IL45970A

IL45970A - 3-(4-pyridyl-2-thiazolyl)urea and thiourea derivatives their preparation and pharmaceutical compositions containing them

Info

Publication number: IL45970A
Application number: IL45970A
Authority: IL
Original assignee: Egyt Gyogyszervegyeszeti Gyar
Priority date: 1973-11-09
Filing date: 1974-10-31
Publication date: 1977-08-31
Also published as: CS183797B2; NL7414583A; AU7512374A; CS183768B2; HU168393B; DE2453082A1; IL45970A0; FR2250525B1; BE822029A; FR2250525A1; GB1437895A

Description

New and thiourea their preparation and pharmaceutical compositions containing them Gyar 43974 This to new thiazolylurea deriva and compositions containing the as well as to a the preparation As several substituted urea end thiourea derivatives possess valuable pharmaceutical for the urea and thiourea derivatives of 1 thiazola possess antiviral activity published German Patent ions and Several methods are known for the preparation of urea and thiourea derivatives 181 Georg Thieme Georg Thieme It is also known that when ing with is obtained 2937 Now has been found that new compounds possessing valuable pharmaceutical effects can be obtained by ing the amino group of into an ureido or thioureido and introducing a pyridyl group into tion as well as a lower group into position of the the invention relates to new substi ed thiaaolylurea and derivatives having the general formula and pharmaceutically acceptable acid addition salts thereof wherein stands for a pyridyl R2 and each stand for hydrogen or a alkyl Y stands for oxygen or and and each stand for a lower aliyl a cycloalkyl phenyl group or a halophenyl group or The invention relates further to a process for the preparation of compounds of the general formula or acid addition salts According to the process of the invention a haloacylpyridine hydrohalide of the formula HX 0 X wherein and R2 each have the same defined above and X stands for is reacted with a compound of the general formula wherein R and Y each the meanings as fined or a of the general formula wherein R and each have the same meanings as defined is reacted with an isocyanate or isothiocyanate of the general wherein and Y each have the same meanings as defined a of the general formula and each have the same meanings as defined is reacted with an alkali cyanra e or thiocyanate a carbamate or the general R wherein R and each have the same meanings as ft fined above and R stands for a lower alkyl or phenyl is reacted with an amine of the general formula wherein R and each have the same meanings as defined or a th azide of the general mula wherein and R2 each have the same meanings as defined is converted by into a isocyanate of the general formula 1 wherein and R each have the same meanings as defined above and I stands for and this compound is pref in the reaction with an amine of the general formula wherein and have the same meanings as defined or a of the general wherein and R each have the same meanings as defined above and stands for is reacted with carbon disulfide and dicyclohexyl end the obtained t isothiocyanate of the general formula wherein and R2 each have the same meanings as above and Y stands for is reacted with an amine of t ve the s wherein 5 and Y each have the same meanings as eneral formula defined or a of the general formula 1 2 wherein each have the same meanings as defined reacted a carbamoyl chloride or chloride of the general formula R and 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 8bove reactions are performed preferably in the presence of an inert solvent or As solvent or diluent preferably lower such as ethanol or such as propyl glycol dimethyl dioxane or te acid amide type such as me thy If or thylacetamide or phosphoric acid aromatic such as toluene or isomeric halogenated such methylene ethylene chloride chloroform as well as dimethyl or a mixture of these solvents can be The reactions are conducted at a temperature ranging from to In order to obtain optimum yield process variant is carried out preferably at to the boiling point of the solvent or an aqueous lower are performed preferably an solvent at the boiling point of the mixture or in dime at 90 to In order to facilitate the reactions according to process variants it is preferable to add in an amount of to 10 by calculated for to the reaction The reactio according to process variant can be performed in an aqueous medium in the presence of a strong in some it is preferred to carry out the reaction in benzene or toluene in the presence of acetic The reaction according to process variant can be performed in a dime thyijsuIfoxide medium at room temperature in the presence of an alkali metal sodium or or an alkali metal hydride sodium or lithium one may also by reacting a compound of the general formula with an excess of the respective amine with or without a solvent In this latter when an amine with a low boiling point is the reaction is preferably carried out in a closed vessel superatmospheric The reaction ing to process variant is performed preferably in the presence of an aromatic at or near to the boilin of the solvent When proceeding accordin to process variants or the reaction is preferably carried ou in a chlorinated hydrocarbon The most preferred acid binding agent for the reaction of process variant is the excess of the respective amine while when proceeding according to process variant preferably a tertiary organic such as or temperature of the reaction fixture is initially maintained at a low optionally by external then the reaction is completed at room or optionally by heating the mixture up to The reactants are applied generally in stoichiome ric amounts in some it is preferable to use the more easily accessible reagent in a slight proceeding according to process variant sometimes a hydrohalide of the desired compound is thus it is optionally necessary to liberate the base from its For this purpose an alkali or alkaline earth metal carbonate or as well as aqueous ammonia can be Aqueous ammonia a particularly ferred reagent to liberate the The bases of the general formula can be ed into their physiologically acceptable acid addition salts by reacting them an organic or mineral For this purpose primarily or acid can be The new compounds of the general formula are valuable therape They exert a high inhibiting effect on the gastric acid secretion in and also inhibit the appearance of experimental A significant advantage of the new compounds in comparison with the known stances capable of inhibiting the gastric acid tha they are completely devoid of parasympatholytic side thus no anticholinergic such as mouth accomodation The effects of the new compounds exerted on the gastric acid secretion and Shay ulcer were examined according to the method of Shay et 43 while their inhibition effects exerted on immobilisation and insulin ulcer were tested according to the method of Borsi et al 38 The mydriatic effects of the new compounds were tested according to the method of 168 in order to determine whether the compounds possess anticholinergic side effects or All experiments were carried out on As reference theline bromide ester with lic was The results of the above tests are summarized in Table data of Table 1 clearly indicate that both the oral and the intraperitoneal toxicities of the compounds according to the invention substantially lower than those of j used as reference For some compounds difference in toxicities reaches almost one order of of the compounds accordin to the the therapeutic indices of the compounds according to the invention are generally more favourable than those of the compounds according to the tion have several over the hitherto known tion inhibiting they have no cholinergic side their toxicities are and their therapeutic indices are Some of the new compounds in addition to the secretion and ulcer inhibiting considerable effect as regard to the flammatory effect the simultaneous existence of the inhibiting effect is very since it is known tha 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 from 10 to The ory activity of the new compounds was examined on with carrageenin oedema test of a carrageenin solution was injected into ind paw of fter this The under examination dministered a dosage of 100 The results of this test are summarized in Table Table 2 Compound Dosage Percentage of tion of oedema 1 100 2 100 40 3 100 61 4 100 6 100 37 9 100 32 10 100 40 11 100 18 14 100 The two cost active compounds have been subjected to further It has been found that the value of compound 3 the carrageenin oedema test with intraperitoneal administration is 110 for compound 4 a of has been The value of phenylbutazone is 40 in the same The activity of compound 4 has also been examined by means of the cotton granuloma according to method In this the value of the compound has been found to be 4 on the basis of a in the same are as 22 2099 The value not be determined for because all the test animals perished upon the of a 100 dosage of for one The of the general formula or their pharmaceutically acceptable acid addition salts can ministered to humans or animals in the form of ical such as coated injectable These pharmaceutical compositions are prepared by known using the conventional ical diluents auxiliary The pharmaceutical compositions can be if The invention is elucidated in detail by the aid of the following 1 Preparation of Method A mixture of of of and of water is tained at for 2 The solution is filtered when the filtrate is heated again to then rendered alkaline with aqueoup ammonia under vigorous The solution is cooled with ice and the separated product is filtered 91 of are Method A solution of of oroacetic acid in of dry toluene is whithin 2 to a pension of of Heterocyclic 9 and 5 of sodium cyanate in of dry under vigorous the addition is the mixture is boiled for 2 thereafter it is and the toluene is The residue is treated with 150 of hydrochloric the mixture is and the pH of the filtrate is justed to with aqueous The separated pitate is filtered and recrystallized from of urea are Example 2 Preparation of A mixture of of 15 of dry of dry and of isopropyl isocyanate is heated at for 2 thereafter the solution is poured 0 of cold The obtained product is filtered washed with and dried at of are tained reoryatallization from methyl ethyl Examples to 9 The procedure described in Example 2 is ethyl cyclohexyl phenyl and The obtained products are listed Table Table of o u c urea 4 urea 5 6 7 8 urea 9 Example 10 Preparation of A mixture of of t iazole prepared by reacting urea with dry 40 of dry and 17 of ethyl isocyanate refluxed for The is evaporated under reduced and the residue is recrystallized from a mixture of isopropanol and petroleum of are 1 11 Preparation of The procedure described in Example 10 is repeated but isopropyl isocyanate are substituted for ethyl of are ecrystallization from Example 12 Preparation of Step Preparation of cyclopropyl isothiocyanate 66 of carbon disulfide are added to a solution of of sodium hydroxide in 100 of and the mixture is cooled to in an ice of propylamine are added to the mixture whithin 25 under and the mixture is stirred for additional Thereafter the mixture is heated to and stirred at this temperature for 2 The mixture is cooled to room 105 of ethyl chloroformate are added whithin and the obtained mixture is stirred for hours at room Thereafter the upper oily phase is separated and the aqueous phase is extracted with The ethereal layer is combined with the oily and the solvent is evaporated under reduced The residue is distilled in of propyl isothiocyanate are Step Preparation of A mixture of of of dry of dry triethylamine and of cyclopropyl isothiocyanate is refluxed for 5 then maintained in refrigerator The obtained crystalline substance is of ea are recrystallization from ethane Examples 13 to 16 The procedure described in step of Example 12 is but is substituted for and allyl methyl isothiocyanate and benzyl isothiocyanat are substituted for cyclopropyl The obtained products are listed in Table Table 4 of Example 14 of Example o d c 16 i Example 17 Preparation of Preparation carboxylic acid hydrazide of hydrazine hydrate are added to a tion of of in 60 of A red solution is and the crystalline product separated some The crystals were filtered of acid hydrazide are recrystallizat ion from Step Preparation of carboxylic azide 1 of aqueous hydrochloric acid is added to a suspension of of acid hydrazide in 25 of and a solution of of sodium nitrite in of water is added dropwise to the stirred mixture under cooling in an ice A yellow suspension is After 15 minutes of stirring the separated product is filtered off and dried at azide are 20 Step of ea of obtained as described in step are heated at in of dry When the evolution of freshly distilled and of dry are added to the and the whole is heated at for additional The mixture is and the parated substance is filtered of are recrystallization from a mixture of formamide and The mixture of this compound with that prepared by reacting with phenyl melts at thus both reactions yield the same product Example 18 Preparation of The procedure described in step G of Example repeated is substituted for of the title compound are Example 19 Preparation of A mixture of of of 730 and of water is stirred at for 1 The is filtered while and the pH of the filtrate is justed to with aqueous The separated product of are le 20 Preparation of The procedure described in Example 1 is repeated with the difference that 2 is used of the title compound are Example 21 The procedure described in Example 19 ia repeated with the difference that 2223 used as of the title compound are insufficientOCRQuality

Claims

1. 45970/2 - 22 - What we claim is: 1·_ Substituted thiazolylurea or -thiourea derivativ of the general formula (I) or pharmaceutically acceptable acid addition salte thereof, wherein R1 stands for a pyridyl group, R2 ar,d R5 each stand for hydrogen or a lower alkyl group, Y stands for oxygen or sulfur, and and R^ each stand for hydrogen, a lower alkyl group, allyl group, a C5_6 cycloalkyl group, phenyl group or a halophenyl group or benzyl. - 23 - 45970/2

2. A process for the preparation of substituted thiazolylurea or -thiourea derivatives of the general formula (I) or pharmaceutically acceptable acid addition salte thereof, wherein R1 standa for a pyridyl group, R anifl each, stand for hydrogen or a lower alkyl group, Y standa for oxygen or sulfur, and 2*" and R^ each stand for hydrogen, a lower alkyl group, a group, a C^_5 cycloalkyl group, phenyl group or a halophenyl group or benzyl. in whic a) a haloacylpyridine hydrohalide of the general formula (II), R1 - C - CH - R2 . HX (II) 0 X 1 wherein R and R each have the same meanings as defined above and X stands for halogen, is reacted with a compound of the general formula (III), wherein R^, R , Br and Y each have the same meanings as de fined above, or b) a 2-aminothiazole of the general formula (IV), wherein Β?~9 R2 and R^ each have the same meanings as defined above, is reacted with an isocyanate or isothiocyanate of the general formula (V), wherein B^, ? and Y each have the same meanings as defined above, or - minothiazole of the eneral formula (IV), where- 45970/2 - 25 - in R , R and ^ each have the same meanings as defined above, is reacted with an alkali metal cyanate or thiocyanate in the presence of a strong mineral or organic acid, or d) a thiazol-2-yl- carbamate or -1 thiocarbamate of the general formula (VI), wherein R"*", R2 and R^ each have the same meanings as defined above and R stands for a lower alkyl o phenyl group, ia reacted with an amine of the general formula (VII), wherein R^ and R^ each have the same meanings as defin above, or e) a thiazole-2-carboxylic azide of the general formula (VIII), "~ CON- wherein R1 and R2 each have the same meanings as defined above, is converted by beat-treatment into a thiazol-2-yl- isocyanate of the ge e al formula (IX), wherein R and ^ e-ach have the same meanings as defined above and Y stands for oxygen, and this compound is reacted, preferably /directly in the reaction medium, with an amine of the general formula (VII), wherein ^ and each have the same meanings as defined above, or f) a 2-aminothiazole of the general formula (IV), wherein R and R each have the same meanings as .defined above and ^ stands for hydrogen, is reacted with carbon disulfide and dicyclohexyl oarbodiimide, and the obtained thiazol-2-yl-isothiocyanate of the general formula (IX) wherein R"*" and R2 each have the same meanings as defined above and Y stands for sulfur, is reacted with an amine of the general formula (VII), wherein ^ and ^ each have the same meanings as defined above, or g) a compound of the general formula (XII), 45970/2 - 27 - fined above, is reacted with an amine of the general formula (VII), wherein R^ and R^ each have the same meanings as defined above, or h) a 2-aminothiazole of the general formula (IV), wherein R , Br and R5 each have the same meanings as defined above, is reacted with a carbamoyl chloride or thiocarbamoyl chloride of the general formula (XIII), N - 0 (XIII) B? C1 wherein B" and R^ each have the same meanings as defined above, and, if desired, a free base of the general formula (I) is converted into its pharmaceutically acceptable acid addi- . tion salt, or a salt is converted into the free base.

3. Pharmaceutical compositions containing a substitut-ed thiazoleurea or -thiourea derivative of the general formula (I) or a pharmaceutically acceptable acid addition salt thereof, wherein R1, R2, B? , R^, and Y each have the same meanings as defined in claim 1, together with a carrier, diluent and/or auxiliary agent. .

4. A-process for the preparation of 1 pharmaceutical composition^ in which a substituted thiazoleurea or -thiourea derivative of the general formula (I) or a pharmaceutically acceptable aoid addition salt thereof, wherein R , R , R% R and Y each have the same meanings as defined in claim 1, is admixed with a carrier, diluent and/or auxiliary agent.

5. # : dompouncfc of the general formula (J), substantially 45970/2 - 28 -as hereinbefore described, with special reference to the Examples .

6. A process for the preparation of compounds of the general formula (I) , substantially as hereinbefore described, with special reference to the Examples.

7. Compounds of the general formula (I) whenever prepared by a process as claimed in claim 2 or 6. HE/ss