preferred methyl, ethyl, n-propyl, isopropyl, n-butyl, 1-sec-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl including their different isomers. More preferred alkyl in R
3
is an unsubstituted straight or branched chain hydrocarbon residue containing 1 to 4 carbon atoms.
The term “cycloalkyl” as used herein denotes an optionally substituted cycloalkyl group containing 3 to 8 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, which can also be fused to an optionally substituted saturated, partially unsaturated or aromatic monocyclic, bicyclic or tricyclic heterocycle or carbocycle, e.g. to phenyl.
Suitable substituents for cycloalkyl can be selected from one or more of those named for alkyl.
Cycloalkyl in R
1
is as defined above, preferably an unsubstituted cycloalkyl group containing 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. More preferred cycloalkyl in R
1
is cyclopentyl or cyclohexyl.
The term “alkoxy” as used herein denotes an optionally substituted straight or branched chain alkyl-oxy group containing 1 to 7 carbon atoms wherein the “alkyl” portion is as defined above. Examples for alkoxy groups are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, 1-sec-butyloxy, iso-butyloxy, tert.-butyloxy, pentyloxy, hexyloxy, heptyloxy including their different isomers.
Suitable substituents for the alkoxy group are selected from aryl, hydroxy, halogen or amino.
The term “alkoxyalkyl” as used herein denotes an alkoxy group containing 1 to 4 carbon atoms as defined above which is bonded to an alkyl group containing 1 to 4 carbon atoms (preferably 1-2 carbon atoms) as defined above. Examples are methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, propyloxypropyl, methoxybutyl, ethoxybutyl, propyloxybutyl, butyloxybutyl, tert.-butyloxybutyl including their different isomers. Preferred alkoxyalkyl group within the invention is C
1-2
-alkoxy-C
1-2
-alkyl.
Alkoxyalkyl in R
3
is preferably methoxymethyl, methoxyethyl
Dymock Brian William
Jones Philip Stephen
Merrett John Herbert
Parratt Martin John
Ford John M.
Hoffmann-La Roche Inc.
Johnston George W.
Liu Hong
Tramaloni Dennis P.
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