Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-28
2003-02-18
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S212010, C514S307000
Reexamination Certificate
active
06521659
ABSTRACT:
BACKGROUND OF INVENTION
1. Field of the Invention
The present invention relates to pharmaceutical compositions, and in particular to pharmaceutical compositions containing an aldose reductase inhibitor (ARI) and an angiotensin converting enzyme (ACE) inhibitor, is useful in the prevention and treatment of the complications of diabetes mellitus. In particular, the invention relates to combinations of an ACE with substituted indole acetic acids.
2. Description of the Related Art
The use of aldose reductase inhibitors (ARIs) for the treatment of diabetic complications is well known. The complications arise from elevated levels of glucose in tissues such as the nerve, kidney, retina and lens that enters the polyol pathway and is converted to sorbitol via aldose reductase. Because sorbitol does not easily cross cell membranes, it accumulates inside certain cells resulting in changes in osmotic pressure, alterations in the redox state of pyridine nucleotides (i.e. increased NADH/AND
+
ratio) and depleted intracellular levels of myoinositol. These biochemical changes, which have been linked to diabetic complications, can be controlled by inhibitors of aldose reductase.
The use of aldose reductase inhibitors for the treatment of diabetic complications has been extensively reviewed, see: (a)
Textbook of Diabetes,
2nd ed.; Pickup, J. C. and Williams, G. (Eds.); Blackwell Science, Boston, Mass. 1997.; (b) Larson, E. R.; Lipinski, C. A. and Sarges,
R., Medicinal Research Reviews,
1988, 8 (2), 159-198; (c) Dvornik, D.
Aldose Reductase Inhibition. Porte
, D. (ed), Biomedical Information Corp., New York, N.Y. Mc Graw Hill 1987; (d) Petrash, J. M., Tarle, I., Wilson, D. K. Quiocho. F. A. Perspectives in Diabetes,
Aldose Reductase Catalysis and Crystalography: Insights From Recent Advances in Enzyme Structure and Function, Diabetes,
1994, 43, 955; (e) Aotsuka, T.; Abe, N.; Fukushima, K.; Ashizawa, N. and Yoshida, M.,
Bioorg. & Med. Chem. Letters,
1997, 7, 1677, (f), T., Nagaki, Y.; Ishii, A.; Konishi, Y.; Yago, H; Seishi, S.; Okukado, N.; Okamoto, K.,
J. Med. Chem.,
1997, 40, 684; (g) Ashizawa, N.; Yoshida, M.; Sugiyama, Y.; Akaike, N.; Ohbayashi, S.; Aotsuka, T.; Abe, N.; Fukushima, K.; Matsuura, A,
Jpn. J. Pharmacol.
1997, 73, 133; (h) Kador, P. F.; Sharpless, N. E.,
Molecular Pharmacology,
1983, 24, 521; (I) Kador, P. F.; Kinoshita, J. H.; Sharpless, N. E.,
J. Med. Chem.
1985, 28 (7), 841; (j) Hotta, N.,
Biomed.
&
Pharmacother.
1995, 5, 232; (k) Mylar, B.; Larson, E. R.; Beyer, T. A.; Zembrowski, W. J.; Aldinger, C. E.; Dee, F. D.; Siegel, T. W.; Singleton, D. H.,
J. Med. Chem.
1991, 34, 108; (l) Dvornik, D.
Croatica Chemica Acta
1996, 69 (2), 613.
Although many aldose reductase inhibitors have been extensively developed, none have demonstrated sufficient efficacy in human clinical trials without significant undesirable side effects. Thus no aldose reductase inhibitors are currently available as approved therapeutic agents in the United States; and consequently, there is still a significant need for new, efficacious and safe medications for the treatment of diabetic complications.
Treatment to normalize the plasma glucose concentration in people afflicted with type 2 diabetes currently includes diet, exercise and oral agents such as sulfonylureas, metformin and glitazone-type compounds. Many of these agents exhibit side effects and have limited efficacy. There is a need for new agents which do not possess these drawbacks. Because of the limited efficacy of each method of treatment often the oral agents are giving in combination of with each other or with insulin.
Elevated serum triglyceride levels are also commonly associated with diabetes; however, this condition is also widely seen in nondiabetic patients. The mechanism causing the presence of elevated triglyceride levels in patients, both diabetic and otherwise, is different from that underlying chronic diabetes-related complications directly treatable by inhibition of aldose reductase activity. There is, therefore, a need for treatment of elevated triglyceride levels in diabetic and/or nondiabetic patients, e.g., cardiac patients.
SUMMARY OF THE INVENTION
This invention provides pharmaceutical compositions that comprise an angiotensin converting enzyme (ACE) inhibitor in combination with compounds that interact with and inhibit aldose reductase. Thus, in a broad aspect, the invention provides pharmaceutical compositions comprising an ACE inhibitor and compounds of Formula I:
or pharmaceutically acceptable salts thereof wherein
A is a C
1
-C
4
alkylene group optionally substituted with C
1
-C
2
alkyl or mono- or disubstituted with halogen, preferably fluoro or chloro;
Z is a bond, O, S, C(O)NH, or C
1
-C
3
alkylene optionally substituted with C
1
-C
2
alkyl;
R
1
is hydrogen, alkyl having 1-6 carbon atoms, halogen, 2-, 3-, or 4-pyridyl, or phenyl, where the phenyl or pyridyl is optionally substituted with up to three groups selected from halogen, hydroxy, C
1
-C
6
alkoxy, C
1
-C
6
alkyl, nitro, amino, or mono- or di(C
1
-C
6
)alkylamino;
R
2
, R
3
, R
4
and R
5
are each independently
hydrogen, halogen, nitro, or an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens);
OR
7
, SR
7
, S(O)R
7
, S(O)
2
(R
7
)
2
, C(O)M(R
7
)
2
, or N(R
7
)
2
, wherein each R
7
is independently hydrogen, an alkyl group of 1-6 carbon atoms (which may be substituted with one or more halogens) or benzyl, where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
--alkoxy, amino, and mono- or di(C
1
-C
6
)alkylamino; phenyl or heteroaryl such as 2-, 3- or 4-imidazolyl or 2-, 3-, or 4-pyridyl, each of which phenyl or heteroaryl is optionally substituted with up to three groups independently selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, amino, and mono- or di(C
1
-C
6
)alkylamino;
phenoxy where the phenyl portion is optionally substituted with up to three groups independently selected from halogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, amino, and mono- or di(C
1
-C
6
)alkylamino; or
a group of the formula
where
J is a bond, CH
2
, oxygen, or nitrogen; and
each r is independently 2 or 3;
R
6
is hydroxy or a prodrug group;
R
a
is hydrogen, C
1
-C
6
alkyl, fluoro, or trifluoromethyl; and
Ar represents aryl or heteroaryl, each of which is optionally substituted with up to five groups.
The compounds of Formula I inhibit aldose reductase. Since aldose reductase is critical to the production of high levels of sorbitol in individuals with diabetes, inhibitors of aldose reductase are useful in preventing and/or treating various complications associated with diabetes. The compounds of the invention are therefore effective for the treatment of diabetic complications as a result of their ability to inhibit aldose reductase.
In another aspect, the invention provides methods for treating and/or preventing chronic complications associated with diabetes mellitus, including, for example, diabetic cataracts, retinopathy, keratopathy, wound healing, diabetic uveitis, diabetic cardiomyopathy, nephropathy, and neuropathy.
The compounds of Formula I also possess antihyperglycemic activity and are therefore useful for the treatment of hyperglycemia. Accordingly, an aspect of the invention is prevention and/or alleviation of complications associated with hyperglycemia with the pharmaceutical compositions of the invention.
The compounds of Formula I have been discovered to lower triglycerides. While serum triglyceride levels are often elevated in diabetic patients, they are also frequently elevated in nondiabetic patients resulting in various diseases and disorders, e.g., cardiac disease. Because of their ability to reduce serum triglyceride levels, the compositions of the present invention are useful in the treatment, i.e., prevention and/or alleviation, of elevated triglyceride levels in both diabetic and nondiabetic patients.
Thus, the compositions of the present invention may be used as antihyperlipidemic and/or anti
Sredy Janet
Van Zandt Michael C.
Institute for Pharmaceutical Discovery, LLC
McDonnell & Boehnen Hulbert & Berghoff
Weddington Kevin E.
LandOfFree
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