CN107011332B - 作为crth2拮抗剂的吡唑化合物 - Google Patents
作为crth2拮抗剂的吡唑化合物 Download PDFInfo
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- CN107011332B CN107011332B CN201710440429.6A CN201710440429A CN107011332B CN 107011332 B CN107011332 B CN 107011332B CN 201710440429 A CN201710440429 A CN 201710440429A CN 107011332 B CN107011332 B CN 107011332B
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- pyrazol
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明涉及式(1a)或(1b)的吡唑化合物及其药学上可接受的盐,其中Ra、Rb、Rc、Rd、Y1、Y2、Y3、Y4、Y5、Z、R1、R2、n及R3具有如说明书及权利要求书中所指明的含义之一;涉及它们作为药物的用途;涉及含有所述化合物的药物制剂及含有所述化合物与一种或多种活性物质的组合的药物制剂。所述化合物具有CRTH2拮抗活性。
Description
本申请是申请日为2012年1月20日、中国申请号为201510362688.2、发明名称为“作为CRTH2拮抗剂的吡唑化合物”的发明申请的分案申请;中国申请号为201510362688.2的申请是申请日为2012年1月20日、中国申请号为201280006303.3、发明名称为“作为CRTH2拮抗剂的吡唑化合物”的发明申请的分案申请。
本发明涉及具有CRTH2拮抗活性的式(Ia)或(Ib)的吡唑化合物及其药学上可接受的盐,
其中Ra、Rb、Rc、Rd、Y1、Y2、Y3、Y4、Y5、Z、R1、R2、n及R3具有如说明书及权利要求书中所指明的含义之一;涉及它们作为药物的用途;涉及含有所述化合物的药物制剂及含有所述化合物与一种或多种活性物质的组合的药物制剂。
发明背景
前列腺素D2(PGD2)为在炎性细胞受到过敏原刺激、炎性刺激或受到组织损伤时由花生四烯酸代谢产生的类花生酸。PGD2主要由肥大细胞释放,其中Th2细胞、树突细胞及巨噬细胞为次级源。PGD2是在受到过敏原激发时由肥大细胞产生的主要花生四烯酸代谢产物(Lewis等人,J.Immunol.1982,129:1627-1631)且在哮喘患者呼吸道中已检测到高浓度的PGD2(Murray等人,N Engl J Med,1986,315:800-804;Liu等人,Am Rev Respir Dis,1990,142 126-132;Zehr等人,Chest,1989,95:1059-63;Wenzel等人,J Allergy Clin Immunol,1991,87540-548)。在患有全身性肥大细胞增多症(Roberts N.Engl.J.Med.1980,303,1400-1404;Butterfield等人,Int Arch Allergy Immunol,2008,147:338-343)、过敏性鼻炎(Naclerio等人,Am Rev Respir Dis,1983,128:597-602;Brown等人,Arch OtolaryngolHead Neck Surg,1987,113:179-183;Lebel等人,J Allergy Clin Immunol,1988,82:869-877)、荨麻疹(Heavy等人,J Allergy Clin Immunol,1986,78:458-461)、慢性鼻及鼻窦炎(Yoshimura等人,Allergol Int,2008,57:429-436)、慢性阻塞性肺病(Csanky等人,Electrophoresis,2009,30:1228-1234)的患者中及在过敏反应期间(Ono等人,Clin ExpAllergy,2009,39:72-80)PGD2生成亦会增加。
向呼吸道中滴注PGD2可引起哮喘反应的特征,包括支气管收缩(Hardy等人,1984,N Engl J.Med 311:209-213;Sampson等人,1997,Thorax 52:513-518)及嗜酸性粒细胞累积(Emery等人,1989,J.Applied Physiol 67:959-962)。PGD2引发炎性反应的潜力已通过人PGD2合酶在小鼠中的过表达证实,该过表达导致响应于过敏原的嗜酸性粒细胞肺部炎症及Th2细胞因子生成增多(Fujitani等人,2002J.Immunol.168:443-449)。
PGD2为两种7次跨膜型G蛋白偶联受体,即PGD2受体DP1(Boie等人,J Biol Chem,1995,270:18910-6)及最近鉴定的CRTH2(化学引诱物受体-表达于Th2细胞上的同源分子)受体(亦称为DP2受体)的激动剂(Nagata等人,J.Immunol.,1999,162:1278-86)。
CRTH2表达于Th2细胞、嗜酸性粒细胞、嗜碱性粒细胞及肥大细胞上(Nagata等人,FEBS Lett,1999,459:195-199;Nagata等人,J Immunol,1999,162:1278-1286;Cosmi等人,Eur J Immunol,2000,30:2972-2979;Boehme等人,Int Immunol,2009,21:621-32)。使用选择性CRTH2激动剂(例如13,14-二氢-15-酮-PGD2(DK-PGD2)及15R-甲基-PGD2)已证实CRTH2活化会引起可导致炎性细胞的募集及活化的细胞过程(Spik等人,J.Immunol.,2005;174:3703-8;Shiraishi,J.Pharmacol.Exp.Ther.,2005,312:954-60;Monneret等人,J.Pharmacol.Exp.Ther.,2003,304:349-355)。使用CRTH2选择性拮抗剂已证实可减少在例如哮喘、过敏性鼻炎、特应性皮炎及COPD等疾病的动物模型中的炎性反应及病理生理变化(Uller等人,Respir Res.2007,8:16;Lukacs等人,Am J Physiol Lung Cell MolPhysiol.2008,295:L767-79;Stearns,Bioorg.Med Chem Lett.2009,19:4647-51;Nomiya,J Immunol,2008,180:5680-5688;Boehme等人,Int Immunol,2009,21:1-17;Boehme等人,Int Immunol,2009,21:81-93;Takeshita等人,Int Immunol,2004,16:947-59;Stebbins等人,J Pharmacol Exp Ther.2009)。此外,小鼠中CRTH2的遗传缺失可减少在过敏症动物模型中的炎性反应(Shiraishi等人,J Immunol.2008;180:541-549;Oiwa,Clin ExpAllergy,2008,38:1357-66;Satoh等人,J Immunol,2006,177:2621-9)。相反,选择性DP1激动剂BW245C不能促进炎性反应,例如Th2淋巴细胞、嗜碱性粒细胞或嗜酸性粒细胞的迁移或活化(Yoshimura-Uchiyama等人,Clin Exp Allergy,2004,34:1283-90;Xue等人,Immunol,2005,175:6531-6;Gervais等人,J Allergy Clin Immunol,2001,108:982-8)。因此,拮抗PGD2在CRTH2受体处的效果的试剂应可用于治疗呼吸或胃肠病状以及关节的炎性疾病及鼻咽、眼睛及皮肤的过敏性疾病。
WO 2004/096777教导式(a)的嘧啶衍生物及其盐,
其中R6为羧基、甲酰胺、腈或四唑基,所述衍生物具有CRTH2拮抗活性且可用于预防及治疗与CRTH2活性相关的疾病。
WO 2009/042138要求保护经烷硫基取代的式(b)的嘧啶化合物,
所述化合物具有CRTH2拮抗活性。
WO 2009/042139要求保护式(c)的2-S-苄基嘧啶化合物,
所述化合物具有CRTH2拮抗活性。
EP 0 480 659要求保护通式(d)的化合物,
其中Z2尤其可为羧基-C1-C10-烷基-C=,且Y可为经取代的苄基,所述化合物可用于治疗高尿酸血症。
WO 2005/040128要求保护通式(e)的化合物,
所述化合物可用于治疗例如疼痛等病况、或炎性、免疫性、骨性、神经退化性或肾脏病症。
WO 01/38325要求保护通式(f)的化合物,
其中A为芳香族环且B为可进一步经取代的含氮5元杂环,所述化合物具有降血糖及降血脂活性。
本发明的目的是提供其他具有CRTH2拮抗活性的化合物。
优选地,在全细胞分析中本发明化合物具有增强的化学稳定性、增强的药物代谢动力学性质(PK)和/或增强的活性。
发明详述
本发明涉及式(Ia)或(Ib)的吡唑化合物或其药学上可接受的盐,
其中
Ra及Rb独立地选自氢、羟基、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基及C3-C8环烷基,或Ra及Rb可与它们所连接的碳原子一起形成羰基,或Ra及Rb与它们所连接的碳原子一起形成3-至8-元环,其中该环可含有选自O、N及S的1或2个杂原子作为环成员,且其中该环的环成员可任选独立地经羟基、卤素、C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基及C3-C8-环烷基取代;
Rc及Rd独立地选自氢、羟基、卤素、C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基及C3-C8-环烷基,或Rc及Rd与它们所连接的碳原子一起形成羰基,或Rc及Rd与它们所连接的碳原子一起形成3-至8-元环,其中该环可含有选自O、N及S的1或2个杂原子作为环成员,且其中该环的环成员可任选独立地经羟基、卤素、C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基及C3-C8-环烷基取代;
Y1、Y2、Y3、Y4及Y5独立地选自N及CRy,其中各Ry独立地选自H、羟基、卤素、氰基、硝基、SF5、C(O)NRfRg、C1-C6-烷基、羟基-C1-C6-烷基、C1-C6-烷氧基-C1-C6-烷基、C3-C8-环烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-烷氧基-C1-C6-烷氧基、C1-C6-卤代烷氧基、C3-C8-环烷氧基、C1-C6-烷基氨基、二-C1-C6-烷基氨基、C1-C6-烷基磺酰基、苯基、苯氧基、5-或6-元杂环基及5-或6-元杂环基氧基,其中Rf及Rg彼此独立地选自H、C1-C6-烷基、C1-C6-卤代烷基、C3-C8-环烷基、C3-C8-环烯基及5-或6-元杂环基或Rf及Rg与它们所连接的氮原子一起形成环胺,该环胺可包含选自O、N及S的其它杂原子作为环成员;
Z选自O、S及NRz,其中Rz为H、C1-C6-烷基或苄基;
R1及R2彼此独立地选自H、卤素、C1-C6-烷基、C2-C6-烯基、C2-C6-炔基、C1-C6-烷氧基、C1-C6-烷硫基、-NRfRg、C3-C8-环烷基、C3-C8-环烷基-C1-C6-烷基、C3-C8-环烷基-C2-C6-烯基、C3-C8-环烯基、C3-C8-环烯基-C1-C6-烷基、C3-C8-环烯基-C2-C6-烯基、苯基、苯基-C1-C6-烷基、苯基-C2-C6-烯基、萘基、萘基-C1-C6-烷基、萘基-C2-C6-烯基、杂环基、杂环基-C1-C6-烷基及杂环基-C2-C6-烯基,其中
上述基团R1及R2中的C1-C6-烷基、C2-C6-烯基及C2-C6-炔基部分未经取代,或携带选自至少一个羟基、卤素、氰基、硝基、C1-C6-烷氧基、C1-C6-卤代烷氧基、C1-C6-烷基氨基、二-C1-C6-烷基氨基及C1-C6-烷基磺酰基的取代基,和/或
其中连接至上述基团R1及R2中的该C1-C6-烷基、C2-C6-烯基及C2-C6-炔基部分的同一碳原子的两个基团可与该碳原子一起形成羰基,且其中
于上述基团R1及R2中的C3-C8-环烷基、环烯基、苯基、萘基及杂环基部分未经取代,或携带选自至少一个羟基、卤素、氰基、硝基、C1-C6-烷基、C3-C8-环烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基、C1-C6-烷基氨基、二-C1-C6-烷基氨基、C1-C6-烷基磺酰基、苯基及5-或6-元杂芳基的取代基,和/或
其中连接至基团R1及R2的该C3-C8-环烷基、C3-C8-环烯基及杂环基部分的同一碳原子的两个基团可与该碳原子一起形成羰基,且其中
Rf及Rg彼此独立地选自H、C1-C6-烷基、C1-C6-卤代烷基、C3-C8-环烷基、C3-C8-环烯基及杂环基,或
Rf及Rg与它们所连接的氮原子一起形成环胺,该环胺可包含选自O、N及S的其它杂原子作为环成员;
n选自0、1、2或3的整数;及
R3若存在则彼此独立地选自卤素、C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基及C3-C8-环烷基。
令人惊奇的是,已发现本发明的式(Ia)或(Ib)化合物具有显著的CRTH2拮抗活性。此外,已发现在全细胞分析中所述化合物通常具有增强的化学稳定性、增强的药物代谢动力学性质(PK)及/增强的活性。
因此,本发明的式(Ia)或(Ib)的吡唑化合物适用于治疗与CRTH2活性相关的疾病。
因此,本发明进一步涉及本发明的式(Ia)或(Ib)的吡唑化合物作为药物的用途。
此外,本发明涉及式(Ia)或(Ib)化合物用于制备用于治疗与CRTH2活性相关的疾病的药物的用途。更特别是,本发明涉及式(Ia)或(Ib)的吡唑化合物在制备用于预防和/或治疗炎性、传染性及免疫调节性病症、呼吸道或胃肠道疾病或病症、关节的炎性疾病及鼻咽、眼睛及皮肤的过敏性疾病的药物中的用途。
本发明进一步涉及用于治疗和/或预防与CRTH2活性相关的疾病的本发明的式(Ia)或(Ib)的化合物。更特别是,本发明涉及用作治疗与CRTH2活性相关的疾病的药物的式(Ia)或(Ib)的化合物。更特别是,本发明涉及式(Ia)或(Ib)的吡唑化合物作为用于预防和/或治疗炎性、传染性及免疫调节性病症、呼吸道或胃肠道疾病或病状、关节的炎性疾病及鼻咽、眼睛及皮肤的过敏性疾病的药物的用途。
此外,本发明涉及药物制剂,其含有一种或多种本发明的式(Ia)或(Ib)的吡唑化合物作为单独活性物质或与选自下列的一种或多种活性物质组合:β模拟物、抗胆碱能药、皮质类固醇、PDE4抑制剂、LTD4拮抗剂、EGFR抑制剂、CCR3拮抗剂、CCR5拮抗剂、CCR9拮抗剂、5-LO抑制剂、组胺-受体拮抗剂、SYK抑制剂及磺胺类。
本发明化合物在全细胞嗜酸性粒细胞形状变化分析中的活性可根据(例如)下列参考文献测定:(i)Mathiesen JM,Ulven T,Martini L,Gerlach LO,Heinemann A,Kostenis E.Identification of indol derivatives exclusively interfering with aG protein-independent signalling pathway of the prostaglandin D2 receptorCRTH2.Mol Pharmacol.2005Aug;68(2):393-402;(ii)Schuligoi R,Schmidt R,Geisslinger G,Kollroser M,Peskar BA,Heinemann A.PGD2metabolism in plasma:kinetics and relationship with bioactivity on DP1 and CRTH2 receptors.BiochemPharmacol.2007 Jun 30;74(1):107-17;(iii)Royer JF,Schratl P,Carrillo JJ,JuppR,Barker J,Weyman-Jones C,Beri R,Sargent C,Schmidt JA,Lang-Loidolt D,Heinemann A.A novel antagonist of prostaglandin D2 blocks the locomotion ofeosinophils and basophils.Eur J Clin Invest.2008Sep;38(9):663-71。
本发明化合物的化学稳定性可在(例如)下列条件下测定:(i)在60℃在0.1N HCl中培育3天(在酸性条件下的水解稳定性);(ii)在60℃在pH 4.0缓冲溶液中3天培育(在弱酸性条件下的水解稳定性);(iii)在60℃在pH 7.4缓冲溶液中培育3天(在生理pH下的水解稳定性);(iv)在20℃在0.3%过氧化氢中培育3天(对氧化剂的稳定性);(v)在UV-辐射下(λ=300-800nm,P=250W/m2)在水中培育24小时(对光的稳定性)。降解动力学可(例如)通过HPLC分析来测定。
本发明化合物的药物代谢动力学性质(PK)可在临床前动物品种(例如,小鼠、大鼠、犬、豚鼠、迷你猪、短尾猴、恒河猴)中测定。化合物的药物代谢动力学性质可通过(例如)下列参数来阐述:平均滞留期、半衰期、分布体积、AUC(曲线下面积)、清除率、口服给予后的生物利用度。
所用术语及定义
鉴于本公开内容及上下文,应给予本文未明确定义的术语本领域技术人员将给予的含义。然而,如说明书中所使用,除非另有说明,否则下列术语具有所指出的含义且遵守下列惯例。
在下文所定义的基团、基团或部分中,通常在基团前说明碳原子个数。举例而言,“C1-C6-烷基”是指具有1个至6个碳原子的烷基或烷基团。
一般而言,对于包含两个或更多个子基团的基团而言,最后命名的基团为基团连接点。
除非另有说明,否则在所有式及基团中假定且达成术语对照的常规定义及常规稳定原子化合价。
一般而言,除非在化合物名称或结构中明确指出特定立体化学或异构形式,否则包含所有互变异构形式及异构形式及混合物,无论异构体、化学结构或化合物的单独几何异构体或光学异构体或外消旋或非外消旋混合物。
本文所用术语“经取代”是指指定原子、部分或基团上的任一个或多个氢经选自所指出基团的基团替代,条件是不超过该指定原子的正常化合价且该取代产生稳定化合物。
本文所公开化合物可以以药学上可接受的盐形式存在。本发明包括呈盐(包括酸加成盐)形式的化合物。适宜的盐包括那些由有机酸及无机酸二者所形成的盐。所述酸加成盐将通常是药学上可接受的。然而,非药学上可接受的盐的盐可用于制备及纯化所述化合物。亦可形成碱加成盐且其是药学上可接受的。有关盐的制备及选择的更完整论述参见Pharmaceutical Salts:Properties,Selection,and Use(Stahl,P.Heinrich.Wiley-VCH,Zurich,Switzerland,2002)。
本文所用术语“药学上可接受的盐”代表本文所公开化合物的盐或两性离子形式,如本文所定义其是水或油可溶或可分散且药学上可接受的。盐可在化合物的最后分离及纯化期间或单独通过使呈游离碱形式的适当化合物与适宜酸反应来制备。代表性酸加成盐包括乙酸盐、己二酸盐、海藻酸盐、L-抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐(苯磺酸盐)、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡糖酸盐、甲酸盐、富马酸盐、龙胆酸盐、戊二酸盐、甘油磷酸盐、羟乙酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐(羟乙基磺酸盐)、乳酸盐、马来酸盐、丙二酸盐、DL-扁桃酸盐、均三甲苯磺酸盐、甲磺酸盐、萘磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、膦酸盐、苦味酸盐、特戊酸盐、丙酸盐、焦谷氨酸盐、琥珀酸盐、磺酸盐、酒石酸盐、L-酒石酸盐、三氯乙酸盐、三氟乙酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对-甲苯磺酸盐(对-甲苯磺酸盐)及十一烷酸盐。此外,本文所公开化合物中的碱性基团可利用下列进行季铵化:甲基、乙基、丙基及丁基氯化物、溴化物及碘化物;二甲基、二乙基、二丁基、及二戊基硫酸盐;癸基、月桂基、肉豆蔻基及硬脂基氯化物、溴化物及碘化物;及苄基及苯乙基溴化物。可用于形成治疗上可接受的酸加成盐的酸的实例包括无机酸(例如盐酸、氢溴酸、硫酸及磷酸)及有机酸(例如草酸、马来酸、琥珀酸及柠檬酸)。亦可通过使所述化合物与碱金属或碱土金属离子配位来形成盐。因此,本发明包含本文所公开化合物的钠、钾、镁及钙盐等。
碱加成盐可通过使羧基与适宜碱(例如金属阳离子的氢氧化物、碳酸盐或碳酸氢盐)或与氨水或一级、二级或三级有机胺在所述化合物的最终分离及纯化期间反应进行制备。药学上可接受的盐的阳离子包括锂、钠、钾、钙、镁及铝,以及无毒四级胺阳离子,例如铵、四甲基铵、四乙基铵、甲基胺、二甲基胺、三甲基胺、三乙基胺、二乙基胺、乙基胺、三丁基胺、吡啶、N,N-二甲基苯胺、N-甲基哌啶、N-甲基吗啉、二环己基胺、普鲁卡因(procaine)、二苄基胺、N,N-二苄基苯乙基胺、1-二苯羟甲胺及N,N′-二苄基亚乙基二胺。其他可用于形成碱加成盐的代表性有机胺包括乙二胺、乙醇胺、二乙醇胺、哌啶及哌嗪。
尽管本发明化合物可能以粗化学品形式给予,但其亦能以药物制剂形式存在。因此,本文提供药物制剂,其包含一种或多种本文所公开特定化合物或其一种或多种药学上可接受的盐、酯、前药、酰胺或溶剂合物、以及一种或多种药学上可接受的载剂及任选一种或多种其他治疗成分。载剂必须在与制剂其它成分相容且不损害其接受者的意义上是“可接受的”。适宜制剂视所选给予途径而定。可在适宜时且如本领域所了解使用任何熟知技术、载剂及赋形剂;例如,在Remington′s Pharmaceutical Sciences中所述。本文所公开的药物组合物可以任一本领域公知的方式制造,例如,借助常规混合、溶解、颗粒化、制糖衣、研磨、乳化、囊封、包裹或压缩工艺。
本文所用术语“卤素”表示选自氟、氯、溴或碘的卤素取代基。
本文所用术语“C1-C6-烷基”(包括C1-C6-烷氧基、C1-C6-烷基氨基、二-C1-C6-烷基氨基、C1-C6-烷硫基等的烷基部分)表示在烷基链任一位置连接至剩余化合物的具有1个至6个碳原子的支链及非支链烷基部分。术语“C1-C4-烷基”相应地表示具有1个至4个碳原子的支链或非支链烷基部分。“C1-C4-烷基”通常是优选的。“C1-C6-烷基”的实例包括:甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或己基。除非另有说明,否则定义丙基、丁基、戊基及己基包括所讨论基团的所有可能的异构体形式。因此,举例而言,丙基包括正丙基及异丙基,丁基包括异丁基、仲丁基及叔丁基等。
本文所用术语“C1-C6-卤代烷基”(包括C1-C6-卤代烷氧基、C1-C6-卤代烷基氨基、二-C1-C6-卤代烷基氨基、C1-C6-卤代烷硫基等的烷基部分)表示具有1个至6个碳原子的支链及非支链烷基部分,其中一个或多个氢原子经选自氟、氯或溴的卤素替代,优选氟及氯,尤其优选氟。术语“C1-C4-卤代烷基”相应地表示具有1个至4个碳原子的支链及非支链烷基部分,其中一个或多个氢原子以与上文所说明类似的方式被替代。C1-C4-卤代烷基通常是优选的。优选实例包括:CH2F、CHF2及CF3。
本文所用术语“C2-C6-烯基”(包括其他基团的烯基部分)表示在烯基链任一位置连接至剩余化合物且具有至少一个双键的具有2个至6个碳原子的支链及非支链烯基。术语“C2-C4-烯基”相应地表示具有2个至4个碳原子的支链及非支链烯基部分。优选的是具有2个至4个碳原子的烯基部分。实例包括:乙烯基或乙烯基、丙烯基、丁烯基、戊烯基或己烯基。除非另有说明,否则定义丙烯基、丁烯基、戊烯基及己烯基包括所讨论部分的所有可能的异构形式。因此,举例而言,丙烯基包括1-丙烯基及2-丙烯基,丁烯基包括1-、2-及3-丁烯基、1-甲基-1-丙烯基、1-甲基-2-丙烯基等。
本文所用术语“C2-C6-炔基”(包括其他基团的炔基部分)表示在炔基链任一位置连接至剩余化合物且具有至少一个叁键的具有2个至6个碳原子的支链及非支链炔基。术语“C2-C4-炔基”相应地表示具有2个至4个碳原子的支链及非支链炔基部分。具有2至4个碳原子的炔基部分是优选的。实例包括:乙炔基、丙炔基、丁炔基、戊炔基或己炔基。除非另有说明,否则定义丙炔基、丁炔基、戊炔基及己炔基包括相应部分的所有可能的异构形式。因此,举例而言,丙炔基包括1-丙炔基及2-丙炔基,丁炔基包括1-、2-及3-丁炔基、1-甲基-1-丙炔基、1-甲基-2-丙炔基等。
本文所用术语“C3-C8-环烷基”(包括其他基团的环烷基部分)表示环丙基、环丁基、环戊基、环己基、环庚基及环辛基。优选的是具有3个至6个碳原子的环状烷基,例如环丙基、环戊基及环己基。
本文所用术语“C3-C8-环烯基”(包括其他基团的环烯基部分)表示具有3个至8个碳原子且含有至少一个、优选一个或两个非共轭双键的碳环基团。实施例为环戊烯基、环戊二烯基、环己烯基及环己二烯基。
本文所用术语“杂环基”(包括其他基团的杂环基部分)表示含有一个、两个或三个选自O、N及S的杂原子作为环成员的5-至7元杂环基团及5-至10元双环杂环基团。杂环基可经碳原子或(若存在)经氮原子连接至分子。本文所用术语“杂环基”涵盖饱和或部分不饱和杂环基以及杂芳基。
本文所用术语“饱和或部分不饱和的杂环基”(包括其他基团的杂环基部分)表示如上文所定义含有多个双键而未形成芳香族系统的5-至7元单环杂环基团以及如上文所定义含有多个双键而在所述环中的至少一个中未形成芳香族系统的5-至10元双环杂环基团。
单环饱和或部分不饱和的杂环基的实例包括吡咯烷基、四氢呋喃基、四氢噻吩基、噻唑烷基、二氧杂环戊烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、硫吗啉基、氧氮杂环庚烷基(oxazepane)等。
本文所用术语“杂芳基”(包括其他基团的杂环基部分)表示如上文所定义含有多个双键以形成芳香族系统的5-至7元单环杂环基团以及如上文所定义含有多个双键以在两个环中均形成芳香族系统的5-至10元双环杂环基团。
双环芳香族杂环基的实例包括吡咯嗪基、吲哚基、吲嗪基、异吲哚基、吲唑基、嘌呤基、喹啉基、异喹啉基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并异噻唑基、吡啶并嘧啶基、蝶啶基、嘧啶并嘧啶基、咪唑并吡啶基、吡唑并吡啶基等。
本文所用术语“稠合的碳环或杂环部分”表示如上文所定义的C3-C8-环烷基、C3-C8-环烯基、苯及杂环基部分,其中所述部分与其所结合的环状部分共用至少一个键。举例而言,稠合至苯的苯为萘。优选的是与其所稠合的环状部分共用一个键的稠合环状部分。其他优选的稠合部分为苯。
本文所用术语“由两个基团连同其所结合的碳原子一起形成的3-至8元环,其中该环可含有1个或2个选自O、N及S的杂原子作为环成员”表示如上文所定义的C3-C8-环烷基、C3-C8-环烯基及杂环基部分。
本文所用术语“由两个基团连同其所结合的氮原子一起形成的环状胺,其中该环可包含另外的选自O、N及S的杂原子作为环成员”表示具有3个至8个、优选5个或6个环成员的环状胺。如此形成的胺的实施例为吡咯烷、哌啶、哌嗪、吗啉、吡咯、咪唑等。
本文所用术语“杂环基-C1-C6-烷基”、“C3-C8-环烷基-C1-C6-烷基”、“苯基-C1-C6-烷基”及“萘基-C1-C6-烷基”表示如上文所定义具有1个至6个碳原子的烷基部分,其中所述氢原子中的任一者经如上文所定义的环状部分替代。在所述术语中,烷基部分优选具有1个至4个碳原子(C1-C4-烷基)。更优选地,烷基部分为甲基或乙基,且最优选为甲基。苯基-C1-C6-烷基的优选实施例为苄基或苯乙基。
本文所用术语“杂环基-C2-C6-烯基”、“C3-C8-环烷基-C2-C6-烯基”、“苯基-C2-C6-烯基”及“萘基-C2-C6-烯基”表示如上文所定义具有2个至6个碳原子的烯基部分,其中所述氢原子中的任一者经如上文所定义的环状部分替代。在所述术语中,烯基部分优选具有2个至4个碳原子(C2-C4-烯基)。更优选地,烯基部分为乙烯基。苯基-C2-C6-烯基的优选实施例为苯乙烯基。
针对下文中各基团及部分Ra、Rb、Rc、Rd、Y1、Y2、Y3、Y4、Y5、Z、R1、R2、n及R3给出的具体及优选定义对它们自身及组合有效。将理解,优选的是式(Ia)或(Ib)的化合物,其中各基团及部分Ra、Rb、Rc、Rd、Y1、Y2、Y3、Y4、Y5、Z、R1、R2、n及R3中的一或多者具有如下文中指出为优选含义之一且其中余下基团及部分为如上文所述。最优选的是式(Ia)或(Ib)的化合物,其中所有各基团及部分Ra、Rb、Rc、Rd、Y1、Y2、Y3、Y4、Y5、Z、R1、R2、n及R3具有如下文指出为优选含义之一。
本发明的一个具体实施方案涉及式(Ia)的吡唑化合物,其中各部分具有说明书中所给出的含义之一。优选的是式(Ia)的化合物,其中各部分具有说明书中所给出优选含义之一。
本发明的另一个具体实施方案涉及式(Ib)的吡唑化合物,其中各部分具有说明书中所给出的含义之一。优选的是式(Ib)的化合物,其中各部分具有说明书中所给出优选含义之一。
优选的是式(Ia)或(Ib)的吡唑化合物,其中Ra及Rb独立地选自氢、C1-C6-烷基、C1-C6-卤代烷基及C3-C8-环烷基。
特别优选的是式(Ia)或(Ib)的吡唑化合物,其中Ra及Rb均为氢。
同样优选的是式(Ia)或(Ib)的吡唑化合物,其中Rc及Rd独立地选自氢、C1-C6-烷基、C1-C6-卤代烷基及C3-C8-环烷基。
特别优选的是式(Ia)或(Ib)的吡唑化合物,其中Rc及Rd均为氢。
同样优选的是式(Ia)或(Ib)的吡唑化合物,其中Y1为CRy1或N,其中Ry1具有针对Ry所给出的含义之一。
更优选的是式(Ia)或(Ib)的吡唑化合物,其中Y1为CRy1,特别是,其中Ry1选自H、C1-C6-烷基、C1-C6-烷氧基-C1-C6-烷基及C1-C6-卤代烷基。
同样优选的是式(Ia)或(Ib)的吡唑化合物,其中Y2为CRy2,Y3为CRy3,Y4为CRy4和/或Y5为CRy5,其中Ry2、Ry3、Ry4及Ry5彼此独立地具有针对Ry所定义的含义之一。
更优选的是式(Ia)或(Ib)的吡唑化合物,其中Y2为CRy2,Y3为CRy3,Y4为CRy4及Y5为CRy5,其中Ry2、Ry3、Ry4及Ry5彼此独立地具有针对Ry所定义的含义之一,特别是其中Ry2、Ry3、Ry4及Ry5独立地选自H、卤素、C1-C6-烷氧基、C1-C6-烷氧基-C1-C6-烷氧基及C1-C6-卤代烷氧基。
本发明的一个具体实施方案涉及式(Ia)或(Ib)的吡唑化合物,其中Z为O,且余下部分具有说明书中所给出的含义之一,优选具有说明书中所给出优选含义之一。
本发明的另一个具体实施方案涉及式(Ia)或(Ib)的吡唑化合物,其中Z为S,且余下部分具有说明书中所给出的含义之一,优选具有说明书中所给出优选含义之一。
本发明的另一个具体实施方案涉及式(Ia)或(Ib)的吡唑化合物,其中Z为NRz,其中Rz为H、C1-C6-烷基或苄基,且余下部分具有说明书中所给出的含义之一,优选具有说明书中所给出优选含义之一。
同样优选的是式(Ia)或(Ib)的吡唑化合物,其中R1及R2彼此独立地选自H、C1-C6-烷基、C3-C8-环烷基、苯基及萘基。
更优选的是式(Ia)或(Ib)的吡唑化合物,其中R1及R2彼此独立地选自H、C1-C4-烷基、C3-C6-环烷基及苯基。
特别优选的是式(Ia)或(Ib)的吡唑化合物,其中R1及R2选自C1-C4-烷基。
同样优选的是式(Ia)或(Ib)的吡唑化合物,其中n为0、1、2或3,特别是,其中n为0或1。
同样优选的是式(Ia)或(Ib)的吡唑化合物,其中R3若存在,则独立地选自卤素、C1-C6-烷氧基及C1-C6-卤代烷氧基。
更优选的是式(Ia)或(Ib)的吡唑化合物,其中R3若存在,则独立地选自卤素,特别是,选自F、Cl及Br。
本发明的一优选具体实施方案涉及选自式(Ia′)的化合物的吡唑化合物,
其中Z、R1、R2、R3、Ry1、Ry2、Ry3、Ry4及Ry5具有如上给出含义之一且n为0或1。
更优选的是吡唑化合物(Ia′),其中部分Z、R1、R2、R3、Ry1、Ry2、Ry3、Ry4及Ry5中的至少一者具有如上给出优选含义之一。
本发明的另一优选具体实施方案涉及选自式(Ib′)的化合物的吡唑化合物,其中Z、R1、R2、R3、Ry1、Ry2、Ry3、Ry4及Ry5具有如上所给出的含义之一。
更优选的是吡唑化合物(Ia′),其中部分Z、R1、R2、R3、Ry1、Ry2、Ry3、Ry4及Ry5中的至少一者具有如上给出优选含义之一。
本发明的另一实施方案涉及式(Ia)或(Ib)化合物,其中式(Ia)或(Ib)化合物以单独光学异构体、各对映异构体混合物或外消旋体形式存在,优选以对映异构体纯化合物形式存在。
本发明的另一实施方案涉及式(Ia)或(Ib)化合物,其中式(Ia)或(Ib)化合物以其与药理上可接受的酸的酸加成盐及任选以溶剂合物和/或水合物形式存在。
制备
本发明化合物可使用本领域技术人员公知且有机合成文献中所述的合成方法来获得。优选地,所述化合物以类似于下文更充分阐释(具体而言如实验部分中所述)的制备方法来获得。
本发明的式(Ia)的化合物依照反应式1制备。
可依照反应式1制备本发明的化合物,其中将(1H-吡唑-4-基)乙酸衍生物用作起始原料I,所述衍生物经取代基Ra、Rb、R1、R2及经羧酸保护基PG取代。这些化合物可(于一些情况中)自市面购置或可依照文献方法(例如,WO2007/141267)制备。适宜保护基团可选自T.W.Greene,Protective Groups in Organic Synthesis,Wiley,第3版,1999。优选保护基团PG为甲基、乙基、叔丁基。中间体I可通过在碱存在下,利用作为起始原料II的适宜的4-硝基苄基化合物将起始原料I烷基化获得,其中LG为适宜的离去基团,如卤素,特别是,Br,或甲磺酸根。适宜的碱为例如碳酸盐,特别是碳酸钾的无机碱。该反应优选在例如二甲基甲酰胺、二甲亚砜、乙腈、四氢呋喃、二氯甲烷或溶剂混合物中实施。该反应一般进行1至48小时。优选反应温度为介于0℃与反应混合物沸点之间。当R1与R2不同时,烷基化反应可产生区域异构体的混合物。各异构体可通过本领域技术人员已知的方法分离,例如,采用适宜溶剂或溶剂混合物的硅胶色谱或采用适宜溶剂梯度的制备型反相色谱,或自适宜溶剂或溶剂混合物进行研制或结晶。
胺中间体II可通过还原中间体I的硝基而制得,例如,在例如钯炭或阮内镍的催化剂存在下进行氢解反应。该反应优选在例如甲醇、乙醇、乙酸、乙酸乙酯或溶剂混合物的惰性有机溶剂中进行。该反应一般进行1至48小时。优选反应温度为介于0℃至50℃之间。优选反应压力为介于大气压至100巴之间。中间体I的硝基亦可依照J.March,Advanced OrganicChemistry,Wiley,第4版,1992,p.1216-1217中所描述的替代方法进行还原。酰胺中间体III可由胺中间体II,在例如2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲四氟硼酸盐(TBTU)的偶合剂及例如二异丙基乙胺的碱存在下,与羧酸(起始原料III)偶合而制备。该反应优选在例如二甲基甲酰胺、四氢呋喃、二氯甲烷或溶剂混合物的惰性有机溶剂中进行。该反应一般进行1至48小时。优选反应温度为介于0℃至30℃之间。羧酸与中间体II的氨基亦可依照J.March,Advanced Organic Chemistry,Wiley,第4版,1992,p.419-421中所描述的替代方法进行偶合。或者,可采用相应酰基氯或酸酐替代羧酸(起始原料III)及偶合剂。
式(Ia)的化合物可由中间体III移除保护基团PG而获得。若羟基羰基为经CH3或C2H5保护时,此转化法可在例如NaOH或LiOH的无机碱存在下,于水性条件中进行。该反应优选在水或水与CH3OH、C2H5OH、四氢呋喃或二烷的混合物中进行。该反应一般进行1至48小时。优选反应温度为介于0℃至反应混合物沸点之间。若PG为叔丁基时,该脱除保护基的反应可在酸性条件下,例如,使用三氟乙酸、盐酸或蒙脱石进行。当使用三氟乙酸时,该反应可在纯净的三氟乙酸中或在例如二氯甲烷的惰性溶剂中进行。该反应一般进行1至48小时。优选反应温度为介于0℃至30℃之间。亦可依照J.March,Advanced Organic Chemistry,Wiley,第4版,1992,p.378-383或T.W.Greene,Protective Groups in OrganicSynthesis,Wiley,第3版,1999中所描述的替代方法裂解保护基团PG。
式(Ib)的化合物可依照反应式1中所描述的方法,使用如式III′的起始原料替代起始原料III获得,
其中Y1、Y2、Y3、Y4、Y5及Z具有上述含义之一。
适应症
本发明的式(Ia)或(Ib)化合物尤其可用于制造用于预防和/或治疗涉及CRTH2-受体活性的疾病的药物。
本发明的一个实施方案涉及制造用于预防和/或治疗多种炎性、传染性及免疫调节性病症、呼吸道或胃肠道疾病或病症、关节的炎性疾病及鼻咽、眼睛及皮肤的过敏性疾病的药物。所述病症、疾病及病状包括哮喘及过敏性疾病、嗜酸性粒细胞疾病、慢性阻塞性肺病、由病原性微生物引起的感染(就定义而言其包括病毒)、以及自身免疫性疾病(例如类风湿性关节炎及动脉粥样硬化)。
优选的是制造用于预防和/或治疗炎性或过敏性疾病及病况的药物,所述炎性或过敏性疾病及病况包括过敏性或非过敏性鼻炎或鼻窦炎、慢性鼻窦炎或鼻炎、鼻息肉、慢性鼻及鼻窦炎、急性鼻及鼻窦炎、哮喘、儿童哮喘、过敏性支气管炎、肺泡炎、农民病(Farmer′sdisease)、高反应性气道、过敏性结膜炎、由感染(例如由细菌或病毒或蠕虫或真菌或原生动物或其他病原体)引起的支气管炎或肺炎、支气管扩张症、成人呼吸窘迫综合征、支气管及肺水肿、由不同原因(例如误吸、吸入有毒气体、蒸气)引起的支气管炎或肺炎或间质性肺炎、由心脏衰弱、X-射线、辐射、化学疗法引起的支气管炎或肺炎或间质性肺炎、与胶原性疾病(例如红斑狼疮、全身性硬皮病、肺纤维化、特发性肺纤维化(IPF))相关的支气管炎或肺炎或间质性肺炎、不同起因(包括石棉沉着病、硅肺、m.Boeck症或肉样瘤病、肉芽肿病、囊性纤维化或黏液黏稠病或αl-抗胰蛋白酶缺乏)引起之间质性肺病或间质性肺炎、嗜酸性粒细胞蜂窝织炎(例如,韦尔斯氏综合征(Well′s syndrome))、嗜酸性粒细胞肺炎(例如,吕弗勒氏综合征(Loeffler′s syndrome)、慢性嗜酸性粒细胞肺炎)、嗜酸性粒细胞筋膜炎(例如,舒尔曼氏综合征(Shulman′s syndrome))、迟发型过敏症、非过敏性哮喘;运动引起的支气管收缩;慢性阻塞性肺病(COPD)、急性支气管炎、慢性支气管炎、咳嗽、肺气肿;全身性过敏反应或超敏性反应、药物过敏(例如,对青霉素、头孢菌素过敏)、因摄入受污染色氨酸引起的嗜酸性细胞增多性肌痛综合征、由昆虫叮咬引起的过敏症;自身免疫性疾病,例如类风湿性关节炎、银屑病关节炎、多发性硬化、全身性红斑狼疮、重症肌无力、免疫性血小板减少症(成人ITP、新生儿血小板减少症、儿童ITP)、免疫性溶血性贫血(自身免疫型及药物诱导型)、埃文斯综合征(Evans syndrome)(血小板及红细胞免疫性血球减少)、新生儿Rh病、古德帕斯丘氏综合征(Goodpasture′s syndrome)(抗GBM疾病)、腹腔自身免疫性心肌病青少年型糖尿病;肾小球肾炎、自身免疫性甲状腺炎、贝切特病(Behcet′s disease);移植物排斥(例如,在移植中),包括同种异体移植物排斥或移植物抗宿主疾病;炎性肠病,例如克罗恩氏病(Crohn′s disease)及溃疡性结肠炎;脊椎关节病;硬皮病;银屑病(包括T-细胞介导的银屑病)及炎性皮肤病(例如皮炎、湿疹、特应性皮炎、过敏性接触性皮炎、荨麻疹);血管炎(例如,坏死性、皮肤性及过敏性血管炎);结节性红斑;嗜酸性粒细胞肌炎、嗜酸性粒细胞筋膜炎、伴随皮肤或器官白细胞渗入的癌症。
治疗方法
因此,本发明的式(Ia)或(Ib)化合物可用于预防和/或治疗多种炎性、传染性及免疫调节性病症及疾病。所述病症及疾病包括(但不限于)哮喘及过敏性疾病、慢性阻塞性肺病、由病原性微生物(就定义而言其包括病毒)引起的感染、自身免疫性疾病(例如类风湿性关节炎及动脉粥样硬化)。
举例而言,可给予抑制哺乳动物CRTH2受体(例如,人CRTH2受体)的一种或多种功能的即溶式(Ia)或(Ib)化合物以抑制(即,减少或阻止)炎症及支气管收缩。由此抑制一种或多种炎性过程,例如白细胞迁出、黏附、趋化、胞吐(例如,酶、生长因子、组胺、细胞毒性蛋白的胞吐)、炎性介质释放、CRTH2表达细胞的存活或增殖。举例而言,可根据本发明方法抑制炎性部位(例如,在哮喘或过敏性鼻炎中)Th2细胞、肥大细胞、嗜碱性粒细胞及嗜酸性粒细胞的活化或募集。
具体而言,在上述分析中使用适当CRTH2激动剂使得下列实施例的化合物具有阻断表达CRTH2受体的细胞活化及迁移的活性。
可利用CRTH2受体功能抑制剂治疗的人疾病或病况包括(但不限于)炎性或过敏性疾病及病况,包括过敏性或非过敏性鼻炎或鼻窦炎、慢性鼻窦炎或鼻炎、鼻息肉、慢性鼻及鼻窦炎、急性鼻及鼻窦炎、哮喘、儿童哮喘、过敏性支气管炎、肺泡炎、农民病(Farmer′sdisease)、高反应性气道、过敏性结膜炎、由感染(例如由细菌或病毒或蠕虫或真菌或原生动物或其他病原体)引起的支气管炎或肺炎、支气管扩张症、成人呼吸窘迫综合征、支气管及肺水肿、由不同原因(例如误吸、吸入有毒气体、蒸气)引起的支气管炎或肺炎或间质性肺炎、由心脏衰弱、X-射线、辐射、化学疗法引起的支气管炎或肺炎或间质性肺炎、与胶原性疾病(例如红斑狼疮、全身性硬皮病、肺纤维化、特发性肺纤维化(IPF))相关的支气管炎或肺炎或间质性肺炎、不同起因(包括石棉沉着病、硅肺、m.Boeck症或肉样瘤病、肉芽肿病、囊性纤维化或黏液黏稠病或αl-抗胰蛋白酶缺乏)引起之间质性肺病或间质性肺炎、嗜酸性粒细胞蜂窝织炎(例如,韦尔斯氏综合征(Well′s syndrome))、嗜酸性粒细胞肺炎(例如,吕弗勒氏综合征(Loeffler′s syndrome)、慢性嗜酸性粒细胞肺炎)、嗜酸性粒细胞筋膜炎(例如,舒尔曼氏综合征(Shulman′s syndrome))、迟发型过敏症、非过敏性哮喘;运动引起的支气管收缩;慢性阻塞性肺病(COPD)、急性支气管炎、慢性支气管炎、咳嗽、肺气肿;全身性过敏反应或超敏性反应、药物过敏(例如,对青霉素、头孢菌素过敏)、因摄入受污染色氨酸引起的嗜酸性细胞增多性肌痛综合征、由昆虫叮咬引起的过敏症;自身免疫性疾病,例如类风湿性关节炎、银屑病关节炎、多发性硬化、全身性红斑狼疮、重症肌无力、免疫性血小板减少症(成人ITP、新生儿血小板减少症、儿童ITP)、免疫性溶血性贫血(自身免疫型及药物诱导型)、埃文斯综合征(Evans syndrome)(血小板及红细胞免疫性血球减少)、新生儿Rh病、古德帕斯丘氏综合征(Goodpasture′s syndrome)(抗GBM疾病)、腹腔自身免疫性心肌病青少年型糖尿病;肾小球肾炎、自身免疫性甲状腺炎、贝切特病(Behcet′s disease);移植物排斥(例如,在移植中),包括同种异体移植物排斥或移植物抗宿主疾病;炎性肠病,例如克罗恩氏病(Crohn′s disease)及溃疡性结肠炎;脊椎关节病;硬皮病;银屑病(包括T-细胞介导的银屑病)及炎性皮肤病(例如皮炎、湿疹、特应性皮炎、过敏性接触性皮炎、荨麻疹);血管炎(例如,坏死性、皮肤性及过敏性血管炎);结节性红斑;嗜酸性粒细胞肌炎、嗜酸性粒细胞筋膜炎、伴随皮肤或器官白细胞渗入的癌症。
组合
本发明的式(Ia)或(Ib)化合物可单独或与其他式(Ia)或(Ib)化合物组合使用。式(Ia)或(Ib)化合物亦可任选与其他药理学活性物质组合。
可用于含有本发明的式(Ia)或(Ib)化合物的药物组合物的所述药理学活性物质可选自(但不限于)由下列组成的类别:β2-肾上腺素受体-激动剂(短效及长效β模拟物)、抗胆碱能药(短效及长效)、抗炎类固醇(口服及局部用皮质类固醇)、经解离的糖皮质激素模拟物、PDE3抑制剂、PDE4抑制剂、PDE7抑制剂、LTD4拮抗剂、EGFR抑制剂、PAF拮抗剂、LipoxinA4衍生物、FPRL1调节剂、LTB4-受体(BLT1、BLT2)拮抗剂、组胺-受体拮抗剂、PI3-激酶抑制剂、非受体酪氨酸激酶(例如LYN、LCK、SYK、ZAP-70、FYN、BTK或ITK)的抑制剂、MAP激酶(例如p38、ERK1、ERK2、JNK1、JNK2、JNK3或SAP)的抑制剂、NF-κB信号转导途径的抑制剂(例如IKK2激酶抑制剂)、iNOS抑制剂、MRP4抑制剂、白三烯生物合成抑制剂(例如5-脂氧合酶(5-LO)抑制剂、cPLA2抑制剂、白三烯A4水解酶抑制剂或FLAP抑制剂)、非甾体抗炎药(NSAID)、DP1-受体调节剂、血栓素受体拮抗剂、CCR1拮抗剂、CCR2拮抗剂、CCR3拮抗剂、CCR4拮抗剂、CCR5拮抗剂、CCR6拮抗剂、CCR7拮抗剂、CCR8拮抗剂、CCR9拮抗剂、CCR10拮抗剂、CXCR1拮抗剂、CXCR2拮抗剂、CXCR3拮抗剂、CXCR4拮抗剂、CXCR5拮抗剂、CXCR6拮抗剂、CX3CR1拮抗剂、神经激肽(NK1、NK2)拮抗剂、鞘胺醇1-磷酸盐受体调节剂、鞘胺醇1-磷酸盐-裂解酶抑制剂、腺苷受体调节剂(例如A2a-激动剂)、嘌呤能受体的调节剂(例如P2X7抑制剂)、组蛋白脱乙酰基酶(HDAC)活化剂、缓激肽(BK1、BK2)拮抗剂、TACE抑制剂、PPARγ调节剂、Rho-激酶抑制剂、白介素1-β转化酶(ICE)抑制剂、Toll样受体(TLR)调节剂、HMG-CoA还原酶抑制剂、VLA-4拮抗剂、ICAM-1抑制剂、SHIP激动剂、GABAa受体拮抗剂、ENaC-抑制剂、黑皮质素受体(MC1R、MC2R、MC3R、MC4R、MC5R)调节剂、CGRP拮抗剂、内皮缩血管肽拮抗剂、粘液调节剂、免疫治疗剂、呼吸道消肿化合物、止咳化合物、CB2激动剂、类视黄醇、免疫抑制剂、肥大细胞稳定剂、甲基黄嘌呤、阿片样受体激动剂、轻泻剂、止泡剂、镇痉剂、5-HT4激动剂,以及两种或三种活性物质的组合。
优选的是两种或三种活性物质的组合,即:本发明CRTH2拮抗剂与下列的组合:β模拟物、抗胆碱能药、皮质类固醇、PDE4抑制剂、LTD4拮抗剂、EGFR抑制剂、CCR3拮抗剂、CCR5拮抗剂、CCR9拮抗剂、5-LO抑制剂、组胺受体拮抗剂、SYK抑制剂及磺胺类,或即:
·CRTH2拮抗剂与β模拟物及皮质类固醇、PDE4抑制剂、CCR3拮抗剂或LTD4拮抗剂的组合,
·CRTH2拮抗剂与抗胆碱能药及β模拟物、皮质类固醇、PDE4抑制剂、CCR3拮抗剂或LTD4拮抗剂的组合,
·CRTH2拮抗剂与皮质类固醇及PDE4抑制剂、CCR3拮抗剂或LTD4拮抗剂的组合,
·CRTH2拮抗剂与PDE4抑制剂及CCR3拮抗剂或LTD4拮抗剂的组合。
视个别化合物而定,式(Ia)或(Ib)的CRTH2拮抗剂可以以选自互变异构体、光学异构体、对映异构体、外消旋体、非对映异构体、药理上可接受的酸加成盐、溶剂合物或水合物的形式(只要所述形式存在)包含于本发明药物组合物中。本发明药物组合物优选包含一种或多种、优选一种呈基本上纯对映异构体形式的化合物1。
在本发明药物组合物中,可存在一种以上式(Ia)或(Ib)的CRTH2拮抗剂及一种以上其他药理学活性化合物。
医药形式
用于给予式(Ia)或(Ib)化合物的适宜制剂包括(例如)片剂、胶囊、栓剂、溶液及粉末等。药学活性化合物的含量以总组成计应介于0.05重量%至90重量%之间,优选0.1重量%至50重量%。
可通过将活性物质与已知赋形剂混合来获得适宜片剂,所述赋形剂为(例如)惰性稀释剂,例如碳酸钙、磷酸钙或乳糖;崩解剂,例如玉米淀粉或海藻酸;黏合剂,例如淀粉或明胶;润滑剂,例如硬脂酸镁或滑石,和/或延迟释放试剂,例如羧甲基纤维素、邻苯二甲酸乙酸纤维素或聚乙酸乙烯酯。片剂亦可包含一些层。
因此,可通过用通常用于片剂包衣的物质(例如可力酮(collidone)或虫胶、阿拉伯树胶、滑石、二氧化钛或糖)将以类似于片剂的方式制备的核芯包衣来制备包衣片剂。为达成延时释放或防止不相容性,该核芯亦可由多层组成。同样,片剂包衣可由多层组成以达成延迟释放,可使用上文所述用于片剂的赋形剂。
含有本发明活性物质或其组合的糖浆或酏剂可另外含有甜味剂(例如糖精、甜精、甘油或糖)及增味剂(例如调味剂,例如香草醛或柑橘萃取物)。其亦可包含助悬剂或增稠剂(例如羧甲基纤维素钠),湿润剂(例如,举例而言脂肪醇与环氧乙烷的缩合产物)或防腐剂(例如对羟基苯甲酸酯)。
溶液系以常规方式制备,例如添加等渗剂、防腐剂(例如对-羟基苯甲酸酯)或稳定剂(例如乙二胺四乙酸的碱金属盐),任选使用乳化剂和/或分散剂,同时(举例而言)若将水用作稀释剂,则可任选将有机溶剂用作增溶剂或助溶剂,并可将溶液转移至注射小瓶或安瓿或输注瓶中。
含有一种或多种活性物质或活性物质组合的胶囊可通过(例如)将活性物质与惰性载剂(例如乳糖或山梨醇)混合并将其装入明胶胶囊中来制备。
适宜栓剂可通过(例如)将其与出于此目的提供的载剂(例如中性脂肪或聚乙二醇或其衍生物)混合来制备。
可用的赋形剂包括(但不限于)水;药学上可接受的有机溶剂,例如石蜡(例如石油馏份)、植物油(例如花生油或芝麻油)、单官能或多官能醇(例如乙醇或甘油);载剂,例如(举例而言)天然矿物粉末(例如高岭土、黏土、滑石、白垩)、合成矿物粉末(例如高分散硅酸及硅酸盐)、糖类(例如蔗糖、乳糖及葡萄糖)、乳化剂(例如木脂素、亚硫酸盐废液、甲基纤维素、淀粉及聚乙烯基吡咯烷酮)及润滑剂(例如硬脂酸镁、滑石、硬脂酸及月桂基硫酸钠)。
对于口服用途而言,片剂中除所说明的载剂外,当然亦可含有例如柠檬酸钠、碳酸钙及磷酸二钙等添加剂,以及例如淀粉(优选为马铃薯淀粉)、明胶等等各种添加物质。例如硬脂酸镁、月桂基硫酸钠及滑石等润滑剂亦可用于制造片剂。在水性悬浮液的情形下,除上述赋形剂外,所述活性物质亦可与各种增味剂或着色剂组合。
式(Ia)或(Ib)化合物亦可呈适用于吸入的制剂或药物制剂形式给予。可吸入制剂包括可吸入粉末、含推进剂的计量式剂量气雾剂或不含推进剂的可吸入溶液。在本发明范围内,术语不含推进剂的可吸入溶液亦包括浓缩物或即用型无菌可吸入溶液。可用于本发明范围内的制剂更详细地阐述于说明书的下一部分中。
本发明可用的可吸入粉末可含有(Ia)或(Ib)本身或其与适宜生理学上可接受的赋形剂的混合物。
若活性物质(Ia)或(Ib)系以与生理学上可接受的赋形剂的混合物形式存在,则可使用下列生理学上可接受的赋形剂制备本发明所述可吸入粉末:单糖(例如葡萄糖或阿拉伯糖)、二糖(例如乳糖、蔗糖、麦芽糖)、寡糖及多糖(例如右旋糖酐)、多元醇(例如山梨醇、甘露醇、木糖醇)、盐(例如氯化钠、碳酸钙)或所述赋形剂的混合物。优选地,使用单糖或二糖,而尤其优选使用乳糖或葡萄糖,但其形式特别是(但不限于)水合物形式。出于本发明的目的,乳糖是尤其优选的赋形剂,而乳糖一水合物尤其是最优选的。
在本发明的可吸入粉末的范围内,赋形剂的最大平均粒径高达250μm,优选介于10μm与150μm之间,最优选介于15μm与80μm之间。向上文所提及的赋形剂中添加平均粒径为1μm至9μm的较细赋形剂部分有时似乎是合适的。所述较细赋形剂亦选自上文所列举的可能赋形剂。最后,为制备本发明的可吸入粉末,优选向所述赋形剂混合物中添加平均粒径优选为0.5μm至10μm、更优选1μm至5μm的微粉化活性物质1。通过研磨及微粉化并最终将各成分混合在一起的制造本发明的可吸入粉末的工艺是现有技术公知的。
可使用现有技术公知的吸入器给予本发明的可吸入粉末。
本发明的含有气体推进剂的吸入式气雾剂可含有溶于气体推进剂中或呈分散形式的式(Ia)或(Ib)化合物。式(Ia)或(Ib)化合物可以以单独制剂形式或以普通制剂形式获得,其中式(Ia)或(Ib)化合物二者均溶解、二者均分散或在每一情形下仅一种组份溶解且其他分散。可用于制备吸入式气雾剂的气体推进剂是现有技术公知的。适宜的气体推进剂选自烃(例如正丙烷、正丁烷或异丁烷)及卤代烃(例如甲烷、乙烷、丙烷、丁烷、环丙烷或环丁烷的氟化衍生物)。上述气体推进剂可单独或一起混合使用。尤其优选的气体推进剂选自TG134a及TG227及其混合物的卤代烷烃衍生物。
推进剂驱动的吸入式气雾剂亦可含有其他成分,例如共溶剂、稳定剂、表面活性剂、抗氧化剂、润滑剂及pH调节剂。所有所述成分均为本领域所公知。
可使用本领域公知的吸入器(MDI=计量式剂量吸入器)给予上文所提及的本发明的推进剂驱动的吸入式气雾剂。
此外,本发明的式(Ia)或(Ib)的活性物质可以不含推进剂的可吸入溶液及悬浮液形式给予。所用溶剂可呈水性或醇性,优选为乙醇溶液。溶剂可为单独的水或水与乙醇的混合物。不限制与于水与乙醇的相对比例,但最大优选至多70%体积、更尤其至多60%体积且最优选至多30%体积。其余体积由水补足。使用适宜酸将含有式(Ia)或(Ib)化合物的溶液或悬浮液调节至pH 2至7,优选2至5。可使用选自无机酸或有机酸的酸来调节pH。尤其适宜无机酸的实例包括盐酸、氢溴酸、硝酸、硫酸和/或磷酸。尤其适宜有机酸的实例包括抗坏血酸、柠檬酸、苹果酸、酒石酸、马来酸、琥珀酸、富马酸、乙酸、甲酸和/或丙酸等。优选无机酸为盐酸及硫酸。亦能使用早已与一种活性物质形成酸加成盐的酸。在有机酸中,抗坏血酸、富马酸及柠檬酸是优选的。若需要,可使用上述酸的混合物,尤其是在除酸化性质外还具有其他性质的酸的情形下,例如作为调味剂、抗氧化剂或络合剂(例如柠檬酸或抗坏血酸)。根据本发明,尤其优选使用盐酸来调节pH。
若需要,在所述制剂中可省略添加乙二胺四乙酸(EDTA)或其常规盐之一的乙二胺四乙酸钠作为稳定剂或络合剂。其他实施方案可含有所述化合物。在优选实施方案中,含量以乙二胺四乙酸钠计小于100mg/100ml、优选小于50mg/100ml、更优选小于20mg/100ml。通常,乙二胺四乙酸钠的含量为0-10mg/100ml的可吸入溶液是优选的。
可将共溶剂和/或其他赋形剂添加至不含推进剂的可吸入溶液中。优选共溶剂是那些含有羟基或其他极性基团者,例如醇(尤其是异丙醇)、二醇(尤其是丙二醇)、聚乙二醇、聚丙二醇、二醇醚、甘油、聚氧乙烯醇及聚氧乙烯脂肪酸酯。在本文中术语赋形剂及添加剂表示任一药理上可接受的物质,其并非活性物质但可将其与一种或多种活性物质在生理学上适宜的溶剂中进行调配以改良活性物质制剂的定性性质。优选地,所述物质无药理效果或与期望疗法联合时无可观或至少无不期望的药理效果。赋形剂及添加剂包括(例如)表面活性剂(例如大豆卵磷脂、油酸、脱水山梨醇酯(例如聚山梨醇酯)、聚乙烯基吡咯烷酮)、其他稳定剂、络合剂、抗氧化剂和/或防腐剂(其保证或延长最终药物制剂的保质期)、调味剂、维生素和/或其他本领域公知的添加剂。添加剂亦包括药理上可接受的盐(例如氯化钠)作为等渗剂。
举例而言,优选赋形剂包括例如抗坏血酸等抗氧化剂,条件是其尚未用于调节人体内存在的pH、维生素A、维生素E、生育酚及类似维生素及维生素原。
防腐剂可用于保护制剂不受病原体污染。适宜防腐剂是那些本领域公知的,尤其是鲸蜡基吡啶盐酸盐、苯扎氯铵或苯甲酸或苯甲酸盐(例如苯甲酸钠),其呈自现有技术所获知的浓度。上文所提及的防腐剂优选以最多50mg/100ml的浓度存在,更优选介于5mg/100ml与20mg/100ml之间。
本发明化合物的剂量本质上极大地取决于给予方法及所治疗的病状。当通过吸入给予时,式(Ia)或(Ib)化合物的特征在于即使在剂量处于μg范围内时仍具有高效力。式(Ia)或(Ib)化合物超过μg范围使用亦可能有效。举例而言,剂量则可处于克范围内。
在另一方面中,本发明涉及特征在于含有式(Ia)或(Ib)化合物的上述药物制剂本身,尤其涉及可通过吸入给予的上述药物制剂。
下列制剂实施例阐释本发明而非限制其范围:
药物制剂的实施例:
将精细研磨的活性物质、乳糖及一些玉米淀粉混合在一起。使该混合物过筛,随后用聚乙烯基吡咯烷酮的水溶液将其润湿,捏合,湿法制粒并干燥。将所述颗粒、剩余玉米淀粉及硬脂酸镁筛分并混合在一起。将混合物压制成适宜形状及尺寸的片剂。
将精细研磨的活性物质、部分玉米淀粉、乳糖、微晶纤维素及聚乙烯基吡咯烷酮混合在一起,筛分混合物并将其与剩余玉米淀粉及水一起处理以形成颗粒,干燥并筛分该颗粒。添加羧甲基淀粉钠及硬脂酸镁并加以混合并压制混合物以形成适宜尺寸的片剂。
C)安瓿溶液
活性物质(Ia)或(Ib) 50mg
氯化钠 50mg
注射用水 5ml
将活性物质溶于水中,其pH为水自身的pH或任选为pH 5.5至6.5,并添加氯化钠使溶液具有等渗性。过滤所得溶液以去除致热源并将滤液在无菌条件下转移至安瓿中,然后将其灭菌并热密封。安瓿含有5mg、25mg及50mg活性物质。
D)计量式气雾剂
活性物质(Ia)或(Ib) 0.005
脱水山梨醇三油酸酯 0.1
单氟三氯甲烷及TG134a∶TG227 2∶1 补足至100
利用计量阀将悬浮液转移至常规气雾剂容器中。优选地,每次致动时释放50μl悬浮液。若需要,活性物质亦可以以更高剂量释放(例如0.02重量%)。
E)溶液(以mg/100ml计)
该溶液可以以常规方式制备。
F)可吸入粉末
活性物质(Ia)或(Ib) 12μg
乳糖一水合物 补足至25mg
所述可吸入粉末以常规方式通过混合单独成分来制备。
下列实施例用于进一步阐释本发明而非限制其范围。
实施例
I.HPLC方法
方法A:
HPLC-MS:Agilent 1100
流动相:
A:含0.032% NH4OH的水
B:甲醇
柱:XBridge C18,3,5μm,4.6×50mm(柱温度:恒温40℃)。通过二极管阵列检测器于210至500nm波长下检测。
方法B:
HPLC-MS:Waters ZQ MS,Alliance 2690/2695HPLC,2996二极管阵列检测器
流动相:
A:含0.1%TFA的水
B:甲醇
柱:Waters XBridge C18,4.6×20mm,3.5μm(柱温度:恒温40℃)。通过二极管阵列检测器在210至400nm波长下检测。
方法C:
HPLC:Waters Acquity,配以DA及MS检测器
流动相:
A:含0.1%TFA的水
B:甲醇
柱:Waters XBridge BEH C18,2.1×30mm,1.7μm(柱温度:恒温60℃)。通过二极管阵列检测器在210至400nm波长下检测。
方法D:
HPLC:Waters Acquity,配以DA及MS检测器
流动相:
A:含0.13%TFA的水
B:含0.05%TFA的甲醇
柱:Waters XBridge BEH C18,2.1×30mm,1.7μm(柱温度:恒温60℃)。通过二极管阵列检测器在210至400nm波长下检测。
方法E:
HPLC:Waters Acquity,配以DA及MS检测器
流动相:
A:含0.1%TFA的水
B:甲醇
柱:Waters XBridge C18,2.1×30mm,2.5μm(柱温度:恒温60℃)。通过二极管阵列检测器在210至400nm波长下检测。
方法F:
HPLC:Agilent 1200,配以DA及MS检测器
流动相:
A:含0.1%TFA的水
B:甲醇
柱:Waters XBridge C18,3×30mm,2.5μm(柱温度:恒温60℃)。通过二极管阵列检测器在210至400nm波长下检测。
方法G:
HPLC-MS:Waters Alliance,配以DA及MS检测器
流动相:
A:含0.1%NH3的水
B:含0.1%NH3的甲醇
柱:Waters XBridge C18,4.6×30mm,3.5μm(柱温度:恒温60℃)。通过二极管阵列检测器在210至400nm波长下检测。
方法H:
HPLC-MS:Waters Alliance,配以DA及MS检测器流动相:
A:含0.1%TFA的水
B:甲醇
柱:Waters SunFire C18,4.6×30mm,3.5μm(柱温度:恒温60℃)。通过二极管阵列检测器在210至400nm波长下检测。
方法J:
HPLC:Waters Acquity,配以DA及MS检测器
流动相:
A:含0.13%TFA的水
B:含0.05%TFA的甲醇
柱:Waters Sunfire C18,2.1×30mm,2.5μm(柱温度:恒温60℃)。通过二极管阵列检测器在210至400nm波长下检测。
方法K:
HPLC-MS:Waters Alliance,配以DA及MS检测器
流动相:
A:含0.1%TFA的水
B:含0.1%TFA的甲醇
柱:Waters XBridge C18,4.6×30mm,3.5μm(柱温度:恒温60℃)。通过二极管阵列检测器在210至400nm波长下检测。
方法L:
HPLC-MS:Waters Alliance,配以DA及MS检测器
流动相:
A:含0.1%TFA的水
B:甲醇
柱:Waters XBridge C18,4.6×30mm,3.5μm(柱温度:恒温60℃)。通过二极管阵列检测器在210至400nm波长下检测。
方法M:
HPLC-MS:Waters 2695HPLC,ZQ MS,2996二极管阵列检测器,2695自动取样机
流动相:
A:含0.1%NH3的水
B:含0.1%NH3的甲醇
柱:Waters XBridge C18,4.6×30mm,3.5μm(柱温度:恒温60℃)。通过二极管阵列检测器在210至400nm波长下检测。
方法N:
HPLC:Waters Acquity,配以DA及MS检测器
流动相:
A:含0.13%TFA的水
B:含0.08%TFA的甲醇
柱:Waters XBridge BEH C18,2.1×30mm,1.7μm(柱温度:恒温60℃)。通过二极管阵列检测器在210至400nm波长下检测。
方法O:
HPLC:Agilent 1200,配以DA及MS检测器
流动相:
A:含0.1%TFA的水
B:甲醇
柱:Waters XBridge C18,3×30mm,2.5μm(柱温度:恒温60℃)。通过二极管阵列检测器在210至400nm波长下检测。
II.起始化合物的合成
A)胺的合成
1.)[1-(4-氨基苄基)-3,5-二甲基-1H-吡唑-4-基]乙酸甲酯
a)将K2CO3(2.76g,19.9mmol)添加至(3,5-二甲基-1H-吡唑-4-基)-乙酸甲酯(3.90g,23mmol)及4-硝基苄基溴(4.60g,20.7mmol)于乙腈中的溶液中,并在室温将混合物搅拌1小时。将反应混合物倾入水中并通过乙酸乙酯萃取两次。通过MgSO4干燥有机相并减压蒸发,获得7.50g的[3,5-二甲基-1-(4-硝基-苄基)-1H-吡唑-4-基]-乙酸甲酯(ESI质谱:[M+H]+=304)。
b)将10%钯炭(500g)添加至[3,5-二甲基-1-(4-硝基-苄基)-1H-吡唑-4-基]-乙酸甲酯(3.90g,10.3mmol)的甲醇(10ml)溶液中并氢化该混合物。滤去催化剂并减压浓缩滤液。
通过制备型反相HPLC(梯度:甲醇溶于水+0.1%NH3中)纯化混合物,获得1.18g标题化合物(ESI质谱:[M+H]+=274;保留时间HPLC:2.13分钟(方法A))。
2.)[1-(4-氨基-2-氯-苄基)-3,5-二甲基-1H-吡唑-4-基]乙酸乙酯
a)将K2CO3(1.59g,11.5mmol)添加至(3,5-二甲基-1H-吡唑-4-基)-乙酸乙酯(1.40g,7.7mmol)及2-氯-4-硝基苄基溴(4.60g,20.7mmol)于20ml乙腈中的溶液中,并在室温将混合物搅拌48小时。通过蒸发移除溶剂并将残余物溶于二氯甲烷/水中。通过二氯甲烷萃取后,通过Na2SO4干燥有机相,并减压蒸发,获得2.79g的[3,5-二甲基-1-(2-氯-4-硝基-苄基)-1H-吡唑-4-基]-乙酸乙酯(ESI质谱:[M+H]+=352;保留时间:1.95分钟(方法A))。
b)将阮内镍(250mg)添加至[3,5-二甲基-1-(2-氯-4-硝基-苄基)-1H-吡唑-4-基]乙酸乙酯(2.39g,6.8mmol)的甲醇(40ml)溶液并使混合物氢化。滤去催化剂并减压浓缩滤液,获得1.18g标题化合物(ESI质谱:[M+H]+=322;保留时间HPLC:1.76分钟(方法A))。
3.)[1-(4-氨基-苄基)-3,5-二乙基-1H-吡唑-4-基]-乙酸乙酯
a)将K2CO3(10.80g,78.1mmol)添加至(3,5-二乙基-1H-吡唑-4-基)-乙酸乙酯(10.95g,52.1mmol)及4-硝基苄基溴(14.625g,68mmol)于乙腈(110ml)中的溶液中,并在室温将混合物搅拌48小时。将反应混合物倾入水中并通过乙酸乙酯萃取两次。通过MgSO4干燥有机相并减压蒸发。通过MPLC使用乙酸乙酯/环己烷纯化残余物,获得12.50g的[3,5-二乙基-1-(4-硝基-苄基)-1H-吡唑-4-基]乙酸乙酯(ESI质谱:[M+H]+=346;保留时间HPLC:1.42分钟(方法B))。
b)将阮内镍(500mg)添加至[3,5-二甲基-1-(4-硝基-苄基)-1H-吡唑-4-基]乙酸乙酯(6.66g,19.3mmol)的甲醇(500ml)溶液中,并在50psi及室温使混合物氢化。滤去催化剂并减压浓缩滤液,获得4.38g标题化合物(ESI质谱:[M+H]+=316;保留时间HPLC:1.09分钟(方法B))。
4.)[1-(4-氨基-2-氟苄基)-3,5-二甲基-1H-吡唑-4-基]乙酸甲酯
a)将K2CO3(10.1g,73.3mmol)添加至(3,5-二甲基-1H-吡唑-4-基)-乙酸甲酯(10g,48.9mmol)及2-氟-4-硝基苄基溴(11.5g,49.1mmol)于乙腈(150ml)中的溶液中,并在60℃将混合物搅拌48小时。通过蒸发移除溶剂并将残余物溶于二氯甲烷/水中。通过二氯甲烷萃取后,通过Na2SO4干燥有机层,并减压蒸发。通过MPLC(环己烷/乙醚7∶3)纯化残余物,获得13g的[3,5-二甲基-1-(2-氟-4-硝基-苄基)-1H-吡唑-4-基]乙酸甲酯(ESI质谱:[M+H]+=322;保留时间(HPLC):0.85分钟(方法C))。
b)将阮内镍(6g)添加至[3,5-二甲基-1-(2-氟-4-硝基-苄基)-1H-吡唑-4-基]乙酸甲酯(13g,40.4mmol)的甲醇(250ml)溶液中,并在50psi及50℃使混合物氢化。滤去催化剂并减压浓缩滤液。通过在二异丙醚中结晶来纯化混合物以获得12.8g标题化合物(ESI质谱:[M+H]+=292;保留时间HPLC:0.61分钟(方法C))。
5.)[1-(4-氨基-2-氯-苄基)-3,5-二甲基-1H-吡唑-4-基]-乙酸叔丁酯
a)将K2CO3(2.575g,18.6mmol)添加至(3,5-二甲基-1H-吡唑-4-基)-乙酸叔丁酯(2.6g,12.4mmol,依照WO2007/141267利用2,4-戊二酮替代3,5-庚二酮制备)及2-氯-4-硝基苄基溴(3.11g,12.4mmol)于乙腈(30ml)中的溶液中,并在室温将混合物搅拌48小时及然后在60℃搅拌2小时。滤去固体并通过蒸发移除溶剂。将残余物溶于二氯甲烷/水中。通过二氯甲烷萃取之后,通过MgSO4干燥有机层并减压蒸发,获得4.4g的[3,5-二甲基-1-(2-氯-4-硝基苄基)-1H-吡唑-4-基]乙酸叔丁酯(ESI质谱:[M+H]+=380)。
b)将阮内镍(440mg)添加至[3,5-二甲基-1-(2-氯-4-硝基苄基)-1H-吡唑-4-基]乙酸叔丁酯(4.40g,11.6mmol)的甲醇(80ml)溶液中,并在50psi及室温使混合物氢化12小时。滤去催化剂并减压浓缩滤液,获得2.4g标题化合物(ESI质谱:[M+H]+=350;保留时间HPLC:0.76分钟(方法D))。
6.)[1-(4-氨基苄基)-3,5-二甲基-1H-吡唑-4-基]乙酸叔丁酯
该标题化合物(ESI质谱:[M+H]+=316;保留时间HPLC:0.65分钟(方法E))为类似方法II.A.5,使用4-硝基苄基溴替代2-氟-4-硝基苄基溴来合成。
7.)[1-(4-氨基-2-氟苄基)-3,5-二甲基-1H-吡唑-4-基]乙酸叔丁酯
a)将K2CO3(6.615g,47.9mmol)添加至(3,5-二甲基-1H-吡唑-4-基)乙酸叔丁酯(10g,47.6mmol,依照WO2007/141267使用2,4-戊二酮替代3,5-庚二酮制备)及2-氟-4-硝基苄基溴(11.2g,47.9mmol)于乙腈(150ml)中的溶液中,并在室温将混合物搅拌24小时。滤去固体并通过蒸发移除溶剂。将残余物溶于二氯甲烷/水中。通过二氯甲烷萃取之后,通过MgSO4干燥有机层并减压蒸发。通过MPLC(环己烷/乙酸乙酯7∶3,硅胶60)纯化残余物,获得13.6g的[3,5-二甲基-1-(2-氟-4-硝基苄基)-1H-吡唑-4-基]乙酸叔丁酯(ESI质谱:[M+H]+=364,TLC:Rf=0.23(环己烷/乙酸乙酯7∶3,硅胶60 F254))。
b)将阮内镍(6g)添加至[3,5-二甲基-1-(2-氟-4-硝基苄基)-1H-吡唑-4-基]乙酸叔丁酯(13.6g,37.4mmol)的甲醇(250ml)溶液中,并在50psi及50℃使混合物氢化12小时。滤去催化剂并减压浓缩滤液,获得11.6g标题化合物(ESI质谱:[M+H]+=334;TLC:Rf=0.53(二氯甲烷/甲醇95∶5,硅胶60 F254))。
B)羧酸的合成
1.)1-乙基-5-氟-1H-吲哚-2-甲酸
a)将叔丁醇钾(108mg,0.965mmol)添加至5-氟吲哚-2-甲酸乙酯(200mg,0.965mmol)的二甲亚砜(6ml)溶液中,并在50℃将混合物搅拌30分钟。冷却至室温之后,添加溴乙烷(0.081ml,1.06mmol)并在室温将混合物搅拌2.5小时。伴随冷却添加水并通过乙酸乙酯萃取混合物。通过水及饱和NaCl水溶液清洗有机层,通过MgSO4干燥及真空蒸发溶剂,获得200mg的1-乙基-5-氟-1H-吲哚-2-甲酸乙酯(ESI质谱:[M+H]+=236)。
b)将NaOH水溶液(1M,1.7ml)添加至1-乙基-5-氟-1H-吲哚-2-甲酸乙酯(200mg,0.85mmol)的二烷(2ml)溶液中,并在60℃将混合物搅拌1小时。蒸发溶剂之后,将残余物悬浮于少量水中并通过乙酸(2M)中和。过滤沉淀物,通过水清洗及干燥,获得140mg的标题化合物(ESI质谱:[M+H]+=208;保留时间HPLC:1.21分钟(方法F))。
以下吲哚羧酸为类似于该方法制备:
1-苄基-1H-吲哚-2-甲酸(ESI质谱:[M+H]+=252保留时间HPLC:0.84分钟(方法E));
1-丁基-1H-吲哚-2-甲酸(ESI质谱:[M+H]+=218);
5-氟-1-丙基-1H-吲哚-2-甲酸(ESI质谱:[M+H]+=222);
1-丁基-5-氟-1H-吲哚-2-甲酸(ESI质谱:[M+H]+=236);
1-丙基-1H-吲哚-2-甲酸(ESI质谱:[M+H]+=204);
1-乙基-4-氟-1H-吲哚-2-甲酸(ESI质谱:[M+H]+=208;保留时间HPLC:0.80分钟(方法E));
1-乙基-6-氟-1H-吲哚-2-甲酸(ESI质谱:[M+H]-=206;保留时间HPLC:0.71分钟(方法E));
6-氟-1-丙基-1H-吲哚-2-甲酸(ESI质谱:[M-H]-=220;保留时间HPLC:0.77分钟(方法E))。
2.)3-乙基-5-氟苯并呋喃-2-甲酸
a)将K2CO3(1.08g,7.8mmol)添加至5-氟-2-羟基-苯丙酮(0.9g,5.2mmol)及溴乙酸叔丁酯(0.9ml,6.1mmol)于乙腈(15ml)中的溶液中,并使混合物回流3小时。冷却至室温之后,将混合物倾入水中并通过乙酸乙酯萃取。通过水清洗有机层两次,通过MgSO4干燥及真空蒸发溶剂,获得1.47g的(4-氟-2-丙酰基苯氧基)乙酸叔丁酯(ESI质谱:[M+H]+=283;保留时间HPLC:0.88分钟(方法D))。
b)将甲醇钠的甲醇(5.4M,20ml)溶液添加至(4-氟-2-丙酰基苯氧基)乙酸叔丁酯(1.47g,5.2mmol)的无水乙醇(20ml)溶液中,并在80℃将混合物搅拌12小时。冷却至室温及蒸发溶剂之后,将残余物溶于水中并通过盐酸(1M)酸化。过滤沉淀物,通过水清洗及干燥,获得440mg的标题化合物(ESI质谱:[M-H]-=207;保留时间HPLC:0.87分钟(方法G))。
以下苯并呋喃羧酸是类似于此方法制备的:
7-氯-3-甲基苯并呋喃-2-甲酸(ESI质谱:[M-H]-=209;保留时间HPLC:1.28分钟(方法H));
5-氟-3-丙基苯并呋喃-2-甲酸(ESI质谱:[M-H]-=221;保留时间HPLC:1.01分钟(方法G));
3-乙基-7-氟苯并呋喃-2-甲酸(ESI质谱:[M-H]-=207;保留时间HPLC:0.77分钟(方法E));
3-乙基-5,7-二氟苯并呋喃-2-甲酸(ESI质谱:[M-H]-=225;保留时间HPLC:1.32分钟(方法L));
6-氯苯并呋喃-2-甲酸(ESI质谱:[M-H]-=195;保留时间HPLC:1.72分钟(方法H))。
III)化合物(Ia)及(Ib)的合成
化合物1:(1-(2-氟-4-[(1H-吲哚-2-羰基)氨基]苄基)-3,5-二甲基-1H-吡唑-4-基)乙酸(偶合方法C1):
a)将TBTU(139mg,0.43mmol)及N,N-二异丙基胺(0.126ml,0.74mmol)添加至吲哚-2-甲酸(80mg,0.50mmol)的N,N-二甲基甲酰胺(1.5ml)溶液中。随后添加[1-(4-氨基-2-氟苄基)-3,5-二甲基-1H-吡唑-4-基]乙酸甲酯(120mg,0.41mmol)。在室温将混合物搅拌12小时。然后添加K2CO3水溶液(2M,0.5ml)。以二氯甲烷/甲醇(9∶1,10ml)将所得混合物冲过Al2O3。真空移除溶剂,获得82.3mg的(1-(2-氟-4-[(1H-吲哚-2-羰基)氨基]苄基)-3,5-二甲基-1H-吡唑-4-基)乙酸甲酯(ESI质谱:[M+H]+=435;保留时间HPLC:0.41分钟(方法N))。
b)将(1-(2-氟-4-[(1H-吲哚-2-羰基)氨基]苄基)-3,5-二甲基-1H-吡唑-4-基)乙酸甲酯(82mg,0.19mmol)溶于甲醇(0.5ml)中。添加NaOH水溶液(4M,0.3ml)并在室温将混合物搅拌2小时。通过甲醇/水稀释所得混合物,滤去固体,并在蒸发之后通过HPLC(Gilson,XRS Pursuit,甲醇/H2O+0.1%浓NH3)纯化残余物。浓缩含有标题化合物的级分并冷冻干燥,获得15mg的标题化合物(ESI质谱:[M+H]+=421;保留时间HPLC:1.04分钟(方法G))。
1H-NMR 400MHz(DMSO-d6):δ[ppm]=2.03(s,3H),2.14(s,3H),2.52(s,3H),3.21(s,2H),5.16(s,2H),6.99(t,1H),7.08(t,1H),7.23(t,1H),7.39(s,1H),7.48(m,2H),7.66(d,1H),7.79(d,1H),10.45(s,1H),11.79(br.,1H)。
下表1的化合物2及3是类似于偶合方法1,使用适宜的起始胺及羧酸制备的。
化合物4:(1-{4-[(5-氟-3-甲基苯并呋喃-2-羰基)氨基]苄基}-3,5-二甲基-1H-吡唑-4-基)乙酸(偶合方法C2):
a)将二异丙基乙胺(1.5ml,8.8mmol)及5-氟-3-甲基-1-苯并呋喃-2-甲酸(369mg,1.9mmol)添加至[1-(4-氨基苄基)-3,5-二甲基-1H-吡唑-4-基]乙酸甲酯(400mg,1.46mmol)于5ml二氯甲烷中的溶液中。在室温搅拌10分钟之后,在冷却下,添加1-丙基膦酸环酐在乙酸乙酯(1.725ml,2.93mmol)中的50%溶液并在室温将混合物搅拌12小时。在真空中蒸发溶剂并通过MPLC(二氯甲烷/甲醇98∶2)纯化残余物,获得410mg的(1-{4-[(5-氟-3-甲基苯并呋喃-2-羰基)氨基]苄基}-3,5-二甲基-1H-吡唑-4-基)乙酸甲酯(ESI质谱:[M+H]+=450;TLC:Rf=0.56(二氯甲烷/甲醇95∶5,硅胶60 F254))。
b)将1M NaOH(2.3ml)添加至(1-{4-[(5-氟-3-甲基苯并呋喃-2-羰基)氨基]苄基}-3,5-二甲基-1H-吡唑-4-基)乙酸甲酯(410mg,0.91mmol)的二烷/水(10ml/10ml)溶液中,并在室温将混合物搅拌24小时。通过水稀释混合物并通过盐酸(1M,3.25ml)酸化。过滤沉淀物,通过水清洗及干燥,获得338mg的标题化合物(ESI质谱:[M+H]+=436;保留时间HPLC:0.85分钟(方法D))。
1H-NMR 400MHz(DMSO-d6):δ[ppm]=2.05(s,3H),2.10(s,3H),2.52(s,3H),3.24(s,2H),5.16(s,2H),7.10(d,2H),7.37(t,1H),7.66(m,2H),7.75(d,2H),10.40(s,1H),12.05(br.,1H)。
下表1及2中的化合物5至26及57至59是类似于偶合方法C2,使用适宜的起始胺及羧酸制备的。
化合物27:(1-{2-氟-4-[(5-氟-3-甲基苯并呋喃-2-羰基)氨基]苄基}-3,5-二甲基-1H-吡唑-4-基)-乙酸(偶合方法C3):
a)将二异丙基乙胺(0.516ml,3mmol)添加至5-氟-3-甲基-1-苯并呋喃-2-甲酸(194mg,1mmol)于5ml二甲基甲酰胺中的溶液中,并添加HATU(399mg,1.05mmol)。在室温搅拌25分钟之后,陆续添加二甲基甲酰胺(1ml)及中间体[1-(4-氨基-2-氟苄基)-3,5-二甲基-1H-吡唑-4-基]乙酸甲酯(291mg,1mmol)。然后添加二异丙基乙胺(0.344ml,2mmol)及二甲基甲酰胺(2ml),并在室温将混合物搅拌48小时。随后添加乙酸乙酯及水及滤去沉淀物。通过乙酸(1N)萃取有机层两次,通过NaHCO3(5重量%)水溶液萃取一次并通过水萃取两次,通过MgSO4干燥。真空蒸发移除溶剂。通过MPLC(二氯甲烷/甲醇96:4)纯化残余物,获得120mg的(1-(2-氟-4-[(5-氟-3-甲基苯并呋喃-2-羰基)-氨基]-苄基)-3,5-二甲基-1H-吡唑-4-基)-乙酸甲酯(ESI质谱:[M+H]+=468;TLC:Rf=0.72(二氯甲烷/甲醇9∶1,硅胶60F254))。
b)将NaOH水溶液(1M,2.3ml)添加至(1-(2-氟-4-[(5-氟-3-甲基苯并呋喃-2-羰基)-氨基]-苄基)-3,5-二甲基-1H-吡唑-4-基)-乙酸甲酯(119mg,0.26mmol)的二烷/水(7ml/7ml)溶液中,并在室温将混合物搅拌12小时并在60℃搅拌2小时。通过水稀释混合物,通过盐酸(1M,1ml)酸化并通过乙酸乙酯萃取。通过MgSO4干燥有机层,真空蒸发溶剂,通过二异丙基醚使残余物结晶并通过过滤分离沉淀物,获得69mg的标题化合物(ESI质谱:[M+H]+=454;保留时间HPLC:0.90分钟(方法D))。
1H-NMR 400MHz(DMSO-d6):δ[ppm]=2.03(s,3H),2.14(s,3H),2.57(s,3H),3.28(s,2H),5.18(s,2H),6.96(t,1H),7.37(t,1H),7.54(d,1H),7.66(m,2H),7.79(d,1H),10.60(s,1H),12.07(br.,1H)。
下表1中的化合物28至31是类似于偶合方法C3,使用适宜的起始胺及羧酸制备的。
化合物32:(1-(4-[(1-乙基-5-氟-1H-吲哚-2-羰基)氨基]-2-氟苄基)-3,5-二甲基-1H-吡唑-4-基)乙酸(偶合方法C4):
a)将草酰氯(0.094ml,0.68mmol)及一滴二甲基甲酰胺添加至1-乙基-5-氟-1H-吲哚-2-甲酸(140mg,0.68mmol)于6ml二氯甲烷中的溶液。在室温搅拌1小时之后,真空蒸发移除溶剂。将残余物溶于二氯甲烷(5ml)中并滴入[1-(4-氨基-2-氟苄基)-3,5-二甲基-1H-吡唑-4-基]乙酸甲酯(177mg,0.61mmol)及二异丙基乙胺(0.23ml,1.35mmol)于二氯甲烷(5ml)中的溶液中。添加4-二甲氨基吡啶(8.255mg,0.069mmol),然后在室温将溶液搅拌12小时。通过盐酸(1M)萃取溶液两次,通过水萃取两次,通过NaOH水溶液(1M)萃取两次并通过水萃取两次。通过MgSO4干燥有机层,过滤及真空蒸发溶剂。通过MPLC(二氯甲烷/甲醇95∶5)纯化残余物,获得160mg的(1-(4-[(1-乙基-5-氟-1H-吲哚-2-羰基)氨基]-2-氟苄基)-3,5-二甲基-1H-吡唑-4-基)乙酸甲酯(ESI质谱:[M+H]+=481;保留时间HPLC:0.93分钟(方法D))。
b)将NaOH水溶液(1M,0.66ml)添加至(1-(4-[(1-乙基-5-氟-1H-吲哚-2-羰基)氨基]-2-氟苄基)-3,5-二甲基-1H-吡唑-4-基)乙酸甲酯(160mg,0.33mmol)的二烷(2ml)溶液中,并在60℃将混合物搅拌1小时。真空蒸发溶剂,并将残余物悬浮于水中并通过乙酸(2M)处理。将沉淀物冻干,溶于甲醇及少量二甲基甲酰胺中,并通过少量水使产物沉淀,过滤及干燥,获得137mg的标题化合物(ESI质谱:[M+H]+=467;保留时间HPLC:0.89分钟(方法D))。
1H-NMR 400MHz(DMSO-d6):δ[ppm]=1.30(t,6H),2.04(s,3H),2.13(s,3H),3.25(s,2H),4.55(q,4H),5.16(s,2H),6.97(t,1H),7.17(t,1H),7.29(s,1H),7.47(m,1H),7.62(dd,1H),7.74(d,1H),10.52(s,1H)。
化合物33:(1-(4-[(7-氯-3-甲基苯并呋喃-2-羰基)氨基]苄基)-3,5-二甲基-1H-吡唑-4-基)乙酸(偶合方法C4):
a)将草酰氯(0.123ml,1.14mmol)及一滴二甲基甲酰胺添加至7-氯-3-甲基苯并呋喃-2-甲酸(185mg,0.88mmol)于6ml二氯甲烷中的溶液。在室温搅拌1小时之后,真空蒸发移除溶剂。将残余物溶于二氯甲烷(5ml)中及滴入呈甲苯磺酸盐形式的[1-(4-氨基苄基)-3,5-二甲基-1H-吡唑-4-基]乙酸叔丁酯(428mg,1mmol)及二异丙基乙胺(0.39ml,2.27mmol)于二氯甲烷(5ml)中的溶液。添加4-二甲氨基吡啶(11mg,0.09mmol),然后在室温将溶液搅拌12小时。通过盐酸(1M)萃取溶液两次,通过水萃取两次,通过NaOH水溶液(1M)萃取两次并通过水萃取两次。通过MgSO4干燥有机层,过滤及真空蒸发溶剂,获得426mg的(1-(4-[(7-氯-3-甲基-苯并呋喃-2-羰基)氨基]苄基)-3,5-二甲基-1H-吡唑-4-基)乙酸叔丁酯(ESI质谱:[M+H]+=508;保留时间HPLC:1.60分钟(方法H))。
b)将三氯乙酸(400ml,5.2mmol)添加至(1-(4-[(7-氯-3-甲基-苯并呋喃-2-羰基)氨基]苄基)-3,5-二甲基-1H-吡唑-4-基)乙酸叔丁酯(426mg,0.84mmol)的二氯甲烷(10ml)溶液中,并在室温将混合物搅拌3天。真空蒸发溶剂,并将残余物悬浮于水中,并通过乙醚处理及滤出沉淀物,获得174mg的标题化合物(ESI质谱:[M+H]+=452;保留时间HPLC:1.39分钟(方法J))。
1H-NMR 400MHz(DMSO-d6):δ[ppm]=2.07(s,3H),2.14(s,3H),2.57(s,3H),3.29(s,2H),5.17(s,2H),7.12(d,2H),7.38(t,1H),7.62(d,1H),7.74(d,2H),7.76(d,1H),10.33(s,1H)。
化合物48:(1-(4-[(3-乙基-5-氟苯并呋喃-2-羰基)氨基]苄基)-3,5-二甲基-1H-吡唑-4-基)-乙酸(偶合方法C4)
a)将草酰氯(0.335ml,3.1mmol)及一滴二甲基甲酰胺添加至3-乙基-5-氟苯并呋喃-2-甲酸(450mg,2.16mmol)于10ml二氯甲烷中的溶液中。在室温搅拌1小时之后,真空蒸发移除溶剂。将残余物溶于二氯甲烷(10ml)中及滴入呈4-甲苯磺酸盐形式的[1-(4-氨基苄基)-3,5-二甲基-1H-吡唑-4-基]乙酸叔丁酯(1.054g,2.16mmol)及二异丙基乙胺(1.3ml,7.57mmol)于二氯甲烷(5ml)中的溶液。添加4-二甲氨基吡啶(26.4mg,0.216mmol),然后在室温将溶液搅拌12小时。真空蒸发溶剂,溶于100ml乙酸乙酯,并通过水萃取溶液两次,通过盐酸(0.5M)萃取一次,通过水萃取一次,通过NaHCO3水溶液(5重量%)萃取一次并通过水萃取一次。通过MgSO4干燥有机层,过滤及真空蒸发溶剂。通过MPLC(二氯甲烷/甲醇98∶2)纯化残余物,获得150mg的1-(4-[(3-乙基-5-氟苯并呋喃-2-羰基)氨基]苄基)-3,5-二甲基-1H-吡唑-4-基)-乙酸叔丁酯(ESI质谱:[M+H]+=506;保留时间HPLC:1.02分钟(方法D))。
b)将蒙脱石KSF(300mg)添加至(1-(4-[(3-乙基-5-氟苯并呋喃-2-羰基)氨基]苄基)-3,5-二甲基-1H-吡唑-4-基)-乙酸叔丁酯(150mg,0.30mmol)的乙腈(25ml)溶液中,并使混合物回流6小时。通过乙腈将混合物稀释至400ml,回流5分钟及过滤。真空蒸发溶剂并通过二甲基甲酰胺(300ml)清洗残余物。在过滤之后,通过蒸发移除溶剂并通过丙酮(200ml)处理残余物。研磨之后,滤出沉淀物并通过丙酮清洗,获得112mg的标题化合物(ESI质谱:[M+H]+=450;保留时间HPLC:0.85分钟(方法E))。
1H-NMR 400MHz(DMSO-d6):δ[ppm]=1.21(t,6H),2.04(s,3H),2.11(s,3H),3.09(q,4H),3.27(s,2H),5.16(s,2H),7.09(d,2H),7.33(t,1H),7.67(m,2H),7.76(d,2H),10.39(s,1H)。
下表1中的化合物34至47及49至56是类似偶合方法C4,使用适宜的起始胺及羧酸制备的。
IV)生物学测试
使用下列生物学测试方法对本发明的式(Ia)或(Ib)化合物进行测试,在整个系统中测定其自CRTH2受体取代PGD2的能力,及其拮抗PGD2在CRTH2受体处的功能性作用的能力。
人CRTH2受体膜的制备及放射性配体结合分析
使用自经人CRTH2受体转染的中国仓鼠卵巢细胞(CHO-K1细胞)(CHO-K1-hCRTH2细胞,Perkin Elmer,目录编号ES-561-C)制得的膜来测定CRTH2拮抗剂的结合。为了制备细胞膜,将CHO-K1-hCRTH2细胞在含补充有400μg/ml G418的CHO SFMII培养基中的悬浮液中培养。通过在室温以300g离心10分钟来收获细胞。将细胞沉淀物重新悬浮于包括蛋白酶抑制剂混合物(Complete,Roche)的磷酸盐缓冲液(PBS)中,并调整至10E7个细胞/ml的浓度。通过氮分解法来破坏CHO-K1-hCRTH2细胞,获得膜制剂。通过离心(在4℃,500g,30分钟)去除细胞碎片,并将上清液转移至新试管中,随后在4℃以40000g再次离心1小时,使膜沉积。将膜悬浮于不含牛血清白蛋白的SPA培育缓冲液(50mM Tris HCl、10mM MgCl2、150mM NaCl、1mM EDTA,pH 7.4)中,通过使其通过一次性针头(Terumo,23Gx1″)而均质化,并分成等份储存在-80℃。
CRTH2受体结合测试以邻近闪烁分析(SPA)模式,利用放射性配体[3H]-PGD2(Perkin Elmer,NET616000MC)来进行。通过使CHO-K1-hCRTH2细胞膜通过一次性针头(Terumo,23Gx1″)再次均质化,并于SPA培育缓冲液中稀释至适宜浓度(0.5-10μg蛋白/孔)。在96孔微量滴定板(Perkin Elmer,目录编号6005040)中在SPA培育缓冲液中建立SPA分析,其中最终体积为200μl/孔且最终浓度为50mM Tris-HCl、10mM MgCl2、150mM NaCl、1mMEDTA pH 7.4、0.1%牛血清白蛋白。SPA分析混合物含有60μl膜悬浮液、80μl经麦胚凝集素涂布的PVT珠粒(GE Healthcare,RPNQ-0001,0.3mg/孔)、于SPA缓冲液中稀释的40μl[3H]-PGD2(最终浓度为1nM(50000dpm))及20μl测试化合物(溶于二甲亚砜中)。在室温将SPA分析混合物培育3小时。利用闪烁计数器(Micro Beta Trilux,Wallac)来测定结合放射性。
在不存在(总结合,Bo)及存在(非特异性结合,NSB)未经标记的PGD2(1μM,CaymanChemical,目录编号12010)或参考CRTH2拮抗剂(10μM CAY10471,Cayman Chemical,目录编号10006735)时测定[3H]-PGD2对CHOK1-hCRTH2细胞膜的结合。
由总结合(Bo)或在指定化合物浓度的测试化合物(B)存在下的结合减去非特异性结合(NSB)的计算法测定测试化合物的亲和性。将NSB值设定为100%抑制。将Bo-NSB值设定为0%抑制。
%抑制值在所指定化合物浓度下(例如在1μM下)获得,测试化合物的%抑制通过公式100-((B-NSB)*100/(Bo-NSB))来计算。通过差异分析(assay varaince)发现,%抑制值高于100%。
通过使用基于质量作用定律的程式“easy sys”对以0.1nM至30000nM剂量范围内的若干化合物浓度获得的实验数据实施迭代拟合来计算解离常数Ki(Schittkowski,NumMath 68,129-142(1994))。
CRTH2 CAMP功能性分析方案
该分析在CHO-K1-hCRTH2细胞中实施。通过用10μM福斯高林(Forskolin)(一种腺苷酸环化酶活化剂)刺激细胞来产生细胞内cAMP。添加PGD2以活化CRTH2受体,从而导致福斯高林诱导的cAMP生成衰减。在CHO-K1-hCRTH2细胞中对测试化合物对于福斯高林诱导的PGD2所介导的cAMP生成衰减的抑制能力进行测试。在转瓶中在补充有400μg/ml G418的CHOSFMII培养基中培养CHO-K1-hCRTH2细胞。通过在室温以300g离心10分钟收获细胞。将细胞沉淀物洗涤并悬浮于PBS中。将细胞调节至4×10E6个细胞/ml的最终浓度。
将测试化合物稀释于二甲亚砜中,并在一些化合物浓度下在介于0.1nM至3000nM间的剂量范围内进行测试。
通过AlphaScreen cAMP分析(Perkin Elmer,目录编号6760625M)在384孔光学板(PerkinElmer,目录编号6007290)中测定cAMP含量,其中总分析体积为50μl。在37℃将10μl细胞(40.000个细胞/孔)培育30分钟,其中10μl刺激混合物含有最终浓度为10μM福斯高林、30nM PGD2、0.5mM IBMX、5mM HEPES、1xHBSS缓冲液、0.1%BSA(调节至pH 7.4)及不同浓度的测试化合物。然后,添加含有SA供体珠粒、生物素化cAMP、抗-cAMP受体珠粒、0.3%Tweeen-20、5mM HEPES、0.1%BSA(调节至pH 7.4)的30μl裂解及检测混合物。在2小时的培育时间后,在AlphaQuest-HTS仪器上读取AlphaScreen信号。通过使用Prism软件来计算IC50值。
其他CRTH2功能性分析方案
所测试化合物拮抗PGD2在CRTH2受体处的功能性作用的能力亦可通过本领域公知的方法来证实,例如通过全细胞结合分析、GTPgS分析、BRET分析、磷酸肌醇累积分析、CRTH2细胞表面表达分析、Ca2+流入量分析、ERK磷酸化分析、细胞迁移分析、嗜酸性粒细胞形状变化分析、Th2细胞脱粒分析或嗜碱性粒细胞活化分析,如下列所述:Mathiesen等人,MolPharmacol.2005,68:393-402;Mimura等人,J Pharmacol Exp Ther,2005,314:244-51;Sandham等人,Bioorg Med Chem Lett,2007,17:4347-50;Sandham Bioorg Med ChemLett,2009,19:4794-8;Crosignani等人,J Med Chem,2008,51:2227-43;Royer等人,Eur JClin Invest,2008,38:663-71;Boehme等人,Int Immunol,2009,21:621-32;Sugimoto等人,Pharmacol Exp Ther,2003,305:347-52;Monneret等人,J Pharmacol Exp Ther,2005,312:627-34;Xue等人,J Immunol,2005,175:6531-6。
表达CRTH2受体的细胞包括那些本质上表达CRTH2受体的细胞,例如AML14.3D10及NCI-H292细胞(Sawyer等人,Br J Pharmacol,2002,137:1163-72;Chiba等人,Int ArchAllergy Immunol,2007,143 Suppl 1:23-7);那些经添加化学品诱导以表达CRTH2受体的细胞,例如经(例如)丁酸处理的HL-60或AML14.3D10细胞(Sawyer等人,Br J Pharmacol,2002,137:1163-72)或经工程改造以表达重组CRTH2受体的细胞系,例如L1.2、CHO、HEK-293、K562或CEM细胞(Liu等人,Bioorg Med Chem Lett,2009,19:6840-4;Sugimoto等人,Pharmacol Exp Ther,2003,305:347-52;Hata等人,Mol Pharmacol,2005,67:640-7;Nagata等人,FEBS Lett,1999,459:195-9)。
最后,在所述分析中可利用血液或组织细胞,例如使用如Hansel等人,J ImmunolMethods,1991,145,105-110所述方法分离得到的人外周血嗜酸性粒细胞、或如Xue等人,JImmunol,2005,175:6531-6所述分离及处理得到的人Th2细胞、或如Monneret等人,JPharmacol Exp Ther,2005,312:627-34所述分离及表征得到的人嗜碱性粒细胞。
具体而言,在上述分析中本发明化合物具有结合CRTH2受体的活性且通过CRTH2配体来抑制CRTH2活化。本文所用“活性”欲指,当在上述分析中进行测量时,化合物在1μM下表现出50%抑制或更高抑制、或Ki值<1μM。此结果指示化合物作为CRTH2受体活性抑制剂的固有活性。所选化合物的拮抗活性显示于下文表1和表2中。
表1:式Ia”化合物
表2:式Ib”化合物
Claims (6)
2.如权利要求1的吡唑化合物在制备用于治疗与CRTH2活性有关的疾病的药物中的用途。
3.如权利要求1的吡唑化合物在制备用于预防和/或治疗炎性、感染性及免疫调节性病症,呼吸道或胃肠道疾病或病症,以及鼻咽、眼睛及皮肤的过敏性疾病的药物中的用途。
4.如权利要求3所述的用途,其中所述炎性病症为关节的炎性疾病。
5.药物制剂,其含有一种或多种如权利要求1的吡唑化合物。
6.药物制剂,其含有一种或多种如权利要求1的吡唑化合物以及一种或多种选自以下的活性物质:β模拟物、抗胆碱能药、皮质类固醇、PDE4抑制剂、LTD4拮抗剂、EGFR抑制剂、CCR3拮抗剂、CCR5拮抗剂、CCR9拮抗剂、5-LO抑制剂、组胺受体拮抗剂、SYK抑制剂及磺胺类药物。
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