Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-12-03
2002-08-13
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...
C514S470000, C549S055000, C549S466000
Reexamination Certificate
active
06433005
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to anti-inflammatory and analgesic compounds, especially to certain benzofuran and benzothiophene derivatives, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.
2. Background of the Invention
Non-steroidal anti-inflammatory drugs (NSAIDs), have a problem of causing serious side-effects such as gastrointestinal tract distress or nephro-toxicity. NSAIDs inhibit the activity of cyclooxygenase (COX), which is an enzyme involved in prostaglandin G/H synthesis, resulting in the inhibition of the biosynthesis of prostaglandins not only in inflammatory loci but also in stomach and kidney. It has been found that COX exists in two forms: COX-1 and COX-2
, Cell
, 83, 345, (1995).
COX-1 is expressed in normal cells and controls the function of stomach and kidney, while COX-2 is induced by mitogens or cytokines in inflammatory sites where inflammation and other immunoreactions occur,
J. Biol. Chem
., 271, 33157(1996).
To avoid the toxicity of NSAIDs due to the inhibition of coexisting COX-1, selective inhibitors of COX-2 have been investigated. The selective COX-2 inhibitors have anti-inflammatory action, pain-relieving action, and/or antipyretic action; with less side effects such as bleeding in the gastrointestinal tract. COX-2 inhibitors may show anticancer activity and lower the induction of asthma in asthmatic patients who are sensitive to conventional NSAIDs. These selective inhibitors of COX-2 may also be used in treating Alzheimer's disease and osteoporosis of women after menopause.
3. Description of Related Art
U.S. Pat. No. 3,331,854 (American Cyanamid) refers to certain novel furan and thiophene compounds.
U.S. Pat. No. 5,426,113 (Warner Lambert) refers to certain tetrazol-benzothiophene carboxamides in preventing ulcer formation.
U.S. Pat. No. 5,731,342 (Eli Lilly) refers to certain benzothiophenes, which are useful for the treatment of the medical indications associated with post-menopausal syndrome and breast cancer treatment and prevention.
U.S. Pat. Nos. 4,663,347; 4,745,127; 4,822,803; 4,933,351; and 4,621,091 (Merck) refer to certain benzofuran-2-carboxylic acid derivatives as 5-lipoxygenase inhibitors.
U.S. Pat. No.4,621,091 (Merck) refers to certain 3-hydroxybenzothiophene-2-sulfide derivatives as 5-lipoxygenase inhibitors.
DE Pat. No. 3,342,624 (Grote) refers to certain 3-hydroxybenzoyl-benzofuran derivatives.
PCT Published Application No. WO 95/02406 (Warner Lambert) refers to certain use of benzothiophene and benzofuran compounds for monitoring inflammation.
SUMMARY OF THE INVENTION
In a first aspect, this invention provides compounds selected from the group of compounds represented by Formula I:
wherein:
Y is O or S;
A is a —CH
2
—, —C(O)—, —O—, —S—, —S(O)—, or —S(O)
2
—;
Ar is an optionally substituted phenyl;
R
1
is hydrogen, alkyl, alkoxy, hydroxy, halo, cyano, —C(O)NR
4
R
5
, —COOR
4
, —NR
4
R
5
, wherein R
4
and R
5
are each independently in each occurrence hydrogen or alkyl;
R
2
is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, nitro, cyano, or —NR
4
R
5
, wherein R
4
and R
5
are as defined previously;
R
3
is —SR
6
, —SOR
6
, —SO
2
R
6
, or —SO
2
NR
4
R
5
wherein R
6
is alkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, or alkoxycarbonylalkyl; and R
4
and R
5
are as defined previously; or
prodrugs, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof.
In a second aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a third aspect, this invention provides a method of treatment of a disease, in particular an inflammatory and autoimmune disease, in a mammal treatable by administration of a prostaglandin G/H synthase inhibitor, comprising administration of a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt.
In a fourth aspect, this invention provides processes for preparing compounds of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
“Alkyl” means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, and the like.
“Alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
“Alkoxy”, “aryloxy”, “aralkyloxy”, or “heteroaralkyloxy” means a radical —OR where R is an alkyl, aryl, aralkyl, or heteroaralkyl respectively, as defined herein, e.g., methoxy, phenoxy, benzyloxy, pyridin-2-ylmethyloxy, and the like.
“Alkoxycarbonylalkyl” means a radical —R
a
C(O)R
b
where R
a
is an alkylene group as defined above and R
b
is an alkoxy group as defined above e.g., methoxycarbonylethyl, ethoxycarbonylbutyl, and the like.
“Aryl” means a monovalent monocyclic or bicyclic aromatic radical of 6 to 10 ring atoms which is substituted independently with one to five substituents, preferably one, two, or three substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, alkylamino, dialkylamino, haloalkyl, haloalkoxy, heteroalkyl, —COR (where R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), —(CR′R″)
n
—COOR (where n is an integer from 0 to 5, R′ and R″ are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl) or —(CR′R″)
n
—CONR
a
R
b
(where n is an integer from 0 to 5, R′ and R″ are independently hydrogen or alkyl, and R
a
and R
b
are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl). More specifically the term aryl includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and 2-naphthyl, and the derivatives thereof.
“Halogen” or “halo” means the radical fluoro, bromo, chloro, and/or iodo.
“Haloalkyl” means alkyl substituted with one or more same or different halo atoms, e.g., —CH
2
Cl, —CF
3
, —CH
2
CF
3
, —CH
2
CCl
3
, and the like, and further includes those alkyl groups such as perfluoroalkyl in which all hydrogen atoms are replaced by fluorine atoms.
“Hydroxyalkyl” means an alkyl radical as defined herein, substituted with one or more, preferably one, two or three hydroxy groups, provided that the same carbon atom does not carry more than one hydroxy group. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxymethyl-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-hydroxymethyl-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-hydroxymethyl-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl and 1-hydroxymethyl-2-hydroxyethyl. Accordingly, as used herein, the term “hydroxyalkyl” is used to define a subset of heteroalkyl groups.
“Optionally substituted phenyl” means a phenyl ring which is optionally substituted independently with one to four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, haloalkyl, haloalkoxy, heteroalkyl, —COR (where R is hydrogen, alkyl, phenyl or phenylalkyl, —(CR′R″)
n
—COOR (where n is an integer from 0 to 5, R″ and R′ are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl), or —(CR′R″)
n
-CONR
a
R
b
(where n is an integer from 0 to 5, R′ and R″ are independently hydrogen
McLaren Kevin L.
Smith David Bernard
Tracy Jahari Laurant
McKane Joseph K.
Pfister Gloria
Syntex (U.S.A.) LLC
Wright Sonya
LandOfFree
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