KR20000059570A - Piperazine derivatives and process for the preparation thereof - Google Patents

Piperazine derivatives and process for the preparation thereof Download PDF

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Publication number
KR20000059570A
KR20000059570A KR1019990007266A KR19990007266A KR20000059570A KR 20000059570 A KR20000059570 A KR 20000059570A KR 1019990007266 A KR1019990007266 A KR 1019990007266A KR 19990007266 A KR19990007266 A KR 19990007266A KR 20000059570 A KR20000059570 A KR 20000059570A
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South Korea
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group
compound
radical
piperazine
methoxypyrazin
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KR1019990007266A
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Korean (ko)
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조의환
정순간
이순환
권호석
이재웅
이영희
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최승주
삼진제약 주식회사
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Priority to KR1019990007266A priority Critical patent/KR20000059570A/en
Priority to KR10-2000-7011876A priority patent/KR100396738B1/en
Priority to EP03078792A priority patent/EP1424072A1/en
Priority to AU29461/00A priority patent/AU763030B2/en
Priority to DE60010988T priority patent/DE60010988T2/en
Priority to CNB008002959A priority patent/CN100354271C/en
Priority to PCT/KR2000/000164 priority patent/WO2000052001A1/en
Priority to EP20000908085 priority patent/EP1075469B1/en
Priority to CA002330942A priority patent/CA2330942C/en
Priority to JP2000602228A priority patent/JP3422486B2/en
Publication of KR20000059570A publication Critical patent/KR20000059570A/en
Priority to US10/105,936 priority patent/US6683184B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid

Abstract

PURPOSE: A novel piperazine derivative is provided which has excellent anti-cancer effect and low toxicity. CONSTITUTION: The piperazine derivatives are shown in a chemical formula I wherein R1, R2, R3, R4, R5 and R6 are respectively hydrogen atom, halogen atom, hydroxy radical, nitro radical, amino radical, low class alkyl radical of C1-C4, low class ester radical of C1-C4, unsaturated alkyl radical of substituted or unsubstituted C3-C8, cyclo alkyl radical with substituted or unsubstituted 3-6 rings of C3-C8, low class alkoxy radical of C1-C4, low class thioalkxoy radical of C1-C4 and substituted or unsubstituted low class alkylamino radical and R7 and R8 are hydrogen atom, low class alkyl radical of C1-C4 or ketone radical or low class alkylhydroxy radical of C1-C4. And in the formula, Y is oxygen atom or sulfur atom and Z is hydrogen atom, hydroxy radical, low class alkoxy radical of C1-C8, low class alkyl radical of C1-C4 and low class thioalkoxy radical of C1-C4.

Description

피페라진 유도체 및 그 제조방법{Piperazine derivatives and process for the preparation thereof}Piperazine derivatives and method for preparing the same

본 발명은 다음 화학식 (I)로 표시되는 신규 피페라진 유도체 및 그 제조방법에 관한 것이다.The present invention relates to a novel piperazine derivative represented by the following formula (I) and a preparation method thereof.

( I )(I)

식중, R1, R2, R3, R4, R5및 R6은 각각 수소원자, 할로겐원자, 하이드록시기, 니트로기, 아미노기, C1∼C4의 저급 알킬기, C1∼C4의 저급 에스테르기, 치환 또는 비치환의 C3∼C8의 불포화 알킬기, C3∼C8의 치환 또는 비치환의 3∼6 원의 사이클로 알킬기, C1∼C4의 저급 알콕시기, C1∼C4의 저급 티오알콕시기, 치환 또는 비치환의 저급 알킬아미노기이며, R7및 R8는 수소원자, C1∼C4의 저급 알킬기 또는 케톤기 또는 C1∼C4의 저급 알킬하이드록시기이다. Y는 산소원자 또는 황원자, Z는 수소원자, 하이드록시기, C1∼C8의 저급 알콕시기, C1∼C4의 저급 알킬기, C1∼C4의 저급 티오알콕시기이다.Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, a C 1 -C 4 lower alkyl group, C 1 -C 4 a lower alkoxy lower ester group, a substituted or unsubstituted C 3 ~C 8 unsaturated alkyl, C 3 ~C 8 cycloalkyl group substituted or unsubstituted 3~6 circle, C 1 ~C 4 of the group, a C 1 ~C 4, a lower thioalkoxy group, a substituted or unsubstituted lower alkyl group of, R 7 and R 8 is a lower alkyl, a hydroxyl group of a hydrogen atom, C 1 ~C 4 lower alkyl group or a ketone group or a C 1 ~C 4 of. Y is an oxygen atom or a sulfur atom, Z is a lower alkoxy of hydrogen atom, hydroxyl group, C 1 ~C 8 lower alkoxy groups, C 1 ~C 4 lower alkyl group, C 1 ~C 4 of the group.

C1∼C4의 저급 알킬기란 메틸, 에틸, 프로필, 이소프로필, n-부틸, 이소부틸, t-부틸기를 의미한다.C 1 ~C 4 lower alkyl group is methyl, ethyl, propyl, isopropyl, n- butyl, isobutyl, means a t- butyl.

C3∼C8의 치환 또는 비치환의 3-6원의 사이클로알킬기란 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 치환사이클로프로필, 치환사이클로펜틸, 치환사이클로헥실등과 같은 치환 또는 비치환의 사이클로알킬기를 의미한다.A substituted or unsubstituted 3-6 membered cycloalkyl group of C 3 to C 8 is a substituted or unsubstituted cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted cyclopropyl, substituted cyclopentyl, substituted cyclohexyl, or the like. Means.

C1∼C4의 저급 에스테르기란 카르복시기가 저급알킬기에 의하여 에스테르화된 기를 의미한다.The lower ester group of C 1 to C 4 means a group in which the carboxyl group is esterified by a lower alkyl group.

C1∼C4의 저급 알콕시란 메톡시, 에톡시, 프로폭시, 이소프로폭시, 부톡시, 이소부톡시, t-부톡시기를 말한다.C 1 -C 4 lower alkoxy refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and t-butoxy groups.

C1∼C4의 저급 티오알콕시기란 메틸티오, 에틸티오, 프로필티오, 이소프로필티오, 부틸티오, 이소부틸티오, t-부틸티오기를 말한다.The lower thioalkoxy group of C 1 to C 4 refers to methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, t-butylthio group.

C1∼C4의 저급 알킬아민기란 메틸아민, 에틸아민, 프로필아민, 부틸아민기를 말한다.Group refers to a lower alkyl amine of the C 1 ~C 4 means group methylamine, ethylamine, propylamine, butylamine.

C1∼C4의 저급 알킬하이드록시기란 메틸하이드록시, 에틸하이드록시, 프로필하이드록시, 부틸하이드록시기를 말한다.The lower alkyl hydroxy group of C 1 to C 4 refers to methyl hydroxy, ethyl hydroxy, propyl hydroxy or butyl hydroxy group.

본 발명자들은 항암활성을 가지는 화합물에 관하여 오랫동안 연구하여 왔다. 그 결과 본 발명자들은 화학식 (I)의 화합물, 그 산부가염들이 탁월한 항암효과를 가지며, 독성이 극히 적은 놀라운 사실을 발견하여 본 발명을 완성하였다.The present inventors have long studied the compound which has anticancer activity. As a result, the present inventors have found a surprising fact that the compound of the formula (I) and its acid addition salts have excellent anticancer effects and have extremely low toxicity, thus completing the present invention.

따라서 본 발명의 목적은 탁월한 항암효과를 가지며 독성이 적은 화학식 (I)의 화합물 및 그 산부가염을 제공하는 것이다.It is therefore an object of the present invention to provide compounds of formula (I) and acid addition salts thereof having excellent anticancer effects and low toxicity.

본 발명의 다른 목적은 화학식 (I)의 화합물 및 그 산부가염을 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing a compound of formula (I) and acid addition salts thereof.

본 발명의 화합물들은 약학적으로 허용되는 부형제등과 혼합하여 약학적으로 통상으로 사용되는 약학적 제제의 제조방법에 따라서 약학적 제제를 제조하여 여러 종류의 종양 예방과 치료에 사용될 수 있다.The compounds of the present invention can be used for the prevention and treatment of various types of tumors by preparing pharmaceutical preparations according to the methods of preparing pharmaceutical preparations commonly used in combination with pharmaceutically acceptable excipients and the like.

그러므로 본 발명의 또 다른 목적은 화학식 (I)의 화합물을 유효성분으로 함유하는 약학적 제제를 제공하는 것이다.It is therefore another object of the present invention to provide a pharmaceutical formulation containing a compound of formula (I) as an active ingredient.

본 발명의 화합물(I)과 반응하여 산부가염을 형성할 수 있는 산은 약학적으로 허용될 수 있는 무기 또는 유기산이며, 염산, 브롬산, 황산, 인산, 질산 등과 같은 무기산; 포름산, 아세트산, 프로피온산, 석신산, 시트르산, 말레인산, 말론산 등과 같은 유기산; 세린, 시스테린, 시스틴, 아스파라긴, 글루타민, 리진, 아르기닌, 파이로신, 프롤린 등과 같은 아미노산; 메탄설폰산, 에탄설폰산, 벤젠설폰산, 톨루엔설폰산 등과 같은 설폰산 등이 사용될 수 있다.Acids capable of reacting with compound (I) of the present invention to form acid addition salts are pharmaceutically acceptable inorganic or organic acids, inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; Organic acids such as formic acid, acetic acid, propionic acid, succinic acid, citric acid, maleic acid, malonic acid and the like; Amino acids such as serine, cysterin, cystine, asparagine, glutamine, lysine, arginine, pyrosine, proline and the like; Sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid and the like can be used.

본 발명에서 화학식 (I)의 화합물을 유효성분으로 함유하는 약학적 제제의 제조에 부형제로 사용될 수 있는 부형제로는 감미제, 결합제, 용해제, 용해보조제, 습윤제, 유화제, 등장화제, 흡착제, 붕해제, 산화방지제, 방부제, 활탁제, 충진제, 방향제 등이 사용될 수 있으며, 예를 들면, 락토스, 덱스트로스, 슈크로스, 만니톨, 솔비톨, 셀룰로오스, 글라이신, 실리카, 탈크, 스테아린산, 스테린, 트라가칸트 고무, 메틸셀룰로오스, 소디움카르복실메틸셀루로오스, 아가, 알지닌산, 물, 에탄올, 폴리에틸렌그리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼륨, 오렌지 엣센스, 딸기엣센스, 바닐라 향 등을 들 수 있다.Excipients that can be used as excipients in the preparation of pharmaceutical preparations containing the compound of formula (I) as an active ingredient in the present invention include sweeteners, binders, solubilizers, dissolution aids, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, Antioxidants, preservatives, lubricants, fillers, fragrances and the like can be used, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, tragacanth rubber And methyl cellulose, sodium carboxymethyl cellulose, agar, alginic acid, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, potassium chloride, orange essence, strawberry essence, vanilla flavor and the like.

본 발명의 화학식 (I)의 화합물의 상용량은 환자의 나이, 성별, 질병 정도등에 따라서 달라질 수 있으나, 일일 1mg 내지 5000mg을 일회 내지 수 회 투여할 수 있다.The normal dose of the compound of formula (I) of the present invention may vary depending on the age, sex, degree of disease, etc. of the patient, but may be administered once to several times daily from 1 mg to 5000 mg.

본 발명 화학식(I)의 화합물은 다음의 반응식 1에 의하여 제조될 수 있다.The compound of formula (I) of the present invention may be prepared by the following Scheme 1.

상기식에서 R1, R2, R3, R4, R5, R6, R7, R8및 Y, Z는 전술한 바와 같으며 Lie는 할로겐원자와 같은 이탈기이다.Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and Y, Z are as described above and Lie is a leaving group such as a halogen atom.

기존의 공지 방법으로 합성한 화학식 (2) 화합물에 -C(=Y)-기 공여시약의 존재하에 화합물(3)을 효과적으로 얻은 후, 연속하여 기존의 방법으로 합성한 화합물(4)와 반응시켜 화합물(5)를 효과적으로 제조한다. 그리고, 알킬, 아릴화제를 염기하에서 반응시켜 일반 화학식(I)을 제조한다.Compound (3) was effectively obtained in the presence of the -C (= Y) -group donor reagent to the compound of formula (2) synthesized by conventional known methods, and subsequently reacted with compound (4) synthesized by conventional methods. Compound (5) is prepared effectively. In addition, alkyl and arylating agents are reacted under a base to prepare general formula (I).

-C(=Y)-기 공여시약으로는 1,1-카르보닐다이이미다졸, 1,1-카르보닐티오다이이미다졸, 포스겐, 티오포스겐, 카르보닐다이페녹시드, 페닐클로로포메이트 등을 사용한다.Examples of the -C (= Y) -group donor reagent include 1,1-carbonyldiimidazole, 1,1-carbonylthiodiimidazole, phosgene, thiophosgene, carbonyldiphenoxide, phenylchloroformate and the like. use.

이 반응은 통상의 유기용매, 예를 들면 테트라하이드로퓨란, 다이클로로메탄, 아세토니트릴, 다이메틸포름아마이드 등을 사용함이 바람직하다.This reaction is preferably using a conventional organic solvent such as tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide and the like.

또한 이 반응은 결합시약의 존재하에 반응시킴이 바람직하다. 이 반응에 사용될 수 있는 결합시약으로는 통상의 무기 또는 유기염기를 사용한다.It is also preferable that the reaction is carried out in the presence of a binding reagent. As a binding reagent that can be used for this reaction, a conventional inorganic or organic base is used.

이 반응은 3oC 내지 용매의 비점온도에서, 바람직하게는 50oC 내지 100oC에서 5 내지 48시간, 바람직하게는 10-24시간 동안 반응시킨다.The reaction is carried out at a boiling point temperature of 3 o C to a solvent, preferably at 50 o C to 100 o C for 5 to 48 hours, preferably 10 to 24 hours.

-C(=Y)-기 공여시약의 사용량은 1∼1.5당량, 바람직하게는 1-1.1당량을 사용한다.The amount of the -C (= Y) -donating reagent is used in the range of 1 to 1.5 equivalents, preferably 1-1.1 equivalents.

화합물(3)에서 화합물(4)와 결합하여 화학식(5)를 제조하는 경우에 있어서, 이 반응은 바람직하게 50oC 내지 100oC에서 5시간 내지 48시간 반응시킨다. 화합물(4)의 사용량은 1에서 1.5당량을 사용한다.In the case of preparing the compound of formula (5) by combining with compound (4) in compound (3), the reaction is preferably reacted at 50 o C to 100 o C for 5 to 48 hours. The amount of compound (4) used is 1 to 1.5 equivalents.

이 반응은 통상의 유기용매, 예를 들면 테트라하이드로퓨란, 디클로로메탄, 아세토니트릴, 클로로포름, 다이메틸포름아마이드 등을 사용함이 바람직하다.This reaction is preferably using a conventional organic solvent such as tetrahydrofuran, dichloromethane, acetonitrile, chloroform, dimethylformamide and the like.

이 반응의 통상의 염기는 수소화나트륨, 수소화칼륨, 수산화나트륨, 수산화칼륨, 탄산나트륨, 탄산칼륨, 탄산세슘, 탄산수소나트륨, 탄산수소칼륨, 트리에틸아민, 피리딘, DBU 등을 사용함이 바람직하다.Common bases for this reaction are preferably sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine, DBU and the like.

일반화합물(5)의 화합물과 알킬화제 또는 아릴화제를 염기하에서 반응시켜 일반구조식 (I)의 화합물을 효과적으로 제조한다.The compound of the general formula (5) and the alkylating agent or the arylating agent are reacted under a base to effectively prepare the compound of the general formula (I).

이 반응의 알킬, 아릴화제는 C1∼C8의 저급알킬할로겐, C1∼C8의 저급알킬 설포네이트, C3∼C8의 치환 또는 비치환 사이클로알킬할로겐, 아릴할로겐, C3∼C8의 치환 또는 비치환 사이클로알킬 설포네이트와 아릴 설포네이트 등이 사용된다.Alkyl and arylating agent of this reaction are C 1 -C 8 lower alkylhalogen, C 1 -C 8 lower alkyl sulfonate, C 3 -C 8 substituted or unsubstituted cycloalkylhalogen, arylhalogen, C 3 -C 8 substituted or unsubstituted cycloalkyl sulfonate, aryl sulfonate and the like are used.

C1∼C8의 저급알킬할로겐이란 염화메탄, 브롬화메탄, 요오드화메탄, 염화에탄, 브롬화에탄, 요오드화에탄, 염화프로판, 브롬화프로판, 요오드화프로판, 염화부탄, 브롬화부탄, 요오드화부탄, 염화펜탄, 브롬화펜탄, 요오드화펜탄, 브로모 에틸아세테이트 등을 말한다.Lower alkylhalogens of C 1 to C 8 are methane chloride, methane bromide, methane iodide, ethane chloride, ethane bromide, ethane iodide, propane chloride, propane bromide, propane iodide, butane chloride, butane bromide, butane iodide, pentane chloride and bromide Pentane, pentane iodide, bromo ethyl acetate, etc. are mentioned.

C1∼C8의 저급알킬 설포네이트이란 메틸설포네이트, 에틸설포네이트, 프로필설포네이트, 부틸설포네이트, 펜틸설포네이트 등을 말한다.Lower alkyl sulfonate of a C 1 ~C 8 refers to methyl sulfonate, ethyl sulfonate, propyl sulfonate, butyl sulfonate, pentyl sulfonate.

C3∼C8의 치환 또는 비치환 사이클로알킬할로겐이란 염화사이클로프로판, 브롬화사이클로프로판, 요오드화사이클로프로판, 염화사이클로부탄, 브롬화사이클로부탄, 요오드화사이클로부탄, 염화사이클로펜탄, 브롬화사이클로펜탄, 요오드화사이클로펜탄, 염화사이클로헥산, 브롬화사이클로헥산, 요오드화사이클로헥산, 염화메틸사이클로프로판, 브롬화메틸사이클로프로판, 요오드화메틸사이클로프로판, 염화메틸사이클로부탄, 브롬화메틸사이클로부탄, 요오드화메틸사이클로부탄, 염화메틸사이클로펜탄, 브롬화메틸사이클로펜탄, 요오드화메틸사이클로펜탄, 염화메틸사이클로헥산, 브롬화메틸사이클로헥산, 요오드화메틸사이클로헥산 등을 말한다.A substituted or unsubstituted C 3 ~C 8 cycloalkyl, halogen is chloride, cyclopropane, cyclopropane bromide, iodide, cyclopropane, cyclobutane chloride, bromide, cyclobutane, iodide, cyclobutane, cyclopentane, chloride, bromide, cyclopentane, cyclopentane iodide, Cyclohexane chloride, cyclohexane bromide, cyclohexane iodide, methylcyclopropane chloride, methylcyclopropane bromide, methylcyclopropane iodide, methylcyclobutane chloride, methylcyclobutane bromide, methylcyclobutane iodide, methylcyclopentane chloride, methylcyclopentane bromide Pentane, methylcyclopentane iodide, methylcyclohexane chloride, methylcyclohexane bromide, methylcyclohexane iodide and the like.

아릴할로겐이란 벤질클로라이드, 벤질브로마이드, 벤질이오다이드, 벤조일클로라이드, 벤조일브로마이드, 벤조일이오다이드, 톨루일클로라이드, 톨루일브로마이드, 톨루일이오다이드 등을 말한다.Arylhalogen refers to benzyl chloride, benzyl bromide, benzyl iodide, benzoyl chloride, benzoyl bromide, benzoyl iodide, toluyl chloride, toluyl bromide, toluyl iodide and the like.

C3∼C8의 치환 또는 비치환 사이클로알킬설포네이트이란 사이클로프로필 설포네이트, 사이클로부틸 설포네이트, 사이클로펜틸 설포네이트, 사이클로헥실 설포네이트, 메틸사이클로프로필 설포네이트, 메틸사이클로부틸 설포네이트, 메틸사이클로펜틸 설포네이트, 메틸사이클로헥실 설포네이트 등을 말한다.C 3 ~C 8 substituted or unsubstituted cycloalkyl of sulfonate is cyclopropyl sulfonate, cyclobutyl sulfonate, cyclopentyl sulfonate, cyclohexyl sulfonate, cyclopropyl methyl sulfonate, cyclobutyl methyl sulfonate, cyclopentyl methyl Sulfonate, methylcyclohexyl sulfonate, and the like.

아릴설포네이트이란 벤질설포네이트, 벤조일설포네이트, 톨루일설포네이트 등을 말한다.Arylsulfonate means benzyl sulfonate, benzoyl sulfonate, toluyl sulfonate, etc.

이 반응은 통상의 유기용매, 예를 들면 테트라하이드로퓨란, 디클로로메탄, 아세토니트릴, 디메틸포름아미드, 디메틸설폭시드 등을 사용함이 바람직하다.This reaction is preferably using a conventional organic solvent such as tetrahydrofuran, dichloromethane, acetonitrile, dimethylformamide, dimethyl sulfoxide and the like.

이 반응의 통상의 염기는 수소화나트륨, 수소화칼륨, 수산화나트륨, 수산화칼륨, 탄산나트륨, 탄산칼륨, 탄산세시윰, 탄산수소나트륨, 탄산수소칼륨, 트리에틸아민, 피리딘, DBU 등을 사용함이 바람직하다.Common bases for this reaction are preferably sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium hydrogen carbonate, triethylamine, pyridine, DBU and the like.

상기의 반응물들중에서 반응시에 산성물질을 부생하는 반응의 경우에는 이들 물질들을 반응계로부터 제거하기 위하여 염기성물질을 첨가한 후 반응시킴이 바람직하다. 이러한 염기성물질로서는 수산화나트륨, 수산화칼륨, 수산화칼슘, 수산화마그네슘, 산화마그네슘, 산화칼슘, 탄산칼륨, 탄산나트륨, 탄산칼슘, 탄산마그네슘, 중탄산마그네슘, 중탄산나트륨, 중탄산칼륨 등과 같은 알칼리금속 또는 알칼리토류금속의 수산화물, 산화물, 탄산염 또는 중탄산염, 및 유기아민 계통의 염기 존재하에 반응시킴이 바람직하다.In the reactions in which acidic substances are by-produced during the reaction, it is preferable to add a basic substance and then react to remove these substances from the reaction system. Such basic substances include alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, magnesium oxide, calcium oxide, potassium carbonate, sodium carbonate, calcium carbonate, magnesium carbonate, magnesium bicarbonate, sodium bicarbonate, potassium bicarbonate, and the like. It is preferred to react in the presence of an oxide, a carbonate or bicarbonate, and a base of an organic amine family.

일반 화학식 (2)의 화합물은 공지의 화합물, 공지문헌(Farmaco(pavia) Ed, Sci., 18(8), 557-65(1963)) 등에 기술되어 있거나 또는 이와 유사한 방법으로 제조하여 사용될 수 있다.Compounds of the general formula (2) are described in known compounds, known publications (Farmaco (pavia) Ed, Sci., 18 (8), 557-65 (1963)) and the like or may be prepared and used in a similar manner. .

실시예Example

상기 기술된 방법에 따라서 다음 화합물들을 제조하였다.The following compounds were prepared according to the method described above.

(I)(I)

상기식에서 R1, R2, R3, R4, R5, R6, R7, R8및 Y, Z는 전술한 바와 같다.Wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and Y, Z are as described above.

실시예Example R1 R 1 R2 R 2 R3 R 3 R4 R 4 R5 R 5 R6 R 6 R7 R 7 R8 R 8 YY ZZ 1One HH HH HH HH HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 22 OCH3 OCH 3 HH HH HH HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 33 HH OCH3 OCH 3 HH OCH3 OCH 3 HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 44 EtEt HH HH HH HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 55 HH HH n-Bun-Bu HH HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 66 iPriPr HH HH HH HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 77 HH CH3 CH 3 HH CH3 CH 3 HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 88 CH3 CH 3 CH3 CH 3 HH CH3 CH 3 CH3 CH 3 HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 99 FF HH HH HH HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 1010 HH BrBr HH HH HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 1111 HH ClCl HH ClCl HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 1212 HH FF HH FF HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 1313 HH CF3 CF 3 HH HH HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 1414 SCH3 SCH 3 HH HH HH HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 1515 HH NO2 NO 2 HH NO2 NO 2 HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3

실시예Example R1 R 1 R2 R 2 R3 R 3 R4 R 4 R5 R 5 R6 R 6 R7 R 7 R8 R 8 YY ZZ 1616 HH NH2 NH 2 HH NH2 NH 2 HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 1717 HH HH AcAc HH HH HH CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 1818 OCH3 OCH 3 HH HH HH HH CH3 CH 3 CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 1919 HH OCH3 OCH 3 HH OCH3 OCH 3 HH CH3 CH 3 CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 2020 HH CH3 CH 3 HH CH3 CH 3 HH CH3 CH 3 CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 2121 HH ClCl HH ClCl HH CH3 CH 3 CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 2222 HH FF HH FF HH CH3 CH 3 CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 2323 SCH3 SCH 3 HH HH HH HH CH3 CH 3 CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 2424 HH NO2 NO 2 HH NO2 NO 2 HH CH3 CH 3 CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 2525 HH NH2 NH 2 HH NH2 NH 2 HH CH3 CH 3 CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 2626 HH OCH3 OCH 3 HH OCH3 OCH 3 HH EtEt CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 2727 HH CH3 CH 3 HH CH3 CH 3 HH EtEt CH3 CH 3 CH3 CH 3 OO OCH3 OCH 3 2828 HH OCH3 OCH 3 HH OCH3 OCH 3 HH HH CH3 CH 3 CH3 CH 3 SS OCH3 OCH 3 2929 EtEt HH HH HH HH HH CH3 CH 3 CH3 CH 3 SS OCH3 OCH 3 3030 HH CH3 CH 3 HH CH3 CH 3 HH HH CH3 CH 3 CH3 CH 3 SS OCH3 OCH 3 3131 HH BrBr HH HH HH HH CH3 CH 3 CH3 CH 3 SS OCH3 OCH 3 3232 HH ClCl HH ClCl HH HH CH3 CH 3 CH3 CH 3 SS OCH3 OCH 3 3333 SCH3 SCH 3 HH HH HH HH HH CH3 CH 3 CH3 CH 3 SS OCH3 OCH 3 3434 HH CH3 CH 3 HH CH3 CH 3 HH HH EtEt EtEt OO OCH3 OCH 3 3535 HH OCH3 OCH 3 HH OCH3 OCH 3 HH HH EtEt EtEt OO OCH3 OCH 3

실시예 1) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-페닐피페라진Example 1) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4-phenylpiperazin

a) 페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트a) Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate

3-아미노-5,6-다이메틸-2-메톡시피라진(1.00그램, 6.53밀리몰)과 페닐클로로포메이트(1.02그램, 6.53밀리몰)를 다이클로로메탄에 용해시킨 후, 실온에서 2시간 동안 교반하였다. 감압농축하여 용매를 제거한 후, 관크로마토그래피로 분리정제하여 상기화합물을 얻었다.3-amino-5,6-dimethyl-2-methoxypyrazine (1.00 grams, 6.53 mmol) and phenylchloroformate (1.02 grams, 6.53 mmol) were dissolved in dichloromethane and stirred at room temperature for 2 hours. It was. Concentrated under reduced pressure to remove the solvent, and then purified by column chromatography to obtain the compound.

수율 : 98.0%Yield: 98.0%

융점 : 101∼103℃Melting Point: 101 ~ 103 ℃

1H NMR(CDCl3) : δ 2.39(3H,s), 2.42(3H,s), 4.02(3H,s), 7.35(4H,m), 7.40(1H,m) 1 H NMR (CDCl 3 ): δ 2.39 (3H, s), 2.42 (3H, s), 4.02 (3H, s), 7.35 (4H, m), 7.40 (1H, m)

b) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-페닐피페라진b) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4-phenylpiperazin

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트(350밀리그램, 1.28밀리몰)와 1-페닐피페라진(208밀리그램, 1.28밀리몰)을 무수 테트라하이드로퓨란에 용해시킨 후, DBU(195밀리그램, 1.28밀리몰)을 가한 후, 실온에서 2시간 동안 교반하였다. 감압농축하여 용매를 제거한 후, 관크로마토그래피로 분리정제하여 상기화합물을 얻었다.Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate (350 mg, 1.28 mmol) and 1-phenylpiperazine (208 mg, 1.28 mmol) were dissolved in anhydrous tetrahydrofuran. After the addition, DBU (195 mg, 1.28 mmol) was added, followed by stirring at room temperature for 2 hours. Concentrated under reduced pressure to remove the solvent, and then purified by column chromatography to obtain the compound.

수율 : 78.5%Yield: 78.5%

융점 : 185∼187℃Melting Point: 185 ~ 187 ℃

1H NMR(CDCl3) : δ 2.37(3H,s), 2.39(3H,s), 3.27(4H,t), 3.74(4H,t), 3.97(3H,s), 6.97(2H,m), 7.31(2H,t) 1 H NMR (CDCl 3 ): δ 2.37 (3H, s), 2.39 (3H, s), 3.27 (4H, t), 3.74 (4H, t), 3.97 (3H, s), 6.97 (2H, m) , 7.31 (2H, t)

실시예 2) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(2-메톡시페닐)피페라진Example 2) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (2-methoxyphenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(2-메톡시페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate and 1- (2-methoxyphenyl) piperazine in the same manner as in Example 1.

수율 : 82.0%Yield: 82.0%

융점 : 184∼185℃Melting Point: 184 ~ 185 ℃

1H NMR(CDCl3) : δ 2.36(3H,s), 2.40(3H,s), 3.13(4H,t), 3.75(4H,t), 3.89(3H,s), 3.97(3H,s), 6.95(3H,m), 7.05(2H,m) 1 H NMR (CDCl 3 ): δ 2.36 (3H, s), 2.40 (3H, s), 3.13 (4H, t), 3.75 (4H, t), 3.89 (3H, s), 3.97 (3H, s) , 6.95 (3H, m), 7.05 (2H, m)

실시예 3) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진Example 3) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(3,5-다이메톡시페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was reacted with phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate and 1- (3,5-dimethoxyphenyl) piperazine in the same manner as in Example 1. Got.

수율 : 85.0%Yield: 85.0%

융점 : 136∼137℃Melting Point: 136 ~ 137 ℃

1H NMR(CDCl3) : δ 2.37(3H,s), 2.39(3H,s), 3.25(4H,t), 3.71(4H,t), 3.79(6H,s), 3.97(3H,s), 6.10(3H,m) 1 H NMR (CDCl 3 ): δ 2.37 (3H, s), 2.39 (3H, s), 3.25 (4H, t), 3.71 (4H, t), 3.79 (6H, s), 3.97 (3H, s) , 6.10 (3H, m)

실시예 4) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(2-에틸페닐)피페라진Example 4) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (2-ethylphenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(2-에틸페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate and 1- (2-ethylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the compound.

수율 : 70.4%Yield: 70.4%

융점 : 197∼199℃Melting Point: 197 ~ 199 ℃

1H NMR(CDCl3) : δ 1.26(3H,t), 2.37(3H,s), 2.41(3H,s), 2.74(2H,q), 2.94(4H,t), 3.68(4H,t), 3.97(3H,s), 6.72(1H,brs), 7.08(2H,m), 7.19(1H,t), 7.25(1H,s) 1 H NMR (CDCl 3 ): δ 1.26 (3H, t), 2.37 (3H, s), 2.41 (3H, s), 2.74 (2H, q), 2.94 (4H, t), 3.68 (4H, t) , 3.97 (3H, s), 6.72 (1H, brs), 7.08 (2H, m), 7.19 (1H, t), 7.25 (1H, s)

실시예 5) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(4-부틸페닐)피페라진Example 5) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (4-butylphenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(4-부틸페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate and 1- (4-butylphenyl) piperazine in the same manner as in Example 1.

수율 : 68.5%Yield: 68.5%

융점 : 121∼123℃Melting Point: 121 ~ 123 ℃

1H NMR(CDCl3) : δ 0.92(3H,t), 1.35(2H,m), 1.57(2H,m), 2.37(3H,s), 2.39(3H,s), 2.56(2H,t), 3.25(4H,t), 3.78(4H,t), 3.97(3H,s), 6.95(2H,brs), 7.14(2H,m) 1 H NMR (CDCl 3 ): δ 0.92 (3H, t), 1.35 (2H, m), 1.57 (2H, m), 2.37 (3H, s), 2.39 (3H, s), 2.56 (2H, t) , 3.25 (4H, t), 3.78 (4H, t), 3.97 (3H, s), 6.95 (2H, brs), 7.14 (2H, m)

실시예 6) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(2-이소프로필페닐)피페라진Example 6) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (2-isopropylphenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(2-이소프로필페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate and 1- (2-isopropylphenyl) piperazine in the same manner as in Example 1.

수율 : 73.0%Yield: 73.0%

융점 : 165∼167℃Melting Point: 165 ~ 167 ℃

1H NMR(CDCl3) : δ 1.23(6H,d), 2.38(3H,s), 2.42(3H,s), 2.95(4H,t), 3.53(1H,m), 3.72(4H,t), 3.98(3H,s), 7.11(1H,m), 7.29(1H,m) 1 H NMR (CDCl 3 ): δ 1.23 (6H, d), 2.38 (3H, s), 2.42 (3H, s), 2.95 (4H, t), 3.53 (1H, m), 3.72 (4H, t) , 3.98 (3H, s), 7.11 (1H, m), 7.29 (1H, m)

실시예 7) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진Example 7) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(3,5-다이메틸페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 1. .

수율 : 84.0%Yield: 84.0%

융점 : 162∼164℃Melting Point: 162 ~ 164 ℃

1H NMR(CDCl3) : δ 2.30(6H,s), 2.37(3H,s), 2.40(3H,s), 3.25(4H,t), 3.75(4H,t), 3.97(3H,s), 6.62(3H,m) 1 H NMR (CDCl 3 ): δ 2.30 (6H, s), 2.37 (3H, s), 2.40 (3H, s), 3.25 (4H, t), 3.75 (4H, t), 3.97 (3H, s) , 6.62 (3H, m)

실시예 8) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(2,3,5,6 -테트라메틸페닐)피페라진Example 8) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (2,3,5,6-tetramethylphenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(2,3,5,6,-테트라메틸페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.Reaction of phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate with 1- (2,3,5,6, -tetramethylphenyl) piperazine in the same manner as in Example 1 To obtain the compound.

수율 : 65.5%Yield: 65.5%

융점 : 202∼204℃Melting Point: 202 ~ 204 ℃

1H NMR(CDCl3) : δ 2.21(6H,s), 2.22(6H,s), 2.38(3H,s), 2.43(3H,s), 3.17(4H,t), 3.67(4H,t), 4.00(3H,s), 6.84(1H,s) 1 H NMR (CDCl 3 ): δ 2.21 (6H, s), 2.22 (6H, s), 2.38 (3H, s), 2.43 (3H, s), 3.17 (4H, t), 3.67 (4H, t) , 4.00 (3H, s), 6.84 (1H, s)

실시예 9) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(2-플로로페닐)피페라진Example 9) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (2-fluorophenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(2-플로로페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate and 1- (2-fluorophenyl) piperazine in the same manner as in Example 1.

수율 : 74.5%Yield: 74.5%

융점 : 170∼172℃Melting Point: 170 ~ 172 ℃

1H NMR(CDCl3) : δ 2.37(3H,s), 2.40(3H,s), 3.14(4H,t), 3.73(4H,t), 3.98(3H,s), 6.99(2H,m), 7.07(2H,m) 1 H NMR (CDCl 3 ): δ 2.37 (3H, s), 2.40 (3H, s), 3.14 (4H, t), 3.73 (4H, t), 3.98 (3H, s), 6.99 (2H, m) , 7.07 (2H, m)

실시예 10) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3-브로모페닐)피페라진Example 10) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3-bromophenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(3-브로모페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate and 1- (3-bromophenyl) piperazine in the same manner as in Example 1.

수율 : 70.0%Yield: 70.0%

융점 : 158∼160℃Melting Point: 158 ~ 160 ℃

1H NMR(CDCl3) : δ 2.37(3H,s), 2.39(3H,s), 3.26(4H,t), 3.70(4H,t), 3.98(3H,s), 6.85(1H,m), 7.01(1H,d), 7.05(1H,s), 7.13(1H,t) 1 H NMR (CDCl 3 ): δ 2.37 (3H, s), 2.39 (3H, s), 3.26 (4H, t), 3.70 (4H, t), 3.98 (3H, s), 6.85 (1H, m) , 7.01 (1H, d), 7.05 (1H, s), 7.13 (1H, t)

실시예 11) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이클로로페닐)피페라진Example 11) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-dichlorophenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(3,5-다이클로로페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was reacted with phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate and 1- (3,5-dichlorophenyl) piperazine in the same manner as in Example 1. Got it.

수율 : 80.5%Yield: 80.5%

융점 : 180∼181℃Melting Point: 180 ~ 181 ℃

1H NMR(CDCl3) : δ 2.37(3H,s), 2.39(3H,s), 3.27(4H,t), 3.69(4H,t), 3.98(3H,s), 6.75(2H,s), 6.84(1H,s) 1 H NMR (CDCl 3 ): δ 2.37 (3H, s), 2.39 (3H, s), 3.27 (4H, t), 3.69 (4H, t), 3.98 (3H, s), 6.75 (2H, s) , 6.84 (1H, s)

실시예 12) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이플로로페닐)피페라진Example 12) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-difluorophenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(3,5-다이플로로페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The above compound was reacted with phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate and 1- (3,5-difluorophenyl) piperazine in the same manner as in Example 1. Got.

수율 : 78.0%Yield: 78.0%

융점 : 152∼154℃Melting Point: 152 ~ 154 ℃

1H NMR(CDCl3) : δ 2.37(3H,s), 2.39(3H,s), 3.27(4H,t), 3.69(4H,t), 3.97(3H,s), 6.30(1H,t), 6.37(2H,d) 1 H NMR (CDCl 3 ): δ 2.37 (3H, s), 2.39 (3H, s), 3.27 (4H, t), 3.69 (4H, t), 3.97 (3H, s), 6.30 (1H, t) , 6.37 (2H, d)

실시예 13) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3-트리플로로톨일)피페라진Example 13) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3-trifluorotolyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(3-트리플로로톨일)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate with 1- (3-trifluorotolyl) piperazine in the same manner as in Example 1. .

수율 : 69.5%Yield: 69.5%

융점 : 168∼170℃Melting Point: 168 ~ 170 ℃

1H NMR(CDCl3) : δ 2.38(3H,s), 2.40(3H,s), 3.31(4H,s), 3.73(4H,t), 3.98(3H,s), 7.09(1H,d), 7.13(2H,m), 7.38(1H,t) 1 H NMR (CDCl 3 ): δ 2.38 (3H, s), 2.40 (3H, s), 3.31 (4H, s), 3.73 (4H, t), 3.98 (3H, s), 7.09 (1H, d) , 7.13 (2H, m), 7.38 (1H, t)

실시예 14) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(2-메틸티오페닐)피페라진Example 14) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (2-methylthiophenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(2-메틸티오페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate and 1- (2-methylthiophenyl) piperazine in the same manner as in Example 1.

수율 : 71.0%Yield: 71.0%

융점 : 202∼204℃Melting Point: 202 ~ 204 ℃

1H NMR(CDCl3) : δ 2.38(3H,s), 2.42(3H,s), 2.43(3H,s), 3.05(4H,t), 3.73(4H,t), 3.99(3H,s), 7.05(1H,brs), 7.13(1H,s) 1 H NMR (CDCl 3 ): δ 2.38 (3H, s), 2.42 (3H, s), 2.43 (3H, s), 3.05 (4H, t), 3.73 (4H, t), 3.99 (3H, s) , 7.05 (1H, brs), 7.13 (1H, s)

실시예 15) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이니트로페닐)피페라진Example 15) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-dinitrophenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(3,5-다이니트로페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was reacted with phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate and 1- (3,5-dinitrophenyl) piperazine in the same manner as in Example 1. Got it.

수율 : 64.5%Yield: 64.5%

융점 : 192∼194℃Melting Point: 192 ~ 194 ℃

1H NMR(CDCl3) : δ 2.39(3H,s), 2.45(3H,s), 3.57(4H,t), 3.88(4H,t), 4.08(3H,s), 7.98(2H,s), 8.45(1H,s) 1 H NMR (CDCl 3 ): δ 2.39 (3H, s), 2.45 (3H, s), 3.57 (4H, t), 3.88 (4H, t), 4.08 (3H, s), 7.98 (2H, s) , 8.45 (1H, s)

실시예 16) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이아미노페닐)피페라진Example 16) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-diaminophenyl) piperazine

1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이니트로페닐)피페라진을 에탄올(30밀리리터)에 녹이고 10% 팔라듐/카본(10밀리그램)을 가한 후, 4시간 동안 수소반응을 시킨다. 10% 팔라듐/카본을 여과하여 제거한다. 여액을 농축한 후, 관크로마토그래피로 분리정제하여 상기화합물을 얻었다.Dissolve 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-dinitrophenyl) piperazine in ethanol (30 milliliters) and 10% palladium Carbon (10 mg) is added and then hydrogenated for 4 hours. 10% palladium / carbon is filtered off. The filtrate was concentrated and separated and purified by column chromatography to obtain the compound.

수율 : 45.0%Yield: 45.0%

융점 : 〉100℃(decomposed)Melting Point:〉 100 ℃ (decomposed)

1H NMR(CDCl3) : δ 2.38(3H,s), 2.40(3H,s), 3.26(4H,t), 3.70(4H,t), 3.98(3H,s), 6.35(1H,s), 6.42(2H,s) 1 H NMR (CDCl 3 ): δ 2.38 (3H, s), 2.40 (3H, s), 3.26 (4H, t), 3.70 (4H, t), 3.98 (3H, s), 6.35 (1H, s) , 6.42 (2H, s)

실시예 17) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(4-아세틸페닐)피페라진Example 17) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (4-acetylphenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)카바메이트와 1-(4-아세틸페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) carbamate and 1- (4-acetylphenyl) piperazine were reacted in the same manner as in Example 1 to obtain the compound.

수율 : 71.5%Yield: 71.5%

융점 : 166∼168℃Melting Point: 166 ~ 168 ℃

1H NMR(CDCl3) : δ 2.38(3H,s), 2.40(3H,s), 2.54(3H,s), 3.46(4H,t), 3.74(4H,t), 3.99(3H,s), 6.88(2H,d), 7.90(2H,d) 1 H NMR (CDCl 3 ): δ 2.38 (3H, s), 2.40 (3H, s), 2.54 (3H, s), 3.46 (4H, t), 3.74 (4H, t), 3.99 (3H, s) , 6.88 (2H, d), 7.90 (2H, d)

실시예 18) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)-N-메틸아미노카르보닐] -4-(2-메톡시페닐)피페라진Example 18) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) -N-methylaminocarbonyl] -4- (2-methoxyphenyl) piperazine

1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(2-메톡시페닐)피페라진(200밀리그램, 0.54밀리몰)을 다이메틸포름아마이드(15밀리리터)에 용해시킨 후, 60% 소디움하이드라이드(21.5밀리그램, 0.54밀리몰)를 가하고 실온에서 15분간 교반한다. 요오드메탄(76.6밀리그램, 0.54밀리몰)을 가하고 실온에서 6시간 동안 교반한다. 감압농축하여 용매를 제거한 후, 관크로마토그래피로 분리정제하여 상기화합물을 얻었다.1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (2-methoxyphenyl) piperazine (200 mg, 0.54 mmol) was converted to dimethylformamide ( 15 milliliters), then 60% sodium hydride (21.5 milligrams, 0.54 mmol) is added and stirred at room temperature for 15 minutes. Iodine methane (76.6 mg, 0.54 mmol) is added and stirred at room temperature for 6 hours. Concentrated under reduced pressure to remove the solvent, and then purified by column chromatography to obtain the compound.

수율 : 92.5%Yield: 92.5%

융점 : 140∼142℃Melting Point: 140 ~ 142 ℃

1H NMR(CDCl3) : δ 2.39(3H,s), 2.40(3H,s), 2.91(4H,t), 3.22(3H,s), 3.46(4H,t), 3.85(3H,s), 3.95(3H,s), 6.89(3H,m), 7.02(1H,m) 1 H NMR (CDCl 3): δ 2.39 (3H, s), 2.40 (3H, s), 2.91 (4H, t), 3.22 (3H, s), 3.46 (4H, t), 3.85 (3H, s) , 3.95 (3H, s), 6.89 (3H, m), 7.02 (1H, m)

실시예 19) 1-[(5,6-다이메틸-2-메톡시피라진-3-일) N-메틸아미노카르보닐] -4-(3,5-다이메톡시페닐)피페라진Example 19) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine

1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진을 실시예 18과 동일한 방법으로 반응시켜 상기화합물을 얻었다.1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine was reacted in the same manner as in Example 18. The compound was obtained.

수율 : 90.5%Yield: 90.5%

융점 : 80∼82℃Melting Point: 80 ~ 82 ℃

1H NMR(CDCl3) : δ 2.39(3H,s), 2.40(3H,s), 3.01(4H,t), 3.21(3H,s), 3.40(4H,t), 3.75(6H,s), 3.92(3H,s), 6.03(3H,s) 1 H NMR (CDCl 3 ): δ 2.39 (3H, s), 2.40 (3H, s), 3.01 (4H, t), 3.21 (3H, s), 3.40 (4H, t), 3.75 (6H, s) , 3.92 (3H, s), 6.03 (3H, s)

실시예 20) 1-[(5,6-다이메틸-2-메톡시피라진-3-일) N-메틸아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진Example 20) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진을 실시예 18과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was reacted with 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine in the same manner as in Example 18. Got.

수율 : 88.4%Yield: 88.4%

융점 : 94∼96℃Melting Point: 94 ~ 96 ℃

1H NMR(CDCl3) : δ 2.26(6H,s), 2.39(3H,s), 2.40(3H,s), 2.99(4H,t), 3.22(3H,s), 3.40(4H,t), 3.93(3H,s), 6.52(3H,m) 1 H NMR (CDCl 3 ): δ 2.26 (6H, s), 2.39 (3H, s), 2.40 (3H, s), 2.99 (4H, t), 3.22 (3H, s), 3.40 (4H, t) , 3.93 (3H, s), 6.52 (3H, m)

실시예 21) 1-[(5,6-다이메틸-2-메톡시피라진-3-일) N-메틸아미노카르보닐]-4-(3,5-다이클로로페닐)피페라진Example 21) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl] -4- (3,5-dichlorophenyl) piperazine

1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이클로로페닐)피페라진을 실시예 18과 동일한 방법으로 반응시켜 상기화합물을 얻었다.1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-dichlorophenyl) piperazine was reacted in the same manner as in Example 18 to The compound was obtained.

수율 : 95.2%Yield: 95.2%

융점 : 97∼99℃Melting Point: 97 ~ 99 ℃

1H NMR(CDCl3) : δ 2.40(3H,s), 2.41(3H,s), 3.03(4H,t), 3.21(3H,s), 3.38(4H,t), 3.93(3H,s), 6.68(2H,s), 6.81(1H,s) 1 H NMR (CDCl 3 ): δ 2.40 (3H, s), 2.41 (3H, s), 3.03 (4H, t), 3.21 (3H, s), 3.38 (4H, t), 3.93 (3H, s) , 6.68 (2H, s), 6.81 (1H, s)

실시예 22) 1-[(5,6-다이메틸-2-메톡시피라진-3-일) N-메틸아미노카르보닐] -4-(3,5-다이플로로페닐)피페라진Example 22) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl] -4- (3,5-difluorophenyl) piperazine

1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이플로로페닐)피페라진을 실시예 18과 동일한 방법으로 반응시켜 상기화합물을 얻었다.1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-difluorophenyl) piperazine was reacted in the same manner as in Example 18. The compound was obtained.

수율 : 94.0%Yield: 94.0%

융점 : 104∼106℃Melting Point: 104 ~ 106 ℃

1H NMR(CDCl3) : δ 2.40(3H,s), 2.41(3H,s), 3.03(4H,t), 3.21(3H,s), 3.39(4H,t), 3.93(3H,s), 6.27(3H,m) 1 H NMR (CDCl 3 ): δ 2.40 (3H, s), 2.41 (3H, s), 3.03 (4H, t), 3.21 (3H, s), 3.39 (4H, t), 3.93 (3H, s) , 6.27 (3H, m)

실시예 23) 1-[(5,6-다이메틸-2-메톡시피라진-3-일) N-메틸아미노카르보닐]-4-(2-메틸티오페닐)피페라진Example 23) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl] -4- (2-methylthiophenyl) piperazine

1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(2-메틸티오페닐)피페라진을 실시예 18과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was reacted with 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (2-methylthiophenyl) piperazine in the same manner as in Example 18. Got it.

수율 : 89.5%Yield: 89.5%

융점 : 133∼134℃Melting Point: 133 ~ 134 ℃

1H NMR(CDCl3) : δ 2.40(9H,s), 2.87(4H,t), 3.22(3H,s), 3.46(4H,t), 3.96(3H,s), 7.02(1H,brs), 7.11(3H,s) 1 H NMR (CDCl 3 ): δ 2.40 (9H, s), 2.87 (4H, t), 3.22 (3H, s), 3.46 (4H, t), 3.96 (3H, s), 7.02 (1H, brs) , 7.11 (3H, s)

실시예 24) 1-[(5,6-다이메틸-2-메톡시피라진-3-일) N-메틸아미노카르보닐]-4-(3,5-다이니트로페닐)피페라진Example 24) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl] -4- (3,5-dinitrophenyl) piperazine

1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이니트로페닐)피페라진을 실시예 18과 동일한 방법으로 반응시켜 상기화합물을 얻었다.1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-dinitrophenyl) piperazine was reacted in the same manner as in Example 18 to The compound was obtained.

수율 : 80.0%Yield: 80.0%

융점 : 133∼135℃Melting Point: 133 ~ 135 ℃

1H NMR(CDCl3) : δ 2.43(6H,s), 3.24(3H,s), 3.27(4H,t), 3.45(4H,t), 3.95(3H,s), 7.89(2H,d), 8.40(1H,s) 1 H NMR (CDCl 3 ): δ 2.43 (6H, s), 3.24 (3H, s), 3.27 (4H, t), 3.45 (4H, t), 3.95 (3H, s), 7.89 (2H, d) , 8.40 (1H, s)

실시예 25) 1-[(5,6-다이메틸-2-메톡시피라진-3-일) N-메틸아미노카르보닐]-4-(3,5-다이아미노페닐)피페라진Example 25) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl] -4- (3,5-diaminophenyl) piperazine

1-[(5,6-다이메틸-2-메톡시피라진-3-일) N-메틸아미노카르보닐]-4-(3,5-다이니트로페닐)피페라진을 실시예 16과 동일한 방법으로 반응시켜 상기화합물을 얻었다.1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) N-methylaminocarbonyl] -4- (3,5-dinitrophenyl) piperazine in the same manner as in Example 16 Reaction gave the above compound.

수율 : 58.5%Yield: 58.5%

융점 : 〉100℃(decomposed)Melting Point:〉 100 ℃ (decomposed)

1H NMR(CDCl3) : δ 2.38(3H,s), 2.39(3H,s), 2.95(4H,t), 3.21(3H,s), 3.37(4H,t), 3.92(3H,s), 5.62(1H,s), 5.65(2H,s) 1 H NMR (CDCl 3 ): δ 2.38 (3H, s), 2.39 (3H, s), 2.95 (4H, t), 3.21 (3H, s), 3.37 (4H, t), 3.92 (3H, s) , 5.62 (1H, s), 5.65 (2H, s)

실시예 26) 1-[(5,6-다이메틸-2-메톡시피라진-3-일) N-에틸아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진Example 26) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) N-ethylaminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine

1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진(250밀리그램, 0.62밀리몰)을 다이메틸포름아마이드(20밀리리터)에 용해시킨 후, 60% 소디움하이드라이드(24.9밀리그램, 0.62밀리몰)을 가하고 실온에서 15분간 교반한 후, 요오드에탄(96.7밀리그램, 0.62밀리몰)을 가한다. 실온에서 6시간 동안 교반한 후, 감압농축하여 용매를 제거하고 관크로마토그래피로 분리정제하여 상기화합물을 얻었다.Dimethyl 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (250 mg, 0.62 mmol) After dissolving in formamide (20 milliliters), 60% sodium hydride (24.9 milligrams, 0.62 mmol) is added and stirred at room temperature for 15 minutes, followed by iodine ethane (96.7 milligrams, 0.62 mmol). After stirring at room temperature for 6 hours, the mixture was concentrated under reduced pressure to remove the solvent and purified by column chromatography to obtain the compound.

수율 : 89.5%Yield: 89.5%

융점 : 78∼80℃Melting Point: 78 ~ 80 ℃

1H NMR(CDCl3) : δ 1.65(3H,t), 2.39(3H,s), 2.40(3H,s), 2.96(4H,t), 3.35(4H,t), 3.74(2H,q), 3.75(6H,s), 3.92(3H,s), 6.02(3H,s) 1 H NMR (CDCl 3 ): δ 1.65 (3H, t), 2.39 (3H, s), 2.40 (3H, s), 2.96 (4H, t), 3.35 (4H, t), 3.74 (2H, q) , 3.75 (6H, s), 3.92 (3H, s), 6.02 (3H, s)

실시예 27) 1-[(5,6-다이메틸-2-메톡시피라진-3-일) N-에틸아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진Example 27) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) N-ethylaminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진을 실시예 26과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was reacted with 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine in the same manner as in Example 26. Got.

수율 : 92.0%Yield: 92.0%

융점 : 68∼70℃Melting Point: 68 ~ 70 ℃

1H NMR(CDCl3) : δ 1.17(3H,t), 2.25(6H,s), 2.39(3H,s), 2.40(3H,s), 2.95(4H,t), 3.36(4H,t), 3.74(2H,q), 3.92(3H,s), 6.50(3H,m) 1 H NMR (CDCl 3 ): δ 1.17 (3H, t), 2.25 (6H, s), 2.39 (3H, s), 2.40 (3H, s), 2.95 (4H, t), 3.36 (4H, t) , 3.74 (2H, q), 3.92 (3H, s), 6.50 (3H, m)

실시예 28) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노티오카르보닐]-4-(3,5-다이메톡시페닐)피페라진Example 28) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine

a) 페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)티오카바메이트a) Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) thiocarbamate

3-아미노-5,6-다이메틸-2-메톡시피라진(500밀리그램, 3.26밀리몰)을 다이클로로메탄에 용해시킨 후, 페닐티오클로로포메이트(564밀리그램, 3.26밀리몰)를 서서히 가한 후, 실온에서 24시간 동안 교반하였다. 감압농축하여 용매를 제거한 후, 관크로마토그래피로 분리정제하여 상기화합물을 얻었다.After dissolving 3-amino-5,6-dimethyl-2-methoxypyrazine (500 mg, 3.26 mmol) in dichloromethane, phenylthiochloroformate (564 mg, 3.26 mmol) was added slowly, followed by room temperature Stirred for 24 h. Concentrated under reduced pressure to remove the solvent, and then purified by column chromatography to obtain the compound.

수율 : 78.5%Yield: 78.5%

융점 : 71∼73℃Melting Point: 71 ~ 73 ℃

1H NMR(CDCl3) : δ 2.43(6H,s), 4.02(3H,s), 6.95(1H,brs), 7.25(2H,m), 7.33(2H,m), 8.60(1H,brs) 1 H NMR (CDCl 3 ): δ 2.43 (6H, s), 4.02 (3H, s), 6.95 (1H, brs), 7.25 (2H, m), 7.33 (2H, m), 8.60 (1H, brs)

b) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노티오카르보닐]-4-(3,5-다이메톡시페닐)피페라진b) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)티오카바메이트(200밀리그램, 0.69밀리몰)와 1-(3,5-다이메톡시페닐)피페라진(154밀리그램, 0.69밀리몰)을 무수테트라하이드로퓨란(25밀리리터)에 용해시킨 후, DBU(105밀리그램, 0.69밀리몰)를 가하고 실온에서 2시간 동안 교반하였다. 감압농축하여 용매를 제거한 후, 관크로마토그래피로 분리정제하여 상기화합물을 얻었다.Phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) thiocarbamate (200 mg, 0.69 mmol) and 1- (3,5-dimethoxyphenyl) piperazine (154 mg, 0.69 mmol) was dissolved in anhydrous tetrahydrofuran (25 milliliters), then DBU (105 milligrams, 0.69 mmol) was added and stirred at room temperature for 2 hours. Concentrated under reduced pressure to remove the solvent, and then purified by column chromatography to obtain the compound.

수율 : 71.5%Yield: 71.5%

융점 : 183∼184℃Melting Point: 183 ~ 184 ℃

1H NMR(CDCl3) : δ 2.32(3H,s), 2.34(3H,s), 3.34(4H,t), 3.78(6H,s), 3.98(3H,s), 4.07(4H,t), 6.12(3H,m) 1 H NMR (CDCl 3 ): δ 2.32 (3H, s), 2.34 (3H, s), 3.34 (4H, t), 3.78 (6H, s), 3.98 (3H, s), 4.07 (4H, t) , 6.12 (3H, m)

실시예 29) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노티오카르보닐]-4- (2-에틸페닐)피페라진Example 29) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminothiocarbonyl] -4- (2-ethylphenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)티오카바메이트와 1-(2-에틸페닐)피페라진을 실시예 28과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) thiocarbamate and 1- (2-ethylphenyl) piperazine in the same manner as in Example 28.

수율 : 64.0%Yield: 64.0%

융점 : 197∼199℃Melting Point: 197 ~ 199 ℃

1H NMR(CDCl3) : δ 1.26(3H,t), 2.35(3H,s), 2.37(3H,s), 2.74(2H,q), 3.02(4H,t), 3.97(3H,s), 4.02(4H,t), 7.09(2H,q), 7.19(1H,t), 7.55(1H,s) 1 H NMR (CDCl 3 ): δ 1.26 (3H, t), 2.35 (3H, s), 2.37 (3H, s), 2.74 (2H, q), 3.02 (4H, t), 3.97 (3H, s) , 4.02 (4H, t), 7.09 (2H, q), 7.19 (1H, t), 7.55 (1H, s)

실시예 30) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노티오카르보닐]-4-(3,5-다이메틸페닐)피페라진Example 30) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminothiocarbonyl] -4- (3,5-dimethylphenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)티오카바메이트와 1-(3,5-다이메틸페닐)피페라진을 실시예 28과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was reacted with phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) thiocarbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 28. Got it.

수율 : 68.4%Yield: 68.4%

융점 : 160∼162℃Melting Point: 160 ~ 162 ℃

1H NMR(CDCl3) : δ 2.29(6H,s), 2.32(3H,s), 2.35(3H,s), 3.31(4H,t), 3.98(3H,s), 4.04(4H,t), 6.59(3H,brs) 1 H NMR (CDCl 3 ): δ 2.29 (6H, s), 2.32 (3H, s), 2.35 (3H, s), 3.31 (4H, t), 3.98 (3H, s), 4.04 (4H, t) , 6.59 (3H, brs)

실시예 31) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노티오카르보닐]-4-(3-브로모페닐)피페라진Example 31) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminothiocarbonyl] -4- (3-bromophenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)티오카바메이트와 1-(3-브로모페닐)피페라진을 실시예 28과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) thiocarbamate and 1- (3-bromophenyl) piperazine in the same manner as in Example 28. .

수율 : 62.5%Yield: 62.5%

융점 : 136∼138℃Melting Point: 136 ~ 138 ℃

1H NMR(CDCl3) : δ 2.32(3H,s), 2.35(3H,s), 3.33(4H,t), 3.98(3H,s), 4.06(4H,t), 6.82(1H,d), 7.01(2H,m), 7.13(1H,t) 1 H NMR (CDCl 3 ): δ 2.32 (3H, s), 2.35 (3H, s), 3.33 (4H, t), 3.98 (3H, s), 4.06 (4H, t), 6.82 (1H, d) , 7.01 (2H, m), 7.13 (1H, t)

실시예 32) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노티오카르보닐]-4-(3,5-다이클로로페닐)피페라진Example 32) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminothiocarbonyl] -4- (3,5-dichlorophenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)티오카바메이트와 1-(3,5-다이클로로페닐)피페라진을 실시예 28과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The above compound was reacted with phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) thiocarbamate and 1- (3,5-dichlorophenyl) piperazine in the same manner as in Example 28. Got.

수율 : 70.8%Yield: 70.8%

융점 : 182∼184℃Melting Point: 182 ~ 184 ℃

1H NMR(CDCl3) : δ 2.44(3H,s), 2.49(3H,s), 3.48(4H,t), 4.05(3H,s), 4.25(4H,t), 6.98(3H,m) 1 H NMR (CDCl 3 ): δ 2.44 (3H, s), 2.49 (3H, s), 3.48 (4H, t), 4.05 (3H, s), 4.25 (4H, t), 6.98 (3H, m)

실시예 33) 1-[(5,6-다이메틸-2-메톡시피라진-3-일)아미노티오카르보닐]-4- (2-메틸티오페닐)피페라진Example 33) 1-[(5,6-dimethyl-2-methoxypyrazin-3-yl) aminothiocarbonyl] -4- (2-methylthiophenyl) piperazine

페닐 N-(5,6-다이메틸-2-메톡시피라진-3-일)티오카바메이트와 1-(2-메틸티오페닐)피페라진을 실시예 28과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (5,6-dimethyl-2-methoxypyrazin-3-yl) thiocarbamate and 1- (2-methylthiophenyl) piperazine in the same manner as in Example 28. .

수율 : 61.4%Yield: 61.4%

융점 : 181∼183℃Melting Point: 181 ~ 183 ℃

1H NMR(CDCl3) : δ 2.35(3H,s), 2.36(3H,s), 2.43(3H,s), 3.12(4H,t), 3.97(3H,s), 4.05(4H,t), 6.87(1H,d), 7.05(1H,brs), 7.13(2H,m) 1 H NMR (CDCl 3 ): δ 2.35 (3H, s), 2.36 (3H, s), 2.43 (3H, s), 3.12 (4H, t), 3.97 (3H, s), 4.05 (4H, t) , 6.87 (1H, d), 7.05 (1H, brs), 7.13 (2H, m)

실시예 34) 1-[(5,6-다이에틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진Example 34) 1-[(5,6-Diethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine

페닐 N-(5,6-다이에틸-2-메톡시피라진-3-일)카바메이트와 1-(3,5-다이메틸페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (5,6-diethyl-2-methoxypyrazin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 1. .

수율 : 77.5%Yield: 77.5%

융점 : 118∼120℃Melting Point: 118 ~ 120 ℃

1H NMR(CDCl3) : δ 1.26(6H,m), 2.30(6H,s), 2.70(2H,t), 2.78(2H,t), 3.25(4H,t), 3.74(4H,t), 3.99(3H,s), 6.65(3H,m) 1 H NMR (CDCl 3 ): δ 1.26 (6H, m), 2.30 (6H, s), 2.70 (2H, t), 2.78 (2H, t), 3.25 (4H, t), 3.74 (4H, t) , 3.99 (3H, s), 6.65 (3H, m)

실시예 35) 1-[(5,6-다이에틸-2-메톡시피라진-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진Example 35) 1-[(5,6-diethyl-2-methoxypyrazin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine

페닐 N-(5,6-다이에틸-2-메톡시피라진-3-일)카바메이트와 1-(3,5-다이메톡시페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The above compound was reacted with phenyl N- (5,6-diethyl-2-methoxypyrazin-3-yl) carbamate and 1- (3,5-dimethoxyphenyl) piperazine in the same manner as in Example 1. Got.

수율 : 78.9%Yield: 78.9%

융점 : 90∼92℃Melting Point: 90 ~ 92 ℃

1H NMR(CDCl3) : δ 1.24(6H,m), 2.69(2H,t), 2.78(2H,t), 3.24(4H,t), 3.71(4H,t), 3.78(6H,s), 3.98(3H,s), 6.07(1H,s), 6.11(2H,brs) 1 H NMR (CDCl 3 ): δ 1.24 (6H, m), 2.69 (2H, t), 2.78 (2H, t), 3.24 (4H, t), 3.71 (4H, t), 3.78 (6H, s) , 3.98 (3H, s), 6.07 (1H, s), 6.11 (2H, brs)

상기와 같이 제조한 본 발명의 화합물들의 항암 약리 활성을 시험하였다. 본 발명의 화합물의 항암 활성은 시험관내(in vitro) 법에 의하여 5가지의 인간종양세포계(Human tumor cell line)와 2가지의 백혈병세포계(leukemia tumor cell line)을 사용하여 각각 시험하였다. 그 결과를 다음 표에 나타내었다. 시험관내시험(in vitro test) 방법은 다음와 같다.The anticancer pharmacological activity of the compounds of the present invention prepared as described above was tested. The anticancer activity of the compounds of the present invention was tested using five human tumor cell lines and two leukemia tumor cell lines by in vitro methods. The results are shown in the following table. The in vitro test method is as follows.

실험예 1)Experimental Example 1

* 인간종양세포계(Human tumor cell lines)에 대한 in vitro 항암효과* In vitro anticancer effect on human tumor cell lines

가. Tumor cell line : A549 (human non-small lung cell)end. Tumor cell line: A549 (human non-small lung cell)

SKOV-3 (human ovarian)SKOV-3 (human ovarian)

HCT-15 (human colon)HCT-15 (human colon)

XF-498 (human CNS)XF-498 (human CNS)

SKMEL-2 (human melanoma)SKMEL-2 (human melanoma)

나. 실험방법 (SRB Assay Method)I. SRB Assay Method

a. 인간고형암세포계(Human solid tumor cell lines)인 A549(non-small lung cell), SKMEL-2 (melanoma), HCT-15(colon), SKOV-3(ovarian), XF-498(CNS)등은 10% FBS가 포함된 RPMI 1640배지를 사용하여 37oC, 5% CO2인큐베이터 (incubator)에서 배양하였으며 계대는 1주일에 1-2회 실시하였다. 세포들은 부착면으로부터 분리할 때는 0.25% 트립신(Trysin) 및 3mM CDTA PBS(-)에 녹인 용액을 사용하였다.a. Human solid tumor cell lines A549 (non-small lung cell), SKMEL-2 (melanoma), HCT-15 (colon), SKOV-3 (ovarian), XF-498 (CNS), etc. RPMI 1640 medium containing% FBS was incubated in 37 ° C., 5% CO 2 incubator and passages were performed 1-2 times a week. Cells used a solution dissolved in 0.25% Trysin and 3 mM CDTA PBS (-) when detached from the adhesion surface.

b. 96 웰플레이트(well plate : Nunc)의 각 웰에 5×103-2×104cells을 가하여 37oC, 5% CO2인큐베이터에서 24시간 배양하였다.b. 5 x 10 3 -2 x 10 4 cells were added to each well of a 96 well plate (Nunc) and incubated in a 37 ° C., 5% CO 2 incubator for 24 hours.

c. 각종 약물들은 소량의 DMSO에 녹여 시험에 원하는 농도까지 실험용 배지로써 희석하여 최종 DMSO 농도는 0.5%이하가 되도록 하였다.c. Various drugs were dissolved in a small amount of DMSO and diluted with the experimental medium to the desired concentration for the test so that the final DMSO concentration was less than 0.5%.

d. 상기 b. 항의 24시간 배양시킨 각 well의 배지를 모두 흡인(aspiration)하여 제거한 후, c. 항에서 제조한 약물들을 각 웰에 200㎕씩 가한 후 48시간 배양하였다. 약물을 가하는 시점에서 Tz(Time zero) 플레이트를 수집(Collection)하였다.d. B. After aspiration of all the culture medium of each well incubated for 24 hours, and c. Drugs prepared in the paragraph was added to each well 200μl and incubated for 48 hours. Tz (Time zero) plates were collected at the time of drug addition.

e. Tz plates 및 각 배양이 끝난 플레이트는 SRB 검정법(assay)에 TCA에 의한 세포고정(cell fixing), 0.4% SRB 용액으로 염색(staining), 1% 아세트산(acetic acid)으로써 세척한 후 10mM 트리스(Tris)용액으로 염료(dye)를 용출(elution)시켜 520nM에서 OD 값을 측정하였다.e. Tz plates and each incubated plate were cell fixed by TCA in an SRB assay, stained with 0.4% SRB solution, washed with 1% acetic acid, and then washed with 10 mM Tris. Dye was eluted with the solution to measure the OD value at 520 nM.

다. 결과 계산All. Calculate the result

a. 약물을 가하여 배양을 시작하는 시간에 수집하여 SRB 프로틴 양의 값을 구하여 Time zero(Tz)로 하였다.a. The drug was added at the beginning of incubation and the SRB protein amount was determined to be Time zero (Tz).

b. 약물을 가하지 않고 세포만 있던 웰의 OD 값을 control value(C)라 하였다.b. The OD value of the cell-only well without adding the drug was called control value (C).

c. 약물을 처리한 웰의 OD 값을 약물처리값(drug-treated test value : T)이라 하였다.c. The OD value of the drug-treated well was called a drug-treated test value (T).

d. Tz, C와 T로부터 growth stimulation, net growth inhibition 및 net killing등으로 약물의 효과를 판단할 수 있었다.d. From Tz, C and T, the effects of drugs could be determined by growth stimulation, net growth inhibition and net killing.

e. 만약 T≥Tz일 경우에는 그 cellular response function은 100×(T-Tz)/(C-Tz)이며, T〈Tz 일 경우에는 100×(T-Tz)/Tz로써 계산하였다. 그 결과를 다음 표에 나타내었다.e. If T≥Tz, the cellular response function is 100 × (T-Tz) / (C-Tz), and if T <Tz, it was calculated as 100 × (T-Tz) / Tz. The results are shown in the following table.

*참고문헌*references

1)P.Skehan, R.Strong, D.Scudiero, A.Monks, J.B.Mcmahan, D.T.Vistica, J.Warren, H.Bokesch, S.Kenney and M.R.Boyd. ; Proc. Am. Assoc. Cancer Res., 30, 612 (1989).1) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. ; Proc. Am. Assoc. Cancer Res., 30, 612 (1989).

2)L.V.Rubinstein, R.H.Shoemaker, K.D.Paull, R.M.Simon, S.Tosini, P.Skehan, D.Scudiero, A.Monks and M.R.Boyd. ; J. Natl. Cancer Inst., 82, 1113 (1990)2) L. V. Rubinstein, R. H. Shoemaker, K. D. Paul, R. M. Simon, S. Tosini, P. Skehan, D. Scudiero, A. Monks and M. R. Boyd. ; J. Natl. Cancer Inst., 82, 1113 (1990)

3)P.Skehan, R.Strong, D.Scudiero, A.Monks, J.B.Mcmahan, D.T.Vistica, J.Warren, H.Bokesch, S.Kenney and M.R.Boyd. ; J. Natl. Cancer Inst., 82, 1107 (1990)3) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. ; J. Natl. Cancer Inst., 82, 1107 (1990)

라. 결과la. result

대조약물인 시스플라틴(Cisplatin)보다 모든 화합물이 동등이상의 항암효과가 인체 고형암에서 관찰되었다.Anti-cancer effect of all compounds was higher than that of the control drug, cisplatin, in human solid cancer.

ED50=㎍/㎖ED 50 = µg / ml 실시예 번호Example number A 549A 549 SK-OV-3SK-OV-3 SK-MEL-2SK-MEL-2 XF-498XF-498 HCT 15HCT 15 22 0.0320.032 0.0880.088 0.0290.029 0.0840.084 0.0190.019 33 0.00160.0016 0.00640.0064 0.00150.0015 0.00220.0022 0.00200.0020 44 0.0470.047 0.2510.251 0.0420.042 0.0890.089 0.0380.038 77 0.00240.0024 0.00720.0072 0.00230.0023 0.00270.0027 0.00280.0028 1212 0.0080.008 0.0690.069 0.0080.008 0.0170.017 0.0010.001 1414 0.2040.204 0.6770.677 0.2830.283 0.3400.340 0.0670.067 1515 0.0790.079 0.1840.184 0.0380.038 0.0960.096 0.0710.071 1919 0.00640.0064 0.1430.143 0.0430.043 0.0930.093 0.0800.080 2020 0.3230.323 0.9040.904 0.2110.211 0.9700.970 0.2950.295 2121 0.0380.038 0.0930.093 0.0240.024 0.0970.097 0.0080.008 2828 0.00010.0001 0.00060.0006 〈0.0001<0.0001 0.00010.0001 0.00010.0001 3030 0.00060.0006 0.00070.0007 〈0.0001<0.0001 0.00050.0005 0.00070.0007 3434 0.00230.0023 0.00380.0038 0.00030.0003 0.00210.0021 0.00210.0021 3535 0.00010.0001 0.00070.0007 〈0.0001<0.0001 0.00010.0001 0.00010.0001 CisplatinCisplatin 0.910.91 1.321.32 0.870.87 0.770.77 3.173.17

실험예2)Experimental Example 2)

* 동물 백혈병세포(leukemia cell)에 대한 시험관내(in vitro) 항암효과* In vitro anticancer effect on animal leukemia cells

가. 실험재료end. Experimental material

Tumor Cell Lines : P388 (mouse의 lymphoid neoplasma cell)Tumor Cell Lines: P388 (mouse lymphoid neoplasma cell)

나. 실험방법 (Dye Exclusion Assay)I. Dye Exclusion Assay

1) 10% FBS를 포함한 RPMI 1640배지에서 배양하고 있는 P388 cells를 1×106cells/ml의 농도로 조절하였다.1) P388 cells incubated in RPMI 1640 medium containing 10% FBS were adjusted to a concentration of 1 × 10 6 cells / ml.

2) Log dose로 희석된 각 농도의 약물을 각각 가하고 37℃, 5% CO2인큐베이터에서 배양하여 48시간에 생존세포수(viable cell number)를 측정하였다. 생존세포수(viable cell number)는 트리판블루(trypan blue)를 이용하여 염료방출시험(dye exclusion test)을 실시하여 측정하였다.2) Each drug of each concentration diluted to a log dose was added and cultured in a 37 ° C., 5% CO 2 incubator to measure viable cell numbers at 48 hours. Viable cell numbers were measured by dye exclusion test using trypan blue.

3) 측정된 세포수(cell number)로부터 대조군(control)에 비하여 50% 세포성장억제(cell growth inhibition)을 나타내는 각 화합물의 농도(IC50)를 산출하였다. 그 결과를 다음 표에 나타내었다.3) From the measured cell number, the concentration of each compound (IC 50 ) showing 50% cell growth inhibition compared to the control was calculated. The results are shown in the following table.

*참고문헌*references

1)P.Skehan, R.Strong, D.Scudiero, A.Monks, J.B.Mcmahan, D.T.Vistica, J.Warren, H.Bokesch, S.Kenney and M.R.Boyd. ; Proc. Am. Assoc. Cancer Res., 30, 612 (1989).1) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. ; Proc. Am. Assoc. Cancer Res., 30, 612 (1989).

2)L.V.Rubinstein, R.H.Shoemaker, K.D.Paull, R.M.Simon, S.Tosini, P.Skehan, D.Scudiero, A.Monks and M.R.Boyd. ; J. Natl. Cancer Inst., 82, 1113 (1990)2) L. V. Rubinstein, R. H. Shoemaker, K. D. Paul, R. M. Simon, S. Tosini, P. Skehan, D. Scudiero, A. Monks and M. R. Boyd. ; J. Natl. Cancer Inst., 82, 1113 (1990)

3)P.Skehan, R.Strong, D.Scudiero, A.Monks, J.B.Mcmahan, D.T.Vistica, J.Warren, H.Bokesch, S.Kenney and M.R.Boyd. ; J. Natl. Cancer Inst., 82, 1107 (1990)3) P. Skehan, R. Strong, D. Scudiero, A. Monks, J. B. Mcmahan, D. T. Vistica, J. Warren, H. Bokesch, S. Kenney and M. R. Boyd. ; J. Natl. Cancer Inst., 82, 1107 (1990)

다. 결과All. result

본 발명의 화합물들은 P388 마우스 백혈병 세포(mouse leukemia cell)에 대한 항암효과를 측정한 결과 표에 있는 모든 화합물에서 대조약물 미토마이이신(mitomycin) C보다 동등 이상의 항암효과를 보였다.Compounds of the present invention measured the anticancer effect on P388 mouse leukemia cells, all of the compounds in the table showed an anticancer effect equal to or higher than the control drug mitomycin C.

실시예 번호Example number P388P388 실시예 번호Example number P388P388 22 0.30.3 2020 1.21.2 33 0.010.01 2121 0.80.8 77 0.020.02 2828 0.040.04 1111 0.020.02 3030 0.070.07 1212 0.10.1 3434 0.140.14 1515 0.700.70 3535 0.010.01 1919 0.20.2 Mitomycin CMitomycin C 1.11.1

실험예 3)Experimental Example 3)

* 급성 독성실험(LD50)* Acute Toxicity Test (LD 50 )

가. 실험방법: 리치필드-윌콕슨 방법end. Test Method: Richfield-Wilcoxon Method

6주령된 ICR 마우스(수컷 30±2.0g)을 구입하여 실험전에 실온 23±1oC, 습도 60±5%의 조건에서 고형사료 및 물을 자유롭게 섭취시켰다. 실험동물을 군당 6마리씩 사용하여 약물을 복강내에 투여하여, 14일간 외견상태와 생사여부를 기록하였고, 폐사동물은 부검하여 육안적 병변을 관찰하였다. LD50값을 리치필드-윌콕슨법에 의해 구하였다.Six-week-old ICR mice (30 ± 2.0 g males) were purchased and freely fed solid feed and water at room temperature 23 ± 1 ° C. and 60 ± 5% humidity. Drugs were administered intraperitoneally using 6 animals per group, and the appearance and live death were recorded for 14 days. The mortality was examined by necropsy. LD 50 value was calculated | required by the Richfield-Wilcoxon method.

나. 결과I. result

본 발명의 화합물들은 급성독성에 있어서 시스플라틴(Cisplatin)보다 안전성이 월등하여 투약량의 제한, 독성에 있어서 선행기술의 화합물들이 지니고 있는 문제점을 상당한 수준까지 극복하는 것을 확인하였다.The compounds of the present invention have been found to overcome the problems of the prior art compounds in limiting dose and toxicity in terms of safety because they are superior to cisplatin in acute toxicity.

실시예 번호Example number LD50(㎎/㎏)LD 50 (mg / kg) i.p.i.p. i.v.i.v. 77 7575 CisplatinCisplatin 9.79.7

본 발명의 화합물은 항암효과가 우수하여 항암치료에 큰 효과가 있을 것으로 기대되며, 독성이 적어 안전성이 월등하여 투약량의 제한, 독성에 있어서 선행기술의 화합물들이 지니고 있는 문제점을 상당한 수준까지 극복하였다.The compound of the present invention is expected to have a great effect in anti-cancer treatment because it is excellent in anticancer effect, it has a low safety and superior safety to overcome the problems of the compounds of the prior art in limiting the dose, toxicity.

Claims (2)

다음의 화학식 (I)로 표시되는 화합물 또는 그 약학적으로 허용되는 산부가염.The compound represented by following formula (I) or its pharmaceutically acceptable acid addition salt. 1 One ( I )(I) 식중, R1, R2, R3, R4, R5및 R6은 각각 수소원자, 할로겐원자, 하이드록시기, 니트로기, 아미노기, C1∼C4의 저급 알킬기, C1∼C4의 저급 에스테르기, 치환 또는 비치환의 C3∼C8의 불포화 알킬기, C3∼C8의 치환 또는 비치환의 3∼6 원의 사이클로 알킬기, C1∼C4의 저급 알콕시기, C1∼C4의 저급 티오알콕시기, 치환 또는 비치환의 저급 알킬아미노기이며, R7및 R8는 수소원자, C1∼C4의 저급 알킬기 또는 케톤기 또는 C1∼C4의 저급 알킬하이드록시기이다. Y는 산소원자 또는 황원자, Z는 수소원자, 하이드록시기, C1∼C8의 저급 알콕시기, C1∼C4의 저급 알킬기, C1∼C4의 저급 티오알콕시기이다.Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, a C 1 -C 4 lower alkyl group, C 1 -C 4 a lower alkoxy lower ester group, a substituted or unsubstituted C 3 ~C 8 unsaturated alkyl, C 3 ~C 8 cycloalkyl group substituted or unsubstituted 3~6 circle, C 1 ~C 4 of the group, a C 1 ~C 4, a lower thioalkoxy group, a substituted or unsubstituted lower alkyl group of, R 7 and R 8 is a lower alkyl, a hydroxyl group of a hydrogen atom, C 1 ~C 4 lower alkyl group or a ketone group or a C 1 ~C 4 of. Y is an oxygen atom or a sulfur atom, Z is a lower alkoxy of hydrogen atom, hydroxyl group, C 1 ~C 8 lower alkoxy groups, C 1 ~C 4 lower alkyl group, C 1 ~C 4 of the group. 다음 화학식(2)의 화합물을 통상의 유기용매 존재하에서 -C(=Y)- 공여시약과 반응시켜 다음 화학식(3)의 화합물을 제조하고, 상기의 화학식(3)을 다음의 화학식(4)의 화합물과 반응시켜서 화학식(5)의 화합물을 제조하고, 화학식(5)의 화합물과 알킬화제 또는 아릴화제를 염기하에서 반응시켜 화학식(I)의 화합물 또는 그 산부가염을 제조하는 방법.The compound of formula (2) is reacted with a -C (= Y) -donating reagent in the presence of a conventional organic solvent to prepare a compound of formula (3), wherein formula (3) is A method of preparing a compound of formula (5) by reacting a compound of formula (5) with a compound of formula (5) and an alkylating or arylating agent under a base to produce a compound of formula (I) or an acid addition salt thereof. 식중, R1, R2, R3, R4, R5및 R6은 각각 수소원자, 할로겐원자, 하이드록시기, 니트로기, 아미노기, C1∼C4의 저급 알킬기, C1∼C4의 저급 에스테르기, 치환 또는 비치환의 C3∼C8의 불포화 알킬기, C3∼C8의 치환 또는 비치환의 3∼6 원의 사이클로 알킬기, C1∼C4의 저급 알콕시기, C1∼C4의 저급 티오알콕시기, 치환 또는 비치환의 저급 알킬아미노기이며, R7및 R8는 수소원자, C1∼C4의 저급 알킬기 또는 케톤기 또는 C1∼C4의 저급 알킬하이드록시기이다. Y는 산소원자 또는 황원자, Z는 수소원자, 하이드록시기, C1∼C8의 저급 알콕시기, C1∼C4의 저급 알킬기, C1∼C4의 저급 티오알콕시기이다.Wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 each represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, an amino group, a C 1 -C 4 lower alkyl group, C 1 -C 4 a lower alkoxy lower ester group, a substituted or unsubstituted C 3 ~C 8 unsaturated alkyl, C 3 ~C 8 cycloalkyl group substituted or unsubstituted 3~6 circle, C 1 ~C 4 of the group, a C 1 ~C 4, a lower thioalkoxy group, a substituted or unsubstituted lower alkyl group of, R 7 and R 8 is a lower alkyl, a hydroxyl group of a hydrogen atom, C 1 ~C 4 lower alkyl group or a ketone group or a C 1 ~C 4 of. Y is an oxygen atom or a sulfur atom, Z is a lower alkoxy of hydrogen atom, hydroxyl group, C 1 ~C 8 lower alkoxy groups, C 1 ~C 4 lower alkyl group, C 1 ~C 4 of the group.
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KR100739233B1 (en) * 2004-11-17 2007-07-13 한국화학연구원 1-[3-Alkoxy-6-substituted-quinoxalin-2-ylaminocarbonyl]-4-heteroarylpiperazine Derivatives

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100739233B1 (en) * 2004-11-17 2007-07-13 한국화학연구원 1-[3-Alkoxy-6-substituted-quinoxalin-2-ylaminocarbonyl]-4-heteroarylpiperazine Derivatives

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