Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-04-16
2003-09-09
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S404000, C514S406000, C514S407000, C548S235000, C548S371400, C548S377100, C548S379100
Reexamination Certificate
active
06617342
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the treatment and control of hyperglycemia, such as occurs in non-insulin-dependent diabetes mellitus (NIDDM). This invention also relates to treatment and control of hyperlipidemia.
BACKGROUND OF THE INVENTION
The disease, diabetes mellitus, is recognized in two forms. Type I diabetes requires exogenous insulin for control of the disease because it appears that endogenous production of insulin by the Isles of Langerhans in the pancreas is extremely poor or non-existent. Type I diabetes is often referred to as insulin-dependent diabetes mellitus (IDDM). Type II, non-insulin-dependent diabetes mellitus (NIDDM), is characterized by defects of insulin sensitivity in peripheral tissues such as adipose tissue and muscle, as described by J. E. Gerich in
New Engl. J. Med.,
321, 1231-1245 (1989).
Hyperlipidemia is often observed in diabetics (
Diabetes Care,
18, Supplement 1, 86-93, 1995). The combination of hyperlipidemia and hyperglycemia greatly increases the risk of cardiovascular diseases in diabetics. Successful treatment of hyperlipidemia and hyperglycemia in diabetics is needed urgently.
Blank reviewed hypoglycemic agents (
Burger's Medicinal Chemistry,
4th Ed., Part II , John Wiley and Sons, N.Y., 1979, 1057-1080). Newer hypoglycemic agents were reviewed by Hulin in
Progress in Medicinal Chemistry,
31, ed. G. P. Ellis and D. K. Luscombe, Elsevier Publishing Co., 1993.
Currently, partial control of NIDDM is achieved by a diet and exercise regimen, by administration of exogenous insulin, by administration of hypoglycemic agents, (e.g. the sulfonylureas), or by some combination of these protocols. Sulfonylureas, such as chloropropamide, acetohexamide and tolbutamide, are useful orally-effective hypoglycemic agents achieving success in the control of NIDDM in a number of patients. However, drugs currently available for the control of the hyperglycemia associated with type II diabetes mellitus (NIDDM) possess significant liabilities or limitations of efficacy. (Ellingboe, et al.,
J. Med. Chem.
36:2485-2493, 1993). Considerable effort has been expended toward developing novel, orally-administered antihyperglycemic drugs. A preferred therapeutic approach for treating NIDDM incorporates drugs that counteract insulin resistance rather than those that stimulate endogenous insulin secretion. (J. R. Colca and D. R. Morton,
New Antidiabetic Drugs
, ed. C. J. Bailey and P. R. Flatt, Smith-Gordon and Company, Ltd., London, Chapter 24, 1990). Drugs that treat insulin resistance are called insulin sensitivity enhancers.
Sato, Y, et al. (
Diabetes Research and Clinical Practice,
12:53-60, 1991) described the hypoglycemic effect of D-phenylalanine derivatives. In normal dogs, the hypoglycemic activity of the compound was greater than that of tolbutamide but less than that of glibenclamide. The compounds exerted a rapid hypoglycemic effect and improved glucose tolerance in genetically diabetic KK mice and in streptozotocin-treated rats. Yamasaki, et al. disclosed a group of 2-quinolone derivatives showing antidiabetic activity in NIDDM (WO 92/21342).
Some known hypoglycemic compounds also reduce serum cholesterol or triglyceride levels. (Clark, et al., U.S. Pat. No. 5,036,079). The combination of these biological activities in one compound is particularly advantageous because diabetics are highly susceptible to hyperlipidemia. Hulin, in U.S. Pat. No. 5,306,726, claimed phenylpropionic acid derivatives and disclosed compounds that had hypoglycemic and hypocholesterolemic activity useful for the treatment of diabetes and atherosclerosis. Miyata, et al. found a class of phosphonic diester derivatives useful for treating diabetes and hyperlipidemia (WO 93/23409). Hypolipidemic amino acid derivatives were disclosed in JA-028189. Highly substituted aryl ethers of tyrosine were reported to have hypocholesterolemic activity (
J. Med. Chem.,
38:695-707, 1995). No aklyl ethers of tyrosine were disclosed.
Pyrazole compounds have been shown to have hypoglycemic effect. For example, U.S. Pat. No. 5,183,825 issued Feb. 2, 1993 disclosed the use of 4-Arylmethyl-5-alkyl-3H-pyrazol-3-ones as hyperlipidermia.
SUMMARY OF THE INVENTION
The present invention provides novel pyrazolones and pyrazolines useful in the treatment of hyperglycemia and/or hyperglycemia.
The present invention is also a method of use of novel pyrazolones and/or pyrazolines in the treatment of hyperlipidemia and/or hyperglycemia.
The present invention also provides a pharmaceutical composition containing a pyrazolone and/or pyrazoline compound of the invention useful for the treatment of non-insulin dependent diabetes mellitus (NIDDM).
The present invention provides novel compounds having utility as hypoglycemic and hypolipidemic agents of formula I;
wherein:
R
1
, R
2
, R
3
, and R
4
are independently alkyl, aryl aralkyl, heteroaryl, heteroalkyl fragments of 1-20 atoms (including, but not limited to, carbon, hydrogen, oxygen, nitrogen, sulfur, phosphorus, halogen) with or without substituents; Z
1
is variously hydrogen, oxygen, sulfur, nitrogen; The dashed bonds are variously single or double; n is an integer from zero to 2.
DEFINITIONS
The terms used to describe the instant invention have the following meanings herein.
A “mammal” is an individual animal that is a member of the taxonomic class mammalia. The class mammalia includes humans, monkeys, chimpanzees, gorillas, cattle, swine, horses, sheep, dogs, cats, mice, and rats.
“C
1-4
alkyl” refers to a straight or branched alkyl radicals having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or t-butyl.
“C
1-4
alkoxy” refers to a straight or branched chain alkyl radicals attached to oxygen having 1 to 4 carbon atoms, for example, methoxy, ethoxy, n-propoxy, isopropoxy, or t-butoxy, and the like.
The terms “active ingredient” and “active compound” as used herein are synonymous and refer to a compound(s) of the present invention as represented by formula I or its pharmaceutically acceptable salts or prodrug individually contained or combined with other compound(s) of formula I in a formulation of the invention.
The term “aralkyl” refers to an aryl(C
1
-C
6
-alkyl) group.
The term “aryl” refers to a substituted or unsubstituted aromatic or heteroaromatic radical (wherein the terms “aromatic group” and “heteroaromatic group” refer to common aromatic rings having 4n+2 pi electrons in a monocyclic or bicyclic conjugated system) selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-naphthyl, 2-naphthyl, 2-benzofuryl, 3-benzofuryl, 4-benzofuryl, 5-benzofuryl, 6-benzofuryl, 7-benzofuryl, 2-benzothieny, 3-benzothienyl, 4-benzothienyl, 5-benzothienyl, 6-benzothienyl, 7-benzothienyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl and 7-indolyl. Aryl groups may be optionally substituted at one or two carbon atoms of the aryl group, and may be with C
1-4
alkyl, C
1-4
alkoxy, halogen, —NO
2
, —CN, —COOH, —CONH
2
, —SO
3
H, —SO
2
NH
2
or trifluoromethyl. Examples of substituted aryl groups are 4-methyl-3-furyl, 3,4-dimethyl-2-thienyl, 2,4-dimethyl-3-thienyl, 3-ethoxy-4-methyl-2-benzofuryl, 2-cyano-3-benzofuryl, 4-trifluoromethyl-2-benzothienyl, 2-chloro-3-benzothienyl, 3,4-dichloro-2-pyridyl, 2-bromo-3-pyridyl, 2-fluoro-4-pyridyl, 4-fluoro-2-furyl, 2-carboxyphenyl, 4-carboxamidophenyl, 3-trifluoromethylphenyl, 2-bromo-1-naphthyl, 2,3-dimethyl-1-naphthyl, 3-carboxy-2-naphthyl, 5-carboxy-8-chloro-1-naphthyl, 3-ethyl-2-furyl, 8-fluoro-2-naphthyl, 5-trifluoromethyl-2-naphthyl, 6-ethoxy-2-naphthyl, 6,7-dimethoxy-2-naphthyl, 3-carboxy-2-naphthyl, and the like.
The term, “alkyl” by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, n-pentyl, and n-hexyl.
The term, “alkenyl” employed alone or in combination wi
Eli Lilly and Company
Ginah Francis O.
McKane Joseph K.
Saeed Kamal
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