Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-01-03
2003-03-25
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C562S451000, C564S165000, C514S532000, C514S539000, C514S540000, C514S567000, C514S568000, C514S617000
Reexamination Certificate
active
06538152
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel phenoxyacetic acid derivatives and pharmaceutically acceptable salts thereof which are useful as medicaments.
BACKGROUND ART
It is known that three subtypes of sympathetic &bgr;-adrenoceptor, which have been classified as &bgr;
1
, &bgr;
2
, and &bgr;
3
are present and that each receptor subtype is distributed in specified organs in living body and has specific function.
For example, &bgr;
2
-adrenoceptor is mainly present in the heart and the stimulation of this receptor leads to increment of heart rate and cardiac contractility. &bgr;
2
-Adrenoceptor is mainly present in smooth muscle of blood vessels, the trachea and uterus. The stimulation of this receptor leads to vasodilation, bronchodilation and inhibition of uterine contraction. &bgr;
3
-Adrenoceptor is mainly present in adipocytes, the gallbladder and intestinal tract. It is known that &bgr;
3
-adrenoceptor is also present in the brain, liver, stomach, prostate and so on. It is reported that the stimulation of this receptor leads to increment of lipolysis, inhibition of intestinal tract motility, increment of glucose uptake, anti-depression and so on (Drugs of the Future, Vol.18, No.6, pp.529-549 (1993); Molecular Brain Research, Vol.29, pp.369-375 (1995); European Journal of Pharmacology, Vol.289, pp.223-228 (1995); Pharmacology, Vol.51, pp.288-297 (1995)).
In addition, it is recently reported that in human bladder &bgr;
3
-adrenoceptor is predominantly present and that human bladder is relaxed by &bgr;
3
-adrenoceptor stimulants (The Japanese Journal of Urology, Vol.88, No.2, p.183 (1997); Neurourology and Urodynamics, Vol.16, No.5, pp.363-365 (1997)).
Up to this time, many &bgr;
1
-adrenoceptor stimulants and &bgr;
2
-adrenoceptor stimulants have been developed and are used for medicinal purposes as cardiotonics, bronchodilators, preventive agents for threatened abortion or premature labor and so on.
On the other hand, it has been found that &bgr;
3
-adrenoceptor stimulants are useful as agents for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hyper-motility, pollakiuria, urinary incontinence, depression, the diseases caused by biliary calculi or hypermotility of biliary tract, or so on. Therefore, studies have been being actively made to develop excellent &bgr;
3
-adrenoceptor stimulants, but any &bgr;
3
-adrenoceptor stimulant has not been sold yet (Drugs of the Future, Vol.18, No.6, pp.529-549(1993); European Journal of Pharmacology, Vol.219, pp.193-201(1992) etc.).
Consequently, it has been greatly desired to develop novel &bgr;
3
-adrenoceptor stimulants having excellent &bgr;
3
-adrenoceptor stimulating effects.
More preferably, it has been desired to develop highly selective and novel &bgr;
3
-adrenoceptor stimulants having potent &bgr;
3
-adrenoceptor stimulating effects in comparison with &bgr;
1
and/or &bgr;
2
-adrenoceptor stimulating effects and resulting in reduced side effects caused by &bgr;
1
and/or &bgr;
2
-adrenoceptor stimulating effects such as palpitation and tremor.
DISCLOSURE OF THE INVENTION
The present invention relates to a phenoxyacetic acid derivative represented by the general formula:
wherein R
1
represents a hydroxy group, a lower alkoxy group, an aralkoxy group, an amino group, or a mono or di(lower alkyl)amino group; one of R
2
and R
3
is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, while the other is a hydrogen atom; R
4
represents a halogen atom, a lower alkyl group, a halo (lower alkyl) group, a hydroxy group, a lower alkoxy group, an aralkoxy group, a cyano group, a nitro group, an amino group, a mono or di(lower alkyl)amino group, a carbamoyl group, a mono or di (lower alkyl)carbamoyl group or a group represented by the general formula:
—NHCOR
5
(wherein R
5
represents a hydrogen atom or a lower alkyl group); the carbon atom marked with (R) represents a carbon atom in R configuration; and the carbon atom marked with (S) represents a carbon atom in S configuration, or a pharmaceutically acceptable salt thereof.
The present invention relates to a pharmaceutical composition comprising as the active ingredient a phenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to an agent for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract, which comprises as the active ingredient a phenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to a method for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract, which comprises administering a therapeutically effective amount of a phenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to a use of a phenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract.
The present invention relates to a use of a phenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as an agent for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hypermotility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract.
The present invention relates to a process for the manufacture of a pharmaceutical composition for the prevention or treatment of obesity, hyperglycemia, the diseases caused by intestinal hyper-motility, pollakiuria, urinary incontinence, depression, or the diseases caused by biliary calculi or hypermotility of biliary tract, characterized in the use, as an essential constituent of said pharmaceutical composition, of a phenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
The present inventors have studied earnestly to solve the above objects. As a result, it was found that phenoxyacetic acid derivatives represented by the above general formula (I) and pharmaceutically acceptable salts thereof have excellent &bgr;
3
-adrenoceptor stimulating effects, thereby forming the basis of the present invention.
In the present invention, the term “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; the term “lower alkyl group” means a straight or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, apropyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a hexyl group or the like; the term “lower alkoxy group” means a straight or branched alkoxy group having 1 to 6 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a hexyloxy group or the like; the term “aralkoxy group” means the above lower alkoxy group substituted by an aryl group such as a phenyl group, a naphthyl group or the like; the term “mono or di(lower alkyl)amino group” means an amino group which is mono- or di-substituted by same or different lower alkyl groups as mentioned above; the term “halo (lower alkyl) group”
Akahane Masuo
Hirabayashi Akihito
Mukaiyama Harunobu
Muranaka Hideyuki
Sato Masa-aki
Killos Paul J.
Kissei Pharmaceutical Co. Ltd.
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