N-substituted pyrrolidine derivatives and process for preparing

Details N-substituted pyrrolidine derivatives and process for preparing N-substituted pyrrolidine derivatives and process for preparing

1999-06-02

2000-06-06

Lambkin, Deborah C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548541, A61K 3140, C07D20700

Patent

active

060719508

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel N-substituted pyrrolidine derivatives having a highly selective and potent antagonism against smooth muscle muscarine receptors rather than cardiac muscarine receptors and being useful for the treatment of altered smooth muscle motility and tone, such as irritable bowel syndrome, diverticulosis, urinary incontinence, esophageal achalasia and chronic obstructive airway disease, and process for preparing the same.


BACKGROUND TECHNOLOGIES

As one of the therapeutic drugs for the irritable bowel syndrome, the anticholinergic agent has been used, but it brings no sufficient therapeutic effect due to, in part, deficit of tissue selectivity. Also, while compounds that was reported to have a selective antagonism against smooth muscle muscarine receptors are disclosed (Japanese Unexamined Patent Publication Nos. Hei 2-282360 and Hei 7-149640, these compounds also do not sufficiently solve the adverse effect such as mydriasis. Moreover, these compounds have diphenylalkyl moiety linked to carbon atom of the pyrrolidine ring, making them different from the structure of the inventive compounds, in which it links to the nitrogen atom of the pyrrolidine ring.
The invention is to provide novel N-substituted pyrrolidine derivatives having a highly selective and potent antagonism against smooth muscle muscarine receptors and being useful for the treatment of irritable bowel syndrome and the like.
As a result of diligent studies directed toward the development of the drug exhibiting a highly selective and potent antagonism against smooth muscle muscarine receptors and less adverse effect of mydriasis, the inventors have found that novel N-substituted pyrrolidine derivatives represented by the following general formula (1) have high safety and are useful for the treatment of irritable bowel syndrome and the like, leading to the completion of the invention.
Namely, the invention relates to N-substituted pyrrolidine derivatives represented by the general formula (1) ##STR1## [wherein R denotes a hydrogen atom, a halogen atom or a lower alkoxy group], pharmaceutically acceptable salt, and a therapeutic drug for the irritable bowel syndrome and the like having at least one or more kinds of them as effective ingredients.
For the pharmaceutically acceptable salts of the compounds represented by the general formula (1) in the invention, acid adducts such as hydrochloride, hydrobromide, benzenesulfonate, citrate, fumarate, gluconate, lactate, maleate, methanesulfonate, succinate and tartrate are mentioned.
For the "lower alkoxy groups" in the invention, straight chain or branched ones with carbon atoms of 1 to 6 such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, isopentoxy, tert-pentoxy, neopentoxy, hexoxy, isohexoxy, sec-hexoxy and tert-hexoxy are mentioned.
For the "halogen atoms", fluorine, chlorine, bromine and iodine atoms are mentioned.
According to the invention, compounds represented by the general formula (1) can be prepared through the following process. ##STR2## [wherein R is as described above].
Compounds having the general formula (1) can be prepared by hydrolyzing the compounds represented by the general formula (4) ##STR3## [wherein R is as described above].
In the case of the use of the acid catalyst, the hydrolysis is performed under heat, preferably at 70 to 110.degree. C., using, for example, inorganic acid such as concentrated sulfuric acid. On the other hand, in the case of the alkali hydrolysis, it can be performed in alcohol, using, for example, alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, and it is preferable to perform in refluxing tert-butanol with potassium hydroxide.
Compounds having the general formula (4) are also novel compounds and can be prepared by the reaction of the compounds represented by the general formula (3) with the compounds represented by the general formula (2), or by the reaction of the compound represented by the general formula (3) that was prepared by the deprotecti

REFERENCES:
patent: 5686464 (1997-11-01), Jahansson et al.
patent: 5776972 (1998-07-01), Barber et al.
patent: 5942537 (1999-08-01), Chamberlin et al.
patent: 5952369 (1999-09-01), Ito
patent: 5962504 (1999-10-01), Kozikowski et al.

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