Sorbitol dehydrogenase inhibitors

Details Sorbitol dehydrogenase inhibitors Sorbitol dehydrogenase inhibitors

2002-02-28

2003-08-05

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S252130, C514S252160, C514S256000, C514S275000, C514S300000, C544S242000, C544S330000, C544S295000, C544S345000, C544S358000, C544S405000

Reexamination Certificate

active

06602875

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention relates to novel pyrimidine derivatives and to the use of such derivatives and related compounds to inhibit sorbitol dehydrogenase (SDH), lower fructose levels, 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 containing such pyrimidine derivatives and related compounds. This invention also relates to pharmaceutical compositions comprising a combination of a sorbitol dehydrogenase inhibitor of formula I and an aldose reductase inhibitor and to the use of such compositions to treat or prevent diabetic complications in mammals. This invention also relates to pharmaceutical compositions comprising a combination of a sorbitol dehydrogenase inhibitor of formula I and an NHE-1 inhibitor and to the use of such compositions to reduce tissue damage resulting from ischemia, and particularly to prevent perioperative myocardial ischemic injury.
S. Ao et al.,
Metabolism
, 40, 77-87 (1991) have shown that significant functional improvement in the nerves of diabetic rats (based on nerve conduction velocity) occurs when nerve fructose levels are pharmacologically lowered, and that such improvement correlates more closely with the lowering of nerve fructose than the lowering of nerve sorbitol. Similar results were reported by N. E. Cameron and M. A. Cotter,
Diabetic Medicine
, 8, Suppl. 1, 35A-36A (1991). In both of these cases, lowering of nerve fructose was achieved using relatively high does of aldose reductase inhibitors, which inhibit the formation of sorbitol, a precursor of fructose, from glucose via the enzyme aldose reductase.
U.S. Pat. Nos. 5,138,058 and 5,215,990, which are hereby incorporated by reference, each disclose compounds of the formula
where R
1
, R
2
, R
3
, R
4
and R
5
are as disclosed therein. Said compounds are disclosed as having utility as tools in screening for aldose reductase inhibitors due to the sorbitol accumulating activity of said compounds.
Commonly assigned U.S. Pat. Nos. 5,728,704 and 5,866,578, which are hereby incorporated by reference, each disclose compounds of the formula A,
wherein R
1
through R
5
are defined as disclosed therein. Further, U.S. Pat. No. 5,728,704 discloses that sorbitol dehydrogenase compounds have utility in the treatment of diabetic complications.
Pyrimidine derivatives of the formula I, as defined below, and their pharmaceutically acceptable salts, lower fructose levels in the tissues of mammals affected by diabetes (e.g., nerve, kidney and retina tissue) and are useful in the treatment and prevention of the diabetic complications referred to above. These compounds, or their metabolites in vivo, are inhibitors of the enzyme sorbitol dehydrogenase, which catalyzes the oxidation of sorbitol to fructose.
SUMMARY OF THE INVENTION
The present invention is directed to a compound of the formula I
a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
R
1
is formyl, acetyl, propionyl, carbamoyl or —C(OH)R
4
R
5
;
R
4
and R
5
are each independently hydrogen, methyl, ethyl or hydroxy-(C
1
-C
3
)alkyl;
R
2
is hydrogen, (C
1
-C
4
)alkyl or (C
1
-C
4
)alkoxy;
R
3
is a radical of the formula
 wherein said radical of formula R
3a
is additionally substituted on the ring by R
6
, R
7
and R
8
;
said radical of formula R
3b
is additionally substituted on the ring by R
18
, R
19
and R
20
; G, G
1
and G
2
are taken separately and are each hydrogen and R
6
is hydrogen, (C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxycarbonyl, (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl, hydroxy-(C
1
-C
4
)alkyl or phenyl optionally independently substituted with up to three hydroxy, halo, hydroxy-(C
1
-C
4
)alkyl, (C
1
-C
4
)alkoxy-(C
1
-C
4
)alkyl, (C
1
-C
4
)alkyl or (C
1
-C
4
)alkoxy, wherein said (C
1
-C
4
)alkyl in the-definition of R
6
and said (C
1
-C
4
)alkoxy in the definition of R
6
are optionally and independently substituted with up to five fluoro; R
7
and R
8
are each independently hydrogen or (C
1
-C
4
)alkyl; or
G and G
1
are taken together and are (C
1
-C
3
)alkylene and R
6
, R
7
, R
8
and G
2
are hydrogen; or
G
1
and G
2
are taken together and are (C
1
-C
3
)alkylene and R
6
, R
7
, R
8
and G are hydrogen;
q is 0 or 1;
X is a covalent bond, —(C═NR
10
)—, oxycarbonyl, vinylenylcarbonyl, oxy(C
1
-C
4
)alkylenylcarbonyl, (C
1
-C
4
)alkylenylcarbonyl, (C
3
-C
4
)alkenylcarbonyl, thio(C
1
-C
4
)alkylenylcarbonyl, vinylenylsulfonyl, sulfinyl-(C
1
-C
4
)alkylenylcarbonyl, sulfonyl-(C
1
-C
4
)alkylenylcarbonyl or carbonyl(C
0
-C
4
)alkylenylcarbonyl; wherein said oxy(C
1
-C
4
)alkylenylcarbonyl, (C
1
-C
4
)alkylenylcarbonyl, (C
3
-C
4
)alkenylcarbonyl and thio(C
1
-C
4
)alkylenylcarbonyl in the definition of X are each optionally and independently substituted with up to two (C
1
-C
4
)alkyl, benzyl or Ar; said vinylenylsulfonyl and said vinylenylcarbonyl in the definition of X are optionally substituted independently on one or two vinylenyl carbons with (C
1
-C
4
)alkyl, benzyl or Ar; and said carbonyl(C
0
-C
4
)alkylenylcarbonyl in the definition of X is optionally substituted independently with up to three (C
1
-C
4
)alkyl, benzyl or Ar;
R
10
is hydrogen or (C
1
-C
4
)alkyl;
R
9
is (C
3
-C
7
)cycloalkyl, Ar
1
—(C
0
-C
3
)alkylenyl or (C
1
-C
6
)alkyl optionally substituted with up to five fluoro; provided that when q=0 and X is a covalent bond, oxycarbonyl or (C
1
-C
4
)alkylenylcarbonyl, then R
9
is not (C
1
-C
6
)alkyl;
Ar and Ar
1
are independently a fully saturated, partially saturated or fully unsaturated five- to eight-membered ring optionally having up to four heteroatoms selected independently from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of two fused independently partially saturated, fully saturated or fully unsaturated five- to seven-membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, or a tricyclic ring consisting of three fused independently partially saturated, fully saturated or fully unsaturated five to seven membered rings, taken independently, optionally having up to four heteroatoms selected independently from nitrogen, sulfur and oxygen, said partially saturated, fully saturated ring or fully unsaturated monocyclic ring, bicyclic ring or tricyclic ring optionally having one or two oxo groups substituted on carbon or one or two oxo groups substituted on sulfur;
Ar and Ar
1
are optionally independently substituted on carbon or nitrogen, on one ring if the moiety is monocyclic, on one or both rings if the moiety is bicyclic, or on one, two or three rings if the moiety is tricyclic, with up to a total of four substituents independently selected from R
11
, R
12
, R
13
and R
14
; wherein R
11
, R
12
, R
13
and R
14
are each taken separately and are each independently 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
15
R
16
, naphthyl, phenyl, imidazolyl, pyridyl, triazolyl, morpholinyl, (C
0
-C
4
)alkylsulfamoyl, N-(C
0
-C
4
)alkylcarbamoyl, N,N-di-(C
1
-C
4
)alkylcarbamoyl, N-phenylcarbamoyl, N-(C
1
-C
4
)alkyl-N-phenylcarbamoyl, N,N-diphenyl carbamoyl, (C
1
-C
4
)alkylcarbonylamido, (C
3
-C
7
)cycloalkylcarbonylamido, phenylcarbonylamido, piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyl, amino, anilino, pyrimidyl, oxazolyl, isoxazolyl, tetrazolyl, thienyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl, 8-(C
1
-C
4
)alkyl-3,8-diaza[3.2.1]bicyclooctyl, 3,5-dioxo-1,2,4-triazinyl, phenoxy, thiophenoxy, (C
1
-C
4
)alkylsulfanyl, (C
1
-C
4
)alkylsulfonyl, (C
3
-C
7
)cycloalkyl, (C
1
-C
4
)alkyl optionally substituted with up to five fluoro or (C
1
-C
4
)alkoxy optionally substituted with up to five fluoro; said

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