US2387879A

US2387879A - Piperidinol esters as antispasmodic agents

Info

Publication number: US2387879A
Application number: US330773A
Authority: US
Inventors: Robert R Burtner
Original assignee: GD Searle LLC
Current assignee: GD Searle LLC
Priority date: 1940-04-20
Filing date: 1940-04-20
Publication date: 1945-10-30
Anticipated expiration: 1962-10-30

Description

Patented Oct. 30, 1945 PIPERIDINOL ESTERS AS ANTISPASMODIC AGENTS Robert R. Burtner, Niles Center, 11]., assignor to G. D. Searle & 00., Chicago, 111., a corporation of Illinois No Drawing. Application April 20, 1940, Serial No. 330,773

Claims.

This invention relates to the preparation of new compounds having a relaxing eiTect on smooth muscle similar to that of atropine and papaverine. More specifically, it relates to the preparation of esters of fluorene-Q-carboxylic acid with 4-hydroxypiperidine, or certain derivatives thereof, the water-soluble salts of which esters exhibit a powerful anti-spasmodic efiect.

In my co-pending application, Serial No. 330,- 771, filed April 20, 1940, I have shown that esters of fiuorene-9-carboxylic acid with certain noncyclic alkylaminoalkanols possess valuable therapeutic properties as anti-spasmodic agents. In another co-pending application, Serial No. 330,- 772, filed April 20, 1940, 'I have further shown that the diphenylacetic acid esters of a group of cyclic aminoalcohols, namely, 4-hydroxypiperidine and certain derivatives thereof, are highly active as spasmolytic agents. I have now found that the fluorene-Q-carboxylic acid esters of this same group of cyclic aminoalcohols are also highly active as spasmolytic agents, being in many instances definitely more effective than the correspending diphenylacetic acid ester. Though the toxicity of these esters is in general also higher than the corresponding diphenylacetic esters, it

is not increased in proportion to the increased pomay be represented by the formula wherein R. represents hydrogen, methyl, or ethyl,

and R re esents hydrogen, an alkyl group containing not more than four carbon atoms, a benzyl group, or a p-phenyl-ethyl group.

These esters, in the form of their hydrochlodinarily powerful neurotropic drug) but at least rides, have been tested for musculotropic relaxing power by measuring their antagonism to contractions caused by histamine in a guinea pig's measuring their antagonism to contractions ten times as great as that of papaverine. The corresponding ester salt of 4-hydroxy-N,2,6-trimethyl piperidine, another preferred form of the invention, was somewhat less active, though at the same time it showed activity approximately twice that of the corresponding diphenylacetic ester. Others of the esters embraced within the present invention have been similarly tested, and

found to be qualitatively similar in activity, though varying among themselves in quantitative potency..

It has further been found that the hydrochlorides of the esters may advantageously be prepared by causing the acid chloride of fluorene-9- carboxylic acid to react upon 4-hydroxypiperidine, or the desired derivative thereof, either with or without the use of an inert diluent. 'The following examples illustrate the manner in which this invention may be carried out.

Example 1'.--21 grams of fluorene-Q-carboxylic acid are converted to the acid chloride in any convenient fashion, as, for instance, by the use of thionyl chloride. After the removal of excess reagent and solvent, if any, the crude acid chlocrystalline material filtered. It is washed with fresh benzene, dried in a vacuum, and finally crystallized from absolute ethanol. When pure, the hydrochloride of the fluorene-Q-carboxylic ester of 4-hydroxy-N-methylpiperidine thus obtained, is a colorless crystalline salt, very soluble in'water, and with a melting point of Zia-219 centigrade.

The free base may be liberated from the above hydrochloride by treatment oi an aqueous solution oi the salt with dilute aqueous alkali, and extracting the oil with ether. Upon removing the ether, the free basic ester remains as a lisht yellow oil. This ester may be converted to salts with a variety of acids, both organic and inorganic, by treatment in an anhydrous solvent (such as dry ether, absolute alcohol, benzene, and the like) with a solution of the desired acid in an anhydrous solvent. Aqueous solutions of such salts may be obtained by direct solution of the ester in dilute aqueous solutions of the desired ac (1.

Example 2.-Other fluorene-Q-carboxylic acid esters, as defined above, may be prepared in a manner exactly analogous to that described in Example 1, using in place of the 4-hydroxy-N- methyl piperidine called for in that example, an equimolecular Portion of other 4-hydroxypiperidine derivatives. Thus, among others, I have prepared the fluorene-9-carboxylic ester of -i-hydroxy-N,2,6-trimethyl piperidine (hydrochloride, M. P. 217--218 0.); of 4-hydroxy-N-butyl piperidine (hydrochloride, M. P. 158 0.); and of 4-hydroxy-N-fl-phenylethyl piperidine (hydrochloride, M. P. 224 C.) by this same method. These salts, as well as salts with other acids, are all water soluble, while the free basic esters are quite insoluble in water, though soluble in many organic solvents, and in dilute aqueous acid solutions (accompanied in the latter case with salt forma tion). These esters may in some cases be distilled in a very high vacuum, though there is generally a definite tendency to decompose during such distillation. These esters may be converted to their corresponding salts by the methods described above.

The 4-hydroxypiperidine derivatives used in preparing the esters described herein may be obtained by the reduction of the corresponding piperidones, using the method oi. reduction described by Emmert in German Patent 292,871.

The spasmolytic activity of the salts described herein is due to the basic ester portion of the .molecule and not to the acid used in forming the salt. It will thus be apparent to one skilled in the art that salts other than the hydrochloride may be used with equal success in the practice of this invention, the hydrochloride having been employed in the above disclosure solely by reason of convenience. Among such other salts are the sulfates, hydrobromides, phosphates, acetates, tartrates, citrates, nitrates, etc. It is to be understood that the term ester as used in the appended claims shall be construed to include not only esters in the free state but also esters as combined with acids in the form of such salts. The invention is therefore not limited except as defined by the appended claims which are to be construed as including a proper range of equivalents.

assure I claim:

1. New compounds prepared for use as antispasmodics consisting of the basic esters of fluorene-Q-carbosylic acid 01 the formula CHI-C C O O C N-R' CHs-C wherein R is one of the group consisting of hydrogen, methyl and ethyl, and R is one f th group consisting of hydrogen, alkyl groups'containing not more than four carbon atoms, benzyl, and B-phenylethyl.

2. New compounds prepared for use as antlspasmodics consisting of the basic esters oi tluorene-Q-carboxylic acid of the formula CHr-CH:

CHr-Cfis wherein R is one oi! the group consisting of hydrogen, an alkyl group containing not more than four carbon atoms, benzyl and fl-phenylethyl.

3. A newcompound prepared for use as an anti-spasmodic consisting of the fluorene-Q-carboxylate o! 4-hydroxy-N-methyl-piperidine of the formula CHg-CH; C 00 C CHr-Cs ROBERT R. BURTNER.

/CHs Clix-CH N-CH: