KR840002439B1 - Process for preparing heterocyclic derivatives of guanidine - Google Patents

Abstract

Guanidine derivs. of the formula Z2-C(=NR3)-NR1R2 (I) and their acid- addn. salts are new. In (I), Z2 is a gp. of formula (II) or (III), the broken line being an optional double bond. R1 is Me or Et; R is lower alkyl, cyclopentyl, cyclohexyl or benzyl; NR1R2 is pyrrolidino, piperidino, morpholino, thiamorpholino, N'-(C1-4) alkylpiperazino or N'-phenylpiperazino; R3 = C4-10 alkyl naphthyl, cyclopentyl, exo-2-norbornyl, 1-adamantyl, ph(C1-4) alkyl, diphenyl- (C1-2) alkyl. I are hypoglycaemic agents, and some compds. are also antisecretory and cardiovascular agent.

Description

Method for preparing a heterocycle derivative of guanidine

The present invention relates to a process for the preparation of a new heterocycle derivative of guanidine with useful pharmaceutical properties, in particular a derivative having the general formula (I):

Where Z is a member selected from the group consisting of:

Wherein: A is selected from the group consisting of O and S; n is 0 but an integer of 1

로 구성된 그룹으로부터 선택한 멤버를 나타내는데; 식중 W는 O, S, N-저급알킬(특히 N-메틸)과 N-아릴(특히 N-페닐)로 구성된 그룹으로부터 선택한 것이며; R₃는 예컨대 tert.-부틸, 네오펜틸, 1,1,3,3-테트라메틸부틸(tert.-옥틸)등과 같은 4-10개의 탄소원자(특히 분자쇄된)를 가진알킬; 페닐; 메티렌디옥시페닐; 1-3개의 할로, 저급알킬 및 저급알콕시로 구성된 그룹으로 부터 선택한 치환기로 치환된 페닐 및 하이드록시, 벤질옥시, 니트로 구성된 그룹으로 부터 선택한 멤버와 함께 치환된 페닐; 트리풀루오로메틸; 및 메틸티오; 나프틸; 5-8개의 탄소원자를 가진 싸이클로 알킬(특히 싸이클로펜틸 및 싸이클로헥실); 예컨대, 엑소-와 엔도-2-노르보르닐, 2-비싸이클로 [2.2.2]-옥틸, 엔도-2-비싸이클로 [3.2.1]옥틸 등과 같은 7-10개의 탄소원자를 가진 비싸이클로알킬; 연컨대, nor-아다만틸, 1- 및 2-아다만틸, 1- 및 2-(2,3,3a,4,5,6,7,7a-옥바하이드로-4,7-메타노인데닐)등과 같은 9-10개의 탄소원자를 가진 트리싸이클로알킬; 예컨대, 벤질, d1-, d-또는 1-a-펜에틸, d1, d- 또는 1-a-메틸벤질, a, a-디메틸벤질, a, a-디메틸-β-펜에틸, d1, d-또는 1-(a-나프틸)에틸 등과 같이 아릴기는 페닐과 나프틸로 구성된 그룹으로 부터 선택한 것이고 알킬기는 1-4개의 탄소원자를 갖는 아릴알킬; 및 예컨대, 디페닐메틸, 1, 2- 및 2, 2-디페닐에틸 등과 같은 알킬기가 1-2개의 탄소원자를 갖는 디페닐알킬로부터 선택한것임.R ₁ is selected from the group consisting of methyl and ethyl and R ₂ is lower alkyl (especially methyl and ethyl), cycloalkyl (especially cyclopentyl and cyclohexyl) and aralkyl (especially benzyl) with 3-6 carbon atoms Selected from the configured group; or

Represents a member selected from a group consisting of: Wherein W is selected from the group consisting of O, S, N-loweralkyl (particularly N-methyl) and N-aryl (particularly N-phenyl); R ₃ is, for example, alkyl having 4-10 carbon atoms (particularly molecularly chained) such as tert.-butyl, neopentyl, 1,1,3,3-tetramethylbutyl (tert.-octyl) and the like; Phenyl; Methyrendioxyphenyl; Phenyl substituted with a substituent selected from the group consisting of 1-3 halo, lower alkyl and lower alkoxy and phenyl substituted with a member selected from the group consisting of hydroxy, benzyloxy, nit; Trifuluromethyl; And methylthio; Naphthyl; Cycloalkyl having 5-8 carbon atoms (especially cyclopentyl and cyclohexyl); Bicycloalkyl having 7-10 carbon atoms such as, for example, exo- and endo-2-norbornyl, 2-bicyclo [2.2.2] -octyl, endo-2-bicyclo [3.2.1] octyl, and the like; In other words, nor-adamantyl, 1- and 2-adamantyl, 1- and 2- (2,3,3a, 4,5,6,7,7a-octahydro-4,7-methanoindenyl Tricycloalkyl, such as 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, for example, an alkyl group such as diphenylmethyl, 1, 2- and 2, 2-diphenylethyl and the like is selected from diphenylalkyl having 1-2 carbon atoms.

As used herein, the term "lower" refers to a group having from 1 to 4 carbon atoms, and the term "halo" refers to a halogen having an atomic weight of less than 127, 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, glycolic acid, pamoic acid, pyruvic acid, maronic acid, rot Sinic 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 aminosarylic acid can be converted to clinically active nontoxic acid addition salts and conversely the salt form can be converted by treatment with alkali 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 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. And the thi group (= S) in the obtained thiourea (IV) is represented by (IV) in which R 'is ethyl or methyl, and X is a halide, in particular iodide, tosyrate, methosulfate, mesrate, and fluorosulfonate. 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 include ethers, especially lower ethyl ketones such as diethyl ether, tetrahydrofuran or dioxane, acetone, 2-buta; Halohydro carbon and lower alkanols, in particular methylenedichloride 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. An alkylthio compound of formula (V) in the form of an acid addition (HX) salt was substituted with lower alkanes such as isopropanol and tert-butanol at a reflux temperature of about 40-100 ° C. in the formulas R ₁ , R ₂ and NR ₁ R base form of _divalent to, banyung the formula suitable amine HNR ₁ R ₂ as described above, and acid addition is to give a gwani derivatives of general formula (ⅰ) in the form, that this, by conventional treatment with suitable alkali Obtained as

The semi-melts can be described as follows.

ller (Ed.), Georg Thieme Verlag (Publ.) Stuttgart, Germany, Vol. 9, Page 867-884 (1955));A. 라샤르트등에 의한 Preparation des Isothiocyanates Aromatiques, Ind. Chim., Belge, 32, 106 (1967); 독일특허 제1,300,559호; J. Org. Chem., 36, 1549 (1971); 미국특허 제2,395,455호 및 3,304,167호; 불란서특허 제1,528,249호; "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); 및 J.Indian Chem. Soc., 52, 148 (1975) 등에 보고된 방법에 의하여 수득할 수 있다.Known isothiocyanates of general formula (III) can be prepared according to conventional processes reported in the literature for the preparation of isothiocyanates. See, for example, Methoden der Organische Chemie Houben-Weyl, Eugen M by M. Tengemann et al.

ller (Ed.), Georg Thieme Verlag (Publ.) Stuttgart, Germany, Vol. 9, Page 867-884 (1955)); 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 J. Indian Chem. Soc., 52, 148 (1975) et al.

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 a slight excess of HNR ₁ R ₂ amine is used, it is advisable to add an equivalent of a tertiary alkylamine such as Et ₃ N to increase the reaction rate. Any by-products generated 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.

가 BF₄

나 OSO₂F

인 일반식(ⅩⅤ)나 (ⅨⅩ)의 탁탐염을 일반식(Ⅶ)의 과니딘 유도체와 반응시킴에 의하여 제조한다.Z in food_OneIn the above synthesis step for preparing the compound of formula (I) which is (f), hydroxyphenyl and lower alkanoyloxyphenyl are R.₃Is excluded from its original definition. Z_OneIs (f) and R₃Is a compound of formula (I) wherein hydroxyphenyl is a corresponding R, for example, by treatment with HBr or HI and acetic acid.₃It is prepared by hydrolysis of methoxyphenyl derivative. Obtained R₃When the hydroxyphenyl derivative is acylated in glacial acetic acid in the presence of excess dicyclohexyl carbodiimide, the corresponding R in formula (I)₃Lower alkanoyloxyderivatives [Z_OneIs (f). 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

Autumn BF₄

Me OSO₂F

Taktam salts of the general formula (XV) or (XIII) are prepared by reacting with guanidine derivatives of the general formula (XV).

To complete the reaction, 4-8 molar equivalents of potassium carbonate is added to the semi-molten mixture after the addition of guanidine. Suitable anhydrous 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, and lower halogenated hydrocarbons such as chloroform, methylene chloride and 1,2-dichloroethane. Generally, for compound (VI), methylene chloride or Tert.-butanol is suitable for (iii). 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) or (iii) in the form of the corresponding HY salts may be subjected to the corresponding base form (I) by treatment with conventional methods, such as alkali or alkali metal hydroxides and suitable alkalis. Can be converted to). The reactions are illustrated by the following schemes.

가 BF₄

인 일반식(Ⅵ)의 슈도우로니움 플루오보레이트 문헌 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 (ⅩII-b)의 플루오로설포네이트로 유사하게 제조된다. 일반적으로, 일반식(Ⅸ)의 싸이클 우레아, 일반식(ⅩⅦ-a)이나 (ⅩⅦ-b)의 락탐 또는 일반식(ⅩII)의 옥소화합물을 적당한 트리알킬옥소니움 플루오로보레이트(Ⅹ)와 반융시키거나 또는 일반식(Ⅸ)나 (ⅩI)의 화합물을 메틸 플루오로설포네이트(XI)과 반융시켜 해당하는 염(Ⅵ)이나 (ⅩII)를 수득한다. 반융은 예컨대, 클로로포름, 1,2-디클로로에탄, 메티렌 디클로라이드(가장 적당)같은 불활성 무수 저급 할로탄화수소용매내에서 불활성 건조대기(예컨대, 질소, 아르곤)하에 0℃-주위온도에서 실시된다. 사용할 수 있는 다른 불활성 무수 기용매로는 예를 들어, 디에틸 에테르, 디옥산, 테트라 하이드로푸란(THF), 1,2-디메톡시에탄 등과 같은 에테르를 포함한다. 상기 반응들은 하기 반응식으로 설명된다.Y

Autumn BF ₄

Pseudouronium fluoroborate documents 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 (XII-b). In general, a cycle urea of formula (VII), a lactam of formula (VII-a) or (VII-b), or an oxo compound of formula (VII) is combined with a suitable trialkyloxonium fluoroborate. Semi-melting or semi-fusing the compound of formula (VII) or (XI) with methyl fluorosulfonate (XI) to give the corresponding salt (VI) or (XI). Semi-melting is carried out at 0 ° C. ambient temperature under an inert dry atmosphere (eg nitrogen, argon) in an inert dry lower halohydrocarbon solvent such as, for example, chloroform, 1,2-dichloroethane, methylene dichloride (most suitable). Other inert anhydrous solvents that may be used include, for example, ethers such as diethyl ether, dioxane, tetra hydrofuran (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 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), including the method described by E. Kure and the continuous displacement of chloride from a suitable isocyanide dichloride (XI) in which 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 E. Kure et al. In Ed., 6, 649 (1967) is carried out in the presence of trialkylamines such as ether inert non-aqueous solvents such as diethyl ether, tetrahydrofuran and the like, Reaction with amine and HNR ₁ R ₂ in a solvent such as halo hydrocarbons and aromatic hydrocarbons affords a monochloride compound (XIII), which is separated from triethylamine hydrochloride by filtration, and then the filtrate is Z ₂ H (II). To the final product to obtain the final 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 halogen acid remover such as triethylamine are used to remove the hydrochloric acid liberated during the reaction. The same base is added. By any means the resulting precipitated acid addition salt can be removed 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 dichloromethyleneammonium salt of formula (XIV) in addition to R ₃ hydroxyphenyl in the presence of 2 equivalents of a suitable acid scavenger such as triethylamine. 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).

(티아몰포린)일 때 후자의 공정이 보다 적당하다.Hydroxyphenyl is excluded from the original definition of R ₃ in the above synthesis process for the preparation of compounds of formula (I) wherein Z is (a), (b) or (c) and in each case is represented by Z ₂ . Formula (I), wherein R ₃ is hydroxyphenyl, corresponds to (i) debenzyl of the corresponding R ₃ = benzyloxyphenyl derivative by conventional methods, such as by reduction through 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,

The latter process is more suitable when (thiamorphorine).

When sulfur is present in organic molecules in a divalent state, it is known that sulfur has a site effect on hydrogenation catalysts such as palladium-activated carbon catalysts. Therefore, compounds of formula (I) wherein NR ₁ R ₂ = thiamorpholine and R ₃ = hydroxyphenyl have the corresponding R ₃ = methoxy- of formula (I) by the action of HBr or HI in acetic acid. It is prepared by hydrolysis of ph or R ₃ = benzyloxy-ph derivatives.

The compounds of the present invention of general formula (I) and acid addition salts thereof have in particular 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, is injected or injected orally. ). Comparative animals provide only equivalents of solvent. A series of blood samples (0.1 ml) were tailed without anesthesia before 30, 60, 90, 120, 150 and 180 minutes after 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 evaluation method described by LP Cowley under the heading "Ultrachemical Analysis of Blood Glucose with Glucose Oxidase Agents" in Path., 32, 195 (1959). Each test time The blood glucose level in is expressed in milligram percent (mg glucose / 100 ml of blood) The average glucose value of the comparative test is statistically compared to the mean value of the test group at each corresponding time to determine if the compound has a 95% confidence limit at any time. The compound is considered to have a hypoglycemic activity if the hypoglycemic is lowered by taking the blood glucose reduction indicated as a percent reduction by dividing the difference between the mean blood glucose level for the test animal and the mean blood glucose level for the comparative animal.

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

Compound (I) of the present invention in base or salt form may be prepared in pharmaceutical unit dosage forms and preparations in conventional liquid and solid forms for oral or parenteral administration according to standard pharmaceutical techniques in the art.

The following examples are for illustrative purposes only without limiting the invention. Unless otherwise noted, all parts are by weight.

Example 1

N- (1-methyl-1H-imidazol-2-yl) -N'-phenyl-1-pyrrolidinecarboxamide fumarate:

A solution of 7.44 g (0.060 mole) of phenylisocyanide dichloride and 6.06 g (0.060 mole) of triethylamine in 45 ml of anhydrous ether in a cooling solution of 4.26 g (0.060 mole) of pyriridine in 45 ml of anhydrous ether. Droplets are added under nitrogen atmosphere. The ice bath was removed and the white suspension was stirred for 2 hours at room temperature, then the precipitated triethylamine hydrochloride was filtered and washed three times with 30 ml of ether. 6.06 g (0.060 mole) triethylamine is added to the combined ether filtrates and the mixture is cooled again in an ice-bath. A solution of 2-amino-1-methylimidazole (prepared from hydrochloride salt and methylene chloride extract corresponding to 50% sodium hydroxide) in merylene chloride is added dropwise to the reaction mixture under nitrogen atmosphere. The colorless solution is allowed to stand at room temperature and stirred overnight under a nitrogen atmosphere. After evaporation of the solvent, the residue is treated with CH ₂ Cl ₂ and converted to freebase form using cooled 3N sodium hydroxide. The organic layer is dried over potassium carbonate, and the solvent is evaporated under vacuum after filtration to give 13.8 g (95%) of oil. Acid-base extraction leads to 6.1 g (42%) of impure free base N- (1-methyl-1H-imidazol-2-yl) -N-phenyl-1-pyrrolidinecarboximide amide. Recrystallization from benzene-hexane (1: 1) to obtain a pure free base having a melting point of 115-118 ° C., which is converted into fumarate salt using 1 equivalent of fumaric acid (2.4 g, 0.002 mol) in isopropane. Switch. 7.0 g of pure salt, N- (1-methyl-1H-imidazol-2-yl) -N'-phenyl-1-pyrrolidine, with a melting point of 156.5-159.5 ° C. that was recrystallized from methanol-ether (1: 1) Carboximideamide fumarate is obtained.

Example 2

N- (1-methylimidazol-2-yl) -N ', except that the equivalent isocyanide dichloride of formula (XII) is used as a reactant with 2-amino-1-methylimidazole. The following N- (1-methyl-1H-imidazol-2-yl) form of the general formula (I) was labeled with free base according to the process of -phenyl-4-morpholine-carboximide hydrochloride. Obtained as acid addition (HX) salt form.

Example 3

N- (1-adamantyl) -N '-(1-methylimidazol-2-yl) -1-pyrrolidinecarboximide amide:

15.13 g (0.1 mole) of 1-adamantylamine and 20.2 g (0.2 mole) in CH ₂ Cl ₂ dried in 18.85 g (0.1 mole) of dichloromethyleneted tamethene ammonium chloride in 100 ml of dry methylene chloride. The solution of triethylamine) was added dropwise while cooling (ice bath) under a dry nitrogen atmosphere, and then the mixture was stirred at room temperature for 3 hours. A drop of dry methylene chloride solution containing 9.71 g (0.1 mole) of 2-amino-1-methylimidazole and 10.1 g (0.1 mole) of triethylamine was added dropwise over 1 hour while cooling, and the mixture was allowed to stand at room temperature. The mixture is stirred overnight under a dry nitrogen atmosphere. The mixture was shaken with excess 3NNaOH, the organic layer was separated, dried (K ₂ CO ₃ ), filtered and the solvent and residual triethylamine removed under vacuum, N- (1-adamanyyl) -N'- Obtain (1-methylimidazol-2-yl) -1-pyrrolidone carboximideamide free base.

Example 4

According to the process of Example 3 but by replacing dichloromethylenetetramethylene ammonium chloride with a suitable dichloromethylene ammonium salt and 1-adamantylamine with a suitable R ₃ NH ₂ amine, the following N- (1-methyl Imidazol-2-yl) -N'-substituted-1- (or 4) carboximideamide is obtained. Treatment with the appropriate acid (HX) yields the indicated acid addition salt.

Example 5

2-imino-1,3-dimethylimidazolidine sulfate (2: 1 salt):

Triethyloxonium tetrafluoroborate is prepared in ether at about 1.2 moles from 327.1 g (1.6 moles) of boron trifluoride etherate and 111.0 g (1.2 moles) epichlorohydrin under dry nitrogen atmosphere. The obtained crystals were washed by decantation with fresh anhydrous ether (2 × 250 ml, then the crystals of triethyloxoniumtetrafluoroborate obtained were dissolved in 1 L of dry methylene chloride, and 114 g (1 Mole) 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 ammonia is then slowly added for 20 minutes. The mixture is filtered from the inorganics, concentrated to 200 ml and left for 1 night, treated with 100 ml of 50% NaOH solution with cooling (ice-water) to convert the product to a free base. thereby. wash the aqueous layer with fresh _{CH 2 Cl 3 (3 × 100ml} ) and the combined, dried (K ₂ CO ₃₎ organic layer was filtered (diatomaceous earth) to obtain a filtrate as clouds slowly heated to the solvent in vacuo Many solids are separated and the solids are separated, 200 ml of ether is added to the oily suspension, the solution is filtered again, and the filtrate is reduced to a volume of about 100 ml and dissolved in MeOH (200 ml). Add concentrated sulfuric acid to pH 6. Boil with stirring and add 2-PrOH to compensate for the lost MeOH and separate the resulting solid fraction from the hot solution Filter the crystals and remove the filtrate until MeOH is removed Add 2-PrOH while concentrating Upon cooling, obtain a second fraction covered with syrup, wash the crystals in the gum with fresh 2-PrOH and combine with the first fraction.The combined fractions are dissolved in MeOH and then filtered (diatomaceous earth), Recrystallization with the addition of 2-PrOH yields pure 2-imino-1,3-dimethylimidazoridine 1/2 sulfate having a melting point of at least 300 ° C. The second fraction is obtained from the mother liquor. The; melting point 300 ℃ total yield 69.5g (42.8%)

Example 6

N- (4-hydroxyphenyl) -N '-(1-methylimidazol-2-yl) -4-thiamorpholin carboximide amide iodide:

3.75 g (0.007 mole) of N- (4-benzyloxyphenyl-N '-(1-methylimidazol-2-yl) -4-thiamorpholin carboximideamide hydroioda in a 50 ml round flask Filled with 5.9 g (0.021 mole) of 50% hydroiodic acid and 6.0 g (0.1 mole) of glacial acetic acid, then the mixture was heated to reflux for 6 hours to remove excess HI and solvent under reduced pressure as a residue. ) 4-hydroxyphenyl) -N '-(1-metalimidazol-2-yl) -4-thiamorpholin carboximideamide. Hydro Iodide

Claims (1)

General formula

A method for preparing a compound of formula (I) and a pharmaceutically useful acid addition salt thereof, wherein the compound of formula I is reacted with a compound of formula Z ₂ H.

Wherein Z ₂ is selected from the group consisting of (a)-(c):

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

, And

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 to 3 substituents each selected from the group consisting of methylene dioxyphenyl, 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 to 4 carbon atoms; And diphenylalkyl having an alkyl group having 1 to 2 carbon atoms.