Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-20
2002-12-10
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...
C548S530000, C548S531000, C548S542000, C548S560000
Reexamination Certificate
active
06492413
ABSTRACT:
This invention is in the field of antiinflammatory pharmaceutical agents and relates to compounds, compositions and methods for treating inflammation and inflammation-associated disorders, such as arthritis. This invention specifically relates to 3,4-diaryl substituted thiophene, furan and pyrrole derivatives and analogs thereof. More particularly, this invention relates to selected effective and safe compounds having antiinflammatory and/or analgesic activity without erosion of the stomach.
BACKGROUND OF THE INVENTION
Prostaglandins play a major role in the inflammation process, and the inhibition of prostaglandin production, especially production of PGG
2
, PGH
2
and PGE
2
, has been a common target of antiinflammatory drug discovery. However, common non-steroidal antiinflammatory drugs (NSAIDs) that are active in reducing the prostaglandin-induced pain and swelling associated with the inflammation process, are also active in affecting other prostaglandin-regulated processes not associated with the inflammation process. Thus, use of high doses of most common NSAIDs can produce severe side effects, including life-threatening ulcers, that limit their therapeutic potential. An alternative to NSAIDs is the use of corticosteroids, which have even more drastic side effects, especially when long-term therapy is involved.
Previous NSAIDs have been found to prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including the enzyme cyclooxygenase (COX). Recently, the sequence of another heretofore unknown enzyme in the human arachidonic acid/prostaglandin pathway has been reported by T. Hla and K. Nielson,
Proc. Natl. Acad. Sci. USA,
89, 7384 (1992) and named “cyclooxygenase II (COX II)” or “prostaglandin G/H synthase II”. The discovery of an inducible enzyme associated with inflammation provides a viable target of inhibition which more effectively reduces inflammation and produces fewer and less drastic side effects. Cyclooxygenase II is inducible by cytokines or endotoxins and such induction is inhibited by glucocortoids (J. Masferrer, et al,
Proc. Natl. Acad. Sci. USA,
89, 3917 (1992)). The 6-methoxy-2-napthylacetic acid metabolite of nabumetone has been found by E. Meade et al to selectively inhibit the COX II enzyme (
J. Biol. Chem.,
268, 6610 (1993)). In addition, Futaki et al (
Gen. Pharmac.,
24, 105 (1993)) has reported that N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide is antiinflammatory and lacks gastric side effects.
The substituted thiophene compounds disclosed herein selectively inhibit cyclooxygenase II over cyclooxygenase I and relieve the effects of inflammation. These compounds, in addition, do not display substantial inhibition of cyclooxygenase I and produce a reduced amount of side effects.
Selected symmetrical 3,4-bis(phenyl, naphthyl or substituted phenyl) thiophenes are known.
Preparation of a wide-variety of asymmetric biaryl compounds including substituted thiophene, furan and pyrrol heterocyles is described in U.S. Pat. No. 4,990,647 having a suggested utility as precursors for brighteners, pharmaceuticals, plant protection active compounds and liquid crystal materials.
U.S. Pat. No. 4,757,084 describes to Biftu analogs of 2,5-diaryl tetrahydrothiophenes having activity as PAF-antagonists which are said to be linked to physiological processes associated with a large group of diseases including inflammatory disease.
U.S. Pat. No. 5,196,532 to Wuest et al, describes 2,4-diaryl substituted thiophenes for cosmetics and the treatment of dermatological disorders.
U.S. Pat. No. 4,427,693 to Haber, describes antiinflammatory 4,5-diarylthiophene-2-methanamines. U.S. Pat. No. 4,432,974 to Haber, describes antiinflammatory and analgesic 2,3-diaryl-5-silylthiophenes. U.S. Pat. No. 4,302,461 to Cherkofsky, describes antiinflammatory 2,3-diarylthiophenes substituted with various alkyl sulfur radicals at position 5. U.S. Pat. No. 4,381,311 to Haber, describes antiinflammatory 4,5-diarylthiophene-2-methanols.
2,3-Diaryl-5-halo thiophenes are described in U.S. Pat. No. 4,590,205 to Haber, as analgesic or antiinflammatory agents. 4-Fluorophenyl and 4-methylsulfonylphenyl are among the various substituted phenyl groups that define the diaryl groups. U.S. Pat. No. 4,820,827 to Haber, describes 2,3-diaryl-5-bromo thiophenes, and specifically 5-bromo-2-(4-methylthiophenyl)-3-(4-fluorophenyl)thiophene, as having antiinflammatory and prostaglandin synthetase inhibitory activity for use in the treatment of inflammation and dysmenorrhea.
Japanese publication 4,335,767 describes photosensitive 3,4-bis(diazosubstitutedphenyl)thiophene pigments for use in photocopiers or facsimile receivers.
U.S. Pat. No. 3,743,656 to Brown et al, a CIP of U.S. Pat. No. 3,644,399, describes thiophene and furan derivatives having antiinflammatory activity, including ethyl 3,4-diphenylthiophene-2-propionate.
The above documents describing antiinflammatory activity show continuing efforts to find a safe and effective antiinflammatory agent.
DESCRIPTION OF THE INVENTION
A class of compounds useful in treating inflammation-related disorders is defined by Formula I:
wherein Y is selected from S, O, and NR
1
;
wherein R
1
is selected from hydrido and C
1
-C
6
alkyl;
wherein X is one or more substituents selected from
a) hydrido, halo, cyano, nitro, hydroxy, acyl, lower alkyl substituted at a substitutable position with a substituent selected from halo, hydroxyl, amino, acylamino, lower alkylamino, lower alkyl(acyl)amino, acyl, aryl optionally substituted with hydroxyl, a heterocyclic group, hydroxyimino and lower alkoxyimino, lower alkenyl optionally substituted at a substitutable position with cyano, amino optionally substituted at a substitutable position with a radical selected from acyl and lower alkylsulfonyl, sulfo, sulfamoyl optionally substituted with a substituent selected from the group consisting of lower alkyl, halo(lower)alkyl, aryl, hydroxyl, lower alkylamino(lower)alkyl, a heterocyclic group and (esterified carboxy)lower alkyl, N-containing heterocyclicsulfonyl, a heterocyclic group optionally substituted at a substitutable position with a substituent selected from the group consisting of hydroxyl, oxo, amino and lower alkylamino,
b) S(O)
n
R
5
, wherein R
5
is C
1
-C
6
alkyl optionally substituted at a substitutable position with fluoro, and n is 0, 1 or 2,
c) C(R
6
)(OR
8
)(R
7
) wherein R
6
and R
7
independently are selected from CF
3
, CF
2
H, CFCl
2
, CF
2
Cl, CClFH, CCl
2
F, CF
3
CF
2
and C
1
-C
2
alkyl, and wherein R
8
is selected from hydrido, C
1
-C
4
alkyl, (C
1
-C
3
alkyl)C(O) and CO
2
R
9
, wherein R
9
is C
1
-C
4
alkyl,
d) C(O)ZR
4
, wherein Z is O, N, or S, and R
4
is selected from hydrido, C
1
-C
6
alkyl and aryl, and when Z is N then R
4
is independently taken twice,
e) C(R
9
)(NHR
11
)(R
10
), wherein R
9
and R
10
are independently selected from CF
3
, CF
2
H, CFCl
2
, CF
2
Cl, CClFH and CCl
2
H, and R
11
is selected from hydrido and C
1
-C
3
alkyl, and
wherein R
2
and R
3
are independently selected from aryl or heteroaryl, wherein the aryl or heteroaryl radical is optionally substituted at a substitutable position with a radical selected from halo, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro, amide, amino, lower alkylamino, sulfamyl and lower alkylsulfonylamino;
provided that at least one of R
2
or R
3
is substituted with lower alkylsulfonyl or sulfamyl;
or a pharmaceutically-acceptable salt thereof.
Compounds of Formula I would be useful for the treatment of inflammation in a subject, and for treatment of other inflammation-associated disorders, for example, as an analgesic in the treatment of pain and headaches, or as an antipyretic for the treatment of fever. For example, compounds of Formula I would be useful to treat arthritis, including but not limited to rheumatoid arthritis, spondyloarthopathies, gouty arthritis, systemic lupus erythematosus, osteoarthritis and juvenile arthritis. Such compounds of Formula I would be useful
Bertenshaw Stephen R
Collins Paul W
Penning Thomas D.
Reitz David B.
Rogers Roland S
Desai Rita
G.D. Searle & Co.
Rotman Alan L.
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