CN1068574A - 腺苷三磷酸类似物的制备方法 - Google Patents
腺苷三磷酸类似物的制备方法 Download PDFInfo
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- CN1068574A CN1068574A CN92103371A CN92103371A CN1068574A CN 1068574 A CN1068574 A CN 1068574A CN 92103371 A CN92103371 A CN 92103371A CN 92103371 A CN92103371 A CN 92103371A CN 1068574 A CN1068574 A CN 1068574A
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- Prior art keywords
- acid
- formula
- compound
- salt
- methylene
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- 238000002360 preparation method Methods 0.000 title claims description 12
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 title description 8
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 title description 6
- 239000000126 substance Substances 0.000 title description 3
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- 229950006790 adenosine phosphate Drugs 0.000 claims description 108
- -1 dichloro methylene-bis Chemical compound 0.000 claims description 82
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 claims description 78
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 claims description 78
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- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 claims description 41
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- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
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- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
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- 125000003118 aryl group Chemical group 0.000 claims description 6
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- 239000001257 hydrogen Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- DQKVIYVRNDHMJD-FRJWGUMJSA-N (2r,3r,4s,5r)-2-(6-amino-2-butylpurin-9-yl)-5-(dihydroxyphosphinothioyloxymethyl)oxolane-3,4-diol Chemical compound C12=NC(CCCC)=NC(N)=C2N=CN1[C@@H]1O[C@H](COP(O)(O)=S)[C@@H](O)[C@H]1O DQKVIYVRNDHMJD-FRJWGUMJSA-N 0.000 claims description 4
- JBYGYARYYCDJPI-FRJWGUMJSA-N [(2r,3s,4r,5r)-5-(6-amino-2-butylpurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate Chemical compound C12=NC(CCCC)=NC(N)=C2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O JBYGYARYYCDJPI-FRJWGUMJSA-N 0.000 claims description 4
- OPFHVWGHMALVKP-WOUKDFQISA-N [(2r,3s,4r,5r)-5-(6-amino-2-propoxypurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate Chemical compound C12=NC(OCCC)=NC(N)=C2N=CN1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O OPFHVWGHMALVKP-WOUKDFQISA-N 0.000 claims description 4
- YFUIPEVGXZHXKD-MCDZGGTQSA-N [C@@H]1([C@H](O)[C@H](O)[C@@H](COP(=O)(O)O)O1)N1C=NC=2C(N)=NC=NC12.C(C)(=O)NC1=C(C=CC=C1O)[As](O)(O)=O Chemical compound [C@@H]1([C@H](O)[C@H](O)[C@@H](COP(=O)(O)O)O1)N1C=NC=2C(N)=NC=NC12.C(C)(=O)NC1=C(C=CC=C1O)[As](O)(O)=O YFUIPEVGXZHXKD-MCDZGGTQSA-N 0.000 claims description 4
- ZBFHWDDFZXPORT-MCDZGGTQSA-N [C@@H]1([C@H](O)[C@H](O)[C@@H](COP(=O)(O)O)O1)N1C=NC=2C(N)=NC=NC12.[S] Chemical compound [C@@H]1([C@H](O)[C@H](O)[C@@H](COP(=O)(O)O)O1)N1C=NC=2C(N)=NC=NC12.[S] ZBFHWDDFZXPORT-MCDZGGTQSA-N 0.000 claims description 4
- 230000000903 blocking effect Effects 0.000 claims description 4
- XUYJLQHKOGNDPB-UHFFFAOYSA-N phosphonoacetic acid Chemical compound OC(=O)CP(O)(O)=O XUYJLQHKOGNDPB-UHFFFAOYSA-N 0.000 claims description 4
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- FXXRIUZMLRLFKP-UUOKFMHZSA-N [(2r,3s,4r,5r)-5-(6-amino-2-chloropurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O FXXRIUZMLRLFKP-UUOKFMHZSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 125000000524 functional group Chemical group 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- UKTNPISPGDSMFG-CRKDRTNXSA-N [(2R,3S,4R,5S)-5-amino-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate Chemical compound P(=O)(O)(O)OC[C@@H]1[C@H]([C@H]([C@@](O1)(N1C=NC=2C(N)=NC=NC12)N)O)O UKTNPISPGDSMFG-CRKDRTNXSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- NCEMUOYFYLEORV-UHFFFAOYSA-N difluoromethylphosphonic acid Chemical compound OP(O)(=O)C(F)F NCEMUOYFYLEORV-UHFFFAOYSA-N 0.000 claims description 2
- UWJJYHHHVWZFEP-UHFFFAOYSA-N pentane-1,1-diol Chemical compound CCCCC(O)O UWJJYHHHVWZFEP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- HKVNXLYENRQHAN-UUOKFMHZSA-N [(2r,3s,4r,5r)-5-(6-amino-2-iodopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl dihydrogen phosphate Chemical compound C1=NC=2C(N)=NC(I)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O HKVNXLYENRQHAN-UUOKFMHZSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 4
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
- C07F9/3821—Acyclic saturated acids which can have further substituents on alkyl substituted by B, Si, P or a metal
-
- C—CHEMISTRY; METALLURGY
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Abstract
本发明公开了用作药物的式Ⅰ化合物和其可药
用的盐(带有某些附带条件)。
Description
本发明涉及医药上有用的化合物及其制备方法。
腺苷三磷酸(ATP)对多种组织具有有效的药理作用,ATP以及其它胞外腺嘌呤核苷酸、腺苷二磷酸(ADP)和腺苷一磷酸(AMP)的活性是由P2-嘌呤受体传递的。然而,在某些组织,例如膀胱中ATP的效力通过在这些组织中存在的外核苷酸酶由于快速脱磷酸作用可降低到AMP和腺苷。
在新近的研究中,已经使用抗脱磷酸作用的ATP类似物作为生物探测剂以探查在多种组织中存在的P2-嘌呤受体。
Cusack等人(Br.J.Pharmacol.,1987,90,791-795)公开了2-甲硫基-5′-腺苷酸与亚甲基双膦酸的单酐,2-甲硫基-5′-腺苷酸与二氯亚甲基双膦酸的单酐和2-甲硫基-5′-腺苷酸与二氟亚甲基双膦酸的单酐对豚鼠结肠带和膀胱的活性。Stone和Cusack(Br.J.Pharmacol.,1989,97,631-635)公开了在探查大鼠海马中的P2-嘌呤受体中特别使用2-甲硫基-5′-腺苷酸与二氟亚甲基双膦酸的单酐。在“Physiological and Regulatory Functions of Adenosine and Adenine Nucleotides”(Ed.H.P.Baer and G.I.Drummond,Raven Press.New York,1979,P.33-43)中Maguire and Satchell公开了2-氯-5′-腺苷酸与亚甲基双膦酸的单酐对豚鼠结肠带的抑制作用。
Cusack和Hourani(Nucleosides &Nucleotides,1991,10(5),1019-1028)还报导了2-甲硫基-5′-腺苷酸与亚甲基双膦酸的单酐抑制ADP-α-S诱导的血小板聚集。
现在我们发现了一组显示药理活性的新的2-取代的ATP衍生物。
按照本发明的第一方面,提供式Ⅰ的化合物及其可药用的盐类,
式中Q表示CR1R2,
R表示O或CR3R4,
W表示O或CH2,
R1、R2、R3和R4各自独立地表示氢或卤素,
X表示S(O)nR5、C1-6烷基、C1-6烷氧基、C1-6酰氨基、CONR6R7、NR8R9、卤素、5-或6-节含S杂环、或任选地由C1-6烷基取代的苯基,
n表示0、1或2,
R5表示芳基或任选地由一个或多个选自羟基、C1-6烷氧基、卤素和芳基的取代基取代的C1-6烷基,
R6、R7、R8和R9各自独立地表示氢或C1-6烷基,
Y表示NH2或C1-6烷氧基,和
Z表示一个酸性基团,
此外,当R表示CR3R4时,而-Q-Z也可以表示羟基或-OP(O)(OH)2,
其条件是:
ⅰ)当R是O,W是O,X是Cl,Y是NH2和Z是-P(O)(CH)2时,而CR1R2不表示CH2;和
ⅱ)当R是O,W是O,X是SCH3,Y是NH2和Z是-P(O)(OH)2时,而CR1R2不表示(a)CH2,(b)CF2或(c)CCl2。
式Ⅰ的化合物可以互变的,对映的和非对映的形式存在,所有这些化合物都包括在本发明的范围之内。
按照本发明,另外还提供了一种制备式Ⅰ化合物及其盐类的方法,该方法包括:
a)通过将式Ⅱ化合物或其盐与式Ⅲ化合物或其盐反应,制备R表示O的式Ⅰ化合物或其盐,
式中W、X和Y如上所定义,而L1表示一个离去基团,
式中Z和Q如上所定义。
b)通过将式Ⅳ化合物或其盐与式Ⅴ化合物或其盐反应,制备R表示CR3R4的式Ⅰ化合物或其盐,
式中W、X、和Y如上所定义,而L2表示一个离去基团,
式中Z、Q、R3和R4如上所定义。
c)通过将其中-Q-Z为羟基的相应的式Ⅰ化合物与式Ⅵ化合物或其盐反应,制备R为CR3R4和-Q-Z为-OP(O)(OH)2的式Ⅰ化合物或其盐,
式中L3是一个离去基团。
d)从其中一个或多个官能团被保护的相应的被保护的式Ⅰ化合物中除去保护基团,和
在需要时或必要时将得到的式Ⅰ化合物或其另一种盐转化成一种其可药用的盐,或反之亦然。
在方法a)和c)中,L1和L3可以表示的离去基团包括胺类,例如二烷基胺类或饱和的或不饱和的环胺类;可提到的特殊离去基团包括吗啉基、咪唑基和三唑基。
在方法b)中,L2可以表示的离去基团包括烷基或芳基磺酰氧基,例如甲磺酰氧基、三氟甲磺酰氧基或对甲苯磺酰氧基;或三氟乙酰氧基。
在方法a)、b)和c)中,所用的溶剂较佳的是一种偶极非质子传递溶剂,例如吡啶、二甲基甲酰胺、乙腈、六甲基磷酰三胺、N,N′-二甲基丙烯脲或1-甲基-2-吡咯烷酮。该反应可以在-20至100℃,例如10至30℃温度下进行。
式Ⅱ至Ⅵ的化合物或是已知的,或可用现有技术中普通技术人员公知的方法或通过类似于实施例中给出的技术来制备。例如,其中L1表示吗啉基的式Ⅱ化合物可以通过在有缩合剂,如二环己基碳化二亚胺存在下,较佳是在有保护(Protic)溶剂或溶剂混合物,如t丁醇和水存在时用吗啉处理,由相应的5′-一磷酸盐来制备。
对于其中W为O的化合物,5′-一磷酸核苷和在制备式Ⅱ和Ⅳ化合物中所用的核苷分别或是已知的,或可以用已知技术,例如参见“Chemistry of Nucleosides and Nucleotides”Vol.2.Ed.Leroy B.Townsend,Plenum Press1991,由已知化合物来制备。
在上述方法中,对原料中存在的任何官能团,例如羟基或氨基,可能必须保护,从而方法d)可以包括除去一种或多种保护基团。
合适的保护基团和将其除去的方法,例如是在“Protective Groups in Organic Chemistry”(Theodora Greene,John Wiley and Sons Inc.,1981)中所描述的那些。羟基,例如可以被芳基甲基,如苯甲基、二苯甲基或三苯甲基,或作为四氢呋喃基衍生物所保护。合适的氨基保护基团包括芳基甲基,如苄基、(R,S)-α-苯乙基、二苯乙基或三苯乙基,和酰基,如乙酰基、三氯乙酰基或三氟乙酰基。可以使用的常规脱除保护的方法包括氢解、酸或碱水解、或光解。芳基甲基例如可以通过在有金属催化剂(如炭上钯)存在下氢解除去。四氢吡喃基可以在酸性条件下通过水解而分解。酰基可以通过用碱,如氢氧化钠或碳酸钾水解而除去,或一种基团,如三氯乙酰基可以通过用例如锌和乙酸还原来除去。
通过将游离酸或其一种盐,或游离碱或其一种盐或其衍生物与一种或多种适当的碱或酸的等同物反应可以形成式Ⅰ化合物的盐类。该反应可以在其中盐是不溶的溶剂或介质中或在其中盐是可溶的溶剂,例如乙醇、四氢呋喃或乙醚中进行,该溶剂可以在真空中或通过冷冻干燥除去。该反应也可以是一种复分解过程或该反应可以在离子交换树脂上进行。
式Ⅰ化合物的可药用盐类包括碱金属盐类,例如钠和钾的盐类;碱土金属盐类,例如钙和镁的盐类;第Ⅲ族元素的盐类,例如铝的盐类;和铵的盐类;含有合适的有机碱的盐类,例如含羟基胺的盐类;低级烷基胺类,例如甲胺或乙胺;含有取代的低级烷基胺类,例如羟基取代的烷基胺类;或含有单环氮杂环化合物,例如哌啶或吗啉;和含有氨基酸,例如含精氨酸、赖氨酸等的盐类,或其N-烷基衍生物;或含一种氨基糖,例如N-甲基-D-葡糖胺或葡糖胺。尽管例如在分离或纯化产品时其它盐类也是有用的,但较佳的是无毒的生理上可接受的盐类。
烷基包括直链、支链或环状、饱和或不饱和烷基。
芳基包括碳环和杂环基团两者。这些基团可以含有不同C-原子数目的环并可以是稠合的环结构。可以提及的特定碳环芳基是苯基和萘基。杂芳基包括氮、氧或硫杂环并可以含有一个或多个杂原子。仅含一个杂原子的杂环实例包括吡咯、呋喃、噻吩和吡啶。含有一个以上杂原子的基团包括吡唑、恶唑、噻唑、三唑、恶二唑、噻二唑等。
X、R1、R2、R3和R4可以表示的卤素包括F、Cl、Br和I。
当Q表示CR1R2时,我们优选R1和R2为相同的,我们特别优选其中R1和R2两者都表示Cl的化合物。
当R表示CR3R4时,我们优选R3和R4为相同的,我们特别优选其中R3和R4两者都表示氢或Cl的化合物。
我们优选其中Q表示CR1R2的式Ⅰ化合物。
我们优选其中R表示O的式Ⅰ化合物。
我们特别优选其中Q表示CR1R2而R表示O的式Ⅰ化合物。
我们优选其中W表示O的式Ⅰ化合物。
X可以表示的含S杂环包括含1或2个S原子的饱和的和不饱和的杂环两者。可以提及的特定杂环基团是噻吩基,特别是2-噻吩基。
我们优选其中X表示S(O)nR5的式Ⅰ化合物,特别是其中n表示O的那些化合物。我们优选其中R5表示C1-6烷基的式Ⅰ化合物,可以提及的特定烷基包括乙基、丁基和丙基,特别是正丙基。
我们优选其中Y表示NH2的化合物。
Z可以表示的酸性基团包括-P(O)(OH)2、-SO3H和-CO2H。
我们优选其中Z表示-P(O)(OH)2的式Ⅰ化合物。
式Ⅰ的化合物是有用的,因为它们在哺乳动物中显示出药理活性。特别是,它们显示出在防止血小板聚集方面的活性。
式Ⅰ化合物作为血小板聚集抑制剂的效力可以由其作为P2T受体拮抗物的能力而测出,参见实施例X。
这些化合物可以在涉及血小板聚集或解聚的任何条件下使用。从而这些化合物可以作为抗血栓形成剂并适用于治疗或预防不稳定心绞痛、血栓栓塞发作和末梢血管病。它们也适用于治疗或预防由血管成形术、血栓溶解、动脉内膜切除术、冠状动脉和血管移植外科手术、肾透析和心肺旁通引起的血栓形成并发症的后遗症。另外的适应症包括治疗或预防散布的血管内血凝固、深静脉血栓形成、惊厥前/惊厥、在外科或意外创伤后的组织补救、脉管炎、动脉炎、血小板增多(thrombocythaemia)、局部缺血以及偏头痛。
按照本发明的另一方面,从而我们提供如上所定义的式Ⅰ化合物作为药物,但不附带条件ⅰ)、ⅱ)(b)和ⅱ)(c)。
根据所用的特定式Ⅰ化合物,治疗的特定条件及其药力,连同其它因素,所服用的剂量将是很宽的。然而,通常总的日剂量为1g可能是合适的,该剂量可以分剂量每天6次服用。
这些化合物通常以医药组合物的形式服用。
从而,按照本发明的另一方面,提供一种混合可药用的辅剂、稀释剂或载体的医药组合物,该组合物较佳含有小于80%(重量/重量),更佳小于50%(重量/重量),例如0.1-20%如上所定义的式Ⅰ化合物或其可药用的盐,而没有附带条件ⅰ)、ⅱ)(b)和ⅱ)(c)。
可以使用的这些医药制剂的实例,以及合适的辅剂、稀释剂或载体如下所述:
对于静脉内注射或注入一纯化水或盐水溶液;
对于吸入组合物-粗乳糖;
对于片剂、胶囊和糖衣丸一微晶纤维素、磷酸钙、硅藻土、糖,如乳糖、右旋糖或甘露糖醇、滑石、硬脂酸、淀粉、碳酸氢钠和/或明胶;
对于栓剂-天然或硬化油或石蜡。
当化合物以水溶液使用时,如对于注入,可能必须掺入其它赋形剂。特别是可提及螯合剂、抗氧化剂、张力调节剂、pH调节剂以及缓冲剂。
如果需要,可以将含有式Ⅰ化合物的溶液蒸发,例如通过冷冻干燥或喷雾干燥,以得到固体组合物,该溶液可以在使用前重新形成。
当不是以溶液形式时,式Ⅰ的化合物较佳的是以具有平均直径0.01-10μm的块状形式。这些组合物也可含有合适的保存、稳定和增湿剂、加溶剂,例如水溶性纤维素聚合物(如羟丙基甲基纤维素)或水溶性二元醇(如丙二醇)、香化剂和着色剂以及调味剂。在合适的场合,可以以持久释放的形式构成这些组合物。
按照本发明的又一方面,从而我们提供将式Ⅰ化合物或其可药用的盐用于制备治疗涉及血小板聚集或解聚状况的医药组合物。
按照本发明的另一方面,从而我们提供一种治疗涉及血小板聚集或解聚状况的方法,该方法包括给遭受该状况的病人服用治疗上有效量的如上所定义的式Ⅰ化合物,而没有附带条件ⅰ)、ⅱ)(b)和ⅱ)(c)。
本发明的化合物其优点在于,它们与上述治疗领域中以前所用的化合物相比毒性较小,更有效,作用时间更长,具有更广的作用范围,药力更强、更稳定、产生更少的付作用,更易于吸收、更易于从体内清除或具有其它有用的药理性能。
通过以下实施例来说明本发明,但决不是对其限制,其中给出的温度为摄氏度。使用化学文摘的术语命名这些实施例。
实施例1
2-丙硫基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,四钠盐ⅰ)2-丙硫基腺苷
将在水(15ml)、甲醇(45ml)和1N氢氧化钠溶液(8.36ml)中的腺苷-2-硫酮(2.5g)在冰浴上冷却并加入碘丙烷(5ml)。四天后,将反应混合物蒸发并将残余物色谱分离(SiO2,乙酸乙酯∶甲醇=9∶1),得到定量产率的小标题化合物。
NMR δ1H(d6DMSO)8.22(s,1H),7.36(brs,2H),5.80(d,1H,J=5.9Hz),5.61(t,1H,J=5.5Hz),5.13(m,1H),3.90(dd,1H,J=4.0和7.7Hz),3.64(dd,1H,J=4.2和11.8Hz),3.52(dd,1H,J=4.4和11.8Hz),3.0-3.2(m,2H),1.67(hextet,2H,J=7.3Hz),0.99(t,3H,J=7.3Hz)。
ⅱ)2-丙硫基-5′-腺苷酸
将步骤ⅰ)的产物(1.0g)在-10℃下加到搅拌的氯氧化磷(1.06ml)和磷酸三乙酯(25ml)的混合物中。3小时后,将反应混合物倒在冰上并用固体碳酸氢钠将PH调至7。用醚(3×150ml)洗涤该溶液,然后冷冻干燥。将得到的固体溶在去离子水中并施于Dowex 50WX8(H+形式)柱,用水洗涤该柱直至洗脱液为PH6,然后用1M氢氧化铵洗脱。冷冻干燥得到小标题化合物(0.4g)。
NMR δ31P(D2O)1.32(s)。
ⅲ)2-丙硫基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,四钠盐
将步骤ⅱ)的产物(0.4g)和三正丁胺(0.175g)在小体积水中混合,然后蒸发该溶液至干。用吡啶(3×15ml),随后用无水二甲基甲酰胺(2×15ml)共沸干燥得到残余物,将残余物溶解在无水二甲基甲酰胺(10ml)中。添加羰基二咪唑(0.77g)。使反应置于室温4小时,然后添加甲醇(0.24g)。30分钟后加入在无水二甲基甲酰胺(30ml)中的二溴亚甲基双膦酸单三正丁铵盐(6.5mmol),将该混合物在室温搅拌18小时。过滤并蒸发得到一种残余物,通过色谱法(DEAE-Sepharose,碳酸氢钠水溶液(0-0.4M)作为洗脱液)将其提纯。冷冻干燥得到铵盐,将其重新溶于水中(200ml)并用三乙胺(10ml)处理。在真空中蒸发得到四重三乙铵盐。将该盐溶解在甲醇(2ml)中并添加碘化钠溶液(丙酮中1M,30ml)使其转化成四钠形式。通过离心法收集沉淀并通过重新悬浮在丙酮中(4×40ml)来洗涤并再次离心。最后,将固体溶解在水中并冷冻干燥,得到白色粉末状的标题盐(0.42g)。
NMR δ31P(D2O)8.95(d,J=36Hz),1.35(dd,J=36和69Hz),-9.15(d,J=69Hz)。
实施例2
按照实施例1的方法制备如下化合物:
a)2-丙硫基-5′-腺苷酸与二氟亚甲基双膦酸的单酐,四钠盐
NMR δ31P(D2O)3.94(dt,J=145.8和196Hz),3.11至-4.92(m),-10.15(d,J=75Hz)。
b)2-丙硫基-5′-腺苷酸与二氯亚甲基双膦酸的单酐,四钠盐
NMR δ31P(D2O)9.4(d,J=46Hz),2.3(dd,J=46和73.1Hz),-9.15(d,J=73.1Hz)。
c)2-戊硫基-5′-腺苷酸与二氯亚甲基双膦酸的单酐,四钠盐
ⅰ)2-戊硫基腺苷
NMR δ1H(d6DMSO)8.22(s,1H),7.35(brs,1H),5.80(d,1H,J=5.9Hz),5.42(d,1H,J=6.16Hz),5.16(d,1H,J=4.86Hz),5.02(t,1H,J=5.6Hz),4.61(q,1H,J=5.76Hz),4.07-4.15(m,1H),3.85-3.95(m,1H),3.6-3.7(m,1H),3.48-3.6(m,1H),3.0-3.15(m,2H),1.6-1.7(m,2H),1.3-1.45(m,4H),0.88(t,3H,J=7.02Hz)。
ⅱ)2-戊硫基-5′-腺苷酸
NMR δ31P(D2O)1.2(s)
ⅲ)2-戊硫基-5′-腺苷酸与二氯亚甲基双膦酸的单酐,四钠盐
NMR δ31P(D2O)8.55(d,J=46.2Hz),2.5-3.5(m),-9.12(d,J=70.34Hz)。
d)2-戊硫基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,一铵盐
通过色谱法(DEAE-Sepharose,0-0.4M碳酸氢铵作为洗脱液)将粗产物提纯得到标题的盐。
NMR δ31P(D2O)7-8(brs),2.5-3.5(m),-9.07(d,J=83.5Hz)。
e)2-乙硫基-5′-腺苷酸与二氯亚甲基双膦酸的单酐,四钠盐
ⅰ)2-乙硫基-5′-腺苷酸,二钠盐
NMR δ31P(D2O)5.01(s)。
ⅱ)2-乙硫基-5′-腺苷酸与二氯亚甲基双膦酸的单酐,四钠盐
NMR δ31P(D2O)8.25(d,J=17.04Hz)3.28(dd,J=18.9和28.22Hz),-9.22(d,J=28.22Hz)。
f)2-乙硫基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,四钠盐
NMR δ31P(D2O)6.5-7.5(m),2.88(dd,J=14.75和27.33Hz),-10.9(d,J=28.22Hz)。
g)2-丁硫基-5′-腺苷酸与二氯亚甲基双膦酸的单酐,一铵盐
ⅰ)2-丁硫基-5′-腺苷酸
NMR δ31P(D2O)1.84(s)。
ⅱ)2-丁硫基-5′-腺苷酸与二氯亚甲基双膦酸的单酐,一铵盐
NMR δ31P(D2O)8.05-8.25(m),3.66(dd,J=18.48和27.8Hz),-9.03(d,J=27.8Hz)。
h)2-丙硫基-5′-腺苷酸与亚甲基双膦酸的单酐,四钠盐
NMR δ31P(D2O)15.8(d,J=8.3Hz),10.7(dd,J=8.4和27Hz),-9.44(d,J=25.8Hz)。
i)2-乙酰氨基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,四钠盐
ⅰ)2-乙酰氨基-5′-腺苷酸
NMR δ31P(D2O)4.16(s)。
ⅱ)2-乙酰氨基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,四钠盐
NMR δ31P(D2O)8.99(d,J=14.7Hz),1.42(dd,J=14.8和28.3Hz),-9.16(d,28.3Hz)。
j)2-氯-5′-腺苷酸与二氯亚甲基双膦酸的单酐,四钠盐
UVλmax(H2O)210nm(ε20,900)265nm(ε12,700)。
k)2-碘-5′-腺苷酸与二氟亚甲基双膦酸的单酐,四钠盐
NMR δ31P(D2O)4.72(dt,J=57和73Hz),-1.89(ddt,J=64、88和31Hz),-9.86(d,J=32Hz)。
l)L-2-甲硫基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,四钠盐
NMR δ31P(D2O)8.12(d,J=15Hz),-0.03(dd,J=15和26Hz),-9.88(d,J=28Hz)。
m)2-丙氨基-5′-腺苷酸与二氯亚甲基双膦酸的单酐,三钠盐
NMR δ31P(D2O)8.87(d),0.99(dd),-9.3(d)。
n)2-丙硫基-5′-腺苷酸与磺基二氟甲基膦酸的单酐,三钠盐
NMR δ31P(D2O)-8.8(dt),-10.0(d)。
o)2-丙硫基-5′-腺苷酸与膦酰乙酸的单酐,三钠盐
NMR δ31P(D2O)11.4(d),-9.57(d)
p)2-(2-噻吩基)-5′-腺苷酸与二溴亚甲基双膦酸的单酐,四钠盐
ⅰ)2-(2-噻吩基)-5′-腺苷酸
NMR δ31P(D2O)2.14(s)
ⅱ)2-(2-噻吩基)-5′-腺苷酸与二溴亚甲基双膦酸的单酐,四钠盐
NMR δ31P(D2O)9.53(d,J=14Hz),3.91(dd,J=14和30Hz),-8.96(d,J=30Hz)。
q)2-苯基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,四钠盐
ⅰ)2-苯基-5′-腺苷酸
NMR δ31P(D2O)0.22(s)。
ⅱ)2-苯基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,四钠盐
NMR δ31P(D2O)8.55(d,J=14.1Hz),2.92(dd,J=14.2和29.6Hz),-9.87(d,J=29.8Hz)。
实施例3
2-丁基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,三钠盐
ⅰ)2-丁基-5′-腺苷酸
将实施例2p)ⅰ)的产物(1.4g)与活化的阮内镍(1.5g)在水中(50ml)于70℃加热2小时。在过滤并用水洗涤固体后,蒸发滤液得到无色固体的小标题化合物(0.56g)。
MS(FAB)404(M++1),426(M++Na),192(100%)。
ⅱ)2-丁基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,三钠盐
NMR δ31P(D2O)8.8(d),1.0(dd),-9.4(d)。
实施例4
2-丙氧基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,四钠盐
ⅰ)2-丙氧基-腺苷酸
将2-氯腺苷(3.5g)加到热的NaOH(3.2g)正丙醇(80ml)溶液中,将该混合物在回流下加热3小时。在真空下除去挥发物,将残余物溶于水(40ml),冷却并用1M盐酸酸化至PH7。15分钟后,将悬浮液过滤并蒸发滤液。将残余物溶于乙醇中并吸附到置于色谱柱中的二氧化硅上。先用9∶1,然后用4∶1CHCl3洗脱得到小标题化合物(0.65g)。
MS(FAB)326(M++H)
ⅱ)2-丙氧基-5′-腺苷酸,一铵盐
用实施例1的方法制备。
NMR δ31P(D2O+NaOD)3.17(s)。
ⅲ)2-丙氧基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,三钠盐
NMR δ31P(D2O)9.4(d,J=14.5Hz),3.77(dd,J=14.3和29.2Hz),-9.0(d,J=29.7Hz)。
实施例5
2-(1-甲基乙基)硫-5′-腺苷酸与二氯亚甲基双膦酸的单酐,三钠盐
ⅰ)2′,3′,5′-三-O-乙酰-6-氯-2-(1-甲基乙基)硫-腺苷
将9-(2′,3′,5′-三-O-乙酰-β-D-呋喃核糖基)-2-氨基-6-氯嘌呤(6.6g)溶于无水乙腈(65ml)中。添加二硫异丙酯(21ml)和亚硝酸异戊酯(12.1ml)将得到的溶液用氮气冲洗45分钟,然后在氮气中于60°加热16小时。在真空下除去挥发物,将残余物色谱分离得到黄色油状的小标题化合物(3.69g)。
NMR δ1H(d6-DMSO)8.70(s,1H),6.29(d,1H),6.02(m,1H),5.61(t,1H),4.39(m,2H),4.20(m,1H),4.00(Septet,1H),2.12、2.07、1.98(3×s,3×1H),1.41(d,6H)。
ⅱ)2-(1-甲基乙基)硫-腺苷
将在乙醇(400ml)中的步骤ⅰ)产物(3.6g)冷却至0°并用氨饱和。使该溶液加温至约15°,然后在高压釜中加热24小时至70°,在真空下除去挥发物,将残余物色谱分离得到小标题化合物(1.95g)。
MS(FAB)342(M++H)(100%)。
ⅲ)2-(1-甲基乙基)硫-5′-腺苷酸
按照实施例1的方法制备小标题化合物。
NMR δ31P(D2O)1.1(s)
ⅳ)2-(1-甲基乙基)硫-5′-腺苷酸与二氯亚甲基双膦酸的单酐,三钠盐
按照实施例1的方法制备标题化合物。
NMR δ31P(D2O)9.21(d,J=21Hz),2.0(dd,J=19和30Hz),9.33(d,J=32Hz)
实施例6
2-丙硫基腺苷酸与双〔(二羟基氧磷基)甲基〕次膦酸的5′-P′-单酯,二钠盐
ⅰ)2′,3′-O,O-(1-甲基亚乙基)-2-丙硫基腺苷
以小份额用1小时将对苯磺酸-水合物(1.46g)加到在AR丙酮(97ml)和2,2-二甲氧基丙烷(11.3ml)中的2-丙硫基腺苷(2.6g)的悬浮液中。在室温将生成的溶液搅拌18小时,用水(300ml)稀释并用三乙胺处理至PH7。在真空下将体积减至一半,剩下的溶液入三氯甲烷(3×100ml)中萃取。将萃取物干燥(MgSO4),过滤并蒸发。通过色谱法(SiO2,乙酸乙酯)提纯残余物,得到小标题化合物(1.8g)。
MS(FAB)382(M++H),BP210。
ⅱ)5′-4-甲苯磺酰-2′,3′-O,O-(1-甲基亚乙基)-5′-脱氧-2-丙硫基腺苷。
将4-二甲基氨基吡啶(1.33g)加到在无水二氯甲烷(100ml)中的步骤ⅰ)产物(1.6g)的冰冷的溶液中,然后用15分钟添加对甲苯磺酰氯(0.88g)的无水二氯甲烷(20ml)溶液。于0-4°下18小时后,在真空下除去挥发物,通过色谱法(SiO2,乙酸乙酯)提纯残余物,得到小标题的化合物(1.9g)。
NMR δ1H(CDCl3)7.7(s,1H),7.6(d,2H),7.1(d,2H),6.0(d,1H),5.7(s,2H),5.4(d,1H),5.0(m,1H),4.4(m,1H),4.2(m,2H),3.0(m,2H),2.4(s,3H),1.7(q,2H),1.6(s,3H),1.4(s,3H),1.1(t,3H)。
ⅲ)2-丙硫基腺苷与双〔(二羟基氧磷基)甲基〕次膦酸的5′-P′-单酯,二钠盐
通过添加40%(重量/体积)氢氧化四丁铵溶液将双〔(二羟基氧磷基)甲基〕次膦酸(0.66g)的水(10ml)溶液调至PH8.7,然后冷冻干燥,得到一种胶,进一步通过反复溶在乙腈中并蒸发溶剂(3×50ml)将该胶干燥。将残余物溶于无水乙腈(10ml)中并用步骤ⅱ)的产物(0.81g)处理,该混合物在真空中浓缩成稠浆。在室温搅拌过夜后,用水稀释该混合物并施于DEAE-Sepharose(Fast Flow)柱。冷冻干燥后用0-0.6M三乙铵的碳酸氢盐洗脱,得到残余物,将该残余物溶于80%(体积/体积)乙酸中并加热4小时至80°。蒸干后,将残余物与水(2×20ml)共沸处理,溶于甲醇(5ml)中并用几滴三乙胺处理。向溶液添加1M碘化钠丙酮溶液以沉淀钠盐,通过离心分离收集钠盐并用丙酮洗涤几次。将固体溶于水中并冷冻干燥以得到无色固体的标题的盐(96mg)。
NMR δ31P(D2O)28.17(d),18.86(dd)16.39(d)。
实施例7
2-丙硫基腺苷与双〔(二氯二羟基氧磷基)甲基〕次膦酸的5′-P′-单酯,四钠盐
ⅰ)双〔(二氯二羟基氧磷基)甲基〕次膦酸,五乙基酯
将双〔(二羟基氧磷基)甲基〕次膦酸五乙基酯(3.94g)的三氯甲烷(100ml)溶液与工业次氯酸钠溶液(5.25%有效氮,400ml)在室温下剧烈搅拌24小时。分离有机相并蒸发,得到小标题化合物(4.7g)
MS(FAB)531/533/535/537(M++H),BP533。
ⅱ)双〔(二氯二羟基氧磷基)甲基〕次膦酸
将在无水二氯甲烷(10ml)中的步骤ⅰ)产物(0.532g)用溴化三甲基硅(0.912g)在室温下处理18小时。在真空中除去挥发物,将残余物溶于甲醇(5ml)中,两小时后蒸发掉甲醇,将生成的油溶于去离子水(10ml)中并用醚完全萃取。添加环己胺直至PH为约10,然后添加甲醇直至持久混浊。收集在冷却时沉积的固体并干燥,然后溶于水(10ml)中并施于Dowex50WX8(H+)柱。用蒸馏水洗脱并冷冻干燥,得到小标题化合物(0.15g)。
NMR δ31P(D2O)9.2(d,J=20.4Hz),17.9(t,J=18.7Hz)。
ⅲ)2-丙硫基腺苷与双〔(二氯二羟基氧磷基)甲基〕次膦酸的5′-P′-单酯,四钠盐
按照实施例6的方法由步骤(ⅱ)的产物(0.35g)制备标题化合物。
NMR δ31P(D2O)20.81(t,J=14.1Hz)11.18(d,J=12.1Hz),9.9(d,J=12.3Hz)。
实施例8
2-丙硫基腺苷与亚甲基双膦酸的5′-P′-单酯,与磷酸的P2-单酐,四钠盐
ⅰ)2-丙硫基腺苷与亚甲基双膦酸的5′-P′-单酯,二钠盐
通过实施例6ⅲ)的方法制备小标题化合物。
NMR δ31P(D2O)20.97(d,J=8.56Hz)15.3(d,J=8.57Hz)。
ⅱ)2-丙硫基腺苷与亚甲基双膦酸的5′-P′-单酯,与磷酸1-(2-硝基苯基)乙酯的P2-单酐,单三乙基铵盐
用去离子水通过Dowex 50WX8(n-Bu4N+形式)柱洗脱步骤ⅰ)的产物,将洗脱液冷冻干燥以得到双膦酸酯物料的四正丁基铵盐。在无水吡啶(5ml)中于室温下将该盐(0.73mmol)和偶磷酰吗啉1-(2-硝基苯基)乙酯,N,N′-二环己基吗啉-1-碳氨肟鎓(carboxamidinium)盐(1.09mmol)搅拌48小时。将溶剂蒸发并将残余物溶于水(100ml)中,并用三氯甲烷(2×50ml)洗涤。在30°将水相的体积减少至10ml并施于DEAE-Sepharose柱,用0-0.4M三乙基铵的碳酸氢盐溶液洗脱该柱。合并适当的馏分并冷冻干燥,得到小标题化合物(0.3g)。
NMR δ31P(D2O)18.43(d,J=11.31Hz)7.8(dd),-10.96(d,J=26.3Hz)。
ⅲ)2-丙硫基腺苷与亚甲基双膦酸的5′-P′-单酯,与磷酸的P2-单酐,四钠盐
在10°下将步骤ⅱ)产物(0.3g)的0.4M含盐酸氨基脲(0.3g)的三乙基铵的碳酸氢盐溶液(100ml)用高压UV灯照射2小时。在真空中于30°除去溶剂并在用0-0.6M三乙基铵的碳酸氢盐缓冲液洗脱的DEAE-Sepharose上通过色谱法将残余物提纯。合并有关的馏分并冷冻干燥,将残余物通过实施例6ⅲ)的方法转化成四钠盐(1.13g)
NMR δ31P(D2O)19.34(d,J=8.56Hz),6.7(dd),-6.6(d,J=20.96Hz)。
实施例9
3-(6-氨基-2-丙硫基-9H-嘌呤-9-基)-5-(羟基-甲基)-1,2-环戊二醇5-磷酸二氢酯与二氯亚甲基双磷酸的单酐,三钠盐
ⅰ)2-丙硫基-嘧啶-4,6-二醇
向4,6-二羟基-2-巯基嘧啶(100g)的氢氧化钾(2.5N,571ml)溶液中加入丙基碘(76.8ml)并将全部溶液搅拌4天。将该溶液酸化至PH2-3并过滤,得到小标题的化合物(15g)。
MS330M+(di-TMS),BP315。
ⅱ)5-硝基-2-丙硫基嘧啶-4,6-二醇
用1小时将步骤i)的产物(2g)加到冰冷却的发烟硝酸(10ml)中并在0°下再搅拌1小时。倾倒在冰上随后干燥,得到本色固体的小标题化合物(1.7g)。
MS375M+(di-TMS),BP360。
ⅲ)4,6-二氯-5-硝基-2-丙硫基嘧啶
将步骤ⅱ)的产物(1.7g)、磷酰氯(10ml)和N,N-二乙基苯胺(3ml)加热1小时至回流,然后浓缩至一半体积并倾倒到冰上得到黑焦油。用醚萃取该焦油得到一种溶液,该溶液经干燥(MgSO4),然后蒸发。将残余物色谱分离(SiO2,轻汽油)得到小标题化合物(0.8g)。
MS267/269/271M+,BP41。
ⅳ)4,6-二氯-2-丙硫基-嘧啶-5-胺
将还原铁粉(1.1g)加到步骤ⅲ)产物(1g)的冰醋酸(10ml)溶液中。通过冷却将温度降至60°,然后在60°加热15分钟。将反应物蒸发至干,残余物萃取入到醚(100ml)中,用稀氢氧化钠溶液洗并干燥。蒸发得到暗油状的小标题化合物(0.8g)。
NMR δ1H(CDCl3)4.2(brs,2H),3.1(t2H),1.71(q,2H),1.05(t,3H)。
ⅴ)3-(5-氨基-6-氯-2-丙硫基嘧啶-4-基氨基)-5-(羟甲基)-环戊烷-1,2-二醇
将步骤ⅳ)的产物(4.6g)加到含有三乙胺(10ml)的3-氨基-5-(羟甲基)-环戊烷-1,2-二醇(1.41g)的丁-1-醇(200ml)溶液中,将全部溶液加热48小时至回流。蒸发得到一种暗色残余物,经色谱分离(SiO2,10%乙醇/二氯甲烷),得到小标题化合物(2.8g)
MS 349/350(M++H),BP349。
ⅵ)3-(6-氨基-丙硫基-9H-嘌呤-9-基)-5-(羟甲基)-1,2-环戊烷二醇-5-磷酸二氢酯
将步骤ⅴ)的产物(0.2g)和乙酸二乙氧基甲酯(10ml)于室温在氮气下搅拌1小时,然后于80°经24小时。蒸发得残余物,将该残余物在高压釜中于60°用液氨处理16小时。将氨蒸发并将残余物于60°在45分钟内溶于0.5M盐酸(10ml)中。在真空中除去挥发物,将剩余的物料溶于水(10ml)中。用浓氨中和时结晶出小标题化合物,并收集和干燥(0.15g)。
MS(FAB)340(M++H),BP340。
ⅶ)3-(6-氨基-2-丙硫基-9H-嘌呤-9-基)-5-(羟甲基)-1,2-环丙烷二醇5-磷酸二氢酯
通过实施例1的方法将步骤ⅵ)的产物转化成小标题化合物。
NMR δ31P(D2O)2.85(s)
ⅷ)3-(6-氨基-2-丙硫基-9H-嘌呤-9-基)-5-(羟甲基)-1,2-环丙烷二醇5-磷酸二氢酯与二氯亚甲基双膦酸的单酐,三钠盐
通过实施例1的方法将步骤ⅶ)的产物转化成标题的盐。
NMR δ31P(D2O)8.54(d,J=18.73Hz),0.84(dd),-9.5(d,J=29.61Hz)。
实施例10
1-(6-甲氧基-2-丙硫基-嘌呤-9-基)-呋喃核糖-5′-基-磷酸酯与二氯亚甲基双膦酸的单酐,三钠盐
ⅰ)2′,3′,5′-三-O-乙酰基-6-氯-2-丙硫基腺苷
按照实施例5ⅰ)的方法,使用二正丙二硫化物制得小标题化合物
NMR δ1H(CDCl3)8.13(s,1H),6.14(d,1H),5.93(t,1H),5.60(t,1H),4.3-4.5(m,3H),3.21(t,2H),2.15,2.13,2.11(3xs,3x3H),1.8(m,2H),1.07(t,3H)。
ⅱ)6-甲氧基-2-丙硫基-9-呋喃核糖基-嘌呤
将步骤ⅰ)的化合物(5.2g)溶于1M甲醇钠的甲醇溶液(53ml)中并在氮气中加热1小时至回流。用水(100ml)稀释,用稀盐酸中和并蒸发甲醇得到一种油。用水,然后用二氯甲烷研制得到无色固体的小标题化合物(1.35g)。
MS(FAB)357(M++H),BP225。
ⅲ)1-(6-甲氧基-乙-丙硫基-嘌呤-9-基)-呋喃核糖-5′-基-磷酸酯
按照实施例1的方法制得小标题化合物。
NMR δ31P(D2O)1.69(s)
ⅳ)1-(6-甲氧基-2-丙硫基-嘌呤-9-基)-呋喃核糖-5′-基-磷酸酯与二氯亚甲基双膦酸的单酐,三钠盐
按照实施例1的方法制得标题的盐。
NMR δ31P(D2O)8.59(d,J=18Hz),1.73(dd,J=18和29Hz),-9.94(d,J=29Hz)。
实施例X
在冲洗的人体血小板中P2T受体兴奋剂/拮抗物活性的定量试验。
制备
将人体静脉血液(100ml)等分在三个试管中,每个试管含3.2%柠檬酸三钠(4ml)作为抗凝血剂。将这些试管在240G离心分离15分钟以得到富血小板的血浆(PRP),向该血浆加入300ng/ml前列环素(PGI2,来自1mg/ml乙醇贮液的1/10盐水稀释液的3μl/ml PRP)以在洗涤步骤中稳定这些血小板。通过在125G离心10分钟,随后在640G再离心15分钟得到无红细胞的PRP。除去上清液并将血小板片状沉淀物重新悬浮在改进的,无钙的台罗德氏液〔(10ml)CFT,组分:NaCl 137mM(8g/l)、NaHCO311.9mM(1g/l)、NaH2PO40.38mM(0.06g/l)、KCl2.86mM(1ml20%溶液/l)、MgCl1.05mM(1ml10%溶液/l)、右旋糖5.55mM(1g/l)〕中,通95%O2/5%CO2气体并保持在37°。再添加300ng/ml PGI2后,立即将汇集的悬浮液于640G再次离心分离15分钟。除去上清液并将血小板最初悬浮在10ml CFT中,再添加CFT以调节最终血小板数至2×105/μl。将最终悬浮液于3°下贮存在隔绝空气的60ml的注射器中。
为了恢复PGI2抑制正常功能,在最后悬浮后不快于2小时将这些血小板用于聚集研究。在全部研究中,将430μl血小板悬浮液的等分试样加到含有CaCl2溶液(10μl45mM溶液,最终浓度1mM)的硅烷化的聚集杯中并在PAP4聚集器(Biodata)中以900rpm搅拌。添加人体纤维蛋白原(Sigma F4883)和8-磺苯基茶碱(8-SPT,以阻碍任何化合物的P1兴奋剂活性),得到最后浓度分别为0.2mg/ml(10μl10mg/ml可凝固蛋白质的盐水溶液)和3×10-4M(10μl5.6mg/ml葡萄糖溶液。然后开始记录聚集。
试验程序
a)接近最大ADP浓度的选择
通过在整个10-300μm范围内绘制浓度/响应曲线选择得到刚好为接近最大响应的ADP浓度。在开始出现聚集迹象后20分钟将合适的ADP溶液加到体积为10μl的聚集杯中。利用透光的最大变化率测量聚集响应,通过PAP4斜率读数器得出指数。将在本程序的这一阶段所选择的接近最大浓度的ADP用于以后对化合物拮抗物效力的评价。所有测定都以双份用每个供体的血小板作用。
b)兴奋剂/拮抗物效力的评价
在开始出现聚集迹象后5分钟,将试验化合物的盐水或适当溶液加到体积为30μl的聚集杯中,得到最终浓度为0、10、100或1000μm。在这一时刻的聚集是兴奋剂活性的征兆,如果发生,则通过在a)得到的对照ACP响应比较测定该兴奋剂效力。如果不发生聚集,在试验化合物之后15分钟加入10μl体积先前选择的接近最大浓度的ADP。将拮抗物效力测定为%抑制对照ADP响应,得到一个近似的IC50。在低浓度范围内重新测试在最初浓度时完全抑制ADP响应的化合物。IC50<10-8M的化合物在有8-SPT存在下也被重新测试以证实没有任何P1兴奋剂活性并用2分钟而不是15分钟培育以检查抑制作用是否与时间有关
结果
以由每4个供体的双份形式得到的拮抗物效力(PIC50)的负对数报导结果。对于PIC50>8的化合物,如果没有P1兴奋剂活性的证据,则作出评论“纯化”。IC50<3定义为“非活性的”。
Claims (9)
1、一种制备式Ⅰ的化合物或其可药用盐类的方法。
式中Q表示CR1R2,
R表示O或CR3R4,
W表示O或CH2,
R1、R2、R3和R4各自独立地表示氢或卤素,
X表示S(O)nR5、C1-6烷基、C1-6烷氧基、C1-6酰氨基、CONR6R7、NR8R9、卤素、5-或6-节含S杂环、或任选地由C1-6烷基取代的苯基,
n表示0、1或2,
R5表示芳基或任选地由一个或多个选自羟基、C1-6烷氧基、卤素和芳基取代的C1-6烷基;
R6、R7、R8和R9各自独立地表示氢或C1-6烷基,
Y表示NH2或C1-6烷氧基,和
Z表示酸性基团
此外,当R表示CR3R4时,则-Q-Z也可以表示羟基或-OP(O)(OH)2,其条件是:
i)当R是O,W是O,X是Cl,Y是NH2和Z是-P(O)(OH)2时,而CR1R2不表示CH2,和
ii)当R是O,W是O,X是SCH3,Y是NH2和Z是-P(O)(OH)2时,而CR1R2不表示CH2,(b)CF2或(c)CCl2,
该方法包括:
a)通过将式Ⅱ的化合物或其盐与式Ⅲ的化合物或其盐反应,制备R表示O的式Ⅰ化合物或其盐,
式中W、X和Y如上所定义,而L1表示一个离去基团,
式中Z和Q如上所定义,
b)通过将式Ⅳ的化合物或其盐与式Ⅴ的化合物或其盐反应,制备R表示CR3R4的式Ⅰ化合物或其盐,
式中W、X和Y如上所定义,而L2表示一个离去基团,
式中Z、Q、R3和R4如上所定义,
c)通过将其中-Q-Z为羟基的相应的式Ⅰ化合物与Ⅵ化合物或其盐反应,制备R为CR3R4和-Q-Z为-OP(O)(OH)2的式Ⅰ化合物或其盐,
式中L2是一个离去基团,
d)从一个或多个官能团被保护的相应的式Ⅰ被保护化合物中除去保护基团,和
在需要时或必要时,将生成的式Ⅰ化合物或其另一种盐转化成一种其可药用的盐,反之亦然。
2、权利要求1的方法,其中Z是-P(O)(OH)2。
3、权利要求1或2的方法,其中R是CR1R2和Q是O。
4、上述权利要求中任一项的方法,其中W是O。
5、上述权利要求中任一项的方法,其中X是S(O)n-烷基。
6、权利要求5的方法,其中n是0。
7、权利要求1的方法,其中式Ⅰ化合物是2-丙硫基-5′-腺苷酸与二氯亚甲基双膦酸的单酐,或其可药用的盐。
8、权利要求1的方法,其中式Ⅰ化合物是
2-丙硫基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,
2-丙硫基-5′-腺苷酸与二氟亚甲基双膦酸的单酐,
2-戊硫基-5′-腺苷酸与二氯亚甲基双膦酸的单酐,
2-戊硫基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,
2-乙硫基-5′-腺苷酸与二氯亚甲基双膦酸的单酐,
2-乙硫基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,
2-丁硫基-5′-腺苷酸与二氯亚甲基双膦酸的单酐,
2-丙硫基-5′-腺苷酸与亚甲基双膦酸的单酐,
2-乙酰氨基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,
2-氯-5′-腺苷酸与二氯亚甲基双膦酸的单酐,
2-碘-5′-腺苷酸与二氟亚甲基双膦酸的单酐,
L-2-甲硫基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,
2-丙氨基-5′-腺苷酸与二氯亚甲基双膦酸的单酐,
2-丙硫基-5′-腺苷酸与磺基二氟甲基膦酸的单酐,
2-丙硫基-5′-腺苷酸与膦酰乙酸的单酐,
2-丁基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,
2-丙氧基-5′-腺苷酸与二溴亚甲基双膦酸的单酐,
2-(1-甲基乙基)硫-5′-腺苷酸与二氯亚甲基双膦酸的单酐,
2-丙硫基腺苷与双〔(二羟基氧磷基)甲基〕次膦酸的5′-P′单酯,
2-丙硫基腺苷与双〔(二氯二羟基氧磷基)甲基〕次膦酸的5′-P′单酯,
2-丙硫基腺苷与亚甲基双膦酸的5′-P′单酯,与磷酸的P2-单酐,
2-丙硫基腺苷与亚甲基双膦酸的5′-P′单酯,
3-(6-氨基-2-丙硫基-9H-嘌呤-9-基)-5-(羟甲基)-1,2-环戊二醇5-磷酸二氢酯与二氯亚甲基双膦酸的单酐,
或其任何一种可药用的盐。
9、一种制备含有如权利要求1所定义的式Ⅰ化合物,但没有附带条件ⅰ)、ⅱ)(b)和ⅱ)(c),或其可药用的盐的医药组合物的方法,该方法包括将式Ⅰ化合物与可药用的载体、稀释剂或辅剂混合。
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CN1938284B (zh) * | 2004-03-31 | 2010-08-11 | 阿斯利康(瑞典)有限公司 | 化学方法 |
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FR2721929B1 (fr) * | 1994-06-30 | 1996-12-20 | Centre Nat Rech Scient | Analogues stables, non hydrolysables, de diphosphates et leurs procedes de preparation |
JP2001504097A (ja) * | 1996-10-30 | 2001-03-27 | ザ・ユニヴァーシティ・オブ・ノース・キャロライナ・アト・チャペル・ヒル | P2yレセプターアンタゴニスト |
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TWI229674B (en) | 1998-12-04 | 2005-03-21 | Astra Pharma Prod | Novel triazolo[4,5-d]pyrimidine compounds, pharmaceutical composition containing the same, their process for preparation and uses |
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SE9903290D0 (sv) * | 1999-09-15 | 1999-09-15 | Astra Pharma Prod | Novel compounds |
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US7452870B2 (en) | 2000-08-21 | 2008-11-18 | Inspire Pharmaceuticals, Inc. | Drug-eluting stents coated with P2Y12 receptor antagonist compound |
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1995
- 1995-06-13 HU HU95P/P00190P patent/HU211334A9/hu unknown
- 1995-08-05 CN CN95109290A patent/CN1120936A/zh active Pending
- 1995-12-05 GR GR950403426T patent/GR3018307T3/el unknown
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1042430C (zh) * | 1993-02-10 | 1999-03-10 | 英国阿斯特拉药品有限公司 | N-烷基-2-取代的atp类似物、其制备方法和用途 |
CN100354268C (zh) * | 2000-06-02 | 2007-12-12 | 阿斯特拉曾尼卡有限公司 | 三唑并嘧啶化合物 |
CN1938284B (zh) * | 2004-03-31 | 2010-08-11 | 阿斯利康(瑞典)有限公司 | 化学方法 |
CN102659691A (zh) * | 2012-05-23 | 2012-09-12 | 山东诚创医药技术开发有限公司 | 一种4,6-二氯-5-氨基-2-丙硫基嘧啶的制备方法 |
CN102659691B (zh) * | 2012-05-23 | 2014-04-02 | 山东诚创医药技术开发有限公司 | 一种4,6-二氯-5-氨基-2-丙硫基嘧啶的制备方法 |
CN103288748A (zh) * | 2013-06-21 | 2013-09-11 | 四川铂瑞生物医药有限公司 | 一种4.6-二氯-5-氨基-2-丙硫基嘧啶的制备方法 |
CN104003943A (zh) * | 2014-05-06 | 2014-08-27 | 南通常佑药业科技有限公司 | 一种替格瑞洛中间体的制备方法 |
Also Published As
Publication number | Publication date |
---|---|
AU648885B2 (en) | 1994-05-05 |
HUT64967A (en) | 1994-03-28 |
EP0579643A1 (en) | 1994-01-26 |
EP0508687B1 (en) | 1995-09-13 |
MX9201577A (es) | 1992-10-01 |
DE69204717D1 (de) | 1995-10-19 |
PL297372A1 (en) | 1993-09-06 |
NO933555L (no) | 1993-10-05 |
HU9302812D0 (en) | 1993-12-28 |
AU1451992A (en) | 1992-11-02 |
CN1031879C (zh) | 1996-05-29 |
FI934366A0 (fi) | 1993-10-05 |
ATE127808T1 (de) | 1995-09-15 |
FI934366A (fi) | 1993-10-05 |
GR3018307T3 (en) | 1996-03-31 |
JP3141028B2 (ja) | 2001-03-05 |
ES2078654T3 (es) | 1995-12-16 |
DE69204717T2 (de) | 1996-04-25 |
IE921091A1 (en) | 1992-10-07 |
WO1992017488A1 (en) | 1992-10-15 |
CA2107667A1 (en) | 1992-10-07 |
IL101485A0 (en) | 1992-12-30 |
JPH06505987A (ja) | 1994-07-07 |
CN1120936A (zh) | 1996-04-24 |
EP0508687A1 (en) | 1992-10-14 |
NO933555D0 (no) | 1993-10-05 |
DK0508687T3 (da) | 1996-02-05 |
NZ242243A (en) | 1993-06-25 |
HU211334A9 (en) | 1995-11-28 |
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