Pyridazinone aldose reductase inhibitors

Details Pyridazinone aldose reductase inhibitors Pyridazinone aldose reductase inhibitors

2002-03-21

2003-06-17

Bernhardt, Emily (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C544S238000, C544S235000, C544S236000, C544S237000, C514S248000, C514S252020, C514S252030, C514S252040, C514S252050, C514S252060

Reexamination Certificate

active

06579879

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel sulfonyl pyridazinone compounds, pharmaceutical compositions comprising those compounds and to methods of using such compounds and compositions to inhibit aldose reductase, lower sorbitol levels and, thus, lower fructose levels, and/or treat or prevent diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. This invention also relates to pharmaceutical compositions and kits comprising a combination of an aldose reductase inhibitor (ARI) of Formula I herein and a sorbitol dehydrogenase inhibitor and to methods of using such compositions or kits to treat or prevent the above diabetic complications in mammals. This invention also relates to other combinations with the ARIs of Formula I, including combinations with NHE-1 inhibitors; adenosine agonists; glycogen phosphorylase inhibitors (GPIs); selective serotonin reuptake inhibitors (SSRIs); &ggr;-amino-butyric acid (GABA) agonists; antihypertensive agents; 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (vastatins); phosphodiesterase-5 (PDE5) inhibitors; and to glucose lowering compounds. This invention also relates to pharmaceutical compositions and kits comprising such combinations and to methods of using such compositions and kits to treat or prevent the aforesaid diabetic complications. This invention also relates to novel compounds that are 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, prodrugs of such compounds and pharmaceutically acceptable salts of such compounds and prodrugs, 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 described as being inhibitors of aldose reductase.
U.S. Pat. No. 4,251,528 discloses various aromatic carbocyclic oxophthalazinyl acetic acid compounds, which are described as possessing aldose reductase inhibitory properties.
Commonly assigned U.S. Pat. No. 4,939,140 discloses heterocyclic oxophthalazinyl acetic acid compounds useful as aldose reductast inhibitors.
Commonly assigned U.S. Pat. No. 4,996,204 discloses pyridopyridazinone acetic acid compounds useful as aldose reductase inhibitors.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of Formula I,
prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein:
A is S, SO or SO
2
;
R
1
and R
2
are each independently hydrogen or methyl;
R
3
is Het
1
, —CHR
4
Het
1
or NR
6
R
7
;
R
4
is hydrogen or (C
1
-C
3
)alkyl;
R
6
is (C
1
-C
6
)aikyl, aryl or Het
2
;
R
7
is Het
3
;
Het
1
is pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolinyl, naphthyridinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyl, pyrimidopyrimidyl, pyridopyrimidyl, pyridopyrazinyl, pyridopyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyc, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyc, benzothiazolyl, indazolyg, benzisoxazolyl, benzisothiazolyi, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazolopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl, thienopyrimidyl, imidazolopyrimidyl, oxazolopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyrrolopyridazinyl, furopyridazinyl, thienopyridazinyl, imidazolopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or isothiazolopyridazinyl; Het
1
is optionally substituted with up to a total of four substituents each independently selected from halo, formyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylenyloxycarbonyl, (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl, C(OH) R
2
R
1
3, (C
1
-C
4
)alkylcarbonylamido, (C
3
-C
7
)cycloalkylcarbonylamido, phenylcarbonylamido, benzyl, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, (C
1
-C
4
)alkylsulfenyl, (C
1
-C
4
)alkylsulfonyl, (C
3
-C
7
)cycloalkyl, (C
1
-C
6
)alkyl optionally substituted with up to three fluoro, or (C
1
-C
4
)alkoxy optionally substituted with up to five fluoro; said benzyl, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, in the definition of substituents for Het
1
are optionally substituted with up to three substituents independently selected from hydroxy, halo, hydroxy-(C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl, (C
1
-C
6
)alkylsulfenyl, (C
1
-C
6
)alkylsulfinyl, (C
1
-C
6
)alkylsulfonyl, (C
1
-C
6
)alkyl optionally substituted with up to five fluoro and (C
1
-C
6
)alkoxy optionally substituted with up to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of substituents for Het
1
are optionally substituted with up to two substituents independently selected from hydroxy, halo, C
1
-C
6
)alkyl, hydroxy-(C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl, C
1
-C
4
)alkyl-phenyl optionally substituted in the phenyl portion with one Cl, Br, OMe, Me or SO
2
-phenyl wherein said SO
2
-phenyl is optionally substituted in the phenyl portion with one Cl, Br, OMe, Me, (C
1
-C
4
)alkyl optionally substituted with up to five fluoro, or (C
1
-C
4
)alkoxy optionally substituted with up to three fluoro;
R
12
and R
13
are each independently hydrogen or (C
1
-C
4
)alkyl;
Het
2
and Het
3
are each independently imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy; Het
2
and Het
3
are each independently optionally substituted with up to a total of four substituents each independently selected from halo, formyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylenyloxycarbonyl, (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl, C(OH)R
18
R
19
, (C
1
-C
4
)alkylcarbonylamido, (C
3
-C
7
)cycloalkylcarbonylamido, phenylcarbonylamido, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, (C
1
-C
4
)alkylsulfenyl, (C
1
-C
4
)alkylsulfonyl, (C
3
-C
7
)cycloalkyl, (C
1
-C
4
)alkyl optionally substituted with up to three fluoro or (C
1
-C
4
)alkoxy optionally substituted with up to five fluoro; said phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrol

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