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KR950701335A - 7-disubstituted methyl-4-oxo-3H, 5H-pyrrolo [3,2-d] pyrimidine and pharmaceutical compositions containing same - Google Patents

7-disubstituted methyl-4-oxo-3H, 5H-pyrrolo [3,2-d] pyrimidine and pharmaceutical compositions containing same

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KR950701335A
KR950701335A KR1019940703788A KR19940703788A KR950701335A KR 950701335 A KR950701335 A KR 950701335A KR 1019940703788 A KR1019940703788 A KR 1019940703788A KR 19940703788 A KR19940703788 A KR 19940703788A KR 950701335 A KR950701335 A KR 950701335A
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시리 나와스
써드 존 에이. 시크리스트
존 에이. 몽고메리
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존 에어. 몽고메리
바이오크리스트 파마슈티컬즈, 인코포레이티드
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Abstract

약학적으로 유용한 하기 일반식(Ⅰ)의 화합물이 기재되어 있다 :Pharmaceutically useful compounds of formula (I) are described below:

식중에서, R1은 H, NH2또는 OCH3이고, R2는 경우에 따라 한개 이상의 헤테로원자를 함유하는 경우에 따라 치환된 시클릭 기이며, R3및 R4는 독립해서 H 또는 C1-4알킬이고, m은 0내지 4의 수이며, n은 0내지 6의 수이고, P는 0내지 1이며, X는 CN, CSNG2, PO(OH)2, COOH, SO2NH2, NH2, OH, CNHNH2, 테트라졸, 트리아졸 또는 COR5이고, 이때 R5는 C1-4알킬, CF3, NH2또는 OC1-4일킬이며, 또 Y는 0또는 NH임.Wherein R 1 is H, NH 2 or OCH 3 , R 2 is optionally a cyclic group optionally substituted with one or more heteroatoms, and R 3 and R 4 are independently H or C 1 -4 alkyl, m is a number from 0 to 4, n is a number from 0 to 6, P is 0 to 1, X is CN, CSNG 2 , PO (OH) 2 , COOH, SO 2 NH 2 , NH 2 , OH, CNHNH 2 , tetrazole, triazole or COR 5, wherein R 5 is C 1-4 alkyl, CF 3 , NH 2 or OC 1-4 yl, and Y is 0 or NH.

Description

7-이치환된 메틸-4-옥소-3H,5H-피롤로[3,2-d]-피리미딘 및 이를 함유하는 약제 조성물7-disubstituted methyl-4-oxo-3H, 5H-pyrrolo [3,2-d] pyrimidine and pharmaceutical compositions containing same

본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음Since this is an open matter, no full text was included.

Claims (37)

하기 구조식의 화합물을 포함하는 퓨린 뉴클레오사이드 포스포릴라제(PNP)억제제 :Purine nucleoside phosphorylase (PNP) inhibitors comprising a compound of the formula: 식중에서, R1은 H, NH2또는 OCH3이고, R2는 경우에 따라 한개 이상의 헤테로원자를 함유하는 경우에 따라 치환된 시클릭 기이며, R3및 R4는 독립해서 H 또는 C1-4알킬이고, m은 0내지 4의 수이며, n은 0내지 6의 수이고, P는 0내지 1이며, X는 CN, CSNG2, PO(OH)2, COOH, SO2NH2, NH2, OH, CNHNH2, 테트라졸, 트리아졸 또는 COR5이고, 이때 R5는 C1-4알킬, CF3, NH2또는 OC1-4일킬이며, 또 Y는 0또는 NH임.Wherein R 1 is H, NH 2 or OCH 3 , R 2 is optionally a cyclic group optionally substituted with one or more heteroatoms, and R 3 and R 4 are independently H or C 1 -4 alkyl, m is a number from 0 to 4, n is a number from 0 to 6, P is 0 to 1, X is CN, CSNG 2 , PO (OH) 2 , COOH, SO 2 NH 2 , NH 2 , OH, CNHNH 2 , tetrazole, triazole or COR 5, wherein R 5 is C 1-4 alkyl, CF 3 , NH 2 or OC 1-4 yl, and Y is 0 or NH. 제1항에 있어서, R2가 비치환된 억제제.The inhibitor of claim 1, wherein R 2 is unsubstituted. 제2항에 있어서, R1이 NH2이고, R3및 R4가 H이며, m이 0이고 또 n이 1인 억제제.The inhibitor of claim 2, wherein R 1 is NH 2 , R 3 and R 4 are H, m is 0 and n is 1. 4 . 제3항에 있어서, R2가 페닐인 억제제.4. The inhibitor of claim 3, wherein R 2 is phenyl. 제4항에 있어서, x가 CN인 억제제.The inhibitor of claim 4, wherein x is CN. 제4항에 있어서, X가 COOH인 억제제.The inhibitor of claim 4, wherein X is COOH. 제4항에 있어서, x가 CONH2인 억제제.The inhibitor of claim 4, wherein x is CONH 2 . 제3항에 있어서, R2가 2- 또는 3- 티엔일, 2- 또는 3- 푸란일, 2-, 3- 또는 4- 피리딘일, 2- 또는 3- 피롤릴 2-, 4-, 또는 5- 티아졸린, 2- 또는 3- 피라진일, 3- 또는 4- 피리다진일, 또는 피라졸릴인 억제제.The compound of claim 3, wherein R 2 is 2- or 3- thienyl, 2- or 3-furanyl, 2-, 3- or 4- pyridinyl, 2- or 3-pyrrolyl 2-, 4-, or Inhibitors that are 5-thiazoline, 2- or 3-pyrazinyl, 3- or 4- pyridazinyl, or pyrazolyl. 제8항에 있어서, X가 CN, COOH 또는 CONH2인 억제제.The inhibitor of claim 8, wherein X is CN, COOH or CONH 2 . 제3항에 있어서, R2가 1- 또는 2-아다만틸, 시클로헥실, 시클로헵실, 2- 또는 3-테트라히드로푸란일, 2- 또는 3-테트라히드로티엔일, 2- 또는 3-테트라히드로피란일, 2-, 3- 또는 4- 피페리딘일, 3- 또는 4-피라졸리딘일, 2-, 4- 또는 5-티아졸리딘일, 2- 또는 3-피레라진일, 2- 또는 3-모르폴린일 또는 헥사히드로피리다진일인 억제제.4. The compound of claim 3, wherein R 2 is 1- or 2-adamantyl, cyclohexyl, cycloheptyl, 2- or 3-tetrahydrofuranyl, 2- or 3-tetrahydrothienyl, 2- or 3-tetra Hydropyranyl, 2-, 3- or 4- piperidinyl, 3- or 4-pyrazolidinyl, 2-, 4- or 5-thiazolidinyl, 2- or 3-pyrazinylyl, 2- or 3 Inhibitors that are morpholinyl or hexahydropyridazinyl. 제10항에 있어서, X가 CN, COOH 또는 CONH2인 억제제.The inhibitor of claim 10, wherein X is CN, COOH or CONH 2 . 제3항에 있어서, R2가 시클로헥실이고 또 X가 COOH인 억제제.4. The inhibitor of claim 3, wherein R 2 is cyclohexyl and X is COOH. 제1항에 있어서, R2가 경우에 따라 치환된 5- 또는 6-원 방향족 또는 헤테로 방향족 기인 억제제.The inhibitor of claim 1, wherein R 2 is optionally substituted 5- or 6-membered aromatic or heteroaromatic group. 제1항에 있어서, R2가 경우에 따라 치환된 치환족 기 또는 5내지 9-원 헤테로지환족 기인 억제제.The inhibitor of claim 1, wherein R 2 is optionally a substituted group or a 5-9 membered heteroalicyclic group. 제1항에 있어서, R2가 적어도 한개의 할로겐, 히도록시, C1-4알콕시, C1-4알킬, 또는 트리플루오로메틸로 치환된 억제제.The inhibitor of claim 1, wherein R 2 is substituted with at least one halogen, hygioxy, C 1-4 alkoxy, C 1-4 alkyl, or trifluoromethyl. 제1항에 따른 유효량의 PNP억제제를 피검체에게 투여하는 것을 포함하는 액성 면역에 감소영향을 주시않고 포유류의 T-세포 기능을 선택적으로 억제하기 위한 방법.A method for selectively inhibiting T-cell function in a mammal without affecting humoral immunity comprising administering to the subject an effective amount of a PNP inhibitor according to claim 1. 제5항에 따른 유효량의 PNP억제제를 피검체에게 투여하는 것을 포함하는 액성 면역에 감소영향을 주지않고 포유류의 T-세포 기능을 선택적으로 억제하기 위한 방법.A method for selectively inhibiting T-cell function in a mammal without affecting humoral immunity comprising administering to the subject an effective amount of a PNP inhibitor according to claim 5. 제6항에 따른 유효량의 PNP억제제를 피검체에게 투여하는 것을 포함하는 액성 면역에 감소영향을 주지않고 포유류의 T-세포 기능을 선택적으로 억제하기 위한 방법.A method for selectively inhibiting T-cell function in a mammal without affecting humoral immunity comprising administering to the subject an effective amount of the PNP inhibitor according to claim 6. 제7항에 따른 유효량의 PNP억제제를 피검체에게 투여하는 것을 포함하는 액성 면역에 감소영향을 주지않고 포유류의 T-세포 기능을 선택적으로 억제하기 위한 방법.A method for selectively inhibiting T-cell function in a mammal without affecting humoral immunity comprising administering to the subject an effective amount of a PNP inhibitor according to claim 7. 제8항에 따른 유효량의 PNP억제제를 피검체에게 투여하는 것을 포함하는 액성 면역에 감소영향을 주지않고 포유류의 T-세포 기능을 선택적으로 억제하기 위한 방법.A method for selectively inhibiting T-cell function in a mammal without affecting humoral immunity comprising administering to the subject an effective amount of a PNP inhibitor according to claim 8. 제10항에 따른 유효량의 PNP억제제를 피검체에게 투여하는 것을 포함하는 액성 면역에 감소영향을 주지않고 포유류의 T-세포 기능을 선택적으로 억제하기 위한 방법.A method for selectively inhibiting T-cell function in a mammal without affecting humoral immunity comprising administering to the subject an effective amount of a PNP inhibitor according to claim 10. 제12항에 따른 유효량의 PNP억제제를 피검체에게 투여하는 것을 포함하는 액성 면역에 감소영향을 주지않고 포유류의 T-세포 기능을 선택적으로 억제하기 위한 방법.A method for selectively inhibiting T-cell function in a mammal without affecting humoral immunity comprising administering to the subject an effective amount of a PNP inhibitor according to claim 12. 유효량의 제1항에 따른 PNP억제제 및 약학적으로 허용되는 담체 또는 희석제를 포함하는 액성 면역에 감소영향 없이 포유류의 T-세포 기능을 선택적으로 억제하기 위한 약제 조성물.A pharmaceutical composition for selectively inhibiting mammalian T-cell function without reducing the humoral immunity comprising an effective amount of the PNP inhibitor according to claim 1 and a pharmaceutically acceptable carrier or diluent. 유효량의 제5항에 따른 PNP억제제 및 약학적으로 허용되는 담체 또는 희석제를 포함하는 액성 면역에 감소영향 없이 포유류의 T-세포 기능을 선택적으로 억제하기 위한 약제 조성물.A pharmaceutical composition for selectively inhibiting mammalian T-cell function without reducing the humoral immunity comprising an effective amount of the PNP inhibitor according to claim 5 and a pharmaceutically acceptable carrier or diluent. 유효량의 제6항에 따른 PNP억제제 및 약학적으로 허용되는 담체 또는 희석제를 포함하는 액성 면역에 감소영향 없이 포유류의 T-세포 기능을 선택적으로 억제하기 위한 약제 조성물.A pharmaceutical composition for selectively inhibiting mammalian T-cell function without reducing the humoral immunity comprising an effective amount of the PNP inhibitor according to claim 6 and a pharmaceutically acceptable carrier or diluent. 유효량의 제7항에 따른 PNP억제제 및 약학적으로 허용되는 담체 또는 희석제를 포함하는 액성 면역에 감소영향 없이 포유류의 T-세포 기능을 선택적으로 억제하기 위한 약제 조성물.A pharmaceutical composition for selectively inhibiting mammalian T-cell function without reducing the humoral immunity, comprising an effective amount of the PNP inhibitor according to claim 7 and a pharmaceutically acceptable carrier or diluent. 유효량의 제8항에 따른 PNP억제제 및 약학적으로 허용되는 담체 또는 희석제를 포함하는 액성 면역에 감소영향 없이 포유류의 T-세포 기능을 선택적으로 억제하기 위한 약제 조성물.A pharmaceutical composition for selectively inhibiting mammalian T-cell function without reducing the humoral immunity comprising an effective amount of the PNP inhibitor according to claim 8 and a pharmaceutically acceptable carrier or diluent. 유효량의 제10항에 따른 PNP억제제 및 약학적으로 허용되는 담체 또는 희석제를 포함하는 액성 면역에 감소영향 없이 포유류의 T-세포 기능을 선택적으로 억제하기 위한 약제 조성물.A pharmaceutical composition for selectively inhibiting mammalian T-cell function without reducing the humoral immunity comprising an effective amount of the PNP inhibitor according to claim 10 and a pharmaceutically acceptable carrier or diluent. 유효량의 제12항에 따른 PNP억제제 및 약학적으로 허용되는 담체 또는 희석제를 포함하는 액성 면역에 감소영향 없이 포유류의 T-세포 기능을 선택적으로 억제하기 위한 약제 조성물.A pharmaceutical composition for selectively inhibiting mammalian T-cell function without reducing the humoral immunity comprising an effective amount of the PNP inhibitor according to claim 12 and a pharmaceutically acceptable carrier or diluent. a)경우에 따라 치환된 시클릭 알데히드를 아세트산 암모늄 존재하에서 시아노아세트산과 반응시켜 3-시클로-치환된 펜탄디니트릴을 제조하고; b)상기 3-시클로-펜탄디니트릴을 알킬 포르메이트 및 염기와 반응시켜 3-시클로-포르밀펜탄디니트릴을 제조하며; c)상기 3-시클로-2-포르밀펜탄디니트릴을 글리신 메틸 에스테를 염산염 및 아세트산 나트륨 또는 아세트산 암모늄과 반응시켜 메틸 N-[(3-시클로-2,4-디사아노)-2-부텐일]글리신을 제조하고; d)상기 메틸 N-[(3-시클로-2,4-디사아노)-2-부텐일]글리신을 알킬 클로로포르메이트 및 DBN 또는 DBU와 반응시켜 메틸 3-아미노-4-(2-시아노-1-시클로-에틸)-1-에틸-1H-피롤-1,2-디카르복실레이트를 제조하며; 또 e)상기 메틸 3-아미노-4-(2-시아노-1-시클로-에틸)-1-에틸-1H-피롤-1,2-디카르복실레이트를 염기와 반응시켜 메틸 3-아미노-4-(2-시아노-1-시클로-에틸)-1H-피롤-2-카르복실레이트를 제조하는 단계를 포함하는 화학물질의 제조방법.a) optionally substituted cyclic aldehydes with cyanoacetic acid in the presence of ammonium acetate to produce 3-cyclo-substituted pentanedinitrile; b) reacting said 3-cyclo-pentanedinitrile with alkyl formate and base to produce 3-cyclo-formylpentanedinitrile; c) The 3-cyclo-2-formylpentanedinitrile is reacted with glycine methyl ester with hydrochloride and sodium acetate or ammonium acetate to give methyl N-[(3-cyclo-2,4-diisano) -2-butenyl ] Glycine is prepared; d) reacting the methyl N-[(3-cyclo-2,4-diisano) -2-butenyl] glycine with alkyl chloroformate and DBN or DBU to yield methyl 3-amino-4- (2-cyano -1-cyclo-ethyl) -1-ethyl-1H-pyrrole-1,2-dicarboxylate; E) methyl 3-amino-4- (2-cyano-1-cyclo-ethyl) -1-ethyl-1H-pyrrole-1,2-dicarboxylate is reacted with a base to give methyl 3-amino- A process for preparing a chemical comprising the step of preparing 4- (2-cyano-1-cyclo-ethyl) -1H-pyrrole-2-carboxylate. 제30에 있어서, f)상기 메틸 3-아미노-4-(2-시아노-1-시클로-에틸)-1H-피롤-1,2-카르복실레이트를 벤조일이소티오시아네이트와 반응시켜 N-벤조일-N′-[4-(2-시아노-1-시클로에틸)-2-메톡시카르보닐-1H-피롤-3-일]티오우레아를 제조하고; g)상기 N-벤조일-N′-[4-(2-시아노-1-시클로에틸)-2-메톡시카르보닐-1H-피롤-3-일]티오우레아를 알킬 할라이드와 반응시켜 N-벤조일-N′-[4-(2-시아노-1-시클로에틸)-2-메톡시카르보닐-1H-피롤-3-일]-S-메틸티오우레아를 제조하며; 또 h)상기 N-벤조일-N′-[4-(2-시아노-1-시클로에틸)-2-메톡시카르보닐-1H-피롤-3-일]-S-메틸티오우레아를 메탄올 암노니아 또는 에탄올 암모니아와 반응시켜 3-시틀로-3[2-아미노-4-옥소-3H,5H-피롤로C3,4-d]피리미딘-7-일]프로판니트릴의 혼합물을 제조하는 추가의 단계를 포함하는 방법.The method of claim 30, wherein f) the methyl 3-amino-4- (2-cyano-1-cyclo-ethyl) -1H-pyrrole-1,2-carboxylate is reacted with benzoylisothiocyanate to give N- To prepare benzoyl-N ′-[4- (2-cyano-1-cycloethyl) -2-methoxycarbonyl-1H-pyrrol-3-yl] thiourea; g) reacting the N-benzoyl-N '-[4- (2-cyano-1-cycloethyl) -2-methoxycarbonyl-1H-pyrrol-3-yl] thiourea with an alkyl halide to yield To prepare benzoyl-N ′-[4- (2-cyano-1-cycloethyl) -2-methoxycarbonyl-1H-pyrrol-3-yl] -S-methylthiourea; And h) N-benzoyl-N ′-[4- (2-cyano-1-cycloethyl) -2-methoxycarbonyl-1H-pyrrol-3-yl] -S-methylthiourea as a methanol arm. Further to react with nonia or ethanol ammonia to produce a mixture of 3-citro-3 [2-amino-4-oxo-3H, 5H-pyrroloC3,4-d] pyrimidin-7-yl] propanenitrile Method comprising the steps. 제31항에 있어서, ⅰ)3-시클로-3-[2-메틸머캅토-4-옥소-3H,5H-피롤로[3,2,-d]피리미딘-7-일]프로판니트릴을 산화제와 반응시켜 3-시클로-3-[2-메틸술포닐-4-옥소-3H,5H-피롤로[3,2,-d]피리미딘-7-일]프로판니트릴을 제조하고; 또 j)상기 3-시클로-3-[2-메틸술포닐-4-옥소-3H,5H-피롤로[3,2,-d]피리미딘-7-일]프로판니트릴을 알콕시화 나트륨과 반응시켜 3-시클로-3-[2-메톡시-4-옥소-3H,5H-피롤로[3,2,-d]피리미딘-7-일]프로판니트릴을 제조하는 추가의 단계를 포함하는방법.The oxidizing agent of claim 31, wherein iii) 3-cyclo-3- [2-methylmercapto-4-oxo-3H, 5H-pyrrolo [3,2, -d] pyrimidin-7-yl] propanenitrile is oxidized To react with 3-cyclo-3- [2-methylsulfonyl-4-oxo-3H, 5H-pyrrolo [3,2, -d] pyrimidin-7-yl] propanenitrile; J) reacting the 3-cyclo-3- [2-methylsulfonyl-4-oxo-3H, 5H-pyrrolo [3,2, -d] pyrimidin-7-yl] propanenitrile with sodium alkoxylated To obtain 3-cyclo-3- [2-methoxy-4-oxo-3H, 5H-pyrrolo [3,2, -d] pyrimidin-7-yl] propanenitrile . 제30항에 있어서, f)메틸 3-아미노-4-[2-시아노-1-시클로-에틸)-1H-피롤-2-카르복실레이트를 디메틸포름아미드 디메틸 아세탈과 반응시켜 메틸 4-(2-시아노-1-시클로-에틸)-3-[N-(디메틸아미노메틸렌)아미노]-1H-피롤-2-카르복실레이트로 제조하고; 또 g)상기 메틸 4-(2-시아노-1-시클로-에틸)-3-[N-(디메틸아미노메틸렌)아미노]-1H-피롤-2-카르복실레이트를 메탄을 암모니아와 반응시켜 3-시클로-3-[4-옥소-3H,5H1-피롤로[3,2,-d]피리미딘-7-일]프로판니트릴을 제조하는 추가의 단계를 포함하는 방법.The method of claim 30, wherein f) methyl 3-amino-4- [2-cyano-1-cyclo-ethyl) -1H-pyrrole-2-carboxylate is reacted with dimethylformamide dimethyl acetal to Prepared with 2-cyano-1-cyclo-ethyl) -3- [N- (dimethylaminomethylene) amino] -1H-pyrrole-2-carboxylate; G) The methyl 4- (2-cyano-1-cyclo-ethyl) -3- [N- (dimethylaminomethylene) amino] -1H-pyrrole-2-carboxylate was reacted with methane to ammonia, and A further step of preparing -cyclo-3- [4-oxo-3H, 5H1-pyrrolo [3,2, -d] pyrimidin-7-yl] propanenitrile. 제30항에 있어서, 시클릭 치환기가 페닐인 방법.The method of claim 30, wherein the cyclic substituent is phenyl. 제30항에 있어서, 시클릭 치환기가 2- 또는 3-티엔일, 2- 또는 3-푸란일, 2-, 3- 또는 4-피리딘일, 2- 또는 3-피롤릴, 2-, 4- 또는 5-티아졸릴, 2- 또는 3-피라진일, 3- 또는 4-피리다진일 또는 3-, 4- 또는 5-피라졸릴인 방법.The cyclic substituent of claim 30, wherein the cyclic substituent is 2- or 3-thienyl, 2- or 3-furanyl, 2-, 3- or 4-pyridinyl, 2- or 3-pyrrolyl, 2-, 4- Or 5-thiazolyl, 2- or 3-pyrazinyl, 3- or 4-pyridazinyl or 3-, 4- or 5-pyrazolyl. 제30항에 있어서, 시클릭 치환기가 1- 또는 2-아다만틸, 시클로펜틸, 시클로헥실, 시클로헵틸 및 모르폴린일인 방법.The method of claim 30, wherein the cyclic substituents are 1- or 2-adamantyl, cyclopentyl, cyclohexyl, cycloheptyl and morpholinyl. 하기 구조식의 화합물 :Compound of formula 식중에서, R1및 R2는 제1항에서 정의한 바와 같다.Wherein R 1 and R 2 are as defined in claim 1. ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.※ Note: The disclosure is based on the initial application.
KR1019940703788A 1992-04-21 1993-03-25 7-disubstituted methyl-4-oxo-3H, 5H-pyrrolo [3,2-d] pyrimidine and pharmaceutical compositions containing same Ceased KR950701335A (en)

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