CN1440396A - 作为血管生成抑制剂的秋水仙醇衍生物 - Google Patents
作为血管生成抑制剂的秋水仙醇衍生物 Download PDFInfo
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- CN1440396A CN1440396A CN01812402A CN01812402A CN1440396A CN 1440396 A CN1440396 A CN 1440396A CN 01812402 A CN01812402 A CN 01812402A CN 01812402 A CN01812402 A CN 01812402A CN 1440396 A CN1440396 A CN 1440396A
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- Prior art keywords
- alkyl
- amino
- hydroxyl
- group
- compound
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- HSDSUBIABLFGDX-AWEZNQCLSA-N (7s)-7-amino-1,2,3-trimethoxy-6,7-dihydro-5h-dibenzo[5,3-b:1',2'-e][7]annulen-9-ol Chemical class C1C[C@H](N)C2=CC(O)=CC=C2C2=C1C=C(OC)C(OC)=C2OC HSDSUBIABLFGDX-AWEZNQCLSA-N 0.000 title abstract description 6
- 239000004037 angiogenesis inhibitor Substances 0.000 title description 6
- 229940121369 angiogenesis inhibitor Drugs 0.000 title description 3
- -1 hydroxy, phosphoryloxy Chemical group 0.000 claims abstract description 142
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 86
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 77
- 239000001257 hydrogen Substances 0.000 claims abstract description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 56
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 44
- 150000002148 esters Chemical class 0.000 claims abstract description 11
- 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 7
- 238000001727 in vivo Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 161
- 150000003839 salts Chemical class 0.000 claims description 79
- 229940002612 prodrug Drugs 0.000 claims description 55
- 239000000651 prodrug Substances 0.000 claims description 55
- 238000000034 method Methods 0.000 claims description 53
- 239000012453 solvate Substances 0.000 claims description 53
- 150000002431 hydrogen Chemical class 0.000 claims description 37
- 239000001301 oxygen Substances 0.000 claims description 34
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 32
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 241001465754 Metazoa Species 0.000 claims description 27
- 230000002792 vascular Effects 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 230000000903 blocking effect Effects 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 150000001412 amines Chemical class 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 11
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 10
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 9
- 230000000254 damaging effect Effects 0.000 claims description 9
- 125000004193 piperazinyl group Chemical group 0.000 claims description 9
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 8
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 125000002757 morpholinyl group Chemical group 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 229910052698 phosphorus Inorganic materials 0.000 claims description 8
- 239000011574 phosphorus Substances 0.000 claims description 8
- 125000005936 piperidyl group Chemical group 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- YFLYRFAUOCDTKT-UHFFFAOYSA-N [Na].[Na].C(CCC)OP(O)(O)=O Chemical compound [Na].[Na].C(CCC)OP(O)(O)=O YFLYRFAUOCDTKT-UHFFFAOYSA-N 0.000 claims description 5
- MHSIXICVDCXRLQ-UHFFFAOYSA-N [Na].[Na].CCP(O)(O)=O Chemical compound [Na].[Na].CCP(O)(O)=O MHSIXICVDCXRLQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000000524 functional group Chemical group 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 5
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 229910052796 boron Inorganic materials 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 43
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 239000002585 base Substances 0.000 description 35
- 206010028980 Neoplasm Diseases 0.000 description 32
- 238000011282 treatment Methods 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 239000002904 solvent Substances 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 15
- 239000000463 material Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000003513 alkali Substances 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 12
- 229910052786 argon Inorganic materials 0.000 description 11
- 239000012298 atmosphere Substances 0.000 description 11
- 239000007789 gas Substances 0.000 description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 210000003205 muscle Anatomy 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 230000000259 anti-tumor effect Effects 0.000 description 8
- 230000008859 change Effects 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 7
- 125000002252 acyl group Chemical group 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
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- 230000015572 biosynthetic process Effects 0.000 description 7
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 6
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- LOVPHSMOAVXQIH-UHFFFAOYSA-N (4-nitrophenyl) hydrogen carbonate Chemical compound OC(=O)OC1=CC=C([N+]([O-])=O)C=C1 LOVPHSMOAVXQIH-UHFFFAOYSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 125000003435 aroyl group Chemical group 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
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Abstract
本发明涉及式(I)的秋水仙醇衍生物:其中:R1、R2和R3分别是羟基、磷酰基氧(-OPO3H2)、C1-4烷氧基或在体内可水解的羟基的酯,附带条件是R1、R2和R3中至少两个是C1-4烷氧基;A是-CO-、-C(O)O-、-CON(R8)-(其中R8是氢、C1-4烷基、C1-3烷氧基C1-3烷基、氨基C1-3烷基或羟基C1-3烷基);a是一个从1到4间的整数;Ra和Rb分别选自氢、羟基和氨基;B是-O-、-CO-、-N(R9)CO-、-CON(R9)-、-N(R9)C(O)O-、-N(R9)CON(R10)-、-N(R9)SO2-、-SO2N(R9)-或一个单键(其中R9和R10分别选自氢、C1-4烷基、C1-3烷氧基C1-3烷基、氨基C1-3烷基和羟基C1-3烷基);b是0或整数1-4,(如果当b是0时,则B是一个单键);D是羧基、磺基、四唑基、咪唑基、磷酰基氧、羟基、氨基、N-(C1-4烷基)氨基、N,N-二(C1-3烷基)氨基、或式-Y1(CH2)OR11或-NHCH(R12)COOH;[其中Y1是一个单键、-O-、-C(O)-、-N(R13)C(O)-或-C(O)N(R13)-(其中R13是氢、C1-4烷基、C1-3烷氧基C2-3烷基、氨基C2-3烷基或羟基C2-3烷基);c是0或整数1-4。
Description
本发明涉及血管损害剂、本发明的化合物在制造用于温血动物如人的能产生抗血管生成作用的药物中的应用、包含该类化合物作为活性成分的药物组合物、治疗与血管生成有关的疾病状态的方法以及该类化合物作为药物的应用。
正常的血管生成在一系列过程中扮演者重要的角色,其中所说的一系列过程包括胚胎发育、伤口愈和女性生殖功能的一些组成部分。不希望的或病理学的血管生成与疾病状态有关,其中所说的疾病状态包括糖尿病性视网膜病、银屑病、癌症、类风湿性关节炎、动脉粥样化、卡波西肉瘤和血管瘤(Fan等,1995,Trends Pharmacol.Sci.16:57-66;Folkman,1995,Nature Medicine 1:27-31)。由血管生成而形成的新的脉管系统是一些疾病的关键病理学特征(J.Folkman,NewEngland Journal of Medicine 333,1757-1763(1995))。例如,对于实体瘤的生长而言,其必须建立自己的血液供应,其主要依靠该血液供应来提供氧气和营养物;如果这种血液供应被机械地切断,则该瘤将会坏死。血管再生也是银屑病中皮肤损害的临床特征,还是类风湿关节炎病人的关节中侵入性关节翳的临床特征以及动脉粥样硬化斑的临床特征。在黄斑变性和糖尿病性视网膜病中视网膜的血管再生是病理性的。
通过损害新形成的血管内皮的血管再生的逆转被预期认为具有有益的疗效。本发明是以三环化合物的发现为基础的,该化合物能令人吃惊的特定损害新形成的脉管系统而不影响主体物种血管内皮的正常形成,该特性在与血管生成有关的疾病状态的治疗中是有价值的特性,其中所说的与血管生成有关的疾病状态如癌症、糖尿病、银屑病、类风湿性关节炎、卡波西肉瘤、血管瘤、急性和慢性肾病、动脉粥样化、动脉再狭窄、自身免疫性疾病、急性炎症、子宫内膜异位、子宫出血功能紊乱和伴有视网膜脉管增生的眼病。
本发明的化合物是秋水仙醇(COLCHINOL)衍生物。秋水仙醇衍生物例如N-乙酰基-秋水仙醇是已知的。在动物模型中已经证明其具有抗肿瘤作用(参见例如-Jnl.Natl.Cancer Inst.1952,13,379-392)。但是,所研究的这种作用是一种总的损害作用(出血、软化和坏死),并没有通过破坏血管再生而治疗不恰当的血管生成的暗示。
虽然并不对本发明形成限制,但认为本发明化合物的应用能损害新形成的脉管系统,例如肿瘤的脉管系统,因此与已知的抗血管生成剂相比,本发明的化合物可以有效的逆转血管生成的过程,而已知的抗血管生成剂在该脉管系统一旦形成之后趋向于低效。
其中:
R1、R2和R3分别独立地是羟基、磷酰氧基(-OPO3H2)、C1-4烷氧基或在体内可水解的羟基的酯,附带条件是R1、R2和R3中至少有两个是C1-4烷氧基;
A是-CO-、-C(O)O-、-CON(R8)-、-SO2-或-SO2N(R8)-其中R8是氢、C1-4烷基、C1-3烷氧基C1-3烷基、氨基C1-3烷基或羟基C1-3烷基;
a是整数1-到4;
Ra和Rb分别选自氢、羟基和氨基;
B是-O-、-CO-、-N(R9)CO-、-CON(R9)-、-C(O)O-、-N(R9)-、-N(R9)C(O)O-、-N(R9)CON(R10)-、-N(R9)SO2-、-SO2N(R9)-或一个单键,其中R9和R10分别选自氢、C1-4烷基、C1-3烷氧基C1-3烷基、氨基C1-3烷基和羟基C1-3烷基;
b是0或整数1-4,条件是如果当b是0时,则B是一个单键;
D是羧基、磺基、四唑基、咪唑基、磷酰氧基、羟基、氨基、
N-(C1-4烷基)氨基、
N,
N-二(C1-3烷基)氨基或式-Y1-(CH2)cR11或-NHCH(R12)COOH;其中:Y1是一个单键、-O-、-C(O)-、-N(R13)-、-N(R13)C(O)-或-C(O)N(R13)-,其中R13是氢、C1-3烷基、C1-3烷氧基C2-3烷基、氨基C2-3烷基或羟基C2-3烷基;c是0或整数1-4;R11是一个环中含有1或2个选自O、S和N杂原子的通过碳或氮连接的5-6员饱和杂环基,或是一个不饱和或部分不饱和的含有1或2个选自O、S和N杂原子的经由碳或氮连接的5-6员杂芳基,该杂环基或杂芳基可以带有1或2个取代基,该取代基选自:
氧代、羟基、卤代、C1-4烷基、C2-4烷氧基、氨基甲酰基、
N-(C1-4烷基)氨基甲酰基、
N,
N-二(C1-4烷基)氨基甲酰基、羟基C1-4烷基、C1-4烷氧基、氰基C1-3烷基、氨基甲酰基C1-3烷基、羧基C1-4烷基、氨基C1-4烷基、
N-C1-4烷基氨基C1-4烷基、
N,
N-二(C1-4烷基)氨基C1-4烷基、C1-4烷氧基C1-4烷基、C1-4烷基磺酰基C1-4烷基和R14,其中R14是一个经由碳或氮连接的含有1或2个选自O、S和N杂原子的5-6员的饱和杂环基,该杂环基可任选被1或2个选自下述的取代基所取代:氧代、羟基、卤代、C1-4烷基、羟基C1-4烷基、C1-4烷氧基、C1-4烷氧基C1-4烷基和C1-4烷基磺酰基C1-4烷基;
R12是一个氨基酸侧链;
R5是C1-4烷氧基;
R4和R6分别独立地选自:氢、氟、硝基、氨基、N-C1-4烷基氨基、N,N-二(C1-4烷基)氨基、羟基、C1-4烷氧基和C1-4烷基;
R7是氢、C1-4烷基、C1-3烷氧基C1-3烷基,氨基C1-3烷基或羟基C1-3烷基;
或其可药用的盐、溶剂化物或其前体药物。
另一方面,本发明涉及一种如上所定义的式(I)的化合物或其可药用的盐。
在本说明书中,“烷基”的一般定义既包括直链烷基,又包括支链烷基。但是所涉及的各个烷基如“丙基”仅特定的指的是直链烷基,所涉及的各个支链烷基“异丙基”则仅特定的指的是支链烷基。其它一般定义也适用类似的规定。
R12是一个氨基酸侧链。包括得自天然或非天然氨基酸的侧链,并且包括R12与NH基团连接形成氨基酸脯氨酸中的环的可能性。其包括α-氨基酸、β-氨基酸和γ-氨基酸。此外,该氨基酸可以是L-异构体或D-异构体,但是优选L-异构体。优选的氨基酸包括甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、蛋氨酸、脯氨酸、苯丙氨酸、色氨酸、丝氨酸、苏氨酸、半胱氨酸、酪氨酸、天冬氨酸(asparaginine)、谷酰胺、天门冬氨酸、谷氨酸、赖氨酸、精氨酸、组氨酸、β-丙氨酸和鸟氨酸。更优选的氨基酸包括谷氨酸、丝氨酸、苏氨酸、精氨酸、甘氨酸、丙氨酸、β-丙氨酸和赖氨酸。尤其优选的氨基酸包括谷氨酸、丝氨酸、苏氨酸、精氨酸、丙氨酸和β-丙氨酸。R12的特定值包括氢、C1-4烷基、C1-4烷基硫代C1-4烷基、羟基C1-4烷基、硫代C1-4烷基、苯基C1-4烷基(可随意的被羟基所取代)、胍基C1-4烷基、羧基C1-4烷基、氨基甲酰基C1-4烷基、氨基C1-4烷基和咪唑基C1-4烷基以及R12与NH基团形成一个吡咯烷基环。R12的优选值包括氢、C1-4烷基、C1-4烷基硫代C1-4烷基、羟基C1-4烷基、硫代C1-4烷基、胍基C1-4烷基、羧基C1-4烷基、氨基甲酰基C1-4烷基和氨基C1-4烷基。
应当明白,由于存在一个或多个不对称碳原子,上面所定义的式(I)的某个化合物可以以光学活性或外消旋的形式存在,在本发明的定义中,本发明包括具有血管损害活性的任何一种该类光学活性或外消旋形式的化合物。该光学活性形态的物质可以用有机化学现有技术中众所周知的标准技术来进行制备,例如通过用具有光学活性的起始材料来进行合成或通过外消旋体的拆分来进行合成。类似地,上述的活性可用下文中所涉及的标准实验室技术来进行评估。
上面所涉及的一般基团的合适值如下所列。在本发明中,应当明白式(I)的化合物或其盐可以显现互变异构的现象,而本说明书中的结构式仅能表现出该互变异构形式中的一种。应当明白,本发明包括具有血管损害活性的任何互变异构形式,不能将其仅仅限定于结构式中所用的任何一种互变异构形式。
还应当知道,式(I)的某种化合物及其盐可以以溶剂化物和非溶剂化物的形式存在,诸如例如水合物的形式。应当明白本发明包含具有血管损害活性的所有的该类溶剂化物形式。
本发明涉及上文所定义的式(I)的化合物及其盐。用于药物组合物中的盐是可药用的盐,但是其它的盐可和其可药用的盐一样用于式(I)的化合物的生产中。本发明可药用的盐可以包括例如前文所定义的具有能形成该类盐的足够碱性的式(I)化合物的酸附加盐。该类酸附加盐包括例如与能提供可药用的阴离子的无机或有机酸所形成的盐,如与卤化氢(尤其是盐酸或氢溴酸,尤其优选盐酸)或与硫酸或磷酸形成的盐、或与三氟醋酸、枸橼酸或马来酸形成所盐。适合的盐包括盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、硫酸氢盐、烷基磺酸盐、芳基磺酸盐、醋酸盐、苯甲酸盐、枸橼酸盐、马来酸盐、延胡索酸盐、琥珀酸盐、乳酸盐和酒石酸盐。此外,在式(I)的化合物具有足够酸性的情况中,可药用的盐可以是与能提供可药用的阳离子的无机或有机碱所形成的盐。该类与无机或有机碱形成的盐包括例如碱金属盐如钠或钾盐、碱土金属盐如钙或镁盐、铵盐或例如与甲胺、二甲胺、三甲胺、哌啶、吗啉或三-(2-羟基乙基)胺所形成的盐。
各种形式的前体药物在现有技术中是已知的。例如这样的前体药物衍生物可参见:
a)前体药物设计,由H.Bundgaard编辑,(Elsevier,1985),和酶学中的方法,第
42卷,第309-396页,由K.Widder等人编辑,(Academic Press,1985);
b)药物设计和开发的教科书,由Krogsgaard-Larsen和H.Bundgaard编辑,第5章“前体药物的设计和应用”,由H.Bundgaard编辑,第113-191页(1991);
c)H.Bundgaard,
高级药物传递系统综述,
8,1-38(1992);d)H.Bundgaard等人,
Journal of Pharmaceutical Sciences,77,285(1988);和
e)N.Kakeya等人,
Chem.Pharm.Bull.,
32,692(1984)。
该类前体药物的实例可以是式(I)的化合物在
体内可裂解的酯的形式。包含羧基的式(I)的化合物在
体内可裂解的酯例如在人和动物体内能裂解产生母体酸的可药用的酯。适合的羧基可药用的酯包括C1-6烷氧基甲基酯,例如甲氧基甲基;C1-6烷酰氧基甲基酯、例如新戊酰氧基甲基;2-苯并[c]呋喃酮基酯;C3-8环烷氧基羰基氧C1-6烷基酯,例如1-环己基羰基氧乙基,1,3-二氧戊环-2-基甲基酯,例如5-甲基-1,3-二氧戊环-2-基甲基;和C1-6烷氧基羰基氧乙基酯,例如1-甲氧基羰基氧乙基;并且可以形成于在本发明化合物的任何羰基上。
R1、R2、R3、R4、R5、R6、R7、R8、R9、R10或R13或D上的各种取代基或R14的适合值包括:
对于卤代 氟代、氯代、溴代和碘代;
对于C1-4烷基: 甲基、乙基、丙基、异丙基和三-丁基; 对于N-C1-4烷基氨基: 甲基氨基、乙基氨基、丙基氨基、异
丙氨基和丁基氨基;对于N,N-二-[C1-4烷基]氨基: 二甲基氨基、二乙基氨基、
N-乙基
-
N-甲基氨基和二异丙基氨基;对于C2-4烷酰基: 乙酰基和丙酰基;对于C1-4烷氧基: 甲氧基和乙氧基;对于氰基C1-4烷基: 氰基甲基和2-氰基乙基;对于
N-C1-4烷基氨基甲酰基:
N-甲基氨基甲酰基、
N-乙基氨基甲
酰基和
N-丙基氨基甲酰基;对于
N,
N-二[(C1-4)烷基]氨基甲酰基:
N,
N-二甲基氨基甲酰
基、
N-乙基-
N-甲基氨基
甲酰基和
N,
N-二乙基氨
基甲酰基;对于C1-4烷基磺酰基烷基: 甲基磺酰基甲基和乙基磺酰基甲基;对于羟基C1-4烷基: 羟基甲基、2-羟基乙基、1-羟基乙基
和视情况而定的3-羟基丙基;对于C1-4烷氧基C1-4烷基: 甲氧基甲基、乙氧基甲基、1-甲氧基
乙基、2-甲氧基乙基、2-乙氧基乙基
和视情况而定的3-甲氧基丙基;对于氨基C1-4烷基: 氨基甲基、2-氨基乙基、1-氨基乙基
和视情况而定的3-氨基丙基;对于N-C1-4烷基氨基C1-4烷基: 甲基氨基甲基、乙基氨基
甲基、1-甲基氨基乙基、
2-甲基氨基乙基、2-乙基
氨基乙基和视情况而定
的3-甲基氨基丙基;对于N,N-二-[C1-4烷基]氨基C1-4烷基: 二甲基氨基甲基、二乙基
氨基甲基、二甲基氨基乙
基、2-二甲基氨基乙基
和视情况而定的3-二甲
基氨基丙基;
对于羧基C1-4烷基: 羧基甲基、1-羧基乙基、2-羧基乙
基、3-羧基丙基和4-羧基丁基;
对于氨基甲酰基C1-4烷基: 氨基甲酰基甲基、1-氨基甲酰基乙
基、2-氨基甲酰基乙基和3-氨基甲
酰基丙基;
对于C1-4烷氧基C1-4烷基: 甲氧基甲基、乙氧基乙基、甲氧基
乙基、和甲氧基丙基。
氨基甲酰基指的是-CONH2。
哌嗪子基指的是哌嗪-1-基。
5-或6-员饱和杂环的实例包括吡咯烷基、咪唑烷基、吡唑烷基、哌啶基、哌嗪基和吗啉基。
5-或6-员不饱和或部分不饱和的杂芳基包括:咪唑基、咪唑啉基吡啶基吡咯基、呋喃基、三唑基、吡嗪基、吡唑啉基、嘧啶基、哒嗪基、异噁唑基、噁唑基、异噻唑基、噻唑基和噻吩基。
优选的R1、R2和R3中至少两个是甲氧基。
优选的R1、R2和R3都是C1-4烷氧基。
最优选的R1、R2和R3都是甲氧基。
优选的R8是氢、甲基、乙基、2-甲氧基乙基、2-氨基乙基或2-羟基乙基。
更优选的R8是氢、2-氨基乙基或2-羟基乙基以及最优选的R8是氢。
优选的A是-CO-、-C(O)O-或-CON(R8)-。更优选的A是-C(O)O-。
优选的a是1、2或3以及最优选的a是2或3。
优选的Ra、和Rb是氢。
优选的B是-N(R9)CO-、-CON(R9)、-C(O)O-、-N(R9)-、-N(R9)C(O)O-、N(R9)CON(R10)-或一个单键。
更优选的B是-CO-、-N(R9)CO-或一个单键。
还更优选的B是-CO-或一个单键。
最优选的B是-CO-。另一方面B是一个单键。
优选的R9和R10分别选自氢、甲基、乙基、2-甲氧基乙基、2-氨基乙基和2-羟基乙基。
更优选的R9和R10分别选自氢、2-氨基乙基和2-羟基乙基。
更优选的R9和R10是氢。
优选的b是0、1或2,更优选的b是0或1以及最优选的b是0。
优选的R11是包含1或2个选自N和O的环杂原子的5或6员饱和杂环。
更优选的R11是包含1或2个选自N和O的环杂原子的6员饱和杂环。
进一步优选的R11包含至少一个环氮原子。
进一步优选的R11是哌嗪基、吗啉基或哌啶基,其中的每一个都是通过环碳或氮环原子连接的,并且每一个环都可随意的被1或2个上述的用于R11的取代基所取代。
进一步优选的R11是通过环氮原子进行连接的。
最优选的R11是哌嗪子基或吗啉代,每一个都可随意的被1或2个如上所述的用于R11的取代基所取代。
毫无疑问,饱和的杂环可以在环碳或环氮原子上被取代。
优选的在R11中用于饱和杂环的取代基包括C1-4烷基、C2-4烷酰基、氨基甲酰基、氰基C1-3烷基、羟基C1-3烷基、羧基C1-3烷基和氨基C1-3烷基。
更优选的在R11中用于饱和杂环的取代基包括C1-3烷基、C2-3烷酰基、氨基甲酰基和羟基C2-3烷基。
还更优选的在R11中用于饱和杂环的取代基包括甲基、乙酰基、氨基甲酰基和2-羟基乙基。
最优选的用于饱和杂环的取代基包括甲基、乙酰基和氨基甲酰基。
优选的在R11中的饱和杂环未被取代或被1个取代基所取代。
当在R11中的饱和杂环是吗啉代时,优选地是未被取代的。当在R11中的饱和杂环是哌嗪子基时,优选地是未被取代的哌嗪子基或在环氮原子上被1个取代基所取代的哌嗪子基。
优选的Y1是-CONH-或-NHCO-。
优选的c是0、1或2。
更优选的c是0。
R11的优选值包括吗啉代、4-甲基哌嗪-1-基和4-乙酰基哌嗪-1-基。
优选的R14是吗啉代或哌嗪-1-基,每一个都可以随意的被1或2个选自C1-3烷基、羟基C2-3烷基、C1-3烷氧基和C1-3烷氧基C1-3烷基的取代基所取代。
更优选的R14是吗啉代、或未被取代的哌嗪-1-基或被甲基取代的哌嗪-1-基。
优选的D是羧基、磷酰基氧、羟基、氨基、
N-C1-4烷基氨基、
N,N-二(C1-4烷基)氨基或式-Y1(CH2)cR11,其中Y1、c和R11的定义同上。
更优选的D是羧基磷酰基氧、羟基、氨基或式-Y1-(CH2)cR11,其中Y1、c和R11的定义同上。
更优选的D是磷酰基氧、氨基或式-Y1-(CH2)cR11,其中Y1、c和R11的定义同上。
还更优选的D是磷酰基氧(phosphoyloxy)、氨基或式-Y1-(CH2)cR11,其中其中Y1和c的定义同上并且R11是吗啉代、咪唑基、或哌嗪基,其中杂环基可以带有一个或更多个如上所定义的取代基。
还更优选的D是磷酰基氧、氨基或式-Y1-(CH2)cR11,其中Y1和c的定义同上并且R11是吗啉代、咪唑基、4-甲基哌嗪-1-基或4-乙酰基哌嗪-1-基。
甚至还更优选的D是磷酰基氧、氨基或式-Y1-(CH2)cR11,其中Y1和c的定义同上并且R11是吗啉代、咪唑基-1-基、4-甲基哌嗪-1-基或4-乙酰基哌嗪-1-基。
优选的R5是甲氧基。
优选的R4和R6分别选自氢、羟基、C1-3烷氧基、和C1-3烷基。
更优选的R4和R6中至少有一个是氢。
更优选的R4和R6都是氢。
优选的R7是氢或甲基。最优选的R7是氢。
一种优选的化合物的种类是式(I)的化合物,其中:
R1、R2、和R3都是C1-4烷氧基;
R4和R6分别选自氢、羟基、C1-3烷氧基、和C1-3烷基;
R5是甲氧基;
A是-CO-、-C(O)O-或-CONH-;
a是1、2或3;
B是-CO-、-NHCO-、-CONH、-C(O)O-、-NH-、-NHC(O)O-、NHCONH-或一个单键;
b是0、1或2;
D是羧基、磺基、磷酰基氧、羟基、氨基、
N-C1-4烷基氨基、
N,
N-二(C1-4烷基)氨基或式-Y1(CH2)cR11(其中Y1是-NHC(O)-或-C(O)NH-;c是1或2;R11是包含1或2个分别选自O和N的环杂原子的5-6-员饱和杂环基(经由氮原子连接起来),该杂环基可以带有1或2取代基,该取代基选自:
C1-4烷基、C2-4烷酰基、氨基甲酰基、氰基C1-3烷基、羟基C1-3烷基、羧基C1-3烷基和氨基C1-3烷基);
R7是氢;
或其可药用的盐、溶剂化物或前体药物。
另一类优选的化合物是式(I)的化合物,其中:
R1、R2、和R3都是甲氧基;
R4和R6分别选自氢、羟基、甲氧基和甲基;
R5是甲氧基;
A是-CO-、-C(O)O-或-CONH-;
a是2或3;
B是-CO-、-NHCO-、-CONH或一个单键;
b是0或1;
D是羧基、磷酰基氧、羟基、氨基、
N-C1-4烷基氨基、
N,
N-二(C1-4烷基)氨基或式-Y1(CH2)cR11(其中Y1是-NHC(O)-或-C(O)NH-;c是1或2;R11是哌嗪基、吗啉基或哌啶基,它们都是通过环氮原子连接起来的,各环都可以随意的被1或2个取代基,该取代基选自:
C1-4烷基、C2-4烷氧基、氨基甲酰基、氰基C1-3烷基、羟基C1-3烷基、羧基C1-3烷基和氨基C1-3烷基);
R7是氢;
或其可药用的盐、溶剂化物或前体药物。
其中a、b、A、B和D如上所定义的;
或其可药用的盐、溶剂化物或体药物。
另一类优选的化合物是式(II)的化合物,其中:
A是-CO-、-C(O)O-或-CONH-;
a是2或3;
B是-CO-、-NHCO-、-CONH或一个单键;
b是0或1;
D是羧基、磷酰基氧、羟基、氨基、
N-C1-4烷基氨基、
N,
N-二(C1-4烷基)氨基或式-Y1(CH2)cR11(其中Y1是-NHC(O)-或-C(O)NH-;c是1或2;R11是哌嗪基、吗啉基或哌啶基,它们都是通过环氮原子进行连接的并且各环可任意的被1或2各取代基所取代,该取代基选自:
C1-4烷基、C2-4烷酰基、氨基甲酰基、氰基C1-3烷基、羟基C1-3烷基、羧基C1-3烷基和氨基C1-3烷基);
或其可药用的盐、溶剂化物或前体药物。
另一类优选的化合物是式(II)的化合物,其中:
A是-CO-、-C(O)O-或-CONH-;
a是2或3;
B是-CO-、-NHCO-、-CONH或一个单键;
b是0或1;
D是磷酰基氧、羧基、氨基或咪唑基;
或其可药用的盐、溶剂化物或前体药物。
另一类优选的化合物是式(II)的化合物,其中:
A是-CO-、-C(O)O-或-CONH-;
a是2或3;
B是-CO-、-NHCO-或一个单键;
b是0或1;
D是磷酰基氧氨基或咪唑基;
或其可药用的盐、溶剂化物或前体药物。
其中:
R1、R2和R3分别是羟基、磷酰基氧(-OPO3H2)、C1-4烷氧基或在体内可水解的羟基的酯,附带条件是R1、R2和R3中的至少两个是C1-4烷氧基;
A是-CO-、-C(O)O-、-CON(R8)-、-SO2-或-SO2N(R8)-(其中R8是氢、C1-4烷基、C1-3烷氧基C2-3烷基、氨基C2-3烷基或羟基C2-3烷基);
a是一个从1到4间的整数;
Ra和Rb分别选自氢、羟基和氨基;
B是-O-、-CO-、-N(R9)CO-、-CON(R9)-、-C(O)O-、-N(R9)-、-N(R9)C(O)O-、-N(R9)CON(R10)-、-N(R9)SO2-、-SO2N(R9)-或一个单键(其中R9和R10分别选自氢、C1-4烷基、C1-3烷氧基C2-3烷基、氨基C2-3烷基和羟基C2-3烷基);
b是0或一个从1到4的整数;
D是一个包含1或2个选自O和N的环杂原子的5-6-员饱和杂环基(经由碳或氮连接),该杂环基可以带有1或2个取代基,该取代基选自:
氧代、羟基、卤代、C1-4烷基、C2-4烷酰基、氨基甲酰基、
N-(C1-4烷基)氨基甲酰基、
N,
N-二-(C1-4烷基)氨基甲酰基、羟基C1-4烷基、C1-4烷氧基、氰基C1-3烷基、氨基甲酰基C1-3烷基、羧基C2-4烷基、氨基C1-4烷基、N-C1-4烷基氨基C1-4烷基、二-
N,
N-(C1-4烷基)氨基C1-4烷基、C1-4烷氧基C1-4烷基、C1-4烷基磺酰基C1-4烷基和R14(其中R14是一个包含1或2个选自O和N的环杂原子的5-6-员饱和杂环基(经由碳或氮连接),该杂环基可以任意的被1或2个取代基所取代,所说的取代基选自:
氧代、羟基、卤代、C1-4烷基、羟基C1-4烷基、C1-4烷氧基、C1-4烷氧基C1-4烷基和C1-4烷基磺酰基C1-4烷基);
R5是C1-4烷氧基;
R4和R6分别选自:
氢、卤代、硝基、氨基、N-C1-4烷基氨基、N,N-二-(C1-4烷基)氨基、羟基、C1-4烷氧基和C1-4烷基;
R7是氢、C1-4烷基、C1-3烷氧基C1-3烷基、氨基C1-3烷基或羟基C1-3烷基;
或其可药用的盐、溶剂化物或前体药物。
另一类优选的化合物是式(III)的化合物,其中:
R1、R2、和R3都是C1-4烷氧基;
R4和R6分别选自氢、羟基、C1-3烷氧基、和C1-3烷基;
R5是甲氧基;
A是-CO-、-C(O)O-或-CONH-;
a是1、2或3;
B是-CO-、-NHCO-、-CONH、-C(O)O-、-NH-、-NHC(O)O-、NHCONH-或一个单键;
b是0、1或2;
D是哌嗪基或吗啉基或哌啶基,各环都可随意的被1或2个取代基所取代,选自C1-4烷基、C2-4烷酰基、氨基甲酰基、氰基C1-3烷基、羟基C1-3烷基、羧基C1-3烷基和氨基C1-3烷基;
R7是氢;
或其可药用的盐、溶剂化物或前体药物。
更优选的另一类化合物是式(III)的化合物,其中:
R1、R2、和R3都是甲氧基;
R4和R6分别选自氢、羟基、甲氧基和甲基;
R5是甲氧基;
A是-CO-、-C(O)O-或-CONH-;
a是2或3;
B是-CO-、-NHCO-、-CONH或一个单键;
b是0或1;
D是哌嗪子基或吗啉代,各环可随意的被1或两个取代基所取代,该取代基选自甲基、乙基、乙酰基、丙酰基、氨基甲酰基和2-羟基乙基;
R7是氢;
或其可药用的盐、溶剂化物或前体药物。
本发明的另一方面设计一种式(IV)的化合物,
其中a、b、A、B和D的定义同式(III)中的相同;
或其可药用的盐、溶剂化物或前体药物。
另一种优选的化合物是式(IV)的化合物,其中
A是-CO-、-C(O)O-或-CONH-;
a是2或3;
B是-CO-、-NHCO-、-CONH或一个单键;
b是0或1;
D是哌嗪子基或吗啉代,各环可随意的被1或2个取代基所取代,该取代基选自甲基、乙基、乙酰基、丙酰基、氨基甲酰基和2-羟基乙基;
或其可药用的盐、溶剂化物或前体药物。
另一类优选的化合物是式(IV)的化合物,其中:
A是-CO-、-C(O)O-或-CONH-;
a是2或3;
B是-CO-、-NHCO-、-CONH或一个单键;
b是0或1;
D是吗啉代、4-甲基哌嗪-1-基或4-乙酰基哌嗪-1-基
或其可药用的盐、溶剂化物或其前体药物。
另一类优选的化合物是式(IV)的化合物,其中:
A是-CO-、-C(O)O-或-CONH-;
a是2或3;
B是-CO-或一个单键;
b是0;
D是吗啉代、4-甲基哌嗪-1-基或4-乙酰基哌嗪-1-基;
或其可药用的盐、溶剂化物或前体药物。
本发明的特定化合物包括:
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]-2-[2-氨基乙酰基氨基]乙酰胺;
4-氧代-4-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基]丁基磷酸二钠;
N-{N-[2-(咪唑-1-基)乙基]氨基甲酰基}-5(S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基胺;和
2-{N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酰基氧}乙基磷酸二钠;
以及它们可药用的盐、溶剂化物或前体药物。
本发明更特定的化合物包括:
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸2-吗啉代乙基酯;
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸3-(1-甲基哌嗪-4-基)丙基酯;
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]-2-[2-氨基乙酰基氨基]乙酰胺;
N-[(5S)-3,9,10,11-四甲氧基-6-7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸2-(1-乙酰基哌嗪-4-基)乙基酯;
N-[(5S)-3,9,10,11-四甲氧基-6-7-二氢-5H-二苯并[a,c]环庚烯-5-基]-4-(1-甲基哌嗪-4-基)-4-氧代丁-1-酰胺;
4-氧代-4-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基]丁基磷酸二钠;
N-{N-[2-(咪唑-1-基)乙基]氨基甲酰基}-5(S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基胺;
N-[(5S)-3,9,10,11-四甲氧基-6-7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸3-(1-乙酰基哌嗪-4-基)丙基酯;
N-1-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酰基氧]乙基磷酸二钠;
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a-c]环庚烯-5-基]氨基甲酸4-吗啉代-4-氧代丁基酯;和
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸4-(1-甲基哌嗪-4-基)-4-氧代丁基酯;
以及它们可药用的盐、溶剂化物或前体药物。
式(I)化合物的合成
式(I)的化合物可以通过许多如下文所描述的一般方法来进行制备,并且更特定的是按下文实施例中的方法进行制备。提供制备式(I)的新型化合物的方法是本发明的另一个特征,将在下文中进行描述。必需的起始材料可以通过有机化学的标准方法来获得。该类起始材料的制备在所附的非限制性实施例中进行了描述。另一种得到必需起始材料的方法是通过与有机化学普通技能中的方法相类似的方法来获得。
因此,依据本发明的另一方面,式(I)的化合物可以通过将至少1个功能基团被保护起来的式(I)的化合物脱保护来形成。例如,在用于制备式(I)的化合物的反应序列期间可将氨基、羟基、羧基或磷酰基氧保护起来。
保护基团一般可选自在文献中进行了描述的任何基团或熟练的化学工作者所公知的视情况而定的保护有问题基团的任何一种基团,并且通过常规的方法进行了介绍。
保护基团可通过任何在文献中所描述的适宜方法或普通化学工作者所公知的视情况而定的用于所讨论的保护基团的方法来除去,所选择的方法可以除去保护基团而对分子中其它基团所产生的干扰最小。
对于羟基而言,适宜的保护基团有,例如芳基甲基(尤其是苯甲基)、三C1-4烷基甲硅烷基(尤其是三甲基甲硅烷基或三-丁基二甲基甲硅烷基)、芳基二-C1-4烷基甲硅烷基(尤其是二甲基苯基甲硅烷基)、二芳基C1-4烷基甲硅烷基(尤其是三-丁基二苯基甲硅烷基)、C1-4烷基(尤其是甲基)、C2-4烯基(尤其是烯丙基)、C1-4烷氧基甲基(尤其是甲氧基甲基)或四氢吡喃基(尤其是四氢吡喃-2-基)。上述保护基团的去保护条件必然随着所选择的保护基团的不同而发生变化。因此,例如,芳基甲基如苯甲基可以通过例如在催化剂如披钯炭上的氢化作用来除去。三烷基甲硅烷基或芳基二烷基甲硅烷基如三-丁基二甲基甲硅烷基或二甲基苯基甲硅烷基可以选择性的通过例如用适宜的酸如盐酸、硫酸、磷酸或三氟醋酸进行处理来除去,或用碱金属或氟化铵如氟化钠或优选的氟化四丁基铵进行处理来除去。或者烷基可以通过用例如碱金属C1-4烷基硫化物如硫代乙醇钠进行处理来除去,或例如通过用碱金属二芳基磷化物如二苯基磷化锂进行处理来除去,或例如通过用硼或铝的三卤化物如三溴化硼进行处理来除去。C1-4烷氧基甲基或四氢吡喃基例如可以通过用适宜的酸如盐酸或三氟醋酸进行处理来除去。
另外的适于保护羟基的基团是例如酰基,如C2-4酰基(尤其是乙酰基)或芳酰基(尤其是苯甲酰基)。上述保护基团的去保护条件必须随着所选择的保护基团的不同而发生变化。因此,例如酰基如烷酰基或芳酰基可以通过例如用适宜的碱如碱金属氢氧化物例如氢氧化锂或氢氧化钠进行水解来除去。
用于氨基、亚氨基或烷基氨基的保护基团有,例如酰基,如C2-4烷酰基(尤其是乙酰基)、C1-4烷氧基羰基(尤其是甲氧基羰基)、乙氧基羰基或三-丁氧基羰基)、芳基甲氧基羰基(尤其是苄氧基羰基)或芳酰基(尤其是苯甲酰基)。上述保护基团的去保护条件必须随着所选择的保护基团的不同而发生变化。因此,例如,酰基如烷酰基、烷氧基羰基或芳酰基可以通过例如用适宜的碱如碱金属氢氧化物例如氢氧化锂或氢氧化钠进行水解来除去。另一种酰基如三-丁氧基羰基可以通过例如用适宜的酸如盐酸、硫酸或磷酸或三氟醋酸进行处理来除去,以及芳基甲氧基羰基如苄氧基羰基可以通过例如用催化剂如披钯炭进行氢化来除去。
用于羧基的适宜的保护基团,例如酯化基团,例如可以通过例如用适宜的碱如碱金属氢氧化物如氢氧化锂或氢氧化钠水解来除去的C1- 4烷基(尤其是甲基或乙基);或例如可以通过例如用适宜的酸如盐酸、硫酸、磷酸或三氟醋酸进行处理来除去的三-丁基。
用于对反应条件和试剂进行一般性指导的读物有高等化学,第4版,J.March,由John Wiley &Sons出版,1992,用于对保护基团进行一般指导的读物涉及有机合成中的保护基团,第2版,T.Green等人,也是由John Wiley & Son出版的。
在下面的说明书中,除非特别说明,符号R1-R7、A、B、D、RaRb、a和b应当被看作是在上述式(I)和(II)中所描述的这些基团。
式(I)的化合物,或其中至少由1个功能基被保护起来的式(I)的化合物可以用下面的方法之一进行制备:
L1-A-[CH(Ra)]aB-[CHRb)]b-D (XI)
其中L1是离去基团;或
b)将式(I)的化合物转化成另一种式(I)的化合物;或
c)当希望得到磷酰基氧时,将相关的羟基化合物与磷酰胺酸盐(phosphoramidite)反应
其中任何一个功能基都可以选择性的被保护起来。
并且其后如果需要的话,可以:
i)将式(I)的化合物转化成另一种式(I)的化合物
ii)除去任何的保护基团;
ii)形成其可药用的盐、溶剂化物或前体药物。
式(X)的化合物和式L1-A-[CH(Ra)]a-B-[CHRb)]b-D的化合物间的反应一般是在标准的酰化或磺酰化条件下进行的。L1通常是卤代,例如氯代或溴代、羟基、甲磺酰基氧、甲苯磺酰基氧或一个“活化的”羟基。准确条件在很大程度上取决于A的性质。
例如,当-A-是-CO-时,L1可以是羟基并且该反应可以在存在偶联剂如二环己基碳二亚胺或1-(3-二甲基氨基丙基)-3-乙基碳二亚胺的情况下进行。任意地,可以使用一种碱,例如一种有机碱如三乙胺。适宜的溶剂通常是质子惰性的溶剂,例如二甲基甲酰胺,或氯化溶剂,例如三氯甲烷或二氯甲烷。该温度通常在约-30℃至约60℃的范围内,方便地在室温或接近室温的温度下进行。
当-A-是-C(O)O-时,L1通常是“活化的”羟基。这是一种以与羟基同样的方式作为一种离去基团的基团,但是其更不稳定。其可以在原来的位置上形成。活化的羟基的一个实例是4-硝基苯氧基,它可以通过将羟基基团(HO-[CH(Ra)]a-B-[CH(Rb)]b-D)与4-硝基苯基氯甲酸盐反应来形成。该反应通常在有机溶剂如二氯甲烷、乙腈或四氢呋喃中进行,在约-20℃至溶剂的回流温度下进行。此外,通常存在有机碱如三乙胺或N-甲基吗啉。作为另外一种选择,式(X)的化合物可以与4-硝基苯基氯甲酸盐反应,并将所得的中间体与HO-[CH(Ra)]a-B-[CH(Rb)]b-D在与上述式(X)的化合物和其中L2是4-硝基苯氧基的式L2-[CH(Ra)]a-B-[CH(Rb)]b-D的化合物进行反应的条件相似的条件下进行反应。
当-A-是-CON(R8)-时,L1优选的是卤代,特别是氯代。另一种可供选择的情况是当-A-是-CONH-时,式(X)的化合物可以与式C=N-[CH(Ra)]a-B-[CH(Rb)]b-D的异氰酸酯反应。这些反应一般在存在碱,尤其是有机碱如三乙胺、吡啶或N-甲基吗啉的条件下,在溶剂如醚溶剂例如四氢呋喃或氯化溶剂例如二氯甲烷中,在约-20℃至溶剂的回流温度的温度下进行。另一种供替代的选择是,式(X)的化合物可以与4-硝基苯基氯甲酸盐反应,并将所得的中间体与R17-NH2在与上述的用于式(X)的化合物与其中L2是4-硝基苯氧基的式L2-[CH(Ra)]a-B-[CH(Rb)]b-D反应的条件相类似的条件下进行反应。
当-A-是式-SO2-或-SO2N(R8)-时,L1优选的是卤代,例如氯代。该反应一般是在存在碱如二甲基苯胺的条件下,在氯化溶剂如三氯甲烷中并且在约-2O℃至约60℃的温度范围内进行的,更优选的是在吡啶中,在-20℃至约60℃的温度范围内进行的。
式(I)的化合物可以通过化学修饰,由另一种式(I)的化合物来进行制备。化学修饰的实例包括标准烷化作用、芳基化作用、异芳基化作用、酰化作用、磺酰化作用、磷酸化作用、芳香卤化和偶合反应。这些反应可用于增加新的取代基或改变现有的取代基。另一种供选择的替代是,式(I)的化合物中的现有取代基可以通过例如氧化、还原、消除、水解或其它的裂解反应来进行修饰以得到其它的式(I)化合物。
因此,例如包含氨基的式(I)的化合物可以在存在碱例如叔胺碱如三乙胺的情况下,在有机溶剂如烃溶剂例如二氯甲烷中,在例如-30℃至120℃的温度范围内的温度下,一般在室温或接近室温的温度下,通过用例如酰卤或酸酐进行处理而将氨基酰化。
在另一个互变过程的常规实例中,式(I)化合物中的氨基可以在存碱例如叔胺碱如三乙胺的条件下,在溶剂例如烃溶剂如二氯甲烷中,在例如-3O℃至120℃的温度范围内的温度下,一般在室温或接近室温的温度下,通过用例如烷基或芳基磺酰基氯或烷基或芳基磺酸酐进行处理而被磺酰化。
在另一个常规实例中,包含羟基的式(I)的化合物可以在存在适宜的催化剂,例如四唑的条件下,通过用例如二-三-丁基二异丙基磷酰胺酸盐或二-三-丁基二乙基磷酰胺酸盐进行处理而被转化成相应的二氢磷酸酯。可使用的一种溶剂是如醚溶剂,例如四氢呋喃。该反应通常在-40℃至40℃范围内的温度下进行,一般在室温下或接近室温的温度下进行,然后用氧化剂例如3-氯过氧苯甲酸在-78℃至40℃,优选-40℃至10℃的范围内的温度下进行处理。在-3O℃至4O℃的范围内的温度下,一般在0℃或接近0℃的温度下,将所得的中间体磷酸三酯用酸,例如三氟醋酸在溶剂如氯化溶剂例如二氯甲烷中进行处理,得到包含二氢磷酸酯的式(I)的化合物。
在另一个常规实例中,包含酰胺的式(I)的化合物可以在溶剂如醇例如甲醇中,在升高的温度下,一般在回流温度下,通过用酸例如盐酸进行处理而被水解。
在另一个常规实例中,烷氧基可以通过与三溴化硼在溶剂如氯化溶剂例如二氯甲烷中,在低温下例如约-78℃下进行反应而被转化成相应的醇(OH)。
在另一个常规实例中,式(I)的化合物可以通过与适宜的烷基化试剂如烷基卤、烷基甲苯磺酸盐、烷基甲烷磺酸盐、或烷基三氟甲磺酸盐反应而被烷基化。该烷基化反应可以在存在碱,例如无机碱如碳酸盐例如碳酸铯或碳酸钾、氢化物如氢化钠或醇化物如叔-丁醇钠的条件下,在适宜的溶剂如质子惰性溶剂例如四氢呋喃中,在约-10℃至80℃的条件下进行。
在另一个实例中,在饱和杂环中未被取代的环氮可以用与上述的氨基基团的酰化条件相类似的条件进行酰化。
中间体的合成
式(X)的化合物是已知的或可以根据国际专利申请PCT/GB98/01977中所描述的方法进行制备。
式(XI)的化合物可以是已知的或根据现有技术中已知的方法进行制备。例如,当A是式-C(O)O-并且L1是4-硝基苯基氧时,式(XI)的化合物可以通过将式:
HO-[CH(R7)]a-B-[CH(R7)]b-D
的化合物与4-硝基苯基氯甲酸盐在存在碱,优选有机碱如三乙胺的条件下,在惰性有机溶剂如二氯甲烷中进行反应来形成。该反应通常是在-30℃至60℃范围的温度内,最常见的是在约室温下进行的。
式(I)的化合物的酸附加盐一般是用常规的方法通过用约一当量的可药用的酸对式(I)的化合物的游离碱的溶液或混悬液进行处理来进行制备的。得自无机或有机碱的式(I)的化合物的盐是用常规的方法通过用约一当量的可药用的有机或无机碱对式(I)的化合物的游离酸的溶液或混悬液进行处理来进行制备的。另一种可供替代的选择是附加盐和得自碱的盐都可以通过用适当的离子交换树脂以标准的方式对母体化合物进行处理来进行制备。在分离该盐时可以使用常规的浓度和重结晶技术。
本发明的化合物能够破坏新形成的脉管系统如肿瘤脉管系统而不影响正常的、成熟的脉管系统。需要对选择性、并且优选的能有效损害新形成的脉管系统的化合物进行鉴定,并且该化合物的鉴定是本发明的主题。可以对该化合物的这种作用能力进行评估,例如用下列方法中的一种或多种来进行评估:
(a)用放射性示踪器测定的对肿瘤脉管系统的活性
这种测定证明了化合物具有选择性损害肿瘤脉管系统的能力。
通过在12周大小的小鼠的后背上的皮肤下注射0.05ml的天然肿瘤细胞混悬液,约106株,来激发皮下CaNT肿瘤。在约3-4星期后,当它们的肿瘤的几何平均直径达到5.5-6.5mm时,选择该动物进行治疗。将化合物溶解于无菌生理盐水中并以每10g体重0.1ml的容积进行腹膜内注射。
在腹膜内给药6小时后,用86RbCl萃取技术对肿瘤、肾、肝、皮肤、肌肉、肠和脑中的肿瘤灌注进行测定(Sapirstein,Amer.Jnl.Physiol.,1958,193,16-168)。在静脉注射86RbCl后1分钟测定组织放射性以用于计算以心输出量的比例方式表示的相对血流量(Hill和Denekamp,Brit.Jn l.Radiol.,1982,55,905-913)。在对照组和治疗组使用5只动物。结果用载体治疗动物相应组织血流量的百分比来表示。
(b)用荧光染料测定的对肿瘤脉管系统的活性
这种测定证实了化合物损害肿瘤脉管系统的活性。
荷CaNT肿瘤的小鼠中的肿瘤功能血管容积是根据Smith等人的方法而用荧光染料Hoechst 33342进行测定的(Brit.Jnl.Cancer1988,57,247-253)。在对照组和治疗组中使用5只动物。以6.25mg/ml的量将该荧光染料溶解于生理盐水中,并在进行腹膜药物治疗后24小时以10mg/kg的剂量进行静脉注射。1分钟后,将动物处死,将肿瘤切除并进行冷冻;在3个不同的水平上分别切下10μm的部分,然后用配有表荧光(epifluoreslence)的Olympus显微镜在UV光下进行观察。通过它们的荧光轮廓来识别血管,用以Chalkley所描述的系统为基础的点记分系统来测定血管容积(Jnl.Natl.Cancer Inst.,1943,4,47-53)。所有的评价都是以在3个不同水平上切下的部分上进行的最少100个区域的计数为基础的。
可以用文献中可获得的大量方法来评估化合物与哺乳动物微管蛋白制剂结合的能力,例如用下面的温度激发的微管蛋白聚合作用在存在和不存在该化合物时通过浊度来判定(例如O.Boye等人,Med.Chem.Res.,1991,1,142-150)。
N-[3-氨基-9,10,11-三甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]乙酰胺对肿瘤脉管系统的活性是用上述的荧光染料法进行测定的(V.Fernholz Justus Liebigs Ann.,1950,568,63-72)。当以50mg/kg的剂量腹膜内给药时,与对照组相比,该化合物可将灌注的血管容积降低88%。在微管蛋白聚合作用测定的该化合物IC50是58微摩尔(O.Boye等人,Med.Chem.Res.,1991,1,142-150)。
(c)HUVEC分离测定
这种测定验证了化合物HUVEC对组织培养物塑料器皿的粘附作用的影响。
以在1mlTCS基质中每株3×104个细胞的浓度将HUVEC接种于0.2%明胶涂层的12孔组织培养物圆盘中。在24小时后,当该细胞在~30%溶合时,将该细胞在37℃,5%CO2的条件下用化合物给药40分钟。在进行孵化后,将包含药物的基质吸去,然后用2ml的HBSS(Hanks′饱和盐溶液,购自Life Technologies Ltd,PaisleyUK;Catalogue &num;24020-083)对该细胞温和的进行洗涤以除去任何分离的细胞。然后除去洗涤溶液,并将粘着的细胞剩余物在室温下用300μl的1x胰蛋白酶-EDTA溶液(Life Technologies Ltd,Paisley,UK;Catalogue &num;43500019)胰蛋白酶化两分钟。然后将该胰蛋白酶化的细胞用TCS生物制品基质制成1ml,然后以2000rpm的转速离心2分钟。然后将该细胞沉淀重新混悬于容积为50μl的TCS生物制品基质中。通过血细胞计数器上的细胞计数来获得总细胞计数。通过将在处理后仍然附着的细胞数与未给药的对照株的数目进行比较来计算细胞解析的量。
(d) Hras5坏死模型
将用Harvey ras,纯系5,(Hras5细胞)转染的NIH 3T3成纤维细胞在37℃下,在通有7.5%二氧化碳和92.5%氧气的潮湿孵化器中,在包含10%胎牛血清(FBS)和1%谷酰胺的Dulbecco改性的Eagles基质(DMEM)中连续传代。随后以2×105个细胞/鼠的接种物量将细胞植入到雄性裸鼠(8-10周大)的左侧腹上。用卡钳对肿瘤进行测定,在植入后9-14天之间将其随机分组,每组2-4只小鼠。将小鼠用化合物进行给药,静脉或腹膜内给药,随机的一天一次,在给药后24小时将该动物挑选出来。将化合物溶解于pH为7的20%羟基丙基β环糊精生理盐水溶液中,给药剂量为每10g体重0.1ml容积。将肿瘤切除、称重并将其放到带有缓冲的福尔马林中。用病理学的苏木紫/曙红染色玻片来评定个体肿瘤的坏死面积,从意味着没有显著改变的0开始记分,记到意味着91-100%坏死的10分。实施例5和7(下文中进行描述)的对肿瘤脉管系统的活性是通过上文所描述的荧光染料法进行测定的。实施例1在100mg/kg的得分为6.0,实施例4在50mg/kg的得分为3.2。
本发明的另一方面提供了一种药物组合物,该药物组合物包含上文所定义的式(I)的化合物或其可药用的盐、溶剂化物或前体药物,以及可药用的赋性剂或载体。
该组合物可以是适于口服给药的形式例如片剂或胶囊剂、适于鼻腔给药或吸入给药的形式例如粉剂或溶液、适于非胃肠道注射的形式(包括静脉、皮下、肌肉、血管外或输液)例如无菌的溶液、混悬液或乳剂、用于局部给药的形式例如软膏或霜剂或直肠给药的形式例如栓剂。一般而言,上述组合物可以用一般的赋性剂用常规的方法进行制备。
本发明的组合物可以有利的以单元剂型的形式存在。该化合物正常地是以动物的每平方米体表面积5-5000mg的单位剂量被给药于恒温动物的,即约0.1-100mg/kg。在该范围内设计一个单位剂量,例如1-100mg/kg,优选1-50mg/kg,该剂量一般就能提供有效治疗剂量。单位剂型如片剂或胶囊剂通常包含例如1-250mg的活性成分。
治疗或预防特定疾病所需的上述剂量尺度必须随着被治疗的主体、给药途径和被治疗疾病的严重程度而变化。优选的使用1-50mg/kg范围内的日剂量。但是,该日剂量必须随着被治疗的主体、特定的给药途径以及被治疗疾病的严重程度而变化。因此,可以由治疗任何特定病人的医师来决定最佳的剂量。
本发明的另一方面提供了一种如上文所定义的在进行人或动物体治疗的治疗方法中治疗所用的式(I)的化合物或其可药用的盐、溶剂化物或前体药物。
本发明的另一方面是用作药品的式(I)的化合物、或其可药用的盐、溶剂化物或前体药物,尤其是用作用于恒温动物如人类的能产生血管损害作用的药物的式(I)的化合物、或其可药用的盐、溶剂化物或前体药物。
因此,本发明另一方面还提供了一种式(I)的化合物、或其可药用的盐、溶剂化物或前体药物在制造用于在恒温动物如人类体内产生血管损害作用的药物的应用。
本发明的另一方面提供了一种在需要进行该种治疗的恒温动物如人类体内产生血管损害作用的方法,该方法包括给所说的动物使用有效量的如上文所定义的式(I)的化合物或其可药用的盐、溶剂化物或前体药物。
本发明还提供了一种式(I)的化合物或其可药用的盐、溶剂化物或其前体药物,优选的以药物组合物的形式存在,当以分割剂量给药(也被称为分解给药)时,产生的抗肿瘤作用比单剂量给药时产生的效果更大。
本发明治疗方法的抗肿瘤作用非限制性的包括对肿瘤生长的抑制、肿瘤生长延迟、肿瘤的消退、肿瘤的减少、肿瘤重新生长的时间增加、延缓疾病进程。期望当本发明的治疗方法被用于需要进行癌症治疗包括实体瘤治疗的恒温动物如人类时,所说的治疗方法将会产生一种效果,该效果可用一种或多种如下的指标来测定:抗肿瘤作用的范围、响应率、疾病进展时间和存活率。
本发明的另一方面提供了一种在恒温动物如人体内产生血管损害作用的方法,该方法包括给所说的动物以分割剂量服用有效量的式(I)的化合物或其可药用的盐、溶剂化物或其前体药物,优选的以药物组合物的形式应用。
本发明的另一方面提供了一种治疗恒温动物包括人的癌症包括实体瘤的方法,该方法包括给所说的动物以分割剂量服用有效量的式(I)的化合物或其可药用的盐、溶剂化物或其前体药物,优选的以药物组合物的形式应用。
本发明的另一方面提供了一种包含两部分或更多部分剂量的式(I)的化合物或其可药用的盐、溶剂化物或其前体药物的药物,优选药物组合物的形式,这些剂量一起组成总的日剂量,以分割剂量给药用于人或动物体的治疗方法中所进行的治疗。
本发明的另一方面提供了一种包含两部分或更多部分剂量的式(I)的化合物或其可药用的盐、溶剂化物或其前体药物的试剂盒,优选药物组合物的形式,这些剂量一起组成总的日剂量,以分割剂量的形式给药。
本发明还提供了一种试剂盒,该试剂盒包括:
a)两部分或更多部分剂量的式(I)的化合物或其可药用的盐、溶剂化物或其前体药物,这些剂量一起组成总的日剂量,以单位剂型用分割剂量给药;和
b)用于容纳所说剂型的包装器具。
本发明还提供了一种试剂盒,该试剂盒包括:
a)两部分或更多部分剂量的式(I)的化合物或其可药用的盐、溶剂化物或其前体药物,这些剂量一起组成总的日剂量,与可药用的赋性剂或载体结合,以单位剂型的形式存在;和
b)用于容纳所说剂型的包装器具。
本发明还提供了一种式(I)的化合物或其可药用的盐、溶剂化物或其前体药物在制造以分割剂量服用以便于在恒温动物如人体内产生血管损害作用的药物中的应用。
本发明还提供了一种式(I)的化合物或其可药用的盐、溶剂化物或其前体药物在制造以分割剂量服用以便于在恒温动物如人体内产生抗癌作用的药物中的应用。
本发明还提供了一种式(I)的化合物或其可药用的盐、溶剂化物或其前体药物在制造以分割剂量服用以便于在恒温动物如人体内产生抗肿瘤作用的药物中的应用。
分割剂量,也被称为分解剂量,指的是被给予恒温动物如人类的总剂量,在任何一天周期内(例如从午夜到午夜的一个24小时的周期内)被分成总剂量的两个或更多个部分,并且这些部分以一定的间期被给药,各部分间的给药间隔在高于0小时至约10小时之间,优选约1小时至约6小时,更优选约2小时至约4小时。总剂量的各部分可以大约相等或不相等。
优选的总剂量被分成可以大约相等或不相等的两部分。
在各剂量间的时间间隔可以选自例如:约1小时、约1.5小时、约2小时约2.5小时、约3小时、约3.5小时、约4小时、约4.5小时、约5小时、约5.5小时和约6小时。
各剂量间的时间间隔可以是0分钟到600分钟间的任何数字(包括非整数),优选45至375分钟之间所包括的间隔。如果多于两个剂量被给药,则各剂量间的时间间隔可以是大约相等或不等。
优选地,两个剂量是以多于或等于1小时并少于6小时之间的间隔被给药的。
更优选地,两个剂量是以多于或等于1小时并少于5小时之间的间隔被给药的。
还是更优选地,两个剂量是以多于或等于1小时并少于4小时之间的间隔被给药的。
该总剂量尤其被分成大约相等或不等的两部分,以高于或等于约2小时并少于约4小时间的时间间隔给药。
该总剂量更特别的被分成大约相等的两部分,以高于或等于约2小时并少于约4小时间的时间间隔给药。
为了避免对于说明书中的时间周期中的“约”的定义的疑惑,在所加的时间上加或减去15分钟,因此,如约1小时指的是45至75分钟,约1.5小时指的是75至105分钟。其它各处的“约”具有其通常的词典含义。
上文所定义的抗血管生成的治疗的可以指单独治疗或除本发明的化合物外,还可以包含一种或多种其它的物质和/或治疗。这种联合治疗可以通过将用于治疗的各组分同时、相继或分别给药来获得。在医学肿瘤学的领域中,实际上通常结合不同形式的治疗来对每个患有癌症的病人进行治疗。在医学肿瘤学中,除了上文所定义的抗肿瘤治疗药物外,其它的用于联合治疗的组成可以是:手术、放疗或化疗。这种化疗可用下列种类的治疗剂:
(i)通过与前文所定义的机理不同的机理起作用的其它的抗血管生成剂(例如linomide、整合素αvβ3功能抑制剂、血管紧张素、endostatin、razoxin、沙利度胺)并且包括血管内皮生长因子(VEGF)受体酪氨酸激酶抑制剂(RTKIs)(例如在国际专利申请WO 97/22596、WO 97/30035、WO 97/32856和WO 98/13354中所述的这些物质,在这里将全部公开文献引入作为参考);
(ii)细胞抑制剂如抗雌激素(例如他昔莫芬、托瑞米芬、雷洛昔芬、屈洛昔芬、艾多昔芬)、孕激素(例如醋酸甲地孕酮)、芳香酶抑制剂(例如anastrozole、来曲唑、vorazole、依西美坦)、抗孕激素、抗雄激素(例如氟他胺、尼鲁米特、比卡鲁胺、醋酸环丙孕酮)、LHRH激动剂和拮抗剂(例如醋酸戈舍瑞林、luprolide)、睾酮5α-二氢还原酶抑制剂(例如非那雄胺)、抗侵袭素(例如金属蛋白酶抑制剂如marimastat和尿激酶纤溶酶原激活剂受体功能的抑制剂)和生长因子功能抑制剂(该类生长因子包括例如表皮生长因子(EGF)、得自生长因子的血小板和肝细胞生长因子,该类抑制剂包括生长因子抗体、生长因子受体抗体、酪氨酸激酶抑制剂和丝氨酸/苏氨酸激酶抑制剂);
(iii)生物响应改性剂(例如干扰素);
(iv)抗体(例如edrecolomab);和
(v)抗增生/抗肿瘤形成药物及其复合物,例如用于医学肿瘤学中的物质,如抗代谢物(例如叶酸拮抗剂如甲氨蝶呤、氟嘧啶如5-氟尿嘧啶、嘌呤和腺苷类似物、胞嘧啶阿拉伯糖苷);抗肿瘤抗生素(例如蒽环类抗生素如阿霉素、柔红霉素、表柔比星和伊达比星、丝裂霉素-C、更生霉素、光辉霉素);铂衍生物(例如顺铂、卡铂),烷化剂(例如氮芥、左旋溶肉瘤素、苯丁酸氮芥、白消安、环磷酰胺、异环磷酰胺、亚硝基脲、噻替哌);抗有丝分裂剂(例如长春花生物碱如长春新碱和紫杉素如紫杉酚、taxotere);酶(例如天冬酰胺酶);胸甘酸合成酶抑制剂(例如raltitrexed);拓扑异构酶抑制剂(例如表鬼臼毒素(epipodophyllotoxins)如依托泊苷和替尼泊苷、安吖啶、托泊替堪、伊立替康)。
在本发明中所定义的如上所述的化合物的好处在于其血管损害作用。期望本发明的该类化合物可用于预防和治疗很广泛的一系列发生了不恰当的血管生成的疾病,包括癌症、糖尿病、银屑病、类风湿性关节炎、卡波西肉瘤、血管瘤、急性和慢性肾病、动脉粥样化、动脉再狭窄、自身免疫性疾病、急性炎症、子宫内膜异位、子宫出血功能紊乱和带有视网膜脉管增生的眼病。特别期望本发明的该类化合物能有利的延缓初发的和复发的例如结肠、胸腺、前列腺、肺和皮肤的实体瘤的生长。
除用于医学治疗外,式(I)的化合物和它们可药用的盐、溶剂化物或前体药物还可以在评估血管损害剂对实验室动物如猫、狗、兔、猴、大鼠和小鼠的作用的体外和体内测试体系中被用作药理学工具,作为新的治疗剂研究的一部分。
应当明白,在本发明中任何地方的“醚”的定义指的是二乙基醚。
将用下面的非限制性实施例对本发明进行说明,在这些实施例中,除非特别说明:
(i)蒸发是在真空下用旋转蒸发进行的,并且检查操作是在通过过滤除去固体如干燥剂后进行的;
(ii)操作是在室温下进行的,即在18-25℃的范围内并在惰性气体如氩或氮的气氛下进行;
(iii)给出收率仅仅是用于解释并不需要是可获得的最大量;
(iv)式(I)的最终产物的结构是用核(一般的质子)磁共振(NMR)和质谱技术进行确定的;质磁共振化学位移值是δ比值,多重峰的表示如下:s,单峰;d,双重峰;t,三重峰;m,多重峰;br,宽峰;q,四重峰;quin,五重峰;
(v)一般不对中间体进行完全的表征,纯度是用薄层色谱(TLC)、高效液相色谱(HPLC)、红外(IR)或NMR分析来进行评定的;
缩写
4-二甲基氨基吡啶 DMAP
1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐 EDCI
二甲基亚砜 DMSO
三氟醋酸 TFA
实施1
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚
烯-5-基]-2-[2-氨基乙酰基氨基]乙酰胺
在室温下,将在二氯甲烷(6ml)中的N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]2-[2-(丁氧基羰基氨基)乙酰基氨基]乙酰胺(0.9g;0.64mmol)用TFA(6ml)处理0.5小时。在蒸发至干燥后,将残余物用固体碳酸氢钠中和至pH6.5并用反相硅胶进行纯化,用30-40%的甲醇/碳酸铵缓冲剂(2g/l,pH7)进行梯度洗脱。将适宜的部分蒸发至干燥,在醚中磨碎得到标题化合物。
收率:65%。
1H NMR(DMSO-d6):1.88-2.21(m,3H);2.58,被DMSO峰部分掩盖(m,1H);3.10(s,2H);3.46(s,3H);3.79(s,3H);3.82(s,3H);3.83(s,3H);3.84(s,3H);4.47-4.58(m,1H);6.77(s,1H);6.87(dd,1H);6.91(d,1H);7.25(d,1H);8.06(m,1H);8.41(d,1H)。
MS-ESI:444[MH]+
元素分析 实测值 C 59.14 H 6.44 N 9.08
C23H29N3O6,1.2 H2O 理论值 C 59.39 H 6.80 N 9.03
起始材料的制备如下:
在氩气气氛下,将(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基胺[Collect.Czech.Chem.Commun.1999,64(2),217-228](0.329g;1.36mmol)、EDCI(0.230g;1.2mmol);DMAP(0.025g,0.2mmol)和2[2-(三-丁氧基羰基氨基)乙酰基氨基]醋酸(0.189g;1.2mmol)在二氯甲烷中的溶液搅拌过夜。将所得的沉淀过滤并用醚进行洗涤,得到白色固态的N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]-2-[2(丁氧基羰基氨基)乙酰基氨基]乙酰胺。
收率:65%。
1H NMR(DMSO-d6):1.33(s,9H);1.94-2.24(m,3H);2.97-3.08(m,1H);3.35(s,3H);3.56(t,3H);3.71-3.77(m,1H);3.75(s,3H);3.78(s,3H);3.80(s,3H);4.48-4.59(m,1H);6.79(s,1H);6.87(dd,1H);6.93(d,1H);7.14(t,IH);7.25(d,IH);8.17(t,IH);8.21(d,1H)。
MS-ESI:544[MH]+
实施例2
4-氧代-4-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并
[a,c1环庚烯-5-基]氨基]丁基磷酸二钠
在氩气气氛下,将N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]-4-[二(三-丁氧基)磷酰基氧]丁酰胺(0.529g;0.892mmol)在(12N)HCl(5ml)和二噁烷(25ml)混合物中的溶液搅拌4小时。在将二噁烷蒸发后,用氢氧化钠溶液(2N)将pH调节到7.2,将残余物用HP20SS树脂进行纯化,用0-40%梯度的甲醇/水进行洗脱,在冷冻干燥后得到标题化合物。
收率:75%。
1H NMR(DMSO-d6):1.71-2.36(m,7H);2.58,被DMSO峰部分掩盖(m,1H);3.49(s,3H);3.78-3.85(m,11H);5.20(dd,1H);5.00(s,1H);6.77(s,1H);6.88(dd,1H);6.91(d,1H);6.26(d,1H)。
用与实施例1的方法相似的方法,通过将(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基胺与4-[二(三-丁氧基)磷酰基氧]丁酸进行反应来制备N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]-4-[二-(三-丁氧基)磷酰基氧]丁酰胺。
收率:89%。
1H NMR(DMSO-d6):1.40(s,18H);1.80(t,2H);1.82-1.94(m,1H);2.00-2.20(m,2H;2.23-2.33(m,2H);2.52-2.58(m,1H);3.48(s,3H);3.78(s,3H);3.80-3.85(m,8H);4.504.59(m,1H);6.78(s,1H);6.89(dd,1H);6.90(d,1H);7.26(d,1H);8.42(d,1H)。
实施例3
将(5S)-3,9,10,11-四甲氧基-6,7-二氢-SH-二苯并[a,c]环庚烯-5-基胺(0.263g;0.8mmol)、4-硝基苯酚氯甲酸盐(0.177g;0.88mmol)和三乙胺(0.123ml;0.88mmol)在二氯甲烷中的溶液在氩气气氛下搅拌1小时。向其中加入2-(咪唑-1-基)三乙胺(0.145ml;1.2mmol)。在搅拌2小时后,将该混合物蒸发至干燥,将残余物用反相硅胶进行纯化,用40-60%梯度的甲醇/碳酸铵缓冲剂(2g/l,pH7)进行洗脱,在蒸发并在醚中磨碎后得到标题化合物。
收率:52%。
1H NMR(DMSO-d6):1.66-1.77(m,1H);1.97-2.10(m,1H);2.13-2.25(m,1H);2.53,被DMSO峰部分掩盖(m,1H);3.12-3.32(m,2H);3.47(s,3H);3.77(s,3H);3.79(s,3H);3.83(s,1H);3.94(t,3H);4.32-4.42(m,1H);5.97(t,1H) ;6.63(d,1H);6.77(s,1H);6.83-6.92(m,3H);7.11(s,1H);7.24(d,1H);7.54(s,1H)。
MS-ESI:481[MH]+
元素分析 实测值C 64.68 H 6.89 N 11.55
C26H32N4O5 理论值C 64.98 H 6.71 N 11.66
实施例4
将2-[二-(苄氧基)磷酰基氧]乙基N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸酯(0.576g;0.85mmol)在甲醇(10ml)和乙酸乙酯(5ml)中的溶液在存在10%C/Pt(0.165mg)的条件下氢化4小时。在硅藻土上过滤并进行蒸发,将残余物在HP2O SS树脂上进行纯化,用0-80%梯度的甲醇/蒸馏水进行洗脱。在蒸发掉甲醇后,将相应部分用含水氢氧化
收率:83%。钠(2N)将pH调节到8。在冷冻干燥后得到白色固态的标题化合物。
1H NMR(DMSO-d6+TFA-d):1.85-1.97(m,1H);1.98-2.09(m,1H);2.13-2.27(m,1H);2.42-2.52(m,IH);3.48(s,3H);3.79(s,3H);3.80(s,3H);3.84(s,3H);3.98(m,2H);4.03-4.18(m,2H);4.04-4.17(m,2H);4.24-4.35(m,1H);6.77(s,1H);6.89(dd,1H);6.96(d,1H);7.27(d,1H)
MS-ESI:498[MH]+
起始材料的制备如下:
将4-硝基苯基氯甲酸盐(1.01g;5.04mmol)在0℃,氩气气氛下加入到2-[二(苄氧基)磷酰基氧]乙醇(1.62g;5.09mmol)和三乙胺(0.7ml;5mmol)在二氯甲烷(20ml)中的溶液中。在室温下将该混合物搅拌30分钟,蒸发,用闪柱色谱进行纯化,用石油醚/乙酸乙酯(40/60)洗脱,得到2-[二(苄氧基)磷酰基氧]乙基4-硝基苯基碳酸酯。
收率:45%
1HNMR(CDC13):4.21-4.30(m,2H);4.41(m,2H);5.01-5.15(m,4H);7.29-7.42(m,12H);8.25(d,2H)。
将(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基胺(0.329;1mmol)和2-[二-(苄氧基)磷酰基氧]乙基4-硝基苯基碳酸盐(0.633g;1.3mmol)在乙腈(8ml)中的溶液在65℃,氩气气氛下加热8小时。在蒸发至干燥后,将残余物用闪柱色谱法进行纯化,用50-80%梯度的乙酸乙酯/石油醚进行洗脱得到2-[二(苄氧基)磷酰基氧]乙基N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H二苯并[a,c]环庚烯-5-基]氨基甲酸酯。
收率:85%
1H NMR(DMSO-d6):1.81-1.93(m,1H);1.94-2.06(m,1H);2.06-2.20(m,1H);2.40-2.52(m,1H);3.43(s,3H);3.73(s,3H);3.77(s,3H);3.82(s,3H);4.11(m,4H);4.20-4.33(m,4H);5.02(d,4H);6.76(s,1H);6.86-dd,1H);6.93(d,1H);7.25(d,1H).7.35(s,10H);7.99(d,1H).
实施例5
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚
烯-5-基]氨基甲酸2-吗啉代乙基酯
将(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基胺[Collect.Czech.Chem.Commun.1999,64(2)217-228](0.263g;0.8mmol)、4-硝基苯基氯甲酸盐(0.177g;0.88mmol)和三乙胺(0.123ml;0.88mmol)在乙腈(5ml)中的溶液在室温下,在氩气气氛下搅拌2小时;然后将4-(2-羟基乙基)吗啉(0.145ml;1.2mmol)加入到上述溶液中。将该混合物加热到60℃,过夜。在蒸发至干燥后,将残余物用闪柱色谱法进行纯化,用乙醇/二氯甲烷(4/96)进行洗脱得到标题化合物。
收率:64%
1H NMR波谱(DMSO-d6+AcO-d4):1.82-2.31(m,3H);2.44(m,4H);2.49(m,2H);2.57 partially obscured by DMSO peak(m,1H);3.47(s,3H);3.56(m,4H);3.78(s,3H);3.79(s,3H);3.83(s,3H);4.03(m,2H);4.17-4.33(m,1H);6.76(s,1H);6.88(dd,1H);6.93(d,1H);7.26(d,1H);7.86(d,1H)。
MS-ESI:487[MH]+
元素分析: 实测值C 63.38 H 7.04 N 5.74
C26H34N2O7,0.3H2O 理论值C 63.48 H 7.09 N 5.69
实施例6
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚
烯-5-基]氨基甲酸3-(1-甲基哌嗪-4-基)丙基酯
用与实施例5所描述的方法相似的方法,将(5S)-3,9,10,11-四甲氧基-6,7二氢-5H-二苯并[a,c]环庚烯-5-基胺与4-(3-羟基丙基)-1-甲基哌嗪反应得到标题化合物。
收率:40%。
1H NMR(DMSO-d6):1.62-2.44(m,20H);2.54被DMSO峰部分掩盖(m,1H);3.46(s,3H);3.77(s,3H);3.78(s,3H);3.82(s,3H);6.78(s,1H);6.89(dd,1H);6.93(d,1H);7.27(d,1H);7.80(d,1H).
MS-ESI:514[MH]+
元素分析: 实测值C 65.42 H 7.54 N 8.18
C28H39N3O6 理论值C 65.48 H 7.65 N 8.18
实施例7
N-[(5S)-3,9,10,11-四甲氧基-6-7-二氢-5H-二苯并[a,c]环庚
烯-5-基]氨基甲酸2-(1-乙酰基哌嗪-4-基)乙基酯
将2-(哌嗪-4-基)乙基-N-[(5S)-3,9,10,11-四甲氧基-6-7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸酯(0.255g;0.525mmol)、乙酰氯(0.038ml;0.53mmol和三乙胺(0.073ml;0.525mmol)在二氯甲烷(10ml)中的溶液在室温下,在氩气气氛下搅拌2小时。在蒸发至干燥后,将残余物用闪柱色谱法进行纯化,用二氯甲烷/乙醇(93/7)进行洗脱得到标题化合物。
收率:90%
1H NMR(DMSO-d6):1.81-2.32(m,3H);1.97(s,3H);2.33(m,2H);2.40(m,2H);2.47pa rtially obscured by DMSO peak(m,2H);2.58被DMSO峰部分掩盖(m,1H);3.38(m,4H);3.46(s,3H);3.77(m,3H);3.80(s,3H);3.82(s,3H);3.92-4.10(m,2H);4.20-4.30(m,1H);6.77(s,1H);6.88(dd,1H);6.92(d,1H);7.25(d,1H);7.87(d,1H)。
MS-ESI:528[MH]+
元素分析: 实测值C 63.21 H 7.30 N 7.86
C28H37N3O7 理论值C 63.52 H 7.08 N 7.94
将
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸2-(1-三-丁氧基羰基哌嗪-4-基)乙基酯用与实施例1所述的方法相似的方法进行制备,但是使用2-[1-(三-丁氧基羰基)哌嗪-4-基]乙醇。
收率:75%
1h NMR(DMSO-d6):1.78-1.94(m,1H);1.95-2.07(m,1H);2.10-2.23(m,1H);2.30(m,4H);2.38-2.53(m,3H);2.65(t,2H);3.46(s,3H);3.77(s,3H);3.78(s,3H);3.82(s,3H);3.99(t,2H);4.20-4.32(m,1H);6.77(s,1H);6.88(dd,1H);6.92(d,1H);7.25(d,1H);7.86(d,1H)。
将在二氯甲烷(10ml)中的N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢5H-二苯并[a,c]环庚烯-5-基]氨基甲酸2-(-1-三-T氧基羰基哌嗪-4-基)乙基酯(0.617g;1.05mmo l)用TFA(5ml)在室温下处理1小时。在蒸发至干燥后,将残余物用氢氧化钠溶液中和至pH为8,用反相硅胶进行纯化,用30-40%甲醇/碳酸铵缓冲剂(2g/l,pH7)梯度洗脱,得到N-[(5S)-3,9,10,11-四甲氧基-6-7二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸2-(哌嗪-4-基)乙基酯。
收率:60%
1H NMR(DMSO-d6):1.39(s,9H);1.81-1.94(m,1H) ;1.95-2.07(m,1H);2.09-2.27(m,1H);2.34(m,4H);2.52-2.64(m,1H);3.28(m,2H);3.36(s,3H);3.46(s,3H);3.77(s,3H);3.82(s,3H);3.94-4.09(m,2H);4.20-4.30(m,1H);6.77(s,1H);6.87(dd,1H);6.92(d,1H);7.25(d,1H) ;7.86(d,1H)。
实施例8
N-[(5S)-3,9,10,11-四甲氧基-6-7-二氢-5H-二苯并[a,c]环庚
烯-5-基]-4-(1甲基哌嗪-4-基)-4-氧代丁-1-酰胺
将4-(1-甲基哌嗪-4-基)-4-氧代丁酸(0.356g;1.78mmol)、EDCI(0.367g;1.78mmol)和DMAP(0.05g;0.41mmol)在二氯甲烷(30ml)中的溶液在氩气气氛下搅拌35分钟。然后将(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基胺(0.45g;1.37mmol)加入到其中,将该混合物在室温下搅拌过夜。在将溶剂蒸发后,将残余物用闪柱色谱法进行纯化,用二氯甲烷/乙醇(95/5)洗脱,在蒸发并在戊烷中磨碎后,得到白色固态的标题化合物。
收率:60%
1H NMR(DMSO-d6):1.85-1.96(m,1H);2.01-2.15(m,1H);2.16(s,3H);2.22(t,2H);2.26(t,2H);2.33-2.42(m,1H);2.47-2.53(m,1H);3.35-3.46(m,4H);3.46(s,3H);3.79(s,3H);3.82(s,3H);3.84(s,3H);4.44-4.56(m,1H).6.79(s,1H);6.86(dd,1H);6.98(d,1H);7.25(d,1H);8.40(d,1H)。
MS-ESI:512[MH]+
元素分析: 实测值C 65.51 H 7.40 N 8.19
C28H37N3O6 理论值C 65.73 H 7.29 N 8.21
实施例9
将(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基胺(0.329g;1mmol)和3-(-4-乙酰基哌嗪子基)丙基4-硝基苯基碳酸盐(0.456g;1.3mmol)在乙腈(8ml)中的溶液在70℃下,在氩气气氛下加热6小时。在蒸发至干燥后,将残余物用闪柱色谱法进行纯化,用二氯甲烷/乙醇(93/7)洗脱得到标题化合物。
收率:80%
1H NMR(DMSO-d6):1.62-2.51(m,12H);1.97(s,3H);3.32-3.44(m,4H);3.46(s,3H);3.77(s,3H);3.78(s,3H);3.82(s,3H);3.87-4.01(m,2H);4.19-4.31(m,1H);6.77(s,1H);6.88(dd,1H);6.92(d,1H);7.25(d,1H);7.80(d,1H)。
MS-ESI:542[MH]+
元素分析: 实测值C 63.48 H 7.25 N 7.72
C29H39N3O7,0.4H2O 理论值C 63.46 H 7.31 N 7.66
在0℃氩气气氛下将4-硝基苯基氯甲酸盐(0.733g;3.63mmol)加入到3-(4-乙酰基哌嗪-1-基)丙醇[Synthesis(1997),6,643-648](0.645g;3.46mmol)和三乙胺(0.51ml;3.36mmol)在二氯甲烷(7ml)中的溶液中。在室温下将该混合物搅拌1小时,蒸发至干燥,用闪柱色谱法进行纯化,用二氯甲烷/乙醇(95/5)洗脱得到3(-4-乙酰基哌嗪子基)丙基4-硝基苯基碳酸酯.
1H NMR(CDCl3):1.96(m,2H);2.09(s,3H);2.39-2.48(m,4H);2.51(t,2H);3.47(t,3H);3.63(t,2H);3.68-3.78(m,2H);4.38(t,2H);7.39(d,2H);8.29(d,2H).
实施例10
N-1[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a-c]环
庚烯-5-基]氨基甲酸4-吗啉代-4-氧代丁基酯
用与实施例9的方法相似的方法制备该化合物,但是用4-吗啉代-4-氧代丁基4-硝基苯基碳酸酯替代3-(4-乙酰基哌嗪子基)丙基4-硝基苯基碳酸盐。
收率:55%。
1H NMR(DMSO-d6):1.71-1.81(m,2H);1.82-1.94(m,1H);1.95-2.07(s,1H);2.11-2.24(s,1H);2.34(t,2H);2.46(m,1H);3.31-3.44(m,4H);3.45(s,3H);3.52(m,4H);3.77(s,3H);3.78(s,3H);3.82(s,3H);3.86-3.98(m,2H);4.20-4.32(m,1H);6.77(s,1H);6.88(dd,1H);6.92(d,1H);7.25(d,1H);7.80(d,1H)。
MS-ESI:529[MH]+
元素分析 实测值C 62.81 H 6.95 N 5.27
C28H36N2O8,0.3H20 理论值C 62.98 H 6.91 N 5.25
用与实施例9的方法相似的方法来制备起始材料,从4-吗啉代-4-氧代丁基4-硝基苯基碳酸酯开始。
收率:92%
1H NMR(CDCl3):2.15(m,2H);2.50(t,2H);3.46-3.53(m,2H);3.51-3.75(m,6H);3.38(t,2H);7.33(d,2H);8.29(d,2H).
实施例11
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H二苯并[a,c]环庚烯
-5-基]氨基甲酸4-(1-甲基哌嗪-4-基)-4氧代丁基酯
标题化合物是用与实施例9的方法相类似的方法来进行制备的,但是用4-甲基哌嗪-1-基)-4-氧代丁基4-硝基苯基碳酸酯替换3-(4-乙酰基哌嗪子基)丙基4-硝基苯基碳酸盐。
收率:65%
1H NMR(DMSO-d6):1.75(m,2H);1.81-2.07(m,2H);2.08-2.40(m,7H);2.15(s,3H);2.50-2.60(m,1H);3.22-3.56(m,4H);3.45(s,3H);3.77(s,3H);3.78(s,3H);3.82(s,3H);3.82-3.99(m,2H);4.12-4.32(m,1H);6.76(s,1H);6.87(dd,1H);6.92(d,1H);7.25(d,1H);7.80(d,1H)。
MS-ESI:542[MH]+
元素分析 实测值C 63.38 H 7.58 N 7.64
C29H39N3O7,0.4H2O 理论值C 63.46 H 7.31 N 7.66
起始材料是用与实施例9的方法相似的方法进行制备的,从4-(4-甲基哌嗪-1-基)-4-氧代丁醇开始。
收率:65%。
1H NMR(CDCl3):2.08-2.19(m,2H);2.32(s,3H);2.35-2.46(m,4H);2.49(t,2H);3.51(t,2H);2.66(t,2H);4.38(t,2H);7.39(d,2H);8.29(d,2H)。
Claims (17)
1.一种下式(I)的化合物或其可药用的盐、溶剂化物或前体药物:
其中:
R1、R2和R3分别独立地是羟基、磷酰氧基(-OPO3H2)、C1-4烷氧基或在体内可水解的羟基的酯,附带条件是R1、R2和R3中至少有两个是C1-4烷氧基;
A是-CO-、-C(O)O-、-CON(R8)-、-SO2-或-SO2N(R8)-其中R8是氢、C1-4烷基、C1-3烷氧基C1-3烷基、氨基C1-3烷基或羟基C1-3烷基;
a是整数1-4;
Ra和Rb分别选自氢、羟基和氨基;
B是-O-、-CO-、-N(R9)CO-、-CON(R9)-、-C(O)O-、-N(R9)-、-N(R9)C(O)O-、-N(R9)CON(R10)-、-N(R9)SO2-、-SO2N(R9)-或一个单键,其中R9和R10分别选自氢、C1-4烷基、C1-3烷氧基C1-3烷基、氨基C1-3烷基和羟基C1-3烷基;
b是0或整数1-4,条件是如果当b是0时,则B是一个单键;
D是羧基、磺基、四唑基、咪唑基、磷酰氧基、羟基、氨基、
N-(C1-4烷基)氨基、
N,
N-二(C1-3烷基)氨基或式-Y1-(CH2)cR11或-NHCH(R12)COOH;其中:Y1是一个单键、-O-、-C(O)-、-N(R13)-、-N(R13)C(O)-或-C(O)N(R13)-,其中R13是氢、C1-3烷基、C1-3烷氧基C2-3烷基、氨基C2-3烷基或羟基C2-3烷基;c是0或整数1-4;R11是一个环中含有1或2个选自O、S和N杂原子的通过碳或氮连接的5-6员饱和杂环基,或是一个不饱和或部分不饱和的含有1或2个选自O、S和N杂原子的经由碳或氮连接的5-6员杂芳基,该杂环基或杂芳基可以带有1或2个取代基,该取代基选自:
氧代、羟基、卤代、C1-4烷基、C2-4烷氧基、氨基甲酰基、
N-(C1-4烷基)氨基甲酰基、
N,
N-二(C1-4烷基)氨基甲酰基、羟基C1-4烷基、C1-4烷氧基、氰基C1-3烷基、氨基甲酰基C1-3烷基、羧基C1-4烷基、氨基C1-4烷基、
N-C1-4烷基氨基C1-4烷基、
N,
N-二(C1-4烷基)氨基C1-4烷基、C1-4烷氧基C1-4烷基、C1-4烷基磺酰基C1-4烷基和R14,其中R14是一个经由碳或氮连接的含有1或2个选自O、S和N杂原子的5-6员的饱和杂环基,该杂环基可任选被1或2个选自下述的取代基所取代:氧代、羟基、卤代、C1-4烷基、羟基C1-4烷基、C1-4烷氧基、C1-4烷氧基 C1-4烷基和C1-4烷基磺酰基C1-4烷基;
R12是一个氨基酸侧链;
R5是C1-4烷氧基;
R4和R6分别独立地选自:氢、氟、硝基、氨基、N-C1-4烷基氨基、N,N-二(C1-4烷基)氨基、羟基、C1-4烷氧基和C1-4烷基;
R7是氢、C1-4烷基、C1-3烷氧基C1-3烷基,氨基C1-3烷基或羟基C1-3烷基。
2.权利要求1的化合物或其可药用的盐、溶剂化物或前体药物,其中所说的R1、R2和R3都是甲氧基。
3.权利要求1的化合物或其可药用的盐、溶剂化物或前体药物,其中:
R1、R2、和R3都是C1-4烷氧基;
R4和R6分别选自氢、羟基、C1-3烷氧基、和C1-3烷基;
R5是甲氧基;
A是-CO-、-C(O)O-或-CONH-;
a是1、2或3;
B是-CO-、-NHCO-、-CONH-、-C(O)O-、-NH-、-NHC(O)O-、NHCONH-或一个单键;
b是0、1或2;
D是羧基、磺基、磷酰氧基、羟基、氨基、
N-C1-4烷基氨基、
N,
N-二(C1-4烷基)氨基或-Y1(CH2)cR11,其中:Y1是-NHC(O)-或-C(O)NH-;c是1或2;R11是经由氮原子连接的含有1或2个选自O和N杂原子的5-6-员饱和杂环基,该杂环基可以带有1或2取代基,该取代基选自:C1-4烷基、C2-4烷酰基、氨基甲酰基、氰基C1-3烷基、羟基C1-3烷基、羧基C1-3烷基和氨基C1-3烷基;和;
R7是氢。
4.权利要求1的化合物或其可药用的盐、溶剂化物或前体药物,其中:
R1、R2、和R3都是甲氧基;
R4和R6分别选自氢、羟基、甲氧基和甲基;
R5是甲氧基;
A是-CO-、-C(O)O-或-CONH-;
a是2或3;
B是-CO-、-NHCO-、-CONH-或一个单键;
b是0或1;
D是羧基、磷酰氧基、羟基、氨基、
N-C1-4烷基氨基、
N,
N-二(C1-4烷基)氨基或式-Y1(CH2)cR11,其中:Y1是-NHC(O)-或-C(O)NH-,c是1或2,R11是哌嗪基、吗啉基或哌啶基,它们都是通过环氮原子连接的,并且它们都可以任选地被1或2个取代基,该取代基选自:
C1-4烷基、C2-4烷氧基、氨基甲酰基、氰基C1-3烷基、羟基C1-3烷基、羧基C1-3烷基和氨基C1-3烷基;和
R7是氢。
6.权利要求5所述的化合物或其可药用的盐、溶剂化物或前体药物,其中:
A是-CO-、-C(O)O-或-CONH-;
a是2或3;
B是-CO-、-NHCO-、-CONH或一个单键;
b是0或1;
D是羧基、磷酰基氧、羟基、氨基、
N-C1-4烷基氨基、
N,
N-二(C1-4烷基)氨基或式-Y1(CH2)cR11,其中:Y1是-NHC(O)-或-C(O)NH-;c是1或2;R11是哌嗪基、吗啉基或哌啶基,它们都是通过环氮原子连接的并且它们可任选地被1或2各取代基所取代,该取代基选自:
C1-4烷基、C2-4烷酰基、氨基甲酰基、氰基C1-3烷基、羟基C1-3烷基、羧基C1-3烷基和氨基C1-3烷基。
7.一种式(III)的化合物或其可药用的盐、溶剂化物或前体药物。:
其中:
R1、R2和R3分别独立地是羟基、磷酰氧基(-OPO3H2)、C1-4烷氧基或在体内可水解的羟基的酯,附带条件是R1、R2和R3中的至少两个是C1-4烷氧基;
A是-CO-、-C(O)O-、-CON(R8)-、-SO2-或-SO2N(R8)-,其中R8是氢、C1-4烷基、C1-3烷氧基C2-3烷基、氨基C2-3烷基或羟基C2-3烷基;
a是整数1-4;
Ra和Rb分别选自氢、羟基和氨基;
B是-O-、-CO-、-N(R9)CO-、-CON(R9)-、-C(O)O-、-N(R9)-、-N(R9)C(O)O-、-N(R9)CON(R10)-、-N(R9)SO2-、-SO2N(R9)-或一个单键,其中R9和R10分别选自氢、C1-4烷基、C1-3烷氧基C2-3烷基、氨基C2-3烷基和羟基C2-3烷基;
b是0或整数1-4;
D是一个经由碳或氮连接的含有1或2个选自O和N杂原子的5-6-员饱和杂环基,该杂环基可以带有1或2个取代基,该取代基选自:
氧代、羟基、卤代、C1-4烷基、C2-4烷酰基、氨基甲酰基、
N-(C1-4烷基)氨基甲酰基、
N,
N-二(C1-4烷基)氨基甲酰基、羟基C1-4烷基、C1-4烷氧基、氰基C1-3烷基、氨基甲酰基C1-3烷基、羧基C1-4烷基、氨基C1-4烷基、
N-C1-4烷基氨基C1-4烷基、
N,
N-二(C1-4烷基)氨基C1-4烷基、C1- 4烷氧基C1-4烷基、C1-4烷基磺酰基C1-4烷基和R14,其中R14是一个经由碳或氮连接的含有1或2个选自O和N杂原子的5-6-员饱和杂环基,该杂环基可以任选地的被1或2个取代基所取代,该取代基选自:
氧代、羟基、卤代、C1-4烷基、羟基C1-4烷基、C1-4烷氧基、C1-4烷氧基C1-4烷基和C1-4烷基磺酰基C1-4烷基;
R5是C1-4烷氧基;
R4和R6分别选自:
氢、卤代、硝基、氨基、N-C1-4烷基氨基、N,N-二(C1-4烷基)氨基、羟基、C1-4烷氧基和C1-4烷基;
R7是氢、C1-4烷基、C1-3烷氧基C1-3烷基、氨基C1-3烷基或羟基C1-3烷基。
8.权利要求7所述的化合物或其可药用的盐、溶剂化物或前体药物,其中:
R1、R2、和R3都是C1-4烷氧基;
R4和R6分别选自氢、羟基、C1-3烷氧基、和C1-3烷基;
R5是甲氧基;
A是-CO-、-C(O)O-或-CONH-;
a是1、2或3;
B是-CO-、-NHCO-、-CONH、-C(O)O-、-NH-、-NHC(O)O-、NHCONH-或一个单键;
b是0、1或2;
D是哌嗪基或吗啉基或哌啶基,它们都可任选地被1或2个取代基所取代,其中所说的取代基选自C1-4烷基、C2-4烷酰基、氨基甲酰基、氰基C1-3烷基、羟基C1-3烷基、羧基C1-3烷基和氨基C1-3烷基;和
R7是氢。
9.权利要求7所述的化合物或其可药用的盐、溶剂化物或前体药物,其中:
R1、R2、和R3都是甲氧基;
R4和R6分别选自氢、羟基、甲氧基和甲基;
R5是甲氧基;
A是-CO-、-C(O)O-或-CONH-;
a是2或3;
B是-CO-、-NHCO-、-CONH或一个单键;
b是0或1;
D是哌嗪子基或吗啉代,它们可任选地被1或两个取代基所取代,该取代基选自甲基、乙基、乙酰基、丙酰基、氨基甲酰基和2-羟基乙基;和
R7是氢。
11.权利要求10所述的化合物或其可药用的盐、溶剂化物或前体药物,其中:
A是-CO-、-C(O)O-或-CONH-;
a是2或3;
B是-CO-、-NHCO-、-CONH或一个单键;
b是0或1;
D是哌嗪子基或吗啉代,它们可任选地被1或2个取代基所取代,该取代基选自甲基、乙基、乙酰基、丙酰基、氨基甲酰基和2-羟基乙基。
12.权利要求10所述的化合物或其可药用的盐、溶剂化物或其前体药物,其中:
A是-CO-、-C(O)O-或-CONH-;
a是2或3;
B是-CO-、-NHCO-、-CONH-或一个单键;
b是0或1;和
D是吗啉代、4-甲基哌嗪-1-基或4-乙酰基哌嗪-1-基。
13.一种化合物,选自:
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]-2-[2-氨基乙酰基氨基]乙酰胺;
4-氧代-4-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基]丁基磷酸二钠;
N-{N-[2-(咪唑-1-基)乙基]氨基甲酰基}-5(S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基胺;
2-{N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酰基氧}乙基磷酸二钠;
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸2-吗啉代乙基酯;
N-[(5S)-3,9,10,l1-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸3-(1-甲基哌嗪-4-基)丙基酯;
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]-2-[2-氨基乙酰基氨基]乙酰胺;
N-[(5S)-3,9,10,11-四甲氧基-6-7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸2-(1-乙酰基哌嗪-4-基)乙基酯;
N-[(5S)-3,9,10,11-四甲氧基-6-7-二氢-5H-二苯并[a,c]环庚烯-5-基]-4-(1-甲基哌嗪-4-基)-4-氧代丁-1-酰胺;
4-氧代-4-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基]丁基磷酸二钠;
N-{N-[2-(咪唑-1-基)乙基]氨基甲酰基}-5(S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基胺;
N-[(5S)-3,9,10,11-四甲氧基-6-7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸3-(1-乙酰基哌嗪-4-基)丙基酯;
N-1-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酰基氧]乙基磷酸二钠;
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a-c]环庚烯-5-基]氨基甲酸4-吗啉代-4-氧代丁基酯;和
N-[(5S)-3,9,10,11-四甲氧基-6,7-二氢-5H-二苯并[a,c]环庚烯-5-基]氨基甲酸4-(1-甲基哌嗪-4-基)-4-氧代丁基酯;
以及它们可药用的盐、溶剂化物或前体药物。
14.一种药物组合物,包含权利要求1至13中任一项所述的化合物或其可药用的盐、溶剂化物或前体药物以及可药用的载体。
15.权利要求1至13中任一项所述的化合物、其可药用的盐、溶剂化物或前体药物在制造用于温血动物产生血管损害作用的药物中的应用。
16.权利要求1至13中任一项所述的化合物或其可药用的盐、溶剂化物或其前体药物在制造以分次剂量给药用于温血动物产生血管损害作用的药物中的应用。
17.一种制备式(I)化合物或其中至少一个功能基被保护起来的式(I)化合物的方法,其中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、A、B、D、a、b和c的定义与权利要求1中的定义相同,该方法包括:
L1-A-[CH(Ra)]aB-[CHRb)]b-D (XI)
其中L1是离去基团;或者
b)将式(I)的一种化合物转化成另一种式(I)化合物;或
c)当想要磷酰氧基时,将相应的羟基化合物与磷酰胺酸盐反应;
其中任何一个功能基都可以选择性的被保护起来;
并且其后,必要时,可以:
i)将式(I)的化合物转化成另一种式(I)的化合物;
ii)除去任何的保护基团;
iii)形成其可药用的盐、溶剂化物或前体药物。
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JP2004504391A (ja) | 2004-02-12 |
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