KR20010102199A - C-21 변형 에포틸론 - Google Patents
C-21 변형 에포틸론 Download PDFInfo
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- KR20010102199A KR20010102199A KR1020017010421A KR20017010421A KR20010102199A KR 20010102199 A KR20010102199 A KR 20010102199A KR 1020017010421 A KR1020017010421 A KR 1020017010421A KR 20017010421 A KR20017010421 A KR 20017010421A KR 20010102199 A KR20010102199 A KR 20010102199A
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- dihydroxy
- thiazolyl
- dioxabicyclo
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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
- C07D417/02—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 two hetero rings
- C07D417/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
화합물 | L929 마우스 | KB-3.1 경부 | KB-V1* 경부 | PC-3-전립선 | SK-OV-3-난소 | A-549 폐 | K-562/U-937 백혈병 |
IC50[ng/㎖] | |||||||
21-클로로-에포 A[3] | 170 | 60 | 8 | 10 | 12 (K-562) | ||
에포 A-20-카르발독심 [22a] | 7 | ||||||
에포 A-20-카르발데히드 히드라존 | 12 | ||||||
21-아지도-에포 A [22b] | 6 | ||||||
21-아미노-에포 A [9] | 8 | 4 | 30 | 3 | 4 | 3 (U-937) | |
20-비닐-에포 A [15] | 3 | 3 | 3 | 0.4 | 1 | 1.5 (U-937) | |
21-아지도-에포 B [7] | 0.6 | 0.5 | 0.5 | 0.4 | |||
21-아미노-에포 B [9] | 0.5 | 0.4 | 1.5 | 1.5 | |||
* 다중내성 세포주 |
Claims (30)
- 하기 화학식 I의 화합물.<화학식 I>식 중,P-Q는 탄소-탄소 이중 결합이거나 또는 에폭시드이고,G는또는이고,R은 H, 알킬 및 치환된 알킬의 군으로부터 선택되고,R1은로 이루어진 군으로부터 선택되고,R2는이고,G1은 H, 할로겐, CN, 알킬 및 치환된 알킬의 군으로부터 선택되고,G2는 H, 알킬 및 치환된 알킬의 군으로부터 선택되고,G3은 O, S 및 NZ1의 군으로부터 선택되고,G4는 H, 알킬, 치환된 알킬, OZ2, NZ2Z3, Z2C=O, Z4SO2및 임의로 치환된 글리코실의 군으로부터 선택되고,G5는 할로겐, N3, NCS, SH, CN, NC, N(Z1)3 +및 헤테로아릴의 군으로부터 선택되고,G6은 H, 알킬, 치환된 알킬, CF3, OZ5, SZ5및 NZ5Z6의 군으로부터 선택되고,G7은 CZ7또는 N이고,G8은 H, 할로겐, 알킬, 치환된 알킬, OZ10, SZ10, NZ10Z11의 군으로부터 선택되고,G9는 O, S, -NH-NH- 및 -N=N-의 군으로부터 선택되고,G10은 N 또는 CZ12이고,G11은 H2N, 치환된 H2N, 알킬, 치환된 알킬, 아릴 및 치한된 아릴의 군으부터 선택되고;Z1, Z6, Z9및 Z11은 H, 알킬, 치환된 알킬, 아실 및 치환된 아실의 군으로부터 독립적으로 선택되고,Z2는 H, 알킬, 치환된 알킬, 아릴, 치환된 아릴 및 헤테로고리의 군으로부터 선택되고,Z3, Z5, Z8및 Z10은 H, 알킬, 치환된 알킬, 아실, 치환된 아실, 아릴 및 치환된 아릴의 군으로부터 독립적으로 선택되고,Z4는 알킬, 치환된 알킬, 아릴, 치환된 아릴 및 헤테로고리의 군으로부터 선택되고,Z7은 H, 할로겐, 알킬, 치환된 알킬, 아릴, 치환된 아릴, OZ8, SZ8및 NZ8Z9의 군으로부터 선택되고,Z12는 H, 할로겐, 알킬, 치환된 알킬, 아릴 및 치환된 아릴의 군으로부터 선택되되;단, R1이인 경우, G1, G2, G3및 G4는 동시에 G1및 G2가 H이고, G3이 0이고, G4가 H 또는 Z2C=O (여기서, Z2는 알킬기임)는 아니다.
- 제1항에 있어서, 하기 화학식 Ia의 화합물.<화학식 Ia>식 중,P-Q는 탄소-탄소 이중 결합 또는 에폭시드이고,R은 H 원자 또는 메틸기이고,G1은 H 원자, 알킬기, 치환된 알킬기 또는 할로겐 원자이고,G2는 H 원자, 알킬기 또는 치환된 알킬기이고,G3은 O 원자, S 원자 또는 NZ1기 (여기서, Z1은 H 원자, 알킬기, 치환된 알킬기, 아실기 또는 치환된 아실기임)이고,G4는 H 원자, 알킬기, 치환된 알킬기, OZ2기, NZ2Z3기, Z2C=O기, Z4SO2기 (여기서, Z2는 H 원자, 알킬기, 치환된 알킬기, 아릴기, 치환된 아릴기 또는 헤테로고리기이고, Z3은 H 원자, 알킬기, 치환된 알킬기, 아실기 또는 치환된 아실기이고, Z4는 알킬, 치환된 알킬, 아릴, 치환된 아릴 또는 헤테로고리기임) 또는 임의로 치환된 글리코실기이되;단, G1, G2, G3및 G4는 동시에 G1및 G2가 H 원자이고, G3이 0 원자이고, G4가 H 원자 또는 Z2C=O (여기서, Z2는 알킬기임)는 아니다.
- 제2항에 있어서, G3이 0 원자인 화합물.
- 제2항에 있어서, G3이 S 원자인 화합물.
- 제2항에 있어서, G3이 NZ1인 화합물.
- 제1항에 있어서, 하기 화학식 Ib의 화합물.<화학식 Ib>식 중,P-Q는 탄소-탄소 이중 결합 또는 에폭시드이고,R은 H 원자 또는 메틸기이고,G1은 H 원자, 알킬기, 치환된 알킬기 또는 할로겐 원자이고,G2는 H 원자, 알킬기 또는 치환된 알킬기이고,G5는 할로겐 원자, N3기, NCS기, SH기, CN기, NC기 또는 헤테로고리기이다.
- 제6항에 있어서, G5가 N3기인 화합물.
- 제6항에 있어서, G5가 NCS기인 화합물.
- 제6항에 있어서, G5가 SH기인 화합물.
- 제6항에 있어서, G5가 CN기인 화합물.
- 제6항에 있어서, G5가 NC기인 화합물.
- 제6항에 있어서, G5가 헤테로고리기인 화합물.
- 제1항에 있어서, 하기 화학식 IIa의 화합물.<화학식 IIa>식 중,P-Q는 탄소-탄소 이중 결합 또는 에폭시드이고,R은 H 원자 또는 메틸기이고,G6은 H 원자, 알킬기, 치환된 알킬기 또는 CF3, OZ5, SZ5또는 NZ5Z6기 (여기서, Z5는 H 원자, 알킬기, 치환된 알킬기, 아실기 또는 치환된 아실기이고, Z6은 H 원자, 알킬기 또는 치환된 알킬기임)이고,G7은 CZ7기 (여기서, Z7은 H 또는 할로겐 원자, 알킬기, 치환된 알킬기, 아릴기 또는 치환된 아릴기이거나 OZ8, SZ8또는 NZ8Z9기이고, Z8은 H 원자 또는 알킬기, 치환된 알킬기, 아실기 또는 치환된 아실기이고, Z9는 H 원자, 알킬기 또는 치환된 알킬기임) 또는 N 원자이고,G8은 H 또는 할로겐 원자, 알킬기, 치환된 알킬기 또는 OZ10, SZ10또는 NZ10Z11기 (여기서, Z10은 H 원자, 알킬기, 치환된 알킬기, 아실기, 치환된 아실기, 아릴기 또는 치환된 아릴기이고, Z11은 H 원자, 알킬기, 치환된 알킬기, 아실기 또는 치환된 아실기임)이다.
- 제1항에 있어서, 하기 화학식 IIb의 화합물.<화학식 IIb>식 중,P-Q는 탄소-탄소 이중 결합 또는 에폭시드이고,R은 H 원자 또는 메틸기이고,G6은 H 원자, 알킬기, 치환된 알킬기 또는 CF3, OZ5, SZ5또는 NZ5Z6기 (여기서, Z5는 H 원자, 알킬기, 치환된 알킬기, 아실기 또는 치환된 아실기이고, Z6은 H 원자, 알킬기 또는 치환된 알킬기임)이고,G9는 O 또는 S 원자이거나 -N=N-기이다.
- 제14항에 있어서, G9가 O 원자인 화합물.
- 제1항에 있어서, 하기 화학식 III의 화합물.<화학식 III>식 중,P-Q는 탄소-탄소 이중 결합 또는 에폭시드이고,R은 H 원자 또는 메틸기이고,G10은 N 원자 또는 CZ12기 (여기서, Z12는 H 또는 할로겐 원자, 알킬기, 치환된 알킬기, 아릴기 또는 치환된 아릴기임)이다.
- 제16항에 있어서, G10이 N 원자인 화합물.
- 제16항에 있어서, G10이 CZ12기인 화합물.
- 제1항에 있어서, 하기 화학식 IV의 화합물.<화학식 IV>식 중,P-Q는 탄소-탄소 이중 결합 또는 에폭시드이고,R은 H 원자 또는 메틸기이고,G11은 H2N기, 치환된 H2N기, 알킬기, 치환된 알킬기, 아릴기 또는 치환된 아릴기이다.
- [1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(아지도메틸)-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(아미노메틸)-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[(1,1-디메틸에톡시)카르보닐]아미노]메틸]-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-[[[(1,1-디메틸에톡시)카르보닐]아미노]메틸]-4-티아졸릴]-1-메틸에테닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-1-옥사-13(Z)-시클로헥사데센-2,6-디온,[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(아미노메틸)-4-티아졸릴]-1-메틸에테닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-1-옥사-13(Z)-시클로헥사데센-2,6-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[(펜타노일옥시)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[(나프토일옥시)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-3-[2-[2-[[(2-메톡시에톡시)아세틸옥시]메틸]-1-메틸-4-티아졸릴]에테닐]-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[(N-프로피오닐아미노)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(3-아세틸-2,3-디히드로-2-메틸렌-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온, N-옥시드,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-3-[2-[2-(메톡시메틸)-4-티아졸릴]-1-메틸에테닐]-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-[2-(페녹시메틸)-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(에틸티오)메틸]-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(에톡시메틸)-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[(2,3,4,6-테트라아세틸-알파-글루코실옥시)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[(2',3',4',6'-테트라아세틸-베타-글루코실옥시)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[(6'-아세틸-알파-글루코실옥시)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-[2-[(p-톨루엔술포닐옥시)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(브로모메틸)-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(5-(브로모-2-메틸-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(시아노메틸)-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(시아노메틸)-4-티아졸릴]-1-메틸에테닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-1-옥사-13(Z)-시클로헥사데센-2,6-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-3-[2-[2-(1H-이미다졸-1-일메틸)-4-티아졸릴]-1-메틸에테닐]-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-포르밀-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-포르밀-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-에테닐-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-3-[2-[2-(메톡시이미노)-4-티아졸릴)-1-메틸에테닐]-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[[(페닐메틸)이미노]메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-아세틸-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-(2-옥시라닐-4-티아졸릴)에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-3-[2-[2-(2-요오도에테닐)-4-티아졸릴]-1-메틸에테닐]-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-에티닐-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-[2-[(메틸아미노)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[2-(디메틸아미노)에틸]아미노]메틸]-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(디메틸아미노)메틸]-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[비스(2-메톡시에틸)아미노]메틸]-4-티아졸릴]-1-메틸에테닐-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-[2-[(4-메틸-1-피페라지닐)메틸]-4-티아졸릴]-에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-디히드록시-8,8,10,12-테트라메틸-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데칸-3-일)-1-프로페닐]-2-티아졸카르복실산,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-디히드록시-8,8,10,12-테트라메틸-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데칸-3-일)-1-프로페닐]-2-티아졸카르복실산 메틸 에스테르로 이루어진 군으로부터 선택된 화합물 및 그의 제약학적으로 허용가능한 염, 용매 및 수화물.
- 하기 화학식 4 또는 5의 화합물을 우선 활성화시키고, 이어서 친핵성 치환시켜 하기 화학식 7의 화합물을 얻고, 생성된 화학식 7의 화합물을 환원시켜 하기 화학식 9의 화합물을 형성시키는, 제2항에 기재된 화학식 Ia (여기서, G1및 G2는 H 원자이고, G3은 NZ1이고, Z1및 G4는 H 원자임)에 상응하는 하기 화학식 9의 화합물의 제조 방법.<화학식 9>식 중, P-Q는 CH=C 또는 CH...C이고, 여기서 ...는 에폭시드 O 가교결합이 있는 탄소-탄소 단일 결합이고, R은 수소 원자 또는 메틸기이고, X는 N3이다.<화학식 4><화학식 5><화학식 7>
- 제21항에 있어서, (i) TosHal (여기서, Hal은 Cl, Br 또는 I임) 및 피리딘으로 활성화시키고, NaN3로 친핵성 치환시키거나, (ii) 디아자비시클로운데센 (DBU) 및 디페닐포스포릴 아지드 (DPPA)로 활성화 및 친핵성 치환시키는 방법.
- 제21항에 있어서, 환원을 (i) 린들라 (Lindlar) 촉매를 사용한 수소화로 또는 (ii) 포스핀을 사용하여 수행하는 방법.
- 활성 성분으로서, 제1항에 따른 화학식 I의 화합물, 제2항에 따른 화학식 Ia의 화합물, 제6항에 따른 화학식 Ib의 화합물, 제13항에 따른 화학식 IIa의 화합물, 제14항에 따른 화학식 IIb의 화합물, 제16항에 따른 화학식 III의 화합물, 제19항에 따른 화학식 IV의 화합물 및 그의 제약학적으로 허용되는 염으로 이루어진 군으로부터 선택되는 1종 이상의 화합물, 및 1종 이상의 그의 제약학적으로 허용되는 담체, 부형제 또는 희석제를 포함하는 제약 조성물.
- 제24항에 있어서, 활성 성분으로서 1종 이상의 항암제 또는 세포독성제인 화합물을 포함하는 제약 조성물.
- 제25항에 있어서, 항암제 또는 세포독성제가[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(아지도메틸)-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(아미노메틸)-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[(1,1-디메틸에톡시)카르보닐]아미노]메틸]-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-[[[(1,1-디메틸에톡시)카르보닐]아미노]메틸]-4-티아졸릴]-1-메틸에테닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-1-옥사-13(Z)-시클로헥사데센-2,6-디온,[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(아미노메틸)-4-티아졸릴]-1-메틸에테닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-1-옥사-13(Z)-시클로헥사데센-2,6-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[(펜타노일옥시)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[(나프토일옥시)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-3-[2-[2-[[(2-메톡시에톡시)아세틸옥시]메틸]-1-메틸-4-티아졸릴]에테닐]-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[(N-프로피오닐아미노)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(3-아세틸-2,3-디히드로-2-메틸렌-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온, N-옥시드,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-3-[2-[2-(메톡시메틸)-4-티아졸릴]-1-메틸에테닐]-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-[2-(페녹시메틸)-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(에틸티오)메틸]-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(에톡시메틸)-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[(2,3,4,6-테트라아세틸-알파-글루코실옥시)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[(2',3',4',6'-테트라아세틸-베타-글루코실옥시)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[(6'-아세틸-알파-글루코실옥시)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-[2-[(p-톨루엔술포닐옥시)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(브로모메틸)-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(5-(브로모-2-메틸-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-(시아노메틸)-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[4S-[4R*,7S*,8R*,9R*,15R*(E)]]-16-[2-[2-(시아노메틸)-4-티아졸릴]-1-메틸에테닐]-4,8-디히드록시-5,5,7,9,13-펜타메틸-1-옥사-13(Z)-시클로헥사데센-2,6-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-3-[2-[2-(1H-이미다졸-1-일메틸)-4-티아졸릴]-1-메틸에테닐]-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-포르밀-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-포르밀-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-에테닐-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-3-[2-[2-(메톡시이미노)-4-티아졸릴)-1-메틸에테닐]-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-[2-[[(페닐메틸)이미노]메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-아세틸-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12-테트라메틸-3-[1-메틸-2-(2-옥시라닐-4-티아졸릴)에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-3-[2-[2-(2-요오도에테닐)-4-티아졸릴]-1-메틸에테닐]-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-(2-에티닐-4-티아졸릴)-1-메틸에테닐]-7,11-디히드록시-8,8,10,12-테트라메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-[2-[(메틸아미노)메틸]-4-티아졸릴]에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[[2-(디메틸아미노)에틸]아미노]메틸]-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[(디메틸아미노)메틸]-4-티아졸릴]-1-메틸에테닐-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-3-[2-[2-[[비스(2-메톡시에틸)아미노]메틸]-4-티아졸릴]-1-메틸에테닐]-7,11-디히드록시-8,8,10,12,16-펜타메틸-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-7,11-디히드록시-8,8,10,12,16-펜타메틸-3-[1-메틸-2-[2-[(4-메틸-1-피페라지닐)메틸]-4-티아졸릴]-에테닐]-4,17-디옥사비시클로[14.1.0]헵타데칸-5,9-디온,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-디히드록시-8,8,10,12-테트라메틸-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데칸-3-일)-1-프로페닐]-2-티아졸카르복실산,[1S-[1R*,3R*(E),7R*,10S*,11R*,12R*,16S*]]-4-[2-(7,11-디히드록시-8,8,10,12-테트라메틸-5,9-디옥소-4,17-디옥사비시클로[14.1.0]헵타데칸-3-일)-1-프로페닐]-2-티아졸카르복실산 메틸 에스테르 및 그의 제약학적으로 허용되는 염, 용매 및 수화물로 이루어진 군으로부터 선택되는 것인 제약 조성물.
- 암 또는 다른 세포증식성 질환을 치료하기 위한 제24항에 따른 제약 조성물의 용도.
- 혈관형성을 억제하기 위한 제24항에 따른 제약 조성물의 용도.
- 세포소멸을 유도하기 위한 제24항에 따른 제약 조성물의 용도.
- 제27항에 있어서, 제약 조성물이 암 또는 다른 세포증식성 질환의 치료에 유용한 다른 치료제와 동시에 또는 순차적으로 사용되는 용도.
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SK (1) | SK287200B6 (ko) |
TR (1) | TR200102401T2 (ko) |
TW (1) | TWI270546B (ko) |
UY (1) | UY26024A1 (ko) |
WO (1) | WO2000050423A1 (ko) |
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