CN1938274A - 用作趋化因子调节剂(ccr)的新哌啶化合物 - Google Patents
用作趋化因子调节剂(ccr)的新哌啶化合物 Download PDFInfo
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- CN1938274A CN1938274A CNA2005800103948A CN200580010394A CN1938274A CN 1938274 A CN1938274 A CN 1938274A CN A2005800103948 A CNA2005800103948 A CN A2005800103948A CN 200580010394 A CN200580010394 A CN 200580010394A CN 1938274 A CN1938274 A CN 1938274A
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- 229950009638 tepoxalin Drugs 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- JKAXJUVESNNXEG-UHFFFAOYSA-N tert-butyl 5-bromo-2-chlorobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC(Br)=CC=C1Cl JKAXJUVESNNXEG-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- BJORNXNYWNIWEY-UHFFFAOYSA-N tetrahydrozoline hydrochloride Chemical compound Cl.N1CCN=C1C1C2=CC=CC=C2CCC1 BJORNXNYWNIWEY-UHFFFAOYSA-N 0.000 description 1
- 229940021790 tetrahydrozoline hydrochloride Drugs 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- ZFEAMMNVDPDEGE-LGRGJMMZSA-N tifuvirtide Chemical compound C([C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(C)=O)[C@@H](C)CC)[C@@H](C)O)[C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)C1=CC=C(O)C=C1 ZFEAMMNVDPDEGE-LGRGJMMZSA-N 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
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- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 1
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- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
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- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
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Abstract
式(I)化合物为趋化因子(例如CCR3)活性的调节剂(用于,例如,治疗哮喘)。
Description
本发明涉及具有药物活性的哌啶衍生物、所述衍生物的制备方法、包含这些衍生物的药物组合物以及这些衍生物作为活性治疗药物的用途。
药物活性的N-(2-羟基丙-1-基)哌啶衍生物已在03/068743中公开。
组胺为一种碱性胺,2-(4-咪唑基)-乙胺,由组氨酸脱羧酶作用从组氨酸形成。在身体的绝大多数组织中存在,但以高浓度存在于肺、皮肤和胃肠道中。在细胞水平的炎性细胞如肥大细胞和嗜碱性粒细胞中存储大量的组胺。目前已经认识到肥大细胞和嗜碱性粒细胞的脱粒以及随后的组胺释放是产生过敏过程临床表现的基本机理。组胺通过影响特定的组胺G-蛋白偶联受体而发挥其作用,所述受体有3种主要类型-H1、H2和H3。组胺H1拮抗剂包括用于治疗患过敏性疾病尤其是鼻炎和荨麻疹病人的大多数药物种类。H1拮抗剂可用于控制过敏反应,通过例如阻滞组胺对后毛细管小静脉平滑肌的作用,导致降低脉管渗透性、渗出和水肿。该拮抗剂也阻断组胺对H1受体对c型痛觉神经纤维的作用,使发痒和打喷嚏减轻。
趋化因子是由各种细胞释放的将巨噬细胞、T细胞、嗜酸性粒细胞、嗜碱性粒细胞以及嗜中性粒细胞吸引到炎症部位的趋化细胞因子,其还在免疫系统细胞的成熟中发挥作用。趋化因子在多种疾病和失调的免疫和炎性反应中发挥中重要作用,这些疾病和失调包括哮喘和过敏性疾病,以及自身免疫性疾病(如类风湿性关节炎)和动脉粥样硬化。这些小的分泌分子属于不断增加的8-14kDa蛋白超家族,该家族特征为保守的4个半光氨酸基序。趋化因子超家族可分成两类主要家族,分别显示出特征性结构基序Cys-X-Cys(C-X-C,或α)和Cys-Cys(C-C,或β)。根据NH-附近的半光氨酸残基对之间插入的单个氨基酸和序列相似性来区分这两个家族。
C-X-C趋化因子包括嗜中性粒细胞的几种强效的化学引诱物和活化剂,如白介素-8(IL-8)和嗜中性粒细胞活化肽2(NAP-2)。
C-C趋化因子包括单核细胞和淋巴细胞(但不包括嗜中性粒细胞)的强效化学引诱物,如人单核细胞趋化蛋白1-3(MCP-1,MCP-2和MCP-3),RANTES(调节活化、正常T表达和分泌)、嗜酸细胞活化趋化因子以及巨噬细胞炎性蛋白1α和1β(MIP-1α和MIP-1β)。
研究表明趋化因子的作用通过G蛋白-偶联受体亚族介导,其中将这些受体称为CCR1、CCR2、CCR2A、CCR2B、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CXCR1、CXCR2、CXCR3和CXCR4。由于调节这些受体的药物可用于治疗上述提及的那些疾病和失调,因此这些受体为较好的药物开发目标。
已知病毒感染会引起肺炎。实验表明普通感冒会增加气道中嗜酸细胞活化趋化因子粘膜分泌。将嗜酸细胞活化趋化因子滴注到鼻腔会产生类似于普通感冒的一些征兆和症状(参见Greiff L等人,Allergy(1999)54(11)1204-8[Experimental common cold increase mucosal output ofeotaxin in atopic individuals]和Kawaguchi M等人,Int.Arch.Allergy Immunol.(2000)122 S1 44[Expression of eotaxin by normal airway epithelial cells aftervirus A infection])。
本发明的化合物可用于治疗CCR3介导的疾病状态(如哮喘和/或鼻炎)并且对CCR3受体相对于存在哺乳动物中的其他受体如G-蛋白偶联受体(例如:α1肾上腺素受体以及5HT2B受体)以及离子通道(例如:人ether-a-go-go-相关基因(hERG)钾通道)而言,显示良好的特异性(例如100-倍的活性差异)。
本发明提供了式(I)化合物:
其中:
R1为任选被卤素、氰基、C1-4烷基或C1-4卤代烷基取代的苯基;
R2为氢、C1-6烷基或C3-6环烷基;以及,
R3为具有NH或OH的基团,其计算或测量的pKa为1.0~8.0;
或可药用盐。
本发明的某些化合物可存在不同的异构体形式(如对映体、非对映体、几何异构体或互变异构体)。本发明覆盖这些异构体和其所有比例的混合物。
合适的盐包括酸加成盐,例如盐酸盐、二盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、乙酸盐、二乙酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、草酸盐、甲磺酸盐或对甲苯磺酸盐。盐还包括金属盐,如碱金属盐(例如钠或钾盐)或碱土金属盐(例如镁或钙)。
本发明化合物可以溶剂化物(如水合物)存在,本发明包含所有这些溶剂化物。
式(I)化合物的pKa利用ACD/Labs 6.00软件计算,所述的软件由Advanced Chemistry Development Inc,90 Adelaide Street,West Toronto,Ontario,Canada提供。式(I)化合物的pKa利用下述描述的方法之一测量。
卤素为,例如,氟或氯。
烷基及部分是直链或支链,并为例如甲基、乙基、正丙基、异丙基或叔丁基。
环烷基为单环的,并且为例如,环丙基、环戊基或环己基。
卤代烷基为带有一或多个(如1~6个)卤素(如氯或氟原子)的烷基,并且,例如,为CF3、CH2CF3或C2F5。
氟代烷基为带有一或多个(如1~6个)氟原子的烷基,并且为例如,CH2F、CF3、CH2CF3或C2F5。
在一方面,本发明提供了式(I)化合物,其中R1为任选被卤素、氰基或C1-4烷基取代的苯基。
在另一方面,本发明提供了式(I)化合物,其中R1为被卤素(如氟或氯)、氰基或C1-4烷基(如甲基)中的一个、两个或三个基团取代的苯基;例如R1为被氟、氯、甲基或氰基中的一个、两个或三个取代的苯基。在另一方面,R1为被氟、氯、氰基或甲基(如氯、氰基或甲基)中的一个、两个或三个(如两个或三个)取代的苯基。R1为,例如,3,4-二氯苯基、2-甲基-3-氯-4-氰基苯基、2-甲基-4-氯苯基、3-甲基-2,4-二氯苯基、2-甲基-3,4-二氯苯基、3-氯-4-氰基苯基、3,4-二氟苯基、3-氟-4-氯苯基或4-氯苯基(如2-甲基-4-氯苯基、3-甲基-2,4-二氯苯基、2-甲基-3,4-二氯苯基、3-氯-4-氰基苯基、3,4-二氟苯基、3-氟-4-氯苯基或4-氯苯基)。在另一方面,R1为3,4-二氯苯基或3-氯-4-氰基苯基。
在本发明的另一方面,R1为被氯或甲基中的一个和多个取代并任选进一步被氟取代的苯基。例如R1为2-甲基-4-氯苯基、3-甲基-2,4-二氯苯基、2-甲基-3,4-二氯苯基、3-氟-4-氯苯基、4-氯苯基或3,4-二氯苯基。
在另一方面,R1为3,4-二氯苯基、2-甲基-4-氯苯基、3-甲基-2,4-二氯苯基、2-甲基-3,4-二氯苯基或2-甲基-3-氯-4-氰基苯基。
在另一方面,本发明提供了式(I)化合物,其中R2为氢或C1-4烷基(如甲基)。
在本发明另一方面,R2为氢。
R3的酸性NH(即NH的计算或测量的pKa为1.0~8.0)可为环的一部分或可为在芳基或杂环基环上的取代基的一部分。R3的酸性OH(即OH的计算或测量的pKa为1.0~8.0)可为取代基或在芳基或杂环基环上的取代基的一部分(如羧基中的OH)。因此,例如,R3的酸性OH可为酸性苯酚、羧酸,或羟基芳香杂环基(如羟基吡啶,其可互变为吡啶酮)中的一部分。
芳基包括任选被取代的苯基和萘基。
杂环基为任选被取代的芳香的或非芳香的5-或6-员环,必要的时候,包括至少一个选自氮、氧和硫的杂原子;或其N-氧化物,或S-氧化物或S-二氧化物。杂环基为,例如,呋喃基、噻吩基(已知也为thiophenyl)、吡咯基、2,5-二氢吡咯基、噻唑基(例如在2-氧代-2,3-二氢-1,3-噻唑基中)、异噻唑基、吡唑基、唑基、异唑基、咪唑基、三唑基(例如在1H-1,2,3-三唑基中)、吡啶基(例如在6-氧代-1,6-二氢-吡啶基中)或嘧啶基。
在本发明一方面,R3的酸性NH为被合适取代的环的一部分(例如为吡咯基、2,5-二氢吡咯基、噻唑基、异噻唑基、吡唑基、唑基、异唑基、咪唑基、三唑基、吡啶基或嘧啶基环一部分)或在被合适取代的芳基(例如苯基或萘基)或被合适取代的杂环基(例如呋喃基、噻吩基、吡咯基、2,5-二氢吡咯基、噻唑基、异噻唑基、吡唑基、唑基、异唑基、咪唑基、三唑基、吡啶基或嘧啶基)环上的取代基的一部分。
在本发明的另一方面,R3的酸性OH为在被合适取代的芳基(例如苯基或萘基)或被合适取代的杂环基(例如呋喃基、噻吩基、吡咯基、2,5-二氢吡咯基、噻唑基、异噻唑基、吡唑基、唑基、异唑基、咪唑基、三唑基、吡啶基或嘧啶基)环上的取代基或取代基的一部分(如羧基上的OH)。因此,例如,R3的酸性OH可为酸性苯酚(取代的或未被取代的),在羧酸中,或在被合适取代的羟基芳香杂环基(如羟基吡啶,其可互变为吡啶酮)中的一部分。被合适取代的羟基芳香杂环基的其他的实例包括羟基喹啉、羟基异喹啉和羟基苯并咪唑。
在本发明另一方面,当R3的酸性NH为被合适取代的环的一部分的时候,其为,例如2-氧代-噻唑-5-基、2-氧代-唑-5-基、2-氧代-咪唑-5-基、1H-1,2,3-三唑-4-基、4-氧代-1H-1,4-二氢吡啶-3-基、2,6-二氧代-1H-1,2,3,6-四氢嘧啶-4-基、6-氧代-1H-1,6-二氢吡啶-3-基或2H-四唑-5-基环的一部分。
在本发明的另一方面,当R3的酸性NH为被合适取代的环的一部分的时候,其为,例如,2-氧代-噻唑-5-基、1H-1,2,3-三唑-4-基或6-氧代-1H-1,6-二氢吡啶-3-基环的一部分。
在本发明的另一方面,当R3的酸性NH为取代基的一部分的时候,其为,例如,NHS(O)2(C1-4烷基)的一部分。
另一方面,本发明提供了式(I)化合物,其中R3为具有NH或OH的基团,具有计算或测量的pKa为3~6.5。
在另一方面,本发明提供了式(I)化合物,其中R3为具有NH或OH的基团,具有计算或测量的pKa为1.0~8.0(例如3~6.5),基团R3为,例如,
●2-氧代-噻唑-5-基,在4-位具有合适的吸电子取代基{如C1-4氟代烷基(例如CF3、CH2CF3或C2F5)、芳基(例如4-氟苯基)、杂环基(例如吡啶基)或基团CH2S(O)2(C1-4烷基)};
●2-氧代-唑-5-基,在4-位具有合适的吸电子取代基{如C1-4氟代烷基(例如CF3、CH2CF3或C2F5)或CH2S(O)2(C1-4烷基)};
●1H-1,2,3-三唑-4-基,在5-位具有合适的取代基{如C1-4烷基(例如CH3或CH(CH3)2)、C3-6环烷基(例如环丙基)、C1-4氟代烷基(例如CF3、CH2CF3或C2F5)、S-R4(其中R4为C1-4烷基[例如CH3]、C1-4氟代烷基[例如CF3、CH2CF3或C2F5]或C3-6环烷基[例如环丙基])、NHS(O)2(C1-4烷基)、N(C1-4烷基)S(O)2(C1-4烷基)、芳基(例如4-氟苯基)、杂环基(例如吡啶基)或基团CH2S(O)2(C1-4烷基)};
●4-氧代-1H-1,4-二氢吡啶-3-基,在2-位具有合适的吸电子取代基{如C1-4氟代烷基(例如C2F5、CF3)};
●2,6-二氧代-1H-1,2,3,6-四氢嘧啶-4-基,在3-位具有合适的取代基{如C1-4烷基(例如CH3)、C3-6环烷基(例如环丙基)或CH2(C1-3氟代烷基)(例如CH2CF3)},并且任选在一个或多个其他的环位置被取代;
●6-氧代-1H-1,6-二氢吡啶-3-基,在2-位和/或5-位具有合适的吸电子取代基{如C1-4氟代烷基(例如CF3、CH2CF3或C2F5)、氰基或苯基},并且任选在一个或多个其他的环位置被取代;
●6-氧代-1H-1,6-二氢吡啶-3-基,在环氮上具有CH2CO2H,并且任选在一个或多个其他的环位置被取代;
●2H-四唑-5-基;
●在任选被取代的苯基、任选被取代的CH2O苯基、任选被取代的萘基环或任选被取代的酰化的(如被C(O)(C1-4烷基)酰化的)二氢异喹啉环上的CO2H、CH2CO2H或OCH2CO2H基团;或者,
●在任选被取代的芳香杂环基环(例如吡啶基、嘧啶基或噻唑基)上的NHS(O)2(C1-4烷基)(例如NHS(O)2CH3)基团;
或者,当可能的时候,其互变体。
在本发明一方面,酰化的(如被C(O)(C1-4烷基)酰化的)二氢异喹啉基在7位上带有CO2H、CH2CO2H或OCH2CO2H基团。
在另一方面,本发明提供了式(I)化合物,其中R3为具有NH或OH的基团,具有计算或测量的pKa为1.0~8.0(例如3~6.5),基团R3为,例如,
●2-氧代-噻唑-5-基,在4-位具有合适的吸电子取代基{如C1-4氟代烷基(例如CF3、CH2CF3或C2F5)、芳基(例如4-氟苯基)、杂环基(例如吡啶基)或基团CH2S(O)2(C1-4烷基)};
●2-氧代-唑-5-基,在4-位具有合适的吸电子取代基{如C1-4氟代烷基(例如CF3、CH2CF3或C2F5)或CH2S(O)2(C1-4烷基)};
●1H-1,2,3-三唑-4-基,在5-位具有合适的取代基{如C1-4烷基(例如CH3)、C3-6环烷基(例如环丙基)、C1-4氟代烷基(例如CF3、CH2CF3或C2F5)、S-R4(其中R4为C1-4烷基[例如CH3]、C1-4氟代烷基[例如CF3、CH2CF3或C2F5]或C3-6环烷基[例如环丙基])、NHS(O)2(C1-4烷基)、芳基(例如4-氟苯基)、杂环基(例如吡啶基)或基团CH2S(O)2(C1-4烷基)};
●4-氧代-1H-1,4-二氢吡啶-3-基,在2-位具有合适的吸电子取代基{如C1-4氟代烷基(例如C2F5、CF3)};
●2,6-二氧代-1H-1,2,3,6-四氢嘧啶-4-基,在3-位具有合适的取代基{如C1-4烷基(例如CH3)、C3-6环烷基(例如环丙基)或CH2(C1-3氟代烷基)(例如CH2CF3)};
●6-氧代-1H-1,6-二氢吡啶-3-基,在2-位或5-位具有合适的吸电子取代基{如C1-4氟代烷基(例如CF3、CH2CF3或C2F5)或氰基},并任选在其他的位置被取代;
●2H-四唑-5-基;
●在任选被取代的苯基或萘基环上的CO2H;或者,
●在任选被取代的芳香杂环基环(例如吡啶基、嘧啶基或噻唑基)上的NHS(O)2(C1-4烷基)(例如NHS(O)2CH3)基团;
或者,当可能的时候,其互变体。
如上所示,R3中的杂环基环可任选被取代,其可任选被下述基团取代,例如:氟、氯、溴、C1-4烷基(例如甲基)、C3-6环烷基(例如环丙基)、C1-4氟代烷基(例如CF3、CH2CF3或C2F5)、S-R4(其中R4为C1-4烷基[例如CH3]、C1-4氟代烷基[例如CF3、CH2CF3或C2F5]或C3-6环烷基[例如环丙基])、氰基、S(O)2(C1-4烷基)(例如S(O)2CH3)或S(O)2NH(C1-4烷基)(例如S(O)2NHCH3)。
如上所示,R3中的苯基或萘基环可任选被取代,其可任选被下述基团取代,例如,卤素、氰基、C1-4烷基、C1-4烷氧基、C1-4氟代烷基(例如CF3、CH2CF3或C2F5)}、OCF3、SCF3、硝基、S(C1-4烷基)、S(O)(C1-4烷基)、S(O)2(C1-4烷基)、S(O)2NH(C1-4烷基)、S(O)2N(C1-4烷基)2、NHC(O)(C1-4烷基)、NHS(O)2(C1-4烷基)。
在本发明一方面,R3为
●2-氧代-噻唑-5-基,在4-位具有C1-4氟代烷基(例如CF3、CH2CF3或C2F5);
●1H-1,2,3-三唑-4-基,在5-位具有合适的取代基{如C1-4烷基(例如CH3)或S-R4(其中R4为C1-4氟代烷基[例如CF3、CH2CF3或C2F5])};
●2,6-二氧代-1H-1,2,3,6-四氢嘧啶-4-基,在3-位具有合适的取代基{如C1-4烷基(例如CH3)或C1-4氟代烷基(例如CF3、CH2CF3或C2F5)};
●6-氧代-1H-1,6-二氢吡啶-3-基,在2-位或5-位具有合适的吸电子取代基{如C1-4氟代烷基(例如CF3、CH2CF3或C2F5)或氰基},并在其他的位置任选被取代;
●在任选被取代的萘基环上的CO2H;或者
●在任选被取代的芳香杂环基环(例如吡啶基、嘧啶基或噻唑基)上的NHS(O)2(C1-4烷基)(例如NHS(O)2CH3);
或者,当可能的时候,其互变体;任选的取代基如上定义。
在另一方面,本发明提供了式(I)化合物,其中R3为:
●2-氧代-噻唑-5-基,在4-位具有合适的吸电子取代基{如C1-4氟代烷基(例如CF3、CH2CF3或C2F5)、苯基(例如4-氟苯基)或杂环基(例如吡啶基)};
●1H-1,2,3-三唑-4-基,在5-位具有合适的取代基{如C1-4烷基(例如CH3或CH(CH3)2)、C1-4氟代烷基(例如CF3、CH2CF3或C2F5)、S-R4(其中R4为C1-4烷基[例如CH3]或C1-4氟代烷基[例如CF3、CH2CF3或C2F5])、N(C1-4烷基)S(O)2(C1-4烷基)或苯基(例如4-氟苯基)};或者
●6-氧代-1H-1,6-二氢吡啶-3-基,在2-位或5-位具有C1-4氟代烷基(例如CF3、CH2CF3或C2F5)或氰基。
在另一方面,本发明提供了式(I)化合物,其中R3为:
●2-氧代-噻唑-5-基,在4-位具有CF3或C2F5;
●1H-1,2,3-三唑-4-基,在5-位具有CF3、C2F5、SCF3、SCH2CF3或SC2F5(例如CF3或SCH2CF3);或者,
●6-氧代-1H-1,6-二氢吡啶-3-基,在2-位具有CF3或C2F5。
在另一方面,本发明提供了式(I)化合物,其中2-羟基具有如下所示的立体化学:
本发明的化合物在下述实施例中举例说明。
本发明的化合物可利用在现有技术(例如WO03/068743)中描述的方法或类似的方法进行制备。所述方法的中间体可利用在现有技术(例如WO03/068743)中描述的方法或类似的方法进行制备。
式(I)化合物可通过将式(II)的化合物:
其中R1和R2如上定义,与式(III)的化合物反应制备得到:
其中L1为离去基(例如羟基或氯离去基),并且R3如上定义;反应在碱(例如三(C1-6烷基)胺碱(如三乙基胺或二异丙基乙基胺)或N,N-二甲基甲酰胺)存在下,在合适的溶剂(例如N,N-二甲基甲酰胺,四氢呋喃、二氯甲烷或二烷,或这些溶剂中的一种和多种的混合物)存在下,任选地在偶联剂(例如溴-三-吡咯烷基鏻六氟磷酸盐,PyBrOP或O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐)存在下。
式(II)的化合物可按照在WO00/58305或WO01/77101中记载的方法制备得到,或通过将式(IV)的化合物:
其中R1如上定义:
(i)与式(V)的化合物反应:
其中L2为离去基(例如氯或硝基苯磺酰氧基{3-NO2-C6H4-S(O)2O-}),然后用氨、胺R2-NH2或叠氮化钠反应,并随后用例如三苯基膦反应;或者
(ii)与式(VI)的化合物反应:
其中P1和P2,单独地或一起,为合适的保护基(例如一起形成邻苯二甲酰亚胺),或P1或P2为R2,然后用脱保护,例如当P1和P2形成邻苯二甲酰亚胺的时候,利用肼。
式(V)的化合物可通过商业途径获得或利用在文献中记载的方法制备得到。
式(VI)的化合物可通过将(R)或(S)缩水甘油在Mitsunobu反应条件下,与例如,邻苯二甲酰亚胺、1,1-(偶氮二羰基)二哌啶以及三丁基膦(TetrahedronLett.1993,34,1639)反应。
此外,式(I)化合物可通过如上描述的路线、在现有技术中描述的方法或下述实施例的改良方法制备得到。如上确定的中间体可通过商业途径获得或利用或改良在现有技术中描述的方法制备得到。
另一方面,本发明提供了制备式(I)化合物的方法。
本发明的化合物具有药物的活性,尤其可作为趋化因子受体(例如CCR3)活性的调节剂,并且可用于治疗自身免疫性疾病、炎症、增生性或高度增生性疾病,或免疫介导的疾病(包括移植器官或组织的排斥以及获得性免疫缺陷综合征(AIDS))。
这些疾病的实例为:
(1)(呼吸道)气道阻塞性疾病包括:慢性阻塞性肺病(COPD)(如不可逆COPD);哮喘{如支气管、过敏性、内源性、外源性或粉尘性哮喘,特别是慢性或成癖哮喘(如迟发性哮喘或气道高反应性)};支气管炎{如嗜酸性支气管炎);急性、过敏性、萎缩性鼻炎或慢性鼻炎包括干酪性鼻炎、肥厚性鼻炎、化脓性鼻炎、干燥性鼻炎或药物性鼻炎;膜性鼻炎包括格鲁布性鼻炎、纤维蛋白性鼻炎或假膜性鼻炎或腺病性鼻炎;季节性鼻炎包括神经性鼻炎(枯草热)或血管运动性鼻炎;肉样瘤病;农夫肺以及相关疾病;鼻息肉病;纤维化肺,特发性间质性肺炎;镇咳药活性,气道炎性疾病相关的慢性咳嗽或医源性咳嗽的治疗;
(2)(骨和关节)关节炎包括类风湿性关节炎、感染性关节炎、自身免疫性关节炎,血清反应阴性脊椎关节病(如强直性脊柱炎、牛皮癣性关节炎和莱特氏病),贝切特(氏)病,斯耶格伦(氏)综合征以及全身性硬化症;
(3)(皮肤和眼睛)牛皮癣、特应性皮炎、接触性皮炎或其他湿疹性皮炎、脂溢性皮炎、扁平红苔癣、天疱疮、大疱性天疱疮、大疱性表皮松解、荨麻疹、血管性水肿、血管炎红斑、皮肤酸性细胞过多、葡萄膜炎、局部性脱发症以及春季结膜炎;
(4)(胃肠道)腹部疾病、直肠炎、嗜酸性肠胃炎、肥大细胞病、节段性回肠炎、溃疡性结肠炎、过敏性肠疾病或具有远离肠的效应的食物相关的过敏症(例如,偏头痛、鼻炎以及湿疹);
(5)(同种异体移植物排斥)慢性和急性的下列移植,例如,肾、心脏、肝、肺、骨髓、皮肤或角膜的移植;或慢性移植物抗宿主病;和/或
(6)(其他组织和疾病)阿耳茨海默(氏)病、多发性硬化症、动脉粥样硬化、获得性免疫缺陷综合征(AIDS)、狼疮病(如红斑狼疮或全身性狼疮)、全身性红斑狼疮、桥本(氏)甲状腺炎、重症肌无力、I型糖尿病、肾病综合征、嗜酸性细胞增多筋膜炎、高IgE综合征、麻风病(如瘤型麻风)、牙周病、塞泽里综合征、先天性血小板减少紫癜或月经周期失调。
本发明的化合物也是H1拮抗剂(因此可用于治疗过敏性疾病)。
本发明的化合物还可以用来控制通常称为感冒的症状和/或征兆(例如普通感冒或流感或其他关联的呼吸系统病毒感染的症状和/或征兆)。
根据本发明的另一特征,提供了用于通过治疗(包括预防)治疗温血动物(例如人)的式(I)化合物或其可药用盐。
根据本发明的其他的特征,提供了一种用于调节需要所述治疗的温血动物(如人)中趋化因子受体活性(例如CCR3受体活性),或拮抗H1的方法,所述的方法包括向所述的动物给药治疗有效量的式(I)化合物或其可药用盐。
本发明还提供了用作药物的式(I)化合物或其可药用盐。
另一方面,本发明提供了式(I)化合物或其可药用盐在制备用于治疗(例如调节温血动物如人中趋化因子受体活性(如CCR3受体活性或者拮抗H1)的药物上的用途。
本发明还提供了式(I)化合物或其可药用盐在制备用于治疗温血动物(如人)的下列疾病的药物中的用途:
(1)(呼吸道)气道阻塞性疾病包括:慢性阻塞性肺病(COPD)(如不可逆COPD);哮喘{如支气管、过敏性、内源性、外源性或粉尘性哮喘,特别是慢性或成癖哮喘(如迟发性哮喘或气道高反应性)};支气管炎{如嗜酸性支气管炎);急性、过敏性、萎缩性鼻炎或慢性鼻炎包括干酪性鼻炎、肥厚性鼻炎、化脓性鼻炎、干燥性鼻炎或药物性鼻炎;膜性鼻炎包括格鲁布性鼻炎、纤维蛋白性鼻炎或假膜性鼻炎或腺病性鼻炎;季节性鼻炎包括神经性鼻炎(枯草热)或血管运动性鼻炎;肉样瘤病;农夫肺以及相关疾病;鼻息肉病;纤维化肺,特发性间质性肺炎;镇咳药活性,气道炎性疾病相关的慢性咳嗽或医源性咳嗽的治疗;
(2)(骨和关节)关节炎包括类风湿性关节炎、感染性关节炎、自身免疫性关节炎,血清反应阴性脊椎关节病(如强直性脊柱炎、牛皮癣性关节炎和莱特氏病),贝切特(氏)病,斯耶格伦(氏)综合征以及全身性硬化症;
(3)(皮肤和眼睛)牛皮癣、特应性皮炎、接触性皮炎或其他湿疹性皮炎、脂溢性皮炎、扁平红苔癣、天疱疮、大疱性天疱疮、大疱性表皮松解、荨麻疹、血管性水肿、血管炎红斑、皮肤酸性细胞过多、葡萄膜炎、局部性脱发症以及春季结膜炎;
(4)(胃肠道)腹部疾病、直肠炎、嗜酸性肠胃炎、肥大细胞病、节段性回肠炎、溃疡性结肠炎、过敏性肠疾病或具有远离肠的效应的食物相关的过敏症(例如,偏头痛、鼻炎以及湿疹);
(5)(同种异体移植物排斥)慢性和急性的下列移植,例如,肾、心脏、肝、肺、骨髓、皮肤或角膜的移植;或慢性移植物抗宿主病;和/或
(6)(其他组织和疾病)阿耳茨海默(氏)病、多发性硬化症、动脉粥样硬化、获得性免疫缺陷综合征(AIDS)、狼疮病(如红斑狼疮或全身性狼疮)、全身性红斑狼疮、桥本(氏)甲状腺炎、重症肌无力、I型糖尿病、肾病综合征、嗜酸性细胞增多筋膜炎、高IgE综合征、麻风病(如瘤型麻风)、牙周病、塞泽里综合征、先天性血小板减少紫癜或月经周期失调。
另一方面,本发明提供了式(I)化合物或其可药用盐,可用于治疗哮喘{如支气管、过敏性、内源性、外源性或粉尘性哮喘,特别是慢性或成癖哮喘(如迟发性哮喘或气道高反应性)};或鼻炎{包括急性、过敏性、萎缩性或慢性鼻炎,如干酪性鼻炎、肥厚性鼻炎、化脓性鼻炎、干燥性鼻炎或药物性鼻炎;膜性鼻炎包括膜性鼻炎包括格鲁布性鼻炎、纤维蛋白性鼻炎或假膜性鼻炎或腺病性鼻炎;季节性鼻炎包括神经性鼻炎(枯草热)或血管运动性鼻炎}。
另一方面,式(I)化合物或其可药用盐可用于治疗哮喘。
本发明还提供了式(I)的化合物或其可药用盐在制备用于治疗哮喘或鼻炎的药物中的用途。
本发明还提供了一种治疗温血动物如人中趋化因子介导的疾病状态(例如CCR3介导的疾病状态,如哮喘)的方法,所述的方法包括向所述的动物给药治疗有效量的式(I)化合物或其可药用盐。
为了使用本发明的化合物或其可药用盐用于治疗温血动物(如人),尤其是用于调节趋化因子受体活性(例如CCR3受体活性),或拮抗H1,所述的成分通常按照标准的制药规范配制成药物组合物。
因此,另一方面本发明提供了一种药物组合物,其包含式(I)化合物,或其可药用盐(活性成分),以及可药用辅剂、稀释剂或载体。另一方面,本发明提供了一种制备所述组合物的方法,包括将活性成分与可药用辅剂、稀释剂或载体进行混合。取决于给药方式,药物组合物例如包含0.05-99%w(重量百分比)、如0.05-80%w、如0.10-70%w、0.10-50%w的活性成分,所有的重量百分比基于总的组合物。
本发明药物组合物可按标准方式对需要治疗的疾病进行给药,例如通过局部(如到肺和/或气道或到皮肤)、口服、直肠或肠胃外给药。为了达到这种目的,本发明化合物可按照本技术领域公知的方式配制成例如气雾剂、干粉制剂、片剂、胶囊、糖浆剂、散剂、颗粒剂、水性或者油性溶液或者悬浮液、(液体)乳剂、可分散散剂、栓剂、软膏剂、乳膏剂、滴剂以及无菌注射水性或者油性溶液或者悬浮剂的形式。
本发明的适宜的药物组合物是一种适于口服的单位剂型,例如包含0.1mg-1g活性成分的片剂或胶囊。
在另一方面本发明的药物组合物为适于静脉内、皮下或肌肉内给药的形式。
每位患者可以例如接受剂量为0.01mgkg-1-100mgkg-1化合物的静脉内、皮下或者肌肉内剂量,优选地为0.1mgkg-1-20mgkg-1的活性成分,组合物每天给药1-4次。或者,静脉内剂量可以一段时间内的连续输液给予。或者,每个患者可接受约相当于每日胃肠外剂量的日口服剂量,该组合物每日分1-4次给予。
本发明还涉及组合疗法或组合物,其中式(I)的化合物,或其可药用盐,或包括式(I)的化合物,或其可药用盐的药物组合物,与用于治疗上述任一种疾病状态的的药物同时地(可能地在同样的组合物中)或先后地给药。
具体地,为了治疗类风湿性关节炎、牛皮癣、炎症性肠病、过敏性肠综合征、COPD、哮喘、过敏性鼻炎的炎性疾病,本发明的化合物可以与药物如TNF-α抑制剂(如抗-TNF单克隆抗体(如Remicade,CDP-870和D2E7)或TNF受体免疫球蛋白分子(如Enbrel.reg.),);非选择性的COX-1/COX-2抑制剂(如吡罗昔康、双氯芬酸;丙酸如萘普生、氟苯布洛芬、非诺洛芬、酮基布洛芬和布洛芬;灭酸如甲灭酸、消炎痛、舒林酸、阿扎丙宗;吡唑酮如保泰松;或水杨酸酯如乙酰水杨酸)、COX-2抑制剂(如美洛昔康、塞来昔布、罗非克西、伐地考昔和艾托考昔)低剂量氨甲蝶呤、lefunomide;环索奈德;羟氯奎,d-青霉胺,金诺芬或肠胃外或口服金制剂(parenteral oralgold)合用。
本发明还涉及本发明的化合物与下述药物的组合
●白细胞三烯生物合成抑制剂,5-脂肪氧合酶(5-LO)抑制剂或5-脂肪氧合酶活化蛋白(FLAP)拮抗剂如齐留通;ABT-761;芬留顿;替泊沙林;Abbott-79175;Abbott-85761;N-(5-取代的)-噻吩-2-烷基磺酰胺;2,6-二-叔-丁基苯酚腙;甲氧基四氢吡喃如Zeneca ZD-2138;SB-210661;吡啶-取代的-2-氰基萘化合物如L-739,010;2-氰基喹啉化合物如L-746,530;吲哚和喹啉化合物如MK-591,MK-886或BAY×1005;
●白细胞三烯LTB4、LTC4、LTD4和LTE4受体拮抗剂,所述拮抗剂选自吩噻嗪-3-酮如L-651,392;脒基化合物如CGS-25019c;苯并噁胺(benzoxalamines)如昂唑司特;benzenecarboximidamides如BIIL 284/260;和化合物如扎鲁司特、阿鲁司特、孟鲁司特、普仑司特、维鲁司特(MK-679)、RG 12525、Ro-245913、伊拉司特(CGP 45715A)或BAY×7195;
●PDE4抑制剂包括同工型PDE4D抑制剂;
●抗组胺的H1受体拮抗体如西替利嗪、氯雷他定、地氯雷他定、非索非那定、阿司咪唑、氮卓司丁和氯苯那敏;
●保护肠胃的H2受体拮抗剂;
●α1和α2肾上腺素能受体激动剂收缩血管的拟交感神经药物,如丙己君、苯肾上腺素、苯丙醇胺、伪麻黄碱、盐酸萘甲唑啉、盐酸氧甲唑啉、盐酸四氢唑啉、盐酸木甲唑啉和盐酸乙基去甲肾上腺素;
●抗胆碱能药物如异丙托溴铵、噻托溴铵;氧托溴铵;哌仑西平;和替仑西平;
●β1-至β4-肾上腺素能受体激动剂如间羟异丙肾上腺素、异丙基肾上腺素、喘息定、沙丁胺醇、沙丁胺醇、福莫特罗、沙美特罗、特布他林、奥西那林、甲磺酸双甲苯喘定或者吡布特罗;或甲基黄嘌呤包括茶碱和氨茶碱;色甘酸钠;或毒蕈碱受体(M1、M2和M3)拮抗剂;
●胰岛素-类生长因子I型(IGF-1)模拟物;
●具有降低的全身副作用的吸入糖皮质激素,如强的松、氢化泼尼松、氟尼缩松、曲安缩松、二丙酸氯地米松、布地奈德、丙酸氟替卡松和莫米松糠酸酯;
●基质金属蛋白酶(MMPs)抑制剂,如,基质溶解素,胶原蛋白酶,或明胶酶以及aggrecanase;如胶原酶-1(MMP-1)、胶原酶-2(MMP-8)、胶原酶-3(MMP-13)、溶质基素-1(MMP-3)、溶质基素-2(MMP-10)和溶质基素-3(MMP-11)或MMP-12;
●其它的趋化因子受体如CCR1、CCR2、CCR2A、CCR2B、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10和CCR11(对C-C家族);CXCR1、CXCR3,CXCR4和CXCR5(对C-X-C家族)和CX3CR1(对C-X3-C家族)的功能调节剂;
●骨质疏松药如雷洛昔芬、屈洛昔芬、拉索昔芬或fosomax;
●免疫抑制剂如FK-506、雷怕霉素、环孢霉素A、硫唑嘌呤或甲氨蝶呤;
●可用于治疗AIDS和/或HIV感染的化合物,例如:预防或抑制病毒蛋白gp120结合宿主细胞CD4的试剂{如可溶的CD4(重组的);抗-CD4抗体(或修饰的/重组的抗体)例如PRO542;抗组120抗体(或修饰的/重组的抗体);或干扰组120结合CD4的另一种试剂例如BMS806};防止被HIV病毒利用结合除CCR5之外的趋化因子受体的试剂{如CXCR4激动剂或拮抗剂或抗-CXCR4抗体};干扰HIV病毒包膜和细胞膜之间融合的化合物{如抗组41抗体;enfuvirtide(T-20)或T-1249};DC-SIGN(还已知为CD209)抑制剂{如抗-DC-SIGN抗体或DC-SIGN结合的抑制剂};核苷/核苷酸类似物逆转录酶抑制剂{例如齐多夫定(AZT)、奈韦拉平、地达诺新(ddI)、扎西他滨(ddC)、司他夫定(d4T)、拉米夫定(3TC)、阿巴卡韦、阿德福韦或替诺福韦(例如为游离碱或为disoproxil fumarate)};非核苷类逆转录酶抑制剂{例如奈韦拉平、地拉韦啶或依法韦仑};蛋白酶抑制剂{例如利托那韦、茚地那韦、沙奎那韦(例如游离碱或甲磺酸盐)、那非那韦(例如游离碱或甲磺酸盐)、安泼那韦、洛匹那韦或atazanavir(例如游离碱或硫酸盐)};核糖核苷酸还原酶抑制剂{例如羟基脲};或抗逆转录病毒药物{例如恩曲他滨};或,
●治疗骨关节炎的现有治疗药物,例如非甾体消炎剂(以下称为NSAID′s)如吡罗昔康、双氯芬酸,丙酸如萘普生、氟苯布洛芬、非诺洛氟、酮基布洛芬和布洛芬,灭酸如甲灭酸,消炎痛,舒林酸,阿扎丙宗,吡唑酮如保泰松,水杨酸酯如乙酰水杨酸,COX-2抑制剂如美洛昔康、塞来昔布、伐地考昔、罗非考昔、艾托考昔,止痛剂和关节内治疗药物如皮质激素和透明质酸如海尔根(hyalgan)和synvisc,或P2X7受体拮抗剂。
本发明更进一步涉及本发明化合物和(i)类胰蛋白酶抑制剂;(ii)血小板活化因子(PAF)拮抗剂;(iii)白介素转换酶(ICE)抑制剂;(iv)IMPDH抑制剂;(v)粘附分子抑制剂包括VLA-4拮抗剂;(vi)组织蛋白酶;(vii)MAP激酶抑制剂;(viii)葡萄糖-6磷酸脱氢酶抑制剂;(ix)细胞分裂素-B1-和B2-受体拮抗体;(x)抗痛风试剂,例如,秋水仙碱;(xi)黄嘌呤氧化酶抑制剂,例如,别嘌呤醇;(xii)促尿酸排泄药物,例如,丙磺舒、苯磺唑酮和苯溴马隆;(xiii)生长激素促分泌剂;(xiv)转化生长因子(TGF);(xv)血小板衍生生长因子(PDGF);(xvi)成纤维细胞生长因子,例如,碱性成纤维细胞生长因子(bFGF);(xvii)粒细胞巨噬细胞集落刺激因子(GM-CSF);(xviii)辣椒素油(capsaicin cream);(xix)速激肽NK1和NK3受体拮抗剂,选自NKP-608C、SB-233412(talnetant)、和D-4418;(xx)弹性蛋白酶抑制剂,选自UT-77和ZD-0892;(xxi)TNFα转化酶抑制剂(TACE);(xxii)诱导的一氧化氮合酶抑制剂(iNOS)或(xxiii)TH2细胞上表达的化学引诱物受体同源分子(CRTH2拮抗剂)的组合。
式(I)化合物的pKa测量利用下述方法之一进行测量。
方法A
使用的设备由Sirius GLpKa仪器以及DPAS(Dip探测器吸收光谱)附件组成。设备的关键元件是Sirius pH电极、搅拌器、滴定分配管、多头分配器、马达驱动的分配注射器、光纤UV探测器以及二极管阵列监测器。此外,离子强度调节(0.10M KCl)蒸馏水、标定的0.50M HCl、标定的0.50M KOH以及80%v/v甲醇∶水的PTFE容器的溶液也装在仪器中。滴定溶液持续地用无氧的氮气充气。氢氧化钾溶液池进一步利用碱石灰预防管防止大气污染隔离。将样品放置在滴定容器中,后者放置在可移动的自动采样器托盘(最大容量48个样品)中。电极、搅拌器、分配管/分配头以及DPAS探测器放置在可移动的、自动的z-塔元件上,当滴定的时候,由软件控制将其定位在滴定容器的适当位置。Sirius GLpKa仪器直接连接到专用的PC支持软件以设定分析以及随后的数据分析。利用GlpKaControl软件进行测定并且结果利用pKaLOGP和pKaUV软件在PC上进行。软件还容许利用综合的曲线拟合分析测定多个pKa。
方法B:电位测定法方法
可进行两种类型的电位测定法滴定以确定化合物的pKa/pKas;纯的水溶液滴定(对较好水溶性化合物推荐使用)以及共溶剂滴定,其中,变化量的甲醇加入到样品中,还加入离子强度调节水(对水不溶的化合物推荐使用)。对于后者,在纯的离子强度调节水中的化合物pKa值可利用Yasuda-Shedlovsky程序估计得到。这涉及在三种已知重量百分比的甲醇∶水(转换为介质的介电常数的倒数,1/εr)的溶液中测定化合物的表观pKa,并且然后外推至0wt%甲醇(1/εr=1.282×10-3)。
GLpKa仪器装置包括两个水洗涤液容器(包含蒸馏水),废液杯(以将外部溶液导入)以及盛有pH7.00缓冲溶液的容器以在滴定期间供电极浸没。在每次进行一批滴定的时候,替换这些溶液。自动采样器中的位置1包含滴定容器,包含pH7.00缓冲溶液(每一批滴定换一次)。对于将要运行的每一批滴定,位置2有滴定容器,其中离子强度调节水分配到其中(通常15.00mL)。其被HCl水溶液调节至pH1.80,并且然后通过逐渐滴加KOH水溶液滴定到pH12.20。这作为空白滴定并用于到pKaLogP软件中以校正pH电极并标准化HCl溶液,利用所谓的four-plus参数程序。定期地,(通常每3个月,或当滴定溶液较少的时候),替换滴定溶液,并将KOH溶液相对于邻苯二甲酸氢钾标准化,利用GLpKa控制软件中的标准化程序。必须精确称量1-2mg的每个样品。将样品放置在提供的玻璃滴定容器中。化合物的重量必须输入到GLpKaControl软件中。需要输入的其他参数为:化合物的分子量、测定方法类型(水溶液,共溶剂)、烧杯中分析的次数(对水溶液滴定为1,共溶剂/混合溶剂滴定为3)、配方(例如,X表示不为盐的化合物,或XHCl表示以盐酸盐的形式导入)、预期的pKas的数值(基于已知的结构)、最小的pH(1.80,电极操作的最小值)、最大的pH(12.20,电极操作的最大值)、首次测定的方向(对碱推荐低至高pH,对酸推荐高到低pH)、起始的水相体积(最小8.00mL,通常对纯水溶液滴定为15.00mL,并且对混合溶剂滴定为9.00mL),以及点间的pH步进(推荐pH=0.10单位)。如果对化合物进行混合溶剂滴定,则需要输入其他的信息:第二次以及第三次滴定的测定方向(参见首次测定方向),以及第二次以及第三次测定的另外的水体积(当利用共溶剂重量百分比工具的时候,自动计算)。
许多样品(最多48个)放置在自动采样器中,并且每次滴定的相关信息(化合物的重量、分子量等)从专用的PC下载到GLpKa仪器上。在GLpKa仪器上选择“运行测定”选项并进行滴定运行。在运行结束的时候,将滴定数据上载到PC上并利用pKaLOGP软件分析。分析的首个样品是空白滴定。曲线拟合程序用来拟合测量数据以得到理论的曲线,以得到HCl溶液的精确浓度的偏差,以及表征电极随pH变化的行为的多种参数(four-plus参数)的值。这些数据然后用于后续的其他的样品的分析。利用进一步的曲线拟合程序对其余的样品进行分析,通过拟合观察数据得到理论的曲线得到化合物的精确的pKa。对于共溶剂滴定,利用pKaLOGP软件中的Yasuda-Shedlovsky程序分析在不同百分比的甲醇分析观察到的各样品的pKa,将观察的pKa值外推到在100%水溶液中的真正的pKa。
方法C:DPAS(Dip探测器吸收光谱)方法
该方法通过测量化合物的UV谱随pH值的变化测定pKa。该方法最适合下述化合物,其中离子化中心位于分子的芳香的或共轭体系附近,离子化程度的变化导致UV谱的变化。由于UV光谱的良好的灵敏度,该方法适于稍微不溶的化合物。
该方法需要按照与电位测定法同样的方式运行空白滴定。但是,对于样品而言,每个样品需要两个瓶。在一个瓶中放入少量的化合物的DMSO溶液(通常50μl的1.5mM溶液)以及一些磷酸盐缓冲液以在滴定过程中获得一定程度上的pH稳定性(通常100μL水溶液,从0.2g正磷酸二氢钾以及100mL0.1M KCl溶液制备得到)。然后滴定器将水(通常10mL)加入至该溶液中,并且然后进行pH滴定,同时在每一个pH收集UV谱。第二个小瓶应该包含等体积的纯的DMSO以及等体积的磷酸盐缓冲液。然后滴定器将等体积的水加入至该溶液中,并记录UV谱作为参考(实际情况是在pH滴定相应的样品溶液之前进行)。
再次,分析的首个样品为空白滴定,容许测定精确的HCl浓度以及four-plus参数的值。然后使用pKaUV软件从在滴定过程中收集的3维数据(吸光度,波长,pH)提取化合物的pKa。软件使用复杂的运算法则(目标因子分析)从初始3维数据提取分子各个质子状态UV谱以及以及分子的各pKa。
本发明现在通过以下非限制性实施例进行说明,其中除非另有说明:
(i)当给出的时候,引用1H NMR数据,并且其为主要诊断质子的δ值形式,相对于作为内标的四甲基甲硅烷(TMS)以百万分之一(ppm)给出,除非另有说明,利用全氘代DMSO-d6(CD3SOCD3)、甲醇-d4(CD3OD)或CDCl3作为溶剂,在300MHz或400MHz测定;
(ii)质谱(MS)用70电子伏特的电子能量以化学离子(CI)方式用直接暴露探针进行测量;其中标明的离子化为电子撞击(EI)或快原子轰击(FAB)的作用;当给出m/z值时,通常只报告表明母体质量的离子,除非另有说明,提供的质量离子为带正电质量离子-(M+H)+;
(iii)实施例和方法中的标题化合物和小标题化合物利用AdvancedChemistry Development Inc公司的ACD/索引命名程序4.55版进行命名;
(iv)除非另由有说明,反相HPLC利用Symmetry NovaPak或Xterra反相硅胶柱进行;并且
(v)使用了下述缩写:
DMF | N,N-二甲基甲酰胺 |
HPLC | 高压液相色谱 |
RPHPLC | 反相高压液相色谱 |
HATU | O-(7-苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐 |
THF | 四氢呋喃 |
DCM | 二氯甲烷 |
d | 天 |
h | 小时 |
min | 分钟 |
制备1
(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇
步骤1:4-(3,4-二氯苯氧基)哌啶
在室温氮气气氛下,将4-羟基哌啶(50g)滴加到叔丁醇钾(110.9g)在THF(900mL)中的悬浮液中。将混合物加热回流并用30分钟滴加1,2-二氯-4-氟苯(98g)。将混合物再搅拌回流1小时,并冷却至室温,用乙酸乙酯(500mL)稀释并用水洗涤(500mL)。将有机相进一步用乙酸乙酯(500mL)稀释并用1M氢氯酸(200mL)萃取。通过加入氢氧化钠溶液调节水性萃取物大于pH10并用叔丁基甲基醚(750mL)萃取两次。将有机萃取物在硫酸镁上干燥、过滤并真空浓缩得到黑色油状的小标题化合物,用于下一步骤。
MS(ESI+ve)246/248[M+H]+
1H NMR
(CDCl3)1.60-1.70(2H,m),1.97-2.03(2H,m),2.75(2H,td),3.15(2H,dt),4.29-4.37(1H,m),6.78(1H,dd),7.00(1H,d),7.31(1H,d)。
步骤2:(2S)-1-叠氮基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇
将(2R)-环氧乙烷-2-基甲基3-硝基苯磺酸酯(21.1g)的DMF溶液(300mL)用三乙基胺(22.6mL)处理,然后用4-(3,4-二氯苯氧基)-哌啶(20g)处理。将混合物在60℃搅拌过夜。将叠氮钠(16g)加入到混合物中,并将反应再搅拌72小时。将溶液小心地在真空浓缩,并将残留物用水稀释(600mL),用乙酸乙酯(1500mL)萃取。将有机层用水(500mL)洗涤两次,然后用盐水(200mL)洗涤并真空浓缩得到油状物。
步骤3:(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇
将步骤2的油状物溶解在含水的四氢呋喃(225mL)中,并用三苯基膦(53.3g)处理。将反应在60℃加热并搅拌4小时。真空下去除溶剂,并将残留物再溶解在2N氢氯酸(1L)中,并将水层用乙酸乙酯萃取(3×700mL)。用2N的氢氧化钠水溶液将水相碱化并用DCM萃取(3×1L)。将合并的有机层用盐水洗涤,在硫酸钠上干燥、过滤并真空浓缩。将粗制的产物经层析(8%7N氨的甲醇溶液/DCM)纯化得到黄色油状的标题化合物(17g)。
MS(APCI+ve)319/321[M+H]+
1H NMR
(CDCl3)1.90-1.72(2H,m),2.06-1.91(2H,m),2.46-2.21(3H,m),2.60-2.49(1H,m),2.65(1H,d),2.72-2.61(1H,m),2.82(1H,d),2.94-2.84(1H,m),3.74-3.62(1H,m),4.0(1H,表观上七重峰),6.75(1H,dd),7.00(1H,d),7.31(1H,d)。
制备2
(2R)-1-氨基-3-[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]丙-2-醇
按照在制备1中描述的方法,利用4-(2,4-二氯-3-甲基苯氧基)-哌啶制备。
MS(APCI+ve)333/335[M+H]+
1H NMRδ(CD3OD)1.92-1.75(2H,m),2.08-1.90(2H,m),2.72-2.57(1H,m),2.93-2.72(4H,m),3.35-3.24(2H,m),3.88-3.71(1H,m),4.54-4.37(1H,m),6.94(2H,d),7.25(2H,d)。
制备3
(R)-1-[4-(3,4-二氯苯氧基)哌啶-1-基]-3-甲基氨基-丙-2-醇
将4-(3,4-二氯苯氧基)-1-[(2R)-环氧乙烷-2-基甲基]哌啶(1.0g),按照在制备1步骤2中描述的方法制备并从DMF中浓缩,以及甲基胺(2.56mL 40%v/v水溶液)在乙醇(15mL)中在密封的容器中在60℃加热16小时。减压蒸发溶剂并将残留物经快速柱层析纯化,利用8%7M氨的甲醇在DCM中的溶液洗脱得到标题化合物(0.875g)。
MS(APCI+ve)333/335[M+H]+
1H NMRδ(CDCl3)2.38-2.27(3H,m),2.46(3H,s),2.48-2.42(2H,m),2.54(1H,dd),2.56-2.51(2H,m),2.65(1H,dd),2.71-2.65(2H,m),2.91-2.86(1H,m),3.86-3.80(1H,m),4.32-4.26(1H,m),6.75(1H,dd),6.99(1H,d),7.31(1H,d)。
制备4
(R)-1-[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]-3-(甲基氨基)丙-2-醇
按照在制备2和3的方法从4-(2,4-二氯-3-甲基苯氧基)哌啶制备得到标题化合物。
1H NMR
(CDCl3)1.58-2.00(4H,m),2.28-2.71(10H,m),2.46(3H,s),2.87-2.95(1H,m),3.49(1H,s),3.82-3.88(1H,m),4.33-4.39(1H,m),6.75(1H,d),7.19(1H,d)。
实施例1
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
将6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-羧酸(Organic Process Researchand Development 1997,1,370-378;0.50g)溶解在亚硫酰氯(10mL)中,并加热回流3小时。蒸发溶剂并将残留物用甲苯(10mL)共蒸。将得到的浅黄色的固体溶解在乙酸乙酯(10mL)中,并滴加到(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.770g)和三乙基胺(1.68mL)在DCM(25mL)中的溶液中。将混合物在室温搅拌18小时,并蒸发溶剂。将残留物溶解在甲醇(20mL)中,并加热回流18小时。蒸发溶剂并经RPHPLC(Novapak,0.1%乙酸铵/乙腈)纯化得到无色固体的标题化合物(0.520g)。
标题化合物具有pKa5.9(利用方法B测量),以及pKa6.3(利用ACD计算)。
MS(APCI+ve)508/510[M+H]+
1H NMRδ(CD3OD)1.89-1.78(2H,m),2.10-1.99(2H,m),2.65-2.51(4H,m),2.99-2.87(2H,m),3.40-3.34(1H,m),3.48(1H,dd),4.04-3.96(1H,m),4.50-4.42(1H,m),6.84(1H,d),6.92(1H,ddd),7.14(1H,dd),7.41(1H,dd),7.75(1H,d)。
实施例2
N-{(2R)-3-[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]-2-羟基丙基}-6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
将6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-羧酸(0.100g)溶解在亚硫酰氯(2mL)中,并加热回流3小时。蒸发溶剂并将残留物用甲苯(5mL)共蒸。将得到的浅黄色固体溶解在四氢呋喃(2mL)中,并滴加至(2R)-1-氨基-3-[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]丙-2-醇(0.161g,以及三乙基胺(0.337mL)在DCM(5mL)中的溶液中。将混合物在室温搅拌18小时,并蒸发溶剂。将残留物溶解在甲醇(10mL)中,并加热回流3小时。蒸发溶剂并经RPHPLC(Symmetry,0.1%乙酸铵/乙腈)纯化得到无色固体的标题化合物(0.520g)。
标题化合物具有pKa6.3(利用ACD计算)。
MS(APCI+ve)522/524[M+H]+
1H NMRδ(CD3OD)1.97-2.23(4H,m),2.48(3H,s),2.81-3.07(4H,m),3.12-3.24(2H,m),3.31-3.52(2H,m),4.08-4.18(1H,m),4.62-4.69(1H,m),6.89(1H,d),7.02(1H,d),7.31(1H,d),7.80(1H,d)。
实施例3
5-溴-N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
步骤1:5-溴-6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-羧酸乙基酯
向6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-羧酸乙基酯(Organic ProcessResearch and Development 1997,1,370-378;0.10g)在四氯化碳的溶液中加N-溴琥珀酰亚胺(0.083g)。将混合物在80℃加热24小时。蒸发并经快速柱层析纯化得到无色固体的小标题化合物(0.10g)。
MS(ES-ve)311/313[M-H]-
步骤2:5-溴-6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-羧酸
将5-溴-6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-羧酸乙基酯(0.25g)悬浮在30%氢氯酸的水溶液中,并加热回流4天。冷却并过滤得到小标题化合物(0.210g)。
1H NMRδ(DMSO-d6)8.40(1H,s),13.40(1H,s),13.70(1H,s)。
步骤3:5-溴-N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
利用实施例1方法的方法制备,利用5-溴-6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-羧酸(0.10g),亚硫酰氯(2mL),(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.112g)和三乙基胺(0.244mL)得到无色固体的标题化合物(0.096g)。
标题化合物具有pKa4.5(利用ACD计算)。
MS(APCI-ve)586[M-H]-
1H NMRδ(CD3OD)1.99-2.13(2H,m),2.14-2.28(2H,m),2.97-3.28(4H,m),3.30-3.50(4H,m),4.13-4.22(1H,m),4.63-4.70(1H,m),6.98(1H,dd),7.22(1H,d),7.44(1H,d),7.88(1H,s)。
实施例4
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2,3-二氢-2-氧代-4-(三氟甲基)-5-噻唑甲酰胺
步骤1:2,3-二氢-2-氧代-4-(三氟甲基)-5-噻唑羧酸
向2,3-二氢-2-氧代-4-(三氟甲基)-5-噻唑羧酸乙基酯(Bionet Research,2.0g)的THF溶液(20mL)中加入氢氧化锂(0.696g)的水溶液(20mL)。将混合物在50℃搅拌72小时,冷却至室温并过滤。将滤液用乙酸乙酯(10mL)洗涤,利用稀氢氯酸酸化至pH3并用乙酸乙酯萃取(2×25mL)。将合并的有机萃取物用水(2×50mL)、饱和盐水溶液洗涤、干燥(Na2SO4)、过滤并真空浓缩得到无色固体的小标题化合物(1.583g)。
MS(APCI-ve)212[M-H]-
13C NMRδ(CDCl3)171.3(s),161.1(s),129.8(q,39.8Hz),122.3(q,272.4Hz),115.1(q,3.0Hz)。
步骤2:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2,3-二氢-2-氧代-4-(三氟甲基)-5-噻唑甲酰胺
按照实施例1的方法,利用2,3-二氢-2-氧代-4-(三氟甲基)-5-噻唑羧酸制备得到浅黄色泡沫的标题化合物(0.183g)。
标题化合物具有pKa4.7(利用方法B测量)。
MS(APCI-ve)512/514[M-H)]-
1H NMRδ(CD3OD)2.06-1.94(2H,m),2.22-2.08(2H,m),3.00-2.86(2H,ddd),3.14-3.00(2H,m),3.30-3.18(2H,m),3.42-3.32(2H,ddd),4.11-4.03(1H,m),4.64-4.56(1H,m),6.94(1H,dd),7.18(1H,d),7.41(1H,d)。
实施例5
N-{(2S)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-N-甲基-2-氧代-4-(三氟甲基)-2,3-二氢-1,3-噻唑-5-甲酰胺
按照实施例1的方法,利用(2R)-1-[4-(3,4-二氯苯氧基)哌啶-1-基]-3-(甲基氨基)丙-2-醇(150mg,0.45mmol)和2-氧代-4-(三氟甲基)-2,3-二氢-1,3-噻唑-5-羧酸(0.096g)制备得到无色固体的标题化合物(0.085g)。
标题化合物具有pKa6.27(利用ACD计算)。
MS(APCI+ve)528/530[M+H]+
1H NMRδ(DMSO-d6,90℃)1.79-1.62(2H,m),2.03-1.88(2H,m),2.62-2.45(2H,m),2.93-2.82(4H,m),3.00(3H,s),3.24(1H,dd),3.52(1H,dd),3.91(1H,五重峰),4.45(1H,七重峰),6.96(1H,dd),7.20(1H,d),7.46(1H,d)。
实施例6
N-{(2S)-3-[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]-2-羟基丙基}-N-甲基-2-氧代-4-(三氟甲基)-2,3-二氢-1,3-噻唑-5-甲酰胺
按照实施例1的方法,利用(2R)-1-[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]-3-(甲基氨基)丙-2-醇(0.156g)和2-氧代-4-(三氟甲基)-2,3-二氢-1,3-噻唑-5-羧酸(0.096g)制备得到无色固体的标题化合物(0.091g)。
标题化合物具有pKa6.3(利用ACD计算)。
MS(APCI+ve)542/544[M+H]+
1H NMRδ(DMSO-d6,90℃)1.83-1.67(2H,m),2.01-1.87(2H,m),2.41(3H,s),2.61-2.50(2H,m),2.93-2.78(4H,m),2.99(3H,s),3.24(1H,dd),3.52(1H,dd),3.91(1H,五重峰),4.47(1H,七重峰),7.05(1H,d),7.31(1H,d)。
实施例7
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-(五氟乙基)-2,3-二氢-1,3-噻唑-5-甲酰胺
步骤1:2-氧代-4-(五氟乙基)-2,3-二氢-1,3-噻唑-5-羧酸
将2-氧代-4-(五氟乙基)-2,3-二氢-1,3-噻唑-5-羧酸乙基酯(J.Het.Chem.221985 1621-1630;0.240g)的THF溶液(6mL)用氢氧化锂(0.120g)的水溶液(5mL)处理并将混合物在50℃加热4天。将混合物过滤并将残留物用水洗涤。将滤液用乙酸乙酯洗涤。将水层用稀氢氯酸酸化并且然后用乙酸乙酯萃取(3×50mL)。将有机萃取物用水和盐水洗涤并且然后在硫酸钠上干燥,过滤并蒸发得到固体的小标题化合物(0.13g)。
步骤2:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-(五氟乙基)-2,3-二氢-1,3-噻唑-5-甲酰胺
按照实施例1的方法,利用(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.158g)和2-氧代-4-(五氟乙基)-2,3-二氢-1,3-噻唑-5-羧酸(0.130g)制备得到无色固体的标题化合物(0.074g)。
标题化合物具有pKa6.1(利用ACD计算)。
MS(APCI+ve)564/566[M+H]+
1H NMRδ(DMSO-d6)1.86-1.72(2H,m),2.08-1.96(2H,m),2.84-2.59(4H,m),3.10-2.90(1H,m,模糊的),3.28-3.16(3H,m),3.85(1H,五重峰),4.53(1H,七重峰),6.98(1H,dd),7.23(1H,d),7.47(1H,d),7.48(1H,s)。
实施例8
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-5-甲基-1H-1,2,3-三唑-4-甲酰胺
按照实施例1的方法,利用5-甲基-1H-1,2,3-三唑-4-羧酸(Berichte 196396,802-812;0.060g)制备得到无色固体的标题化合物(0.063mg)。
标题化合物具有pKa7.5(利用方法B测量),并且pKa7.5(利用ACD计算)。
MS(APCI+ve)428/430[M+H]+
1H NMRδ(DMSO-d6)1.73-1.60(2H,m),1.97-1.86(2H,m),2.41-2.28(4H,m),2.45(3H,s),2.79-2.67(2H,m),3.43-3.24(2H,m),3.78(1H,五重峰),4.39(1H,七重峰),6.95(1H,dd),7.18(1H,d),7.44(1H,d),7.90(1H,t),
实施例9
N-{(2R)-3-[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]-2-羟基丙基}-5-甲基-1H-1,2,3-三唑-4-甲酰胺
按照实施例1的方法,利用(2R)-1-氨基-3-[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]丙-2-醇(0.158g)和5-甲基-1H-1,2,3-三唑-4-羧酸制备得到无色固体的标题化合物(0.037g)。
标题化合物具有pKa7.5(利用ACD计算)。
MS(APCI+ve)442/444[M+H]+
1H NMRδ(DMSO-d6,90℃)1.78-1.65(2H,m),1.97-1.86(2H,m),2.43-2.32(4H,m),2.41(3H,s),2.45(3H,s),2.79-2.67(2H,m),3.28(1H,dt),3.40(1H,dt),3.78(1H,五重峰),4.43(1H,七重峰),7.03(1H,d),7.30(1H,d),7.89(1H,t)。
实施例10
5-氰基-N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
将5-氰基-6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-羧酸(Farmaco 1997,52(5),331-337;0.115g)溶解在亚硫酰氯(3mL)中,并加热回流2小时。蒸发溶剂并将残留物用甲苯(10mL)共蒸。将得到的固体溶解在THF(5mL)中,并滴加至(2R)-1-[4-(3,4-二氯苯氧基)-哌啶-1-基]-3-甲基氨基-丙-2-醇(0.150g)和三乙基胺(0.3mL)在DCM(5mL)中的溶液中。将混合物在室温搅拌18小时,并蒸发溶剂。经过RPHPLC(Novapak,0.1%乙酸铵/乙腈)以及正相层析(NH3/甲醇/DCM)纯化得到无色固体的标题化合物(0.123g)。
标题化合物具有pKa3.4(利用ACD计算)。
MS(APCI+ve)533/535[M+H]+
1H NMRδ(CD3OD)2.13-1.99(2H,m),2.28-2.13(2H,m),3.10(2H,dt),3.34-3.14(2H,m),3.50-3.36(4H,m),4.21-4.12(1H,m),4.71-4.63(1H,m),6.96(1H,dd),7.21(1H,d),7.42(1H,d),7.85(1H,s)。
实施例11
5-氰基-N-{(2R)-3-[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]-2-羟基丙基}-6-氧代-2-(三氟甲基)-1,6-二氢吡啶-3-甲酰胺
按照实施例1的方法,利用(2R)-1-氨基-3-[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]丙-2-醇制备得到无色固体的标题化合物(0.121g)。
标题化合物具有pKa3.0(利用方法B测量),以及pKa3.4(利用ACD计算)。
MS(APCI+ve)547/549[M+H]+
1H NMRδ(DMSO-d6+ND4OD)1.72-1.61(2H,m),1.93-1.84(2H,m),2.37-2.24(4H,m),2.40(3H,s),2.72-2.63(2H,m),3.07(1H,dd),3.23(1H,dd),3.71(1H,五重峰),4.48(1H,七重峰),7.10(1H,d),7.34(1H,d),7.66(1H,s)。
实施例12
5-氰基-N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-6-氧代-2-苯基-1,6-二氢吡啶-3-甲酰胺
将5-氰基-6-氧代-2-苯基-1,6-二氢吡啶-3-羧酸(European Journal ofMedicinal Chemistry 24(5),517-519,1989;0.112g)溶解在亚硫酰氯(4mL)中,并加热回流2小时。将溶剂真空浓缩,并将残留物用甲苯(10mL)共蒸。将得到的浅黄色固体溶解在THF(4mL)中,并滴加至(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.150g)和三乙基胺(0.7mL)在DCM(2mL)中的溶液中。将混合物在室温搅拌过夜并将挥发性成分真空去除。将残留物溶解在乙腈(6mL)中,并经RPHPLC(Novapak,0.1%乙酸铵/乙腈)纯化得到白色固体的标题化合物(0.025g)。
标题化合物具有pKa3.0(利用方法B测量),以及pKa6.3(利用ACD计算)。
MS(APCI+ve)541/543[M+H]+
1H NMRδ(DMSO-d6)1.54-1.64(2H,m),1.84-1.95(2H,m),2.12-2.35(4H,m),2.62-2.73(2H,m),2.92-3.00(1H,m),3.11-3.20(1H,m),3.53-3.61(1H,m),4.38-4.49(1H,m),4.56-4.76(1H,brs),6.98(1H,dd),7.25(1H,d),7.42-7.53(6H,m),8.11(1H,t),8.23(1H,s)。
实施例13
5-氰基-N-{(2R)-3-[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]-2-羟基丙基}-6-氧代-2-苯基-1,6-二氢吡啶-3-甲酰胺
将5-氰基-6-氧代-2-苯基-1,6-二氢吡啶-3-羧酸(European Journal ofMedicinal Chemistry 24(5),517-519,1989;0.112g)溶解在亚硫酰氯(4mL)中,并加热回流2小时。将溶剂真空浓缩,并将残留物用甲苯(10mL)共蒸。将得到的浅黄色固体溶解在THF(4mL)中,并滴加至(2R)-1-氨基-3-[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]丙-2-醇(0.150g)和三乙基胺(0.7mL)在DCM(2mL)中的溶液中。将混合物在室温搅拌过夜并将挥发性成分真空去除。将残留物溶解在乙腈(6mL)中,并经RPHPLC(Novapak,0.1%乙酸铵/乙腈)纯化得到干燥黄色粉末的标题化合物(0.011g)。
标题化合物具有pKa6.3(利用ACD计算)。
MS(APCI+ve)555/557[M+H]+
1H NMRδ(CDCl3)1.92-2.01(2H,m),2.06-2.21(3H,m),2.47(3H,s),2.50-2.56(2H,m),2.76-2.83(1H,m),2.87(1H,td),2.96-3.05(2H,m),3.06-3.15(1H,m),3.35-3.43(1H,m),4.50-4.55(1H,m),6.33-6.39(1H,m),6.74(1H,d),7.22(1H,d),7.47-7.51(5H,m),7.51-7.57(1H,m),8.22(1H,s)
实施例14
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-3-甲基-2,6-二氧代-1,2,3,6-四氢嘧啶-4-甲酰胺
步骤1:3-甲基-2,6-二氧代-1,2,3,6-四氢嘧啶-4-羧酸
小标题化合物根据在Pharmazie 48 1993,H.11 861-862中描述的步骤进行合成。
步骤2:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-3-甲基-2,6-二氧代-1,2,3,6-四氢嘧啶-4-甲酰胺
将3-甲基-2,6-二氧代-1,2,3,6-四氢嘧啶-4-羧酸(Pharmazie 48 1993,H.11,861-862;0.173g)溶解在亚硫酰氯(8mL)中,并加热回流2小时。将溶剂真空浓缩,并将残留物用甲苯(10mL)共蒸。将得到的浅黄色固体溶解在THF(4mL)中,并滴加至(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.325g)和三乙基胺(1.56mL)在DCM(4.5mL)中的溶液中。将混合物在室温搅拌过夜并将挥发性成分真空去除。将残留物溶解在乙腈(6mL)中,并经RPHPLC(Novapak,0.1%乙酸铵/乙腈)纯化然后用DCM研磨得到黄色粉末的标题化合物(0.008g)。
标题化合物具有pKa6.9(利用ACD计算)。
MS(APCI+ve)471/473[M+H]+
1H NMR
(CD3OD)1.26-1.36(2H,m),1.78-1.85(2H,m),1.99-2.05(2H,m),2.55-2.60(2H,m),2.83-2.95(2H,m),3.11-3.14(1H,m),3.32(3H,s),3.49-3.52(1H,m),3.89-4.01(1H,m),4.41-4.47(1H,m),5.58(1H,s),5.78(1H,d),6.88-6.91(1H,m),7.11(1H,d)7.38(1H,d)。
实施例15
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2,6-二氧代-3-(2,2,2-三氟乙基)-1,2,3,6-四氢嘧啶-4-甲酰胺
步骤1:2,6-二氧代-3-(2,2,2-三氟乙基)-1,2,3,6-四氢嘧啶-4-羧酸
小标题化合物根据在Pharmazie 48 1993,H.11 861-862中描述的步骤进行制备。
步骤2:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2,6-二氧代-3-(2,2,2-三氟乙基)-1,2,3,6-四氢嘧啶-4-甲酰胺
向(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.134g)在干燥的DMF(3mL)的溶液中,加入N,N-二异丙基乙基胺(0.14mL),2,6-二氧代-3-(2,2,2-三氟乙基)-1,2,3,6-四氢嘧啶-4-羧酸(0.100g)和HATU(0.178g)。将反应混合物在0℃在氮气气氛下搅拌20分钟,然后用饱和的碳酸氢钠溶液(10mL)中止,并放置过夜。将混合物用乙酸乙酯萃取(3×10mL)。将合并的有机物用盐水洗涤(2×10mL),在硫酸镁上干燥,并将挥发性成分真空去除得到油状物(0.205g)。经过RPHPLC(Novapak,0.1%乙酸铵/乙腈)纯化得到干燥黄色粉末的标题化合物(0.028g)。
标题化合物具有pKa5.9(利用ACD计算)。
MS(APCI+ve)539/541(M+H)+
1H NMR(CD3OD)δ1.83-1.68(2H,m),2.03-1.90(2H,m),2.29-2.24(1H,m),2.45-2.34(1H,m),2.69-2.51(4H,m),2.97-2.84(2H,m),3.03(1H,五重峰),3.26-3.23(1H,m),3.34-3.32(1H,m),3.37-3.35(1H,m),3.90(1H,五重峰),4.40(1H,五重峰),5.39(1H,s),5.93(1H,s),6.82(1H,dd),7.04(1H,d)7.30(1H,d)。
实施例16
5-氰基-2-环丙基-N-[(2R)-3-[4-(3,4-二氯苯氧基)-1-哌啶基]-2-羟基丙基]-1,6-二氢-6-氧代-3-吡啶甲酰胺
将搅拌的5-氰基-2-环丙基-6-氧代-1,6-二氢吡啶-3-羧酸(0.080g)(J.Med.Chem.2002,45,1887)的亚硫酰氯溶液(2.5mL)加热回流2小时。从冷却的溶液中真空去除亚硫酰氯。将残留物溶解在THF(4mL)中,并在室温将该溶液滴加至(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.125g)和三乙基胺(0.7mL)在DCM(2mL)中的溶液中,然后搅拌过夜。将反应混合物真空浓缩,并再溶解在9∶1乙腈/水(4mL)中,然后进行RPHPLC(梯度0.1%乙酸铵/乙腈95%to 50%)得到白色固体(0.022g)。
标题化合物具有pKa3.8(利用方法B测量),以及pKa7.5(利用ACD计算)。
MS(ES+ve)505/507[M+H]+
1H NMR
(DMSO-d6)1.02-1.08(2H,m),1.11-1.17(2H,m),1.57-1.68(2H,m),1.89-1.97(2H,m),2.30-2.43(4H,m),2.53-2.61(1H,m),2.72-2.85(2H,m),3.05-3.14(1H,m),3.74-3.81(1H,m),4.42-4.49(1H,m),6.98(1H,dd),7.26(1H,d),7.50(1H,d),8.10(1H,s),8.32(1H,t);在~3.3(1H,m)的共振被HDO掩盖。
实施例17
5-氰基-2-环丙基-N-[(2R)-3.[4-(2,4-二氯-3-甲基苯氧基)-1-哌啶基]-2-羟基丙基]-1,6-二氢-6-氧代-3-吡啶甲酰胺
标题化合物具有pKa7.5(利用ACD计算)。
MS(ES+ve)519/521[M+H]+
1H NMR
(DMSO-d6)1.00-1.07(2H,m),1.10-1.17(2H,m),1.62-1.73(2H,m),1.86-1.93(2H,m),2.30-2.39(4H,m),2.40(3H,s),2.52-2.61(1H,m),2.66-2.78(2H,m),3.04-3.13(1H,m),3.73-3.80(1H,m),4.46-4.54(1H,m),7.10(1H,d),7.35(1H,d),8.07(1H,s),8.29(1H,t);在~3.3(1H,m)的共振被HDO掩盖。
实施例18
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-6-[(甲基磺酰基)氨基]-4-(三氟甲基)烟酰胺
步骤1:6-氯-N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-4-(三氟甲基)烟酰胺
在室温下,将4-三氟甲基-6-氯烟酰氯(0.585g)的THF溶液(3mL)滴加至搅拌的(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.735g)和三乙基胺(0.7mL)的DCM溶液(2mL)中。18小时后,将反应混合物真空浓缩,并进行快速柱层析(洗脱液96∶4二氯甲烷/7N氨的甲醇溶液)得到黄色的油状物(1.02g)。将小量(0.1g)再溶解在9∶1乙腈/水(4mL)中,并进行RPHPLC(梯度0.1%乙酸铵/乙腈95%~5%)得到白色固体(0.025g)。
MS(ES+ve)526/528[M+H]+
1H NMR
(CD3OD)1.66-1.80(2H,m),1.87-2.00(2H,m),2.42-2.57(4H,m),2.76-2.90(2H,m),3.27(1H,dd),3.44(1H,dd),3.86-3.95(1H,m),4.30-4.41(1H,m),6.80(1H,dd),7.02(1H,d),7.29(1H,d),7.78(1H,s),8.56(1H,s)。
步骤2:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-6-[(甲基磺酰基)氨基]-4-(三氟甲基)烟酰胺
将6-氯-N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-4-(三氟甲基)烟酰胺(0.28g),甲烷磺酰胺(0.12g)以及碳酸钾(0.148g)在N-甲基-2-吡咯烷酮中的搅拌溶液在微波辐照(100W)下在100℃加热15分钟。将反应混合物真空浓缩,并再溶解在4∶1∶1乙腈/水/乙酸(6mL)中,并进行RPHPLC(梯度0.1%乙酸铵/乙腈95%to5%)得到白色固体(0.025g)。
标题化合物具有pKa5.3(利用方法B测量)。
MS(ES+ve)585/587[M+H]+
1H NMR
(CD3OD)1.86-2.02(2H,m),2.06-2.20(2H,m),2.74-2.98(4H,m),3.07-3.22(2H,m),3.24(3H,s),3.36-3.56(2H,m),4.05-4.16(1H,m),4.52-4.62(1H,m),6.95(1H,dd),7.12(1H,s),7.18(1H,d),7.42(1H,d),8.44(1H,s)
实施例19
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-5-[(2,2,2-三氟乙基)硫代]-1H-1,2,3-三唑-4-甲酰胺
步骤1:1-(4-甲氧基苄基)-5-[(2,2,2-三氟乙基)硫代]-1H-1,2,3-三唑-4-羧酸乙基酯
将氢化钠(0.018g)加入到3,3,3-三氟乙醇(0.060mL)在干燥的DMF(1.5mL)中的溶液中。在室温搅拌30分钟后加入5-氯-1H-1,2,3-三唑-4-羧酸乙基酯(0.20g,J.Chem.Soc.Perkin I,1982,627)在干燥的DMF(1mL)中的溶液。将混合物在80℃加热18小时然后冷却并在乙醚(50mL)和水(50mL)之间分配。将水层再用乙醚(2×50mL)萃取,并将合并的萃取液在无水的硫酸钠上干燥。真空浓缩,并在硅胶上层析(0-50%梯度EtOAc/异己烷)得到小标题化合物(0.127g)。
MS(ES+ve)376[M+H]+
1H NMR
(CDCl3)1.44(3H,t),3.66(2H,q),3.78(3H,s),4.46(2H,q),5.62(2H,s),6.89-6.83(2H,m),7.29-7.24(2H,m)。
步骤2:5-[(2,2,2-三氟乙基)硫代]-1H-1,2,3-三唑-4-羧酸乙基酯
1-(4-甲氧基苄基)-5-[(2,2,2-三氟乙基)硫代]-1H-1,2,3-三唑-4-羧酸乙基酯(0.127g)溶解在三氟乙酸(2mL)中,并在65℃加热4小时。真空去除三氟乙酸并将残留物用甲苯共蒸(3×10mL),然后真空干燥得到小标题化合物(0.086g)。
MS(ES-ve)234[M-HF]-
步骤3:5-[(2,2,2-三氟乙基)硫代]-1H-1,2,3-三唑-4-羧酸
将5-[(2,2,2-三氟乙基)硫代]-1H-1,2,3-三唑-4-羧酸乙基酯(0.086g)悬浮在1N氢氧化钠水溶液中,并在70℃加热3小时。将反应混合物过滤并且然后用浓氢氯酸酸化。真空浓缩得到无色的固体,将其用冰冷的水洗涤得到小标题化合物(0.080g)。
MS(ES-ve)226[M-H]-
步骤4:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-5-[(2,2,2-三氟乙基)硫代]-1H-1,2,3-三唑-4-甲酰胺
将5-[(2,2,2-三氟乙基)硫代]-1H-1,2,3-三唑-4-羧酸(0.080g)溶解在DCM(2mL)中,并用草酰氯(0.060mL)和DMF(1滴)处理。将溶液在室温搅拌1小时然后真空浓缩,并用无水的甲苯(5mL)共蒸。将残留物再溶解在干燥的THF中,并滴加至搅拌的(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.108g)和三乙基胺(0.142mL)在DCM中的溶液中。将混合物搅拌1小时,真空蒸发溶剂并将产物经RPHPLC(梯度0.1%乙酸铵/乙腈50%~5%)纯化得到无色固体的标题化合物(0.058g)。
标题化合物具有pKa5.2(利用方法B测量),以及pKa4.6(利用ACD计算)。
MS(ES+ve)528/530[M+H]+
1H NMR
(CD3OD)1.92-1.84(2H,m),2.09-1.98(2H,m),2.92-2.72(4H,m),3.13-3.04(2H,m),3.42-3.32(2H,m),3.82(2H,q),4.03-3.97(1H,m),4.50-4.43(1H,m),6.83(1H,dd),7.07(1H,d),7.30(1H,d)。
实施例20
4-[({(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}氨基)-羰基]-1-萘甲酸
向萘-1,4-二羧酸(0.100g),(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.147g)和三乙基胺(0.193mL)在N-甲基-2-吡咯烷酮(20mL)中的溶液中加入PyBrOP(0.258g)。将反应混合物搅拌16小时,并真空去除溶剂。将残留物经RPHPLC(Symmetry,0.1%乙酸铵/乙腈)纯化得到无色固体的标题化合物(0.050g,20%)。
标题化合物具有pKa3.1(利用ACD计算)。
MS(APCI+ve)517/519[M+H]+
1H NMR
(CD3OD)2.02-2.30(4H,m),3.09-3.20(2H,m),3.22-3.30(2H,m),3.38-3.47(2H,m),3.51-3.67(2H,m),4.26-4.35(1H,m),4.66-4.73(1H,m),6.99(1H,dd),7.23(1H,d),7.45(1H,d),7.53-7.59(2H,m),7.64(1H,d),7.69(1H,d),8.23-8.26(1H,m),8.57-8.60(1H,m)。
实施例21
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2-[(甲基磺酰基)氨基]-4-(三氟甲基)-1,3-噻唑-5-甲酰胺
步骤1:2-[(甲基磺酰基)氨基]-4-(三氟甲基)-1,3-噻唑-5-羧酸
在室温下,向搅拌的乙基-2-氨基-4-(三氟甲基)-5-噻唑羧酸酯(1.2g)和三乙基胺(2.1mL)的THF溶液(12mL)中小部分加入甲烷磺酸酐(1.74g)。2小时后,将反应混合物真空浓缩,并将残留物在二烷(5mL)和1N NaOH水溶液(5mL)中搅拌16小时。将反应混合物真空浓缩,并向残留物的水溶液(20mL)和THF(30mL)溶液中加入氢氧化锂一水合物(1.8g),然后在50℃加热12小时。向冷却的反应混合物中加入1N氢氯酸水溶液(30mL)并萃取到EtOAc(2×25mL)中,在硫酸钠上干燥,过滤、并真空浓缩。
1H NMR
(DMSO-d6)3.26(3H,m)。
步骤2:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2-[(甲基磺酰基)氨基]-4-(三氟甲基)-1,3-噻唑-5-甲酰胺
将搅拌的2-[(甲基磺酰基)氨基]-4-(三氟甲基)-1,3-噻唑-5-羧酸(0.145g)在亚硫酰氯(3mL)中的溶液加热回流2小时。从冷却的溶液中真空去除亚硫酰氯。将残留物溶解在THF(4mL)中,并将该溶液在室温下滴加到(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.144g)和三乙基胺(0.7mL)在DCM(2mL)中的溶液中,然后搅拌过夜。将反应混合物真空浓缩,并再溶解在9∶1乙腈/水(4mL)中,然后进行RPHPLC(Novapak,梯度0.1%乙酸铵/乙腈95%~50%)得到白色固体(0.028g)。
保留时间:1.46分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
标题化合物具有pKa7.5(利用方法B测量)。
MS(ES+ve)591/593[M+H]+
1H NMR
(CD3OD)1.88-2.04(2H,m),2.05-2.19(2H,m),2.82(3H,s),2.97(1H,t),3.10(1H,d),3.14-3.41(4H,m),4.05-4.14(1H,m),4.55-4.62(1H,m),6.87(1H,dd),7.12(1H,d),7.32(1H,d),2个共振被模糊。
实施例22
N,-{(2R)-3-[4-(4-氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-(三氟甲基)-2,3-二氢-1,3-噻唑-5-甲酰胺
按照实施例4的方法,从(2R)-1-氨基-3-[4-(4-氯-2-甲基苯氧基)-哌啶-1-基]丙-2-醇[WO 2003068743(A1)]制备得到白色固体(0.046g)。
保留时间:1.37分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
标题化合物具有pKa6.1(利用ACD计算)。
MS(ES+ve)494/496[M+H]+
1H NMR
(CD3OD)1.97-2.10(2H,m),2.11-2.21(2H,m),2.22(3H,s),2.93(1H,dd),3.02(1H,dd),3.08-3.21(2H,m),3.21-3.30(2H,m),3.33-3.42(2H,m),4.06-4.13(1H,m),4.57-4.63(1H,m),6.92(1H,d),7.11(1H,dd),7.15(1H,d)。
实施例23
[5-[({(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]-2-氧代-4-(三氟甲基)吡啶-1(2H)-基]乙酸
步骤1:1-(2-甲氧基-2-氧代乙基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-羧酸
在室温下,向搅拌的6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-羧酸(0.207g)和碳酸钾(0.553g)在甲醇(5mL)中的悬浮液中加入溴代乙酸甲基酯(0.104mL)。16小后,反应没有完全,因此再加入溴代乙酸甲基酯(0.15mL)。再搅拌16小时后,将混合物真空浓缩然后加入1N氢氯酸水溶液(30mL)并萃取到乙酸乙酯(3×25mL)中,在Na2SO4上干燥,过滤,并真空浓缩得到白色固体(300mg)。
MS(ES-ve)278[M-H]-
步骤2:[5-[({(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]-2-氧代-4-(三氟甲基)吡啶-1(2H)-基]乙酸甲基酯
将搅拌的1-(2-甲氧基-2-氧代乙基)-6-氧代-4-(三氟甲基)-1,6-二氢吡啶-3-羧酸(0.140g)在亚硫酰氯(4mL)中的溶液加热回流2小时。从冷却的溶液真空去除亚硫酰氯。将残留物溶解在THF(4mL)中,并在室温下将该溶液加入到(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.144g)和三乙基胺(0.7mL)的DCM溶液(2mL)中,然后搅拌过夜。将反应混合物真空浓缩,并直接用于后续步骤。
步骤3:[5-[({(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]-2-氧代-4-(三氟甲基)吡啶-1(2H)-基]乙酸
将[5-[({(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]-2-氧代-4-(三氟甲基)吡啶-1(2H)-基]乙酸甲基酯(0.1g)和氢氧化锂(0.022g)在THF(3mL)和水(1mL)中的溶液在室温搅拌16小时。将反应混合物真空浓缩,并再溶解在9∶1乙腈/水(4mL)中,并用乙酸酸化至pH5然后进行反相HPLC(Novapak,梯度0.1%乙酸铵/乙腈95%~50%)得到白色固体(0.032g)。
保留时间:1.29分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
标题化合物具有pKa3.6(利用ACD计算)。
MS(ES+ve)566/568[M+H]+
1H NMR
(CD3OD)1.97-2.07(2H,m),2.08-2.23(2H,m),2.93(1H,dd),3.03(1H,dd),3.06-3.16(2H,m),3.21-3.29(2H,m),3.36(1H,dd),3.45(1H,dd),4.08-4.15(1H,m),4.58(2H,d),4.59-4.65(1H,m),6.85(1H,s),6.95(1H,dd),7.19(1H,d),7.41(1H,d),8.07(1H,s)。
实施例24
N-{(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-(三氟甲基)-2,3-二氢-1,3-噻唑-5-甲酰胺
标题化合物按照实施例4的方法制备得到白色固体的(0.10g)。
标题化合物具有pKa6.1(利用ACD计算)。
MS(APCI+ve)528/530[M+H]+
1H NMR
(CD3OD)1.87-2.02(2H,m),2.02-2.21(2H,m),2.25(3H,s),2.79-2.97(2H,m),2.97-3.20(2H,m),3.22-3.33(4H,m),4.00(1H,td),4.54(1H,s),6.87(1H,d),7.21(1H,dd)。
实施例25
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-4-(4-氟苯基)-2-氧代-2,3-二氢-1,3-噻唑-5-甲酰胺
步骤1:4-(4-氟苯基)-2-氧代-2,3-二氢-1,3-噻唑-5-羧酸甲基酯
根据J.Het.Chem.22,1985,1621-30,利用(2E)-3-氨基-3-(4-氟苯基)丙烯酸甲基酯[Angew.Chem.2003,42(8),913-6]制备得到黄色固体(3.67g)。
保留时间:2.62分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈95%~50%,3分钟;流速2mL/分钟)。
MS(ES-ve)252[M-H]-
步骤2:4-(4-氟苯基)-2-氧代-2,3-二氢-1,3-噻唑-5-羧酸
按照针对实施例4的方法制备得到浅黄色固体(0.38g)。
MS(ES+ve)240[M+H]+
步骤3:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-4-(4-氟苯基)-2-氧代-2,3-二氢-1,3-噻唑-5-甲酰胺
按照实施例4的方法制备得到白色固体(0.06g)。
标题化合物具有pKa7.4(利用方法B测量)。
MS(APCI+ve)538/540[M+H]+
1H NMR
(DMSO-d6)1.51-1.63(2H,m),1.83-1.93(2H,m),2.15-2.29(4H,m),2.59-2.71(2H,m),2.97-3.04(1H,m),3.15-3.21(1H,m),3.60(1H,五重峰),4.42(1H,七重峰),4.60(1H,s),6.98(1H,dd),7.25(1H,d),7.26-7.34(3H,m),7.49(1H,d),7.56(2H,q)。
实施例26
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-5-(4-氟苯基)-1H-1,2,3-三唑-4-甲酰胺
步骤1:5-(4-氟苯基)-1H-1,2,3-三唑-4-羧酸甲基酯
将钠(0.25g)逐渐地加入到干燥的无水乙醇(4.6mL)中。加入3-(4-氟苯基)-3-氧代丙酸甲基酯(1.44g),然后加入4-甲氧基苄基叠氮化物。将混合物加热回流18小时,并然后冷却并真空浓缩。将混合物倾入到冰水中,并用稀氢氯酸酸化。过滤形成的沉淀并干燥得到黄色的固体。将其在三氟乙酸(8mL)中在65℃加热8小时。将混合物真空浓缩,并用甲苯共蒸,并且然后用乙酸乙酯处理并过滤得到黄色固体的标题化合物(0.5g)。不经纯化使用。
步骤2:5-(4-氟苯基)-1H-1,2,3-三唑-4-羧酸
按照针对实施例8的方法制备。得到白色固体。
保留时间:0.87分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈95%~50%,3分钟;流速2mL/分钟)。
MS(ES-ve)206[M-H]-
步骤3:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-5-(4-氟苯基)-1H-1,2,3-三唑-4-甲酰胺
按照实施例8的方法制备。得到白色的固体(0.10g)。
标题化合物具有pKa6.1(利用方法B测量)。
MS(APCI+ve)508/510[M+H]+
1H NMR
(DMSO-d6)1.59-1.70(2H,m),1.87-1.97(2H,m),2.28-2.46(4H,m),2.67-2.82(2H,m),3.24-3.41(2H,m),3.81(1H,五重峰),4.45(1H,七重峰),4.86(1H,s),6.98(1H,dd),7.26(1H,t),7.29(2H,tt),7.49(1H,d),7.99-8.04(2H,m),8.44(1H,t)。
实施例27
N-{(2R)-3-[4-(3-氯-4-氰基苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-(三氟甲基)-2,3-二氢-1,3-噻唑-5-甲酰胺
得到白色固体的标题化合物(0.07g)。
标题化合物具有pKa6.1(利用ACD计算)。
MS(APCI+ve)505/507[M+H]+
1H NMR
(DMSO-d6)1.69-1.82(2H,m),1.95-2.06(2H,m),2.51-2.67(4H,m),2.87-2.95(2H,m),3.15-3.29(2H,m),3.80(1H,五重峰),4.65(1H,七重峰),7.10(1H,dd),7.30(1H,d),7.52(1H,s),7.79(1H,d)。
实施例28
N-{(2S)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-(三氟甲基)-2,3-二氢-1,3-噻唑-5-甲酰胺
得到白色固体的标题化合物(0.14g)。
标题化合物具有pKa6.1(利用ACD计算)。
MS(APCI+ve)514/516(M+H)+
1H NMR
(DMSO-d6 90℃)1.69-1.82(2H,m),1.92-2.06(2H,m),2.52-2.75(4H,m),2.88-3.13(2H,m),3.83(1H,五重峰),4.50(1H,七重峰),6.98(1H,dd),7.23(1H,d),7.47(1H,d),7.53(1H,s)。
实施例29
N-{(2S)-3-[4-(3-氯-4-氰基苯氧基)哌啶-1-基]-2-羟基丙基}-N-甲基-2-氧代-4-(三氟甲基)-2,3-二氢-1,3-噻唑-5-甲酰胺
得到白色固体的标题化合物(0.13g)。
标题化合物具有pKa6.3(利用ACD计算)。
MS(APCI+ve)519/521[M+H]+
1H NMR
(DMSO-d6 90℃)1.65-1.79(2H,m),1.91-2.03(2H,m),2.35-2.59(4H模糊的,m),2.80-2.89(2H模糊的,m),3.00(3H模糊的,s),3.23(1H,dd),3.53(1H,dd),3.90(1H,五重峰),4.62(1H,七重峰),7.09(1H,dd),7.30(1H,d),7.79(1H,d)。
实施例30
N-{(2R)-3-[4-(2,4-二氯-3-甲基苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-(三氟甲基)-2,3-二氢-1,3-噻唑-5-甲酰胺
得到白色固体的标题化合物(0.08g)。
标题化合物具有pKa6.1(利用ACD计算)。
MS(APCI+ve)528/530[M+H]+
1H NMR
(DMSO-d6)1.74-1.87(2H,m),1.93-2.05(2H,m),2.41(3H,s),2.51-2.72(4H,m),2.88-2.98(2H,m),3.14-3.30(2H,m),3.82(1H,五重峰),4.52(1H,七重峰),7.07(1H,d),7.32(1H,d),7.54(1H,s)。
实施例31
N-{(2R)-3-[4-(3-氯-4-氰基苯氧基)哌啶-1-基]-2-羟基丙基}-5-异丙基-1H-1,2,3-三唑-4-甲酰胺
步骤1:5-异丙基-1H-1,2,3-三唑-4-羧酸乙基酯
按实施例8照的方法制备,利用4-甲基-3-氧代戊酸乙基酯。不经纯化使用。
步骤2:5-异丙基-1H-1,2,3-三唑-4-羧酸
按照实施例8的方法制备得到琥珀色油性的固体。
MS(ES+ve)156[M+H]+
保留时间:0.49分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈95%~50%,3分钟;流速2mL/分钟)。
步骤3:N-{(2R)-3-[4-(3-氯-4-氰基苯氧基)哌啶-1-基]-2-羟基丙基}-5-异丙基-1H-1,2,3-三唑-4-甲酰胺
按照实施例8的方法制备标题化合物并得到白色固体(0.04g)。
标题化合物具有pKa7.3(利用ACD计算)。
MS(APCI+ve)447/449[M+H]+
1H NMR
(DMSO-d6 90℃)1.25(6H,d),1.64-1.74(2H,m),1.89-1.99(2H,m),2.30-2.43(4H,m),2.68-2.79(2H,m),3.29(1H,dt),3.39(1H,dt),3.65(1H,七重峰),3.78(1H,五重峰),4.57(1H,七重峰),4.58(1H,s),7.08(1H,dd),7.28(1H,d),7.78(1H,d),7.96(1H,s)。
实施例32
N-{(2S)-3-[4-(3-氯-4-氰基苯氧基)哌啶-1-基]-2-羟基丙基}-5-异丙基-N-甲基-1H-1,2,3-三唑-4-甲酰胺
标题化合物按照实施例8的方法制备并得到白色固体(0.03g)。
标题化合物具有pKa8.0(利用ACD计算)。
MS(APCI+ve)461/463[M+H]+
1H NMR
(DMSO-d6)1.22(6H,d),1.54-1.70(2H,m),1.83-1.95(2H,m),2.19-2.39(4H,m),2.56-2.76(2H,m),3.09(3H,s),3.18-3.35(2H,m),3.68(1H,dd),3.87(1H,s),4.54(1H,s),7.07(1H,dd),7.26(1H,s),7.78(1H,d)。
实施例33
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-(2,2,2-三氟乙基)-2,3-二氢-1,3-噻唑-5-甲酰胺
步骤1:5,5,5-三氟-3-氧代戊酸苄基酯
将3,3,3-三氟丙酸(5g)的干燥的THF溶液(50mL)用N,N-羰基二咪唑(7.6g)处理并将混合物在室温搅拌6小时。加入2,2-二甲基-1,3-二烷-4,6-二酮(5.63g)和三乙基胺(5.4mL),并将混合物在室温搅拌18小时。加入硫酸氢钾的水溶液(10%w/v),并将混合物用乙醚萃取。分离出有机层并用水洗涤,然后用盐水洗涤并在硫酸钠上干燥并过滤。将溶剂真空浓缩得到浅黄色固体。加入甲苯,然后加入苄基醇。将混合物在80℃加热6小时,并然后真空浓缩。经过纯化快速层析(洗脱液5∶95乙酸乙酯/异己烷)得到浅褐色固体的标题化合物(3.1g)。
MS(ES-ve)259[M-H]-
步骤2:(2E)-3-氨基-5,5,5-三氟戊-2-烯酸苄基酯
将5,5,5-三氟-3-氧代戊酸苄基酯(2.1g)的乙醇溶液(15mL)用乙酸铵(2g)处理。将混合物在80℃加热18小时,并然后真空浓缩。加入水和DCM。分离出有机相并用碳酸氢钠和水洗涤,并且然后在硫酸钠上干燥并过滤。将溶剂真空浓缩得到无色油状的标题化合物(0.71g)。
保留时间:3.34分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈95%~50%,3分钟;流速2mL/分钟)。
MS258[M-H]-(ES-)。
步骤3:2-氧代-4-(2,2,2-三氟乙基)-2,3-二氢-1,3-噻唑-5-羧酸苄基酯根据J.Het.Chem.22,1985,1621-30制备,利用(2E)-3-氨基-5,5,5-三氟戊-2-烯酸苄基酯。得到浅黄色固体(0.61g)。
保留时间:3.10分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
MS318(ES+ve)[M+H]+
步骤4:2-氧代-4-(2,2,2-三氟乙基)-2,3-二氢-1,3-噻唑-5-羧酸
将2-氧代-4-(2,2,2-三氟乙基)-2,3-二氢-1,3-噻唑-5-羧酸苄基酯(0.6g)的乙醇溶液用处理5%钯-碳处理并在3bar下氢化8天。过滤后,蒸发溶剂得到无色油状的标题化合物(0.15g)。
保留时间:0.37分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈95%~50%,3分钟;流速2mL/分钟)。
MS(ES-ve)226[M-H]-
步骤5:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-(2,2,2-三氟乙基)-2,3-二氢-1,3-噻唑-5-甲酰胺
按照实施例4的方法制备。得到白色固体(0.12g)。
标题化合物具有pKa6.6(利用方法B测量)。
MS(APCI+ve)528/530[M+H]+
1H NMR
(DMSO-d6)1.56-1.68(2H,m),1.86-1.96(2H,m),2.23-2.39(4H,m),2.65-2.79(2H,m),3.09-3.27(2H,m),3.73(1H,五重峰),3.97(2H,q),4.44(1H,七重峰),4.75(1H,s),6.98(1H,dd),7.26(1H,d),7.49(1H,d),7.81(1H,t)。
实施例34
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-吡啶-2-基-2,3-二氢-1,3-噻唑-5-甲酰胺
步骤1:乙基(2E)-3-氨基-3-吡啶-2-基丙烯酸酯
按照实施例33步骤2的方法制备,利用乙基3-氧代-3-吡啶-2-基丙酸酯得到褐色油状的标题化合物(2.5g)。
保留时间:2.92分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈95%~50%,3分钟;流速2mL/分钟)。
1H NMR
(CDCl3)1.32(3H,t),4.21(2H,q),5.34(1H,s),7.34(1H,ddd),7.75(2H,td),8.63(1H,dt)。
步骤2:2-氧代-4-吡啶-2-基-2,3-二氢-1,3-噻唑-5-羧酸乙基酯
根据J.Het.Chem.22,1985,1621-30制备。
MS(ES+ve)251[M+H]+
1H NMR
(DMSO-d6)1.08(3H,t),4.09(2H,q),7.51(1H,ddd),7.82(1H,dt),7.92(1H,td),8.67(1H,dq),12.32(1H,s)。
步骤3:2-氧代-4-吡啶-2-基-2,3-二氢-1,3-噻唑-5-羧酸
按照针对实施例4的方法制备得到浅黄色固体的标题化合物。
保留时间:0.49分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈95%~50%,3分钟;流速2mL/分钟)。
MS(ES+ve)223[M+H]+
步骤4:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-吡啶-2-基-2,3-二氢-1,3-噻唑-5-甲酰胺
按照实施例15步骤2的方法制备得到白色固体的标题化合物(0.032g)。
标题化合物具有pKa7.1(利用ACD计算)。
MS(APCI+ve)523/525(M+H)+
1H NMR
(DMSO-d6)1.52-1.65(2H,m),1.82-1.94(2H,m),2.20-2.34(4H,m),2.61-2.73(2H,m),3.05-3.17(1H,m),3.42(1H,d0,3.72(1H,五重峰),4.42(1H,七重峰),4.83(1H,s),6.97(1H,dd),7.25(1H,d),7.49(1H,d),7.56(1H,dd),7.85(1H,d),8.04(1H,td),8.71(1H,d),10.85(1H,s),11.96(1H,s)。
实施例35
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-6-氧代-2-(五氟乙基)-1,6-二氢吡啶-3-甲酰胺
步骤1:6-氧代-2-(五氟乙基)-1,4,5,6-四氢吡啶-3-羧酸乙基酯
将丙烯酰胺(4.11g),4,4,5,5,5-五氟-3-氧代戊酸乙基酯(16.5g)和对甲苯磺酸(0.120g)在氯苯(40mL)中的悬浮液超声30分钟然后通过微波(150W,120℃)辐照3小时。将反应混合物真空浓缩,并进行快速柱层析(洗脱液1∶3乙酸乙酯/异己烷)得到无色固体(0.697g)。
MS(ES-ve)286[M-H]+
1H NMR
(CDCl3)7.13(s,1H),4.25(q,J=7.2Hz,2H),2.79-2.73(m,2H),2.62-2.57(m,2H),1.30(t,J=7.1Hz,3H)。
步骤2:6-氧代-2-(五氟乙基)-1,6-二氢吡啶-3-羧酸乙基酯
将6-氧代-2-(五氟乙基)-1,4,5,6-四氢吡啶-3-羧酸乙基酯(0.690g)和N-溴代琥珀酰亚胺(0.427g)在四氯化碳(5mL)中的溶液在80℃加热20小时。将反应混合物真空浓缩,并进行快速柱层析(洗脱液1∶3乙酸乙酯/异己烷)得到无色固体(0.30g)。
MS(ES-ve)284[M-H]-
步骤3:6-氧代-2-(五氟乙基)-1,6-二氢吡啶-3-羧酸
将6-氧代-2-(五氟乙基)-1,6-二氢吡啶-3-羧酸乙基酯(0.300g)在浓盐酸(10mL)中的溶液加热回流20小时。将反应混合物冷却并过滤出无色的固体(0.30g)。
MS(ES-ve)256[M-H]-
1H NMR
(DMSO-d6)6.98(1H,d),8.04(1H,d),12.03(1H,s)。
步骤4:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-6-氧代-2-(五氟乙基)-1,6-二氢吡啶-3-甲酰胺
将搅拌的6-氧代-2-(五氟乙基)-1,6-二氢吡啶-3-羧酸(0.105g)在亚硫酰氯(5mL)中的溶液加热回流3小时。从冷却的溶液中真空去除亚硫酰氯。将残留物溶解在THF(4mL)中,并在室温下将该溶液滴加到(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.130g)和三乙基胺(0.4mL)在DCM(5mL)中的溶液中,然后搅拌过夜。将反应混合物真空浓缩,并再溶解在9∶1乙腈/水(4mL)中,然后进行RPHPLC(梯度0.1%乙酸铵/乙腈95%至50%)得到白色固体的标题化合物(125mg)。
标题化合物具有pKa6.3(利用ACD计算)。
MS(ES+ve)558/560[M+H]+
1H NMR
(CD3OD)1.69-1.79(2H,m),1.90-1.99(2H,m),2.48-2.60(4H,m),2.81-2.91(2H,m),3.26(1H,dd),3.35(1H,dd),3.87-3.93(1H,m),4.34-4.39(1H,m),6.77(1H,d),6.81(1H,dd),7.02(1H,d),7.29(1H,d),7.64(1H,d)。
实施例36
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-5-(甲硫基)-1H-1,2,3-三唑-4-甲酰胺
向搅拌的5-(甲硫基)-1H-1,2,3-三唑-4-羧酸[J.Chem.Soc.Perkin.Trans.l1982,627](0.085g)的DCM溶液(2mL)中加入草酰氯(0.09mL),然后加入DMF(1滴)。将反应混合物在室温搅拌1小时。将反应混合物真空浓缩,并将残留物溶解在THF(2mL)中,并在室温将该溶液滴加至(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.169g)和三乙基胺(0.22mL)的DCM溶液(5mL)中。搅拌1小时后,将反应混合物真空浓缩,并再溶解在甲醇(4mL)中,然后进行RPHPLC(梯度0.1%乙酸铵/乙腈95%~50%)得到白色固体(0.091g)。
标题化合物具有pKa5.5(利用方法B测量)。
MS(ES+ve)460/462[M+H]+
1H NMR
(CD3OD)1.76-1.88(2H,m),1.93-2.06(2H,m),2.45(3H,s),2.63-2.77(4H,m),2.92-3.04(2H,m),3.35(2H,t),3.91-3.99(1H,m),4.38-4.46(1H,m),6.82(1H,dd),7.05(1H,d),7.30(1H,d)。
实施例37
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-(三氟甲基)-2,3-二氢-1,3-唑-5-甲酰胺
将2-氧代-4-(三氟甲基)-2,3-二氢-1,3-唑-5-羧酸乙基酯(0.3g)[EP 0 027020 A1]用氢氧化锂溶解在3∶1 THF/水(6mL)中的溶液处理并在50℃加热1小时。将反应混合物在水(10mL)和乙酸乙酯(10mL)之间分配。利用稀氢氯酸将水相酸化至pH3,然后用用乙酸乙酯萃取(3×10mL)。合并有机物并用水(2×10mL)和盐水(10mL)洗涤,然后干燥(Na2SO4)、过滤、并真空浓缩得到为灰白色固体的酸(0.175g)。在胺树脂上进行纯化,利用甲醇洗脱以去除杂质,然后用5%甲酸的甲醇溶液洗脱以分离产物。
将搅拌的2-氧代-4-(三氟甲基)-2,3-二氢-1,3-唑-5-羧酸(0.032g)的亚硫酰氯溶液(4mL)加热回流2小时。从冷却的溶液真空去除过量的亚硫酰氯。将残留物溶解在IHF(2mL)中,并在室温下将该溶液滴加至(2R)-1-氨基-3-[4-(3,4-二氯苯氧基)哌啶-1-基]丙-2-醇(0.051g)和三乙基胺(0.24mL)在DCM(1mL)中的溶液中,然后搅拌过夜。
将反应混合物真空浓缩,并将残留物再溶解在包含2-3滴水、甲醇和乙酸的乙腈中,然后进行RPHPLC Novapak(梯度0.1%乙酸铵/乙腈95%~50%),然后用用7N NH3的甲醇溶液/二氯甲烷的3/17混合物进行正相洗脱。得到为黄色固体的期望的产物(0.016g)。
标题化合物具有pKa5.8(利用ACD计算)。
MS(ES-ve)498/496[M-H]-
1H NMR
(CD3OD)1.77(s,1H),2.07(s,1H),2.94-2.91(m,1H),3.02-2.98(m,1H),3.18-3.06(m,3H),3.42-3.36(m,3H),3.74-3.69(m,1H),4.62(五重峰,1H),5.25(s,1H),5.43(s,1H),5.53(s,1H),5.70(s,1H),6.95(dd,2.8Hz,1H),7.18(d,1H),7.40(d,1H)。
实施例38
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-5-(三氟甲基)-1H-1,2,3-三唑-4-甲酰胺
步骤1:5-(三氟甲基)-1H-1,2,3-三唑-4-羧酸
将5-(三氟甲基)-1H-1,2,3-三唑-4-羧酸乙基酯(0.312g)在1N的氢氧化钠的水溶液(3.8mL)中搅拌并加热回流90分钟。用氢氯酸的水溶液酸化冷却的溶液并用乙酸乙酯萃取。将萃取物用盐水洗涤然后干燥并蒸发得到无色的固体(0.226g)。
MS(ES-ve)180[M-H]-
步骤2:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-5-(三氟甲基)-1H-1,2,3-三唑-4-甲酰胺
利用实施例8的方法制备得到标题化合物(0.113g)。
标题化合物具有pKa4.0(利用方法B测量)。
MS(APCI+ve)482/484/486[M+H]+
1H NMR
(CD3OD)2.04(4H,m),2.99(1H,m),3.13(3H,m),3.32(2H,m),3.39(2H,m),4.10(1H,m),4.58(1H,m),6.88(1H,dd),7.13(1H,d),7.34(1H,d)。
实施例39
N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-5-[甲基(甲基磺酰基)氨基]-1H-1,2,3-三唑-4-甲酰胺
步骤1:5-氨基-1-(4-甲氧基苄基)-1H-1,2,3-三唑-4-羧酸乙基酯
将氰基乙酸乙基酯(1.96mL)加入到乙醇钠的溶液中,从钠(0.423g)和乙醇(45mL)制备得到,并将溶液搅拌30分钟。滴加4-甲氧基苄基叠氮化物(3.0g)的乙醇溶液(5mL),并将混合物加热回流5小时。将冷却的混合物倾入到水中,并用稀氢氯酸酸化然后用乙酸乙酯萃取。将萃取液用水、盐水洗涤并蒸发。经过纯化快速层析(乙酸乙酯/二氯甲烷1∶9然后15∶85)得到为浅黄色固体的产物(0.85g)。
MS(APCI-ve)275[M-H]+
步骤2:1-(4-甲氧基苄基)-5-[(甲基磺酰基)氨基]-1H-1,2,3-三唑-4-羧酸
将5-氨基-1-(4-甲氧基苄基)-1H-1,2,3-三唑-4-羧酸乙基酯(0.85g)和甲烷磺酰氯(0.72mL)在吡啶(20mL)中搅拌4天。再加入甲烷磺酰氯(0.72mL)并继续搅拌24小时。再加入甲烷磺酰氯(0.5mL)并继续搅拌24小时。将混合物真空浓缩。将残留物悬浮在稀氢氯酸中,并用乙酸乙酯萃取。将萃取物用稀氢氯酸和水洗涤然后蒸发。将残留物收集在乙醇(70mL)和2M氢氧化钠溶液(70mL)中,并搅拌18小时。将混合物浓缩至一半体积并用稀氢氯酸酸化。将混合物用乙酸乙酯萃取,并将萃取物用水和盐水洗涤,然后干燥并蒸发得到白色固体(0.90g)。
步骤3:1-(4-甲氧基苄基)-5-[甲基(甲基磺酰基)氨基]-1H-1,2,3-三唑-4-羧酸甲基酯
将1-(4-甲氧基苄基)-5-[(甲基磺酰基)氨基]-1H-1,2,3-三唑-4-羧酸(0.9g)和碳酸钾(1.15g)在干燥的DMF(10mL)中搅拌。加入碘甲烷(0.83mL)并将混合物搅拌5小时。将混合物倾入到水中,并用乙酸乙酯萃取。将萃取液用稀氢氯酸、水和盐水洗涤并且干燥然后蒸发。经过纯化快速层析(乙酸乙酯/DCM 1∶9)得到褐色固体的小标题化合物(0.54g)。
MS(APCI+ve)355[M+H]+
步骤4:5-[甲基(甲基磺酰基)氨基]-1H-1,2,3-三唑-4-羧酸甲基酯
将1-(4-甲氧基苄基)-5-[甲基(甲基磺酰基)氨基]-1H-1,2,3-三唑-4-羧酸甲基酯(0.54g)在三氟乙酸(5mL)中在60℃搅拌6小时。将混合物蒸发并将残留物与甲苯共蒸。经过快速层析(1∶49甲醇/DCM)纯化得到胶状的小标题化合物(0.36g)。
MS(APCI+ve)235[M+H]+
步骤5:5-[甲基(甲基磺酰基)氨基]-1H-1,2,3-三唑-4-羧酸
将5-[甲基(甲基磺酰基)氨基]-1H-1,2,3-三唑-4-羧酸甲基酯(0.36g)在THF(5mL)中与2N的氢氧化钠水溶液(1.7mL)搅拌18小时。将混合物真空浓缩。向含水的残留物中加入稀乙酸并将其用乙酸乙酯萃取(2×15mL)。将萃取物用水和盐水洗涤并且然后干燥并蒸发得到小标题化合物(0.07g)。
MS(APCI-ve)219[M-H]-
步骤6:N-{(2R)-3-[4-(3,4-二氯苯氧基)哌啶-1-基]-2-羟基丙基}-5-[甲基(甲基磺酰基)氨基]-1H-1,2,3-三唑-4-甲酰胺
利用5-[甲基(甲基磺酰基)氨基]-1H-1,2,3-三唑-4-羧酸(0.07g),利用实施例8的方法制备得到标题化合物(0.25g)。
标题化合物具有pKa4.2(利用ACD计算)。
MS(APCI-ve)519[M-H]-
1H NMR
(CD3OD)1.95-2.06(2H,m),2.08-2.22(2H,m),2.94(1H,m),3.01(1H,m),3.06(3H,s),3.07-3.15(1H,m),3.18-3.29(3H,m),3.33(3H,s),3.49(2H,d),4.12(1H,m),4.60(1H,m),6.94(1H,dd),7.18(1H,d),7.41(1H,d)。
实施例40
N-{(2R)-3-[4-(3-氯-4-氰基-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-(三氟甲基)-2,3-二氢-1,3-噻唑-5-甲酰胺
步骤1:2-氯-4-羟基-3-甲基苄腈
将搅拌的4-溴-3-氯-2-甲基苯酚(0.427g)、氰化锌(0.271g)以及四[三苯基膦]钯(0.056g)在N-甲基-2-吡咯烷酮(5mL)中的溶液在微波辐照(150W)下在130℃加热35分钟。将反应混合物滤过无水的硫酸镁,在1∶2乙酸乙酯/乙醚(15mL)和水(15mL)之间分配。将水相再用1∶2乙酸乙酯/乙醚(2×15mL)萃取。合并有机物,用水洗涤(2×20mL),在硫酸镁上干燥、过滤并真空浓缩。将化合物利用柱层析纯化,利用1∶9乙酸乙酯/异己烷作为洗脱液,得到桃红色固体的期望的产物(174mg,54%)。
保留时间:1.60分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
MS(ES-ve)166/168[M-H]+
1H NMRδ(CD3OD)2.27(s,3H),6.82(d,J=8.5Hz,1H),7.44(d,J=8.8Hz,1H)。
步骤2:4-(3-氯-4-氰基-2-甲基苯氧基)哌啶-1-羧酸叔丁基酯
根据专利WO 0220484 A1中的方法制备。
保留时间:2.83分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
1H NMRδ(CDCl3)1.48(s,9H),1.86-1.75(m,2H),1.99-1.89(m,2H),2.32(s,3H),3.51-3.42(m,2H),3.65-3.57(m,2H),4.64-4.57(m,1H),6.80(d,J=8.7Hz,1H),7.49(d,J=8.7Hz,1H)
步骤3:2-氯-3-甲基-4-(哌啶-4-基氧基)苄腈
根据制备1步骤2制备。
保留时间:1.17分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
MS(ES+ve)251/253[M+H]+
1H NMRδ(CDCl3)1.80-1.70(m,2H),2.06-1.96(m,2H),2.32(s,3H),2.83-2.75(m,2H),3.18-3.09(m,2H),4.54-4.47(m,1H),6.79(d,J=8.9Hz,1H),7.47(d,J=8.7Hz,1H)。
步骤4:4-({1-[(2R)-3-氨基-2-羟基丙基]哌啶-4-基}氧基)-2-氯-3-甲基苄腈
根据制备1步骤3的方法制备。
保留时间:1.20分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
MS(ES+ve)324/326[M+H]+
1H NMRδ(CDCl3)1.29-1.22(m,2H),1.94-1.81(m,2H),2.08-1.95(m,2H),2.31(s,3H),2.31(s,3H),2.46-2.33(m,3H),2.67-2.59(m,3H),2.90-2.80(m,2H),3.73-3.66(m,1H),4.51-4.44(m,1H),6.79(d,J=8.8Hz,1H),7.47(d,J=8.7Hz,1H)。
步骤5:N-{(2R)-3-[4-(3-氯-4-氰基-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}-2-氧代-4-(三氟甲基)-2,3-二氢-1,3-噻唑-5-甲酰胺
根据实施例4的方法制备。
保留时间:1.18分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
标题化合物具有pKa4.7(利用方法B测量),以及pKa6.1(利用ACD计算)。
MS(ES+ve)519/521[M+H]+,(ES-ve)517/519[M-H]-
1H NMRδ(DMSO-d6)1.81-1.91(m,2H),2.02-2.10(m,2H),2.33(s,3H),2.54-2.70(m,4H),2.88-2.95(m,2H),3.24-3.31(m,1H),3.34-3.41(m,1H),3.87(五重峰,1H),4.63-4.69(m,1H),7.17(d,1H),7.54-7.64(m,1H),7.68(d,1H)。
实施例41
N-{(2R)-3-[4-(3-氯-4-氰基苯氧基)哌啶-1-基]-2-羟基丙基}-5-(三氟甲基)-1H-1,2,3-三唑-4-甲酰胺
利用实施例31方法制备得到标题化合物(0.64g)。
标题化合物具有pKa2.1(利用ACD计算)。
MS(APCI+ve)473/475[M+H]+
1H NMR
(CD3OD)2.39-2.67(4H,m),3.44(1H,m),3.55-3.90(6H,m),3.84(1H,m),7.45(1H,dd),7.65(1H,d),8.08(1H,d)。
实施例42
2-氯-5-[({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]苯甲酸
步骤1:3-叔丁基1-甲基4-氯间苯二甲酸酯
将5-溴-2-氯苯甲酸叔丁基酯(1.9g)(WO2003095430)与N,N-二异丙基乙基胺(2mL)和二氯双(三苯基膦)-钯(II)(0.134g)溶解在甲醇(18ml)中。将混合物在85℃羰基化12小时。蒸发冷却的溶液并经过快速层析纯化,用5∶95乙酸乙酯/异己烷洗脱,得到无色油状的小标题化合物(0.67g)。
1H NMR
(CDCl3)1.62(9H,s),3.94(3H,s),7.49(1H,dd),8.02(1H,dd),8.35(1H,d)。
步骤2:3-(叔丁氧基羰基)-4-氯苯甲酸
将3-叔丁基1-甲基4-氯间苯二甲酸酯(0.37g)的THF溶液(5mL)用氢氧化锂(0.17g)的水溶液(5mL)处理并将混合物搅拌18小时。蒸发溶剂。加入水和乙酸乙酯。分离水萃取物并用稀氢氯酸酸化。将产物萃取到乙酸乙酯中。将溶液在硫酸钠上干燥,过滤并蒸发溶剂得到小白色固体的标题化合物(0.32g)。
保留时间:1.98分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈95%~50%,3分钟;流速2mL/分钟)。
MS(ES-ve)255[M-H]-
1H NMR
(DMSO-d6)1.56(9H,s),7.69(1H,d),8.03(1H,dd),8.18(1H,d)。
步骤3:2-氯-5-[({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶,1-基]-2-羟基丙基}氨基)羰基]苯甲酸叔丁基酯
按照针对实施例15步骤2的方法制备并得到无色油状的小标题化合物(0.14g)。
保留时间:2.93分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
MS(ES+ve)571[M+H]+
步骤4:2-氯-5-[({(2R)-3-[4-(3,4-二-氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]苯甲酸
将2-氯-5-[({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]苯甲酸叔丁基酯(0.14g)的DCM溶液(5mL)用三氟乙酸(1.5mL)处理并将混合物搅拌1.5小时,蒸发溶剂。产物经RPHPLC(Symmetry,0.1%乙酸铵/乙腈)纯化得到白色固体的标题化合物(0.05g)。
标题化合物具有测量的pKa2.3,以及计算的pKa2.6(利用ACD计算)。
MS(APCI-ve)513/517[M-H]-
1H NMR
(CD3OD+NaOD)1.79-1.91(2H,m),1.98-2.09(2H,m),2.34(3H,s),2.47-2.58(2H,m),2.52(2H,d),2.75-2.87(2H,m),3.43(1H,dd),3.53(1H,dd),4.02(1H,五重峰),4.44-4.53(1H,m),6.95(1H,d),7.31(1H,d),7.49(1H,d),7.77(1H,dd),7.96(1H,d)。
实施例43
4-氯-3-[({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]苯甲酸
步骤1:4-氯-3-[({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]苯甲酸甲基酯
按照针对实施例15步骤2的方法,利用2-氯-5-(甲氧基羰基)苯甲酸(FR2842805)和(2R)-1-氨基-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]丙-2-醇制备并得到无色的油状物(0.1g)。
保留时间:2.42分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
MS(ES-ve)529/531[M-H]-
步骤2:4-氯-3-[({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]苯甲酸
按照针对实施例23步骤3的方法制备,并得到白色的固体(0.022g)。
标题化合物具有pKa3.7(利用ACD计算)。
MS(APCI-ve)513/517[M-H]-
1H NMR
(CD3OD)1.78-1.89(2H,m),1.97-2.08(2H,m),2.34(3H,s),2.47-2.62(4H,m),2.79-2.90(2H,m),3.49(2H,ddd),4.03(1H,五重峰),4.46(1H,七重峰),6.95(1H,d),7.30(1H,d),7.48(1H,d),8.00(1H,dd),8.06(1H,d)。
实施例44
4-氯-3-[2-({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)-2-氧代乙氧基]苯甲酸
步骤1:3-(2-叔丁氧基-2-氧代乙氧基)-4-氯苯甲酸甲基酯
将4-氯-3-羟基苯甲酸甲基酯[Chem.Pharm.Bull.1994,42(11),2365-9](0.73g)、碳酸铯(1.27g)以及溴乙酸叔丁基酯(0.58mL)在DMF(6mL)中的溶液在60℃加热搅拌3小时。加入水并将产物萃取到乙酸乙酯中。将萃取物在硫酸钠上干燥,过滤并蒸发溶剂。将得到的油状物经快速层析纯化,利用1∶10乙酸乙酯/异己烷作为洗脱液,得到无色油状的小标题化合物(1.25g)。
步骤2:[2-氯-5-(甲氧基羰基)苯氧基]乙酸
按照实施例42步骤4的方法,制备得到灰白色固体的小标题化合物(0.18g)。
MS(ES-ve)243[M-H]-
步骤3:4-氯-3-[2-({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)-2-氧代乙氧基]苯甲酸甲基酯
按照针对实施例15步骤2的方法制备,利用[2-氯-5-(甲氧基羰基)-苯氧基]乙酸和(2R)-1-氨基-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]丙-2-醇得到无色油状的小标题化合物(0.084g)。
MS(ES+ve)561/3[M+H]+
保留时间:2.58分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
步骤4:4-氯-3-[2-({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)-2-氧代乙氧基]苯甲酸
按照针对实施例23步骤3的方法制备。得到白色固体的标题化合物(0.02g)。
标题化合物具有pKa3.8(利用ACD计算)。
MS(APCI-ve)545/547[M-H]-
1H NMR
(CD3OD)1.98-2.13(2H,m),2.16-2.31(2H,m),2.34(3H,s),2.94-3.11(2H,m),3.15-3.26(2H,m),3.34(2H,s),3.40(2H,d),4.10-4.17(1H,m),4.64-4.70(1H,m),4.71(2H,d),6.99(1H,d),7.32(1H,d),7.41(1H,d),7.58(1H,dd),7.59(1H,s)。
实施例45
{2-氯-5-[({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]苯氧基}乙酸
步骤1:3-(2-叔丁氧基-2-氧代乙氧基)-4-氯苯甲酸
将3-(2-叔丁氧基-2-氧代乙氧基)-4-氯苯甲酸甲基酯(0.7g)在9∶1叔丁醇∶水中的溶液利用Antarctica B脂肪酶处理6天。过滤并蒸发溶剂得到灰白色固体的小标题化合物(0.6g)。
MS(ES-ve)285[M-H]-
步骤2:{2-氯-5-[({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]苯氧基}乙酸叔丁基酯
按照针对实施例15步骤2的方法,利用3-(2-叔丁氧基-2-氧代乙氧基)-4-氯苯甲酸和(2R)-1-氨基-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]丙-2-醇制备得到无色油状的小标题化合物(0.14g)。
MS(ES+ve)603/5[M+H]+
保留时间:2.98分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
步骤3:{2-氯-5-[({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]苯氧基}乙酸
按照实施例42步骤4的方法制备得到白色固体的标题化合物(0.085g)。
标题化合物具有pKa3.0(利用ACD计算)。
MS(APCI-ve)543/547[M-H]-
1H NMRδ(CD3OD+NaOD)1.74-1.86(2H,m),1.95-2.05(2H,m),2.31(3H,s),2.41-2.52(4H,m),2.74-2.84(2H,m),3.32-3.38(1H,m),3.50(1H,dd),3.98(1H,五重峰),4.42(1H,七重峰),4.54(2H,s),6.91(1H,d),7.27(1H,d),7.37(1H,dd),7.38(1H,s),7.44(1H,d)。
实施例46
3-[2-({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)-2-氧代乙氧基]苯甲酸
步骤1:3-[2-({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)-2-氧代乙氧基]苯甲酸甲基酯
按照针对实施例15步骤2的方法,利用[3-(甲氧基羰基)苯氧基]乙酸[Asian Journal of Chemistry 1992,4(4),920-3]和(2R)-1-氨基-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]丙-2-醇制备得到浅黄色油状的小标题化合物(0.11g)。
MS(ES+ve)525/527[M+H]+
保留时间:2.35分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
步骤2:3-[2-({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)-2-氧代乙氧基]苯甲酸
按照针对实施例23步骤3的方法制备得到白色固体的标题化合物(0.049g)。
标题化合物具有测量的pKa2.6以及计算的pKa4.0(利用ACD计算)。
MS(APCI-ve)509/511[M-H]-
1H NMRδ(CD3OD+NaOD)1.73-1.85(2H,m),1.94-2.03(2H,m),2.30(3H,s),2.33-2.47(4H,m),2.68-2.78(2H,m),3.32-3.44(2H,m),3.90(1H,五重峰),4.37-4.46(1H,m),4.57(2H,s),6.92(1H,d),7.04-7.08(1H,m),7.24-7.34(2H,m),7.56-7.61(2H,m)。
实施例47
{3-[({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]苯氧基}乙酸
步骤1:{3-[({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]苯氧基}乙酸叔丁基酯
按照针对实施例15步骤2的方法,利用3-(2-叔丁氧基-2-氧代乙氧基)苯甲酸[WO 00/78317A1]和(2R)-1-氨基-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]丙-2-醇制备得到小白色固体的标题化合物(0.11g)。
MS(ES+ve)567/569[M+H]+
保留时间:2.65分钟(反相分析性HPLC(Hewlett Packard Series 1100):Waters“Symmetry”C8柱3.5μm;4.6×50mm柱,梯度:0.1%乙酸铵/乙腈75%~5%,3分钟;流速2mL/分钟)。
步骤2:{3-[({(2R)-3-[4-(3,4-二氯-2-甲基苯氧基)哌啶-1-基]-2-羟基丙基}氨基)羰基]苯氧基}乙酸
按照实施例42步骤4的方法制备得到白色固体的标题化合物(0.063g)。
标题化合物具有pKa3.1(利用ACD计算)。
MS(APCI+ve)511/513[M+H]+
1H NMR
(CD3OD+NaOD)1.75-1.87(2H,m),1.96-2.05(2H,m),2.31(3H,s),2.42-2.54(4H,m),2.75-2.85(2H,m),3.37(1H,dd),3.50(1H,dd),3.99(1H,五重峰),4.47(3H,s),6.91(1H,d),7.08-7.12(1H,m),7.27(1H,dd),7.32-7.40(3H,m)。
实施例48
药理分析:钙流[Ca2+]i测定
人嗜伊红粒细胞
按照前述方法(Hansel等,J.Immunol.Methods,1991,145,105-110)从EDTA抗凝的外周血中分离出人嗜伊红粒细胞。室温下将细胞悬浮(5×106ml-1)并负载5μM FLUO-3/AM+Pluronic F127 2.2μl/ml(Molecular Probes)的低钾溶液(LKS;NaCl 118mM,MgSO4 0.8mM,葡萄糖5.5mM,Na2CO38.5mM,KCl 5mM,HEPES 20mM,CaCl2 1.8mM,BSA 0.1%,pH7.4)一小时。负载后,将细胞在200g离心5分钟并以2.5×106ml-1的密度再悬浮于LKS中。然后将细胞以25μl/孔转移至96孔FLIPr板(Becton Dickinson的聚赖氨酸板,用5μM纤连蛋白预孵育2小时)中。将板在200g离心5分钟并将细胞用LKS(200μl;室温)洗涤两次。
将实施例化合物预溶于DMSO中,并加入至0.1%(v/v)DMSO的终浓度。加入A50浓度的嗜伊红粒细胞趋化蛋白启动测定,并利用FLIPR(FluorometricImaging Plate Reader,Molecular Devices,Sunnyvale,U.S.A.)检测fluo-3荧光(lEx=490nm和lEm=520nm)的瞬时增加。
如果嗜伊红粒细胞趋化蛋白(选择性CCR3激动剂)诱导的荧光增加受到浓度依赖的方式的抑制,就认为实施例化合物为拮抗剂。抑制50%荧光所需要的拮抗剂的浓度可用来定义为CCR3受体拮抗剂的IC50。
实施例49
人嗜伊红粒细胞趋化性
按照前述方法(Hansel等,J.Immunol.Methods,1991,145,105-110)从EDTA抗凝的外周血终分离得到人嗜伊红粒细胞。室温下,将细胞以10×106ml-1的密度悬浮在RPMl中,该培养基包含200IU/ml青霉素、200μg/ml硫酸链霉素并补加10%HIFCS。
将嗜伊红粒细胞(700μl)与7μl载体或化合物(100×需要的终浓度的10%DMSO溶液)在37℃预孵育15分钟。趋化性板(ChemoTx,3μm孔,Neuroprobe)通过下述方式进行负载:将28μl包含各种浓度的实施例化合物或溶剂的0.1~100nM浓度的嗜伊红粒细胞趋化蛋白(在此浓度范围的选择性CCR3激动剂)加入到趋化性板下层孔中。然后将滤器放置在孔上,并将25μl嗜伊红粒细胞悬浮液加入到滤器的上部。将板在湿度培养箱中与95%空气/5%CO2氛在37℃培养1小时使之发生趋化性。
从滤器上部小心地吸出包含没有迁移细胞的培养基并弃去。将滤器用包含5mM EDTA的磷酸缓冲盐(PBS)洗涤一次以去除任何粘附的细胞。离心(在室温300×g离心5分钟)沉淀迁移通过滤器的细胞并去除滤器,并将上清液转移至96-孔板(Costar)的各孔中。加入28μl包含0.5%Triton×100的PBS然后通过两轮冻/融裂解沉淀的细胞。然后将细胞裂解液加入到上清液中。根据Strath等,J.Immunol.Methods,1985,83,209的方法通过测定上清液中的嗜伊红粒细胞过氧化物酶活性定量迁移的嗜伊红粒细胞数。
如果响应嗜伊红粒细胞趋化蛋白的浓度移到对照曲线的右侧,就认为实施例化合物为嗜伊红粒细胞趋化蛋白介导的人嗜伊红粒细胞趋化性的拮抗剂。在有或无化合物存在的条件下测量给出50%趋化性需要的嗜伊红粒细胞趋化蛋白的浓度计算出化合物对CCR3的表观亲和力,或者测定可用来测定一组浓度的化合物对预定浓度的嗜伊红粒细胞趋化蛋白的化合物活性。
实施例50
分离的豚鼠气管
(参见例如,Harrison,R.W.S.,Carswell,H.。& Young,J.M.(1984)EuropeanJ.Pharmacol.,106,405-409.)
将雄性白化Dunkin-Hartley豚鼠(250g)经颈脱位法处死并取出整个气管。清除粘附的结缔组织后,将气管切成6个环形片段,各有3根软骨带宽,然后悬浮在20ml器官培养液中,所述溶液包含下述成分的Krebs-Henseleit溶液(mM):NaCl 117.6,NaH2PO4 0.9,NaHCO3 25.0,MgSO41.2,KCl 5.4,CaCl2 2.6和葡萄糖11.1。将缓冲液保持在37℃并通入5%CO2的氧气。将消炎痛(2.8μM)加入到Krebs溶液中以防止由于环-加氧酶产物的合成导致的平滑肌的扩张。将气管环悬挂在两个平行的钨丝钩之间,一端连接Ormed杆等力传感器并且另一端连接在器官培养液固定的支持物。在2-道Sekonic平床制图记录仪上记录等力的变化。
实验方案
在每次实验的开始,对组织施用1g的力,用60分钟平衡时间进行恢复直到实现稳定不动的反应。随后,在各组织中以0.5log10单位增量建立累积的组胺浓度效果(E/[A])曲线。然后清洗组织并且约30分钟后,加入受试化合物或溶媒(20%DMSO)。孵育60分钟后进行组胺的第二个E/[A]曲线。
浓度响应记录为第一曲线最大值的百分比。
数据分析
分析实验E/[A]曲线数据以评价有和无受试化合物存在下的组胺活性(p[A50]值)。随后用下述等式计算出受试化合物的亲和力(pA2)值:
log(r-1)=log[B]+pA2
其中r=测试化合物存在下的[A]50/无拮抗剂下的[A]50,并且[B]为受试化合物的浓度。发现实施例化合物为H1拮抗剂。
实施例51
本发明化合物的组胺H1受体结合活性通过下述方法进行评价:室温下在测定缓冲液(50mM Tris pH7.4包含2mM MgCl2,250mM蔗糖和100mMNaCl)中,通过测定1小时期间1nM[3H]-吡拉明(Amersham,Bucks,产品代号TRK608,比活性30Ci/mmol)对从表达人H1受体的重组CHO-K1细胞(Euroscreen SA,Brussels,Belgium,产品代号ES-390-M)制备得到的2μg膜的竞争性置换。
本发明的下述化合物显示出对[3H]吡拉明结合的抑制性:
实施例 | H1 pKi |
5 | 6.9 |
8 | 7.8 |
10 | 6.9 |
14 | 6.9 |
16 | 7.6 |
18 | 6.5 |
20 | 6.7 |
24 | 7.7 |
25 | 7.8 |
27 | 6.6 |
28 | 7.4 |
31 | 6.8 |
37 | 6.7 |
39 | 6.9 |
42 | 6.9 |
44 | 7.9 |
45 | 7.2 |
Claims (14)
2.权利要求1的式(I)化合物,其中R1为被一、二或三个下述取代基取代的苯基:卤素、氰基或C1-4烷基。
3.权利要求1或2的式(I)化合物,其中R2为氢。
4.权利要求1、2或3的式(I)化合物,其中R3的酸性NH为芳基或杂环的一部分或在芳基或杂环上的取代基的一部分。
5.权利要求1、2或3的式(I)化合物,其中R3的酸性OH为在芳基或杂环上的取代基或取代基的一部分。
6.权利要求1、2、3或4的式(I)化合物,其中R3的酸性NH为被合适取代的2-氧代-噻唑-5-基、2-氧代-唑-5-基、2-氧代-咪唑-5-基、1H-1,2,3-三唑-4-基、4-氧代-1H-1,4-二氢吡啶-3-基、2,6-二氧代-1H-1,2,3,6-四氢嘧啶-4-基、6-氧代-1H-1,6-二氢吡啶-3-基或2H-四唑-5-基环的一部分。
7.权利要求1、2或3的式(I)化合物,其中R3为:
·2-氧代-噻唑-5-基,在4-位具有合适的吸电子取代基;
·2-氧代-唑-5-基,在4-位具有合适的吸电子取代基;
·1H-1,2,3-三唑-4-基,在5-位具有合适的取代基;
·4-氧代-1H-1,4-二氢吡啶-3-基,在2-位具有合适的吸电子取代基;
·2,6-二氧代-1H-1,2,3,6-四氢嘧啶-4-基,在3-位具有合适的取代基并任选在一或多个其他的环位置被取代;
·6-氧代-1H-1,6-二氢吡啶-3-基,在2-位和/或5-位具有合适的吸电子取代基,并任选在一或多个其他的环位置被取代;
·6-氧代-1H-1,6-二氢吡啶-3-基,在环氮上具有CH2CO2H,并任选在一或多个其他的环位置被取代;
·2H-四唑-5-基;
·在任选被取代的苯基、任选被取代的CH2O苯基或任选被取代的萘基环上的CO2H、CH2CO2H或OCH2CO2H基团;或者
·在任选被取代的芳香杂环上的NHS(O)2(C1-4烷基);
或者,在可能的情形下,其互变异构体。
8.权利要求1、2、3、4、6或7的式(I)化合物,其中R3为
·2-氧代-噻唑-5-基,在4-位具有合适的吸电子取代基;
·1H-1,2,3-三唑-4-基,在5-位具有合适的取代基;或者
·6-氧代-1H-1,6-二氢吡啶-3-基,在2-位或5-位具有C1-4氟代烷基或氰基。
11.一种药物组合物,包括权利要求1的式(I)的化合物,或其可药用盐,以及可药用佐剂、稀释剂或载体。
12.用于治疗的权利要求1的式(I)的化合物,或其可药用盐。
13.权利要求1的式(I)的化合物,或其可药用盐在制备用于治疗的药物中的用途。
14.一种治疗患有趋化因子介导的疾病状态或处于患所述疾病状态危险的哺乳动物的所述疾病的方法,包括向需要这种治疗的哺乳动物给药治疗有效量的如权利要求1所述的式(I)化合物或其可药用盐。
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CN113121417A (zh) * | 2019-12-30 | 2021-07-16 | 苏州盛迪亚生物医药有限公司 | 一种新型哌啶衍生物及其药物用途 |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102076663A (zh) * | 2008-06-25 | 2011-05-25 | 百时美施贵宝公司 | 作为趋化因子受体活性的调节剂的哌啶衍生物 |
CN102076663B (zh) * | 2008-06-25 | 2013-07-17 | 百时美施贵宝公司 | 作为趋化因子受体活性的调节剂的哌啶衍生物 |
CN113121417A (zh) * | 2019-12-30 | 2021-07-16 | 苏州盛迪亚生物医药有限公司 | 一种新型哌啶衍生物及其药物用途 |
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