IL27838A - Pharmaceutical compositions containing 2-cyclohexyl-and 2-phenyl-2-hydroxycyclohexane-1-carboxylic and-1-acetic acids and salts and basic ester thereof;novel compounds of this group and their preparation - Google Patents

Description

invention generally relates to pharmaceutical compositions having a strong choleretic activity or a substantial antispasmodic She invention further consists in certain novel therapeutically active compounds and particularly to some acids and esters thereof with various as well as of the basic Finall invention also provides methods for preparing said novel acids and The pharmaceutical compositions accordin tp the present invention comprise as active ingredients at least one compound having the general in which R is phenyl or cyclohexyls is a group wherein is hydrogen or a groups R is X may also a group or pharmaceutically The pharmaceutical compositions to invention may in addition to the above mentioned active other conventional such as magnesium stearate o and or additional therapeutically active such as glycosides of easeara rhubarb artichoke belladonna vitamin PP or sodium se The compounds of formula I except the acids of I i which 1 is phenyl and X is a group are novel constitute one aspect of present inventio She invention extends also to the of the el basic esters with therapeutically tolerable anions of inorganic and organic acids as tartaric and to the derivatives of these basic esters with such as or with The novel compounds according to the present invention can be prepared by the synthesis of the acids of the general formula 1 if the transformation of these acids into their corresponding if the transformation of the esters into their acid addition salts or quaternary The following methods Can be acids of the general formula in which X a group can be prepared by reacting with a or a reagent in an ether and oxidizing or hen drox chromic mixture or with dilute nitric acid can also be prepared by acid over in an acetic acid at and under a hydrogen pressure of 20 acid of the formula I in which is phenyl and X is the group can be prepared by the ethyl ester of ic a id with a and the thus with basic esters of formula I in which the group is other than can prepared by reacting the potassium salt of the corresponding free in alcoholic with an selected from the following propyl h and As alternatives to the above the basic esters represented by the general formula have also been prepared by the following Some of the basic esters of formula I above can also be prepared by reacting the potassium salts of the corresponding acids of formula I in which X the group with such and and reacting the product obtained with a secondary such as The antispasmodic activity of the esters of formula to the and their salts determined on segments of various isolated organs and it could be observed that most of the tested products inhibit o prevent contraction caused by the various spasmogen agents both of hormonal and humoral as well as of a different for some of the tested compounds such inhibitory or preventive activity is already apparent at a concentration 1x10 and 1x10 antispasmodic activity of the compounds according to the invention is better shown in in terms of the inhibiting the spasm of isolated organs are given s terminal ascending rats produced by some spasmogen such as histamine acetyl and In the along with some products according to the there are also given some commerciall available and the respective values of prove that the new compounds may be advantageously compared with the 2 Products S p a s m o g e n s ear oxylate 9 carboxylate carboxylate carboxylate bromide of diethylaminoethylamide of the monoethyl ester of the The products according to the invention are much less toxic than papaverine and the thereo by endoperitoneal route in a 15 about 220 105 Drugs according to the invention do not show hypotensive effects and are particularly suitable for spasms of biliar organs and the alimentary canal both because they removed by th biliary tract and for their clearly choline which is of the same as that of For these reasons the compounds of the present invention are therapeutic agents useful for treatingoany unhealthy ditions biliary and and in the therapy of spastic conditions of digestive biliary urinary organs and genital invention is illustrated by the limiting acid This known acid formula can obtained as follows 25 of in 20 of were into a vessel containing a ether suspension of of magnesium 128 of enzene in 300 of ether according to usual with stirring and external cooling with The mixture stirred for some then the magnesium compound was decomposed by pouring t carefully into water and the magnesium hydroxide was dissolved in of a saturated solution of the ether layer was separated and the aqueous layer extracted with a further portion of The combined ether extracts were dried and evaporated and th residue upon distillation in acuo 15 of a thick at oil having mm Such a crystallized b dissolving in ether and with petroleum ether 7 The glycol thus was dried and finely powdered and then suspended of an aqueous solution of 14 and 7 of and the suspension was thoroughly stirred one After removing of thus formed by a small amount of added till the violet coloration removed again and the alkaline solution was acidified with concentrated After standing for one day in a the product washed with water and yielding 5 of of acid were dissolved in 75 of glaGial acetic acid and reduced in an autoclave in the presence of of platinum oxide under a hydrogen pressure of 22 and at a temperature of After the hydrogen absorption was the solution was filtered and evaporated to of its volume and cooled in a precipitate was filtered and washed with wate and then crystallized from yielding 4 of ex III An ether solution of bromide from of of and 100 of absolute was added during about 2 a nitrogen with and cooling with to a solution of 18 of ethyl in 100 of absolute After one hour stirring at the reaction mixture was carefully treated with o organic layer was the aqueous suspension washed with ether and the combined ether extracts were dried over eva orated to treating the product with petroleum ether and drying it in it solidified and was recrystallized from petroleum yielding a colourless melting at and corresponding to the of the desired 8 of this refluxed for 5 hours in a solution of 5 of of After evaporation of the methanol dissolving the residue in of washing the aqueous solution with ether and subsequent acidification with dilute sulphuric of the desired acid were obtained after reerystallizatlon from an ether mixture a colourless IV e of acid were dissolved in 15 of absolute isopropanol and 7 of a methanol solution containing of potassium methoxide and of added in this order to the The solution was refluxed for 3 hours and the inorganic precipitate was filtered off and the alcohol evaporated under residue was extracted with 50 of the extract was washed twice with made alkaline with and the oil thus formed was extracted with The extract was dried and evaporated to yield an oleous residue which a vacuum distillation yielded o as a colourless at 20 of methanol solution containing of potassium methoxido were added to 10 of carboxylic dissolved in 40 of and the resulting solution was slowly dropped into of dissolved in 10 of isopropanol wit stirring and reflux After the addition was continued for further and the solution then filtered from inorganic precipitate and residue thus was extracted with washed with dilute solution sodium carbonate and with and finally dried and te dissolved in 50 of ether were reacted with From the resulting solution an oily product separated at this product after repeated washings had the form of colourless hygroscopic of and of methyl iodide were dissolved in 5 of methanol and the solution was heated a closed vessel at for 7 By evaporation of the reaction solutio a product was obtained which after washings with ether and crystallizations from the form of light yellow By the general methods previously described the following compounds 5 carboxylate late colourless light yellow carboxylate earboxylate ox colourless yellow 1 carbox yellowish acid addition salts of the above with inorganic as hydrochloric acid and sulphuric and organic acids as citric and the quaternary derivatives with halides as methyl methyl ethyl ethyl butyl and generally in the form of or amorphous resins and only in eases they crystalline e moat significant of these compounds Siethy colourless thick its elemental analysis agrees the tharetic ate ethyliodide resinous solid methylio low amorphous yellow 2 yellow thick WITH ACTIVE Pills weighing about of which acid 100 Lactose 110 Avicel Inert excipients Sugar 240 Talc 7 3 pills meal time Tablets weighing and 10 Starch 40 Lactose 30 Inert exeipients Tele 15 Magnesium stearate 5 tablets a day out of ANTISPASMODIC WITH Tablets weighing and 10 Sodium Active ingredient metasulphonate 200 Starch Lactose 5 Inert ingredients Talc 25 stearate 10 tablets a day out of insufficientOCRQuality

Claims (1)

1. CLAIMS Pharmaceutical compositions comprising as active ingredients at least one compound having the general formula in which is or X is a group wherein is hydroge a group when R is X may also be a group or or at least one pharmaceutically acceptable salt of these compositions according to Claiss also comprising as additional ingredients at least one of the following anthraquinone glycosides of cascara rhubarb artichoke belladonna vitamin PP or sodium Compounds of the general formula I in 1 except those compounds which E is phenyl and X is a group or pharmaceutically acceptable salts thereof and quaternary ammonium derivatives of the compounds of formula X in which is other than hydrogen with alkyl or A process for preparing compounds according to Claim 3 in which is a group cyclohexanone is reacted with an appropriate the resulting glycol is oxidized to the ponding acid of formula I in Claim in which X is a group if the acid is converted into a corresponding ester of in Claim in which X is a group where is other than A process for preparing the compound according to Claim which R s phenyl and X is the group wherein cyclohexanone acid is reacted with a phenyl Grignard reagent and the ing is converted into the desired A process according to Claim wherein the obtained in the first stage of the is reacted with y ethylene and the ester thus produced is reacted with h A process for preparing compounds according to Claim 3 in which R is wherein acid reduced catalytically with hydrogen under if the acid thus verted into ah ester of formula I in Claim in which R is cyclohexyl and is where is other than A process for preparing compounds according to Claim in which X is other than the group wherein the potassium salt of the corresponding acid of formula I in Claim in which X is the group or is reacted with an appropriate aminoalkyl A process for preparing compounds according to Claim which is other than the group wherein the corresponding acid of formula I in Claim in which is the group or is with an dihalide and the thus produced reacted with an appropriate secondary A method for preparing compounds according to Claim substantially as herein described with reference to the For COM insufficientOCRQuality