KR810000058B1 - Process for preparing heterocyclic derivatives of guanidine - Google Patents

Abstract

Title compds. (I; R1 = H, C1-8 alkyl, C3-6 cycloalkyl, C3-5 alken-2-yl, hydroxy low alkyl, aralkyl, aryl, R2 = H, C1-6 alkyl, aryl; R3 = H, C1-8 alkyl, aryl, R4 = H, methyl, ethyl, R5 = C1-4 alkyl, C3-7 cycloalkyl, aralkyl, aryl; n = 1,2,3, etc), with hypoglycemic activity, were prepd. Thus, compd. (II) was reacted with compd. (III) in anhydrous organic solvent at 0-100≰C to give compd. (IV), which was treated with alkali to produce corresponding heterocyclic derivs. of guanidine(I).

Description

[Name of invention]

Method for preparing heterocyclic derivatives of guanidine

Detailed description of the invention

The present invention relates to a novel heterocycle derivative of guanidine with excellent pharmaceutical properties, in particular a process for the preparation of the following general formula.

In the food

n is an integer of 1, 2 or 3

R ¹ is hydrogen, alkyl with 1-8 carbons, cycloalkyl with 3-6 carbons (especially cyclopentyl and cyclohexyl), alken-2-yl with 3-5-carbon, hardoxy loweralkyl (Especially hydroxyethyl), aralkyl (especially benzyl) and aryl (especially phenyl) and R ₂ is selected from hydrogen, alkyl having 1-6 carbons and aryl (especially phenyl)

R ₃ is selected from hydrogen, alkyl with 1-8 carbons and aryl (especially phenyl)

R ₄ is selected from hydrogen, methyl and ethyl

는 3-7-멤버가 포화된 헤테로싸이클 고리를 나타내는 것으로 만일 -NR₄R₅가 6-멤버 고리일때(i)상기 고리는 필요에 따라 산소나 유황 원자에 의하여 또는 저급 알킬, 페닐이나 벤질로 치환될 수 있는 부가적 질소원자에 의하여 보호되거나 또는(ii)상기 고리는 카르복스이미드아미드기에 결합된 한개의 바로 인접한 질소 원자 이외의 다른 탄소 원자에 저급알킬로 치한되는 것으로 예를들면 아지리디닐, 아제티디닐, 피로리디닐, 피페리디노, 2,3,4,5,7-헥사하이드로-아제피닐, 몰포리노, 티아몰포리노, 티아몰포리노-1-옥사이드, 티아몰포리노-1,1-디옥사이드, 2,6-디저급알킬몰포린노(특히 2,6-디메틸-몰포리노), 4-저급알킬-피페라지닐(특히 4-메틸-피페라지닐), 4-페닐-피페라지닐, 4-벤질-피페라지닐, 2,6-디저급알킬-피페라지닐(특히 2,6-디메틸-피페라지닐등이 있으며 R는 예컨데-부틸, 네오펜틸, 1,1-3,3-테트라메틸부틸 같은 4-10탄소(특히 분지쇄된)를 가진 알킬; 5-8 탄소를 가진 싸이클로알킬(특히 싸이크로펜틸 및 싸이크로헥실); 예컨데 엑소-및 엔도-2-노르보르닐, 2-비싸이크로 [2,2,2]-옥틸-엔도-2-비싸이크로]3,2,1) 옥틸 등과 같은 비싸이크로로알킬; 예컨데 안티-7-노르보르네일등과 같은 7-10탄소를 가진 비싸이크로 알케닐; 예컨데-아다만틸, 1-및 2-아다만틸, 1-및 2-(2,3,3a,4,5,6,7,7a-옥타히드로-4,7-메타노인다닐)등과 같은 9-10탄소를 가진 트리싸이크로알킬; 1-아다만틸메틸; 예컨데 3-(2,3,6,6a-테트라히드로-1H-1,3a-에타노펜타레닐), 5(3a,4,5,6,7,7a-헥사히드로-4,7-메타노인데닐등과 같은 9-10 탄소를 가진 트리싸이크로알케닐; 예컨데 벤질, d-또는 1-α-페네틸, α,α-디메틸벤질, α,α-디메틸-β-페네틸, d-또는 1-(α-나프틸)에틸등과 같은 아릴기가 페닐 및 나프틸로 부터 선택한 것이고 알킬기가 1-4 탄소 원자로부터 선택한 아릴알킬; α,α-테트라메티렌-페네틸; 예컨데 디페닐메틸, 2,2-디페닐에틸 같은 알킬기가 1-2 탄소를 가진 디페닐알킬; α- 및 β-나프틸을 포함한 나프틸; 예컨데 9-풀루오레닐, 5-아세나프틸 같은 융합된 디아릴 싸이크로알킬; 예컨데 4-(2,3-디하이드로 1H-인데닐), 1-(1,2,3,4-테트라하이드로나프틸), 7-(비싸이크로 [4, 2, 0] 옥타-1, 3, 5-트리에닐) 등과 같은 융합된 아릴 싸이크로알킬; 예컨데 시스-또는 트란스-2-페닐싸이크로펜틸, 시스-또는 트란스-2-페닐 싸이크로헥실, 시스-또는 트란스-2-페닐 싸이크로 헵틸 등과 같은 사이크로알킬기가 5-7 탄소를 가진 페닐 싸이크로알킬; 예컨데 시스-또는 트란스-2-씨이크로헥실 싸이크로펜틸, 시스-또는 트란스-2-싸이크로펜틸 싸이크로 펜틸 등과 같은 각 싸이크로알킬기가 5-7탄소원자를 가진 싸이크로 알킬 싸이크로알킬; 페닐; 메티렌디옥시페닐; 할로, 저급 알킬 및 저급 알콕시로 부터 각각 선택한 1-3치환기로 치환된 페닐; 아미노, 디메틸아미노, 메틸에틸아미노, 디에틸아미노, 저급알카노일아미노, 티오저급알킬, 술피닐 저급알킬, 술포닐저급알킬, 트리풀루오로 메틸, 하이드록시, 벤질옥시, 저급알카노일옥시, 저급알칸노일 및 니트로로 치환된 페닐; 3-피리디닐; 예컨데 메톡시-3-피리디닐, 6-크로로-3-피리디닐, 2,6-디메틸-3-피리디닐, 2,6-디크로로-3-피리디닐, 2,6-디메톡시-3-피리디닐 등과 같은 각각 할로, 저급알킬 및 저급알콕시로부터 선택한 1-2 치환기로 치환된 3-피리딜과 예컨데 5-푸릴 및 2-티에닐 같은 5-멤버의 헤테로싸이클로 부터 선택한 것임.R ₅ is alkyl having 1-4 carbons, cycloalkyl having 3-7 carbons (especially cyclopentyl and cyclohexyl), aralkyl (especially benzyl) and aryl (especially phenyl and halo, lower alkyl and lower alkoxy) 1-3 substituents selected from are selected from substituted phenyl and taken together with R ₅

Denotes a heterocycle ring in which 3-7-members are saturated. If -NR ₄ R ₅ is a 6-membered ring, (i) the ring is decomposed by oxygen or sulfur atoms or by lower alkyl, phenyl or benzyl, if necessary. Protected by an additional nitrogen atom which may be substituted or (ii) the ring is substituted by lower alkyl at another carbon atom other than one immediately adjacent nitrogen atom bonded to the carboximideamide group, for example aziridinyl , Azetidinyl, pyridinyl, piperidino, 2,3,4,5,7-hexahydro-azinyl, morpholino, thiamorpholino, thiamorpholino-1-oxide, thiamorpholino-1 , 1-dioxide, 2,6-di lower alkylmorpholino (particularly 2,6-dimethyl-morpholino), 4-lower alkyl-piperazinyl (particularly 4-methyl-piperazinyl), 4-phenyl- Piperazinyl, 4-benzyl-piperazinyl, 2,6-di loweralkyl-piperazinyl (especially 2,6-dimethyl-piperazinyl, etc.) R is an alkyl having 4-10 carbons (especially branched) such as, for example, -butyl, neopentyl, 1,1-3,3-tetramethylbutyl; cycloalkyl having 5-8 carbons (especially cyclopentyl and Cyclohexyl); for example bicyclo such as exo- and endo-2-norbornyl, 2-bicyclo [2,2,2] -octyl-endo-2-bicyclo] 3,2,1) octyl, etc. Alkyl; Bicyclo alkenyl having 7-10 carbons such as for example anti-7-norbornale; Eg, adamantyl, 1- and 2-adamantyl, 1- and 2- (2,3,3a, 4,5,6,7,7a-octahydro-4,7-methanoindanyl) Tricycloalkyl having 9-10 carbons; 1-adamantylmethyl; For example 3- (2,3,6,6a-tetrahydro-1H-1,3a-ethanopentarenyl), 5 (3a, 4,5,6,7,7a-hexahydro-4,7-methanoin Tricycloalkenyls having 9-10 carbons such as denyl and the like; for example benzyl, d- or 1-α-phenethyl, α, α-dimethylbenzyl, α, α-dimethyl-β-phenethyl, d-or Aryl groups such as 1- (α-naphthyl) ethyl and the like are selected from phenyl and naphthyl and alkyl groups are selected from 1-4 carbon atoms; α, α-tetramethylene-phenethyl; for example diphenylmethyl, Diphenylalkyl having an alkyl group such as 2,2-diphenylethyl having 1-2 carbons; naphthyl including α- and β-naphthyl; fused diaryl cyclyls such as 9-puluorenyl, 5-acenaphthyl Chromalkyl; for example 4- (2,3-dihydro 1H-indenyl), 1- (1,2,3,4-tetrahydronaphthyl), 7- (bicyclo [4, 2, 0] octa- Fused aryl cycloalkyls such as 1,3,5-trienyl), etc., eg cis- or trans-2-phenylcyclophene Phenyl cycloalkyl having 5-7 carbons, such as cis- or trans-2-phenyl cyclohexyl, cis- or trans-2-phenyl cycloheptyl, etc .; for example cis- or trans-2-ci Each cycloalkyl group, such as chromhexyl cyclopentyl, cis- or trans-2-cyclopentyl cyclopentyl, etc., cycloalkyl cycloalkyl having 5-7 carbon atoms; phenyl; methylenedioxyphenyl; halo, lower alkyl And phenyl substituted with 1-3 substituents each selected from lower alkoxy; amino, dimethylamino, methylethylamino, diethylamino, lower alkanoylamino, thio lower alkyl, sulfinyl lower alkyl, sulfonyl lower alkyl, triful Phenyl substituted with fluoro methyl, hydroxy, benzyloxy, lower alkanoyloxy, lower alkanoyl and nitro; 3-pyridinyl; for example methoxy-3-pyridinyl, 6-chloro-3-pyridinyl, 2 , 6-dimethyl-3-pyridinyl 3-pyridyl substituted with 1-2 substituents selected from halo, lower alkyl and lower alkoxy, for example, 2,6-dichloro-3-pyridinyl, 2,6-dimethoxy-3-pyridinyl, and the like Selected from 5-membered heterocycles such as 5-furyl and 2-thienyl.

As used herein, the term "lower" indicates that the directly related group has 1-4 carbons and the term "halo" refers to halogens of atomic weight below 127 such as chromo, bromo, pullouro and iodo. . In particular, when one of R ₂ and R ₃ described above is alkyl or aryl, the other is hydrogen, and when n is an integer 2 or 3, R ₂ and R ₃ are hydrogen.

British Patent 1,409,768 describes several heterocycle derivatives of guanidine wherein the heterocycle portion is a saturated 1,3-diazacarbocycle-2-iridene of 5- or 6-members. These derivatives are not substituted by the imino nitrogen of the guanidine moiety, whereas the compounds of the present invention differ from the presence of saturated mono-azaheterocycle derivatives of guanidine and they also have huge substituents on the imino nitrogen of the guanidine moiety. It is.

Additional conventional patents related to this specification include German Patents 2,321,330 and 2,502,397.

Due to the presence of trivalent nitrogen in the compound of general formula (1), acid addition salts and tetravalent salts thereof are easily obtained, and these pharmaceutically acceptable salts are also within the scope of the present invention. Belongs. Compounds (1) of the present invention are suitable acids such as hydrochloric acid, hydrochloric acid such as hydrochloric acid, bromic acid, inorganic acids such as sulfuric acid, nitric acid, phosphoric acid and vinegar, propionic acid, glycolic acid, pamoic acid, pyruvic acid, maronic acid, succinic acid, maleic acid, fumaric acid. Such as, malic acid, tartaric acid, citric acid, benzic acid, cinnamic acid, mandelsin methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, P- torrenesulfonic acid, cyclorohexane sulfamic acid, salicic acid, P-amino salicylic acid Treatment with organic acids can convert these pharmaceutically active non-toxic acid addition salts and, conversely, the salt form can be treated with alkali to convert it to the free base form.

Pharmaceutically active tetravalent ammonium salts can be prepared by formulating a compound of formula (1) as an alkylating agent such as methyl iodide, ethyl bromide, propyl bromide, aryl chromazide, benzyl fluoride, alkyl, alkenyl or aralkyl. Prepared by reacting with halides or sulfates or sulfonate esters, such as lower-alkylsulphates, dimethylsulfates, diethylsulfates, lower alkylsulfonates, methyl P-toluene sulfonates, methyl pullurosulfonates . The tetrahydration reaction is carried out in a closed vessel under atmospheric pressure or pressure at room temperature or cooling temperature in the presence or absence of a solvent, depending on whether the tetravalent agent itself can act as a solvent. . Suitable reaction inert organic solvents for this purpose include diethylether and ether benzenes such as tetrahydrofuran and hydrocarbons such as heptane, ketones such as acetone and butanone, lower alkanols such as ethanol, propanol and butanol or organic acid amides such as formamide or dimethyl formamide. And so on.

The anion function of the tetravalent salt can be easily exchanged by the conventional ion exchange method.

In view of hypoglycemic activity, the most suitable compounds of the present invention are compounds of the general formula and their weakly acceptable acid addition salts and tetravalent salts.

In the food

n = 1 or 2

R ₆ is selected from lower alkyl, aryl, hydroxy and benzyl

R ₇ is methyl or ethyl,

R ₈ is selected from lower alkyl, cyclopentyl and cyclohexyl,

-NR ₇ R ₈ taken together is selected from pyridino, piperidino, morpholino and thia morpholino,

R ₉ is phenyl, substituted phenyl as described above other than sulfonylloweralkylphenyl, 1-amantyl and 1,1,3,3-tetramethylbutyl, cyclohexyl, diphenylmethyl, naphthyl and 9-pullu It's chosen from orenyl,

R ₁₀ is selected from hydrogen and alkyl of 1-3 carbons and R ₁₁ is selected from hydrogen and alkyl of 1-3 carbons wherein at least one of R ₁₀ and R ₁₁ is hydrogen.

The compound of formula (1) is n, R ₁ , R ₂ are the same as described above, X is methoxy or ethoxy, YQ is BF ₄ Q or OS0 ₂ FQ in the lactam salt of formula (II) R ₄ , R ₅ and NR ₄ R ₅ are prepared by reacting stoichiometrically with guanidine derivatives of the general formula (IV) as described above. Suitable anhydrous organic solvents for inducing a reaction include, for example, lower fatty alcohols such as methanol, ethanol, 2-propanol, t-butanol and the like; Ether chloroform such as diethyl ether tetrahydrofuran, dioxane and the like, lower halogenated hydrocarbons such as methylene chromide, 1,2-dichloroethane and aromatic hydrocarbons such as benzene toluene and xylene Etc. Generally ambient temperature-0 ° C is used.

In the form of the corresponding HY salt, the product (V) is converted to the corresponding base form (1) by treatment with a suitable alkali such as an alkali metal or alkaline earth metal hydroxide and carbonate. It is illustrated by the following scheme.

가 BF₄

인 일반식(Ⅲ)의 락탐풀루오 보레이트는 일반적으로 공지 되였으며 예컨데 캐나다특허 850,116호; 미국특허 3,876,658호; Ber 89 2063 (1956) 및 org. Synth 46 113, 120 (1966) 문헌에 기술된 공지에 따라 수득할수 있다. Y

가 OSO₂F

인 일반식(Ⅲ)의 라탐 풀루오로술포네이트로 유사하게 제조할수 있다. 일반적으로 일반식(Ⅵ)의 락탐은 적당한 트리알킬 옥소니움 풀루오로보레이트(Ⅶ)이나 메틸 풀루오로술포네이트(Ⅷ)과 반응시켜 해당하는 락탐염을 수득한다. 이 반응은 0℃ 주위 온도 및 불활성 건조 기권(예컨데 질소, 아르곤) 하에 예컨데 크로로폼, 1,2-디크로로에탄, 메티렌 디크로라이드(가장적당)등과 같은 불활성 무수 저급할로겐화 탄화수소 용매내에서 실시한다. 사용할 수 있는 다른 불활성 무수 유기 용매는 예컨데 디에틸에테르, 디옥산, 테트라하이드로 푸란(THF), 1,2-디메톡시에탄등과 같은 에테르 및 벤젠, 톨루엔, 키시렌등과 같은 방향족 탄화수소등을 포함 한다. 상기 반응은 하기와 같이 설명된다.Meal Y

Autumn BF ₄

Lactampuloborate of the general formula (III) is generally known and is described, for example, in Canadian Patents 850,116; US Patent 3,876,658; Ber 89 2063 (1956) and org. Synth 46 113, 120 (1966). Y

OSO ₂ F

It can be prepared similarly with the ratam pullurosulfonate of the general formula (III). In general, the lactam of formula (VI) is reacted with a suitable trialkyl oxonium pulluoroborate or methyl pullurosulfonate to obtain the corresponding lactam salt. This reaction is carried out in an inert, anhydrous, lower halogenated hydrocarbon solvent such as, for example, chromoform, 1,2-dichloroethane, methylene dichloride (most suitable), under ambient temperature and inert dry atmosphere (e.g. nitrogen, argon). To be carried out in Other inert anhydrous organic solvents that may be used include, for example, ethers such as diethyl ether, dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane and aromatic hydrocarbons such as benzene, toluene, xylene and the like. do. The reaction is explained as follows.

In addition, the corresponding 2-lower alkythiolactam ether of the general formula (III-C) is formula (VI) according to the process of R. gomper and W. elser in Org.S.yn, Coll, Vol V P780-783. Lactam is reacted with P ₂ S ₅ to obtain thiolactam of formula (VIa). Obtained and prepared thiolactam. The thiolactam is treated with a lower alkylating agent, such as methyliodide, methylfluorosulfonate, dimethyl sulfonate, methyltosyrate, methyl mesacrylate, and the like to obtain the desired 2-lower alkylthiolactam ether as the corresponding salt. The lower alkyl thiolactam ether salt derived as described above is reacted with a suitable guanidine of formula (IV) to give the corresponding salt of formula (1).

The side reactions of the general formula (III-a) lactam pullourosulfonate with general formula (IV) and nidine are carried out in the above-mentioned reaction conditions to obtain a by-product of the following form which can be separated by a conventional recovery method.

Such salts are tetravalent derivatives of general formula (1) having antisecretory and hypoglycemic activity.

A suitable method for preparing compounds of formula (1) wherein R ₁ is hydrogen is to react the guanidine derivative (IV) described below with the free base form of (III) rather than pulloborate or pullurosulfonate salt. Standard salts of the general formula (III) are treated with alkali in a halokenated hydrocarbon solvent such as methylene dichloride, croroform to obtain the free base, and then, for example, methanol, isopropanol, t-butanol, and the like. Reaction with the desired guanidine derivative (IV) in anhydrous lower alkanol solvent affords the corresponding compound of formula (1) in which tautomeric forms exist. The elevated temperature above reflux is used during the latter stage as well as using a stoichiometric excess free base.

Another method for preparing the compound of formula (1) is to react the reaction conditions described by Brederek in Chem Ber 96 1350 (1963) by internally interacting lactam (IV) with dimethylsulfate (III). The corresponding methosulfate salts are obtained. The reaction can be carried out by, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; It is carried out in anhydrous acyclic organic solvents such as ether such as tetrahydrofuran, dioxane or halocarbon such as 1,2-dichloroethane, chromoform and the like. When the obtained meto sulfate salt (XII) is reacted with the desired guanidine derivative (IV) at 25 ° -100 ° C as before, the corresponding methyl sulfate salt of the general formula (I) is obtained, which is treated with alkali. It can be converted into the corresponding free base of the general formula (1).

The free base of formula (1) is also known as chem. Ber. 97 3081-3087 (1964) reacted with alkali metal lower alkoxides, in particular sodium methoxide or sodium ethoxide, in the corresponding lower alkanol solvents according to the reaction conditions described by H. Bettederek to give the general formula (VIIIIa). It can be obtained from the metosulfate salt (XII) by obtaining the corresponding lactam acetal of The lactam acetal is also reacted with the appropriate guanidine of formula (IV) to give the free base of formula (1).

The reactions can be represented by the following scheme.

Formula (1) Other methods for preparing the compound are, for example, ethers such as diethyl ether, dioxane and THF; Guanitin precursors (IV) are commonly used in anhydrous non-aqueous solvents such as chlorohydrocarbons such as chromoform, methylene dichromide and 1,3-dichloroethane and aromatic hydrocarbons such as benzene, toluene and xylene. It is made to react with the chloride salt of Formula (XIII).

The chromide salts (XIII) together with the release of CO ₂ or SO ₂ are found in chem. Lactam (VI) is obtained by activating with phosgene (clcocl) or thionyl chloride (SOC1 ₂ ) according to the instructions of W. Gentsch and M. Seeder in Ber., 98 274 (1965). The reactions are illustrated by the following schemes.

The compounds of the present invention of formula (1) may be prepared from imino compounds of formula (XIV) in which n, R ₁ , R ₂ and R ₃ in the formula are described above instead of the lactam (VI) starting material described above. . The 2-imino compounds (XIV) have been described in most literature and can be obtained according to the method of Canadian Patent 950,464 (see eg Example 14). These 2-imino precursors are of the same molar number of 2, wherein R is as described above, but in particular other than iso- 9- pulloenyl, isothiocyanate of formula (XV), benzene, ethylenedichloride, chromo The reaction is carried out in a foam-like reaction-inert organic solvent at 0 ° C-ambient temperature for 2-24 hours. The thi groups (= S) in the thioureas (XVI) obtained, several of which are described in US Pat. No. 3,717,6, wherein R ₁ is ethyl or methyl, iga iodide, tosyrate, methosulfate, mesionate, It is converted into an alkyl thi group (-SR ') by reacting an alkylating agent of the general formula R ₁ X, which is a pullourosulfonate, with (XVI). Representative solvents for such alkylation include ethers such as dimethyl ether, tetrahydrofuran or dioxane; Lower ketones such as acetone, 2-butanone, halohydrocarbons and lower alkanols such as methylene dichloride and methanol. In particular, methyl iodide is suitable as alkylating agent in methanol, and a stoichiometric excess of alkylating agent is used from the same equivalent depending on the reactivity of thiourea (XVI) or solubility in the solvent used. The alkylation reaction is carried out at temperatures in the ambient and reflux temperature ranges. Alkylthio compounds of the general formula in the form of acid addition (HX) salts are reacted with higher temperatures in the ambient temperature to reflux temperature range or in sealed containers. The alkylthio compound of formula (III) in the form of acid addition (HX) salt is as described above under R ₄ and R ₅ in reflux temperature in a lower alkanol solvent such as isopropanol and t-butanol, but R ₅ is phenyl or substituted By reacting with a suitable amine of the general formula HNR ₄ R ₅ , other than phenyl, to give a guanidine derivative of the general formula (1) in the form of a similar acid addition, which is obtained by treating with a suitable alkali to obtain the corresponding base form. It can be easily obtained by.

Isothiocyanates of general formula (XV), which are usually known, can be prepared according to the processes reported in the literature for preparing isocyanates. See, eg, M. Beaugemann, et al., Volume 9,867-884 (1955) of Methods der organische chemie Houben-Weyl; Lnd. Chim., Beige. 32 106 (1967), for the preparation of “isocyanate aromatics” reported by A. Rassault, German Patent No. 1,300,559; J.org.chem. 36,1549 (1971); U.S. Patents 2,395,455 and 3,304,167; French Patent 1,528,249; Aliphatic sodanate, 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).

In the reaction of (iii) with amine HNR ₄ R ₅ , it is preferred to use a stoichiometric excess of amine such as 1: 1.05-1: 2.0 mol. If only a few excess HNR ₄ R ₅ amines were used, it is preferred to add equivalents of tertiary alkylamines such as Et ₃ N to increase the reaction rate. By-products such as haga are produced during the reaction.

The by-products are separated from the desired general formula (1) product by standard methods known in the art such as fractional dissolution.

Another method for preparing the general formula (1) cargo from the 2-imino-precursor of general formula (XIV) is to prepare 2 roll equivalents of the free base (XIV) in which R ₄ , R ₅ and R are as described above. It is made to react with the compound of Formula (iii). An equivalent of 2-imino precursor in salt form (XIX) is produced during the reaction. The reaction is preferably carried out in a nonaqueous solvent in which the desired product of formula (1) in base form is dissolved and the acid addition salt (XIX) is precipitated. The two products are thus easily separated by filtration and the acid addition salts are converted back to the free base by treatment with alkali. Representative solvents suitable for the above include ethers such as diethyl ether and THF; Lower alkanones and esters such as acetone, methyl ethyl ketone, ethyl acetate: aromatic hydrocarbons such as benzene, toluene xylene; Solvents similar to acetonitrile; diethyl ether is generally suitable. The reaction is explained as follows.

The preparation of many guanidine derivatives has been reported in the literature. Thus, the guanidine precursor of formula (IV) can be obtained by various synthetic routes. For example, R is represented by the general formula of thio urea as described above [RL Frank and PV Smith, Oeg. Syn. Coll. 111, P 735 (1955); A. Radwigt, Ind. Chim. Belge, 32 106 (1967); G Barnico and J Bodecker, J. Fur Prakt chemie, 313, 1148 (1971); RG Neville and JJ McGee, Org.Syn. 45, 69 (1969); CP Assistants and KN Nazakh Haran, Chem. Ind. P. 750 (1974); And J. Chem. Soc. Transactions, P. 1702 (1924), are alkylated with the aforementioned R'X alkylating agents to convert to alkylthio of the general formula (XXI). And the obtained alkyl thio compound (XXI) is R ₅ is phenyl or is reacted with a of the general formula HNR ₄ R ₅ is other than phenyl appropriate substituted amine acid addition (HX) to yield the salt form of gwani derivatives (XXII) This derivative can be converted to the corresponding base form (IV) by treatment with alkali. Tertiary alkylamines such as Et ₃ N are used to increase the reaction rate and the reaction conditions are the same as described above for the conversion of thiourea (XvI) to alkylthio compound (XVII) and final product (1). .

See L.A. Ki / elev et al., C.A., 82 86179t (1975).

Formula (IV) is a process for preparing guanidine in which R is phenyl or substituted phenyl, R ₄ is hydrogen, R ₅ is wasteyl or substituted phenyl, wherein Ar and Ar ¹ are each phenyl or substituted phenyl ArNHC (= S) Reacts with ammonia according to the method described in J. Org.chem. (USSR) 2, 2144, (966), starting with the appropriate N, N'-diarylthiourea of NHAr ¹ It is to let.

Formulas (IV) and nidine in which R is alkyl, cycloalkyl, aralkyl, diphenylalkyl, phenyl and lower alkyl, lower alkoxy, halo and nitro substituted phenyl are described in E. Kuhle, Angew. . chem. internat. Ed. 8 24, 26, (1969) and references cited, including the continuation of chromide, from the appropriate isocyanate amide dihalides (XIII). Angew. Chem. internat. Ed. 6649 (1967) to (ⅩⅩⅢ) prepared by the method described by in the E kyure diethyl ether halo hydrocarbons, in the presence of a trialkylamine, such as ethyl Tiree in a suitable reaction inert anhydrous solvent such as aromatic hydrocarbons, amines R ₅ is phenyl Or react with an amine HNR ₄ R ₅ other than substituted phenyl to give a monohalide compound (IV). The reaction mixture is treated with excess anhydrous ammonia and then diluted with alkalis such as alkali metal hydroxides or carbonates to give the corresponding guanidine derivative (IV).

Additional methods for preparing general formula (IV) and nidine, wherein R is phenyl or substituted phenyl, are described in British Patent No. 1,341,245 in N.M. By cycline and C.A. 79 660 525f (1973) 80, 95571a (1974), 82 86179t (1975) and 68, 86760 g (1968), reacting an appropriate aniline (XV) with cyanamide of the general formula (XVI). To obtain the guanidine salt (XII). See also US Pat. No. 3,976,643, filed Aug. 24, 1976 by J. Diamond.

Another method for preparing general formula (IV) and nirin wherein R is phenyl or substituted phenyl is tetrahedron, 29, 691,699, which describes acid hydrolysis of suitable 2-isothiocyanatoamidines of general formula (VII). (1973), W. Abram and G.

The compounds of the present invention of general formula (1) and their acid additions and tetravalent salts have valuable pharmaceutical properties, in particular anti-secretory and hypoglycemic properties. For example, the compounds of the present invention of general formula (1) and their salts have anti-secretory activity according to the exact gastric fistula test. The anti-secretory activity of the tested compounds is tested after injection of the compound in the dosage range within the range of 2.4-4 mg / kg body weight for Sprague-Daurey female mice. Mice are fasted for 24 hours with water only in their intestines before testing. On the test day mice are weighed and each rat is selected to have a weight in the range of ± 20 g.

길이의 중간 절개을 하고 위와 장을 노출시킨다. 이때 위가 음식물이나 찌꺼기 물질로 채워졌다면 쥐를 버린다. 4-0 봉합을 사용하여 혈관을 다치지 않고 위(胃)의 저부상에 낭사 봉합을 실시하고 낭사의 중앙내의 위(胃)에 작은 눈금을 만들고 한 첨단상에 프랜즈를 가진 작은 비닐 관으로 구성된 배출관을 위(胃)내에 넣고 낭사 봉합을 프랜지 주위에 시켜 단단히 밀폐시킨다. 그리고 즉시 시험 화합물을 100gr 쥐 당 0.5㎖의 용량으로 급여한다. 일반적으로 시험될 각 투약량에 대하여 3마리의 쥐를 사용하고 비교 쥐는 시험 용매 일반적으로 0.5% 수용성 에틸 셀루로즈만을 급여한다.Surgery is performed under mild ether anesthesia, and as soon as the rat is anesthetized, small pinchers are used to remove each tooth. And on the abdomen

Make an incision in the middle of the length and expose the stomach and intestines. If the stomach is filled with food or debris, discard the rat. Using 4-0 sutures, the cysts are sutured to the base of the stomach without injuring the blood vessels, making a small scale in the stomach in the middle of the cyst, and consisting of a small vinyl tube with a friend on one tip. Place the discharge tube in the stomach and seal it tightly with the cyst sutures around the flange. Immediately the test compound is fed at a dose of 0.5 ml per 100 gr rats. In general, three rats are used for each dose to be tested and the comparison rats are fed only test solvent generally 0.5% water soluble ethyl cellulose.

After feeding the test compound, the gastric wall and epidermis are brought into close contact with three to four 18 mm rolled creases simultaneously and a return tube is placed on the discharge tube. And put each rat in a box to make a horizontal inclination so that the discharge pipe hanging freely so that there is no inconvenience in the movement of the rat. After the rats are stabilized for 30 minutes, the collection tube on the discharge tube is discarded and replaced with a clean tube to receive gastric juice. Recover for 1 hour, remove the drain tube and sacrifice the rat.

The collected gastric fluid sample is placed in a centrifuge tube and centrifuged to settle. Read the dose, place 1 ml of supernatant into a beaker containing 10 ml of distilled water, and titrate with 0.01 N sodium hydroxide until pH 7. The result is determined as the dose, the acid to be titrated and the total acid output, where dose = gastric juice-total ml of precipitate; Acid to be titrated (pre-equivalent / 1) = titer of 0.01 N caustic soda and total acid yield = titrated acid capacity. The results are reported as% inhibition versus comparison and indicate a minimum of 5% inhibition as anti-secretory action.

In addition, the compound (1) of the present invention and salts thereof were found to have a hypoglycemic action (ie, a hypoglycemic property), as shown in the glucose tolerance test for the compound of general formula (III), in particular in the following mice.

The rat glucose tolerance test is a standard and extremely sensitive process used to diagnose diabetes and hypoglycemia.

Sprague-Dauray male rats (Culles River 184-250gm) are watered and fasted 24 hours prior to testing. A series of blood samples (0.1 ml) are taken at 0, 30, 60, 90, 120, 150 and 180 minutes from the tail without anesthesia after oral feeding of 1 g of glucose / kg body weight in 1 ml of water. Blood samples were immediately deproteinized with aqueous solutions of Ba (OH) ₂ and ZnSO ₄ and analyzed for ultra-low concentrations of blood glucose as a “glucose oxidase” as listed in Amer, J. Path., 32 195 (1959). Glucose levels are determined using the glucose oxidase method described by LP Cowley.

2-5 rats were used in each test and comparison group and the test compound (1-200 mg / kg) SC or ip) was fed in a suspension of 0.5 or 1.0 ml in 0.5-1.0% methylcellulose. Feed only equivalents of solvent. The blood glucose value is expressed in mg% (mg glucose / 100 ml of blood) at each time. The mean glucose value of the control group was statistically compared to the mean glucose value of the test group at each time of challenge, and if the compound lowered blood glucose by 95% at any time, the compound is considered to have a blood glucose reducing effect.

Example 1

A.N- (1-methyl-2-pyrrolidinylidene) -N'-phenylthiourea:

5 ml of 50% aqueous sodium hydroxide solution was added to 6.73 g (0.05 mole) 2-imino-1-methyl-pyrrolidine hydrochloride in benzene as a starting suspension and stirred for 2 minutes, followed by stirring the organic phase with potassium carbonate (excellent). Follow phase and extract twice with fresh benzene. The combined extracts are dried and then rapidly filtered (diatomaceous earth ped) under reduced pressure to minimize contact with air to avoid carbonate formation, and then 6.76 g (0.05 mole) of phenylisocyanate is added in small portions. The solid obtained after 3 hours of stirring is recovered. The second impurity product is obtained as a mother liquor and recrystallization from ethyl acetate gives a pure product, N- (1-methyl-2-pyrrolidylidene) -N'-phenylthiourea, having a melting point of 142-143.5 ° C.

B. Methyl N- (1-methyl-2-pyrrolidinylidene) -N'-carbamidothioate hydroiodide:

시간을 환류 시킨다음 실온에서 다시 1시간 방치한다. 냉각((얼음 중탕)하면 고체가 결정화되며 이것을 메탄올-이소프로판올로 부터 재결정화 재결정화시키면 용융점이 145-147℃인 순수한 메틸 N-(1-메틸-2-피로리디리덴)-N'-페닐카르밤 이미도티 오에이트 하이드로 요다이드를 수득한다.To a solution of 34.86 g (0.15 mol) of N- (1-methyl-2-pyrrolidinylene) -N'-phenylthiourea in 500 ml of acetone, 21.3 g (0.15 mol) of iodomethane in acetone were added and reacted. Mixture

The temperature was refluxed and left for 1 hour at room temperature. Cooling (ice bath) crystallizes the solid and recrystallises it from methanol-isopropanol. Recrystallizes pure methyl N- (1-methyl-2-pyrrolidylidene) -N'-phenylcarr with a melting point of 145-147 ° C. Chestnut imidoti ate hydro iodide is obtained.

C. The compounds of Example 1-A in lower alkanol solvents, acetone or lower halo hydrocarbons are substituted with methyl P-toluenesulfonate, dimethylsulfonate, methyl pullurosulfonate, trimethyloxonium pulluoborate or methyl methane. Treatment with sulfonate gives the methylthio compound of Example 1-B as the corresponding salt.

D. N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximide amidehydroiotate:

15.02 g (0.04 mole) of Example 1-B compound and 4.31 g (0.06 water) of 99% pyriridine solution were refluxed for 24 hours in 100 ml of isopropanol, followed by cooling (ice) to crystallize the solid. The crystals are recovered by filtration and the mother liquor is stored (see Example XXVI). Pure N- (1-methyl-2-pyrrolidylidene) -N with isopropanol and methanol-ether recrystallization melting point 206-208 ° C. '-Phenyl-1-pyrrolidinecarboxyimideamide hydroiodine dide is obtained.

Example 11

The following acid addition salts of the 2-imido compound of general formula (XIV) are obtained according to Canadian Patent 950,464.

a. 2-imino-1-methyl-5-phenyl pyriridine pullorate: melting point 128-31 ° C

b. 2-imino-1-methyl-pyrrolidine pulloborate, melting point 109-11 ° C.

c. 2-imino-1-ethyl-pyrrolidin hydrochlorideide melting point 181-85 ° C

d. 2-imino-1-n-butyl-pyrrolidine cyclohexane sulfamate melting point 110-114.5 ° C

e. 2-imino-1-benzyl-pyrrolidine proborate melting point 112-114 ° C

f. 2-imino-1,5-dimethyl-pyrrolidine proborate melting point 100-102 ° C

g. 2-imino-1-methyl-piperidine hydrochloride

h. Hexahydro-2-imino-1-ethyl-1H-azepine. Cyclohexanesulfamate melting point 143-45 ℃

i. 1-hydroethylethyl-2-imino pyriridine cyclo hexane sulfamate melting point: 105-108 ° C

Each of these salts is converted to the free base by treatment with 50% sodium hydroxide as shown in Example 1-A.

Example 3

Angew for preparing isothiocyanates. chem. internat. The following compounds are obtained following the procedure described by J. C. Jomms and A. Siriger in Ed., 6 (2), 174 (1976).

a. 1- and 2- (2,3,3a, 4,5,6,7,7a-octahydro 4,7-methanoindanyl) isothiocyanate

b. 1,1-dimethyl phenethyl isothiocyanate

c. 1-α-pinethyl isothiocyanate

d. d-α-phenethyl isothiocyanate

e. 1-benzyl cyclopentyl isothiocyanate

f. 7- (bicyclo [4.2.0] octa-1,3,5-trienyl) isothiocyanate

g. 1-adamantyl methyl isothiocyanate

h. 2-adamantyl isothiocyanate

i. Trans-2-phenylcyclopentyl isothiocyanate

j. Cis-2-phenyl cyclopentyl isothiocyanate

k. Trans-2-cyclohexyl cyclopentyl isothiocyanate

l. Cis-2-cyclohexyl cyclopentyl isothiocyanate

m. Cis-2-phenylcycloheptyl isothiocyanate

Example IV

Except for using the equivalent 2-imino-, compound obtained in Example II as a starting material for reacting with an equivalent isothiocyanate equivalent, according to the procedure of Example 1-A To obtain thiourea,

a. N-2- (hexahydro-1H-1-methyl-azapyriden-N'-phenylthio urea: melting point 157-159 ° C

b. N-1-methyl-2-pyrrolidinylidene-N'-diphenylmethyl thiourea melting point 112-114 deg. C (pullymorph), 119-120 deg.

c. N-1-methyl-2-pyrrolidinylidene-N'-P-nitrophenyl thiurea: melting point 179-180.5 ° C

d. N-1-methyl-5-phenyl-2-lauridinilidene-N'-phenylthiourea melting point 135-140 ° C

e. N-1-methyl-2-pyrrolidinilidene-N'-P-propenyl thiourea: melting point 152-54 deg.

f. N-1-methyl-2-pyrrolidinilidene-N'-benzylthiourea melting point (71) 74-81 ° C

g. N-1-methyl-2-pyrrolidinylidene-N'-2-naphthylthio urea: melting point 159-162 ° C

h. N-1-methyl-2-pyrrolidinylidene-N'-cyclohexyl thiourea: melting point 88-93 ° C

i. N-1-methyl-2-pyrrolidinilidene-N'-P-methoxy phenyl thiourea: melting point (149) 150-152 ° C. (deck)

j. N-1-methyl-2-pyrrolidinylidene-N'-P-chlorophenyl thiourea: melting point 154-156.5 ° C. (deck)

k. N-1-methyl-2-pyrrolidinylidene-N'-2,6-dimethyl phenyl thiourea: melting point (164) 165-68 deg.

l. N-1-methyl-2-pyrrolidinilidene-N'-1,1,3,3, -tetramethyl butyl-thiourea: melting point 115-110: 5 ° C

m. N-1-methyl-2-pyrrolidinylidene-N'-1-amaanthyl thiourea: melting point 150-152 ° C

n. N-1-methyl-2-pyrrolidinilidene-N'-phenylthio urea: melting point 158 ° C

o. N-1-methyl-2-pyrrolidinylidene-N'-P-methoxy phenyl thiourea: melting point 128-30 deg.

p. N-1-methyl-2-pyrrolidinilidene-N'-phenylthio urea: melting point 132-34 ° C

Example V

Using the following solvent together with the thiourea precursor of Example IV as the starting material to be methylated, the following methyl thio hydroiodide of the general formula (VII) is obtained according to the S-methylation process of Example 1-B.

EXAMPLE

Example VI

Suitable methylthio hydroiodide precursors obtained in Examples 1-B and V and suitable amines of the general formula HNR ₄ R ₅ in reflux isopropanol, in particular t-butanol, as starting materials in a 1: 1-1: 3 molar ratio Except for using the process of Example 1-D to prepare the guanidine derivative of formula (1) with an organic base or an acid addition salt, the product of formula (1) as the corresponding hydroiodide salt, respectively Obtained and isolated or treated with aqueous alkali to convert to the corresponding base form or to other acid addition salts by reacting with an acid having the base form indicated.

In addition, general formula (IV) and nidine are produced as by-products and are separated from the reaction mixture by selective dissolution or fractional crystallization, for example in the form of organic bases or acid addition salts.

TABLE 1a

TABLE 1b

EXAMPLE VII

A. This example shows Org. Syn. Co ll. R. L. described in 111lll P 735 (1955). Frank and P.V. The preparation of N-benzoyl thiourea according to Smith's method (see also Q. Barnico and J. Bodecker, J. Prakt. Chemie, 313, 1148 (1971)). Thus, the following benzoylthiourea is produced.

a. N-benzoyl-N'-3,4-dimethoxyphenylthiourea melting point 133-34 ° C

b. N-benzoyl-NL Benzyloxyphenyl Thiourea Melting Point (120) 132-37 ° C

c. N-benzoyl-N '-(4-methylthiophenyl) thiourea melting point 160-161 ° C

d. Substitute carbenethoxy isocyanate with benzoyl isothiocinarate to form N-carbethoxy-N '-(3,4-methylenedioxyphenyl) thiourea with a melting point (137) of 146-148 ° C. To obtain.

EXAMPLE VII

This example is Org. Syn. Coll. R.L. in Vol 1 III.P735 (1955). The hydrolysis of benzoylthiourea and carbethoxythiourea suitable as thiourea of the general formula according to the method described by Frank and P.V Smith is described.

A. 3,4-dimethoxyphenyl thiourea:

To 1 l beaker containing 95.85 g (0.302 mole) of N-benzoyl-N'-3.4-dimethoxyphenyl urea, 230 ml of 10-12% sodium hydroxide solution and 60 ml of water were added and the mixture was stirred at 60-80 ° C. Heat for 5-10 minutes until complete hydrolysis.

The hot solid was filtered, washed with water until the filtrate was neutral, washed with methanol and dried to give 3,4-dimethoxy phenylthiourea having a melting point of 234-242 ° C. (decomposition).

B. P-benzyloxyphenyl thiourea.

Except for using the equivalent of N-benzoyl-N'-P-benzyloxyphenylthiourea as the starting material to be hydrolyzed, the above-described process of Example X-A was repeated to give P having a melting point of 193-95 ° C as a product. -Benzyloxyphenylthiourea is obtained.

C. 4-methylthiophenylthiourea,

Melting point 187 193-191 ° C. is similarly obtained.

D. 3,4-methylene dioxyphenylthiourea, melting point 207-209 ° C. Alkaline hydrolyzed N-carboxethoxy N ′-(3,4-dimethyleneoxyphenyl) thiourea under the conditions described above. Neutralization with the next inorganic acid (Caution: CO ₂ occurs violently) yields 3,4-methylene dioxyphenylthiourea with a melting point of 207-209 ° C.

EXAMPLE VII

This example is Chem. Ind. The preparation of the general formula thiourea is described according to the methods of C. P crude and K. N rajasekharan in P759 (1974).

A. 4-n-butylphenylthiourea:

To 100 ml of hot hydrochloric acid (18%) add 90.2 g (0.605 mole) of Pn-butylaniline (97%) followed by 46,1 g (0.605 mole) of NH ₄ SON. The resulting mixture was refluxed for about 1 hour and poured onto ice to form crystals which were recrystallized from ethyl acetate to give pure 4-n-butylphenylthiourea having a melting point of 123-25 ° C.

B. 3,4-methylenedioxyphenylthiourea, melting point 208-210 ℃

C. 4-methoxyphenylthiourea, melting point 207-210 ° C.

Example Ⅹ]

This example, which describes another method of making generalized thiourea, generally involves reacting excess ammonia with a suitable isocyanate in a solvent in ether form.

A. 1- (exo-norbornyl) thiourea;

Exo-2-norbornyl isothiocyanate (produced by Dibere et al. In J. Org. Chem., 34, 616 (1969)) in a dry monogram (27.17 g, 0.178 mole) in 200 ml dry After 5 hours of treatment with ammonia gas, the mixture is left overnight. The product was filtered off and washed with ether to give 1- (exo-2-norbornyl) thiourea with a melting point of 181-183 ° C.

B. N- (9-fluorenyl) -thiourea;

Excess anhydrous ammonia is added to 16.5 g (0.074 moles) of 9-fluorenylisothiocyanate in ether while cooling. The reaction mixture was left at 0 ° C. for 1 night and then filtered to yield N- (9-fluorenyl) -thiourea having a melting point of (158 ° C.) 192-189 ° C.

C. The following products are obtained by repeating the above process of this example, except that the same equivalent of isothiocyanate is reacted with excess ammonia.

2- (bicyclo [2,2,2] octyl) thiourea; Ento-2- (bicyclo [3,2,1] octyl) thiourea anti-7-norbornenyl thiourea

1-end 2- (2,3,3a, 4,5,6,7,7a-octahydro-4,7-methanoindanyl) thioureas

3- (2,3,6,6a-tetrahydro-1H-1,3a-ethanopentanenyl) thiourea,

5- (3a, 4,5,6,7,7a-hexahydro-4,7-methano indinyl) thiourea

1,1-diethylphenethyl thiourea

Di-α-phenethyl thiourea

1-α-phenethylthiourea

1-benzylcyclopentyl thiourea

1-bicyclo [4,2,0] octa-1,3,5-trienyl thiourea

1-adamantylmethyl thiourea

2-adamantyl thiourea

Cis-2-phenylcyclopentyl thiourea

Cis-2-phenylcyclopentyl thiourea

Cis-2-cyclohexyl cyclopentyl thiourea

[Example XI]

A. Methyl N- (9-fluorenyl) carbamidothioate hydroiodade:

To 7.85 g (0.033 mole) N- (9-fluorenyl) thiourea in 200 mL acetone is added 4.68 g (0.033 mole) methyl iodide and the mixture is left at room temperature for about 4 hours. After adding ether (400 mL) and leaving the mixture filtered, the resulting crystals were filtered to give methyl N- (9-fluorenyl) carbodiamidothioate hydro iodide having a melting point (208) 212-14 ° C. To obtain.

B. Except for reacting the equivalent thiourea with methyl iodide in the molar ratio indicated and using the solvent indicated, as the hydro iodide salt of the formula The following product is obtained.

C. Repeat the above S-methylation process of Example VII-A and use the equivalent of each thiourea obtained in Example XC with stoichiometric slightly excess methyliodide in methanol as reaction solvent. The corresponding carbamimidothioate hydro iodide of formula (XI) is obtained.

[Example II]

A. N- (4-tolyl) -1-carboximideamide hydroidide:

54-torylthiourea (33.2 g 0.2 mol) in 200 ml of acetone was refluxed with methyl iodide (31.4 g, 0.221 mol), heated for 3 hours, the solvent was removed under vacuum, and the resulting 2-methyl-1 -(4-toryl) -2-thioshudoureahydro iodide is dissolved in 200 ml t-butanol. Pyridine (28.4 g, 0.4 mol) is added and the mixture is refluxed for 18 hours, the reaction mixture is cooled, diluted with ether, and the resulting solid is separated. Recrystallization from acetone-ether gives N- (4-tolyl) -1-pyrrolidine carboximide amide hydroiodide with a melting point of 166-168 ° C. Treatment of the salts with water-soluble (10-20%) sodium hydroxide in ethirine dichloride leads to the corresponding free bases.

B. N-2,6-Dichlorophenyl-1-Pytoridine Carboximideamide Hydrochloride

Reflowing a mixture of 14.52 g (0.04 mole) of methyl-N-2,6-dichlorophenyl carboximidothioate hydroiodide, 5.69 g (0.08 mole) of dry pyriridine and 30 ml of + -butanol Under heating for 3 days. The solvent was removed in vacuo and the resulting amorphous hydro iodide salt was converted to a freebase using 20% sodium hydroxide cooled in ethylene dichloride, dried (K ₂ CO ₃ ), then the solvent was removed and in isopropanol The base obtained in is converted to HCL salt using anhydrous hydrochloric acid. Recrystallization from isopropanol with sufficient methineol yields N-2,6-dichlorophenyl-1-pyrrolidinecarboximide hydrochloride having a melting point of 292-295 ° C. as a pure product.

C. Reacting an appropriate amount of methylthio hydroiodide of the general formula (XXI) with an appropriate amine (HNR ₄ R ₅ ) in reflux t-butanol in the indicated molar ratio, with or without additional equivalents of triethylamyl The reaction was carried out according to the above procedure of Examples XII-A and B to obtain the following guinidines as free base or as indicated acid addition salt.

D. Each of the acid addition salts obtained in Example XII-c can be converted to the corresponding free base by treatment with alkali.

[Example III]

N-phenyl-1-pyrrolidinecarboximide amide hydrochloride:

A mixture obtained by adding 1.74 g (0.01 mole) of phenyl isocyanide dichloride to 0.71 (0.01 mole) pyriridine and 1.01 g (0.01 mole) triethylamine while stirring and cooling under a nitrogen stream in dry ether. After stirring for 30 minutes, the produced Et ₃ N.HCl is filtered. The filtrate is added to a saturated solution of anhydrous ammonia in isopropanol, the resulting ammonium chloride is filtered and the filtrate is concentrated in vacuo to remove excess ammonia and dry HCl is added to give crystalline product. Recrystallization of this with methanol-isopropanol yields N-phenyl-1-pyrrolidine carboximideamide hydrochloride having a melting point of 181-184 ° C.

[Example IV]

N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidine carboximideadide L-(+)-tartrate:

1.02 g (0.0011 mol) of epichlorohydrin is added to 1.84 g (0.013 mol) of boron trifluolide etherate in Et ₂ O (anhydrous) under nitrogen and stirred vigorously for 3 hours. The resulting crystalline triethyl oxonium pullorate is washed with fresh anhydrous ether by pouring under nitrogen.

The obtained crystals are dissolved in dry ethylene dichloride and 1.09 g (0.011 mol) of 1-methyl-2-pyrrolidinone is added to the solution and the mixture is stirred for 2 hours. 0.01 mol of N-phenyl-1-pyrrolidine carboximideamide is added to the obtained melt while cooling in an ice-water bath and the reaction mixture is stirred for 1 minute (about 16 hours). The mixture was evaporated to dryness in vacuo and then diluted with ether to give impure crystalline HBF ₄ of N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidine carboximide. Recrystallization of this crystal from acetone gives a pure pulloborate salt with a melting point of 164-166 ° C.)

The pulloborate salt is converted to the free base by treatment with sodium hydroxide (20%) in ice in ethylene dichloride. The organic layer is dried over anhydrous potassium carbonate, filtered and evaporated to dryness in vacuo to give a free base. The same molar number of free base in methanol is added, and the resulting solution is concentrated with isopropanol until all the methanol evaporates, followed by cooling to form a tartrate salt. This was recrystallized from isopropanol and a small amount of methanol and pure N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidine carboximideamide L-(+)-having a melting point of 153.5 156 占 폚. Get tartrate.

Example IV

Except for reacting the appropriate lactam bulovoborate of formula (IIIa) with the appropriate guanidine of formula (IV) in the indicated molar ratio, the following compounds of formula (1) Obtained as the indicated acid addition salt.

[Example VI]

N- (2,6-dimethylphenyl) -N '-(1-methyl-2-pyrrolidinylidene) -1-pyrrolidine carboximideamide fumarate:

To 3.43 g (0.035 mole) of dry 1-methyl-2-pyrrolidinone solution in dry ethylene dichloride under dry nitrogen, 3.99 g (0.035 mole) of methyl pullulosulfonate was added and dried for 2 hours. 6.52 g (0.03 mol) of N- (2,6-dimethylphenyl) -1-pyrrolidinecarboximide amide free base solution in styrene dichloride was added in small portions with stirring at room temperature and then stirred overnight at ambient temperature. And the reaction mixture is basified with excess cooled sodium hydroxide (20%). The organic phase is separated and the aqueous phase is extracted with 2 x 50 ml of fresh ethylene dichloride, the combined organic phases are dried over anhydrous carritic carbonate, filtered and the solvent is removed in vacuo. The residual oil is dissolved in ether, the solution is filtered through diatomaceous earth and the filtrate is treated with a hot solution of fumaric acid in isopropanol until neutral to give the product as a fumarate salt. This is recrystallized from isopropanol (filter when hot) and pure N- (2,6-dimethylphenyl) -N '-(1-methyl-2-pyrrolidinylidene)-with a melting point of 182-84 ° C. (slight decomposition). 1-pyrrolidinecarboximideamide fumarate is obtained.

EXAMPLE VII

Except that N- (2,6-dimethylphenyl) -1-pyrrolidinecarboximideamide used is substituted with a suitable guanidine of formula (IV) to react with a suitable compound of formula (IIIb) in the molar ratio indicated. The process of Example VI is repeated to yield the following products of formula (1) as free base or as indicated acid addition salts.

EXAMPLE VII

This example describes the preparation of the tetravalent salt of the compound of formula (1).

A. N- (2, 6-dichlorophenyl) -N '-(1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximideminimetofulurosulfonate:

To 6.83 g (0.02 mol) of N-2,6-dichlorophenyl) -N '-(1-methyl-2-pyrrolidylidene) -1-pyrrolidinecarboximideamide in dry ethylene dichloride 2.70 g (0.023 mole) of methyl pullulosulfonate is added under stirring with nitrogen, and the mixture is stirred overnight and then evaporated in vacuo to leave an oily residue that is triturated with ether to form a crystal. This is pure N- (2,6-dichlorophenyl) -N '-(1-methyl-2-pyrrolidinylidene) -1-pyrroli having a melting point of 148-150 ° C. from acetone and then recrystallized from ethyl acetate. Treatment gives an oily precipitate that is recrystallized from t-butanol to give the corresponding metofulurosulfonate salt with a melting point of 135.5-137 ° C.

EXAMPLE VII

N-phenyl-N '-(2-pyrrolidinylidene) -1-pyrrolidinecarboximideamide hydroiodide.

A 0.17 mole triethyloxonium pullulorate solution in dry ethylene dichloride was prepared in a conventional manner. To this solution was added 6.08 g (0.07 mole) of 2-pyrrolidinone and stirred for 2 and a half hours. The reaction mixture is cooled and basified with ice-water bath) sodium hydroxide (50%). The organic layer is separated, dried over potassium carbonate, filtered and treated with 12.2 g (0.065 mol of N-phenyl-pyrrolidyl carboximideamide).

The CH ₂ C1 ₂ solution is evaporated while replacing with t-butanol to give the dine carboximide amidinium metofulurosulfonate.

B. N- (1-Methyl-2-pyrrolidinide-N'-phenyl-1-pyrrolidine-carboximide amidinium metiodide

0.05 mole of a solution of N- (1-methyl-2-pyrrolidinylidene-N'-phenyl-1-pyrrolidinecarboximide (EX. ID) free base in 30 ml of acetone (0.05 water) After 2 days of treatment with methyl iodide, the crystals were recovered and recrystallized from acetone. Pure N- (1-methyl-2-pyrrolidinylidene-N'-phenyl-1-pyrrolidine with a melting point of (156) 162-164 ° C was obtained. Carboximidedium metiodide is obtained.

Calcd for analysis C ₁₇ H ₂₅ N ₄ I C, 49.52; H, 6.11; N, 13,59

Found C, 49.58; H, 6.11; N, 13.59;

C. Similarly, the solution obtained as product (0.05 mol) of Example (ID) as methyl free fluorosulfonate (0.05 mol) as free base in ether (dry) is refluxed for 22 hours. The reaction mixture is cooled to room temperature and then triturated with HI (47%) to give impure HI salts. Recrystallization of this salt from t-butanol yields pure N'-phenyl- (2-pyrrolidinylidene) -1-pyrrolidine carboximideamide hydroiodide with a melting point of 223-225 ° C (decomposition). .

EXAMPLE VII

N- (1-methyl-2-pyrrolidinylidene) N'-phenyl-1-pyrrolidinecarboximideamide L-(+) tartrate 1.74 g (0.01 mole) of phenyl isocyanate dichroic in dry Et ₂ O 0.71 g (0.01 water) of pyriridine is added to the ride with cooling under nitrogen and 1.01 g (0.01 mol) Et ₃ N with stirring. The mixture was stirred for half an hour and then filtered to remove the precipitated Et ₃ N.HCl and to the filtrate was added 1.96 g (0.02 mol) of 1-methyl-2-iminopyrrolidine in an ice-water bath. The resulting mixture was stirred overnight under nitrogen and then filtered to remove N-methyl-2-imino-pyrrolidine hydrochloride having a melting point of 182-188 占 폚. The filtrate is evaporated in vacuo to give an oil which is dissolved in methanol (10 mL) and treated with the same molar L (+)-tartaric acid. The obtained solution is concentrated with the addition of i-PrOH to form crystals. Recrystallization of this crystal from isopropanol-acetonitrile results in pure N- (1-methyl-2-pyrrolidinide) -N'-phenyl-1-pyrrolidine carboximide amide L-(+) having a melting point of 153-56 ° C. To obtain the tartrate salt.

[Example XI]

N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidine carboximideamide L-(+)-tartrate 0.99 g (0.01 mol) of 1-methyl- in dry benzyl 1.26 g (0.01 mol) of dimethyl sulfamates are slowly added under reflux with stirring to 2-pyrrolidone. The reaction mixture is stirred for 5 hours and 1.89 g (0.01 mol) of N-phenyl-1-pyrrolidine carboximideamide is slowly added to the mixture.

The resulting mixture was stirred overnight at room temperature, the mixture was dried under vacuum and then dissolved in CH ₂ Cl ₂ and converted to the free base using sodium hydroxide (50%) in ice. The organic phase is dried (K ₂ CO ₃ ), filtered and evaporated in vacuo to give 2.7 g of oil. The oil was dissolved in methanol and then the product obtained by adding 1.5 g (0.01 mol) of L (+)-tartaric acid was recrystallized from methanol-isopropanol to give N- (1-methyl-2 with a melting point of 153-156 ° C. -Pyrrolidinirene) -N'-phenyl-1-pyrrolidinecarboximideamide L-(+)-titrate is obtained.

[Example II]

N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidinecarboximidamide L-(+)-tarrate:

To a cold solution of 1.98 g (0.02 water) of 1-methyl-2-pyrrolidone in dry toluene is added 3.95 g (0.04 mole) of phosgene and the resulting mixture is stirred for 45 minutes at room temperature under nitrogen to give a white precipitate. Excess phosgene and solvent are removed with the aid of a filter stick (under nitrogen), fresh toluene is added and then removed under reduced pressure to completely remove residual phosgene. The crystals were washed two more times with fresh toluene and dissolved in dry CH ₂ Cl ₂ , followed by 1.89 g (0.01 mole) of N-phenyl-1-pyrrolidine carboximideamide and 1.01 g (0.01 mole) of triethylamine Add. The resulting mixture was exchanged overnight under nitrogen and the mixture was dried under vacuum, then the residue was dissolved in CH ₂ Cl ₂ and this solution was treated with sodium hydroxide (50%) in ice. The organic phase, including the free form of the product, is separated, dried over anhydrous potassium carbonate, filtered and evaporated under vacuum to leave an oily residue. Dissolve this oil in isopropanol and add L-(+)-tartaric acid to pH 6-7. The obtained crystals were recrystallized from this sopropanol to obtain pure N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyritidinecarboximideamide L-( +)-Tartrate is obtained.

[Example III]

2.57 (0.01 mol) of 1-methyl-2-methylthio in N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidine carboximideamide hydro iodide t-butanol 1.89 g (00.1 mole) of N-phenyl-1-pyrrolidine carboximideamide is added to -1-pyrrolidinium iodide and the resulting mixture is left overnight at reflux temperature. The releasing MeSH is captured in concentrated sodium hydroxide solution. The reaction mixture was cooled and scraped to give 3.65 (92%) of impure product, which was recrystallized from t-butanol to give pure N- (1-methyl-) with a melting point of 206-207 ° C. identical to that of Example (ID). 2-Pyrrolidinilidene-N'-phenyl- (1-pyrrolidine carboximide amide hydroiodide is obtained.

[Example IV]

N- (1-methyl-2-pyrrolidinylidene-N'-phenyl-1-pyrrolidencarboximideamide L-(+)-tartrate:

To 1.29 g (0.0075 mol) of 2.2-diethoxy-1-methylpyrrolidine in dry benzene is added 1.42 g (0.0075 mol) of N-phenyl-1-pyrrolidinecarboximideamide and the mixture is vacuumed after 1 night reflux. To dry. The residue is treated with dilute hydrochloric acid (10%) and then basified with cooled sodium hydroxide (20%) and then the free product is extracted with ether.

The dried (K ₂ CO ₃ ) extract was evaporated in vacuo, the residual oil was poured into isopropanol, treated with 1 mole of L-(+)-tartaric acid and recrystallized from methanol-isopropanol to give a pure melting point of 153-156 ° C. N-1-methyl-2-pyrrolidinirrylene-1N'-phenyl-1-pyrrolidine carboximideamide L-(+) tartrate is obtained.

Example IV

Conversion of N- (1-methyl-2-pyrrolidinylidene) -N'-phenyl-1-pyrrolidine-carboximideamide to the following organic or inorganic pharmaceutically active acid addition salts by treatment with the indicated acids, respectively Let's do it.

Fumarate; Melting Point 156-57 ℃

Phosphate; Melting Point 200-01 ° C (Decomposition)

Hydrobromide; Melting Point (206) 207-09 ° C

Oxarate: Melting Point 129-31 ° C

Pamoate: melting point 253-56 (decomposition)

Nitrate; Melting Point 170-71 ° C (Slightly Decomposed)

Marate; Melting Point 115-17 ℃

P-hydroxy benzoate; Melting Point 179-80 ℃

[Example VI]

A.N-phenyl-1-pyrrolidine carboximideamide and

B.1- (1-Methyl-2-pyrrolidididene) pyridinium iodide hydrate

A. The mother liquor stored in Example 1-D is evaporated in vacuo and the residue is placed in methylene chromide and basified with cold diluted sodium hydroxide. The combined organic extract was extracted three times with CH ₂ Cl ₂ (200 mL), dried over anhydrous K ₂ CO _3, filtered and dried in vacuo to leave a brown heavy syrup. The syrup is milled and extracted with hexane (2 x 200 mL) and ether (3 x 200 mL) to leave only black residue. (Storage) The organic layers are combined, treated with charcoal, filtered and evaporated in vacuo to give brown syrup. This was converted to HCl salt and recrystallized from isopropanol-ether to give N-phenyl-1-pyrrolidinecarboximideamide hydrochloride having a melting point of 181-84 ° C.

Analyzes: Calcd for C11H15N3HCl: C. 58.53; H, 7.15%

Found: C, 58.59; H. 7.08%

몰 H₂O로 수화물 형태를 이룬 1-(1-메틸-2-피로리디니리덴)피로리디니움 요오다이드의 백색 결정을 수득한다. 습도가 높은 날에 결정은 잉여의 물을 흡수하여 녹으나 습도가 떨어지면 다시 고체화 한다.B. The black residue stored above is placed in isopropanol, treated with a large amount of charcoal and then filtered to remove the solvent in vacuo to yield a reddish brown glass material. When it is crushed with charcoal in acetone, it has a melting point of (98) 108-110 ° C.

Obtain white crystals of 1- (1-methyl-2-pyrrolidinylidene) pyrrolidinium iodide hydrated with molar H ₂ O. On high humidity days, the crystals absorb excess water and melt, but solidify again when the humidity drops.

^{_{Analysis: C 19 H 17 N 2 +}} · 1 - calculated for 1/4 H ₂ O; C, 37.98, H, 6.02, I, 44.58, H ₂ O, 1.58%

Found: C, 35. 15, H, 6.11, I, 45.25, H ₂ O, 1.13%

EXAMPLE VII

N- (4-aminophenyl) -N '-(1-methyl-2-pyrrolidylidene) -1-pyrrolidinecarboximide amide hydrobromide

2.46 g of N- (1-methyl-2-pyrrolidinylidene) -N '-(4-nitrophenyl) -1-pyrrolidine carboximideamide (product 4 of Example XVII) in 50 mL of absolute ethanol (0.0078 moles) is hydrogenated (3 atm) using a Raney Nickel catalyst directly on a stirrer. After 30 minutes of absorption of hydrogen, the catalyst was separated by filtration and washed with ethanol. The combined filtrates were evaporated in vacuo and the residue was dissolved in ethanol to neutralize with 1 equivalent of aqueous H Br solution (48%). The obtained solid was recrystallized from ethanol-ether to obtain pure N- (4-aminophenyl) -N '-(1-methyl-2-pyrrolidinylidene) -1-dirrolidinecar having a melting point of 241-241.5 占 폚. Obtain voximideamide hydrobromide.

Analysis: Calcd for C ₁₆ H ₂₃ N ₅ HBr: C, 52.46; H. 6.60; N, 19.12%

Found: C, 52.44; H. 6.60; N, 19.09%

EXAMPLE VII

N- (4-acetylaminophenyl) -N '-(1-methyl-2-pyrrolidinylidene-1-pyrrolidine carboximide amide hydrobromide:

3.4 g (0.0119 mol) of N- (4-aminophenyl-N '-(1-methyl-2-pyrrolidinylidene-1-dirrolidine carboximide (product of Example VII)) as its free base The reaction mixture was heated with 25 ml of anhydrous vinegar and steamed for 1 hour in a steam bath, then diluted with ethanol and heated for another hour.The volatile components were removed in vacuo and the residue was treated with dilute aqueous sodium hydroxide solution and extracted with methylene fluoride. The extract was dried over K ₂ CO ₃ and filtered to remove the solvent to give a residual oil, which was converted to the corresponding HBr acid addition salt in ether-ethanol and recrystallized from ethanol-ether to obtain a melting point of 246-247. Pure N- (4-acetylaminophenyl) -N '-(1-methyl-2-pyrrolidinylidene-1-pyrrolidinecarboximideamide, which is ° C, is obtained.

EXAMPLE VII

N- (1-methyl-2-pyrrolidinylidene) -N '-(4-methylsulfonylphenyl) -4-morpholine carboximideamide;

1.98 g (0.0006 mol) of N- (4-methylthiophenyl) -N '-(1-methyl-2-pyrrolidinylidene) -4-morpholine carboximideamide (Compound of Example XV) as free base 31) was added into dry methylene fluoride and cooled to 0 ° C. and stirred to add 3.6 g (0.018 mole) of m-chloroperoxybenzoic acid while maintaining the temperature below 5 ° C. The mixture is stirred at this temperature for 30 minutes and then washed with a saturated solution of sodium bicarbonate (3 x 40 mL) and sodium chloride (3 x 35 mL), respectively. The organic phase is dried (K ₂ CO ₃ ), filtered, evaporated in vacuo, and diluted with methanol, leaving a weakly insoluble substance that is filtered off. Crystals form when the filtrate is evaporated in a steam bath and diluted with ether. The crystal has a melting point of 160-169 ° C, which is recrystallized from ether and is pure N- (1-methyl-2-phytinidinylidene) -N '-(4-methylsulphur with melting point (165) 167-170 ° C. Phonylphenyl) -4-morpholine carboximideamide is obtained.

Analysis: Calcd for C ₁₇ H ₂₄ N ₄ O ₃ S: C, 56.03; H, 6.64%

Found value; C, 56.05; H, 6.69%

EXAMPLE VII

N- (1-methyl-2-pyrrolidinylidene) -N '-(4-methylsulfinylphenyl) -4-morpholinecarboximideamide:

1.98 g (0.006 mol) of N- (4-methylthiophenyl) -N '-(1-methyl-2-pyrrolidinylidene) -4-morpholinecarboxide as a free base in CH ₂ Cl ₂ at 5 ° C 1.22 g (0.006 mole) of m-chloroperoxybenzoic acid is added while maintaining the temperature of 5 ° C. of the stirred solution of the mid amide (compound 31 of Example XV). The reaction mixture is allowed to warm to room temperature and then stirred for another 2 hours. The organic layer is washed with saturated sodium bicarbonate solution (3 x 30 mL) and saturated sodium chloride solution (3 x 30 mL), dried over K ₂ CO ₃ (anhydrous), filtered and the solvent removed in vacuo. Treatment of the residue with ether-hexane yields an impure product, which is recrystallized from ether-hexane to give pure N- (1-methyl-2-pyrrolidinylidene) -N '-(with melting point (115) 117-120 ° C). 4-methylsullinylphenyl-4-morpholine carbox imideamide is obtained.

Analysis: Calcd for C ₁₇ H ₂₄ N ₄ O ₂ S; C, 58.60; H, 6.94 Found: C, 58.58; H, 6.91

[Example XI]

N- (4-hydroxyphenyl) -N '-(1-methyl-2-pyrrolidinilidene) -1-pyrrolidinecarboximideamide hydroiomide:

26.6 g (0.071 mol) of N- (1-methyl-2-pyrrolidiniritene) -N '-(4-benzyloxyphenyl) -1-pyrrolidine carboximide as the corresponding free base in 50 ml of vinegar acid A solution of amide (product 27 of Example XV) is placed in a Parr stirrer and hydrogenated for 2 hours on a 10% pb / c catalyst at 3 atmospheres of air at room temperature. The reaction mixture is filtered to remove the solvent in vacuo, leaving a viscous oil that is placed in acetone and treated with 1 equivalent of HI (aqueous aqueous solution). Recrystallization of impure crystals from methanol-acetone-ether gives pure N- (4-hydroxyphenyl) -N '-(1-methyl-2-pyridinylidene) -1-pyrrolidinecar with a melting point of 174-178 ° C. Iodide is obtained with voximide hydride.

Analyzes: Calcd for C16H22N4OHI: C, 46.39; h, 5.60; N, 13.52 Found: C, 46.62: H, 5.59; N, 13.63

[Example II]

N- (4-acetoxyphenyl) -N '-(1-methyl-2-pyrrolidinylidene) -1-pyrrolidinecarboximideamide hydro iodide:

12 g (0.20 mole) of glacial acetic acid was added to 5.15 g (0.0124 mole) of N- (4-hydroxyphenyl) -N'-1-methyl-2-pyrrolidinylidene) -1-pyrrolidinkar in 400 ml of acetone. To a solution of voximide amide hydro iodide (compound of Example XI) and 41.2 g (0.20 mol) of N, N'-dicyclohexylcarbodiimide, the reaction mixture is stirred at room temperature under nitrogen for 3 days. . The N, N'-dicyclohexyl urea is removed by filtration and the filtrate is concentrated in vacuo to give an oil. This is stirred with ether to give a yellow solid. Recrystallization from acetone-ether yields a white solid with a melting point of (188) 195-197 ° C. Recrystallization of this again from methanol-acetone-ether gives a pure N- (4-acetium as a white solid with a melting point of 196-199 ° C. To obtain oxyphenyl) -N '-(1-methyl-2-iroridinylidene) -1-pyrrolidinecarboximideamide hydroiodide.

Anal: calcd for C ₁₈ H ₂₄ N ₄ O ₂ HI-: C, 47.33; H, 5.52; N, 12.28 Found: C, 47.31; H, 5157; N, 12.26

Claims (1)

The compound of the following general formula (V) obtained by reacting the compound of the following general formula (III) with the compound of the following general formula (IV) at a temperature of 0 ° C-100 ° C in a suitable anhydrous organic solvent was treated with alkali Method for producing a heterocyclyl derivative of guanidine represented by the following general formula (I) in the form of a base.

In the food n is 1,2 or 3: R ₁ is hydrogen, alkyl with 1-8 carbons, cycloalkyl with 3-6 carbons, alken-2-yl with 3-5 carbons: hydroxyl loweralkyl, aralkyl and aryl: R ₂ is hydrogen, alkyl with 1-6 carbons and aryl: R ₃ is hydrogen, alkyl with 1-8 carbons and aryl: R ₄ is hydrogen, methyl and ethyl: R ₅ is alkyl having 1-4 carbons, cycloalkyl having 3-7 carbons, aralkyl and aryl:

Together represent a saturated heterocycle of 3-7-membered. If -NR ₄ R ₅ is a 6-membered ring, (i) the ring may be substituted with an oxygen or sulfur atom or a lower alkyl phenyl or benzyl. Interrupted by an additional nitrogen atom present or (ii) the ring may be substituted by lower alkyl at a carbon atom other than one adjacent nitrogen atom bonded to the carboximide amide, for example aziridinyl, azetidi Neil, Pyridinyl, Piperidino, 2,3,4,5,6,7-hexahydro-azinyl, morpholino, thiamorpholino, taamulforino-1-oxide, thiamorpholino-1 , 1-dioxide, 2,6-di loweralkyl-piperazinyl (particularly 2.t-dimethyl-morpholino), 4-lower alkyl-piperazinyl (particularly 4-methyl-piperazinyl), 4-phenyl -Piperazinyl. R is alkyl having 4-10 carbons, cycloalkyl having 5-8 carbons, bicycloalkyl having 7-10 carbons, bicycloalkenyl having 7-10 carbons, tricycloalkyl having 9-10 carbons, 1-adamantylmethyl, tricycloalkenyl with 9-10 carbons, aryl groups from phenyl and naphthyl. A-tetramethylene-phenethyl, diphenylalkyl having 1-2 carbons in alkyl group, naphthyl, fused diarylcyclo alkenyl, fused arylcycloalkyl, phenylcycloalkyl having 5-7 carbons in cycloalkyl group , Cycloalkyl-cycloalkyl, each cycloalkyl group having 5-7 carbons, phenyl, methylenedioxyphenyl; Phenyl substituted with 1-3 substituents selected from halo, lower alkyl and lower alkoxy; Phenyl substituted with amino, dimethylamino, methylethylamino, diethylamino, lower alkanoylamino, trifluomethyl, hydroxy, benzyloxy, lower alkanoyloxy, lower alkanoyl and nitro; 3-pyridyl: and 3-pyridyl substituted with 1-2 substituents selected from halolowalkyl and lower alkoxy.