IL45995A - 4-pyridylthiazole-2-carboxamides and acetamides their preparation and pharmaceutical compositions containing them - Google Patents

Description

their preparation and pharmaceutical compositions containing them EGYT 45988 2 This invention relates to new substituted and acetamides and pharmaceutical compositions containing the as well as to a process for the preparation The compounds according fco the invention correspond to the general formula wherein R stands for a pyridyl stands for is equal to 0 or and each represent lower a a h ethyl rylmetlryl benzyl phenyl group and R may together with the adjacent nitrogen up of the or n represents to Y of formula are of basic character and acid addition various mineral or organic The pharmaceutic acceptable acid salts of t e compounds having the general formula are also included by the scope The compounds of the general formula or pharmaceutically acceptable acid addition salts can be according to the as a halo of the general formula wherein and each have the same meanings as defined above and X stands for is with a compound of the general formula wherein and m each have the same meanings as a or acid of the formula s 1 R and each have the same meanings as defined above and Z stands for lower or azido is reacted with an amine of the general formula wherein and R each have the same meanings as defined if a free base of the general formula is converted into its pharmaceutically acceptable acid addition or a salt is converted into the free The above reactions are performed preferably in the presence of an inert solvent or diluen As solvent or diluent preferably suc ethanol or propanols or aromatic as toluene such as diethyl diisopropyl dioxane or or a mixtu of such can be Depending on the of the group and on the reaction conditions the compounds of the general formula either as free bases or as hydrohalide Both the free bases and the salts can be separated from the reaction ture by known per and con also be used practical purposes without any subsequent If a h is to be converted into tho free one proceed dissolving the salt in rendering alkaline the aqueous and separating the base of general by usual As basic substances alkali and alkaline earth metal carbonates or hydrogen as well as aqueous or organic ammonia solutions as alcoholic ammonia can be The bases of the general formula can be ed their physiologically acceptable acid addition salts by reacting them with an appropriate For this pose primarily or acid can be The new compounds of the general formula are valuable They exert a high inhibiting effect on the gastric acid secretion in and also inhibit the appearance of experimental ulcers A significant vantage of the new compounds in comparison with the known substances capable of inhibiting the gastric acid that they are completely devoid of lytic side thus no an such as mouth accomodation take place upon the administration of the new The effects of new compounds exerted on the gastric acid secretion end Shay ulcer were examined ing to the method of 43 while their inhibiting effect exerted on immobilisation and insulin ulcer were tested according to the method of Borsi et 151 The mydriatic effects of the new compounds were examined according to the method of 168 307 in order to determine whether the compounds possess anticholinergic side effects or All experiments were carried out on As reference methantheline ammonium bromide was The result of the above tests are summarized in Table Table 1 2 45 23 20 15 1 4 35 28 5 40 25 8 13 40 17 8 The data of Table 1 clearly indicate that both the oral and the intrape i toxicities of the compounds according to the invention are substantially lower than those of used as reference For some compounds the difference in toxicities reaches almost one order of magnitude in favour of the compounds according to the the therapeutical indices of the compounds according to the invention are generally more favourable than those of methantheline the compounds according to the tion have several advantages over the hitherto known tion inhibiting they have no cholinergic side their toxicities are and their therapeutical indices are Some of the new compounds h in eddition to the secretion and ulcer inhibiting considerable inflammatory effect as With regard to the flammatory effect the simultaneous existence of the inhibiting effect is very since it is that the general side effect of the stances applied in the therapy so far is the induction of gastric The effective daily dosage of the compounds having the general formula ranges to 500 The ory activity of the new compounds was examined on with carrageenin oedema test 544 of a 10 carrageenin solution was into the hind paw of and the increase in volume was measured three hours this compounds under ion were ministered in dosage of 100 The results of this test are summarized in Table Table 2 Compound Dosage Percentage of tion of oedema 2 100 5 100 19 The most active 3 has been subjected to further In addition to the inhibition of carrageenin the activity exerted in the cotton granuloma test was also The following results were oedema 91 granuloma er one week of The compounds of the general formula or their pharmaceutically acceptable acid addition salts can be ministered to humans or animals in the form of such as coated injectable prepar These pharmaceutical compositions are prepared by known using the conventional ical diluents auxiliary The pharmaceutical compositions can be if required The invention is elucidated in detail by the of the following 1 Proportion of are added to a birred of 25 of rae thanol and of aqueous A deep yellow solution is and soon begins the separation of a crystalline The separated crystals are filtered off and dried at of are recrystallization from a mixture of dimethylformamide and Example 2 Preparation of carboxamide 25 of a methanol solution of metliylamine are added to a solution of in 25 of and the tion is allowed to stand at room temperature for days in a well baffled The separated crystalline substance is filtered and the filtrate is concentrated to obtain a further amount of the A total amount of 7 of 3 is recrystallization from Examples g to 15 The procedure described in Example 2 is but the following compounds are used as propylamine and The obtained products are listed in Table Table 5 o 3 HC1 67 4 isopropyl HC1 80 5 3 HC1 64 6 3 98 86 7 80 8 dihydrochloride 63 9 dihydrochloride 73 10 84 11 53 12 of r o d u c t Yield Example 12 55 13 48 14 carbonylj 84 15 96 75 Example 16 Preparation of 4 hydrochloride 5 of cyclopropylainine are added to a suspension of acid ethyl ester hydrobromide in of and the tained red solution is stirred at temperature for 2 Thereafter the solvent and the excess of ore evaporated under reduced the residue is taken in 20 of and this solution is acidified to pH J with isopropanolic hydrochloric The ide is separated and recrystallized of the title compound are Example 17 Preparation of aqueous and 12 of During the addition the mixture is cooled with an ice Thereafter the mixture is stirred at room ure for 6 and finally allowed to stand in refrigerator of are recrystallization from Example 18 Preparation of 3 hydrochloride A mixture of of hydrobromide JO of methanol and 9 of cyclopropylamine is maintained at room temperature for 48 The solvent and the excess of the amine removed under reduced pressure and the residue is dissolved in The aqueous solution is rendered alkaline with sodium and the separated oily substance is ed into The chloroform solution is evaporated to end the residue is taken up in This solution is treated with an isopropcnol tion of dry hydrochloric acid to obtain of the title tion from Example 19 Preparation of acetamide The procedure described in Example 18 is repeated with the difference that allylamine is used as and the product is not converted into its of the title compound are 10 Example 20 Preparation of mixture of of methyl hydrobromide of methanol and 5 of cyclopropylemine is maintained at room temperature for 20 Thereafter the solvent and the excess of the amine are removed under reduced and the residue is crystallized from a mixture of acetone and of title compound are insufficientOCRQuality

Claims (1)

1. 5 CLAIMS Substituted amides of the general formula or pharmaceutically acceptable acid addition wherein stands for a p ridyl p R stands for is equal to 0 or and each represent lower a hydroxyalkyl a cycloalkyl ethyl h benzyl phenyl group or and may together the adjacent nitrogen a saturated heterocyclic group of the general formula or 16 Υ η represents an integer of from and Y stands for A process for the preparation of substituted amides of the general formula or pharmaceutically acceptable acid addition salts R stands for a pyridyl stands for is equal to 0 or and each represent lower a hydroxyalkyl a cycloalkyl gro hylaminoe hyl benzyl phenyl group or 17 R may together the adjacent saturated he group of the general formula or wherein n represents an integer of from to X stands for in which a haloketone of the general formula CH R2 0 X 2 wherein R and each have the same meanings as defined above and X stands for is reacted with a compound of the general formula R3 C CO S wherein and m each have the same meanings as defined or a substituted acid or ic acid derivative of the general formula 1 2 wherein R R and each have the same meanings defined above and Z stands for lower or azido is reacted with an amine of the general formula wherein and each have the same meanings as defined if a free base of the general formula is converted into its pharmaceutically acceptable acid eddition or a salt is converted into the free Pharmaceutical compositions containing a stituted amide of the general formula or pharmaceutically acceptable acid addition salts wherein and each have the same meanings as defined in claim together with a diluent or auxiliary A process for the reparation of in which a substituted amide of the general formula or a pharmaceu ically acceptable acid addition salt wherein R and each have the same meanings as defined in claim is admixed with a diluent or auxiliary β Compounds of the general formula substantiall 19 as hereinbefore with special reference to the A process for the preparation of of the general formule substantially as hereinbefore with special reference to the A compound of the general formula whenever prepared by a process as claimed in claim 2 or HE insufficientOCRQuality