CN101921220A - 治疗与骨质损失有关的疾病的含有ep4激动剂作为活性成分的药物组合物 - Google Patents
治疗与骨质损失有关的疾病的含有ep4激动剂作为活性成分的药物组合物 Download PDFInfo
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
- C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
- C07C405/0033—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing sulfur
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
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Abstract
一种局部给药的药物组合物,其包含EP4激动剂作为活性成分,用于预防和/或治疗与骨质损失有关的疾病。EP4激动剂的典型实例中具有前列腺素骨架的化合物,其具有促进骨生成的作用。因而,该药物的局部给药可以很好地用于预防和/或治疗与骨质损失有关的疾病,如原发性骨质疏松,继发性骨质疏松症,癌的骨转移,高钙血症,Paget氏疾病,骨损失和骨坏死,术后成骨作用,及骨移植代替疗法。
Description
本申请是国际申请日为2002年7月22日的申请号为02816932.8的中国发明专利申请“以EP4激动剂为活性成分的治疗与骨质损失有关的疾病的药物”的分案申请。
技术领域
本发明涉及
(1)一种局部给药的药物组合物,其包含EP4激动剂作为活性成分,用于预防和/或治疗与骨质减少有关的疾病,
(2)一种缓释制剂,其包含激动剂作为活性成分,
(3)下面式(I-2)的前列腺素衍生物:
(其中所有符号如下文中所定义的),
或其无毒盐,或其环糊精包合物,及其制备方法以及以它为活性成分的药物组合物,
(4)下面式(I-3)的8-氮杂前列腺素衍生物:
(其中所有符号如下文中所定义的),
或其无毒盐,或其环糊精包合物,及其制备方法以及以它为活性成分的药物组合物,及
(5)选自下列的化合物:
(1)(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-8-氮杂前列腺(azaprost)-13-烯酸,
(2)(15α,13E)-9-氧代-15-羟基-16-(3-苯基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(3)(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(4)(15α,13E)-9-氧代-15-羟基-16-(3-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(5)(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(6)(15α,13E)-9-氧代-15-羟基-16-(4-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(7)(15α,13E)-9-氧代-15-羟基-16-(2-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(8)(15α,13E)-9-氧代-15-羟基-16-(2-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(9)(15α,13E)-9-氧代-15-羟基-16-(3-三氟甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(10)(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(11)(15α,13E)-9-氧代-15-羟基-16-(3-乙基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(12)(15α,13E)-9-氧代-15-羟基-16-(3,4-二氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(13)(15α,13E)-9-氧代-15-羟基-16-(3,5-二氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(14)(15α,13E)-9-氧代-15-羟基-16-(3-丙基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(15)(15α,13E)-9-氧代-15-羟基-16-(3-乙氧基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(16)(15α,13E)-9-氧代-15-羟基-16-(3-异丙氧基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(17)(15α,5Z,13E)-9-氧代-15-羟基-16-(3-三氟甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸,
(18)(15α,5Z,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸,
(19)(15α,13E)-9-氧代-15-羟基-16-(3,5-二甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(20)(15α,5Z,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸,
(21)(15α,13E)-9-氧代-15-羟基-16-(3,4-二氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸,
(22)(15α,5Z,13E)-9-氧代-15-羟基-16-(3-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸,
(23)(15α,5Z,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸,
(24)(15α)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺烷酸,及
(25)(15α,13E)-9-氧代-15-羟基-16-苯基-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸3-苯基苯基酯,
或其无毒盐,或其环糊精包合物,及其制备方法以及以它为活性成分的药物组合物。
背景技术
已知前列腺素E2(简称PGE2)为各级花生四烯酸酯的代谢物。还已知的是,PGE2具有细胞保护活性,子宫收缩活性,引发疼痛的作用,促进消化蠕动的作用,唤醒作用,抑制胃酸分泌的作用,降血压活性和利尿活性等。
近来的研究证实,存在物理作用彼此不同的各种PGE亚型受体。目前,四种受体亚型是已知的,它们分别称作EP1,EP2,EP3,及EP4(Negishi M.,etal.,J.Lipid Mediators Cell Signaling,12,379-391(1995))。
据教导,EP4亚型受体与产生TNF-α的抑制及产生IL-10的加速有关。因此,预期能与EP4亚型受体结合的化合物可用于预防和/或治疗免疫疾病体免疫疾病如肌萎缩侧索硬化(ALS),多发性硬化,Sjoegren综合症,慢性风湿性关节病及全身性红斑狼疮等,及器官移植后的排斥等),哮喘,神经细胞死亡,关节炎,肺衰竭,肺纤维化,肺气肿,支气管炎,慢性阻塞性呼吸系统疾病,肝损伤,急性肝炎,肾炎(急性肾炎,慢性肾炎),肾机能不全,高血压,心肌缺血,全身性炎症应答综合症,败血症,噬红细胞性综合症,巨噬细胞活化综合症,斯提耳病,川畸病,烧伤,全身性肉芽肿,溃疡性结肠炎,Crohn氏疾病,透析时的高细胞因子血症,多发性器官衰竭,及休克等。
另外,据教导,EP4亚型受体与粘膜保护有关。因此,预期能与EP4亚型受体结合的化合物可用于预防和/或治疗诸如胃溃疡和十二指肠溃疡等胃肠道溃疡和口腔炎。据教导,EP4亚型受体还与毛发生长功能有关。因此,预期能与EP4亚型受体结合的化合物可用于预防和/或治疗毛发损害和脱发。而且,据教导,EP4亚型受体也涉及子宫颈的发育成熟。因此,预期能与EP4亚型受体结合的化合物可用作子宫颈发育成熟的促进剂。
此外,能与EP4亚型受体结合的化合物还具有加速骨形成的作用,因此预期它可用于预防和/或治疗与骨质减少有关的疾病,例如
1)原发性骨质疏松(例如,伴随衰老的原发性骨质疏松,绝经后的原发性骨质疏松,卵巢切除后的原发性骨质疏松等),
2)继发性骨质疏松症(例如,糖皮质激素诱发的骨质疏松,甲状腺机能亢进诱发的骨质疏松,固定化导致的骨质疏松,肝素诱发的骨质疏松,免疫抑制诱发的骨质疏松,肾衰竭导致的骨质疏松,炎性骨质疏松,Cushing氏综合症后的骨质疏松,风湿性骨质疏松等),
3)骨病,如癌的骨转移,高钙血症,Paget氏疾病,骨损失(牙槽骨损失,颚骨损失,儿童先天性骨损失等),骨坏死等。
除上述疾病的治疗之外,本发明还包括药物组合物,该药物组合物用于加速骨手术之后的骨形成(例如,骨折后的骨形成,骨移植后的骨形成,人造关节手术后的骨形成,脊柱融合后的骨形成,及其它骨再生手术后的骨形成等),或促进其治疗,或作为骨移植的替代疗法。
再者,据教导,EP4亚型受体涉及生理睡眠的诱导和血小板聚集的抑制,因此预期这种化合物可用于预防和/或治疗睡眠紊乱及血栓形成。
可与EP4受体结合的化合物选择性地不具有可能是EP1导致的诱发疼痛的作用,可能是EP2导致的子宫松弛作用,及可能是EP3导致的子宫收缩作用,所以认为它们是对上述作用没有任何效果的药剂。
美国专利4177346的说明书中公开了下面式(A)的化合物:
(式中QA选自-COOR3A,四唑-5-基和-CONHR4A;
AA为单键或顺式-双键;
BA为单键或反式-双键;
R2A选自α-噻吩基,苯基,苯氧基,单取代的苯基和单取代的苯氧基,且取代基选自氯,氟,苯基,甲氧基,三氟甲基及C1-3烷基;
R3A选自氢,C1-5烷基,苯基及对联苯基;
R4A选自-COR5A和-SO2R5A;
R5A选自苯基和C1-5烷基),
及其C5的差向异构体,具有羧基和四唑-5-基的化合物的碱金属和碱土金属盐及铵盐。
JP-A-2001-181210的说明书中所公开的是,选择性的式(A)的EP 4受体激动剂可用于治疗骨质疏松。
英国专利1553595的说明书中公开了下面式(B)的吡咯烷酮衍生物:
(式中R1B为具有多达10个碳原子的直链或支链的饱和或不饱和脂族烃基,或者具有3~7个碳原子的脂环族烃基,该脂环族烃基可以被一个或多个下列基团所取代或未取代:
e)3~7个碳原子的环烷基,
f)可具有1或2个取代基的苯基,噻吩基或呋喃基,所述取代基选自任选卤化的具有1~3个碳原子的烷基,卤原子,及具有1~4个碳原子的烷氧基,
R2B为具有多达6个碳原子的直链或支链的饱和或不饱和脂肪族或脂环族烃基,或者具有7或8个碳原子的芳脂族烃基,及
nB为整数2,3或4,删节其它符号的定义),
及相应的酸,盐,特别是生理上可接受的金属盐和胺盐。
在英国专利1569982和1583163的说明书中,公开了接近于式(B)化合物的化合物。
在美国专利4320136的说明书中,公开了下面式(C)的化合物:
(式中AC为CH=CH(顺式或反式),C≡C或CH2CH2;
RC为H,C1-C12直链烷基,支链烷基或环烷基等;
R1C为H,CH3或C2H5;
R2C为苯基或者单取代或二取代的苯基,取代基选自F,Cl,CH3,OCH3,NO2或CF3;
当R2C为苯基或取代苯基时,nC为0~2,删节其它符号的定义)。
WO00/03980的说明书中公开了用作EP4受体结合剂的式(I-1)化合物。
WO01/37877的说明书公开了用于治疗与骨质减少有关疾病的式(I-1)的EP4受体激动剂。
据公开,式(A)和(I-1)的EP4受体激动剂可用于治疗与骨有关的疾病,并对局部给药进行了概述。因此,它未在实验上证实EP4受体激动剂的局部给药可用于治疗与骨有关的疾病。
存在四种物理作用彼此不同的PGE2亚型受体,每种亚型分别称为EP1,EP2,EP3,及EP4,且各自具有不同的药理作用。所以,能选择性地与EP4亚型受体结合并且与其它亚型受体结合弱的化合物可以是副作用较小的药物,因为它们不表现出其它活性。因此需要寻求这样的药物。
另一方面,至今已经发现很多具有EP4激动剂活性的化合物。然而,它们均具有前列腺素骨架,所以认为它们在全身给药如经口给药或静脉灌注时,影响循环系统(例如降低血压或增加心律),或者导致副作用如腹泻。因此,它们的重大问题在于可安全给药的剂量受到限制。
作为与EP4激动剂有关的疾病,对与骨质减少有关的疾病已经进行了很多研究。此外,据认为,全身给药会导致副作用,所以希望开发出副作用较小的药物。同时也期望发现可局部给药的长效药物。
发明内容
本发明人进行了研究发现能与EP4亚型受体特定结合并具有强烈激动活性的化合物。最终发现式(I-2)和(I-3)的化合物符合该目的,并由此实现了本发明。
本发明人发现了能与EP4和EP2亚型受体结合的化合物。预期能与EP4和EP2亚型受体结合的化合物在治疗与两种亚型受体有关的疾病时具有附加或倍增作用。
本发明人还认为,如果EP4激动剂可以局部给药,则可以制备全身给药时没有副作用的治疗药剂(特别是用于治疗与骨质减少有关的疾病的治疗药剂)。发明人还想到,如果能够发现缓释型的且可以局部给药的EP4激动剂,则可以制备全身给药时没有副作用且给药频度低的治疗药剂(特别是用于治疗与骨质减少有关的疾病的治疗药剂)。
因此,为解决前一个目的,本发明人进行了深入的研究并发现,本发明的目的可以利用式(I-1)、(I-2)和(I-3)的化合物的缓释制剂来实现,进而完成了本发明。
式(I-2)和(I-3)的化合物完全是新的化合物。
本发明涉及
i)一种局部给药的药物组合物,其包含EP4激动剂作为活性成分,用于预防和/或治疗与骨质减少有关的疾病,
ii)一种缓释制剂,其包含EP4激动剂作为活性成分,
iii)一种局部给药的用于预防和/或治疗与骨质减少有关的疾病的药物组合物,其包含以EP4激动剂为活性成分的缓释制剂,
iv)一种用于预防和/或治疗与骨质减少有关的疾病的药物组合物,其特征在于将包含选自下列式(I-1)的化合物的制剂局部给药:
式中R1-1为羟基,C1-6烷氧基,或NR6-1R7-1,其中R6-1和R7-1各自独立地为氢原子或C1-4烷基,
R2-1为氧代,卤素,或O-COR8-1,其中R8-1为C1-4烷基,苯基或苯基(C1-4烷基),
R3-1为氢原子或羟基,
R4a-1和R4b-1各自独立地为氢原子或C1-4烷基,
R5-1为苯基,其被以下列基团所取代:
(i)1~3个
C1-4烷氧基-C1-4烷基,
C2-4链烯氧基-C1-4烷基,
C2-4炔氧基-C1-4烷基,
C3-7环烷氧基-C1-4烷基,
C3-7环烷基(C1-4烷氧基)-C1-4烷基,
苯氧基-C1-4烷基,
苯基-C1-4烷氧基-C1-4烷基,
C1-4烷硫基-C1-4烷基,
C2-4链烯基硫基-C1-4烷基,
C2-4炔基硫基-C1-4烷基,
C3-7环烷硫基-C1-4烷基,
C3-7环烷基(C1-4烷硫基)-C1-4烷基,或者
苯硫基-C1-4烷基或苯基-C1-4烷硫基-C1-4烷基,
(ii)C1-4烷氧基-C1-4烷基和C1-4烷基,
C1-4烷氧基-C1-4烷基和C1-4烷氧基,
C1-4烷氧基-C1-4烷基和羟基,
C1-4烷氧基-C1-4烷基和卤素,
C1-4烷硫基-C1-4烷基和C1-4烷基,
C1-4烷硫基-C1-4烷基和C1-4烷氧基,
C1-4烷硫基-C1-4烷基和羟基,或者
C1-4烷硫基-C1-4烷基和卤素,
(iii)卤代烷基或羟基-C1-4烷基,或者
(iv)C1-4烷基和羟基;
其中当R2-1为O-COR8-1时,C8-9位为双键,
或其无毒盐,或其环糊精包合物作为活性成分,
v)缓释制剂,其包含选自式(I-1)的化合物,或其无毒盐,或其环糊精包合物作为活性成分,
vi)用于预防和/或治疗与骨质减少有关的疾病的药物组合物,其特征在于将包含选自下列式(I-2)的化合物的制剂局部给药:
式中R1-2为
(1)-CO-(NH-氨基酸残基-CO)m-2-OH,
(2)-COO-Y2-R9-2,
(3)-COO-Z1-2-Z2-2-Z3-2,
其中Y2为化学键或C1-10亚烷基,
R9-2为(1)苯基或(2)联苯基,其任选被1~3个C1-10烷基,C1-10烷氧基或卤原子所取代,
Z1-2为
(1)C1-15亚烷基,
(2)C2-15亚链烯基,或者
(3)C2-15亚炔基,
Z2-2为
(1)-CO-,
(2)-OCO-,
(3)-COO-,
(4)-CONR11-2-,
(5)-NR12-2CO-,
(6)-O-,
(7)-S-,
(8)-SO-,
(9)-SO2-,
(10)-NR13-2-,
(11)-NR14-2CONR15-2-,
(12)-NR16-2COO-,
(13)-OCONR17-2-,或者
(14)-OCOO-,
Z3-2为
(1)氢原子,
(2)C1-15烷基,
(3)C2-15链烯基,
(4)C2-15炔基,
(5)环12,或者
(6)C1-10烷基,其被C1-10烷氧基,C1-10烷硫基,C1-10烷基-NR18-2-或环12所取代,
环12为
(1)C3-15的一碳环,二碳环或三碳环芳基,其可以是部分或完全饱和的,或者
(2)3~15员的一杂环,二杂环或三杂环芳基,其包含1~4个选自氧、氮和硫的杂原子,其可以是部分或完全饱和的,
R11-2,R12-2,R13-2,R14-2,R15-2,R16-2,R17-2和R18-2各自独立地为氢原子或C1-15烷基,
R11-2和Z3-2可与其相连的氮原子结合起来形成5~7员的饱和单杂环,且该杂环可包含另一个选自氧、氮和硫的杂原子,
环12及由R11-2,Z3-2和与Z3-2相连的氮原子形成的饱和单杂环可以被1~3个选自下列的基团所取代:
(1)C1-15烷基,
(2)C2-15链烯基,
(3)C2-15炔基,及
(4)C1-10烷基,其被C1-10烷氧基,C1-10烷硫基或C1-10烷基-NR19-2所取代,
R19-2为氢原子或C1-10烷基,
m-2为1或2,
其它符号的定义同前,
或其无毒盐,或其环糊精包合物作为活性成分,
vii)缓释制剂,其包含选自式(I-2)的化合物,或其无毒盐,或其环糊精包合物作为活性成分,
viii)用于预防和/或治疗与骨质减少有关的疾病的药物组合物,其特征在于将包含选自下面式(I-3)的化合物的制剂局部给药:
R19-3和R20-3各自独立地为(1)氢原子,(2)C1-10烷基或(3)卤原子,
T3为(1)氧原子或(2)硫原子,
X3为(1)-CH2-,(2)-O-或(3)-S-,
A3为A1-3或A2-3,
A1-3为
(1)C2-8直链的亚烷基,其任选被1~2个C1-4烷基所取代,
(2)C2-8直链的亚链烯基,其任选被1~2个C1-4烷基所取代,或者
(3)C2-8直链的亚炔基,其任选被1~2个C1-4烷基所取代,
A2-3为-G1-3-G2-3-G3-3-,
G1-3为
(1)C1-4直链的亚烷基,其任选被1~2个C1-4烷基所取代,
(2)C2-4直链的亚链烯基,其任选被1~2个C1-4烷基所取代,或者
(3)C2-4直链的亚炔基,其任选被1~2个C1-4烷基所取代,
G2-3为
(1)-Y3-,
(2)-(环13)-,
(3)-Y3-(环13)-,
(4)-(环13)-Y3-,或者
(5)-Y3-(C1-4亚烷基)-(环13)-,
Y3为(1)-S-,(2)-SO-,(3)-SO2-,(4)-O-或(5)-NR1-3-,
R1-3为(1)氢原子,(2)C1-10烷基或(3)C2-10酰基,
G3-3为
(1)化学键,
(2)C1-4直链的亚烷基,其任选被1~2个C1-4烷基所取代,
(3)C2-4直链的亚链烯基,其任选被1~2个C1-4烷基所取代,或者
(4)C2-4直链的亚炔基,其任选被1~2个C1-4烷基所取代,
D3为D1-3或D2-3,
D1-3为
(1)-COOH,
(2)-COOR2-3,
(3)四唑-5-基,或者
(4)CONR3-3SO2R4-3,
R2-3为(1)C1-10烷基,(2)苯基,(3)苯基取代的C1-10烷基或(4)联苯基,
R3-3为(1)氢原子或(2)C1-10烷基,
R4-3为(1)C1-10烷基或(2)苯基,
D2-3为
(1)-CH2OH,
(2)-CH2OR5-3,
(3)羟基,
(4)-OR5-3,
(5)甲酰基,
(6)-CONR6-3R7-3,
(7)-CONR6-3SO2R8-3,
(8)-CO-(NH-氨基酸残基-CO)m-3-OH,
(9)-O-(CO-氨基酸残基-NH)m-3-H,
(10)-COOR9-3,
(11)-OCO-R10-3,
(12)-COO-Z1-3-Z2-3-Z3-3,
R5-3为C1-10烷基,
R6-3和R7-3各自独立地为(1)氢原子或(2)C1-10烷基,
R8-3为苯基取代的C1-10烷基,
R9-3为(1)联苯基取代的C1-10烷基,所述联苯基任选被1~3个C1-10烷基,C1-10烷氧基或卤原子所取代,或(2)联苯基,其任选被1-3个C1-10烷基,C1-10烷氧基或卤原子所取代,
R10-3为(1)苯基或(2)C1-10烷基,
m-3为1或2,
Z1-3为(1)C1-15亚烷基,(2)C2-15亚链烯基或(3)C2-15亚炔基,
Z2-3为(1)-CO-,(2)-OCO-,(3)-COO-,(4)-CONR11-3-,(5)-NR12-3CO-,(6)-O-,(7)-S-,(8)-SO-,(9)-SO2-,(10)-NR13-3-,(11)-NR14-3CONR15-3-,(12)-NR16-3COO-,(13)-OCONR17-3-或(14)-OCOO-,
Z3-3为(1)氢原子,(2)C1-15烷基,(3)C2-15链烯基,(4)C2-15炔基,(5)环23,或(6)C1-10烷基,其任选被C1-10烷氧基,C1-10烷硫基,C1-10烷基-NR18-3-或环23所取代,
R11-3,R12-3,R13-3,R14-3,R15-3,R16-3,R17-3和R18-3各自独立地为(1)氢原子或(2)C1-15烷基,
R11-3和Z3-3可与其相连的氮原子结合起来形成5~7员的饱和单杂环,且该杂环可以包含另一个选自氧、氮和硫原子的杂原子。
E3为E1-3或E2-3,
E1-3为
(1)C3-7环烷基,或者
(2)环33,
E2-3为
(1)C3-7环烷基,
(2)环43,或者
(3)环53,
环13和环53任选被1~3个R21-3和/或R22-3所取代,
环33任选被1~2个R21-3所取代,
E2-3所示的C3-7环烷基被R21-3或R22-3之一所取代,并任选被另外的1~2个R21-3和/或R22-3所取代,
环43被一个R22-3所取代,并任选被另外1~2个R21-3和/或R22-3所取代,及
任选被R11-3,Z3-3及与Z3-3相连的氮原子所形成的杂环所取代,或者环23可被R23-3所取代,
R21-3为(1)C1-10烷基,(2)C1-10烷氧基,(3)卤原子,(4)硝基,(5)被1~3个卤原子取代的C1-10烷基,或(6)苯基,
R22-3为(1)C2-10链烯基,(2)C2-10炔基,(3)C1-10烷硫基,(4)羟基,(5)-NR24-3R25-3,(6)被C1-10烷氧基取代的C1-10烷基,(7)被C1-10烷氧基取代的C1-10烷基,所述C1-10烷氧基被1~3个卤原子所取代,(8)被-NR24-3R25-3取代的C1-10烷基,(9)环63,(10)-O-环73,(11)被环73取代的C1-10烷基,(12)被环73取代的C2-10链烯基,(13)被环73取代的C2-10炔基,(14)被环73取代的C1-10烷氧基,(15)被-O-环73取代的C1-10烷基,(16)-COOR26-3,或(17)被1~3个卤原子取代的C1-10烷氧基,
R24-3,R25-3和R26-3各自独立地为(1)氢原子或(2)C1-10烷基,
R23-3为(1)C1-15烷基,(2)C2-15链烯基,(3)C2-15炔基,或(4)C1-10烷基,其被C1-10烷氧基,C1-10烷硫基或C1-10烷基-NR27-3-所取代,
R27-3为(1)氢原子或(2)C1-10烷基,
环13,环23,环53,环63和环73为
(1)C3-15的一碳环,二碳环或三碳环芳基,其可以是部分或完全饱和的,或者
(2)3~15员的一杂环,二杂环或三杂环芳基,其可以包含1~4个选自氧、氮和硫的杂原子,其可以是部分或完全饱和的,
环33和环43为(1)噻吩基,(2)苯基或(3)呋喃基,
环63和环73可以被1-3个R28-3所取代,
R28-3为(1)C1-10烷基,(2)C2-10链烯基,(3)C2-10炔基,(4)C1-10烷氧基,(5)被C1-10烷氧基取代的C1-10烷基,(6)卤原子,(7)羟基,(8)被1~3个卤原子取代的C1-10烷基,或(9)被C1-10烷氧基取代的C1-10烷基,所述C1-10烷氧基被1~3个卤原子所取代,及
其中
(1)当T3为氧原子,X3为CH2-,A3为A1-3,及D3为D1-3时,E3为E2-3,
(2)环53不为C3-7环烷基,苯基,噻吩基或呋喃基,
(3)环63为苯基,则该苯基至少具有一个R28-3,
或其无毒盐,或其环糊精包合物作为活性成分,
ix)缓释制剂,其包含选自式(I-3)的化合物,或其无毒盐,或其环糊精包合物作为活性成分,
x)下面式(I-2)的前列腺素衍生物:
其中所有符号的定义与vi)中的相同,
或其无毒盐,或其环糊精包合物,
xi)一种制备式(I-2)的前列腺素衍生物,或其无毒盐,或其环糊精包合物的方法,
xii)一种药物组合物,其包含式(I-2)的前列腺素衍生物,或其无毒盐,或其环糊精包合物作为活性成分,
xiii)选自下面式(I-3)的化合物:
其中所有符号的定义与viii)中的相同,
或其无毒盐,或其环糊精包合物,
xiv)一种制备式(I-3)的8-氮杂前列腺素衍生物,或其无毒盐,或其环糊精包合物的方法,
xv)一种药物组合物,其包含式(I-3)的8-氮杂前列腺素衍生物,或其无毒盐,或其环糊精包合物作为活性成分,
xvi)一种用于预防和/或治疗与骨质减少有关的疾病的药物组合物,其特征在于将包含选自下列的化合物或其无毒盐或其环糊精包合物作为活性成分的制剂局部给药:
(1)(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(2)(15α,13E)-9-氧代-15-羟基-16-(3-苯基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(3)(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(4)(15α,13E)-9-氧代-15-羟基-16-(3-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(5)(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(6)(15α,13E)-9-氧代-15-羟基-16-(4-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(7)(15α,13E)-9-氧代-15-羟基-16-(2-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(8)(15α,13E)-9-氧代-15-羟基-16-(2-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(9)(15α,13E)-9-氧代-15-羟基-16-(3-三氟甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(10)(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(11)(15α,13E)-9-氧代-15-羟基-16-(3-乙基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(12)(15α,13E)-9-氧代-15-羟基-16-(3,4-二氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(13)(15α,13E)-9-氧代-15-羟基-16-(3,5-二氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(14)(15α,13E)-9-氧代-15-羟基-16-(3-丙基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(15)(15α,13E)-9-氧代-15-羟基-16-(3-乙氧基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(16)(15α,13E)-9-氧代-15-羟基-16-(3-异丙氧基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(17)(15α,5Z,13E)-9-氧代-15-羟基-16-(3-三氟甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸,
(18)(15α,5Z,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸,
(19)(15α,13E)-9-氧代-15-羟基-16-(3,5-二甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸,
(20)(15α,5Z,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸,
(21)(15α,13E)-9-氧代-15-羟基-16-(3,4-二氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸,
(22)(15α,5Z,13E)-9-氧代-15-羟基-16-(3-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸,
(23)(15α,5Z,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸,
(24)(15α)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺烷酸,及
(25)(15α,13E)-9-氧代-15-羟基-16-苯基-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸3-苯基苯基酯,
或者缓释制剂,其包含选自前述组的化合物,或其无毒盐,或其环糊精包合物作为活性成分,
或者选自前述组的化合物,或其无毒盐,或其环糊精包合物,以及制备这些化合物及含有所述化合物作为活性成分的药物组合物的方法。
在本发明中,C1-4烷基是指甲基,乙基,丙基,丁基及其异构体。
在本发明中,C1-10烷基是指甲基,乙基,丙基,丁基,戊基,己基,庚基,辛基,壬基,癸基及其异构体。
在本发明中,C1-15烷基是指甲基,乙基,丙基,丁基,戊基,己基,庚基,辛基,壬基,癸基,十一烷基,十二烷基,十三烷基,十四烷基,十五烷基及其异构体。
在本发明中,C2-10链烯基是指乙烯基,丙烯基,丁烯基,戊烯基,己烯基,庚烯基,辛烯基,壬烯基,癸烯基及其异构体。
在本发明中,C2-15链烯基是指乙烯基,丙烯基,丁烯基,戊烯基,己烯基,庚烯基,辛烯基,壬烯基,癸烯基,十一烯基,十二烯基,十四烯基,十五烯基及其异构体。
在本发明中,C2-10炔基是指乙炔基,丙炔基,丁炔基,戊炔基,己炔基,庚炔基,辛炔基,壬炔基,癸炔基及其异构体。
在本发明中,C2-15炔基是指乙炔基,丙炔基,丁炔基,戊炔基,己炔基,庚炔基,辛炔基,壬炔基,癸炔基,十一炔基,十二炔基,十三炔基,十四炔基,十五炔基及其异构体。
在本发明中,直链的C1-4亚烷基是指亚甲基,亚乙基,三亚甲基和四亚甲基。
在本发明中,直链的C2-8亚烷基是指亚甲基,亚乙基,三亚甲基,四亚甲基,五亚甲基,六亚甲基,七亚甲基和八亚甲基。
在本发明中,C1-4亚烷基是指亚甲基,亚乙基,三亚甲基,四亚甲基及其异构体。
在本发明中,C1-10亚烷基是指亚甲基,亚乙基,三亚甲基,四亚甲基,五亚甲基,六亚甲基,七亚甲基,八亚甲基,九亚甲基,十亚甲基及其异构体。
在本发明中,C1-15亚烷基是指亚甲基,亚乙基,三亚甲基,四亚甲基,五亚甲基,六亚甲基,七亚甲基,八亚甲基,九亚甲基,十亚甲基,十一亚甲基,十二亚甲基,十三亚甲基,十四亚甲基,十五亚甲基及其异构体。
在本发明中,直链的C2-4亚链烯基是指亚乙烯基,亚丙烯基,亚丁烯基及其异构体。
在本发明中,直链的C2-8亚链烯基是指具有1~2个双键的C2-8亚链烯基。它是指亚乙烯基,亚丙烯基,亚丁烯基,亚戊烯基,亚己烯基,亚庚烯基,亚辛烯基,亚戊二烯基,亚己二烯基,亚庚二烯基和亚辛二烯基。
在本发明中,C2-15亚链烯基是指亚乙烯基,亚丙烯基,亚丁烯基,亚戊烯基,亚己烯基,亚庚烯基,亚辛烯基,亚壬烯基,亚癸烯基,亚十一烯基,亚十二烯基,亚十三烯基,亚十四烯基,亚十五烯基及其异构体。
在本发明中,直链的C2-4亚炔基是指亚乙炔基,亚丙炔基,亚丁炔基。
在本发明中,直链的C2-8亚炔基是指具有1~2个三键的C2-8亚炔基。它是指亚乙炔基,亚丙炔基,亚丁炔基,亚丁二炔基,亚戊炔基,亚戊二炔基,亚己炔基,亚己二炔基,亚庚炔基,亚庚二炔基,亚辛炔基,亚辛二炔基。
在本发明中,C2-15亚炔基是指亚乙炔基,亚丙炔基,亚丁炔基,亚戊炔基,亚己炔基,亚庚炔基,亚辛炔基,亚壬炔基,亚癸炔基,亚十一炔基,亚十二炔基,亚十三炔基,亚十四炔基,亚十五炔基及其异构体。
在本发明中,C1-10烷氧基是指甲氧基,乙氧基,丙氧基,丁氧基,戊氧基,己氧基,庚氧基,辛氧基,壬氧基,癸氧基及其异构体。
在本发明中,C1-10烷硫基是指甲硫基,乙硫基,丙硫基,丁硫基,戊硫基,己硫基,庚硫基,辛硫基,壬硫基,癸硫基及其异构体。
在本发明中,卤原子是指氯,溴,氟和碘原子。
在本发明中,联苯基是指2-苯基苯基,3-苯基苯基或4-苯基苯基。
在本发明中,C2-10酰基是指乙酰基,丙酰基,丁酰基,戊酰基,己酰基,庚酰基,辛酰基,壬酰基,癸酰基及其异构体。
在本发明中,亚苯基是指具有两个可连接键的苯环,即
任何位置均可被取代,优选1,4-或1,3-二取代。
在本发明中,亚噻吩基是指具有两个可连接键的噻吩环,即
任何位置均可被取代,优选2,5-二取代。
在本发明中,亚呋喃基是指具有两个可连接键的呋喃环,即
任何位置均可被取代,优选2,5-二取代。
在本发明中,亚噻唑基是指具有两个可连接键的噻唑环,即
任何位置均可被取代,优选2,5-二取代。
在本发明中,亚噁唑基是指具有两个可连接键的噁唑环,即
任何位置均可被取代,优选2,5-二取代。
在本发明中,C3-5亚环烷基是指具有两个可连接键的环丙基,环丁基环戊基,即
任何位置均可被取代,优选1,1-二取代。
在本发明中,氨基酸残基是指天然氨基酸或异常氨基酸的氨基酸残基。天然氨基酸或异常氨基酸的实例包括甘氨酸,丙氨酸,缬氨酸,亮氨酸,异亮氨酸,丝氨酸,苏氨酸,半胱氨酸,蛋氨酸,脯氨酸,天冬酰胺,谷氨酸,苯丙氨酸,酪氨酸,色氨酸,天冬氨酸,谷氨酸,赖氨酸,精氨酸,组氨酸,β-丙氨酸,丙氨酸丁氨酸硫醚,胱氨酸,高丝氨酸,异亮氨酸,羊毛硫氨酸,正亮氨酸,正缬氨酸,鸟氨酸,肌氨酸,甲状腺原氨酸。
当氨基酸残基具有其它氨基时,前述的氨基酸残基包括具有保护基的氨基酸。
氨基的保护基包括例如苄氧基羰基,叔丁氧基羰基,三氟乙酰基,9-芴基甲氧基羰基。
在本发明中,5~7员的饱和单环杂环是指可包含另一个选自氧、氮和硫的杂原子的5~7员的饱和单环杂环。其实例包括吡咯烷,咪唑烷,吡唑烷,哌啶,哌嗪,全氢哒嗪,全氢氮杂庚因,全氢二氮杂庚因,四氢噁唑(噁唑烷),四氢异噁唑(异噁唑烷),四氢噻唑(噻唑烷),四氢异噻唑(异噻唑烷),四氢噁嗪,全氢氧氮杂庚因,四氢噻嗪,全氢硫氮杂庚因,吗啉,硫代吗啉环。
在本发明中,可以部分或完全饱和的C3-15的一碳环,二碳环或三碳环还包括螺碳环和桥碳环。其实例包括环丙烷,环丁烷,环戊烷,环己烷,环庚烷,环辛烷,环壬烷,环癸烷,环十一烷,环十二烷,环十三烷,环十四烷,环十五烷,环丙烯,环丁烯,环戊烯,环己烯,环庚烯,环辛烯,环戊二烯,环己二烯,环庚二烯,环辛二烯,苯,并环戊二烯,全氢并环戊二烯,甘菊环,全氢甘菊环,茚,全氢化茚,茚满,萘,二氢萘,四氢萘,全氢萘,庚搭烯,全氢庚搭烯,偶苯,不对称引达省(indacene),对称引达省,苊烯,苊,芴,非那烯,菲,蒽,9,10-二氢蒽,螺[4.4]壬烷,螺[4.5]癸烷,螺[5.5]十一烷,二环[2.2.1]庚烷,二环[2.2.1]庚-2-烯,二环[3.1.1]庚烷,二环[3.1.1]庚-2-烯,二环[3.3.1]-2-庚烯,二环[2.2.2]辛烷,二环[2.2.2]辛-2-烯,金刚烷,降金刚烷等。
在本发明中,在包含1~4个选自氧、氮、硫的杂原子,且其可以是部分或完全饱和的3~15员单杂环、二杂环或三杂环芳基中,含1~4个选自氧、氮、硫的杂原子的3~15员单杂环、二杂环或三杂环芳基的实例包括吡咯,咪唑,三唑,四唑,吡唑,吡啶,吡嗪,嘧啶,哒嗪,氮杂庚因,二氮杂庚因,呋喃,吡喃,氧杂庚因,噻吩,硫代吡喃,硫杂庚因,噁唑,异噁唑,噻唑,异噻唑,呋咱,噁二唑,噁嗪,噁二嗪,氧氮杂庚因,氧杂二氮杂庚因,噻二唑,噻嗪,噻二嗪,硫氮杂庚因,硫杂二氮杂庚因,吲哚,异吲哚,中氮茚,苯并呋喃,异苯并呋喃,苯并噻吩,异苯并噻吩,二硫杂萘,吲唑,喹啉,异喹啉,喹嗪,嘌呤,酞嗪,喋啶,萘啶,喹喔啉,喹唑啉,噌啉,苯并噁唑,苯并噻唑,苯并咪唑,色烯,苯并氧杂庚因,苯并氧氮杂庚因,苯并氧杂二氮杂庚因,苯并硫杂庚因,苯并硫氮杂庚因,苯并硫杂二氮杂庚因,苯并氮杂庚因,苯并二氮杂庚因,苯并呋咱,苯并噻二唑,苯并三唑,咔唑,β-咔啉,吖啶,吩嗪,二苯并呋喃,夹氧杂蒽,二苯并噻吩,吩噻嗪,吩噁嗪,夹氧硫杂蒽(phenoxathiin),噻蒽,菲啶,菲咯啉,萘嵌间二氮杂苯环等。
包含1~4个选自氧、氮、硫的杂原子,且其可以是部分或完全饱和的3~15员单杂环、二杂环或三杂环芳基包括氮丙啶,氮杂环丁烷,吡咯啉,吡咯烷,咪唑啉,咪唑烷,三唑啉,三唑烷,四唑啉,四唑烷,吡唑啉,吡唑烷,二氢吡啶,四氢吡啶,哌啶,二氢吡嗪,四氢吡嗪,哌嗪,二氢嘧啶,四氢嘧啶,全氢嘧啶,二氢哒嗪,四氢哒嗪,全氢哒嗪,二氢氮杂庚因,四氢氮杂庚因,全氢氮杂庚因,二氢二氮杂庚因,四氢二氮杂庚因,全氢二氮杂庚因,氧杂丙环,氧杂丁环,二氢呋喃,四氢呋喃,二氢吡喃,四氢吡喃,二氢氧杂庚因,四氢氧杂庚因,全氢氧杂庚因,硫杂丙环,硫杂丁环,二氢噻吩,四氢噻吩,二氢硫代吡喃,四氢硫代吡喃,二氢硫杂庚因,四氢硫杂庚因,全氢硫杂庚因,二氢噁唑,四氢噁唑(噁唑烷),二氢异噁唑,四氢异噁唑(异噁唑烷),二氢噻唑,四氢噻唑(噻唑烷),二氢异噻唑,四氢异噻唑(异噻唑烷),二氢呋咱,四氢呋咱,二氢噁二唑,四氢噁二唑(噁二唑烷),二氢噁嗪,四氢噁嗪,二氢噁二嗪,四氢噁二嗪,二氢氧氮杂庚因,四氢氧氮杂庚因,全氢氧氮杂庚因,二氢氧杂二氮杂庚因,四氢氧杂二氮杂庚因,全氢氧杂二氮杂庚因,二氢噻二唑,四氢噻二唑(噻二唑烷),二氢噻嗪,四氢噻嗪,二氢噻二嗪,四氢噻二嗪,二氢硫氮杂庚因,四氢硫氮杂庚因,全氢硫氮杂庚因,二氢硫杂二氮杂庚因,四氢硫杂二氮杂庚因,全氢硫杂二氮杂庚因,吗啉,硫代吗啉,氧硫杂环己烷,二氢吲哚,异二氢吲哚,二氢苯并呋喃,全氢苯并呋喃,二氢异苯并呋喃,全氢异苯并呋喃,二氢苯并噻吩,全氢苯并噻吩,二氢异苯并噻吩,全氢异苯并噻吩,二氢吲唑,全氢吲唑,二氢喹啉,四氢喹啉,全氢喹啉,二氢异喹啉,四氢异喹啉,全氢异喹啉,二氢酞嗪,四氢酞嗪,全氢酞嗪,二氢萘啶,四氢萘啶,全氢萘啶,二氢喹喔啉,四氢喹喔啉,全氢喹喔啉,二氢喹唑啉,四氢喹唑啉,全氢喹唑啉,二氢噌啉,四氢噌啉,全氢噌啉,苯并氧硫杂环己烷,二氢苯并噁嗪,二氢苯并噻嗪,吡嗪并吗啉,二氢苯并噁唑,全氢苯并噁唑,二氢苯并噻唑,全氢苯并噻唑,二氢苯并咪唑,全氢苯并咪唑,二氢苯并氮杂庚因,四氢苯并氮杂庚因,二氢苯并二氮杂庚因,四氢苯并二氮杂庚因,苯并二氧杂庚环,二氢苯并氧氮杂庚因,四氢苯并氧氮杂庚因,二氢咔唑,四氢咔唑,全氢咔唑,二氢吖啶,四氢吖啶,全氢吖啶,二氢二苯并呋喃,二氢二苯并噻吩,四氢二苯并呋喃,四氢二苯并噻吩,全氢二苯并呋喃,全氢二苯并噻吩,二氧戊环,二氧己环,二硫戊环,二噻烷,二氧杂茚满,苯并二氧己环,色满,苯并二硫杂戊环,苯并二噻烷,8-氮杂-1,4-二氧杂螺[4.5]癸烷,3-氮杂螺[5.5]十一烷,1,3,8-三氮杂螺[4.5]癸烷环。
在本发明中,C1-6烷氧基是指甲氧基,乙氧基,丙氧基,丁氧基,戊氧基,己氧基及其异构体。
在本发明中,C1-4烷氧基是指甲氧基,乙氧基,丙氧基,丁氧基及其异构体。
在本发明中,C1-4烷硫基是指甲硫基,乙硫基,丙硫基,丁硫基及其异构体。
在本发明中,C2-4链烯氧基是指乙烯氧基,丙烯氧基,丁烯氧基及其异构体。
在本发明中,C2-4链烯基硫基是指乙烯基硫基,丙烯基硫基,丁烯基硫基及其异构体。
在本发明中,C2-4炔氧基是指乙炔氧基,丙炔氧基,丁炔氧基及其异构体。
在本发明中,C2-4炔基硫基是指乙炔硫基,丙炔硫基,丁炔硫基及其异构体。
在本发明中,C3-7环烷基是指环丙基,环丁基,环戊基,环己基,环庚基及其异构体。
在本发明中,C3-7环烷氧基是指环丙氧基,环丁氧基,环戊氧基,环己氧基,环庚氧基及其异构体。
在本发明中,C3-7环烷基硫基是指环丙硫基,环丁硫基,环戊硫基,环己硫基,环庚硫基及其异构体。
除非另外说明,所有异构体均包含在本发明中。例如,烷基,链烯基,炔基,烷氧基,烷硫基,亚烷基、亚链烯基及亚炔基是指直链或支链的基团。另外,双键、环、稠环(E-,Z-,顺-,反-异构体)的异构体,由不对称碳原子产生的异构体(R-,S-,α-,β-异构体,对映体,非对映体),光活性异构体(D-,L-,d-,1-异构体),色谱分离所产生的极性化合物(大极性化合物,小极性化合物),平衡化合物,及其任意比例的混合物和外消旋混合物,也包括在本发明中。
在本发明中,除非另外说明,符号是指取代基从纸后面连接于其上(即α-构型),符号是指取代基从纸的前面连接于其上(即β-构型),符号是指α-构型,β-构型,或者α-构型与β-构型的混合物,符号是指存在α-构型与β-构型的混合物,这是本领域的技术人员十分清楚的。
本发明的化合物可以通过常规方法转化成相应的无毒盐。
本发明的化合物的无毒盐包括所有药学上可接受的盐,并优选水溶性的盐。
本发明的化合物的无毒盐的实例包括:碱金属(例如钾,钠,锂等)盐,碱土金属(例如钙,镁等)盐,铵盐(例如四甲基铵盐,四丁基铵盐等),有机胺(例如三乙胺,甲胺,二甲胺,环戊胺,苄胺,苯乙胺,哌啶,一乙醇胺,二乙醇胺,三(羟甲基)甲胺,赖氨酸,精氨酸,N-甲基-D-葡糖胺等)盐和酸加成盐(无机酸加成盐(例如盐酸盐,氢溴酸盐,氢碘酸盐,硫酸盐,磷酸盐,硝酸盐等),有机酸加成盐(例如乙酸盐,三氟乙酸盐,乳酸盐,酒石酸盐,草酸盐,富马酸盐,马来酸盐,苯甲酸盐,柠檬酸盐,甲磺酸盐,乙磺酸盐,苯磺酸盐,甲苯磺酸盐,2-羟基乙磺酸盐,葡糖醛酸盐,葡糖酸盐等),等)。
本发明的化合物的无毒盐包括其溶剂化物或其碱金属盐、碱土金属盐、铵盐、有机胺盐和酸加成盐的溶剂化物。
优选无毒的和水溶性的溶剂化物。本发明的化合物的溶剂化物包括例如水合物,醇(乙醇等)溶剂化物等。
本发明的化合物可以通过如下方法转化成相应的环糊精包合物,所述方法见JP-B-50-3362,52-31404或61-52146的说明书,其中使用α-,β-或γ-环糊精或其混合物。转化成相应的环糊精包合物用于增加化合物在水中的稳定性和溶解性,从而使其可以作为药物来使用。
如果具有EP4激动剂活性,使用本发明的化合物作为EP4激动剂就足够了。可以使用选择性的EP4激动剂,也可以使用非选择性的EP4激动剂。
此外,本发明的EP4激动剂除了目前已知的之外,还包括未来新发现的EP4激动剂。
例如,目前已知的EP4激动剂是前列腺素E1(PGE1),前列腺素E2(PGE2),13,14-二氢前列腺素E1,WO00/54808中所述的化合物,WO01/37877中所述的化合物,JP-A-2001-181210中所述的化合物,WO00/03980中所述的式(I-1)、(I-2)和(I-3)的化合物。更优选前列腺素E2,式(I-1)、(I-2)和(I-3)的化合物。
在本发明的式(I-3)的化合物中,优选A3为A1-3或A2-3。更优选A3为A2-3。
在本发明的式(I-3)的化合物中,优选G1-3为(1)C1-4直链亚烷基,其任选被1~2个C1-4烷基所取代,或(2)C2-4直链亚链烯基,其任选被1~2个C1-4烷基所取代。1)更优选C1-4直链亚烷基,其任选被1~2个C1-4烷基所取代。
在本发明的式(I-3)的化合物中,优选G2-3为(1)-Y3-,(2)-(环13)-,或(3)-Y3-(环13)-。1)更优选-Y3-。
在本发明的式(I-3)的化合物中,优选Y3为-S-或-O-。更优选-S-。
在本发明的式(I-3)的化合物中,优选G3-3为(1)化学键,(2)C1-4直链的亚烷基,其任选被1~2个C1-4烷基所取代,或(3)C2-4直链亚链烯基,其任选被1~2个C1-4烷基所取代。(2)更优选C1-4直链亚烷基,其任选被1~2个C1-4烷基所取代。
在式(I-3)的化合物中,优选T3为氧原子或硫原子。更优选氧原子。
在式(I-3)的化合物中,优选X3为-CH2-,-O-或-S-。更优选-CH2-。
在式(I-3)的化合物中,优选D3为-COOH,-COOR2-3,-COOR9-3-,COO-Z1-3-Z2-3-Z3-3,四唑-5-基,更优选-COOH,-COOR2-3,-COOR9-3-或COO-Z1-3-Z2-3-Z3-3。最优选-COOH或COO-Z1-3-Z2-3-Z3-3。
在式(I-3)的化合物中,优选R19-3和R20-3为氢原子。
在式(I-3)的化合物中,优选E3为环33,环43或环53。
在式(I-3)的化合物中,优选环33为苯基。
在式(I-3)的化合物中,优选环43为苯基。
在式(I-3)的化合物中,优选环53为C5-10的一碳环或二碳环芳基,其可以是部分或完全饱和的,或者5~10员包含1~2个选自氧、氮、硫的杂原子的单杂环或二杂环芳基,其可以是部分或完全饱和的。优选其可以是部分或完全饱和的5~10员包含1~2个选自氧、氮、硫的杂原子的单杂环或二杂环芳基为呋喃,噻吩,噁唑,噻唑,咪唑,吡啶,嘧啶,苯并呋喃,吲哚,苯并噻唑。
在式(I-3)的化合物中,优选15-位的羟基为α-构型。
在式(I-3)的化合物中,优选C13-14为双键。
在式(I-3)的化合物中,优选Z1-3为C1-15亚烷基。更优选C1-8亚烷基。最优选C1-4亚烷基。
在式(I-3)的化合物中,优选Z2-3为-CO-,-OCO-,-COO-,-CONR11-3-,-OCONR17-3-或-OCOO-。更优选-OCO-,-OCONR17-3-,-OCOO-。
在式(I-3)的化合物中,优选Z3-3为C1-15烷基或C1-10烷基,其被C1-10烷氧基,C1-10烷硫基,C1-10烷基-NR18-3-或环23所取代。更优选C4-12烷基。
在式(I-2)的化合物中,优选R1-2为-COO-Y2-R9-2或-COO-Z1-2-Z2-2-Z3-2。更优选COO-Z1-2-Z2-2-Z3-2。
在式(I-2)的化合物中,优选Z1-2为C1-15亚烷基。更优选C1-8亚烷基。最优选C1-4亚烷基。
在式(I-2)的化合物中,优选Z2-2为-CO-,-OCO-,-COO-,-CONR11-2-,-OCONR17-2-或-OCOO-。更优选-OCO-,-CONR17-2或-OCOO-。
在式(I-2)的化合物中,优选Z3-2为C1-15烷基,C1-10烷基,其被C1-10烷氧基,C1-10烷硫基,C1-10烷基-NR18-2-或环12所取代。更优选C4-12烷基。
在式(I-3)的化合物中,优选的化合物为下面化合物:
式(I-3-A-1)的化合物
(其中所有符号与前文中所定义的相同),
式(I-3-A-2)的化合物
(其中所有符号与前文中所定义的相同),
式(I-3-A-3)的化合物
(其中所有符号与前文中所定义的相同),
式(I-3-A-4)的化合物
(其中所有符号与前文中所定义的相同),及
式(I-3-A-5)的化合物
(其中所有符号与前文中所定义的相同)。
在式(I-2)的化合物中,优选的化合物为下面的化合物:
式(I-2-A-1)的化合物
(其中所有符号与前文中所定义的相同),
式(I-2-A-2)的化合物
(其中所有符号与前文中所定义的相同),
式(I-2-A-3)的化合物
(其中所有符号与前文中所定义的相同),
式(I-2-A-4)的化合物
(其中所有符号与前文中所定义的相同),
式(I-2-A-5)的化合物
(其中所有符号与前文中所定义的相同),及
式(I-2-A-6)的化合物
(其中所有符号与前文中所定义的相同)。
在式(I-1)的化合物中,优选的化合物为下面的化合物:
式(I-1-A-1)的化合物
(其中所有符号与前文中所定义的相同),
式(I-1-A-2)的化合物
(其中所有符号与前文中所定义的相同),
式(I-1-A-3)的化合物
(其中所有符号与前文中所定义的相同),
式(I-1-A-4)的化合物
(其中所有符号与前文中所定义的相同),
式(I-1-A-5)的化合物
(其中所有符号与前文中所定义的相同),及
式(I-1-A-6)的化合物
(其中所有符号与前文中所定义的相同)。
具体地,本发明的化合物如下面的表1~120所示,实施例中的化合物及其无毒盐。
表1
表5
表6
表8
表25
表39
表42
表44
表45
表46
表61
表62
表66
表75
表76
表83
表85
表87
表97
表100
表102
表106
在式(I-1)的化合物中,优选的化合物为WO00/03980的实施例中所述的化合物。更优选的化合物为下列的化合物(1)~(8)。
化合物(1)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸甲酯
化合物(2)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲基-4-羟基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸甲酯
化合物(3)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-乙氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸甲酯
化合物(4)
(9β,11α,15α,13E)-9-氟-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸甲酯
化合物(5)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸
化合物(6)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲基-4-羟基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸
化合物(7)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-乙氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸
化合物(8)
(9β,11α,15α,13E)-9-氟-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸
制备本发明的化合物的方法:
在本发明的化合物中,式(I-1)的化合物可以根据WO00/03980中所述的方法制备。
在本发明的化合物中,式(I-3)的化合物可以根据下述方法或根据下述实施例中所述的方法制备。
1)在式(I-3)的化合物中,其中T3为氧且13-14位为双键的化合物,即下面式(IA)的化合物:
其中所有符号与上文中所定义的相同,
可以根据下述方法制备。
式(IA)的化合物可以通过还原下面式(II)的化合物来制备:
式中A3′,D3′和E3′分别与A3,D3和E3同义,但是需要时可以对A3′,D3′和E3′所代表的基团中羟基,氨基,羧基或甲酰基实施保护;其它符号的定义同上,
然后任选从所得产物中除去保护基。
还原反应是已知的,而且可以如此实施,例如,在有机溶剂(例如,四氢呋喃,二甲氧基乙烷,甲苯,二氯甲烷,乙醚,二氧己环)中,在还原剂(例如,硼氢化物-四氢呋喃络合物,硼氢化物-二甲亚砜络合物,乙硼烷)和不对称诱导剂(例如,(R)-2-甲基-CBS-氧氮硼杂赖氨酸(oxazaborolysine),(S)-2-甲基-CBS-氧氮硼杂赖氨酸)存在下,于-20~50℃下处理该化合物。
保护基的去除可以根据下述方法进行。
除去羧基,羟基,氨基或甲酰基的保护基的反应是众所周知的,包括实例如下:
(1)碱性水解,
(2)酸性条件下的去保护,
(3)通过氢解去保护,
(4)甲硅烷基去保护,
(5)用金属去保护,
(6)用有机金属去保护。
现将详述这些方法。
(1)通过碱性水解的去保护可以如此实施,例如,在有机溶剂(例如,甲醇,四氢呋喃,二氧己环)中,利用碱金属氢氧化物(例如,氢氧化钠,氢氧化钾,氢氧化锂),碱土金属氢氧化物(例如,氢氧化钡,氢氧化钙)或碳酸盐(例如,碳酸钠,碳酸钾),或其水溶液或者它们的混合物,在0~40℃下实施。
(2)酸性条件下的去保护可以如此实施,例如,在有机溶剂(例如,二氯甲烷,氯仿,二氧己环,乙酸乙酯,茴香醚)中,利用有机酸(例如,乙酸,三氟乙酸,甲磺酸,对甲苯磺酸)或无机酸(例如,盐酸,硫酸)或其混合物(溴化氢/乙酸),在0~100℃下进行。
(3)通过氢解的去保护可以如此实施,例如,在溶剂(例如,醚溶剂(如四氢呋喃,二氧己环,二甲氧基乙烷,乙醚),醇溶剂(如甲醇,乙醇),苯型溶剂(如苯,甲苯),酮溶剂(如丙酮,甲乙酮),腈溶剂(如乙腈),酰胺溶剂(如二甲基甲酰胺),水,乙酸乙酯,乙酸,或其中两种或多种的混合溶剂)中,在催化剂(例如,钯-碳,钯黑,氢氧化钯,氧化铂,Raney镍)存在下,在常压或增压的氢气氛下或者甲酸铵存在下,于0~200℃进行。
(4)用甲硅烷基的去保护可以如此实施,例如,在水混溶的有机溶剂(例如,四氢呋喃,乙腈)中,利用氟化四丁基铵,于0~40℃下进行。
(5)用金属的去保护可以如此实施,例如,在酸性溶剂(乙酸,pH为4.2~7.2的缓冲液,或其溶液与有机溶剂如四氢呋喃的混合物)中,在锌粉存在下,施加或不施加超声波,于0~40℃下进行。
(6)采用金属络合物的去保护可以如此实施,例如,在有机溶剂(如二氯甲烷,二甲基甲酰胺,四氢呋喃,乙酸乙酯,乙腈,二氧己环,乙醇),水或其混合溶剂中,在捕获剂(如氢化三丁基锡,三乙基硅烷,双甲酮,吗啉,二乙胺,吡咯烷),有机酸(如乙酸,甲酸,2-乙基己酸)和/或有机酸盐(如2-乙基己酸钠,2-乙基己酸钾)存在下,在存在或不存在膦型试剂(如三苯基膦)的情况下,利用金属络合物(四(三苯基膦)钯(0),二氯二(三苯基膦)钯(II),乙酸钯(II),氯三(三苯基膦)铑(I)),于0~40℃下进行。
除上述方法之外,去保护也可以根据例如T.W.Greene,Protective Groupsin Organic Synthesis,Wiley,New York,1999中所述的方法进行。
羧基保护基的实例包括甲基,乙基,烯丙基,叔丁基,三氯乙基,苄基(Bn),及苯甲酰甲基。
羟基保护基的实例包括甲基,三苯甲基,甲氧基甲基(MOM),1-乙氧基乙基(EE),甲氧基乙氧基乙基(MEM),2-四氢吡喃基(THP),三甲基甲硅烷基(TMS),三乙基甲硅烷基(TES),叔丁基二甲基甲硅烷基(TBDMS),叔丁基二苯基甲硅烷基(TBDPS),乙酰基(Ac),新戊酰基,苯甲酰基,苄基(Bn),对甲氧基苄基,烯丙氧基羰基(Alloc),及2,2,2-三氯乙氧基羰基(Troc)。
氨基保护基的实例包括苄氧基羰基,叔丁氧基羰基,烯丙氧基羰基(Alloc),1-甲基-1-(4-联苯基)乙氧基羰基(Bpoc),三氟乙酰基,9-芴基甲氧基羰基,苄基(Bn),对甲氧基苄基,苄氧基甲基(BOM),及2-(三甲基甲硅烷基)乙氧基甲基(SEM)。
甲酰基保护基的实例包括乙缩醛(如二甲基乙缩醛)。
羧基,羟基,氨基或甲酰基保护基可以是上述之外的可以容易和选择性地除去的任何其它保护基,对此并没有具体的限制。例如,可以采用T.W.Greene,Protective Groups in Organic Synthesis,3rd Ed,Wiley,New York,1999中所述的保护基。
通过选择性地使用去保护反应,可很容易地制备本预期的本发明的化合物,这是本领域的技术人员很容易理解的。
2)在式(I-3)的化合物中,其中T3为氧且13-14位为单键的化合物,即下面式(IB)的化合物:
其中所有符号与上文中所定义的相同,
可以根据下述方法制备。
式(IB)的化合物可通过氢化下面式(III)的化合物来制备:
式中R29-3代表氢,或羟基保护基,其它符号的定义同上,
然后任选从所得产物中除去保护基。
氢化反应是已知的,而且其可以如此实施,例如,在有机溶剂(例如,醚溶剂(如四氢呋喃,二氧己环,二甲氧基乙烷,乙醚),醇溶剂(如甲醇,乙醇),苯型溶剂(如苯,甲苯),酮溶剂(如丙酮,甲乙酮),腈溶剂(如乙腈),酰胺溶剂(如二甲基甲酰胺),水,乙酸乙酯,乙酸,或其中两种或多种的混合溶剂),在催化剂(例如,钯-碳,钯黑,氢氧化钯,氧化铂,Raney镍)存在下,在常压或增压的氢气氛下或甲酸铵存在下,于0~200℃处理所述化合物。
保护基的去除可按与本文中所述方法相同的方法进行。
3)在式(I-3)的化合物中,其中T3为硫的化合物,即下面式(IC)的化合物:
其中所有符号与上文中所定义的相同,
可以根据下述方法制备。
式(IC)的化合物可以通过硫代酰胺化下面式(IV)的化合物来制备:
其中所有符号与上文中所定义的相同,
然后任选从所得产物中除去保护基。
硫代酰胺化反应是已知的,而且其可以如此进行,例如,在有机溶剂(例如,甲苯,乙醚,二氯甲烷,氯仿,二氧己环,四氢呋喃)中,在硫代试剂(例如,Rawson试剂(2,4-二(4-甲氧基苯基)-1,3-二硫杂-2,4-二磷杂环丁烷(diphosphetan)-2,4-二硫化物),五氧化二磷)存在下,于0~150℃下处理所述化合物。
保护基的去除可按与本文中所述方法相同的方法进行。
4)在式(I-3)的化合物中,其中D3为-CH2OH的化合物,即下面式(ID)的化合物:
其中所有符号与上文中所定义的相同,
可以根据下述方法制备。
式(ID)的化合物可通过还原下面式(V)的化合物来制备:
式中R30-3代表C1-10烷基,其它符号的定义同上,
然后任选从所得产物中除去保护基。
该还原反应是已知的,而且其可以如此进行,例如,在有机溶剂(例如,四氢呋喃,二甲氧基乙烷,乙醚,二甲基甲酰胺,二氧己环,甲醇,乙醇,异丙醇)或其水溶液中,在还原剂(如硼氢化钠,硼氢化锂)存在下,于0~70℃下处理所述化合物。
保护基的去除可按与本文中所述方法相同的方法进行。
5)在式(I-3)的化合物中,其中D3为-CONR3-3SO2R4-3,-CONR6-3R7-3,-CONR6-3SO2R8-3,或-CO-(NH-氨基酸残基-CO)m-3-OH的化合物,即下面式(IE)的化合物:
式中D3″代表-CONR3-3SO2R4-3,-CONR6-3R7-3,-CONR6-3SO2R8-3,或-CO-(NH-氨基酸残基-CO)m-3-OH,其它符号的定义同上,
可以根据下述方法制备。
式(IE)的化合物可通过酰胺化下面式(VI)的化合物来制备:
其中所有符号与上文中所定义的相同,
所述酰胺化使用下面式(VII-1)的化合物:
H-NR3-3SO2R4-3 (VII-1)
其中所有符号与上文中所定义的相同,
或者下面式(VII-2)的化合物:
H-NR6-3R7-3 (VII-2)
其中所有符号与上文中所定义的相同,
或者下面式(VII-3)的化合物:
H-NR6-3SO2R8-3 (VII-3)
其中所有符号与上文中所定义的相同,
或者下面式(VII-4)的化合物:
H-(NH-氨基酸残基-CO)m-3-OH (VII-4)
其中所有符号与上文中所定义的相同,但是可以根据需要保护式(VII-4)的化合物中的氨基,羟基或羧基,
然后任选从所得产物中除去保护基。
酰胺化反应是已知的,例如,包括下列方法:
(1)采用酰卤的酰胺化,
(2)采用混合酰卤的酰胺化,
(3)采用缩合剂的酰胺化。
下面详述这些方法。
(1)采用酰卤的方法包括,例如,使羧酸与酰卤化试剂(如草酰氯,亚硫酰氯)在有机溶剂(如氯仿,二氯甲烷,乙醚,四氢呋喃)中或不存在溶剂的情况下,于-20℃至回流温度下反应,然后使所得酰卤与胺在惰性有机溶剂(如氯仿,二氯甲烷,乙醚,四氢呋喃)中,在碱(吡啶,三乙胺,二甲基苯胺,二甲氨基吡啶,二异丙基乙基胺)存在下,于0~40℃下反应。需要时,可以利用碱性水溶液(如碳酸氢钠水溶液,氢氧化钠水溶液),使酰卤在有机溶剂(如二氧己环,四氢呋喃)中,于0~40℃下反应。
(2)采用混合酰酸酐的方法包括,例如,使羧酸与酰卤(如新戊酰氯,甲苯磺酰氯,甲磺酰氯)或酸衍生物(如氯甲酸乙酯,氯甲酸异丁酯)在有机溶剂(如氯仿,二氯甲烷,乙醚,四氢呋喃)中或无溶剂的情况下,在碱(如吡啶,三乙胺,二甲基苯胺,二甲氨基吡啶,二异丙基乙基胺)存在下,于0~40℃下反应,然后使所得混合酸酐与胺在有机溶剂(如氯仿,二氯甲烷,乙醚,四氢呋喃)中,于0~40℃下反应。
(3)采用缩合剂的方法包括,例如,使羧酸与胺在有机溶剂(如氯仿,二氯甲烷,二甲基甲酰胺,乙醚,四氢呋喃)中或无溶剂的情况下,在碱(如吡啶,三乙胺,二甲基苯胺,二甲氨基吡啶)存在或不存在下,利用缩合剂(如1,3-二环己基碳二亚胺(DCC),1-乙基-3-[3-(二甲氨基)丙基]碳二亚胺(EDC),1,1′-碳基二咪唑(CDI),2-氯-1-甲基吡啶鎓碘化物,1-丙烷磷酸环酸酐(PPA)),并利用或不利用1-羟基苯并三唑(HOBt)或1-甲磺酰氧基苯并三唑,于0~40℃下反应。
优选反应(1),(2)和(3)均在惰性气体(如氩气,氮气)气氛和无水条件下进行。
保护基的去除可按与本文中所述方法相同的方法进行。
6)在式(I-3)的化合物中,其中D3为-O-(CO-氨基酸残基-NH)m-3-H或-OCO-R10-3的化合物,即下面式(IF)的化合物:
式中D3″′代表-O-(CO-氨基酸残基-NH)m-3-H或-OCO-R10-3,其它符号的定义同上,
可以根据下述方法制备。
式(IF)的化合物可以通过酯化下面式(VIII)的化合物来制备:
式中R31-3代表-OH或-CH2OH,其它符号的定义同上,
所述酯化采用下面式(IX-1)的化合物:
HO-(CO-氨基酸残基-NH)m-3-H (IX-1)
其中所有符号与上文中所定义的相同,但是需要时,可以对式(IX-1)的化合物中的氨基,羟基或羧基实施保护,
或者下面式(IX-2)的化合物
HOOC-R10-3(IX-2)
式中R10-3的意义同上,
然后任选从所得产物中除去保护基。
酯化反应是已知的,例如,其包括下列方法:
(1)采用酰卤进行酯化,
(2)采用混合酰卤进行酯化,
(3)采用缩合剂进行酯化。
这些方法详述如下。
(1)采用酰卤的方法包括,例如,使羧酸与酰卤化试剂(如草酰氯,亚硫酰氯)在有机溶剂(例如,氯仿,二氯甲烷,乙醚,四氢呋喃)中或不存在溶剂的情况下,于-20℃至回流温度下反应,然后使所得酰卤与醇在碱(吡啶,三乙胺,二甲基苯胺,二甲氨基吡啶,二异丙基乙基胺)存在下,在惰性有机溶剂(如氯仿,二氯甲烷,乙醚,四氢呋喃)中,于0~40℃下反应。需要时,可使酰卤在有机溶剂(如二氧己环,四氢呋喃)中,利用碱性水溶液(如碳酸氢钠水溶液,氢氧化钠水溶液),于0~40℃下进行反应。
(2)采用混合酸酐的方法包括,例如,使羧酸与酰卤(如新戊酰氯,甲苯磺酰氯,甲磺酰氯)或酸衍生物(如氯甲酸乙酯,氯甲酸异丁酯)在有机溶剂(如氯仿,二氯甲烷,乙醚,四氢呋喃)中或不存在溶剂的情况下,在碱(如吡啶,三乙胺,二甲基苯胺,二甲氨基吡啶,二异丙基乙基胺)存在下,于0~40℃下反应,然后使所得混合酸酐与醇在有机溶剂(如氯仿,二氯甲烷,乙醚,四氢呋喃)中,于0~40℃下反应。
(3)采用缩合剂的方法包括,例如,使羧酸与胺在有机溶剂(如氯仿,二氯甲烷,二甲基甲酰胺,乙醚,四氢呋喃)中或不存在溶剂的情况下,在碱(如吡啶,三乙胺,二甲基苯胺,二甲氨基吡啶)存在或不存在的情况下,利用缩合剂(如1,3-二环己基碳二亚胺(DCC),1-乙基-3-[3-(二甲氨基)丙基]碳二亚胺(EDC),1,1′-碳基二咪唑(CDI),2-氯-1-甲基吡啶鎓碘化物,1-丙烷磷酸环酸酐(PPA)),并利用或不利用1-羟基苯并三唑(HOBt),于0~40℃下进行反应。
优选反应(1),(2)和(3)均在惰性气体(如氩气,氮气)气氛中和无水条件下进行。
保护基的去除可按与本文中所述方法相同的方法进行。
7)在式(I-3)的化合物中,其中D3为甲酰基的化合物,即下面式(IG)的化合物:
其中所有符号与上文中所定义的相同,
可以根据下述方法制备。
式(IG)的化合物可以通过氧化下面式(X)的化合物来制备:
其中所有符号与上文中所定义的相同,
然后任选从所得产物中除去保护基。
氧化反应是已知的,例如,其包括下列方法:
(1)Swern氧化反应,
(2)采用Dess-Martin试剂的氧化反应,
(3)采用TEMPO试剂的氧化反应。
下面详述这些方法。
(1)Swern氧化反应包括,例如,使草酰氯与二甲亚砜在有机溶剂(如氯仿,二氯甲烷)中于-78℃下反应,然后使所得溶液与醇化合物反应,并进一步与叔胺(如三乙胺,N,N-二异丙基乙基胺,N-甲基吗啉,N-乙基哌啶,二氮杂二环[5.4.0]十一碳-7-烯)在-78~20℃反应。
(2)采用Dess-Martin试剂的氧化反应包括,例如,在有机溶剂(如氯仿,二氯甲烷,1,2-二氯乙烷,四氢呋喃,乙腈,叔丁醇)中,在Dess-Martin试剂(I,I,I-三乙酰氧基-I,I-二氢-1,2-苯并碘代氧杂环戊烯(benzoiodoxol)-3-(1H)-酮)存在下,在存在或不存在碱(如吡啶)的情况下,于0~40℃处理化合物。
(3)采用TEMPO试剂的方法包括,例如,在有机溶剂(如氯仿,二氯甲烷,四氢呋喃,甲苯,乙腈,乙酸乙酯,水)或其混合溶剂中,在TEMPO试剂(2,2,6,6-四甲基-1-哌啶氧基,自由基)和再氧化试剂(过氧化氢水溶液,次氯酸钠,3-氯过苯甲酸,碘苯二乙酸盐,过一硫酸钾(Oxon,商品名))存在下,在存在或不存在季铵盐(如氯化四丁基铵,溴化四丁基铵)的情况下,及存在或不存在无机盐(如溴化钠,溴化钾),存在或不存在无机碱(如碳酸氢钠,乙酸钠)的情况下,于20~60℃下处理化合物。
氧化反应不限于上述氧化反应,也可以是能够容易和选择性地将醇氧化至酮的任何其它氧化方法。例如,本发明中可Johns氧化,PCC(氯铬酸吡啶)氧化,三氧化硫-吡啶络合物氧化,或《广义有机转化》(ComprehensiveOrganic Transformations)(Richard C.Larock,VCH Publishers,Inc.,(1989),pp.604-614)中所述的任何方法。
保护基的去除可按与本文中所述方法相同的方法进行。
8)在式(I-3)的化合物中,其中D3为-COOR2-3,-COOR9-3,或-COO-Z1-3-Z2-3-Z3-3的化合物,即下面式(IH)的化合物:
式中D3″″代表-COOR2-3,-COOR9-3,或-COO-Z1-3-Z2-3-Z3-3,其它符号的定义同上,
可以根据下述方法制备。
式(IH)的化合物可通过酯化下面式(VI)的化合物来制备:
其中所有符号与上文中所定义的相同,
所述酯化采用下面式(XI-1)的化合物:
R31-3-R2-3(XI-1)
式中R31-3代表羟基或卤素,其它符号的定义同上,
或者下面式(XI-2)的化合物:
R31-3-R9-3(XI-2)
其中所有符号与上文中所定义的相同,
或者下面式(XI-3)的化合物:
R31-3-Z1-3-1-Z2-3-1-Z3-3-1(XI-3)
式中Z1-3-1,Z2-3-1和Z3-3-1分别与Z1-3,Z2-3和Z3-3同义,但需要时,可任选地对Z1-3-1-Z2-3-1-Z3-3-1基团中的羟基,氨基,羧基或甲酰基实施保护,
然后任选从所得产物中除去保护基。
采用式(XI-1),(XI-2)和(XI-3)的化合物的酯化(其中R31-3为羟基),可按与上述相同的方法来进行。
采用式(XI-1),(XI-2)和(XI-3)的化合物的酯化(其中R31-3为卤素),可如此进行,例如,在有机溶剂(如二甲基甲酰胺,四氢呋喃,二氧己环,乙醚,二甲基乙酰胺)中,在存在碱(如碳酸钾,碳酸铯,碳酸钠,碳酸氢钾,碳酸氢钠,氢氧化钾,氢氧化钠)的情况下,于0~150℃下进行。
保护基的去除可按与本文中所述方法相同的方法进行。
9)在式(I-3)的化合物中,其中E3的取代基为氨基的化合物可以通过硝基的还原来制备。
硝基还原反应是已知的,且其可以如此进行,例如其可以通过氢化和有机金属还原来进行。
氢解反应是已知的,而且可以通过氢解实施去保护,例如,在惰性溶剂(例如,醚溶剂(如四氢呋喃,二氧己环,二甲氧基乙烷,乙醚),醇溶剂(如甲醇,乙醇),苯型溶剂(如苯,甲苯),酮溶剂(如丙酮,甲乙酮),腈溶剂(如乙腈),酰胺溶剂(如二甲基甲酰胺),水,乙酸乙酯,乙酸,或其中两种或多种的混合溶剂),在氢化催化剂(例如,钯-碳,钯黑,钯,氢氧化钯,二氧化铂,镍,Raney镍,氯化钌)存在下,在存在或不存在无机酸(例如,盐酸,硫酸,次氯酸,硼酸,四氟硼酸)或有机酸(例如,乙酸,对甲苯磺酸,草酸,三氟乙酸,甲酸)的情况下,在常压或加压的氢气氛中或者存在甲酸铵的情况下,于0~200℃下进行。如果使用,也可以用酸的盐代替所述的酸。
采用有机金属的还原反应是已知的,而且其可以如此进行,例如,在水混溶的溶剂(如乙醇,甲醇)中,在存在或不存在盐酸水溶液的情况下,利用有机金属(如,锌,铁,锡,氯化锡,氯化铁),于50~150℃下进行。
10)在式(I-3)的化合物中,其中T3为氧且X3为-CH2-的化合物,即下面式(IJ)的化合物:
其中所有符号与上文中所定义的相同,
可以根据下述方法制备。
式(IJ)的化合物可以通过还原胺化下面式(XII)的化合物来制备:
其中所有符号与上文中所定义的相同,
所述还原胺化采用下面式(XIII)的化合物:
OHC-A3″—D3′(XIII)
式中A3″代表A1′-3或A2′-3,
A1′-3代表
1)直链的C1-7亚烷基,其任选被1或2个C1-4烷基所取代,
2)直链的C2-7亚链烯基,其任选被1或2个C1-4烷基所取代,或者
3)直链的C2-7亚炔基,其任选被1或2个C1-4烷基所取代,
A2′-3代表-G1′-3-G2-3-G3-3-,
G1′-3代表
1)单键,
2)直链的C1-3亚烷基,其任选被1或2个C1-4烷基所取代,
3)直链的C2-3亚链烯基,其任选被1或2个C1-4烷基所取代,或者
4)直链的C2-3亚炔基,其任选被1或2个C1-4烷基所取代,
其它符号的定义同上,
然后任选从所得产物中除去保护基。
还原胺化反应是已知的,且其可以如此进行,例如,在有机溶剂(例如,乙酸乙酯,二氯乙烷,二氯甲烷,二甲基甲酰胺,四氢呋喃,乙酸,或其混合物)中,在还原剂(例如,三乙酰氧基硼氢化钠,氰基硼氢化钠,硼氢化钠,硼氢化锌,氢化二异丁基铝)存在下,于-15~100℃下进行,或者在有机溶剂(例如,乙酸乙酯,二氯乙烷,二氯甲烷,甲醇,乙醇,乙酸,或其混合物)在,在催化剂(例如,钯-碳,钯黑,氢氧化钯,氧化铂,Raney镍)存在下,在常压或增压的氢气氛中,于0~200℃下进行。
保护基的去除可按与本文中所述方法相同的方法进行。
在本发明的化合物中,式(I-2)的化合物可以根据下述方法或者根据下述实施例中所述的方法来制备。
1)在式(I-2)的化合物中,其中R1-2为-CO-(NH-氨基酸残基-CO)m-2-OH的化合物,即下面式(IK)的化合物:
式中R1-2-1代表-CO-(NH-氨基酸残基-CO)m-2-OH,其它符号的定义同上,
可以根据下述方法制备。
式(IK)的化合物可以通过胺化其中R1-1为羟基的式(I-1)的化合物,即下面式(I-1-1)的化合物来制备:
其中所有符号与上文中所定义的相同,
所述胺化采用下面式(XIV)的化合物:
H-(NH-氨基酸残基-CO)m-2-OH (XIV)
其中所有符号与上文中所定义的相同,但是需要时,可任选地对式(XIV)化合物中的氨基,羟基或羧基实施保护,
然后任选从所得产物中除去保护基。
胺化和去保护可按与上述相同的方法进行。
2)在式(I-2)的化合物中,其中R1-2为-COO-Y2-R9-2,或-COO-Z1-2-Z2-2-Z2-3的化合物,即下面式(IL)的化合物:
式中R1-3-2代表-COO-Y2-R9-2,或-COO-Z1-2-Z2-2-Z2-3,其它符号的定义同上,
可以根据下述方法制备。
式(IL)的化合物可以通过酯化下面式(I-1-1)的化合物来制备:
其中所有符号与上文中所定义的相同,
所述脂化采用下面式(XV-1)的化合物:
R23-2-Y2-R9-2(XV-1)
式中R23-2代表羟基或卤素,其它符号的定义同上,
或者下面式(XV-2)的化合物:
R23-2-Z1-2-1-Z2-2-1-Z3-2-1(XV-2)
式中Z1-2-1,Z2-2-1和Z3-2-1分别与Z1-2,Z2-2和Z3-2同义,但需要时,可任选对基团Z1-2-1-Z2-2-1-Z3-2-1中的羟基,氨基,羧基或甲酰基实施保护。
然后任选从所得产物中除去保护基。
用其中R23-2为羟基的的式(XV-1)和(XV-2)的化合物的酯化,可按与上述相同的方法来进行。
用其中R23-2为卤素的式(XV-1)和(XV-2)的化合物的酯化,也可按与上述相同的方法来进行。
去保护同样可按与上述相同的方法来进行。
式(II),(VII-1),(VII-2),(VII-3),(IX-1),(IX-2),(XI-1),(XI-2),(XII),(XIII),(XIV),(XV-1)和(XV-2)的化合物本身是已知的,或者容易根据已知方法制得。
例如,式(II)和(XII)的化合物可根据下面反应流程1,2和3来制备。
在这些反应流程中,Boc代表叔丁氧基羰基,R32-3代表羟基保护基,Ac代表乙酰基,R33-3代表卤素,R34-3代表C1-3亚烷基,R35-3代表C1-4亚烷基,R36-3代表氨基保护基,其它符号的定义同上。
反应流程1
反应流程2
反应流程3
在反应流程1,2和3中,式(XVI),(XVII),(XXIII),(XXVII),(XXVIII),(XXXII)和(XXXIII)的起始化合物是已知的,或者容易根据已知方法制备。
在本说明书中,各反应阶段的反应产物可根据常规手段进行纯化,例如,通过常压或减压蒸镏,通过高压液相色谱,薄层色谱或者硅胶或硅酸镁柱色谱,或者通过洗涤或重结晶纯化。纯化可以在每一反应阶段中或某些反应阶段之后进行
工业实用性
在药物制剂中的应用:
式(I-2)和(I-3)所示的本发明的化合物专门和强烈地作用于PGE受体EP4亚型,因而被视为可用于预防和/或治疗免疫疾病(例如,自体免疫疾病如肌萎缩侧索硬化(ALS),多发性硬化,Sjogren氏综合症,慢性风湿病和全身性红斑狼疮,器官移植后的排斥)及如下的疾病,如哮喘,神经细胞死亡,关节炎,肺病,纤维化肺,肺气肿,支气管炎,慢性阻塞性呼吸系统疾病,肝病,急性肝炎,肾炎(急性肾炎,慢性肾炎),肾机能不全,高血压,心肌缺血,全身性炎症应答综合症,脓毒病,吞噬血细胞作用综合症,巨噬细胞活化综合症,斯蒂尔病,川畸病,热烧伤,全身性肉芽肿,溃疡性结肠炎,克罗恩病,透析期间的高细胞因子症,多发性器官功能障碍综合症和休克。EP4受体还参与粘膜的膜保护作用,因而被视为可用于预防和/或治疗消化道溃疡如胃溃疡和十二指肠溃疡及口腔炎。EP4受体也参与促毛发生长作用和毛发生长作用,因而被视为可用于预防和/或治疗脱发。此外,EP4受体还参与子宫颈管的成熟作用,因而被视为可用作子宫颈管的催熟剂。
此外,与EP4受体结合的化合物还具有加速成骨作用,因而被视为不仅可以用于预防和/或治疗骨量减少的骨病,例如,1)原发性骨质疏松,其是因为衰老、绝经和卵巢切除而导致的,2)继发性骨质疏松症(如糖皮质激素诱发的骨质疏松,甲状腺机能亢进诱发的骨质疏松,固定化导致的骨质疏松,肝素诱发的骨质疏松,免疫抑制诱发的骨质疏松,肾机能不全导致的骨质疏松,炎性骨质疏松,Cushing氏综合症诱发的骨质疏松,风湿性骨质疏松等),3)骨病,如癌的骨转移,高钙血症,Behcet氏疾病,骨缺乏(如牙槽骨缺乏,下颌骨缺乏,婴儿原发性骨缺乏)和骨坏死,而且可以用作加速成骨作用/骨手术(如骨折,骨移植物,人造关节形成术,脊柱融合,其它骨修复)后的治疗的药剂,或者骨转移的替代药物。
而且,EP4参与诱导生理睡眠和抑制血小板聚集,因而与EP4受体结合的化合物可用于预防睡眠障碍和血栓形成。
与EP4选择性结合的化合物既没有可能归因于EP1的产生疼痛的作用,也没有可能归因于EP3的子宫收缩作用,因而被认为是没有这类作用的药剂。
式(I-3)所示的化合物是与EP4受体及EP2受体相连的化合物。与EP2受体相连的化合物被认为可用于预防和/或治疗免疫疾病(例如,自体免疫疾病如肌萎缩侧索硬化(ALS),多发性硬化,Sjogren氏综合症,慢性风湿病及全身性红斑狼疮,器官移植后的排斥)和如下的疾病,如哮喘,神经细胞死亡,早产,流产,部分视网膜神经疾病如青光眼,勃起机能不全,关节炎,肺病,肺纤维化,肺气肿,支气管炎,慢性阻塞性呼吸系统疾病,肝病,急性肝炎,休克,肾炎,肾机能不全,循环系统疾病(例如,高血压,心肌缺血,慢性动脉梗阻,振动病),全身性炎症应答综合症,脓毒病,吞噬血细胞作用综合症,巨噬细胞活化综合症,斯蒂尔病,川畸病,热烧伤,全身性肉芽肿,溃疡性结肠炎,克罗恩病,透析期间高细胞因子症,多发性器官功能障碍综合症和骨疾病(例如,骨折,再骨折,骨连接不足,假关节,骨软化,骨Behcet氏疾病,脊椎炎,癌的骨转移,骨关节炎,类似疾病导致的骨/软骨损坏)。也认为,与EP2受体结合的化合物也可用作加速成骨作用/骨手术(如骨折,骨移植物,人造关节形成术,脊柱融合,多发性骨髓瘤手术,肺癌,乳腺癌等,及其它骨修复)之后的治疗的药剂,或者骨转移的替代药。还认为该化合物可用作加速牙周质(peridontium)疾病中牙周质再生的药剂。
预期与EP4受体和EP2受体结合的化合物对与两种受体有关的疾病发挥辅助或协同作用。
式(I-1),(I-2)或(I-3)所示的化合物或其无毒盐可与其它药物制剂组合给药,以实现下列目的:
1)补偿和/或增强要组合的化合物的预防和/或治疗效果;
2)提高要组合的化合物的动力学/吸收并降低该化合物的剂量;和/或
3)消除要组合的化合物的副作用。
式(I-1),(I-2)或(I-3)所示化合物及其它药物制剂可以这些组分混于一种制剂中的制剂给药,也可以单独的制剂给药。对于这些药剂以单独的制剂给药的情形,它们可以同时或不同时给药。对于后者,式(I-1),(I-2)或(I-3)所示化合物可先于其它药物制剂给药。作为选择,其它药物制剂也可先于式(I-1),(I-2)或(I-3)所示化合物给药。这些药剂的给药方法可以相同或相异。
对前述组合制剂发挥预防和/或治疗效果的疾病没有具体的限制,但可以是式(I-1),(I-2)或(I-3)所示化合物补偿和/或增强预防和/或治疗效果的疾病。
用于补偿和/或增强式(I-1),(I-2)或(I-3)所示化合物预防和/或治疗骨病效果的其它药物制剂的实例包括磷酸二酯酶-4抑制剂,二膦酸酯制剂,维生素D制剂,钙佐剂,雌激素制剂,降钙素制剂,异黄酮基制剂,合成代谢的类固醇制剂,维生素K制剂,组织蛋白酶K抑制剂,前列腺素,抑制素,甲状旁腺素,及生长因子。
用于补偿和/或增强式(I-1),(I-2)或(I-3)所示化合物预防和/或治疗慢性阻塞性肺部疾病和/或哮喘效果的其它药物制剂的实例包括磷酸二酯酶-4抑制剂,类固醇制剂,β2肾上腺素受体兴奋剂,白细胞三烯受体拮抗剂,血栓素合成酶抑制剂,血栓素A2受体拮抗剂,介质释放抑制剂,抗组安剂,黄嘌呤衍生物,抗胆碱能制剂,细胞因子抑制剂,前列腺素,金属蛋白酶(metaprotease)抑制剂,除痰剂,及抗生素。
用于补偿和/或增强式(I-1),(I-2)或(I-3)所示化合物预防和/或治疗关节炎或慢性关节风湿病效果的其它药物制剂的实例包括金属蛋白酶抑制剂,免疫抑制剂,非类固醇基消炎剂(NSAID),类固醇制剂,及磷酸二酯酶-4抑制剂。
用于补偿和/或增强式(I-1),(I-2)或(I-3)所示化合物预防和/或治疗勃起机能不全效果的其它药物制剂的实例包括磷酸二酯酶-5抑制剂。
用于补偿和/或增强式(I-1),(I-2)或(I-3)所示化合物预防和/或治疗休克效果的其它药物制剂的实例包括弹性蛋白酶抑制剂。
用于补偿和/或增强式(I-1),(I-2)或(I-3)所示化合物预防和/或治疗结肠炎效果的其它药物制剂的实例包括类固醇制剂,磷酸二酯酶-4抑制剂,非类固醇基消炎剂,血栓素A2受体拮抗剂,白细胞三烯受体拮抗剂,血管紧张素II拮抗剂,血管紧张素转化酶抑制剂,及利尿剂。
用于补偿和/或增强式(I-1),(I-2)或(I-3)所示化合物预防和/或治疗高血压效果的其它药物制剂的实例包括钙拮抗剂,血管紧张素II拮抗剂,血管紧张素转化酶抑制剂,磷酸二酯酶-4抑制剂,及利尿剂。
磷酸二酯酶-4抑制剂的实例包括咯利普兰,西洛司特(商品名:Ariflo),Bay 19-8004,NIK-616,西洛司特(BY-217),西潘荼碱(BGL-61063),atizolam(CP-80633),SCH-351591,YM-976,V-11294A,PD-168787,D-4386,及IC-485。
磷酸二酯酶-5抑制剂的实例包括昔多芬。
二膦酸盐制剂的实例包括阿伦膦酸钠,chlodronate二钠,帕米膦酸二钠,ethydronate二钠,ivandronate,英卡膦酸二钠,minodronate,奥帕膦酸盐,利塞膦酸钠,tildronate,及zoIedronate。
降钙素制剂的实例包括降钙素,及依降钙素。
前列腺素(下文中简称为″PG″)的实例包括PG受体激动剂,及PG受体拮抗剂。
PG受体的实例包括PGE受体(EP1,EP2,EP3,EP4),PGD受体(DP),PGF受体(FP),及PGI受体(IP)。
外用类固醇制剂的实例包括丙酸氯氟美松,乙酸二氟拉松,氟轻松,单强的松呋喃羧酸酯,倍他米松二丙酸酯,倍他米松丁酯丙酯,戊酸倍他米松,醋丁二氟龙,戊酸布地奈德,安西奈德,哈西奈德,地塞米松,丙酸地塞米松,戊酸地塞米松,乙酸地塞米松,乙酸氢化可的松,丁酸氢化可的松,氢化可的松乙酯丙酯,丙酸地泼罗酮,泼尼松龙戊酯乙酯,氟氢松,二丙酸倍氯米松,曲安奈德,特戊酸二氟美松,去氢氢化可的松,丙酸倍氯米松,及氟氢缩松。
内用类固醇制剂的实例包括醋酸可的松,氢化可的松,磷酸氢化可的松钠,琥珀酸氢化可的松钠,醋酸氟氢可的松,泼尼松龙,醋酸泼尼松龙,琥珀酸泼尼松龙钠,泼尼松龙丁酯乙酯,磷酸泼尼松龙钠,醋酸卤泼尼松,甲基泼尼松龙,醋酸甲基泼尼松龙,琥珀酸甲基泼尼松龙钠,去炎松,醋酸去炎松,曲安奈德,地塞米松,乙酸地塞米松,磷酸地塞米松钠,棕榈酸地塞米松,醋酸对氟米松,及倍他米松。
作为吸入剂的类固醇制剂的实例包括丙酸倍氯米松,丙酸氟替卡松,布地奈德,氟尼缩松,去炎松,ST-126P,环索奈德,软脂酸地塞米松,单强的松呋喃羧酸酯,磺酸普拉雄酮,去氟可特,甲基泼尼松龙sreptanate,甲基泼尼松龙琥珀酸钠。
β2肾上腺素受体兴奋剂的实例包括氢溴酸非诺特罗,硫酸沙丁胺醇,硫酸叔丁喘宁,富马酸福莫特罗,沙美特罗昔萘酸酯,硫酸isoprotenol,硫酸奥西那林,硫酸氯普鲁卡因,肾上腺素,叔丁氯喘通盐酸盐,硫酸海索那林甲磺酸酯,美喘清盐酸盐,妥洛特罗盐酸盐,妥洛特罗,吡布特罗盐酸盐,克仑特罗盐酸盐,马布特罗盐酸盐,利托君盐酸盐,班布特罗,多培沙明盐酸盐,酒石酸meradrin,AR-C68397,左沙丁胺醇,R,R-福莫特罗,KUR-1246,KUL-7211,AR-C89855,及S-1319。
白细胞三烯受体拮抗剂的实例包括水合普仑司特,孟鲁司特,扎鲁司特,塞曲司特,MCC-847,KCA-757,CD-615,YM-158,L-740515,CP-195494,LM-1484,RS-635,A-93178,S-36496,BIIL-284,及ONO-4057。
血栓素合成酶抑制剂的实例包括盐酸奥扎格雷,及咪曲司特钠。
血栓素A2受体拮抗剂的实例包括塞曲司特,雷马曲班,多米曲班钙二水合物,及KT-2-962。
介质释放抑制剂的实例包括曲尼司特,色甘酸钠,anlexanox,瑞吡司特,异丁司特,他扎司特,及吡嘧司特钠。
抗组安剂的实例包括富马酸酮替芬,美喹他嗪,盐酸氮卓斯汀,奥沙米特,特非那定,富马酸依美斯汀,盐酸依匹斯汀,阿司咪唑,依巴斯汀,盐酸西替利嗪,贝他斯汀,非索非那定,lolatadine,deslo1atadine,盐酸奥洛他定,TAK-427,ZCR-2060,NIP-530,莫米松,咪唑斯汀,BP-294,安多司特,金诺芬,及acribastin。
黄嘌呤衍生物的实例包括氨茶碱,茶碱,多索茶碱,cipamphilline,及二羟丙荼碱。
抗胆碱能制剂的实例包括异丙托溴铵,氧托溴铵,氟托溴铵,替米维林,噻托溴铵,及瑞伐托酯(UK-112166)。
细胞因子抑制剂的实例包括甲磺司特(商品名:IPD)。
去痰剂的实例包括氨制茴香醑,碳酸氢钠,必嗽平盐酸盐,羧甲司坦,盐酸安溴素,盐酸缓释安溴素,盐酸甲基半胱氨酸,乙酰半胱氨酸,盐酸L-乙基半胱氨酸,及泰洛沙泊。
生长因子的实例包括成纤维细胞生长因子(FGF),血管内皮生长因子(VEGF),肝细胞生长因子(HGF),及类胰岛素生长因子。
非类固醇基消炎剂的实例包括水杨酰水杨酸,水杨酸钠,阿司匹林,阿司匹林二铝酸制剂,双氟尼酸,吲哚美辛,舒洛芬,乌芬那酯,二甲基异丙基阿祖耳,丁苯羟酸,联苯乙酸,双氯芬酸,甲苯酰吡酸钠,奇诺力,芬布芬,napmetone,丙谷美辛,消炎痛法尼酯,醋炎痛,马来酸丙谷美辛,氨芬酸钠,莫苯唑酸,依托度酸,布洛芬,布洛芬吡啶甲醇,萘普生,氟比洛芬,乙酰氟比洛芬,酮洛芬,非诺洛芬钙,噻咯吩,奥沙普秦,普拉洛芬,洛索洛芬钠,aluminoprofen,扎托洛芬,甲芬那酸,甲灭酸铝,托芬那酸,夫洛非宁,酮保泰松,oxyfenbutazone,吡罗昔康,替诺昔康,anpiroxicam,联苯乙酸膏,依匹唑,羟哌苯酮盐酸盐,替诺立定盐酸盐,依莫法宗,安乃近,米格来宁,散利痛,Sedes G,氨丙毗酮N,Sorbon,嘌呤(pyrine)系退热药,扑热息痛,非那西汀,甲磺酸胺磺异丙嗪,西美曲特制剂,及安替比林系退热药。
利尿剂的实例包括甘露醇,呋塞米,乙酰唑胺,双氯非那胺,醋甲唑胺,三氯噻嗪,美夫西特,spinolactone,及氨茶碱。
式(I-1),(I-2)或(I-3)所示化合物与其它药物制剂的重量比没有具体的限制。
任意两种或多种其它药物制剂可以组合给药。
用于补偿和/或增强式(I-1),(I-2)或(I-3)所示化合物的预防和/或治疗效果的其它药物制剂的实例不仅包括目前已经发现药剂,还包括根据前述机理将要发现的药剂。
为了使式(I-2)和(I-3)所示的本发明的化合物或者式(I-1),(I-2)或(I-3)所示化合物与其它药物制剂组合使用,这些化合物一般都经口或非经胃肠整体或局部给药于人体。
这些化合物的剂量取决于患者的年龄、体重和症候,治疗价值,给药方法,治疗时间等。然而在实践中,这些化合物每个成人每日经口给药一次或几次,每天1ng至100mg,每个成人每日非经胃肠给药一次或几次,每天0.1ng至100mg,或者每天连续静脉给药1~24小时。
当然,这些化合物的剂量可以小于前述的剂量,也可能需要超过前述的剂量范围,因为剂量是根据前述条件而变化的。
当式(I-2)和(I-3)所示的本发明的化合物或式(I-1),(I-2)或(I-3)所示化合物与其它药物制剂组合给药时,它们以固体或液体药剂的形式用于经口给药,及非经口给药的注射剂,外用药剂,栓剂,滴剂或吸入剂等。
经口给药的固体药剂的实例包括片剂,丸剂,胶囊,粉剂,及颗粒。胶囊的实例包括硬胶囊和软胶囊。
在这种内用的固体药剂中,采用普通方法制备的制剂中仅使用一种或多种活性物质,或者其与下列为混合物:赋形剂(如乳糖,甘露醇,葡萄糖,微晶纤维素,淀粉),粘结剂(如羟丙基纤维素,聚乙烯吡咯烷酮,偏硅铝酸镁),崩解剂(如纤维素乙醇酸钙),助流剂(如硬脂酸镁),稳定剂,溶解助剂(如谷氨酸,天冬氨酸)等。固体药剂可以涂有包衣剂(如白糖,明胶,羟丙基纤维素,邻苯二甲酸羟丙基甲基纤维素)或者两层或多层包衣剂。作为选择,固体药剂可以通过明胶等可吸收物质微胶囊化。
经口给药的液体药剂的实例包括药学上可接受的水溶液,悬浮液,乳液,糖浆,及酏剂。在这种液体药剂中,一种或多种活性药剂溶解、悬浮或乳化于常用的稀释剂(如纯水,乙醇,其混合物)中。此外,这种液体药剂可以包含润湿剂,悬浮剂,乳化剂,甜味剂,调味剂,防腐剂,缓冲剂等。
非经胃肠给药的药剂可以为例如软膏,凝胶,乳膏,湿敷布,糊剂,擦剂,薄翳,吸入剂,喷剂,滴眼剂,滴鼻剂等。这些药剂各自包含一种或多种活性物质,并且通过任何已知方法或常用配方制备。
软膏通过任何已知方法或常用配方制备。例如,将一种或多种活性物质研磨或溶解于基质中制成这种软膏。软膏基质选自已知的或常用的材料。略微具体地,可以单独使用高级脂肪酸或高级脂肪酸酯(例如,己二酸,肉豆蔻酸,棕榈酸,硬脂酸,油酸,己二酸酯,肉豆蔻酸酯,棕榈酸酯,硬脂酸酯,油酸酯),蜡(如蜂蜡,鲸蜡,地蜡),表面活性剂(如聚氧乙烯烷基醚磷酸酯),高级醇(如鲸蜡醇,硬脂醇,setostearyl醇),硅油(如二甲基聚硅氧烷),烃(如亲水矿脂,白矿脂,纯羊毛脂,液体石蜡),二醇(如乙二醇,二甘醇,丙二醇,聚乙二醇,聚乙二醇(macrogol)),植物油(如蓖麻油,橄榄油,香油,松节油),水,吸收促进剂和皮炎预防剂,或者使用其两种或多种的混合物。基质还可以包含保湿剂,防腐剂,稳定剂,抗氧剂,香料等。
凝胶通过任何已知方法或常用配方制备。例如,将一种或多种活性物质溶解于基质中制成这种凝胶。凝胶基质选自已知的或常用的材料。例如,单独使用低级醇(如乙醇,异丙醇),胶凝剂(如羧基甲基纤维素,羟乙基纤维素,羟丙基纤维素,乙基纤维素),中和剂(如三乙醇胺,二异丙醇胺),表面活性剂(如聚乙二醇单硬脂酸酯),树胶,水,吸收促进剂,及皮炎预防剂,或者它们的两种或多种的混合物。凝胶基质还可以包含保湿剂,抗氧剂,香料等。
乳剂通过任何已知方法或常用配方制备。例如,将一种或多种活性物质溶解于基质中制成这种乳剂。乳剂基质选自已知的或常用的材料。例如,可以单独使用高级脂肪酸酯,低级醇,烃,多元醇(如丙二醇,1,3-丁二醇),高级醇(如2-己基癸醇,鲸蜡醇),乳化剂(如聚氧乙烯烷基醚,脂肪酸酯),水,吸收促进剂,及皮炎预防剂,或者使用其两种或多种的混合物。乳剂基质还可以包含保湿剂,抗氧剂,香料等。
湿敷布通过任何已知方法或常用配方制备。例如,将一种或多种活性物质溶解于基质制成捏制的混合物,然后将其展开于载体上制成湿敷布。湿敷布基质选自已知的或常用的材料。例如,可以单独使用增稠剂(如聚丙烯酸,聚乙烯吡咯烷酮,阿拉伯树胶,淀粉,明胶,甲基纤维素),润湿剂(如尿素,甘油,丙二醇),填料(如高岭土,氧化锌,滑石,钙,镁),水,溶解助剂,增粘剂,及皮炎预防剂,或者使用其两种或多种的混合物。湿敷布基质还可以包含保湿剂,抗氧剂,香料等。
糊剂通过任何已知方法或常用配方制备。例如,将一种或多种活性物质溶解于基质制成捏制的混合物,然后将其展开于载体上制成这种糊剂。糊剂基质选自已知的或常用的材料。例如,可以单独使用聚合物基质,油脂,高级脂肪酸,增粘剂和皮炎预防剂,或者使用其两种或多种的混合物。糊剂基质还可以包含保湿剂,抗氧剂,香料等。
擦剂通过任何已知方法或常用配方制备。例如,将一种或多种活性物质溶解、悬浮或乳化于单独的水,醇(如乙醇,聚乙二醇),高级脂肪酸,甘油,肥皂,乳化剂,悬浮剂等中,或其两种或多种的混合物中,制成这种擦剂。擦剂还可以包含保湿剂,抗氧剂,香料等。
薄翳,吸入剂和喷剂可以各自包含稳定剂如亚硫酸氢钠和能够提供等渗性的缓冲剂如等渗剂(如氯化纳,柠檬酸钠,柠檬酸)。制备喷剂的方法可参考US 2868691和US 3095355。这些药剂可以是气溶胶形式。
非经胃肠给药的注射剂可以是溶液,悬浮液,乳浊液,及使用时溶解或悬浮于溶剂中的固体注射剂。注射剂通过溶解、悬浮或乳化一种或多种活性物质与溶剂中来制备。作为这种溶剂,可以单独或组合使用注射用蒸馏水,生理盐水,植物油,醇如丙二醇、聚乙二醇和乙醇等。注射剂还可以包含稳定剂,溶解助剂(如谷氨酸,天冬氨酸,Polysolvate 80(商品名)),悬浮剂,乳化机,安慰剂,缓冲剂,防腐剂等。注射剂在最终步骤灭菌,或者通过无菌工艺制备。作为选择,可以在使用前,使无菌固体药剂如事先制成的冻干制品灭菌或溶解于无菌的注射用蒸馏水或其它溶剂中。
非经胃肠给药滴眼剂可以是液体,悬浮液,乳剂或软膏的形式,也可以在使用前溶解于溶剂。
这些滴眼剂根据任何已知的方法制备。例如,将一种或多种活性物质溶解、悬浮或乳化于溶剂中。作为滴眼剂的溶剂,可以单独或组合使用无菌纯水,生理盐水及其它含水或非水溶剂(如植物油)。滴眼剂可以根据需要适当地和选择性地包含等渗剂(如氯化纳,浓缩甘油),缓冲剂(如磷酸钠,乙酸钠),表面活性剂(如Polysolvate 80(商品名),硬脂酸聚烃氧基酯40,聚氧乙烯硬化的蓖麻油),稳定剂(柠檬酸钠,乙二胺四乙酸钠),防腐剂(如苯扎氯铵,尼泊金酯)等。滴眼剂在最终步骤灭菌,或者通过无菌方法制备。作为选择,可以在使用前,使无菌固体药剂如事先制成的冻干制品灭菌或溶解于无菌的注射用蒸馏水或其它溶剂中。
非经胃肠给药的吸入剂可以是气溶胶,用于吸入的粉末或者用于吸入的液体的形式。供吸入的液体在使用中可以溶解或悬浮于水或其它适宜介质中。
这些吸入剂通过任何已知的方法制备。
例如,用于吸入的液体可以根据需要由适当的材料制备,该材料选自防腐剂(如苯扎氯铵,尼泊金酯),着色剂,缓冲剂(如磷酸钠,乙酸钠),等渗剂(如氯化纳,浓缩甘油),增稠剂(如羧基乙烯基聚合物),吸收促进剂等。
用于吸入的粉末可以根据需要由选自助流剂(如硬脂酸及其盐),粘结剂(如淀粉,糊精),赋形剂(如乳糖,纤维素),着色剂,防腐剂(如苯扎氯铵,尼泊金酯),吸收促进剂等的材料制备。
为了将供吸入的液体给药,一般可以使用喷撒器(如雾化器,喷雾器)。为了将供吸入的粉末给药,一般可以使用粉末吸入器。
经口给药的组合物的其它实例包括直肠给药的栓剂和阴道给药的阴道栓,其是通过包含一种或多种活性物质的常规配方而制备的。
局部应用:
至于本发明的局部给药,EP4激动剂可以局部地给药于发病部位(特别是其中骨质减少的骨疾病)。EP4激动剂的形式不受其给药方法的限制。EP4激动剂可以是注射剂,固体药剂如埋植剂、颗粒和粉末软膏,以便给药于肌肉、皮下或关节部位。
缓释制剂不受其形式的限制,只要EP4激动剂可以连续给药于患病部位(特别是其中骨质减少的骨病)。缓释制剂可以为,例如,缓释注射剂(如微囊制剂,微球制剂,纳米球制剂),埋植制剂(如膜状制剂)等。
本发明的微囊制剂,微球制剂和纳米球制剂均为细分的药物组合物,其具有可体内降解的聚合物,包含式(I-1),(I-2)或(I-3)所示化合物作为活性成分,及任选组合使用的其它药物制剂。
本发明的可体内降解的聚合物的实例包括脂肪酸酯聚合物及其共聚物,聚丙烯酸酯,聚羟基丁酸,聚亚烷基草酸酯,聚原酸酯,聚碳酸酯,及聚氨基酸。可以单独使用这些化合物,或者使用其两种或多种的混合物。脂肪酸酯聚合物及其共聚物的实例包括聚乳酸,聚乙醇酸,聚柠檬酸,聚苹果酸,及乳酸-乙醇酸共聚物。可以单独使用这些化合物,或者使用其两种或多种的混合物。除了这些化合物之外,也可以使用聚α-氰基丙烯酸酯,聚β-羟基丁酸,聚乙二酸亚丙酯,聚原酸酯,聚原碳酸酯,聚乙烯碳酸酯,聚γ-苄基-L-谷氨酸和聚-L-丙氨酸,或者使用其两种或多种的混合物。在这些化合物中,优选聚乳酸,聚乙醇酸和乳酸-乙醇酸共聚物,更优选乳酸-乙醇酸共聚物。
本发明中所使用的这些可体内降解的聚合物的平均分子量优选为约2000~800000,更优选为约5000~200000。例如,聚乳酸的重均分子量优选为约5000~100000,更优选为约6000~50000。聚乳酸可以根据任何已知的制备方法合成。在乳酸-乙醇酸共聚物中,乳酸与乙醇酸的组成比优选为约100/0至50/50(w/w),特别是约90/10至50/50。乳酸-乙醇酸共聚物的重均分子量优选为约5000~100000,更优选为约10000~80000。乳酸-乙醇酸共聚物可以根据任何已知的制备方法合成。
本文所用术语″重均分子量″是指通过凝胶渗透色谱(GPC)测定的以聚苯乙烯当量表示的分子量。
前述可体内降解的聚合物可以根据式(I-1),(I-2)和(I-3)所示化合物及想要释放的药物的药活性强度而变化,只要能够实现前述的本发明的目的。例如,可体内降解的聚合物的用量为生理活性物质重量的约0.2~10000倍,优选为约1~1000倍,更优选为约1~100倍。
微球、微囊和纳米球制剂的制备方法的实例包括浸没(submerged)干燥法(如o/w法,w/o法,w/o/w法),相分离法,喷雾干燥法,超临界流体造粒法,及与之相类似的方法。
下文中将更详细地说明浸没干燥法(o/w法)喷雾干燥法。
(1)浸没干燥法(o/w法),首先在有机溶剂中将可体内降解的聚合物制成溶液。制备微球、微囊和纳米球制剂中所使用的有机溶剂优选具有120℃或更低的沸点。可用于本发明的有机溶剂的实例包括卤代烃(如二氯甲烷,氯仿),脂肪酸酯(如乙酸乙酯),醚,芳烃,及酮(如丙酮)。这些化合物可以适当比例的两种或多种的混合物使用。在这些有机溶剂中,优选二氯甲烷和乙腈,特别是二氯甲烷。可体内降解的聚合物于有机溶液中的浓度取决于可体内降解的聚合物的分子量,有机溶剂的种类等,但一般预定为约0.01~80%(v/w),优选约0.1~70%(v/w),更优选为约1~60%(v/w)。
然后,将式(I-1),(I-2)或(I-3)所示化合物加到如此获得的可体内降解聚合物于有机溶剂中的溶液中,任选与其它药物制剂一起加入。任选与其它药物制剂组合加入的式(I-1),(I-2)或(I-3)所示化合物的量,取决于要加入的药剂的种类,药剂在成骨中的作用,该作用的持续时间等,但一般为约0.001~90%(w/w),优选为约0.01~80%(w/w),更优选为约0.3~30%(w/w),按其在可体内降解聚合物之有机溶液中的浓度计。
接着,将所制备的有机溶液加到水相中,然后用搅拌器,乳化剂等处理,形成o/w乳液。预定该过程中水相体积为油相体积的约1~10000倍,优选约2~5000倍,特别是约5~2000倍。乳化剂可加到作为外相的水相中。这种乳化剂可以是常用的能够形成稳定o/w乳液的任何材料。可用于本发明的乳化剂的实例包括阴离子表面活性剂,非离子表面活性剂,聚氧乙烯蓖麻油衍生物,聚乙烯吡咯烷酮,聚乙烯醇,羧基甲基纤维素,卵磷脂,及明胶。这些化合物可以适当地组合使用。乳化剂在外部水相中的浓度优选为约0.001~20%(w/w),更优选为约0.01~10%(w/w),特别是约0.05~5%(w/w)。
油相溶剂的蒸发可以通过任何常用的方法完成。略为详细地,溶剂的蒸发可以通过搅拌器、磁搅拌器等搅拌,在常压或逐步降压下进行,也可以利用旋转蒸发器同时调节压力来进行。然后通过离心分离或过滤使如此得到的微球制剂分级。该微球制剂用表面活性剂溶液、醇等洗涤数次,以从其表面除去游离的式(I-1),(I-2)或(I-3)所示的化合物,任选组合使用的其它药物制剂,及乳化剂,再次分散于蒸馏水或含分散剂的赋形剂(如甘露醇,山梨糖醇,乳糖)中,然后冷冻干燥。在前述o/w方法中,微球制剂也可以这样的方法制备,该方法包括将式(I-1),(I-2)或(I-3)所示化合物及任选的其它药物制剂分散在可体内降解的聚合物于有机溶剂中的溶液中,即s/o/w法。
(2)为了通过喷雾干燥法制备微球制剂,将其中溶解有可体内降解的聚合物和式(I-1),(I-2)或(I-3)所示化合物,及任选组合使用的其它药物制剂的有机溶剂或乳液,通过喷嘴喷雾至喷雾干燥器的干燥室中,使雾滴中的有机溶剂或水在极短的时间内蒸发,从而制得微球制剂。可用于本发明的喷嘴的实例包括双液体喷嘴,压力喷嘴,及转盘。为了抑制微球聚集,可以根据需要,在喷射o/w乳液的同时喷射有机溶剂或聚集抑制剂(如甘露醇,乳糖,明胶)的水溶液。然后将如此得到的微球制剂减压,并任选进行加热,以除去其中的水和溶剂。
膜状制剂的实例包括通过如下方法制备的膜状物:将前述可体内降解的聚合物和式(I-1),(I-2)或(I-3)所示化合物,及任选组合使用的其它药物制剂溶解于有机溶剂,然后将该溶液蒸干;及通过如下方法得到的胶凝物:将前述可体内降解的聚合物和式(I-1),(I-2)或(I-3)所示的化合物,及任选组合使用的其它药物制剂溶解于适当的溶剂中,然后向该溶液中加入粒化剂(如纤维素,聚碳酸酯)。
本发明的微球,微囊及纳米球可以直接使用。作为选择,药物组合物可以加工成球形,棒状,针状,粒状,膜状或奶油状的原料,以提供各种形状的制剂。
此外,该制剂可以用作局部给药的非经胃肠药剂(如注射剂,固体药剂如埋植剂,丸剂和粉剂,液体药剂如悬浮液,软膏等给药于肌肉,皮下,器官或关节部位)。例如,为了由微球制剂制备注射剂,将微球制剂与分散剂,防腐剂,等渗剂,缓冲剂,pH调节剂等一起悬浮,制成含水悬浮液,作为实用的注射制剂。作为选择,微球制剂可用植物油分散,任选用植物油与磷脂如卵磷脂的混合物分散,也可以用中等链的脂肪酸甘油三酸酯(如Mygliol-812)分散,以制成油悬浮液,作为可以实用的注射剂。
微球制剂的粒径是任意的,只要其满足所需的分散性,并且在用作注射悬浮液时能够通过注射器。举例来说,微球制剂的平均粒径为约0.1~300μm,优选为约1~150μm,更优选为约2~100μm。优选本发明的药物组合物为上述的悬浮液的形式。还优选的本发明的药物组合物为颗粒的形式。这是因为该药物组合物在利用注射器通过普通皮下注射或肌肉注射给药时,很少给患者带来过度疼痛。特别优选本发明的药物组合物为注射剂的形式。使微球制剂灭菌的方法的实例包括所有步骤中全部无菌的方法,采用伽马射线灭菌的方法,添加防腐剂的方法。然而,本发明并不限于这些方法。
本发明的药物组合物可用于治疗骨质减少的骨疾病,因为式(I-1),(I-2)或(I-3)所示化合物,任选组合使用的其它药物制剂,一般可以逐步释放1周至3个月,虽然这取决于可体内降解的聚合物的种类和加入量。在这些骨疾病的治疗中,骨折的治疗通常需要将断裂部分固定并用石膏绷带包裹,给药只进行一次而不是经常进行。因此,要求这种给药可以持续地促进治疗。因而,本发明的药物组合物特别适用于这种治疗。
本发明的药物组合物的剂量取决于式(I-1),(I-2)或(I-3)所示化合物(任选与其它药物制剂组合使用)的类型、含量和形式,药剂释放的持续时间,需要给药的动物等,但可以是有效量的式(I-1),(I-2)或(I-3)所示化合物,其任选与其它药物制剂组合使用。例如,成人(体重50kg)骨折给药微球制剂的一次剂量为约0.001~500mg,优选约0.01~50mg,按有效组分计。本发明的药物组合物可以按前述剂量每周至3个月给药一次。
实施本发明的最佳方式
下面的参考例和实施例用于说明本发明,而不是对本发明的限制。
色谱分离部分括号中的溶剂示出了展开溶剂或洗脱溶剂及所用各溶剂的体积比。
除非具体说明,NMR数据均在CDCl3溶液中测定。而且,NMR数据部分括号中的溶剂示出了测定中使用的溶剂。
TBS为叔丁基二甲基甲硅烷基,THP为四氢吡喃-2-基,Boc为叔丁氧基羰基,Me为甲基,Et为乙基,Ac为乙酰基,Bu为丁基,Ms为甲磺酰基,及TMS为三甲基甲硅烷基。
参考例1
(5R)-5-叔丁基二甲基甲硅烷氧基甲基吡咯烷-2-酮
在氩气氛和室温下,向(5R)-5-羟甲基吡咯烷-2-酮(10g)和咪唑(8.8g)于干燥二甲基甲酰胺(50mL)中的溶液中加入叔丁基二甲基甲硅烷基氯(15.6g)的干燥二甲基甲酰胺(50mL)溶液,并将该混合物搅拌5小时。向该混合物中加入乙酸乙酯和己烷的混合溶剂。所稀释的溶液依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(21.41g),其物理数据如下。
TLC:Rf 0.52(乙酸乙酯)。
参考例2
9-氧代-13-叔丁基二甲基甲硅烷氧基-14,15,16,17,18,19,20-七去甲基-8-氮杂前列腺烷酸乙酯
在氩气氛和室温下,向氢化钠(3.42g;63.1%油悬浮液)的干燥四氢呋喃(90mL)悬浮液中加入参考例1中制备的化合物(20.8g)的干燥四氢呋喃(90mL)溶液。然后向该混合物中加入二甲基甲酰胺(180mL),并将该混合物在50℃搅拌45分钟。向该混合物中加入7-溴庚酸乙酯(22.4g)的二甲基甲酰胺(20mL)溶液,并将该混合物搅拌4小时。冷却之后,加入乙酸乙酯和己烷的混合溶剂。有机层依次用0.5N盐酸,水和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(34.9g),其物理数据如下。
TLC:Rf 0.51(乙酸乙酯∶己烷=2∶1)。
参考例3
9-氧代-13-羟基-14,15,16,17,18,19,20-七去甲基-8-氮杂前列腺烷酸乙酯
向在参考例2中制备的化合物(34.9g)的乙醇(43mL)溶液中,加入对甲苯磺酸(2.96g),并将该混合物在50℃搅拌过夜。将其冷却至室温,向该混合物中加入三乙胺(2.4mL),减压浓缩并通过硅胶柱色谱进行纯化(由乙酸乙酯∶己烷=1∶1至仅仅乙酸乙酯),得到标题化合物(13.15g),其物理数据如下。
TLC:Rf 0.18(乙酸乙酯);
NMR:δ4.12(q,J=7Hz,2H),3.85-3.6(m,4H),3.05-2.9(m,1H),2.55-2.4(m,1H),2.4-2.25(m,3H),2.2-2.05(m,1H),2.0-1.9(m,1H),1.85-1.7(br,1H),1.7-1.2(m,8H),1.27(t,J=7Hz,3H)。
参考例4
9-氧代-12-甲酰基-13,14,15,16,17,18,19,20-八去甲基-8-氮杂前列腺烷酸乙酯
在氩气氛下,向在参考例3中制备的化合物(1.25g)的乙酸乙酯(10mL)和干燥二甲亚砜(7mL)溶液中加入二异丙基乙基胺(5.1mL)。然后,在冰浴下,将三氧化硫吡啶络合物(2.32g)加到该混合物中,并将该混合物在0~15℃搅拌1小时。向反应混合物中加入少量的水,使反应终止。将氯仿(10mL)加到该混合物中。有机层用0.5N盐酸洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(1.25g),其物理数据如下,其不经纯化即可用于下一步反应。
TLC:Rf0.45(氯仿∶甲醇=9∶1)。
参考例5
(13E)-9,15-二氧代-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸乙酯
在氩气氛下,向3-(3-甲氧基甲基苯基)-2-氧代丙基膦酸二甲酯(1.81g)的干燥四氢呋喃(35mL)溶液中加入氢化钠(222mg;63.1%油悬浮液),并将该混合物在室温下搅拌30分钟。向该悬浮液中,加入在参考例4中制备的化合物(1.25g)的四氢呋喃(5mL)溶液,并将该混合物搅拌3小时。然后将乙酸乙酯加到该混合物中。所稀释的溶液依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(乙酸乙酯∶己烷=2∶1~3∶1,然后仅乙酸乙酯),得到标题化合物(1.23g),其物理数据如下。
TLC:Rf0.72(氯仿∶甲醇=9∶1);
NMR:δ7.35-7.10(m,4H),6.65(dd,J=16,8Hz,1H),6.23(d,J=16Hz,1H),4.42(s,2H),4.2-4.1(m,3H),3.85(s,2H),3.6-3.5(m,1H),3.38(s,3H),2.8-2.65(m,1H),2.5-2.2(m,5H),1.85-1.7(m,1H),1.7-1.5(m,2H),1.5-1.2(m,9H)。
实施例1
(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸乙酯
在氩气氛和室温下,向在参考例5中制备的化合物(1.23g)的干燥四氢呋喃(10mL)溶液中加入1.0M(R)-2-甲基-CBS-氧氮硼杂茂啶(oxazaborolidine)/甲苯溶液(0.57mL)。然后将硼烷四氢呋喃络合物(2.32mL)滴加到该混合物中,并将该混合物搅拌45分钟。向该混合物中加入1N盐酸和乙酸乙酯。有机层依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(由仅乙酸乙酯至乙酸乙酯∶己烷=19∶1),得到标题化合物(1.05g),其物理数据如下。
TLC:Rf 0.60(氯仿∶甲醇=9∶1);
NMR:δ7.38-7.10(m,4H),5.73(dd,J=15.3,6.0Hz,1H),5.50(dd,J=15.3,8.0Hz,1H),4.48-4.35(m,3H),4.17-3.98(m,3H),3.53-3.36(m,4H),2.92-2.68(m,3H),2.44-2.05(m,6H),1.81-1.20(m,12H)。
实施例2
(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
向在实施例1中制备的化合物(1.05g)的甲醇(5mL)溶液中加入2N氢氧化钠水溶液(4ml),并将该混合物搅拌过夜。向该混合物中加入乙醚(10mL)和水(20mL),并搅拌该混合物。将1N盐酸加到水层进行酸化,然后用乙酸乙酯萃取。有机层依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(由仅仅氯仿至氯仿∶甲醇=100∶1,然后50∶1,然后25∶1),得到标题化合物(837mg),其物理数据如下。
TLC:Rf0.41(氯仿∶甲醇=9∶1);
NMR:δ7.36-7.11(m,4H),5.75(dd,J=15.3,6.0Hz,1H),5.51(dd,J=15.3,8.0Hz,1H),4.49-4.38(m,3H),4.08-3.99(m,1H),3.50-3.36(m,4H),2.94-2.75(m,3H),2.49-2.14(m,6H),1.79-1.20(m,9H)。
实施例2(a)至实施例2(bbb)
按与参考例1,2,3,4,5及实施例1和2中所述相同的方法,利用7-溴庚酸乙酯或相应的卤化物衍生物,及3-(3-甲氧基甲基苯基)-3-氧代丙基膦酸二甲酯或相应的磷酸酯衍生物,得到具有下列物理数据的本发明的化合物。
实施例2(a)
(5S,15α,13E)-5-甲基-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.28(甲醇∶氯仿=1∶10);
NMR:δ7.40-7.10(m,4H),5.78(dd,J=15.2,5.2Hz,1H),5.55(dd,J=15.2,8.4Hz,1H),4.50-4.35(m,1H),4.46(s,2H),4.10-3.95(m,1H),3.60-3.35(m,1H),3.42(s,3H),3.00-2.70(m,4H),2.50-2.10(m,5H),1.80-1.00(m,8H),0.91(d,J=5.8Hz,3H)。
实施例2(b)
(15α,13E)-5,5-二甲基-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.38(氯仿∶甲醇=9∶1);
NMR:δ7.33-7.12(m,4H),5.78(dd,J=15,5Hz,1H),5.59(dd,J=15,8Hz,1H),4.48(s,2H),4.45-4.36(m,1H),4.12-4.03(m,1H),3.51(dt,J=12,5Hz,1H),3.43(s,3H),2.91-2.81(m,2H),2.76(dd,J=14,8Hz,1H),2.47-2.10(m,5H),1.78-1.63(m,1H),1.61-1.40(m,3H),1.32-1.10(m,3H),0.92(s,3H),0.89(s,3H)。
实施例2(c)
(15α,13E)-5,5-桥亚乙基-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.38(氯仿∶甲醇=9∶1);
NMR:δ7.33-7.13(m,4H),5.81(dd,J=15,5Hz,1H),5.61(dd,J=15,8Hz,1H),4.46(s,2H),4.48-4.39(m,1H),4.12-4.04(m,1H),3.54(ddd,J=14,11,5Hz,1H),3.43(s,3H),2.98(ddd,J=14,11,5Hz,1H),2.90(dd,J=14,9Hz,1H),2.47-2.12(m,5H),1.79-1.52(m,4H),1.36-1.10(m,3H),0.37-0.22(m,4H)。
实施例2(d)
(5R,15α,13E)-5-甲基-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.55(甲醇∶氯仿=1∶5);
NMR:δ7.40-7.10(m,4H),5.78(dd,J=15.4,5.6Hz,1H),5.54(dd,J=15.4,8.4Hz,1H),4.50-4.35(m,1H),4.41(s,2H),4.10-3.98(m,1H),3.60-3.45(m,1H),3.42(s,3H),3.00-2.75(m,3H),2.50-2.10(m,5H),1.80-1.10(m,8H),0.91(d,J=5.8Hz,3H)。
实施例2(e)
(15α,13E)-9-氧代-15-羟基-16-(3-(2,2,2-三氟乙氧基甲基)苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.38(甲醇∶乙酸乙酯=1∶10);
NMR:δ7.40-7.10(m,4H),5.75(dd,J=15.6,5.6Hz,1H),5.52(dd,J=15.6,8.4Hz,1H),4.67(s,2H),4.50-4.35(m,1H),4.10-3.98(m,1H),3.86(q,J=8.8Hz,2H),3.60-3.35(m,1H),3.00-1.80(m,6H),2.33(t,J=7.0Hz,2H),1.80-1.55(m,3H),1.55-1.10(m,6H)。
实施例2(f)
(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.36(甲醇∶乙酸乙酯=1∶10);
NMR:δ7.35-7.15(m,3H),7.15-7.00(m,1H),5.72(dd,J=15.8,5.8Hz,1H),5.48(dd,J=15.8,8.2Hz,1H),4.42(q,J=6.6Hz,1H),4.10-3.98(m,1H),3.60-3.40(m,1H),2.83(d,J=6.6Hz,2H),3.00-2.10(m,4H),2.34(t,J=7.2Hz,2H),1.80-1.55(m,3H),1.55-1.10(m,6H)。
实施例2(g)
(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-2,3,4,17,18,19,20-七去甲基-1,5-(2,5-间亚噻吩基)-8-氮杂前列腺-13-烯酸
TLC:Rf0.22(氯仿∶甲醇=9∶1);
NMR:δ7.63(d,J=3Hz,1H),7.33-7.25(m,2H),7.19(d,J=8Hz,1H),7.13(d,J=8Hz,1H),6.81(d,J=3Hz,1H),5.73(dd,J=15,5Hz,1H),5.50(dd,J=15,9Hz,1H),4.52(d,J=11Hz,1H),4.45(d,J=11Hz,1H),4.40-4.30(m,1H),4.2-3.0(br),4.02(q,J=9Hz,1H),3.46(s,3H),3.50-3.35(m,1H),2.98-2.68(m,5H),2.50-2.10(m,3H),2.00-1.68(m,3H)。
实施例2(h)
(15α,13E)-9-氧代-15-羟基-16-(3-苯基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.32(氯仿∶甲醇=9∶1);
NMR:δ7.60-7.37(m,8H),7.24-7.17(d,J=8.2Hz,1H),5.74(dd,J=15.0,6.0Hz,1H),5.49(ddd,J=15.0,8.6,1.2Hz,1H),4.51-4.40(m,1H),4.08-3.99(m,1H),3.50-3.39(m,1H),2.91(d,J=6.6Hz,2H),2.78-2.64(m,1H),2.42-2.05(m,6H),1.77-1.51(m,.3H),1.42-1.06(m,6H)。
实施例2(i)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.34(氯仿∶甲醇=10∶1);
NMR:δ7.22-7.17(m,1H),7.07-6.98(m,3H),5.74(dd,J=15.3,5.7Hz,1H),5.50(ddd,J=15.3,8.4,1.2Hz,1H),4.41(m,1H),4.03(m,1H),3.47(m,1H),2.90-2.70(m,3H),2.40-2.10(m,6H),2.33(s,3H),1.76-1.22(m,9H)。
实施例2(j)
(15α,13E)-9-氧代-15-羟基-16-(3-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.30(氯仿∶甲醇=10∶1);
NMR:δ7.32-7.23(m,1H),6.99-6.90(m,3H),5.72(dd,J=15.3,6.0Hz,1H),5.50(ddd,J=15.3,8.4,1.2Hz,1H),4.42(m,1H),4.03(m,1H),3.46(m,1H),2.85(d,J=6.0Hz,2H),2.70(m,1H),2.40-2.10(m,6H),1.75-1.20(m,9H)。
实施例2(k)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.47(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.16(m,2H),7.00(m,2H),5.72(dd,J=15.4,6.0Hz,1H),5.49(dd,J=15.4,8.2Hz,1H),4.38(m,1H),4.03(m,1H),3.47(m,1H),2.82(d,J=6.6Hz,2H),2.72(m,1H),2.41-2.31(m,2H),2.34(t,J=7.2Hz,2H),2.21(m,1H),1.67(m,1H),1.66-1.58(m,2H),1.50-1.20(m,6H)。
实施例2(1)
(15α,13E)-9-氧代-15-羟基-16-(4-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.26(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.12(d,J=8.2Hz,2H),7.07(d,J=8.2Hz,2H),5.73(dd,J=15.4,5.8Hz,1H),5.47(dd,J=15.4,8.8Hz,1H),4.38(m,1H),4.03(m,1H),3.46(m,1H),2.81(d,J=6.9Hz,2H),2.72(m,1H),2.40-2.27(m,4H),2.34(s,3H),2.21(m,1H),1.72(m,1H),1.67-1.58(m,2H),1.50-1.18(m,6H)。
实施例2(m)
(15α,13E)-9-氧代-15-羟基-16-(2-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.27(氯仿∶甲醇=8∶1);
NMR:δ7.28-7.00(m,4H),5.76(dd,J=15.2,6.0Hz,1H),5.49(ddd,J=15.2,8.4,0.6Hz,1H),4.42(m,1H),4.04(m,1H),3.46(m,1H),2.87(d,J=7.0Hz,2H),2.72(m,1H),2.50-2.04(m,6H),2.34(s,3H),1.85-1.10(m,9H)。
实施例2(n)
(15α,13E)-9-氧代-15-羟基-16-(2-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.27(氯仿∶甲醇=8∶1);
NMR:δ7.34-6.94(m,4H),5.74(dd,J=15.2,6.0Hz,1H),5.45(ddd,J=15.2,8.4,0.8Hz,1H),4.47(m,1H),4.02(m,1H),3.44(m,1H),3.40-1.90(m,9H),1.80-0.90(m,9H)。
实施例2(o)
(15α,13E)-9-氧代-15-羟基-16-(3-三氟甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.18(氯仿∶甲醇=8∶1);
NMR:δ7.60-7.35(m,4H),5.73(dd,J=15.3,5.9Hz,1H),5.50(ddd,J=15.3,8.3,0.9Hz,1H),4.46(m,1H),4.03(m,1H),4.00-3.00(br,2H),3.46(m,1H),2.91(d,J=6.3Hz,2H),2.71(m,1H),2.48-2.06(m,5H),1.76-1.12(m,9H)。
实施例2(p)
(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.16(氯仿∶甲醇=8∶1);
NMR:δ7.23(dd,J=7.8,7.8Hz,1H),6.86-6.70(m,3H),5.73(dd,J=15.3,6.0Hz,1H),5.48(dd,J=15.3,8.4Hz,1H),4.41(m,1H),4.03(m,1H),3.80(s,3H),3.46(m,1H),2.82(d,J=6.6Hz,2H),2.71(m,1H),2.50-2.04(m,5H),1.80-1.10(m,10H)。
实施例2(q)
(15α,13E)-9-氧代-15-羟基-16-(3-乙基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.25(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.24(t,J=7.3Hz,1H),7.11-6.97(m,3H),5.74(dd,J=15.1,5.9Hz,1H),5.50(ddd,J=15.1,8.3,1.0Hz,1H),4.42(m,1H),4.04(m,1H),3.45(m,1H),2.84-2.80(m,2H),2.75(m,1H),2.63(q,J=7.8Hz,2H),2.43-2.32(m,2H),2.35(t,J=7.3Hz,2H),2.21(m,1H),1.71(m,1H),1.68-1.57(m,2H),1.54-1.20(m,6H),1.24(t,J=7.8Hz,3H)。
实施例2(r)
(15α,13E)-9-氧代-15-羟基-16-(3,4-二氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.30(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.14-7.00(m,3H),6.92(m,1H),5.71(dd,J=15.4,5.8Hz,1H),5.50(dd,J=15.4,8.6Hz,1H),4.38(m,1H),4.04(m,1H),3.44(m,1H),2.82(d,J=6.6Hz,2H),2.73(m,1H),2.43-2.32(m,2H),2.34(t,J=7.1Hz,2H),2.22(m,1H),1.69(m,1H),1.65-1.55(m,2H),1.51-1.20(m,6H)。
实施例2(s)
(15α,13E)-9-氧代-15-羟基-16-(3-氯-4-羟基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.26(氯仿∶甲醇=9∶1);
NMR:δ7.14(d,J=2.1Hz,1H),6.94(dd,J=8.4,2.1Hz,1H),6.88(d,J=8.4Hz,1H),5.65(dd,J=15,6.3Hz,1H),5.41(ddd,J=15,8.0,1.2Hz,1H),4.33(m,1H),4.01(m,1H),3.41(m,1H),2.85-2.62(m,3H),2.57-2.10(m,8H),1.79-1.56(m,3H),1.54-1.19(m,6H)。
与苯环相连的羟基用THP基团保护,并在酯水解之前用酸除去保护基(实施例2的方法)。
实施例2(t)
(15α,13E)-9-氧代-15-羟基-16-(3,5-二氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.34(氯仿∶甲醇=9∶1);
NMR:δ6.80-6.65(m,3H),5.71(dd,J=15,5.7Hz,1H),5.50(dd,J=15,8.7Hz,1H),4.41(m,1H),4.03(m,1H),3.48(m,1H),3.10-2.50(m,4H),2.47-2.10(m,6H),1.79-1.59(m,3H),1.58-1.20(m,6H)。
实施例2(u)
(15α,13E)-9-氧代-15-羟基-16-(3-丙基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.26(氯仿∶甲醇=10∶1);
NMR:δ7.25-7.19(m,1H),7.08-7.00(m,3H),5.75(dd,J=15.3,5.7Hz,1H),5.51(ddd,J=15.3,8.4,0.9Hz,1H),4.41(m,1H),4.05(m,1H),3.48(m,1H),2.90-2.70(m,3H),2.57(t,J=7.2Hz,2H),2.50-2.10(m,5H),1.80-1.20(m,11H),0.94(t,J=7.2Hz,3H)。
实施例2(v)
(15α,13E)-9-氧代-15-羟基-16-((E)-1-丙烯基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.30(氯仿∶甲醇=10∶1);
NMR:δ7.23-7.21(m,2H),7.14(s,1H),7.02(m,1H),6.37(dd,J=15.6,1.5Hz,1H),6.27(dq,J=15.6,6.3Hz,1H),5.74(dd,J=15.3,6.0Hz,1H),5.49(ddd,J=15.3,8.4,1.2Hz,1H),4.41(m,1H),4.02(m,1H),3.45(m,1H),2.83(d,J=6.9Hz,2H),2.70(m,1H),2.40-2.10(m,5H),1.88(dd,J=6.3,1.5Hz,3H),1.80-1.20(m,9H)。
实施例2(w)
(15α,13E)-9-氧代-15-羟基-16-(3-(2-氟苯基)苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.27(氯仿∶甲醇=8∶1);
NMR:δ7.60-6.80(m,8H),5.72(m,1H),5.48(m,1H),5.00-3.00(br,2H),4.43(m,1H),4.01(m,1H),3.43(m,1H),2.98-2.60(m,3H),2.48-2.00(m,5H),1.98-0.88(m,9H)。
实施例2(x)
(15α,13E)-9-氧代-15-羟基-16-(3-(4-氟苯基)苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.27(氯仿∶甲醇=8∶1);
NMR:δ7.64-7.00(m,8H),5.72(m,1H),5.48(m,1H),4.60-3.00(br,2H),4.45(m,1H),4.02(m,1H),3.44(m,1H),2.96-2.60(m,3H),2.48-2.02(m,5H),1.78-0.78(m,9H)。
实施例2(y)
(15α,13E)-9-氧代-15-羟基-16-(3-(5-甲基呋喃-2-基)苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.25(氯仿∶甲醇=8∶1);
NMR:δ7.60-6.96(m,4H),6.53(d,J=3.0Hz,1H),6.05(m,1H),5.72(m,1H),5.48(m,1H),4.60-2.80(br,2H),4.44(m,1H),4.02(m,1H),3.44(m,1H),2.96-2.60(m,3H),2.48-2.02(m,8H),1.80-1.06(m,9H)。
实施例2(z)
(15α,13E)-9-氧代-15-羟基-16-(萘-2-基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.45(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.83-7.76(m,3H),7.65(s,1H),7.51-7.41(m,2H),7.33(dd,J=8.5,1.7Hz,1H),5.77(dd,J=15.4,6.1Hz,1H),5.44(ddd,J=15.4,8.5,0.8Hz,1H),4.54(m,1H),4.01(m,1H),3.38(m,1H),3.02(d,J=6.9Hz,2H),2.63(m,1H),2.37-2.32(m,2H),2.34(t,J=7.2Hz,2H),2.19(m,1H),1.64(m,1H),1.63-1.55(m,2H),1.40-1.12(m,6H)。
实施例2(aa)
(15α,13E)-9-氧代-15-羟基-16-(3-(2-甲氧基苯基)苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.23(氯仿∶甲醇=8∶1);
NMR:δ7.50-6.92(m,8H),5.74(m,1H),5.50(m,1H),4.43(m,1H),4.03(m,1H),3.81(s,3H),3.45(m,1H),3.40-1.90(br,2H),3.00-2.64(m,3H),2.48-2.14(m,5H),1.78-1.10(m,9H)。
实施例2(bb)
(15α,13E)-9-氧代-15-羟基-16-(3-(2-羟基苯基)苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.26(氯仿∶甲醇=8∶1);
NMR:δ7.46-7.08(m,7H),6.97(m,1H),5.72(m,1H),5.47(m,1H),4.42(m,1H),4.02(m,1H),3.43(m,1H),2.98-2.62(m,3H),2.50-2.06(m,5H),1.80-1.08(m,9H)。
与苯环相连的羟基用THP基团保护,并在酯水解之前用酸除去保护基(实施例2的方法)。
实施例2(cc)
(15α,13E)-9-氧代-15-羟基-16-(3-(3-羟基苯基)苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.21(氯仿∶甲醇=8∶1);
NMR:δ7.48-6.80(m,8H),5.70(dd,J=15.3,6.3Hz,1H),5.51(m,1H),4.44(m,1H),4.06(m,1H),3.49(m,1H),3.06-2.60(m,3H),2.54-1.96(m,5H),1.82-1.00(m,9H)。
与苯环相连的羟基用THP基团保护,并在最终步骤除去保护基。
实施例2(dd)
(15α,13E)-1,5-(2,5-间亚噻吩基)-9-氧代-15-羟基-16-(3-氯苯基)-2,3,4,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.20(氯仿∶甲醇=10∶1);
NMR:δ7.68(d,J=3.6Hz,1H),7.23-7.18(m,3H),7.08(m,1H),6.83(d,J=3.6Hz,1H),5.71(dd,J=15.3,6.0Hz,1H),5.48(ddd,J=15.3,8.7,0.9Hz,1H),4.39(m,1H),4.02(m,1H),3.53(m,1H),3.40(br s,1H),2.90-2.70(m,5H),2.50-2.10(m,3H),1.90-1.60(m,3H)。
实施例2(ee)
(15α,13E)-9-氧代-15-羟基-16-(3-环丙基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.45(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.19(t,J=7.7Hz,1H),7.02-6.89(m,3H),5.73(dd,J=15.4,5.8Hz,1H),5.48(ddd,J=15.4,8.5,1.0Hz,1H),4.42(m,1H),4.04(m,1H),3.45(m,1H),2.81(d,J=6.6Hz,2H),2.75(m,1H),2.43-2.30(m,2H),2.32(t,J=7.1Hz,2H),2.21(m,1H),1.86(m,1H),1.71(m,1H),1.67-1.56(m,2H),1.52-1.19(m,6H),1.00-0.90(m,2H),0.74-0.63(m,2H)。
实施例2(ff)
(13E)-9-氧代-15-羟基-16,16-二氟-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.34(氯仿∶甲醇=9∶1);
NMR:δ7.57-7.35(m,4H),5.78-5.59(m,2H),4.61-4.43(m,3H),4.04(m,1H),3.50-3.32(m,4H),2.82(m,1H),2.43-2.10(m,5H),1.72-1.20(m,9H)。
实施例2(gg)
(15α,13E)-9-氧代-15-羟基-16-(3-乙氧基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.48(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.22(t,J=7.7Hz,1H),6.81-6.73(m,3H),5.73(dd,J=15.4,6.1Hz,1H),5.48(ddd,J=15.4,8.5,1.1Hz,1H),4.41(m,1H),4.03(m,1H),4.02(q,J=7.1Hz,2H),3.45(m,1H),2.81(d,J=6.6Hz,2H),2.72(m,1H),2.42-2.32(m,4H),2.21(m,1H),1.76-1.58(m,3H),1.48-1.20(m,6H),1.42(t,J=7.1Hz,3H)。
实施例2(hh)
(15α,13E)-9-氧代-15-羟基-16-(3-异丙氧基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.45(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.20(t,J=7.7Hz,1H),6.80-6.75(m,3H),5.73(dd,J=15.4,6.0Hz,1H),5.49(ddd,J=15.4,8.5,1.1Hz,1H),4.55(m,1H),4.40(m,1H),4.04(m,1H),3.54(m,1H),2.80(d,J=6.6Hz,2H),2.74(m,1H),2.42-2.32(m,4H),2.21(m,1H),1.77-1.58(m,3H),1.50-1.20(m,6H),1.38(d,J=6.0Hz,6H)。
实施例2(ii)
(15α,13E)-9-氧代-15-羟基-16-(3-苄氧基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.49(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.45-7.28(m,5H),7.23(t,J=7.7Hz,1H),6.89-6.76(m,3H),5.71(dd,J=15.4,6.0Hz,1H),5.45(ddd,J=15.4,8.5,0.8Hz,1H),5.03(s,2H),4.39(m,1H),4.01(m,1H),3.45(m,1H),2.81(d,J=6.9Hz,2H),2.71(m,1H),2.41-2.27(m,4H),2.20(m,1H),1.75-1.54(m,3H),1.48-1.20(m,6H)。
实施例2(jj)
(15α,5Z,13E)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸
TLC:Rf0.31(氯仿∶甲醇=9∶1);
NMR:δ7.32-7.11(m,4H),5.70(dd,J=16,5Hz,1H),5.60-5.48(m,2H),5.34-5.25(m,1H),4.44(s,2H),4.50-4.39(m,1H),4.20(dd,J=15,5Hz,1H),4.03(dt,J=8,5Hz,1H),3.49(dd,J=15,8Hz,1H),3.42(s,3H),2.92-2.78(m,2H),2.50-2.05(m,7H),1.77-1.61(m,3H)。
实施例2(kk)
(15α,5Z,13E)-9-氧代-15-羟基-16-(3-三氟甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸
TLC:Rf0.27(氯仿∶甲醇=8∶1);
NMR:δ7.62-7.26(m,4H),5.67(dd,J=15.6,5.7Hz,1H),5.62-5.44(m,2H),5.28(m,1H),4.45(m,1H),4.21(dd,J=15.0,6.6Hz,1H),4.03(m,1H),3.80-2.40(br,2H),3.45(m,1H),2.90(d,J=6.6Hz,2H),2.48-2.02(m,7H),1.76-1.52(m,3H)。
实施例2(11)
(15α,5Z,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸
TLC:Rf0.32(氯仿∶甲醇=8∶1);
NMR:δ7.19(dd,J=7.5,7.5Hz,1H),7.10-7.05(m,3H),5.68(dd,J=15.6,5.7Hz,1H),5.61-5.40(m,2H),5.30(m,1H),4.41(m,1H),4.21(m,1H),4.03(m,1H),3.70-2.60(br,2H),3.44(m,1H),2.80(d,J=6.6Hz,2H),2.48-2.04(m,10H),1.78-1.56(m,3H)。
实施例2(mm)
(15α,13E)-9-氧代-15-羟基-16-(3,5-二甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.36(氯仿∶甲醇=10∶1);
NMR:δ6.88(s,1H),6.81(s,2H),5.74(dd,J=15.3,5.7Hz,1H),5.51(dd,J=15.3,8.4Hz,1H),4.39(m,1H),4.04(m,1H),3.48(m,1H),2.83-2.69(m,3H),2.50-2.10(m,5H),2.29(s,6H),1.80-1.20(m,9H)。
实施例2(nm)
(15α,13E)-9-氧代-15-羟基-16-(3-(苯并呋喃-2-基)苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.26(氯仿∶甲醇=10∶1);
NMR:δ7.74-7.72(m,2H),7.59-7.50(m,2H),7.39(m,1H),7.32-7.18(m,3H),7.03(d,J=1.2Hz,1H),5.77(dd,J=15.3,6.3Hz,1H),5.51(ddd,J=15.3,8.7,0.9Hz,1H),4.48(m,1H),4.03(m,1H),3.43(m,1H),2.93(d,J=6.6Hz,2H),2.69(m,1H),2.45-2.10(m,5H),1.75-1.10(m,9H)。
实施例2(oo)
(15α,13E)-2,7-(1,3-间亚苯基)-9-氧代-15-羟基-16-(3-甲基苯基)-3,4,5,6,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.42(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.27-6.97(m,8H),5.62(dd,J=15.4,5.8Hz,1H),5.41(ddd,J=15.4,8.8,1.1Hz,1H),4.74(d,J=14.6Hz,1H),4.36(m,1H),3.87(m,1H),3.81(d,J=14.6Hz,1H),3.60(s,2H),2.78(d,J=6.6Hz,2H),2.55-2.35(m,2H),2.32(s,3H),2.15(m,1H),1.69(m,1H)。
实施例2(pp)
(15α,13E)-9-氧代-15-羟基-16-(3-(2-苯基乙炔基)苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.21(氯仿∶甲醇=8∶1);
NMR:δ7.60-7.14(m,9H),5.72(dd,J=15.3,6.0Hz,1H),5.47(dd,J=15.3,8.4Hz,1H),4.43(m,1H),4.03(m,1H),3.46(m,1H),2.94-2.62(m,3H),2.48-2.12(m,5H),1.80-1.16(m,9H)。
实施例2(qq)
(15α,5Z,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸
TLC:Rf0.31(氯仿∶甲醇=8∶1);
NMR:δ7.40-7.00(m,4H),5.66(dd,J=15.6,5.7Hz,1H),5.61-5.22(m,3H),4.41(m,1H),4.22(m,1H),4.03(m,1H),3.80-2.80(br,2H),3.44(m,1H),2.90-2.70(m,3H),2.48-2.02(m,6H),1.76-1.54(m,3H)。
实施例2(rr)
(15α,13E)-9-氧代-15-羟基-16-(3,4-二氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸
TLC:Rf0.24(氯仿∶甲醇=8∶1);
NMR:δ7.20-6.84(m,3H),5.66(dd,J=15.3,5.7Hz,1H),5.62-5.22(m,3H),4.38(m,1H),4.21(m,1H),4.04(m,1H),4.02-3.00(br,2H),3.46(m,1H),2.79(d,J=6.6Hz,2H),2.50-2.02(m,7H),1.80-1.54(m,3H)。
实施例2(ss)
(15α,13E)-2,7-(1,4-间亚苯基)-9-氧代-15-羟基-16-(3-甲基苯基)-3,4,5,6,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.25(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.24-6.96(m,8H),5.62(dd,J=15.4,6.0Hz,1H),5.43(ddd,J=15.4,8.2,0.8Hz,1H),4.78(d,J=14.8Hz,1H),4.37(m,1H),3.89(m,1H),3.77(d,J=14.8Hz,1H),3.62(s,2H),2.80(d,J=6.6Hz,2H),2.55-2.37(m,2H),2.36(s,3H),2.15(m,1H),1.74(m,1H)。
实施例2(tt)
(15α,5Z,13E)-9-氧代-15-羟基-16-(3-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸
TLC:Rf0.28(氯仿∶甲醇=8∶1);
NMR:δ7.25(m,1H),7.04-6.86(m,3H),5.66(dd,J=15.3,5.7Hz,1H),5.60-5.20(m,3H),4.42(m,1H),4.40-2.80(br,2H),4.21(m,1H),4.03(m,1H),3.44(m,1H),2.90-2.72(m,2H),2.48-2.02(m,7H),1.78-1.56(m,3H)。
实施例2(uu)
(15α,5Z,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-5,13-二烯酸
TLC:Rf0.28(氯仿∶甲醇=8∶1);
NMR:δ7.22-7.10(m,2H),7.05-6.93(m,2H),5.66(dd,J=15.6,5.7Hz,1H),5.61-5.20(m,3H),4.70-3.20(br,2H),4.38(m,1H),4.20(m,1H),4.02(m,1H),3.44(m,1H),2.81(d,J=6.6Hz,2H),2.48-2.02(m,7H),1.78-1.56(m,3H)。
实施例2(vv)
(15α,5Z,13E)-9-氧代-15-羟基-16-(3-氯苯基)-2,6-(1,3-间亚苯基)-3,4,5,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.30(氯仿∶甲醇=9∶1);
NMR:δ7.25-7.0(m,8H),5.51(dd,J=15,6Hz,1H),5.25(dd,J=15,8Hz,1H),4.4-4.3(m,1H),3.75-3.65(m,1H),3.62(s,2H),3.65-3.55(m,1H),3.3-2.4(br),3.0-2.7(m,5H),2.4-2.2(m,2H),2.1-1.95(m,1H),1.65-1.5(m,1H)。
实施例2(ww)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-1,5-(2,5-间亚噻吩基)-2,3,4,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.31(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.68(d,J=3.8Hz,1H),7.19(t,J=7.4Hz,1H),7.07-6.96(m,3H),6.83(d,J=3.8Hz,1H),5.75(dd,J=15.4,6.0Hz,1H),5.47(ddd,J=15.4,8.8,1.1Hz,1H),4.38(m,1H),4.02(m,1H),3.53(m,1H),2.90-2.76(m,5H),2.46-2.37(m,2H),2.33(s,3H),2.21(m,1H),1.90-1.65(m,3H)。
实施例2(xx)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-5-(5-(5-氧代-1,2,4-噁二唑-3-基)噻吩-2-基)-1,2,3,4,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯
TLC:Rf 0.24(氯仿∶甲醇=9∶1);
NMR(DMSO-d6):δ12.98(br.s,1H),7.52(d,J=4.0Hz,1H),7.22-7.14(m,2H),7.08-6.99(m,3H),5.62(dd,J=15.0,6.2Hz,1H),5.30(dd,J=15.0,8.8Hz,1H),4.97(br.s,1H),4.16(m,1H),4.00(m,1H),3.28(m,2H),2.81-2.58(m,4H),2.22-2.03(m,3H),1.77-1.50(m,3H)。
酯水解(实施例2的方法)未进行。连接在1,2,4-噁二唑环上的NH基团用Boc基团保护,并在最终步骤除去保护基。
实施例2(yy)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-1,5-(2,5-间亚呋喃基)-2,3,4,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.25(氯仿∶甲醇=2∶1);
NMR:δ7.20-7.14(m,3H),7.04-6.94(m,2H),6.21(d,J=3.6Hz,1H),5.73(dd,J=15.4,5.8Hz,1H),5.49(dd,J=15.4,8.8Hz,1H),5.14(brs,2H),4.38(m,1H),4.06(m,1H),3.51(m,1H),2.86(m,1H),2.81(d,J=6.6Hz,2H),2.66(t,J=7.4Hz,2H),2.48-2.29(m,2H),2.18(m,1H),1.93-1.80(m,2H),1.72(m,1H)。
实施例2(zz)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-3,7-(2,5-间亚噻吩基)-4,5,6,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.48(氯仿∶甲醇=9∶1);
NMR(CDCl3+CD3OD):δ7.25-7.15(m,2H),7.05-6.95(m,2H),6.7-6.6(m,2H),5.72(dd,J=16,6Hz,1H),5.45(dd,J=16,8Hz,1H),4.78(d,J=15Hz,1H),4.37(q,J=6Hz,1H),4.05-3.95(m,1H),3.90(d,J=15Hz,1H),3.09(t,J=7Hz,2H),2.83(d,J=6Hz,2H),2.65(t,J=7Hz,2H),2.5-2.25(m,2H),2.25-2.1(m,1H),1.8-1.6(m,1H)。
实施例2(aaa)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-5-(5-(四唑-5-基)噻吩-2-基)-1,2,3,4,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯
TLC:Rf 0.52(氯仿∶甲醇=2∶1);
NMR(DMSO-d6):δ7.59(d,J=3.7Hz,1H),7.21-7.13(m,2H),7.08-6.99(m,3H),5.62(dd,J=15.4,6.2Hz,1H),5.31(dd,J=15.4,8.8Hz,1H),4.97(br,1H),4.17(m,1H),4.02(m,1H),3.33(m,1H),2.82-2.58(m,5H),2.27-2.03(m,3H),1.80-1.49(m,3H)。
酯水解(实施例2的方法)未进行。连接在1,2,4-噁二唑环上的NH基团用Boc基团保护,并在最终步骤除去保护基。
实施例2(bbb)
(15α,13E)-9-氧代-15-羟基-16-(萘-1-基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.45(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ8.04(m,1H),7.87(m,1H),7.76(m,1H),7.57-7.46(m,2H),7.44-7.32(m,2H),5.78(dd,J=15.4,6.1Hz,1H),5.45(ddd,J=15.4,8.5,1.1Hz,1H),4.57(m,1H),3.97(m,1H),3.35(m,1H),3.32(d,J=6.6Hz,2H),2.64(m,1H),2.37-2.32(m,2H),2.34(t,J=7.1Hz,2H),2.15(m,1H),1.64-1.55(m,3H),1.43-1.15(m,6H)。
参考例6
2-((5R)-5-叔丁基二甲基甲硅烷氧基甲基-2-氧代吡咯烷-1-基)乙酸甲酯
在氩气氛和水浴下,将叔丁醇钾(11.58g)的干燥四氢呋喃(100mL)溶液加到在参考例1中制备的化合物(21.41g)的四氢呋喃(200mL)溶液中。搅拌该混合物1小时之后,向其中加入溴乙酸甲酯(9.75mL)的四氢呋喃(50mL)溶液。然后将己烷加到该混合物中。所稀释的溶液依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(乙酸乙酯∶己烷=由1∶2至1∶1,然后3∶1),得到标题化合物(22.13g),其物理数据如下。
TLC:Rf0.48(乙酸乙酯∶己烷=1∶1)。
参考例7
2-((5R)-5-叔丁基二甲基甲硅烷氧基甲基-2-氧代吡咯烷-1-基)乙醇
向在参考例6中制备的化合物(22.0g)的四氢呋喃(100mL)溶液中加入硼氢化钠(8.28g),并将该混合物搅拌5分钟。向其中加入甲醇(20mL),并将该混合物搅拌15分钟。向其中再次加入甲醇(30mL),并将该混合物搅拌1小时。向该混合物中加水之后,向其中加入乙酸乙酯。有机层依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(19.75g),其物理数据如下。
TLC:Rf0.43(乙酸乙酯)。
参考例8
硫代乙酸(5R)-2-(5-叔丁基二甲基甲硅烷氧基甲基-2-氧代吡咯烷基)乙基酯
在氩气氛和-5℃下,向在参考例7中制备的化合物(22.0g),三乙胺(13.0mL)和干燥四氢呋喃(150mL)的混合物中滴加甲磺酰氯(6.7mL),并将该混合物搅拌45分钟。反应停止后,向其中加入甲醇(0.81mL),并将该混合物搅拌15分钟。向该混合物中加入碳酸钾(20.0g),硫代乙酸钾和干燥二甲基甲酰胺(150mL)的混合物,并将该混合物在50℃搅拌3小时,然后在室温下搅拌2天。然后将乙酸乙酯和己烷的混合溶剂加到该混合物中。所稀释的溶液依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(26.8g),其物理数据如下。
TLC:Rf0.83(乙酸乙酯)。
参考例9
9-氧代-13-(叔丁基二甲基甲硅烷氧基)-14,15,16,17,18,19,20-七去甲基-5-硫杂-8-氮杂前列腺烷酸甲酯
在氩气氛下,向在参考例8中制备的化合物(26.8g)和4-碘代丁酸甲酯(19.9g)的甲醇(150mL)溶液中加入碳酸钾(14.0g),并将该混合物搅拌2小时。然后将乙醚和乙酸乙酯的混合溶剂加到该混合物中。所稀释的溶液依次用0.5N盐酸,水和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(31.28g),其物理数据如下。
TLC:Rf 0.67(乙酸乙酯∶己烷=1∶1)。
参考例10
9-氧代-13-羟基-14,15,16,17,18,19,20-七去甲基-5-硫杂-8-氮杂前列腺烷酸甲酯
向在参考例9中制备的化合物(31.28g)的甲醇(70mL)溶液中加入对甲苯磺酸一水合物(2.41g),并将该混合物在50℃搅拌4小时。将其冷却至室温,向该混合物中加入三乙胺(1.95mL),减压浓缩并通过硅胶柱色谱进行纯化(由乙酸乙酯∶己烷=1∶1至乙酸乙酯∶甲醇=100∶1),得到标题化合物(16.67g),其物理数据如下。
TLC:Rf 0.14(乙酸乙酯)。
参考例11
9-氧代-12-甲酰基-13,14,15,16,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺烷酸甲酯
在氩气氛和冰浴下,向在参考例10中制备的化合物(1.04g)和二异丙基乙基胺(3.8mL)于乙酸乙酯(6mL)及二甲亚砜(6mL)的混合溶剂中的溶液中,加入三氧化硫吡啶络合物(1.72g),并将该混合物搅拌40分钟。将0.5N盐酸加到反应混合物中,然后用氯仿萃取该混合物。有机层用无水硫酸钠干燥,减压浓缩得到标题化合物(1.0g),其物理数据如下。
TLC:Rf 0.50(氯仿∶甲醇=9∶1)。
实施例3(a)至实施例3(rr)
按与参考例5,实施例1和2中所述相同的方法,利用在参考例11中制备的化合物或相应的醛衍生物代替在参考例4中制备的化合物,得到具有下列物理数据的本发明的化合物。
实施例3(a)
(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.35(甲醇∶氯仿=1∶5);
NMR:δ7.40-7.10(m,4H),5.79(dd,J=15.4,5.2Hz,1H),5.54(dd,J=15.4,8.4Hz,1H),4.50-4.40(m,1H),4.46(s,2H),4.20-4.05(m,1H),3.70-3.50(m,1H),3.42(s,3H),3.20-2.90(m,1H),2.90-2.80(m,2H),2.80-2.10(m,9H),2.00-1.60(m,3H)。
实施例3(b)
(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.45(甲醇∶氯仿=1∶5);
NMR:δ7.30-7.20(m,3H),7.20-7.05(m,1H),5.75(dd,J=15.4,5.4Hz,1H),5.49(dd,J=15.4,8.6Hz,1H),4.50-4.35(m,1H),4.20-4.05(m,1H),3.75-3.55(m,1H),3.10-2.85(m,1H),2.85(d,J=6.6Hz,2H),2.80-2.10(m,9H),2.00-1.80(m,2H),1.80-1.60(m,1H)。
实施例3(c)
(15α,13E)-9-氧代-15-羟基-16-(3-环丙氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.47(氯仿∶甲醇=9∶1);
NMR:δ7.37-7.11(m,4H),5.80(dd,J=15,5Hz,1H),5.55(dd,J=15,8Hz,1H),4.56(s,2H),4.50-4.40(m,1H),4.17-4.08(m,1H),3.63-3.51(m,1H),3.42-3.36(m,1H),3.11-3.00(m,1H),2.89(dd,J=14,6Hz,1H),2.80(dd,J=14,8Hz,1H),2.72-2.32(m,8H),2.31-2.17(m,1H),1.98-1.83(m,2H),1.79-1.65(m,1H),0.71-0.49(m,4H)。
实施例3(d)
(15α,13E)-9-氧代-15-羟基-16-(3-(2,2,2-三氟乙氧基甲基)苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.47(氯仿∶甲醇=9∶1);
NMR:δ7.38-7.14(m,4H),5.77(dd,J=15,6Hz,1H),5.53(dd,J=15,8Hz,1H),4.65(s,2H),4.50-4.40(m,1H),4.18-4.08(m,1H),3.86(q,J=9Hz,2H),3.68-3.55(m,1H),3.08-2.94(m,1H),2.94-2.79(m,2H),2.68-2.32(m,8H),2.32-2.17(m,1H),1.98-1.82(m,2H),1.78-1.63(m,1H)。
实施例3(e)
(15α,13E)-9-氧代-15-羟基-16-(3-丙基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.50(甲醇∶乙酸乙酯=1∶5);
NMR:δ7.30-7.20(m,1H),7.10-7.00(m,3H),5.78(dd,J=15.4,5.4Hz,1H),5.52(dd,J=15.4,8.4Hz,1H),4.50-4.40(m,1H),4.20-4.05(m,1H),3.75-3.55(m,1H),3.20-2.10(m,14H),2.00-1.80(m,2H),1.80-1.55(m,3H),0.94(t,J=7.2Hz,3H)。
实施例3(f)
(15α,13E)-9-氧代-15-羟基-16-环戊基-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.26(氯仿∶甲醇=9∶1);
NMR:δ5.75(dd,J=15.3,6.0Hz,1H),5.53(ddd,J=15.3,8.0,1.0Hz,1H),4.29-4.10(m,2H),3.77-3.60(m,1H),3.20-3.08(m,1H),2.79-1.43(m,22H),1.22-1.04(m,2H)。
实施例3(g)
(15α,13E)-9-氧代-15-羟基-16-(噻吩-2-基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.18(氯仿∶甲醇=9∶1);
NMR:δ7.19(d,J=5.1Hz,1H),6.95(dd,J=5.1,3.3Hz,1H),6.86(d,J=3.3Hz,1H),5.75(dd,J=15.0,5.4Hz,1H),5.55(dd,J=15.0,8.6Hz,1H),4.48-4.39(m,1H),4.19-4.06(m,1H),3.70-3.59(m,1H),3.42-2.75(m,4H),2.70-2.18(m,10H),1.99-1.84(m,2H),1.79-1.62(m,1H)。
实施例3(h)
(15α,13E)-9-氧代-15-羟基-16-(3-三氟甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.40(氯仿∶甲醇=9∶1);
NMR:δ7.59-7.38(m,4H),5.82-5.71(m,1H),5.60-5.41(m,1H),4.57-4.40(m,1H),4.20-4.06(m,1H),3.70-3.59(m,1H),3.15-2.81(m,3H),2.80-2.01(m,10H),1.99-1.80(m,2H),1.79-1.60(m,1H)。
实施例3(i)
(15α,13E)-9-氧代-15-羟基-16-苯基-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.40(氯仿∶甲醇=10∶1);
NMR:δ7.32-7.19(m,5H),5.77(dd,J=15.3,5.4Hz,1H),5.51(ddd,J=15.3,8.4,1.2Hz,1H),4.41(m,1H),4.11(m,1H),3.62(m,1H),2.95(m,1H),2.86(d,J=6.6Hz,2H),2.65-2.20(m,9H),2.00-1.80(m,2H),1.70(m,1H)。
实施例3(j)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.32(氯仿∶甲醇=10∶1);
NMR:δ7.21(m,1H),7.07-6.98(m,3H),5.78(dd,J=15.3,5.4Hz,1H),5.52(ddd,J=15.3,8.7,1.2Hz,1H),4.43(m,1H),4.11(m,1H),3.62(m,1H),2.95(m,1H),2.83-2.20(m,11H),2.34(S,3H),2.00-1.80(m,2H),1.70(m,1H)。
实施例3(k)
(15α,13E)-9-氧代-15-羟基-16-(3-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.38(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.27(m,1H),7.00-6.89(m,3H),5.75(dd,J=15.4,5.5Hz,1H),5.50(dd,J=15.4,8.5Hz,1H),4.42(m,1H),4.11(m,1H),3.62(m,1H),2.92(m,1H),2.84(d,J=6.9Hz,2H),2.67-2.51(m,4H),2.50-2.41(m,2H),2.38(t,J=7.1Hz,2H),2.22(m,1H),1.94-1.83(m,2H),1.66(m,1H)。
实施例3(l)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.38(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.20-7.16(m,2H),7.04-6.96(m,2H),5.75(dd,J=15.4,6.0Hz,1H),5.50(ddd,J=15.4,8.5,1.1Hz,1H),4.39(m,1H),4.11(m,1H),3.62(m,1H),2.95(m,1H),2.82(d,J=6.6Hz,2H),2.67-2.53(m,4H),2.52-2.43(m,2H),2.39(t,J=7.1Hz,2H),2.22(m,1H),1.94-1.83(m,2H),1.68(m,1H)。
实施例3(m)
(15α,13E)-9-氧代-15-羟基-16-(3,4-二氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.24(氯仿∶甲醇=10∶1);
NMR:δ7.14-7.00(m,2H),6.92(m,1H),5.76(dd,J=15.6,5.4Hz,1H),5.54(ddd,J=15.6,8.4,1.2Hz,1H),4.40(m,1H),4.12(m,1H),3.63(m,1H),3.00(m,1H),2.82-2.10(m,11H),2.00-1.60(m,3H)。
实施例3(n)
(15α,13E)-9-氧代-15-羟基-16-(萘-2-基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.27(氯仿∶甲醇=10∶1);
NMR:δ7.82-7.77(m,3H),7.65(s,1H),7.50-7.40(m,2H),7.32(dd,J=8.4,1.5Hz,1H),5.80(dd,J=15.6,5.1Hz,1H),5.51(ddd,J=15.6,8.4,1.2Hz,1H),4.53(m,1H),4.11(m,1H),3.53(m,1H),3.02(d,J=6.6Hz,2H),2.86(m,1H),2.60-2.10(m,9H),2.00-1.60(m,3H)。
实施例3(o)
(15α,13E)-2,3-桥亚甲基-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.37(氯仿∶甲醇=10∶1);
NMR:δ7.26-7.19(m,3H),7.09(m,1H),5.73(dd,J=15.3,5.7Hz,1H),5.48(m,1H),4.41(m,1H),4.12(m,1H),3.62(m,1H),3.05-2.20(m,9H),2.83(d,J=6.3Hz,2H),1.80-1.60(m,2H),1.34(m,1H),0.90(m,1H)。
实施例3(p)
(15α,13E)-9-氧代-15-羟基-16-(3-叔丁基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.43(氯仿∶甲醇=9∶1);
NMR:δ7.38-7.20(m,3H),7.06-6.99(m,1H),5.79(dd,J=15.3,5.4Hz,1H),5.54(dd,J=15.3,8.4Hz,1H),4.43(m,1H),4.12(m,1H),3.62(m,1H),3.37-2.20(m,14H),1.99-1.83(m,2H),1.73(m,1H),1.31(s,9H)。
实施例3(q)
(13E)-9-氧代-15-羟基-16α-甲基-16-苯基-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.32(氯仿∶甲醇=8∶1);
NMR:δ7.40-7.12(m,5H),5.58(dd,J=15.3,6.3Hz,1H),5.36(ddd,J=15.3,8.4,0.9Hz,1H),4.26(m,1H),4.02(m,1H),3.90-2.80(br,2H),3.52(m,1H),2.85(m,1H),2.66(m,1H),2.60-2.06(m,9H),1.98-1.80(m,2H),1.61(m,1H),1.35(d,J=7.2Hz,3H)。
C15位的立体化学未测定,但该化合物为单一的异构体。
实施例3(r)
(13E)-9-氧代-15-羟基-16β-甲基-16-苯基-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.25(氯仿∶甲醇=8∶1);
NMR:δ7.42-7.14(m,5H),5.73(dd,J=15.3,6.3Hz,1H),5.55(dd,J=15.3,8.1Hz,1H),4.24(dd,J=6.6,6.3Hz,1H),4.15(m,1H),3.71(m,1H),3.60-2.70(br,2H),3.06(m,1H),2.84(m,1H),2.76-2.14(m,9H),2.00-1.82(m,2H),1.71(m,1H),1.27(d,J=7.2Hz,3H)。
C15位的立体化学未测定,但该化合物为单一的异构体。
实施例3(s)
(15α,13E)-9-氧代-15-羟基-16-(3-乙基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.49(氯仿∶甲醇=9∶1);
NMR:δ7.24(m,1H),7.13-6.98(m,3H),5.78(dd,J=15.4,5.5Hz,1H),5.52(ddd,J=15.4,8.2,1.1Hz,1H),4.42(m,1H),4.12(m,1H),3.63(m,1H),3.00(m,1H),2.90-2.77(m,2H),2.67-2.35(m,10H),2.23(m,1H),1.95-1.85(m,2H),1.72(m,1H),1.22(t,J=7.4Hz,3H)。
实施例3(t)
(15α,13E)-9-氧代-15-羟基-16-(4-氟-3-三氟甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.35(氯仿∶甲醇=8∶1);
NMR:δ7.52-7.35(m,2H),7.14(dd,J=9.3,9.3Hz,1H),5.77(dd,J=15.3,5.4Hz,1H),5.54(ddd,J=15.3,8.1,0.9Hz,1H),4.42(m,1H),4.14(m,1H),4.06-1.10(m,18H)。
实施例3(u)
(15α,13E)-9-氧代-15-羟基-16-(4-氟-3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.26(氯仿∶甲醇=8∶1);
NMR:δ7.06-6.88(m,3H),5.75(dd,J=15.3,5.4Hz,1H),5.51(dd,J=15.3,8.4Hz,1H),4.39(m,1H),4.12(m,1H),3.80-2.80(br,2H),3.63(m,1H),2.99(m,1H),2.86-2.06(m,14H),1.98-1.62(m,3H)。
实施例3(v)
(15α,13E)-9-氧代-15-羟基-16-(3-氯-4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.22(氯仿∶甲醇=8∶1);
NMR:δ7.24(m,1H),7.13-7.04(m,2H),5.75(dd,J=15.3,5.7Hz,1H),5.51(ddd,J=15.3,8.4,0.9Hz,1H),4.40(m,1H),4.13(m,1H),4.10-3.10(br,2H),3.63(m,1H),2.99(m,1H),2.88-2.14(m,11H),2.00-1.56(m,3H)。
实施例3(w)
(15β,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.48(氯仿∶甲醇=9∶1);
NMR:δ7.32-7.18(m,3H),7.10(m,1H),5.75(dd,J=15.0,6.6Hz,1H),5.41(dd,J=15.0,8.7Hz,1H),4.39(m,1H),4.11(m,1H),3.62(m,1H),3.18-2.12(m,13H),1.98-1.82(m,2H),1.60(m,1H)。
实施例3(x)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-5-(5-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf 0.62(氯仿∶甲醇∶乙酸=18∶2∶1);
NMR:δ8.17(s,1H),7.14(t,J=8Hz,1H),7.0-6.9(m,3H),5.68(dd,J=15,7Hz,1H),5.35(dd,J=15,9Hz,1H),4.31(q,J=7Hz,1H),4.25-4.1(m,1H),3.7-3.55(m,1H),3.4-3.2(m,2H),3.05-2.9(m,1H),2.88(dd,J=13,6Hz,1H),2.63(dd,J=13,7Hz,1H),2.4-2.25(m,5H),2.25-2.1(m,1H),1.75-1.6(m,1H)。
实施例3(y)
(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-4-(3-羟基异噁唑-5-基)-1,2,3,17,18,19,20-七去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf0.44(氯仿∶甲醇=8∶1);
NMR:δ7.25-7.16(m,3H),7.08(m,1H),5.87(s,1H),5.72(dd,J=15.3,5.7Hz,1H),5.48(ddd,J=15.3,8.4,1.2Hz,1H),4.44(m,1H),4.06(m,1H),3.75-3.52(m,3H),2.93(m,1H),2.88-2.48(m,6H),2.42-2.30(m,2H),2.22(m,1H),1.67(m,1H)。
酯水解(实施例2的方法)未进行。与异噁唑环相连的羟基用甲氧基甲基保护,并在最终步骤除去保护基。
实施例3(z)
(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-2-(5-氧代-1,2,4-噁二唑-3-基)-1,17,18,19,20-五去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf0.39(氯仿∶甲醇=9∶1);
NMR:δ7.38-7.15(m,3H),7.14-7.02(m,1H),5.74(dd,J=15.3,6.0Hz,1H),5.46(ddd,J=15.3,8.7,1.0Hz,1H),4.41(m,1H),4.02(m,1H),3.57(m,1H),3.00-2.19(m,12H),2.17-1.60(m,3H)。
酯水解(实施例2的方法)未进行。连接在1,2,4-噁二唑环上的NH基团用Boc基团保护,并在最终步骤除去保护基。
实施例3(aa)
(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-2-(5-氧代-1,2,4-噻二唑-3-基)-1,17,18,19,20-五去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf0.30(氯仿∶甲醇=9∶1);
NMR:δ7.37-7.18(m,3H),7.12-7.04(m,1H),5.74(dd,J=15.0,6.0Hz,1H),5.47(ddd,J=15.0,8.7,1.2Hz,1H),4.42(m,1H),4.03(m,1H),3.60(m,1H),3.00-2.70(m,4H),2.69-2.38(m,7H),2.28(m,1H),2.15-1.70(m,3H)。
酯水解未进行(实施例2的方法)。连接在1,2,4-噁二唑环上的NH基团用Boc基团保护,并在最终步骤除去保护基。
实施例3(bb)
(15α,13E)-1-甲氧基-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf0.57(氯仿∶甲醇=9∶1);
NMR:δ7.32-7.18(m,3H),7.10(m,1H),5.74(dd,J=15.4,5.8Hz,1H),5.51(ddd,J=15.4,8.5,0.8Hz,1H),4.41(m,1H),4.14(m,1H),3.62(m,1H),3.40(m,2H),3.32(s,3H),2.94(m,1H),2.82(d,J=6.6Hz,2H),2.71-2.48(m,4H),2.42-2.35(m,2H),2.24(m,1H),1.77-1.63(m,5H)。
酯的水解(实施例2的方法)未进行。
实施例3(cc)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf0.18(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ8.09(s,1H),7.18-7.12(m,2H),7.06-6.95(m,2H),5.79(dd,J=15.3,5.7Hz,1H),5.51(dd,J=15.3,9.0Hz,1H),4.39(m,1H),4.11(m,1H),3.73(m,1H),3.40-2.19(m,10H),1.74(m,1H)。
实施例3(dd)
(15α,13E)-1-甲氧基-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf 0.59(氯仿∶甲醇=9∶1);
NMR:δ7.19-7.15(m,2H),7.04-6.98(m,2H),5.74(dd,J=15.3,5.7Hz,1H),5.50(ddd,J=15.3,8.4,1.2Hz,1H),4.37(m,1H),4.10(m,1H),3.62(m,1H),3.40-3.36(m,2H),3.30(s,3H),2.96(m,1H),2.88-2.75(m,2H),2.69-2.49(m,4H),2.40-2.34(m,2H),2.24(m,1H),1.76-1.64(m,5H)。
酯的水解未进行(实施例2的方法)。
实施例3(ee)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-5-(5-(5-氧代-1,2,4-噁二唑-3-基)噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf0.50(氯仿∶甲醇∶乙酸=9∶1∶0.2);
NMR(CDCl3+CD3OD):δ8.03(s,1H),7.20-7.07(m,2H),7.02-6.94(m,2H),5.72(dd,J=15.3,5.7Hz,1H),5.44(dd,J=15.3,8.7Hz,1H),4.35(m,1H),4.14(m,1H),3.68(m,1H),3.65-3.10(m,3H),2.91-2.67(m,2H),2.46-2.11(m,3H),1.72(m,1H)。
酯水解(实施例2的方法)未进行。连接在1,2,4-噁二唑环上的NH基团用Boc基团保护,并在最终步骤除去保护基。
实施例3(ff)
(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂-10-氧杂前列腺-13-烯酸
TLC:Rf0.35(氯仿∶甲醇=9∶1);
NMR:δ7.32-7.20(m,3H),7.10(m,1H),5.88(dd,J=15.4,5.2Hz,1H),5.56(ddd,J=15.4,8.5,1.4Hz,1H),4.50-4.29(m,2H),4.43(dd,J=8.5,8.2Hz,1H),3.89(dd,J=8.5,8.2Hz,1H),3.46(m,1H),3.10(m,1H),2.84-2.80(m,2H),2.77-2.44(m,6H),1.98-1.87(m,2H)。
实施例3(gg)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂-10-氧杂前列腺-13-烯酸
TLC:Rf0.34(氯仿∶甲醇=9∶1);
NMR:δ7.20-7.13(m,2H),7.08-6.98(m,2H),5.88(dd,J=15.4,5.2Hz,1H),5.57(ddd,J=15.4,8.5,1.4Hz,1H),4.47-4.28(m,2H),4.42(dd,J=8.5,8.2Hz,1H),3.91(dd,J=8.5,8.2Hz,1H),3.46(m,1H),3.12(m,1H),2.90-2.78(m,2H),2.75-2.43(m,6H),1.97-1.86(m,2H)。
实施例3(hh)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂-10-氧杂前列腺-13-烯酸
TLC:Rf0.35(氯仿∶甲醇=9∶1);
NMR:δ7.22(t,J=7.4Hz,1H),7.11-6.97(m,3H),5.90(dd,J=15.4,5.2Hz,1H),5.57(ddd,J=15.4,8.8,1.4Hz,1H),4.51-4.28(m,3H),3.91(dd,J=8.2,8.0Hz,1H),3.45(m,1H),3.11(m,1H),2.89-2.44(m,8H),2.36(s,3H),1.96-1.85(m,2H)。
实施例3(ii)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基氨基甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸盐酸盐
TLC:Rf 0.11(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR(CD3OD):δ7.50-7.30(m,4H),5.76(dd,J=15.0,6.6Hz,1H),5.45(dd,J=15.0,8.7Hz,1H),4.40(m,1H),4.24-4.11(m,3H),3.50(m,1H),2.96-2.80(m,3H),2.71(s,3H),2.63-2.43(m,3H),2.42-2.20(m,4H),1.93-1.62(m,3H)。
与苯环相连的氨基用Boc基团保护,并在最终步骤除去保护基。
实施例3(jj)
(15α,13E)-9-氧代-15-羟基-16-(3-乙基-4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.35(氯仿∶甲醇=9∶1);
NMR:δ7.08-6.93(m,3H),5.75(dd,J=15.3,5.4Hz,1H),5.52(ddd,J=15.3,8.7,1.2Hz,1H),4.40(m,1H),4.12(m,1H),3.62(m,1H),3.00(m,1H),2.87-2.18(m,11H),1.98-1.82(m,2H),1.71(m,1H),1.22(t,J=7.5Hz,3H)。
实施例3(kk)
(15α,13E)-9-氧代-15-羟基-16-(5-甲基呋喃-2-基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.34(氯仿∶甲醇=9∶1);
NMR:δ5.99(d,J=2.7Hz,1H),5.88(m,1H),5.75(dd,J=15.3,5.4Hz,1H),5.55(ddd,J=15.3,8.7,1.0Hz,1H),4.47(m,1H),4.15(m,1H),3.63(m,1H),3.06(m,1H),2.92-2.78(m,2H),2.75-2.18(m,12H),2.00-1.81(m,2H),1.72(m,1H)。
实施例3(11)
(15α,13E)-9-氧代-15-羟基-16-(2-甲基噁唑-5-基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.35(氯仿∶甲醇∶乙酸=18∶2∶1);
NMR:δ6.95(s,1H),5.80(dd,J=16,5Hz,1H),5.66(dd,J=16,8Hz,1H),4.6-4.5(m,1H),4.25-4.1(m,1H),3.7-3.55(m,1H),3.2-3.05(m,1H),3.0-2.8(m,2H),2.75-2.5(m,7H),2.5-2.35(m,4H),2.35-2.2(m,1H),2.0-1.85(m,2H),1.85-1.7(m,1H)。
实施例3(mm)
(15α,13E)-9-氧代-15-羟基-16-(苯并呋喃-2-基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.43(氯仿∶甲醇=19∶1);
NMR:δ7.55-7.5(m,1H),7.41(d,J=7Hz,1H),7.25-7.15(m,2H),6.52(s,1H),5.80(dd,J=15,6Hz,1H),5.57(dd,J=15,8Hz,1H),4.63(q,J=6Hz,1H),4.15-4.05(m,1H),3.58(pent,J=7Hz,1H),3.04(d,J=6Hz,2H),3.0-2.9(m,1H),2.65-2.3(m,8H),2.3-2.1(m,1H),1.95-1.8(m,2H),1.75-1.6(m,1H)。
实施例3(nn)
(15α,13E)-9-氧代-15-羟基-16-(5-乙基呋喃-2-基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.29(氯仿∶甲醇=9∶1);
NMR:δ6.00(d,J=3.0Hz,1H),5.88(d,J=3.0Hz,1H),5.75(dd,J=15.3,5.4Hz,1H),5.55(ddd,J=15.3,8.4,1.0Hz,1H),4.48(m,1H),4.15(m,1H),3.64(m,1H),3.03(m,1H),2.93-2.78(m,2H),2.71-2.18(m,12H),1.99-1.82(m,2H),1.72(m,1H),1.21(t,J=7.2Hz,3H)。
实施例3(oo)
(15α,13E)-9-氧代-15-羟基-16-(4,5-二甲基呋喃-2-基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.31(氯仿∶甲醇=9∶1);
NMR:δ5.89(s,1H),5.75(dd,J=15.3,5.1Hz,1H),5.55(dd,J=15.3,8.7Hz,1H),4.44(m,1H),4.15(m,1H),3.63(m,1H),3.07(m,1H),2.86-2.09(m,15H),1.99-1.63(m,6H)。
实施例3(pp)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基呋喃-2-基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.41(氯仿∶甲醇=9∶1);
NMR:δ7.24(d,J=1.8Hz,1H),6.19(d,J=1.8Hz,1H),5.75(dd,J=16,6Hz,1H),5.53(dd,J=16,9Hz,1H),4.53-4.44(m,1H),4.18-4.08(m,1H),3.70-3.59(m,1H),3.10-2.97(m,1H),2.83(d,J=6Hz,2H),2.72-2.32(m,8H),2.30-2.18(m,1H),2.0-1.8(m,5H),1.81-1.64(m,1H)。
实施例3(qq)
(15α,13E)-9-氧代-15-羟基-16-(3-硝基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.59(氯仿∶甲醇=9∶1);
NMR:δ8.01(m,1H),7.60-7.42(m,3H),5.78(dd,J=15.0,5.4Hz,1H),5.55(dd,J=15.0,8.4Hz,1H),4.50(m,1H),4.16(m,1H),3.60(m,1H),3.10-2.18(m,13H),1.98-1.81(m,2H),1.78-1.59(m,1H)。
实施例3(rr)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基异噁唑-5-基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.42(氯仿∶甲醇=9∶1);
NMR:δ5.96(s,1H),5.79(dd,J=15.3,5.1Hz,1H),5.60(dd,J=15.3,8.1Hz,1H),4.59(m,1H),4.17(m,1H),4.00-3.20(m,2H),3.10-2.99(m,3H),2.75-2.20(m,12H),1.98-1.80(m,2H),1.71(m,1H)。
实施例4
(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯-1-醇
室温下,向在实施例1中制备的化合物(220mg)的四氢呋喃(2mL)溶液中加入硼氢化锂(23mg),并将该混合物在室温下搅拌2.5小时,然后在50℃搅拌3小时。冷却之后,向该混合物中加入乙醇和水,并用乙酸乙酯萃取。有机层用盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(用乙酸乙酯∶己烷=50∶1至10∶1),得到标题化合物(171mg),其物理数据如下。
TLC:Rf0.16(乙酸乙酯∶甲醇=85∶15);
NMR:δ7.38-7.11(m,4H),5.73(dd,J=15.3,6.0Hz,1H),5.50(ddd,J=15.3,8.0,1.2Hz,1H),4.50-4.37(m,3H),4.08-3.99(m,1H),3.62(t,J=6.6Hz,2H),3.53-3.37(m,4H),2.92-2.70(m,3H),2.46-2.12(m,3H),1.94(bs,1H),1.78-1.20(m,12H)。
实施例4(a)至实施例4(w)
按与实施例4相同的方法,利用相应的羧酸酯衍生物代替在实施例1中制备的化合物,得到具有下列物理数据的本发明的化合物。
实施例4(a)
(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf 0.18(乙酸乙酯∶甲醇=50∶1);
NMR:δ7.35-7.10(m,4H),5.77(dd,J=15,6Hz,1H),5.52(dd,J=15,9Hz,1H),4.43(s,2H),4.45-4.35(m,1H),4.15-4.05(m,1H),3.70-3.55(m,3H),3.42(s,3H),3.05-2.95(m,1H),2.9-2.75(m,2H),2.7-2.45(m,4H),2.4-2.3(m,2H),2.3-2.15(m,1H),2.1-1.9(br,2H),1.8-1.5(m,5H)。
实施例4(b)
(15α,13E)-9-氧代-15-羟基-16-(3,4-二氟苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯-1-醇
TLC:Rf0.18(乙酸乙酯);
NMR:δ7.15-7.00(m,2H),6.93(m,1H),5.72(dd,J=15.4,5.8Hz,1H),5.50(dd,J=15.4,9.3Hz,1H),4.38(m,1H),4.03(m,1H),3.62(t,J=6.3Hz,2H),3.48(m,1H),2.80(d,J=6.6Hz,2H),2.74(m,1H),2.46-2.26(m,2H),2.22(m,1H),1.76-1.20(m,11H)。
实施例4(c)
(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯-1-醇
TLC:Rf0.39(氯仿∶甲醇=9∶1);
NMR:δ7.24-7.18(m,3H),7.08(m,1H),5.71(dd,J=15.4,6.0Hz,1H),5.48(ddd,J=15.4,8.2,0.8Hz,1H),4.42(m,1H),4.04(m,1H),3.63(t,J=6.6Hz,2H),3.47(m,1H),2.82(d,J=6.6Hz,2H),2.72(m,1H),2.44-2.26(m,2H),2.21(m,1H),1.77-1.20(m,11H)。
实施例4(d)
(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf0.17(乙酸乙酯);
NMR:δ7.29-7.19(m,3H),7.08(m,1H),5.74(dd,J=15.4,5.8Hz,1H),5.49(dd,J=15.4,8.5Hz,1H),4.40(m,1H),4.10(m,1H),3.70-3.67(m,2H),3.65(m,1H),2.95(m,1H),2.84(d,J=6.6Hz,2H),2.68-2.47(m,4H),2.40-2.34(m,2H),2.23(m,1H),2.09(br.s,1H),1.75-1.58(m,5H)。
实施例4(e)
(15α,13E)-9-氧代-15-羟基-16-苯基-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf0.18(乙酸乙酯);
NMR:δ7.37-7.16(m,5H),5.76(dd,J=15.4,5.8Hz,1H),5.49(ddd,J=15.4,8.5,1.1Hz,1H),4.42(m,1H),4.09(m,1H),3.71-3.56(m,3H),2.96(m,1H),2.84(d,J=6.6Hz,2H),2.67-2.43(m,4H),2.41-2.35(m,2H),2.23(m,1H),1.79-1.60(m,5H)。
实施例4(f)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf 0.32(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.21(t,J=7.4Hz,1H),7.19-6.97(m,3H),5.76(dd,J=15.4,5.8Hz,1H),5.50(ddd,J=15.4,8.5,1.1Hz,1H),4.40(m,1H),4.10(m,1H),3.68-3.58(m,3H),2.95(m,1H),2.84-2.78(m,2H),2.67-2.48(m,4H),2.41-2.35(m,2H),2.36(s,3H),2.26(m,1H),1.78-1.62(m,5H)。
实施例4(g)
(15α,13E)-9-氧代-15-羟基-16-(3-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf 0.35(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.29(m,1H),7.01-6.89(m,3H),5.75(dd,J=15.4,5.8Hz,1H),5.50(ddd,J=15.4,8.5,1.1Hz,1H),4.41(m,1H),4.12(m,1H),3.70-3.57(m,3H),2.94(m,1H),2.84(d,J=6.6Hz,2H),2.66-2.54(m,4H),2.41-2.35(m,2H),2.24(m,1H),1.78-1.60(m,5H)。
实施例4(h)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf0.35(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.20-7.13(m,2H),7.05-6.96(m,2H),5.74(dd,J=15.4,5.5Hz,1H),5.50(ddd,J=15.4,8.5,1.4Hz,1H),4.38(m,1H),4.10(m,1H),3.71-3.57(m,3H),2.95(m,1H),2.82(d,J=6.9Hz,2H),2.66-2.48(m,4H),2.40-2.33(m,2H),2.24(m,1H),1.78-1.60(m,5H)。
实施例4(i)
(15α,13E)-9-氧代-15-羟基-16-(3-丙基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf0.20(乙酸乙酯);
NMR:δ7.21(d,J=7.8Hz,1H),7.06(d,J=7.8Hz,1H),7.04-7.00(m,2H),5.76(dd,J=15.0,6.0Hz,1H),5.51(ddd,J=15.0,8.0,1.2Hz,1H),4.40(m,1H),4.10(m,1H),3.72-3.59(m,3H),2.98(m,1H),2.90-2.78(m,2H),2.73-2.43(m,8H),2.41-2.10(m,3H),1.90(bs,1H),1.80-1.75(m,6H),0.94(t,J=7.5Hz,3H)。
实施例4(j)
(15α,13E)-9-氧代-15-羟基-16-(3-三氟甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf0.20(乙酸乙酯);
NMR:δ7.60-7.30(m,4H),5.76(dd,J=15.0,5.7Hz,1H),5.52(ddd,J=15.0,8.0,1.0Hz,1H),4.43(m,1H),4.11(m,1H),3.73-3.69(m,3H),3.06-2.83(m,3H),2.72-2.50(m,4H),2.42-2.00(m,5H),1.80-1.53(m,5H)。
实施例4(k)
(15α,13E)-9-氧代-15-羟基-16-(3-乙基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf 0.43(氯仿∶甲醇=9∶1);
NMR:δ7.24(m,1H),7.13-6.98(m,3H),5.78(dd,J=15.4,6.0Hz,1H),5.52(ddd,J=15.4,8.5,1.1Hz,1H),4.41(m,1H),4.12(m,1H),3.68-3.57(m,3H),3.00(m,1H),2.90-2.75(m,2H),2.67-2.52(m,6H),2.42-2.35(m,2H),2.25(m,1H),1.77-1.60(m,5H),1.23(t,J=7.7Hz,3H)。
实施例4(1)
(15α,13E)-9-氧代-15-羟基-16-(3,4-二氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf0.18(乙酸乙酯);
NMR:δ7.15-7.00(m,2H),6.93(m,1H),5.74(dd,J=15.4,5.5Hz,1H),5.52(dd,J=15.4,8.5Hz,1H),4.38(m,1H),4.12(m,1H),3.71-3.57(m,3H),2.98(m,1H),2.80(d,J=6.9Hz,2H),2.68-2.48(m,4H),2.42-2.36(m,2H),2.25(m,1H),1.77-1.60(m,5H)。
实施例4(m)
(15α,13E)-9-氧代-15-羟基-16-(4-氟-3-三氟甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf 0.47(氯仿∶甲醇=8∶1);
NMR:δ7.52-7.34(m,2H),7.15(dd,J=9.6,9.6Hz,1H),5.76(dd,J=15.3,5.4Hz,1H),5.53(ddd,J=153,8.7,0.9Hz,1H),4.42(m,1H),4.12(m,1H),3.74-3.54(m,3H),3.26-1.40(m,17H)。
实施例4(n)
(15α,13E)-9-氧代-15-羟基-16-(4-氟-3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf0.33(氯仿∶甲醇=8∶1);
NMR:δ7.06-6.90(m,3H),5.75(dd,J=15.3,5.4Hz,1H),5.51(ddd,J=15.3,8.4,0.9Hz,1H),4.37(m,1H),4.10(m,1H),3.74-3.56(m,3H),2.99(m,1H),2.86-2.16(m,12H),2.00-1.44(m,7H)。
实施例4(o)
(15α,13E)-9-氧代-15-羟基-16-(3-氯-4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf0.35(氯仿∶甲醇=8∶1);
NMR:δ7.26(m,1H),7.14-7.04(m,2H),5.74(dd,J=15.3,5.4Hz,1H),5.51(ddd,J=15.3,8.7,0.9Hz,1H),4.39(m,1H),4.11(m,1H),3.78-3.56(m,3H),2.99(m,1H),2.84-1.86(m,10H),1.82-1.54(m,6H)。
实施例4(p)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-1,5-(2,5-间亚噻吩基)-2,3,4,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯-1-醇
TLC:Rf0.22(乙酸乙酯);
NMR:δ7.19(t,J=7.4Hz,1H),7.08-6.94(m,3H),6.79(d,J=3.3Hz,1H),6.64(d,J=3.3Hz,1H),5.69(dd,J=15.4,6.0Hz,1H),5.43(ddd,J=15.4,8.5,1.1Hz,1H),4.72(s,2H),4.37(m,1H),4.02(m,1H),3.53(m,1H),2.85-2.74(m,5H),2.44-2.33(m,2H),2.36(s,3H),2.20(m,1H),1.87-1.64(m,3H)。
实施例4(q)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-5-(5-羟甲基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf0.20(乙酸乙酯);
NMR:δ7.48(s,1H),7.20(t,J=8Hz,1H),7.1-6.95(m,3H),5.68(dd,J=15,6Hz,1H),5.47(dd,J=15,9Hz,1H),4.78(s,2H),4.34(q,J=6Hz,1H),4.13(q,J=7Hz,1H),3.7-3.6(m,1H),3.4-3.15(m,3H),2.77(d,J=6Hz,2H),2.4-2.1(m,6H),1.8-1.6(m,1H)。
实施例4(r)
(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂-10-氧杂前列腺-13-烯-1-醇
TLC:Rf0.36(氯仿∶甲醇=9∶1);
NMR:δ7.32-7.20(m,3H),7.10(m,1H),5.86(dd,J=15.4,5.5Hz,1H),5.56(ddd,J=15.4,8.8,1.4Hz,1H),4.48-4.29(m,2H),4.43(dd,J=8.2,8.2Hz,1H),3.91(dd,J=8.2,8.2Hz,1H),3.70-3.63(m,2H),3.45(m,1H),3.09(m,1H),2.82(d,J=6.0Hz,2H),2.75-2.56(m,4H),1.78-1.54(m,4H)。
实施例4(s)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂-10-氧杂前列腺-13-烯-1-醇
TLC:Rf0.37(氯仿∶甲醇=9∶1);
NMR:δ7.20-7.13(m,2H),7.06-6.98(m,2H),5.87(dd,J=15.4,5.5Hz,1H),5.57(ddd,J=15.4,8.5,1.4Hz,1H),4.44-4.28(m,2H),4.43(dd,J=8.5,8.2Hz,1H),3.91(dd,J=8.5,8.2Hz,1H),3.69-3.64(m,2H),3.46(m,1H),3.11(m,1H),2.90-2.76(m,2H),2.74-2.55(m,4H),1.78-1.62(m,4H)。
实施例4(t)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-3,7-(2,5-间亚噻吩基)-4,5,6,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯-1-醇
TLC:Rf0.46(乙酸乙酯∶甲醇=19∶1);
NMHR:δ7.25-7.1(m,2H),7.05-6.95(m,2H),6.66(d,J=3Hz,1H),6.62(d,J=3Hz,1H),5.73(dd,J=16,6Hz,1H),5.47(dd,J=16,9Hz,1H),4.85(d,J=15Hz,1H),4.45-4.35(m,1H),4.05-3.95(m,1H),3.88(d,J=15Hz,1H),3.70(t,J=6Hz,2H),2.95-2.8(m,4H),2.5-2.3(m,2H),2.25-2.1(m,1H),2.0-1.85(m,2H),1.8-1.6(m,1H)。
实施例4(u)
(15α,13E)-9-氧代-15-羟基-16-(3-乙基-4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf 0.28(乙酸乙酯∶甲醇=9∶1);
NMR:δ7.06-6.91(m,3H),5.75(dd,J=15.6,5.7Hz,1H),5.52(ddd,J=15.6,9.0,1.5Hz,1H),4.39(m,1H),4.10(m,1H),3.72-3.59(m,3H),3.00(m,1H),2.84-2.43(m,8H),2.41-2.19(m,3H),1.90(bs,2H),1.80-1.60(m,5H),1.22(t,J=7.5Hz,3H)。
实施例4(v)
(15α,13E)-9-氧代-15-羟基-16-(5-甲基呋喃-2-基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf 0.35(乙酸乙酯∶甲醇=19∶1);
NMR:δ5.99(d,J=3.0Hz,1H),5.88(m,1H),5.76(dd,J=15.3,5.7Hz,1H),5.55(ddd,J=15.3,8.4,1.0Hz,1H),4.42(m,1H),4.11(m,1H),3.74-3.60(m,3H),3.06(m,1H),2.94-2.77(m,2H),2.71-2.50(m,4H),2.43-2.09(m,7H),1.92-1.56(m,6H)。
实施例4(w)
(15α,13E)-9-氧代-15-羟基-16-(5-乙基呋喃-2-基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇
TLC:Rf 0.16(乙酸乙酯∶甲醇=19∶1);
NMR:δ6.01(d,J=3.0Hz,1H),5.89(d,J=3.0Hz,1H),5.75(dd,J=15.3,5.4Hz,1H),5.55(dd,J=15.3,8.7Hz,1H),4.45(m,1H),4.10(m,1H),3.71-3.59(m,3H),3.03(m,1H),2.92-2.78(m,2H),2.72-2.45(m,6H),2.42-2.10(m,4H),2.00-1.59(m,6H),1.21(t,J=7.8Hz,3H)。
实施例5
(15α)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺烷酸乙酯
在氩气氛下,将钯-碳(44mg)加到在实施例1中制备的化合物(440mg)的乙醇(10mL)溶液中,并周氢气置换氩气。待将混合物搅拌4小时之后,滤除催化剂。将滤液减压浓缩并通过硅胶柱色谱进行纯化(乙酸乙酯∶甲醇=50∶1至20∶1),得到标题化合物(384mg),其物理数据如下。
TLC:Rf0.16(乙酸乙酯∶甲醇=85∶15)。
实施例6
(15α)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺烷酸
按与实施例2相同的方法,利用在实施例5中制备的化合物(227mg)代替在实施例1中制备的化合物,得到具有下列物理数据的本发明的化合物(173mg)。
TLC:Rf0.45(氯仿∶甲醇=9∶1);
NMR:δ7.38-7.11(m,4H),4.45(s,2H),3.91-3.80(m,1H),3.67-3.53(m,2H),3.42(s,3H),3.00-2.64(m,3H),2.50-2.03(m,5H),1.94-1.89(m,1H),1.86-1.20(m,13H)。
实施例6(a)至实施例6(c)
按与实施例5和6相同的方法,利用相应的羧酸酯衍生物代替在实施例1中制备的化合物,得到具有下列物理数据的本发明的化合物。
实施例6(a)
(15α)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺烷酸
TLC:Rf0.37(氯仿∶甲醇=10∶1);
NMR:δ7.22(t,J=6.9Hz,1H),7.08-6.99(m,3H),3.86(m,1H),3.63-3.54(m,2H),2.92(m,1H),2.80(dd,J=13.5,4.8Hz,1H),2.67(dd,J=13.5,8.4Hz,1H),2.34(s,3H),2.40-1.20(m,18H)。
实施例6(b)
(15α)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺烷酸
TLC:Rf 0.32(氯仿∶甲醇=10∶1);
NMR:δ7.21(t,J=7.8Hz,1H),7.08-6.98(m,3H),3.90(m,1H),3.78-3.62(m,2H),3.40(br s,1H),3.17(m,1H),2.80-2.30(m,10H),2.34(s,3H),2.14(m,1H),2.00-1.40(m,7H)。
实施例6(c)
(15α)-9-氧代-15-羟基-16-(3-三氟甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺烷酸
TLC:Rf0.6(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.57-7.39(m,4H),3.95(m,1H),3.78-3.63(m,2H),3.19(m,1H),2.92-2.67(m,4H),2.65-2.34(m,6H),2.16(m,1H),2.00-1.47(m,7H)。
参考例12
(15α,13E)-9-氧代-15-(叔丁基二甲基甲硅烷氧基)-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸乙酯
将在实施例1中制备的化合物(1.26g)的二甲基甲酰胺(3mL)溶液冷却,然后加入咪唑(275mg)和叔丁基二甲基甲硅烷基氯(446mg)的二甲基甲酰胺(2mL)溶液。待将混合物在室温下搅拌1小时之后,向其中加水,并用乙酸乙酯萃取。萃取液依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(3.39g),其物理数据如下。
TLC:Rf0.62(乙酸乙酯)。
参考例13
(15α,13E)-9-氧代-15-(叔丁基二甲基甲硅烷氧基)-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
向在参考例12中制备的化合物(420mg)于甲醇(2mL)和四氢呋喃(2mL)混合溶剂中的溶液中加入2N氢氧化钠水溶液(1.2mL),并将该混合物搅拌2小时。向混合物中加入盐酸进行酸化,然后用乙酸乙酯萃取。萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(398mg),其物理数据如下。
TLC:Rf0.48(氯仿∶甲醇=8∶1)。
参考例14
(15α,13E)-9-氧代-15-(叔丁基二甲基甲硅烷氧基)-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸N-甲磺酰胺
向在参考例13中制备的化合物(90mg)的二氯甲烷(1mL)溶液中加入甲磺酰胺(41mg),二甲氨基吡啶(32mg)和1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(67mg),并将该混合物在室温下搅拌过夜。向该混合物中加入稀盐酸,然后用乙酸乙酯萃取。萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(100mg),其物理数据如下。
TLC:Rf0.23(己烷∶乙酸乙酯=1∶3)。
实施例7
(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸N-甲磺酰胺
向在实施例14中制备的化合物(100mg)的四氢呋喃(1mL)溶液中加入氟化四丁基铵(0.35mL;1.0M的四氢呋喃溶液),并将该混合物在室温下搅拌3小时。将混合物倒入冷的氯化铵水溶液中,用乙酸乙酯萃取。萃取液用盐水洗涤,干燥,减压浓缩并通过硅胶柱色谱进行纯化(由己烷∶乙酸乙酯=1∶3至氯仿∶甲醇=10∶1),得到标题化合物(35mg),其物理数据如下。
TLC:Rf0.38(氯仿∶甲醇=8∶1);
NMR:δ9.97(brs,1H),7.38-7.08(m,4H),5.75(dd,J=15.3,5.4Hz,1H),5.50(dd,J=15.3,8.1Hz,1H),4.44(s,2H),4.43(m,1H),4.04(m,1H),3.41(s,3H),3.40(m,1H),3.26(s,3H),3.06-2.72(m,3H),2.52-2.10(m,5H),1.86-1.12(m,10H)。
实施例7(a)至实施例7(d)
按与参考例14和实施例7相同的方法,利用在参考例13中制备的化合物或相应的羧酸衍生物及相应的磺酰胺衍生物代替甲磺酰胺,得到具有下列物理数据的本发明的化合物。
实施例7(a)
(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸N-苯磺酰胺
TLC:Rf 0.42(氯仿∶甲醇=8∶1);
NMR:δ9.84(brs,1H),8.05(d,J=7.2Hz,1H),7.68-7.46(m,3H),7.38-7.08(m,5H),5.75(dd,J=15.3,5.4Hz,1H),5.50(dd,J=15.3,8.7Hz,1H),4.45(s,2H),4.45(m,1H),4.03(m,1H),3.41(s,3H),3.40(m,1H),3.06-2.68(m,3H),2.54-2.12(m,5H),1.90-1.06(m,10H)。
实施例7(b)
(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸N-苄磺酰胺
TLC:Rf0.44(氯仿∶甲醇=8∶1);
NMR:δ9.46(brs,1H),7.46-7.04(m,9H),5.71(dd,J=15.3,5.7Hz,1H),5.46(dd,J=15.3,8.7Hz,1H),4.63(s,2H),4.42(s,2H),4.40(m,1H),3.98(m,1H),3.37(s,3H),3.30(m,1H),3.00-2.62(m,3H),2.40-2.06(m,5H),1.82-1.08(m,10H)。
实施例7(c)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-1,5-(2,5-间亚噻吩基)-2,3,4,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯酸N-苄磺酰胺
TLC:Rf0.12(氯仿∶甲醇=9∶1);
NMR:δ9.15(br.s,1H),7.52(d,J=3.9Hz,1H),7.39-7.30(m,5H),7.18-7.11(m,2H),7.03-6.96(m,2H),6.79(d,J=3.9Hz,1H),5.71(dd,J=15.4,5.8Hz,1H),5.43(ddd,J=15.4,8.8,1.1Hz,1H),4.76(s,2H),4.38(m,1H),4.00(m,1H),3.41(m,1H),2.86-2.74(m,5H),2.38-2.07(m,3H),1.84-1.60(m,3H)。
实施例7(d)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-5-(5-苄基磺酰基氨甲酰基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf0.46(氯仿∶甲醇∶乙酸=9∶1∶0.2);
NMR:δ8.20(s,1H),7.34(s,5H),7.18-7.07(m,2H),7.02-6.95(m,2H),5.71(dd,J=15.3,5.1Hz,1H),5.47(dd,J=15.3,9.0Hz,1H),4.73(s,2H),4.37(m,1H),4.03(m,1H),3.63(m,1H),3.39(m,1H),3.28-3.10(m,2H),2.82-2.71(m,2H),2.25-2.03(m,3H),1.75-1.55(m,1H)。
参考例15
(15α,13E)-9-硫代-15-叔丁基二甲基甲硅烷氧基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸丁酯
向(15α,13E)-9-氧代-15-叔丁基二甲基甲硅烷氧基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸丁酯(170mg;该化合物按与参考例12相同的方法,利用(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸丁酯代替在实施例1中制备的化合物而得到)的甲苯(2mL)溶液中加入2,4-二(4-甲氧基苯基)-1,3-二硫杂-2,4-二磷杂环丁烷-2,4-二硫化物(Lawesson试剂)(74mg),并将该混合物在50℃搅拌1小时。冷却之后,反应混合物通过硅胶柱色谱进行纯化(己烷∶乙酸乙酯=5∶1),得到标题化合物(175mg),其物理数据如下。
TLC:Rf0.53(己烷∶乙酸乙酯=4∶1)。
实施例8
(15α,13E)-9-硫代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸丁酯
向在参考例15中制备的化合物(160mg)的四氢呋喃(1.4mL)溶液中加入氟化四丁基铵(1.4mL;1.0M的四氢呋喃溶液),并将该混合物在室温下搅拌3小时。将混合物倒入饱和的氯化铵水溶液中,并用乙酸乙酯萃取。萃取液依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(由己烷∶乙酸乙酯=2∶1至仅乙酸乙酯),得到标题化合物(110mg),其物理数据如下。
TLC:Rf0.38(己烷∶乙酸乙酯=1∶1)。
实施例9
(15α,13E)-9-硫代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
按与实施例2相同的方法,用在实施例8中制备的化合物代替在实施例1中制备的化合物,得到具有下列物理数据的本发明的化合物。
TLC:Rf0.40(氯仿∶甲醇=8∶1);
NMR:δ7.22(dd,J=7.5,7.5Hz,1H),7.11-6.95(m,3H),5.82(dd,J=15.3,5.1Hz,1H),5.55(ddd,J=15.3,8.7,1.2Hz,1H),4.52-4.38(m,2H),4.13(m,1H),3.37(m,1H),3.10-2.39(m,12H),2.35(s,3H),2.27(m,1H),2.00-1.70(m,3H)。
实施例9(a)
(15α,13E)-9-硫代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸
按与参考例15,实施例8和9相同的方法,用在参考例12中制备的化合物代替(15α,13E)-9-氧代-15-叔丁基二甲基甲硅烷氧基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸丁酯,得到具有下列物理数据的本发明的化合物。
TLC:Rf0.31(甲醇∶氯仿=1∶10);
NMR:δ7.40-7.10(m,4H),5.82(dd,J=15.4,5.0Hz,1H),5.59(dd,J=15.4,8.4Hz,1H),4.50-4.25(m,2H),4.47(s,2H),4.02-3.85(m,1H),3.43(s,3H),3.38-3.10(m,1H),3.10-2.75(m,4H),2.40-2.15(m,2H),2.33(t,J=7.2Hz,2H),1.90-1.20(m,10H)。
参考例16
(15α,13E)-9-氧代-15-叔丁基二甲基甲硅烷氧基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-基叔丁氧基羰基甘氨酰甘氨酸酯
向(15α,13E)-9-氧代-15-叔丁基二甲基甲硅烷氧基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇(170mg;该化合物通过用叔丁基二甲基甲硅烷基(TBS基团)保护在实施例3(j)中制备的化合物的甲酯的C15位的羟基,然后按与实施例4相同的方法制备)于二氯甲烷(2mL)与二甲基甲酰胺(1mL)的混合溶剂中的溶液中,加入叔丁氧基羰基甘氨酰甘氨酸(96mg),甲基3-甲基-2-氟吡啶鎓甲苯磺酸盐(257mg)和二异丙基胺(0.18mL),并将该混合物在室温下搅拌过夜。将反应混合物倒入冷水中,并用乙酸乙酯萃取。萃取液依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(由己烷∶乙酸乙酯=1∶2至仅乙酸乙酯),得到标题化合物(170mg),其物理数据如下。
TLC:Rf 0.53(氯仿∶甲醇=8∶1)。
实施例10
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-基叔丁氧基羰基甘氨酰甘氨酸酯
向在实施例16中制备的化合物(170mg)的二氧己环(0.14mL)溶液中加入1N盐酸(0.14mL),并将该混合物在室温下搅拌过夜。将该混合物倒入饱和氯化纳水溶液中,并用乙酸乙酯萃取。萃取液用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(由己烷∶乙酸乙酯=1∶2至仅乙酸乙酯,然后氯仿∶甲醇=30∶1),得到标题化合物(100mg),其物理数据如下。
TLC:Rf0.33(氯仿∶甲醇=8∶1)。
实施例11
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-基甘氨酰甘氨酸酯一盐酸盐
向在实施例10中制备的化合物(65mg)的苯(0.55mL)溶液中,加入4N的氯化氢-乙酸乙酯溶液(0.14mL),并将该混合物在室温下搅拌2小时。将该混合物与甲苯共沸蒸馏,得到标题化合物(54mg),其物理数据如下。
TLC:Rf 0.41(氯仿∶甲醇=4∶1);
NMR(CD3OD):δ7.15(dd,J=7.5,7.5Hz,1H),7.08-6.94(m,3H),5.70(dd,J=15.3,6.6Hz,1H),5.37(dd,J=15.3,8.7Hz,1H),4.33(m,1H),4.24-4.07(m,3H),4.06-3.94(m,2H),3.73(s,2H),3.60-3.40(m,2H),2.95-2.12(m,14H),1.82-1.54(m,5H)。
实施例11(a)至实施例11(c)
按与参考例16,实施例10和11所述相同的方法,利用相应的氨基酸衍生物代替叔丁氧基羰基甘氨酰甘氨酸,得到具有下列物理数据的本发明的化合物。
实施例11(a)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-基甘氨酸酯甲磺酸盐
TLC:Rf 0.27(氯仿∶甲醇=8∶1);
NMR(CD3OD):δ7.15(dd,J=7.5,7.5Hz,1H),7.06-6.94(m,3H),5.70(dd,J=15.3,6.6Hz,1H),5.37(ddd,J=15.3,8.7,0.9Hz,1H),4.33(m,1H),4.27(t,J=6.3Hz,2H),4.13(m,1H),3.83(s,2H),3.50(m,1H),2.96-2.10(m,15H),1.88-1.54(m,5H)。
实施例11(b)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-基色氨酸酯二-三氟乙酸盐
TLC:Rf0.40(氯仿∶甲醇=8∶1);
NMR(CD3OD):δ7.53(d,J=8.1Hz,1H),7.39(d,J=8.1Hz,1H),7.24-6.92(m,7H),5.67(dd,J=15.6,6.6Hz,1H),5.34(dd,J=15.6,9.0Hz,1H),4.30(t,J=6.9Hz,2H),4.28-4.00(m,3H),3.52-3.30(m,3H),2.94-2.60(m,3H),2.56-2.08(m,10H),1.74-1.32(m,5H)。
实施例11(c)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-基酪氨酸酯三氯乙酸盐
TLC:Rf0.37(氯仿∶甲醇=8∶1);
NMR(CD3OD):δ7.22-6.92(m,6H),6.77(d,J=8.4Hz,2H),5.69(dd,J=15.3,6.6Hz,1H),5.36(dd,J=15.3,8.7Hz,1H),4.33(m,1H),4.27-4.15(m,3H),4.12(m,1H),3.47(m,1H),3.16-3.04(m,2H),2.96-2.06(m,13H),1.80-1.48(m,5H)。
实施例12
(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸异丙氧基羰基甲酯
向在实施例3(b)中制备的化合物(31.5mg)的二甲基甲酰胺(0.7mL)溶液中加入2-溴乙酸异丙酯(16.5mg)和碳酸钾(16mg),并将该混合物在60℃搅拌1.5小时。冷却之后,向反应混合物中加水和乙酸乙酯。有机层依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(氯仿∶甲醇=50∶1),得到标题化合物(35mg),其物理数据如下。
TLC:Rf0.45(氯仿∶甲醇=9∶1);
NMR:δ7.32-7.20(m,3H),7.14-7.06(m,1H),5.74(dd,J=15.3,6.0Hz,1H),5.50(dd,J=15.3,8.6Hz,1H),5.06(m,1H),4.57(s,2H),4.40(m,1H),4.12(m,1H),3.62(m,1H),2.96(m,1H),2.82(d,J=6.0Hz,2H),2.71-2.50(m,6H),2.41-2.19(m,3H),2.00-1.90(m,2H),1.73(m,1H),1.25(d,J=6.3Hz,6H)。
实施例12(a)至实施例12(c)
按与实施例12所述相同的方法,利用在实施例3(b)中制备的化合物或相应的羧酸衍生物及相应的卤化物衍生物代替2-溴乙酸异丙酯,得到具有下列物理数据的本发明的化合物。
实施例12(a)
(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸二甲氨基羰基甲酯
TLC:Rf 0.35(氯仿∶甲醇=9∶1);
NMR:δ7.28-7.19(m,3H),7.12-7.08(m,1H),5.77(dd,J=15.3,5.1Hz,1H),5.54(ddd,J=15.3,8.7,1.2Hz,1H),4.70(s,2H),4.40(m,1H),4.15(m,1H),3.54(m,1H),3.04(m,1H),2.95(s,3H),2.91(s,3H),2.82(d,J=6.0Hz,2H),2.78-2.53(m,6H),2.40-2.18(m,3H),2.03-1.93(m,2H),1.71(m,1H)。
实施例12(b)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸乙酯
TLC:Rf0.44(氯仿∶甲醇=9∶1);
NMR:δ7.21-7.14(m,2H),7.05-6.96(m,2H),5.75(dd,J=15.6,6.0Hz,1H),5.50(dd,J=15.6,8.4Hz,1H),4.19(m,1H),4.18-4.03(m,3H),3.60(m,1H),2.97(m,1H),2.85-2.79(m,2H),2.70-2.18(m,9H),2.01-1.82(m,3H),1.79-1.60(m,1H),1.25(t,J=7.2Hz,3H)。
实施例12(c)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸丁酯
TLC:Rf0.47(乙酸乙酯∶甲醇=20∶1);
NMR:δ7.2-7.1(m,2H),7.05-6.95(m,2H),5.75(dd,J=15,6Hz,1H),5.51(dd,J=15,8Hz,1H),4.45-4.35(m,1H),4.15-4.05(m,1H),4.07(t,J=7Hz,2H),3.7-3.55(m,1H),3.05-2.9(m,1H),2.82(d,J=7Hz,2H),2.7-2.45(m,4H),2.4-2.3(m,4H),2.3-2.15(m,1H),2.0(d,J=4Hz,1H),1.95-1.85(m,2H),1.8-1.65(m,1H),1.65-1.55(m,2H),1.45-1.3(m,2H),0.93(t,J=7Hz,3H)。
参考例17
(15α,13E)-9-氧代-15-(四氢吡喃-2-基氧基)-16-(3-甲基苯基)-1,5-(2,5-间亚噻吩基)-2,3,4,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯酸甲酯
向(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-1,5-(2,5-间亚噻吩基)-2,3,4,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯酸甲酯(111mg;该化合物为在实施例2(ww)中制备的化合物的甲酯)的甲苯(2mL)溶液中,加入二氢吡喃(0.5mL)和对甲苯磺酸(1mg),并将该混合物在室温下搅拌6小时。向该混合物中加入水和乙酸乙酯。有机层依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(146mg),其物理数据如下。
参考例18
(15α,13E)-9-氧代-15-(四氢吡喃-2-基氧基)-16-(3-甲基苯基)-1,5-(2,5-间亚噻吩基)-2,3,4,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯-1-醇
向在参考例17中制备的化合物(146mg)的四氢呋喃(2.5mL)溶液中,加入硼氢化锂(62mg),并将该混合物在50℃搅拌7小时。向该混合物中加入水和乙酸乙酯。有机层依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(101mg),其物理数据如下。
参考例19
(15α,13E)-9-氧代-15-(四氢吡喃-2-基氧基)-16-(3-甲基苯基)-1,5-(2,5-间亚噻吩基)-2,3,4,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯-1-醛
在氩气氛下,向在参考例18中制备的化合物(100mg)于乙酸乙酯(1mL)和二甲亚砜(1.5mL)的混合溶剂中的溶液中加入二异丙基乙基胺(0.22mL)。然后在冰浴下,将三氧化硫吡啶络合物(100mg)加到混合物中,并将该混合物搅拌15分钟。向反应混合物中加水和乙酸乙酯。有机层依次用1N盐酸,饱和碳酸氢钠水溶液和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(103mg),其物理数据如下。
TLC:Rf0.51(乙酸乙酯)。
实施例13
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-1,5-(2,5-间亚噻吩基)-2,3,4,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯-1-醛
向在参考例19中制备的化合物(100mg)于乙腈(1mL)和甲醇(0.5mL)混合溶剂中的溶液中,加入0.1N盐酸,并将该混合物在35℃搅拌1小时。向该反应混合物中加水和乙酸乙酯。有机层依次用饱和碳酸氢钠水溶液和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(由乙酸乙酯∶己烷=4∶1至仅乙酸乙酯),得到标题化合物(70mg),其物理数据如下。
TLC:Rf0.34(乙酸乙酯);
NMR:δ9.80(s,1H),7.60(d,J=3.9Hz,1H),7.20(t,J=7.4Hz,1H),7.08-6.96(m,3H),6.93(d,J=3.9Hz,1H),5.73(dd,J=15.4,5.8Hz,1H),5.48(ddd,J=15.4,8.8,1.4Hz,1H),4.39(m,1H),4.02(m,1H),3.52(m,1H),2.90-2.77(m,5H),2.47-2.25(m,2H),2.36(s,3H),2.20(m,1H),1.88-1.64(m,3H)。
实施例13(a)
(15α,13E)-9-氧代-15-羟基-16-(3-氯苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醛
按与参考例17,18,19及实施例13相同的方法,用在实施例3(b)中制备的化合物的甲酯代替在实施例2(ww)中制备的化合物的甲酯,得到具有下列物理数据的本发明的化合物。
TLC:Rf0.13(己烷∶乙酸乙酯=1∶5);
NMR:δ9.80(t,J=1.5Hz,1H),7.27-7.20(m,3H),7.09(m,1H),5.75(dd,J=15.6,5.4Hz,1H),5.51(ddd,J=15.6,8.7,1.2Hz,1H),4.43(m,1H),4.09(m,1H),3.60(m,1H),2.95(m,1H),2.84(d,J=6.6Hz,2H),2.70-2.20(m,9H),2.00-1.60(m,3H)。
实施例14
(15α,13E)-9-氧代-15-羟基-16-(3-氨基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
在氩气氛下,向(15α,13E)-9-氧代-15-羟基-16-(3-硝基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸丁酯(90mg,该化合物是按与参考例5和实施例1相同的方法,用9-氧代-12-甲酰基-13,14,15,16,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺烷酸丁酯代替在参考例4中制备的化合物,及用3-(3-硝基苯基)-2-氧代丙基膦酸二甲酯代替3-(3-甲氧基甲基苯基)-2-氧代丙基膦酸二甲酯而制备的)于甲醇(1.4mL),四氢呋喃(0.9mL),水(0.45mL)和乙酸(0.27mL)混合溶剂中的溶液中,加入锌粉(37mg),并将该混合物在室温下搅拌30分钟。向反应混合物中加水和乙酸乙酯。有机层依次用饱和碳酸氢钠水溶液和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(氯仿∶甲醇=100∶1),并按与实施例2相同的方法制备,得到标题化合物(44mg),其物理数据如下。
TLC:Rf0.46(氯仿∶甲醇=9∶1);
NMR:δ7.15-7.04(m,1H),6.64-6.50(m,3H),5.75(dd,J=15.0,6.0Hz,1H),5.50(dd,J=15.0,8.4Hz,1H),4.40(m,1H),4.10(m,1H),4.00-3.55(m,4H),2.99(m,1H),2.80-2.19(m,11H),1.98-1.80(m,2H),1.78-1.61(m,1H)。
实施例15(a)至实施例15(c)
按与参考例16和实施例10所述相同的方法,利用(15α,13E)-9-氧代-15-叔丁基二甲基甲硅烷氧基-16-苯基-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇代替(15α,13E)-9-氧代-15-叔丁基二甲基甲硅烷氧基-16-(3-甲基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯-1-醇,并用相应的羧酸衍生物代替叔丁氧基羰基甘氨酰甘氨酸,得到具有下列物理数据的本发明的化合物。
另外,实施例15(c)的化合物是按与实施例11相同的方法制备的。
实施例15(a)
(15α,13E)-1-苯甲酰氧基-9-氧代-15-羟基-16-苯基-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯
TLC:Rf0.50(氯仿∶甲醇=10∶1);
NMR:δ8.05-8.02(m,2H),7.55(m,1H),7.46-7.41(m,2H),7.34-7.18(m,5H),5.73(dd,J=15.3,6.0Hz,1H),5.49(ddd,J=15.3,8.4,1.2Hz,1H),4.40(m,1H),4.31(t,J=6.6Hz,2H),4.02(m,1H),3.48(m,1H),2.85(d,J=6.6Hz,2H),2.68(m,1H),2.45-2.10(m,3H),1.80-1.20(m,11H)。
实施例15(b)
(15α,13E)-1-丁酰氧基-9-氧代-15-羟基-16-苯基-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯
TLC:Rf0.41(氯仿∶甲醇=10∶1);
NMR:δ7.34-7.19(m,5H),5.73(dd,J=15.3,6.3Hz,1H),5.49(ddd,J=15.3,8.4,1.2Hz,1H),4.41(m,1H),4.05(t,J=6.6Hz,2H),4.03(m,1H),3.47(m,1H),2.85(d,J=6.6Hz,2H),2.68(m,1H),2.45-2.10(m,5H),1.80-1.20(m,13H),0.95(t,J=7.2Hz,3H)。
实施例15(c)
(15α,13E)-1-(2-氨基乙酰氧基)-9-氧代-15-羟基-16-苯基-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯三氟甲磺酸盐
TLC:Rf0.10(氯仿∶甲醇=10∶1);
NMR:δ7.32-7.17(m,5H),5.72(dd,J=15.6,6.3Hz,1H),5.45(dd,J=15.6,8.7Hz,1H),4.39(m,1H),4.19(t,J=6.3Hz,2H),4.01(m,1H),3.77(br,2H),3.39(m,1H),2.91-2.78(m,2H),2.66(m,1H),2.40-2.10(m,3H),1.75-1.15(m,11H)。
实施例16
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸2-戊酰氧基乙酯
将在实施例3(1)中制备的化合物(100mg),2-戊酰氧基乙醇(370mg)和三乙胺(0.071mL)的乙酸乙酯(1.3mL)溶液搅拌5分钟。向反应混合物中加入1-甲磺酰氧基苯并三唑(65mg),并将该混合物在室温下搅拌3小时。向反应混合物中加水,并用乙酸乙酯萃取。萃取液依次用水,饱和碳酸氢钠水溶液和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(由乙酸乙酯∶己烷=3∶1至仅乙酸乙酯),得到标题化合物(110mg),其物理数据如下。
TLC:Rf0.33(乙酸乙酯);
NMR:δ7.23-7.15(m,2H),7.06-6.97(m,2H),5.76(dd,J=15.0,5.4Hz,1H),5.50(dd,J=15.0,8.7Hz,1H),4.40(m,1H),4.27(s,4H),4.10(m,1H),3.60(m,1H),2.98(m,1H),2.82(d,J=6.0Hz,2H),2.68-2.20(m,11H),1.96-1.83(m,3H),1.78-1.57(m,3H),1.41-1.29(m,2H),0.92(t,J=7.2Hz,3H)。
实施例16(a)至实施例16(k)
按与实施例16相同的方法,利用在实施例3中制备的化合物或相应的羧酸衍生物及相应的醇衍生物代替2-戊酰氧基乙醇,得到具有下列物理数据的本发明的化合物。
实施例16(a)
(15α,13E)-9-氧代-15-羟基-16-苯基-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸4-苯基苄基酯
TLC:Rf0.57(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.63-7.56(m,4H),7.48-7.18(m,10H),5.71(dd,J=15.4,5.8Hz,1H),5.46(ddd,J=15.4,8.2,1.1Hz,1H),5.17(s,2H),4.40(m,1H),3.99(m,1H),3.44(m,1H),2.82(d,J=6.6Hz,2H),2.66(m,1H),2.40-2.31(m,4H),2.20(m,1H),1.70-1.61(m,3H),1.50-1.20(m,6H)。
实施例16(b)
(15α,13E)-9-氧代-15-羟基-16-苯基-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸3-苯基苯基酯
TLC:Rf0.48(己烷∶乙酸乙酯=1∶3);
NMR:δ7.61-7.55(m,2H),7.48-7.17(m,11H),7.05(m,1H),5.72(dd,J=15.4,5.8Hz,1H),5.48(ddd,J=15.4,8.5,1.1Hz,1H),4.40(m,1H),4.02(m,1H),3.48(m,1H),2.83(d,J=6.6Hz,2H),2.72(m,1H),2.59(t,J=7.4Hz,2H),2.41-2.34(m,2H),2.21(m,1H),1.81-1.62(m,3H),1.54-1.22(m,6H)。
实施例16(c)
(15α,13E)-9-氧代-15-羟基-16-苯基-17,18,19,20-四去甲基-8-氮杂前列腺-13-烯酸2-二甲氨基乙酯盐酸盐
TLC:Rf0.39(氯仿∶甲醇=9∶1);
NMR(CD3OD):δ7.30-7.12(m,5H),5.68(dd,J=15.3,6.6Hz,1H),5.36(dd,J=15.3,9.0Hz,1H),4.43-4.29(m,3H),4.07(m,1H),3.45(m,2H),3.38-3.20(m,1H),2.94-2.89(m,7H),2.72(m,1H),2.54(m,1H),2.44-2.17(m,5H),1.76-1.56(m,3H),1.55-1.18(m,6H)。
实施例16(d)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸2-己酰氧基乙酯
TLC:Rf0.27(乙酸乙酯);
NMR:δ7.21-7.12(m,2H),7.07-6.97(m,2H),5.75(dd,J=15.0,6.0Hz,1H),5.51(dd,J=15.0,8.6Hz,1H),4.39(m,1H),4.27(s,4H),4.10(m,1H),3.61(m,1H),2.96(m,1H),2.82(d,J=6.6Hz,2H),2.70-2.14(m,11H),1.99-1.82(m,3H),1.79-1.55(m,2H),1.40-1.22(m,4H),0.90(t,J=7.0Hz,3H)。
实施例16(e)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸2-庚酰氧基乙酯
TLC:Rf0.29(乙酸乙酯);
NMR:δ7.21-7.13(m,2H),7.06-6.97(m,2H),5.75(dd,J=15.0,6.0Hz,1H),5.50(dd,J=15.0,8.4Hz,1H),4.39(m,1H),4.27(s,4H),4.10(m,1H),3.61(m,1H),2.97(m,1H),2.82(d,J=6.6Hz,2H),2.68-2.16(m,11H),1.97-1.83(m,3H),1.76-1.55(m,2H),1.40-1.20(m,6H),0.89(t,J=7.0Hz,3H)。
实施例16(f)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸2-辛酰氧基乙酯
TLC:Rf0.26(乙酸乙酯∶甲醇=20∶1);
NMR:δ7.22-7.12(m,2H),7.07-6.97(m,2H),5.75(dd,J=15.3,5.4Hz,1H),5.51(dd,J=15.3,8.4Hz,1H),4.45-4.36(m,1H),4.26(s,4H),4.18-4.07(m,1H),3.70-3.57(m,1H),3.02-2.90(m,1H),2.82(d,J=5.4Hz,2H),2.70-2.50(m,4H),2.45(t,J=7.2Hz,2H),2.40-2.18(m,5H),1.98-1.86(m,3H),1.80-1.50(m,3H),1.40-1.20(m,8H),0.89(t,J=7.2Hz,3H)。
实施例16(g)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸N-庚酰基-N-甲基氨甲酰基甲酯
TLC:Rf0.69(氯仿∶甲醇=9∶1);
NMR:δ7.21-7.14(m,2H),7.04-6.97(m,2H),5.75(ddd,J=15.0,5.4,1.2Hz,1H),5.53(dd,J=15.,8.7Hz,1H),4.73-4.65(m,2H),4.39(m,1H),4.13(m,1H),3.58(m,1H),3.39-3.24(m,1H),3.20-3.10(m,1H),3.06(m,1H),2.93-2.77(m,5H),2.71-2.15(m,9H),2.00-1.89(m,2H),1.78-1.42(m,3H),1.40-1.20(m,8H),0.95-0.82(m,3H)。
实施例16(h)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸(4-己基哌嗪-1-基)羰基甲酯
TLC:Rf 0.71(氯仿∶甲醇=9∶1);
NMR:δ7.22-7.12(m,2H),7.06-6.96(m,2H),5.76(dd,J=15.3,5.4Hz,1H),5.52(dd,J=15.3,8.7Hz,1H),4.70(s,2H),4.43-4.35(m,1H),4.18-4.07(m,1H),3.70-3.50(m,3H),3.41-3.32(m,2H),3.09-2.97(m,1H),2.81(d,J=6.6Hz,2H),2.72-2.5(m,6H),2.5-2.2(m,9H),2.01-1.89(m,2H),1,80-1.58(m,1H),1.58-1.41(m,2H),1.41-1.22(m,6H),0.90(t,J=7.2Hz,3H)。
实施例16(i)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸N-乙基-N-(2-二乙氨基乙基)氨甲酰基甲酯
TLC:Rf0.29(氯仿∶甲醇=9∶1);
NMR:δ7.25-7.10(m,2H),7.05-6.95(m,2H),5.76(dd,J=15.0,5.4Hz,1H),5.60-5.45(m,1H),4.79and 4.71(s,2H),4.38(q,J=6.0Hz,1H),4.12(q,J=7.2Hz,1H),3.65-3.50(m,1H),3.45-3.20(m,4H),3.10-2.95(m,1H),2.82(d,J=6.0Hz,2H),2.75-2.40(m,10H),2.40-2.15(m,4H),2.05-1.85(m,2H),1,80-1.60(m,1H),1.22and 1.12(t,J=7.2Hz,3H),1.05(t,J=7.2Hz,3H),1.04(t,J=7.2Hz,3H)。
实施例16(j)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸2-(2-(二丙氨基)乙酰氧基)乙酯
TLC:Rf0.47(氯仿∶甲醇=9∶1);
NMR:δ7.21-7.15(m,2H),7.04-6.97(m,2H),5.76(dd,J=15.3,5.7Hz,1H),5.50(ddd,J=15.3,8.4,1.0Hz,1H),4.40(m,1H),4.37-4.20(m,4H),4.10(m,1H),3.60(m,1H),3.35(s,2H),2.97(m,1H),2.80(d,J=6.0Hz,2H),2.65-2.19(m,13H),1.97-1.84(m,3H),1.78-1.40(m,5H),0.88(t,J=7.5Hz,6H)。
实施例16(k)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸2-(2-(二乙氨基)乙酰氧基)乙酯
TLC:Rf0.46(氯仿∶甲醇=9∶1);
NMR:δ7.20-7.14(m,2H),7.06-6.95(m,2H),5.75(dd,J=15.3,5.7Hz,1H),5.50(dd,J=15.3,8.4Hz,1H),4.42-4.20(m,5H),4.10(m,1H),3.60(m,1H),3.34(s,2H),2.97(m,1H),2.80(d,J=7.0Hz,2H),2.70-2.17(m,13H),2.00-1.83(m,3H),1.70(m,1H),1.06(t,J=7.2Hz,6H)。
实施例17
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸壬酰氧基甲酯
按与实施例12相同的方法,利用在实施例3(1)中制备的化合物代替在实施例3(b)中制备的化合物,用壬酰氧基甲基氯代替2-溴乙酸异丙酯,得到具有下列物理数据的本发明的化合物。
TLC:Rf 0.31(己烷∶乙酸乙酯=1∶4);
NMR:δ7.21-7.12(m,2H),7.06-6.96(m,2H),5.81-5.69(m,3H),5.50(dd,J=15.3,8.4Hz,1H),4.39(m,1H),4.10(m,1H),3.61(m,1H),3.00-2.78(m,3H),2.69-2.17(m,11H),2.00-1.50(m,4H),1.40-1.19(m,10H),0.88(t,J=7.2Hz,3H)。
参考例20
(9α,11α,15α,13E)-9-羟基-11,15-二(四氢吡喃-2-基氧基)-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸
向(9α,11α,15α,13E)-9-羟基-11,15-二(四氢吡喃-2-基氧基)-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸甲酯(5g,其为WO00/03980之参考例28中所述的化合物)的甲醇(8mL)溶液中,加入2N氢氧化钠水溶液(8.1mL),并将该混合物在室温下搅拌1.5小时。冷却之后,向水层加入2N盐酸进行酸化,然后将混合物用乙酸乙酯萃取。萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物,其物理数据如下,其不经纯化即可用于下一步反应。
TLC:Rf0.55(乙酸乙酯);
NMR:δ7.3-7.1(m,4H),5.7-5.3(m,2H),4.8-3.1(m,9H),3.5-3.1(m,5H),3.0-2.0(m,10H),2.0-1.3(m,18H)。
参考例21
(9α,11α,15α,13E)-9-羟基-11,15-二(四氢吡喃-2-基氧基)-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-壬酰氧基乙酯
向在参考例20中制备的化合物的二甲基甲酰胺(16mL)溶液中,加入壬酸2-溴乙酯(2.35g),碘化钠(121mg)和碳酸钾(1.67g),并将该混合物在50℃搅拌2小时。冷却之后,向该混合物中加入水,并用乙酸乙酯萃取。萃取液用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(乙酸乙酯∶己烷=1∶1),得到标题化合物(6.33g),其物理数据如下。
TLC:Rf0.43(己烷∶乙酸乙酯=1∶1);
NMR:δ7.3-7.1(m,4H),5.7-5.3(m,2H),4.75-4.45(m,2H),4.42(s,2H),4.27(s,4H),4.3-3.7(m,3H),3.5-3.2(m,5H),3.0-2.7(m,2H),2.6-2.4(m,6H),2.33(t,J=7.2Hz,2H),2.3-2.0(m,1H),2.0-1.2(m,31H),0.90(t,J=7.2Hz,3H)。
参考例22
(11α,15α,13E)-9-氧代-11,15-二(四氢吡喃-2-基氧基)-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-壬酰氧基乙酯
在冰浴下,向在参考例21中制备的化合物(6.33g)的乙酸乙酯(28mL)溶液中,加入二异丙基乙基胺(8.35mL)。然后向该混合物中加入三氧化硫吡啶络合物(3.82g)和二甲亚砜(14mL),并将该混合物搅拌20分钟。向反应混合物中加水,并用乙酸乙酯萃取。萃取液依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(乙酸乙酯∶己烷=1∶1),得到标题化合物(5.12g),其物理数据如下。
TLC:Rf0.50(己烷∶乙酸乙酯=1∶1);
NMR:δ7.3-7.1(m,4H),5.8-5.25(m,2H),4.8-4.5(m,2H),4.42(s,2H),4.4-3.75(m,8H),3.55-3.2(m,5H),3.0-2.65(m,3H),2.65-2.4(m,7H),2.4-2.05(m,4H),1.95-1.2(m,28H),0.88(t,J=7.2Hz,3H)。
实施例18
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-壬酰氧基乙酯
向在参考例22中制备的化合物(5.12g)于甲醇(26mL),1,2-二甲氧基乙烷(26mL)和乙腈(26mL)混合溶剂中的溶液中,加入0.1N盐酸(26mL),并将该混合物在35℃搅拌3小时。向反应混合物中加水,并用乙酸乙酯萃取。萃取液依次用饱和碳酸氢钠水溶液和盐水洗涤,用无水硫酸镁干燥,减压浓缩并通过硅胶柱色谱进行纯化(乙酸乙酯∶己烷=3∶1至4∶1,然后仅乙酸乙酯),得到标题化合物(2.71g),其物理数据如下。
TLC:Rf0.33(乙酸乙酯);
NMR:δ7.30(t,J=8.1Hz,1H),7.23-7.11(m,3H),5.76(dd,J=15.3,6.0Hz,1H),5.53(dd,J=15.3,8.4Hz,1H),4.48-4.39(m,3H),4.26(s,4H),4.00-3.90(m,1H),3.42(s,3H),3.15-3.08(br,1H),2.91(dd,J=13.5,5.4Hz,1H),2.83(dd,J=13.5,6.9Hz,1H),2.70(dd,J=18.6,7.5Hz,1H),2.65-2.50(m,2H),2.52(t,J=7.2Hz,2H),2.44(t,J=7.2Hz,2H),2.36(t,J=7.2Hz,2H),2.40-2.13(m,4H),1.95-1.82(m,3H),1.74-1.60(m,3H),1.40-1.20(m,10H),0.89(t,J=7.2Hz,3H)。
实施例18(a)至实施例18(q)
按与参考例21,22和实施例18所述相同的方法,利用相应的卤化物代替壬酸2-溴乙酯,得到具有下列物理数据的本发明的化合物。
实施例18(a)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸新戊酰氧基甲酯
TLC:Rf 0.63(氯仿∶甲醇=9∶1);
NMR:δ7.33-7.10(m,4H),5.74(s,2H),5.73(dd,J=15,6.0Hz,1H),5.53(ddd,J=15,8.7,0.7Hz,1H),4.48-4.37(m,3H),3.94(m,1H),3.42(s,3H),2.90(dd,J=13,5.6Hz,1H),2.83(dd,J=13,6.9Hz,1H),2.70(ddd,J=19,7.5,1.1Hz,1H),2.62-2.43(m,6H),2.38-2.12(m,3H),1.95-1.81(m,3H),1.74-1.59(m,1H),1.21(s,9H)。
实施例18(b)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸1-环己氧基羰氧基乙酯
TLC:Rf0.63(氯仿∶甲醇=9∶1);
NMR:δ7.33-7.09(m,4H),6.75(q,J=5.4Hz,1H),5.73(dd,J=15,6.3Hz,1H),5.53(dd,J=15,8.6Hz,1H),4.63(m,1H),4.48-4.34(m,3H),3.94(m,1H),3.41(s,3H),2.88(dd,J=14,5.6Hz,1H),2.82(dd,J=14,6.9Hz,1H),2.69(ddd,J=19,7.6,1.0Hz,1H),2.64-2.41(m,6H),2.37-2.12(m,3H),1.98-1.17(m,14H),1.51(d,J=5.4Hz,3H)。
实施例18(c)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸N,N-二乙氨基羰基甲酯
TLC:Rf 0.18(乙酸乙酯∶甲醇=50∶1);
NMR:δ7.3-7.1(m,4H),5.76(dd,J=15,6Hz,1H),5.55(dd,J=15,8Hz,1H),4.70(s,2H),4.42(s,2H),4.5-4.4(m,1H),3.90(q,J=8Hz,1H),3.41(s,3H),3.37(q,J=7Hz,2H),3.24(q,J=7Hz,2H),2.95-2.8(m,2H),2.69(dd,J=18,7Hz,1H),2.65-2.5(m,6H),2.4-2.1(m,4H),2.4-1.8(m,br),2.0-1.8(m,2H),1.75-1.6(m,1H),1.22(t,J=7Hz,3H),1.15(t,J=7Hz,3H)。
实施例18(d)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-乙酰氧基乙酯
TLC:Rf0.28(乙酸乙酯);
NMR:δ7.3-7.1(m,4H),5.76(dd,J=15,6Hz,1H),5.53(dd,J=15,8Hz,1H),4.5-4.4(m,3H),4.27(s,4H),3.94(brq,1H),3.42(s,3H),3.05-3.0(br,1H),2.91(dd,J=14,6Hz,1H),2.83(dd,J=14,7Hz,1H),2.70(dd,J=18,7Hz,1H),2.65-2.5(m,2H),2.51(t,J=7Hz,2H),2.45(t,J=7Hz,2H),2.4-2.1(m,4H),2.08(s,3H),1.95-1.8(m,3H),1.8-1.6(m,1H)。
实施例18(e)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸苯甲酰基甲酯
TLC:Rf 0.32(乙酸乙酯);
NMR:δ7.92-7.88(m,2H),7.65-7.59(m,1H),7.52-7.46(m,2H),7.34-7.10(m,4H),5.77(dd,J=15.6,5.7Hz,1H),5.54(dd,J=15.6,8.4Hz,1H),5.35(s,2H),4.50-4.38(m,3H),4.00-3.89(m,1H),3.41(s,3H),2.87-2.54(m,9H),2.41-2.18(m,3H),2.04-1.84(m,3H),1.78-1.65(m,1H)。
实施例18(f)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸异丙氧基羰基甲酯
TLC:Rf 0.30(乙酸乙酯);
NMR:δ7.35-7.12(m,4H),5.75(dd,J=15.0,5.7Hz,1H),5.53(dd,J=15.0,8.4Hz,1H),5.07(m,1H),4.56(s,2H),4.47-4.37(m,3H),3.93(m,1H),3.42(s,3H),3.05-2.50(m,10H),2.39-2.14(m,4H),1.98-1.83(m,3H),1.78-1.60(m,1H),1.25(d,J=6.3Hz,6H)。
实施例18(g)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸N,N-二乙氨基羰氧基甲酯
TLC:Rf 0.34(乙酸乙酯);
NMR:δ7.3-7.1(m,4H),5.76(s,2H),5.75(dd,J=15,6Hz,1H),5.53(dd,J=15,8Hz,1H),4.5-4.35(m,3H),3.93(brq,1H),3.42(s,3H),3.4-3.2(m,4H),2.95-2.8(m,2H),2.70(dd,J=19,8Hz,1H),2.65-2.45(m,6H),2.4-2.1(m,4H),1.95-1.8(m,4H),1.75-1.6(m,1H),1.2-1.05(m,6H)。
实施例18(h)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸叔丁氧基羰基甲酯
TLC:Rf0.36(乙酸乙酯);
NMR:δ7.35-7.12(m,4H),5.73(dd,J=15.0,6.0Hz,1H),5.51(dd,J=15.0,8.0Hz,1H),4.50(s,2H),4.43-4.35(m,3H),3.99-3.88(m,1H),3.42-3.20(m,4H),2.89-2.15(m,11H),1.95-1.60(m,6H),1.47(s,9H)。
实施例18(i)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸1-异丙氧基羰基乙酯
TLC:Rf0.44(乙酸乙酯);
NMR:δ7.36-7.12(m,4H),5.76(dd,J=15.0,5.4Hz,1H),5.53(dd,J=15.0,8.4Hz,1H),5.10-4.97(m,1H),4.47-4.38(m,3H),3.99-3.87(m,1H),3.42(s,3H),2.97-2.14(m,12H),1.97-1.61(m,7H),1.46(d,J=7.2Hz,3H),1.27and1.23(d,J=7.0Hz,6H)。
实施例18(j)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸1-苯甲酰基乙酯
TLC:Rf 0.37(乙酸乙酯);
NMR:δ7.92(d,J=8.4Hz,2H),7.63-7.57(m,1H),7.51-7.44(m,2H),7.31-7.25(m,1H),7.19-7.10(m,3H),5.95(q,J=7.20Hz,1H),5.74(ddd,J=15.3,5.7,4.2Hz,1H),5.52(ddd,J=15.3,7.5,1.8Hz,1H),4.47-4.35(m,3H),4.09-3.94(m,1H),3.41(s,3H),3.02-2.13(m,14H),1.97-1.65(m,4H),1.52(d,J=7.2Hz,3H)。
实施例18(k)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸甲氧基羰基甲酯
TLC:Rf0.36(氯仿∶甲醇=10∶1);
NMR:δ7.32-7.15(m,4H),5.74(dd,J=15.3,6.3Hz,1H),5.53(dd,J=15.3,8.7Hz,1H),4.62(s,2H),4.42(m,2H),4.39(m,1H),3.94(m,1H),3.76(s,3H),3.41(s,3H),3.24(brs,1H),2.91-2.51(m,8H),2.41-2.14(m,4H),1.95-1.83(m,3H),1.74-1.62(m,2H)。
实施例18(1)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-十三酰氧基乙酯
TLC:Rf0.36(乙酸乙酯);
NMR:δ7.3-7.1(m,4H),5.77(dd,J=15,6Hz,1H),5.53(dd,J=15,8Hz,1H),4.5-4.4(m,3H),4.25(s,4H),4.0-3.9(brq,1H),3.42(s,3H),2.92(dd,J=14,5Hz,1H),2.84(dd,J=14,7Hz,1H),2.70(dd,J=19,8Hz,1H),2.65-2.5(m,2H),2.50(t,J=7Hz,2H),2.45(t,J=7Hz,2H),2.33(t,J=7Hz,2H),2.4-2.1(m,5H),1.95-1.8(m,3H),1.75-1.5(m,3H),1.4-1.2(m,18H),0.87(t,J=7Hz,3H)。
实施例18(m)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-庚酰氧基乙酯
TLC:Rf0.35(乙酸乙酯);
NMR:δ7.3-7.1(m,4H),5.74(dd,J=15,6Hz,1H),5.52(dd,J=15,8Hz,1H),4.5-4.3(m,3H),4.26(s,4H),4.0-3.9(m,1H),3.42(s,3H),3.35-3.3(br,1H),2.89(dd,J=14,6Hz,1H),2.81(dd,J=14,7Hz,1H),2.70(dd,J=19,8Hz,1H),2.65-2.5(m,2H),2.52(t,J=7Hz,2H),2.47(t,J=7Hz,2H),2.5-2.4(br,1H),2.4-2.15(m,5H),1.95-1.8(m,3H),1.75-1.55(m,3H),1.4-1.2(m,6H),0.90(t,J=7Hz,3H)。
实施例18(n)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-辛酰氧基乙酯
TLC:Rf0.22(己烷∶乙酸乙酯=1∶1);
NMR:δ7.35-7.10(m,4H),5.76(dd,J=15.3,5.7Hz,1H),5.53(dd,J=15.3,8.7Hz,1H),4.48-4.38(m,3H),4.27(s,4H),3.96(m,1H),3.42(s,3H),3.00-2.80(m,3H),2.78-2.40(m,7H),2.39-2.13(m,6H),1.96-1.80(m,3H),1.78-1.57(m,3H),1.40-1.20(m,8H),0.88(t,J=7.0Hz,3H)。
实施例18(o)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-癸酰氧基乙酯
TLC:Rf0.23(己烷∶乙酸乙酯=1∶1);
NMR:δ7.36-7.12(m,4H),5.76(dd,J=15.0,6.0Hz,1H),5.53(dd,J=15.0,8.0Hz,1H),4.44-4.39(m,3H),4.27(s,4H),3.96(m,1H),3.42(s,3H),2.99-2.80(m,3H),2.78-2.40(m,7H),2.39-2.12(m,6H),1.95-1.80(m,3H),1.77-1.60(m,3H),1.39-1.19(m,12H),0.88(t,J=6.9Hz,3H)。
实施例18(p)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸烯丙氧基羰基甲酯
TLC:Rf0.58(乙酸乙酯);
NMR:δ7.4-7.1(m,4H),6.0-5.8(m,1H),5.78(dd,J=16,6Hz,1H),5.53(dd,J=16,8Hz,1H),5.4-5.25(m,2H),4.7-4.6(m,4H),4.5-4.4(m,3H),4.0-3.85(m,1H),3.42(s,3H),3.0-2.8(m,2H),2.72(dd,J=19,10Hz,1H),2.65-2.5(m,6H),2.4-2.1(m,4H),2.0-1.6(m,5H)。
实施例18(q)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸壬酰氧基甲酯
TLC:Rf0.25(己烷∶乙酸乙酯=1∶4);
NMR:δ7.35-7.10(m,4H),5.81-5.69(m,3H),5.52(dd,J=15.0,8.7Hz,1H),4.48-4.37(m,3H),3.95(m,1H),3.42(s,3H),3.10(bs,1H),2.92-2.42(m,9H),2.40-2.11(m,6H),1.97-1.80(m,3H),1.78-1.58(m,3H),1.40-1.20(m,10H),0.88(t,J=7.2Hz,3H)。
参考例23
(11α,15α,13E)-9-氧代-11,15-二(四氢吡喃-2-基氧基)-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-(四氢吡喃-2-基氧基)乙酯
按与参考例21和22相同的方法,用1-(四氢吡喃-2-基氧基)-2-溴乙烷代替壬酸2-溴乙酯,得到具有下列物理数据的标题化合物。
TLC:Rf0.51(己烷∶乙酸乙酯=1∶1)。
实施例19
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-羟基乙酯
按与实施例18相同的方法,利用在参考例23中制备的化合物代替在参考例22中制备的化合物,得到具有下列物理数据的本发明的化合物。
TLC:Rf 0.35(乙酸乙酯∶甲醇=19∶1);
NMR:δ7.32-7.11(m,4H),5.77(dd,J=15.3,5.7Hz,1H),5.54(dd,J=15.3,8.1Hz,1H),4.48-4.38(m,3H),4.22-4.17(m,2H),4.00-3.90(m,1H),3.82-3.75(m,2H),3.42(s,3H),3.12-2.91(br,1H),2.92(dd,J=13.5,5.4Hz,1H),2.84(dd,J=13.5,6.9Hz,1H),2.71(dd,J=18.9,7.5Hz,1H),2.65-2.50(m,2H),2.52(t,J=7.2Hz,2H),2.47(t,J=7.2Hz,2H),2.45-2.15(m,5H),1.95-1.80(m,3H),1.76-1.60(m,1H)。
参考例24
(9α,11α,15α,13E)-9-三甲基甲硅烷氧基-11,15-二(四氢吡喃-2-基氧基)-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸
在氩气氛和室温下,向在参考例20中制备的化合物(680mg)的干燥四氢呋喃(5mL)溶液中,依次加入三乙胺(0.94mL),三甲基甲硅烷基氯(0.57mL)及催化剂量的二甲氨基吡啶,并将该混合物在室温下搅拌5小时。向反应混合物中加水,并用乙酸乙酯萃取。萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物,其物理数据如下,其不经纯化即可用于下一步反应。
TLC:Rf0.45(乙酸乙酯)。
参考例25
(9α,11α,15α,13E)-9-羟基-11,15-二(四氢吡喃-2-基氧基)-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸苯基酯
在室温和氩气氛下,向在参考例24中制备的化合物,三乙胺(0.15mL)和苯酚(53mg)的乙腈(3mL)溶液中,加入1-羟基苯并三唑(50mg)和1-乙基-3-(3-二甲氨基丙基)碳二亚胺一盐酸盐(142mg),并将该混合物在室温下搅拌2小时。向反应混合物中加入乙酸乙酯,依次用1N盐酸(两次),水,饱和碳酸氢钠水溶液和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(乙酸乙酯∶己烷=1∶1),得到标题化合物(115mg),其物理数据如下。
TLC:Rf0.35(己烷∶乙酸乙酯=1∶1)。
实施例20
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸苯基酯
按与参考例22和实施例18相同的方法,利用在参考例25中制备的化合物代替在参考例21中制备的化合物,得到具有下列物理数据的本发明的化合物。
TLC:Rf0.34(乙酸乙酯);
NMR:δ7.4-7.0(m,9H),5.74(dd,J=15,6Hz,1H),5.51(dd,J=15,8Hz,1H),4.5-4.3(m,3H),3.93(brq,1H),3.42(s,3H),3.2-3.1(br,1H),2.88(dd,J=14,6Hz,1H),2.80(dd,J=14,7Hz,1H),2.75-2.5(m,7H),2.4-2.1(m,4H),2.1-1.95(m,2H),2.0-1.85(m,1H),1.8-1.6(m,1H)。
实施例21
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸羧基甲酯
在氩气氛下,向在实施例18(p)中制备的化合物的干燥四氢呋喃(1.5mL)溶液中,加入四(三苯基膦)合钯(0)(15mg)。向该混合物中滴加吗啉(68μL),并将该混合物在室温下搅拌30分钟。向反应混合物中加入乙酸乙酯,依次用1N盐酸,水,饱和碳酸氢钠水溶液和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(乙酸乙酯∶乙酸=100∶1),得到标题化合物(52mg),其物理数据如下。
TLC:Rf 0.30(氯仿∶甲醇∶乙酸=45∶5∶1);
NMR:δ7.3-7.1(m,4H),5.80(dd,J=15,6Hz,1H),5.57(dd,J=15,8Hz,1H),4.58(s,2H),4.47(s,2H),4.5-4.4(m,1H),4.0-3.9(m,1H),3.23(s,3H),2.93(dd,J=14,5Hz,1H),2.81(dd,J=14,7H z,1H),2.8-2.5(m,7H),2.5-2.2(m,3H),2.0-1.8(m,3H),1.8-1.65(m,1H)。
实施例22(a)至实施例22(e)
按与参考例21,22及实施例18相同的方法,利用相应的卤化物代替壬酸2-溴乙酯,得到具有下列物理数据的本发明的化合物。
实施例22(a)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸二丙基氨甲酰基甲酯
TLC:Rf0.32(乙酸乙酯);
NMR:δ7.32-7.27(m,1H),7.22-7.13(m,3H),5.74(dd,J=15.9,6.3Hz,1H),5.54(ddd,J=15.9,8.4,1.2Hz,1H),4.71(s,2H),4.42(m,3H),3.94(m,1H),3.41(s,3H),3.28(m,2H),3.19-3.08(m,3H),2,95-2.80(m,2H),2.78-2.50(m,8H),2.40-2.18(m,3H),2.00-1.83(m,3H),1.76-1.50(m,5H),0.94(t,J=7.5Hz,3H),0.88(t,J=7.5Hz,3H)。
实施例22(b)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸二丁基氨甲酰甲酯
TLC:Rf0.36(乙酸乙酯);
NMR:δ7.32-7.26(m,1H),7.22-7.13(m,3H),5.74(dd,J=15.6,6.0Hz,1H),5.54(dd,J=15.6,8.4Hz,1H),4.71(s,2H),4.42(m,3H),3.94(m,1H),3.41(s,3H),3.31(m,2H),3.17(m,2H),3.02(m,1H),2.93-2.82(m,2H),2.77-2.50(m,8H),2.40-2.19(m,3H),2.00-1.83(m,3H),1.77-1.43(m,5H),1.41-1.21(m,4H),0.96(t,J=7.5Hz,3H),0.91(t,J=7.5Hz,3H)。
实施例22(c)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸4-戊基苯甲酰基甲酯
TLC:Rf0.38(己烷∶乙酸乙酯=1∶4);
NMR:δ7.81(d,J=8.4Hz,2H),7.36-7.23(m,3H),7.21-7.10(m,3H),5.78(dd,J=15.0,5.4Hz,1H),5.55(dd,J=15.0,8.1Hz,1H),5.33(s,2H),4.47-4.39(m,3H),3.95(m,1H),3.41(s,3H),2.97-2.55(m,12H),2.40-2.18(m,4H),2.03-1.84(m,3H),1.80-1.58(m,3H),1.40-1.22(m,4H),0.89(t,J=6.6Hz,3H)。
实施例22(d)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸1,1-二甲基庚氧基羰基甲酯
TLC:Rf 0.42(己烷∶乙酸乙酯=1∶4);
NMR:δ7.35-7.12(m,4H),5.76(dd,J=15.3,5.7Hz,1H),5.53(dd,J=15.3,8.1Hz,1H),4.51-4.40(m,5H),3.95(m,1H),3.42(s,3H),3.00(bs,1H),2.96-2.81(m,2H),2.70(dd,J=18.6,7.5Hz,1H),2.61-2.48(m,6H),2.40-2.19(m,4H),2.00-1.83(m,3H),1.79-1.60(m,3H),1.44(s,6H),1.38-1.20(m,8H),0.88(t,J=6.6Hz,3H)。
实施例22(e)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸二戊基氨甲酰基甲酯
TLC:Rf 0.33(己烷∶乙酸乙酯=1∶4);
NMR:δ7.36-7.12(m,4H),5.76(dd,J=15.0,5.4Hz,1H),5.55(dd,J=15.0,8.7Hz,1H),4.70(s,2H),4.45-4.39(m,3H),3.95(m,1H),3.41(s,3H),3.30(m,2H),3.17(m,2H),3.00(bs,1H),2.98-2.80(m,2H),2.77-2.50(m,8H),2.40-2.19(m,3H),2.00-1.82(m,3H),1.78-1.50(m,5H),1.40-1.20(m,8H),0.98-0.84(m,6H)。
实施例23
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-辛氧基乙酯
向(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸(150mg;其为WO00/03980之实施例3中所述的化合物),2-辛氧基乙醇(296mg)和三乙胺(0.12mL)的乙酸乙酯(3mL)溶液中,加入1-甲磺酰氧基苯并三唑(145mg),并将该混合物在室温下搅拌4小时。向反应混合物中加入乙酸乙酯。所稀释的溶液依次用饱和碳酸氢钠水溶液,水和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(由乙酸乙酯∶己烷=2∶1至仅乙酸乙酯),得到标题化合物(137mg),其物理数据如下。
TLC:Rf0.22(乙酸乙酯∶己烷=3∶1);
NMR:δ7.35-7.15(m,4H),5.75(dd,J=15.3,6.0Hz,1H),5.53(dd,J=15.3,8.7Hz,1H),4.50-4.37(m,3H),4.22(t,J=5.1Hz,2H),4.00-3.90(m,1H),3.62(t,J=5.1Hz,2H),3.46(t,J=6.9Hz,2H),3.42(s,3H),2.90(dd,J=13.5,5.4Hz,1H),2.83(dd,J=13.5,7.2Hz,1H),2.70(dd,J=18.6,7.5Hz,1H),2.65-2.40(m,6H),2.40-2.10(m,4H),1.95-1.80(m,4H),1.80-1.50(m,3H),1.40-1.20(m,10H),0.90(t,J=6.9Hz,3H)。
实施例23(a)至实施例23(j)
按与实施例23相同的方法,利用相应的醇衍生物代替2-辛氧基乙醇,得到具有下列物理数据的本发明的化合物。
实施例23(a)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-(2,2-二甲基戊酰氧基)乙酯
TLC:Rf0.28(乙酸乙酯∶己烷=3∶1);
NMR:δ7.35-7.10(m,4H),5.77(dd,J=15.3,5.7Hz,1H),5.53(dd,J=15.3,8.4Hz,1H),4.50-4.40(m,3H),4.25(s,4H),4.00-3.90(m,1H),3.41(s,3H),2.96-2.80(m,3H),2.67(dd,J=18.3,7.5Hz,1H),2.65-2.50(m,2H),2.50(t,J=7.2Hz,2H),2.43(t,J=7.2Hz,2H),2.40-2.10(m,4H),1.95-1.80(m,3H),1.75-1.60(m,1H),1.55-1.45(m,2H),1.30-1.20(m,2H),0.88(t,J=7.2Hz,3H).
实施例23(b)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸3-丁氧基丙基酯
TLC:Rf0.30(乙酸乙酯∶己烷=3∶1);
NMR:δ7.30-7.10(m,4H),5.77(dd,J=15.3,5.7Hz,1H),5.53(dd,J=15.3,8.4Hz,1H),4.50-4.40(m,3H),4.17(t,J=7.2Hz,2H),4.00-3.90(m,1H),3.48(t,J=7.2Hz,2H),3.42(s,3H),3.40(t,J=6.6Hz,2H),2.97-2.80(m,3H),2.70(dd,J=19.2,7.5Hz,1H),2.65-2.50(m,2H),2.50(t,J=7.2Hz,2H),2.41(t,J=7.2Hz,2H),2.36-2.14(m,4H),1.95-1.82(m,3H),1.75-1.60(m,1H),1.60-1.50(m,2H),1.42-1.30(m,2H),0.92(t,J=7.2Hz,3H)。
实施例23(c)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-丁氧基乙基酯
TLC:Rf0.32(乙酸乙酯);
NMR:δ7.35-7.11(m,4H),5.75(dd,J=15.3,5.7Hz,1H),5.53(dd,J=15.3,8.7Hz,1H),4.48-4.39(m,3H),4.21(m,2H),3.95(m,1H),3.61(m,2H),3.46(t,J=6.6Hz,2H),3.42(s,3H),3.00(m,1H),2.98-2.80(m,2H),2.78-2.18(m,11H),1.98-1.81(m,3H),1.78-1.53(m,3H),1.38(m,2H),0.92(t,J=7.5Hz,3H)。
实施例23(d)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-戊氧基乙基酯
TLC:Rf0.36(乙酸乙酯);
NMR:δ7.35-7.11(m,4H),5.75(dd,J=15.3,5.7Hz,1H),5.53(dd,J=15.3,8.7Hz,1H),4.48-4.39(m,3H),4.21(m,2H),3.95(m,1H),3.61(m,2H),3.46(t,J=6.6Hz,2H),3.42(s,3H),2.98-2.80(m,3H),2.78-2.18(m,11H),1.98-1.81(m,3H),1.78-1.53(m,3H),1.38(m,4H),0.92(t,J=7.5Hz,3H)。
实施例23(e)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-己氧基乙基酯
TLC:Rf0.39(乙酸乙酯);
NMR:δ7.36-7.12(m,4H),5.76(dd,J=15.3,5.7Hz,1H),5.53(dd,J=15.3,8.7Hz,1H),4.48-4.40(m,3H),4.21(m,2H),3.95(m,1H),3.61(m,2H),3.47-3.40(m,5H),2.98-2.80(m,3H),2.78-2.40(m,7H),2.38-2.18(m,4H),1.97-1.82(m,3H),1.70(m,1H),1.63-1.52(m,2H),1.40-1.25(m,6H),0.88(t,J=7.2Hz,3H)。
实施例23(f)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-(2,2-二甲基辛酰氧基)乙酯
TLC:Rf0.20(乙酸乙酯∶己烷=3∶1);
NMR:δ7.35-7.10(m,4H),5.75(dd,J=15.3,6.0Hz,1H),5.53(dd,J=15.3,8.4Hz,1H),4.50-4.35(m,3H),4.26(s,4H),4.00-3.90(m,1H),3.42(s,3H),3.20-3.10(br,1H),2.90(dd,J=13.5,5.4H z,1H),2.83(dd,J=13.5,7.2Hz,1H),2.70(dd,J=18.6,7.2Hz,1H),2.63-2.50(m,2H),2.50(t,J=7.5Hz,2H),2.43(t,J=7.2Hz,2H),2.40-2.15(m,4H),1.95-1.80(m,3H),1.80-1.60(m,1H),1.55-1.50(m,2H),1.40-1.15(m,8H),0.90(t,J=6.9Hz,3H)。
实施例23(g)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-(2,2-二乙基戊酰氧基)乙酯
TLC:Rf 0.21(乙酸乙酯∶己烷=3∶1);
NMR:δ7.35-7.10(m,4H),5.76(dd,J=15.3,6.0Hz,1H),5.53(dd,J=15.3,8.4Hz,1H),4.50-4.35(m,3H),4.27(s,4H),4.00-3.90(m,1H),3.42(s,3H),3.05-3.00(br,1H),2.92(dd,J=13.5,5.4H z,1H),2.83(dd,J=13.5,7.2Hz,1H),2.70(dd,J=18.0,7.2Hz,1H),2.65-2.40(m,6H),2.40-2.10(m,4H),1.95-1.80(m,3H),1.80-1.50(m,7H),1.25-1.10(m,2H),0.90(t,J=7.2Hz,3H),0.78(t,J=7.2Hz,6H)。
实施例23(h)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸4-(4-氯苯基)苯基酯
TLC:Rf0.22(己烷∶乙酸乙酯=1∶3);
NMR:δ7.52(d,J=8.7Hz,2H),7.47(d,J=8.6Hz,2H),7.40(d,J=8.6Hz,2H),7.24(m,1H),7.20-7.08(m,5H),5.72(dd,J=15.3,6.6Hz,1H),5.51(dd,J=15.3,8.4Hz,1H),4.45-4.30(m,3H),3.95(m,1H),3.63(bs,1H),3.40(s,3H),2.90-2.50(m,9H),2.39-2.13(m,3H),2.09-1.82(m,3H),1.70(m,1H)。
实施例23(i)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-(金刚烷-1-基羰氧基)乙酯
TLC:Rf 0.33(乙酸乙酯∶己烷∶甲醇=30∶10∶1);
NMR:δ7.32-7.11(m,4H),5.75(dd,J=15.3,6.0Hz,1H),5.52(dd,J=15.3,9.0Hz,1H),4.48-4.36(m,3H),4.31-4.22(m,4H),4.02-3.89(m,1H),3.42(s,3H),3.20-3.12(br,1H),2.90(dd,J=13.8,5.4Hz,1H),2.82(dd,J=13.8,7.2Hz,1H),2.70(dd,J=18.3,7.2Hz,1H),2.65-2.13(m,10H),2.07-1.97(m,3H),1.96-1.80(m,9H),1.80-1.60(m,7H)。
实施例23(j)
(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-(2,2-二丙基戊酰氧基)乙酯
TLC:Rf 0.38(乙酸乙酯∶己烷∶甲醇=30∶10∶1);
NMR:δ7.32-7.12(m,4H),5.75(dd,J=15.3,6.0Hz,1H),5.52(dd,J=15.3,8.7Hz,1H),4.48-4.32(m,3H),4.25(s,4H),4.02-3.88(m,1H),3.42(s,3H),3.27-3.20(br,1H),2.90(dd,J=13.5,5.4Hz,1H),2.82(dd,J=13.5,6.9Hz,1H),2.70(dd,J=18.3,7.2Hz,1H),2.65-2.12(m,10H),1.94-1.82(m,3H),1.75-1.60(m,1H),1.55-1.45(m,6H),1.22-1.09(m,6H),0.89(t,J=7.2Hz,9H)。
实施例24
(15α,13E)-9-氧代-15-羟基-16-(4-氨基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
按与参考例5,实施例1,11和2相同的方法,利用在参考例11中制备的化合物代替在参考例4中制备的化合物,用3-(4-叔丁氧基羰基氨基苯基)-2-氧代丙基膦酸二甲酯代替3-(3-甲氧基甲基苯基)-2-氧代丙基膦酸二甲酯,得到具有下列物理数据的本发明的化合物。
TLC:Rf 0.17(氯仿∶甲醇=9∶1);
NMR:δ6.98(d,J=8.4Hz,2H),6.66(d,J=8.4Hz,2H),5.73(dd,J=15.9,6.3Hz,1H),5.47(dd,J=15.9,8.4Hz,1H),4.38(m,1H),4.10(m,1H),3.61(m,1H),3.10-2.15(m,15H),2.00-1.81(m,2H),1.73(m,1H)。
参考例26
(2R)-1-(2-甲磺酰氧基乙基)-2-叔丁基二甲基甲硅烷氧基甲基吡咯烷-5-酮
在氩气氛下,向在参考例7中制备的化合物(11.9g)的四氢呋喃(50mL)溶液中,加入三乙胺(9.07mL)。然后在0℃向该混合物中滴加甲磺酰氯(3.68mL),并将该混合物搅拌30分钟。向该混合物中加入水,并用乙酸乙酯萃取。萃取液依次用1N盐酸,饱和碳酸氢钠水溶液和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物,其物理数据如下,其不经纯化即可用于下一步反应。
TLC:Rf 0.46(乙酸乙酯)。
参考例27
(2R)-1-(2-碘代乙基)-2-叔丁基二甲基甲硅烷氧基甲基吡咯烷-5-酮
在氩气氛下,向在参考例26中制备的化合物的乙腈(120mL)溶液中,加入碘化钠(19.5g),并将该混合物在80℃搅拌过夜。将其冷却至室温,向该混合物中加入水,并用乙酸乙酯萃取。萃取液依次用饱和碳酸氢钠水溶液和盐水洗涤,用无水硫酸镁干燥,减压浓缩并通过硅胶柱色谱进行纯化(乙酸乙酯∶己烷=1∶3至1∶1),得到标题化合物(11.3g),其物理数据如下。
TLC:Rf0.63(己烷∶乙酸乙酯=1∶1);
NMR:δ3.92(m,1H),3,81-3.69(m,2H),3.62-3.45(m,2H),3.35(m,1H),3.22(m,1H),2.50-2.26(m,2H),2.14(m,1H),1.78(m,1H),0.86(s,9H),0.03(s,3H),0.02(s,3H)。
参考例28
5-(2-((2R)-2-叔丁基二甲基甲硅烷氧基甲基-5-氧代吡咯烷-1-基)乙硫基)噻吩-2-羧酸乙酯
在氩气氛下,向噻吩-2-羧酸乙酯(936mg)的四氢呋喃(50mL)溶液中,加入硫粉(240mg),并将该混合物冷却至-78℃。向该混合物中滴加2.0M的二异丙基胺化锂(4.0mL),并将其搅拌35分钟。然后加入在参考例27中制备的化合物(1.92g)的四氢呋喃(5mL)溶液,并将该混合物在室温下搅拌1.5小时。将混合物倒入饱和的氯化铵水溶液中,并用叔丁基甲基醚萃取。萃取液用饱和碳酸氢钠水溶液洗涤,用无水硫酸镁干燥,减压浓缩并通过硅胶柱色谱进行纯化(乙酸乙酯∶己烷=1∶3至1∶1),得到标题化合物(1.86g),其物理数据如下。
TLC:Rf 0.54(己烷∶乙酸乙酯=1∶1);
NMR:δ7.65(d,J=3.9Hz,1H),7.09(d,J=3.9Hz,1H),4.32(q,J=7.5Hz,2H),3.86-3.61(m,3H),3.55(m,1H),3.32(m,1H),3.22-3.00(m,2H),2.50-2.21(m,2H),2.10(m,1H),1.80(m,1H),1.36(t,J=7.5Hz,3H),0.86(s,9H),0.03(s,3H),0.02(s,3H)。
参考例29
5-(2-((2R)-2-羟甲基-5-氧代吡咯烷-1-基)乙硫基)噻吩-2-羧酸乙酯
在氩气氛下,向在参考例28中制备的化合物(1.85g)的四氢呋喃(4mL)溶液中,加入氟化四丁基铵(6.28mL),并将该混合物在室温下搅拌过夜。向该混合物中加入水,并用乙酸乙酯萃取。萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(1.15g),其物理数据如下。
TLC:Rf0.15(乙酸乙酯);
NMR:δ7.64(d,J=3.9Hz,1H),7.10(d,J=3.9Hz,1H),4.33(q,J=6.9Hz,2H),3.80-3.68(m,3H),3.60(m,1H),3.40(m,1H),3.17(t,J=7.0Hz,2H),2.58-2.28(m,2H),2.10(m,1H),1.98-1.80(m,2H),1.37(t,J=7.2Hz,3H)。
实施例25(a)至实施例25(c)
按与参考例11,5,实施例1和2相同的方法,利用在参考例29中制备的化合物代替在参考例10中制备的化合物,用相应的膦酸酯衍生物代替3-(3-甲氧基甲基苯基)-2-氧代丙基膦酸二甲酯,得到具有下列物理数据的本发明的化合物。
实施例25(a)
(15α,13E)-1,5-(2,5-间亚噻吩基)-9-氧代-15-羟基-16-(4-氟苯基)-2,3,4,17,18,19,20-七去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.20(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ7.68(d,J=3.9Hz,1H),7.15(dd,J=8.4,5.4Hz,2H),7.06(d,J=3.9Hz,1H),6.98(t,J=8.4Hz,2H),5.71(dd,J=15.0,5.4Hz,1H),5.48(dd,J=15.0,9.0Hz,1H),4.37(m,1H),4.11(m,1H),3.82-3.30(m,2H),3.19-2.93(m,3H),2.70(d,J=6.9Hz,2H),2.50-2.18(m,3H),1.71(m,1H)。
实施例25(b)
(15α,13E)-1,5-(2,5-间亚噻吩基)-9-氧代-15-羟基-16-(3-氯-4-氟苯基)-2,3,4,17,18,19,20-七去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.15(氯仿∶甲醇=9∶1);
NMR:δ7.66(d,J=4.2Hz,1H),7.22(d,J=6.9Hz,1H),7.10-7.00(m,3H),5.69(dd,J=15.3,5.4Hz,1H),5.48(dd,J=15.3,8.7Hz,1H),4.50(bs,2H),4.37(m,1H),4.10(m,1H),3.75-3.60(m,1H),3.20-2.93(m,3H),2.80-2.68(m,2H),2.50-2.12(m,3H),1.70(m,1H)。
实施例25(c)
(15α,13E)-1,5-(2,5-间亚噻吩基)-9-氧代-15-羟基-16-(4-氟-3-三氟甲基苯基)-2,3,4,17,18,19,20-七去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.23(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ7.65(d,J=3.9Hz,1H),7.50-7.30(m,2H),7.20-7.00(m,2H),5.72(dd,J=15.3,5.1Hz,1H),5.51(dd,J=15.3,8.7Hz,1H),4.82(bs,2H),4.40(m,1H),4.12(m,1H),3.65(m,1H),3.23-2.93(m,3H),2.90-2.73(m,2H),2.50-2.10(m,3H),1.70(m,1H)。
参考例30
(4R)-4-叔丁氧基羰基氨基-4-甲酰基丁酸乙酯
在氩气氛和0℃下,向(4R)-5-羟基-4-叔丁氧基羰基氨基戊酸乙酯(15.0g),三乙胺(32.0mL)和二甲亚砜(39mL)的乙酸乙酯(120mL)溶液中,加入三氧化硫吡啶络合物(18.3g)于乙酸乙酯(30mL)和二甲亚砜(75mL)混合溶剂中的溶液,并将该混合物搅拌1小时。在0℃下,向反应混合物中加水(5mL)并加入1N盐酸(240mL)。分出的水层用乙酸乙酯萃取。合并的有机层依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(14.7g),其物理数据如下。
TLC:Rf 0.63(乙酸乙酯∶己烷=1∶1);
NMR:δ9.60(s,1H),5.25-5.15(m,1H),4.35-4.20(m,1H),4.13(q,J=7.2Hz,2H),2.50-2.35(m,2H),2.35-2.20(m,1H),2.00-1.85(m,1H),1.43(s,9H),1.27(t,J=7.2Hz,3H)。
参考例31
(4R,5E)-4-叔丁氧基羰基氨基-7-氧代-8-(4-氟苯基)辛-5-烯酸乙酯
在氩气氛和0℃下,向氢化钠(2.40g;62.6%油悬浮液)的四氢呋喃(620mL)溶液中,加入3-(4-氟苯基)-2-氧代丙基膦酸二甲酯(17.7g)的四氢呋喃(100mL)溶液,并将该混合物搅拌1小时。在0℃下,向反应混合物中加入在参考例30中制备的化合物(14.7g)的四氢呋喃(80mL)溶液,并将该混合物搅拌20分钟。向反应混合物中加入叔丁基甲基醚(800mL)和水(800mL)。有机层依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物(25.3g)。将1g该粗化合物通过硅胶柱色谱进行纯化(乙酸乙酯∶己烷=1∶3),得到标题化合物(636mg),其物理数据如下。
TLC:Rf0.74(乙酸乙酯∶己烷=1∶1);
NMR:δ7.20-7.10(m,2H),7.08-6.96(m,2H),6.76(dd,J=15.3,5.1Hz,1H),6.24(d,J=15.3Hz,1H),4.7-4.6(m,1H),4.4-4.25(m,1H),4.14(q,J=7.2Hz,2H),3.82(s,2H),2.38(t,J=7.2Hz,2H),2.00-1.75(m,2H),1.42(s,9H),1.25(t,J=7.2Hz,3H)。
参考例32
(4R,5E,7S)-4-叔丁氧基羰基氨基-7-羟基-8-(4-氟苯基)辛-5-烯酸乙酯
向在参考例31中制备的化合物(5.56g)及(R)-2-甲基-CBS-氧氮硼杂茂啶(4.3mL;1.0M的甲苯溶液)溶液于干燥四氢呋喃(30mL)中的溶液中,加入硼烷四氢呋喃络合物(8.6mL;1.0M),并将该混合物搅拌15分钟。向该混合物中加入甲醇,并用乙酸乙酯稀释。所稀释的溶液依次用1N盐酸,水和盐水洗涤,用无水硫酸镁干燥,减压浓缩得到标题化合物,其物理数据如下。
TLC:Rf0.80(乙酸乙酯);
NMR:δ7.20-7.09(m,2H),7.02-6.93(m,2H),5.67(dd,J=15.6,5.7Hz,1H),5.52(dd,J=15.6,6.0Hz,1H),4.56-4.43(br,1H),4.35-4.27(m,1H),4.20-4.05(m,3H),2.85-2.68(m,2H),2.30(t,J=6.9Hz,2H),1.90-1.70(m,2H),1.43(s,9H),1.26(t,J=7.2Hz,3H)。
参考例33
(4R,5E,7S)-4-氨基-7-羟基-8-(4-氟苯基)辛-5-烯酸盐酸盐
在0℃下,向在参考例32中制备的化合物的乙醇(12mL)溶液中,加入4N的氯化氢-二氧己环溶液(14mL),并将该混合物搅拌4小时。将该混合物减压浓缩。通过加热将所得粗产物溶解于乙酸乙酯(25mL),然后冷却至室温过夜。滤集沉淀物,用冷的乙酸乙酯洗涤,干燥,得到标题化合物(2.37g),其物理数据如下。
TLC:Rf0.05(乙酸乙酯);
NMR(CD3OD):δ7.28-7.19(m,2H),7.04-6.93(m,2H),5.92(dd,J=15.6,4.8Hz,1H),5.53(dd,J=15.6,8.7Hz,1H),4.41-4.32(m,1H),4.15(q,J=7.2Hz,2H),3.80-3.70(m,1H),2.81(d,J=5.7Hz,2H),2.28(t,J=6.9Hz,2H),2.09-1.97(m,1H),1.84-1.75(m,1H),1.24(t,J=7.2Hz,3H)。
实施例26
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸乙酯
在氩气氛和室温下,向4-(甲酰基甲硫基)丁酸乙酯(1.82g)的干燥四氢呋喃(15mL)溶液中,加入在参考例33中制备的化合物(2.27g),并将该混合物搅拌1.5小时。然后向该混合物中加入三乙酰氧基硼氢化钠(2.91g),并将该混合物在室温下搅拌过夜。将反应混合物用乙酸乙酯稀释。所稀释的溶液依次用水,1N盐酸和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱(乙酸乙酯∶甲醇=30∶1)进行纯化,得到标题化合物(1.80g),其物理数据如下。
TLC:Rf0.33(乙酸乙酯)。
TLC:Rf0.44(氯仿∶甲醇=9∶1);
NMR:δ7.21-7.14(m,2H),7.05-6.96(m,2H),5.75(dd,J=15.6,6.0Hz,1H),5.50(dd,J=15.6,8.4Hz,1H),4.19(m,1H),4.18-4.03(m,3H),3.60(m,1H),2.97(m,1H),2.85-2.79(m,2H),2.70-2.18(m,9H),2.01-1.82(m,3H),1.79-1.60(m,1H),1.25(t,J=7.2Hz,3H)。
实施例27
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
按与实施例2相同的方法,利用在实施例26中制备的化合物代替在实施例1中制备的化合物,得到具有下列物理数据的本发明的化合物。
TLC:Rf0.38(氯仿∶甲醇∶水=9∶1∶0.1);
NMR:δ7.20-7.16(m,2H),7.04-6.96(m,2H),5.75(dd,J=15.4,6.0Hz,1H),5.50(ddd,J=15.4,8.5,1.1Hz,1H),4.39(m,1H),4.11(m,1H),3.62(m,1H),2.95(m,1H),2.82(d,J=6.6Hz,2H),2.67-2.53(m,4H),2.52-2.43(m,2H),2.39(t,J=7.1Hz,2H),2.22(m,1H),1.94-1.83(m,2H),1.68(m,1H)。
实施例27(a)至实施例27(i)
按与参考例31,32,33,实施例26和2相同的方法,利用相应的膦酸酯衍生物代替3-(4-氟苯基)-2-氧代丙基膦酸二甲酯,并用相应的羧酸酯衍生物代替4-(甲酰基甲硫基)丁酸乙酯,得到具有下列物理数据的本发明的化合物。
另外,实施例27(b)的化合物是在参考例32的方法之后,按与实施例5相同的方法制备的。
实施例27(a)
(15α,13E)-9-氧代-15-羟基-16-(3-(苯并呋喃-2-基)苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.53(氯仿∶甲醇=9∶1);
NMR:δ7.76-7.70(m,2H),7.59(d,J=8.4Hz,1H),7.52(d,J=8.4Hz,1H),7.40(dd,J=8.4,8.4Hz,1H),7.33-7.17(m,3H),7.04(s,1H),5.79(dd,J=15.3,5.7Hz,1H),5.51(dd,J=15.3,8.4Hz,1H),4.55-4.44(m,1H),4.16-4.07(m,1H),3.68-3.54(m,1H),3.02-2.90(m,3H),2.70-2.10(m,9H),1.92-1.78(m,2H),1.78-1.62(m,1H)。
实施例27(b)
(15α)-9-氧代-15-羟基-16-(3-甲基苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺烷
TLC:Rf0.19(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ8.07(s,1H),7.21(t,J=7.2Hz,1H),7.10-6.95(m,3H),3.97-3.80(m,2H),3.72(m,1H),3.60-3.25(m,3H),2.84-2.63(m,2H),2.55-2.22(m,5H),2.14(m,1H),1.93(m,1H),1.78-1.41(m,4H)。
实施例27(c)
(15α,13E)-1,6-(1,4-间亚苯基)-9-氧代-15-羟基-16-(3-甲基苯基)-2,3,4,5,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.27(氯仿∶甲醇=9∶1);
NMR:δ8.02(d,J=8.1Hz,2H),7.30-7.15(m,3H),7.10-6.97(m,3H),5.64(dd,J=15.6,6.3Hz,1H),5.37(dd,J=15.6,8.7Hz,1H),4.41-4.32(m,1H),3.83-3.70(m,2H),3.09-2.95(m,1H),2.95-2.75(m,4H),2.48-2.25(m,5H),2.20-2.13(m,1H),1.72-1.58(m,1H)。
实施例27(d)
(15α,13E)-7-(6-羧基吲哚-3-基)-9-氧代-15-羟基-16-(3-甲基苯基)-1,2,3,4,5,6,17,18,19,20-十去甲基-8-氮杂前列腺-13-烯
TLC:Rf 0.21(二氯甲烷∶甲醇=9∶1);
NMR(DMSO-d6):δ8.08(d,J=1.2Hz,1H),7.68(d,J=8.1Hz,1H),7.56(d,J=8.1Hz,1H),7.20-7.10(m,2H),7.10-6.95(m,3H),5.60(dd,J=15.3,6.6Hz,1H),5.43(dd,J=15.3,5.4Hz,1H),4.95-4.80(m,2H),4.37(q,J=6.6Hz,1H),3.90-3.75(m,2H),2.91(dd,J=13.5,6.6Hz,1H),2.70(dd,J=13.5,7.5Hz,1H),2.50-2.20(m,5H),2.15-2.00(m,1H),1.75-1.60(m,1H)。
实施例27(e)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯
TLC:Rf0.25(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ8.12(s,1H),7.18(m,1H),7.05-6.97(m,3H),5.75(dd,J=15.3,5.7Hz,1H),5.60-5.20(m,3H),4.40(m,1H),4.07(m,1H),3.51(m,1H),3.07-2.85(m,3H),2.79(d,J=6.6Hz,2H),2.50-2.12(m,6H),2.04-1.90(m,2H),1.70(m,1H)。
实施例27(f)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-5-(4-羧基噁唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯
TLC:Rf 0.21(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ8.19(s,1H),7.20(m,1H),7.06-6.97(m,3H),5.78(dd,J=15.3,6.0Hz,1H),5.50(ddd,J=15.3,9.0,1.2Hz,1H),4.40(m,2H),4.07(m,1H),3.47(m,1H),2.94(m,1H),2.83-2.75(m,4H),2.50-2.10(m,6H),2.05-1.83(m,2H),1.64(m,1H)。
实施例27(g)
(15α,13E)-1,7-(2,5-间亚噻吩基)-9-氧代-15-羟基-16-(3-甲基苯基)-2,3,4,5,6,17,18,19,20-九去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.18(二氯甲烷∶甲醇=9∶1);
NMR:δ7.70(d,J=3.9Hz,1H),7.21(t,J=7.8Hz,1H),7.10-6.98(m,3H),6.88(d,J=3.9Hz,1H),5.75(dd,J=15.0,6.0Hz,1H),5.46(dd,J=15.0,8.7Hz,1H),4.88(d,J=16.2Hz,1H),4.50-4.40(m,1H),4.10-4.00(m,1H),3.88(d,J=16.2Hz,1H),2.82(d,J=6.6Hz,2H),2.50-2.15(m,6H),1.80-1.70(m,1H)。
实施例27(h)
(15α,13E)-1,6-(1,4-间亚苯基)-9-氧代-15-羟基-16-(3-(苯并呋喃-2-基)苯基)-2,3,4,5,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf 0.31(二氯甲烷∶甲醇=9∶1);
NMR:δ7.98(d,J=8.1Hz,2H),7.78-7.70(m,2H),7.58(d,J=8.1Hz,1H),7.51(d,J=8.1Hz,1H),7.38(t,J=7.8Hz,1H),7.34-7.16(m,5H),7.03(s,1H),5.65(dd,J=15.0,6.0Hz,1H),5.37(dd,J=15.0,7.8Hz,1H),4.50-4.40(m,1H),3.80-3.65(m,2H),3.05-2.60(m,5H),2.40-2.20(m,2H),2.20-2.00(m,1H),1.70-1.55(m,1H)。
实施例27(i)
(15α,13E)-1,5-(2,5-间亚噻吩基)-9-氧代-15-羟基-16-(3-(苯并呋喃-2-基)苯基)-2,3,4,17,18,19,20-七去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.59(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR:δ7.74-7.68(m,2H),7.61(d,J=3.9Hz,1H),7.57(d,J=8.4Hz,1H),7.50(d,J=8.4Hz,1H),7.38(t,J=7.8Hz,1H),7.32-7.14(m,3H),7.02(s,1H),6.73(d,J=3.9Hz,1H),5.75(dd,J=15.3,6.3Hz,1H),5.47(dd,J=15.3,8.4Hz,1H),4.50-4.40(m,1H),4.05-3.95(m,1H),3.65-3.40(m,1H),2.90(d,J=6.9Hz,2H),2.85-2.70(m,3H),2.50-2.10(m,3H),1.85-1.65(m,3H)。
参考例34
(2R)-1-(2-(3-环戊基丙酰氧基)乙基)-2-叔丁基二甲基甲硅烷氧基甲基吡咯烷-5-酮
在氩气氛和0℃下,向在参考例7中制备的化合物(3.78g)和三乙胺(2.9mL)的二氯甲烷(30mL)溶液中,加入3-环戊基丙酰氯(2.67g),并将该混合物搅拌2小时。将该混合物倒入水中并用乙醚萃取。萃取液用盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物,其物理数据如下,其不经纯化即可用于下一步反应。
TLC:Rf 0.40(乙酸乙酯∶己烷=1∶1)。
参考例35
(2R)-1-(2-(3-环戊基丙酰氧基)乙基)-2-羟甲基吡咯烷-5-酮
在氩气氛和室温下,向在参考例34中制备的化合物的四氢呋喃(20mL)溶液中,加入氟化四丁基铵(16.6mL;1.0M的四氢呋喃溶液),并将该混合物搅拌2小时。将该混合物倒入饱和氯化铵水溶液中,并用乙酸乙酯萃取。萃取液依次用饱和氯化铵水溶液和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱(由乙酸乙酯∶己烷=2∶1至乙酸乙酯∶甲醇=40∶1)进行纯化,得到标题化合物(2.40g),其物理数据如下。
TLC:Rf0.35(乙酸乙酯∶甲醇=20∶1)。
参考例36
(2R)-1-(2-(3-环戊基丙酰氧基)乙基)-2-甲酰基吡咯烷-5-酮
在氩气氛下,向在参考例35中制备的化合物(2.40g)和二异丙基乙基胺(8.7mL)于乙酸乙酯(15mL)和二甲亚砜(15mL)混合溶剂中的溶液中,加入三氧化硫吡啶络合物(3.98g),并将该混合物搅拌30分钟。向反应混合物中加入少量的水,并将其倒入1N盐酸中,用乙酸乙酯萃取。萃取液依次用水和盐水洗涤,用无水硫酸镁干燥,减压浓缩得到标题化合物,其物理数据如下,其不经纯化即可用于下一步反应。
TLC:Rf 0.57(乙酸乙酯∶甲醇=20∶1)。
参考例37
(13E)-9,15-二氧代-16-(4-氟苯基)-6-(3-环戊基丙酰氧基)-1,2,3,4,5,17,18,19,20-九去甲基-8-氮杂前列腺-13-烯
在氩气氛和室温下,向3-(4-氟苯基)-2-氧代丙基膦酸二甲酯(2.31g)的干燥四氢呋喃(90mL)溶液中,加入氢化钠(341mg;62.6%油悬浮液),并将该混合物搅拌30分钟。然后向该混合物中加入在参考例36中制备的化合物,并将该混合物搅拌1小时。将反应混合物用叔丁基甲基醚稀释。所稀释的溶液依次用水和盐水洗涤,用无水硫酸镁干燥,减压浓缩得到标题化合物,其物理数据如下,其不经纯化即可用于下一步反应。
TLC:Rf 0.75(乙酸乙酯∶甲醇=20∶1)。
参考例38
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-6-(3-环戊基丙酰氧基)-1,2,3,4,5,17,18,19,20-九去甲基-8-氮杂前列腺-13-烯
在氩气氛和0℃下,向在参考例37中制备的化合物和(R)-2-甲基-CBS-氧氮硼杂茂啶(2.7mL;1.0M甲苯溶液)的干燥四氢呋喃(10mL)溶液中,加入硼烷四氢呋喃络合物(5.4mL;1.0M的四氢呋喃溶液),并将该混合物搅拌20分钟。向该混合物中加入甲醇,并用乙酸乙酯稀释。有机层依次用1N盐酸,水和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(由乙酸乙酯∶己烷∶甲醇=30∶10∶1至乙酸乙酯∶甲醇=30∶1),得到标题化合物(2.58g),其物理数据如下。
TLC:Rf 0.50(乙酸乙酯∶甲醇=20∶1)。
参考例39
(15α,13E)-9-氧代-15-叔丁基二甲基甲硅烷氧基-16-(4-氟苯基)-6-(3-环戊基丙酰氧基)-1,2,3,4,5,17,18,19,20-九去甲基-8-氮杂前列腺-13-烯
在氩气氛和室温下,向在参考例38中制备的化合物(2.08g)和咪唑(0.61g)的二甲基甲酰胺(15mL)溶液中,加入叔丁基二甲基甲硅烷基氯(1.13g)。在将混合物搅拌过夜之后,将反应混合物用叔丁基甲基醚稀释。萃取液依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(乙酸乙酯∶己烷=1∶2至1∶1),得到标题化合物(1.56g),其物理数据如下。
TLC:Rf0.81(乙酸乙酯)。
参考例40
(15α,13E)-9-氧代-15-叔丁基二甲基甲硅烷氧基-16-(4-氟苯基)-6-羟基-1,2,3,4,5,17,18,19,20-九去甲基-8-氮杂前列腺-13-烯
室温下,向在参考例39中制备的化合物(1.56g)于甲醇(5mL)和1,2-二甲氧基乙烷(5mL)混合溶剂中的溶液中,加入2N的氢氧化钠水溶液(3mL),并将该混合物搅拌1小时。将反应混合物用叔丁基甲基醚和四氢呋喃稀释。所稀释的溶液依次用水和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物,其物理数据如下,其不经纯化即可用于下一步反应。
TLC:Rf0.15(乙酸乙酯)。
参考例41
(15α,13E)-9-氧代-15-叔丁基二甲基甲硅烷氧基-16-(4-氟苯基)-6-甲磺酰氧基-1,2,3,4,5,17,18,19,20-九去甲基-8-氮杂前列腺-13-烯
在氩气氛和0℃下,向在参考例40中制备的化合物(600mg)和三乙胺(0.31mL)的四氢呋喃(6mL)溶液中,加入甲磺酰氯(0.14mL),并将该混合物搅拌1小时。将反应混合物用叔丁基甲基醚稀释。所稀释的溶液依次用1N盐酸,水和盐水洗涤,用无水硫酸钠干燥,减压浓缩得到标题化合物,其物理数据如下,其不经纯化即可用于下一步反应。
TLC:Rf 0.60(乙酸乙酯)。
参考例42
(15α,13E)-9-氧代-15-叔丁基二甲基甲硅烷氧基-16-(4-氟苯基)-6-碘-1,2,3,4,5,17,18,19,20-九去甲基-8-氮杂前列腺-13-烯
将在参考例41中制备的化合物和碘化钠(450mg)的乙腈(15mL)悬浮液回流12小时。将其冷却至室温,将该混合物倒入水中,并用叔丁基甲基醚萃取。萃取液依次用饱和硫代硫酸钠水溶液和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(乙酸乙酯∶己烷=1∶2),得到标题化合物(630mg),其物理数据如下。
TLC:Rf 0.92(乙酸乙酯)。
参考例43
(15α,13E)-3,3-桥亚乙基-9-氧代-15-叔丁基二甲基甲硅烷氧基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸甲酯
在氩气氛和室温下,向在参考例42中制备的化合物(90mg)和2-(1-(乙酰硫基甲基)环丙基)乙酸甲酯(42mg)的干燥甲醇(2mL)溶液中,加入碳酸钾(58mg),并将该混合物搅拌6小时。将反应混合物用叔丁基甲基醚稀释。所稀释的溶液依次用饱和氯化铵水溶液和盐水洗涤,用无水硫酸钠干燥,减压浓缩并通过硅胶柱色谱进行纯化(乙酸乙酯∶己烷=1∶3至1∶1),得到标题化合物(90mg),其物理数据如下。
TLC:Rf0.42(乙酸乙酯∶己烷=1∶1)。
实施例28
(15α,13E)-3,3-桥亚乙基-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
按与实施例7和2相同的方法,利用在参考例43中制备的化合物代替在参考例14中制备的化合物,得到具有下列物理数据的本发明的化合物。
TLC:Rf0.50(氯仿∶甲醇=9∶1);
NMR:δ7.22-7.13(m,2H),7.08-6.96(m,2H),5.76(dd,J=15.3,5.7Hz,1H),5.51(dd,J=15.3,8.7Hz,1H),4.48-4.38(m,1H),4.16-4.05(m,1H),3.67-3.53(m,1H),3.10-2.95(m,1H),2.88-2.79(m,2H),2.76(d,J=13.5Hz,1H),2.68-2.50(m,4H),2.43-2.16(m,5H),1.75-1.63(m,1H),0.65-0.50(m,4H)。
实施例28(a)至实施例28(b)
按与参考例43,实施例7和2相同的方法,利用相应的衍生物代替2-(1-(乙酰硫基甲基)环丙基)乙酸甲酯,得到具有下列物理数据的本发明的化合物。
实施例28(a)
(15α,13E)-1,5-(1,4-间亚苯基)-9-氧代-15-羟基-16-(4-氟苯基)-2,3,4,17,18,19,20-七去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.45(氯仿∶甲醇=9∶1);
NMR:δ8.00(d,J=8.4Hz,2H),7.38(d,J=8.4Hz,2H),7.20-7.10(m,2H),7.07-6.96(m,2H),5.65(dd,J=15.3,5.4Hz,1H),5.47(dd,J=15.3,9.3Hz,1H),4.35(m,1H),4.10(m,1H),3.67(m,1H),3.30-3.00(m,3H),2.75(d,J=6.9Hz,2H),2.48-2.08(m,3H),1.70(m,1H)。
实施例28(b)
(15α,13E)-1,5-(1,3-间亚苯基)-9-氧代-15-羟基-16-(4-氟苯基)-2,3,4,17,18,19,20-七去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.45(氯仿∶甲醇=9∶1);
NMR:δ8.05(m,1H),7.88(d,J=7.8Hz,1H),7.58(d,J=8.4Hz,1H),7.38(t,J=7.8Hz,1H),7.18-7.02(m,2H),7.01-6.93(m,2H),5.68(dd,J=15.6,5.7Hz,1H),5.45(dd,J=15.6,8.7Hz,1H),4.60(bs,2H),4.33(m,1H),4.10(m,1H),3.64(m,1H),3.22-2.98(m,3H),2.75(d,J=6.6Hz,2H),2.50-2.08(m,3H),1.68(m,1H)。
实施例29(a)至实施例29(m)
按与参考例5,实施例1和2相同的方法,利用在参考例11中制备的化合物或相应的羧酸酯衍生物代替在参考例4中制备的化合物,并用相应的膦酸酯衍生物代替3-(3-甲氧基甲基苯基)-2-氧代丙基膦酸二甲酯,得到具有下列物理数据的本发明的化合物。
实施例29(a)
(15α,13E)-9-氧代-15-羟基-16-(3-(4-三氟甲基苄氧基)苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.44(氯仿∶甲醇=9∶1);
NMR:δ7.65(d,J=8.1Hz,2H),7.55(d,J=8.1Hz,2H),7.28-7.20(m,1H),6.88-6.78(m,3H),5.75(dd,J=15.3,5.7Hz,1H),5.48(dd,J=15.3,8.1Hz,1H),5.12(s,2H),4.41(q,J=6.3Hz,1H),4.3-3.4(br),4.17-4.07(m,1H),3.68-3.57(m,1H),3.01-2.88(m,1H),2.82(d,J=6.3Hz,2H),2.70-2.10(m,9H),1.96-1.82(m,2H),1.78-1.62(m,1H)。
实施例29(b)
(15α,13E)-9-氧代-15-羟基-16-(3-(吡啶-3-基甲氧基)苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.47(氯仿∶甲醇=9∶1);
NMR:δ8.72(s,1H),8.45(d,J=3.3Hz,1H),7.85(d,J=7.8Hz,1H),7.39(dd,J=7.8,3.3Hz,1H),7.16(dd,J=8.1,8.1Hz,1H),7.04(s,1H),6.80-6.75(m,2H),5.85(dd,J=15.3,4.8Hz,1H),5.62(dd,J=15.3,8.7Hz,1H),5.24(d,J=13.2Hz,1H),5.17(d,J=13.2Hz,1H),4.35-4.30(m,1H),4.20-4.10(m,1H),3.53-3.40(m,1H),3.30-3.16(m,1H),2.8-2.3(m,10H),2.3-2.1(m,1H),1.95-1.8(m,2H),1.8-1.6(m,1H)。
实施例29(c)
(15α,13E)-9-氧代-15-羟基-16-环丙基-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.39(氯仿∶甲醇=9∶1);
NMR:δ5.80(dd,J=15.6,6.0Hz,1H),5.58(ddd,J=15.6,8.4,1.0Hz,1H),4.30(m,1H),4.15(m,1H),3.77-3.05(m,4H),2.77-2.08(m,9H),2.00-1.70(m,3H),1.53-1.41(m,2H),0.72(m,1H),0.60-0.42(m,2H),0.20-0.02(m,2H)。
实施例29(d)
(15α,13E)-9-氧代-15-羟基-16-苯基-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf0.24(氯仿∶甲醇=9∶1);
NMR:δ8.09(s,1H),7.38-7.14(m,5H),5.80(dd,J=15.3,6.0Hz,1H),5.47(dd,J=15.3,8.7Hz,1H),4.40(m,1H),4.21-3.61(m,4H),3.38-3.16(m,3H),2.97-2.79(m,2H),2.52-2.18(m,3H),1.76(m,1H)。
实施例29(e)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf0.27(氯仿∶甲醇=9∶1);
NMR:δ8.08(s,1H),7.20(m,1H),7.08-6.95(m,3H),5.80(dd,J=15.3,5.7Hz,1H),5.50(dd,J=15.3,8.7Hz,1H),4.40(m,1H),4.12(m,1H),3.70(m,1H),3.50-2.95(m,5H),2.85-2.78(m,2H),2.50-2.19(m,6H),1.77(m,1H)。
实施例29(f)
(15α,13E)-9-氧代-15-羟基-16-(3-(吡啶-2-基甲氧基)苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.30(氯仿∶甲醇=9∶1);
NMR:δ8.57(d,J=5.4Hz,1H),7.80(dt,J=1.5,7.5Hz,1H),7.60(d,J=7.5Hz,1H),7.32(m,1H),7.22(t,J=7.8Hz,1H),6.99-6.85(m,2H),6.80(d,J=7.8Hz,1H),5.85(dd,J=15.0,4.8Hz,1H),5.59(ddd,J=15.0,8.7,1.2Hz,1H),5.32(s,2H),4.43(m,1H),4.11(m,1H),3.43(m,1H),3.18(m,1H),2.88-2.18(m,13H),1.97-1.83(m,2H),1.72(m,1H)。
实施例29(g)
(15α,13E)-9-氧代-15-羟基-16-(3-(吡啶-4-基甲氧基)苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.30(氯仿∶甲醇=9∶1);
NMR:δ8.58(d,J=6.0Hz,2H),7.39(d,J=6.0Hz,2H),7.22(t,J=7.8Hz,1H),6.88-6.70(m,3H),5.72(dd,J=15.3,5.7Hz,1H),5.45(dd,J=15.3,8.1Hz,1H),5.12(s,2H),4.32(m,1H),4.11(m,1H),3.59(m,1H),3.30(m,1H),2.99(m,1H),2.78(m,2H),2.69-2.12(m,10H),1.98-1.80(m,2H),1.63(m,1H)。
实施例29(h)
(15α,13E)-9-氧代-15-羟基-16-(3-(吡啶-2-基)苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.37(氯仿∶甲醇=9∶1);
NMR:δ8.74(m,1H),7.93(s,1H),7.84(dt,J=1.8,7.8Hz,1H),7.72(d,J=7.8Hz,1H),7.65(d,J=8.1Hz,1H),7.42(t,J=7.5Hz,1H),7.37-7.23(m,2H),5.88(dd,J=15.0,4.5Hz,1H),5.64(ddd,J=15.0,9.0,1.5Hz,1H),5.45(bs,2H),4.58(m,1H),4.10(m,1H),3.40(m,1H),3.21(m,1H),3.02-2.80(m,2H),2.78-2.10(m,9H),1.99-1.82(m,2H),1.73(m,1H)。
实施例29(i)
(15α,13E)-9-氧代-15-羟基-16-环戊基-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf0.22(氯仿∶甲醇=9∶2);
NMR:δ8.10(s,1H),5.79(dd,J=15.6,6.0Hz,1H),5.55(d,J=15.6,8.7Hz,1H),4.40-3.63(m,5H),3.58-3.24(m,3H),2.57-2.08(m,3H),1.98-1.40(m,10H),1.10(m,2H)。
实施例29(j)
(15α,13E)-9-氧代-15-羟基-16-(3-(2,2,2-三氟乙氧基甲基)苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf 0.19(氯仿∶甲醇=9∶2);
NMR:δ8.08(s,1H),7.37-7.10(m,4H),5.80(dd,J=15.3,5.7Hz,1H),5.52(dd,J=15.3,8.4Hz,1H),4.80-4.50(m,3H),4.41(m,1H),4.11(m,1H),3.94-3.62(m,4H),3.39-3.19(m,3H),2.88-2.79(m,2H),2.50-2.17(m,3H),1.72(m,1H)。
实施例29(k)
(15α,13E)-9-氧代-15-羟基-16-(3-(苯并呋喃-2-基)苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf 0.24(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ8.05(s,1H),7.80-7.65(m,2H),7.58(d,J=7.5Hz,1H),7.51(d,J=7.5Hz,1H),7.39(t,J=7.8Hz,1H),7.35-7.15(m,3H),7.03(s,1H),5.82(dd,J=15.0,5.7Hz,1H),5.52(d,J=15.0,8.7Hz,1H),4.50(m,1H),4.19-4.02(m,1H),3.70(m,1H),3.36-3.08(m,3H),3.00-2.82(m,2H),2.50-2.10(m,3H),1.72(m,1H)。
实施例29(1)
(15α,13E)-9-氧代-15-羟基-16-(5-甲基呋喃-2-基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf 0.26(二氯甲烷∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ8.09(s,1H),5.96(d,J=3.0Hz,1H),5.90-5.84(m,1H),5.79(dd,J=15.3,6.0Hz,1H),5.55(ddd,J=15.3,6.0,1.2Hz,1H),4.45(q,J=6.3Hz,1H),4.12(q,J=7.5Hz,1H),3.84-3.72(m,1H),3.46-3.18(m,3H),2.82(d,J=6.3Hz,2H),2.50-2.20(m,3H),2.24(s,3H),1.80-1.70(m,1H)。
实施例29(m)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-5-(6-羧基吡啶-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf 0.21(氯仿∶甲醇=4∶1);
NMR:δ7.97(m,1H),7.69(m,1H),7.38(m,1H),7.21-7.15(m,2H),7.06-6.97(m,2H),5.75(dd,J=15.0,5.7Hz,1H),5.51(ddd,J=15.0,8.4,1.0Hz,1H),4.40(m,1H),4.10(m,1H),3.58(m,1H),3.38-3.15(m,3H),2.83(d,J=6.6Hz,2H),2.57-2.20(m,3H),1.77(m,1H)。
实施例30(a)至实施例30(e)
按与实施例16相同的方法,利用在实施例3(1)或实施例29(e)中制备的化合物及相应的醇衍生物代替2-戊酰氧基乙醇,得到具有下列物理数据的本发明的化合物。
实施例30(a)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸二丁基氨甲酰甲酯
TLC:Rf0.73(氯仿∶甲醇=9∶1);
NMR:δ7.17(m,2H),6.99(m,2H),5.75(dd,J=15.6,5.1Hz,1H),5.52(dd,J=15.6,8.4Hz,1H),4.69(s,2H),4.40(m,1H),4.11(m,1H),3.58(m,1H),3.28(m,2H),3.20-3.00(m,3H),2.81(d,J=6.6Hz,2H),2.70-2.47(m,7H),2.40-2.18(m,3H),1.95(m,2H),1.88-1.42(m,5H),1.41-1.22(m,4H),1.00-0.83(m,6H)。
实施例30(b)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸2-(2,2-二乙基戊酰氧基)乙酯
TLC:Rf0.29(乙酸乙酯);
NMR:δ7.22-7.13(m,2H),7.07-6.97(m,2H),5.75(dd,J=15.3,6.0Hz,1H),5.50(dd,J=15.3,8.7Hz,1H),4.43-4.32(m,1H),4.25(s,4H),4.18-4.06(m,1H),3.79-3.56(m,1H),3.02-2.88(m,1H),2.86-2.79(m,2H),2.70-2.48(m,4H),2.48-2.31(m,4H),2.31-2.17(m,1H),1.97-1.82(m,3H),1.78-1.60(m,1H),1.60-1.48(m,6H),1.22-1.10(m,2H),0.89(t,J=7.2Hz,3H),0.77(t,J=7.5Hz,6H)。
实施例30(c)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸2-(金刚烷-1-基羰氧基)乙酯
TLC:Rf 0.64(二氯甲烷∶甲醇=9∶1);
NMR:δ7.20-7.10(m,2H),7.05-6.95(m,2H),5.74(dd,J=14.7,6.0Hz,1H),5.50(ddd,J=14.7,8.4,1.5Hz,1H),4.45-4.35(m,1H),4.30-4.20(m,4H),4.15-4.05(m,1H),3.70-3.55(m,1H),3.00-2.90(m,1H),2.81(d,J=6.0Hz,2H),2.70-2.35(m,8H),2.30-2.15(m,1H),2.05-1.95(m,3H),1.95-1.80(m,9H),1.80-1.60(m,6H)。
实施例30(d)
(15α,13E)-9-氧代-15-羟基-16-(4-氟苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸2-(1-乙基-1-甲基丁酰氧基)乙酯
TLC:Rf0.34(乙酸乙酯);
NMR:δ7.20-7.10(m,2H),7.05-6.95(m,2H),5.23(dd,J=15.6,6.0Hz,1H),5.50(ddd,J=15.6,8.4,1.5Hz,1H),4.40-4.30(m,1H),4.27(s,4H),4.15-4.05(m,1H),3.70-3.50(m,1H),3.00-2.90(m,1H),2.81(d,J=6.6Hz,2H),2.70-2.15(m,8H),1.95-1.85(m,3H),1.75-1.60(m,3H),1.50-1.40(m,2H),1.09(s,3H),0.82(t,J=7.5Hz,6H)。
实施例30(e)
(15α,13E)-9-氧代-15-羟基-16-(3-甲基苯基)-5-(4-(2-(1-乙基-1-甲基丁酰氧基)乙氧基羰基)噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺-13-烯
TLC:Rf0.30(乙酸乙酯);
NMR:δ7.99(s,1H),7.17(t,J=7.5Hz,1H),7.05-7.00(m,1H),7.00-6.90(m,2H),5.80(dd,J=15.3,6.0Hz,1H),5.50(ddd,J=16.2,8.7,1.5Hz,1H),4.56-4.45(m,2H),4.40-4.30(m,3H),4.25-4.15(m,1H),3.75-3.65(m,1H),3.40(t,J=6.6Hz,2H),3.30-3.15(m,1H),2.80-2.75(m,2H),2.40-2.15(m,6H),2.08(d,J=4.5Hz,1H),1.80-1.60(m,3H),1.50-1.40(m,2H),1.09(s,3H),0.80(t,J=7.5Hz,6H)。
实施例31
(15α,13E)-9-氧代-15-羟基-16-(3,4-二羟基苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
按与参考例5,实施例1,7和2相同的方法,利用9-氧代-12-甲酰基-13,14,15,16,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺烷酸丁基酯代替在参考例4中制备的化合物,并用3-(3,4-二(叔丁基二甲基甲硅烷氧基)苯基)-2-氧代丙基膦酸二甲酯代替3-(3-甲氧基甲基苯基)-2-氧代丙基膦酸二甲酯,得到具有下列物理数据的本发明的化合物。
TLC:Rf0.14(二氯甲烷∶甲醇∶乙酸=90∶10∶1);
NMR(CD3OD):δ6.67(d,J=7.8Hz,1H),6.61(d,J=1.8Hz,1H),6.49(dd,J=7.8,1.8Hz,1H),5.68(dd,J=15.3,7.2Hz,1H),5.33(dd,J=15.3,9.0Hz,1H),4.30-4.20(m,1H),4.20-4.10(m,1H),3.55-3.45(m,1H),2.90-2.70(m,2H),2.70-2.15(m,10H),1.95-1.80(m,2H),1.80-1.60(m,1H)。
实施例32
(15α,13E)-1,6-(1,4-间亚苯基)-9-氧代-15-羟基-16-(3-(2-甲基苯基)苯基)-2,3,4,5,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯酸
按与参考例31,32,33,实施例26和2相同的方法,用3-(3-(2-甲基苯基)苯基)-2-氧代丙基膦酸二甲酯代替3-(4-氟苯基)-2-氧代丙基膦酸二甲酯,并用4-(甲酰基甲基)苯甲酸乙酯代替4-(甲酰基甲硫基)丁酸乙酯,得到具有下列物理数据的本发明的化合物。
TLC:Rf0.41(二氯甲烷∶甲醇=9∶1);
NMR:δ7.99(d,J=8.4Hz,2H),7.40-7.14(m,10H),5.65(dd,J=15.3,6.0Hz,1H),5.39(dd,J=15.3,8.7Hz,1H),4.45-4.35(m,1H),3.85-3.70(m,2H),3.05-2.70(m,5H),2.40-2.20(m,5H),2.20-2.00(m,1H),1.70-1.55(m,1H)。
实施例32(a)至实施例32(s)
按与参考例31,32,33,实施例26和2相同的方法,利用相应的膦酸酯代替3-(3-(2-甲基苯基)苯基)-2-氧代丙基膦酸二甲酯,并用相应的羧酸酯衍生物代替4-(甲酰基甲基)苯甲酸乙酯,得到具有下列物理数据的本发明的化合物。
实施例32(a)
(15α,13E)-1,6-(1,4-间亚苯基)-9-氧代-15-羟基-16-(3-(3-甲基苯基)苯基)-2,3,4,5,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.32(二氯甲烷∶甲醇=9∶1);
NMR:δ7.98(d,J=8.4Hz,2H),7.50-7.30(m,6H),7.24-7.14(m,4H),5.64(dd,J=15.3,6.0Hz,1H),5.36(dd,J=15.3,8.4Hz,1H),4.50-4.40(m,1H),3.80-3.65(m,2H),3.00-2.70(m,5H),2.45-2.20(m,5H),2.20-2.00(m,1H),1.70-1.55(m,1H)。
实施例32(b)
(15α,13E)-1,6-(1,4-间亚苯基)-9-氧代-15-羟基-16-(3-(4-甲基苯基)苯基)-2,3,4,5,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.32(二氯甲烷∶甲醇∶水=9∶1);
NMR:δ7.98(d,J=8.4Hz,2H),7.50-7.44(m,3H),7.44-7.32(m,2H),7.28-7.14(m,5H),5.64(dd,J=15.6,6.0Hz,1H),5.36(dd,J=15.6,8.7Hz,1H),4.45-4.35(m,1H),3.80-3.65(m,2H),3.00-2.70(m,5H),2.40-2.20(m,5H),2.20-2.00(m,1H),1.70-1.55(m,1H)。
实施例32(c)
(15α,13E)-1,6-(1,4-间亚苯基)-9-氧代-15-羟基-16-(3-(4-三氟甲基苯基)苯基)-2,3,4,5,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.51(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ8.00(d,J=8.1Hz,2H),7.69(m,4H),7.55-7.13(m,6H),5.65(dd,J=15.0,6.0Hz,1H),5.39(dd,J=15.0,8.4Hz,1H),4.41(m,1H),3.81-3.69(m,2H),3.10-2.70(m,5H),2.43-1.30(m,5H)。
实施例32(d)
(15α,13E)-1,6-(1,4-间亚苯基)-9-氧代-15-羟基-16-(3-(3,5-二(三氟甲基)苯基)苯基)-2,3,4,5,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.53(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ8.01-7.98(m,4H),7.86(s,1H),7.58-7.40(m,3H),7.37-7.20(m,3H),5.68(dd,J=15.6,6.0Hz,1H),5.44(dd,J=15.6,8.4Hz,1H),4.43(m,1H),3.83-3.78(m,2H),3.18-2.80(m,6H),2.42-2.22(m,2H),2.14(m,1H),1.65(m,1H)。
实施例32(e)
(15α,13E)-1,6-(1,4-间亚苯基)-9-氧代-15-羟基-16-(3-(4-叔丁基苯基)苯基)-2,3,4,5,17,18,19,20-八去甲基-8-氮杂前列腺-13-烯酸
TLC:Rf0.51(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ7.98(d,J=8.4Hz,2H),7.59-7.33(m,7H),7.25-7.16(m,3H),5.63(dd,J=15.3,5.7Hz,1H),5.39(dd,J=15.3,9.0Hz,1H),4.21(m,1H),3.80-3.65(m,2H),3.00-2.68(m,6H),2.40-1.40(m,4H),1.35(s,9H)。
实施例32(f)
(15α)-9-氧代-15-羟基-16-(3-苯基苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺烷
TLC:Rf 0.32(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ1.72(m,1H)2.30(m,3H)3.06(m,7H)3.68(m,1H)4.11(m,1H)4.47(m,1H)5.51(dd,J=15.38,8.79Hz,1H)5.82(dd,J=15.38,5.77Hz,1H)7.35(m,9H)8.07(s,1H)。
实施例32(g)
(15α)-9-氧代-15-羟基-16-(3-(4-甲基苯基)苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺烷
TLC:Rf0.33(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ1.71(m,1H)2.38(m,8H)2.92(m,2H)3.23(m,3H)3.69(m,1H)4.10(m,1H)4.47(m,1H)5.51(dd,J=15.38,8.52Hz,1H)5.82(dd,J=15.38,5.77Hz,1H)7.31(m,8H)8.01(s,1H)。
实施例32(h)
(15α)-9-氧代-15-羟基-16-(3-(4-氯苯基)苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺烷
TLC:Rf 0.28(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ1.69(m,1H)2.30(m,3H)2.90(m,2H)3.44(m,6H)4.11(m,1H)4.46(m,1H)5.52(dd,J=15.38,8.79Hz,1H)5.83(dd,J=15.38,5.77Hz,1H)7.35(m,8H)8.07(s,1H)。
实施例32(i)
(15α)-9-氧代-15-羟基-16-(3-(4-甲氧基苯基)苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺烷
TLC:Rf0.32(氯仿∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ1.70(m,1H)2.53(m,7H)3.21(m,3H)3.69(m,1H)3.85(s,3H)4.09(m,1H)4.46(m,1H)5.51(dd,J=15.38,8.79Hz,1H)5.82(dd,J=15.38,6.04Hz,1H)7.22(m,8H)8.07(s,1H)。
实施例32(j)
(15α,13E)-9-氧代-15-羟基-16-(3-(萘-2-基)苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.46(氯仿∶甲醇=9∶1);
NMR:δ8.03(s,1H),7.94-7.82(m,3H),7.73(dd,J=8.7,2.1Hz,1H),7.64-7.57(m,1H),7.57-7.40(m,4H),7.21(d,J=7.5Hz,1H),5.79(dd,J=15.3,6.0Hz,1H),5.49(ddd,J=15.3,8.7,1.2Hz,1H),4.54-4.44(m,1H),4.14-4.04(m,1H),3.66-3.52(m,1H),3.00-2.85(m,3H),2.60-2.10(m,9H),1.90-1.60(m,3H)。
实施例32(k)
(15α,13E)-9-氧代-15-羟基-16-(3-(苯并噁唑-2-基)苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.43(氯仿∶甲醇=9∶1);
NMR:δ8.31and 8.24(s,1H),8.08(d,J=7.8Hz,1H),7.82-7.74(m,1H),7.64-7.56(m,1H),7.48(t,J=7.8Hz,1H),7.44-7.34(m,3H),5.89(dd,J=15.6,4.5Hz,1H),5.63(dd,J=15.6,7.5Hz,1H),4.65-4.55and 4.55-4.45(m,1H),4.20-4.05(m,1H),3.55-3.40(m,1H),3.30-3.10(m,1H),3.30(dd,J=13.8,5.1Hz,1H),2.89(dd,J=13.8,8.7Hz,1H),2.75-2.15(m,9H),1.95-1.85(m,2H),1.80-1.60(m,1H)。
实施例32(1)
(15α,13E)-9-氧代-15-羟基-16-(3-(苯并噻唑-2-基)苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.38(氯仿∶甲醇=9∶1);
NMR:δ8.14(s,1H),8.09(d,J=8.1Hz,1H),7.91(d,J=7.8Hz,1H),7.84(d,J=7.8Hz,1H),7.56-7.32(m,4H),5.88(dd,J=15.0,5.1Hz,1H),5.61(ddd,J=15.0,8.7,1.5Hz,1H),4.60-4.45(m,1H),4.20-4.05(m,1H),3.55-3.40(m,1H),3.25-3.05(m,1H),3.01(dd,J=13.8,4.8Hz,1H),2.88(dd,J=13.8,8.7Hz,1H),2.70-2.10(m,9H),1.96-1.82(m,2H),1.80-1.60(m,1H)。
实施例32(m)
(15α-9-氧代-15-羟基-16-(3-(萘-2-基)苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺烷
TLC:Rf 0.40(二氯甲烷∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ8.05-8.00(m,2H),7.93-7.82(m,3H),7.71(dd,J=8.4,1.8Hz,1H),7.61(d,J=7.8Hz,1H),7.56-7.47(m,4H),7.42(t,J=7.8Hz,1H),7.19(d,J=7.8Hz,1H),5.84(dd,J=15.3,5.7Hz,1H),5.52(dd,J=15.3,8.7Hz,1H),4.49(q,J=6.0Hz,1H),4.15-4.05(m,1H),3.75-3.65(m,1H),3.35-3.05(m,3H),2.95(dd,J=7.2,3.3Hz,2H),2.50-2.10(m,3H),1.80-1.60(m,1H)。
实施例32(n)
(15α)-9-氧代-15-羟基-16-(3-(苯并噁唑-2-基)苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺烷
TLC:Rf 0.36(二氯甲烷∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ8.45and 8.32(s,1H),8.12(s,1H),8.06(d,J=7.5Hz,1H),7.90-7.82(m,1H),7.64-7.58(m,1H),7.50-7.36(m,4H),5.94(dd,J=15.6,4.5Hz,1H),5.78(dd,J=15.6,6.3Hz,1H),4.70-4.50(m,1H),4.15(q,J=7.2Hz,1H),3.60-3.20(m,4H),3.00(dd,J=14.4,4.2Hz,1H),2.85(dd,J=14.4,9.0Hz,1H),2.50-2.15(m,3H),1.85-1.70(m,1H)。
实施例32(o)
(15α)-9-氧代-15-羟基-16-(3-(苯并噻唑-2-基)苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺烷
TLC:Rf 0.37(二氯甲烷∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ8.29(s,1H),8.20-8.14(m,1H),8.11(s,1H),7.92(d,J=7.2Hz,1H),7.79(d,J=7.8Hz,1H),7.60-7.30(m,4H),5.90(dd,J=15.3,3.9Hz,1H),5.71(dd,J=15.3,9.0Hz,1H),4.60-4.45(m,1H),4.20-4.05(m,1H),3.60-3.15(m,4H),2.98(dd,J=14.1,4.5Hz,1H),2.83(dd,J=14.1,9.0Hz,1H),2.50-2.10(m,3H),1.85-1.70(m,1H)。
实施例32(p)
(15α,13E)-9-氧代-15-羟基-16-(3-(异二氢吲哚-2-基)苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf 0.36(氯仿∶甲醇=9∶1);
NMR:δ1.79(m,3H)2.72(m,13H)3.59(m,1H)4.12(m,1H)4.49(m,1H)4.78(m,4H)5.55(dd,J=15.66,8.79Hz,1H)5.81(dd,J=15.66,5.49Hz,1H)6.57(m,2H)7.33(m,6H)。
实施例32(q)
(15α,13E)-9-氧代-15-羟基-16-(3-(吲哚-5-基)苯基)-17,18,19,20-四去甲基-5-硫杂-8-氮杂前列腺-13-烯酸
TLC:Rf0.40(氯仿∶甲醇=9∶1);
NMR:δ2.09(m,13H)2.90(m,3H)3.54(m,1H)4.07(m,1H)4.48(m,1H)5.46(ddd,J=15.38,8.79,1.10Hz,1H)5.78(dd,J=15.38,5.77Hz,1H)6.60(m,1H)7.14(m,1H)7.25(m,2H)7.46(m,4H)7.84(m,1H)8.35(brs.,1H)。
实施例32(r)
(15α)-9-氧代-15-羟基-16-(3-(异二氢吲哚-2-基)苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺烷
TLC:Rf0.38(二氯甲烷∶甲醇∶乙酸=9∶1∶0.1);
NMR:δ8.04(s,1H),7.70-7.00(m,5H),6.60-6.40(m,3H),6.00-5.75(m,1H),5.65-5.50(m,1H),4.64(s,4H),4.50-4.40(m,1H),4.20-4.10(m,1H),3.80-3.60(m,1H),3.50-3.00(m,3H),3.00-2.75(m,2H),2.50-2.10(m,3H),1.85-1.65(m,1H)。
实施例32(s)
(15α)-9-氧代-15-羟基-16-(3-(吲哚-5-基)苯基)-5-(4-羧基噻唑-2-基)-1,2,3,4,17,18,19,20-八去甲基-5-硫杂-8-氮杂前列腺烷
TLC:Rf0.36(二氯甲烷∶甲醇∶乙酸=9∶1∶0.1);
NMR(CD3OD):δ10.47(s,1H),8.17and 8.14(s,1H),7.80-7.74(m,1H),7.50-7.22(m,6H),7.14-7.05(m,1H),6.50-6.46(m,1H),5.74(dd,J=15.0,6.9Hz,1H),5.28(dd,J=15.0,9.0Hz,1H),4.45-4.30(m,1H),4.30-4.15(m,1H),3.55-3.45(m,1H),3.30-3.20(m,1H),3.20-2.70(m,4H),2.35-2.00(m,3H),1.70-1.50(m,1H)。
制剂例1:
将下列化合物按常规方法混合并冲压,得到100个药片,每个药片含0.5mg的活性成分。
(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基
-8-氮杂前列腺-13-烯酸·α-环糊精 250mg(活性成分50mg)
羧甲基纤维素钙 200mg
硬脂酸镁 100mg
微晶纤维素 9.2g
制剂例2:
将下列成分按常规方法混合,并将该溶液按常规方法灭菌,将1ml一份的溶液置于安瓿中并按常规方法冷冻干燥,得到100个安瓿,每个安瓿中含有0.2mg的活性成分。
(15α,13E)-9-氧代-15-羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基
-8-氮杂前列腺-13-烯酸·α-环糊精 100mg(活性成分20mg)
甘露醇 5g
蒸馏水 100ml
制剂例3:
制备乳酸-乙醇酸共聚物(简称PLGA)(乳酸∶乙醇酸=1∶1(摩尔%),重均分子量80000,90mg,Mitsui chemical有限公司)与本发明的化合物(10mg)的二氯甲烷(3mL)溶液。向用TK robomix(Tokusyukika,MARK II 2.5型)以6000rpm搅拌的0.1%的聚乙烯醇(Nacalai Tesque)溶液(300m1)中,加入上面制备的溶液,并将该混合物在室温下搅拌2分钟,制得O/W乳液。将该O/W乳液在室温下搅拌3小时,蒸发二氯甲烷。待油层固化之后,利用离心机(Hitachi,05PR-22)以1000rpm的速度,离心分离剩余物10分钟。除去上清液之后,将剩余物分散在注射用蒸馏水(35mL)中,用离心机以1000rpm的速度将其再次离心10分钟(两次),冲洗样品以除去游离的药物等。最后,在除去上清液和减压干燥沉淀物之后,制得微球。
用于这种微球药剂的本发明的化合物如下所示。
制剂例3(1):实施例18
制剂例3(2):实施例16(f)
制剂例3(3):实施例16(e)
制剂1的试验:
向用制剂例3(1)和3(2)制备的微球中加入含适当内标物的乙腈溶液,并用超声波处理,以便溶解。利用用PLC测定溶液中化合物的含量,然后通过下列等式计算出微球中化合物的包含物的比例:
化合物的包含物的比例=所测量的含量/理论含量×100
制剂例3(1),3(2)和3(3)的比例分别为93%,100%和96%。
制剂例2的试验:
将用制剂例3(1)制备的微球悬浮于盐水中(使得化合物的含量为10mg/kg)。通过皮下注射,将该悬浮液给药于SD-品系雄性大鼠的颈后区。给药之后,在乙醚麻醉下,以均匀的时间间隔采集血样。对从血样中分离出的血浆进行固相萃取,并利用液相色谱质谱仪(LC/MS/MS)测量浓度。
可以证实,化合物的血液浓度一直持续到第21天。
本发明的化合物的药理活性:
举例来说,本发明的化合物的药理活性可以在利用表达类前列腺素受体亚型的细胞于实验室中进行的实验中得到证实。
(i)采用表达类前列腺素受体亚型的细胞的受体结合实验
根据Sugimoto等人(J.Bio1.Chem.,267,6463-6466(1992))的方法,制备表达类前列腺素受体亚型(分别为小鼠EP1,EP2,EP3α,及EP4)的CHO细胞,并用作膜真实样品。
将包含所制备的膜组分(0.5mg/ml)和3H-PGE2的反应溶液(200μl)在室温下培养1小时。用冰冷的缓冲液(3ml)使反应终止,并通过玻璃过滤器(GF/B)将反应混合物抽吸过滤,在该过滤器上捕获到结合的3H-PGE2,并通过液体闪烁器测定该结合体的放射性。
Kd值得自Acatchard图[Ann.N.Y.Acad.Sci.,51,660(1949)]。所得非特异性结合体为过量(2.5μM)未标记PGE2存在下的结合体。通过加入3H-PGE2(2.5nM)及系列浓度的本发明的化合物,测量3H-PGE2与本发明的化合物的结合抑制性。在该反应中,所有情况下均使用下列缓冲液。
缓冲液:10mM磷酸钾(pH 6.9),1mM EDTA,10mM MgCl2,及0.1MNaCl。
各化合物的解离常数Ki(μM)根据下列等式计算:
Ki=IC50/(1+([C]/Kd))
本发明的化合物对EP4受体的结合活性如下面的表121所示。
表121
(ii)EP4受体激动剂的活性
用表达类前列腺素受体亚型的细胞进行测量EP4受体激动剂活性的实验。
根据Nishigaki等人(FEBS lett.,364,339-341(1995))的方法,制备表达小鼠EP4受体亚型的CHO细胞,在24-孔微量培养板上以105细胞/孔进行培养,并且培养2天以用于实验。每个孔用500μl的MEM(最低基础培养基)洗涤,加入450μl试验培养基(含1mmol/L的IBMX和1%的BSA的MEM),并在37℃培养10分钟。然后加入50μl单独包含PGE2或PGE2和试验化合物的溶液,以开始反应,该反应在37℃进行10分钟,并通过加入500ul冰冷的三氯乙酸(10%w/v)而终止。将反应混合物进行一次冷冻(-80℃)和解冻处理,用刮刀除去细胞,并在13000rpm下离心3分钟,得到上清液,并用cAMP试剂盒测定它的AMP浓度。换言之,将[125I]cAMP测定试剂盒(Amersham)的缓冲液加到125μl上述上清液中至500μl,其与1ml 0.5mol/L的三辛基胺/氯仿溶液混合,以消除氯仿层中所含的三氯乙酸。根据[125I]cAMP测定试剂盒使用说明书中所述的方法,测量水层样品,以确定样品中cAMP的量。
通过计算50%的cAMP产率,确定本发明的化合物的激动效果(EC50值),按单独的PGE2的最大效果为100%计。
结果,发现本发明的化合物具有显著和有效的EP4受体激动剂的活性。
(iii)对TNF-α产生的抑制作用
在雄性SD大鼠中,通过尾静脉注射LPS(10μg/2ml/kg),并在90分钟之后,在肝素化条件下,从腹部静脉采集血样,以制备血浆。通过ELISA试剂盒(大鼠TNF-α免疫测定试剂盒;Biosource)测定血浆中TNF-α的量。将本发明的化合物溶解于等摩尔量的0.02摩尔/L的氢氧化钠水溶液中,用蒸馏水稀释,并在LPS给药之前30分钟经口给药。将TNF-α产生被抑制50%的浓度视为有效浓度(IC50),对照组(LPS-处理的但未给用化合物的组)的血浆TNF-α浓度为100%。结果表明,本发明的化合物对TNF-α的产生具有显著的抑制作用。
(iv)对慢性关节风湿病的抑制作用
(1)用胶原诱导大鼠关节炎
根据Osterman等人(Inflamm.Res.,44,258-263)的方法进行实验。通过皮内注射,在雌性DA/Slc大鼠背部的四个位置,施用诱导剂(通过将等体积的生理盐水和2当量体积的不完全Freund佐剂加到0.3%的牛源II型胶原的溶液中而制得的乳液)各0.1ml。一周之后,进一步通过皮内注射施用相同的诱导剂于尾根部,以诱导关节炎。在第27天,根据红肿程度对四肢进行评分,且满分为30分。将本发明的化合物溶解于等摩尔量的0.02摩尔/L的氢氧化钠水溶液中,用蒸馏水稀释,并从诱导剂第一次给药的第二天起,每天经口给用三次。
结果:
本发明的化合物对胶原诱导的大鼠关节炎的作用示于表122中。
表122
*:p<0.05
结果,与对照组(蒸馏水每日经口给用三次)相比,给用本发明的化合物可以显著地改善关节炎症状,并抑制四肢体积(水肿)的增加。
(2)用混合抗体诱导小鼠关节炎
静脉内施用II型胶原抗体的混合物于雄性DBA/1JNCrj小鼠,剂量为2mg/0.5ml/只小鼠。3天之后,腹膜内施用脂多糖,剂量为25μg/0.1ml/只小鼠,以诱导关节炎。在第10天,根据红肿程度和水肿对四肢进行评分,满分为4分。将本发明的化合物溶解于等摩尔量的0.02摩尔/L的氢氧化钠水溶液中,用蒸馏水稀释,并在脂多糖给药前30分钟,每天经口给药三次。
结果,与对照组(蒸馏水每日经口给用三次)相比,给用本发明的化合物可以显著地改善关节炎症状,并抑制四肢体积(水肿)的增加。
(v)促进成骨作用1
采用雌性SD大鼠(11周龄;均重271g),每组5只大鼠。在戊巴比妥麻醉下,将大鼠在侧腹部切开,以除去卵巢,然后缝合。在伪装组中,也进行切口和缝合,但不除去卵巢。
手术6天之后,将本发明的化合物(溶解于等摩尔量的0.02摩尔/L的氢氧化钠水溶液中,用蒸馏水稀释)每日三次经口给药2个月。对照组和伪装组给用生理盐水。试验结束后,杀死各组的动物并进行尸体解剖。利用外周骨骨密度测量仪(XCT-960A,Norland/StratecH)测定左大腿骨之网状骨质区的固密度。
结果,与对照组(未给药)相比,本发明的化合物显著地增加骨密度。
(vi)促进成骨作用2
利用大约6月龄的小猎犬/CSK犬,可以检验成骨作用的促进效果。
将本发明的化合物溶解于生理盐水,并经口给用4周。对照组给用等体积的生理盐水。给药完成之后,将犬杀死,进行尸体解剖,测量骨面积和骨密度。
(1)骨面积的测量
将卸下的股骨用10%的缓冲福尔马林溶液固定,并将其在垂直于骨轴方向上,于位于滑车窝25mm的中心位置,以10mm的宽度环切成片;在接近骺的表面以一定的距离用照相机进行拍照,并将图像输入计算机,以便通过图像分析对骨表面进行测量。
(2)骨密度的测量
从侧面拍摄(1)中所用宽度1cm的样品的X光照片,并将图像输入计算机,以测量一定宽度的面积中每单位面积的辐射剂量,进而确定骨密度(MicroFocus X-Ray Enlargement Camera System μFX-1000(FUJIFILM))。
(vii)加速骨折治愈的作用1
这可以通过Markel等人的方法(J.Bone and Joint Surgery,73A,914-923,1991)来实现。利用大约6月龄的小猎犬/CSK犬,在麻醉下使股骨的胫骨骨折并定期地拍摄X光照片3个月,以评价治愈过程。这样可以容易判断加速骨折治愈的作用。本发明的化合物每天经口给药。对照组给用蒸馏水。验证加速治愈作用时,卸下胫骨,并且可以测量骨密度和骨强度,以进一步地进行定量的评价。
(viii)对胃溃疡的抑制作用
将SD大鼠经口给药20mg/kg的消炎痛以诱导胃溃疡。6小时之后,除去胃以测量胃粘膜的溃疡面积。在消炎痛给药前30分钟,将本发明的化合物经口给药。结果,与对照组(未给药)相比,本发明的化合物显著地减小溃疡面积。
(ix)加速骨折治愈的作用
根据R.Sakai(Bone,25,191-196(1999)),H.Kawaguchi(Endocrinology,135,774-781(1994))及T.Hoshino(J.Biomed Mater Res.,51,229-306(2000))的方法,用8周龄的雄性IGS大鼠制备骨折模型。在戊巴比妥Na麻醉下,除去左后肢的毛,并肌肉注射氨苄西林S 500(500mg效能)(Meiji Seika),剂量为10mg效能/100μl蒸馏水/个体。然后,切下腓骨上的皮(从膝关节的后部至跟腱),除去肌肉组织,暴露出腓骨。在大约中央位置将腓骨切断,制得骨折部,然后将其恢复至从前的状况,并通过缝合关闭切开部,用碘酊/消毒乙醇消毒。制得骨折部之后及闭合手术伤口之前,仅加入一次在制剂例3(1)中制备的生理盐水溶液,其含0.2%的Tween 80微球(含0.3mg/kg作为活性药剂;约60μ1)。另外,化合物(1)作为用于比较的对照,通过连接在颈动脉上的导管每日两次地连续灌注2小时。这一直进行到实验的最后一天。在实验的第21天,将大鼠进行CO2安乐死,除去后肢的结缔组织(包括肌肉),得到两个腓骨。对回收的腓骨拍摄X光照片,以根据骨折线的出现和骨痂的形成,评价骨折治愈的进展情况,并测量骨折部周围的骨密度和骨强度。
(1)利用微焦X-射线放大照相系统测量骨痂区的骨密度
测量回收腓骨骨折部的骨痂区的骨密度,参照C.Matsumoto(CalcifTissue Int,55,324-329(1994)),Kaoru Yamazaki(Nihon Rinsyo,56,1464-1468(1998)),及Keiichi Nakagawa(Sentan Iryo,4(6),(1996))的报导。利用微焦X-射线放大照相系统(FUJIFILM)/成像板(BAS-IP MS 2025;FUJIFILM)拍摄4倍的X光照片,辐射条件为40kV的管电压,100μA的管电流,辐射时间为5秒。在拍摄期间,同时设置定量分析小鼠骨盐的仿真模型(phantom)(KyotoKagaku Co.),以便制备骨密度测量的分析曲线。图像通过生物成像分析仪BAS-1800(FUJIFILM)/图像读取器(FUJIFILM)读取,并通过Image Gauge(FUJIFILM,3.1.12版)进行处理。根据骨折线(表面),分别沿最远(踝关节)方向和最近(膝关节)方向3mm的位置设定感兴趣的区域(下文中有时称为ROI),作为骨痂区,以由定量分析曲线计算各ROI的骨密度,所述定量分析曲线得自骨盐定量分析仿真模型。骨折侧面骨痂区的骨密度根据下列等式计算,并用平均值±标准偏差(mg/cm2)表示:
骨痂区的骨密度={([最近骨痂区的骨密度]×A)+([最远骨痂区的骨密度]×B)}/(A+B)
A代表最近骨痂区中的ROI面积;
B代表最远骨痂区中的ROI面积。
(2)通过三点弯曲试验测量骨强度
根据T.Hoshino(J Biomed Mater Res.,51,229-306(2000))的报导,进行三点弯曲试验。利用Instron Universal Material Testing Machine Type 5544(Instron Japan)/Merlin(Instron Japan;version 22043),在2.5mm/秒弯曲速度和10mm样品夹具宽度的条件下,测定骨折强度和能量吸收。针对各个不同的个体,骨强度数据以非骨折一侧对骨折一侧的相对强度来计算,并以平均值±标准偏差(%完整无损的骨)来表示。
结果:
仅用在制剂例3(1)中制备的微球(含0.3mg/kg活性药剂)或空白样(含0.2%Tween 80的生理盐水)处理一次时的加速骨折治愈的效果示于表123中。
仅用在制剂例3(3)中制备的微球(含1mg/kg活性药剂)或空白样(含0.2%Tween 80的生理盐水)处理一次时的加速骨折治愈的效果示于表124中。
表123
表124
化合物(1)(50ng/1kg/min和空白样(生理盐水)经静脉内给药2小时,一天两次,共21天,加速骨折治愈的效果示于表125中。
表125
通过与表125比较,可由表123和124清楚地看出,仅采用制剂例3(1)和3(3)中制备的微球处理一次的加速骨折治愈效果,远高于静脉内给药21天的化合物(1)的加速骨折治愈效果。
(x)对溃疡性结肠炎的抑制效果
7%右旋糖酐硫酸钠水溶液(下文中简写为SDS)自由地给用于雄性C57BL/6小鼠。从饮用开始,每隔一天记录体重和临床分数。临床分数以腹泄分数(正常:0;软:2;腹泄:4)和便血分数(正常:0;流血:2;严重流血:4)的总和来计算。在给用SDS水溶液之后的第十天,在乙醚麻醉和肝素存在下,由腔静脉采集血样,并通过血细胞计数器测量血细胞比容值。在给用SDS水溶液之后的第0~10天期间,本发明的化合物每天经口给药两次,剂量为10,30,100或300μg/10ml/kg。结果表明,本发明的化合物具有显著的抑制溃疡性结肠炎的效果。
Claims (4)
1.下面式(I-2)的化合物:
式中
R2-1为氧代,卤素,或O-COR8-1,其中R8-1为C1-4烷基,苯基或苯基(C1-4烷基),
R3-1为氢原子或羟基,
R4a-1和R4b-1各自独立地为氢原子或C1-4烷基,
R5-1为苯基,其被以下列基团所取代:
(i)1~3个
C1-4烷氧基-C1-4烷基,
C2-4链烯氧基-C1-4烷基,
C2-4炔氧基-C1-4烷基,
C3-7环烷氧基-C1-4烷基,
C3-7环烷基(C1-4烷氧基)-C1-4烷基,
苯氧基-C1-4烷基,
苯基-C1-4烷氧基-C1-4烷基,
C1-4烷硫基-C1-4烷基,
C2-4链烯基硫基-C1-4烷基,
C2-4炔基硫基-C1-4烷基,
C3-7环烷硫基-C1-4烷基,
C3-7环烷基(C1-4烷硫基)-C1-4烷基,或者
苯硫基-C1-4烷基或苯基-C1-4烷硫基-C1-4烷基,
(ii)C1-4烷氧基-C1-4烷基和C1-4烷基,
C1-4烷氧基-C1-4烷基和C1-4烷氧基,
C1-4烷氧基-C1-4烷基和羟基,
C1-4烷氧基-C1-4烷基和卤素,
C1-4烷硫基-C1-4烷基和C1-4烷基,
C1-4烷硫基-C1-4烷基和C1-4烷氧基,
C1-4烷硫基-C1-4烷基和羟基,或者
C1-4烷硫基-C1-4烷基和卤素,
(iii)卤代烷基或羟基-C1-4烷基,或者
(iv)C1-4烷基和羟基;
为单键或双键,
其中当R2-1为O-COR8-1时,C8-9位为双键,
R1-2为
(1)-CO-(NH-氨基酸残基-CO)m-2-OH,
(2)-COO-Y2-R9-2,
(3)-COO-Z1-2-Z2-2-Z3-2,
其中Y2为化学键或C1-10亚烷基,
R9-2为(1)苯基或(2)联苯基,其任选被1~3个C1-10烷基,C1-10烷氧基或卤原子所取代,
Z1-2为
(1)C1-15亚烷基,
(2)C2-15亚链烯基,或者
(3)C2-15亚炔基,
Z2-2为
(1)-CO-,
(2)-OCO-,
(3)-COO-,
(4)-CONR11-2-,
(5)-NR12-2CO-,
(6)-O-,
(7)-S-,
(8)-SO-,
(9)-SO2-,
(10)-NR13-2-,
(11)-NR14-2CONR15-2-,
(12)-NR16-2COO-,
(13)-OCONR17-2-,或者
(14)-OCOO-,
Z3-2为
(1)氢原子,
(2)C1-15烷基,
(3)C2-15链烯基,
(4)C2-15炔基,
(5)环12,或者
(6)C1-10烷基,其被C1-10烷氧基,C1-10烷硫基,C1-10烷基-NR18-2-或环12所取代,
环12为
(1)C3-15的一碳环,二碳环或三碳环芳基,其可以是部分或完全饱和的,或者
(2)3~15员的一杂环,二杂环或三杂环芳基,其包含1~4个选自氧、氮和硫的杂原子,其可以是部分或完全饱和的,
R11-2,R12-2,R13-2,R14-2,R15-2,R16-2,R17-2和R18-2各自独立地为氢原子或C1-15烷基,
R11-2和Z3-2可与其相连的氮原子结合起来形成5~7员的饱和单杂环,且该杂环可以包含另一个选自氧、氮和硫的杂原子,
环12及通过R11-2,Z3-2及与Z3-2相连的氮原子形成的饱和单杂环可以被1~3个选自下列的基团所取代:
(1)C1-15烷基,
(2)C2-15链烯基,
(3)C2-15炔基,及
(4)C1-10烷基,其被C1-10烷氧基,C1-10烷硫基或C1-10烷基-NR19-2所取代,
R19-2为氢原子或C1-10烷基,
m-2为1或2,
或其无毒盐,或其环糊精包合物。
2.根据权利要求1的化合物,该化合物选自:
(1)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-壬酰氧基乙酯,
(2)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸新戊酰氧基甲酯,
(3)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸1-环己氧基羰氧基乙酯,
(4)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸N,N-二乙氨基羰基甲酯,
(5)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-乙酰氧基乙酯,
(6)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸苯甲酰基甲酯,
(7)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸异丙氧基羰基甲酯,
(8)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸N,N-二乙氨基羰氧基甲酯,
(9)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸叔丁氧基羰基甲酯,
(10)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸1-异丙氧基羰基乙酯,
(11)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸1-苯甲酰基乙酯,
(12)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸甲氧基羰基甲酯,
(13)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-十三酰氧基乙酯,
(14)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-庚酰氧基乙酯,
(15)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-辛酰氧基乙酯,
(16)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-癸酰氧基乙酯,
(17)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸烯丙氧基羰基甲酯,
(18)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸壬酰氧基甲酯,
(19)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-羟基乙酯,
(20)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸苯基酯,
(21)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸羧基甲酯,
(22)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸二丙基氨甲酰基甲酯,
(23)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸二丁基氨甲酰甲酯,
(24)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸4-戊基苯甲酰基甲酯,
(25)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸1,1-二甲基庚氧基羰基甲酯,
(26)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸二戊基氨甲酰基甲酯,
(27)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-辛氧基乙酯,
(28)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-(2,2-二甲基戊酰氧基)乙酯,
(29)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸3-丁氧基丙基酯,
(30)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-丁氧基乙基酯,
(31)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-戊氧基乙基酯,
(32)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-己氧基乙基酯,
(33)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-(2,2-二甲基辛酰氧基)乙酯,
(34)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-(2,2-二乙基戊酰氧基)乙酯,
(35)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸4-(4-氯苯基)苯基酯,
(36)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-(金刚烷-1-基羰氧基)乙酯,及
(37)(11α,15α,13E)-9-氧代-11,15-二羟基-16-(3-甲氧基甲基苯基)-17,18,19,20-四去甲基-5-硫杂前列腺-13-烯酸2-(2,2-二丙基戊酰氧基)乙酯,
或其无毒盐,或其环糊精包合物。
3.一种局部给药的用于预防和/或治疗与骨质减少有关的疾病的药物组合物,其包含选自权利要求1的式(I-2)的化合物,或其无毒盐,或其环糊精包合物。
4.一种缓释制剂,其包含选自权利要求1的式(I-2)的化合物,或其无毒盐,或其环糊精包合物。
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Publication number | Priority date | Publication date | Assignee | Title |
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TWI562778B (zh) * | 2011-08-02 | 2016-12-21 | Ono Pharmaceutical Co |
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