Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-06-19
2002-03-05
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C560S037000, C560S039000, C562S451000
Reexamination Certificate
active
06353025
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel phenylaminoalkyl-carboxylic acid derivatives and pharmaceutically acceptable salts thereof which are useful as medicaments.
BACKGROUND ART
It is known that three subtypes of sympathomimetic &bgr;-adrenoceptors, 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 the living body and has specific functions.
For example, &bgr;
1
-adrenoceptor is mainly present in the heart and the stimulation of this receptor leads to increase 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 gall bladder and intestinal tract. It is known that &bgr;
3
-adrenoceptor is also present in the brain, liver, prostate and stomach. It has been reported that the stimulation of &bgr;
3
-adrenoceptor leads to increase of lipolysis, inhibition of intestinal tract motility, increase 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 has been recently reported that &bgr;
3
-adrenoceptor is predominantly present in the human bladder and that the human bladder is relaxed by a &bgr;
3
-adrenoceptor stimulant (The Japanese Journal of Urology, Vol.88, No.2, p.183 (1997); NEUROUROLOGY AND URODYNAMICS, Vol.16, No.5, pp.363-365 (1997)).
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 one 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 hypermotility, pollakyuria, urinary incontinence, depression, the diseases caused by biliary calculi or hypermotility of the biliary tract (hereafter simply “biliary tract”) and so on. Consequently, studies have been actively made to develop agents for the prevention or treatment of such diseases, but no &bgr;
3
-adrenoceptor stimulant has 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.).
Therefore, it has been desired to develop novel &bgr;
3
-adrenoceptor stimulants having excellent &bgr;
3
-adrenoceptor stimulating effects.
More preferably, it has been desired to develop novel and higher selective &bgr;
3
-adrenoceptor stimulants having potent &bgr;
3
-adrenoceptor stimulating effects in comparison with &bgr;
1
and/or &bgr;
2
-adrenoceptor stimulating effects and having attenuated side effects aused by &bgr;
1
and &bgr;
2
-adrenoceptor stimulating effects such as alpitation and tremor.
DISCLOSURE OF THE INVENTION
The present inventors have studied extensively to meet the above objects. As a result, it was found that certain phenylaminoalkylcarboxylic acid derivatives have potent stimulating effects on &bgr;3-adrenoceptors, thereby forming the basis of the present invention.
Accordingly, the present invention relates to a phenylaminoalkylcarboxylic acid derivative represented by the general formula:
(wherein R
1
represents a hydroxy group, a lower alkoxy group, an aralkoxy group, an amino group, an alicyclic amino group or a mono or di(lower alkyl)amino group which may have a hydroxy group or a lower alkoxy group as a substituent; R
2
represents a hydrogen atom or a lower alkyl group; R
3
represents a hydrogen atom or a halogen atom; R
4
and R
5
are the same or different and each represents a hydrogen atom, a halogen atom or a lower alkyl group; A represents a lower alkylene 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 the phenylaminoalkylcarboxylic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to a &bgr;
3
-adrenoceptor stimulant comprising as the active ingredient the phenylaminoalkylcarboxylic 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 the phenylaminoalkylcarboxylic 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 administrating a therapeutically effective amount of the phenylaminoalkylcarboxylic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to a use of the phenylaminoalkylcarboxylic 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 the phenylaminoalkylcarboxylic 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 hypermotility, 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 the phenylaminoalkylcarboxylic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt.
In the compounds represented by the above general formula (I) of the present invention, 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 and a butoxy group; the term “aralkoxy group” means the above lower alkoxy group having an aryl group such as a phenyl group and a naphthyl group; 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, a propyl group, an isopropyl group and a butyl group; the term “alicyclic amino group” means an aliphatic cycloamino group which may have an oxygen atom in the ring chain such as a piperidino group, a morpholino group and a 1-pyrrolidinyl group; the term “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; and the term “lower alkylene group” means a straight alkylene group having 1 to 6 carbon atoms such as a methylene group, an e
Akahane Masuo
Hirabayashi Akihito
Mukaiyama Harunobu
Muranaka Hideyuki
Sato Masa-aki
Geist Gary
Kissei Pharmaceutical Co. Ltd.
Sughrue Mion Zinn Macpeak & Seas, PLLC
Tucker Zachary C.
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