Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-02-19
2001-03-20
Stockton, Laura L. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S277000, C546S339000, C548S236000
Reexamination Certificate
active
06204277
ABSTRACT:
This application is a 371 of PCT/JP97/02873 filed Aug. 19, 1997.
TECHINCAL FIELD
The present invention relates to novel propionic acid derivatives. More particularly, the present invention relates to novel propionic acid derivatives and pharmaceutical compositions containing said derivatives, which have hypoglycemic action, which are expected to have hypolipidemic action, and which are useful as therapeutic agents of diabetes mellitus and complications thereof, diabetes-related diseases such as hyperlipemia, and the like.
BACKGROUND ART
In general, the treatment of non-insulin-dependent diabetes mellitus (NIDDM) involves a combination of alimentotherapy, kinesitherapy, and administration of insulin or orally active hypoglycemic agents. As the oral hypoglycemic agents, there are currently known sulfonylureas such as tolbutamide, chlorpropamide, acetohexamide, glibenclamide and tolazamide, and biguanides such as phenformin, buformin and metformin.
While the sulfonylureas have strong hypoglycemic action, they sometimes induce severe and prolonged hypoglycemia, and chronic use thereof may impair their effectiveness. In addition, the biguanides frequently induce severe lactic acidosis. For these reasons, the use of these medications has required considerable amount of attention.
Meanwhile, Japanese Patent Unexamined Publication No. 85372/1986 discloses that thiazolidinedione derivatives, such as 5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-2,4-thiazolidinedione, have hypoglycemic action.
Japanese Patent Unexamined Publication No. 170478/1991 teaches that oxazolidinedione derivatives, such as 5-[4-[2-(2-phenyl-5-methyloxazol-4-yl)ethoxy]benzyl]-2,4-oxazolidinedione, have hypoglycemic action and hypocholesterolemic action, and Japanese Patent Unexamined Publication No. 165735/1995 teaches that oxazolidinedione derivatives, such as 5-[3-[4-[(2-benzo[b]thien-2-yl-5-methyl-4-oxazolyl)methoxy]phenyl]propyl]-2,4-oxazolidinedione, also have hypoglycemic action and hypocholesterolemic action.
Japanese Patent Application under PCT laid-open under Kohyo No. 5-507920 discloses that 3-aryl-2-hydroxypropionic acid derivatives, such as &agr;-methoxy-4-[2-(5-methyl-2-phenyl-4-phenyl-4-oxazolyl)ethoxy]benzenepropanic acid and ethyl &agr;-acetylthio-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzenepropionate, have hypoglycemic action. This publication also recites ethyl &agr;-hydroxy-4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzenepropanate as an intermediate compound. In addition, Japanese Patent Application under PCT laid-open under Kohyo No. 5-508654 discloses that hydroxyurea derivatives, such as N-[(methoxycarbonyl)oxy]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]urea, have hypoglycemic action.
WO95/18125 discloses that isoxazolidinedione derivatives, such as 4-[4-[2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxazolidinedione, have hypoglycemic action.
WO94/13650 discloses that dimethyl 2-[4-[2-[N-(2-benzooxazolyl)-N-methylamino]ethoxy]phenylmethyl]propane-1,3-dioate and dimethyl 2-[4-[2-[N-(2-benzooxazolyl)-N-methylamino]ethoxy]phenylmethylene]propane-1,3-dioate have hypoglycemic action.
Japanese Patent Unexamined Publication No. 53555/1995 recites ethyl 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamate as an intermediate compound.
Japanese Patent Unexamined Publication No. 101945/1995 describes ethyl (E)-4-[2-(5-ethyl-2-pyridyl)ethoxy]cinnamate as a reference compound.
The above-mentioned compounds do not necessarily show satisfactory activities. Rather, the use of these compounds gives rise to concerns about the side effects such as toxicity. Moreover, the above-mentioned literatures do not suggest a propionic acid derivative such as the compounds of the present invention.
Further, WO95/18125 discloses diesters of malonic acid, such as dimethyl 4-[2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy]benzilidenemalonate, as an intermediate compound for isoxazolidinedione derivatives such as 4-[4-[2-(2-phenyl-5-methyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxazolidinedione. Nevertheless, it does not suggest that such diesters of malonic acid have hypoglycemic action, much less gives any data suggesting the hypoglycemic action.
DISCLOSURE OF THE INVENTION
The present inventors have conducted intensive studies in an attempt to provide a compound useful for the treatment of diabetes mellitus, its complications and hyperlipemia, and found a novel propionic acid derivative which is low toxic and has superior hypoglycemic action and hypolipidemic action, which resulted in the completion of the present invention.
Accordingly, the present invention provides pharmaceutical compositions inclusive of the novel propionic acid derivatives of the following (1) to (3), and pharmaceutical compositions such as the therapeutic agents of diabetes mellitus of the following (4) to (7).
(1) A novel propionic acid derivative of the formula (I):
wherein R is a group of the formula:
wherein
R′ is an optionally substituted aromatic hydrocarbon, an optionally substituted alicyclic hydrocarbon, an optionally substituted heterocyclic group or an optionally substituted fused heterocyclic group, and
R
5
is a lower alkyl;
R
4
is a hydrogen atom or a lower alkyl;
R
6
is a hydrogen atom or forms, together with R
9
, a double bond;
R
7
is a carboxy, an acyl, an optionally substituted alkoxycarbonyl, an optionally substituted lower alkyl, an optionally substituted carbamoyl, an optionally substituted aryloxycarbonyl, an optionally substituted aralkyloxycarbonyl or a group of the formula —Y—R
8
wherein Y is —NH— or an oxygen atom and R
8
is an optionally substituted acyl or an optionally substituted alkoxycarbonyl;
R
9
is a hydrogen atom, an optionally substituted lower alkyl or an optionally substituted lower alkoxycarbonyl; and
R
10
is a hydroxy, an optionally substituted amino, an optionally substituted lower alkoxy, an optionally substituted lower alkyl, an optionally substituted aryloxy or an optionally substituted aralkyloxy,
provided that when R
7
is an alkoxycarbonyl and R
9
is a hydrogen atom, R
10
is not a lower alkoxy,
and a pharmaceutically acceptable salt thereof.
(2) The novel propionic acid derivative of (1) above, having the formula (I):
wherein
R is a group of the formula
wherein
R′ is an aromatic hydrocarbon or a fused heterocyclic group, and
R
5
is a lower alkyl;
R
4
is a hydrogen atom;
R
6
is a hydrogen atom;
R
7
is a carboxy, an acyl, an alkoxycarbonyl, a lower alkyl substituted by alkoxycarbonyl, a lower alkyl, a carbamoyl, a carbamoyl optionally substituted by alkoxyalkyl or acyl, an aryloxycarbonyl, an aralkyloxycarbonyl or a group of the formula —Y—R
8
wherein Y is —NH— or an oxygen atom and R
8
is an acyl or an alkoxycarbonyl;
R
9
is a hydrogen atom or a lower alkyl optionally substituted by alkoxycarbonyl; and
R
10
is a hydroxy, an amino optionally substituted by lower alkyl, a lower alkoxy, a lower alkyl, an aryloxy or an aralkyloxy,
provided that when R
7
is an alkoxycarbonyl and R
9
is a hydrogen atom, R
10
is not a lower alkoxy,
and a pharmaceutically acceptable salt thereof.
(3) The novel propionic acid derivative of (1) or (2) above, which is a member selected from the group consisting of:
2-methoxycarbonyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid,
methyl 2-carbamoyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate,
2-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]malonic acid,
methyl 2-methoxycarbonylcarbamoyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionate,
2-methoxycarbonyl-2-methyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid,
methyl 2-carbamoyl-2-methyl-3-[4-[2-(5-met
Ohrui Satoshi
Shibata Tsutomu
Shinkai Hisashi
Foley & Lardner
Japan Tobacco Inc.
Stockton Laura L.
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