Thienopyrrolidinones

Details Thienopyrrolidinones Thienopyrrolidinones

2001-06-26

2003-03-04

Higel, Floyd D. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S455000, C548S453000, C548S364100, C514S415000, C514S399000

Reexamination Certificate

active

06528653

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to bicyclic sulfur containing heteroaryls. More particularly, the invention is directed to substituted thieno[2,3-b]pyrrolidin-5-one derivatives, a process for their manufacture and pharmaceutical preparations containing them. This invention is further directed to intermediates useful in the preparation of the foregoing compounds and to processes for the preparation of such compounds. These novel thienopyrrolidinones inhibit or modulate the production of tumour necrosis factor (TNF-&agr;) from cells. Compounds of the invention also inhibit the proliferation of cells. These compounds and their pharmaceutically acceptable salts are useful as anti-inflammatory agents, particularly useful in the treatment of rheumatoid arthritis, neuro-degenerative diseases such as Alzheimer's, cardiovascular diseases and in cancer therapy. The invention is also directed to pharmaceutical compositions containing these compounds.
SUMMARY OF THE INVENTION
The present invention relates to thienopyrrolidinones of the formula
wherein R
1
, R
2
and R
3
are as defined below.
These compounds inhibit or modulate TNF-&agr; from cells and also inhibit cell proliferation. These compounds are useful as anti-inflammatory agents, particularly in the treatment of rheumatoid arthritis.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to thienopyrrolidinones of the formula
and pharmaceutically acceptable salts thereof,
wherein
R
1
represents a 5- or 6-membered monocyclic aromatic ring containing one or more, preferably 1-4, hetero atoms independently selected from N, S and O, the remaining atoms being carbon, said 5- or 6-membered aromatic ring optionally being fused to a benzene ring, said 5- or 6-membered monocyclic aromatic ring and said benzene ring each being independently optionally substituted with one or more substituents selected from the group consisting of lower alkl, lower alkoxy, optionally substituted aryl, optionally substituted aryl-lower alky, optionally substituted aryl-lower alkoxy, halogen, haloalkyl, nitro, hydroxy, cyano, —C(O)R
7
, —(CH
2
)
n
CO
2
R
8
, and —(CH
2
)
n
CONR
7
R
8
;
R
7
is selected from the group consisting of hydrogen, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, heterocyclyl, and lower alkyl that optionally may be mono substituted by cycloalkyl, optionally substituted aryl or heterocyclyl;
R
8
is selected from the group consisting of hydrogen, cycloalkyl, heterocyclyl and lower alkyl that optionally may be mono substituted by cycloalkyl, optionally substituted aryl, hydroxy, lower alkoxy, optionally substituted heteroaryl, heterocyclyl or hydroxy-loweralkoxy, or, when
R
7
and R
8
are both attached to nitrogen, R
7
and R
8
together with the nitrogen atom to which they are attached represent a 5- or 6-membered heterocycle optionally containing an additional heteroatom selected from N, S and O and optionally being substituted by lower alkyl, lower alkoxy or hydroxy-lower alkyl;
n is 0-3;
R
2
is H;
R
3
is selected from the group consisting of hydrogen, —COR
4
, —CONR
4
R
5
, —CONHOR
6
, cyano, halogen, —CO
2
R
5
, —SO
2
NR
4
R
5
, —OR
4
, lower alkyl optionally substituted independently by cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, heterocyclyl, hydroxy, —CONR
4
R
5
, or —CO
2
R
5
, and lower alkenyl optionally substituted independently by cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, heterocyclyl, hydroxy, —CONR
4
R
5
or —CO
2
R
5
;
R
4
is selected from the group consisting of hydrogen, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, heterocyclyl, and lower alkyl that may be optionally mono substituted by cycloalkyl, optionally substituted aryl or heterocyclyl;
R
5
is selected from the group consisting of hydrogen, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, heterocyclyl, and lower alkyl optionally substituted independently by —CONH
2
, cycloalkyl, optionally substituted aryl, optionally substituted aryloxy, hydroxy, lower alkoxy, optionally substituted heteroaryl, heterocyclyl, hydroxy-loweralkoxy or —NR′R″ wherein R′ is hydrogen or lower alkyl optionally substituted by optionally substituted aryl and R″ is —COCH
3
, lower alkyl or optionally substituted aryl;
 or alternatively, when R
4
and R
5
are both attached to nitrogen, R
4
and R
5
together with the nitrogen atom to which they are attached represent a 5- or 6-membered heterocycle optionally containing an additional heteroatom selected from N, S and O and optionally being independently substituted at one or more carbon and/or N-atoms by lower alkyl, lower alkoxy or hydroxy-lower alkyl;
R
6
represents hydrogen or heterocyclyl.
The compounds of the present invention, depending on the nature of the substituents, may possess one or more asymmetric carbon atoms. The invention include all such forms (e.g., enantiomers, diastereoisomers) and to mixtures thereof, including enantiomeric mixtures (racemates), diastereoisomeric mixtures and mixtures of both such mixtures.
As used herein, the term “lower alkyl” means a saturated straight-chain or branched-chain hydrocarbon containing from 1 to 7, preferably from 1 to 4, carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.butyl, tert.butyl, n-pentyl, n-hexyl, n-heptyl and the like.
The term “lower alkoxy” means a lower alkyl group as defined earlier which is bonded via an oxygen atom, with examples of lower alkoxy groups being methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec.butoxy, tert-butoxy, n-pentoxy and the like.
The term “lower alkenyl” means a lower alkyl group as defined earlier which contains one double bond of either E or Z stereochemistries, for example ethenyl, prop-2-enyl, but-2-enyl, 2-ethenyl-butyl and the like.
The term “cycloalkyl” means a saturated cyclic hydrocarbon group of 3 to 8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
The term “benz-fused” means fused to a benzene ring or a substituted benzene ring.
The term “optionally substituted aryl” means a phenyl or an optionally partly saturated naphthyl group which is unsubstituted or optionally substituted with one or more, preferably one or two, substituents selected from halogen, lower alkoxy, haloalkyl, hydroxy, —COOR′ (wherein R′ is H, lower alkyl), nitro, amino, sulfamoyl, phenyl or lower alkyl optionally mono substituted by lower alkoxy or hydroxy, particularly by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, nitro, amino or sulfamoyl. The term “partly saturated naphthyl” means a naphthyl group, to which one or two H
2
molecules were added. An example of a partially saturated naphthyl group is 1,2,3,4-tetrahydro-1-naphthyl.
The term “aryloxy” means a group R
a
—O—, wherein R
a
is optionally substituted aryl as defined above.
The term “optionally substituted heteroaryl” means an aromatic group of 5- or 6 ring atoms containing one or more, preferably 1-4, hetero atoms independently selected from N, S and O, the remaining ring atoms being C, and which aromatic group is optionally fused with a benzene ring (i.e. “benz-fused”). The heteroaryl is optionally substituted independently at one or more, preferably one or two, ring atoms by halogen, lower alkyl optionally substituted by lower alkoxy or hydroxy, lower alkoxy, haloalkyl, hydroxy, —COOR′ (wherein R′ is H, lower alkyl), nitro, amino, sulfamoyl or optionally substituted aryl; particularly by halogen, lower alkyl, lower alkoxy, trifluoromethyl, hydroxy, nitro, amino or sulfamoyl. Examples of heteroaryl groups are pyrrolyl, pyrazolyl, thienyl, furanyl, pyridyl, pyrimidinyl, quinolyl, indolyl, benzofuranyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl and, if benz-fused, indolyl, benzofuranyl, or benzimidazolyl. Examples of substituted heteroaryl groups are 5-methyl-3H-imidazol-4-yl, 1-methyl-2-pyrrolyl, 3-methoxy-1H-pyrrol-2-yl, 3-phenyl-1H-p

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