KR20020051675A - 4-phenylaminothiano [3,2-d] pyrimidine derivative and preparing method thereof - Google Patents

4-phenylaminothiano [3,2-d] pyrimidine derivative and preparing method thereof Download PDF

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KR20020051675A
KR20020051675A KR1020000081139A KR20000081139A KR20020051675A KR 20020051675 A KR20020051675 A KR 20020051675A KR 1020000081139 A KR1020000081139 A KR 1020000081139A KR 20000081139 A KR20000081139 A KR 20000081139A KR 20020051675 A KR20020051675 A KR 20020051675A
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formula
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pyrimidine
phenylaminothieno
chlorothieno
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이상남
송양헌
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이상남
라이프테크놀러지(주)
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

PURPOSE: Provided is a 4-phenylaminothieno (3,2-d) pyrimidine derivative which inhibits the activity of tyrosine kinase and its producing method. CONSTITUTION: The 4-phenylaminothieno (3,2-d) pyrimidine derivative is represented by formula(4), wherein R1 and R2 are the same or different and represent hydrogen, C1-C4 alkyl, C1-C4 alkoxy or halide compound. The method for producing the 4-phenylaminothieno (3,2-d) pyrimidine derivative comprises the steps of: reacting 3-amino-2-carbamoylthiopen represented by formula(5) with a formic acid to produce a compound represented by formula(6); chlorination of the compound of formula(6) to produce 4-chlorothieno (3,2-d) pyrimidine represented by formula(7); and reacting 4-chlorothieno (3,2-d) pyrimidine with an aniline derivative, wherein R1 and R2 are the same or different, and hydrogen, C1-C4 alkyl, C1-C4 alkoxy or halide compound.

Description

4-페닐아미노티에노 [3,2-디] 피리미딘 유도체 및 이의 제조방법{4-phenylaminothiano [3,2-d] pyrimidine derivative and preparing method thereof}4-phenylaminothieno [3,2-di] pyrimidine derivatives and preparation method thereof {4-phenylaminothiano [3,2-d] pyrimidine derivative and preparing method

본 발명은 4-페닐아미노티에노 [3,2-d] 피리미딘 유도체 및 이의 제조방법에 관한 것으로, 좀 더 구체적으로는 사람의 암세포에서 발현되는 티로신 키나제를 억제하여 항암제로서 가능성이 기대되는 4-페닐아미노티에노 [3,2-d] 피리미딘 유도체와 이의 제조방법에 관한 것이다.The present invention relates to 4-phenylaminothieno [3,2-d] pyrimidine derivatives and a method for preparing the same, and more particularly, to inhibit tyrosine kinases expressed in human cancer cells, thereby being expected as an anticancer agent. -Phenylaminothieno [3,2-d] pyrimidine derivatives and methods for their preparation.

최근에 상피 성장인자 리셉터(epidermal growth factor recepter)의 티로신 키나제(tyrosine kinase)의 강력한 억제제(inhibitor)들이 광범위하게 연구되고 있다(참조: J. Med. Chem., 42, 1803(1999); J. Med. Chem., 41, 742(1998) 등). 상피 성장인자 리셉터는 사람의 암세포에서 발현되기 때문에 티로신 키나제의 억제제는 강력한 항암제로서 주목되고 있는 실정이다(참조: Exp. Opin. Thet. Pat., 8, 1599(1998)등). 예를 들면, 하기 화학식 1로 표시되는 4-페닐아미노퀴나졸린이나 하기 화학식 2 또는 3으로 표시되는 4-페닐아미노피리도 피리미딘 등은 이러한 목적으로 최근에 개발되었다(참조: J. Med. Chem., 40, 3915(1997) 등).Recently, powerful inhibitors of tyrosine kinase of epidermal growth factor receptors have been extensively studied (see J. Med. Chem., 42, 1803 (1999); Med. Chem., 41, 742 (1998), and the like. Since epidermal growth factor receptors are expressed in human cancer cells, inhibitors of tyrosine kinases have been noted as potent anticancer agents (Exp. Opin. Thet. Pat., 8, 1599 (1998), etc.). For example, 4-phenylaminoquinazoline represented by the following formula (1) or 4-phenylaminopyrido pyrimidine represented by the following formula (2) or (3) has recently been developed for this purpose (see J. Med. Chem). , 40, 3915 (1997) and the like.

상기 식에서, R은 수소, 탄소수 1∼4의 알킬기, 탄소수 1∼4의 알콕시기, 또는 할라이드 화합물이다.In the above formula, R is hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halide compound.

한편, 메틸 3-아미노-2-티오펜카르복실레이트를 출발물질로 하여 4번 위치가 치환된 4-치환 아미노티에노 [3, 2-d] 피리미딘들의 합성이 전에 보고되었지만(참조: Tetrhedron, 27, 487(1971)), 그 합성방법은 효과적이지 못했고, 4-페닐아미노티에노 [3, 2-d] 피리미딘 유도체들의 합성은 아직 보고된바 없다.On the other hand, the synthesis of 4-substituted aminothieno [3,2-d] pyrimidines substituted at position 4 with methyl 3-amino-2-thiophenecarboxylate as starting material has been reported previously (see Tetrhedron). , 27, 487 (1971)), the synthesis method was not effective and the synthesis of 4-phenylaminothieno [3,2-d] pyrimidine derivatives has not been reported yet.

실제로 4-페닐아미노티에노 [3, 2-d] 피리미딘 유도체를 합성하기 위해서 기존의 방법을 시도하였으나 원하는 화합물을 극히 미량밖에 얻을 수 없었다.In fact, attempts were made to synthesize 4-phenylaminothieno [3,2-d] pyrimidine derivatives, but only a very small amount of the desired compound could be obtained.

이에 본 발명에서는 이러한 항암제로서 가능성이 기대되는 4-페닐아미노티에노 [3, 2-d] 피리미딘 유도체들을 새롭게 합성하였고, 합성방법도 기존방법과 다른 효과적인 합성방법을 개발하였으며, 이 화합물들에 대한 물리적 성질을 조사하였다. 본 발명은 이에 기초하여 완성되었다.Accordingly, the present invention newly synthesized 4-phenylaminothieno [3,2-d] pyrimidine derivatives, which are expected as anticancer agents, and developed an effective synthesis method that is different from the existing methods. The physical properties were investigated. The present invention has been completed based on this.

따라서, 본 발명의 목적은 사람의 암세포에서 발현되는 티로신 키나제를 억제하여 항암제로서 가능성이 기대되는 4-페닐아미노티에노 [3,2-d] 피리미딘 유도체를 제공하는데 있다.Accordingly, an object of the present invention is to provide a 4-phenylaminothieno [3,2-d] pyrimidine derivative which is expected to be a potential anticancer agent by inhibiting tyrosine kinase expressed in human cancer cells.

본 발명의 다른 목적은 상기 4-페닐아미노티에노 [3,2-d] 피리미딘 유도체의 제조방법을 제공하는데 있다.Another object of the present invention is to provide a method for preparing the 4-phenylaminothieno [3,2-d] pyrimidine derivative.

상기 목적을 달성하기 위한 본 발명의 4-페닐아미노티에노 [3,2-d] 피리미딘 유도체는 하기 화학식 4로 표시된다.4-phenylaminothieno [3,2-d] pyrimidine derivative of the present invention for achieving the above object is represented by the following formula (4).

여기서, R1및 R2는 서로 같거나 다르게 수소, 탄소수 1∼4의 알킬기, 탄소수 1∼4의 알콕시기, 또는 할라이드 화합물이다.Here, R 1 and R 2 are the same as or different from each other, hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halide compound.

본 발명의 다른 목적을 달성하기 위한 상기 화학식 4로 표시되는 4-페닐아미노티에노 [3,2-d] 피리미딘 유도체의 제조방법은 하기 화학식 5로 표시되는 3-아미노-2-카바모일티오펜과 포름산을 반응시켜 하기 화학식 6으로 표시되는 화합물을 얻는 단계; 상기 화학식 6으로 표시되는 화합물을 염소화 반응시켜 하기 화학식 7로 표시되는 4-클로로티에노 [3, 2-d] 피리미딘을 얻는 단계; 및 상기 화학식 7로 표시되는 4-클로로티에노 [3, 2-d] 피리미딘과 아닐린 유도체와 반응시키는 단계를 포함한다.Method for producing a 4-phenylamino thieno [3,2-d] pyrimidine derivative represented by the formula (4) for achieving another object of the present invention is 3-amino-2-carbamoyl tea represented by the formula (5) Reacting offenfen and formic acid to obtain a compound represented by the following formula (6); Chlorination of the compound represented by Chemical Formula 6 to obtain 4-chlorothieno [3,2-d] pyrimidine represented by Chemical Formula 7; And reacting the 4-chlorothieno [3,2-d] pyrimidine and aniline derivative represented by Chemical Formula 7.

이하 본 발명을 좀 더 구체적으로 살펴보면 다음과 같다.Looking at the present invention in more detail as follows.

본 발명은 기존의 방법을 개선하여 새로운 4-페닐아미노티에노 [3, 2-d] 피리미딘 유도체를 효과적으로 합성할 수 있었다. 즉, 하기 반응식 1로 부터 알 수 있는 바와 같이, 화학식 5로 표시되는 3-아미노-2-카바모일티오펜과 과량의 포름산을 반응시키면 고리화 반응을 일으켜 화학식 6으로 표시되는 화합물을 얻을 수 있다. 그 다음, 화학식 6으로 표시되는 화합물을 과량의 염소화합물로 염소화 반응시키면 화학식 7로 표시되는 4-클로로티에노 [3, 2-d] 피리미딘을 얻는다. 이를 아닐린 유도체와 연속적으로 반응시키면 본 발명의 4-페닐아미노티에노 [3,2-d] 피리미딘 유도체를 매우 우수한 수율로 짧은 시간 내에 합성할 수 있다. 이때의 반응조건은 알코올이나 일반적인 유기용매 또는 그들의 혼합용매에서 1 내지 24시간 환류하여 4-페닐아미노티에노 [3, 2-d] 피리미딘 유도체를 제조한다.The present invention was able to effectively synthesize new 4-phenylaminothieno [3,2-d] pyrimidine derivatives by improving existing methods. That is, as can be seen from Scheme 1 below, the reaction of 3-amino-2-carbamoylthiophene represented by Formula 5 with an excess of formic acid causes a cyclization reaction to give a compound represented by Formula 6 . Then, the chlorination reaction of the compound represented by the formula (6) with an excess of chlorine compound to give 4-chlorothieno [3, 2-d] pyrimidine represented by the formula (7). By continuously reacting this with the aniline derivative, the 4-phenylaminothieno [3,2-d] pyrimidine derivative of the present invention can be synthesized in a very good yield in a short time. At this time, the reaction conditions are refluxed for 1 to 24 hours in alcohol, a general organic solvent or a mixed solvent thereof to prepare 4-phenylaminothieno [3,2-d] pyrimidine derivative.

상기 식에서, R1및 R2는 서로 같거나 다르게 수소, 탄소수 1∼4의 알킬기, 탄소수 1∼4의 알콕시기, 또는 할라이드 화합물이다.In the above formula, R 1 and R 2 are the same as or different from each other, hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halide compound.

본 발명의 화합물에 사용되는 상기 할라이드 화합물은 Cl, Br, I, F 등이 있다.The halide compounds used in the compounds of the present invention include Cl, Br, I, F and the like.

전술한 바와 같이, 상기 화학식 4로 표시되는 4-페닐아미노티에노 [3, 2-d] 피리미딘 유도체는 사람의 암세포에서 발현되는 티로신 키나제를 억제하여 항암제로서 사용이 가능하다.As described above, the 4-phenylaminothieno [3,2-d] pyrimidine derivative represented by Formula 4 can be used as an anticancer agent by inhibiting tyrosine kinase expressed in human cancer cells.

이하 실시예를 통하여 본 발명을 좀 더 구체적으로 설명하지만, 하기 예에 본 발명의 범주가 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to the following Examples.

제조예 1Preparation Example 1

상기 화학식 6으로 표시되는 디티에노 [3, 2-d]피리미딘-4(3H)-온의 합성Synthesis of dithieno [3,2-d] pyrimidin-4 (3H) -one represented by Chemical Formula 6

상기 화학식 5로 표시되는 3-아미노-2-카바모일티오펜과 과량의 포름알데히드를 끓는점에서 4시간 가열하여 축합반응에 의해 티에노 [3, 2-d]피리미딘-4(3H)-온을 얻었다.Thieno [3,2-d] pyrimidin-4 (3H) -one by condensation reaction of 3-amino-2-carbamoylthiophene represented by Formula 5 with excess formaldehyde at a boiling point for 4 hours by heating Got.

녹는점(mp): 222-223℃, 수율: 90%Melting point (mp): 222-223 ° C., yield: 90%

제조예 2Preparation Example 2

상기 화학식 7로 표시되는 4-클로르티에노 [3, 2-d] 피리미딘의 합성Synthesis of 4-chlorothieno [3,2-d] pyrimidine represented by Formula 7

제조예 1에서 얻은 티에노 [3, 2-d]피리미딘-4(3H)-온과 과량의 POCl3를 2시간 반응시켜 4-클로르티에노 [3, 2-d] 피리미딘을 얻고, 처리하여 정량적인 4-클로르티에노 [3, 2-d] 피리미딘을 얻었다.Thieno [3,2-d] pyrimidin-4 (3H) -one obtained in Preparation Example 1 was reacted with excess POCl 3 for 2 hours to obtain 4-chlorthieno [3,2-d] pyrimidine, Treatment gave quantitative 4-chlorthieno [3, 2-d] pyrimidine.

녹는점(mp): 123-124℃, 수율: 90%Melting point (mp): 123-124 ° C., yield: 90%

실시예 1Example 1

하기 화학식 4a로 표시되는 4-(3'-브로모페닐아미노)티에노 [3, 2-d]피리미딘의 합성Synthesis of 4- (3'-bromophenylamino) thieno [3,2-d] pyrimidine represented by Formula 4a

2-프로판올/THF/HCI(소량)으로 형성된 용매안에 제조예 2에서 얻은 4-클로르티에노 [3, 2-d] 피리미딘 450㎎ (2.64 mmol)과 아닐린 유도체로 3-브로모아닐린 516㎎(3.0 mmol)을 가한 후 환류시켰다. TLC로 반응의 진행 정도를 확인하면서 조사하였다. 반응이 끝난 후 반응액을 농축하고 다시 소량의 에틸 아세테이트로 녹인 후 탄산수로칼슘 용액과 에틸 아세테이트 용액에 분산시켰다. 유기용매 층을 농축하고 실리카겔을 이용하여 크로마토그래피를 실시한 후 최종 생성물(화학식 4a)를 743㎎(92%) 에탄올에서 생성물을 재결정하여 프리즘 모양의 순수한 물질을 얻었다.450 mg (2.64 mmol) of 4-chlorothieno [3,2-d] pyrimidine obtained in Preparation Example 2 and 516 mg of 3-bromoaniline as an aniline derivative in a solvent formed of 2-propanol / THF / HCI (small amount) (3.0 mmol) was added and then refluxed. Investigation was carried out by confirming the progress of the reaction by TLC. After the reaction was completed, the reaction solution was concentrated, dissolved in a small amount of ethyl acetate, and then dispersed in a calcium carbonate solution and an ethyl acetate solution. The organic solvent layer was concentrated and chromatographed using silica gel, and the final product (Formula 4a) was recrystallized from 743 mg (92%) ethanol to obtain a prism-shaped pure material.

녹는점(mp): 201∼202℃, 수율: 92%Melting point (mp): 201-202 ° C., yield: 92%

H+NMR(300 MHz, DMSO-d6): δ9.80(s,1H), 8.64(s,1H), 8.24(d,1H), 8.18(s,1H), 7.82(dd,1H), 7.48(d,1H), 7.30(t,1H), 7.25(dd,1H), MS(m/z) 306H + NMR (300 MHz, DMSO-d6): δ9.80 (s, 1H), 8.64 (s, 1H), 8.24 (d, 1H), 8.18 (s, 1H), 7.82 (dd, 1H), 7.48 (d, 1H), 7.30 (t, 1H), 7.25 (dd, 1H), MS (m / z) 306

실시예 2∼9Examples 2-9

4-페닐아미노티에노 [3, 2-d]피리미딘 유도체의 합성Synthesis of 4-phenylaminothieno [3,2-d] pyrimidine derivatives

상기 실시예 1에서 아닐린 유도체를 하기 표 1에 기재된 R로 특정한 것을 제외하고는 동일하게 실시하였고, 그 결과 또한 하기 표 1에 기재하였다.The aniline derivatives in Example 1 were carried out in the same manner except for the specific R in Table 1, and the results are also described in Table 1 below.

4-페닐아미노티에노 [3, 2-d]피리미딘 유도체4-phenylaminothieno [3,2-d] pyrimidine derivatives 실시예Example RR 시간(h)Hours (h) 수율(%)yield(%) 녹는점(℃)Melting Point (℃) 22 HH 55 8888 186∼187186-187 33 2'-CH3 2'-CH 3 55 9090 220∼221220 to 221 44 4'-Cl4'-Cl 33 9595 101∼102101-102 55 3'-I3'-I 33 8585 139∼140139 to 140 66 4'-OMe4'-OMe 55 9191 155∼156155-156 77 3',5'-diCl3 ', 5'-diCl 33 9292 167∼168167-168 88 2',6'-diEt2 ', 6'-diEt 55 9090 65∼6665-66 99 4'-iPr4'-iPr 44 8888 121∼122121-122

전술한 바와 같이, 본 발명은 항암제로서 가능성이 기대되는 4-페닐아미노티에노 [3, 2-d] 피리미딘 유도체를 고수율로 제조할 수 있다.As described above, the present invention can produce a high yield of 4-phenylaminothieno [3,2-d] pyrimidine derivative, which is expected as an anticancer agent.

Claims (3)

하기 화학식 4로 표시되는 4-페닐아미노티에노 [3,2-d] 피리미딘 유도체.4-phenylaminothieno [3,2-d] pyrimidine derivative represented by the following formula (4). 화학식 4Formula 4 여기서, R1및 R2는 서로 같거나 다르게 수소, 탄소수 1∼4의 알킬기, 탄소수 1∼4의 알콕시기, 또는 할라이드 화합물이다.Here, R 1 and R 2 are the same as or different from each other, hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halide compound. 하기 화학식 5로 표시되는 3-아미노-2-카바모일티오펜과 포름산을 반응시켜 하기 화학식 6으로 표시되는 화합물을 얻는 단계;Reacting 3-amino-2-carbamoylthiophene represented by Formula 5 with formic acid to obtain a compound represented by Formula 6; 상기 화학식 6으로 표시되는 화합물을 염소화 반응시켜 하기 화학식 7로 표시되는 4-클로로티에노 [3, 2-d] 피리미딘을 얻는 단계; 및Chlorination of the compound represented by Chemical Formula 6 to obtain 4-chlorothieno [3,2-d] pyrimidine represented by Chemical Formula 7; And 상기 화학식 7로 표시되는 4-클로로티에노 [3, 2-d] 피리미딘과 아닐린 유도체와 반응시키는 단계를 포함하는 하기 화학식 4로 표시되는 4-페닐아미노티에노 [3,2-d] 피리미딘 유도체의 제조방법.4-phenylaminothieno [3,2-d] pyri represented by the following formula (4) comprising the step of reacting with 4-chlorothieno [3, 2-d] pyrimidine and aniline derivatives represented by the formula (7) Method for preparing midine derivatives. 화학식 5Formula 5 화학식 6Formula 6 화학식 7Formula 7 화학식 4Formula 4 여기서, R1및 R2는 서로 같거나 다르게 수소, 탄소수 1∼4의 알킬기, 탄소수 1∼4의 알콕시기, 또는 할라이드 화합물이다.Here, R 1 and R 2 are the same as or different from each other, hydrogen, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a halide compound. 제2항에 있어서, 상기 화학식 7로 표시되는 4-클로로티에노 [3, 2-d] 피리미딘과 아닐린 유도체와의 반응은 알코올, 유기용매 또는 이들의 혼합용매에서 1 내지 24시간 환류시키는 존건하에서 수행됨을 특징으로 하는 4-페닐아미노티에노 [3,2-d] 피리미딘 유도체의 제조방법.The method according to claim 2, wherein the reaction of 4-chlorothieno [3,2-d] pyrimidine and aniline derivative represented by Chemical Formula 7 is refluxed for 1 to 24 hours in an alcohol, an organic solvent or a mixed solvent thereof. A process for the preparation of 4-phenylaminothieno [3,2-d] pyrimidine derivatives, characterized in that it is carried out under.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01316383A (en) * 1988-03-02 1989-12-21 Yoshitomi Pharmaceut Ind Ltd 3,4-dihydrothieno(2,3,-d)pyrimidine compound and medicinal use thereof
KR20000023813A (en) * 1996-07-13 2000-04-25 Glaxo Group Ltd Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
KR20010031908A (en) * 1997-11-11 2001-04-16 실버스타인 아써 에이. Thienopyrimidine and thienopyridine derivatives useful as anticancer agents

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Publication number Priority date Publication date Assignee Title
JPH01316383A (en) * 1988-03-02 1989-12-21 Yoshitomi Pharmaceut Ind Ltd 3,4-dihydrothieno(2,3,-d)pyrimidine compound and medicinal use thereof
KR20000023813A (en) * 1996-07-13 2000-04-25 Glaxo Group Ltd Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
KR20010031908A (en) * 1997-11-11 2001-04-16 실버스타인 아써 에이. Thienopyrimidine and thienopyridine derivatives useful as anticancer agents

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