Sulfonyl pyridazinone compounds useful as aldose reductase...

Details Sulfonyl pyridazinone compounds useful as aldose reductase... Sulfonyl pyridazinone compounds useful as aldose reductase...

2002-02-26

2004-05-04

Shah, Mukund J. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S240000

Reexamination Certificate

active

06730674

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to novel sulfonyl pyridazinone compounds useful as aldose reductase inhibitors in the treatment or prevention of certain complications arising from diabetes mellitus, pharmaceutical compositions comprising the sulfonyl pyridazinone compounds, pharmaceutical compositions comprising a combination of the sulfonyl pyridazinone compounds together with a second pharmaceutical agent, therapeutic methods comprising the administration of the sulfonyl pyridazinone compounds to a mammal and therapeutic methods comprising the administration of the sulfonyl pyridazinone compounds in combination with a second pharmaceutical agent to a mammal. The invention also relates to novel compounds useful as intermediates for preparing the sulfonyl pyridazinone compounds of this invention.
BACKGROUND OF THE INVENTION
The enzyme aldose reductase is involved in regulating the reduction of aldoses, such as glucose and galactose, to their corresponding polyols, such as sorbitol and galactitol. Sulfonyl pyridazinone compounds of formula I of this invention are useful as aldose reductase inhibitors in the treatment and prevention of diabetic complications of humans and other mammals associated with increased polyol levels in certain tissues (e.g., nerve, kidney, lens and retina tissue) of affected humans and other mammals.
French Patent Publication No. 2647676 discloses pyridazinone derivatives having substituted benzyl side chains and benzothiazole side chains as being inhibitors of aldose reductase.
U.S. Pat. No. 4,251,528 discloses various aromatic carbocyclic oxophthalazinyl acetic acid compounds, as possessing aldose reductase inhibitory properties.
Commonly assigned U.S. Pat. No. 4,939,140 discloses heterocyclic oxophthalazinyl acetic acid compounds.
Commonly assigned U.S. Pat. No. 4,996,204 discloses pyridopyridazinone acetic acid compounds useful as aldose reductase inhibitors.
U.S. Pat. No. 6,218,409 discloses pharmaceutical compositions comprising an insulin sensitivity enhancer in combination with one or more anti-diabetics, including aldose reductase inhibitors.
SUMMARY OF THE INVENTION
One aspect of this invention is compounds of formula I
prodrugs thereof or pharmaceutically acceptable salts of said compounds or said prodrugs,
wherein,
R
1
and R
2
are independently hydrogen or methyl,
X is a covalent bond, NR
3
or CHR
4
, wherein,
R
3
is (C
1
-C
3
)alkyl or a phenyl that is optionally substituted with one or more substituents selected from OH, F, Cl, Br, I, CN, CF
3
, (C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkyl, S(O)
n
—(C
1
-C
6
)alkyl and SO
2
—NR
6
R
7
, and R
4
is hydrogen or methyl, and
Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, I, CN, CF
3
, (C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkyl, S(O)
n
—(C
1
-C
6
)alkyl and SO
2
—NR
6
R
7
, or
X and Y together are CH
2
—CH(OH)—Ar or CH
2
—C(O)—Ar,
wherein,
Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF
3
, (C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkyl, S(O)
n
—(C
1
-C
6
)alkyl and SO
2
—NR
6
R
7
,
n is independently for each occurrence 0, 1 or 2,
R
6
is independently for each occurrence H, (C
1
-C
6
)alkyl, phenyl or naphthyl, and
R
7
is independently for each occurrence (C
1
-C
6
)alkyl, phenyl or naphthyl,
with provisos that:
when X is a covalent bond, R
1
is hydrogen and R
2
is hydrogen, then Y is not an unsubstituted phenyl ring and Y is not a phenyl ring that is mono-substituted at the 4 position with methyl; and
when X is CHR
4
, R
4
is H, R
1
is hydrogen and R
2
is hydrogen, then Y is not an unsubstituted phenyl ring.
Another aspect of this invention is pharmaceutical compositions comprising a compound of formula I
wherein,
R
1
and R
2
are independently hydrogen or methyl,
X is a covalent bond, NR
3
or CHR
4
, wherein,
R
3
is (C
1
-C
3
)alkyl or a phenyl that is optionally substituted with one or more substituents selected from OH, F, Cl, Br, I, CN, CF
3
, (C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkyl, S(O)
n
—(C
1
-C
6
)alkyl and SO
2
—NR
6
R
7
, and R
4
is hydrogen or methyl, and
Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, I, CN, CF
3
, (C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkyl, S(O)
n
—(C
1
-C
6
)alkyl and SO
2
—NR
6
R
7
, or
X and Y together are CH
2
—CH(OH)—Ar or CH
2
—C(O)—Ar,
wherein,
Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF
3
, (C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkyl, S(O)
n
—(C
1
-C
6
)alkyl and SO
2
—NR
6
R
7
,
n is independently for each occurrence 0, 1 or 2,
R
6
is independently for each occurrence H, (C
1
-C
6
)alkyl, phenyl or naphthyl, and
R
7
is independently for each occurrence (C
1
-C
6
)alkyl, phenyl or naphthyl, a prodrug of said compound and pharmaceutically acceptable salt of said compound or said prodrug, and a pharmaceutically acceptable vehicle, diluent or carrier.
An additional aspect of this invention is pharmaceutical compositions comprising a first compound of formula I
wherein,
R
1
and R
2
are independently hydrogen or methyl,
X is a covalent bond, NR
3
or CHR
4
, wherein,
R
3
is (C
1
-C
3
)alkyl or a phenyl that is optionally substituted with one or more substituents selected from OH, F, Cl, Br, I, CN, CF
3
, (C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkyl, S(O)
n
—(C
1
-C
6
)alkyl and SO
2
—NR
6
R
7
, and R
4
is hydrogen or methyl, and
Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, I, CN, CF
3
, (C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkyl, S(O)
n
—(C
1
-C
6
)alkyl and SO
2
—NR
6
R
7
, or
X and Y together are CH
2
—CH(OH)—Ar or CH
2
—C(O)—Ar,
wherein,
Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, CF
3
, (C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkyl, S(O)
n
—(C
1
-C
6
)alkyl and SO
2
—NR
6
R
7
,
n is independently for each occurrence 0, 1 or 2,
R
6
is independently for each occurrence H, (C
1
-C
6
)alkyl, phenyl or naphthyl, and
R
7
is independently for each occurrence (C
1
-C
6
)alkyl, phenyl or naphthyl,
a prodrug of said first compound and a pharmaceutically acceptable salt of said first compound or said prodrug,
and a second compound selected from:
a sorbitol dehydrogenase inhibitor;
a selective serotonin reuptake inhibitor;
a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor;
an angiotensin converting enzyme inhibitor;
a glycogen phosphorylase inhibitor;
an angiotensin II receptor antagonist;
a &ggr;-aminobutyric acid (GABA) agonist;
a phosphodiesterase type 5 inhibitor,
a prodrug of said second compound and a pharmaceutically acceptable salt of said second compound or said prodrug.
A further aspect of this invention is kits comprising:
a first dosage form comprising a compound of formula I
wherein,
R
1
and R
2
are independently hydrogen or methyl,
X is a covalent bond, NR
3
or CHR
4
, wherein,
R
3
is (C
1
-C
3
)alkyl or a phenyl that is optionally substituted with one or more substituents selected from OH, F, Cl, Br, 1, CN, CF
3
, (C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkyl, S(O)
n
—(C
1
-C
6
)alkyl and SO
2
—NR
6
R
7
, and R
4
is hydrogen or methyl, and
Y is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from Ar, OH, F, Cl, Br, 1, CN, CF
3
, (C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkyl, S(O)
n
—(C
1
-C
6
)alkyl and SO
2
—NR
6
R
7
, or
X and Y together are CH
2
—CH(OH)—Ar or CH
2
—C(O)—Ar,
wherein,
Ar is a phenyl or naphthyl ring optionally substituted with one or more substituents selected from F, Cl, Br, 1, CN, CF
3
, (C
1
-C
6
)alkyl, O—(C
1
-C
6
)alkyl, S(O)
n
—(C
1
-C
6
)alkyl and SO
2
—NR
6
R
7
,
n is independently for each occurrence 0, 1 or 2,
R
6
is independently for each occurrence H, (C
1
-C
6
)alkyl, phenyl or naphthyl, and
R
7
is independently for each occurrence (C
1
-C
6
)alkyl, phenyl or naphthyl,
a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug;
a second dosage form c

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