KR790001914B1 - Process for the preparation of dipeptides - Google Patents

Abstract

About 50 title compds. I (e.g., R = H, Me, -CH2CN, diethylaminoethyl ; R1 = H, Me, iso-Bu, iso-Pr, Ph ; R2 = H, Me ; R3 = H, carbobenzoxy, trityl, phthalyl; A = Ph, PhCl, PhF ; B = PhCl), useful as sedatives and muscl relaxants with LD50 1000 mg/kg orally in mice, were prepd. by peptide condenstion of amine(II) and glycine(III) (5 different methods). Thus, Trityl-Gly-Gly in hexamethyl phosphoric triamide was treated with SOCl3 flowowed by addn. of 2-amino-5-chlorobenzo and recrystallization to give I (R = R2=R3=H; A = PH; B = C1C6H3)

Description

디펩티드 유도체의 제조법Preparation of Dipeptide Derivatives

본 발명은 디펩티드 유도체류 및 그의 제조법에 관한 것이다. 더 상세하게는, 본 발명은 다음과 같은 일반식(I)로 표시되는 디펩티드 유도체류 및 그의 산부가염류의 제조법에 관한 것이며, 이것은 항불안제, 진정제, 항경련제, 최면제, 근이완제 및 이들의 합성 중간체류로서 유용하다.The present invention relates to dipeptide derivatives and methods for their preparation. More specifically, the present invention relates to a method for preparing dipeptides derivatives represented by the following general formula (I) and acid addition salts thereof, which are anti-anxiety agents, sedatives, anticonvulsants, hypnotics, muscle relaxants and synthetic intermediates thereof. It is useful as a stay.

상기 식에서,Where

R는 수소, C₁~C₆알킬기, C₂~C₇알케닐기, C₂~C₇시아노알킬기, C₂~C₇카르바모일알킬기, C₃~C₁₀디알킬아마노알킬기 또는 사이클로프로필메틸기를 나타내고, R¹은 수소, C₁~C₆알킬기, C₇~C₁₄아랄킬시, C₇~C₁₄하이드록시아랄킬기, C₆~C₁₂아릴기, C₂~C₇카르바모일알킬기, C₂~C₇카르복시알킬기, C₁~C₆아미노알킬기, C₄~C₁₀구아니딜알킬기, C₁~C₆메르캅토알킬기, C₂~C₇알킬티오알킬기, C₉~C₁₅인돌릴알킬기 또는 C₄~C₉이미다졸릴알킬기를 나타내고,R is hydrogen, a C ₁ to C ₆ alkyl group, a C ₂ to C ₇ alkenyl group, a C ₂ to C ₇ cyanoalkyl group, a C ₂ to C ₇ carbamoylalkyl group, a C ₃ to C ₁₀ dialkylamanoalkyl group or cyclopropyl Represents a methyl group, R ¹ represents hydrogen, a C ₁ to C ₆ alkyl group, C ₇ to C ₁₄ aralkyl, C ₇ to C ₁₄ hydroxyaralkyl, C ₆ to C ₁₂ aryl, C ₂ to C ₇ carba together alkyl, C ₂ ~ C ₇ carboxyalkyl group, C ₁ ~ C ₆ aminoalkyl group, C ₄ ~ C ₁₀ guanidyl pyridyl group, C ₁ ~ C ₆ mercapto group, C ₂ ~ C ₇ alkylthio group, C ₉ ~ A C ₁₅ indolylalkyl group or a C ₄ to C ₉ imidazolylalkyl group,

R²는 수소, C₁~C₆알킬기, C₇~C₁₄아랄킬기, C₆~C₁₂아릴기, 글리실기 또는 글리실-글리실기를 나타내고,R ² represents hydrogen, a C ₁ to C ₆ alkyl group, a C ₇ to C ₁₄ aralkyl group, a C ₆ to C ₁₂ aryl group, a glycyl group or a glycyl-glycyl group,

R³은 수소, C₁~C₆알킬기 또는 아미노-보호기를 나타내고, R¹및 R²는 임의로 결합하여 C₂~C₄알킬렌기를 형성하며, R²-N'-R³기는 임의로 푸탈릴이미도기, 피페리디노기, 4-하이드록시-4-(p-할로게노페닐)피페리디노, 모르폴리노 또는 C₁~C₆알킬기 또는 페닐기에 의하여 치환된 피페라지노기를 나타내고, A환은 할로겐에 의하여 임의로 치환된 벤젠환 또는 피리딘환을 나타내며, B환은 할로겐, 트리플루오로메틸기, 메틸술포닐기, 니트로기 또는 C₁~C₆알킬기에 의해 임의로 치환된 벤젠환 또는 티오펜환을 나타낸다.R ³ represents hydrogen, a C ₁ to C ₆ alkyl group or an amino-protecting group, R ¹ and R ² are optionally bonded to form a C ₂ to C ₄ alkylene group, and the R ² -N′-R ³ group is optionally putaryl imido group, a piperidino group, 4-hydroxy -4- (p- halogeno phenyl) piperidino, morpholino, or C ₁ ~ C ₆ represents a piperazinyl group substituted by a large group or a phenyl group, a ring is a halogen Represents a benzene ring or a pyridine ring optionally substituted by B, and a B ring represents a benzene ring or a thiophene ring optionally substituted by a halogen, trifluoromethyl group, methylsulfonyl group, nitro group or C ₁ -C ₆ alkyl group.

상기 정의에 대한 구체적인 설명을 다음에 제시한다.A detailed description of the above definition follows.

알킬기(예, 메틸, 에틸, 이소프로필, 부틸, 펜틸), 알케닐기(예, 알릴, 부테닐, 펜타디에닐), 시아노알킬기(예, 시아노메틸, 시아노에틸, 시아노프로필, 시아노부틸), 카르바모일알킬기(예, 카르바모일메틸, 카르바모일에틸, 카르바모일프로필), 카르복시알킬기(예, 카르복시메틸, 카르복시에틸, 카르복시프로필), 아미노알킬기(예, 아미노메틸, 아미노에틸, 아미노프로필, 아미노부틸), 하이드록시알킬기(예, 하이드록시메틸, 하이드록시에틸, 하이드록시프로필, 하이드록부틸), 구아니딜알킬기(예, 구아니딜메틸, 구아니딜에틸, 구아니딜프로필), 메르캅토알킬기(메르캅토메틸, 메프캅토에틸, 메르캅토프로필, 메르캅토부틸), 알킬티오알킬기(예, 메틸티오메틸, 에틸티오프로필, 메틸티오부틸), 인돌릴알킬기(예, 인돌릴메틸, 인돌릴에틸, 인돌릴프로필), 아랄킬기(예, 벤질, 펜에틸, 페닐프로필), 하이드록시아랄킬기(예, 하이드록시벤질, 하이드록시펜에틸), 아릴기(페닐, 나프틸), 할로겐(염소, 취소, 불소,옥소), 알킬렌기(예, 디메틸렌, 트리메틸렌, 테트라메틸렌), 아미노보호기(예, 카르보벤족시, 메톡시카르보닐, t-부톡시카르보닐, p-메톡시벤질옥시카르보닐, o-니트로페닐술페닐, 클로로벤질옥시카르보닐, 트리틸) 및 디알킬아미노알킬기(예, 디메틸아미노에틸, 디에틸아미노에틸, 디에틸아미노프로필).Alkyl groups (e.g. methyl, ethyl, isopropyl, butyl, pentyl), alkenyl groups (e.g. allyl, butenyl, pentadienyl), cyanoalkyl groups (e.g. cyanomethyl, cyanoethyl, cyanopropyl, cya Nobutyl), carbamoylalkyl groups (e.g. carbamoylmethyl, carbamoylethyl, carbamoylpropyl), carboxyalkyl groups (e.g. carboxymethyl, carboxyethyl, carboxypropyl), aminoalkyl groups (e.g., aminomethyl, Aminoethyl, aminopropyl, aminobutyl), hydroxyalkyl groups (e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl), guanidylalkyl groups (e.g. guanidylmethyl, guanidylethyl, Guanidylpropyl), mercaptoalkyl group (mercaptomethyl, mecapcaptoethyl, mercaptopropyl, mercaptobutyl), alkylthioalkyl group (e.g. methylthiomethyl, ethylthiopropyl, methylthiobutyl), indolylalkyl group ( Eg, indolylmethyl, indolylethyl, indolylpropyl), Carboxyl groups (e.g. benzyl, phenethyl, phenylpropyl), hydroxyaralkyl groups (e.g. hydroxybenzyl, hydroxyphenethyl), aryl groups (phenyl, naphthyl), halogens (chlorine, clear, fluorine, oxo), Alkylene groups (e.g. dimethylene, trimethylene, tetramethylene), amino protecting groups (e.g. carbobenzoyl, methoxycarbonyl, t-butoxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrophenyl Sulfenyl, chlorobenzyloxycarbonyl, trityl) and dialkylaminoalkyl groups (eg dimethylaminoethyl, diethylaminoethyl, diethylaminopropyl).

디펩티드 유도체류(I)는 다음식에 나타낸 바와 같이하여 제조될 수 있다.Dipeptide derivatives (I) can be prepared as shown in the following formula.

상기 식들에서 X 및 X¹은 각각 할로겐을 나타내고, R, R¹, R², R³, A환 및 B환은 각각 상기에서 정의한 바와 같으나, X¹및 XII에서 B환은 벤젠환이다.In the formulas, X and X ¹ each represent halogen, and R, R ¹ , R ² , R ³ , ring A and ring B are as defined above, but ring B in X ¹ and XII is a benzene ring.

A 경로A path

이 경로는 출발물질(Ⅱ)와 글리신유도체(Ⅲ)을 공지의 방법으로 아미드 결합을 형성시켜 펩티드 축합시키는 것이다. 아미도 결합형성은 실질적으로 아민(Ⅱ)의 아미노기와 글리신 유도체(Ⅲ)의 카르복시기를 축합시켜 펩티드 결합을 형성시키는 것을 기본으로 하지만, 이 목적을 달성시키기 위한 부수적 처리, 예를 들면 아미노 결합 형성에 앞서 글리신 유도체(Ⅲ)의 카르복시기를 그의 반응성 유도체롤 전환시키는 처리, 반응에 참여할 수 없는 활성기(예, 아미노기, 카르복시기)의 사전보호처리 및 아미도결합 형성 후에 이와 같은 보호기를 제거하기 위한 처리를 포함한다. 글리신 유도체(Ⅲ)의 그의 반응성 유도체로의 전환은 할로겐화, 무수물형성, 아미드형성, 활성에스테르 형성들을 포함한다. 이와 같은 보호기들의 도입과 제거는 상용법으로 행할 수 있다. 아미노기에 대해서 일례를 들면, 펩티드의 아미노기는 알칼리 존재하에 염화카르보벤족시로 처리함으로서 보호될 수 있으며, 최종제품(I)의 이 아미노-보호기는 산으로서 취화 수소산, 불화수소산 또는 트리플루오로초산으로 처리하거나 또는 액체암모니아/금속나트륨으로 수소첨가 또는 환원시킴으로써 제거될 수 있다. 트리틸기는 염기 존재하에 염화트리틸로 처리하므로서 도입될 수 있으며 묽은 초산으로 처리하므로서 제거될 수 있고, 푸탈릴기는 하이드라진하이드레이트로 처리함으로서 제거될 수 있다. 이 단계는 일반적으로 냉각 또는 가열하에 실온에서 불활성용매(예, 염화메틸렌, 디메틸포름아미드, 디메틸술폭사이드, 헥사메틸포스포릭트리아미드, 클로로포름, 디옥산, 벤젠, 테트라하이드로푸란, 그의 혼합물)중에서 행한다. A 경로에서 기술한 아미도결합 형성에 대한 일반적인 방법은 이 후에 기술되는 다른 결로의 아미도 결합형성에 유사하게 이용된다.This route is to condense the starting material (II) and glycine derivative (III) by forming an amide bond in a known manner. Amido linkages are substantially based on condensation of the amino groups of the amine (II) groups with the carboxyl groups of the glycine derivatives (III) to form peptide bonds. A process for converting the carboxyl group of the glycine derivative (III) to its reactive derivative, a preprotection treatment of an active group (e.g., an amino group, a carboxyl group) which cannot participate in the reaction, and a treatment for removing such a protecting group after the formation of an amido bond do. Conversion of glycine derivative (III) to reactive derivatives includes halogenation, anhydride formation, amide formation, active ester formations. Introduction and removal of such protecting groups can be carried out by commercial methods. As an example for the amino group, the amino group of the peptide can be protected by treatment with carbobenzoxyl chloride in the presence of alkali, and this amino-protecting group of the final product (I) is an embrittlement of hydrofluoric acid, hydrofluoric acid or trifluoroacetic acid as an acid. Or by hydrogenation or reduction with liquid ammonia / sodium metal. Trityl groups can be introduced by treatment with trityl chloride in the presence of a base and can be removed by treatment with dilute acetic acid, and footyl groups can be removed by treatment with hydrazine hydrate. This step is generally carried out in an inert solvent (eg methylene chloride, dimethylformamide, dimethylsulfoxide, hexamethylphosphorictriamide, chloroform, dioxane, benzene, tetrahydrofuran, mixtures thereof) at room temperature under cooling or heating. . The general method for the formation of amido bonds described in the A pathway is similarly used for amido bond formation of other condensation described later.

B 경로B path

이 경로는 글리실아미드(Ⅳ)와 아미노산(Ⅴ)와를 아미도 결합을 형성시켜 축합시키는 것이다. 산부가염류(예, 취화수소, 염화수소)형태인 출발물질 글리실아미드는 또한 아민(Ⅱ)과 글리신의 아미도 결합 형성에 의해 또한 제조된다. 이 경로의 아미도 결합형성은 실질적으로 A 경로에서와 같이 행한다. 예를 들면, 글리실아미드(Ⅳ)를 적당한 용매(예, 디메틸포름아미드, 헥사메틸포스포릭트리아미드) 중에서 푸탈릴-글리실클로라이드와 처리하여 푸탈릴-글리실-글리실아미드(Ⅰ)를 제조하고, 이것을 하이드라진 분해에 의해 최종제품(Ⅰ)으로 전환시킨다.This pathway condenses glycylamide (IV) and amino acid (V) to form amido bonds. Starting material glycylamides in the form of acid addition salts (eg hydrogen embrittlement, hydrogen chloride) are also prepared by amido linkage formation of amines (II) and glycine. Amido bond formation of this pathway is performed substantially as in the A pathway. For example, glycylamide (IV) is treated with futhlyl-glycosyl chloride in a suitable solvent (e.g., dimethylformamide, hexamethylphosphorictriamide) to give the phthalyl-glycyl-glycileamide (I). It is prepared and converted to the final product (I) by hydrazine decomposition.

C 경로C path

이 경로는 2단계로 행하는데, 제 1단계에서 글리실아미드(Ⅳ), 바람직하게는 그의 산부가염(예, 염화수소, 취화수소)을 할로게노아세틸할라이드(Ⅵ)와 반응시켜 할로게노아세틸-글리실아미드(Ⅶ)를 제조하고, 제 2단계에서 이 후자의 화합물을 암모니아, 푸탈이미도 또는 아민(Ⅷ)과 반응시킨다. 중간체(Ⅶ)의 반응성을 높이기 위해, 화합물(Ⅶ)의 할로겐을 제 2단계 전에보다 활성인 다른 할로겐으로 치환시킬 수 있는데, 예를 들면, 알칼리할라이드(예, 옥화칼륨, 옥화나트륨, 취화칼륨)로 치환시킨다. 이들 반응은 상용법에 따라서 냉각 또는 가열하에 실온에서 불활성용매(예, 디메틸포름아미드, 헥사메틸포스포릭트리아미드, 테트라하이드로푸란, 아세톤, 클로로포름, 디글림)중에서 행한다.This route is carried out in two stages, in the first stage glycylamide (IV), preferably its acid addition salts (e.g. hydrogen chloride, hydrogen embrittlement) are reacted with halogenoacetyl halide (VI) to produce halogenoacetyl-glycol. Lysylamide is prepared and the latter compound is reacted with ammonia, futalimido or amine in the second step. In order to increase the reactivity of the intermediate, the halogen of the compound can be replaced with another halogen which is more active than before the second step, for example alkali halides (e.g. potassium iodide, sodium iodide, potassium embrittlement). Replace with. These reactions are carried out in an inert solvent (e.g., dimethylformamide, hexamethylphosphoric triamide, tetrahydrofuran, acetone, chloroform, diglyme) at room temperature under cooling or heating according to a commercial method.

D 경로D path

이 경로는 2단계로 행하는데, 즉 처음에 메틸화합물(Ⅸ)과 글리신 유도체(Ⅲ)를 아미도 결합을 시킨 다음에 생성되는 펩티드(Ⅹ)를 산화시킨다. 출발물질 메틸롤(Ⅸ)은 상응하는 카르보닐화합물(Ⅱ)을 환원시켜 제조될 수 있다. 아미도 결합형성 반응은 A 경로에서와 같이 행하며, 산화는 상용법에 따라서 존스 시약(크롬산/황산/물), 이산화망간, 크롬산 무수물등과 같은 산화제로 처리하여 행한다.This route is carried out in two steps, namely, the methyl compound (III) and glycine derivative (III) are subjected to amido bonds and the resulting peptide is oxidized. Starting material methylol can be prepared by reducing the corresponding carbonyl compound (II). Amido bond formation reactions are carried out as in the A route, and oxidation is carried out by treatment with an oxidizing agent such as Jones reagent (chromic acid / sulfuric acid / water), manganese dioxide, and chromic anhydride according to a commercial method.

E 경로E path

이 경로는 2단계로 행하는데, 즉 처음에 2-아미노메틸인돌(ⅩⅠ)과 아미노산(Ⅴ)을 아미도 결합을 형성한 다음에 생성되는 아미드(ⅩⅡ)를 산화시킨다. 아미드 결합형성 반응은 A경로에서와 같이 행한다. 산화는 상용법에 따라서 산소, 오존, 과산화수소, 크롬산, 과산(예, 과초산), 과망간산칼륨, 이산화망간 또는 과옥소산나트륨과 같은 산화제를 사용하여 이중결합을 카르보닐기로 산화시켜 행한다.This route is carried out in two steps, namely, 2-aminomethylindole (XI) and amino acid (V) form an amido bond, and then the amide (XI) produced is oxidized. The amide bond formation reaction is carried out as in the A route. Oxidation is carried out by oxidizing a double bond to a carbonyl group using an oxidizing agent such as oxygen, ozone, hydrogen peroxide, chromic acid, peracid (e.g., peracetic acid), potassium permanganate, manganese dioxide or sodium peroxate, according to a commercial method.

생성물(Ⅰ)이 아미노-보호기를 함유하는 경우에는, 이것은 그의 필요에 따라 제거될 수 있다. 따라서 펩티드류로 부터 아미노-보호기를 제거하기 위한 상용법이 A경로에서 기술된 바와 같이 적용될 수 있다.If the product (I) contains an amino-protecting group, it can be removed as necessary. Thus, a commercial method for removing amino-protecting groups from peptides can be applied as described in route A.

생성물(Ⅰ)은 제조, 결정화, 용해도 또는 안정도의 증대 등의 필요에 따라 무기산(예, 염산, 황산, 질산, 인산, 티오시안산) 또는 유기산(예, 초산, 호박산, 옥살산, 말레인산, 능금산, 프탈산, 메틸술폰산)과 같은 적당한 산부가염으로 전환될 수 있다.The product (I) may be formed from inorganic acids (e.g. hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid) or organic acids (e.g. acetic acid, succinic acid, oxalic acid, maleic acid, nitric acid, Suitable acid addition salts such as phthalic acid, methylsulfonic acid).

이와같이 하여, 얻어지는 디펩티드 유도체류(Ⅰ)와 이들의 산부가염은 항불안제, 진정제, 항경련제, 최면제, 근이완제 또는 이들의 합성중간체류서 유용하다. 몇개의 디펩티드 유도체류(Ⅰ)의 약리학적 활성을 클로로디아제폭사이드와 디아제팜과 비교하여 다음 표에 나타내었다.Thus, the obtained dipeptide derivatives (I) and acid addition salts thereof are useful as anti-anxiety agents, sedatives, anticonvulsants, hypnotics, muscle relaxants, or synthetic intermediates thereof. The pharmacological activity of several dipeptide derivatives (I) is shown in the following table in comparison with chlorodiazepoxide and diazepam.

1. 시험화합물:1. Test compound:

2. 시험방법:2. Test method:

1) 항-펜틸렌테트라졸 활성:1) anti-pentylenetetrazole activity:

이 시험은 10DS 생쥐 수컷 군에 대해서 측정하였다. 펜틸렌테트라졸 125㎎/㎏ 피하주사한 후 15분 이내에, 생쥐는 치명적으로 그치는 강직성 경련을 나타내었다. 이 시험에서, 시험화합물은 펜틸렌테트라졸을 투여하기 60분전에 경구로 투여하였다. 펜틸렌테트라졸을 투여한 후 2시간 동안 관찰을 하였다. 항-경련활성의 기준을 사망율에 대한 완전보호로서 측정하였다. 경련은 무시되었다. 결과를 ED₅₀[Goodman, et al. : J. Pharmacol., 108, 168(1953)]로서 나타내었다.This test was measured for the 10DS mouse male group. Within 15 minutes after subcutaneous injection of pentylenetetrazole 125 mg / kg, the mice had a lethal spasticity. In this test, the test compound was administered orally 60 minutes prior to pentylenetetrazole. Observations were made for 2 hours after pentylenetetrazole was administered. The criterion of anti-convulsive activity was measured as complete protection against mortality. Convulsions were ignored. The results are reported in ED ₅₀ [Goodman, et al. : J. Pharmacol., 108, 168 (1953).

2) 유순활성(Taming activity):2) Taming activity:

이 시험은 DS 생쥐 수컷에 대해서 측정하였다.This test was measured on DS mouse males.

5Hz 스퀘어 웨이브 펄스(100msc. 50v)를 그리드 복스(grid box)내에 있는 생쥐에 전달했을 때에, 몇몇쌍의 생쥐들은 3분 동안 15~20회의 호전적인 태도를 보였다. 이들 쌍을 이루고 있는 생쥐들은 아침에 선택하여 오후에 약품시험에 사용하였다. 시험 화합물을 실험하기 60분 전에 모든 생쥐에게 투여했다. 그 결과를 5쌍의 군으로 호전감응 억제의 백분율로서 얻었으며, ED₅₀[Tedeschi, et al. : J. Pharmacol Thev., 125, 28-34(1959)]로 나타내었다.When a 5 Hz square wave pulse (100 msc. 50v) was delivered to the mice in a grid box, several pairs of mice showed 15-20 aggressive behaviors in 3 minutes. These paired mice were selected in the morning and used for drug testing in the afternoon. Test compounds were administered to all mice 60 minutes before the experiment. The results were obtained as a percentage of antagonism inhibition in 5 pairs of groups, ED ₅₀ [Tedeschi, et al. : J. Pharmacol Thev., 125, 28-34 (1959).

3) 로타로드 실행활성3) Rota load execution activity

이 시험은 DS 생쥐 수컷에 대해서 측정하였다.This test was measured on DS mouse males.

생쥐를 껍질을 베낀 나무막대 위에 올려놓고 매분당 5회전의 속도로 회전시켰다. 계속적인 시도에서 3분 이상 동안 막대 위에 남을 수 있는 생쥐를 선택하여 각각의 투여량에 대해 생쥐 10마리의 군으로 놓았다. 만약 생쥐가 2분 이내에 막대기로 부터 떨어지면, 시험화합물은 유효한 것으로 사료되었다. 그 결과를 ED₅₀[Dunham, et al.: J.Am. Pharm. Assoc., 46, 208(1957)]으로 나타내었다.Mice were placed on bark bars and spun at 5 revolutions per minute. Mice were allowed to remain on the rods for at least 3 minutes in subsequent trials and placed in groups of 10 mice for each dose. If the mouse fell from the rod within 2 minutes, the test compound was considered to be valid. The results are described in ED ₅₀ [Dunham, et al .: J. Am. Pharm. Assoc., 46, 208 (1957).

4) 급성 독성:4) Acute Toxicity:

시험 화합물을 DS생쥐 수컷에게 상이한 단일투여량으로 경구로 투여하였다. 각각의 투여량에 대해, 10마리의 생쥐를 사용하였으며, 이들의 중량은 20~23g 사이이다. 시험 화합물을 투여한 후 이 생쥐를 72시간 동안 관찰했다. 사망율을 블리스법(Bliss method)[Bliss:Ann.Appl.Bial., 22, 134 307(1935)Qant. J. Pharmacol., 11, 192(1938)]으로 산출하였다.Test compounds were orally administered to DS male mice at different single doses. For each dose 10 mice were used and their weight was between 20-23 g. The mice were observed for 72 hours after administration of the test compound. Mortality was determined by the Bliss method [Bliss: Ann. Appl. Bio., 22, 134 307 (1935) Qant. J. Pharmacol., 11, 192 (1938).

3. 결과3. Results

[제 1 표][Table 1]

4. 결론4. Conclusion

다섯개의 시험화합물 각각은 급성독성에 극히 약하며, 이들 사이에 현저한 차이는 관찰되지 않았다. 본 발명의 화합물(화합물 제 1번~3번)은 로타로드 실행에 기인하는 운동근육 공동작용의 교란효과에 있어서 디아제팜(제 5번 화합물)보다 약 2~4배로 효능이 적었다. 항-펜틸렌테트라졸 활성과 유순활성에 있어서, 2-벤조일-4-클로로-N-메틸-N^α-글리실-글리신아닐라이드(제 1번 화합물)는 클로로디아제폭사이드(제 4번 화합물)보다도 약 2~3배 이상 더 효능이 있으며, 2-0-클로로벤조일-4-클로로-N-메틸-N^α-글리실-글리신아닐라이드하이드레이트(제 2번 화합물)와 2-o-플루오로벤조일-4-클로로-N-메틸-N^α-글리실글리신아닐라이드 디하이드로클로라이드(제 3번 화합물)는 디아제팜(제 5번 화합물)보다도 약 2~4배 이상 더 효능이 있다.Each of the five test compounds is extremely vulnerable to acute toxicity and no significant difference was observed between them. Compounds of the present invention (compounds 1 to 3) were about 2 to 4 times less effective than diazepam (compound 5) in the disturbing effects of motor muscle coordination due to rotarod performance. For anti-pentylenetetrazole activity and docile activity, 2-benzoyl-4-chloro-N-methyl-N ^α -glycyl-glycineanilide (Compound No. 1) is a chlorodiazepoxide (Compound No. 4). ) Is about 2 to 3 times more effective than), 2-0-chlorobenzoyl-4-chloro-N-methyl-N ^α -glysyl-glycineanilide hydrate (Compound No. 2) and 2-o-fluoro Robenzoyl-4-chloro-N-methyl-N ^α -glyciglycineylidene dihydrochloride (Compound No. 3) is about 2-4 times more effective than Diazepam (Compound No. 5).

디펩티드 유도체류(I)와 약물학적으로 허용되는 이들의 산부가염은 단독으로 또는 소맥전분, 옥수수전분, 감자전분, 젤라틴 등과 같은 약학적으로 적합한 담체와 결합하여 사용한다. 담체의 선택은 투여의 적합한 경로, 물질의 용해도 및 표준약물실행에 의해 측정된다. 약제의 예로 정제, 캡슐, 환제, 현탁액, 시럽, 분말 및 용액이 있다. 이들 약제는 상용법으로 제제한다. 디펩티드 유도체류(I) 또는 약학적으로 허용되는 이들의 산 부가염의 적합한 투여량은 성인에 대해서 1일 약 1~30㎎이다.Dipeptide derivatives (I) and their pharmaceutically acceptable acid addition salts are used alone or in combination with pharmaceutically suitable carriers such as wheat starch, corn starch, potato starch, gelatin and the like. The choice of carrier is determined by the suitable route of administration, the solubility of the substance and the standard drug practice. Examples of medicaments include tablets, capsules, pills, suspensions, syrups, powders and solutions. These agents are formulated by conventional methods. Suitable dosages of the dipeptide derivatives (I) or pharmaceutically acceptable acid addition salts thereof are about 1-30 mg per day for adults.

디펩티드 유도체류(I)와 이들의 산부가염은 가축 또는 가금의 성장촉진제로서 유용하다.Dipeptide derivatives (I) and acid addition salts thereof are useful as growth promoters of livestock or poultry.

본 발명의 적합한 실시태양은 다음의 실시예에서 구체적으로 설명될 것이다.Suitable embodiments of the invention will be specifically described in the following examples.

[실시예 1]Example 1

(1) 헥사메틸포스포릭트리아미드(24㎖)중의 트리틸-글리실-글리신(5g)의 용액에 염화티오닐(1.6g)을 -8 내지 -2℃에서 적가하여 생성되는 혼합물을 -5℃에서 20분간 교반하였다. 이 혼합물을 2-아미노-5-클로로벤조페논(3.08g)과 혼합하고 실온에서 철야 방치하였다. 반응혼합물을 중탄산나트륨 수용액으로 중화시키고 클로로포름을 가해 흔들어주었다. 유기층을 물로 세척한 다음에 건조시키고 증발시켜 용매를 제거하였다. 잔류물을 에테르로 졀정화하여 2-벤조일-4-클로로-N^α-트리틸-글리실-글리신아닐라이드(1.7g)을 얻었다. 생성물을 초산에틸로 재결정화하여 187~189℃에서 용융하는 침상형 결정을 얻었다.(1) To a solution of trityl-glycyl-glycine (5 g) in hexamethylphosphoric triamide (24 ml) was added dropwise thionyl chloride (1.6 g) at -8 to -2 deg. Stir at 20 ° C. for 20 minutes. This mixture was mixed with 2-amino-5-chlorobenzophenone (3.08 g) and left overnight at room temperature. The reaction mixture was neutralized with aqueous sodium bicarbonate solution and shaken by addition of chloroform. The organic layer was washed with water, then dried and evaporated to remove the solvent. The residue was triturated with ether to give 2-benzoyl-4-chloro-N ^α -trityl-glycyl-glycineanilide (1.7 g). The product was recrystallized with ethyl acetate to obtain acicular crystals that were melted at 187 to 189 ° C.

UV:

237.5, 274(sh.), 343mμ(logε: 4.51, 4.03, 3.53).UV:

237.5, 274 (sh.), 343 mμ (logε: 4.51, 4.03, 3.53).

(2)50% 초산(20ml)중의 2-벤조일-4-클로로-N^α-트리틸-글리실-글리신아닐라이드(1.7g)의 현탁액을 20분 동안 수욕상에서 가열시켰다. 냉각 후 침전된 결정을 여과하였다.(2) A suspension of 2-benzoyl-4-chloro-N ^α -trityl-glycyl-glycineanilide (1.7 g) in 50% acetic acid (20 ml) was heated on a water bath for 20 minutes. After cooling the precipitated crystals were filtered off.

여액을 중탄산나트륨 수용액으로 중화시키고 클로로포름을 가해 흔들어 주었다. 유기층을 물로 세척하고, 건조시킨 다음, 증발시켜 용매를 제거하여, 2-벤조일-4-클로로-N^α-글리실-글리신아닐라이드(0.8g)을 얻었다. 생성물을 초산에틸로 재결정화하여 135~136℃에서 용융하는 프리즘상 결정을 얻었다.The filtrate was neutralized with an aqueous sodium bicarbonate solution and shaken with addition of chloroform. The organic layer was washed with water, dried and evaporated to remove the solvent, yielding 2-benzoyl-4-chloro-N ^α -glycyl-glycineanilide (0.8 g). The product was recrystallized with ethyl acetate to obtain prism phase crystals that melt at 135 to 136 ° C.

UV:

241, 275(sh.), 340mμ(logε: 4.44, 4.03, 3.55).UV:

241, 275 (sh.), 340 mμ (log ε: 4.44, 4.03, 3.55).

[실시예 2~5]EXAMPLES 2-5

다음의 출발물질(Ⅱ)및 (Ⅲ)을 사용하여, 반응을 실시예 1과 같이 행하여 상응하는 제품(Ia)및 (Ib)을 얻었다.Using the following starting materials (II) and (III), the reaction was carried out as in Example 1 to obtain the corresponding products (Ia) and (Ib).

식중, R³는 아미노-보호기를 나타내고, R, R¹, R²는 상기에서 정의한 바와 같다.In the formula, R ³ represents an amino-protecting group, and R, R ¹ and R ² are as defined above.

[표 2]TABLE 2

주: 표중의 약자는 다음과 같은 의미를 갖는다.Note: The abbreviations in the table have the following meanings.

H(수소), Me(메틸기), Bu(부틸기), Cbz(카르보벤족시기), Tri(트리틸기), i-(이소-), mp(융점), a) (L-형).H (hydrogen), Me (methyl group), Bu (butyl group), Cbz (carbobenzoic group), Tri (trityl group), i- (iso-), mp (melting point), a) (L-type).

[실시예 6]Example 6

(1) 건조염화메틸렌(50ml)중의 카르보벤족시-L-류우실-글리신(4.05g)의 용액에 트리에틸아민(1.75ml) 및 에틸클로로카르보케이트(1.2ml)를 -10℃에서 첨가하고 이 혼합물을 20분동안 동일한 온도에서 교반하였다. 또한 건조 염화메틸렌(50ml)중의 2-아미노-5-클로로벤조페논(2.91g)의 용액을 거기에 0℃에서 서서히 첨가하여 생성되는 혼합물을 빙냉하에서 1시간 15분 동안 그리고 실온에서는 1시간 30분 동안 교반한 다음에 철야 환류시켰다. 반응 혼합물을 탄산칼륨 및 얼음과의 혼합물에 주입하고 염화메틸렌을 첨가해서 흔들어 주었다. 유기층을 물로 세척하고, 건조시킨 다음, 증발시켜 용매를 제거하였다. 잔류물을 물(3%)을 함유하는 실리카겔의 컬럼으로 크로마토그라피이하고, 이것을 벤젠으로 용출하여 출발물질 2-아미노-5-클로로벤조페논(1.21g)을 회수한 다음에 벤젠/초산에틸(9: 1)로 용출하여 생성물을 얻었다. 이 제품을 에테르로 재결정화하여 98~100℃에서 용융하는 결정으로서 2-벤조일-4-클로로-N^α-카르보벤족시-L-류이실-글리신아닐라이드(3.13g)를 얻었다.(1) To a solution of carbobenzoxyl-L-leucil-glycine (4.05 g) in dry methylene chloride (50 ml) was added triethylamine (1.75 ml) and ethylchlorocarbocate (1.2 ml) at -10 ° C. Was added and the mixture was stirred at the same temperature for 20 minutes. In addition, a solution of 2-amino-5-chlorobenzophenone (2.91 g) in dry methylene chloride (50 ml) was slowly added thereto at 0 ° C for 1 hour 15 minutes under ice-cooling and 1 hour 30 minutes at room temperature. After stirring, the mixture was refluxed overnight. The reaction mixture was poured into a mixture with potassium carbonate and ice and shaken by addition of methylene chloride. The organic layer was washed with water, dried and evaporated to remove solvent. The residue was chromatographed with a column of silica gel containing water (3%), eluted with benzene to recover the starting material 2-amino-5-chlorobenzophenone (1.21 g), followed by benzene / ethyl acetate (9 Eluting with 1) gave a product. This product was recrystallized from ether to obtain 2-benzoyl-4-chloro-N ^α -carbobenzoxy-L-leucyl-glycineanilide (3.13 g) as crystals melting at 98 to 100 ° C.

IR: 3,425, 3,315, 1,700, 1,640cm^-1(CHCl₃)IR: 3,425, 3,315, 1,700, 1640 cm ^-1 (CHCl ₃ )

(2) 취화수소산(24%)을 함유하는 초산용액(15ml)에 2-벤조일-4-클로로-N^α-카르보벤족시-L-류우실-글리신아닐라이드(3.1g)를 빙냉하에 용해시켜 생성되는 용액을 1.5시간동안 실온에서 교반하였다. 이 용액을 에테르와 혼합한 다음에 30분 동안 방치했다. 침전물을 여과하고, 냉수에 용해시킨 다음에 염화메틸렌/에테르(1: 2)를 가해 흔들어 주었다. 유기층을 제거한 후에, 수용액층을 탄산칼륨 수용액으로 알칼리성으로 하고, 염화나트륨으로 포화시킨 다음에 클로로포름을 가해 흔들어 주었다. 클로로포름층을 물로 세척하고, 무수황산마그네슘 상에서 건조시킨 다음 증발시켜 용매를 제거하였다. 잔류물을 에테르로 재결정화하여 145~147℃에서 용융하는 결정으로서 2-벤조일-4-클로로-N^α-L-류이실-글리신아닐라이드(1.628g)을 얻었다.(2) Dissolve 2-benzoyl-4-chloro-N ^α -carbobenzoxy-L-leucine-glycineanilide (3.1 g) in acetic acid solution (15 ml) containing hydrochloric acid (24%) under ice-cooling. The resulting solution was stirred for 1.5 hours at room temperature. This solution was mixed with ether and left for 30 minutes. The precipitate was filtered off, dissolved in cold water, and shaken by addition of methylene chloride / ether (1: 2). After removing the organic layer, the aqueous layer was made alkaline with an aqueous potassium carbonate solution, saturated with sodium chloride, and then shaken by addition of chloroform. The chloroform layer was washed with water, dried over anhydrous magnesium sulfate and then evaporated to remove the solvent. The residue was recrystallized from ether to give 2-benzoyl-4-chloro-N ^α- L-leucyl-glycineanilide (1.628 g) as crystals melting at 145 to 147 캜.

IR: 3,325, 1,685, 1,639cm^-1(CHCl₃).IR: 3,325, 1,685, 1,639 cm ⁻¹ (CHCl ₃ ).

+50.7±0.9^o(EtOH), Mass, m/e 401(M⁺).

+ 50.7 ± 0.9 ^o (EtOH), Mass, m / e 401 (M ⁺ ).

[실시예 7~9]EXAMPLES 7-9

다음의 출발물질(Ⅱ)및 (Ⅲ)을 사용하여, 반응을 실시예 6에서와 같이 행하여 상응하는 생성물(Ⅰa)및 (Ⅰb)를 얻었다.Using the following starting materials (II) and (III), the reaction was carried out as in Example 6 to obtain the corresponding products (Ia) and (Ib).

식중, R, R¹, R²및 R³는 각각 상기에서 정의한 바와 같다.Wherein R, R ¹ , R ² and R ³ are each as defined above.

[표 3]TABLE 3

주: 주중의 약자는 다음과 같은 의미를 갖는다.Note: The abbreviation for weekday has the following meaning.

Pr(프로필기), Ph(페닐기), 기타는 상기에서 정의한 바와 같다.Pr (propyl group), Ph (phenyl group), and others are as defined above.

[실시예 10]Example 10

헥사메틸포스포릭트리아미드(8ml)중의 카르보벤족시-글리신(1.05g)의 용액에, 염화티오닐(0.6g)을 -4내지 -6℃에서 첨가하고, 이 혼합물을 10분동안 -6℃에서 교반하였다. 이 혼합물에 2-벤조일-4-클로로-클리신아닐라이드(1.44g)을 첨가하여 생성되는 혼합물을 2시간동안 0℃이하의 온도에서 교반한 다음에 실온에서 철야 방치하였다. 반응혼합물을 중탄산나트륨 수용액을 첨가하여 알칼리성으로 하고 클로로포름을 가해 흔들어 주었다. 유기층을 물로 세척하고, 건조시킨 다음 증발시켜 용매를 제거하였다. 잔류물을 에테르/물로 재결정화하여 163~164℃에서 용융하는 결정으로서 2-벤조일-4-클로로-N^α-카르보벤족시-글리실-글리신아닐라이드(1.9g)을 얻었다.To a solution of carbobenzoxy-glycine (1.05 g) in hexamethylphosphorictriamide (8 ml), thionyl chloride (0.6 g) is added at -4 to -6 deg. C and the mixture is -6 for 10 minutes. Stir at ° C. 2-benzoyl-4-chloro-clicinanilide (1.44 g) was added to the mixture, and the resulting mixture was stirred at a temperature of 0 ° C. or lower for 2 hours and then left at room temperature overnight. The reaction mixture was made alkaline by adding an aqueous sodium bicarbonate solution, and chloroform was added thereto and shaken. The organic layer was washed with water, dried and evaporated to remove the solvent. The residue was recrystallized from ether / water to give 2-benzoyl-4-chloro-N ^α -carbobenzoxy-glycid-glycineanilide (1.9 g) as crystals melting at 163 to 164 ° C.

[실시예 11]Example 11

무수피리딘(15ml)중의 N, N-디메틸글리신 하이드로클로라이드(0.97g)의 현탁액에, 트리페닐포스파이트(2.15g)를 첨가하고, 생성되는 혼합물을 실온에서 철야 교반하였다. 건조피리딘(10ml)중의 2-벤조일-4-클로로-N^α-글리실아닐라이드(2.0g)의 용액을 여기에 첨가하여 생성되는 혼합물을 103시간동안 실온에서 교반하였다. 반응혼합물을 감압하에서 증발시켰다. 잔류물을 탄산칼륨 수용액을 첨가하여 알칼리성으로 하고 염화메틸렌/에테르(1 : 2)를 가해 흔들어 주었다. 유기층을 물로 세척하고 증발시켰다. 잔류물을 3N 염산을 가해 산성으로 하고 에테르를 가해 흔들어 주었다. 에테르층을 제거한 후에, 수용액층을 탄산칼륨 수용액을 가해 알칼리성으로 하고 에테르를 가해 흔들어 주었다. 에테르층을 포화식염용액으로 세척하고, 무수황산나트륨으로 건조시킨 다음에 증발시켜 용매를 제거하였다. 잔류물(1.9g)을 메타놀(2ml)에 용해시키고, 물(2ml)에 용해시킨 옥살산(0.64g)의 용액과 혼합한 다음에 감압하에서 증발시켜 건조하였다. 얻어진 결정을 에테르로 4회 세척하여 약 90^oC(분해)이상의 온도에서 용융하는 결정으로서 2-벤조일-클로로-N-메틸-N^α-디메틸글리실-글리신아닐라이드옥살레이트(1.75g)를 얻었다.Triphenylphosphite (2.15 g) was added to a suspension of N, N-dimethylglycine hydrochloride (0.97 g) in anhydrous pyridine (15 ml), and the resulting mixture was stirred overnight at room temperature. A solution of 2-benzoyl-4-chloro-N ^α -glycianylide (2.0 g) in dry pyridine (10 ml) was added thereto and the resulting mixture was stirred at room temperature for 103 hours. The reaction mixture was evaporated under reduced pressure. The residue was made alkaline by the addition of aqueous potassium carbonate solution, and the mixture was shaken by addition of methylene chloride / ether (1: 2). The organic layer was washed with water and evaporated. The residue was acidified with 3N hydrochloric acid and shaken with ether. After removing the ether layer, the aqueous layer was made alkaline by adding an aqueous potassium carbonate solution and shaken by adding ether. The ether layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and then evaporated to remove the solvent. The residue (1.9 g) was dissolved in methanol (2 ml), mixed with a solution of oxalic acid (0.64 g) dissolved in water (2 ml) and then evaporated to dryness under reduced pressure. The obtained crystals were washed four times with ether and melted at a temperature of about 90 ^° C. (decomposition), and 2-benzoyl-chloro-N-methyl-N ^α -dimethylglysil-glycineanilide oxalate (1.75 g) was added. Got it.

IR: 3,463, 1,719, 1,694(sh.), 1,668(sh.), 1,640cm^-1(CHCl₃).IR: 3,463, 1,719, 1,694 (sh.), 1,668 (sh.), 1,640 cm ⁻¹ (CHCl ₃ ).

[실시예 12]Example 12

(1) 헥사메틸포스포릭트리 아미드(16ml)중의 N-카르보벤족시-페닐알라닌(3g)의 용액에, 염화티오닐(1.2g)을 -6내지 -2℃에서 5분 이내에 적가하여, 생성되는 혼합물을 10분 동안 -6내지 -8℃에서 교반하였다. 이 혼합물에 미리 트리에틸아민으로 처리한 에테르(5ml)중의 1-메틸-2-아미노메틸-3-o-클로로페닐-5-클로로인돌하이드로클라이드(3.52g)의 현탁액을 첨가하고, 생성되는 혼합물을 실온에서 철야 방치하였다. 이 반응혼합물을 중탄산나트륨 수용액으로 중성으로 하고 에테르를 첨가하여 흔들어 주었다. 유기층을 건조시킨 다음에 증발시켜 에테르를 제거하였다. 잔류물을 에테르로 결정화하여 1-메틸-2-(N^α-카르보벤족시-페닐알라닐아미노메틸)-3-o-클로로페닐-5-클로로인돌(3.15g)을 얻었다. 이 물질을 초산에틸로 재결정화하여 174~176℃에서 용융하는 침상형 결정을 얻었다. 수율 54%.(1) To a solution of N-carbobenzoxy-phenylalanine (3 g) in hexamethylphosphoric triamide (16 ml), thionyl chloride (1.2 g) was added dropwise at -6 to -2 deg. The resulting mixture was stirred for 10 minutes at -6 to -8 ° C. To this mixture was added a suspension of 1-methyl-2-aminomethyl-3-o-chlorophenyl-5-chloroindolehydroclide (3.52 g) in ether (5 ml) previously treated with triethylamine, resulting mixture It was left overnight at room temperature. The reaction mixture was neutralized with an aqueous sodium bicarbonate solution and shaken with ether. The organic layer was dried and then evaporated to remove ether. The residue was crystallized with ether to give 1-methyl-2- (N ^α -carbobenzoxy-phenylalanylaminomethyl) -3-o-chlorophenyl-5-chloroindole (3.15 g). This material was recrystallized from ethyl acetate to obtain acicular crystals which melted at 174 to 176 캜. Yield 54%.

UV:

232, 285mμ(logε=4.88, 3.28).UV:

232, 285 mμ (logε = 4.88, 3.28).

2) 초산(15ml)중의 1-메틸-2-(N^α-카르보벤족시페닐알라닐아미노메틸)-3-o-클로로페닐-5-클로로인돌(2.86g)의 용액에 물(1.4ml)에 크롬산무수물(1.59g)을 용해시킨 용액을 5분동안 13내지 21℃의 온도에서 적가하여 생성되는 혼합물을 4시간 동안 실온에서 교반하였다. 반응 혼합물을 빙수로 혼합하고 클로로포름을 가해 흔들어 주었다. 유기층을 물로 세척하고 건조시킨 다음에 증발시켜 용매를 제거 하였다. 잔류물을 실리카겔의 컬럼으로 크로마토그라피이하고, 이것을 에테르로 용출하여 젤라틴성 물질로서 2-o-클로로벤조일-4-클로로-메틸-N-N^α-카르보벤족시-페닐알라닐-클리신아닐라이드(1.75g)를 얻었다. UV:

256(sh.), 298(sh.)mμ(logε=4.01, 3.44).2) Water (1.4 ml) in a solution of 1-methyl-2- (N ^α -carbobenzoxyphenylalanylaminomethyl) -3-o-chlorophenyl-5-chloroindole (2.86 g) in acetic acid (15 ml) ) Was added dropwise a solution of chromic anhydride (1.59 g) at a temperature of 13 to 21 ° C. for 5 minutes, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was mixed with ice water and chloroform was added and shaken. The organic layer was washed with water, dried and evaporated to remove the solvent. The residue was chromatographed with a column of silica gel, which was eluted with ether to give 2-o-chlorobenzoyl-4-chloro-methyl-NN ^α -carbobenzoxy-phenylalanyl-clicinanilide (as gelatinous material). 1.75 g). UV:

256 (sh.), 298 (sh.) Mμ (logε = 4.01, 3.44).

3)초산중의 취화수소산(21.8%)의 용액을 2-o-클클로벤조일-4-클로로-N-메틸-N^α-카르보벤족시-페닐알라닐-글리신아닐라이드(1.65g)에 첨가하여 생성되는 혼합물을 실온에서 1.5시간 동안 교반하였다. 반응혼합물을 건조 에테르로 혼합하고, 침전된 결정들을 여과하여 206~209℃(분해)에서 용융하는 결정으로서 2-o-클로로벤조일-4-클로로-N-메틸-N^α-페닐알라닐-글리신아닐라이드 하이드로브로마이드하이드레이트(1.3g)를 얻었다.3) A solution of hydrochloric acid (21.8%) in acetic acid is added to 2-o-cloclobenzoyl-4-chloro-N-methyl-N ^α -carbobenzoxy-phenylalanyl-glycineanilide (1.65 g). The resulting mixture was stirred at rt for 1.5 h. The reaction mixture is mixed with dry ether, and the precipitated crystals are filtered to melt at 206-209 ° C (decomposition) as 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^α -phenylalanyl-glycine Anilide hydrobromide hydrate (1.3 g) was obtained.

UV:

258(sh.), 300(sh.)mμ(logε=3.97, 3.35).UV:

258 (sh.), 300 (sh.) Mμ (logε = 3.97, 3.35).

[실시예 13]Example 13

(1) 1-메틸-2-아미노메틸-3-o-클로로페닐-5-클로로인돌하이드로클로라이드와 N-트리틸글리신을 사용하여, 반응을 실시예 12(1)과 같이 행하여 1-메틸-2-(N-트리틸-글리실아미노메틸)-3-o-클로로페닐-5-클로로인돌을 198~200℃에서 용융하는 결정으로서 얻었다.(1) The reaction was carried out in the same manner as in Example 12 (1) using 1-methyl-2-aminomethyl-3-o-chlorophenyl-5-chloroindolehydrochloride and N-tritylglycine to give 1-methyl- 2- (N-trityl-gylsilaminomethyl) -3-o-chlorophenyl-5-chloroindole was obtained as crystals melting at 198 to 200 ° C.

(2) 초산(10ml)중의 1-메틸-2-(N-트리틸-글리실아미노메틸)-3-o-클로로페닐-5-클로로인돌(2.02g)의 현탁액에, 물(0.6ml)에 용해시킨 크롬산무수물(0.81g)의 용액을 첨가하여, 생성되는 혼합물을 실온에서 22시간 동안 교반하였다. 반응혼합물을 물(22ml)과 혼합하고, 침전되는 결정들을 여과하였다. 여액을 28%암모니아수용액(12ml)으로 혼합한 다음에 클로로포름을 가해 흔들어 주었다. 유기층을 물로 세척하고, 건조시킨 다음에 증발시켜 용매를 제거하였다. 잔류물을 에타놀에 용해시키고 에타놀 중의 옥살산의 용액과 혼합하였다. 침전되는 결정(0.5g)을 에타놀로 재결정화하여 167℃이하의 온도에서 용융하는 결정으로서 2-o-클로로벤조일-4-클로로-N-메틸-Nα-글리실-글리신아닐라이드옥살레이트를 얻었다. UV:

253, 298(sh.)mμ(logε=3.98, 3.34).(2) To a suspension of 1-methyl-2- (N-trityl-gylsilaminomethyl) -3-o-chlorophenyl-5-chloroindole (2.02 g) in acetic acid (10 ml), water (0.6 ml) A solution of chromic anhydride (0.81 g) dissolved in was added and the resulting mixture was stirred at room temperature for 22 hours. The reaction mixture was mixed with water (22 ml) and the precipitated crystals were filtered off. The filtrate was mixed with an aqueous 28% ammonia solution (12 ml) and then shaken by addition of chloroform. The organic layer was washed with water, dried and evaporated to remove solvent. The residue was dissolved in ethanol and mixed with a solution of oxalic acid in ethanol. Precipitated crystals (0.5 g) were recrystallized with ethanol to obtain 2-o-chlorobenzoyl-4-chloro-N-methyl-Nα-glycyl-glycineanilide oxalate as crystals which were melted at a temperature of 167 캜 or lower. . UV:

253, 298 (sh.) Mμ (log ε = 3.98, 3.34).

[실시예 14]Example 14

(1)1-메틸-2-아미노메틸-3-o-클로로페닐-5-클로로인돌하이드로클로라이드와 N-카르보벤족시-글리신을 사용하여, 반응을 실시예12(1)과 같이 행하여 1-메틸-2-(N-카르보벤족시-글리실아미노메틸)-3-o-클로로페닐-5-클로로인돌을 96~98℃에서 용융하는 결정으로서 얻었다.(1) The reaction was carried out in the same manner as in Example 12 (1) using 1-methyl-2-aminomethyl-3-o-chlorophenyl-5-chloroindolehydrochloride and N-carbobenzoxy-glycine. -Methyl-2- (N-carbobenzoxy-glyciylaminomethyl) -3-o-chlorophenyl-5-chloroindole was obtained as crystals melting at 96 to 98 ° C.

(2)초산(55ml)중의 1-메틸-2-(N-카르보벤족시-글리실아미노메틸)-3-o-클로로페닐-5-클로로인돌(9.1g)의 용액에, 물(5.1ml)에 용해시킨 크롬산무수물(5.5g)의 용액을 20℃이하의 온도에서 적가하여, 생성되는 용액을 실온에서 철야 방치하였다. 생성되는 혼합물을 빙수와 혼합하고 초산에틸을 가해 흔들어 주었다. 유기층을 물로 세척하고, 건조시킨 다음에 증발시켜 용매를 제거하였다. 잔류물을 실리카겔의 컬럽을 크로마토그라피이하고, 이것을 초산에틸로 전개하여 젤라틴성 물질로서 2-o-클로로벤조일-4-클로로-N-메틸-N^α-카르보벤족시-글리실-글리신아닐라이드(3.6g)을 얻었다. 이 물질을 초산(11.5ml)중의 취화수소산(21.8%)의 용액과 혼합하고, 실온에서 1.5시간 동안 교반하였다. 반응혼합물을 에테르와 혼합하여 결정을 침전시켰다. 결정을 여과하여 물에 용해시키고 중탄산나트륨 수용액으로 중화시켰다. 침전물을 여과하여 2-o-클로로벤조일-4-클로로-N-메틸-N^α-글리실-글리신아닐라이드하이드레이트(1.8g)를 얻었다. 이 물질을 알코올수용액으로 재결정하여 95~100℃에서 용융하는 프리즘형 결정을 얻었다.(2) To a solution of 1-methyl-2- (N-carbobenzoxy-glycylaminomethyl) -3-o-chlorophenyl-5-chloroindole (9.1 g) in acetic acid (55 ml), water (5.1) A solution of chromic anhydride (5.5 g) dissolved in ml) was added dropwise at a temperature of 20 DEG C or lower, and the resulting solution was left overnight at room temperature. The resulting mixture was mixed with ice water and shaken with addition of ethyl acetate. The organic layer was washed with water, dried and evaporated to remove solvent. The residue was chromatographed with a silica gel column, which was then developed with ethyl acetate to form 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^α -carbobenzoxy-glycile-glycineanilide as a gelatinous substance. (3.6 g) was obtained. This material was mixed with a solution of hydrochloric acid (21.8%) in acetic acid (11.5 ml) and stirred at room temperature for 1.5 hours. The reaction mixture was mixed with ether to precipitate crystals. The crystals were filtered off, dissolved in water and neutralized with aqueous sodium bicarbonate solution. The precipitate was filtered to give 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^α -glycyl-glycineanilide hydrate (1.8 g). This material was recrystallized from alcohol aqueous solution, and the prism type crystal which melt | dissolves at 95-100 degreeC was obtained.

[실시예 15~21][Examples 15-21]

다음의 출발물질(ⅩⅠ)및(Ⅴ)을 사용하고, 반응을 실시예 14에서와 같이 행하여 상응하는 생성물(ⅩⅡ),(Ⅰa)및 (Ⅰb)를 얻었다.The following starting materials (XI) and (V) were used and the reaction was carried out as in Example 14 to obtain the corresponding products (XI), (IA) and (IB).

[제 4 표][Table 4]

주: 이 표중의 약자는 다음과 같은 의미를 갖는다.Note: The abbreviations in this table have the following meanings.

Cm(카르보메톡시기), Cl(염소), d(분해), F(불소), a) 레보, b) 덱스트로 및 기타는 상기에서 정의한 바와 같다.Cm (carbomethoxy group), Cl (chlorine), d (decomposition), F (fluorine), a) levo, b) dextrose and others are as defined above.

[실시예 22]Example 22

(1) 디옥산(300ml) 중에 용해시킨 조잡한 1-메틸-2-아미노메틸-3-o-클로로페닐-5-클로로인돌(9.97g)의 용액에, 탄산칼륨(2.48g)을 실온에서 교반하면서 첨가하여 이 혼합물을 N-프탈릴글리실클로라이드(8.036g)와 혼합하였다. 생성되는 혼합물을 30분 동안 실온에서 교반하였다. 반응혼합물을 약 100ml의 용적으로 농축하고, 이것을 n-헥산(100ml)과 혼합하였다. 침전된 결정을 여과하고, 클로로포름(2L)/메타놀(100ml)에 용해시켜 용액을 만든 다음에 이것을 물로 세척하고, 무수황산나트륨 상에서 건조시킨 다음에 증발시켜 용매를 제거하였다. 잔류물을 에테르로 세척하여 1-메틸-2-(N^α-프탈릴-글리실아미노메틸)-3-o-클로로페닐-5-클로로인돌(9.642g)을 얻었다. 동일한 생성물(450mg)을 디옥산/n-헥산모액과 에테르성 세척액으로부터 얻었다. 수율 62.8%, 이 물질을 메타놀/클로로포름으로 재결정화하여 3~254℃에서 용융하는 결정을 얻었다.(1) To a solution of crude 1-methyl-2-aminomethyl-3-o-chlorophenyl-5-chloroindole (9.97 g) dissolved in dioxane (300 ml), potassium carbonate (2.48 g) was stirred at room temperature This mixture was mixed with N-phthalyl glycyl chloride (8.036 g) while adding. The resulting mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated to a volume of about 100 ml, which was mixed with n-hexane (100 ml). The precipitated crystals were filtered, dissolved in chloroform (2 L) / methanol (100 ml) to form a solution, which was then washed with water, dried over anhydrous sodium sulfate and then evaporated to remove the solvent. The residue was washed with ether to give 1-methyl-2- (N ^α -phthalyl-glyciaminoaminomethyl) -3-o-chlorophenyl-5-chloroindole (9.642 g). The same product (450 mg) was obtained from dioxane / n-hexane mother liquor and etheric washings. Yield 62.8%, this material was recrystallized with methanol / chloroform to obtain crystals which melted at 3 to 254 ° C.

(2) 초산(25ml)중의 1-메틸-2-(N^a-프탈릴-글리실아미노메틸-3-o-클로로페닐-5-클로로인돌(1.00g)의 용액에, 물(2ml)에 용해시킨 크롬산 무수물(406mg)의 용액을 교반하면서 서서히 첨가하였다. 생성되는 혼합물을 4시간 동안 22~25℃에서 교반한 다음에 용적이 약 반으로 줄때까지 감압하에서 농축하였다. 잔류물을 얼음과 혼합하고, 침전물을 여과시켰다. 이 여액을 초산에틸을 첨가하여 흔들어 주고, 상기의 침전물을 초산에틸 층에 용해시켰다. 초산에틸층을 실리카겔을 컬럼으로 크로마토그라피이하고 용출을 증발시켜 침전물을 얻고, 이것을 염화메틸렌/메타놀로 재결정화하여 216~218℃에서 용융하는 결정으로서 2-o-클로로벤조일-4-클로로-N-메틸-N^α-프탈릴글리실-글리신아닐라이드(580mg)를 얻었다. 수율 54.5%(2) To ^a solution of 1-methyl-2- (N ^a -phthalyl-glyciylaminomethyl-3-o-chlorophenyl-5-chloroindole (1.00 g) in acetic acid (25 ml) in water (2 ml) A solution of dissolved chromic anhydride (406 mg) was added slowly with stirring The resulting mixture was stirred at 22-25 ° C. for 4 hours and then concentrated under reduced pressure until the volume was reduced to about half. The precipitate was filtered, the filtrate was shaken with the addition of ethyl acetate, and the precipitate was dissolved in an ethyl acetate layer.The ethyl acetate layer was chromatographed with silica gel on a column and the elution was evaporated to obtain a precipitate, which was then chloride 2-o-chlorobenzoyl-4-chloro-N-methyl- ^Nα -phthalylglyciyl-glycineanilide (580 mg) was obtained as a crystal which was recrystallized from methylene / methanol and melted at 216 to 218 ° C. Yield 54.5%

(3) 디메틸포름아미드(20ml)중의 2-o-클로로벤조일-4-클로로-N-메틸-N^α-프탈릴-글리실-글리신아닐라이드(1.056g)의 용액에, 디메틸포름아미드(4ml)에 용해시킨 하이드라진하이드레이트(180mg)의 용액을 교반하면서 -8 내지 -6℃에서 첨가하여 생성되는 혼합물을 -8 내지 실온에서 1시간동안 교반하였다. 0℃에서 냉각한 후에, 반응 혼합물을 N-염산(4ml)과 20분간 혼합한 다음에 17시간동안 0℃에서 교반하였다. 이 반응 혼합물을 빙수(200ml)와 초산에틸(100ml)과의 혼합물에 주입하고 28% 암모니아수용액으로 pH 8까지 알칼리성으로 하였다. 초산에틸층을 분리하고, 물로 세척하고, 무수황산나트륨상에서 건조시킨 다음에 감압하에서 증발시켜 잔류물(500mg)을 얻었다. 동일한 물질(410mg)을 수용액층과 세척액으로 부터 얻었다. 양자를 화합하여 에탄올(10ml)에 용해시키고, 0℃이하의 온도로 냉각하면서 물(25ml)과 혼합하였다. 침전된 결정들을 여과하여 95~100℃에서 용융하는 결정으로서 2-o-클로로벤조일-4-클로로-N-메틸-N^a-글리실-글리신아닐라이드하이드레이트(722mg)를 얻었다. 헤미사이트레이트는 114~116℃에서 용융한다. 수율: 87%(3) Dimethylformamide (4 ml) in a solution of 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^α -phthalyl-glycyl-glycineanilide (1.056 g) in dimethylformamide (20 ml). A solution of hydrazine hydrate (180 mg) dissolved in) was added at −8 to −6 ° C. while stirring, and the resulting mixture was stirred at −8 to room temperature for 1 hour. After cooling at 0 ° C., the reaction mixture was mixed with N-hydrochloric acid (4 ml) for 20 minutes and then stirred at 0 ° C. for 17 hours. The reaction mixture was poured into a mixture of ice water (200 ml) and ethyl acetate (100 ml) and made alkaline to pH 8 with an aqueous 28% ammonia solution. The ethyl acetate layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a residue (500 mg). The same material (410 mg) was obtained from the aqueous layer and the wash solution. Both were combined and dissolved in ethanol (10 ml) and mixed with water (25 ml) while cooling to a temperature below 0 ° C. Precipitated crystals were filtered to obtain 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^a -glycyl-glycineanilide hydrate (722 mg) as a crystal which was melted at 95 to 100 ° C. Hemisiterate melts at 114-116 degreeC. Yield: 87%

[실시예 23~25][Examples 23-25]

다음의 화합물(ⅩⅠ)와 N-푸탈릴글리실클로라이드를 사용하고, 반응을 실시예 22에서와 같이 행하여 상응하는 생성물(ⅩⅡ),(Ⅰa) 및 (Ⅰb)를 얻었다.Using the following compound (XI) and N-phthalyl glycyl chloride, the reaction was carried out as in Example 22 to obtain the corresponding products (XI), (IA) and (IB).

[제 5 표][Table 5]

주: 표중의 약자는 상기에서 정의한 바와 같다.Note: The abbreviations in the table are as defined above.

(1) 벤젠(80ml)중의 2',5-디클로로-2-메틸아미노벤조페논(3.20g)의 용액에, 푸탈릴-글리실-글리실클로라이드(4.0g)를 첨가하여 생성되는 혼합물을 1시간동안 70~80℃에서 교반하였다. 침전된 결정들을 여과하고, 벤젠으로 세척한 다음에 에탄올로 세척한 다음 건조시켜, 2-o-클로로벤조일-4-클로로-N-메틸-N^α-푸탈릴-글리실글리신아닐라이드(5.6g)를 첨가하고, 이것을 에탄올로 재결정화하여 217℃에서 용융하는 결정을 얻었다.(1) To a solution of 2 ', 5-dichloro-2-methylaminobenzophenone (3.20 g) in benzene (80 ml), a mixture obtained by adding putylyl-glycyl-glycichloride (4.0 g) to 1 Stir at 70-80 ° C for hours. Precipitated crystals were filtered off, washed with benzene and then with ethanol and dried to give 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^α -phthalyl-glyciglycineylide (5.6 g). ) Was added and this was recrystallized from ethanol to obtain a crystal that melted at 217 ° C.

(2) 에탄올(50ml)중의 2-o-클로로벤조일-4-클로로-N-메틸-N^a-푸탈릴-글리실-글리신아닐라이드(81.0g)의 현탁액을 하이드라진하이드레이트(20ml)와 혼합하여 생성되는 혼합물을 약 30분동안 환류하였다. 냉각 후에, 반응 혼합물을 여과하여 불용성 푸탈하이드라지드를 제거하였다. 여액을 증발시켜 용매를 제거하였다. 잔류물을 묽은 에탄올로 결정화하고 에테르로 세척하여 2-o-클로로벤조일-4-클로로-N-메틸-N^α-글리실-글리신아닐라이드하이드레이트(55.3g)를 얻었다. 이 물질을 묽은 에탄올로 재결정화하여 95~100℃에서 용용하는 결정들을 얻었다.(2) A suspension of 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^a -phthalyl-glycyl-glycineanilide (81.0 g) in ethanol (50 ml) was mixed with hydrazine hydrate (20 ml) The resulting mixture was refluxed for about 30 minutes. After cooling, the reaction mixture was filtered to remove insoluble phthalhydrazide. The filtrate was evaporated to remove the solvent. The residue was crystallized with dilute ethanol and washed with ether to give 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^α -glycyl-glycineanilide hydrate (55.3 g). This material was recrystallized from dilute ethanol to obtain crystals that were dissolved at 95-100 ° C.

[실시예 27]Example 27

(1) 테트라하이드로푸란(10ml)중의 수소화붕소나트륨(1.2g)의 현탁액에, 테트라하이드로푸란(20ml)에 용해시킨 2', 5-디클로로-2-메틸아미노벤조페논(3.12g)의 용액을 적가하였다. 생성되는 혼합물을 물(5ml)로 혼합하고 실온에서 철야 교반하였다. 반응 혼합물을 소량의 물과 혼합하고 감압하에서 증발시켜 용매를 제거하였다. 잔류물을 묽은 염산으로 pH8~9로 만든 다음에 클로로포름을 가해 흔들어 주었다. 유기층을 건조시키고, 증발시켜 2', 5-디클로로-2-메틸아미노벤즈하이드롤(3.05g)을 얻었다. 이 물질을 에테르/n-헥산으로 재결정화하여 105.5-106.5℃에서 용융하는 결정을 얻었다. 수율 97.1%.(1) A solution of 2 ', 5-dichloro-2-methylaminobenzophenone (3.12 g) dissolved in tetrahydrofuran (20 ml) in a suspension of sodium borohydride (1.2 g) in tetrahydrofuran (10 ml) Added dropwise. The resulting mixture was mixed with water (5 ml) and stirred overnight at room temperature. The reaction mixture was mixed with a small amount of water and evaporated under reduced pressure to remove the solvent. The residue was made up to pH 8-9 with dilute hydrochloric acid, and then shaken with chloroform. The organic layer was dried and evaporated to give 2 ', 5-dichloro-2-methylaminobenzhydrol (3.05 g). This material was recrystallized from ether / n-hexane to give a crystal which melted at 105.5-106.5 ° C. Yield 97.1%.

(2) 헥사메틸포스포릭트리아미드(20ml)/아세토니트릴(10ml)중의 카르보벤족시-글리실-글리신(4.0g)의 용액에, 염화티오닐(1.77g)을 -18℃에서 적가하여, 생성되는 혼합물을 -18℃에서 3분동안 교반시켰다. 여기에 헥사메틸포스포릭트리아미드(10ml)/아세토니트릴(5ml)중의 2', 5-디클로로-2-메틸아미노벤즈하이드롤(2.2g)의 용액을 -18℃에서 적가하고, 동일한 온도에서 8시간 동안 교반한 다음에 -20℃에서 철야 방치하였다. 반응 후에, 반응 혼합물을 물/에테르와 혼합하고, 중탄산나트륨 수용액으로 알칼리성으로 만든 다음에, 에테르를 가해 흔들어 주었다. 유기층을 건조시키고 증발시켜 용매를 제거하였다. 잔류물을 실리카겔의 컬럼으로 크로마토그라피이하고, 이것을 초산에틸로 용출하여 57~60℃에서 용융하는 결정으로서 2-o-클로로-α-하이드록시벤질-4-클로로-N-메틸-N^α-카르보벤족시글리실-글리신아닐라이드(3.31g)를 얻었다.(2) To a solution of carbobenzoxy-glycyl-glycine (4.0 g) in hexamethylphosphoric triamide (20 ml) / acetonitrile (10 ml), thionyl chloride (1.77 g) was added dropwise at -18 deg. The resulting mixture was stirred at -18 ° C for 3 minutes. To this was added dropwise a solution of 2 ', 5-dichloro-2-methylaminobenzhydrol (2.2 g) in hexamethylphosphorictriamide (10 ml) / acetonitrile (5 ml) at -18 deg. After stirring for an hour, it was left overnight at -20 ° C. After the reaction, the reaction mixture was mixed with water / ether, made alkaline with an aqueous sodium bicarbonate solution and then shaken by addition of ether. The organic layer was dried and evaporated to remove the solvent. The residue was chromatographed with a column of silica gel, which was eluted with ethyl acetate and melted at 57-60 ° C. as 2-o-chloro-α-hydroxybenzyl-4-chloro-N-methyl-N ^α -carbox Bobenziglycyl-glycineanilide (3.31 g) was obtained.

(3) 아세톤(300ml)중의 2-o-클로로-α-하이드록시벤질-N-메틸-N^α-카르보벤족시-글리실-글리신아닐라이드(21.8g)의 용액에 존스시약(물 중의 크롬산과 황산과의 용액)을 반응 혼합물이 적색으로 될때까지 적가하였다. 이 반응 혼합물을 여과하여 침전물을 제거하였다. 적색여액을 적색용액이 녹색으로 될때까지 이소프로판올로 혼합하였다. 혼합물을 여과하며, 이 여액을 중탄산나트륨 수용액으로 중화시킨 다음에 증발시켰다. 잔류물을 물과 혼합하고 클로로포름을 가해 흔들어 주었다. 클로로포름층을 활성탄으로 정제하여 2-o-클로로벤조일-4-클로로-N-메틸-N^α-카르보벤족시-글리실-글리신아닐라이드(21.3g)를 얻었다. 수율 98.5%(3) Jones reagent (in water) in a solution of 2-o-chloro-α-hydroxybenzyl-N-methyl-N ^α -carbobenzoxoxy-glysil-glycineanilide (21.8 g) in acetone (300 ml) Solution of chromic acid and sulfuric acid) was added dropwise until the reaction mixture turned red. The reaction mixture was filtered to remove precipitate. The red filtrate was mixed with isopropanol until the red solution turned green. The mixture is filtered and the filtrate is neutralized with aqueous sodium bicarbonate solution and then evaporated. The residue was mixed with water and shaken by addition of chloroform. The chloroform layer was purified with activated charcoal to obtain 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^α -carbobenzoxy-glycyl-glycineanilide (21.3 g). Yield 98.5%

[실시예 28~33][Examples 28-33]

다음의 화합물(Ⅸ)을 사용하고, 실시예 27에서와 같이 반응을 행하였으나 아미노-보호기로서 푸탈릴기를 적용한 경우에는, 이것을 하이드라진 분해로 제거함으로서, 상응하는 화합물(Ⅹ), (Ⅰa)및 (Ⅰb)를 얻었다.When the following compound (iii) was used and the reaction was carried out as in Example 27, but a putylyl group was applied as the amino-protecting group, the corresponding compounds (ix), (Ia) and ( Ib) was obtained.

[제 6 표][Table 6]

주: 표중의 약자는 다음과 같은 의미를 갖는다.Note: The abbreviations in the table have the following meanings.

Ft(푸탈릴기), De(디에틸아미노에틸기), a) 레보 및 기타는 상기에서 정의한 바와 같다.Ft (phthalyl group), De (diethylaminoethyl group), a) levo and others are as defined above.

[실시예 34]Example 34

(1) 헥사메틸포스포릭트리아미드(10ml) 중의 2-o-클로로벤조일-4-클로로-N-메틸-글리신아닐라이드하이드로브로마이드(1.18g)의 용액에 클로로아세틸클로라이드(0.73g)를 빙냉하에 첨가하였다. 생성되는 혼합물을 2시간 동안 빙냉하에 교반하고, 실온에서 3시간동안 교반하였다. 반응 혼합물에 에테르를 가해 흔들어 주고 유기층을 암모니아 수용액을 첨가하여 알카리성으로 만든 다음에 물로 세척하고 증발시켜 2-o-클로로벤조일-4-클로로-N-메틸-N^α-클로로아세틸-글리신아닐라이드(1.6g)를 얻었다. 이 물질을 초산에틸로 재결정화하여 134~136℃에서 용융하는 무색침상형 결정을 얻었다.(1) To a solution of 2-o-chlorobenzoyl-4-chloro-N-methyl-glycineanilide hydrobromide (1.18 g) in hexamethylphosphoric triamide (10 ml), chloroacetyl chloride (0.73 g) was ice-cooled. Added. The resulting mixture was stirred for 2 hours under ice cooling and for 3 hours at room temperature. Ether was added to the reaction mixture, the mixture was shaken, the organic layer was made alkaline by addition of aqueous ammonia solution, washed with water and evaporated to 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^α -chloroacetyl-glycineanilide ( 1.6 g) was obtained. This material was recrystallized from ethyl acetate to obtain colorless needle crystals which melted at 134 to 136 캜.

(2)2-o-클로로벤조일-4-클로로-N-메틸-N^α-클로로아세틸-글리신아닐라이드(6.2g), 옥화칼륨(2.74g)및 아세톤(60ml)과의 혼합물을 1시간동안 환류시켰다. 반응혼합물을 증발시켜 아세톤을 제거하고 잔류물을 클로로포름에 용해시켰다. 유기층을 물로 세척하고, 건조시킨 다음 증발시켰다. 잔류물을 에테르로 세척하여 2-o-클로로벤조일-4-클로로-N-메틸-Nα-요오도아세틸글리신아닐라이드(6.9g)를 얻었다. 이 물질을 초산에틸로 재결정화하여 168.5~169.5℃에서 용융하는 무색침상형 결정을 얻었다.(2) Mixture of 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^α -chloroacetyl-glycineanilide (6.2 g), potassium iodide (2.74 g) and acetone (60 ml) for 1 hour It was refluxed. The reaction mixture was evaporated to remove acetone and the residue was dissolved in chloroform. The organic layer was washed with water, dried and evaporated. The residue was washed with ether to give 2-o-chlorobenzoyl-4-chloro-N-methyl-Nα-iodoacetylglycineanilide (6.9 g). This material was recrystallized from ethyl acetate to obtain colorless needle crystals which melted at 168.5 to 169.5 ° C.

(3) 테트라하이드로푸란(20ml)중의 2-o-클로로벤조일-4-클로로-N-메틸-Nα-요오도아세틸-글리신아닐라이드(1.1g)의 현탁액중에 암모니아가스를 30분간 도입하고, 이 혼합물을 실온에서 5시간 동안 교반하였다. 반응 혼합물을 증발시켜 테트라하이드로푸란을 제거하였다. 잔류물을 클로로포름에 용해시켰다. 유기층을 중탄산나트륨 수용액으로 세척한 다음에 물로 세척하고, 건조시킨 다음 증발시켜 클로로포름을 제거하였다. 잔류물을 실리카겔의 컬럼으로 크로마토그라피이하고, 이것을 메타놀로 용출하여 2-o-클로로벤조일-4-클로로-N-메틸-N^α-글리실-글리신아닐라이드를 얻었다.(3) Ammonia gas was introduced into a suspension of 2-o-chlorobenzoyl-4-chloro-N-methyl-Nα-iodoacetyl-glycineanilide (1.1 g) in tetrahydrofuran (20 ml) for 30 minutes. The mixture was stirred at rt for 5 h. The reaction mixture was evaporated to remove tetrahydrofuran. The residue was dissolved in chloroform. The organic layer was washed with aqueous sodium bicarbonate solution followed by water, dried and evaporated to remove chloroform. The residue was chromatographed with a column of silica gel, which was eluted with methanol to give 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^α -glycosyl-glycineanilide.

[실시예 35]Example 35

(1) 반응을 클로로아세틸클로라이드 대신에 브로모아세틸브로마이드를 사용하여, 실시예 34(1)에서와 같이 행하여 2-o-클로로벤조일-4-클로로-N-메틸-N^α-브로모아세틸글리신아닐라이드를 153~155℃에서 용융하는 무색침상형 결정으로서 얻었다. 수율 69%(1) The reaction was carried out as in Example 34 (1), using bromoacetylbromide instead of chloroacetyl chloride to give 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^α -bromoacetylglycine Anilide was obtained as colorless needle-like crystals melted at 153 to 155 ° C. Yield 69%

(2) 디메틸포름아미드(10ml) 중의 2-o-클로로벤조일-4-클로로-N-메틸-Nα-브로모아세틸-글리신아닐라이드(1.01g)의 용액에 칼륨프탈아미드(0.34g)를 첨가하고, 생성되는 혼합물을 실온에서 3시간 동안 교반하고 실온에서 철야 방치하였다. 반응 혼합물을 물(100ml)과 혼합하고, 침전물을 여과하고 물로 세척하여 2-o-클로로벤조일-4-클로로-N-메틸-N^α-푸탈릴-글리실-글리신아닐라이드(1.0g)을 얻었다.(2) Potassiumphthalamide (0.34 g) was added to a solution of 2-o-chlorobenzoyl-4-chloro-N-methyl-Nα-bromoacetyl-glycineanilide (1.01 g) in dimethylformamide (10 ml). The resulting mixture was stirred for 3 hours at room temperature and left overnight at room temperature. The reaction mixture was mixed with water (100 ml) and the precipitate was filtered and washed with water to afford 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^α -phthalyl-glycyl-glycineanilide (1.0 g). Got it.

[실시예 36]Example 36

(1) 디메틸포름아미드(7ml)중의 2-o-클로로벤조일-4-클로로-N-메틸-글리신아닐라이드하이드로브로마이드(0.628g)의 용액에 푸탈릴-글리실클로라이드(0.437g)을 첨가하여 생성되는 혼합물을 3시간동안 교반하였다. 반응혼합물을 증발시켜 용매를 제거하였다. 잔류물에 클로로포름을 가해 흔들어 주고, 클로로포름층을 물로 세척하고, 건조시킨 다음 증발시켰다. 잔류물을 에테르로 세척하여 2-o-클로로벤조일-4-클로로-N-메틸-Nα-푸탈릴-글리실글리신아닐라이드(0.71g)를 얻었다. 수율 93.5%(1) To a solution of 2-o-chlorobenzoyl-4-chloro-N-methyl-glycineanilidehydrobromide (0.628 g) in dimethylformamide (7 ml) was added futaryl-glycichloride (0.437 g). The resulting mixture was stirred for 3 hours. The reaction mixture was evaporated to remove the solvent. Chloroform was added to the residue and shaken, the chloroform layer was washed with water, dried and evaporated. The residue was washed with ether to give 2-o-chlorobenzoyl-4-chloro-N-methyl-Nα-phthalyl-glycyglycineylide (0.71 g). Yield 93.5%

(2) 상기의 생성물을 하이드라진하이드레이트로 처리하여 2-o-클로로벤조일-4-클로로-N-메틸-N^α-글리실-글리신아닐라이드하이드레이트를 얻었다.(2) The above product was treated with hydrazine hydrate to give 2-o-chlorobenzoyl-4-chloro-N-methyl-N ^α -glycyl-glycineanilide hydrate.

[실시예 37~46]EXAMPLES 37-46

암모니아 대신에 다음의 아민을 사용하고, 반응을 실시예 34(3)에서와 같이 행하여 상응하는 생성물(Ⅰ)를 얻었다.The following amine was used instead of ammonia and the reaction was carried out as in Example 34 (3) to afford the corresponding product (I).

[제 7 표][Table 7]

주: 표중의 약자는 상기에서 정의한 바와 같다.Note: The abbreviations in the table are as defined above.

[실시예 47~51][Examples 47-51]

반응을 실시예 1에서와 같이 행하여 다음의 생성물(Ⅰ)은 얻었다.The reaction was carried out as in Example 1 to obtain the following product (I).

Claims (1)

하기 일반식(Ⅱ)의 아민과 하기 일반식(Ⅲ)의 글리신 유도체를 아미도 결합을 형성시켜 펩티드 축합시키는 것을 특징으로 하는 하기 일반식(Ⅰ)의 디펩티드 유도체의 제조방법.A method for producing a dipeptide derivative of the general formula (I) below, wherein the amine of the general formula (II) and the glycine derivative of the following general formula (III) form peptides by condensing an amido bond.

상기식에서,In the above formula, R는 수소, C₁~C₆알킬기, C₂~C₇알케닐기, C₂~C₇시아노알킬기, C₂~C₇카르바모일알킬기, C₃~C₁₀디알킬아미노알킬기 또는 사이클로프로필메틸기를 나타내고,R is hydrogen, C ₁ -C ₆ alkyl group, C ₂ -C ₇ alkenyl group, C ₂ -C ₇ cyanoalkyl group, C ₂ -C ₇ carbamoylalkyl group, C ₃ -C ₁₀ dialkylaminoalkyl group or cyclopropyl Represents a methyl group, R¹은 수소, C₁~C₆알킬기, C₇~C₁₄아랄킬기, C₇~C₁₄하이드록시아랄킬기, C₆~C₁₂아릴기, C₂~C₇카르바모일알킬기, C₂~C₇카르복시알킬기, C₁~C₆아미노알킬기, C₄~C₁₀구아니딜알킬기, C₁~C₆메르캅토알킬기, C₂~C₇알킬티오알킬기, C₉~C₁₅인돌릴알킬기 또는 C₄~C₉이미다졸릴알킬기를 나타내고,R ¹ is hydrogen, C ₁ ~ C ₆ alkyl group, C ₇ ~ C ₁₄ aralkyl group, C ₇ ~ C ₁₄ hydroxy aralkyl group, C ₆ ~ C ₁₂ aryl group, C ₂ ~ C ₇ carbamoyl group, C ₂ ˜C ₇ carboxyalkyl group, C ₁ to C ₆ aminoalkyl group, C ₄ to C ₁₀ guanidylalkyl group, C ₁ to C ₆ mercaptoalkyl group, C ₂ to C ₇ alkylthioalkyl group, C ₉ to C ₁₅ indolylalkyl group Or a C ₄ to C ₉ imidazolylalkyl group, R²는 수소, C₁~C₆알킬기, C₇~C₁₄아랄킬기, C₆~C₁₂아릴기, 글리실기 또는 글리실-글리실기를 나타내고,R ² represents hydrogen, a C ₁ to C ₆ alkyl group, a C ₇ to C ₁₄ aralkyl group, a C ₆ to C ₁₂ aryl group, a glycyl group or a glycyl-glycyl group, R³은 수소, C₁~C₆알킬기 또는 아미노-보호기를 나타내고, R¹및 R²는 임의로 결합하여 C₂~C₄알킬렌기를 형성하며, R²-N'-R³기는 임의로 푸탈릴이미도기, 피페리디노기, 4-하이드록시-4-(p-할로게노페닐) 피페리디노, 모르폴리노, 또는 C₁~C₆알킬기 또는 페닐기에 의하여 치환된 피페라지노기를 나타내고, A환은 할로겐에 의하여 임의로 치환된 벤젠환 또는 피리딘환을 나타내며, B환은 할로겐, 트리플루오로메틸기, 메틸술포닐기, 니트로기 또는 C₁~C₆알킬기에 의해 임의로 치환된 벤젠환 또는 티오펜환을 나타낸다.R ³ represents hydrogen, a C ₁ to C ₆ alkyl group or an amino-protecting group, R ¹ and R ² are optionally bonded to form a C ₂ to C ₄ alkylene group, and the R ² -N′-R ³ group is optionally putaryl imido group, a piperidino group, 4-hydroxy -4- (p- halogeno phenyl) piperidino, morpholino, or C ₁ ~ C ₆ represents a piperazinyl group substituted by a large group or a phenyl group, a ring A benzene ring or a pyridine ring optionally substituted with halogen is indicated, and the B ring represents a benzene ring or thiophene ring optionally substituted with halogen, trifluoromethyl group, methylsulfonyl group, nitro group or C ₁ -C ₆ alkyl group.