Hypoglycemic and hypolipidemic compounds

Details Hypoglycemic and hypolipidemic compounds Hypoglycemic and hypolipidemic compounds

1998-12-18

2001-02-27

Gerstl, Robert (Department: 1613)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S236000, C548S235000

Reexamination Certificate

active

06194446

ABSTRACT:

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 numbers 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.
SUMMARY OF THE INVENTION
This invention provides compounds of the Formula I
wherein:
Q is selected from the group consisting of —(CH
2
)
p
— and —CH
2
—O—CH
2
—;
R
0
is selected from the group consisting of
R
2
is selected from the group consisting of C
1-4
alkylaminocarbonyl, arylcarbonyl, aryloxycarbonyl, aryloxy C
1-4
alkylcarbonyl, arylaminocarbonyl, aryl C
1-4
acyl, aryl C
1-4
alkoxycarbonyl, aryl C
1-4
alkylaminocarbonyl, aryl C
1-4
alkylsulfonyl and amino protecting groups;
R
3
and R
4
are independently hydrogen, or C
1-4
alkyl;
R
5
is —COOH, —CONR
10
R
11
, —CN, —CONHOH, or
R
6
is hydrogen, C
1-4
alkyl, aryl, or aryl C
1-4
alkyl;
R
7
is hydrogen, halogen, or C
1-4
alkyl;
R
9
is hydrogen, C
1-4
alkyl, or aryl;
R
10
and R
11
are independently hydrogen, C
1-4
alkyl, or aryl;
W is —(CH
2
)
n
—;
Y is attached at position 3 or at position 4 or the ring, and is —O—, —S—, —SO—, —SO
2
—, —NH—, —CONR
9
—, —NR
9
—SO
2
—, or —SO
2
—NR
9
—;
n is 1 to 4; and
p is 1, 2, or 3;
or a pharmaceutically-acceptable salt thereof;
provided that when R
6
is either hydrogen or C
1-4
alkyl, then R
7
is halogen, and that when p=1, then R
0
is
or a pharmaceutically acceptable salt thereof.
This invention also provides pharmaceutical formulations of the compounds of Formula I, and methods for treating hyperglycemia associated with non-insulin dependent diabetes and for treating hyperlipidemia by administering to a mammal an effective dose of a compound of the Formula I.
DETAILED DESCRIPTION
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.
“Halogen” refers to fluoro, chloro, bromo or iodo.
“C
1-4
alkyl” refers to straight or branched alkyl radicals having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, and t-butyl.
“C
1-4
alkoxy” refers to straight or branched chain alkyl radicals attached to oxygen having 1 to 4 carbon atoms, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, t-butoxy, and the like.
“C
1-4
alkylaminocarbonyl” refers to radicals of the formula:
, and includes, for example, methylaminocarbonyl, ethylaminocarbonyl, 2-propylaminocarbonyl, and the like.
“Aryl” refers to a substituted or unsubstituted aromatic radical 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-benzothieny, 4-benzothieny, 5-benzothieny, 6-benzothieny, 7-benzothienyl, 1indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, and 8-indolyl. The optional substitutions of aryl may be 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, 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.
“Arylcarbonyl” refers to radicals of the formula:
, for example, phenylcarbonyl, 4-methyl-1-naphthylcarbonyl, 3-trifluoromethylphenylcarbonyl, and the like.
“Aryloxycarbonyl” refers to radicals of the formula:
, and includes, for example, phenyloxycarbonyl, 1-naphthyloxycarbonyl, 3-benzofuryloxycarbonyl, 2-benzothienyloxycarbonyl, 3-benzothienyloxycarbonyl, 2-pyridyloxycarbonyl, 3-pyridylo

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