KR20040015172A - 헤테로시클릭 화합물 및 이를 유효 성분으로 하는 항종양제 - Google Patents
헤테로시클릭 화합물 및 이를 유효 성분으로 하는 항종양제 Download PDFInfo
- Publication number
- KR20040015172A KR20040015172A KR10-2003-7014035A KR20037014035A KR20040015172A KR 20040015172 A KR20040015172 A KR 20040015172A KR 20037014035 A KR20037014035 A KR 20037014035A KR 20040015172 A KR20040015172 A KR 20040015172A
- Authority
- KR
- South Korea
- Prior art keywords
- compound
- morpholino
- triazine
- dimethylmorpholino
- alkyl
- Prior art date
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- 150000002391 heterocyclic compounds Chemical class 0.000 title claims abstract description 8
- 239000004480 active ingredient Substances 0.000 title claims abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 5
- -1 piperidino, pyrrolidinyl Chemical group 0.000 claims abstract description 39
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 15
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 3
- 125000000160 oxazolidinyl group Chemical group 0.000 claims abstract description 3
- 125000005505 thiomorpholino group Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 97
- 230000000259 anti-tumor effect Effects 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 2
- 239000003085 diluting agent Substances 0.000 claims 1
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- 238000000034 method Methods 0.000 description 7
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Abstract
하기 화학식(Ⅰ)로 표시되는 헤테로시클릭 화합물 또는 이의 약제학적으로 허용되는 염, 및 이 헤테로시클릭 화합물을 유효 성분으로 하는 항종양제에 관한 것이다:
상기 식에서,
X는 질소 원자 또는 CH이며;
R1은 CHnF3-n(n은 1 또는 2), 히드록시 C1-C6알킬, NHR6[R6는 수소 원자, COR(R은 수소 원자, C1-C6알킬, C1-C6알콕시)임]이며;
R2는 모르폴리노(1 내지 4개의 C1-C6알킬로 치환될 수 있음), 티오모르폴리노, 피페리디노, 피롤리디닐(히드록시 C1-C6알킬로 치환될 수 있음), 옥사졸리디닐(1 또는 2개의 C1-C6알킬로 치환될 수 있음), 테트라히드로-1,4-티아진-1-옥소-4-일이며;
R3및 R4는 수소 원자 또는 C1-C6알킬이며;
R5는 수소 원자, 아미노 또는 수산기이다.
Description
s-트라아진[1,3,5-트리아진] 유도체, 피리미딘 유도체는, 종래, 합성 수지, 합성 섬유, 염료 또는 농약의 각 분야에서 연구되어, 수많은 화합물이 합성되어 있다. 또한, 의약 분야에서는 항종양, 항염증, 진통, 경련 진정 등의 각 영역에서 연구되어, 특히 항종양제 트리에틸렌멜라민(Triethylenemelamine: TEM)의 유사체로서 개발된 헥사메틸멜라민(Hexamethylmelamine: HMM)이 널리 공지되어 있다[B.L. Johnson et al. Cancer, 42: 2157-2161(1978)].
TEM은 알킬화제로서 널리 공지되어 있고, 살세포 작용에 근거한 항종양 작용을 갖는 s-트리아진 유도체이다. 또한, HMM은 이미 유럽에서 난소암, 폐 소세포암에 대한 적응을 지닌 약제로서 시판되고 있으며, 이의 고형암에 대한 작용이 주목되고 있다.
더욱이, s-트리아진 유도체 중에서, 살세포 작용과 선택적 아로마테이스 저해 작용을 둘 다 갖는 이미다졸릴-s-트리아진 유도체가 있으며, 에스트로겐 의존성 질환(자궁내막증, 다낭포성 난소증, 양성 유방증, 자궁내막암, 유방암 등)의 치료제로서 제안되어 있다(PCT 국제공개공보 WO93/17009).
그러나, HMM의 고형암에 대한 항종양 스펙트럼이나 항종양 활성의 세기에 대해서는 아직 개선의 여지가 남아 있다. 또한, 이미다졸릴-s-트리아진 유도체에 대해서는, 살세포 작용에 비해 아로마테이스 저해 작용이 상당히 강하고, 에스트로겐 의존성 질환 이외의 암 환자에게 응용했을 경우, 에스트로겐의 결핍으로 인한 월경 이상 등의 부작용 발현으로 이어지는 것도 생각할 수 있어 그 응용 범위가 한정되기 때문에, 아로마테이스 저해 작용을 갖지 않고 고형암에 대해 유효한 약제의 개발이 요망되고 있었다.
본 발명은, 하기 화학식(Ⅰ)로 표시되는 헤테로시클릭 화합물 또는 이의 약제학적으로 허용되는 염, 및 이 헤테로시클릭 화합물을 유효 성분으로 하는 항종양제에 관한 것이다:
상기 식에서,
X는 질소 원자 또는 CH이며;
R1은 CHnF3-n(n은 1 또는 2), 히드록시 C1-C6알킬, NHR6[R6는 수소 원자, COR(R은 수소 원자, C1-C6알킬, C1-C6알콕시)임]이며;
R2는 모르폴리노(1 내지 4개의 C1-C6알킬로 치환될 수 있음), 티오모르폴리노, 피페리디노, 피롤리디닐(히드록시 C1-C6알킬로 치환될 수 있음),옥사졸리디닐(1 또는 2개의 C1-C6알킬로 치환될 수 있음), 테트라히드로-1,4-티아진-1-옥소-4-일이며;
R3및 R4는 수소 원자 또는 C1-C6알킬이며;
R5는 수소 원자, 아미노 또는 수산기이다.
이러한 상황에서, 본 발명자들은 HMM의 항종양 작용의 증감과 이미다졸릴-s-트리아진 유도체의 아로마테이스 저해 작용의 감소를 목표로 하여 연구를 진행한 결과, 벤즈이미다졸을 치환한 s-트리아진 및 피리미딘 유도체를 발견하였다(PCT 국제공개공보 WO99/05138, WO00/43385).
그러나, 이들 화합물도 항종양 활성면에서 만족하지 못했기 때문에, 더욱 연구를 진행하여, 벤즈이미다졸 고리의 제 2 위치에 특정한 치환기를 갖는 화학식(Ⅰ)의 헤테로시클릭 화합물로부터 현저한 활성 개선이 얻어짐을 발견하여 본 발명을 완성하였다.
본 발명의 헤테로시클릭 화합물은 상기 화학식(Ⅰ)로 표현되는데, 상기 식중 각 기호의 정의에 사용되는 어구의 의미와 예를 이하에 설명한다.
「C1-C6」는, 특별히 한정되지 않는 한 탄소수 1∼6개의 기를 의미한다.
「C1-C6알킬」로서는, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 3차-부틸, n-펜틸, n-헥실 등의 직쇄 또는 분지쇄 형태의 알킬기를 예로 들 수 있다.
「히드록시 C1-C6알킬」은, 상기 「C1-C6알킬」에서 정의되는 기중 어느 하나의 탄소 원자에 히드록시기가 결합된 기를 의미한다.
「C1-C6알콕시」로서는, 메톡시, 에톡시, n-프로폭시, 이소프로폭시, n-부톡시, 3차-부톡시, n-펜틸옥시, n-헥실옥시 등의 직쇄 또는 분기쇄 형태의 알콕시기를 예로 들 수 있다.
본 발명의 화합물로서는, 예컨대 이하의 화합물을 예시할 수 있는데, 본 발명은 이들의 화합물에 한정되지 않는다.
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(시스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4,6-디모르폴리노피리미딘
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-티오모르폴리노피리미딘
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노피리미딘
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(2-메틸모르폴리노)-6-모르폴리노피리미딘
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-[2,2,5(R)-트리메틸모르폴리노]피리미딘
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-[2,2,5(S)-트리메틸모르폴리노]피리미딘
·4-(시스-2,3-디메틸모르폴리노)-2-(2-플루오로메틸벤즈이미다졸-1-일)-6-모르폴리노피리미딘
·2-(2-아미노벤즈이미다졸-1-일)-4-(시스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘
·2-(2-아미노벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘
·4-(시스-2,3-디메틸모르폴리노)-2-(2-히드록시메틸벤즈이미다졸-1-일)-6-모르폴리노피리미딘
·4-(시스-2,3-디메틸모르폴리노)-2-(2-히드록시메틸벤즈이미다졸-1-일)-6-피페리디노피리미딘
·4-(시스-2,3-디메틸모르폴리노)-2-(2-히드록시메틸벤즈이미다졸-1-일)-6-(2-히드록시메틸피롤리딘-1-일)피리미딘
·2-(6-아미노-2-디플루오로메틸벤즈이미다졸-1-일)-4,6-디모르폴리노피리미딘
·2-(6-아미노-2-디플루오로메틸벤즈이미다졸-1-일)-4-(시스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘
·2-(2-디플루오로메틸-5-히드록시벤즈이미다졸-1-일)-4,6-디모르폴리노피리미딘
·2-(2-디플루오로메틸-4-히드록시벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노피리미딘
·2-(2,4-디아미노벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노피리미딘
·2-(2,4-디아미노벤즈이미다졸-1-일)-4,6-디모르폴리노피리미딘
·2-(2-아미노-4-히드록시벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노피리미딘
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(시스-2,3-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-티오모르폴리노-1,3,5-트리아진
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(2-메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(트랜스-2,5-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-[2,2,5(R)-트리메틸모르폴리노]-1,3,5-트리아진
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-(테트라히드로-1,4-티아진-1-옥소-4-일)-1,3,5-트리아진
·2-(2-아세틸아미노벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진
·2-(2-아세틸아미노벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘
·2-(2-포르밀아미노벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진
·2-(2-프로피오닐아미노벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
·2-(트랜스-2,3-디메틸모르폴리노)-4-(2-포르밀아미노벤즈이미다졸-1-일)-6-모르폴리노-1,3,5-트리아진
·4-(트랜스-2,3-디메틸모르폴리노)-2-(2-포르밀아미노벤즈이미다졸-1-일)-6-모르폴리노피리미딘
·2-(시스-2,6-디메틸모르폴리노)-4-(2-포르밀아미노벤즈이미다졸-1-일)-6-모르폴리노-1,3,5-트리아진
·2-(2-메톡시카르보닐아미노벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진
·2-(2-아미노벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진
·2-(2-아미노벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
·2-(2-아미노벤즈이미다졸-1-일)-4-(시스-2,3-디메틸모르폴리노)-6-피페리디노-1,3,5-트리아진
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-피페리디노-1,3,5-트리아진
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-(2-히드록시메틸피롤리딘-1-일)-1,3,5-트리아진
·2-(6-아미노-2-디플루오로메틸벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
·2-(6-아미노-2-디플루오로메틸벤즈이미다졸-1-일)-4-(시스-2,3-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
·2-(4-아미노-2-디플루오로메틸벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진
·2-(2-디플루오로메틸-5-히드록시벤즈이미다졸-1-일)-4-(2,3-시스-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
·2-(2-디플루오로메틸-6-히드록시벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
·2-(2-디플루오로메틸-5-히드록시벤즈이미다졸-1-일)-4-(2,2-디메틸옥사졸리딘-3-일)-6-모르폴리노-1,3,5-트리아진
·2-(2-디플루오로메틸-4-히드록시벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진
·2-(2-디플루오로메틸-4-히드록시벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
·2-(2,4-디아미노벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
·2-(2,4-디아미노벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진
·2-(2-아미노-4-히드록시벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진
본 발명의 화합물은, 이의 구조 중에 비대칭 탄소 원자를 갖는 경우, 비대칭 탄소 원자에서 유래된 이성질체(isomer) 및 이들의 혼합물(라세미체)이 존재하는데, 이들 모두 본 발명의 화합물에 포함되는 것으로 한다.
또한, 본 발명의 화합물은 약제학적으로 허용되는 염으로서 산 부가염의 형태를 취할 수 있다. 적당한 산 부가염으로는, 무기산염으로는 예컨대, 염산염, 황산염, 브롬화수소산염, 질산염, 인산염 등이 사용되고, 유기산염으로는 예컨대, 초산염, 옥살산염, 프로피온산염, 글리콜산염, 유산염, 피루빈산염, 마론산염, 호박산염, 말레인산염, 푸마르산염, 사과산염, 주석산염, 구연산염, 안식향산염, 계피산염, 메탄술폰산염, 벤젠술폰산염, p-톨루엔술폰산염, 살리실산염 등이 사용된다.
[제조 공정]
화학식(Ⅰ)로 표현되는 본 발명의 화합물은, 하기 반응식에 나타난 바와 같이, 염화시아누르 또는 2,4,6-트리클로로피리미딘(화합물 Ⅱ)을 출발 원료로 해서 벤즈이미다졸 화합물(화합물 Ⅴ), 모르폴린 화합물(화합물 Ⅵ) 및 R2H(화합물 Ⅶ)을 순차적으로 반응시킴으로써 제조될 수 있다.
[반응식]
(상기 반응식에서,
R1, R2, R3, R4, R5, X는 상기 정의된 바와 동일하며,
R'는 수소 원자, 니트로 또는 3차-부틸디메틸실릴옥신이다)
이하에 각각의 제조 공정에 대해서 설명한다.
1) 중간체 Ⅲ의 제조 공정(ⅰ)
(상기 식에서,
R1, R', X는 상기 정의된 바와 동일하다)
용매 중에서, 염화수소 포착제의 존재하에, 염화시아누르 또는 2,4,6-트리클로로피리미딘(화합물 Ⅱ)과 벤즈이미다졸 화합물(화합물 Ⅴ)을 반응시킴으로써 중간체 Ⅲ가 수득된다.
이 반응에 사용되는 염화수소 포착제로서는, 예컨대 수산화나트륨, 수산화칼륨, 탄산나트륨, 탄산칼륨, 트리에틸아민 또는 피리딘 등을 예로 들 수 있고, 용매로서는 아세톤, 톨루엔, 헥산, 크실렌, 디옥산, 테트라히드로푸란 또는 디클로로에탄, N,N-디메틸포름아미드(DMF) 등을 예로 들 수 있다.
이 반응에서는, 화합물 Ⅱ 1몰비에 대해 0.5∼1.2몰의 화합물 Ⅴ을 0.5∼2몰의 염화수소 포착제의 존재하에 -15℃∼-5℃의 온도에서 0.5∼2시간, 다시 실온에서 5∼50 시간 반응시킨다.
한편, 화합물 Ⅴ을 염화수소 포착제로서 사용할 수도 있다.
2) 중간체 Ⅳ의 제조 공정(ⅱ)
(상기 식에서,
R1, R3, R4, R', X는 상기 정의된 바와 동일하다)
용매 중에서, 염화수소 포착제의 존재하에, 상기 제조 공정(ⅰ)로 수득된 중간체 Ⅲ과 모르폴린 화합물(화합물 Ⅵ)을 반응시킴으로써 중간체 Ⅳ가 수득된다. 이 반응에 사용되는 염화수소 포착제로서는, 상기 제조 공정(ⅰ)의 염화수소 포착제와 동일한 것을 예로 들 수 있고, 용매로는, DMF, 아세톤, 톨루엔, 크실렌, 디클로로에탄, 디클로로메탄 등을 예로 들 수 있다.
이 반응에 있어서는, 중간체 Ⅲ 1몰에 대해 0.5∼1.2몰의 화합물 Ⅵ을 0.5∼3몰의 염화수소 포착제의 존재하에 -5℃∼0℃의 온도에서 0.5∼3시간, 다시 실온에서 5∼50시간 반응시킨다.
한편, 화합물 Ⅵ을 염화수소 포착제로서 사용할 수도 있다.
3) 화합물 Ⅰ의 제조 공정(ⅲ)
(상기 식에서,
R1, R2, R3, R4, R5, R', X는 상기 정의된 바와 동일하다)
용매 중에서, 염화수소 포착제의 존재하에, 상기 제조 공정(ⅱ)로 수득된 중간체 Ⅳ와 R2H(화합물 Ⅶ)을 반응시킴으로써, 본 발명의 화합물 Ⅰ이 수득된다.
이 반응에 사용되는 염화수소 포착제로서는, 상기 제조 공정(ⅰ)의 염화수소 포착제와 동일한 것을 예로 들 수 있고, 용매로는, DMF, 디메틸설폭시드(DMSO), 크실렌, 디클로로에탄 등을 예로 들 수 있다.
이 반응에 있어서는, 중간체 Ⅳ 1몰에 대해 1∼5몰의 R2H(화합물 Ⅶ)을 실온∼140℃에서, 0.1∼16시간 반응시킨다. 한편, 염화수소 포착제의 존재하에서 반응시키는 경우는, 중간체 Ⅳ 1몰에 대해 1∼5몰의 염화수소 포착제를 사용한다. 한편, 화합물 Ⅶ을 염화수소 포착제로서 사용할 수도 있다.
단, 화합물 Ⅰ의 제조시에 화합물 Ⅵ과 화합물 Ⅶ이 동일한 경우에는, 제조 공정(ⅱ), (ⅲ)을 한 단계로 해서 화합물 Ⅰ을 얻을 수 있다. 그럴 경우는, 화합물 Ⅲ 1몰에 대해 2∼10몰의 화합물 Ⅵ 또는 Ⅶ을 이용해 -10℃∼5℃에서 0.1∼5시간 반응시키고, 다시 실온∼120℃에서 3∼50시간 반응시키는 것 이외에는 상기 제조 공정(ⅱ)의 반응 조건에 따른다.
또한, 제조 공정(ⅰ), (ⅱ), (ⅲ)에서 사용되는 화합물 Ⅴ, Ⅵ 또는 Ⅶ의 반응성이 낮을 경우는, 수소화나트륨으로 처리한 후 각 공정의 반응을 진행시키는 것이 바람직하다. 수소화나트륨을 사용할 경우에는, 각 공정의 출발 물질(화합물 Ⅱ, Ⅲ 또는 Ⅳ) 1몰에 대해 1.0∼1.2몰의 수소화나트륨을 사용한다.
한편, R1이 수산기를 포함할 경우, 또는 R5가 수산기일 경우에는, 통상적인 방법에 따라 3차-부틸디메틸실릴 등의 알킬실릴기로 수산기를 보호한 벤즈이미다졸 화합물을 이용하여 반응시키고, 마지막 공정에서 보호기를 이탈시킴으로써 목적으로 하는 화합물이 수득된다. R5가 아미노기일 경우는, 니트로기를 치환한 벤즈이미다졸을 이용해 반응을 진행시키고, 마지막 공정에서 수소 분위기 하에 통상적인 방법에 의해 접촉 환원시킴으로써 목적으로 하는 화합물이 수득된다.
또한, 상기 제조 공정(ⅰ), (ⅱ), (ⅲ)은, 순서가 뒤바뀔 수도 있으며, 그 때의 반응 조건의 변경은 당업자에게 자명한 범위에서 할 수 있다.
한편, 상기 각 공정에서 얻어지는 생성물은 필요에 따라 통상의 방법, 예컨대, 추출, 농축, 중화, 여과, 재결정, 칼럼 크로마토그래피 등으로 분리 정제할 수 있다.
본 발명의 화학식(Ⅰ)의 화합물의 산 부가염은, 해당 기술분야에서 주지된각종 방법에 의해 제조될 수 있다. 사용할 적당한 산으로는, 무기산으로는 예컨대, 염산, 황산, 브롬화수소산, 질산, 인산 등을 들 수 있고, 유기산으로는 예컨대, 초산, 옥살산, 프로피온산, 글리콜산, 유산, 피루빈산, 마론산, 호박산, 말레인산, 푸마르산, 사과산, 주석산, 구연산, 안식향산, 계피산, 메탄술폰산, 벤젠술폰산, p-톨루엔술폰산, 살리실산 등을 들 수 있다.
이하, 화학식(Ⅰ)로 표현되는 본 발명의 화합물의 항종양 효과를 설명한다. 한편, 시험 1 및 2에서의 피시험 화합물 번호는 하기 실시예의 화합물 번호에 상응한다.
또한, 비교 화합물로서 이하의 s-트리아진계의 항종양제 또는 에스트로겐 의존성 질환 치료제를 이용하였다.
화합물 A : 2-(벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-모르
폴리노피리미딘 [국제공개공보 (WO99/05138)에 기재된 대표예]
화합물 B : 2-(2-메틸벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진
[국제공개공보 (WO99/05138)에 기재된 대표예]
화합물 C : 2-(이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진 [국제공개
공보 (WO93/17009)에 기재된 대표예]
화합물 D : 헥사메틸멜라민(HMM)
시험 1
MEM 배지에 10% 우태아 혈청, 25mM HEPES 및 0.1mg/ml 카나마이신을 첨가한 배양액 중에서 37℃, 5% 탄산가스의 조건하에서 계대 유지한 MCF-7 사람의 유방암세포를 시험에 사용했다. 대수 증식기에 있는 MCF-7 세포를 트립신/EDTA 처리에 의해 단일 부유 세포로 만들고, MEM 배지(10% 우태아 혈청, 25mM HEPES, 0.1mg/ml 카나마이신 첨가)에서, 1ml당 4×104개의 단일 세포 부유액을 조제하였다. 피시험 화합물은 DMSO에 용해시킨 후, RPMI1640 배지(10% 우태아 혈청, 25mM HEPES, 0.1mg/ml 카나마이신 첨가)에 의해 희석시켜, 농도를 2.0×10-4∼2.0×10-9M으로 조제하였다.
96구멍의 마이크로 플레이트에 1웰당 이 세포 현탁액 0.1ml를 넣고, 24시간 배양하여 세포를 마이크로 플레이트에 접착시킨 후, 시료 용액 0.1ml를 첨가하여, 5% 탄산가스 중에서, 37℃에서 72시간 배양하였다.
여러 가지 시료 농도에서의 증식 저해도로부터 50% 증식 저해 농도(GI50μM)를 산출하여, 이 결과를 하기 표 1에 표시한다.
표 1
| 피시험 화합물 | GI50(μM) | 피시험 화합물 | GI50(μM) |
| 화합물 1화합물 2화합물 3화합물 4화합물 5화합물 6화합물 8화합물 9화합물 10화합물 11화합물 12화합물 14화합물 15화합물 16화합물 17화합물 18화합물 19화합물 20화합물 21화합물 22 | 0.110.210.380.180.220.290.320.200.130.200.390.160.130.350.120.180.090.220.340.23 | 화합물 23화합물 25화합물 26화합물 27화합물 29화합물 30화합물 31화합물 32화합물 33화합물 34화합물 35화합물 36화합물 37화합물 38화합물 39화합물 40화합물 A화합물 B화합물 C화합물 D | 0.190.19＜0.040.160.250.250.240.180.080.080.140.290.090.030.060.212.23.720＞100 |
상기 시험 결과로부터, 본 발명의 화합물은 사람의 유방암 세포에 대해, 공지된 비교 화합물 A, B, C, D에 비해 확실히 뛰어난 항종양 작용을 가진다는 것이 판명되었다.
또한, 본 발명의 화합물은 사람의 비소세포성 폐암 세포, 사람의 결장암 세포를 이용한 시험관내 시험에서도 유효했기 때문에, 각종 사람의 고형암 치료에 대한 응용이 기대된다.
시험 2
돌연변이계 BALA/c 누드 마우스를 이용하여 계대시킨 사람의 결장암 WiDr의 2mm 각절편을 종양 이식편으로 하여 돌연변이계 BALA/c 누드 마우스의 좌흉부 피하에 이식해, 종양이 지수 증식기에 달한 시점에서 1그룹에 5마리로 무리를 나누어, 실험에 사용했다. 시험화합물을 생리 식염수에 용해시키거나 마노유발에서 1% HPC액에 현탁시켜, 각각 200mg/kg의 투여량으로 1일 1회, 주 6회 2주간 복강내 투여하였다. 시간 경과에 따라 종양의 장경 및 단경을 계측하고, 종양 체적을 산출하였다. 각 계측일의 종양 체적을 시험 화합물 투여 개시일의 종양 체적으로 나누어 상대 종양 증식율을 산출하고, 시험화합물 투여군의 상대 종양 증식율(T) 및 대조군의 상대 종양 증식율(C)로부터 T/C(%)를 산출하였다. 마지막 날의 T/C(%)가 50% 이하이고 Mann-Whitney의 U 검정에 의해 한쪽편 1%의 위험율에서 유의차가 있는 경우를 유효(+)로 판정하며, 이 결과를 하기 표 2에 표시한다.
표 2
| 피시험 화합물 | 판정 |
| 화합물 14화합물 19화합물 22화합물 31화합물 32화합물 33화합물 A | ++++++- |
이하, 본 발명의 화합물을 포유류 그 중에서도 특히 사람에게 적용하는 경우의 투여 방법, 제형, 투여량에 대해 설명한다.
본 발명의 화합물은 경구적 또는 비경구적으로 투여할 수 있으며, 경구 투여의 제형으로는 정제, 코팅 정제, 산제, 과립제, 캡슐제, 마이크로캡슐제, 시럽제 등을 사용할 수 있고, 또한 비경구적 투여의 제형으로는 주사제(사용시 용해시켜 사용하는 주사용 동결 건조제를 포함함), 좌제 등을 사용할 수 있다. 이들 제형의조제는 약제학적으로 허용되는 부형제, 결합제, 활택제, 붕괴제, 현탁화제, 유화제, 방부제, 안정화제 및 분산제, 예컨대 유당, 백당, 전분, 덱스트린, 결정 셀룰로오스, 카올린, 탄산칼슘, 활석, 스테아린산 마그네슘, 증류수 또는 생리 식염수를 이용하여 행해진다.
투여량은 환자의 증상, 연령, 체중 등에 따라 달라지는데, 성인에 대한 1일량으로서 100∼1,000mg을 2∼3회로 나누어 투여할 수 있다.
이하, 본 발명의 화합물을 실시예를 참조로 하여 더욱 구체적으로 설명하겠으나, 본 발명은 이에 한정되지 않는다.
실시예 1)
2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(시스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘 (화합물 1)
(1) DMF 25ml에 2-디플루오로메틸벤즈이미다졸 0.84g(5mmol)을 용해시키고, 60% 수소화나트륨 0.24g(6mmol)을 첨가하고 실온에서 30분간 반응시켰다. 이 현탁액을, DMF 25ml에 2,4,6-트리클로로피리미딘 0.92g(5mmol)을 용해시킨 용액에 첨가하고, 실온에서 1.5 시간 교반하였다. 반응액을 물 속에 붓고 생성된 불용물을 메탄올로 재결정시켜, 4,6-디클로로-2-(2-디플루오로메틸벤즈이미다졸-1-일)피리미딘 0.98g(수율 62%)을 수득하였다.
(2) DMF 10ml에 4,6-디클로로-2-(2-디플루오로메틸벤즈이미다졸-1-일)피리미딘 0.32g(1.0mmol), 시스-2,3-디메틸모르폴린염산염 0.16g(1.0mmol) 및 무수탄산칼륨 0.3g(2.2mmol)을 첨가하고, 실온에서 16시간 교반하였다. 반응액을 물 속에 붓고 에틸아세테이트로 추출하여, 유기층을 분리한 다음 물로 세정하고, 무수황산마그네슘으로 건조시켰다. 감압하에 용매를 제거시키고, 잔류물을 실리카겔 칼럼 크로마토그래피에 의해 정제하여 4-클로로-2-(2-디플루오로메틸벤즈이미다졸-1- 일)-6-(시스-2,3-디메틸모르폴리노)피리미딘 0.33g(수율 84%)을 수득하였다.
(3) 수득된 4-클로로-2-(2-디플루오로메틸벤즈이미다졸-1-일)-6-(시스-2,3-디메틸모르폴리노)피리미딘 0.33g(0.8mmol)을 모르폴린 0.70g(8.0mmol)에 용해시키고 70℃에서 1시간 교반하였다. 반응 혼합물로부터 감압하에 용매를 제거시키고, 잔류물을 실리카겔 칼럼 크로마토그래피에 의해 정제하여, 표제 화합물을 무색 결정으로서 0.326g(수율 90%) 수득하였다.
융점 : 167-169℃
실시예 1)과 동일하게 하여, 그에 상당하는 출발 원료로부터 하기 화합물을 제조하였다.
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4,6-디모르폴리노피리미딘 (화합물 2)
융점 : 201-202℃
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-티오모르폴리노피리미딘 (화합물 3)
융점 : 173-175℃
MS m/z: 432(M
+
)
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘 (화합물 4)
융점 : 172-174℃
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노피리미딘 (화합물 5)
융점 : 149-152℃
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(2-메틸모르폴리노)-6-모르폴리노피리미딘 (화합물 6)
융점 : 126-131℃
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-[2,2,5(R)-트리메틸모르폴리노]피리미딘 (화합물 7)
융점 : 113-116℃
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-[2,2,5(S)-트리메틸모르폴리노]피리미딘 (화합물 8)
융점 : 113-116℃
·4-(시스-2,3-디메틸모르폴리노)-2-(2-플루오로메틸벤즈이미다졸-1-일)-6-모르폴리노피리미딘 (화합물 9)
융점 : 163-165℃
실시예 2)
2-(2-아미노벤즈이미다졸-1-일)-4-(시스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘
실시예 1)의 (1)의 2-디플루오로메틸벤즈이미다졸을 2-아미노벤즈이미다졸로 바꾸는 것 이외에는 실시예 1)과 동일하게 하여, 표제 화합물을 무색 결정으로서 27mg(수율 90%) 수득하였다.
융점 : 129-133℃
실시예 2)와 동일하게 하여, 그에 상당하는 출발 원료로부터 하기 화합물을 제조하였다.
·2-(2-아미노벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘
융점 : 118-123℃
실시예 3)
4-(시스-2,3-디메틸모르폴리노)-2-(2-히드록시메틸벤즈이미다졸-1-일)-6-모르폴리노피리미딘 (화합물 10)
실시예 1)의 (1)의 2-디플루오로메틸벤즈이미다졸을 2-3차-부틸디메틸실릴옥시메틸벤즈이미다졸로 바꾸는 것 이외에는 실시예 1)과 동일하게 하여, 2-(2-3차-부틸디메틸실릴옥시메틸벤즈이미다졸-1-일)-4-(시스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘 1.62g(수율 80%)을 수득하였다. 생성된 화합물 1.62g(3.0mmol)을 THF 10ml에 용해시키고, 테트라부틸암모늄 플로라이드 1.18g(4.5mmol)을 첨가하고 실온에서 30분간 교반하였다. 반응액을 물 속에 붓고 실시예 1)의 2)와 동일하게처리를 한 후, 칼럼 크로마토그래피에 의해 정제하여 표제 화합물을 무색 결정으로서 0.86g(수율 67%) 수득하였다.
융점 : 125-128℃
MS m/z: 424 (M
+
)
실시예 3)과 동일하게 하여, 그에 상당하는 출발 원료로부터 하기 화합물을 제조하였다.
·4-(시스-2,3-디메틸모르폴리노)-2-(2-히드록시메틸벤즈이미다졸-1-일)-6-피페리디노피리미딘 (화합물 11)
융점 : 141-143℃
·4-(시스-2,3-디메틸모르폴리노)-2-(2-히드록시메틸벤즈이미다졸-1-일)-6-(2-히드록시메틸피롤리딘-1-일)피리미딘 (화합물 12)
융점 : 104-108℃
실시예 4)
2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(시스-2,3-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진 (화합물 13)
(1) DMF 250ml에 2,4-디클로로-6-모르폴리노-1,3,5-트리아진 11.8g(50mmol), 2-디플루오로메틸벤즈이미다졸 8.41g(50mmol) 및 무수탄산칼륨 55.3g(400mmol)을 첨가하고, 실온에서 16시간 교반하였다. 반응액을 물 속에 붓고, 생성된 불용물을 DMF 및 에탄올 세정하여, 4-클로로-2-(2-디플루오로메틸벤즈이미다졸-1-일)-6-모르폴리노-1,3,5-트리아진 15.7g(수율 86%)을 수득하였다.
(2) DMF 10ml에 수득된 4-클로로-2-(2-디플루오로메틸벤즈이미다졸-1-일)-6-모르폴리노-1,3,5-트리아진 0.36g(0.98mmol), 시스-2,3-디메틸모르폴린염산염 0.16g(1.0mmol) 및 무수탄산칼륨 0.3g(2.2mmol)을 첨가하고, 실온에서 16시간 교반하였다. 반응액을 물 속에 붓고 에틸아세테이트로 추출하여, 유기층을 분리한 다음 물로 세정하고, 무수황산마그네슘으로 건조시켰다. 감압하에 용매를 제거시키고, 잔류물을 실리카겔 칼럼 크로마토그래피에 의해 정제하여, 표제 화합물을 무색 결정으로서 0.38g(수율 87%) 수득하였다.
융점 : 207-210℃
실시예 4)와 동일하게 하여, 그에 상당하는 출발 원료로부터 하기 화합물을 제조하였다.
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진 (화합물 14)
융점 : 135-138℃
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진 (화합물 15)
융점 : 176-178℃
MS m/z: 445 (M
+
)
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-티오모르폴리노-1,3,5-트리아진 (화합물 16)
융점 : 215-217℃
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(2-메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진 (화합물 17)
융점 : 188-191℃
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-(트랜스-2,5-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진 (화합물 18)
융점 : 166-169℃
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진(화합물 19)
융점 : 211-214℃
·2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-[2,2,5(R)-트리메틸모르폴리노]-1,3,5-트리아진 (화합물 20)
융점 : 169-171℃
실시예 5)
2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-(테트라히드로-1,4-티아진-1-옥소-4-일)-1,3,5-트리아진 (화합물 21)
2-(2-디플루오로메틸벤즈이미다졸-1-일)-4-모르폴리노-6-티오모르폴리노-1,3,5-트리아진 0.61mg(1.4mmol)을 디클로로메탄 20ml에 용해시키고, m-클로로과안식향산 0.35g(2.0mmol)을 첨가하여, 실온에서 16시간 교반하였다. 반응액을 물 속에 붓고 에틸아세테이트로 추출하여, 유기층을 분리시킨 후 물로 세정하고, 무수황산마그네슘으로 건조시켰다. 감압하에 용매를 제거시키고, 잔류물을 실리카겔 칼럼 크로마토그래피에 의해 정제하여, 표제 화합물을 무색 결정으로서 0.27g(수율 42%) 수득하였다.
융점 : 225-226℃
MS m/z: 449 (M
+
)
실시예 6)
2-(2-아세틸아미노벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진 (화합물 22)
(1) DMF 300ml에 2-아미노벤즈이미다졸 9.32g(70mmol)을 용해시키고, 60% 수소화나트륨 2.80g(70mmol)을 첨가하고, 실온에서 30분간 반응시켰다. 이 현탁액을, DMF 200ml에 2-클로로-4,6-디모르폴리노-1,3,5-트리아진 14.3g(50mmol)을 용해시킨 용액에 첨가하고, 실온에서 2시간 교반하였다. 반응액을 물 속에 붓고 생성된 불용물을 물, 메탄올로 세정하여, 2-(2-아미노벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진 17.7g(수율 93%) 수득하였다.
(2) 클로로포름 5ml에 2-(2-아미노벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진 0.38g(1.0mmol) 및 초산 0.24g(4.0mmol)을 첨가하고, DDC 0.83g(4.0mmol)을 더 첨가하고 실온에서 4시간 교반하였다. 반응액을 물 속에 붓고 에틸아세테이트로 추출하여, 유기층을 분리한 다음 물로 세정하고, 무수황산마그네슘으로 건조시켰다. 감압하에 용매를 제거시키고, 잔류물을 실리카겔 칼럼 크로마토그래피에 의해 정제하여, 표제 화합물을 무색 결정으로서 0.31g(수율 73%) 수득하였다.
융점 : 243-245℃
실시예 6)과 동일하게 하여, 그에 상당하는 출발 원료로부터 하기 화합물을 제조하였다.
·2-(2-아세틸아미노벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘 (화합물 23)
융점 : 150-153℃
·2-(2-포르밀아미노벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진 (화합물 24)
융점 : 221-223℃
·2-(2-프로피오닐아미노벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진 (화합물 25)
융점 : 166-168℃
·2-(트랜스-2,3-디메틸모르폴리노)-4-(2-포르밀아미노벤즈이미다졸-1-일)-6-모르폴리노-1,3,5-트리아진 (화합물 26)
융점 : 189-191℃
MS m/z: 438 (M
+
)
·4-(트랜스-2,3-디메틸모르폴리노)-2-(2-포르밀아미노벤즈이미다졸-1-일)-6-모르폴리노피리미딘 (화합물 27)
융점 : 143-146℃
·2-(시스-2,6-디메틸모르폴리노)-4-(2-포르밀아미노벤즈이미다졸-1-일)-6-모르폴리노-1,3,5-트리아진 (화합물 28)
융점 : 242-244℃
실시예 7)
2-(2-메톡시카르보닐아미노벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진 (화합물 29)
DMF 2ml에 실시예 6)의 (1)에서 합성된 2-(2-아미노벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진 0.19g(0.50mmol) 및 60% 수소화나트륨 24g(0.60mmol)을 첨가하고, 실온에서 1시간 반응시켰다. 이 반응 혼합물에, 클로로포름산메틸0.040ml(0.55mmol)을 첨가하고, 실온에서 16시간 반응하였다. 반응액을 물 속에 붓고 에틸아세테이트로 추출하여, 유기층을 분리한 다음 물로 세정하고, 무수황산마그네슘으로 건조시켰다. 감압하에 용매를 제거시키고, 잔류물을 실리카겔 칼럼 크로마토그래피에 의해 정제하여, 표제 화합물을 무색 결정으로서 100mg(수율 46%) 수득하였다.
융점 : 206-209℃
실시예 8)
2-(6-아미노-2-디플루오로메틸벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노-1,3,5-트라아진 (화합물 32)
(1) 아세톤 700ml에 2,4-디클로로-6-모르폴리노-1,3,5-트리아진 49.4g(210mmol), 2-디플루오로메틸-5-니트로벤즈이미다졸 44.8g(210mmol) 및 탄산칼륨 34.5g을 첨가하고, 실온에서 16시간 교반하였다. 반응액을 물 속에 붓고, 생성된 석출물을 물과 아세톤으로 세정하여, 4-클로로-2-(2-디플루오로메틸-5-니트로벤즈이미다졸-1-일)-6-모르폴리노-1,3,5-트리아진과 4-클로로-2-(2-디플루오로메틸-6-니트로벤즈이미다졸-1-일)-6-모르폴리노-1,3,5-트리아진의 혼합물 61.4g(수율 71%)을 수득하였다.
(2) 생성된 혼합물 0.72g과 2,2-디메틸모르폴린염산염 0.32g(2.1mmol) 및 탄산칼륨 0.6g을 DMF 10ml에 첨가하고, 실온에서 16시간 교반하였다. 반응액을 물 속에 붓고 에틸아세테이트로 추출하여, 유기층을 분리한 다음 물로 세정하고, 무수황산마그네슘으로 건조하여, 2-(2-디플루오로메틸-5-니트로벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진 및 2-(2-디플루오로메틸-6-니트로벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진의 혼합물 0.76g(수율 89%)을 수득하였다.
(3) 상기 (2)로부터 생성된 혼합물 0.76g을 에탄올 50ml에 현탁시키고, 촉매로서 10% Pd-C 0.10g의 존재하에, 실온에서 수소 분위기하에, 접촉 환원시켰다. 불용 부분을 여별하여, 감압하에 용매를 제거시키고, 잔류물을 실리카겔 칼럼 크로마토그래피에 의해 정제하여, 표제 화합물을 무색 결정으로서 0.65g(수율 92%) 수득하였다.
융점 : 226-227℃(분해)
실시예 8)과 동일하게 하여, 그에 상당하는 출발 원료로부터 하기 화합물을 제조하였다.
·2-(6-아미노-2-디플루오로메틸벤즈이미다졸-1-일)-4-(2,3-시스-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진 (화합물 33)
융점 : 220-222℃(분해)
·2-(4-아미노-2-디플루오로메틸벤즈이미다졸-1-일)-4,6-디모르폴리노-1,3,5-트리아진 (화합물 34)
융점 : 214-216℃(분해)
실시예 9)
2-(6-아미노-2-디플루오로메틸벤즈이미다졸-1-일)-4,6-디모르폴리노피리미딘 (화합물 35)
실시예 1)의 (1)의 2-디플루오로메틸벤즈이미다졸을 2-디플루오로-6-니트로벤즈이미다졸로 바꾸는 것 이외에는 실시예 1)과 동일하게 하여, 2-(2-디플루오로메틸-5-니트로벤즈이미다졸-1-일)-4,6-디모르폴리노피리미딘 및 2-(2-디플루오로메틸-6-니트로벤즈이미다졸-1-일)-4,6-디모르폴리노피리미딘의 혼합물을 수득하였다. 이 혼합물 0.92g(2.0mmol)을 이용하여 실시예 8)의 (3)과 동일하게 하여, 표제 화합물을 무색 결정으로서 0.76g(수율 88%) 수득하였다.
융점 : 218-219℃(분해)
실시예 9)와 동일하게 하여, 그에 상당하는 출발 원료로부터 하기 화합물을 제조하였다.
·2-(6-아미노-2-디플루오로메틸벤즈이미다졸-1-일)-4-(2,3-시스-디메틸모르폴리노)-6-모르폴리노피리미딘 (화합물 36)
융점 : 155-158℃(분해)
실시예 10)
2-(2-디플루오로메틸-5-히드록시벤즈이미다졸-1-일)-4-(2,3-시스-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진 (화합물 37)
실시예 4)의 (1)의 2-디플루오로메틸벤즈이미다졸을 2-디플루오로메틸-5-3차-부틸디메틸실릴옥시벤즈이미다졸로 바꾸는 것 이외에는 실시예 4)와 동일하게 하여, 2-(2-디플루오로메틸-5-3차-부틸디메틸실릴옥시벤즈이미다졸-1-일)-4-(2,3-시스-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진을 수득하였다. 얻어진 화합물 120mg(0.22mmol)을 THF 2ml에 용해시키고, 테트라부틸암모늄 플로라이드 1M THF 용액 0.51ml를 첨가하고, 실온에서 30분간 교반하였다. 반응액을 물 속에 붓고 에틸아세테이트로 추출하여, 유기층을 분리한 다음 물로 세정하고, 무수황산마그네슘으로 건조시켰다. 감압하에 용매를 제거시키고, 잔류물을 실리카겔 칼럼 크로마토그래피에 의해 정제하여, 표제 화합물을 무색 결정으로서 75mg(수율 79%) 수득하였다.
융점 : 170-175℃(분해)
실시예 10)과 동일하게 하여, 그에 상당하는 출발 원료로부터 하기 화합물을 제조하였다.
·2-(2-디플루오로메틸-4-히드록시벤즈이미다졸-1-일)-4-(2,2-디메틸모르폴리노)-6-모르폴리노-1,3,5-트리아진 (화합물 38)
융점 : 228-231℃(분해)
·2-(2-디플루오로메틸-5-히드록시벤즈이미다졸-1-일)-4-(2,2-디메틸옥사졸리딘-3-일)-6-모르폴리노-1,3,5-트리아진 (화합물 39)
융점 : 239-243℃(분해)
실시예 11)
2-(2-디플루오로메틸-5-히드록시벤즈이미다졸-1-일)-4,6-디모르폴리노피리미딘 (화합물 40)
실시예 1)의 (1)의 2-디플루오로메틸벤즈이미다졸을 2-디플루오로메틸-5-3 차-부틸디메틸실릴옥시벤즈이미다졸로 바꾸는 것 이외에는 실시예 1)과 동일하게 하여, 2-(2-디플루오로메틸-5-3차-부틸디메틸실릴옥시벤즈이미다졸-1-일)-4,6-디모르폴리노피리미딘을 수득하였다. 생성된 화합물 0.55mg(1.0mmol)을 THF 10ml에 용해시키고, 테트라부틸암모늄 플로라이드 1M THF 용액 2ml를 첨가하고, 실온에서 30분간 교반하였다. 반응액을 물 속에 붓고 에틸아세테이트로 추출하여, 유기층을 분리한 다음 물로 세정하고, 무수황산마그네슘으로 건조시켰다. 감압하에 용매를 제거시키고, 잔류물을 실리카겔 칼럼 크로마토그래피에 의해 정제하여, 표제 화합물을 무색 결정으로서 0.40g(수율 93%) 수득하였다.
융점 : 223-226℃(분해)
실시예 12)
2-(2-아미노벤즈이미다졸-1-일)-4-(시스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘염산염 (화합물 30)
실시예 2)에서 수득된 2-(2-아미노벤즈이미다졸-1-일)-4-(시스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘 1.23g(3.0mmol)을 2N 염산 3.0ml에 용해시킨 후, 감압하에 농축시켜서 생성된 결정을 여과 추출하여, 표제 화합물을 무색 결정으로서 1.20g(수율 90%) 수득하였다.
융점 : 151-155℃
실시예 12)와 동일하게 하여, 그에 상당하는 출발 원료로부터 하기 화합물을 제조하였다.
·2-(2-아미노벤즈이미다졸-1-일)-4-(트랜스-2,3-디메틸모르폴리노)-6-모르폴리노피리미딘염산염 (화합물 31)
융점 : 141-145℃
본 발명의 화합물은 아로마테이스의 저해 작용 없이 종래의 s-트리아진 유도체, 피리미딘 유도체에 비해 확실히 강력한 항종양 작용을 가지므로, 고형암의 치료에 응용할 수 있다.
Claims (10)
- 하기 화학식(Ⅰ)로 표시되는 헤테로시클릭 화합물 또는 이의 약제학적으로 허용되는 염.상기 식에서,X는 질소 원자 또는 CH이며;R1은 CHnF3-n(n은 1 또는 2), 히드록시 C1-C6알킬, NHR6[R6는 수소 원자, COR(R은 수소 원자, C1-C6알킬, C1-C6알콕시)임]이며;R2는 모르폴리노(1 내지 4개의 C1-C6알킬로 치환될 수 있음), 티오모르폴리노, 피페리디노, 피롤리디닐(히드록시 C1-C6알킬로 치환될 수 있음), 옥사졸리디닐(1 또는 2개의 C1-C6알킬로 치환될 수 있음), 테트라히드로-1,4-티아진-1-옥소-4-일이며;R3및 R4는 수소 원자 또는 C1-C6알킬이며;R5는 수소 원자, 아미노 또는 수산기이다.
- 제 1 항에 있어서, R1이 디플루오로메틸임을 특징으로 하는 화합물.
- 제 1 항에 있어서, R1이 디플루오로메틸이며, R2가 1 내지 3개의 메틸로 치환될 수 있는 모르폴리노이며, R3및 R4가 수소 원자 또는 메틸임을 특징으로 하는 화합물.
- 제 1 항에 있어서, R1이 디플루오로메틸이며, R2가 1 내지 3개의 메틸로 치환될 수 있는 모르폴리노이며, R3및 R4가 수소 원자이며, R5가 아미노 또는 수산기임을 특징으로 하는 화합물.
- 제 1 항에 있어서, R1이 히드록시메틸임을 특징으로 하는 화합물.
- 제 1 항에 있어서, R1이 히드록시메틸이며, R2가 1 또는 2개의 메틸로 치환될 수 있는 모르폴리노이며, R3및 R4가 수소 원자 또는 메틸임을 특징으로 하는 화합물.
- 제 1 항에 있어서, R1이 아미노, 포르밀아미노 또는 아세틸아미노임을 특징으로 하는 화합물.
- 제 1 항에 있어서, R1이 아미노, 포르밀아미노 또는 아세틸아미노이며, R2가 1 또는 2개의 메틸로 치환될 수 있는 모르폴리노이며, R3및 R4가 수소 원자임을 특징으로 하는 화합물.
- 제 1 항 내지 제 8 항 중 어느 한 항에 따른 하나 이상의 화합물을 유효 성분으로 하는 항종양제.
- 약제학적으로 허용되는 희석제 또는 담체와 함께, 항종양 활성 성분으로서 제 1 항 내지 제 8 항에 따른 화합물을 함유하는 약제 조성물.
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| JP2001132250 | 2001-04-27 | ||
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| PCT/JP2002/004227 WO2002088112A1 (fr) | 2001-04-27 | 2002-04-26 | Compose heterocyclique et agent antitumoral contenant ce dernier en tant qu'ingredient actif |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101130913B1 (ko) * | 2004-03-31 | 2012-03-28 | 젠야쿠코교가부시키가이샤 | 헤테로시클릭 화합물 및 이를 활성 성분으로서 포함하는항악성종양제 |
| KR101331341B1 (ko) * | 2008-05-23 | 2013-11-19 | 와이어쓰 엘엘씨 | Ｐｉ３ 키나제 및 ｍｔｏｒ 억제제로서의 트리아진 화합물 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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- 2002-04-26 KR KR1020037014035A patent/KR100833371B1/ko not_active IP Right Cessation
- 2002-04-26 ES ES02722829T patent/ES2280530T3/es not_active Expired - Lifetime
- 2002-04-26 CN CNB028126173A patent/CN1310907C/zh not_active Expired - Lifetime
- 2002-04-26 WO PCT/JP2002/004227 patent/WO2002088112A1/ja active IP Right Grant
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- 2002-04-26 CA CA2445395A patent/CA2445395C/en not_active Expired - Fee Related
- 2002-04-26 DK DK02722829T patent/DK1389617T3/da active
- 2002-04-26 JP JP2002585412A patent/JP3836436B2/ja not_active Expired - Lifetime
- 2002-04-26 AT AT02722829T patent/ATE350376T1/de active
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- 2006-07-03 US US11/478,647 patent/US7307077B2/en not_active Expired - Fee Related
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101130913B1 (ko) * | 2004-03-31 | 2012-03-28 | 젠야쿠코교가부시키가이샤 | 헤테로시클릭 화합물 및 이를 활성 성분으로서 포함하는항악성종양제 |
| KR101331341B1 (ko) * | 2008-05-23 | 2013-11-19 | 와이어쓰 엘엘씨 | Ｐｉ３ 키나제 및 ｍｔｏｒ 억제제로서의 트리아진 화합물 |
Also Published As
| Publication number | Publication date |
|---|---|
| DE60217322T2 (de) | 2007-10-04 |
| DK1389617T3 (da) | 2007-05-07 |
| EP1389617B1 (en) | 2007-01-03 |
| DE60217322D1 (de) | 2007-02-15 |
| US20060247232A1 (en) | 2006-11-02 |
| US7307077B2 (en) | 2007-12-11 |
| JPWO2002088112A1 (ja) | 2004-08-19 |
| CY1106522T1 (el) | 2012-01-25 |
| ATE350376T1 (de) | 2007-01-15 |
| CA2445395A1 (en) | 2002-11-07 |
| CA2445395C (en) | 2010-03-30 |
| PT1389617E (pt) | 2007-04-30 |
| EP1389617A4 (en) | 2006-03-29 |
| KR100833371B1 (ko) | 2008-05-28 |
| CN1538967A (zh) | 2004-10-20 |
| JP3836436B2 (ja) | 2006-10-25 |
| EP1389617A1 (en) | 2004-02-18 |
| US7071189B2 (en) | 2006-07-04 |
| CN1310907C (zh) | 2007-04-18 |
| AU2002253619B2 (en) | 2007-05-17 |
| WO2002088112A1 (fr) | 2002-11-07 |
| ES2280530T3 (es) | 2007-09-16 |
| US20040116421A1 (en) | 2004-06-17 |
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