KR840002440B1 - Process for preparing heterocyclic derivatives of guanidine - Google Patents

Abstract

Heterocyclic guanidine derivs. of formula (I) and their pharmaceutically acceptable salts are prepd. by reacting compds. of formula (V) with compds. of formula NHR1R2 in a lower alkanol solvent at 40-100≰C. In the formulas, R1 is methyl or ethyl; R2 is lower alkyl, cyclopentyl, cyclohexyl, or benzyl; R3 is C4-10 alkyl, phenyl, methylenedioxyphenyl, naphthyl, cyclopentyl, cyclohexyl, oxo-2- norbornyl, endo-2-norbornyl, 1-adamantyl, etc.; Z1 is selected from the gps. (a), (b), (c), and (f); and HX is an acid-addition salt.

Description

Method for preparing cycle derivatives by Haitai's Haitai

The present invention relates to a process for the preparation of novel heterocycle derivatives of guanidine with useful pharmaceutical properties, in particular derivatives having the general formula (I) below;

In the diet:

Z is a member selected from a group consisting of:

In the above formula:

A is selected from the group consisting of O and S:

n is an integer of 0 or 1.

R ₁ is selected from the group consisting of methyl and ethyl

R ₂ is selected from the group consisting of lower alkyl (particularly methyl and ethyl), cycloalkyl (particularly cyclopentyl and cyclohexyl) and aralkyl (particularly benzyl) having 3-6 carbon atoms; or

A member selected from the group consisting of: wherein W is selected from the group consisting of O, S, N-lower alkyl (particularly N-methyl) and N-aryl (particularly N-pentyl);

R ₃ is, for example, alkyl having 4-10 carbon atoms (particularly branched) such as tert.-butyl, neopentyl, 1,1,3,3-tetramethylbutyl (tert.-octyl) and the like; Spent neil; Pentyl substituted with a substituent selected from the group consisting of 1-3 halo, lower alkyl and lower alkoxy; And pentyl substituted with a member selected from the group consisting of hydroxy, benzyloxy, nitro; Trifluoromethyl and methylthio; Naphthyl; Cycloalkyl having 5-8 carbon atoms (especially cyclopentyl and cyclohexyl); Bicyclo alkyl with 7-10 carbon atoms such as exo- and endo-2-norbornyl, 2-bicyclo [2.2.2] -octyl, endo-2-bicyclo [3.2.1] octyl, etc. ; For example nor-adamantyl, 1- and 2-adamantyl, 1- and 2- (2,3,3a, 4,5,6,7,7a-octahydro-4,7-methanoindenyl) and the like. Tricycloalkyl having the same 9-10 carbon atoms; For example benzyl, d1-, d- or 1-a-phenethyl, d1, d- or 1-a-methylbenzyl, a, a-dimethylbenzyl, a, a-dimethyl-β-phenethyl, d1, d Or an aryl group, such as 1- (a-naphthyl) ethyl and the like, is selected from the group consisting of phenyl and naphthyl and the alkyl group is arylalkyl having 1-4 carbon atoms; And diphenylalkyl having an alkyl group having 1-2 carbon atoms, for example, diphenylmethyl, 1,2- and 2,2-diphenylethyl and the like.

As used herein, the term "lower" refers to a group having from 1 to 4 carbon atoms, and the term "halo" refers to halogens having an atomic weight of 127 or less, such as chloro, bromo, fluoro and iodo. Indicates.

Due to the presence of nitrogen atoms such as amines in the compound of formula (I), acid addition salts thereof can also be easily obtained, and such pharmaceutically acceptable salts are also within the scope of the present invention. Compounds (I) of the present invention are suitable acids such as halogen acids, i.e. hydrochloric acid, bromic acid and the like, inorganic acids such as sulfuric acid, nitric acid, phosphoric acid, or the like, for example, acetic acid, propionic acid, glyconic acid, pamoic acid, pyruvic acid, maronic acid, Succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid, cyclohexanesulfonic acid, salicylic acid, P Treatment with organic acids, such as aminosacrylic acids, can be converted to non-toxic acid addition salts of clinical activity, whereas salt forms can be converted by treatment with alkalis in free base form.

Compounds of formula (I) are prepared from starting materials of formula (II) in which Z ₁ is the same as Z but Z is other than (d) or (e) and in case of (f) A is sulfur and n is 0 do. The starting material (Z ₁ H) is as described above except that R ₃ is hydroxyphenyl, and when Z ₁ is (f), R ₃ is as described above, but other than hydroxyphenyl and lower alkinoyloxyphenyl The isothiocyanate of formula (III) is reacted with an equivalent in a reaction inert organic solvent such as benzene, ethylene chloride, chloroform for 2 to 24 hours in the ambient and reflux temperature range. Thio (= S) in the obtained thiourea (IV) is represented by (IV) in which R 'is ethyl or methyl and X is halide, especially iodide, tosyrate, methosulfate, mesate, fluorosulfonate, etc. It is converted into an alkylthio group (-SR ') by reacting with an alkylating agent of the general formula R'X. Representative solvents for such alkylation are ethers, in particular diethyl ether, lower ketones such as tetrahydrofuran or dioxane, acetone, 2-butanone; Halohydrocarbons and lower alkanols, in particular methylene dichloride and methanol. Methyl iodide is particularly suitable as alkylating agent in methanol. Generally, an excess of alkylating agent is used in a chemical equivalent, and an amount depending on the reactivity of thiourea (IV) or its solubility in solvent is used. The alkylation reaction is carried out in an ambient temperature to reflux temperature range in a suitable high temperature closed vessel. The acid addition (HX) salt of an alkyl thio compounds of formula (Ⅴ) in the form at the reflux temperature of about 40-100 ℃ in a lower alkanol solvent such as isopropanol and tert.- butanol wherein R _1, R _2, and NR ₁ R ₂ is reacted with a suitable amine of the general formula HNR ₁ R ₂ as described above to give a guanidine derivative of the general formula (I) in acid addition form, which corresponds to conventional treatment with a suitable alkali. Obtained in base form. The reactions can be explained as follows.

Known isothiocyanates of the general formula (III) can be produced according to conventional processes reported in the literature for the production of isothiocyanates. See, eg, Methoden der organische chemie Houbenweyl, Eugen Muller (Ed.), Georg Thime Verlag (Publ.) Stuttgart, Germany, Vol. 9, Page 867-884 (1955); A. Preparation des Isothiocyanates Aromatiques, Ind. Chim., Belge, 32, 106 (1967); German Patent No. 1,300,559: J. Org. Chem., 36, 1549 (1971); US Patent Nos. 2,395,455 and 3,304,167; French Patent No. 1,528,249; "A New Synthesis of Aliphatic Isothiocyanates" Angew. Chem. Internat. Ed., 6, 174 (1967); Bull. Chem. Soc. Japan, 48, 2981 (1975); Tetrahedron, 29, 691 (1973); Chem. Ber., 101, 1746 (1968); And in J. Indian Chem. Soc., 52, 148 (1975) and the like can be obtained by the method.

In the above reaction of (V) with the amine HNR ₁ R ₂ , it is suitable to use, for example, an equivalent excess of amine of 1: 1.05-1: 2.0 in molar ratio. If slightly excess HNR ₁ R ₂ amines are used, it is advisable to add equivalents of tertiary alkylamines such as Et ₃ N to increase the reaction rate. Certain by-products produced during the reaction can be separated from the desired product of formula (I) by standard techniques known in the art, such as by fractional dissolution.

In the above synthesis process for preparing a compound of formula (I) wherein Z ₁ is (f), hydroxyphenyl and lower alkanoyl oxyphenyl are excluded from the original definition of R ₃ . Compounds of general formula (I) wherein Z ₁ is (f) and R ₃ is hydroxyphenyl, are subjected to hydrolysis of the corresponding R ₃ = methoxypentyl derivatives by treatment with conventional methods such as HBr or HI and acetic acid. To manufacture. When the obtained R ₃ = hydroxyphenyl derivative is acylated in glacial acetic acid in the presence of excess dicyclohexylcarbodiimide, the corresponding R ₃ = lower alkanoyloxy derivative of general formula (I) [Z ₁ is (f) To get.

x가 BF₄

x나 OSO₂F

인 일반식(ⅩⅤ)나 (ⅨⅩ)의 락탐염을 일반식(Ⅶ)의 과니딘 유도체와 반응시킴에 의하여 제조한다.R_One, R₂, NR_OneR₂And R₃Compounds of the general formula (I) in which (other than hydroxyphenyl) are as described above and in which Z is represented by (b), (d), (e), and (f) are prepared using chemical equivalents of reactants. Pseudouronium salt of formula (VI), or wherein

x is BF₄

x or OSO₂F

The lactam salt of phosphorus general formula (XV) or (XIII) is prepared by reacting with the guanidine derivative of general formula (XV).

It is preferable to add 4-8 molar equivalents of potassium carbonate to the reaction mixture after the addition of guanidine to complete the reaction. Suitable organic solvents for the reaction include, for example, lower aliphatic alcohols such as methanol, ethanol, 2-propanol, tert.-butanol and the like; Ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; Lower halogenated hydrocarbons such as chloroform, methene chloride, 1,2-dichloroethane, generally, methylene chloride for compound (VI) and tert.-butanol for compound (XV) or (iii). It is suitable.

In the case of compound (VI), a temperature of ambient temperature of 0 ° C is used, and in the case of compound (XV) or (v), ambient temperature-reflux temperature (about 80 ° C) is used. The products (iii), (vii) and (iii) in the form of the corresponding HY salts are conventional methods such as alkali metal or alkaline earth metal hydroxides; And the appropriate base form (I) by treatment with a suitable alkali such as carbonate. The reactions are illustrated by the following schemes:

가 BF₄

인 일반식(Ⅵ)의 슈도우로니움 플루오보레이트문헌, 즉 카나다특허 제850,116호 및 950,464호; 미국특허 제3,876,658호 ; Ber. 89, 2063(1956); 및 Org. Synth. 46, 113, 120 (1966)에 기술된 방법에 따라 수득한다. Y

가 OSO₂F

인 일반식(Ⅵ-b)이나 (XⅩII-b)의 플루오로설포네이트로 유사하게 제조된다. 일반적으로, 일반식(Ⅸ)의 싸이클우레아, 일반식(ⅩⅦ-a)이나 (ⅩⅦ-b)의 락탐 또는 일반식(XXI)의 옥소화합물을 적당한 트리알킬 옥소니움플루오보레이트(Ⅹ)와 반응시키거나 또는 일반식(Ⅸ)나 (XXI)의 화합물을 메틸플루오로설포네이트(XI')과 반응시켜 해당하는 염(Ⅵ)이나 (XXII)를 수득한다. 반응은 예컨대, 클로로포름, 1,2-디클로로에탄, 메티렌 디클로라이드(가장 적당)같은 불활성무수저급할로탄화수소용매에서 불활성 건조대기(예컨대, 질소, 아르곤)하에 0℃-주위온도에서 실시된다. 사용할 수 있는 다른 불활성 무수유기용매로는 예를들어, 디에틸에테르, 디옥산, 테트라하이드로푸란(THF), 1,2-디메톡시에탄등과 같은 에테르를 포함한다.Y

Autumn BF ₄

Pseudouronium fluoroborate of the general formula (VI), ie, Canadian Patent Nos. 850,116 and 950,464; US Patent No. 3,876,658; Ber. 89, 2063 (1956); And Org. Synth. Obtained according to the method described in 46, 113, 120 (1966). Y

OSO ₂ F

Similarly prepared with fluorosulfonates of the general formula (VI-b) or (XⅩII-b). Generally, the reaction of a general cycle urea, a general formula (VII-a) or (VII-b) lactam, or an oxo compound of the general formula (XXI) with an appropriate trialkyl oxonium fluorborate Or by reacting a compound of formula (X) or (XXI) with methylfluorosulfonate (XI ′) to afford the corresponding salt (VI) or (XXII). The reaction is carried out at 0 ° C. ambient temperature under an inert dry atmosphere (eg nitrogen, argon) in an inert anhydrous low halohydrocarbon solvent such as, for example, chloroform, 1,2-dichloroethane, methylene dichloride (most suitable). Other inert anhydrous organic solvents that can be used include, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane and the like.

The reactions are illustrated by the following schemes:

In the above synthesis of the compound of general formula (I) wherein Z is (d) or (e), hydroxyphenyl and lower alkanoyloxyphenyl are excluded from the original definition of R ₃ . Compounds of the general formula (I) wherein R ₃ is hydroxyphenyl are subjected to hydrolysis of the corresponding R ₃ = methoxyphenyl or benzyloxyphenyl derivatives by conventional processes such as, for example, treatment with HBr or HI in acetic acid. To manufacture. Acylating the obtained R ₃ = hydroxyphenyl derivative with lower alkanoic acid in the presence of excess dicyclohexyl carbodiimide yields the corresponding R ₃ = lower alkanoyloxy derivative of general formula (I).

Another method for producing a compound of formula (I) wherein Z is (a), (b) or (c), and in each case Z is represented by Z ₂ , is described in Angew. Chem. Internat. Ed., 8,24,26, (1969), comprising the process described by E. Kure and the continuous displacement of chloride from a suitable isocyanide dichloride (XII), wherein R ₃ is other than hydroxyphenyl. It utilizes the methods in the literature described herein.

Angew. Chem. Internat. Preparation according to the method described by Ed., 6, 649 (1967) in Kure et al. Is carried out in the presence of trialkylamines such as triethylamine, non-reactive non-solvents such as ethers such as dimethyl ether, tetrahydrofuran, halohydrocarbons. And reacted with an amine and HNR ₁ R ₂ in a solvent such as an aromatic hydrocarbon to obtain a monochloride compound (VIIIII), which was separated from triethylamine hydrochloride by filtration, and then the filtrate was reacted with Z ₂ H (II). It is used in the reaction to give the crude product (I).

It is preferable to react 2 molar equivalents of Z ₂ H (II) with each molar equivalent of (XIII). When Z ₂ is the same as the diaza group represented by the letter (c), 1: 1 molar equivalents of reactants are used, in which case molar equivalents of a suitable halide acid scavenger, such as triethylamine, are used to remove the free hydrochloric acid during the reaction. The same base is added. By any route, the resultant precipitated acid addition salt can be raised from the reaction mixture by filtration and the desired product (I) remaining in the filtrate can be separated by conversion to the acid addition salt by conventional means.

Another method for preparing a compound of formula (I) is to prepare a suitable dichloromethylene ammonium salt of formula (XIV) in the presence of two equivalents of a suitable acid scavenger such as triethylamine, other than R ₃ hydroxyphenyl. Angew. To react with a suitable equivalent amine of the general formula (XV) to give the above-mentioned product (XIII) and then to react with Z ₂ H (II) to give the final product (I) as described above. Chem. Internat. H. Vihe and Z. Janosek described in Ed., 12 (10), 806 (1973).

In the above synthesis process for the preparation of compounds of general formula (I) wherein Z is (a), (b) or (c) and in each case represented by Z ₂ , hydroxyphenyl is excluded from the original definition of R ₃ . The general formula (I) compound wherein R ₃ is hydroxyphenyl is prepared by (i) a conventional method, e.g. debenzyl of the corresponding R ₃ = benzyloxyphenyl derivative by reduction via hydrogenation in the presence of a palladium-carbon catalyst. By hydrolysis of the corresponding R ₃ = benzyloxyphenyl and methoxyphenyl derivatives by oxidization or (ii) by conventional methods, such as by treatment with HBr or HI in acetic acid, wherein sulfur is in the molecular state. When present, for example,

(티이몰포릴)일때 후자의 공정이 보다 적당하다.

The latter process is more suitable when (timomorphyl).

When sulfur is present in the oil-bearing molecule in a divalent state, it is known that sulfur has a positional effect on a hydrogenation catalyst such as a palladium-slide catalyst. Therefore, NR ₁ R ₂ = thiazol morpholine, and R ₃ = hydroxy-phenyl compounds of general formula (Ⅰ) is, R ₃ = methoxy corresponding to the general formula (Ⅰ) by HBr and the function of the HI in acetic acid It is prepared by hydrolysis of oxy-Ph or R ₃ = benzyloxy-Ph derivatives.

The compounds of the present invention of general formula (I) and their acid addition salts, in particular, have valuable pharmaceutical properties as blood glucose reducing agents. Their activity in lowering blood glucose was determined in glucose tolerance tests in the following rats, the standard method used to diagnose diabetes and hypoglycemic conditions.

In this test, Sprague-Dauray male rats (Higgs River 184-250 g) are given water only and fasted 24 hours prior to testing. Two to five rats are used for each test and comparative test, and 1-200 mg / kg of test compound suspended in 0.5-1.0 ml of solvent, in particular 0.5-1.0% methylcellulose solvent (injection or oral). . Comparative animals provide only equivalents of solvent. A series of blood samples (0.1 ml) were fed without glucose and anesthesia at 30, 60, 90, 120, 150 and 180 minutes before feeding glucose and 0.8-1.0 g of glucose per kg of body weight in 1 ml of water. (Glucose is given orally if the test compound is given parenterally and glucose is given parenterally if the test compound is given orally). Blood samples were immediately deproteinized with aqueous solutions of Ba (OH) ₂ and ZnSO ₄ , followed by Amer. J. Clin. Glucose levels are determined using the glucose oxidase assay described by LP Cowley under the heading "Ultra Trace Chemical Analysis of Blood Glucose with Glucose Oxidase" in Path., 32, 195 (1959). Blood glucose levels at each test time are expressed in milligram percent (mg glucose / 100 ml of blood). The average glucose value of the comparative study was statistically compared to the mean of the test group at each time of interest, and if the compound lowered blood glucose at a 95% confidence limit at any time, the compound is considered to have hypoglycemic activity.

The hypoglycemic depression, expressed as a percent reduction, is obtained by dividing the difference between the mean blood glucose level for the test animal and the flat blood glucose level for the comparative animal.

In addition to hypoglycemic activity, certain compounds have anti-secretory activity and cardiovascular activity, as shown in the tests described in our specification No. 828,561 filed on August 29, 1977 under the name "heterocycle derivative of guanidine". Has been found to have activity.

Compounds (I) of the present invention in base or salt form may be prepared in pharmaceutical unit dosage forms and formulations of conventional liquids and solids for oral or parenteral tours according to standard pharmaceutical techniques in the art.

The following examples are for the purpose of limiting the invention only. All parts are by weight unless otherwise indicated.

Example 1

N- (1-methyl-2-imidazoridinilidene) -N'-phenyl-thioutea:

2-amino-1-methylimidazoline hydroiodide (26.75 g, 0.117 mol) is converted to its free base form by treatment with 50% sodium hydroxide solution. Extract with methylene chloride with free base, extract is dried over potassium carbonate and filtered. Phenylisothiocyanate (15.81 g, 0.117 mol) is added to this solution and the reaction mixture is refluxed for 3 hours. The hot solution was filtered, concentrated in small amounts under vacuum, ether was added, cooled and the resulting solid was filtered to give 23.6 g (86.1 g) of N- (1-methyl-2) with a melting point of 205-208 ° C. -Imidazoridinilidene) -N'-phenyl-riourea is obtained.

Example 2

Methyl N- (1-methyl-2-imidazolidinidide) -N'-phenylcarbamimidothioate hydroiodide:

2.5 hours of a mixture of 22.0 g (0.094 mole) of N- (1-methyl-2-imidazoridinilidene) -N'-phenylthiourea with 14.9 g (0.105 mole) of methyl iodide and 500 ml of acetone The oil obtained by refluxing and evaporating the reaction mixture in vacuo was crystallized from acetone-ether (1: 1) to give 30 g (85%) of methyl N- (1-methyl-2-imide with a melting point of 122-126 ° C. Cooked dinylidene) -N'-phenyl-carbamimidothioate hydroiodide is obtained.

Example 3

The desired thiourea of formula (IV) was prepared according to the procedure of Examples 1 and 2, except that equivalent equivalents of reactants of formulas (II) and (III) were used, followed by treatment with a suitable S-methylating agent. The indicated salts of Pseudothiourea of Formula (V) listed are obtained as final product.

Example 4

N- (1-methyl-2-imidazoridinilidene) -N'-phenyl-pyrrolidinecarboximideamide fumate

6.4 g (0.090 mole) of 10.0 g (0.042 mole) of methyl N- (1-methyl-2-imidazoridinilidene) -N'-phenylcarbamididothioate hydroiodide in 200 ml of t-butanol The mixture of pyriridine is refluxed for one night (about 16 hours) under low nitrogen flow.

After removing the methyl mercaptan formed during the reaction by using sodium hypochlorite and NaOH trap, the reaction mixture was cooled, ether was added, and the resulting solid was filtered to give 11.4 g (67%) of molten 237-240 ° C. To obtain a hydroidide salt of The conversion to the free base is done by distributing the hydroidide between 3N sodium hydroxide and methyl chloride. The organic layer is dried over potassium carbonate and evaporated in vacuo after filtration to give 7.6 g (0.028 mol) of free base which is converted to the fumarate salt using an equivalent of fumaric acid in 2-propanol. 7.5 g (68%) of pure, N- (1-methyl-2-imidazoridinilidene) -N'-phenyl-1-pyrrolidincar with a melting point of 163-165 ° C., recrystallized twice from ethanol-ether Voximide amide fumarate is obtained.

Example 5

Except for reacting an equivalent of each pseudothiouronium salt with an equivalent of an appropriate amine (HNR ₁ R ₂ ) in Example 3, following the procedure of Example 4, the final product was converted or not converted into the indicated acid addition salt. The following compounds of the general formula (I) are obtained. In the table, the compound number corresponds to the compound number in the table of Example 3.

Example 6

N- (1-methylimidazol-2-yl) -N'-phenylthiourea:

4.8 g (0.036 mol) of 2-amino-1-methylimidazole hydrochloride sample is suspended in 20 ml of methylenechloride and plated with 10 ml of 50% NaOH. The organic layer was separated and the aqueous layer was extracted twice with 20 ml of fresh methylene chloride. The combined organic extracts were dried over K ₂ CO ₃ and filtered, and then the filtrate was treated with 4.86 g (0.036 mol) of phenylisothiocyanate. The solution was refluxed for 4 hours, the solvent was evaporated under vacuum and the residue was recrystallized from acetone-ether (1: 1) and MeOH-ether (1: 1) to give N- (1-methyl with a melting point of 170-172 ° C. Imidazol-2-yl) -N'-phenylthiourea is obtained.

Example 7

Methyl N- (1-methylimidazol-2-yl) -N'-phenylcarbamimidothioate hydroiodide:

To a solution of 3.0 g (0.013 mol) of N- (1-methylimidazol-2-yl) -N'-phenylthiourea in 50 ml of methanol was added 2.13 g (0.015 mol) of methyl iodide, The solution was heated to reflux for 2 hours to evaporate the solvent and recrystallize the residue from acetone-ether to give methyl N- (1-methylimidazol-2-yl) -N'-phenylcarba having a melting point of 115-118 ° C. Balimidothioate hydroiodide is obtained.

Example 8

Use of an equivalent isothiocyanate equivalent to an appropriate isothiocyanate instead of fused isothiocyanate, according to the process of Example 6, followed by the procedure of Example 7 using the equivalent amount of thiourea as a precursor. By methylation, the following pseudothiourea of the general formula (V) is obtained.

Example 9

N- (1-methylimidazol-2-yl) -N'-phenyl-1-morpholine carboximideamide hydrochloride:

1.5 g (0.004 mole) of methyl N- (1-methylimidazol-2-yl) -N'-phenylcarbamididothioate hydroiodide and 0.73 g (0.0084 mole) in 30 ml of t-BuOH The solution of porin is refluxed overnight. After cooling, ether is added and morpholine hydroiodide is removed by filtration, the filtrate is dried to dissolve the residue in CH ₂ Cl ₂ and then converted to the free base as 3N NaOH. The organic gun was separated, dried over K ₂ CO ₃ , filtered and the solvent evaporated in vacuo to N- (1-methylimidazol-2-yl) -N'-phenyl-4-morpholin carboximide A residue of amide is obtained, which is dissolved in acetone and converted to the hydrochloride salt as ether HCl.

Example 10

Except for reacting the equivalent of each pseudothiourea obtained in Example 8 with an equivalent amine of the general formula HNR ₁ R ₂ , the following products of the general formula (I) are obtained according to the process of Example 9.

Example 11

N- (4,5-dihydro-1-methylimidazol-2-yl)-(4-hydroxyphenyl) -1-pyrrolidinecarboximidehydroiodide:

37.8 g (0.1 mole) of N- (4-benzyloxyphenyl) -N'-4,5-dihydro-1-methylimidazol-2-yl-1 in 150 ml of glacial acetic acid in a 500 ml hydrogenation bottle To the pyrrolidinecarboximideamide solution, 0.5 g of 30% pd / c catalyst is added, the mixture is hydrogenated at a starting pressure of 60 p.si for 4 hours, the catalyst is filtered off and acetic acid is removed in vacuo. . The residue was dissolved in tert.-butanol and treated with 48% HI of chemical equivalents, and ether was added to give N- (4, 5-dihydro-1-methylimidazol-2-yl) -N '-( 4-hydroxyphenyl) -1-pyrrolidine carboximideamide hydroiodide precipitates.

Example 12

The following R ₃ = hydroxyphenyl derivatives of the general formula (I) were prepared in the form of hydroiodide salts according to the debenzylation process of Example 11, except that an appropriate equivalent of R ₃ = benzyloxyphenyl precursor was first used. To obtain.

Example 13

2-imino-1,3-dimethylimidazolidinesulfate (2: 1 salt):

Triethyloxonium tetrafluoroborate is prepared in ether at about 1.2 moles from 327.1 g (1.6 moles) of borontrifluoride etherate and 111.0 g (1.2 moles) epichlorohydrin under a dry nitrogen atmosphere. The obtained crystals were washed with fresh anhydrous ether (2 × 250 ml) by decantation, and then the obtained crystals of triethyloxonium tetra fluoroborate were dissolved in 1? Dry methylene chloride, and 114 g ( 1 mole) of 1, 3-dimethylimidazoridin-2-one are added. The mixture is stirred at ambient temperature for 3 hours and anhydrous ammonia is added for 10 minutes. The mixture is warmed and again slowly added ammonia for 20 minutes and stirred for another 30 minutes. The mixture is filtered from the inorganic material, concentrated to a volume of 200 ml and left overnight. The product is converted to a free base by treatment with 100 ml of 50% NaOH solution while cooling (in ice water). The aqueous layer was washed with fresh CH ₂ Cl ₂ (3 × 100 ml), combined and the dried (K ₂ CO ₃ ) organic layer was filtered (diatomaceous earth) to obtain a cloud-like filtrate. Slow heating under vacuum removes the solvent and many replacements are separated. 200 ml of ether is added to the oily suspension and the solution is refiltered and the filtrate is reduced to a volume of about 100 m and then dissolved in MeOH (200 ml). Concentrated sulfuric acid is added to pH 6 while cooling the obtained solution. Boil with stirring and 2-PrOH is added to compensate for the lost MeOH and the resulting replacement fraction is separated from the hot solution. Filter the crystals and add 2-PrOH with concentration of the filtrate until MeOH is removed. Upon cooling, a second fraction covered with syrup is obtained and the crystals in the gum phase are washed with fresh 2-PrOH and combined with the first fraction. The combined fractions were dissolved in MeOH, filtered (diatomaceous earth) and recrystallized by the addition of 2-PrOH to give pure 2-imino-1, 3-dimethylimidazolidine 1/2 sulfate having a melting point of at least 300 ° C. The second fraction is obtained from the mother liquor; Melting Point 300 ℃, Yield 69,5g Total Quantity (42.8%)

Example 14

N- (3-methyl-2-thiazolidinylidene) -N'-phenylthiourea:

A solution of 5.9 g (0.043 mol) of 2-imino-3-methylthiazolidine in 70 ml of dry benzene was refluxed under a nitrogen atmosphere for 2.5 hours, a little ether was added to the cooled reaction compound, and the solid was filtered. 9.8 g (90%) of product are obtained. Recrystallization from acetonitrile-ether (1: 1) yields 8.0 g (75%) of pure N- (3-methyl-2-thiazolidinylidene) -N'-phenylthiourea with a melting point of 168.5-170.5 ° C. Get

Example 15

By repeating the process of Example 14 but using the equivalent phenyl isothiocyanate with an equivalent equivalent of R ₃ NCS, in each case the following N- [2- (3-) of formula (IV) wherein Z is (f) Methyl) -thiazoridinilidene-N'-R ₃ thiourea is obtained.

Example 16

Methyl N- (3-methyl-2-thiazolidinylidene) -N'-phenylcarbamimidothioatehydroiodide:

A suspension of 17.0 g (0.067 mol) of N- (3-methyl-2-thiazolidinylidene) -N'-phenylthiourea and 11.1 g (0.078 mol) of iodomethane in 350 ml of acetone was refluxed for 1 hour. . The solution is cooled overnight at room temperature (about 16 hours) and the resulting solid is filtered to give a melting point of 159.5-161.5 ° C., 25.1 g (95.2%). Recrystallization from methanol-ether (1: 1) yields pure methyl N- (3-methyl-2-thiazoridinilidene) -N'-phenylcarbamididothioate with a melting point of 163.5-165 ° C.

Example 17

By repeating the S-methylation process of Example 16 with each thiourea of Example 15, each corresponding methylcarbamimidothioate hydroiodide salt of formula (V) is obtained (wherein Z is ( f).

Example 18

N- (3-methyl-2-thiazolidinylidene) -N'-phenyl-1-pyrrolidinecarboximideamide hydroiodide:

4.4 g (0.062 mole) of pyridine of 11.9 g (0.030 mole) of N- (1-methyl-2-thiazoridinylidene) -N'-phenylcarbamididothioate hydroiodide alc in 200 ml of t-butanol Is refluxed for 24 hours under a stream of nitrogen. Sodium hypochlorite and NaOH traps are used to remove methylmercaptan produced during the reaction. The reaction mixture is cooled, ether is added, and the resulting solid is filtered to yield 9.3 g (75%) of product. Recrystallization from acetone-ethylacetate (1: 1), 7.8 g (62%) of pure N- (3-ethyl-2-thiazolidinylidene) -N-phenyl-1-pyro with a melting point of 157.5-160 ° C. Ridinecarboxyimide amide hydro iodide is obtained.

Example 19

N- (3-methyl-2-thiazolidinylidene) -N'-phenyl-4-morpholin carboximideamide hydroiodide:

The procedure of Example 18 was repeated except that the equivalent of morpholine was used for the pyridine, and the product N- (3-methyl-2-thiazolidinylidene) -N 'having a melting point (188 ° C) of 190-191.5 ° C. -Phenyl-4-morpholinecarboximide hydroiodide is obtained.

Example 20

N- (4-methoxyphenyl) -N '-(3-methyl-2-thiazoridinilidene) -1-piperidinecarboximideamide fumarate:

The process of Example 18 is repeated except that pyridine is replaced with an equivalent of piperidine and the equivalent of the pseudothiouronium salt (Compound No. 14) of Example 17 is used as the reactant. The obtained HI salt was basified with an aqueous NaOH solution, and then the base was treated with an equivalent of fumaric acid to give N- (4-methoxyphenyl) -N- (3-methyl-2-thiazoli having a melting point of 159.5-160 ° C. Diniriden) -1-pyriridine carboxide amide fumarate is obtained.

Example 21

The process of Example 18 was repeated but each of the following compounds of formula (I) was obtained as a hydroiodide salt using the equivalent R ₁ R ₂ NH amine as the starting material and the appropriate pseudothiourea from Example 17 do.

Example 22

N-[(2, 3, 5, 6-tetrahydro-4-methyl) -1, 4-thia except for using the equivalent of R ₃ = 4-methoxyphenyl derivative as a precursor to be hydrolyzed According to the hydrolysis process of jin-3-yriden] -N'-hydroxyphenyl) -1-piperidinecarboximide hydroiodide, each of R < ₃ > of the following formula (I) = hydroxy Obtain oxyphenyl derivative (converted to free base).

Precursor: Compound No. 14. of Example 21.

Product: N- (4-hydroxyphenyl) -N '-(3-methyl-2-thiazolidinylidene) -1-morpholinecarboximide amide.

Example 23

N- (4-hydroxyphenyl) -N '-(3-methyl-2-thiazoridinilidene) -1-piperidinecarboximide hydroidide:

Example 20 R ₃ = 4- methoxyphenyl derivatives of a mixture of glacial acetic acid and 4.0g 50% HI, and the obtained (as the free base) 4.92g (19.2 mmol) in of 2.56g (7.7 mmol) It is heated at reflux for 1 night (oil bath). The excess HI and acetic acid were removed under vacuum and the residue was washed several times with ether and scraped to form crystals which were suspended in t-BuOH, filtered and then washed with ether to give a melting point of 174-176 ° C. To obtain. Recrystallization from t-BuOH (containing a small amount of MeOH to dissolve the crystals, followed by evaporation of MeOH), pure N- (4-hydroxyphenyl) -N dried under vacuum with a melting point of 175-177 ° C. '-(3-methyl-2-thiazolidinylidene) -1-piperidinecarboximideamide hydroiodide is obtained.

Claims (1)

Heteroimide of guanidine having the general formula (I) characterized by reacting a compound of the general formula (V) with a compound of the general formula HNR ₁ R ₂ at a reflux temperature of about 40-100 ° C. in a lower alkanol solvent. Cycle derivatives and pharmaceutically useful methods of preparing these acid addition salts.

In the above formula Z ₁ is selected from the group consisting of (a), (b), (c) and (f):

In the above formula R ₁ is selected from the group consisting of methyl and ethyl; R ₂ is selected from the group consisting of lower alkyl, cyclopentyl, cyclohexyl and benzyl; or

Together

Selected from the group consisting of: wherein W is selected from the group consisting of O, S, N-loweralkyl and N-aryl; R ₃ is alkyl having 4-10 carbon atoms; Phenyl; Phenyl substituted with 1-3 substituents each selected from the group consisting of methylenedioxyphenyl, halo, lower alkyl, and lower alkoxy; Phenyl substituted with a group selected from the group consisting of hydroxy, benzyloxy, nitro; Trifluoromethyl and methylthio; Naphthyl; Cyclopentyl; Cyclohexyl; Exo-2-norbornyl; Endo-2-norbornyl; 1-adamantyl; Arylalkyl in which the aryl group is phenyl and the alkyl group has 1-4 carbon atoms; And an alkyl group selected from the group consisting of diphenylalkyl having 1-2 carbon atoms. In the above formula (Ⅴ) R <_3> is as above-mentioned except hydroxyphenyl, and when Z <_1> is (f), R <_3> is as above-mentioned except hydroxyphenyl and lower alkanoyloxyphenyl. HX is acid addition salt.