Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-07
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...
C514S469000, C548S236000, C549S471000
Reexamination Certificate
active
06617343
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to certain N,N-arylsulfonylglycine compounds, having utility as hypoglycemic agents, methods for their use, pharmaceutical compositions containing them and intermediates useful in their preparation.
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).
Hypoglycemic agents have been reviewed; references to earlier reviews, together with a review of newer agents, are to be found in Hulin [
Progress in Medicinal Chemistry
, Vol. 31, ed. By G. P. Ellis and D. K. Luscombe, Elsevier Publishing Co. (1993)].
Naphthalene sulfonamides containing amino acid moieties have been described as selective synthetic thrombin inhibitors (
Eur. J. Med. Chem
. (1988), 26 (6), 577-585). Some arylsulfonyl derivatives of substituted indoline-2-carboxamides were disclosed in EP 92-402213, published Aug. 03, 1992, as oxytocin and vasopressin antagonists. Aryl (but not alkyl) sulfonamides of N-aryl glycine derivatives, containing a rhodanine moiety, were disclosed as aldose reductase inhibitors for the treatment of diabetic complications (see JP 04099770 A2; published Mar. 31, 1992).
In view of these precedents, the observation of hypoglycemic activity in the object compounds of the present invention is novel and unexpected.
SUMMARY OF THE INVENTION
The present invention provides N,N-arylsulfonyylglycines useful in the treatment of hyperglycemia and/or hyperlipidemia.
The present invention provides a method of use of N,N-arylsulfonylglycines in the treatment of hyperglycemia and/or hyperlipidemia.
The present invention also provides a pharmaceutical composition containing N,N-arylsulfonylglycines useful for the treatment of non-insulin dependent diabetes mellitus (NIDDM).
The present invention relates to novel N,N-arylsulfonylglycine compounds of formula I:
wherein,
R
1
and R
2
are independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, or aralkyl;
R
3
is selected from alkyl, alkenyl, alkynyl, aryl, aralkyl heteroaryl, or heteroaralkyl fragments of 1 to 8 carbon atoms with or without substituents;
X is a group selected from alkoxyalkyl, alkoxyaryl, alkoxyalkylaryl, aralkylalkoxy, alkoxyalkylheterocycle optionally substituted with alkyl, aryl, alkylaryl, aralkyl, heteroaryl, or heteroaralkyl fragments of 1 to 8 carbon atoms with or without substituents, attached to the aromatic ring ortho, meta, or para to the nitrogen substituent, or fused directly to any side of the aromatic ring, with or without additional fusion to the aromatic ring or pharmaceutically acceptable salts thereof.
This invention relates to a compound of formula I:
wherein,
R
1
, R
2
, and R
3
independently represent hydrogen, alkyl, alkenyl, alkynyl, aryl, or aralkyl groups having 1 to 8 carbon atoms;
X represents an alkoxyalkyl, alkoxyaryl, alkoxyalkylaryl, aralkylalkoxy, or alkoxyalkylheterocycle; or a pharmaceutically acceptable salt or prodrug thereof.
The present invention also provides a compound depicted by formula II:
wherein,
R
1
, R
2
, and R
3
are as described for formula I and and R
4
is a group selected from aryl, aralkyl, alkyaryl, alkyl heterocyclic, alkylarylheterocyclic, or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
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. “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, l-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-carb
Eli Lilly and Company
Ginah Francis O.
Kelley James J.
McKane Joseph K.
Shiao Rei
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