CN1788001B - 可用于治疗赘生性疾病、炎性和免疫系统病症的2,4-二(苯氨基)嘧啶 - Google Patents
可用于治疗赘生性疾病、炎性和免疫系统病症的2,4-二(苯氨基)嘧啶 Download PDFInfo
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- CN1788001B CN1788001B CN2004800130419A CN200480013041A CN1788001B CN 1788001 B CN1788001 B CN 1788001B CN 2004800130419 A CN2004800130419 A CN 2004800130419A CN 200480013041 A CN200480013041 A CN 200480013041A CN 1788001 B CN1788001 B CN 1788001B
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- 239000000546 pharmaceutical excipient Substances 0.000 description 1
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- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
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- 239000001509 sodium citrate Substances 0.000 description 1
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- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- 239000004408 titanium dioxide Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- DPUOLQHDNGRHBS-MDZDMXLPSA-N trans-Brassidic acid Chemical compound CCCCCCCC\C=C\CCCCCCCCCCCC(O)=O DPUOLQHDNGRHBS-MDZDMXLPSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
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- 230000004614 tumor growth Effects 0.000 description 1
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- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
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- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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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
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
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- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
本发明公开了式(I)的新嘧啶衍生物,
Description
本发明涉及新的嘧啶衍生物、它们的制备方法、它们作为药物的用途以及包含它们的药物组合物。
更具体而言,本发明第一方面提供了式I化合物及其盐
其中
每个R0、R1、R2和R3独立地为氢、C1-C8烷基、C2-C8链烯基、C2-C8炔基、C3-C8环烷基、C3-C8环烷基C1-C8烷基、C5-C10芳基C1-C8烷基、羟基C1-C8烷基、C1-C8烷氧基C1-C8烷基、氨基C1-C8烷基、卤代C1-C8烷基、未取代或取代的C5-C10芳基、未取代或取代的包含1、2或3个选自N、O和S的杂原子的5或6元杂环基、羟基、C1-C8烷氧基、羟基C1-C8烷氧基、C1-C8烷氧基C1-C8烷氧基、卤代C1-C8烷氧基、未取代或取代的C5-C10芳基C1-C8烷氧基、未取代或取代的杂环基氧基或未取代或取代的杂环基C1-C8烷氧基、未取代或取代的氨基、C1-C8烷硫基、C1-C8烷基亚磺酰基、C1-C8烷基磺酰基、C5-C10芳基磺酰基、卤素、羧基、C1-C8烷氧基羰基、未取代或取代的氨甲酰基、未取代或取代的氨磺酰基、氰基或硝基;
或R0和R1、R1和R2和/或R2和R3和它们所连接的碳原子一起形成包含0、1、2或3个选自N、O和S的杂原子的5或6元碳环或杂环;
R4是氢或C1-C8烷基;
每个R5和R6独立地为氢、C1-C8烷基、C1-C8烷氧基C1-C8烷基、卤代C1-C8烷基、C1-C8烷氧基、卤素、羧基、C1-C8烷氧基羰基、未取代或取代的氨甲酰基、氰基或硝基;
每个R7、R8、R9和R10独立地为C1-C8烷基、C2-C8链烯基、C2-C8炔基、C3-C8环烷基、C3-C8环烷基C1-C8烷基、C5-C10芳基C1-C8烷基、羟基C1-C8烷基、C1-C8烷氧基C1-C8烷基、氨基C1-C8烷基、卤代C1-C8烷基、未取代或取代的C5-C10芳基、未取代或取代的包含1、2或3个选自N、O和S的杂原子的5或6元杂环基、羟基、C1-C8烷氧基、羟基C1-C8烷氧基、C1-C8烷氧基C1-C8烷氧基、卤代C1-C8烷氧基、未取代或取代的C5-C10芳基C1-C8烷氧基、未取代或取代的杂环基氧基或未取代或取代的杂环基C1-C8烷氧基、未取代或取代的氨基、C1-C8烷硫基、C1-C8烷基亚磺酰基、C1-C8烷基磺酰基、C5-C10芳基磺酰基、卤素、羧基、C1-C8烷氧基羰基、未取代或取代的氨甲酰基、未取代或取代的氨磺酰基、氰基或硝基;其中R7、R8和R9彼此独立地也可以为氢;
或R7和R8、R8和R9和/或R9和R10和它们所连接的碳原子一起形成包含0、1、2或3个选自N、O和S的杂原子的5或6元碳环或杂环;
A为C或N,最优选为C。
除非另外指出,上下文中所用的通用术语在本公开的范围内优选具有以下含义。
当复数用于化合物、盐等时,其也意指单个化合物、盐等。
任何不对称碳原子可以以(R)-、(S)-或(R,S)-构型存在、优选(R)-或(S)-构型。由此,化合物可以以异构体混合物或纯异构体存在,优选为对映体纯的非对映体。
本发明还涉及式I化合物的可能的互变异构体。
C1-C8烷基表示具有1至8个、特别是1至4个碳原子的烷基,所述基团为直链或具有一个或多个分支的支链;优选地,C1-C8烷基为丁基如正-丁基、仲-丁基、异丁基、叔-丁基、丙基如正-丙基或异丙基、乙基或甲基;特别为甲基、丙基或叔丁基。
C2-C8链烯基表示具有2至8个、特别是2至5个碳原子的链烯基,所述基团为直链或具有一个或多个分支的支链;优选地,C2-C8链烯基为戊烯基如3-甲基-2-丁烯-2-基、丁烯基如1-或2-丁烯基或2-丁烯-2-基、丙烯基如1-丙烯基或烯丙基,或乙烯基。
C2-C8炔基表示具有2至8个、特别是2至5个碳原子的炔基,所述基团为直链或支链;优选地,C2-C8炔基为丙炔基如1-丙炔基或炔丙基,或乙炔基。
C3-C8环烷基表示具有3至8个碳原子的环烷基,如环丙基、环丁基、环戊基、环己基、环庚基或环辛基,优选环丙基、环戊基或环己基。
C1-C8烷氧基特别是甲氧基、乙氧基、异丙氧基或叔丁氧基。
羟基C1-C8烷基特别是羟基甲基、2-羟基乙基或2-羟基-2-丙基。
羟基C1-C8烷氧基特别是2-羟基乙氧基或3-羟基丙氧基。
C1-C8烷氧基C1-C8烷氧基特别是2-甲氧基乙氧基。
C1-C8烷氧基C1-C8烷基特别是甲氧基甲基、2-甲氧基乙基或2-乙氧基乙基。
卤素优选为氟、氯、溴或碘,特别是氟、氯或溴。
卤代C1-C8烷基优选为氯代C1-C8烷基或氟代C1-C8烷基、特别是三氟甲基或五氟乙基。
卤代C1-C8烷氧基优选为氯代C1-C8烷氧基或氟代C1-C8烷氧基,特别为三氟甲氧基。
C1-C8烷氧基羰基特别是叔丁氧羰基、异-丙氧基羰基、甲氧基羰基或乙氧基羰基。
未取代或取代的氨甲酰基为被一个或两个取代基取代的氨甲酰基,所述取代基选自氢、C1-C8烷基、C2-C8链烯基、C2-C8炔基、C3-C8环烷基、C3-C8环烷基C1-C8烷基、C5-C10芳基C1-C8烷基、羟基C1-C8烷基、C1-C8烷氧基C1-C8烷基、卤代C1-C8烷基、未取代或取代的C5-C10芳基或氨基C1-C8烷基,或其中取代基和氨甲酰基的氮原子代表还含有0、1或2个选自N、O和S的杂原子的5或6元杂环的氨甲酰基;且优选为氨甲酰基、甲基氨甲酰基、二甲基氨甲酰基、丙基氨甲酰基、羟基乙基-甲基-氨甲酰基、二(羟基乙基)氨甲酰基、二甲基氨基乙基氨甲酰基或吡咯烷子基羰基、哌啶子基羰基、N-甲基哌嗪子基羰基或吗啉代羰基,特别是氨甲酰基或二甲基氨甲酰基。
未取代或取代的氨磺酰基为被一或两个取代基取代的氨磺酰基,所述取代基选自氢、C1-C8烷基、C2-C8链烯基、C2-C8炔基、C3-C8环烷基、C3-C8环烷基C1-C8烷基、C5-C10芳基C1-C8烷基、羟基C1-C8烷基、C1-C8烷氧基C1-C8烷基、卤代C1-C8烷基、未取代或取代的C5-C10芳基或氨基C1-C8烷基,或其中取代基和氨磺酰基的氮原子代表还含有0、1或2个选自N、O和S的杂原子的5或6元杂环的氨磺酰基;且优选氨磺酰基、甲基氨磺酰基、丙基氨磺酰基、环丙基甲基-氨磺酰基、2,2,2-三氟乙基氨磺酰基、二甲基氨基乙基氨磺酰基、二甲基氨磺酰基、羟基乙基-甲基-氨磺酰基、二(羟基乙基)氨磺酰基,或吡咯烷子基磺酰基、哌啶子基磺酰基、N-甲基哌嗪子基磺酰基或吗啉代磺酰基,特别是氨磺酰基或甲基氨磺酰基。
未取代或取代的氨基为被一或两个取代基取代的氨基,所述取代基选自氢、C1-C8烷基、C2-C8链烯基、C2-C8炔基、C3-C8环烷基、C3-C8环烷基C1-C8烷基、C5-C10芳基C1-C8烷基、羟基C1-C8烷基、C1-C8烷氧基C1-C8烷基、卤代C1-C8烷基、未取代或取代的C5-C10芳基、氨基C1-C8烷基、酰基例如甲酰基、C1-C8烷基羰基、C5-C10芳基羰基、C1-C8烷基磺酰基或C5-C10芳基磺酰基,且优选为氨基、甲基氨基、二甲基氨基、丙基氨基、苄基氨基、羟基乙基-甲基-氨基、二(羟基乙基)氨基、二甲基氨基乙基氨基、乙酰基氨基、乙酰基-甲基-氨基、苯甲酰基氨基、甲基磺酰基氨基或苯基磺酰基氨基,特别是氨基或二甲基氨基。
氨基C1-C8烷基特别为氨基乙基、甲基氨基乙基、二甲基氨基乙基或二甲基氨基丙基。
未取代或取代的C5-C10芳基为例如苯基、茚基、二氢化茚基、萘基或1,2,3,4-四氢萘基,任选被C1-C8烷基、C1-C8烷氧基C1-C8烷基、卤代C1-C8烷基、羟基、C1-C8烷氧基、亚甲二氧基、氨基、取代的氨基、卤素、羧基、C1-C8烷氧基羰基、氨甲酰基、氨磺酰基、氰基或硝基取代;优选苯基、甲苯基、三氟甲基苯基、甲氧基苯基、二甲氧基苯基、亚甲二氧基苯基、氯苯基或溴苯基,其中取代基可以位于邻位、间位或对位,优选间位或对位。
C5-C10芳氧基特别为苯氧基或甲氧基苯氧基,例如对-甲氧基苯氧基。
C5-C10芳基C1-C8烷基特别为苄基或2-苯基乙基。
C5-C10芳基C1-C8烷氧基特别为苄氧基或2-苯基乙氧基。
未取代或取代的包含1、2或3个选自N、O和S的杂原子的5或6元杂环基可以是不饱和的、部分不饱和或饱和的,且进一步与苯并基团或5或6元杂环基稠合,且可通过杂原子或碳原子连接,例如为吡咯基、吲哚基、吡咯烷基、咪唑基、苯并咪唑基、吡唑基、三唑基、苯并三唑基、四唑基、吡啶基、喹啉基、异喹啉基、1,2,3,4-四氢喹啉基、哌啶基、嘧啶基、吡嗪基、哌嗪基、嘌呤基、四嗪基、噁唑基、异噁唑基、吗啉基、噻唑基、苯并噻唑基、噁二唑基和苯并噁二唑基。所涉及的取代基有C1-C8烷基、羟基C1-C8烷基、C1-C8烷氧基C1-C8烷基、C1-C8烷氧基C1-C8烷氧基、卤代C1-C8烷基、羟基、氨基、取代的氨基、C1-C8烷氧基、卤素、羧基、C1-C8烷基羰基、C1-C8烷氧基羰基、氨甲酰基、C1-C8烷基氨甲酰基、氰基、氧代或本段中所定义的未取代或取代的5或6元杂环基。5或6元杂环优选包含1或2个选自N、O和S的杂原子,且特别为吲哚基、吡咯烷基、吡咯烷酮基、咪唑基、N-甲基咪唑基、苯并咪唑基、S,S-二氧代异噻唑烷基、哌啶基、4-乙酰基氨基哌啶基、4-甲基氨甲酰基哌啶基、4-哌啶子基哌啶基、4-氰基哌啶基、哌嗪基、N-甲基哌嗪基、N-(2-羟基乙基)哌嗪基、吗啉基、1-氮杂-2,2-二氧代-2-硫杂环己基或环丁砜基。
在未取代或取代的杂环基氧基中,杂环基具有如上所定义的含义,且特别为N-甲基-4-哌啶基氧基。在未取代或取代的杂环基C1-C8烷氧基中,杂环基具有如上所定义的含义,且特别为2-吡咯烷子基乙氧基、2-吗啉代乙氧基、3-吗啉代丙氧基、1-甲基-哌啶-3-基甲氧基、3-(N-甲基哌嗪子基)丙氧基或2-(1-咪唑基)乙氧基。
在包含0、1、2或3个选自N、O和S的杂原子且由两个相邻的取代基与苯环一起形成的5或6元碳环或杂环中,所述环可进一步被例如C1-C8烷基、C1-C8烷氧基、卤代C1-C8烷基、羟基、氨基、取代的氨基、C1-C8烷氧基、卤素、羧基、C1-C8烷氧基羰基、氨甲酰基、氰基或氧代取代。形成所述环的两个相邻的取代基优选为亚丙基、亚丁基、1-氮杂-2-亚丙烯基(propylidene)、3-氮杂-1-亚丙烯基、1,2-二氮杂-2-亚丙烯基、2,3-二氮杂-1-亚丙烯基、1-氧杂亚丙基、1-氧杂亚丙烯基、亚甲二氧基、二氟亚甲二氧基、2-氮杂-1-氧代亚丙基、2-氮杂-2-甲基-1-氧代亚丙基、1-氮杂-2-氧代亚丙基、2-氮杂-1,1-二氧代-1-硫杂亚丙基或形成6元环的相应的亚丁基衍生物。
盐特别为式I化合物的可药用盐。
所述盐例如以酸加成盐形成,优选用无机或有机酸自具有碱性氮原子的式I化合物形成,特别是可药用盐。适合的无机酸例如有卤酸,如盐酸、硫酸或磷酸。适合的有机酸有例如羧酸、膦酸、磺酸或氨基磺酸,例如乙酸、丙酸、辛酸、癸酸、十二烷酸、羟基乙酸、乳酸、富马酸、琥珀酸、己二酸、庚二酸、辛二酸、壬二酸、苹果酸、酒石酸、柠檬酸、氨基酸如谷氨酸或天冬氨酸、马来酸、羟马来酸、甲基马来酸、环己烷羧酸、金刚烷羧酸、苯甲酸、水杨酸、4-氨基水杨酸、邻苯二甲酸、苯乙酸、扁桃酸、肉桂酸、甲磺酸或乙磺酸、2-羟基乙磺酸、乙烷-1,2-二磺酸、苯磺酸、2-萘磺酸、1,5-萘二磺酸、2-、3-或4-甲基苯磺酸、甲基硫酸、乙基硫酸、十二烷基硫酸、N-环己基氨磺酸、N-甲基-、N-乙基-或N-丙基-氨磺酸,或其他有机质子酸如抗坏血酸。
为了分离或纯化目的,也可以使用不可药用盐,例如苦味酸盐或高氯酸盐。用于治疗时,仅使用可药用盐或游离化合物(适用时为药物制剂形式),因此优选可药用盐或游离化合物。
鉴于游离形式或盐形式、包括那些可用作中间体的盐例如用于新化合物的纯化和鉴定的盐的新化合物之间的密切关系,上下文中凡提及游离化合物也应理解为还酌情涉及相应的盐。
式I化合物具有有价值的药理学特性,如上下文中所述。
在式I中,优选以下独立、联合或以任何组合或亚组合形式的定义。
在以下每个定义中,A为C或N,优选C:
(a)每个R0或R2独立地为氢、C1-C8烷基例如甲基、乙基或异丙基、羟基C1-C8烷基例如羟基乙基或羟基丁基、卤代C1-C8烷基例如三氟甲基、未取代或取代的C5-C10芳基例如苯基或甲氧基苯基、未取代或取代的包含1或2个选自N、O和S的杂原子的5或6元杂环,例如吗啉代、哌啶子基、哌嗪子基或N-甲基哌嗪子基、C1-C8烷氧基例如甲氧基、乙氧基或异丙氧基、卤代C1-C8烷氧基例如三氟甲氧基、C5-C10芳氧基例如苯氧基、未取代或取代的杂环基氧基例如1-甲基-4-哌啶基氧基、未取代或取代的杂环基C1-C8烷氧基例如2-(1-咪唑基)乙氧基、3-吗啉代丙氧基或2-吗啉代乙氧基、未取代或取代的氨基例如甲基氨基、二甲基氨基或乙酰基氨基、C1-C8烷基磺酰基例如甲基磺酰基、卤素例如氟或氯、未取代或取代的氨甲酰基例如环己基氨甲酰基、哌啶子基羰基、哌嗪子基羰基、N-甲基哌嗪子基羰基或吗啉代羰基、未取代或取代的氨磺酰基,例如氨磺酰基、甲基氨磺酰基或二甲基氨磺酰基;优选氢、哌嗪子基、N-甲基哌嗪子基或1-甲基-4-哌啶氧基,尤其是氢;
(b)R1为氢、C1-C8烷基例如甲基、乙基或异丙基、羟基C1-C8烷基例如羟基乙基或羟基丁基、卤代C1-C8烷基例如三氟甲基、未取代或取代的C5-C10芳基例如苯基或甲氧基苯基、未取代或取代的包含1或2个选自N、O和S的杂原子的5或6元杂环基例如吗啉代、哌啶子基、哌嗪子基或N-甲基哌嗪子基、C1-C8烷氧基例如甲氧基、乙氧基或异丙氧基、卤代C1-C8烷氧基例如三氟甲氧基、C5-C10芳氧基例如苯氧基、未取代或取代的杂环基氧基例如1-甲基-4-哌啶基氧基、未取代或取代的杂环基C1-C8烷氧基例如2-(1-咪唑基)乙氧基、3-吗啉代丙氧基或2-吗啉代乙氧基、未取代或取代的氨基例如甲基氨基、二甲基氨基或乙酰基氨基、C1-C8烷基磺酰基例如甲基磺酰基、卤素例如氟或氯、未取代或取代的氨甲酰基例如环己基氨甲酰基、哌啶子基羰基、哌嗪子基羰基、N-甲基哌嗪子基羰基或吗啉代羰基、未取代或取代的氨磺酰基例如氨磺酰基、甲基氨磺酰基或二甲基氨磺酰基;优选氢、哌嗪子基、N-甲基哌嗪子基、吗啉代、1-甲基-4-哌啶基氧基、3-吗啉代丙氧基或2-吗啉代乙氧基、尤其是氢;
(c)R3为氢、C1-C8烷基例如甲基或乙基、羟基C1-C8烷基例如羟基乙基或羟基丁基、卤代C1-C8烷基例如三氟甲基、未取代或取代的包含1或2个选自N、O和S的杂原子的5或6元杂环基例如2-吡咯烷酮基或S,S-二氧代异噻唑烷基、C1-C8烷氧基例如甲氧基、取代的氨基例如乙酰基氨基、乙酰基-甲基-氨基、苯甲酰氨基、甲基磺酰基氨基或苯基磺酰基-氨基、C1-C8烷基磺酰基例如甲基磺酰基、C5-C10芳基磺酰基例如苯基磺酰基、卤素例如氟或氯、羧基、取代或未取代的氨甲酰基例如氨甲酰基、甲基氨甲酰基或二甲基氨甲酰基、未取代或取代的氨磺酰基例如氨磺酰基、甲基氨磺酰基、丙基氨磺酰基、异丙基氨磺酰基、异丁基氨磺酰基、环丙基甲基-氨磺酰基、2,2,2-三氟乙基氨磺酰基、二甲基氨磺酰基或吗啉代磺酰基;优选氨磺酰基、甲基氨磺酰基或丙基氨磺酰基;
(d)每对相邻的取代基R0和R1或R1和R2或R2和R3为-CH2-NH-CO-、-CH2-CH2-NH-CO-、-CH2-CO-NH-、-CH2-CH2-CO-NH-、-CH2-NH-SO2-、-CH2-CH2-NH-SO2-、-CH2-SO2-NH-、-CH2-CH2-SO2-NH-、-CH2-CH2-SO2-、-CH2-CH2-CH2-SO2-、-O-CH2-O-或-O-CF2-O-,以及其中NH中的H被C1-C8烷基替代的所述取代基对;优选所述相邻取代基对R0和R1或R1和R2为-O-CH2-O-,且所述相邻取代基对R2和R3为-CH2-NH-CO-或-CH2-NH-SO2-。
(e)R4为氢或C1-C8烷基,例如甲基;优选氢;
(f)R5为氢;C1-C8烷基例如甲基或乙基、卤素例如氯或溴、卤代C1-C8烷基例如三氟甲基、氰基或硝基;优选氢、甲基、乙基、氯、溴、三氟甲基或硝基;尤其是氯或溴;
(g)R6为氢;
(h)每个R7和R9独立地为氢、C1-C8烷基例如甲基、乙基或异丙基、羟基C1-C8烷基例如羟基乙基或羟基丁基、卤代C1-C8烷基例如三氟甲基、未取代或取代的C5-C10芳基例如苯基或甲氧基苯基、未取代或取代的包含1或2个选自N、O和S的杂原子的5或6元杂环,例如吗啉代、哌啶子基、哌嗪子基或N-甲基哌嗪子基、C1-C8烷氧基例如甲氧基、乙氧基或异丙氧基、卤代C1-C8烷氧基例如三氟甲氧基、C5-C10芳氧基例如苯氧基、未取代或取代的杂环基氧基例如1-甲基-4-哌啶基氧基、未取代或取代的杂环基C1-C8烷氧基例如2-(1-咪唑基)乙氧基、3-吗啉代丙氧基或2-吗啉代乙氧基、未取代或取代的氨基例如甲基氨基、二甲基氨基或乙酰基氨基、C1-C8烷基磺酰基例如甲基磺酰基、卤素例如氟或氯、未取代或取代的氨甲酰基例如环己基氨甲酰基、哌啶子基羰基、哌嗪子基羰基、N-甲基哌嗪子基羰基或吗啉代羰基、未取代或取代的氨磺酰基例如氨磺酰基、甲基氨磺酰基或二甲基氨磺酰基;优选氢、甲基、异丙基、三氟甲基、苯基、甲氧基苯基、哌啶子基、哌嗪子基、N-甲基哌嗪子基、吗啉代、甲氧基、乙氧基、异丙氧基、苯氧基、3-吗啉代丙氧基、2-吗啉代乙氧基、2-(1-咪唑基)乙氧基、二甲基氨基、氟、吗啉代羰基、哌啶子基羰基、哌嗪子基羰基或环己基氨甲酰基;
(i)R8为氢、C1-C8烷基例如甲基、乙基或异丙基、羟基C1-C8烷基例如羟基乙基或羟基丁基、卤代C1-C8烷基例如三氟甲基、C5-C10芳基例如苯基或甲氧基苯基、未取代或取代的包含1或2个选自N、O和S的杂原子的5或6元杂环基例如吗啉代、哌啶子基、哌嗪子基或N-甲基哌嗪子基、C1-C8烷氧基例如甲氧基、乙氧基或异丙氧基、卤代C1-C8烷氧基例如三氟甲氧基、C5-C10芳氧基例如苯氧基、未取代或取代的杂环基氧基例如1-甲基-4-哌啶基氧基、未取代或取代的杂环基C1-C8烷氧基例如2-(1-咪唑基)乙氧基、3-吗啉代丙氧基或2-吗啉代乙氧基、未取代或取代的氨基例如甲基氨基或二甲基氨基、C1-C8烷基磺酰基例如甲基磺酰基、卤素例如氟或氯、未取代或取代的氨甲酰基例如环己基氨甲酰基、哌啶子基羰基、哌嗪子基羰基、N-甲基哌嗪子基羰基或吗啉代羰基、未取代或取代的氨磺酰基例如氨磺酰基、甲基氨磺酰基或二甲基氨磺酰基、氰基或硝基;优选氢、甲基、哌啶子基、哌嗪子基、N-甲基哌嗪子基、吗啉代、甲氧基、乙氧基、三氟甲氧基、苯氧基、1-甲基-4-哌啶基氧基、3-吗啉代丙氧基、2-吗啉代乙氧基、3-(N-甲基哌嗪子基)-丙氧基、甲基氨基、氟、氯、氨磺酰基或硝基;
(j)R10为C1-C8烷基例如甲基、乙基或丁基、羟基C1-C8烷基例如羟基乙基或羟基丁基、卤代C1-C8烷基例如三氟甲基、C1-C8烷氧基例如甲氧基或乙氧基、未取代或取代的杂环基C1-C8烷氧基例如2-(1-咪唑基)乙氧基、未取代或取代的氨基例如甲基氨基或二甲基氨基、卤素例如氟或氯;羧基、氨甲酰基或未取代或取代的氨磺酰基例如氨磺酰基、甲基氨磺酰基或二甲基氨磺酰基;优选甲基、丁基、甲氧基、乙氧基、2-(1-咪唑基)乙氧基、甲基氨基、二甲基氨基或氟;且
(k)每对相邻的取代基R7和R8或R8和R9或R9和R10为-NH-CH=CH-、-CH=CH-NH-、-NH-N=CH-、-CH=N-NH-、-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-、-CH2-CH2-O-、-CH=CH-O-、-O-CH2-O-或-O-CF2-O-;优选所述相邻取代基对R7和R8或R8和R9为-O-CH2-O-或所述相邻取代基对R9和R10为-NH-CH=CH-、-CH=N-NH-、-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-或-O-CF2-O-。
更优选以下独立、联合或任何组合或亚组合形式的含义:
(a’)每个R0或R2独立地为氢、C1-C8烷基例如甲基、乙基或异丙基、卤代C1-C8烷基例如三氟甲基、未取代或取代的包含1或2个选自N、O和S的杂原子的5或6元杂环基例如吗啉代、哌啶子基、哌嗪子基或N-甲基哌嗪子基、C1-C8烷氧基例如甲氧基、乙氧基或异丙氧基、未取代或取代的杂环基氧基例如1-甲基-4-哌啶基氧基、未取代或取代的杂环基C1-C8烷氧基例如2-(1-咪唑基)乙氧基、3-吗啉代丙氧基或2-吗啉代乙氧基、未取代或取代的氨基例如甲基氨基、二甲基氨基或乙酰基氨基、卤素例如氟或氯;优选氢、哌嗪子基、N-甲基哌嗪子基或1-甲基-4-哌啶基氧基,尤其是氢;
(b’)R1为氢、C1-C8烷基例如甲基、乙基或异丙基、卤代C1-C8烷基例如三氟甲基、未取代或取代的包含1或2个选自N、O和S的杂原子的5或6元杂环基例如吗啉代、哌啶子基、哌嗪子基或N-甲基哌嗪子基、C1-C8烷氧基例如甲氧基、乙氧基或异丙氧基、未取代或取代的杂环基氧基例如1-甲基-4-哌啶基氧基、未取代或取代的杂环基C1-C8烷氧基例如2-(1-咪唑基)乙氧基、3-吗啉代丙氧基或2-吗啉代乙氧基、未取代或取代的氨基例如甲基氨基、二甲基氨基或乙酰基氨基、卤素例如氟或氯;优选氢、哌嗪子基、N-甲基哌嗪子基、吗啉代、1-甲基-4-哌啶基氧基、3-吗啉代丙氧基或2-吗啉代乙氧基,尤其是氢;
(c’)R3为氢、C1-C8烷基例如甲基或乙基、卤代C1-C8烷基例如三氟甲基、未取代或取代的包含1或2个选自N、O和S的杂原子的5或6元杂环基例如2-吡咯烷酮基或S,S-二氧代异噻唑烷基、C1-C8烷氧基例如甲氧基、取代的氨基例如乙酰基氨基、乙酰基-甲基-氨基、苯甲酰基氨基、甲基磺酰基氨基或苯基磺酰基氨基、C1-C8烷基磺酰基例如甲基磺酰基、C5-C10芳基磺酰基例如苯基磺酰基、卤素例如氟或氯、羧基、取代或未取代的氨甲酰基例如氨甲酰基、甲基氨甲酰基或二甲基氨甲酰基、未取代或取代的氨磺酰基例如氨磺酰基、甲基氨磺酰基、丙基氨磺酰基、异丙基氨磺酰基、异丁基氨磺酰基、环丙基甲基-氨磺酰基、2,2,2-三氟乙基氨磺酰基、二甲基氨磺酰基或吗啉代磺酰基;优选氨磺酰基、甲基氨磺酰基或丙基氨磺酰基;
(d’)每对相邻的取代基R0和R1或R1和R2或R2和R3为-CH2-NH-CO-、-CH2-NH-SO2-、-CH2-CH2-SO2-、-O-CH2-O-或-O-CF2-O-以及其中NH中的H被C1-C8烷基替代的所述取代基对;优选地,相邻的取代基对R0和R1或R1和R2为-O-CH2-O-,且相邻的取代基对R2和R3为-CH2-NH-CO-或-CH2-NH-SO2-;
(e’)R4为氢;
(f’)R5为氢、卤素例如氯或溴、卤代C1-C8烷基例如三氟甲基,或硝基;优选氢、氯、溴、三氟甲基或硝基;尤其是氯或溴;
(g’)R6为氢;
(h’)每个R7和R9独立地为氢、C1-C8烷基例如甲基、乙基或异丙基、卤代C1-C8烷基例如三氟甲基、未取代或取代的C5-C10芳基例如苯基或甲氧基苯基、未取代或取代的含有1或2个选自N、O和S的杂原子的5或6元杂环,例如吗啉代、哌啶子基、哌嗪子基或N-甲基哌嗪子基、C1-C8烷氧基例如甲氧基、乙氧基或异丙氧基、未取代或取代的杂环基氧基例如1-甲基-4-哌啶基氧基、未取代或取代的杂环基C1-C8烷氧基例如2-(1-咪唑基)乙氧基、3-吗啉代丙氧基或2-吗啉代乙氧基、未取代或取代的氨基例如甲基氨基、二甲基氨基或乙酰基氨基、卤素例如氟或氯、未取代或取代的氨甲酰基例如环己基氨甲酰基、哌啶子基羰基、哌嗪子基羰基、N-甲基哌嗪子基羰基或吗啉代羰基、未取代或取代的氨磺酰基例如氨磺酰基、甲基氨磺酰基或二甲基氨磺酰基;优选氢、甲基、异丙基、三氟甲基、苯基、邻-、间-或对-甲氧基苯基、哌啶子基、哌嗪子基、N-甲基哌嗪子基、吗啉代、甲氧基、乙氧基、异丙氧基、苯氧基、3-吗啉代丙氧基、2-吗啉代乙氧基、2-(1-咪唑基)乙氧基、二甲基氨基、氟、吗啉代羰基、哌啶子基羰基、哌嗪子基羰基或环己基氨甲酰基;
(I’)R8为氢、C1-C8烷基例如甲基、乙基或异丙基、卤代C1-C8烷基例如三氟甲基、C5-C10芳基例如苯基或甲氧基苯基、未取代或取代的包含1或2个选自N、O和S的杂原子的5或6元杂环基例如吗啉代、哌啶子基、哌嗪子基或N-甲基哌嗪子基、C1-C8烷氧基例如甲氧基、乙氧基或异丙氧基、卤代C1-C8烷氧基例如三氟甲氧基、C5-C10芳氧基例如苯氧基、未取代或取代的杂环基氧基例如1-甲基-4-哌啶基氧基、未取代或取代的杂环基C1-C8烷氧基例如2-(1-咪唑基)乙氧基、3-吗啉代丙氧基或2-吗啉代乙氧基、未取代或取代的氨基例如甲基氨基或二甲基氨基、卤素例如氟或氯、未取代或取代的氨磺酰基例如氨磺酰基、甲基氨磺酰基或二甲基氨磺酰基,或硝基;优选氢、甲基、哌啶子基、哌嗪子基、N-甲基哌嗪子基、吗啉代、甲氧基、乙氧基、三氟甲氧基、苯氧基、1-甲基-4-哌啶基氧基、3-吗啉代丙氧基、2-吗啉代乙氧基、3-(N-甲基哌嗪子基)-丙氧基、甲基氨基、氟、氯、氨磺酰基或硝基;
(j’)R10为C1-C8烷基例如甲基、乙基或丁基、卤代C1-C8烷基例如三氟甲基、C1-C8烷氧基例如甲氧基或乙氧基、未取代或取代的杂环基C1-C8烷氧基例如2-(1-咪唑基)乙氧基、未取代或取代的氨基例如甲基氨基或二甲基氨基、卤素例如氟或氯;优选甲基、丁基、甲氧基、乙氧基、2-(1-咪唑基)乙氧基、甲基氨基、二甲基氨基或氟;且
(k’)每对相邻的取代基R7和R8或R8和R9或R9和R10为-NH-CH=CH-、-CH=CH-NH-、-NH-N=CH-、-CH=N-NH-、-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-、-O-CH2-O-或-O-CF2-O-;优选相邻的取代基对R7和R8或R8和R9为-O-CH2-O-或相邻的取代基对R9和R10为-NH-CH=CH-、-CH=N-NH-、-CH2-CH2-CH2-、-CH2-CH2-CH2-CH2-或-O-CF2-O-。
最优选的式I化合物是其中取代基具有实施例中所给出含义的那些化合物。
本发明还提供了制备式I化合物的方法,包括使式II化合物
其中R0、R1、R2、R3、R4、R5和R6如上所定义且Y为离去基团、优选卤素如溴、碘,或尤其是氯,
与式III化合物反应,
其中R7、R8、R9和R10如上所定义;
并且如果需要将其中取代基具有如上所定义含义的式I化合物转化为另一种所定义的式I化合物;
并且以游离或盐形式回收所得式I化合物,并且当需要时将所得游离形式的式I化合物转化为所需的盐,或将所得的盐转化为游离形式。
该反应可以按照本身已知的方式进行,反应条件特别取决于离去基团Y的反应性和式III苯胺中氨基的反应性,通常在适合的溶剂或稀释剂或其混合物存在下且必要时在酸或碱存在下,冷却或优选加热,例如在约-30℃至约+150℃、特别是约0℃至+100℃、优选室温(约+20℃)至+80℃的温度范围内,在开放或封闭的反应容器中和/或在惰性气体例如氮气氛下。
如果在式II或III化合物中,一个或多个其他官能团例如羧基、羟基或氨基被保护或需要保护,因为它们不应参加反应,这些是肽化合物、头孢菌素和青霉素以及核酸衍生物和糖的合成中通常使用的基团。
保护基可已经存在于前体中并应该保护所涉及的官能团以免于不需要的次级反应,如取代反应或溶剂分解。保护基的特征是它们自身易于除去,即无不可取的次级反应,通常通过溶剂分解、还原、光解或还通过酶活性除去,例如在类似于生理条件的条件下,并且它们不会出现在终产物中。专业人员了解或能够容易地确定哪些保护基适合于以上所提及的反应。
具有成盐基团的式I化合物的盐可以以本身已知的方式制备。由此式I化合物的酸加成盐可以通过用酸或用适合的阴离子交换剂处理而获得。
通常可将盐转化为游离形式的化合物,例如通过用适合的碱性试剂、例如用碱金属碳酸盐、碱金属碳酸氢盐或碱金属氢氧化物、通常为碳酸钾或氢氧化钠处理。
立体异构混合物例如非对映体混合物可以以本身已知的方式、借助适合的分离方法分离为它们相应的异构体。非对映体混合物例如可以借助分步结晶、色谱、溶剂分配和类似方法分离为它们的单个非对映体。该分离可在起始化合物阶段或对式I化合物自身进行。对映体可以通过形成非对映盐、例如通过与对映体纯的手性酸成盐或借助色谱法、例如通过HPLC、使用具有手性配体的色谱底物进行分离。
应该强调的是:类似于本章所述转化的反应也可以在适合的中间体阶段进行。
式I化合物、包括它们的盐,也可以以水合物的形式获得,或它们的晶体可以包括例如用于结晶的溶剂(以溶剂合物存在)。
用作原料的式II化合物可以如下获得:使式IV化合物
与式V化合物反应,
其中R1、R2、R3、R4、R5和R6如上所定义,且Y1和Y2为相同或不同的如上对Y所定义的离去基团。反应条件是以上对式II化合物与式III化合物的反应所提及的那些。
式IV和V化合物是已知的或可以按照已知方法制备。
式I化合物及它们的可药用盐当在体外于无细胞激酶试验和细胞试验中测试时显示有价值的药理学特性,因此可用作药物。具体而言,本发明化合物是粘着斑激酶的抑制剂,可用作治疗与粘着斑激酶相关联的信号级联功能障碍所导致病症的药物,尤其是以下所述的肿瘤。
粘着斑激酶FAK是整联蛋白介导的外-内信号级联中的一种关键酶(D.Schlaepfer等,Prog Biophys Mol Biol 1999,71,435-478)。细胞和细胞外基质(ECM)蛋白之间的相互作用通过细胞表面受体、整联蛋白被转化为对生长、存活和迁移重要的细胞内信号。FAK在这些整联蛋白介导的外-内信号级联中扮演必不可少的角色。该信号转换级联由Y397的自磷酸化触发。磷酸化的Y397是Scr家族酪氨酸激酶的SH2停靠点。结合的c-Src激酶可磷酸化FAK中其他酪氨酸残基。其中,磷酸化Y925成为Grb2小衔接蛋白的SH2位点的结合部位。Grb2与FAK的直接结合是激活下游靶点如Ras-ERK2/MAP激酶级联的关键步骤之一。
抑制内源性FAK信号传导导致运动性减低并在某些情况下诱导细胞死亡。另一方面,通过外源性表达增强FAK信号传导可增加细胞运动性并传达来自ECM的细胞存活信号。此外,FAK在侵袭性和转移性上皮、间叶细胞、甲状腺和前列腺癌中过度表达。因此,FAK抑制剂可能成为抗肿瘤生长和转移的药物。本发明的化合物因此适用于例如预防和/或治疗患有赘生性疾病的脊椎动物且更具体为哺乳动物,所述赘生性疾病特别是乳腺癌、肠(结肠和直肠)癌、胃癌和卵巢和前列腺癌、非小细胞肺癌、小细胞肺癌、肝癌、黑素瘤、膀胱肿瘤和头颈癌。
FAK抑制和免疫系统之间的关系在例如G.A.van Seventer等,Eur.J.Immunol.2001,31,1417-1427中述及。因此,本发明化合物可例如用于预防和/或治疗脊椎动物且更具体为哺乳动物,其患有免疫系统病症、由T淋巴细胞、B淋巴细胞、肥大细胞和/或嗜酸性粒细胞介导的疾病或病症,例如急性或慢性器官或组织同种或异种移植物排斥、动脉粥样硬化、由于血管损伤如血管成型术导致的血管阻塞、再狭窄、高血压、心衰、慢性阻塞性肺病、CNS疾病如阿尔茨海默病或肌萎缩性侧索硬化、癌症、感染性疾病如AIDS、脓毒性休克或成人呼吸窘迫综合征、缺血/再灌注损伤例如心肌梗死、中风、消化道缺血、肾衰或出血性休克或创伤性休克。本发明的活性剂也可用于治疗和/或预防急性或慢性炎性疾病或病症或自身免疫疾病,例如类风湿性疾病、骨关节炎、系统性红斑狼疮、桥本甲状腺炎、多发性硬化、重症肌无力、糖尿病(I型和II型)和与其有关的病症、呼吸系统疾病如哮喘或炎性肝损伤、炎性肾小球损伤、免疫学介导的病症或疾病的皮肤症状、炎性和高增殖性皮肤疾病(如银屑病、特应性皮炎、过敏性接触性皮炎、刺激性接触性皮炎和湿疹性皮炎、脂溢性皮炎)、炎性眼病例如Sjoegren综合征、角膜结膜炎或葡萄膜炎、炎性肠病、局限性回肠炎或溃疡性结肠炎。
本发明化合物在实施例所述的FAK试验系统中具有活性,并显示抑制IC50在1nM至100nM范围内。尤其具有活性的是以下所述的实施例3-12和3-17的化合物,显示IC50值在1至5nM范围内。
本发明的一些化合物还具有ZAP-70(70kD的zeta链-相关蛋白)蛋白酪氨酸激酶抑制活性。本发明活性剂的ZAP-70蛋白酪氨酸激酶相互作用可通过其防止例如LAT-11(活化T细胞的连接物)被人ZAP-70蛋白酪氨酸激酶在水溶液中磷酸化的能力得到证实,如实施例所述。本发明的化合物因此适用于预防或治疗其中ZAP-70抑制发挥作用的病症或疾病。
本发明的化合物在实施例所述的ZAP-70试验系统中具有活性,并显示抑制IC50在1μM至10μM范围内,例如以下所述的实施例2和3-2的化合物。
本发明化合物还是优良的IGF-IR(胰岛素样生长因子受体1)抑制剂,因此可用于治疗IGF-1R介导的疾病,例如包括增殖性疾病的疾病,如肿瘤,例如乳腺、肾、前列腺、结直肠、甲状腺、卵巢、胰、神经元、肺、子宫和胃肠道肿瘤以及骨肉瘤和黑素瘤。本发明化合物作为IGF-IR酪氨酸激酶活性抑制剂的功效可使用细胞“捕获ELISA”证实。在该试验中,测定了本发明化合物对胰岛素样生长因子I(IGF-I)诱导的IGF-IR自磷酸化的活性。
本发明化合物还显示对NPM-ALK融合蛋白和间变型(anaplastic)淋巴瘤激酶(ALK)的酪氨酸激酶活性的强大抑制作用。该蛋白酪氨酸激酶来自于核仁磷酸蛋白(nucleophosmin)(NPM)和间变型淋巴瘤激酶(ALK)的基因融合,使蛋白酪氨酸激酶活性与ALK配体无关。NPM-ALK在众多导致血液学或赘生性疾病的造血和其他人细胞中的信号传导中扮演关键角色,例如在间变型大细胞淋巴瘤(ALCL)和非霍奇金淋巴瘤(NHL)中、尤其在ALK+NHL或Alkomas中、在炎性肌成纤维细胞肿瘤(IMT)和成神经细胞瘤中(Duyster J等,2001 Oncogene 20,5623-5637)。除NPM-ALK外,在人造血和赘生性疾病中已鉴定了其他基因融合,主要是TPM3-ALK(非肌肉原肌球蛋白与ALK的融合)。
对ALK酪氨酸激酶活性的抑制可采用已知方法、例如采用ALK的重组激酶域、类似于J.Wood等,Cancer Res.60,2178-2189(2000)所述的VEGF-R激酶试验证实。使用GST-ALK蛋白酪氨酸激酶的体外酶试验作为过滤结合试验在96孔板中于20mM Tris·HCl,pH=7.5、3mM MgCl2、10mM MnCl2、1mM DTT、0.1μCi/试验(=30μl)[γ-33P]-ATP、2μM ATP、3μg/ml聚(Glu,Tyr 4∶1)聚-EY(Sigma P-0275)、1%DMSO、25ng ALK酶中进行。将试验物在环境温度下孵育10分钟。加入50μl 125mM EDTA终止反应,并将反应混合物转移至MAIP Multiscreen板上(Millipore,Bedford,MA,USA),该板预先用甲醇润湿并用H2O再水合5分钟。洗涤(0.5%H3PO4)后,将板在液闪计数器中计数。通过对百分抑制进行线性回归分析,计算IC50值。与无抑制剂的对照相比,式I化合物例如在浓度为0.001至0.5μM、尤其是0.01至0.1μM时可将酶活性抑制50%(IC50)。
式I化合物可强有力地抑制过度表达人NPM-ALK的鼠BaF3细胞的生长(DSMZ Deutsche Sammlung von Mikroorganismen undZellkulturen GmbH,Braunschweig,德国)。NPM-ALK的表达是通过用编码NPM-ALK的表达载体pCIneoTM(Promega Corp.,Madison WI,USA)转染BaF3细胞系、随后选择耐G418细胞获得。未转染的BaF3细胞依赖于IL-3存活。相比之下,表达NPM-ALK的BaF3细胞(以下称为BaF3-NPM-ALK)可在IL-3不存在时增殖,因为它们通过NPM-ALK激酶获得增殖信号。因此,NPM-ALK激酶的假定抑制剂消除生长信号并导致抗增殖活性。但是,NPM-ALK激酶的假定抑制剂的抗增殖活性可通过加入IL-3加以克服,其通过与NPM-ALK无关的机制提供生长信号。[就使用FLT3激酶的类似细胞系统而言,请参见E Weisberg等,Cancer Cell;1,433-443(2002)]。简言之,式I化合物的抑制活性如下测定:将BaF3-NPM-ALK细胞(15,000微升/板孔)转移至96-控微量滴定板中。将供试化合物[溶于二甲亚砜(DMSO)]以一系列浓度(稀释系列)加入,加入的方式可使DMSO的终浓度不大于1%(v/v)。加入后,将板孵育两天,期间无供试化合物的对照培养物能够经历两次细胞分裂周期。BaF3-NPM-ALK细胞的生长借助YoproTM染色[T Idziorek等,J.Immunol.Methods;185:249-258(1995)]测量:将由20mM柠檬酸钠pH4.0、26.8mM氯化钠、0.4%NP40、20mM EDTA和20mM组成的25μl溶解缓冲液加入各孔。细胞溶解在室温下于60分钟内完成,与DNA结合的Yopro的总量通过使用Cytofluor II 96-孔读数仪(PerSeptive Biosystems)测量确定,设置如下:激发(nm)485/20,发射(nm)530/25。
IC50值通过计算机辅助系统、使用以下公式确定:
IC50=[(ABS供试-ABS起始)/(ABS对照-ABS起始)]×100,(ABS=吸收)
这些试验中的IC50值以导致细胞计数较使用无抑制剂的对照所获得的计数低50%的所涉及供试化合物的浓度表示。式I化合物显示抑制活性,IC50约0.01至1μM。
式I化合物的抗增殖作用也可使用与以上对BaF3-NPM-ALK细胞系所述相同的方法在人KARPAS-299淋巴瘤细胞系(DSMZ DeutscheSammlung von Mikroorganismen und Zellkulturen GmbH,Braunschweig,德国)[WG Dirks等,Int.J.Cancer 100,49-56(2002)述及]中确定。式I化合物可显示抑制活性,IC50约0.01至1μM。
式I化合物对ALK自磷酸化的作用可以在人KARPAS-299淋巴瘤细胞系中、借助免疫印迹确定,如WG Dirks等,Int.J.Cancer 100,49-56(2002)所述。在该试验中,式I化合物具有约0.001至1μM的IC50。
在式I化合物中,2-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯甲酰胺是尤其强效的ALK抑制剂,因为该化合物抑制BaF3-NPM-ALK细胞生长的IC50为97nM。更加优选的抑制间变型淋巴瘤激酶(ALK)酪氨酸激酶活性的化合物是以下实施例7A和7B以及7-2、7-15、7-36、7-39、7-44和7-52所述的化合物,所有它们的IC50均处于<0.5至200nM范围内。
就以上治疗赘生性疾病和免疫系统病症的用途而言,所需的剂量当然随施用方式、待治疗的具体病症和所需效果而异。通常,约0.1至约100mg/kg体重的日剂量适合于获得全身性满意结果。较大的哺乳动物、例如人的适用日剂量处于约0.5mg至约2000mg范围内,方便地例如以不超过每天4次的分剂量或以延迟形式施用。
本发明化合物可通过任何常规途径施用,特别是胃肠外,例如以可注射溶液或混悬液形式;肠内、优选口服,例如以片剂或胶囊形式;局部,例如以洗液、凝胶、软膏或霜剂形式,或以鼻用或栓剂形式。包含本发明化合物以及至少一种可药用载体或稀释剂的药物组合物可以按照常规方式、通过与可药用载体或稀释剂混合而制备。用于口服施用的单位剂量形式含有例如约0.1mg至约500mg活性物质。局部施例如用于皮肤。局部施用的另一种形式是用于眼部。
本发明的药物组合物以本身已知的方式制备,例如借助常规的混合、制粒、包衣、溶解或冻干方法。
优选使用活性成分的溶液,还有混悬液或分散体,尤其是等渗水溶液、分散体或混悬液,其例如就包含单独的活性成分或还含有载体例如甘露糖醇的冻干组合物而言,可于使用前配制。药物组合物可以是灭菌的或可包含赋形剂,例如防腐剂、稳定剂、润湿剂和/或乳化剂、增溶剂、调节渗透压的盐和/或缓冲剂,并以本身已知的方式制备,例如借助常规的溶解和冻干方法。所述溶液或混悬液可包含增稠剂,通常为羧甲基纤维素钠、羧甲基纤维素、葡聚糖、聚乙烯吡咯烷酮或明胶,或还有增溶剂,例如Tween80(聚氧乙烯(20)脱水山梨醇单油酸酯)。
油中混悬液包含常规用于注射目的的植物、合成、半合成油作为油性组分。在这方面,可特别提及液体脂肪酸酯,其含有作为酸性组分的具有8至22、特别是12至22个碳原子的长链脂肪酸,例如月桂酸、十三烷酸、肉豆蔻酸、十五烷酸、棕榈酸、十七烷酸、硬脂酸、花生酸、二十二酸或相应的不饱和酸,例如油酸、反油酸、芥子酸、巴西烯酸或亚油酸,如果需要,加入抗氧化剂,例如维生素E、β-胡萝卜素或3,5-二-叔丁基-4-羟基甲苯。这些脂肪酸酯的醇组分具有最多6个碳原子且为单价或多价、例如单价、二价或三价醇,例如甲醇、乙醇、丙醇、丁醇或戊醇或其异构体,但特别是乙二醇或甘油。因此,提及以下脂肪酸酯:油酸乙酯、肉豆蔻酸异丙酯、棕榈酸异丙酯、“Labrafil M 2375”(聚氧乙烯甘油)、“Labrafil M1944 CS”(通过醇解杏仁油而制备的不饱和聚乙二醇化甘油酯,由甘油酯和聚乙二醇酯组成)、“Labrasol”(通过醇解TCM而制备的饱和聚乙二醇化甘油酯,由甘油酯和聚乙二醇酯组成,均得自Gattefossé,法国)和/或“Miglyol 812”(链长C8至C12的饱和脂肪酸的甘油三酯,来自Hüls AG,德国),但特别是植物油如棉子油、杏仁油、橄榄油、蓖麻油、芝麻油、大豆油,更特别为花生油。
可注射制剂的制备通常在无菌条件下进行,例如灌装至安瓿或小瓶中以及容器的密封。
用于口服施用的药物组合物可例如如下获得:将活性成分与一种或多种固体载体合并,如果需要将所得混合物制粒,并且如需要或必要通过掺入额外的赋形剂加工混合物或颗粒,以形成片剂或片芯。
适合的载体特别为填充剂如糖,例如乳糖、蔗糖、甘露糖醇或山梨糖醇、纤维素制品和/或磷酸钙、例如磷酸三钙或磷酸氢钙;还有粘合剂如淀粉、例如玉米、小麦、稻米或马铃薯淀粉、甲基纤维素、羟丙甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮,和/或如果需要崩解剂,如以上提及的淀粉,还有羧甲基淀粉、交联聚乙烯吡咯烷酮、海藻酸或其盐如海藻酸钠。其他赋形剂特别为流动调节剂和润滑剂,例如硅酸、滑石、硬脂酸或其盐如硬脂酸镁或硬脂酸钙和/或聚乙二醇或其衍生物。
片芯可具有适合的任选肠溶的包衣,通过使用尤其是浓缩糖溶液,其可包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛,或使用适合的有机溶剂或溶剂混合物中的包衣溶液,或为了制备肠溶包衣使用适合的纤维素制品溶液,如醋酸纤维素酞酸酯或羟丙甲基纤维素酞酸酯。可将染料或色素加入片剂或片剂包衣,例如出于鉴别目的或指示活性成分的不同剂量。
用于口服施用的药物组合物还可包括由明胶组成的硬胶囊,还有由明胶和增塑剂如甘油或山梨糖醇组成的软密封胶囊。硬胶囊可含有颗粒形式的活性成分,例如与填充剂如玉米淀粉、粘合剂和/或助流剂如滑石或硬脂酸镁以及任选的稳定剂的混合物。在软胶囊中,活性成分优选溶解或混悬于适合的液体赋形剂中,如脂肪油、石蜡油或液体聚乙二醇或乙二醇或丙二醇的脂肪酸酯,也可向其中加入稳定剂和清洁剂,例如聚氧乙烯脱水山梨糖醇酐脂肪酸酯型。
适合于直肠施用的药物组合物有例如由活性成分组合栓剂基质组成的栓剂。适合的栓剂基质有例如天然或合成的甘油三酯、烷属烃、聚乙二醇或高级链烷醇。
对于胃肠外施用,特别适合的有水溶性形式、例如水溶性盐形式的活性成分的水溶液,或含有增稠物质以及需要时的稳定剂的注射水悬液,所述增稠物质例如羧甲基纤维素钠、山梨糖醇和/或葡聚糖。活性成分、任选以及赋形剂也可呈冻干物的形式并可于胃肠外施用前通过加入适合的溶剂制成溶液。
如用于例如胃肠外施用的溶液也可用作输注溶液。
优选的防腐剂有例如抗氧化剂如抗坏血酸,或杀微生物剂如山梨酸或苯甲酸。
本发明化合物可作为唯一的活性成分施用或与其他可用于对抗赘生性疾病或可用于免疫调节方案的药物一起施用。例如,根据本发明,本发明的活性剂可与对上述各种疾病有效的药学成分组合使用,例如环磷酰胺、5-氟尿嘧啶、氟达拉滨、吉西他滨、顺铂、卡铂、长春新碱、长春碱、依托泊苷、伊立替康、紫杉醇、多西他赛、单克隆抗体IDEC-G2B8(rituxan)、阿霉素、gefitinib或伊马替尼(imatinib),或还有环孢菌素、雷帕霉素、子囊霉素或它们的免疫抑制类似物例如环孢菌素A、环孢菌素G、FK-506、西罗莫司或everolimus,皮质类固醇例如泼尼松,环磷酰胺、咪唑巯嘌呤、甲氨蝶呤、金盐、柳氮磺吡啶、抗疟疾药、白瑞夸尔、来氟洛米、咪唑立宾、霉酚酸、霉酚酸酯(麦考酚酸吗啉乙酯)、15-脱氧斯潘格宁、免疫抑制单克隆抗体、例如白细胞受体的单克隆抗体,例如MHC、CD2、CD3、CD4、CD7、CD25、CD28、CD40、CD45、CD58、CD80、CD86、CD152、CD137、CD154、ICOS、LFA-1、VLA-4或它们的配体,或其他免疫调节化合物,例如CTLA4Ig。
依据以上所述,本发明还提供了:
(1)用作药物的本发明化合物;
(2)用作FAK抑制剂、ALK抑制剂和/或ZAP-70抑制剂、例如用于任何以上所列具体适应征的本发明化合物;
(3)例如用于任何以上所列适应征的药物组合物,包含作为活性成分的本发明化合物以及一种或多种可药用稀释剂或载体;
(4)在有需要的个体中治疗以上所列任何具体适应征的方法,包括施用有效量的本发明化合物或包含本发明化合物的药物组合物;
(5)本发明化合物在制备用于治疗或预防其中FAK、ALK和/或ZAP-70的活化扮演角色或被牵涉的疾病或病症的药物中的用途;
(6)以上(4)下所定义的方法,包括共同施用、例如并行或相继施用治疗有效量的本发明化合物和一种或多种其他药物物质,所述其他药物物质可用于任何以上所列具体适应征;
(7)一种组合产品,包含治疗有效量的本发明化合物和一种或多种其他药物物质,所述其他药物物质可用于任何以上所列具体适应征;
(8)本发明化合物在制备用于治疗或预防对抑制间变型淋巴瘤激酶有响应的疾病的药物中的用途;
(9)根据(8)的用途,其中所要治疗的疾病选自间变型大细胞淋巴瘤、非霍奇金淋巴瘤、炎性成肌纤维细胞瘤和成神经细胞瘤;
(10)根据(8)或(9)的用途,其中的化合物为2-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯甲酰胺或其可药用盐,或任何以下实施例所述化合物或任何这些化合物的可药用盐;
(11)治疗对抑制间变型淋巴瘤激酶有响应的疾病、特别是选自间变型大细胞淋巴瘤、非霍奇金淋巴瘤、炎性成肌纤维细胞瘤和成神经细胞瘤的疾病的方法,包括施用有效量的本发明化合物、特别是2-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯甲酰胺或其可药用盐。
其他优选的如此前所述有用的本发明化合物是实施例中具体提及的化合物。
可用作FAK抑制剂、ALK抑制剂或用于抑制二者且可基本上按照此前所述的方法制备的其他优选的本发明化合物有以下化合物:
2-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯甲酰胺,
N2-(4-[1,4′]联哌啶基-1′-基-2-甲氧基-苯基)-5-氯-N4-[2-(丙烷-1-磺酰基)-苯基]-嘧啶-2,4-二胺,
2-{5-氯-2-[2-甲氧基-4-(4-甲基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基氨基}-N-异丙基-苯磺酰胺,
2-[5-溴-2-(2-甲氧基-5-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯磺酰胺,
2-{2-[5-(1-乙酰基-哌啶-4-基氧基)-2-甲氧基-苯基氨基]-5-溴-嘧啶-4-基氨基}-N-甲基-苯磺酰胺,
N-[5-溴-2-(2,5-二甲氧基-苯基氨基)-嘧啶-4-基]-N-(4-吗啉-4-基-苯基)-甲磺酰胺,
5-溴-N-4-(4-氟-苯基)-N*2*-(2-甲氧基-4-吗啉-4-基-苯基)-嘧啶-2,4-二胺,
2-[5-氯-2-(2-甲氧基-4-哌嗪-1-基-苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯磺酰胺,
2-[5-溴-2-(5-氟-2-甲氧基-苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯磺酰胺,
2-[5-氯-2-(5-氟-2-甲氧基-苯基氨基)-嘧啶-4-基氨基]-N-异丁基-苯磺酰胺,和
2-{5-氯-2-[2-甲氧基-5-(4-甲基-哌嗪-1-基甲基)-苯基氨基]-嘧啶-4-基氨基}-N-甲基-苯磺酰胺。
本发明还提供了下式化合物:2-{5-氯-2-[4-(3-甲基氨基-吡咯烷-1-基)-苯基氨基]-嘧啶-4-基氨基}-N-异丙基-苯磺酰胺。
以下实施例用于阐述本发明而非限制本发明的范围。
实施例
缩写
AcOH=乙酸,ALK=间变型淋巴瘤激酶,ATP=腺苷5’-三磷酸,盐水=饱和氯化钠溶液,BSA=牛血清白蛋白,DIAD=偶氮二羧酸二异丙酯,DIPCDI=N,N’-二异丙基碳二亚胺,DMAP=4-二甲基氨基吡啶,DMF=N,N-二甲基甲酰胺,DTT=1,4-二硫代-D,L-苏糖醇,EDTA=乙二胺四乙酸,Et=乙基,EtOAc=乙酸乙酯,EtOH=乙醇,Eu-PT66=LANCETM铕-W1024-标记的抗磷酸酪氨酸抗体(Perkin Elmer),FAK=粘着斑激酶,FRET=荧光共振能量转移,HEPES=N-2-羟基乙基哌嗪-N’-2-乙磺酸,HOAt=1-羟基-7-氮杂苯并三唑,Me=甲基,RT-PCR=逆转录聚合酶链反应,SA-(SL)APC=与SuperLightTM别藻蓝蛋白(Perkin Elmer)缀合的抗生物素蛋白链菌素,subst.=取代的,TBTU=O-(苯并三唑-1-基)-N,N,N’,N’-四甲基四氟硼酸铵,THF=四氢呋喃。
实施例1:2-[2-(2,5-二甲氧基-苯基氨基)-5-硝基-嘧啶-4-基氨基]-N-甲基-苯
磺酰胺
在室温下向2-(2-氯-5-硝基-嘧啶-4-基氨基)-N-甲基-苯磺酰胺(100mg,0.29mmol)在EtOH(3mL)中的溶液中加入2,5-二甲氧基苯胺(49mg,0.32mmol)。将该混合物在78℃加热5小时。蒸发溶剂,混合物经反相HPLC纯化,得到标题产物。
Rf=0.47(正己烷∶乙酸乙酯=1∶1)。1H-NMR(400MHz,CDCl3),δ(ppm):2.36(d,3H),3.57(s,3H),3.73(s,3H),6.72(d,1H),6.99(d,1H),7.17(s,1H),7.35(t,1H),7.4-7.6(m,1H),7.63(d,1H),7.81(d,1H),8.0-8.2(m,1H),9.13(s,1H),9.41(br.s,1H),11.0(s,1H)。
2-(2-氯-5-硝基-嘧啶-4-基氨基)-N-甲基-苯磺酰胺的制备:
将2,4-二氯-5-硝基-嘧啶(1.94g,10mmol)和2-氨基-N-甲基-苯磺酰胺(1.86g,10mmol)溶于CHCl3(30mL)。将该反应混合物在61℃加热2小时。蒸发溶剂并将残余物用醚洗涤,得到标题产物。
Rf=0.5(正己烷∶乙酸乙酯=1∶1)。1H-NMR(400MHz,CDCl3),δ(ppm):2.67(d,3H),4.6-4.7(m,2H),7.41(dd,1H),7.7(dd,1H),8.04(d,1H),8.15(d,1H),9.21(s,1H),11.2(s,1H)。
实施例2:2-[5-溴-2-(2,4-二甲氧基-苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯
磺酰胺
向2-(5-溴-2-氯-嘧啶-4-基氨基)-N-甲基-苯磺酰胺(300mg,0.79mmol)、2,4-二甲氧基苯胺(181.5mg,1.18mmol)在乙醇(3mL)中的溶液中加入1N盐酸(0.03mL),并在回流条件下搅拌5小时。将该反应混合物冷却至室温、倾入水中并用乙酸乙酯萃取两次。将有机层连续用水和盐水洗涤,经硫酸镁干燥并在真空中蒸发。残余物经硅胶柱色谱纯化(正己烷∶乙酸乙酯=5∶1至1∶1),得到标题化合物。
1H-NMR(CDCl3),δ(ppm):8.95(s,1H),8.44(d,1H),8.20(s,1H),7.98(dd,1H),7.58(ddd,1H),7.22-7.32(m,1H),6.51(d,1H),6.40(d,1H),4.56-4.48(m,1H),3.86(s,3H),3.81(s,3H),2.64(d,3H)。Rf(正己烷∶乙酸乙酯=1∶1):0.31。
2-(5-溴-2-氯-嘧啶-4-基氨基)-N-甲基-苯磺酰胺的制备
将5-溴-2,4-二氯嘧啶(684mg,3.0mmol)和2-氨基-N-甲基-苯磺酰胺(559mg,3.0mmol)在合有碳酸钾(830mg,6.0mmol)的N,N-二甲基甲酰胺(10mL)中的溶液在室温下搅拌23小时。加入饱和氯化铵水溶液,将混合物倾入水中并用乙酸乙酯萃取两次。将有机层用盐水洗涤、经硫酸钠干燥并在真空中蒸发。残余物经硅胶柱色谱纯化(正己烷-乙酸乙酯梯度),得到标题化合物,为浅黄色固体。
1H-NMR(CDCl3),δ(ppm):2.67(d,3H),4.79(q,1H),7.26(s,1H),7.29(ddd,1H),7.66(ddd,1H),7.95(dd,1H),8.37(s,1H),8.48(d,1H),9.52(s,1H)。Rf(正己烷∶乙酸乙酯=10∶3):0.33。
实施例3:
按照实施例2的步骤,自2-(5-溴-2-氯-嘧啶-4-基氨基)-N-甲基-苯磺酰胺和相应的苯胺制备以下2-[5-溴-2-(取代的苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯磺酰胺:
实施例4:2-[5-溴-2-(取代的苯基氨基)-嘧啶-4-基氨基]-N-丙基-苯磺酰胺
这些化合物类似于实施例2制备,使用2-(5-溴-2-氯-嘧啶-4-基氨基)-N-丙基-苯磺酰胺和相应的苯胺,得到化合物4-1至4-31,所述化合物具有实施例3下对化合物3-1至3-31所列的取代基Rx。
2-(5-溴-2-氯-嘧啶-4-基氨基)-N-丙基-苯磺酰胺的制备
向5-溴-2,4-二氯嘧啶(90μL,0.70mmol)和2-氨基-N-丙基-苯磺酰胺(100mg,0.47mmol)的溶液中加入DMSO(1.0mL)中的氢化钠(54.2mg,0.56mmol)并将所得溶液在80℃下搅拌3.0小时。将该混合物倒入水中并用乙酸乙酯萃取三次。用水、然后用盐水洗涤有机层、经硫酸钠干燥并真空蒸发。残余物经硅胶柱色谱纯化(正己烷∶乙酸乙酯=5∶1),得到标题化合物,为浅黄色固体。
1H-NMR(δ,ppm):0.89(t,3H),1.41(q,2H),3.56(t,2H),4.92(br.s,2H),6.71(dd,1H),6.77(dd,1H),7.33(dd,1H),7.54(dd,1H),8.79(s,1H)Rf(己烷∶乙酸乙酯=1∶1):0.64。
实施例5:2-[5-三氟甲基-2-(取代的苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯磺
酰胺
这些化合物类似于实施例2制备,使用2-(2-氯-5-三氟甲基-嘧啶-4-基氨基)-N-甲基-苯磺酰胺和相应的苯胺,得到化合物5-1至5-31,所述化合物具有实施例3下对化合物3-1至3-31所列的取代基Rx。
2-(2-氯-5-三氟甲基-嘧啶-4-基氨基)-N-甲基-苯磺酰胺的制备
在环境温度下向2,4-二氯-5-三氟甲基-嘧啶(386mg,1.79mmol)的乙腈(10mL)溶液相继加入2-氨基-N-甲基-苯磺酰胺(333mg,1.79mmol)和1,8-二氮杂[5.4.0]双环-7-十一烯(280μL,1.88mmol)。在室温下搅拌15小时后,向混合物加入二氯甲烷(30mL),将溶液用饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤、经硫酸镁干燥并真空蒸发。所得固体经快速色谱纯化。
1H NMR(CDCl3)δ3.73(s,3H),6.67-6.69(m,1H),6.72-6.73(m,1H),7.27-7.31(m,1H),7.78(dd,1H),8.60(s,1H)。Rf(己烷∶乙酸乙酯=1∶1):0.28。
实施例6:2-[5-溴-2-(2,3-[二氟亚甲二氧基]苯基氨基)-嘧啶-4-基氨基]-苯磺
酰胺
按照实施例2的方法,在2-(5-溴-2-氯嘧啶-4-基氨基)-N-甲基-苯磺酰胺与2,3-(二氟亚甲二氧基)苯胺反应时经N-脱甲基化作用,得到该化合物,为副产物。其也可以通过2-(5-溴-2-氯嘧啶-4-基氨基)苯磺酰胺与2,3-(二氟亚甲二氧基)苯胺反应而制备。
Rf(正己烷∶乙酸乙酯=1∶1):0.46。
1H-NMR:(CDCl3)4.83(bs,2H),6.77(dd,1H),6.86(s,1H),6.97(dd,1H),7.31-7.24(m,1H),7.57(dd,1H),7.81(d,1H),8.02(dd,1H),8.28(d,1H),8.29(s,1H),8.88(s,1H)。
2-(5-溴-2-氯嘧啶-4-基氨基)苯磺酰胺的制备:
向5-溴-2,4-二氯嘧啶(300mg,1.32mmol)和2-氨基-苯磺酰胺(340mg,1.97mmol)的2-丙醇(3mL)溶液中加入浓盐酸(0.06mL),将混合物在90℃搅拌4.5小时。将混合物倒入碳酸氢钠水溶液中并用乙酸乙酯萃取三次。有机层用水洗涤、经硫酸钠干燥、真空蒸发。残余物经柱色谱纯化(己烷∶乙酸乙酯=2∶1),得到标题化合物。
Rf(己烷∶乙酸乙酯=1∶1):0.55。1H-NMR(400MHz,CDCl3)δ:4.78(br.s,2H),7.22(dd,1H),7.61(ddd,1H),7.95(dd,1H),8.35(s,1H),8.35(d,1H),9.18(s,1H)。
实施例7A:2-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-N-
甲基-苯甲酰胺
向2-(2,5-二氯-嘧啶-4-基-氨基)-N-甲基-苯甲酰胺(5.05g,17.0mmol)的90mL 2-甲氧基乙醇悬液中加入2-甲氧基-4-吗啉代苯胺二盐酸盐(4.56g,16.2mmol)和17.0mL 1N的氯化氢乙醇溶液(17.0mmol)。将反应混合物在110℃搅拌4小时并冷却至室温后,将混合物用1N NaOH水溶液中和并用EtOAc萃取(100mL×3)。有机层用盐水洗涤、经Na2SO4干燥、减压浓缩。所得黑色固体用EtOH(90mL)洗涤,然后经硅胶柱色谱纯化(CH2Cl2至CH2Cl2∶AcOEt=1∶2),得到2-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯甲酰胺,为淡黄色固体。
1H-NMR(400MHz,DMSO-d6,δ):2.80(d,3H,J=4.52Hz),3.10-3.20(m,4H),3.78(s,3H),3.70-3.80(m,4H),6.49(dd,1H,J=8.56,2.52Hz),6.66(d,1H,J=2.52Hz),7.08(dd,1H,J=8.04,8.04Hz),7.44(d,1H,J=8.56Hz),7.71(dd,1H,J=8.04,1.48Hz),8.10(s,1H),8.13(s,1H),8.59(d,1H,J=8.04Hz),8.68-8.75(m,1H),11.59(S,1H)。MS m/z 469,471(M+1)+。
以下2-[5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯甲酰胺由2-(2,5-二氯-嘧啶-4-基氨基)-N-甲基-苯甲酰胺和相应的苯胺、按照实施例7A的方法制备。
以下2-[5-溴-2-(取代的苯基氨基)-嘧啶-4-基氨基]-N-乙基-苯甲酰胺由2-(5-溴-2-氯-嘧啶-4-基氨基)-N-乙基-苯甲酰胺和相应的苯胺、按照实施例7A的方法制备。
以下2-[5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基]-N-乙基-苯甲酰胺由2-(2,5-二氯-嘧啶-4-基氨基)-N-乙基-苯甲酰胺和相应的苯胺、按照实施例7A的方法制备。
以下2-[5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基]-6,N-二甲基-苯甲酰胺由2-(2,5-二氯-嘧啶-4-基氨基)-6,N-二甲基-苯甲酰胺和相应的苯胺、按照实施例7A的方法制备。
以下2-[5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基]-5-氟-N-甲基-苯甲酰胺由2-(2,5-二氯-嘧啶-4-基氨基)-5-氟-N-甲基-苯甲酰胺和相应的苯胺、按照实施例7A的方法制备。
12-17-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-2-甲基
-2,3-二氢-异吲哚-1-酮的制备
7-(2,5-二氯-嘧啶-4-基氨基)-2-甲基-2,3-二氢-异吲哚-1-酮的合成方法
N-甲基-7-硝基-2,3-二氢异吲哚-1-酮:在室温下,将2-溴甲基-6-硝基苯甲酸甲酯(1.26g,4.63mmol)的THF(13mL)溶液用2M甲胺的THF(14mL)溶液处理,搅拌5小时,用EtOAc(100mL)稀释,用饱和NaHCO3水溶液(15mL)和盐水(15mL)洗涤,经(MgSO4)干燥并蒸发。进行快速色谱(30g硅胶;CH2Cl2/EtOAc 1∶1),得到N-甲基-7-硝基-2,3-二氢异吲哚-1-酮(0.561g,2.92mmol),产率63%。黄色固体。Rf(CH2Cl2/EtOAc 1∶1)0.46。1H-NMR(400MHz,CDCl3)3.21(s),4.44(s),7.63-7.69(m,2H),7.70-7.75(m,1H)。
7-氨基-N-甲基-2,3-二氢异吲哚-1-酮:在室温下,将N-甲基-7-硝基-2,3-二氢异吲哚-1-酮(561.0mg,2.92mmol)的EtOAc(8.4mL)溶液用SnCl2·2H2O(2.68g)处理,在80℃、回流下搅拌5小时,并用30mL 5N NaOH在0℃处理。分离两层后,水层用EtOAc(2×8mL)萃取,合并萃取液,用盐水(5mL)洗涤,干燥(MgSO4)并蒸发,得到7-氨基-N-甲基-2,3-二氢异吲哚-1-酮(455.9g,2.81mmol),产率96%,黄色固体。Rf(CH2Cl2/EtOAc 1∶1)0.53。1H-NMR(400MHz,CDCl3)3.12(s),4.28(s),5.20(br.s),6.56(d,J=8.0),6.68(d,J=8.0),7.21(dd,J=8.0,8.0)。
7-(4-氨基-2,5-二氯嘧啶-4-基)氨基-N-甲基-2,3-二氢异吲哚-1-酮:在0℃下,将7-氨基-N-甲基-2,3-二氢异吲哚-1-酮(232.6mg,1.43mmol)的DMF(2.0mL)溶液用60%NaH(89.8mg)处理,在相同温度下搅拌1.5小时,用2,4,5-三氯嘧啶(0.557g)的DMF(3.5mL)溶液处理,搅拌1小时,并温至室温。进一步搅拌13小时后,将混合物用饱和NH4Cl水溶液(6mL)处理,过滤收集所得棕色沉淀,然后用H2O、己烷和CH3CN洗涤,得到7-(4-氨基-2,5-二氯嘧啶-4-基)氨基-N-甲基-2,3-二氢异吲哚-1-酮(130.2g,0.416mmol),产率26%,棕色固体。Rf(CH2Cl2/EtOAc 1∶1)0.50。1H-NMR(400MHz,CDCl3):3.22(s),4.43(s),7.15(d,J=8.0),7.59(dd,J=8.0,8.0),8.24(s),8.71(d,J=8.0),11.05(br.s)。
以下7-[5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基]-2-甲基-2,3-二氢异吲哚-1-酮由7-(2,5-二氯-嘧啶-4-基氨基)-2-甲基-2,3-二氢异吲哚-1-酮和相应的苯胺、按照实施例7A的方法制备。
7-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-2-甲基-2,3-二
氢异吲哚-1-酮
1H-NMR(400MHz,DMSO-d6,δ):3.07(s,3H),3.13-3.17(m,4H),3.75(s,3H),3.34-3.78(m,4H),4.46(s,2H),6.54(dd,1H,J=8.6,2.5Hz),6.67(d,1H,J=2.5Hz),7.15(d,1H,J=7.6Hz),7.25-7.34(m,1H)7.36(d,1H,J=8.6Hz),8.13(s,1H),8.36(s,1H),8.37-8.50(m,1H),10.57(s,1H)。MS(ESI)m/z 481.483(M+1)+。
以下7-(5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基)-2-甲基-2,3-二氢异吲哚-1-酮由7-(2,5-二氯-嘧啶-4-基氨基)-2-甲基-2,3-二氢异吲哚-1-酮和相应的苯胺、按照实施例2的方法制备。
以下7-(5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基)-2-乙基-2,3-二氢吲哚-1-酮由7-(2,5-二氯-嘧啶-4-基氨基)-2-乙基-2,3-二氢-异吲哚-1-酮和相应的苯胺、按照实施例2的方法制备:
实施例7B:2-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-N-
甲基-苯甲酰胺(实施例7A的备选合成法)
在-5℃下向2-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-苯甲酸(5.5g,12.1mmol)的100mL THF悬液中加入Et3N(2.06mL,14.8mmol)和氯甲酸异丁酯(1.7mL,12.8mmol)。在相同温度下搅拌30分钟后,将反应混合物在室温下进一步搅拌1小时,然后向反应混合物加入H2O。过滤收集所得沉淀,用H2O洗涤,在减压下干燥,得到中间体(4.80g)(10.96mmol,91%),为黄色固体。
NMR(400MHz,DMSO-d6,δ):3.10-3.20(m,4H),3.70-3.80(m,4H),3.93(s,3H),6.53(dd,1H,J=9.08,2.0Hz),6.70(d,1H,J=2.0Hz),7.49-7.54(m,1H),7.67(d,1H,J=8.56Hz),7.89(s,1H),7.85-7.95(m,1H),8.23(d,1H,J=9.08Hz),8.26(d,1H,J=8.56Hz),12.60(s,1H)。
向1M甲胺的THF溶液(560μl,0.56mmol)中加入82mg所得中间体(0.187mmol),然后滴加1M NaHMDS的THF溶液(560μl,0.56mmol)。将反应混合物搅拌10分钟后,加入5mL H2O并用AcOEt进行萃取。有机层用盐水洗涤,经Na2SO4干燥,在减压下浓缩,并经硅胶柱色谱纯化(己烷∶AcOEt=1∶1至AcOEt),得到标题化合物,为淡黄色固体。数据示于实施例7A。
重复上述操作、使用适合的原料和条件,得到如下所鉴定的以下化合物。
以下2-(5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基)-N-甲基-5-吡咯烷-1-基-苯甲酰胺由2-(5-氯-2-甲基-嘧啶-4-基氨基)-N-甲基-5-吡咯烷-1-基-苯甲酰胺和相应的苯胺、按照实施例2的方法制备:
以下2-[5-氯-2-(4-氟-2-甲氧基-苯基氨基)-嘧啶-4-基氨基]-5-取代的-N-甲基-苯甲酰胺由相应的苯胺、按照实施例2的方法制备:
实施例16B
CDCl3:3.01-3.10(m,4H),3.63-3.68(m,4H),3.89(s,3H),6.59(ddd,1H),6.66(dd,1H),7.20-7.26(m,1H),7.36(s,1H),7.57-7.63(m,1H),7.84(dd,1H),8.09-8.14(m,1H),8.14(s,1H),8.53(d,1H),9.30(s,1H)。
实施例16C
CDCl3:3.56-3.65(m,2H),3.88(s,3H),5.11-5.19(m,1H),6.50-6.56(m,1H),6.61-6.66(m,1H),7.25-7.29(m,1H),7.38(brs,1H),7.58-7.62(m,1H),7.97(dd,1H),8.02-8.10(m,1H),8.15(s,1H),8.41(dd,1H),8.81(s,1H)。
以下2-(5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基)-5-氟-N-甲基-苯甲酰胺由2-(2,5-二氯-嘧啶-4-基氨基)-5-氟-N-甲基-苯甲酰胺和相应的苯胺、按照实施例2的方法制备:
以下2-[5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基]-N-异丙基-苯磺酰胺由2-(5-氯-2-氯-嘧啶-4-基氨基)-N-异丙基-苯磺酰胺和相应的苯胺、按照实施例7A的方法制备:
以下2-[5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯磺酰胺由2-(5-氯-2-氯-嘧啶-4-基氨基)-N-甲基-苯磺酰胺和相应的苯胺、按照实施例A的方法制备:
以下2-[5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基]-N-仲-丁基-苯磺酰胺由2-(5-氯-2-氯-嘧啶-4-基氨基)-N-仲-丁基-苯磺酰胺和相应的苯胺、按照实施例7A的方法制备:
以下2-[5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基]-N-异-丁基-苯磺酰胺由2-(5-氯-2-氯-嘧啶-4-基氨基)-N-仲-丁基-苯磺酰胺和相应的苯胺、按照实施例7A的方法制备:
以下2-[5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基]-N-(1-乙基-丙基)-苯磺酰胺由2-(5-氯-2-氯-嘧啶-4-基氨基)-N-(1-乙基-丙基)-苯磺酰胺和相应的苯胺、按照实施例7A的方法制备:
以下2-[5-氯-2-(取代的苯基氨基)-嘧啶-4-基氨基]-N-异-丁基-苯磺酰胺由2-(5-氯-2-氯-嘧啶-4-基氨基)-N-环丁基-苯磺酰胺和相应的苯胺、按照实施例7A的方法制备:
以下5-氯-N2-(取代的苯基)-N4-[2-(丙烷-1-磺酰基)-苯基]-嘧啶-2,4-二胺由(2,5-二氯-嘧啶-4-基)-[2-(丙烷-1-磺酰基)-苯基]-胺和相应的苯胺、按照实施例7A的方法制备:
以下5-氯-N2-(取代的苯基)-N4-[2-乙烷磺酰基-苯基]-嘧啶-2,4-二胺由(2,5-二氯-嘧啶-4-基)-[2-乙烷磺酰基-苯基]-胺和相应的苯胺、按照实施例7A的方法制备:
HPLC条件
柱子:YMC CombiScreen ODS-A(5um,12nm),50×4.6mm I.D.
流速:2.0ml/min
洗脱剂:A)TFA/水(0.1/100),B)TFA/乙腈(0.1/100)
梯度:5-100%B(0-5分钟)
检测:UV 215nm
以下5-氯-N2-(取代的苯基)-N4-[2-(丙烷-2-磺酰基)-苯基]-嘧啶-2,4-二胺由(2,5-二氯-嘧啶-4-基)-[2-(丙烷-2-磺酰基)-苯基]-胺和相应的苯胺、按照实施例7A的方法制备:
实施例36(左侧苯胺的中间体)
36-1:2-氨基-N-甲基-苯甲酰胺的制备
在室温下向16.3g(100mmol)靛红酸酐的100mL H2O悬液中分批加入100mL 2N甲基胺-四氢呋喃溶液(200mmol)。将反应混合物搅拌1小时,然后用AcOEt萃取。有机层用H2O和盐水洗涤,经Na2SO4干燥,在减压下浓缩,得到13.79g所需产物2-氨基-N-甲基-苯甲酰胺(92mmol,92%),为无色固体。
NMR(400MHz,CDCl3,δ):2.97(d,3H,J=4.52Hz),5.49(bs,1H),6.07(bs,1H),6.64(ddd,1H,J=8.04,7.56,1.0Hz),6.68(dd,1H,J=8.32,1.0Hz),7.20(ddd,1H,J=8.32,7.56,1.52Hz),7.29(dd,1H,J=8.04,1.52Hz)。
36-2:2-(2,5-二氯-嘧啶-4-基氨基)-N-甲基-苯甲酰胺
向15.0g(99.8mmol)2-氨基-N-甲基-苯甲酰胺的DMF溶液(300mL)中加入2,4,5-三氯嘧啶(23.8g,130mmol)和碳酸钾(17.9g,130mmol)。将反应混合物在75℃下搅拌5小时,冷却至室温,然后倒入H2O(600mL)中。过滤收集所得沉淀,然后用50%CH3CN水溶液(200mL)洗涤并在减压下干燥(40℃,10小时),得到所需的2-(2,5-二氯-嘧啶-4-基-氨基)-N-甲基-苯甲酰胺,为象牙色固体(26.4g,88.9mmol,89%)。
NMR(400MHz,DMSO-d6,δ):2.81(d,3H,J=4.52Hz),7.22(dd,1H,J=8.56,8.04Hz),7.60(ddd,1H,J=8.56,8.56,1.0Hz),7.81(dd,1H,J=8.04,1.0Hz),8.48(s,1H),8.52(d,1H,J=8.56Hz),8.80-8.90(m,1H),12.18(s,1H)。
根据上述方法,制备以下化合物。
36-3:2-(5-溴-2-氯-嘧啶-4-基氨基)-N-甲基-苯甲酰胺
NMR(400MHz,DMSO-d6,δ):2.81(d,3H),7.23(ddd,1H,J=7.54,7.54,1.0Hz),7.59(ddd,1H,J=7.93,8.06,1.52Hz),7.79(dd,1H,J=7.8,1.52Hz),8.47(dd,1H J=8.06,1.0Hz),8.55(s,1H),8.81-8.87(m,1H),12.0(brs,1H)。Rf:0.46(正己烷∶AcOEt=7∶3)。
36-4:2-(2,5-二氯-嘧啶-4-基氨基)-N-乙基-苯甲酰胺
NMR(400MHz,CDCl3,δ):1.28(t,d=7.04,3H),3.48-3.57(m,2H),6.22(br.s,1H),7.11-7.17(m,1H),7.51(dd,J=1.0,8.04,1H),7.53-7.61(m,1H),8.22(s,1H),8.69-8.74(m,1H),11.66(br.s,1H)。Rf:0.60(己烷∶AcOEt=1∶1)。
36-5:2-(5-溴-2-氯-嘧啶-4-基氨基)-N-甲基-苯磺酰胺的制备
将5-溴-2,4-二氟嘧啶(684mg,3.0mmol)和2-氨基-N-甲基-苯磺酰胺(559mg,3.0mmol)在含有碳酸钾(830mg,6.0mmol)的N,N-二甲基甲酰胺(10mL)中的悬液在室温下搅拌23小时。加入饱和氯化铵水溶液,将混合物倒入水中并用乙酸乙酯萃取两次。有机层用盐水洗涤,经硫酸钠干燥并真空蒸发。残余物经硅胶柱色谱纯化(正己烷-乙酸乙酯梯度),得到标题化合物,为浅黄色固体。
1H-NMR(CDCl3),δ(ppm):2.67(d,3H),4.79(q,1H),7.26(s,1H),7.29(ddd,1H),7.66(ddd,1H),7.95(dd,1H),8.37(s,1H),8.48(d,1H),9.52(s,1H)。Rf(正己烷∶乙酸乙酯=10∶3):0.33。
根据上述方法,制备以下化合物。
36-6:2-(2,5-二氯-嘧啶-4-基氨基)-N-甲基-苯磺酰胺
1H-NMR(400MHz,CDCl3,δ);2.67(d,3H),4.97-5.04(m,1H),7.29(ddd,1H,J=7.54,7.54,1.0Hz),7.66(ddd,1H,J=7.93,8.08,1.48Hz),7.94(dd,1H,J=8.04,1.52Hz),8.24(s,1H),8.51(dd,1H J=8.06,1.0Hz),9.64(brs,1H)。Rf:0.45(正己烷∶AcOEt=4∶1)。
36-7:2-(2,5-二氯-嘧啶-4-基氨基)-N-异丙基-苯磺酰胺
在0℃下向2-氨基-N-异丙基-苯磺酰胺(16.1g,75.1mmol)的DMI溶液(150mL)中分批加入氢化钠(6.6g,165.3mmol)。将混合物在室温下搅拌1小时后,在0℃加入2,4,5-三氯嘧啶(20.7g,112.7mmol)。进一步在室温下搅拌5小时后,加入水,用AcOEt将混合物萃取三次。有机层用盐水洗涤,经硫酸钠干燥并在减压下蒸发。残余物经硅胶柱色谱纯化(己烷至己烷∶AcOEt=4∶1),得到标题化合物,为淡棕色固体(10.2g,38%)。
1H-NMR(400MHz,CDCl3,δ);1.06(d,6H),3.43-3.53(m,1H),4.38(d,1H),7.29(dd,1H),7.66(dd,1H),7.98(d,1H),8.29(s,1H),8.51(d,1H),9.51(brs,1H)。Rf:0.45(正己烷∶AcOEt=4∶1)。
以与上述相同的方式制备以下化合物。
36-10:2-(2-氯-5-硝基-嘧啶-4-基氨基)-N-甲基-苯磺酰胺的制备
将2,4-二氯-5-硝基-嘧啶(1.94g,10mmol)和2-氨基-N-甲基-苯磺酰胺(1.86g,10mmol)溶解于CHCl3(30mL)中。将反应混合物在61℃下加热2小时。蒸发溶剂,残余物用醚洗涤,得到标题产物。
Rf=0.5(正己烷∶乙酸乙酯=1∶1)。1H-NMR(400MHz,CDCl3),δ(ppm):2.67(d,3H),4.6-4.7(m,2H),7.41(t,1H),7.7(t,1H),8.04(d,1H),8.15(d,1H),9.21(s,1H),11.2(s,1H)。
36-11:(2,5-二氯-嘧啶-4-基)-[2-(丙烷-1-磺酰基)-苯基]-胺的制备
在0℃下向2-(丙烷-1-磺酰基)-苯基胺(3.69g,18.5mmol)的N,N-二甲基甲酰胺溶液(40mL)中分批加入氢化钠(1.48g,37mmol)。搅拌后,加入2,4,5-三氯嘧啶(2.1mL,18.5mmol)。将混合物在0℃搅拌30分钟并进一步在室温下搅拌7小时。加入饱和氯化铵水溶液后,将混合物倒入水中并用乙酸乙酯萃取两次。有机层用盐水洗涤,经硫酸钠干燥并真空蒸发。残余物经硅胶柱色谱纯化(正己烷-乙酸乙酯梯度),得到标题化合物,为无色固体。
1H-NMR(CDCl3),δ(ppm):0.99(t,3H),1.77(d,2H),3.07-3.11(m,2H),7.26(s,1H),7.32(ddd,1H),7.73(ddd,1H),7.95(dd,1H),8.31(s,1H),8.61(dd,1H),9.94(bs,1H)。Rf(正己烷∶乙酸乙酯=3∶1):0.63。
根据上述方法,制备以下化合物。
实施例36-16:市售不可得的取代胺的合成
3-氨基-4’-甲氧基-4-甲基联苯的制备
向4-甲氧基苯基-硼酸(500mg,3.29mmol)的甲苯(5.2mL)和乙醇(1.3mL)溶液中加入碳酸钾(910mg,6.58mmol)、四(三苯基膦)钯(228.1mg,0.099mmol)和4-溴-1-甲基-2-硝基苯(711mg,3.29mmol),并在100℃搅拌7小时。将混合物倒入水中并用乙酸乙酯萃取两次。有机层用水、然后用盐水洗涤,经硫酸镁干燥,并真空蒸发。残余物经硅胶柱色谱纯化(正己烷∶乙酸乙酯=5∶1),得到4’-甲氧基-4-甲基-3-硝基联苯,为黄色固体。
1H-NMR(δ,ppm):2.62(s,3H),3.86(s,3H),7.02-6.98(m,2H),7.37(d,1H),7.54(dd,2H),7.68(dd,1H),8.18(d,1H)。Rf(己烷∶乙酸乙酯=3∶1):0.40。
将4′-甲氧基-4-甲基-3-硝基联苯(630mg,2.95mmol)和10%披钯碳(63mg,0.059mmol)在甲醇(6mL)中的悬液在氢气氛下搅拌12小时。过滤除去钯催化剂,将所得溶液在真空下蒸发,得到标题化合物。
1H-NMR(δ,ppm):2.20(s,3H),3.84(s,3H),6.87(d,1H),6.89(dd,1H),6.95(d,2H),7.09(d,1H),7.48(d,2H)。Rf(正己烷∶乙酸乙酯=1∶1):0.50。
4-(3-氨基-4-甲基苯甲酰基)-哌嗪-1-甲酸叔丁酯的制备
向4-甲基-3-硝基-苯甲酸(300mg,2.76mmol)、N-丁氧基羰基-哌嗪(340mg,1.83mmol)的DMF(3.0mL)溶液中加入三乙胺(300μL,3.59mmol)、TBTU(800mg,2.49mmol)和HOAt(270.5mg,1.99mmol),并在室温下搅拌24小时。将混合物倒入水中,用乙酸乙酯萃取两次。有机层用水、然后用盐水洗涤,经硫酸镁干燥,在真空中蒸发。残余物经硅胶柱色谱纯化(正己烷∶乙酸乙酯=5∶1),得到4-(4-甲基-3-硝基苯甲酰基)-哌嗪-1-甲酸叔丁酯,为无色固体。
1H-NMR(δ,ppm):1.47(s,9H),2.64(s,3H),3.28-3.88(m,8H),7.42(d,1H),7.56(dd,1H),8.03(d,1H)。Rf(己烷∶乙酸乙酯=10∶1):0.13。
通过用氢经10%披钯碳在甲醇溶液中还原,得到标题化合物。
4-(3-氨基-4-甲基苯基)-吗啉的制备
向4-溴-1-甲基-2-硝基苯(225mg,1.04mmol)、吗啉(125μL,1.25mmol)和碳酸铯(474.4mg,1.46mmol)的甲苯溶液中加入二醋酸钯(31.2mg,0.139mmol)和2-(二叔丁基膦)联苯(125mg,0.403mmol),并在100℃搅拌5小时。冷却后,将混合物过滤,除去不溶物。将滤液倒入水中,用乙酸乙酯萃取两次。有机层用水、然后用盐水洗涤,经硫酸镁干燥,真空蒸发。残余物经硅胶柱色谱纯化(正己烷∶乙酸乙酯=5∶1),得到4-(4-甲基-3-硝基苯基)-吗啉,为黄色固体。
1H-NMR(δ,ppm):2.50(s,3H),3.17-3.19(m,4H),3.86-3.88(m,4H),7.04(dd,1H),7.21(d,1H),7.47(d,1H)。Rf(己烷∶乙酸乙酯=5∶1):0.20。
通过用氢经10%披钯碳在甲醇溶液中还原,得到标题化合物。
实施例37:市售不可得的取代胺的合成
37-1:1-(3-甲氧基-4-硝基-苯基)-哌啶-4-醇的合成
向哌啶-4-醇(2.79g,28mmol)和碳酸钾(3.88g,28mmol)的N,N-二甲基甲酰胺(40mL)悬液中加入4-氟-2-甲氧基-1-硝基-苯(4.0g,23mmol),在室温下搅拌24小时。将混合物倒入水中,过滤收集沉淀。将所得固体在500℃真空干燥,得到1-(3-甲氧基-4-硝基-苯基)-哌啶-4-醇(5.23g),为黄色固体,产率89%。
1H-NMR(400MHz,CDCl3,δ,ppm):1.54(d,1H),1.62-1.71(m,2H),1.98-2.04(m,2H),3.22(ddd,4H),3.73-3.80(m,2H),3.95(s,3H),3.98-4.02(m,1H),6.33(d,1H),6.43(dd,1H),8.00(d,1H)。
重复上述操作、使用适合的原料和条件,得到以下化合物。
38:1-[4-(4-甲氧基-3-硝基-苯基)-哌嗪-1-基]-乙酮的制备
向5-溴-1-甲氧基-2-硝基苯(300mg,1.29mmol)的二噁烷溶液中加入1-乙酰基哌嗪(400mg,3.12mmol)、碳酸铯(1.0g,3.07mmol)、二醋酸钯(29.0mg,0.129mmol)和2-(二叔丁基膦)联苯(77mg,0.258mmol),在100℃搅拌8小时。冷却后,将混合物过滤,除去不溶物。将滤液倒入水中,用乙酸乙酯萃取两次。有机层用水、然后用盐水洗涤,经硫酸镁干燥,真空蒸发。残余物经硅胶柱色谱纯化(正己烷∶乙酸乙酯梯度),得到1-[4-(4-甲氧基-3-硝基-苯基)-哌嗪-1-基]-乙酮(319mg,44%),为黄色固体。
1H-NMR(400MHz,CDCl3,δ,ppm):2.14(s,3H),3.63(ddd,4H),3.63(t,2H),3.78(t,2H),3.92(s,3H),7.03(d,1H),7.12(d,1H),7.41(d,1H)。Rf(乙酸乙酯):0.18。
39:1-(3-甲氧基-4-硝基-苯基)-哌啶-4-酮的制备
向4-哌啶酮盐酸盐单水合物(10.0g,0.065mol)的DMF(80mL)溶液中加入4-氟-2-甲氧基-1-硝基-苯(10.0g,0.058mol)和碳酸钾(20.2g),将混合物在70℃搅拌20小时。过滤后,将滤液倒入H2O(约300mL)中,过滤收集所得沉淀,然后用H2O洗涤数次,得到标题化合物(8.98g),产率61%,为橙色固体。1H-NMR(400MHz,CDCl3,δ):2.65-2.62(4H,m),3.81-3.78(4H,m),3.98(3H,s),6.34(1H,d),6.45(1H,dd),8.05(1H,d)。
40:1-[1-(3-甲氧基-4-硝基-苯基)-哌啶-4-基]-4-甲基-哌嗪的制备
在0℃下向1-(3-甲氧基-4-硝基-苯基)-哌啶-4-酮(4.96g,0.020mol)的二氯乙烷(50ml)溶液中加入N-甲基哌嗪(2.7ml,0.024mol),将混合物在室温下搅拌。4小时后,加入三乙酰氧基硼氢化钠(5.04g,0.024mol),将混合物进一步在室温下搅拌24小时。在0℃加入1N氢氧化钠后,将混合物倒入水中并用二氯甲烷萃取三次。合并有机层,用1N盐酸萃取三次。将水层用2N氢氧化钠碱化,用二氯甲烷萃取三次。有机层用盐水洗涤,经硫酸钠干燥,真空蒸发,得到标题化合物,为黄色固体(6.04g),产率91%。
1H-NMR(400MHz,CDCl3,δ):1.70-1.57(2H,m),2.03-1.93(2H,m),2.29(3H,s),2.55-2.38(5H,m),2.70-2.56(4H,m),2.97(2H,ddd),3.97-3.92(2H,m),3.95(3H,s),6.31(1H,d,),6.42(1H,dd),8.00(1H,d)。
41:4′-甲氧基-4-甲基-3-硝基-联苯的制备
向4-甲氧基苯基-硼酸(500mg,3.29mmol)在甲苯(5.2mL)和乙醇(1.3mL)中的溶液中加入碳酸钾(910mg,6.58mmol)、四(三苯基膦)钯(228.1mg,0.099mmol)和4-溴-1-甲基-2-硝基苯(711mg,3.29mmol),并在100℃搅拌7小时。将混合物倒入水中,用乙酸乙酯萃取两次。有机层用水、然后用盐水洗涤,经硫酸镁干燥,真空蒸发。残余物经硅胶柱色谱纯化(正己烷∶乙酸乙酯=5∶1),得到4’-甲氧基-4-甲基-3-硝基联苯(630mg,79%),为黄色固体。
1H-NMR(400MHz,CDCl3,δ,ppm):2.62(s,3H),3.86(s,3H),7.02-6.98(m,2H),7.37(d,1H),7.54(dd,2H),7.68(dd,1H),8.18(d,1H)。Rf(己烷∶乙酸乙酯=3∶1):0.40。
42:4-(2-乙氧基-乙氧基)-1-(3-甲氧基-4-硝基-苯基)-哌啶的制备
向1-(3-甲氧基-4-硝基-苯基)-哌啶-4-醇(300mg,1.2mmol)的N,N-二甲基甲酰胺(3.0mL)溶液中加入氢化钠(1.52g,3.8mmol)。搅拌后,加入2-溴乙基甲基醚(150μl,1.6mmol),将混合物进一步在70℃下搅拌15小时。加入饱和氯化铵水溶液后,将混合物倒入水中,用乙酸乙酯萃取两次。有机层用盐水洗涤,经硫酸钠干燥,真空蒸发。残余物经硅胶柱色谱纯化(正己烷-乙酸乙酯梯度),得到4-(2-甲氧基-乙氧基)-1-(3-甲氧基-4-硝基-苯基)-哌啶(111mg,29%),为黄色油。
1H-NMR(400MHz,CDCl3,δ,ppm):1.52(t,3H),1.95-2.00(m,2H),1.70-1.79(m,2H),3.23(ddd,2H),3.58-3.64(m,2H),3.65-3.68(m,2H),3.64-3.72(m,2H),3.95(s,3H),6.31(d,1H),6.42(dd,1H),8.00(d,1H)。Rf 0.53(正己烷∶AcOEt=1∶1)。
根据上述操作、使用适合的烷基卤,制备以下化合物。
实施例43
2-甲氧基-4-(1-甲基-哌啶-4-基氧基)-苯基胺
4-(3-甲氧基-4-硝基-苯氧基)-1-甲基-哌啶
在室温下向4-氟-2-甲氧基-1-硝基-苯(10.3g,60mmol)在甲苯(50mL)和25%KOH水溶液(50mL)中的溶液中加入4-羟基-1-甲基哌啶(13.8g,120mmol)和四正丁基溴化铵(3.87g,12mmol)。将混合物在60℃加热1天。将反应混合物冷却至室温,倒入冰水并用乙酸乙酯萃取两次。有机层相继用稀HCl和盐水洗涤,经硫酸钠干燥,真空蒸发,以定量产率得到粗制化合物(13.4g)。
Rf=0.22(甲醇∶二氯甲烷=1∶4)。1H-NMR(400MHz,CDCl3,δ,ppm):1.84-1.92(m,2H),2.0-2.1(m,2H),2.3-2.4(m,2H),2.33(s,3H),2.65-2.75(m,2H),3.94(s,3H),4.39-4.46(m,1H),6.49(dd,1H),6.99(d,1H),6.54(d,1H),7.99(d,1H)。
实施例44
2-甲氧基-4-(2-吗啉-4-基-乙氧基)-苯基胺
3-甲氧基-4-硝基-苯酚
在0℃下,向3-氟-4-硝基-苯酚(15.7g,100mmol)的THF(300mL)溶液中加入含30%KOMe的甲醇(49mL,210mmol)。将混合物加热至轻微回流达18小时。
4-[2-(3-甲氧基-4-硝基-苯氧基)-乙基]-吗啉
在室温下向3-甲氧基-4-硝基-苯酚(1.69g,10mmol)的DMF(25mL)溶液中加入4-(2-氯乙基)吗啉盐酸盐(2.05g,11mmol)、K2CO3(1.52g,11mmol)、KI(332mg,2mmol)。将混合物加热至轻微回流达4小时。将反应混合物冷却至室温并用水淬灭。将所得混合物用乙酸乙酯萃取两次,然后相继用水和盐水洗涤有机层,经硫酸钠干燥,过滤,真空蒸发,得到粗制化合物,产率90%(2.55g)。
Rf=0.11(单独的AcOEt)。1H-NMR(400MHz,CDCl3),δ(ppm):2.56-2.61(m,4H),2.83(t,
将反应混合物冷却至室温,缓慢用1N HCl水溶液在0℃淬灭。所得混合物用乙酸乙酯萃取两次,然后将有机层相继用盐水洗涤,经硫酸钠干燥,过滤,真空蒸发,得到粗制化合物,产率94%(15.9g)。
Rf=0.22(甲醇∶二氯甲烷=1∶4)。1H-NMR(400MHz,CDCl3),δ(ppm):3.95(s,3H),5.49(s,1H),6.44(dd,1H,J=8.8,2.52Hz),6.54(d,1H,J=2.52Hz),7.96(d,1H J=8.6Hz)。
3.72-3.76(m,4H),3.94(s,3H),4.18(t,2H),6.51(dd,1H,J=9.08,2.52Hz),6.56(d,1H,J=2.48Hz),8.00(d,1H J=9.08Hz).2H),
实施例45
2-甲氧基-4-(2-吗啉-4-基-乙氧基)-苯基胺
乙酸4-甲氧基-3-硝基-苯基酯
在室温下向4-甲氧基苯酚(12.4g,100mmol)的AcOH(50mL)溶液中加入Ac2O(50mL)。将混合物加热至轻微回流达1.5小时。将反应混合物冷却至室温,在0℃下缓慢加入浓HNO3(d=1.38,10mL)。将混合物加热至55℃达1.5小时。将反应混合物冷却至室温并用0℃的水淬灭。所得固体用Buchner漏斗过滤,得到粗制化合物,产率76%(16.0g)。
Rf=0.59(AcOEt∶正己烷=3∶7)。1H-NMR(400MHz,CDCl3),δ(ppm):2.31(s,3H),3.96(s,3H),7.08(d,1H,J=9.04Hz),7.31(dd,1H,J=9.04,3.04Hz),7.96(d,1H J=3.04Hz)。
4-甲氧基-3-硝基-苯酚
在0℃下向乙酸4-甲氧基-3-硝基-苯基酯(1.06g,5mmol)的EtOH(20mL)溶液中加入1N NaOH水溶液(5.5mL)。将混合物在室温下搅拌2小时。将反应混合物用AcOH淬灭,用乙酸乙酯萃取两次。有机层相继用水和盐水洗涤,经硫酸钠干燥,过滤,真空蒸发,以定量产率得到粗制化合物(840mg)。
Rf=0.59(AcOEt∶正己烷=3∶7)。1H-NMR(400MHz,CDCl3),δ(ppm):3.91(s,3H),6.99(d,1H,J=9.04Hz),7.17(dd,1H,J=9.04,3.00Hz),7.38(d,1HJ=3.04Hz)。
4-[2-(4-甲氧基-3-硝基-苯氧基)-乙基]-吗啉
在室温下向4-甲氧基-3-硝基-苯酚(1.01g,6mmol)的DMF(15mL)溶液中加入4-(2-氯乙基)吗啉盐酸盐(1.34g,7.2mmol)、K2CO3(2.49g,18mmol)、KI(2.99g,18mmol)。将混合物加热至80℃达4小时。将反应混合物冷却至室温并用饱和氯化铵水溶液淬灭。将所得混合物用乙酸乙酯萃取两次,然后有机层相继用水和盐水洗涤,经硫酸钠干燥,过滤,真空蒸发,以定量产率得到粗制产物(1.70g)。Rf=0.14(单独的AcOEt)。1H-NMR(400MHz,DMSO,δ,ppm):2.36-2.51(m,4H),2.67(t,J=5.5,2H),3.52-3.60(m,4H),3.86(s,3H),4.11(t,J=6.0,2H),7.25-7.29(m,2H),7.46-7.49(m,1H)。
2-甲氧基-4-(1-甲基-哌啶-4-基氧基)-苯基胺的制备:
在氮气氛下向4-(3-甲氧基-4-硝基-苯氧基)-1-甲基-哌啶(3.0g,11.3mmol)的乙醇(50mL)溶液中加入5%披钯碳(300mg)。反应容器装备有球形接管并通入氢,抽空三次,直至反应处于氢气氛下。将反应搅拌过夜。反应混合物经硅藻土垫过滤,用甲醇洗涤。在真空中浓缩滤液,以定量产率的得2-甲氧基-4-(1-甲基-哌啶-4-基氧基)-苯基胺(2.7g)。
Rf=0.41(甲醇∶二氯甲烷=1∶1)。1H-NMR(400MHz,CDCl3),δ(ppm):1.75-1.86(m,2H),1.92-2.05(m,2H),2.2-2.32(m,2H),2.30(s,3H),3.4-3.7(brs,2H),3.82(s,3H),4.1-4.2(m,1H),6.37(dd,1H),6.46(d,1H),6.61(d,1H)。
重复上述操作、使用适合的原料的条件,得到以下化合物。
47:4-(3-氨基-4-甲基苯甲酰基)-哌嗪-1-甲酸叔丁酯
向4-甲基-3-硝基-苯甲酸(300mg,2.76mmol)、N-丁氧羰基-哌嗪(340mg,1.83mmol)的DMF(3.0mL)溶液中加入三乙胺(300μL,3.59mmol)、TBTU(800mg,2.49mmol)和HOAt(270.5mg,1.99mmol),并在室温下搅拌24小时。将混合物倒入水中,用乙酸乙酯萃取两次。有机层用水、然后用盐水洗涤,经硫酸镁干燥,真空蒸发。残余物经硅胶柱色谱纯化(正己烷∶乙酸乙酯=5∶1),得到4-(4-甲基-3-硝基苯甲酰基)-哌嗪-1-甲酸叔丁酯,为无色固体。
1H-NMR(δ,ppm):1.47(s,9H),2.64(s,3H),3.88-3.28(m,8H),7.42(d,1H),7.56(dd,1H),8.03(d,1H)。Rf(己烷∶乙酸乙酯=10∶1):0.13。
通过用氢经10%披钯碳于甲醇溶液中还原,得到标题化合物。
48:4-(3-氨基-4-甲基苯基)-吗啉的制备
向4-溴-1-甲基-2-硝基苯(225mg,1.04mmol)、吗啉(125μL,1.25mmol)和碳酸铯(474.4mg,1.46mmol)的甲苯悬液中加入二醋酸钯(31.2mg,0.139mmol)和2-(二叔丁基膦)联苯(125mg,0.403mmol),在100℃搅拌5小时。冷却后,将混合物过滤,除去不溶物。将滤液倒入水中,用乙酸乙酯萃取两次。有机层用水、然后用盐水洗涤,经硫酸镁干燥,真空蒸发。残余物经硅胶柱色谱纯化(正己烷∶乙酸乙酯=5∶1),得到4-(4-甲基-3-硝基苯基)-吗啉,为黄色固体。
1H-NMR(δ,ppm):2.50(s,3H),3.19-3.17(m,4H),3.88-3.86(m,4H),7.04(dd,1H),7.21(d,1H),7.47(d,1H)。Rf(己烷∶乙酸乙酯=5∶1):0.20。
通过用氢经10%披钯碳于甲醇溶液中还原,得到标题化合物。
49:2-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-苯甲酸的制
备
向1.0g(3.37mmol)2-(2,5-二氯-嘧啶-4-基氨基)-N-甲基-苯甲酰胺的15mL乙酸悬液中加入2-甲氧基-4-吗啉代苯胺二盐酸盐(1.9g,6.73mmol)和6.0mL氯化氢的1N乙醇溶液(6.0mmol)。将反应混合物在120℃下搅拌16小时并冷却至室温后,加入NaHCO3水溶液,调节酸度为pH5至pH6。过滤收集所得沉淀,减压干燥,得到2-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基-氨基)-嘧啶-4-基氨基]-苯甲酸(970mg,2.12mmol,63%),为象牙色固体。
NMR(400MHz,DMSO-d6,δ):3.10-3.20(m,4H),3.78(s,3H),3.70-3.80(m,4H),6.52(dd,1H,J=8.56,2.52Hz),6.67(d,1H,J=2.52Hz),7.08(dd,1H,J=8.04,8.04Hz),7.39(d,1H,J=8.56Hz),7.35-7.45(m,1H),7.99(dd,1H,J=8.04,1.52Hz),8.14(s,1H),8.28(s,1H),8.70-8.80(m,1H)。
实施例50:磺酰胺部分如下制备:
2-氨基-4-氯-5-甲基-苯磺酰氯的制备
向2-氨基-5-氯-4-甲基-苯磺酸(3.0g,1.35mmol)的二氯乙烷(10mL)溶液中加入磺酰氯(4.4mL,3.83mmol)并在60℃搅拌。1小时后,加入亚硫酰氯(1.3mL),将混合物进一步在100℃搅拌7.0小时。将混合物倒入冰水,用醚萃取三次。有机层用水、然后用盐水洗涤,经硫酸钠干燥,真空蒸发。
1H-NMR(δ,ppm):2.35(s,3H),6.68(s,1H),7.75(s,1H)。
使该取代的磺酰氯与适合的胺反应。例如与甲基胺反应后,形成2-氨基-5-氯-4,N-二甲基苯磺酰胺。
实施例51
2-[5-溴-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-N,N-二甲基-苯
磺酰胺的制备
向2-[5-溴-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯磺酰胺(实施例3-19)(1.0g,1.82mmol)的DMF(10mL)溶液中加入碳酸钾(300mg,2.17mmol)和碘代甲烷(116μl,1.86mmol)。将所得悬液在50℃搅拌1小时。向反应混合物中加入水,用乙酸乙酯萃取三次。有机层用水洗涤,经硫酸钠干燥,在真空中浓缩。残余物经氧化铝柱色谱纯化(AcOEt),得到标题化合物(728mg,71%产率)。
NMR(400MHz,CDCl3,δ):2.74((s,6H),3.05-3.18(m,4H),3.84-3.93(m,4H),3.88(s,3H),6.43(dd,1H),6.53(d,1H),7.24(m,1H),7.31(s,1H),7.56(m,1H),7.87(dd,1H),8.05(d,1H),8.21(s,1H),8.49(d,1H),8.49(d,1H),9.27(s,1H)。Rf:0.23(AcOEt∶己烷=1∶1)。
实施例52
2-[5-溴-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-5-氟-N-甲基-苯
磺酰胺的制备
7-氟-1,1-二氧代-1,4-二氢-2H-1λ
6
-苯并[1,2,4]噻二嗪-3-酮的制备
在0℃下向氯磺酰异氰酸酯(1.2mL,13.5mmol)的硝基乙烷(10mL)溶液中滴加4-氟苯胺(1.0g,8.97mmol),将反应混合物搅拌30分钟。在0℃下向该溶液中加入氯化铝(1.3g,9.87mmol),将混合物在100℃搅拌1小时。冷却至室温后,加入水,将混合物用乙酸乙酯萃取两次。有机层用盐水洗涤,经硫酸钠干燥,减压浓缩。过滤收集所得固体,用醚洗涤,得到浅灰色固体(803.9mg,41%)。
NMR(400MHz,DMSO-d6,δ):7.22-7.28(m,1H),7.45-7.57(m,1H),7.60(m,1H),11.15.11.30(m,1H)。Rf:0.43(MeOH∶AcOEt=1∶5)。
7-氟-2-甲基-1,1-二氧代-1,4-二氢-2H-1λ
6
-苯并[1,2,4]噻二嗪-3-酮的制备
向7-氟-1,1-二氧代-1,4-二氢-2H-1-λ6-苯并[1,2,4]噻二嗪-3-酮(5.19g,24.0mmol)的DMF(50mL)溶液中相继加入氢化钠(1.04g,26.0mmol)和碘代甲烷(1.5mL,24.0mmol),将混合物在70℃搅拌1小时。冷却至室温后,将混合物倒入水中,过滤收集沉淀,相继用水和己烷洗涤,得到浅灰色固体(5.38g,94%)。
NMR(400MHz,DMSO-d6,δ):3.32(s,3H),7.44(dd,1H),7.75(ddd,1H),7.94(dd,1H)。Rf(MeOH∶AcOEt=1∶5):0.21;Rf:0.39(己烷∶AcOEt=1∶1)。
2-氨基-5-氟-N-甲基-苯磺酰胺的制备
将6.79g 7-氟-2-甲基-1,1-二氧代-1,4-二氢-2H-1λ6-苯并[1,2,4]噻二嗪-3-酮(29.5mmol)溶解于20%氢氧化钠水溶液中,将所得溶液在100℃搅拌13.5小时。将混合物冷却至室温并倒入水。加入78mL 5M HCl水溶液,过滤收集沉淀,用水洗涤,得到浅紫色固体(3.96g,65%)。
NMR(400MHz,CDCl3,δ):2.60(d,3H),4.55-4.82(m,3H),6.74(dd,1H),7.05-7.12(m,1H),7.45(dd,1H)。Rf:0.41(己烷∶AcOEt=1∶1)。
2-(5-溴-2-氯-嘧啶-4-基氨基)-5-氟-N-甲基-苯磺酰胺
以与实施例B所述相同的方式进行嘧啶和2-氨基-5-氟-N-甲基-苯磺酰胺的反应。
NMR(400MHz,CDCl3,δ):2.67(d,3H),4.56(m,1H),7.36-7.45(m,1H),7.68(dd,1H),8.39(s,1H),8.42(dd,1H),9.26(s,1H)。Rf 0.59(己烷∶AcOEt=1∶1)。
2-[5-溴-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-5-氟-N-甲基-苯
磺酰胺
根据实施例A所述方式引入取代的苯胺。
NMR(400MHz,CDCl3,δ):2.65(d,3H),3.09-3.16(m,4H),3.87(s,3H),4.50(q,1H),6.41(dd,1H),6.52(d,1H),7.25-7.33(m,2H),7.69(dd,1H),7.95(d,1H),8.20(s,1H),8.37(dd,1H),8.70(s,1H)。Rf 0.30(己烷∶AcOEt=1∶1)。
实施例53:FAK试验
所有步骤均在96-孔黑色微量滴定板中进行。将纯化的重组六组氨酸标记的人FAK激酶域用稀释缓冲液(含50mM HEPES,pH7.5、0.01%BSA、0.05%Tween-20的水)稀释至浓度为94ng/mL(2.5nM)。通过混合10μL 5x激酶缓冲液(含250mM HEPES,pH7.5、50μM Na3VO4、5mM DTT、10mMMgCl2、50mM MnCl2、0.05%BSA、0.25%Tween-20的水)、20μL水、5μL4μM生物素化的肽底物(Biot-Y397)的水溶液、5μL供试化合物的DMSO溶液和5μL重组酶溶液,制备反应混合物,并在室温下孵育30分钟。通过加入5μL含5μM ATP的水启动酶反应,并将混合物在37℃孵育3小时。加入200μL检测混合物(含1nM Eu-PT66、2.5μg/mL SA-(SL)APC、6.25mMEDTA的稀释缓冲液)终止反应,在室温下孵育30分钟后,通过ARVOsx+L(Perkin Elmer)测量铕至别藻蓝素的FRET信号。使用665nm与615nm的荧光强度比例作为用于数据分析的FRET信号,以便抵消供试化合物的消色作用。结果表示为酶活性的抑制百分数。DMSO和0.5M EDTA分别用作0%和100%抑制的对照。使用OriginPro 6.1程序(OriginLab)、通过非线性曲线拟合分析测定IC50值。
Biot-Y397肽(生物素-SETDDYAEIID铵盐)被设计为具有与人S392至D402区域相同的氨基酸序列(GenBank Accession Number L13616)并按照标准方法制备。
纯化的重组六组氨酸标记的人FAK激酶域以以下方法得到:通过PCR扩增用5’PCR引物(ATGGCAGCTGCTTACCTTGAC)和3’PCR引物(TCAGTGTGGTCTCGTCTGCCC)从人胎盘Marathon-ReadyTM cDNA(Clontech,No.7411-1)分离全长人FAK cDNA,并亚克隆至pGEM-T载体(Promega,No.A3600)。用AccIII消化后,用Klenow片段处理纯化的DNA片段。将该cDNA片段用BamHI消化并克隆至预先用BamHI和Stu I切割的pFastBacHTb质粒(Invitrogen Japan K.K.,Tokyo)中。对所得质粒hFAK KD(M384-G706)/pFastBacHTb测序以确证其结构。所得DNA编码364氨基酸蛋白,其含有六组氨酸标记、间隔区和N-末端的rTEV蛋白酶裂解位点,以及位置29至351的FAK(Met384-Gly706)激酶域。
使用MaxEfficacy DH10Bac E.coli细胞将供体质粒移位至杆状病毒基因组。通过Bac-to-Bac杆状病毒表达系统(Invitrogen)中所述的简单碱性裂解方案制备Bacmid DNA。基于供应商(CellFECTIN,Invitrogen)提供的方案转染Sf9昆虫细胞。通过SDS-PAGE和使用抗人FAK单克隆抗体(来自Transduction实验室的克隆#77)的Western印迹法分析FAK在各溶解物中的表达。
将显示最高表达的病毒克隆通过感染至Sf9细胞进一步扩增。ExpresSF+细胞(Protein Sciences Corp.,Meriden,Connecticut,USA)中的表达获得几乎不降解的高水平蛋白。将细胞溶解产物加载于填充有硫酸镍并用50mM HEPES pH7.5、0.5M NaCl和10mM咪唑平衡的HiTrapTMChelating Sepharose HP(Amersham Biosciences)柱上。所捕获的蛋白用含递增量咪唑的HEPES缓冲液/NaCl洗脱,并进一步通过在50mM HEPESpH 7.5、10%甘油和1mM DTT中透析而纯化。
实施例54:无细胞ZAP-70激酶试验
ZAP-70激酶试验基于时间分辨荧光共振能量转移(FRET)。将80nMZAP-70与80nM Lck(淋巴样T-细胞蛋白酪氨酸激酶)和4μM ATP于ZAP-70激酶缓冲液(20mM Tris,pH7.5、10μM Na3VO4、1mM DTT、1mMMnCl2、0.01%BSA、0.05%Tween-20)中、在室温下、于硅化聚丙烯试管中孵育1小时。然后,加入选择性Lck抑制剂PP2(1-叔丁基-3-(4-氯苯基)-1H-吡唑并[3,4-d]嘧啶-4-基胺;Alexis Biochemicals)(终浓度为1.2μM)并进一步孵育10分钟。将10μL该溶液与作为底物的10μL生物素化肽LAT-11(1μM)和20μL抑制剂的系列稀释液混合并在室温下孵育4小时。用EDTA在检测缓冲液(20mM Tris,pH7.5、0.01%BSA、0.05%Tween-20)中的10μL 10mM溶液终止激酶反应。加入50μL铕标记的抗磷酸酪氨酸抗体(Eu-PT66;终浓度为0.125nM)和50μL含抗生物素蛋白链菌素-别藻蓝素(SA-APC;终浓度为40nM)的检测缓冲液。在室温下孵育1小时后,于Victor2 Multilabel计数仪(Wallac)中于665nm处测量荧光。在供试样品和ATP不存在时获得背景值(低对照)并将其从所有数值中减去。供试样品不存在时获得的信号作为100%(高对照)。将供试化合物存在时获得的抑制计算为高对照的百分抑制。导致50%抑制的供试化合物浓度(IC50)从剂量-效应曲线测定。在该试验中,本发明活性剂的IC50值在10nM至2μM、优选10nM至100nM范围内。
重组ZAP-70激酶如下获得:由Jurkat cDNA文库、通过RT-PCR扩增编码全长人ZAP-70的核酸(GenBank#L05148)并克隆至pBluescript KS载体(Stratagene,California,USA)中。ZAP-70 cDNA插入物的真实性通过全序列分析验证。然后使用该供体质粒构建重组杆状病毒转移载体,基于还具有N-末端六组氨酸标记特征的质粒pVL1392(Pharmingen,California,USA)。在用AcNPV病毒DNA共转染后,经由蚀斑-纯化获得10个独立的病毒分离物,小规模扩增,随后通过Western印迹法、使用市售可得的抗-ZAP-70抗体(克隆2F3.1,Upstate Biotechnology,Lake Placid,NY,USA)对重组ZAP-70表达进行分析。进一步扩增一个阳性重组蚀斑后,制备经滴定的病毒原种并用于感染Sf9细胞,该细胞在所定义的优化条件下生长于无血清SF900 II培养基(Life Technologies,Basel,瑞士)中。
通过亲和色谱、用Ni-NTA柱(Qiagen,Basel,瑞士)从感染的Sf9细胞的溶解产物分离ZAP-70蛋白。
重组His-标记的ZAP-70也可从PanVera LLC,Madison,Wisconsin,USA获得。
LAT-11(T细胞激活连接物):在ZAP-70激酶试验中用作底物的生物素化肽LAT-11(生物素-EEGAPDYENLQELN)以类似于肽合成的已知方法制备。使用含哌啶20%的DMF将其中Asn含量约0.5mmol/g的Fmoc-Asn(Trt)-氧甲基-4-苯氧基甲基-(聚苯乙烯-1%-二乙烯基-苯)共聚物的N-αFmoc基团裂除。使用含DIPCDI和HOBt的DMF将四当量侧链被保护[Asp(OtBu)、Glu(OtBu)、Asn(Trt)、Gln(Trt)和Tyr(tBu)]的Fmoc-氨基酸的每个氨基基团偶联。肽链装配完全后,如前所述用含哌啶的DMF除去末端Fmoc-保护基。然后,使用含DIPCDI和HOBt的DMF、使用四当量试剂、在室温下将L(+)-生物素基-氨基己酸偶联到末端氨基达四天。使用由TFA中5%十二烷基甲基硫醚和5%水组成的试剂在室温下达2小时,将肽从树脂支持物上裂除,同时除去所有侧链上的保护基。滤出树脂微粒,用TFA洗涤,通过加入10至20体积的二乙醚从合并的滤液中沉淀出产物,用醚洗涤并干燥。产物经C-18大孔硅胶柱色谱、使用含乙腈的2%磷酸水溶液梯度纯化。收集合有纯化合物的级分,经阴离子交换树脂(Biorad,AG4-X4醋酸盐型)过滤并冻干,得到标题化合物。MS:1958.0(M-H)-1。
实施例55:FAK的磷酸化水平
通过夹层ELISA对FAK在Tyr397处的磷酸化水平进行定量。将鼠乳癌4T1细胞(1×105)接种于96-孔培养板的各孔中,并在有或没有各种浓度的抑制剂存在下于含0.5%BSA的Dulbecco修饰eagle培养基中孵育1小时。除去培养基,将细胞溶解于200μL 50mM Tris-HCl,pH7.4,其含有1%NP-40、0.25%脱氧胆酸钠、150mM NaCl、1mM EDTA、1mM PMSF、1mM Na3VO4、1mM NaF、1μg/mL抑酶肽、1μg/mL亮肽素和1μg/mL抑胃肽。离心后,对上清液进行夹层ELISA,以定量磷酸化的FAK和总FAK。将细胞溶解产物应用于96-孔平底ELISA板,该板已预先在4℃下以100μL/孔用4μg/mL鼠单克隆抗-FAK抗体(克隆77,Becton DickinsonTransduction Laboratories)于含150mM NaCl的50mM Tris-HCl,pH 9.5中包被18小时,并用300μL BlockAce(Dainippon Pharmaceuticals Co.)的1∶4水稀释液在室温下封闭2小时。用TBSN(20mM Tris-HCl,pH 8.3,含300mM NaCl,0.1%SDS和0.05%NP-40)洗涤后,用100μL 1μg/ml抗-FAK多克隆抗体(#65-6140,Upstate Biology Inc.)检测总FAK,用100μL含0.25μg/μL抗-磷酸化FAK(Y397)抗体(Affinity BioReagents,#OPA1-03071)的BlockAce 1∶10水稀释液检测磷酸化FAK。在室温下孵育1小时后,将板用TBSN洗涤,并将用BlockAce的1∶10水稀释液稀释的100μL生物素化抗-兔IgG(#65-6140,Zymed Laboratolies Inc.)在室温下孵育1小时。用TBSN、ABTS溶液洗涤后,使用底物试剂盒(#00-2011,Zymed LobolatoriesInc.)进行显色。在室温下孵育20分钟后,测量405nm处的吸收值。测定引起FAK磷酸化水平减少50%的化合物浓度。
实施例56:不依赖帖壁肿瘤细胞生长试验
将鼠乳癌4T1细胞(5×103)接种于96-孔Ultra低附着板(#3474,CorningInc.)中的100μL含10%FBS的Dulbecco’s修饰eagle培养基中。将细胞培养2小时并加入各种浓度的抑制剂,DMSO终浓度为0.1%。48小时后,用使用水溶性四唑盐WST8的细胞计数试剂盒-8(Wako Pure Chemical)测定细胞生长。向每孔加入20μL试剂并将细胞进一步培养2小时。测量450nm处的光密度。确定引起50%生长抑制的化合物浓度。
实施例57:体外T细胞迁移试验
FAK抑制剂对免疫细胞运动性的抑制活性通过以下体外研究确证。即,将Jurkat T人白血病细胞系以1×105细胞置于具有8μm孔的Fluoroblok(Beckton Dickinson,UK)的上室中,依赖胎牛血清(10%FBS)浓度梯度,使其在37℃、95%空气-5%CO2中经四小时培养进行迁移。通过用HBSS中8μg/ml的钙黄绿素-AM(Molecular Probes,荷兰)标记1小时,以迁移至下室中的细胞数评价细胞运动性。就FAK抑制剂的评价而言,上室和下室中均加入各种浓度的FAK抑制剂(0.03-1μM)。通过用Ascent(Ex:485nm,Em:538nm)测量的荧光强度相比介质处理组的减量计算IC50值。
实施例58:采用细胞“捕获ELISA”试验法试验对IGF-I诱导的IGF-IR
的活性
该试验如下进行:
对于该试验而言,使用如Kato等,J.Biol.Chem.268,2655-61,1993所述制备的用人IGF-IR cDNA(完全人IGF-IR cDNA:GenBank Acc.No.NM_000875)转染的NIH-3T3鼠成纤维细胞。将过度表达人IGF-IR的细胞在含有10%胎牛血清(FCS)的Dulbecco’s极限必需培养基(DMEM)中培养。进行试验时,将5,000细胞/孔于第1天接种于96-孔板(Costar#3595)中的正常生长培养基中并在37℃标准CO2细胞培养箱中培养2天。在第3天细胞的密度不超过70-80%。在第3天,弃去培养基,将细胞在极限培养基(DMEM,含0.5%FCS)中孵育24小时。加入式I化合物[由10mM二甲亚砜(DMSO)储备液开始],使终浓度为0.01、0.03、0.1、0.3、1、3和10μM,以测定IC50值。将细胞在式I化合物存在下孵育90分钟。之后用50μl IGF-I(孔中IGF-I的终浓度=10ng/ml;IGF-I得自Sigma;产品编号:I3769)刺激细胞并在37℃孵育10分钟。
弃去培养基,将细胞用PBS/O(=不含CaCl2的磷酸盐缓冲的盐水)洗涤两次,用50μl/孔RIPA-缓冲液[50mM Tris·HCl,pH=7.2,120mM NaCl、1mM EDTA、6mM EGTA、1%NP-40、20mM NaF、1mM苄脒、15mM焦磷酸钠、1mM苯基甲基磺酰氟(PMSF)和0.5mM Na3VO4]在冰上溶解15分钟,并使用96-孔平板振荡器振荡10分钟(=细胞提取物)。
将Packard HTRF-96黑色板用50μl浓度为5μg/ml的IGF-IR单克隆抗体(mAB)(Santa Cruz;分类号:SC-462)在4℃包被过夜。将板用含0.05%(v/v)Tween-20的磷酸盐缓冲的盐水(PBS)洗涤两次并用超纯(nanopure)水洗涤一次。在室温(RT)下用含3%牛血清白蛋白(BSA)的TBS-T缓冲液(20mM Tris·HCl,pH=7.6,137mM NaCl,0.05%Tween-20)封闭2小时。封闭后,将板用超纯水洗涤一次。
将细胞提取物(40μl/孔)吸移至经包被的Packard板上,以及40μl与碱性磷酸酶(AP)缀合的抗磷酸酪氨酸鼠mAB PY-20(用RIPA缓冲液1∶1000稀释,抗体得自Transduction Labs;分类号:P11120)。
将提取物和二抗在4℃孵育2小时后,弃去提取物,将板用含0.05%(v/v)Tween-20的PBS洗涤两次,用超纯水洗涤一次。
然后加入90μl/孔的AP底物(CDP-Star,得自Tropix;分类号:MS100RY)并将板在室温暗处下孵育45分钟,然后于Packard Top Count微量滴定板闪烁计数仪中测量AP活性。经由线性回归分析、使用GraphPad Instat程序(GraphPad Software,USA)计算式I化合物的IC50值。发现IC50值处于5nM至1μM、特别是5nM至300nM范围内。
实施例59:在裸鼠异种移植物模型中的体内活性:
将雌性或雄性BALB/c裸鼠(5-8周龄,Charles River Japan,Inc.,Yokohama,日本)保存于无菌条件下,水和食物随意获取。在Forene麻醉(Abbott Japan Co.,Ltd.,Tokyo,日本)下向鼠的左右肋腹皮下注射肿瘤细胞(人上皮细胞系MIA PaCa-2;European Collection of Cell Cultures(ECACC),Salisbury,Wiltshire,UK,分类号85062806;细胞系得自一名65岁老年高加索男性;未分化的人胰腺癌细胞系),以诱发肿瘤。当平均肿瘤体积达到约100mm3时,开始用供试化合物治疗。每周两次以及最后一次治疗后1天,通过测定两个垂直轴的长度测量肿瘤的生长。根据公开的方法(参见Evans等,Brit.J.Cancer 45,466-8,1982)计算肿瘤体积。将抗肿瘤功效确定为经治疗动物肿瘤体积的平均增长除以未治疗动物(对照)肿瘤体积的平均增长,之后乘以100,表示为ΔT/C[%]。将肿瘤消退报告为受治疗动物肿瘤体积的平均变化除以治疗开始时的平均肿瘤体积,再乘以100,表示为消退率[%]。无论用药与否,每日口服施用供试化合物。
作为细胞系MIA PaCa-2的替代选择,也可以以相同方式使用另一种细胞系,例如:
-4T1乳腺癌细胞系(ATCC号CRL-2539;也可参见Cancer.88(12增刊),2979-2988,2000),雌性BALB/c小鼠(注射进入乳房脂垫)。
基于这些研究,根据本发明的式I化合物显示出特别是针对应答酪氨酸激酶抑制的增殖性疾病的治疗功效。
实施例60:片剂
以常规方式制备了包含50mg活性成分、例如实施例1-131所述的式I化合物之一并具有如下组成的片剂。
组成:
活性成分 50mg
小麦淀粉 150mg
乳糖 125mg
胶态硅酸 12.5mg
滑石 22.5mg
硬脂酸镁 2.5mg
总计: 362.5mg
制备:将活性成分与一部分小麦淀粉以及乳糖和胶态硅酸混合,并将该混合物过筛。将另一部分的小麦淀粉在水浴上用五倍量的水制成糊状,并将粉末混合物与所述糊状物捏制在一起,直至获得略具塑性的团块。将塑性团块压制通过筛目尺寸约3mm的筛子并干燥,将所得干颗粒再次过筛。然后将其余的小麦淀粉、滑石和硬脂酸镁混入并将混合物压制形成重145mg并具有断裂刻痕的片剂。
实施例61:软胶囊
以常规方式制备了5000粒每粒包含50mg活性成分、例如实施例1-131所述的式I化合物之一的软明胶胶囊。
组成:
活性成分 250g
Lauroglykol 2升
制备:将微粉化的活性成分悬浮于Lauroglykol(丙二醇月桂酸酯,GattefosséS.A.,Saint Priest,法国)并在湿粉碎机中研磨至粒径约1至3μm。然后使用胶囊填充机将各份0.419g混合物填充至软明胶胶囊中。
生物学结果:
实施例 | FAK IC50(nM) | Phos IC50(μM) | 生长IC50(μM) | T细胞迁移IC50(μM) | IGF-1RIC50(μM) |
1.00 | 140 | 0.7 | >10 | ||
2.00 | 13 | 1.2 | |||
3.01 | 44 | 0.34 | >10 | ||
3.02 | 36 | 0.85 | 4 | ||
3.03 | 9.1 | 0.14 | 0.8 | ||
3.04 | 32 | 0.53 | 2 | ||
3.05 | 21 | 0.17 | 2 | >10 | |
3.06 | 13 | 0.11 | 2 | ||
3.07 | 16 | 0.45 | 2 | ||
3.08 | 74 | 0.3 | 6 |
实施例 | FAK IC50(nM) | Phos IC50(μM) | 生长IC50(μM) | T细胞迁移IC50(μM) | IGF-1RIC50(μM) |
3.09 | 48 | 0.5 | 0.7 | ||
3.10 | 52 | 0.95 | >10 | ||
3.11 | 9 | 0.04 | 0.3 | 0.2 | |
3.12 | 5.4 | 0.01 | 1 | ||
3.13 | 58 | 1.7 | 0.6 | 0.74 | |
3.14 | 54 | 0.4 | 5 | ||
3.15 | 7 | 0.02 | 0.8 | 0.94 | |
3.16 | 48 | 1.1 | 3 | ||
3.17 | 2.8 | 0.03 | 0.2 | <0.08 | |
3.18 | 130 | 1.5 | 9 | ||
3.19 | 6.8 | 0.35 | 0.8 | 0.1 | |
3.20 | 16 | 0.22 | 0.3 | ||
3.22 | 120 | 0.9 | 2 | ||
3.23 | 38 | 0.39 | 0.5 | ||
3.24 | 64 | 3.5 | 5 | ||
3.25 | 22 | 0.3 | 0.3 | 0.81 | |
3.26 | 50 | 0.79 | 2 | ||
3.28 | 43 | 0.71 | 0.7 | ||
3.29 | 89 | 0.6 | >10 | ||
3.30 | 69 | 0.6 | 3 | ||
3.31 | 13 | 1.1 | 5 |
实施例 | FAK IC50(nM) | Phos IC50(μM) | 生长IC50(μM) | T细胞迁移IC50(μM) | IGF-1RIC50(μM) |
3.32 | 14 | 0.18 | 0.49 | 0.28 | 0.12 |
3.33 | 2.9 | 0.03 | 0.05 | 0.09 | 0.13 |
3.34 | 7 | 0.1 | 0.24 | 0.13 | <0.08 |
3.35 | 13 | 0.02 | 0.17 | 0.8 | 3.55 |
3.36 | 43 | 1.8 | 2.8 | ||
3.37 | 39 | 1.1 | 2.6 | ||
3.38 | 64 | 1.7 | 3.8 | ||
3.39 | 2 | 0.02 | 0.03 | 1 | 0.09 |
3.40 | 9 | >10 | 0.9 | ||
3.41 | 22 | >10 | 0.43 | ||
3.42 | 29 | 0.35 | 0.3 | ||
3.43 | 5.6 | 0.2 | 0.11 | 0.27 | |
3.44 | 11 | 0.05 | 0.09 | 0.09 | |
3.45 | 0.9 | 0.02 | 0.02 | ||
3.46 | 4 | 0.1 | 0.18 | 0.3 | |
3.47 | 1 | 0.1 | 0.06 | ||
3.48 | 7 | 0.07 | 0.3 | 0.21 | |
3.49 | 39 | 10 | 0.39 | ||
3.50 | 13 | 0.12 | 1 | 1.19 | |
3.51 | 29 | 0.2 | 0.4 | 0.41 |
3.40 | 9 | >10 | 0.9 | ||
3.52 | 29 | 0.42 | 2 | ||
3.53 | 6 | 0.07 | 0.21 | ||
3.54 | 0.9 | 0.01 | 0.07 | <0.08 | |
3.55 | 34 | >10 | 3 | ||
3.56 | 28 | 0.53 | 0.15 | ||
3.57 | 28 | 0.61 | 3 | ||
3.58 | 21 | 0.08 | 0.3 | 0.14 | |
3.59 | 95 | 1.2 | >10 | ||
3.60 | 90 | 0.93 | 2 | ||
3.61 | 12 | 10 | >10 | ||
3.62 | 63 | >10 | >10 | ||
3.63 | 27 | >10 | >10 | ||
3.64 | 5 | 0.13 | 0.7 | 0.21 | |
3.65 | 8 | 0.08 | 0.1 | 0.15 | |
3.66 | 1 | 0.08 | 0.07 | 0.25 | |
3.67 | 6 | 0.38 | 0.39 | ||
3.68 | 5.5 | 0.2 | 0.63 | 1 | |
3.69 | 4 | 0.2 | 0.11 | 0.58 | |
3.70 | 3.5 | 0.02 | 0.13 | ||
3.71 | 11 | 0.05 | 0.08 | ||
3.72 | 2.1 | 0.11 | 0.06 | ||
3.73 | 11 | 0.03 | 0.29 | 1.63 |
3.40 | 9 | >10 | 0.9 | ||
3.74 | 15 | 0.1 | 0.15 | ||
3.75 | 72 | 0.5 | 1.3 | ||
3.76 | 15 | 0.29 | 1.3 | 0.7 | |
3.77 | 65 | >10 | 3 | ||
3.78 | 10 | >10 | 0.22 | ||
3.79 | 5 | 1.3 | 0.12 | ||
3.80 | 12 | 0.22 | 0.45 | 5 | |
3.81 | 21 | 0.52 | 0.98 | >10 |
3.82 | 4.8 | 0.2 | 0.07 | ||
3.83 | 20 | 0.08 | 0.32 | 0.68 | |
3.84 | 10 | 1 | 0.08 | ||
6.00 | 110 | 0.35 | 5 | ||
7.00 | 5.3 | 0.21 | 0.47 | 0.04 | 0.19 |
7.01 | 4.7 | 0.6 | 0.54 | 0.19 | |
7.02 | 7.5 | 0.1 | 0.36 | 0.77 | |
7.03 | 2.9 | 0.3 | 0.39 | 0.27 | |
7.04 | 5.2 | 1 | 0.29 | ||
7.05 | 6.2 | 0.3 | 0.2 | 0.25 | |
7.06 | 17 | 0.8 | 1.09 | 0.25 | |
7.07 | 4.1 | 0.9 | 0.18 | ||
7.08 | 8.7 | 0.8 | 1 | ||
7.09 | 8.2 | 1 | 0.85 |
3.82 | 4.8 | 0.2 | 0.07 | ||
7.10 | 6.6 | 1 | 0.98 | ||
7.11 | 2.5 | 0.6 | 1.2 | 0.77 | |
7.12 | 1.9 | 0.9 | 1 | 0.31 | 0.62 |
7.13 | 5.5 | 0.8 | 1.22 | ||
7.14 | 7.6 | 0.3 | 0.36 | 0.33 | |
7.15 | 4.5 | 0.06 | 0.19 | 0.26 | |
7.16 | 6.4 | 0.2 | 0.42 | ||
7.17 | 4.3 | 0.7 | 0.69 | ||
7.18 | 6.2 | 0.5 | 0.7 | ||
7.19 | 13 | 0.33 | |||
7.20 | 2.5 | >10 | 0.11 | ||
7.21 | 3.3 | >10 | 0.46 | ||
7.22 | 25 | 0.48 | |||
7.23 | 1.4 | 0.25 | |||
7.24 | 5.1 | 0.09 | |||
7.25 | 13 | 0.2 | 0.73 | ||
7.25 | 2 | >10 | 0.57 | ||
7.26 | 4.1 | 0.15 | |||
7.27 | 21 | 0.5 | 0.22 | ||
7.28 | 34 | 1 | 0.15 | ||
7.29 | 57 | 2 | 0.48 | ||
7.30 | 2.1 | 0.3 | 1 |
3.82 | 4.8 | 0.2 | 0.07 | ||
8.01 | 6.6 | 0.6 | 0.33 | ||
8.02 | 2.4 | 0.5 | 0.99 | ||
8.03 | 13 | 0.22 | 1 | >10 | |
8.04 | 8 | >10 | 1.1 | ||
9.01 | 22 | 0.36 | 1 | 0.6 | |
9.02 | 15 | 0.5 | 0.81 |
9.03 | 18 | 0.1 | 0.37 | ||
9.04 | 13 | 0.2 | 0.73 | ||
9.05 | 22 | 0.36 | 1.6 | 0.6 | |
9.06 | 23 | 3 | 0.4 | 0.3 | |
9.07 | 17 | >10 | 0.26 | ||
10.01 | 39 | 1 | 0.44 | ||
10.02 | 26 | 0.9 | 1.06 | ||
10.03 | 23 | 0.9 | 2.4 | ||
11.01 | 9 | 0.7 | 0.85 | ||
11.02 | 4.1 | 0.8 | 0.69 | ||
11.03 | 26 | 0.41 | 0.1 | ||
11.04 | 4.3 | >10 | 3.2 | ||
12.01 | 2.5 | 0.09 | 0.4 | 0.22 | |
12.02 | 1.6 | 0.05 |
9.03 | 18 | 0.1 | 0.37 | ||
12.03 | 2.3 | 0.25 | |||
12.04 | 1.1 | 0.14 | |||
12.06 | 2.6 | ||||
13.01 | 65 | 0.81 | |||
14.01 | 19 | 0.2 | 1.47 | 0.28 | |
14.02 | 190 | 2 | 1.1 | 1 | |
14.03 | 30 | 10 | 1.01 | ||
14.04 | 18 | 0.54 | |||
14.05 | 37 | >10 | 1 | ||
14.06 | 63 | 10 | 1.11 | ||
14.07 | 7.5 | 0.2 | 1.4 | ||
15.01 | 15 | 10 | 0.47 | ||
15.02 | 21 | >10 | 0.66 | ||
15.03 | 44 | 2 | 1.67 | ||
16.01 | 44 | >10 | 4 | ||
16.02 | 6 | >10 | 0.6 | ||
16.03 | 21 | 3 | >10 | ||
16.04 | 9.5 | >10 | 0.92 | ||
16B | 11 | 3 | 7 | ||
16.C | 28 | 0.9 | >10 |
9.03 | 18 | 0.1 | 0.37 | ||
18.01 | 19 | >10 | 1.29 | ||
19.01 | <1 | 0.2 | 0.3 | 0.29 | 1.41 |
19.02 | 1.6 | 0.13 | 0.38 | 0.91 | |
19.03 | <1 | 0.3 | 0.09 | 0.64 | |
19.04 | 1.6 | 0.2 | 0.34 | 0.14 | |
19.05 | 1.8 | 0.2 | 0.67 | 0.07 | 0.47 |
19.06 | 5 | 1 | 0.7 | ||
19.07 | 2.1 | 0.3 | 0.11 |
19.08 | 3.2 | 0.03 | 0.4 | 0.29 | 0.13 |
19.09 | 1.3 | 0.17 | 0.39 | 0.3 | 0.48 |
19.10 | 1.3 | 0.06 | 0.56 | 1.02 | |
19.11 | 38 | >10 | 2 | ||
19.12 | 9 | >10 | 0.7 | 0.63 | |
19.13 | 2.5 | 0.3 | 1.1 | ||
19.14 | 2.6 | 0.4 | 1.13 | 0.44 | |
19.15 | 3.1 | 0.5 | 0.36 | ||
19.16 | 2.3 | 0.7 | 1.1 | ||
19.17 | 1 | >10 | 0.17 | ||
19.18 | 7 | 0.13 | 0.87 |
19.08 | 3.2 | 0.03 | 0.4 | 0.29 | 0.13 |
19.19 | 5.7 | 0.4 | |||
19.20 | 1.6 | 0.03 | 0.07 | 0.23 | |
19.21 | 84 | >10 | 1.71 | ||
19.22 | 3.4 | 0.12 | 0.51 | ||
19.23 | 6.4 | 0.7 | 0.71 | ||
19.24 | 1.8 | 0.05 | 0.12 | ||
19.25 | 7.2 | 1 | 0.49 | 0.24 | |
19.26 | 6.1 | 0.1 | 0.3 | ||
19.27 | 1.5 | 0.3 | 0.4 | ||
19.28 | 4.8 | 0.1 | 0.12 | 0.3 | 0.46 |
19.29 | 1.9 | ||||
19.30 | <1 | 0.06 | 0.1 | ||
19.31 | 1.8 | 0.4 | 0.38 | ||
19.32 | 1.4 | 0.2 | 0.31 | ||
20.01 | 10 | 0.3 | 0.18 | 0.25 | 0.7 |
20.02 | 9 | 0.12 | 0.17 | 0.75 | 0.52 |
20.03 | 42 | 0.4 | 2.5 | 2.78 | |
20.04 | 23 | 0.58 | 1.9 | ||
20.05 | 6.8 | 0.87 | 1.46 | ||
20.06 | 5 | 0.36 | 0.14 | 49 |
19.08 | 3.2 | 0.03 | 0.4 | 0.29 | 0.13 |
20.07 | 3 | 0.1 | 0.05 | 0.38 | |
20.08 | 6.8 | 0.17 | 0.05 | 0.29 | |
20.09 | 2 | 0.3 | 0.01 | ||
20.10 | 2 | 0.1 | 0.02 | ||
20.11 | 26 | 2 | 0.4 | ||
20.12 | 9.5 | ||||
20.13 | 6.3 | 0.04 | |||
20.14 | 33 | 0.32 | |||
20.15 | 14 | 0.4 | 0.97 | 0.3 | |
20.16 | 7.5 | 0.06 | |||
20.17 | 2 | 0.14 |
20.18 | 15 | 0.81 | |||
20.19 | 28 | 0.21 | |||
20.20 | 3.12 | 0.1 | |||
20.21 | 26 | 3 | 0.68 | ||
20.22 | 8 | >10 | 0.19 | ||
20.23 | 30 | 0.49 | 3 | ||
20.24 | 19 | 0.48 | 2 | ||
20.25 | 6.2 | 0.21 | 0.06 |
20.18 | 15 | 0.81 | |||
20.26 | 5.3 | 0.76 | 0.27 | ||
20.27 | 12 | 0.85 | 0.05 | 0.29 | |
20.28 | 9.2 | 0.17 | 0.08 | 0.42 | |
20.29 | 6.1 | 0.2 | 0.05 | 0.31 | |
20.30 | 7.6 | 0.3 | 0.08 | 0.67 | |
20.31 | 39 | 0.5 | |||
20.32 | 13 | 0.11 | |||
20.33 | 2.5 | 0.38 | |||
20.34 | 13 | 1 | 0.12 | ||
20.35 | 8.7 | 0.09 | 0.09 | 0.15 | |
21.01 | 1 | 0.07 | 0.19 | 0.47 | |
21.02 | 8.5 | 0.33 | >10 | ||
21.03 | 1.7 | 0.3 | 0.3 | ||
21.04 | 1.8 | 0.05 | 0.3 | ||
22.01 | 43 | >10 | >10 | ||
22.02 | 26 | 1 | 3 | ||
22.03 | 6.6 | 0.09 | 0.15 | 0.26 | |
23.01 | 3.4 | 0.6 | 0.2 | 0.63 | 0.53 |
23.02 | 1.5 | 0.2 | 0.4 | 0.8 | |
23.03 | 1.7 | 1 | 1.12 | 0.82 |
20.18 | 15 | 0.81 | |||
23.04 | 1.2 | 0.9 | 1.07 | 0.6 | |
23.05 | 1.9 | >10 | 0.59 | ||
23.06 | 16 | 1 | 0.57 | ||
23.07 | 2.1 | 3 | 0.84 | ||
23.08 | 6.7 | 0.3 | 0.49 | ||
23.09 | 2.1 | 0.2 | 0.28 | ||
24.01 | 3.6 | 0.11 | 0.44 | 0.05 | |
24.02 | 2.1 | 0.5 | 0.11 | 0.39 | |
24.03 | 1 | 0.3 | 1.08 | ||
25.01 | 8.5 | 3 | 1 | ||
25.02 | 3 | 0.4 | 0.13 | 0.64 | |
26.01 | 4.4 | 0.05 | 0.35 | 0.29 | |
26.02 | 1.9 | 0.03 | 0.12 | 0.09 | 0.39 |
26.03 | 1.4 | 0.1 | 0.13 | 0.23 |
26.04 | 4.9 | 0.05 | 0.43 | 0.29 | 1.16 |
26.05 | 2.1 | 0.09 | 0.23 | 1.5 | |
26.06 | 4.4 | 0.1 | 0.35 | ||
26.07 | 11 | 0.5 | 0.95 | ||
26.08 | 2.9 | 0.01 | 0.18 |
26.04 | 4.9 | 0.05 | 0.43 | 0.29 | 1.16 |
26.09 | 2.3 | 0.04 | 0.22 | ||
26.10 | 2 | 0.01 | 0.14 | ||
26.11 | 4.4 | 0.4 | 0.78 | 0.5 | |
26.12 | 3.7 | 0.2 | 0.19 | ||
26.13 | 1.6 | 0.2 | 0.44 | ||
26.14 | 5 | 0.19 | |||
26.15 | 6.9 | 1.2 | 0.08 | 0.07 | |
26.16 | 9 | 0.32 | 2 | ||
26.17 | 17 | 0.3 | 0.1 | 0.26 | |
26.18 | 1.3 | 6 | 1.17 | ||
26.19 | 9.2 | 0.43 | 0.79 | ||
26.20 | 10 | 0.14 | 0.22 | 0.6 | 0.49 |
26.21 | 1.1 | 0.1 | 0.49 | ||
26.22 | <1 | 0.1 | 0.28 | ||
26.23 | 1.4 | 0.3 | 0.09 | 0.3 | 0.18 |
26.24 | 1 | 0.5 | 0.48 | 0.9 | |
26.25 | <1 | 0.6 | 0.73 | 0.3 | |
26.26 | 1.9 | 0.2 | 0.07 | 0.34 | |
26.27 | 4.8 | 0.6 | 1.49 | ||
26.28 | 2.1 | 0.5 | 1.52 |
26.04 | 4.9 | 0.05 | 0.43 | 0.29 | 1.16 |
26.29 | <1 | 0.31 | 0.26 | ||
26.30 | 4.4 | 1 | 0.76 | ||
26.31 | 2 | 0.3 | 0.16 | ||
26.32 | 1.6 | 0.05 | 0.6 | ||
26.33 | 4 | 0.06 | 0.23 | ||
26.34 | 7 | 0.1 | 0.25 | ||
26.35 | 4.5 | 0.05 | 0.3 | ||
26.36 | 1.9 | 0.07 | 0.09 | ||
26.37 | <1 | ||||
26.38 | <1 | ||||
26.39 | 3.1 | ||||
27.01 | 14 | 0.06 | 0.47 | ||
27.02 | 5.1 | 0.5 | 1.1 | ||
27.03 | 6.3 | >10 | 0.56 | ||
27.04 | 11 | 0.1 | 0.27 | ||
27.05 | 8.2 | 0.04 | 0.3 | ||
27.06 | 1 | 0.08 | 0.31 |
27.07 | 5.5 | 2 | 0.57 | ||
27.08 | 9.3 | 0.6 | 0.75 |
27.07 | 5.5 | 2 | 0.57 | ||
27.09 | 4.2 | 0.5 | 0.36 | ||
28.01 | 12 | 0.3 | 0.46 | 0.3 | |
28.02 | 1.9 | 0.08 | 0.44 | 3.71 | |
28.03 | 7.4 | 0.07 | 0.29 | ||
28.04 | 7.5 | 0.3 | 0.3 | ||
28.05 | 6.7 | 0.1 | 0.12 | 1.39 | |
28.06 | 17 | 0.6 | 0.56 | ||
28.07 | 47 | 3 | >10 | ||
28.08 | 4.6 | 0.4 | 0.37 | ||
28.09 | 3.1 | 0.5 | 0.36 | ||
28.10 | 20 | 3 | 1.85 | ||
28.11 | 4.2 | 0.5 | 0.63 | ||
28.12 | 3.2 | 0.3 | 0.43 | 0.1 | |
28.13 | 7.8 | 0.1 | 0.55 | 0.29 | |
28.14 | 3 | 0.1 | 1.44 | ||
28.15 | 10 | 0.5 | 0.69 | ||
28.16 | 11 | 0.11 | 1 | 0.6 | |
28.17 | 15 | 0.16 | 1.9 | ||
28.18 | 9.1 | >10 | 2.03 | ||
28.19 | 3.7 | 0.5 | 0.14 |
27.07 | 5.5 | 2 | 0.57 | ||
28.20 | 4.4 | 2 | 0.4 | ||
28.21 | 1.3 | 0.1 | 0.23 | ||
28.22 | 1.3 | 0.1 | 0.3 | ||
28.23 | 5.9 | 0.5 | 0.28 | ||
28.24 | 2.9 | 0.2 | 0.09 | 2.57 | |
28.25 | 3.9 | 0.04 | 0.13 | ||
28.26 | 6.6 | 0.2 | 0.57 | ||
28.27 | 2.4 | 0.3 | 0.42 | 0.5 | |
28.28 | 5.2 | 0.4 | 0.52 | 1 | |
28.29 | 11 | 0.4 | 0.36 | ||
28.30 | 2.3 | 0.9 | 0.11 | ||
28.31 | 7.4 | 0.06 | 1.06 | ||
29.01 | 13 | 0.7 | 2.2 | 0.09 | |
29.02 | 3.3 | 0.7 | 1.1 | ||
29.03 | 5.6 | 0.1 | 0.99 | ||
30.01 | 22 | 0.2 | 0.89 | ||
30.02 | 12 | 0.2 | 0.47 | ||
30.03 | 19 | 0.5 | 0.68 | ||
30.04 | 25 | 0.3 | 0.99 | ||
30.05 | 8.5 | 2 | 0.29 |
30.06 | 15 | 1 | 1.03 | ||
30.07 | 8.8 | 0.6 | 0.47 | ||
31.01 | 30 | >10 | 1.6 | ||
31.02 | 31 | 0.28 | 0.29 | 0.42 | |
32.01 | 4.1 | 0.1 | 0.29 | ||
32.02 | 5.9 | 0.05 | 0.37 | 0.12 | |
33.01 | 2.5 | 0.08 | 0.25 | ||
33.02 | 5.2 | 0.06 | 0.25 | 0.1 | |
34.01 | 8 | 0.1 | 0.37 | 0.28 | |
34.02 | 11 | 0.08 | 1.17 | ||
34.03 | 33 | 0.19 | 2.25 | ||
34.04 | 13 | >10 | 1.22 | ||
34.05 | 51 | 0.36 | 5.1 | ||
34.06 | 14 | >10 | 3 | ||
34.07 | 27 | >10 | 2.7 | ||
34.08 | 8.7 | >10 | 1.9 | ||
35.01 | 6.8 | >10 | 1.43 | ||
35.02 | 6.1 | 0.7 | 0.23 | ||
51.00 | 8.1 | 0.013 | 0.19 | 0.2 | |
52.00 | 13 | 0.2 | 0.41 | <0.08 |
Claims (9)
1.一种化合物,其选自一组具有如下名称或结构式的化合物:
2-[2-(2,5-二甲氧基-苯基氨基)-5-硝基-嘧啶-4-基氨基]-N-甲基-苯磺酰胺;
2-[5-溴-2-(2,4-二甲氧基-苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯磺酰胺;
下式化合物:
其中Rx具有下表中给出的含义之一:
2-[5-溴-2-(2,3-[二氟亚甲二氧基]苯基氨基)-嘧啶-4-基氨基]-苯磺酰胺;
2-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯甲酰胺;
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
7-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-2-甲基-2,3-二氢异吲哚-1-酮;
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物
其中Ry具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Ry具有下表中给出的含义之一:
下式化合物:
下式化合物:
下式化合物:
下式化合物;
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
;
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
下式化合物:
其中Ry具有下表中给出的含义之一:
下式化合物:
其中Rx具有下表中给出的含义之一:
2-[5-溴-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-N,N-二甲基-苯磺酰胺;
2-[5-溴-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-5-氟-N-甲基-苯磺酰胺;
或其可药用盐。
2.药物组合物,包含权利要求1所定义的化合物或其可药用盐作为活性成分以及一种或多种可药用稀释剂或载体。
3.权利要求1所定义的化合物或其可药用盐在制备用于治疗或预防赘生性疾病或免疫系统病症的药物中的用途。
4.组合产品,包含治疗有效量的权利要求1所定义的化合物或其可药用盐和一种或多种其他药物物质,所述其他药物物质是用于治疗赘生性疾病或免疫系统病症的药物。
5.权利要求1所定义的化合物或其可药用盐在制备用于治疗或预防对抑制IGF-1受体有响应的疾病的药物中的用途。
6.权利要求5的用途,其中所要治疗的疾病选自增殖性疾病。
7.权利要求6的用途,其中所要治疗的增殖性疾病选自乳房、肾、前列腺、甲状腺、卵巢、胰腺、神经元、肺、子宫的肿瘤和胃肠道肿瘤以及骨肉瘤和黑素瘤。
8.权利要求7的用途,其中的胃肠道肿瘤为结直肠肿瘤。
9.权利要求5至8任一项的用途,其中的化合物是2-[5-氯-2-(2-甲氧基-4-吗啉-4-基-苯基氨基)-嘧啶-4-基氨基]-N-甲基-苯甲酰胺或其可药用盐。
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