Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-03-29
2001-09-25
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S229000
Reexamination Certificate
active
06294538
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, 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 and combinations comprising a sorbitol dehydrogenase inhibitor of formula I and an aldose reductase inhibitor and the use of such compositions or combinations to treat diabetic complications. This invention also relates to pharmaceutical compositions containing such pyrimidine derivatives and related compounds. This invention also relates to pharmaceutical compositions and combinations comprising a combination of a sorbitol dehydrogenase inhibitor of formula I and an NHE-1 inhibitor and to the use of such compositions or combinations 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
1
, 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, discloses a method for treating or preventing diabetic complications that can be treated or prevented by inhibiting the enzyme sorbitol dehydrogenase. That patent also discloses compounds of the formula A,
wherein R
1
through R
5
are defined as disclosed therein.
Further, U.S. Patent Nos., assigned to Hoechst, disclose as having utility in detecting levels of sorbitol dehydrogenase.
We have found that pyrimidine derivatives of the formulas I, II, III and IV, 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
This invention is directed to a compound of formula I,
a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein:
R is N,N-dimethylamino or isopropyl.
A preferred compound of formula I is the compound of the formula
Another preferred compound of formula I is the compound of the formula
This invention is also directed to a pharmaceutical composition, designated Composition A, comprising a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent.
This invention is also directed to a method, designated Method A, of inhibiting sorbitol dehydrogenase in a mammal in need of such inhibition comprising administering to said mammal a sorbitol dehydrogenase inhibiting amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said compound.
This invention is also directed to a method of treating diabetes in a mammal suffering from diabetes comprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said compound.
This invention is also directed to a method, designated Method B, of treating or preventing diabetic complications in a mammal comprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said compound.
A preferred method of Method B is wherein said mammal is suffering from diabetes.
Another preferred method of Method B is wherein said diabetic complication is diabetic neuropathy.
Another preferred method of Method B is wherein said diabetic complication is diabetic nephropathy.
Another preferred method of Method B is wherein said diabetic complication is diabetic retinopathy.
Another preferred method of Method B is wherein said diabetic complication is foot ulcers.
Another preferred method of Method B is wherein said diabetic complication is a cardiovascular condition.
This invention is also directed to a pharmaceutical composition, designated Composition B, comprising a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said compound, and an aldose reductase inhibitor (ARI), a prodrug of said ARI or a pharmaceutically acceptable salt of said ARI or said prodrug.
A preferred composition within Composition B additionally comprises a pharmaceutically acceptable carrier or diluent.
This invention is also directed to a method of treating diabetes in a mammal suffering from diabetes comprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said compound, and an aldose reductase inhibitor (ARI), a prodrug of said ARI or a pharmaceutically acceptable salt of said ARI or said prodrug.
This invention is also directed to a method, designated Method C, of treating or preventing diabetic complications in a mammal comprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said compound, and an aldose reductase inhibitor (ARI), a prodrug of said ARI or a pharmaceutically acceptable salt of said ARI or said prodrug.
A preferred method within Method C is wherein said mammal is suffering from diabetes.
Another preferred method within Method C is wherein said diabetic complication is diabetic neuropathy.
Another preferred method within Method C is wherein said diabetic complication is diabetic nephropathy.
Another preferred method within Method C is wherein said diabetic complication is diabetic retinopathy.
Another preferred method within Method C is wherein said diabetic complication is foot ulcers.
Another preferred method within Method C is wherein said diabetic complication is a cardiovascular condition.
This invention is also directed to a pharmaceutical composition, designated Composition C, comprising a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said compound, and a sodium hydrogen ion exchange (NHE-1) inhibitor, a prodrug of said NHE-1 inhibitor or a pharmaceutically acceptable salt of said NHE-1 inhibitor or said prodrug.
This invention is also directed to a method, designated Method D, of treating ischemia in a mammal suffering from ischemia comprising administering to said mammal an effective amount of a compound of formula I, a prodrug thereof or a pharmaceutically acceptable salt of said prodrug or said compound, and a sodium hydrogen ion exchange (NHE-1) inhibitor, a prodrug of said NHE-1 inhibitor or a pharmaceutically acceptable salt of said NHE-1 inhibitor or said prodrug.
A preferred method within Method D is wherein said ischemia is
Benson Gregg C.
Munchhof Martha G.
Pfizer Inc.
Reamer James H.
Richardson Peter C.
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