Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-06-13
2004-05-18
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S276400
Reexamination Certificate
active
06737429
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention is concerned with novel pyrrole derivatives, a process for their manufacture, pharmaceutical compositions and the use of such compounds 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 are useful in the treatment or therapy of diseases mediated by the human immunodeficiency virus (HIV).
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's 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.
Certain pyrrole derivatives have been disclosed to have therapeutic utilities.
U.S. Pat. No. 3,644,631 describes pyrrole derivatives effective for the therapy of inflammatory syndromes.
U.S. Pat. No. 4,282,242 describes pyrrole derivatives effective for the therapy of lowering the blood glucose level in hyperglycemic mammals.
SUMMARY OF THE INVENTION
The object of the present invention is to provide novel compounds which are potent inhibitors of the human immunodeficiency virus reverse transcriptase enzyme, which is involved in viral replication, and which accordingly are useful as antiviral drugs. Specifically, this invention is directed to the compounds of formula I
wherein R
1
, R
2
, R
3
, R
4
, and R
5
are as defined below.
This invention is also directed to pharmaceutical compositions containing compounds for formula I and the use of the compositions in the treatment or therapy of HIV.
DETAILED DESCRIPTION OF THE INVENTION
This invention is directed, inter alia, to a compound of formula
wherein
R
1
is alkyl, cycloalkyl, aryl or heterocyclyl;
R
2
is alkyl cycloalkyl, aryl or heterocyclyl;
R
3
is hydrogen, alkyl, cycloalkyl, aryl or heterocyclyl;
R
4
is hydrogen, alkyl, carboxyl, C(═O)R, CONR′R″, cyano or alkenyl;
R is hydrogen, alkyl, alkoxy, trifluoromethyl, methyl-oxy-carbonyl or ethyl-oxy-carbonyl;
R′ and R″, are each independently selected from hydrogen, alkyl or aryl;
R
5
is alkyl, aryl or a group —Z—C(═O)R′″;
Z is a single bond or —CH═CH—;
R′″ is hydrogen or alkyl;
X represents S, S(O), S(O)
2
, O, N(alkyl), or X—R
2
together represent CH
2
-aryl or CH
2
-heterocyclyl;
provided that only one of R
3
and R
4
is hydrogen, and provided further that alkyl in R
3
is not CF
3
;
or hydrolyzable esters or ethers of the foregoing compound, or a pharmaceutically acceptable salt thereof.
The term “alkyl” as used herein, and if not otherwise specified by the number of carbon atoms, denotes an optionally substituted straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert.-butyl, pentyl, hexyl, heptyl, including their different isomers.
Suitable substituents for the alkyl chain can be selected from one or more of
aryl, heterocyclyl,
carboxyl,
alkoxy, cycloalkyl oxy, aryl oxy, heterocyclyl oxy, hydroxy,
amino carbonyl oxy, alkyl amino carbonyl oxy, dialkyl amino carbonyl oxy, aryl amino carbonyl oxy, heterocyclyl amino carbonyl oxy,
alkyl carbonyl, cycloalkyl carbonyl, aryl carbonyl, heterocyclyl carbonyl,
hydroxy carbonyl, alkoxy carbonyl, cycloalkyl oxy carbonyl, aryl oxy carbonyl, heterocyclyl oxy carbonyl,
amino carbonyl, alkyl amino carbonyl, dialkyl amino carbonyl, cycloalkyl amino carbonyl, aryl amino carbonyl, heterocyclyl amino carbonyl,
amino, alkyl amino, dialkyl amino, cycloalkyl amino, aryl amino, heterocyclyl amino,
alkyl carbonyl amino, cycloalkyl carbonyl amino, aryl carbonyl amino, heterocyclyl carbonyl amino,
alkoxy carbonyl amino, cycloalkyl oxy carbonyl amino, aryloxy carbonyl amino, heterocylyl oxy carbonyl amino,
alkyl amino carbonyl amino, dialkyl amino carbonyl amino, cycloalkyl amino carbonyl amino,
aryl amino carbonyl amino, heterocyclyl amino carbonyl amino,
alkyl sulfonyl amino, cycloalkyl sulfonyl amino, aryl sulfonyl amino, heterocyclyl sulfonyl amino,
nitro,
alkyl sulfinyl, cycloalkyl sulfinyl, aryl sulfinyl, heterocyclyl sulfinyl,
alkyl sulfonyl, cycloalkyl sulfonyl, aryl sulfonyl, heterocyclyl sulfonyl,
alkyl thio, cycloalkyl thio, aryl thio, heterocyclyl thio or halogen.
In case more than one substituent is attached to the alkyl group, these substituents can be identical or different from each other.
The suitable substituents for the alkyl group aryl and heterocyclyl may be substituted with 1-3 substituents, preferably 1-2 substituents, more preferably 1 substituent selected from C
1-4
-alkyl (preferably methyl), C
1-4
-alkoxy (preferably methoxy), halogen (preferably chlorine) or trifluoromethyl. Examples for substituted alkyl are cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 2-pyridylmethyl, 2-pyridylethyl, 2-pyridylpropyl, 2-pyridylbutyl, methyl-2-pyridyl-methyl, methyl-2-pyridyl-ethyl, dimethyl-2-pyridyl-methyl, ethyl-2-pyridyl-methyl, methoxy-2-pyridyl-methyl, methoxy-2-pyridyl-ethyl, dimethoxy-2-pyridyl-methyl, fluoro-2-pyridyl-methyl, difluoro-2-pyridyl-methyl, chloro-2-pyridyl-methyl, chloro-2-pyridyl-ethyl, dichloro-2-pyridyl-methyl, dichloro-2-pyridyl-methyl, bromo-2-pyridyl-methyl, dibromo-2-pyridyl-methyl, 3-pyridyl-methyl, 3-pyridyl-ethyl, 3-pyridyl-propyl, 3-pyridyl-butyl, methyl-3-pyridyl-methyl, methyl-3-pyridyl-ethyl, dimethyl-3-pyridyl-methyl, ethyl-3-pyridyl-methyl, methoxy-3-pyridyl-methyl, methoxy-3-pyridyl-ethyl, dimethoxy-3-pyridyl-methyl, fluoro-3-pyridyl-methyl, difluoro-3-pyridyl-methyl, chloro-3-pyridyl-methyl, chloro-3-pyridyl-ethyl, dichloro-3-pyridyl-methyl, dichloro-3-pyridyl-methyl, bromo-3-pyridyl-methyl, dibromo-3-pyridyl-methyl, 4-pyridyl-methyl, 4-pyridyl-ethyl, 4-pyridyl-propyl, 4-pyridyl-butyl, methyl-4-pyridyl-methyl, methyl-4-pyridyl-ethyl, dimethyl-4-pyridyl-methyl, ethyl-4-pyridyl-methyl, 2-(trifluoromethyl)-4-pyridyl-1-methyl, 3-(trifluoromethyl)-4-pyridyl-1-methyl, 2-(trifluoromethyl)-3-pyridyl-1-methyl, 4-(trifluoromethyl)-3-pyridyl-1-methyl, 3-(trifluoromethyl)-2-pyridyl-1-methyl, 4-(trifluoromethyl)-2-pyridyl-1-methyl, methoxy-4-pyridyl-methyl, methoxy-4-pyridyl-ethyl, dimethoxy-4-pyridyl-methyl, fluoro-4-pyridyl-methyl, difluoro-4-pyridyl-methyl, chloro-4-pyridyl-methyl, chloro-4-pyridyl-ethyl, dichloro-4-pyridyl-methyl, dichloro-4-pyridyl-methyl, bromo-4-pyridyl-methyl, dibromo-4-pyridyl-methyl, phenylmethyl (benzyl), phenylethyl, phenylpropyl, phenylbutyl, 2-methylphenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl, 2-methylphenylethyl, 3-methylphenylethyl, 4-methylphenylethyl, 2,3-dimethylphenylmethyl, 2,4-dimethylphenylmethyl, 2,5-dimethylphenylmethyl, 2,6-dimethylphenylmethyl, 3,4-dimethylphenylmethyl, 3,5-dimethylphenylmethyl, 3,6-dimethylphenylmethyl, 2-ethyphenylmethyl, 3-ethylphenylmethyl, 4-ethylphenylmethyl, 2,3-diethylphenylmethyl, 2,4-diethylphenylmethyl, 2,5-diethylphenylmethyl, 2,6-diethylphenylmethyl, 3,4-diethylphenylmethyl, 3,5-diethylphenylmethyl, 3,6-diethylphenylmethyl, 2-trifluoromethyl-phenylmethyl, 3-trifluoromethyl-phenylmethyl, 4-trifluoromethyl-phenylmethyl, 2-trifluoromethyl-phenylethyl, 3-trifluoromethyl-phenylethyl, 4-t
Dymock Brian William
Jones Philip Stephen
Merrett John Herbert
Parratt Martin John
Hoffmann-La Roche Inc.
Johnston George W.
Robinson Binta
Rotman Alan L.
Smith Lyman H.
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