Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-03-31
2002-06-04
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C560S037000, C562S442000
Reexamination Certificate
active
06399660
ABSTRACT:
TECHNICAL FIELD
The present invention relates to aminoethylphenoxyacetic acid derivatives and pharmaceutically acceptable salts thereof which are useful as medicaments.
BACKGROUND ART
Urolithiasis is a disease generating calculi by a series of events such as nucleation of the urinary component, crystallization, aggregation, concretion and enlargement in the lumen of the entire urinary tract from the kidney to the urethra. Urinary flow is often obstructed by calculi, which results in the rise of intra-ureteral pressure, leading to pain. At present, an analgesic and an antispastic are prescribed for the pain. However, the use of the analgesic is only a temporary symptomatic therapy for the pain, and is not expected to treat urolitiasis fundamentally at all. The effectiveness of the antispastic such as an anti-cholinergic is also not satisfactory. Therefore, useful drugs for the causual treatment of urolithiasis, for example, the drugs which relieve pain and promote the removal of calculi by widening the ureter with their strong relaxing effects are desired (The Journal of Urology, Vol.152, pp.1095-1098 (1994)).
It was recently confirmed that both &bgr;
2
- and &bgr;
3
-adrenoceptors are present in human ureter as &bgr;-adrenoceptor subtypes. It is reported that a drug having stimulating effects on both &bgr;
2
- and &bgr;
3
-adrenoceptors is extremely useful as an agent for relieving pain and promoting the removal of calculi in urolithiasis because a compound having stimulating effects on both &bgr;
2
- and &bgr;
3
-adrenoceptors shows potent relaxing effects on ureter (International application publication No. WO97/19700).
DISCLOSURE OF THE INVENTION
The present inventors have studied earnestly to find compounds being useful as agents for relieving pain and promoting the removal of calculi in urolithiasis. As a result, it was found that certain aminoethylphenoxyacetic acid derivatives have potent stimulating effects on both &bgr;
2
- and &bgr;
3
-adrenoceptors and show excellent ureteral relaxation effects, thereby forming the basis of the present invention.
The present invention relates to aminoethylphenoxyacetic acid derivatives represented by the general formula:
(wherein R
1
represents a hydrogen atom, a lower alkyl group or an aralkyl group; R
2
represents a hydrogen atom or a halogen atom; 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) and pharmaceutically acceptable salts thereof.
The present invention relates to pharmaceutical compositions comprising an aminoethylphenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to agents for relieving pain and promoting the removal of calculi which comprises as the active ingredient an aminoethylphenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to methods for relieving pain and promoting the removal of calculi in urolithiasis which comprises administering a therapeutically effective amount of an aminoethylphenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
The present invention relates to uses of an aminoethylphenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of urolithiasis.
The present invention relates to uses of an aminoethylphenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof as agents for relieving pain and promoting the removal of calculi in urolithiasis.
The present invention relates to processes for the manufacture of a pharmaceutical composition for the treatment of urolithiasis, characterized in the use, as an essential constituent of said pharmaceutical composition, of an aminoethylphenoxyacetic acid derivative represented by the above general formula (I) or a pharmaceutically acceptable salt thereof.
In the present invention, the term “lower alkyl group” means an alkyl group having from 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group and a hexyl group; the term “aralkyl group” means the above lower alkyl group substituted by an aryl group such as a phenyl group and a naphthyl group; and the term “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
The compounds represented by the above general formula (I) of the present invention can be prepared according to the following procedures. For example, the compounds of the present invention can be prepared by subjecting a phenylpropanolamine derivative represented by the formula:
(wherein the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above) to alkylation using an alkylating agent represented by the general formula:
(wherein R
1a
represents a lower alkyl group or an aralkyl group; X
1
represents a chlorine atom or a bromine atom; and R
2
has the same meaning as defined above), and hydrolyzing the ester group of the resulting compound in the usual way as occasion demands.
Of the compounds represented by the above general formula (I) of the present invention, compounds represented by the general formula:
(wherein R
1a
, R
2
, the carbon atom marked with (R) and the carbon atom marked with (S) have the same meanings as defined above) can be also prepared by esterification of the corresponding aminoethylphenoxyacetic acid derivative (compounds represented by the general formula (Ib) described below).
The phenylpropanolamine derivative represented by the above formula (II) used as a starting material in the above production process can be prepared by optical resolution of a commercially available enantiomeric mixture in the usual way or a method described in a literature (J. Med. Chem., Vol. 20, No. 7, pp. 978-981(1977)).
The alkylating agents represented by the above general formula (III) used as starting materials in the above production process can be prepared by allowing an anisole derivative represented by the general formula:
(wherein R
2
has the same meaning as defined above) to react with a compound represented by the general formula:
(wherein X
2
represents a chlorine atom or a bromine atom; and X
1
has the same meaning as defined above) in the presence of a Lewis acid such as aluminum chloride, removing the methyl group as occasion demands, reducing the carbonyl group using a reducing agent such as triethylsilane to give a phenol derivative represented by the general formula:
(wherein R
2
and X
1
have the same meanings as defined above), and allowing the resulting compound to react with an alkyl halogenoacetate in the presence of a base such as potassium carbonate.
The aminoethylphenoxyacetic acid derivatives represented by the above general formula (I) of the present invention obtained by the above production processes can be readily isolated and purified by conventional separation means such as fractional recrystallization, purification using column chromatography and solvent extraction.
The aminoethylphenoxyacetic acid derivatives represented by the above general formula (I) of the present invention can be converted into their pharmaceutically acceptable salts in the usual way. Examples of the such salts include acid addition salts formed with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, acid addition salts formed with organic acids such as formic acid, acetic acid, propionic acid, citric acid, tartaric acid, fumalic acid, butyric acid, oxalic acid, succinic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, methane
Akahane Masuo
Hirabayashi Akihito
Mukaiyama Harunobu
Muranaka Hideyuki
Sato Masa-aki
Geist Gary
Kissei Pharmaceutical Co. Ltd.
Tucker Zachary C.
LandOfFree
Aminoethylphenoxyacetic acid derivatives and drugs for pain... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Aminoethylphenoxyacetic acid derivatives and drugs for pain..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aminoethylphenoxyacetic acid derivatives and drugs for pain... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2911771