TWI258481B - Hexacyclic compounds - Google Patents
Hexacyclic compounds Download PDFInfo
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- TWI258481B TWI258481B TW091134463A TW91134463A TWI258481B TW I258481 B TWI258481 B TW I258481B TW 091134463 A TW091134463 A TW 091134463A TW 91134463 A TW91134463 A TW 91134463A TW I258481 B TWI258481 B TW I258481B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Description
1258481 X為氧或硫, 及其醫藥可接受鹽。 2. 根據申請專利範圍第1項之化合物,其中式[1 ]化合物之 9位之立體化學為S組態。 3. 根據申請專利範圍第1或2項之化合物,其係以下式[1A] 表示,
其中X為氧,R1,R3及R4如申請專利範圍第1項中定義, 及其醫藥可接受鹽。 4.根據申請專利範圍第3項之化合物,其中 R1為氫;或 (C1-C8)烷基,視需要地經一至三個獨立選自下列所組 成之族群中:(C1-C3)烷氧基,羥基,鹵素,胺基,一 -(C1-C3)烷基胺基,二-(C1-C3)烷基胺基,雜環,及芳 基之基取代,其中芳環視需要地經一至三個獨立選自 下列所組成之族群中:羥基,(C1-C3)烷氧基,及鹵素 之基取代;及 R3及R4為氫。 81621-960216.doc
1258481 5·根據申請專利範圍第4項之化合物,其中…為(C1C8)烷 基’苯基-(C1-C8)燒基,雜環_(C1_C8)烧基,(C1C8)烷氧 基苯基(C1-C8)烧基’或鹵素苯基(C1C8)烷基。 6. 根據申請專利範圍第5項之化合物,其中Rl為曱基,乙 基,正丙基,1-曱基乙基,正丁基,u_二甲基乙基, 2-甲基丙基,2,2-二甲基丙基,正戊基,3_甲基丁基, 2-正己基’ 3,3-二曱基丁基,正庚基,正辛基,苯甲基, 苯乙基,2-(二甲基胺基;)乙基,2-(4-嗎啉基)乙基,3-(二 曱基胺基)丙基’2-(吡啶-2-基)乙基,2-(吡啶-3-基)乙基 ’ 2-(4-曱氧基苯基)乙基,2_(4_氣苯基)乙基,2_(4_氟苯基) 乙基,或3 -苯基汚基。 7. 根據申請專利範圍第3項之化合物,係選自下列所組成 之族群中: a) (9S)-1-丁基-9、乙基 _9·羥基 _1H,12H-哌喃并[3”,4,,:6,,7,]啕 畊并[1’,2’:6,5]吡啶并[4,3,2-(16]喳唑啉-2,10,13(311,911,1511)- 三酮; b) (9S)-9-乙基-9-羥基-ΐ·[2-(4-嗎啉基)乙基]-1H,12H-哌 喃并[3”,4”:6’,7’]峋畊并[1’,2’:6,5]吡啶并[4,3,2-(16]喹唑 啉-2,10,13(311,911,1511)-三酮鹽酸鹽; c) (9S)-l-[3-(二甲基胺基)丙基]-9-乙基-9-羥基-1H,12H-哌喃并[3”,4”:6’,7’]啕畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹 唑啉-2,10,13(311,911,1511)-三酮鹽酸鹽; d) (9S)-9-乙基-9-羥基-1-笨乙基-1H,12H-哌喃并[3”,4”:6’,7,] 口 畊并[1’,2\6,5]吡啶并[4,3,2-(16]喳唑啉-2,10,13(311,911,1511)- 81621-960216.doc 1258481 三酮; e) (9S)-9-乙基-9-輕基 比 定-2-基)乙基]-iH,!〗!!-1»辰 喃并[3,,,4,,:6,,7,]〃?丨畊并[1,,2,:6,5]吡啶并[4,3,2-知]喳唑啉 -2,10,13(3Η,9Η,15Η)-三酮鹽酸鹽; f) (9S)-9-乙基-1-庚基-9-羥基-1H,12H-哌喃并[3,,,4,,:6,,7,]㈤ 畊并[1’,2’:6,5]吡啶并[4,3,2-如]喹唑淋-2,1〇,13(;311,91191511)_ 三酮; g) (9S)-9-乙基-9-羥基-卜丙基-1H,12H-哌喃并 畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹唑啉_2,10,13(3H,9H,15H)_ 三酮; h) (9S)-9-乙基-9-經基小[2十比咬·3_基)乙基]1H,12Ht^ 喃并[3,’,4,,:6’,7,;^卜井并[1,,2,:6,5]吡啶并[4,3,2_心]喹唑啉 -2,10,13(311,911,1511)-三酮鹽酸鹽; i) (9S)-9-乙基-9-經基-1·(3-笨基丙基)_1H,12H_哌喃并 -2,10,13(3H,9H,15H)-S_; j) (9S)-9-乙基-9-經基-H2-曱基丙基)]h,12h•哌〇南并 [SMi’J,]十井并Π’,2’:6,5]吡啶并[4,3,2_d小奎哇啉 -2,10,13(3氏911,1511)-三酮; k) (9S)·9-乙基小己基-9-羥基-1H,12H-哌喃并 ρ,,,4,,·6,,7,]ρ?| ^#[1%2>:6,5]^^#[45352^]^#.25105 13(3^9^15^- 三蜩; 81621-960216.doc -4· 1 (9S)冬乙基-9-經基-1·戊基]Η,12Η_ 略喃并[3,,,4,,:6,,7,^
1258481 三酮; m) (9S)-9-乙基-9-羥基-l-[2-(4-曱氧基苯基)乙基] -1H,12H-哌喃并[3”,4”:6’,7’]呻啡并[Γ,2’··6,5]吡啶并 [4,3,2-de]喹唑 4 -2,10,13(3Η,9Η,15Η)-三酮; n) (9S)-1-苯甲基-9-乙基-9-羥基-1Η,12Η-哌喃并 [3”,4”:6’,7’]啕畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -2,10,13(3H,9H,15H)-三酮; 〇) (9S)-9-乙基-9-羥基-1-(3-曱基丁基)-1Η,12Η-哌喃并 [3”,4”:6’,7,]啕畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -2,10,13(3H,9H,15H)-三酮; p) (9S)-1,9-二乙基-9-羥基-1H,12H-哌喃并[3”,4”:6’,7’]啕 畊并[1’,2’:6,5]吡啶并[4,3,2-€^]喳唑啉-2,10,13(311,911,1511)-三酮; q) (9S)-l-[2-(4-氯苯基)已基]-9 -乙基-9 -經基-1Η,12 Η -p泉 喃并[3”,4,,:6’,7’]4丨畊并[1’,2’:6,5]吡啶并[4,3,246]喹唑 啉-2,10,13(3H,9H,15H)-i_; r) (9S)-9-乙基- l-[2-(4-氟苯基)乙基]-9-羥基-1H,12H-哌 喃并[3,,,4”:6,,7,]啕畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑 啉-2,10,13(3氏911,1511)-三酮; s) (9S)-9-乙基-9 -羥基-1-(1-甲基乙基)-1Η,12Η-哌喃并 [3”,4”··6’,7,] Η丨啡并[Γ,2’:6,5]吡啶并[4,3,2-de]喳唑啉 -2,10,13(3H,9H,15H)-S_;及 t) (9S)-l-(3,3-二曱基丁基)-9-乙基-9-羥基-1H,12H-哌喃 并[3”,4”:6’,7’]'1?丨畊并[1’,2’:6,5]吡啶并[4,3,2-(16]喹唑啉 81621-960216.doc 1258481 -2,10,13(3H,9H,15H)-三酮。 8.根據申請專利範圍第7項之化合物,係選自下列所組成 之族群中: a) (9S)-1-丁基-9-乙基-9-羥基-1H,12H-哌喃并[3”,4”:6’,7’]β 畊并[Γ,2’_·6,5]吡啶并[4,3,2-de]喹唑啉 ; b) (9S)-9-乙基-9-羥基-1-苯乙基-1H,12H-哌喃并[3”,4”:6’,7’]啕 畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑啉 ; c) (9S)-9-乙基-9-羥基-1-(2-曱基丙基)-1Η,12Η-哌喃并 [3,,,4,,:6,,7’] W 啡并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -2,10,13(3H,9H,15H)-三酮; d) (9S)-9-乙基-1-己基-9-羥基-1H,12H-哌喃并[3”,4”·_6’,7,]吲 畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑啉-2,10,13(3Η,9Η,15Η)-三酮; e) (9S)-9-乙基-9-羥基-1-戊基-1H,12H-哌喃并[3”,4”:6’,7’]吲畊 并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑啉-2,10,13(3H,9H,15H)-三酮 ; f) (9S)-9-乙基-9-羥基-1-(3-甲基丁基)-1Η,12Η-哌喃并 [3”,4”__6’,7,] 4丨畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -2,10,13(3H,9H,15H)-三酮; g) (9S)-l-[2-(4-氯苯基)乙基]-9-乙基-9-羥基-1H,12H-哌 喃并[3”,4”:6’,7,]吲畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑 啉-2,10,13(3H,9H,15H)-S_; 81621-960216.doc 1258481 ^«酬 h) (9S)-9-乙基- l-[2-(4-氟苯基)乙基]-9-羥基哌 喃并[3”,4”:6’,7’]啕畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑 啉-2,10,13(3H,9H,15H)-S_ ;及 i) (9S)-l-(3,3-二曱基丁基)-9-乙基-9-羥基-1H,12H-哌喃 并[3”,4’’:6’,7’]啕畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -2,10,13(3H,9H,15H)-三酮。 9.根據申請專利範圍第1或2項之化合物,具有下式[1A],
其中X為硫,R1,R3及R4如申請專利範圍第1項中定義, 及其醫藥可接受鹽。 10. 根據申請專利範圍第9項之化合物,其中 R1為氫;(C1-C8)烷基,視需要地經一至三個獨立選自下 列所組成之族群中:(C1-C3)烷氧基,羥基,鹵素,胺 基,一 -(C1-C3)烷基胺基,二-(C1-C3)烷基胺基,雜環 ,或芳基之基取代,其中芳環視需要地經一至三個獨 立選自下列所組成之族群中:羥基,(C1-C3)烷氧基, 或鹵素之基取代;及 R3及R4為氫。 11. 根據申請專利範圍第10項之化合物,其中R1為(C1-C8) 烷基或苯基(C 1-C8)烷基。 81621-960216.doc -7-
1258481 12. 根據申請專利範圍第1 1項之化合物,其中R1為苯乙基, 3-曱基丁基,或正戊基。 13. 根據申請專利範圍第9項之化合物,係選自下列所組成 之族群中: a) (9S)-9-乙基-9-羥基-1-(3-甲基丁基)-1Η,12Η-哌喃并 [3”,4’’:6’,7,]⑼畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -2(3H)-硫酮-10,13(9H,15H)-二酮; b) (9S)-9-乙基-9-羥基-1-苯乙基-1H,12H-哌喃并 [3”,4”:6’,7’] < 畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -2(3H)-硫酮-10,13(9H,15H)-二酮;及 c) (9S)-9-乙基-9-羥基-1-戊基-1H,12H-哌喃并[3’’,4”:6’,7,] 啕畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹唑啉-2(3H)-硫酮 -10,13(9H,15H)-二酮。 14. 根據申請專利範圍第1或2項之化合物,具有下式[1B],
其中R1,R2,R3及R4如申請專利範圍第1項中定義,及其 醫藥可接受鹽。 15.根據申請專利範圍第14項之化合物,其中 R1為氫; (C1-C8)烷基,視需要地經一至三個獨立選自下列所組 81621-960216.doc
1258481 成之族群中:(Cl-C3)烷氧基,羥基,鹵素,胺基,一 -(C1-C3)烷基胺基,二-(C1-C3)烷基胺基,雜環,及芳 基之基取代,其中芳環視需要地經一至三個獨立選自 下列所組成之族群中:羥基,(C1-C3)烷氧基,及鹵素 之基取代; R2為氫; 胺基; (C1-C5)烷基,選擇性經一至三個獨立選自(C1-C5)烷氧 基,羥基,鹵素,胺基,一 -(C1-C5)烷基胺基及二 -(C1-C5)烷基胺基之基取代;(C1-C5)烷硫基;(C1-C5) 烷氧基;一 -(C1-C5)烷基胺基;及二-(C1-C5)烷基胺基 > R3為氫或(C1-C3)烷基;及 R4為氫。 16.根據申請專利範圍第1 5項之化合物,其中 R1為曱基,乙基,正丙基,1-曱基乙基,正丁基,1,1-二曱基乙基,2-曱基丙基,2,2-二曱基丙基,正戊基 ,3 -曱基丁基,2-正己基,3,3-二曱基丁基,正庚基, 正辛基,苯曱基,苯乙基,2-(二曱基胺基)己基,2-(4-嗎啉基)乙基,3 -(二甲基胺基)丙基,2 -(吡啶-2 -基)乙 基,2-(吡啶-3-基)乙基,2-(4-曱氧基苯基)乙基,2-(4-氯苯基)乙基,2-(4-氟笨基)乙基,或3-苯基丙基; R2為氫,甲基,乙基,丙基,羥基曱基,胺基曱基,(曱 基胺基)曱基,(二曱基胺基)曱基,氯曱基,三氟曱 81621-960216.doc
1258481 基,甲氧基,乙氧基,曱硫基,乙硫基,曱胺基,丁 胺基’或二曱基胺基; R3為氫或甲基;及 R4為氮。 17.根據申請專利範圍第1 4項之化合物,係選自下列所組成 之族群中: a) (9S)-1-丁基-9-乙基-9-羥基-1H,12H-哌喃并[3”,4”:6’,7,] β p井并[1,,2,:6,5]吡啶并[4,3,2-de]喹唑啉-10,13(9H,15H)-二酮; b) (9S)-9-乙基-9 -羥基- l-[2-(4 -嗎啉基)乙基]-1H,12H-哌喃并[3”,4”:6’,7’]啕 p井并[Γ,2’:6,5]吡啶并[4,3,2-de]喹 唑啉-10,13(9H,15H)-二酮鹽酸鹽; c) (9S)-9-乙基-9-羥基-1 -丙基-1H,12H-哌喃并[3”,4”:6’,7,] 4 畊并[1’,2’:6,5]吡啶并[4,3,2-de]喳唑啉-10,13(9H,15H)-二酮;
d) (9S)-1-苯甲基-9-乙基-9-羥基-1H,12H-哌喃并[3”,4”:6’,7,] 啕畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹唑啉-10,13(9H,15H)-二酮; e) (9S)-9-乙基-9-羥基-1-苯乙基-1H,12H-哌喃并[3”,4”:6’,7’] 旬啩并[1’,2’:6,5]吡啶并[4,3,2-(16]喹唑啉-10,13(911,1511)-二酮; f) (9S)-2,9-二乙基-9 -羥基-1-苯乙基-1H,12H-哌喃并 [3”,4”:6’,7’]啕畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -10,13(9H,15H)-二酮; 81621-960216.doc -10- 1258481 g) (9S)-9-乙基-9 -羥基-1-(3-苯基丙基)-1Η,12Η-哌喃并 [3”,4”:6’,7’]吲畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -10,13(9H,15H)-二酮; h) (9S)-9-乙基-9 -羥基-1-(3-曱基丁基)-1Η,12Η-哌喃并 [3”,4”:6’,7’]啕啩并[1’,2’:6,5]吡啶并[4,3,2-(16]喹唑啉 -10,13(9H,15H)-二酮; i) (9 8)-2,9-二乙基-9-羥基-1-(3-曱基丁基)-111,1211-哌喃 并[3”,4”:6’,7’]4丨畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -10,13(9H,15H)-二酮; j) (9S)-2,9-二乙基-9-羥基-1-(2-甲基丙基)-1Η,12Η-哌喃 并[3’’,4”:6,,7’]峭 p井并[1’,2’:6,5]吡啶并[4,3,2-de]喳唑口林 -10,13(9H,15H)-二酮; k) (9S)-9-乙基-1-庚基-9-羥基-1H,12H-哌喃并[3”,4”:6’,7’] 吲畊并[1’,2’:6,5]吡啶并[4,3,2-(16]喳唑啉-10,13(911,1511)-二酮;
1) (9S)-9-乙基-9-羥基-1-甲基-1H,12H-哌喃并[3”,4”:6’,7’] 钏畊并[1’,2’:6,5]吡啶并[4,3,2-(16]喳唑啉-10,13(911,1511)-二酮; m) (9S)-9-乙基-9 -羥基-1-(2-甲基丙基)-1Η,12Η-哌喃并 [3”,4”:6’,7,]吲畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -10,13(9H,15H)-二酮; n) (9S)-9-乙基-1-己基-9-羥基-1Η,12Η-哌喃并[3”,4”:6’,7’] 啕畊并[1’,2’:6,5]吡啶并[4,3,246]喹唑啉-10,13(911,15印-二酮; 81621-960216.doc -11 -
1258481 〇) (9S)-9-乙基-9-羥基-1-戊基-1Η,12Η-哌喃并[3”,4’’:6’,7’] 啕畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹唑啉-10,13(9Η,15Η)-二酮; p) (9S)-1,9-二乙基-9-羥基-1Η,12Η-哌喃并[3”,4”:6’,7’]»?| 畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑啉-10,13(9Η,15Η)-二 酮;
q) (9S)-9-乙基-9-羥基-l-[2-(4-曱氧基苯基)乙基] -111,1211-哌喃并[3’’,4”:6’,7’]啕呼并[1’,2’__6,5]吡啶并 [4,3,2-de]喹唑啉-10,13(9H,15H)-二酮; r) (9S)_l-[2-(4-氣苯基)乙基]-9-乙基-9-羥基-1H,12H-哌 喃并[3”,4”:6’,7’]4丨畊并[1’,2’:6,5]吡啶并[4,3,2-(16]喹 唑啉-10,13(9H,15H)-二酮; s) (9S)-9-乙基-l-[2-(4-氟苯基)乙基]-9-羥基-1H,12H-哌 喃并[3”,4”:6’,7’]㈣畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹
t) (9S)-9-乙基-l-[2-(4-氟苯基)乙基]-9-羥基-2-曱基 -111,1211-哌喃并[3”,4”:6’,7’]'^丨哺并[1’,2’:6,5]吡啶并 [4,3,2-(16]喹唑啉-10,13(911,1511)-二酮; u) (9S)-9-乙基-9-羥基-1-(1-甲基乙基)-1Η,12Η-哌喃并 [3”,4”:6’,7’]啕哺并[Γ,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -10,13(9H,15H)-二酮; v) (9S)-l-(3,3-二甲基丁基)-9-乙基-9-羥基-1H,12H-哌喃 并[3”,4”:6’,7’]啕畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑 啉-10,13(9H,15H)-二酮; 81621-960216.doc -12-
1258481 w) (9S)-9-乙基-9-羥基-2-甲氧基-1-(3-甲基丁基) -1H,12H-哌喃并[3”,4”:6’,7,]呻畊并[Γ,2’:6,5]吡啶并 [4,3,2-(16]喹唑淋-10,13(911,1511)-二酮; X) (9S)-2,9-二乙基-9-羥基-1-(3-甲基丁基)-1Η,12Η-哌喃 并[3||,4”:6|,7']啕啡并[1’,2’:6,5]吡啶并[4,3,2-(16]喹唑啉 -10,13(9Η,15Η)-二酮;
y) (9RS)-9-乙基-9-羥基-4 -甲基-1-戊基-1H,12H-哌喃并 [3Π,4":6',7·]啕畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹唑 4木 -10,13(9H,15H)_二酮; z) (9S)-9-乙基-9-羥基-1-(2-羥基丁基)-1Η,12Η-哌喃并 [3”,4”:6,,7’]啕畊并[1’,2,:6,5]吡啶并[4,3,2-de]喹唑啉 -10,13(9H,15H)-二酮; aa) (9S)-9-乙基-9-羥基-1-(2-羥基乙基)-2-曱基-1H,12H-哌喃并[3”,4”:6’,7’]啕畊并[Γ,2’:6,5]吡啶并[4,3,2-de] 喹唑啉 _1〇,13(9Η,15Η)_二酮;
bb) (9S)-9-乙基-9-羥基-2 -曱基-1-戊基-1H,12H-哌喃并 [3’’,4”:6’,7’]啕畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -10,13(9艮1511)-二酮; cc) (9S)-2,9-二乙基-9-羥基-1-戊基-1H,12H-哌喃并 [3’’,4”:6’,7’]>1引畊并[1’,2’:6,5]吡啶并[4,3,2-€^]喹唑啉 -10,13(9H,15H)-二酮; dd) (9S)-9-乙基-9-羥基-1-戊基-2-丙基-1H,12H-哌喃并 [3”,4”:6’,7,]吲畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑啉 81621-960216.doc -13-
1258481 ee) (9S)-9-乙基-9 -羥基-2 -羥基甲基-1-戊基-1H,12H-哌 喃并[3”,4”:6’,7’]啕畊并[1’,2’:6,5]吡啶并[4,3,2-(16]喳 唑啉-10,13(9H,15H)-二酮;
ff) (9S)-9-乙基-9-羥基-2-羥基曱基-1-(2-曱基丙基) -111,1211-哌喃并[3”,4”:6’,7’]沔丨畊并[1’,2’:6,5]吡啶并 [4,3,2-(16]喹唑啉-10,13(911,1511)-二酮; gg) (9S)-9-乙基-9-羥基-2-羥基曱基-1-(3 -曱基丁基) -1H,12H-哌喃并[3”,4’’:6’,7’]啕畊并[Γ,2’:6,5]吡啶并 [4,3,246]喹唑啉-10,13(911,1511)-二酮; hh) (9S)-2-氯甲基-9-乙基-9-羥基-1-(3-曱基丁基) -1H,12H-哌喃并[3”,4,’:6’,7’]沔丨畊并[1’,2,:6,5]吡啶并 [4,3,2-de]<4,4-10,13(9H,15H)-:_; ii) (9S)-2-胺基甲基-9 -乙基-9-羥基-1-戊基-1H,12H-哌 喃并[3”,4”:6’,7’]吲畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喹 唑啉-10,13(9H,15H)-二酮;
jj) (9S)-9-乙基-9-羥基-1-戊基-2-三氟曱基-1Η,12Η-哌 喃并[3”,4”··6’,7’]β 畊并[1’,2’:6,5]吡啶并[4,3,2-(16]喹 唑啉-10,13(9Η,15Η)-二酮; kk) (9S)-9-乙基-9-羥基-1-(3-甲基丁基)-2-曱硫基-1H,12H-哌喃并[3”,4”:6’,7’]β 畊并[Γ,2’:6,5]吡啶并[4,3,2-de] 喹唑啉-10,13(9H,15H)-二酮; 11) (9S)-9-乙基-2-乙硫基-9-羥基-1-(3-甲基丁基)-1Η,12Η- 哌喃并[3”,4’’:6’,7’]啕畊并[Γ,2’:6,5]吡啶并[4,3,2-de] 喹唑啉-10,13(9H,15H)-二酮; 81621-960216.doc -14-
1258481 mm) (9S)-2-(二曱基胺基)-9-乙基-9-羥基-1-(2-甲基丙基) -111,1211-哌喃并[3”,4”:6’,7’]啕畊并[1’,2’:6,5]吡啶并 [4,3,2-(16]喹唑啉-10,13(911,1511)-二酮鹽酸鹽;及 nn) (9S)-2-( 丁基胺基)-9-乙基-9-羥基-1-(3-甲基丁基) -1H,12H-哌喃并[3”,4”:6’,7’]吲畊并[Γ,2’:6,5]吡啶并 [4,3,2-de]喹唑啉-10,13(9Η,15Η)-二酮鹽酸鹽。 18.根據申請專利範圍第1 7項之化合物,係選自下列所組成 之族群中: a) (9S)-1-丁基-9-乙基-9-羥基旅喃并[3”,4”:6’,7,] 啕畊并[1,,2,:6,5]吡啶并[4,3,2-心]喳唑啉-1〇,13(911,1511)-二酮; b) (9S)-9-乙基-9-羥基·1 -苯乙基旅喃并 [3,,,4,,:6,,7,]4丨 p井并[1,,2’:6,5]吡啶并[4,3,2-de]喳唑啉 -10,13(9H,15H)-二酮; c) (9S)-9-乙基-9-羥基-1-0甲基丁基)-1Η,12Η-哌喃并 [3,,,4,,:6’,7,] 4丨啩并[1’,2’:6,5]吡唆并[4,3,246]喹唑淋 -10,13(9H,15H)-二酮; d) (9S)-9-乙基-9-羥基-l-(2-甲基丙基)-1Η,12Η-哌喃并 [3,,,4,,:6,,7,]啕畊并[1’,2’:6,5]吡啶并[4,3,2-(16]喹唑啉 -10,13(9H,15H)-二酮; e) (9S)-9-乙基-9-羥基-卜戊基-1H,12H-哌喃并[3”,4”:6’,7,] >•5丨畊并[1,,2,:6,5]吡啶并[4,3,2-de]喹唑啉-10,13(9H,15H)-二酮; f) (9S)-9-乙基- l-[2-(4-氟苯基)乙基]-9 -羥基-1H,12H-哌 81621-960216.doc -15- 1258481 喃并[3”,4”:6’,7’]呻畊并[Γ,2’:6,5]说啶并[4,3,2-de]喹唑啉 -10,13(9H,15H)-二酮; g) (9S)-l-(3,3-二甲基丁基)-9-乙基-9-羥基-1H,12H-哌 喃并[3”,4”:6’,7’]啕畊并[Γ,2’:6,5]吡啶并[4,3,2-de]喳唑啉 -10,13(9H,15H)-二酮; h) (9S)-9-乙基-9-羥基-2-曱基-1-戊基-1H,12H-哌喃并 [3,,,4,,··6,,7,] 口?I 畊并[Γ,2,:6,5]ρ比啶并[4,3,2-de] 口奎唑啉 -10,13(9H,15H)-二酮; i) (9S)-9-乙基-9-羥基-2-羥基曱基-1-戊基-1H,12H-哌 喃并[3”,4”:6’,7’]啕畊并[1’,2’:6,5]吡啶并[4,3,2-de]喹唑啉 -10,13(9H,15H)-二酮:及 j) (9S)-2-胺基甲基-9-乙基-9-羥基-1-戊基-1H,12H-哌 喃并[3,,,4,,:6’,7’]'>5丨啡并[1’,2’:6,5]吡啶并[4,3,2-(16]喳唑啉 -10,13(9H,15H)-二酮。 19. 一種根據申請專利範圍第1項之化合物用於製備藥物之 用途,該藥物係用以治療細胞增生疾病。 20. —種根據申請專利範圍第1項之化合物用於製備藥物之 用途,該藥物係用以治療癌症。 21. —種用於治療細胞增生疾病之醫藥組合物,包含治療有 效量之根據申請專利範圍第1項之化合物。 22. 根據申請專利範圍第2 1項之醫藥組合物,其適合經口或 非經腸施用。 23. 根據申請專利範圍第2 1項之醫藥組合物,係用於治療癌 症。 81621-960216.doc -16-
1258481 24. 根據申請專利範圍第23項之醫藥組合物,係用於治療固 體腫瘤。 25. 根據申請專利範圍第2 1項之醫藥組合物,係用於治療結 腸直腸癌,肺癌,乳癌,胃癌,子宮頸癌,及膀胱癌。 26. —種製造下式[2 ]化合物之方法,
其中R1,R3,R4及X如申請專利範圍第1項中定義,R5為 (C1-C5)烷醯基,其包含一種下式[3]化合物或其鹽,
其中R1,R3,R4及R5如上述定義,與一種下式[4]化合物,
其中X為氧或硫,及L1及L2獨立為離去基;在一種鹼存 在下反應。 27. —種製造下式[5 ]化合物之方法, 81621-960216.doc 1258481
I 其中R1,R2,R3,及R4如申請專利範圍第1項中定義,R5 為(C1-C5)烷醯基, 其包含一種下式[3]化合物或其鹽,
其中R1,R3,R4及R5如上述定義,與一種下式[6]化合物 反應,
其中 R2如申請專利範圍第1項中定義;R6為氧;硫;=(〇R7)2 ,其中R7為(C1-C3)烷基;=NR8,其中R8為氫,(C1-C3)烷 基,(C1-C3)烷醯基,烷氧基羰基;=N+R9R1Q,其中R9及 R10獨立為(C1-C3)烷基;或鹵素;及L1為離去基。 28. —種製造根據申請專利範圍第1項之式[1 ]化合物或其 醫藥可接受鹽之方法, 81621-960216.doc -18-
1258481
其中Z,R1,R2,R3,及R4如上述申請專利範圍第1項中定 義,其包含一種下式[1,]之化合物,
其中Z,R1,R2,及R4如上述定義;R5為(C1-C5)烷硫基, 以一種J井或其衍生物去醯化。 29. —種根據申請專利範圍第26或27項之方法所製備之化 合物。 30. —種根據申請專利範圍第2 8項之方法所製備之化合物。 31. 根據申請專利範圍第1項之化合物,係用於治療細胞增 生疾病。 81621-960216.doc -19-
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JP3359955B2 (ja) * | 1992-07-16 | 2002-12-24 | 第一製薬株式会社 | 抗腫瘍剤 |
GB9402934D0 (en) * | 1994-02-16 | 1994-04-06 | Erba Carlo Spa | Camptothecin derivatives and process for their preparation |
US5663177A (en) * | 1995-05-31 | 1997-09-02 | Smithkline Beecham Corporation | Water soluble camptothecin analogs |
CA2280905C (en) | 1997-02-14 | 2006-08-29 | Bionumerik Pharmaceuticals, Inc. | Highly lipophilic camptothecin derivatives |
GB9715821D0 (en) * | 1997-07-25 | 1997-10-01 | Pharmacia & Upjohn Spa | Amidino-camptothecin derivatives |
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