Anti-HIV imidazolone derivatives

Details Anti-HIV imidazolone derivatives Anti-HIV imidazolone derivatives

2001-11-06

2003-02-11

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S392000, C544S274000, C548S314700, C548S320100

Reexamination Certificate

active

06518293

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention to compounds and methods for the treatment of infection by the human immunodeficiency virus (HIV). The disease Acquired Immune Deficiency 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.
Imidazolone derivatives have been described in the literature with different uses in the treatment of the human body.
WO 94/10168 describes imidazolone derivatives and their use as tachykinin receptor antagonists.
WO 96/38421 describes imidazolone derivatives and their use as anti-coagulants.
WO 00/35907 describes imidazolone derivatives and their use in treating benign prostatic hyperplasia.
SUMMARY OF THE INVENTION
The invention is concerned with novel imidazolone derivatives, a process for their manufacture, pharmaceutical compositions and the use of such compounds in medicine. 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 caused by HIV infection.
DETAILED DESCRIPTION OF THE INVENTION
The present invention comprises compounds of formula I which are active against HIV:
wherein
R
1
is hydrogen, alkyl, cycloalkyl, aryl or alkyl substituted with optionally substituted phenyl;
R
2
is hydrogen, alkenyl, alkyl or alkyl substituted with optionally substituted phenyl;
R
3
is alkyl, cycloalkyl, optionally substituted phenyl, optionally substituted benzyl or heterocyclyl;
A is alkyl, hydroxy-alkyl, alkenyl, substituted alkenyl, aryl-CH(OH)—, substituted alkyl, or
A is a group of formula Z—CH
2
—Y—CH
2
—,
wherein Y is O or NR wherein R is hydrogen or alkyl and
Z is heterocyclyl or optionally substituted aryl;
X is S or O;
with the provisos that
(i) only one of R
1
and R
2
is hydrogen;
(ii) when X is O, then R
1
cannot be aryl;
as well as hydrolyzable esters or ethers of compounds of formula I and pharmaceutically acceptable salts thereof.
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, sec-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl including their different isomers. Preferably, the term “alkyl” denotes an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms.
Substituents for the alkyl chain are selected from one or more of aryl, heterocyclyl, alkoxy, hydroxy or halogen.
Aryl or heterocyclyl as substituents for the alkyl group are preferably substituted with 1, 2, 3, 4, 5 or where possible more methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, tert.-butyloxy, hydroxy, fluorine, chlorine, bromine or iodine.
Alkyl in R
1
, R
2
and R
3
is preferably an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms. Preferred substituents for such alkyl groups are selected from aryl, heterocyclyl, hydroxy or halogen. Preferred alkyl groups in R
1
, R
2
and R
3
are unsubstituted straight or branched chain hydrocarbon residues containing 1 to 7 carbon atoms and more preferred alkyl groups in R
1
, R
2
and R
3
are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl or pentyl. Most preferred alkyl group in R
1
, R
2
and R
3
are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl.
Alkyl for R
1
is preferably isopropyl.
Alkyl for R
2
is preferably methyl.
Alkyl for the substituent A is as defined above, preferably a straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms. More preferred alkyl group for the substituent A are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl or pentyl.
The term “alkoxy” as used herein denotes an optionally substituted straight or branched chain alkyl-oxy group wherein the “alkyl” portion is as defined above such as methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy, tert.-butyloxy, pentyloxy, hexyloxy, heptyloxy including their different isomers. More preferred alkoxy groups within the invention are methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butyloxy, iso-butyloxy or tert.-butyloxy.
The term “C
1-4
-alkyl substituted with C
1-4
-alkoxy, C
1-4
-alkyl-carbonyl-oxy- or heterocyclyl-oxy” as used herein denotes a C
1-4
-alkyl, preferably C
1-2
-alkyl as defined above which may be substituted with 1-3, preferably 1-2 and more preferably on substituents selected from C
1-4
-alkoxy (preferred C
1-2
-alkoxy), C
1-4
-alkyl-carbonyl-oxy- (preferred C
1-2
-alkyl-carbonyl-oxy-) and heterocyclyl-oxy. Preferred examples are methoxymethyl, ethoxymethyl, methyl-carbonyl-oxy-, ethyl-carbonyl-oxy-, 4-pyridyl-oxy-methyl, 3-pyridyl-oxy-methyl, 2-pyridyl-oxy-methyl.
The term “C
1-4
-alkyl substituted with optionally substituted phenyl” as used herein denotes a C
1-4
-alkyl, preferably C
1-2
-alkyl as defined above which may be substituted with a phenyl group or with a substituted phenyl group which may be substituted with 1,2,3,4 or 5 substituents, preferably 1, 2 or 3 substituents selected from C
1-4
-alkyl, C
1-4
-alkoxy, hydroxy, fluorine, chlorine or bromine, preferably methyl, ethyl, methoxy, ethoxy, hydroxy, fluorine, chlorine or bromine. Examples are phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, tolylmethyl, tolylethyl, tolylpropyl, tolylbutyl, 2,3-dimethylphenylmethyl, 2,4-dimethylphenylmethyl, 2,5-dimethylphenylmethyl, 2,6-dimethylphenylmethyl, 3,4-dimethylphenylmethyl, 3,5-dimethylphenylmethyl, 3,6-dimethylphenylmethyl, 2-methoxy-phenylmethyl, 3-methoxy-phenylmethyl, 4-methoxy-phenylmethyl, methoxy-phenylethyl, methoxy-phenylpropyl, methoxy-phenylbutyl, dimethoxy-phenylmethyl, dimethoxy-phenylethyl, dimethoxy-phenylpropyl, dimethoxy-phenylbutyl, 2-hydroxyphenylmethyl, 3-hydroxyphenylmethyl, 4-hydroxyphenylmethyl, 2,3-dihydroxyphenylmethyl, 2,4-dihydroxyphenylmethyl, 2,5-dihydroxyphenylmethyl, 2,6-dihydroxyphenylmethyl, 3,4-dihydroxyphenylmethyl, 3,5-dihydroxyphenylmethyl, 3,6-dihydroxyphenylmethyl, 2-hydroxyphenylethyl, 3- hydroxyphenylethyl, 4-hydroxyphenylethyl, 2-hydroxyphenylpropyl, 3-hydroxyphenylpropyl, 4-hydroxyphenylpropyl, 2-hydroxyphenylbutyl, 3-hydroxyphenylbutyl, 4-hydroxyphenylbutyl, 2-fluorophenylmethyl, 3-fluorophenylmethyl, 4-fluorophenylmethyl, 2,3-difluorophenylmethyl, 2,4-difluorophenylmethyl, 2,5-difluorophenylmethyl, 2,6-difluorophenylmethyl, 3,4-difluorophenylmethyl, 3,5-difluorophenylmethyl, 3,6-difluorophenylmethyl, 2- fluorophenylethyl, 3- fluorophenylethyl or 4-fluorophenylethyl, 2-chlorophenylmethyl, 3-chlorophenylmethyl, 4-chlorophenylmethyl, 2,3-dichlorophenylmethyl, 2,4-dichlorophenylmethyl, 2,5-dichlorophenylmethyl, 2,6-dichlorophenylmethyl, 3,4-dichlorophenylmethyl, 3,5-dichlorophenylmethyl, 3,6-dichlorophenylmethyl, 2-chlorophenylethyl, 3-chlorophenylethyl, 4- chlorophenylethyl, 2-bromophenylmethyl, 3-bromophen

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