KR100204319B1 - Novel piperazine derivatives and their preparation method - Google Patents
Novel piperazine derivatives and their preparation method Download PDFInfo
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- KR100204319B1 KR100204319B1 KR1019970022985A KR19970022985A KR100204319B1 KR 100204319 B1 KR100204319 B1 KR 100204319B1 KR 1019970022985 A KR1019970022985 A KR 1019970022985A KR 19970022985 A KR19970022985 A KR 19970022985A KR 100204319 B1 KR100204319 B1 KR 100204319B1
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- 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
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- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
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- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
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- 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
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
본 발명은 다음의 일반구조식 (I)로 표시되는 화합물 및 그 제약학적으로 허용되는 산 부가염에 관한 것이다.The present invention relates to a compound represented by the following general formula (I) and a pharmaceutically acceptable acid addition salt thereof.
[일반구조식 1][General Structural Formula 1]
R3, R4, R5, R6, R7및 R8은 각각 수소원자, 할로겐원자, 하이드록시기, 니트로기, C1-C4의 저급에스테르기, C1-C4의 저급알킬기, C3-C8의 치환 또는 비치환의 3-6원의 사이클로알킬기, C1-C4의 저급알콕시기, C1-C4의 저급티오알콕시기, 치환 또는 비치환의 아릴기, 치환 또는 비치환의 아릴저급알콕시기, 치환 또는 비치환의 저급알킬아미노기, 또는 저급알킬치환 또는 비치환의 카바메이트기이며, X는 산소원자, 유황원자, 치환 또는 비치환의 아민기이며, Z는 수소원자, 하이드록시기, C1-C4의 저급알콕시기, C1-C4의 저급티오알콕시기, 치환된 아릴옥시기, C1-C4의 저급알킬아민기, 질소원자 1 내지 5개까지를 함유할 수 있는 환상아민기, 치환된 피리딘기 그리고 치환된 티오펜기 등을 의미한다. R 3, R 4, R 5 , R 6, R 7 and R 8 are each a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a lower ester of a C 1 -C 4, a lower alkyl group of C 1 -C 4 , a substituted C 3 -C 8 cycloalkyl or unsubstituted 3-6 circle alkyl group, a lower thioalkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkoxy group of C 1 -C 4, C 1 -C 4 An aryl lower alkoxy group of a ring, a substituted or unsubstituted lower alkylamino group, or a lower alkyl substituted or unsubstituted carbamate group, X is an oxygen atom, a sulfur atom, a substituted or unsubstituted amine group, Z is a hydrogen atom, a hydroxy group , C 1 -C 4 lower alkoxy group, C 1 -C 4 lower thioalkoxy group, substituted aryloxy group, C 1 -C 4 lower alkylamine group, may contain up to 1 to 5 nitrogen atoms Cyclic amine group, substituted pyridine group and substituted thiophene group.
본 발명에 따른 화합물은 탁월한 항암활성을 가지며 그 독성이 매우 낮아 항암제로서 우수한 효과가 기대된다.The compound according to the present invention has excellent anticancer activity and its low toxicity is expected to be an excellent anticancer agent.
Description
본 발명은 다음 일반구조식 (I)로 표시되는 신규 피페라진유도체 및 그 제조방법에 관한 것이다.The present invention relates to a novel piperazine derivative represented by the following general structural formula (I) and a preparation method thereof.
[일반구조식 1][General Structural Formula 1]
R3, R4, R5, R6, R7및 R8은 각각 수소원자, 할로겐원자, 하이드록시기, 니트로기, C1-C4의 저급에스테르기, C1-C4의 저급알킬기, C3-C8의 치환 또는 비치환의 3-6원의 사이클로알킬기, C1-C4의 저급알콕시기, C1-C4의 저급티오알콕시기, 치환 또는 비치환의 아릴기, 치환 또는 비치환의 아릴저급알콕시기, 치환 또는 비치환의 저급알킬아미노기, 또는 저급알킬치환 또는 비치환의 카바메이트기이며, X는 산소원자, 유황원자, 치환 또는 비치환의 아민기이며, Z는 수소원자, 하이드록시기, C1-C4의 저급알콕시기, C1-C4의 저급티오알콕시기, 치환된 아릴옥시기, C1-C4의 저급알킬아민기, 질소원자 1 내지 5개까지를 함유할 수 있는 환상아민기, 치환된 피리딘기 그리고 치환된 티오펜기 등을 의미한다. R 3, R 4, R 5 , R 6, R 7 and R 8 are each a hydrogen atom, a halogen atom, a hydroxyl group, a nitro group, a lower ester of a C 1 -C 4, a lower alkyl group of C 1 -C 4 , a substituted C 3 -C 8 cycloalkyl or unsubstituted 3-6 circle alkyl group, a lower thioalkoxy group, a substituted or unsubstituted aryl group, a substituted or unsubstituted lower alkoxy group of C 1 -C 4, C 1 -C 4 An aryl lower alkoxy group of a ring, a substituted or unsubstituted lower alkylamino group, or a lower alkyl substituted or unsubstituted carbamate group, X is an oxygen atom, a sulfur atom, a substituted or unsubstituted amine group, Z is a hydrogen atom, a hydroxy group , C 1 -C 4 lower alkoxy group, C 1 -C 4 lower thioalkoxy group, substituted aryloxy group, C 1 -C 4 lower alkylamine group, may contain up to 1 to 5 nitrogen atoms Cyclic amine group, substituted pyridine group and substituted thiophene group.
퀴놀린환에 결합된 N-치환체는 3-위치 또는 4-위치에 결합되며, 3-위치에 결합된 경우는 다음 일반구조식 (I)'로 표시되며, 4-위치에 결합된 경우는 다음 일반구조식 (I)로 표시된다.The N-substituent bonded to the quinoline ring is bonded to 3-position or 4-position, and when bonded to 3-position is represented by the following general structural formula (I) ', and when bonded to 4-position, the following general structural formula It is represented by (I).
[일반구조식 1'][General structure 1 ']
[일반구조식 1][General Structural Formula 1]
C1-C4의 저급알킬기란 메틸, 에틸, 프로필, 이소프로필, n-부틸, 이소부틸, t-부틸을 의미한다.Lower alkyl group of C 1 -C 4 means methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl.
C3-C8의 치환 또는 비치환의 3-6원의 사이클로알킬기란 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로프로필메틸, 사이클로부틸메틸, 사이클로펜틸, 사이클로헥실메틸, 치환사이클로프로필, 치환사이클로펜틸, 치환사이클로헥실 등과 같은 치환 또는 비치환의 사이클로알킬기를 의미한다.C 3 -C 8 substituted or unsubstituted 3-6 membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentyl, cyclohexylmethyl, substituted cyclopropyl, substituted It means a substituted or unsubstituted cycloalkyl group, such as cyclopentyl, substituted cyclohexyl and the like.
C1-C4의 저급에스테르기란 카르복실기가 저급알킬기에 의하여 에스테르화된기를 의미한다.The lower ester group of C 1 -C 4 means a group in which a carboxyl group is esterified by a lower alkyl group.
C1-C4의 저급알콕시란 메톡시, 에톡시, 프로폭시, 이소프로폭시, 부톡시, 이소부톡시, t-부톡시기를 말한다.Lower alkoxy of C 1 -C 4 refers to a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy group.
C1-C4의 저급티오알콕시란 티오메톡시, 티오에톡시, 티오프로폭시, 티오이소프로폭시, 티오부톡시, 티오이소부톡시, 티오-t-부톡시기를 말한다.Lower thioalkoxy of C 1 -C 4 refers to a thiomethoxy, thioethoxy, thiopropoxy, thioisopropoxy, thiobutoxy, thioisobutoxy, or thio-t-butoxy groups.
치환된 아릴옥시기란 페녹시기, 치환페녹시기, 나프틸옥시기, 또는 치환나프틸 옥시기를 의미한다.Substituted aryloxy group means a phenoxy group, a substituted phenoxy group, a naphthyloxy group, or a substituted naphthyl oxy group.
C1-C4의 저급알킬아민기란 메틸아민, 에틸아민, 프로필아민, 부틸아민기를 의미한다.The lower alkylamine group of C 1 -C 4 means a methylamine, ethylamine, propylamine, or butylamine group.
질소원자 1 내지 5개까지를 함유할 수 있는 환상아민기란 피롤리딘닐기, 피롤리닐기, 이미다졸릴기, 이미다졸리디닐기, 피라졸기, 피라졸리닐기, 피라졸리디닐기, 트리아졸릴기, 테트라졸릴기, 피페라지닐기 등을 의미한다.The cyclic amine group which may contain from 1 to 5 nitrogen atoms is pyrrolidinyl group, pyrrolidinyl group, imidazolyl group, imidazolidinyl group, pyrazole group, pyrazolinyl group, pyrazolidinyl group, triazolyl group , Tetrazolyl group, piperazinyl group and the like.
피리딘의 치환기는 메틸, 에틸, 프로필, 부틸 등과 같은 저급알킬기 및 치환아릴기 등을 의미한다.Substituents of pyridine mean lower alkyl groups such as methyl, ethyl, propyl, butyl and the like and substituted aryl groups.
티오펜의 치환기는 메틸, 에틸, 프로필, 부틸 등과 같은 저급알킬기 및 치환아릴기 등을 의미한다Substituent of thiophene means lower alkyl groups, such as methyl, ethyl, propyl, butyl, and substituted aryl groups, etc.
본 발명자들은 항암활성을 가지는 화합물에 관하여 오랫동안 연구하여 왔다. 그 결과 본 발명자들은 일반구조식 (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 the surprising fact that the compound of the general formula (I), its acid addition salts have an excellent anticancer effect, and extremely low toxicity, and completed the present invention.
따라서 본 발명의 목적은 탁월한 항암효과를 가지며 독성이 적은 일반구조식 (I)의 화합물 및 그 산부가염을 제공하는 것이다.It is therefore an object of the present invention to provide compounds of general formula (I) and acid addition salts thereof having excellent anticancer effects and low toxicity.
본 발명의 다른 목적은 일반구조식 (I)의 화합물 및 그 산부가염을 제조하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method of preparing a compound of the general formula (I) and an acid addition salt thereof.
본 발명의 화합물들은 약학적으로 허용되는 부형제 등과 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 which are commonly used in combination with pharmaceutically acceptable excipients and the like.
그러므로 본 발명의 또 다른 목적은 일반구조식 (I)의 화합물을 유효성분으로 함유하는 약학적 제제를 제공하는 것이다.It is therefore another object of the present invention to provide a pharmaceutical formulation containing the compound of the general 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, 말레익산, 말론산 등과 같은 유기산 ; 세린, 시스테린, 시트틴, 아스파라긴산, 글루타민산, 리진, 아르기닌, 파이로신, 프롤린 등과 같은 아미노산; 메탄설폰산, 에탄설폰산, 벤젠설폰산, 톨루엔설폰산 등과 같은 설폰산등이 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, and 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, cysteine, citin, aspartic acid, glutamic acid, 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 일반구조식 (I)의 화합물을 유효성분으로 함유하는 약학적 제제의 제조에 부형제로 사용될 수 있는 부형제로는 감미제, 결합제, 용해제, 용해보조제, 습융제, 유화제, 등장화제, 흡착제, 붕해제, 산화방지제, 방부제, 활택제, 충진제, 방향제등이 사용될 수 있으며, 예를 들면, 락토스, 덱스트로스, 슈크로스, 만니톨, 솔미톨, 셀룰로오스, 글라이신, 실리카, 탈크, 스테아린산, 스테린, 트리가칸트 고무, 메틸셀룰로오스, 소디움카르복실메틸셀룰로오스, 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 compounds of the general formula (I) as an active ingredient in the present invention include sweeteners, binders, solubilizers, dissolution aids, humectants, emulsifiers, isotonic agents, adsorbents, boric acid. Releases, antioxidants, preservatives, glidants, fillers, fragrances and the like can be used, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, tri Gancan rubber, methyl cellulose, sodium carboxymethyl cellulose, agar, alginate, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, potassium chloride, orange essence, strawberry essence, vanilla scent, and the like. .
본 발명의 일반구조식 (I)의 화합물의 상용량은 환자의 나이, 성별, 질병의 정도 등에 따라서 달라질 수 있으나, 일일 1㎎ 내지 5000㎎을 일회 내지 수 회 투여할 수 있다.The usual dose of the compound of the general 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 발명의 일반구조식 (I)의 화합물은 다음의 스킴 1에 의하여 제조될 수 있다.Compounds of the general formula (I) of the present invention can be prepared by the following scheme 1.
[스킴1][Scheme 1]
상기식에서 R3, R4, R5, R6, R7, R8, X, Z은 전술한 바와 같다.In the above formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Z are as described above.
기존의 공지 방법으로 합성한 구조식 (2) 화합물에 -C(=X)-기 공여시약의 존재하에 반응시켜 화합물(3)을 효과적으로 얻은 후, 연속하여 기존의 방법으로 합성한 화합물(4)과 반응시켜 일반 화합물(5)을 효과적으로 제조한다. 그리고 알킬, 아릴화제를 염기하에서 반응시켜 일반주조식 (I)을 제조한다.Compound (3) was effectively reacted with a compound of formula (2) synthesized by a conventionally known method in the presence of a -C (= X) -group donor reagent to effectively obtain compound (3), and then compound (4) synthesized by a conventional method continuously Reaction to effectively prepare general compound (5). Then, general casting formula (I) is prepared by reacting alkyl and arylating agents under a base.
-C(=X)-기 공여시약으로는 1,1-카르보닐디이미다졸, 1,1-카르보닐티오디이미다졸, 포스겐, 티오포스겐, 카르보닐디페녹시드, 페닐클로로포메이트 등을 사용한다.Examples of the -C (= X) -group donor reagent include 1,1-carbonyldiimidazole, 1,1-carbonylthiodiimidazole, phosgene, thiophosgen, carbonyldiphenoxide, phenylchloroformate and the like. use.
이 반응은 통상의 유기용매, 예를들면 테트라하이드로퓨란, 디클로로메탄, 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 3℃ 내지 용매의 비점온도에서, 바람직하게는 50℃에서 100℃까지 5시간 내지 48시간, 바람직하게는 10-24시간 반응시킨다.The reaction is carried out at a boiling point temperature of 3 ° C. to the solvent, preferably from 50 ° C. to 100 ° C. for 5 hours to 48 hours, preferably 10-24 hours.
-C(=X)-기 공여시약의 사용량은 1-1.5당량, 바람직하게는 1-1.1당량을 사용한다.The amount of -C (= X) -donating reagent used is 1-1.5 equivalents, preferably 1-1.1 equivalents.
화합물(3)에서 화합물(4)과 결합하여 일반구조식(5)를 제조하는 경우에 있어서, 이 반응은 바람직하게 50℃에서 100℃까지 5시간 내지 48시간 반응시킨다. 화합물(4)의 사용량은 1에서 1.5당량을 사용한다.In the case of preparing General Structural Formula (5) by combining with Compound (4) in Compound (3), the reaction is preferably reacted for 5 hours to 48 hours from 50 ° C to 100 ° C. 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 화합물을 알킬, 아릴화제를 염기하에서 반응시켜 일반구조식 (I)을 효과적으로 제조한다.General compound (I) is efficiently prepared by reacting a compound of general compound (5) with an alkyl or an arylating agent under a base.
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 agents of this reaction are C 1 -C 8 lower alkylhalogens, C 1 -C 8 lower alkyl sulfonates, C 3 -C 8 substituted or unsubstituted cycloalkylhalogens, arylhalogens, 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.C 1 -C 8 lower alkylhalogen is 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, bromide Pentane, pentane iodide, bromo ethyl acetate, etc. are mentioned.
C1-C8의 저급알킬 설포네이트이란 메틸설포네이트, 에틸설포네이트, 프로필설포네이트, 부틸설포네이트, 펜틸설포네이트 등을 말한다.Lower alkyl sulfonates of C 1 -C 8 refer to methylsulfonate, ethylsulfonate, propylsulfonate, butylsulfonate, pentylsulfonate and the like.
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.Substituted or unsubstituted cycloalkylhalogen of C 3 -C 8 is cyclopropane chloride, cyclopropane bromide, cyclopropane iodide, cyclobutane chloride, cyclobutane bromide, cyclobutane iodide, cyclopentane chloride, cyclopentane chloride, 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.Substituted or unsubstituted cycloalkylsulfonates of C 3 -C 8 are cyclopropyl sulfonate, cyclobutyl sulfonate, cyclopentyl sulfonate, cyclohexyl sulfonate, methylcyclopropyl sulfonate, methylcyclobutyl sulfonate, methylcyclopentyl 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, 예를들면 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 알칼리토금 속의 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 materials include hydroxides in alkali metals or alkaline earth, 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. Oxides, carbonates or bicarbonates; And in the presence of a base of an organic amine family.
일반구조식(2), (4)의 화합물은 공지의 화합물, J. Med. Chem., 35, 3792(1992) 등에 기술되어 있거나 또는 이와 유사한 방법으로 제조하여 사용될 수 있다.Compounds of the general formulas (2) and (4) are known compounds, J. Med. Chem., 35, 3792 (1992), or the like, or prepared and used in a similar manner.
[실시예]EXAMPLE
상기 기술된 방법에 따라서 다음 화합물들을 제조하였다.The following compounds were prepared according to the method described above.
[일반화합물 5][General Compound 5]
[일반구조식 1][General Structural Formula 1]
상기식에서 R3, R4, R5, R6, R7, R8, X, Z은 전술한 바와 같다.In the above formula, R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , X, Z are as described above.
[실시예 1]Example 1
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine
a) 페닐 N-(2-메톡시퀴놀린-3-일)카바메이트a) phenyl N- (2-methoxyquinolin-3-yl) carbamate
3-아미노-2-메톡시퀴놀린(4그램, 23밀리몰)과 페닐클로로포메이트(4.04그램, 25밀리몰)를 다이클로로메탄에 녹이고 실온에서 2시간 교반하였다. 감압농축하여 다이클로로메탄을 제거한 후 관 크로마토그래피(헥산:에테르=8:1)로 분리 정제하여 상기화합물을 얻었다.3-amino-2-methoxyquinoline (4 grams, 23 mmol) and phenylchloroformate (4.04 grams, 25 mmol) were dissolved in dichloromethane and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to remove dichloromethane, and then purified by column chromatography (hexane: ether = 8: 1) to obtain the compound.
수율 : 75%Yield: 75%
융점 : 오일상Melting Point: Oil Phase
b) 1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진b) 1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트(148밀리그램, 0.5밀리몰)와 1-(3,5-다이메톡시페닐)피페라진(112밀리그램, 0.5밀리몰)을 무수 테트라하이드로퓨란에 녹이고 DBU(117밀리그램, 0.75밀리몰)를 가한 후 실온에서 2시간 교반하였다. 감압농축하여 테트라하이드로퓨란을 제거한 후 관 크로마토그래피(헥산:에테르=5:1)로 분리 정제하여 상기화합물을 얻었다.Phenyl N- (2-methoxyquinolin-3-yl) carbamate (148 mg, 0.5 mmol) and 1- (3,5-dimethoxyphenyl) piperazine (112 mg, 0.5 mmol) are anhydrous tetrahydrofuran It dissolved in and added DBU (117 mg, 0.75 mmol) and stirred at room temperature for 2 hours. Concentrated under reduced pressure to remove tetrahydrofuran, and then purified by column chromatography (hexane: ether = 5: 1) to obtain the compound.
수율 : 81%Yield: 81%
융점 : 200-201℃Melting Point: 200-201 ℃
Mass(EI) m/z : 422.1952(MH, C23H26N4O4계산치 : 422.1954)Mass (EI) m / z: 422.1952 (MH, C 23 H 26 N 4 O 4 calc .: 422.1954)
[실시예 2]Example 2
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(3,5-다이메틸페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 1.
수율 : 79%Yield: 79%
융점 : 143-145℃Melting Point: 143-145 ℃
Mass(EI) m/z : 390.2066(MH, C23H26N4O2계산치 : 390.2055)Mass (EI) m / z: 390.2066 (MH, C 23 H 26 N 4 O 2 calcd: 390.2055)
[실시예 3]Example 3
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(2,3-다이메틸페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (2,3-dimethylphenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(2,3-다이메틸페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (2,3-dimethylphenyl) piperazine in the same manner as in Example 1.
수율 : 83%Yield: 83%
융점 : 174-175℃Melting Point: 174-175 ℃
[실시예 4]Example 4
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이플로로페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-difluorophenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(3,5-다이플로로페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate with 1- (3,5-difluorophenyl) piperazine in the same manner as in Example 1.
수율 : 78%Yield: 78%
융점 : 158-159℃Melting Point: 158-159 ℃
[실시예 5]Example 5
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이클로로페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dichlorophenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(3,5-다이클로로페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (3,5-dichlorophenyl) piperazine in the same manner as in Example 1.
수율 : 56%Yield: 56%
융점 : 156-158℃Melting Point: 156-158 ℃
Mass(EI) m/z : 430.0977(MH, C21H20N4O2Cl1계산치 : 430.0963)Mass (EI) m / z: 430.0977 (MH, C 21 H 20 N 4 O 2 Cl 1 calc .: 430.0963)
[실시예 6]Example 6
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(2-플로로페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (2-fluorophenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(2-플로로페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (2-fluorophenyl) piperazine in the same manner as in Example 1.
수율 : 81%Yield: 81%
융점 : 156-158℃Melting Point: 156-158 ℃
[실시예 7]Example 7
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(2-클로로페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (2-chlorophenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(2-클로로페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (2-chlorophenyl) piperazine in the same manner as in Example 1.
수율 : 78%Yield: 78%
융점 : 79-80℃Melting Point: 79-80 ℃
[실시예 8]Example 8
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3-클로로페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3-chlorophenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(3-클로로페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (3-chlorophenyl) piperazine in the same manner as in Example 1.
수율 : 73%Yield: 73%
융점 : 97-98℃Melting Point: 97-98 ℃
[실시예 9]Example 9
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3-하이드록시페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3-hydroxyphenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(3-하이드록시페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (3-hydroxyphenyl) piperazine in the same manner as in Example 1.
수율 : 75%Yield: 75%
융점 : 190-191℃Melting Point: 190-191 ℃
[실시예 10]Example 10
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(2-메톡시페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (2-methoxyphenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(2-메톡시페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (2-methoxyphenyl) piperazine in the same manner as in Example 1.
수율 : 88%Yield: 88%
융점 : 159-161℃Melting Point: 159-161 ℃
[실시예 11]Example 11
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(2-메틸티오페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (2-methylthiophenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(2-메틸티오페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (2-methylthiophenyl) piperazine in the same manner as in Example 1.
수율 : 78%Yield: 78%
융점 : 147-149℃Melting Point: 147-149 ℃
[실시예 12]Example 12
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3-이소프로폭시페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3-isopropoxyphenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(3-이소프로폭시페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (3-isopropoxyphenyl) piperazine in the same manner as in Example 1.
수율 : 93%Yield: 93%
융점 : 111-113℃Melting Point: 111-113 ℃
[실시예 13]Example 13
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3-사이클로프로필메틸옥시페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3-cyclopropylmethyloxyphenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(3-사이클로프로필메틸옥시페닐)피페라진을 실시예 12과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (3-cyclopropylmethyloxyphenyl) piperazine in the same manner as in Example 12.
수율 : 90%Yield: 90%
융점 : 146-147℃Melting Point: 146-147 ℃
[실시예 14]Example 14
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(2-메톡시-5-메틸페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (2-methoxy-5-methylphenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(2-메톡시-5-메틸페닐)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (2-methoxy-5-methylphenyl) piperazine in the same manner as in Example 1.
수율 : 76%Yield: 76%
융점 : 115-116℃Melting Point: 115-116 ℃
[실시예 15]Example 15
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(2-메톡시-5-페닐페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (2-methoxy-5-phenylphenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(2-메톡시-5-페닐페닐) 피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (2-methoxy-5-phenylphenyl) piperazine in the same manner as in Example 1.
수율 : 77%Yield: 77%
융점 : 122-123℃Melting Point: 122-123 ℃
[실시예 16]Example 16
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(5-메톡시-2-메틸페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (5-methoxy-2-methylphenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(5-메톡시-2-메틸페닐) 피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (5-methoxy-2-methylphenyl) piperazine in the same manner as in Example 1.
수율 : 82%Yield: 82%
융점 : 128-130℃Melting Point: 128-130 ℃
[실시예 17]Example 17
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(1-나프틸)피페라진1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (1-naphthyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)카바메이트와 1-(1-나프틸)피페라진을 실시예 1과 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) carbamate and 1- (1-naphthyl) piperazine in the same manner as in Example 1.
수율 : 68%Yield: 68%
융점 : 158-160℃Melting Point: 158-160 ℃
[실시예 18]Example 18
1-[N-(2-메톡시퀴놀린-3-일)-N-메틸아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진1- [N- (2-methoxyquinolin-3-yl) -N-methylaminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진(106밀리그램, 0.25밀리몰)을 다이메틸포름아마이드(15밀리리터)에 녹이고 소디움하이드라이드(6.0밀리그램, 0.25밀리몰)을 가하고 실온에서 15분간 교반한 후, 요오드메탄(35밀리그램, 0.25밀리몰)을 가한다. 그리고 실온에서 16시간 동안 교반하였다. 감압농축하여 다이메틸포름아마이드를 제거한 후 관 크로마토그래피(에틸아세테이트 : 헥산 = 1:2)로 분리 정제하여 상기화합물을 얻었다.1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (106 milligrams, 0.25 mmol) in dimethylformamide (15 milliliters) Dissolve and add sodium hydride (6.0 mg, 0.25 mmol), stir at room temperature for 15 minutes, and then add iodine methane (35 mg, 0.25 mmol). And stirred for 16 hours at room temperature. Concentrated under reduced pressure to remove dimethylformamide, and then purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.
수율 : 93%Yield: 93%
융점 : 88-89℃Melting Point: 88-89 ℃
Mass(EI) m/z : 436.2105(MH, C24H28N4O2계산치 : 436.2110)Mass (EI) m / z: 436.2105 (MH, C 24 H 28 N 4 O 2 Calculated value: 436.2110)
[실시예 19]Example 19
1-[N-에틸-N-(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진1- [N-ethyl-N- (2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진(106밀리그램, 0.25밀리몰)을 다이메틸포름아마이드(15밀리리터)에 녹이고 소디움하이드라이드(6.0밀리그램, 0.25밀리몰)를 가하고 실온에서 15분간 교반한 후, 요오드에탄(39밀리그램, 0.25밀리몰)을 가한다. 그리고 실온에서 16시간 동안 교반하였다. 감압농축하여 다이메틸포름아마이드를 제거한 후 관 크로마토그래피(에틸아세테이트 : 헥산 = 1:2)로 분리 정제하여 상기화합물을 얻었다.1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (106 milligrams, 0.25 mmol) in dimethylformamide (15 milliliters) Dissolve and add sodium hydride (6.0 mg, 0.25 mmol), stir at room temperature for 15 minutes, and then add iodine ethane (39 mg, 0.25 mmol). And stirred for 16 hours at room temperature. Concentrated under reduced pressure to remove dimethylformamide, and then purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.
수율 : 91%Yield: 91%
융점 : 118-120℃Melting Point: 118-120 ℃
Mass(EI) m/z : 450.2206(MH, C25H30N4O4계산치 : 450.2227)Mass (EI) m / z: 450.2206 (MH, C 25 H 30 N 4 O 4 calcd: 450.2227)
[실시예 20]Example 20
1-[N-이소프로필-N-(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진1- [N-isopropyl-N- (2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진(106밀리그램, 0.25밀리몰)을 다이메틸포름아마이드(15밀리리터)에 녹이고 소디움하이드라이드(6.0밀리그램, 0.25밀리몰)를 가하고 실온에서 15분간 교반한후, 2-요오드프로판(42밀리그램, 0.25밀리몰)을 가한다. 그리고 실온에서 16시간 동안 교반하였다. 감압농축하여 다이메틸포름아마이드를 제거한 후 관 크로마토그래피(에틸아세테이트 : 헥산 = 1:2)로 분리 정제하여 상기화합물을 얻었다.1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (106 milligrams, 0.25 mmol) in dimethylformamide (15 milliliters) Dissolve and add sodium hydride (6.0 mg, 0.25 mmol), stir at room temperature for 15 minutes, then add 2-iodine propane (42 mg, 0.25 mmol). And stirred for 16 hours at room temperature. Concentrated under reduced pressure to remove dimethylformamide, and then purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.
수율 : 87%Yield: 87%
융점 : 123-125℃Melting Point: 123-125 ℃
[실시예 21]Example 21
1-[N-사이클로프로필메틸-N-(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진1- [N-cyclopropylmethyl-N- (2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진(106밀리그램, 0.25밀리몰)을 다이메틸포름아마이드(15밀리리터)에 녹이고 소디움하이드라이드(6.2밀리그램, 0.26밀리몰)를 가하고 실온에서 15분간 교반한 후, 브로모메틸사이클로프로판(22밀리그램, 0.26밀리몰)을 가한다. 그리고 실온에서 16시간 동안 교반하였다. 감압농축하여 다이메틸포름아마이드를 제거한 후 관 크로마토그래피(에틸아세테이트 : 헥산 = 1:2)로 분리 정제하여 상기화합물을 얻었다.1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (106 milligrams, 0.25 mmol) in dimethylformamide (15 milliliters) Dissolve and add sodium hydride (6.2 mg, 0.26 mmol) and stir at room temperature for 15 minutes, then add bromomethylcyclopropane (22 mg, 0.26 mmol). And stirred for 16 hours at room temperature. Concentrated under reduced pressure to remove dimethylformamide, and then purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.
수율 : 78%Yield: 78%
융점 : 118-120℃Melting Point: 118-120 ℃
[실시예 22]Example 22
1-[N-벤질-N-(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진1- [N-benzyl-N- (2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진(114밀리그램, 0.27밀리몰)을 다이메틸포름아마이드(15밀리리터)에 녹이고 소디움하이드라이드(6.6밀리그램, 0.27밀리몰)를 가하고 실온에서 15분간 교반한 후, 벤질브로마이드(46밀리그램, 0.27밀리몰)을 가한다. 그리고 실온에서 16시간 동안 교반하였다. 감압농축하여 다이메틸포름아마이드를 제거한 후 관 크로마토그래피(에틸아세테이트 : 헥산 = 1:2)로 분리 정제하여 상기화합물을 얻었다.1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine (114 mg, 0.27 mmol) in dimethylformamide (15 mL) Dissolve and add sodium hydride (6.6 mg, 0.27 mmol), stir at room temperature for 15 minutes, and then add benzyl bromide (46 mg, 0.27 mmol). And stirred for 16 hours at room temperature. Concentrated under reduced pressure to remove dimethylformamide, and then purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.
수율 : 90%Yield: 90%
융점 : 오일상Melting Point: Oil Phase
[실시예 23]Example 23
1-[N-(2-메톡시퀴놀린-3-일)-N-메틸아미노카르보닐]-4(3,5-다이메틸페닐)피페라진1- [N- (2-methoxyquinolin-3-yl) -N-methylaminocarbonyl] -4 (3,5-dimethylphenyl) piperazine
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진을 실시예 18과 동일한 방법으로 반응시켜 상기화합물을 얻었다.1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine was reacted in the same manner as in Example 18 to obtain the compound.
수율 : 92%Yield: 92%
융점 : 142-143℃Melting Point: 142-143 ℃
Mass(EI) m/z : 404.2225(MH, C24H28N4O2계산치 : 404.2212)Mass (EI) m / z: 404.2225 (MH, C 24 H 28 N 4 O 2 calc .: 404.2212)
[실시예 24]Example 24
1-[N-에틸-N-(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진1- [N-ethyl-N- (2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진을 실시예 19와 동일한 방법으로 반응시켜 상기화합물을 얻었다.1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine was reacted in the same manner as in Example 19 to obtain the compound.
수율 : 89%Yield: 89%
융점 : 84-86℃Melting Point: 84-86 ℃
[실시예 25]Example 25
1-[N-이소프로필-N-(2-메톡시퀴놀린 -3-일)아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진1- [N-isopropyl-N- (2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진을 실시예 20과 동일한 방법으로 반응시켜 상기화합물을 얻었다.1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine was reacted in the same manner as in Example 20 to obtain the compound.
수율 : 84%Yield: 84%
융점 : 114-115℃Melting Point: 114-115 ℃
[실시예 26]Example 26
1-[N-벤질-N-(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진1- [N-benzyl-N- (2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진을 실시예 22과 동일한 방법으로 반응시켜 상기화합물을 얻었다.1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine was reacted in the same manner as in Example 22 to obtain the compound.
수율 : 90%Yield: 90%
융점 오일상Melting Point Oil Phase
[실시예 27]Example 27
1-[N-(2-메톡시퀴놀린-3-일)-N-메틸아미노카르보닐]-4-(3-이소프로폭시페닐)피페라진1- [N- (2-methoxyquinolin-3-yl) -N-methylaminocarbonyl] -4- (3-isopropoxyphenyl) piperazine
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3-이소프로폭시페닐)피페라진을 실시예 18과 동일한 방법으로 반응시켜 상기화합물을 얻었다.1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3-isopropoxyphenyl) piperazine was reacted in the same manner as in Example 18 to obtain the compound.
수율 : 92%Yield: 92%
융점 : 오일상Melting Point: Oil Phase
[실시예 28]Example 28
1-[N-에틸-N-(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3-이소프로폭시페닐)피페라진1- [N-ethyl-N- (2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3-isopropoxyphenyl) piperazine
1-[(2-메톡시퀴놀린-3-일)아미노카르보닐]-4-(3-이소프로폭시페닐)피페라진을 실시예 19와 동일한 방법으로 반응시켜 상기화합물을 얻었다.1-[(2-methoxyquinolin-3-yl) aminocarbonyl] -4- (3-isopropoxyphenyl) piperazine was reacted in the same manner as in Example 19 to obtain the compound.
수율 : 87%Yield: 87%
융점 : 오일상Melting Point: Oil Phase
[실시예 29]Example 29
1-[(2-메톡시퀴놀린-3-일)아미노티오카르보닐]-4-(3,5-다이메톡시페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)티오카바메이트(56밀리그램, 0.5밀리몰)와 1-(3,5-다이메톡시페닐)피페라진(111밀리그램, 0.5밀리몰)을 무수 테트라하이드로퓨란에 녹이고 DBU(117밀리그램, 0.75밀리몰)를 가한 후 실온에서 2시간 동안 교반하였다. 감압농축하여 테트라하이드로퓨란을 제거한 후 관 크로마토그래피(헥산:에테르=5:1)로 분리 정제하여 상기화합물을 얻었다.Phenyl N- (2-methoxyquinolin-3-yl) thiocarbamate (56 mg, 0.5 mmol) and 1- (3,5-dimethoxyphenyl) piperazine (111 mg, 0.5 mmol) were anhydrous tetrahydro It was dissolved in furan and added DBU (117 mg, 0.75 mmol) and stirred at room temperature for 2 hours. Concentrated under reduced pressure to remove tetrahydrofuran, and then purified by column chromatography (hexane: ether = 5: 1) to obtain the compound.
수율 : 76%Yield: 76%
융점 : 171-172℃Melting Point: 171-172 ℃
[실시예 30]Example 30
1-[(2-메톡시퀴놀린-3-일)아미노티오카르보닐]-4-(3,5-다이메틸페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminothiocarbonyl] -4- (3,5-dimethylphenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)티오카바메이트와 1-(3,5-다이메틸페닐)피페라진을 실시예 29와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) thiocarbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 29.
수율 : 79%Yield: 79%
융점 : 170-171℃Melting Point: 170-171 ℃
[실시예 31]Example 31
1-[(2-메톡시퀴놀린-3-일)아미노티오카르보닐]-4-(3,5-다이플로로페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminothiocarbonyl] -4- (3,5-difluorophenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)티오카바메이트와 1-(3,5-다이플로로페닐)피페라진을 실시예 29와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) thiocarbamate and 1- (3,5-difluorophenyl) piperazine in the same manner as in Example 29.
수율 : 78%Yield: 78%
융점 : 140-142℃Melting Point: 140-142 ℃
[실시예 32]Example 32
1-[(2-메톡시퀴놀린-3-일)아미노티오카르보닐]-4-(3,5-다이클로로페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminothiocarbonyl] -4- (3,5-dichlorophenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)티오카바메이트와 1-(3,5-다이클로로페닐)피페라진을 실시예 29와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) thiocarbamate and 1- (3,5-dichlorophenyl) piperazine in the same manner as in Example 29.
수율 : 62%Yield: 62%
융점 : 181-183℃Melting Point: 181-183 ℃
[실시예 33]Example 33
1-[(2-메톡시퀴놀린-3-일)아미노티오카르보닐]-4-(3-메톡시페닐)피페라진1-[(2-methoxyquinolin-3-yl) aminothiocarbonyl] -4- (3-methoxyphenyl) piperazine
페닐 N-(2-메톡시퀴놀린-3-일)티오카바메이트와 1-(3-메톡시페닐)피페라진을 실시예 29와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methoxyquinolin-3-yl) thiocarbamate and 1- (3-methoxyphenyl) piperazine in the same manner as in Example 29.
수율 : 81%Yield: 81%
융점 : 오일상Melting Point: Oil Phase
[실시예 34]Example 34
1-[(2-메틸퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진1-[(2-methylquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine
a) 페닐 N-(2-메틸퀴놀린-3-일)카바메이트a) phenyl N- (2-methylquinolin-3-yl) carbamate
3-아미노-2-메틸퀴놀린(4그램, 25밀리몰)과 페닐클로로포메이트(4.04그램, 25밀리몰)를 메틸렌클로라이드에 녹이고 실온에서 2시간 교반하였다. 감압농축하여 메틸렌클로라이드를 제거한 후 관 크로마토그래피(에틸아세테이트 : 헥산 = 1:10)로 분리 정제하여 상기화합물을 얻었다.3-amino-2-methylquinoline (4 grams, 25 mmol) and phenylchloroformate (4.04 grams, 25 mmol) were dissolved in methylene chloride and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to remove methylene chloride, and then purified by column chromatography (ethyl acetate: hexane = 1:10) to obtain the compound.
수율 : 88%Yield: 88%
b) 1-[(2-메틸퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메톡시페닐)피페라진b) 1-[(2-methylquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)카바메이트(140밀리그램, 0.5밀리몰)와 1-(3,5-다이메톡시페닐)피페라진(112밀리그램, 0.5밀리몰)을 무수 테트라하이드로퓨란에 녹이고 DBU(117밀리그램, 0.75밀리몰)를 가한 후, 실온에서 2시간 동안 교반하였다. 감압농축하여 테트라하이드로퓨란을 제거한 후 관 크로마토그래피(에틸아세테이트 : 헥산=1:2)로 분리 정제하여 상기화합물을 얻었다.Phenyl N- (2-methylquinolin-3-yl) carbamate (140 mg, 0.5 mmol) and 1- (3,5-dimethoxyphenyl) piperazine (112 mg, 0.5 mmol) were added to anhydrous tetrahydrofuran. After dissolving and adding DBU (117 mg, 0.75 mmol), the mixture was stirred at room temperature for 2 hours. Concentrated under reduced pressure to remove tetrahydrofuran and purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.
수율 : 84%Yield: 84%
융점 : 199-200℃Melting Point: 199-200 ℃
[실시예 35]Example 35
1-[(2-메틸퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이메틸페닐)피페라진1-[(2-methylquinolin-3-yl) aminocarbonyl] -4- (3,5-dimethylphenyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)카바메이트와 1-(3,5-다이메틸페닐)피페라진을 실시예 34와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methylquinolin-3-yl) carbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 34.
수율 : 86%Yield: 86%
융점 : 230-232℃Melting Point: 230-232 ℃
[실시예 36]Example 36
1-[(2-메틸퀴놀린-3-일)아미노카르보닐]-4-(2,3-다이메틸페닐)피페라진1-[(2-methylquinolin-3-yl) aminocarbonyl] -4- (2,3-dimethylphenyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)카바메이트와 1-(2,3-다이메틸페닐)피페라진을 실시예 34와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methylquinolin-3-yl) carbamate and 1- (2,3-dimethylphenyl) piperazine in the same manner as in Example 34.
수율 : 81%Yield: 81%
융점 : 169-170℃Melting Point: 169-170 ℃
[실시예 37]Example 37
1-[(2-메틸퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이플로로페닐)피페라진1-[(2-methylquinolin-3-yl) aminocarbonyl] -4- (3,5-difluorophenyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)카바메이트와 1-(3,5-다이플로로페닐)피페라진을 실시예 34와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methylquinolin-3-yl) carbamate with 1- (3,5-difluorophenyl) piperazine in the same manner as in Example 34.
수율 : 81%Yield: 81%
융점 : 238-240℃Melting Point: 238-240 ℃
[실시예 38]Example 38
1-[(2-메틸퀴놀린-3-일)아미노카르보닐]-4-(3,5-다이클로로페닐)피페라진1-[(2-methylquinolin-3-yl) aminocarbonyl] -4- (3,5-dichlorophenyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)카바메이트와 1-(3,5-다이클로로페닐)피페라진을 실시예 34와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methylquinolin-3-yl) carbamate and 1- (3,5-dichlorophenyl) piperazine in the same manner as in Example 34.
수율 : 65%Yield: 65%
융점 : 247-249℃Melting Point: 247-249 ℃
[실시예 39]Example 39
1-[(2-메틸퀴놀린-3-일)아미노카르보닐]-4-(2-메톡시페닐)피페라진1-[(2-methylquinolin-3-yl) aminocarbonyl] -4- (2-methoxyphenyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)카바메이트와 1-(2-메톡시페닐)피페라진을 실시예 34와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methylquinolin-3-yl) carbamate and 1- (2-methoxyphenyl) piperazine in the same manner as in Example 34.
수율 : 83%Yield: 83%
융점 : 135-136℃Melting Point: 135-136 ℃
[실시예 40]Example 40
1-[(2-메틸퀴놀린-3-일)아미노카르보닐]-4-(2-플로로페닐)피페라진1-[(2-methylquinolin-3-yl) aminocarbonyl] -4- (2-fluorophenyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)카바메이트와 1-(2-플로로페닐)피페라진을 실시예 34와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methylquinolin-3-yl) carbamate and 1- (2-fluorophenyl) piperazine in the same manner as in Example 34.
수율 : 84%Yield: 84%
융점 : 201-203℃Melting Point: 201-203 ℃
실시예 41) 1-[(2-메틸퀴놀린-3-일)아미노카르보닐]-4-(2-클로로페닐)피페라진Example 41) 1-[(2-methylquinolin-3-yl) aminocarbonyl] -4- (2-chlorophenyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)카바메이트와 1-(2-클로로페닐)피페라진을 실시예 34와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methylquinolin-3-yl) carbamate and 1- (2-chlorophenyl) piperazine in the same manner as in Example 34.
수율 : 72%Yield: 72%
융점 : 180-181℃Melting Point: 180-181 ℃
[실시예 42]Example 42
1-[(2-메틸퀴놀린-3-일)아미노카르보닐]-4-(2-메틸티오페닐)피페라진1-[(2-methylquinolin-3-yl) aminocarbonyl] -4- (2-methylthiophenyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)카바메이트와 1-(2-메틸티오페닐)피페라진을 실시예 34와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methylquinolin-3-yl) carbamate and 1- (2-methylthiophenyl) piperazine in the same manner as in Example 34.
수율 : 76%Yield: 76%
융점 : 165-166℃Melting Point: 165-166 ℃
[실시예 43]Example 43
1-[(2-메틸퀴놀린-3-일)아미노카르보닐]-4-(2-메톡시-5-메틸페닐)피페라진1-[(2-methylquinolin-3-yl) aminocarbonyl] -4- (2-methoxy-5-methylphenyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)카바메이트와 1-(2-메톡시-5-메틸페닐)피페라진을 실시예 34와 동일한 방법으로 반응시켜 상기화합물을 얻었다.Phenyl N- (2-methylquinolin-3-yl) carbamate and 1- (2-methoxy-5-methylphenyl) piperazine were reacted in the same manner as in Example 34 to obtain the compound.
수율 : 80%Yield: 80%
융점 : 오일상Melting Point: Oil Phase
[실시예 44]Example 44
1-[(2-메틸퀴놀린-3-일)아미노카르보닐]-4-(1-나프틸)피페라진1-[(2-methylquinolin-3-yl) aminocarbonyl] -4- (1-naphthyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)카바메이트와 1-(1-나프틸)피페라진을 실시예 34와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methylquinolin-3-yl) carbamate and 1- (1-naphthyl) piperazine in the same manner as in Example 34.
수율 : 64%Yield: 64%
융점: 220-222℃Melting point: 220-222 ℃
[실시예 45]Example 45
1-[(2-메틸퀴놀린-3-일)아미노티오카르보닐]-4-(3,5-다이메톡시페닐)피페라진1-[(2-methylquinolin-3-yl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine
a) 페닐 N-(2-메틸퀴놀린-3-일)티오카바메이트a) phenyl N- (2-methylquinolin-3-yl) thiocarbamate
3-아니노-2-메틸퀴놀린(4그램, 25밀리몰)과 페닐클로로티오포메이트(4.32그램, 25밀리몰)를 메틸렌클로라이드에 녹이고 실온에서 2시간 동안 교반하였다. 감압농축하여 메틸렌클로라이드를 제거한 후 관 크로마토그래피(에틸아세테이트:헥산=1:2)로 분리 정제하여 상기화합물을 얻었다.3-anino-2-methylquinoline (4 grams, 25 mmol) and phenylchlorothioformate (4.32 grams, 25 mmol) were dissolved in methylene chloride and stirred at room temperature for 2 hours. Concentrated under reduced pressure to remove methylene chloride, and then purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.
수율 : 78%Yield: 78%
b) 1-[(2-메틸퀴놀린-3-일)아미노티오카르보닐]-4-(3,5-다이메톡시페닐)피페라진b) 1-[(2-methylquinolin-3-yl) aminothiocarbonyl] -4- (3,5-dimethoxyphenyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)티오카바메이트(147밀리그램, 0.5밀리몰)와 1-(3,5-다이메톡시페닐)피페라진(112밀리그램, 0.5밀리몰)을 무수 테트라하이드로퓨란에 녹이고 DBU(117밀리그램, 0.75밀리몰)를 가한 후 실온에서 2시간 동안 교반하였다. 감압농축하여 테트라하이드로퓨란을 제거한 후 관 크로마토그래피(에틸아세테이트:헥산=1:2)로 분리 정제하여 상기화합물을 얻었다.Phenyl N- (2-methylquinolin-3-yl) thiocarbamate (147 mg, 0.5 mmol) and 1- (3,5-dimethoxyphenyl) piperazine (112 mg, 0.5 mmol) are anhydrous tetrahydrofuran It was dissolved in and added DBU (117 mg, 0.75 mmol) and stirred for 2 hours at room temperature. Concentrated under reduced pressure to remove tetrahydrofuran, and then purified by column chromatography (ethyl acetate: hexane = 1: 2) to obtain the compound.
수율 : 86%Yield: 86%
융점 : 211-212℃Melting Point: 211-212 ℃
[실시예 46]Example 46
1-[(2-메틸퀴놀린-3-일)아미노티오카르보닐]-4-(3,5-다이메틸페닐)피페라진1-[(2-methylquinolin-3-yl) aminothiocarbonyl] -4- (3,5-dimethylphenyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)티오카바메이트와 1-(3,5-다이메틸페닐)피페라진을 실시예 45와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methylquinolin-3-yl) thiocarbamate and 1- (3,5-dimethylphenyl) piperazine in the same manner as in Example 45.
수율 : 81%Yield: 81%
융점 : 196-197℃Melting Point: 196-197 ℃
[실시예 47]Example 47
1-[(2-메틸퀴놀린-3-일)아미노티오카르보닐]-4-(3,5-다이플로로페닐)피페라진1-[(2-methylquinolin-3-yl) aminothiocarbonyl] -4- (3,5-difluorophenyl) piperazine
페닐 N-(2-메틸퀴놀린-3-일)티오카바메이트와 1-(3,5-다이플로로페닐)피페라진을 실시예 45와 동일한 방법으로 반응시켜 상기화합물을 얻었다.The compound was obtained by reacting phenyl N- (2-methylquinolin-3-yl) thiocarbamate and 1- (3,5-difluorophenyl) piperazine in the same manner as in Example 45.
수율 : 74%Yield: 74%
융점 : 211-213℃Melting Point: 211-213 ℃
[실시예 48]Example 48
1-{[2-(피리딘-2-일)퀴놀린-4-일]아미노카르보닐}-4-(3,5-다이메톡시페닐)피페라진1-{[2- (pyridin-2-yl) quinolin-4-yl] aminocarbonyl} -4- (3,5-dimethoxyphenyl) piperazine
페닐 N-[2-(피리딘-2-일)퀴놀린-4-일]카바메이트(171밀리그램, 0.5밀리몰)와 1-(3,5-다이메톡시페닐)피페라진(111밀리그램, 0.5밀리몰)을 무수 테트라하이드로퓨란에 녹이고 DBU(117밀리그램, 0.75밀리몰)를 가한 후 실온에서 2시간 교반하였다. 감압농축하여 테트라하이드로퓨란을 제거한 후 관 크로마토그래피(다이클로로메탄:메탄올=20:1)로 분리 정제하여 상기화합물을 얻었다.Phenyl N- [2- (pyridin-2-yl) quinolin-4-yl] carbamate (171 mg, 0.5 mmol) and 1- (3,5-dimethoxyphenyl) piperazine (111 mg, 0.5 mmol) Was dissolved in anhydrous tetrahydrofuran, DBU (117 mg, 0.75 mmol) was added, followed by stirring at room temperature for 2 hours. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, and then purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain the compound.
수율 : 73%Yield: 73%
융점 : 97-98℃Melting Point: 97-98 ℃
Mass(EI) m/z : 517.3244(MH, C31H27N5O3계산치 : 517.2113)Mass (EI) m / z: 517.3244 (MH, C 31 H 27 N 5 O 3 Calculated Value: 517.2113)
[실시예 49]Example 49
1-{[2-(피리딘-3-일)퀴놀린-4-일]아미노카르보닐}-4-(3,5-다이메톡시페닐)피페라진1-{[2- (pyridin-3-yl) quinolin-4-yl] aminocarbonyl} -4- (3,5-dimethoxyphenyl) piperazine
페닐 N-[2-(피리딘-3-일)퀴놀린-4-일]카바메이트(171밀리그램, 0.5밀리몰)와 1-(3,5-다이메톡시페닐)피페라진(111밀리그램, 0.5밀리몰)을 무수 테트라하이드로퓨란에 녹이고 DBU(117밀리그램, 0.75밀리몰)를 가한 후 실온에서 2시간 교반하였다. 감압농축하여 테트라하이드로퓨란을 제거한 후 관 크로마토그래피(다이클로로메탄:메탄올=20:1)로 분리 정제하여 상기화합물을 얻었다.Phenyl N- [2- (pyridin-3-yl) quinolin-4-yl] carbamate (171 mg, 0.5 mmol) and 1- (3,5-dimethoxyphenyl) piperazine (111 mg, 0.5 mmol) Was dissolved in anhydrous tetrahydrofuran, DBU (117 mg, 0.75 mmol) was added, followed by stirring at room temperature for 2 hours. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, and then purified by column chromatography (dichloromethane: methanol = 20: 1) to obtain the compound.
수율 : 67%Yield: 67%
융점 : 95-96℃Melting Point: 95-96 ℃
[실시예 50]Example 50
1-{[2-(티엔-2-일)퀴놀린-4-일]아미노카르보닐}-4-(3,5-다이메톡시페닐)피페라진1-{[2- (thien-2-yl) quinolin-4-yl] aminocarbonyl} -4- (3,5-dimethoxyphenyl) piperazine
페닐 N-[2-(티엔-2-일)퀴놀린-4-일]카바메이트(173밀리그램, 0.5밀리몰)와 1-(3,5-다이메톡시페닐)피페라진(111밀리그램, 0.5밀리몰)을 무수 테트라하이드로퓨란에 녹이고 DBU(117밀리그램, 0.75밀리몰)를 가한 후 실온에서 2시간 교반하였다. 감압농축하여 테트라하이드로퓨란을 제거한 후 관 크로마토그래피(에틸아세테이트:헥산=1:1)로 분리 정제하여 상기화합물을 얻었다.Phenyl N- [2- (thien-2-yl) quinolin-4-yl] carbamate (173 mg, 0.5 mmol) and 1- (3,5-dimethoxyphenyl) piperazine (111 mg, 0.5 mmol) Was dissolved in anhydrous tetrahydrofuran, DBU (117 mg, 0.75 mmol) was added, followed by stirring at room temperature for 2 hours. Concentrated under reduced pressure to remove tetrahydrofuran, and then purified by column chromatography (ethyl acetate: hexane = 1: 1) to obtain the compound.
수율 : 61%Yield: 61%
융점 : 오일상Melting Point: Oil Phase
[실시예 51]Example 51
1-{[2-(피리딘-3-일)퀴놀린-4-일]아미노카르보닐}-4-(3,5-다이메틸페닐)피페라진1-{[2- (pyridin-3-yl) quinolin-4-yl] aminocarbonyl} -4- (3,5-dimethylphenyl) piperazine
페닐 N-[2-(피리딘-3-일)퀴놀린-4-일]카바메이트(171밀리그램, 0.5밀리몰)와 1-(3,5-다이메틸페닐)피페라진(95밀리그램, 0.5밀리몰)을 무수 테트라하이드로퓨란에 녹이고 DBU(117밀리그램, 0.75밀리몰)를 가한 후 실온에서 2시간 교반하였다. 감압농축하여 테트라하이드로퓨란을 제거한 후 관 크로마토그래피(에틸아세테이트:헥산=1:1)로 분리 정제하여 상기화합물을 얻었다.Phenyl N- [2- (pyridin-3-yl) quinolin-4-yl] carbamate (171 mg, 0.5 mmol) and 1- (3,5-dimethylphenyl) piperazine (95 mg, 0.5 mmol) After dissolving in tetrahydrofuran and adding DBU (117 mg, 0.75 mmol), the mixture was stirred at room temperature for 2 hours. Concentrated under reduced pressure to remove tetrahydrofuran, and then purified by column chromatography (ethyl acetate: hexane = 1: 1) to obtain the compound.
수율 : 64%Yield: 64%
융점 : 211-213℃Melting Point: 211-213 ℃
화합물의 항암 활성은 in vitro 법에 의하여 5가지의 Human tumor cell line와 2가지의 leukemia tumor cell line을 사용하여 각각 시험하였는데, 그 결과를 다음표에 나타내었다. in vitro test 방법은 다음와 같다.The anticancer activity of the compounds was tested using five human tumor cell lines and two leukemia tumor cell lines by in vitro methods, and the results are shown in the following table. The in vitro test method is as follows.
[실험예 1]Experimental Example 1
* Human tumor cell lines에 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. Human solid tumor cell lines인 A549(non-small lung cell), SKMEL-2(melanoma), HCT-15(colon), SKOV-3(ovarian), XF-498(CNS）등은 10% (FBS)가 포함된 RPMI 1640배지를 사용하여 37℃, 5% CO2incubator에서 배양 하였으며 계대는 1주일에 1-2회 실시하였다. 세포들은 부착면으로부터 분리할 때는 0.25% 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) and XF-498 (CNS) are 10% (FBS). Cultures were incubated in a 5% CO 2 incubator at 37 ° C using a RPMI 1640 medium included and passaged 1-2 times a week Cells were separated into 0.25% Trysin and 3 mM CDTA PBS (-) The dissolved solution was used.
b. 96 well plate(Nunc)의 각 well에 5×103-2×104cells을 가하여 37℃, 5% CO2incubator에서 24시간 배양하였다.b. 5 × 10 3 -2 × 10 4 cells were added to each well of a 96 well plate (Nunc) and incubated in 37 ° C., 5% CO 2 incubator for 24 hours.
c. 각종 약물들은 소량의 DMSO에 녹여 시험에 원하는 농도까지 실험용 배지로서 희석하여 최종 DMSO 농도는 0.5%이하가 되도록 하였다.c. Various drugs were dissolved in a small amount of DMSO and diluted as 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 aspiration하여 제거한 후, c. 항에서 제조한 약물들을 각 well에 200㎕씩 가한 후 48시간 배양하였다. 약물을 가하는 시점에서 Tz(Time zero) plate를 Collection하였다.d. B. After aspiration to remove all the medium of each well cultured for 24 hours, and c. Drugs prepared in the section was added to each well 200μl and incubated for 48 hours. At the time of drug addition, Tz (Time Zero) plates were collected.
e. Tz plates 및 각 배양이 끝난 plate는 SRB assay 방법에 TCA에 의한 cell fixing, 0.4% SRB 용액으로 staining, 1% acetic acid로써 washing을 실시한 후 10mM Tris용액으로 dye를 elution 시켜 520nM에서 OD 값을 측정하였다.e. Tz plates and each cultured plate were subjected to cell fixing by TCA, staining with 0.4% SRB solution, washing with 1% acetic acid, and dyeing with 10 mM Tris solution to measure OD at 520 nM. .
다. 결과 계산All. Calculate the result
a. 약물을 가하여 배양을 시작하는 시간에 collection하여 SRB protein양의 값을 구하여 Time zero(Tz)로 하였다.a. At the beginning of incubation with the addition of the drug, the SRB protein amount was obtained and time zero (Tz) was obtained.
b. 약물을 가하지 않고 세포만 있던 well의 OD 값을 control value(C)라 하였다.b. The OD value of the wells in which cells were not added was called control value (C).
c. 약물을 처리한 well의 OD 값을 drug-treated test value(T)라 하였다.c. The OD value of drug-treated wells was called drug-treated test value (T).
d. Tz, C와 T로부터 growth stimulation, net growth inhibition 및 net killing 등의 약물의 효과를 판단할 수 있었다.d. From Tz, C and T, the effects of drugs such as growth stimulation, net growth inhibition and net killing could be determined.
e. 만약 T≥Tz일 경우에는 그 cellular response function은 100×(T-Tz)/(C-Tz)이며, TTz 일 경우에는 100×(T-Tz)/Tz로써 계산하였다.e. If T≥Tz, the cellular response function was 100 × (T-Tz) / (C-Tz), and for TTz, it was calculated as 100 × (T-Tz) / Tz.
그 결과를 다음 표에 나타내었다.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.Paull, 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
본 발명의 화합물들은 in vitro 실험에서 대조약물인 Cisplatin보다 5개의 고형 암세포실험에서 월등한 항암효과가 관찰되었다. 실시예 중 대부분의 실험화합물들이 대조약물인 Cisplatin보다 매우 높은 항암효과가 관찰되었으며, 그 중 실시예 번호 1번, 2번, 18번의 화합물의 대조약물인 Adriamycin보다 동등 이상의 항암효과가 관찰되었다.The compounds of the present invention showed superior anticancer effects in five solid cancer cell experiments than Cisplatin, a control drug, in vitro. Most of the experimental compounds in Examples were found to have a much higher anticancer effect than Cisplatin, a control drug, and among them, the anticancer effect of Adriamycin, which is equivalent to or higher than that of the control drugs of Examples 1, 2, and 18, was observed.
[실험예 2]Experimental Example 2
* Mouse P388 세포에 대한 in vivo 항암 효과 실험* In vivo anticancer effect experiment on mouse P388 cells
가. 실험재료end. Experimental material
BDF1 mouse를 사용하였다.BDF1 mouse was used.
나. 실험방법I. Experiment method
1) 6주령 BDF1 mouse 8마리를 한군으로 하여 DBA/2 mouse에서 계대중인 P388세포를 각각의 mouse에 1×10 cells/0.1ml씩 복강에 이식하였다.1) One 6-week-old BDF1 mouse was used as a group, and 1 × 10 P388 cells passaged from DBA / 2 mice to each mouse. Cells / 0.1ml were implanted into the abdominal cavity.
2) 시험약물은 0.5% Tween 80에 현탁시켜 day 1, 5, 9이나 everyday 9의 시간별로 각각의 농도로서 복강내에 주사하였다.2) The test drug was suspended in 0.5% Tween 80 and injected intraperitoneally at different concentrations for each day of day 1, 5, 9 or everyday 9.
3) Mouse를 매일 관찰하면서 생존률을 측정하고 각 실험군의 median survival time으로부터 대조군에 대한 투여군의 평균 생존일의 증가된 비율(T/C%)을 계산하여 항암효과를 판정하였다. 그 결과를 다음표에 나타내었다.3) Survival was measured while observing mice daily, and the anticancer effect was determined by calculating the increased ratio (T / C%) of the average survival days of the control group to the control group from the median survival time of each experimental group. The results are shown in the following table.
* 참고문헌* references
·A. Goldin et al : Europ. J. Cancer, 17, 129(1981)A. Goldin et al: Europ. J. Cancer, 17, 129 (1981)
다. 결과All. result
P388 mouse cancer cell을 이용한 in vivo실험을 통하여 1번, 2번, 18번 등의 발명물질들의 항암효과 유의성이(T/C125%)이 관찰되었다.In vivo experiments using P388 mouse cancer cell showed significant antitumor effect (T / C125%) of 1, 2 and 18 inventions.
[실험예 3]Experimental Example 3
* 급성 독성실험(LD)* Acute Toxicity Test (LD)
가. 실험방법 : 리치필드 - 윌콕슨 방법end. Experimental method: Lichfield-Wilcockson method
6주령된 ICR 마우스(수컷 30±2.0g)를 구입하여 실험전에 실온 23±1℃, 습도 60±5%의 조건에서 고형사료 및 물을 자유롭게 섭취 시켰다. 실험동물을 군당 6마리씩 사용하여 약물을 복강내에 투여하여, 14일간 외견상태와 생사여부를 기록하였고, 폐사동물은 부검하여 육안적 병변을 관찰하였다. LD값을 리치필드-윌콕슨법에 의해 구하였다. 그 결과를 다음 표에 나타내었다.Six-week-old ICR mice (male 30 ± 2.0g) were purchased and fed with solid feed and water freely at room temperature 23 ± 1 ℃ and humidity 60 ± 5% before the experiment. 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 value was calculated | required by the Richfield-Wilcoxon method. The results are shown in the following table.
본 발명의 화합물들은 급성독성에 있어서 Cisplatin이나 Adriamycin보다 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 dosage and toxicity in terms of safety because they are superior to Cisplatin or Adriamycin in acute toxicity.
Claims (2)
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| KR1019970022985A KR100204319B1 (en) | 1996-06-29 | 1997-06-03 | Novel piperazine derivatives and their preparation method |
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| PL97325341A PL325341A1 (en) | 1996-06-29 | 1997-06-28 | Derivatives od piperazine and method of obtaining them |
| JP10504004A JP3032303B2 (en) | 1996-06-29 | 1997-06-28 | Piperazine derivative and method for producing the same |
| AU34642/97A AU713171B2 (en) | 1996-06-29 | 1997-06-28 | Piperazine derivatives and process for the preparation thereof |
| CNB971908001A CN1152015C (en) | 1996-06-29 | 1997-06-28 | Piperazine devivatives and process for preparation thereof |
| EP97930868A EP0850222B1 (en) | 1996-06-29 | 1997-06-28 | Piperazine derivatives and process for the preparation thereof |
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| CZ98593A CZ59398A3 (en) | 1996-06-29 | 1997-06-28 | Piperazine derivatives and process for preparing thereof |
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