Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1995-06-07
2001-01-16
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S235200, C514S252010, C514S255030, C514S256000, C514S323000, C514S339000, C514S361000, C514S363000, C514S365000, C514S372000, C514S374000, C514S378000, C514S381000, C514S383000, C514S385000, C514S396000, C514S403000, C514S418000, C544S062000, C544S153000, C544S238000, C544S333000, C544S336000, C544S366000, C544S367000, C544S369000, C544S370000, C544S371000, C544S373000, C546S201000, C546S273100, C548S136000, C548S143000, C548S181000, C548S235000, C548S253000, C548S266200, C548S312100, C548S335100, C548S
Reexamination Certificate
active
06174883
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel 3-substituted-2-oxindole derivatives which are inhibitors of prostaglandin H
2
synthase, 5-lipoxygenase and interleukin-1 biosynthesis. The compounds of the invention are useful as inhibitors of prostaglandin H
2
synthase and interleukin-1 biosynthesis, per se, and as analgesic, antiinflammatory and antiarthritic agents in the treatment of chronic inflammatory diseases. This invention also relates to pharmaceutical compositions comprising said 3-substituted-2-oxindole derivatives; to methods of inhibiting prostaglandin H
2
synthase and biosynthesis of interleukin-1; and to treating chronic inflammatory diseases in a mammal with said compounds. Further, this invention relates to certain novel carboxylic acids useful as intermediates in the preparation of the 3-substituted-2-oxindole derivatives of this invention and to a process for the preparation of the 3-substituted-2-oxindole derivatives.
BACKGROUND ART
U.S. Pat. No. 4,569,942 discloses certain 2-oxindole-1-carboxamides of the formula
wherein, inter alia, X is H, fluoro, chloro, bromo, (C
1
-C
4
)alkyl, (C
3
-C
7
)cycloalkyl, (C
1
-C
4
)alkoxy, (C
1
-C
4
)alkylthio, trifluoromethyl, (C
1
-C
4
)alkylsulfinyl, (C
1
-C
4
)alkylsulfonyl, nitro, phenyl, (C
2
-C
4
)-alkanoyl, benzoyl, thenoyl, (C
1
-C
4
)alkanamido, benzamido or N,N-dialkylsulfamoyl having 1 to 3 carbons in each of said alkyls; Y is, H, fluoro, chloro, bromo, (C
1
-C
4
)alkyl, (C
3
-C
7
)cycloalkyl, (C
1
-C
4
) alkoxy, (C
1
-C
4
)alkylthio and trifluoromethyl; R
1
is (C
1
-C
6
)-alkyl, (C
3
-C
7
)cycloalkyl, (C
4
-C
7
)cycloalkenyl, phenyl, substituted phenyl, phenylalkyl having 1 to 3 carbons in said alkyl, (substituted phenyl)alkyl having 1 to 3 carbons in said alkyl, (substituted phenoxy)alkyl having 1 to 3 carbons in said alkyl, (thiophenoxy)alkyl having 1 to 3 carbons in said alkyl, naphthyl, bicyclo-[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl or —(CH
2
)
n
—Q—R
0
; n is zero, 1 or 2; Q is a divalent radical derived from furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, 1,2,3-thiadiazole, 1,3,4-thiadiazole, 1,2,5-thiadiazole, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran, pyridine, pyrimidine, pyrazine, benzofblfuran and benzo[b]-thiophene; R
0
is H or (C
1
-C
3
)alkyl; and R
2
is (C
1
-C
6
)alkyl, (C
3
-C
7
)cycloalkyl, benzyl, furyl, thienyl, pyridyl or
where R
3
and R
4
are each H, fluoro, chloro, (C
1
-C
4
)-alkyl, (C
1
-C
4
)alkoxy or trifluoromethyl.
That patent also discloses that said 2-oxindole-1-carboxamides are inhibitors of cyclooxygenase and lipoxygenase, possess analgesic activity in mammals and are useful in treatment of pain and alleviation of symptoms of chronic diseases such as inflammation and pain associated with rheumatoid arthritis and osteoarthritis.
U.S. Pat. No. 4,556,672 discloses certain 3-acyl substituted-2-oxindole-1-carboxamides of the formula
wherein X, Y and R
1
are as described above for the compounds of U.S. Pat. No. 4,569,942. The compounds of U.S. Pat. No. 4,556,672 are disclosed as having the same activity as the compounds of U.S. Pat. No. 4,569,942 discussed above.
U.S. Pat. No. 4,861,794 discloses the use of compounds of the formula
and the pharmaceutically-acceptable base salts thereof wherein X is H, Cl or F, Y is H or Cl and R is benzyl or thienyl to inhibit biosynthesis of interleukin-1 (IL-1) and to treat IL-1 mediated disorders and dysfunctions.
PCT patent application Ser. No. PCT/US88/03658, filed Oct. 18, 1988, describes non-steroidal antiinflammatory agents of the formula
wherein each of X and Y is hydrogen, fluoro or chloro; R
1
is 2-thienyl or benzyl; and R is alkanoyl, cycloalkylcarbonyl, phenylalkanoyl, benzoyl and certain substituted benzoyl groups, thenoyl, omega-alkoxycarbonylalkanoyl, alkoxycarbonyl, phenoxycarbonyl, 1-alkoxycarbonyloxy, alkylsulfonyl, methylphenylsulfonyl and dialkyl phosphonate.
Interleukin-1 (IL-1) has been reported to stimulate bone resorption both in vitro and in vivo. Hayward, M. and Fiedler-Nagy, Ch., Agents and Actions, 22, 251-254 (1987). It is also reported therein that IL-1, inter alia, induces the production of prostaglandin E
2
(PGE
2
). PGE
2
is a stimulator of bone resorption and has been implicated in bone loss. See Hayward, M. A. and Caggiano, T. J., Annual Reports in Medicinal Chemistry, 22, Sect. IV, Chapter 17, 169-178 (1987). Osteoporosis is defined as a debilitory loss of bone mineral which results in higher fracture rates. See Hayward, M. A. and Caggiano, T. J., supra, and references cited therein.
Interleukin-1 has been reported to be involved in the pathogenesis of many diseases. See Dinarello, C. A., J. Clin. Immunol., 5, 287-297 (1985), the teachings of which are incorporated herein by reference. Further still, elevated levels of IL-1 like material have been found to be associated with psoriasis. Camp, R. D., et al., J. Immunol., 137, 3469-3474 (1986).
DISCLOSURE OF THE INVENTION
The present invention provides novel 3-substituted-2-oxindole compounds of the formula
and the pharmaceutically-acceptable salts thereof, wherein
X is H, F, Cl, Br, (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, NO
2
, CF
3
, CN, SH, S(O)
m
R
3
, OR
4
, COR
4
or CONR
4
R
5
;
Y is H, F, Cl, Br, (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, NO
2
, CF
3
, CN, SH, S(O)
q
R
17
, COR
18
OR
18
or CONR
18
R
19
;
R
1
is H, alkanoyl of two to ten carbon atoms, cycloalkylcarbonyl of five to seven carbon atoms, phenylalkanoyl of seven to ten carbon atoms, chlorobenzoyl, methoxybenzoyl, thenoyl, omega-alkoxycarbonylalkanoyl, said alkoxy having one to three carbon atoms and said alkanoyl having three to five carbon atoms, alkoxy carbonyl of two to ten carbon atoms, phenoxycarbonyl, 1-(acyloxv)alkyl wherein acyl has one to four carbon atoms and said alkyl has two to four carbon atoms, 1-(alkoxycarbonyloxy)alkyl wherein said alkoxy has two to five carbon atoms and said alkyl has one to four carbon atoms, alkyl of one to three carbon atoms, alkylsulfonyl of one to three carbon atoms, methylphenylsulfonyl or dialkylphosphonate wherein each of said alkyl is one to three carbon atoms;
R
2
is COR
6
, CONR
7
R
8
, (C
1
-C
6
)alkyl, (C
3
-C
8
)cycloalkyl, phenyl or mono- or disubstituted phenyl wherein the substituent or substituents are each Cl, F, Br, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy or CF
3
;
Q is
or
Q
2
-A
1
;
A is H, F, Cl, Br, I, CF
3
, OR
9
, S(O)
p
R
10
, COOR
11
, CONR
9
R
11
, CN, NO
2
, COR
10
, CH
2
OR
11
, OCOR
10
, NR
9
R
11
, N(R
9
)COR
11
, SO
2
NR
9
R
11
,
B is H, F, Cl, Br, I, CF
3
, OR
13
, S(O)
t
R
14
, COOR
15
, CONR
13
R
15
, CN, NO
2
, COR
14
, CH
2
OR
15
, OCOR
14
, NR
13
R
15
, N(R
13
)COR
15
or SO
2
NR
13
R
15
;
provided that A and B cannot both be H; or A and B are taken together, bonded to the same ring carbon of Q
1
and equal oxo, or when A is not H, B is as defined above or (C
1
-C
4
)alkyl;
A
1
is F, Cl, Br, I, CF
3
, OR
9
, S(O)
p
R
10
, COOR
11
, CONR
9
R
11
, CN, NO
2
, COR
10
, CH
2
OR
11
, OCOR
10
, NR
9
R
11
, N(R
9
)COR
11
or SO
2
NR
9
R
11
;
m, n, p, q and t are each zero, one or two;
W and Z are each O, S or NR
11
;
W
1
and W
2
are each O, S or NR
10
provided that when one of W
1
or W
2
is O, S or NR
10
, the other is O or S;
R
3
, R
6
, R
10
, R
14
and R
17
are each (C
1
-C
6
)alkyl or phenyl; R
5
, R
8
, R
11
, R
15
and R
19
are each H, (C
1
-C
6
)alkyl or phenyl; R
4
, R
7
, R
9
, R
13
and R
18
are each H or (C
1
-C
6
)alkyl; and R
12
is H, F, Cl, Br, CF
3
or (C
1
-C
6
)alkyl.
While the compounds of formula I, above, are shown as enols, enol ethers and esters, it is to be understood that when R
1
is H the compounds of formula I can assume their tautomeric form of a ketone. That is,
All such tautomeric forms are within the scope of this invention and the appendant claims, and are deemed to be depicted by formula I. Further, the substituents on the exocyclic double bond at the 3-position of the compounds for formula I can be syn, anti or a mixture of both. Thus,
Ehrgott Frederick J.
Goddard Carl J.
Schulte Gary R.
Benson Gregg C.
Ford John M.
McKenzie Thomas
Peter C. Richardson
Pfizer Inc.
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