Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1999-04-12
2000-09-26
Huang, Evelyn Mei
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
514438, 514531, 514534, 549 77, 560102, A61K 31216, A61P 100, A61P 1310
Patent
active
06124354&
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to arylcycloalkane carboxylic esters having pharmacological properties, and to processes for their preparation. The invention also relates to pharmaceutical compositions containing arylcycloalkane carboxylic esters, methods of treating disorders related to urinary incontinence and irritable bowel syndrome (IBS), respectively, by administering an arylcycloalkane carboxylic ester, as well as methods for the manufacture of pharmaceutical compositions for treating disorders related to urinary incontinence and irritable bowel syndrome (IBS), respectively.
BACKGROUND OF THE INVENTION
A number of arylcycloalkane carboxylic esters, including arylcyclopropane, arylcyclobutane, arylcyclopentane and arylcyclohexane carboxylic acid esters, are known to possess anticholinergic activity. Some of them have a pronounced spasmolytic or anticonvulsant activity and have therefore been proposed to be used as substitutes for atropine in the treatment of sarin poisoning (sarin is an organophosphorous anticholinesterase agent acting as a nerve gas). Other activities related to that type of compounds are antipsychotic, anti-ischemic, anti-stroke and antidementia.
Specific arylcyclopropane carboxylic esters having anticholinergic activities are, for example, described in Beres, J. A., et al., J. Pa. Acad. Sci. (1992), 66(1), 2; U.S. Pat. No. 4,418,202; Mnjoyan, A. L., et al., Arm. Khim. Zh. (1976), 29(2) 194-9; Kuzuna, S., et al., Takeda Kenyosho Hu (1975), 34(4), 467-73; and WO 92/02481.
Arylcyclobutane carboxylic esters having anticholinergic activities are, for example, described in Bannard, R. A. B., et al., Can. J. Phys. Pharm. 47 (1969) 1036 (2',2'-diisopropylaminoethyl 1-phenylcyclobutane-carboxylate, 1'-methylpiperidyl-4' 1-phenylcyclobutane-carboxylate); CH--B--240160 (diethylaminoethyl 1-phenylcyclobutanecarboxylate); Parkkari, J. H., et al., Can. J. Chem. 43 (1965) 3119 (N-methyl-4-piperidyl 1-p-methylphenylcyclobutanecarboxylate, N-methyl-4-piperidyl 1-p-methoxyphenylcyclobutanecarboxylate); and Mnoyan, A.L. et al., supra (dimethylaminoethyl and diethylaminoethyl 1-benzophenylcyclobutylcarboxylates).
Arylcyclopentane carboxylic esters having anticholinergic activities are, for example, described in Bannard, R. A. B., et al., Can. J. Chem. 40 (1962) 1909-1916; Stubbins, J. F., et al, Med. Chem. Res. 2 (1992) 384-393; JP-A-02062823; U.S. Pat. No. 3,317,526; FR-A-1461314; FR-A-2155927; DD-A-289411 and FR-A-2168881.
Arylcyclohexane carboxylic esters having anticholinergic activities are, for example, described in Zbigniew, J., et al., Pol. J. Pharmacol. Pharm. 35 (1983) 103-107; Tsung-Ping Su et al., Pharmacology and Exp. Therapeutics 259 (1991) 543-550; Wolinski, J., and Cessak, M., Acta Pol. Pharm. 36 (1979) 635-40; WO 92/02481 and FR-A-2155927.
SUMMARY OF THE INVENTION
According to the present invention it has now been found that a defined group of arylcyclopropane, arylcyclobutane, arylcyclopentane and arylcyclohexane carboxylic esters, some of which are novel compounds, possess a selective antimuscarinic activity on the urinary bladder smooth muscle, and on the small intestine muscle, and are therefore indicated for the treatment of disorders of the urinary bladder, such as urge incontinence, as well as for the treatment of disorders of the small intestine, such as irritable bowel syndrome (IBS).
In one aspect, the present invention provides novel arylcycloalkane carboxylic esters of the general Formula I: ##STR1## wherein: A is an optionally substituted cycloalkane ring having 3 to 6 carbon atoms and attached at a single ring carbon atom thereof, independently are hydrogen, lower alkyl, lower alkoxy, halo, hydroxy, trifluoromethyl, nitro or amino, or R.sub.1 and R.sub.2 together form lower alkylenedioxy or optionally substituted benzo, and and R.sub.10 and R.sub.11 each are lower alkyl or R.sub.10 and R.sub.11 together with the nitrogen atom form a saturated azacyclic or azabicyclic ring system; or (ii) --(CH.sub.2).sub.m -Q, in which m is 0 or 1 and Q is th
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.ANG.kerblom Eva
Beierlein Katarina
Haraldsson Martin
Johansson Rolf
Ringberg Erik
Huang Evelyn Mei
Pharmacia & UpJohn AB
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