CN1732171A - 吡啶并吡咯里嗪和吡啶并吲嗪衍生物 - Google Patents
吡啶并吡咯里嗪和吡啶并吲嗪衍生物 Download PDFInfo
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- CN1732171A CN1732171A CN 200380107732 CN200380107732A CN1732171A CN 1732171 A CN1732171 A CN 1732171A CN 200380107732 CN200380107732 CN 200380107732 CN 200380107732 A CN200380107732 A CN 200380107732A CN 1732171 A CN1732171 A CN 1732171A
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- Prior art keywords
- alkyl
- compound
- independently
- chloro
- halogen
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- WBDYUBOQSGMRIY-UHFFFAOYSA-N 9h-pyrido[3,2-a]pyrrolizine Chemical compound N1=CC=CC2=C3CC=CN3C=C21 WBDYUBOQSGMRIY-UHFFFAOYSA-N 0.000 title abstract description 3
- QRGZLKNNVGYPQL-UHFFFAOYSA-N pyrrolo[2,1-f][1,6]naphthyridine Chemical class C12=CC=CN=C2C=CN2C1=CC=C2 QRGZLKNNVGYPQL-UHFFFAOYSA-N 0.000 title abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 34
- 201000010099 disease Diseases 0.000 claims abstract description 30
- 230000001404 mediated effect Effects 0.000 claims abstract description 14
- 206010028735 Nasal congestion Diseases 0.000 claims abstract description 12
- 208000006673 asthma Diseases 0.000 claims abstract description 10
- 206010039085 Rhinitis allergic Diseases 0.000 claims abstract description 6
- 201000010105 allergic rhinitis Diseases 0.000 claims abstract description 6
- 229940122144 Prostaglandin receptor antagonist Drugs 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 162
- -1 amino, carboxyl Chemical group 0.000 claims description 112
- 239000000203 mixture Substances 0.000 claims description 73
- 238000000034 method Methods 0.000 claims description 44
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 41
- 150000002367 halogens Chemical class 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 238000002360 preparation method Methods 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- 102100029100 Hematopoietic prostaglandin D synthase Human genes 0.000 claims description 17
- 101000988802 Homo sapiens Hematopoietic prostaglandin D synthase Proteins 0.000 claims description 17
- BHMBVRSPMRCCGG-OUTUXVNYSA-N prostaglandin D2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)[C@@H](O)CC1=O BHMBVRSPMRCCGG-OUTUXVNYSA-N 0.000 claims description 17
- BHMBVRSPMRCCGG-UHFFFAOYSA-N prostaglandine D2 Natural products CCCCCC(O)C=CC1C(CC=CCCCC(O)=O)C(O)CC1=O BHMBVRSPMRCCGG-UHFFFAOYSA-N 0.000 claims description 17
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 15
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- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 12
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
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- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
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- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
- NPDLYUOYAGBHFB-WDSKDSINSA-N Asn-Arg Chemical compound NC(=O)C[C@H](N)C(=O)N[C@H](C(O)=O)CCCN=C(N)N NPDLYUOYAGBHFB-WDSKDSINSA-N 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 4
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- 239000002089 prostaglandin antagonist Substances 0.000 claims description 4
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 3
- 125000001118 alkylidene group Chemical group 0.000 claims description 3
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- 239000012964 benzotriazole Substances 0.000 claims description 3
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- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 3
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 3
- 125000000081 (C5-C8) cycloalkenyl group Chemical group 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
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- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 230000008485 antagonism Effects 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 150000002617 leukotrienes Chemical class 0.000 claims description 2
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- 239000011541 reaction mixture Substances 0.000 description 23
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- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 20
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- 239000005557 antagonist Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
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- 238000012360 testing method Methods 0.000 description 11
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
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- 238000002347 injection Methods 0.000 description 7
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
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- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 7
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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Abstract
吡啶并吡咯里嗪和吡啶并吲嗪衍生物是前列腺素受体拮抗剂,它们适用于治疗前列腺素介导的过敏性鼻炎、鼻充血和哮喘等疾病。
Description
发明背景
本发明涉及治疗前列腺素介导疾病的化合物和方法及其某些药用组合物。更具体地讲,本发明化合物与甾族化合物、抗组胺药或肾上腺素能激动剂的结构不同,是D-型前列腺素的鼻充血和肺充血效应的拮抗剂。
两篇综述描述了前列腺素类受体和最常用的选择性激动剂和拮抗剂的特征和治疗意义:Eicosanoids:From Biotechnology toTherapeutic Application(类花生酸:从生物技术到治疗应用),Folco,Samuelsson,Maclouf,和Velo编著,Plenum Press,New York,1996,第14章,137-154和Journal of Lipid Mediators and Cell Signalling,1996,14,83-87。T.Tsuri等,发表于1997年Journal of Medicinal Chemistry,第40卷,第3504-3507页的文章指出,“PGD2被认为是过敏性鼻炎、过敏性哮喘、过敏性结膜炎和过敏性皮炎等多种过敏性疾病的重要介质”。最近,Matsuoka等,
Science(2000),287:2013-7,将PGD2描述为过敏性哮喘的关键介质。此外,美国专利4,808,608等认为前列腺素拮抗剂适用于治疗过敏性疾病,特别是过敏性哮喘。PGD2拮抗剂描述于,例如欧洲专利申请837,052和PCT申请WO98/25919以及WO99/62555。
发明概述
本发明提供作为前列腺素受体拮抗剂的新型化合物;更准确地讲,其为前列腺素D2受体(DP受体)拮抗剂。本发明化合物适用于治疗各种前列腺素介导的疾病和紊乱;因此,本发明提供用本文公开的新型化合物以及含有该化合物的药用组合物治疗前列腺素介导疾病的方法。
发明详述
本发明涉及下式I的化合物及其药学上可接受的盐和水合物,
其中:
A选自任选被1-4个卤原子、O(CH2)1-2和S(CH2)1-2取代的C1-3烷基;
Ar为各自任选被1-4个独立选自Rg的基团取代的芳基或杂芳基;
Q选自:
(1)COOH,
(2)CONRaRb,
(3)C(O)NHSO2Rc,
(4)SO2NHRa,
(5)SO3H,
(6)PO3H2,和
(7)四唑基;
X1、X2、X3或X4之一为氮原子,其余的独立选自CH和C-Rg;
Y1选自-(CRdRe)a-X-(CRdRe)b-、亚苯基、C3-6环烷叉基和C3-6亚环烷基,其中a和b为0-1的整数,以使a和b的和等于0、1或2,X为化学键、O、S、NRa、C(O)、CH(ORa)、OC(O)、C(O)O、C(O)NRa、OC(O)NRa、NRaC(O)、CRd=CRe或C≡C;
Y2选自(CRdRe)m和CRd=CRe;
R1选自H、CN、ORa、S(O)nC1-6烷基和任选被1-6个独立选自卤素、ORa和S(O)nC1-6烷基的基团取代的C1-6烷基;
R2选自H和任选被1-6个卤素取代的C1-6烷基;或
R1和R2一起表示氧代基;或
R1和R2结合在一起形成3元环或4元环,该环含有0个或1个选自NRf、S、和O的杂原子并且任选被1个或2个选自F、CF3和CH3的基团取代;
R3选自H和任选被1-6个独立选自ORa和卤素的基团取代的C1-6烷基;
Ra和Rb独立选自H、C1-10烷基、C2-10烯基、C2-10炔基、Cy和CyC1-10烷基,其中所述烷基、烯基、炔基和Cy任选被1-6个独立选自以下的取代基取代:卤素、氨基、羧基、C1-4烷基、C1-4烷氧基、芳基、杂芳基、芳基C1-4烷基、羟基、CF3、OC(O)C1-4烷基、OC(O)NRiRj和芳氧基;或者Ra和Rb与连接它们的原子一起形成含有0-2个独立选自氧、硫和N-Rf等额外杂原子的4-7元杂环;
Rc选自任选被1-6个卤素、芳基和杂芳基取代的C1-6烷基,其中所述芳基和杂芳基任选被1-3个选自卤素、OC1-6烷基、O-卤代C1-6烷基、C1-6烷基和卤代C1-6烷基的基团取代;
Rd和Re独立地为H、卤素、芳基、杂芳基、C1-6烷基或卤代C1-6烷基;
Rf选自H、C1-6烷基、卤代C1-6烷基、Cy、C(O)C1-6烷基、C(O)卤代C1-6烷基和C(O)-Cy;
Rg选自:
(1)卤素,
(2)CN,
(3)任选被1-8个独立选自芳基、杂芳基、卤素、NRaRb、C(O)Ra、C(ORa)RaRb、SRa和ORa的基团取代的C1-6烷基,其中芳基、杂芳基和烷基各自任选被1-6个独立选自卤素、CF3和COOH的基团取代,
(4)任选被1-6个独立选自卤素和ORa的基团取代的C2-6烯基,
(5)Cy,
(6)C(O)Ra,
(7)C(O)ORa,
(8)CONRaRb,
(9)OCONRaRb,
(10)OC1-6烷基,其中烷基任选被1-6个选自卤素、芳基、杂芳基、OH和OC(O)Ra的取代基取代,
(11)O-Cy,
(12)S(O)nC1-6烷基,其中烷基任选被1-6个选自卤素、芳基、杂芳基、OH、和OC(O)Ra的取代基取代,
(13)S(O)n-Cy,
(14)-NRaS(O)nRb,
(15)-NRaRb,
(16)-NRaC(O)Rb,
(17)-NRaC(O)ORb,
(18)-NRaC(O)NRaRb,
(19)S(O)nNRaRb,
(20)NO2,
(21)C5-8环烯基,
其中Cy任选被1-8个独立选自卤素、C(O)Ra、ORa、C1-3烷基、芳基、杂芳基和CF3的基团取代;
Ri和Rj独立选自H、C1-10烷基、Cy和Cy-C1-10烷基;或
Ri和Rj与连接它们的氮原子一起形成含有0-2个独立选自O、S和N-Rf的额外杂原子的5-7元环;
Cy选自杂环基、芳基和杂芳基;
m为1、2或3;且
n为0、1或2。
本发明也包括含有式I化合物的药用组合物以及用式I化合物治疗或预防前列腺素介导疾病的方法。
除非另有说明,用以下定义详细描述本发明。
术语“卤素”或“卤基”包括F、Cl、Br和I。
术语“烷基”是指含有指定原子数目的直链、支链和环状以及双环结构及其组合。烷基的非限制性实例包括甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、戊基、己基、庚基、辛基、壬基、十一烷基、十二烷基、十三烷基、十四烷基、十五烷基、二十烷基、3,7-二乙基-2,2-二甲基-4-丙基壬基、环丙基、环丁基、环戊基、环己基、环庚基、环丙基甲基、环戊基乙基、甲基取代的环丙基、乙基取代的环丁基、金刚烷基、环十二烷基甲基、2-乙基-1-二环[4.4.0]癸基等。例如,术语C1-6烷基包括具有指定碳原子数目的无环烷基,以及-Cx烷基-Cz环烷基,其中x为0-3,z为3-6,前提条件是x+z=3-6。
“环烷叉基”是指下述二价基,其中连接点在同一碳原子上:
“亚环烷基”是指下述二价基,其中连接点在不同碳原子上:
“亚苯基”是指下述二价基,并且包括1,2-亚苯基、1,3-亚苯基和1,4-亚苯基:
“卤代烷基”是指其中一个或多个氢原子被卤原子置换,直到所有氢原子被卤基完全取代的上述烷基。例如,C1-6卤代烷基包括-CF3、-CH2CF3、-CF2CF3等。
“烷氧基”是指具有指定碳原子数目的直链、支链或环状构型的烷氧基。例如,C1-6烷氧基包括甲氧基、乙氧基、丙氧基、异丙氧基等。
“卤代烷氧基”是指其中一个或多个氢原子被卤原子置换,直到所有氢原子被卤基完全取代的上述烷氧基。例如,C1-6卤代烷氧基包括-OCF3、-OCH2CF3、-OCF2CF3等。
“烯基”是指含有指定碳原子数目的并具有至少一个碳-碳双键的直链和支链结构及其组合,其中氢可被额外碳-碳双键置换。例如,C2-6烯基包括乙烯基、丙稀基、1-甲基乙烯基、丁烯基等。
“杂环基”是指具有1-4个杂原子的非芳族环,所述环是孤离的,或者与第二个选自含有0-4个杂原子的3-7元脂环、芳基和杂芳基稠合,其中所述杂原子独立选自O、N和S。杂环基的非限制性实例包括氧杂环丁烷基、1,3-二硫杂环戊烷、二氢苯并呋喃等。
“芳基”是指6-14元碳环芳环体系,包括1-3个苯环。如果存在两个或更多个环,则环稠合在一起,使得相邻环共享共用键。实例包括苯基和萘基。
本文所用的术语“杂芳基”(Het)表示5-10元芳环体系,含有1个环或2个稠环和1-4个选自O、S和N的杂原子。Het包括但不限于四唑基、苯并噻吩基、喹啉基、苯并噻唑基、呋喃基、嘧啶基、嘌呤基、萘啶基、咪唑基、异噁唑基、异噻唑基、噁二唑基、噁唑基、吡唑基、吡啶基、吡咯基、四嗪基、噻唑基、噻二唑基、噻吩基、三嗪基、三唑基、1H-吡咯-2,5-二酮基、2-吡喃酮、4-吡喃酮、吡咯并吡啶、呋喃并吡啶和噻吩并吡啶。
“治疗有效量”是指由研究人员、兽医、医学博士或其它临床医师所确定的药物在组织、系统、动物或人中引发生物反应或药物反应的量。
术语“治疗”包括减轻、改善、缓解或以其它方式减少疾病或紊乱相关的体征或症状。
术语“预防”是指防止或延迟疾病或紊乱的发生或发展,或者所述疾病或病症相关的体征或症状。
术语“组合物”,当指药用组合物时,意指包括含有活性成分和形成载体的惰性成分(药学上可接受的赋形剂)的制品,以及任何直接或间接生产自以下方式的制品:任两种或更多种成分复合、络合或聚集;或一种或多种成分解离;或一种或多种成分间其它类型的反应或相互作用。因此,本发明药用组合物包括任何由式I化合物和药学上可接受的赋形剂混合制成的组合物。
就式I化合物而言,A的实例包括但不限于CH2、CH2CH2、CH2CH(CH3)、CH(Cl)、CH2CF2CH2、CH(Cl)CH2CH(F)、OCH2、OCH2CH2、SCH2和SCH2CH2。Q的实例包括但不限于CO2H、CONH2、CONHCH3、CONHPh、CON(CH3)2、CON(CH2)4、CONHSO2CH3、SO2NHPh、四唑基等。
Y1的实例包括但不限于CH2、CH2CH2、CH2CH(CH3)、CH(Cl)、CH(Ph)、CH2CH(CF3)、CF2CH2、CH(Cl)CH2CH(F)、OCH2、OCH2CH2、SCH2、CH2SCH2、S、O、C(O)、CH2C(O)、CH2C(O)O、CH2C(O)OCH2、NH、NHC(O)、CH2NHC(O)、CH2NHC(O)CH2、CH=CH、CH2CH=CHCH2、CH2C=C、1,4-亚苯基、1,1-环丙叉基、1,3-亚环己基等。
Ar的实例包括但不限于苯基、2-氯苯基、3-氯苯基、4-氯苯基、2-溴苯基、3-溴苯基、4-溴苯基、2-氟苯基、3-氟苯基、4-氟苯基、3,4-二氯苯基、2,3-二氯苯基、2,4-氯苯基、2,5-二氯苯基、2,6-二氯苯基、3,5-二氯苯基、3-氯-4-氟苯基、2-氯-4-氟苯基、4-氯-2-氟苯基、2-氰基苯基、4-甲基苯基、4-异丙基苯基、4-三氟甲基苯基、联苯基、萘基、3-甲氧苯基、3-羧基苯基、2-甲酰胺基苯基、4-甲氧基苯基、3-苯氧基苯基、4-(4-吡啶基)苯基、4-甲磺酰基苯基、3-二甲氨基苯基、5-四唑基、1-甲基-5-四唑基、2-甲基-5-四唑基、2-苯并噻吩基、2-苯并呋喃基、2-吲哚基、2-喹啉基、7-喹啉基、2-苯并噻唑基、2-苯并咪唑基、1-苯并三唑基、2-呋喃基、3-呋喃基、2-咪唑基、5-咪唑基、5-异噁唑基、4-异噁唑基、4-异噻唑基、1,2,4-噁二唑-5-基、2-噁唑基、4-噁唑基、4-吡唑基、5-吡唑基、2-吡啶基、3-吡啶基、2-吡嗪基、5-嘧啶基、2-吡咯基、4-噻唑基、1,2,4-噻二唑-3-基、1,2,5-噻二唑-4-基、1,2,3-噻二唑-4-基、1,2,5-噁二唑-4-基、1,2,3-噁二唑-4-基、1,2,4-三唑-5-基、1,2,3-三唑-4-基、3-噻吩基、1,2,4-三唑-5-基、吡咯并吡啶、呋喃并[3,2-b]吡啶-2-基、噻吩并[2,3-b]吡啶-2-基、5(H)-2-氧代-4-呋喃基、5(H)-2-氧代-5-呋喃基、(1H,4H)-5-氧代-1,2,4-三唑-3-基、4-氧代-2-苯并吡喃基等。
Y2的实例包括但不限于CH2、CH2CH2、CH2CH2CH2、CH(Cl)、CCl2、CH(CF3)、CH(Ph)、CH2CHCl、C(Cl)=CH2、C(Cl)=C(Cl)、CH=CH、CH=C(CF3)等。
X1、X2、X3和X4的实例包括但不限于N、CH、C-CH3、C-CH(CH3)2、C-Ph、C-Cl、C-Br、C-F、C-CF3、C-C(O)CH3、C-C(O)OH、C-C(O)NH2、C-C(O)N(CH2)2O(CH2)2、C-OCH3、C-OCF3、C-OPh、C-SCH3、C-SOCH3、C-SO2CH3、C-SO2Ph、C-NH2、C-N(CH3)2、C-N(CH3)C(O)CH3、C-N(CH3)C(O)OCH3、C-NHC(O)NHCH3、C-环丙基、C-环丁基、C-环戊基等。
R1的实例包括但不限于氢、氰基、CH3、CH2CH3、CF3、CH2CH2Cl、环丙基等。
R2的实例包括但不限于氢、CH3、CH2CH3、CF3、CH2CH2Cl、环丙基等。
R3的实例包括但不限于氢、CH3、CH2CH3、CF3、CH2CH2Cl、CH2CH2OH、环丙基等。
在式I的一个实施方案中,A-Q部分为CH2CO2H。
在式I的第二个实施方案中,化合物中Y1-Ar部分是S-芳基或C(O)-芳基,其中所述芳基为任选被1-2个选自Rg的基团取代的萘基或苯基。在其一个子集中,Y1-Ar是任选被1个或2个选自卤素、C1-6烷基和三氟甲基取代的S-苯基。
在式I的第三个实施方案中,化合物中X1是氮,X2、X3和X4独立选自CH和CRg。在一个子集中,X2、X3和X4之一是CRg,其余的是CH。在另一子集中,X2、X3和X4之一是CH,其余的是CRg。
在式I的第四个实施方案中,化合物中X3是氮,X1、X2和X4独立选自CH和CRg。在一个子集中,X1、X2和X4之一是CRg,其余的是CH。在另一个子集中,X1、X2和X4之一是CH,其余的是CRg。
在式I的第五个实施方案中,化合物中X1、X2或X3之一是氮,其余的是CH或CRg,X4是CRg。在一个子集中,X1、X2或X3之一是氮,其余的是CH或C-C1-6烷基,X4是任选被ORa取代的C-S(O)n-C1-6烷基或C-C1-6烷基。
在式I的第六个实施方案中,化合物中Y2选自CH2和CH2CH2。
在式I的第七个实施方案中,化合物中R1、R2和R3各自为氢,或者R1和R2一起为氧代基,R3为氢。
式I化合物的一个基团由式Ia表示:
其中X2和X3独立地为CH或C-Rg,A、Ar、Q、Y1、R1、R2、m和Rg如式I所定义。在式Ia的一个实施方案中,化合物中X2和X3各自为CH。在另一实施方案中,化合物中R1和R2各自为H。在又一实施方案中,A-Q是CH2CO2H。在又一实施方案中,Y1-Ar为任选被1个或2个独立选自卤素、C1-6烷基和三氟甲基的基团取代的S-苯基。在又一实施方案中,Rg选自SO2-C1-6烷基和C1-6烷基。
式I化合物的另一基团由式Ib表示:
其中X1和X2独立地为CH或C-Rg,A、Ar、Q、Y1、R1、R2、m和Rg如式I所定义。在式Ia的一个实施方案中,化合物中X1和X2各自为CH。在另一实施方案中,化合物中R1和R2各自为H。在又一实施方案中,A-Q是CH2CO2H。在又一实施方案中,Y1-Ar是任选被独立选自卤素、C1-6烷基和三氟甲基的1个或2个基团取代的S-苯基。在又一实施方案中,Rg选自SO2-C1-6烷基和C1-6烷基。
式I化合物的另一基团由式Ic代表:
其中X1、X2和X3中的一个是N,其余的各自为CH,X4是CRg,m是1或2,Ar、Y1和m如式I所定义。在一个实施方案中,Ar为任选被1个或2个独立选自卤素、C1-3烷基和三氟甲基的基团取代的苯基。在另一实施方案中,Y1是S或C(O)。在又一实施方案中,X4选自任选被ORa取代的C-S(O)n-C1-6烷基和C-C1-6烷基。
代表性的式I化合物列于下表:
X1 | X2 | X3 | X4 | Ar | Y1 | m |
N | CH | CH | C(SO2CH3) | 4-Cl-Ph | S | 2 |
N | CH | CH | C(SCH3) | 4-Cl-Ph | S | 2 |
N | CH | CH | C(SO2CH3) | 3,4-二氯-Ph | S | 2 |
N | CH | CH | C(SO2CH3) | 4-Cl-Ph | C(O) | 2 |
N | CH | CH | C(SO2CH3) | 4-Br-Ph | S | 2 |
CH | CH | N | C(SO2CH3) | 3,4-二氯-Ph | S | 1 |
CH | CH | N | C(SO2CH3) | 3,4-二氯-Ph | S | 2 |
N | CH | CH | C(SO2CH3) | 4-CF3-Ph | S | 2 |
N | CH | CH | C(SO2CH3) | 2-Cl-4-F-Ph | S | 2 |
N | CH | CH | C(SO2CH3) | 2-萘基 | S | 2 |
N | CH | CH | C(SO2CH3) | 2,3-二氯-Ph | S | 2 |
N | CH | CH | C(SO2CH3) | 4-CH3-Ph | S | 2 |
X1 | X2 | X3 | X4 | Ar | Y1 | m |
N | CH | CH | C(SO2CH3) | Ph | S | 2 |
N | CH | CH | C(SO2CH3) | 2,4-二氯-Ph | S | 2 |
CH | N | CH | C(SO2CH3) | 4-Cl-Ph | S | 2 |
CH | CH | N | C(SO2CH3) | 4-Cl-Ph | S | 2 |
N | C(CH3) | CH | C(SO2CH3) | 4-Cl-Ph | S | 2 |
N | CH | C(CH3) | C(SO2CH3) | 4-Cl-Ph | S | 2 |
CH | C(CH3) | N | C(SO2CH3) | 4-Cl-Ph | S | 2 |
C(CH3) | CH | N | C(SO2CH3) | 4-Cl-Ph | S | 2 |
N | CH | CH | C(CH(CH3)2) | 4-F-Ph | S | 2 |
N | CH | CH | C(CH(CH3)2) | 4-Cl-Ph | S | 2 |
N | CH | CH | C(CH(CH3)2) | 2,4-二氯-Ph | S | 2 |
N | CH | CH | C(CH(CH3)2) | 4-Br-Ph | S | 2 |
N | CH | CH | C(CH(CH3)2) | 2-Cl-4-F-Ph | S | 2 |
N | CH | CH | C(CH(CH3)2) | 3,4-二氯-Ph | S | 2 |
CH | CH | N | C(CH(CH3)2) | 4-F-Ph | S | 2 |
CH | CH | N | C(CH(CH3)2) | 4-Cl-Ph | S | 2 |
CH | CH | N | C(CH(CH3)2) | 2,4-二氯-Ph | S | 2 |
CH | CH | N | C(CH(CH3)2) | 4-Br-Ph | S | 2 |
CH | CH | N | C(CH(CH3)2) | 2-Cl-4-F-Ph | S | 2 |
CH | CH | N | C(CH(CH3)2) | 3,4-二氯-Ph | S | 2 |
CH | CH | N | C(CH(CH3)2) | 4-F-Ph | S | 1 |
CH | CH | N | C(CH(CH3)2) | 4-Cl-Ph | S | 1 |
CH | CH | N | C(CH(CH3)2) | 2,4-二氯-Ph | S | 1 |
CH | CH | N | C(CH(CH3)2) | 4-Br-Ph | S | 1 |
CH | CH | N | C(CH(CH3)2) | 2-Cl-4-F-Ph | S | 1 |
CH | CH | N | C(CH(CH3)2) | 3,4-二氯-Ph | S | 1 |
CH | N | CH | C(CH(CH3)2) | 4-F-Ph | S | 1 |
CH | N | CH | C(CH(CH3)2) | 4-Cl-Ph | S | 1 |
CH | N | CH | C(CH(CH3)2) | 2,4-二氯-Ph | S | 1 |
CH | N | CH | C(CH(CH3)2) | 4-Br-Ph | S | 1 |
CH | N | CH | C(CH(CH3)2) | 2-Cl-4-F-Ph | S | 1 |
CH | N | CH | C(CH(CH3)2) | 3,4-二氯-Ph | S | 1 |
X1 | X2 | X3 | X4 | Ar | Y1 | m |
CH | N | CH | C(CH(CH3)2) | 4-F-Ph | S | 2 |
CH | N | CH | C(CH(CH3)2) | 4-Cl-Ph | S | 2 |
CH | N | CH | C(CH(CH3)2) | 2,4-二氯-Ph | S | 2 |
CH | N | CH | C(CH(CH3)2) | 4-Br-Ph | S | 2 |
CH | N | CH | C(CH(CH3)2) | 2-Cl-4-F-Ph | S | 2 |
CH | N | CH | C(CH(CH3)2) | 3,4-二氯-Ph | S | 2 |
N | CH | CH | C(CH(OCH3)(CH2CH3)) | 4-Cl-Ph | S | 2 |
N | CH | CH | C(CH(OCH3)(CH2CH3)) | 4-Cl-Ph | S | 1 |
CH | N | CH | C(CH(OCH3)(CH2CH3)) | 4-Cl-Ph | S | 1 |
CH | N | CH | C(CH(OCH3)(CH2CH3)) | 4-Cl-Ph | S | 2 |
CH | CH | N | C(CH(OCH3)(CH2CH3)) | 4-Cl-Ph | S | 2 |
CH | CH | N | C(CH(OCH3)(CH2CH3)) | 4-Cl-Ph | S | 1 |
N | CH | CH | C(C(CH3)3) | 4-Cl-Ph | S | 2 |
N | CH | CH | C(C(CH3)3) | 3,4-二氯-Ph | S | 2 |
N | CH | CH | C(C(CH3)3) | 4-Br-Ph | S | 2 |
N | CH | CH | C(C(CH3)3) | 4-CF3-Ph | S | 2 |
N | CH | CH | C(C(CH3)3) | 2-Cl-4-F-Ph | S | 2 |
N | CH | CH | C(C(CH3)3) | 2-萘基 | S | 2 |
N | CH | CH | C(C(CH3)3) | 2,3-二氯-Ph | S | 2 |
N | CH | CH | C(C(CH3)3) | 4-CH3-Ph | S | 2 |
N | CH | CH | C(C(CH3)3) | Ph | S | 2 |
N | CH | CH | C(C(CH3)3) | 2,4-二氯-Ph | S | 2 |
Ar | Y1 |
5-四唑基 | S |
2-吡咯基 | S |
1,2,4-三唑-3-基 | S |
1,2,3-三唑-4-基 | S |
5-咪唑基 | S |
4-吡唑基 | S |
5-吡唑基 | S |
(1H,4H)-5-氧代-1,2,4-三唑-3-基 | S |
4-异噻唑基 | S |
1,2,5-噻二唑-5-基 | S |
1,2,5-噁二唑-5-基 | S |
3-呋喃基 | S |
1,2,3-噻二唑-4-基 | S |
1,2,3-噁二唑-4-基 | S |
4-异噁唑基 | S |
3-噻吩基 | S |
4-噁唑基 | S |
4-噻唑基 | S |
(5H)-2-氧代-5-呋喃基 | S |
(5H)-2-氧代-4-呋喃基 | S |
1,2,4-噁二唑-5-基 | S |
3-吡啶基 | S |
2-吡嗪基 | S |
5-嘧啶基 | S |
2-吲哚基 | S |
2-苯并噻吩基 | S |
2-苯并呋喃基 | S |
4-氧代-苯并吡喃-2-基 | S |
2-喹啉基 | S |
2-苯并咪唑基 | S |
2-苯并噁唑基 | S |
2-苯并噻唑基 | S |
1-苯并三唑基 | CH2S |
噻吩并[2,3-b]吡啶-2-基 | S |
对于本说明书而言,下述缩写具有指定的含义:
Ac =乙酰基
AcO =乙酸酯
BOC =叔丁氧羰基
CBZ =苄氧羰基
CDI =羰基二咪唑
DCC =1,3-二环己基碳二亚胺
DCE =1,2-二氯乙烷
DIBAL =二异丁基氢化铝
DIEA =N,N-二异丙基乙胺
DMAP =4-(二甲氨基)吡啶
DMF =二甲基甲酰胺
EDCI =1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐
EDTA =乙二胺四乙酸,四钠盐水合物
FAB =快原子轰击
FMOC =9-芴甲氧羰基
HMPA =六甲基磷酰三胺
HATU =六氟合磷酸O-(7-氮杂苯并三唑-1-
基)N,N,N′,N′-四甲基脲鎓
HOBt =1-羟基苯并三唑
HRMS =高分辨率质谱仪
ICBF =氯甲酸异丁酯
KHMDS =六甲基二硅氮烷钾
LDA =二异丙基氨基锂
MCPBA =间氯过苯甲酸
MMPP =单过氧邻苯二甲酸镁六水合物
Ms =甲磺酰基
MsO =甲磺酸酯
NBS =N-溴代琥珀酰亚胺
NMM =4-甲基吗啉
NMP =N-甲基吡咯烷酮
PCC =氯铬酸吡啶鎓
PDC =重铬酸吡啶鎓
Ph =苯基
PPTS =对甲苯磺酸吡啶鎓
pTSA =对甲苯磺酸
PyH·Br3 =吡啶氢溴酸盐·合溴
r.t./RT =室温
rac. =外消旋的
TFA =三氟乙酸
TfO =三氟甲磺酸酯
THF =四氢呋喃
TLC =薄层色谱法
TMSCl =三甲基甲硅烷基氯
烷基缩写
Me =甲基
Et =乙基
n-Pr =正丙基
i-Pr =异丙基
c-Pr =环丙基
n-Bu =正丁基
i-Bu =异丁基
c-Bu =环丁基
s-Bu =仲丁基
t-Bu =叔丁基
光学异构体-非对映体-互变异构体
式I化合物含有一种或多种不对称中心,可因此作为外消旋体和外消旋体混合物、单一对映体、非对映体混合物和单一非对映体存在。本发明意指包括所有这种式I化合物的异构体形式。
本文所述的一些化合物可存在有不同的氢连接点,称为互变异构体。这种实例可以是称为酮-烯醇式互变异构体的酮及其烯醇。单一互变异构体及其混合物也在式I化合物范围内。
可将式I化合物分成对映体的非对映异构体对,方法为,例如在甲醇或乙酸乙酯或其混合物等合适的溶剂中分级结晶。这种方法得到的对映体对可用常规方法分成单一立体异构体,例如用旋光酸或碱作为拆分剂,或用手性柱通过HPLC等手性分离技术分离。
或者,任何通式I或Ia化合物的对映体可用已知构型的旋光纯的原料或试剂通过立体有择合成获得。
盐
术语“药学上可接受的盐”是指由药学上可接受的包括无机碱或有机碱在内的无毒碱制成的盐。从无机碱衍生的盐包括铝盐、铵盐、钙盐、铜盐、三价铁盐、二价铁盐、锂盐、镁盐、三价锰盐、二价锰盐、钾盐、钠盐、锌盐等。特别优选的盐是铵盐、钙盐、镁盐、钾盐和钠盐。从药学上可接受的有机无毒碱衍生的盐包括伯胺盐、仲胺盐和叔胺盐,取代胺(包括天然存在的取代胺)、环胺和碱性离子交换树脂,例如精氨酸、甜菜碱、咖啡因、胆碱、N,N′-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基-吗啉、N-乙基哌啶、葡糖胺、氨基葡糖、组氨酸、海巴胺、异丙胺、赖氨酸、甲葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
当本发明化合物为碱性时,则其盐可从包括无机酸和有机酸在内的药学上可接受的无毒酸制备。这些酸包括乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、富马酸、葡糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、扑姆酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、对甲苯磺酸等。特别优选的是柠檬酸、氢溴酸、盐酸、马来酸、磷酸、硫酸和酒石酸。
不言而喻,除非另有说明,所涉及的式I化合物也意指包括在药学上可接受的盐范围内。
实用性
式I化合物是前列腺素D2的拮抗剂。式I化合物与前列腺素D2受体相互作用的能力使得其适用于预防或逆转由前列腺素引起的哺乳动物,尤其是病人的不良症状。前列腺素D2的拮抗作用表明所述化合物及其药用组合物适用于治疗、预防或改善哺乳动物、尤其是人的下述疾病:呼吸系统疾病、过敏性疾病、疼痛、炎性疾病、粘液分泌紊乱、骨病、睡眠障碍、生育机能障碍、血液凝固障碍、视觉障碍以及免疫和自身免疫病。此外,这种化合物可抑制细胞致瘤性转化和转移瘤生长,因此可用于治疗癌症。式I化合物也可用于治疗和/或预防前列腺素D2介导的增殖性疾病,例如可发生在糖尿病性视网膜病和肿瘤血管生成。式I化合物也可通过拮抗收缩性前列腺素类或模拟松弛性前列腺素类来抑制前列腺素类诱导的平滑肌收缩,并因此可适用于治疗痛经、早产和嗜酸性细胞相关疾病。
因此,本发明另一方面提供治疗或预防前列腺素D2介导疾病的方法,包括给予需要这种治疗的哺乳动物患者治疗或预防所述前列腺素D2介导疾病有效量的式I化合物。前列腺素D2介导的疾病包括但不限于过敏性鼻炎、鼻充血、鼻溢、常年性鼻炎、鼻炎、包括过敏性哮喘在内的哮喘、慢性阻塞性肺病和其它形式的肺炎;肺循环低血压;睡眠障碍和睡眠/觉醒周期紊乱;前列腺素类诱导的平滑肌收缩相关的痛经和早产;嗜酸性细胞相关疾病;血栓形成;青光眼和视觉疾病;闭塞性血管病,例如动脉粥样硬化;充血性心力衰竭;外伤后或外科手术后等需要抗凝治疗的疾病或病症;类风湿性关节炎和其它炎性疾病;坏疽;雷诺病(Raynaud′s disease);包括细胞保护作用在内的粘液分泌病;疼痛和偏头痛;骨质疏松症等需要控制骨形成和重吸收的疾病;休克;包括发热在内的热调节;器官移植和分流术的排斥以及需要免疫调节的免疫疾病或病症。更具体地讲,待治疗的疾病为前列腺素D2介导的鼻充血、过敏性鼻炎、肺充血和包括过敏性哮喘在内的哮喘等疾病。
剂量范围
式I的化合物的预防性或治疗性剂量大小,理所当然会随所治疗疾病的性质和严重程度以及具体式I的化合物及其给药途径变化而变化。也会随包括年龄、体重、总体健康状况、性别、饮食、给药时间、排泄率、药物组合和患者的个体反应在内的各种因素的变化而变化。一般来讲,每哺乳动物日剂量为约0.001mg/kg至约100mg/kg体重,优选0.01mg/kg至约10mg/kg。另一方面,在一些情况下有必要用应用这些限制以外的剂量。
活性成分可与载体材料结合以生产单剂型,其用量根据待治疗宿主和具体给药模式而变化。例如,目的在于人用的口服给药制剂可含有0.05mg至5g的活性剂,该剂与占总组合物约5%至约99.95%的适当和方便量的载体材料混合。剂量单位形式通常会含有约0.1mg至约0.4g的活性成分,典型的为0.5mg、1mg、2mg、5mg、10mg、25mg、50mg、100mg、200mg或400mg。
药用组合物
本发明另一发面提供包含式I化合物和药学上可接受的载体的药用组合物。术语“组合物”,当指药用组合物时,意指包括含有活性成分和形成载体的惰性成分(药学上可接受的赋形剂)的制品,以及任何直接或间接生产自以下方式的制品:任两种或更多种成分复合、络合或聚集;或一种或多种成分解离;或一种或多种成分间其它类型的反应或相互作用。因此,本发明药用组合物包括任何由式I化合物、另外的活性成分和药学上可接受的赋形剂混合制成的组合物。
为治疗任何前列腺素类介导的疾病,式I化合物可以含有常规无毒药学上可接受的载体、辅药和赋形剂的单位剂量剂型,通过吸入喷雾口腔给药、局部给药、胃肠外给药或直肠给药。本文所用的术语胃肠外包括皮下注射、静脉内、肌内、胸骨内注射或输注技术。除治疗小鼠、大鼠、马、牛、绵羊、狗、猫等温血动物外,本发明化合物可有效治疗人类。
含有活性成分的药用组合物可以口腔适用的形式,例如片剂、药片、锭剂、水性或油性混悬剂、散剂或颗粒剂、乳剂、硬或软胶囊剂或糖浆剂或酏剂。打算做口腔应用的组合物可根据本领域任何已知制备药用组合物的方法制备,这种组合物可含有一种或多种选自以下的添加剂:甜味剂、矫味剂、着色剂、防腐剂,以提供药用精美和适口的制剂。片剂含有活性成分和适用于制备片剂的无毒药学上可接受的赋形剂的混合物。这些赋形剂可以是,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠等惰性稀释剂;玉米淀粉或海藻酸等制粒剂和崩解剂;淀粉、明胶或阿拉伯胶等粘合剂以及硬脂酸镁、硬脂酸或滑石粉等润滑剂。片剂可以是素片,或用已知技术包衣以延迟胃肠道内的崩解和吸收并因此提供较长时间的持续作用。例如,可以使用单硬脂酸甘油酯或二硬脂酸甘油酯等时间延迟材料。也可以使用美国专利4,256,108、4,166,452和4,265,874描述的包衣技术以制备控释渗透治疗片。
应用于口腔的剂型也可以硬明胶胶囊剂存在,其中活性成分与碳酸钙、磷酸钙或高岭土等惰性固体稀释剂混合在一起,或以软明胶胶囊形式存在,其中活性成分与丙二醇、聚乙二醇和乙醇等水混溶性溶剂混合在一起,或与花生油、液体石蜡或橄榄油等油性介质混合在一起。
水性混悬剂含有活性材料与适用于制备水性混悬剂的赋形剂的混合物。这种赋形剂是羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、西黄蓍胶和阿拉伯胶等悬浮剂;分散剂或湿润剂可以是卵磷脂等天然存在磷脂,或硬脂酸聚氧乙烯酯等烯化氧与脂肪酸的缩合物,或十七烷乙烯氧基鲸蜡醇等环氧乙烷与长链脂肪族醇的缩合物,或单油酸聚氧乙烯山梨醇酯等环氧乙烷与从脂肪酸和己糖醇得来的偏酯的缩合物,或单油酸聚乙烯脱水山梨醇酯等环氧乙烷与从脂肪酸和己糖醇脱水物得来的偏酯的缩合物。水性混悬剂也可含有一种或多种防腐剂如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯等、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂如蔗糖、糖精或天冬甜素。
油性混悬剂可通过使活性成分悬浮于植物油(例如花生油、橄榄油、芝麻油或椰子油)或矿物油(例如液体石蜡)中来配制。油性混悬剂可含有增稠剂,例如蜂蜡,固体石蜡或鲸蜡醇。可加入上述甜味剂和矫味剂以提供适口的口服制剂。这些组合物可通过加入抗坏血酸等抗氧化剂加以保存。
适用于加水制备成水性混悬剂的散剂和颗粒剂,提供与分散剂或湿润剂、悬浮剂以及一种或多种防腐剂混合的活性成分。通过以上叙述示例了合适的分散剂或湿润剂、悬浮剂。也可存在甜味剂、矫味剂和着色剂等额外赋形剂。
本发明药用组合物也可以是水包油型乳剂形式。油相可以是橄榄油或花生油等植物油,也可以是液体石蜡等矿物油,或是上述油的混合物。合适的乳化剂可以是大豆磷脂、卵磷脂等天然存在的磷脂,可以是单油酸脱水山梨醇酯等从脂肪酸和己糖醇脱水物得到的酯或偏酯,也可以是单油酸聚氧乙烯脱水山梨醇酯等所述偏酯与环氧乙烷的缩合物。所述乳剂也可含有甜味剂和矫味剂。
糖浆剂和酏剂可用甜味剂调配,例如甘油、丙二醇、山梨醇或蔗糖。这种制剂也可含有缓和剂、防腐剂以及矫味剂和着色剂。所述药用组合物可以是无菌注射水性或油性混悬剂形式。这种混悬剂可根据已知技术用上述合适的分散剂或湿润剂调配。所述无菌注射制剂也可为溶于或混悬于无毒胃肠外稀释剂或溶剂的无菌注射液或悬浮液,例如1,3-丁二醇溶液。与所述可接受载体和溶剂一道可以被利用的有水、林格氏液和等渗氯化钠溶液。也可以使用乙醇、丙二醇或聚乙二醇等助溶剂。此外,无菌的固定油照例用作溶剂或悬浮介质。为了这一目的,可使用任何温和的包括合成甘油单酯或甘油二酯在内的固定油。此外,油酸等脂肪酸可用于注射制剂。
式I化合物也可以用于直肠给药的栓剂形式给予。这些组合物可通过混合药物与合适的非刺激性赋形剂来制备,所述赋形剂在环境温度下是固体,但在直肠温度下是液体,因此在直肠内融化释放出药物。这种材料是可可脂和聚乙二醇。
用于局部,使用含有式I的化合物的乳膏剂、软膏剂、凝胶剂、溶液剂或混悬剂等。(为了这种应用的目的,局部应用应包括漱口剂和含漱剂)。局部制剂通常可包括药用载体、助溶剂、乳化剂、渗透增强剂、防腐系统和软化剂。
与其它药物联用
为治疗和预防前列腺素介导的疾病,式I化合物可与其它治疗药共同给药。因此,本发明另一方面提供治疗前列腺素D2介导疾病的药用组合物,其包含治疗有效量的式I的化合物和一种或多种其它治疗药。适合于与式I的化合物联合治疗的治疗药包括:(1)前列腺素受体拮抗剂;(2)曲安奈德等皮质类固醇;(3)β-激动剂,例如沙美特罗、福莫特罗、特布他林、奥西那林、沙丁胺醇等;(4)白三烯调节剂,例如白三烯拮抗剂、或脂加氧酶抑制剂例如孟鲁司特、扎鲁司特、普仑司特或齐留通;(5)抗组胺药(组胺H1拮抗药)例如溴非尼拉敏、氯苯那敏、右氯苯那敏、曲普利啶、氯马斯汀、苯海拉明、二苯拉林、曲吡那敏、羟嗪、甲地嗪、异丙嗪、阿利马嗪、阿扎他定、赛庚啶、安他唑啉、非尼拉敏、美吡拉敏、阿司咪唑、诺阿斯米唑、特非那定、氯雷他定、西替利嗪、左西替利嗪、非索非那定、地氯雷他定等;(6)减充血药,包括苯福林、苯丙醇胺、伪麻黄碱、羟甲唑啉、肾上腺素、萘甲唑啉、赛洛唑啉、六氢脱氧麻黄碱或左旋去氧麻黄碱;(7)镇咳药,包括可卡因、二氢可待因酮、卡拉美芬、喷托维林或右甲吗喃;(8)另一前列腺素配体,包括前列腺素F激动剂,例如拉坦前列素;米索前列醇、恩前列素、利奥前列素、奥诺前列醇或罗沙前列醇;(9)利尿药;(10)非甾体抗炎药(NSAID),例如丙酸衍生物(阿明洛芬、苯噁洛芬、布氯酸、卡洛芬、芬布芬、非诺洛芬、氟洛芬、氟比洛芬、布洛芬、吲哚洛芬、酮洛芬、咪洛芬、萘普生、奥沙丙秦、吡洛芬、普拉洛芬、舒洛芬、噻洛芬酸和硫噁洛芬)、乙酸衍生物(吲哚美辛、阿西美辛、阿氯芬酸、环氯茚酸、双氯芬酸、芬氯酸、芬克洛酸、芬替酸、呋罗芬酸、异丁芬酸、伊索克酸、庚乙酸、舒林酸、硫平酸、托美丁、齐多美辛和佐美酸)、芬那酸衍生物(氟芬那酸、甲氯芬那酸、甲芬那酸、尼氟芬那酸和托芬那酸)、联苯羧酸衍生物(二氟尼柳和氟苯柳)、苯并噻嗪类(伊索昔康、吡罗昔康、舒多昔康和替诺昔康)、水杨酸盐(乙酰水杨酸、柳氮磺胺吡啶)和吡唑啉酮(阿扎丙宗、苄哌吡酮、非普拉宗、莫非布宗、羟布宗、保泰松);(11)环氧合酶-2(COX-2)抑制剂,例如塞来考昔和罗非考昔、艾托考昔和伐地考昔;(12)磷酸二酯酶IV型(PDE-IV)抑制剂,例如吲达帕胺、罗氟司特;(13)趋化因子受体拮抗剂,尤其是CCR-1、CCR-2和CCR-3拮抗剂;(14)降胆固醇药,例如HMG-CoA还原酶抑制剂(洛伐他汀、辛伐他汀和普伐他汀、氟伐他汀、阿托伐他汀和其它他汀类药物)、螯合剂(考来烯胺和考来替泊)、烟酸、非诺贝酸衍生物(吉非贝齐、氯贝特、非诺贝特和苯扎贝特)和普罗布考;(15)抗糖尿病药,例如胰岛素、磺酰脲类、双胍(二甲双胍)、α-糖苷酶抑制剂(阿卡波糖)和格列酮类(曲格列酮、匹格列酮、恩格列酮、罗格列酮等);(16)干扰素β制剂(干扰素β-1a、干扰素β-1b);(17)抗胆碱能药,例如毒蕈碱拮抗剂(异丙托溴铵和噻托溴铵)以及选择性毒蕈碱M3拮抗剂;(18)类固醇,例如倍氯米松、甲泼尼龙、倍他米松、泼尼松、地塞米松和氢化可的松;(19)通常用于治疗偏头痛的曲坦类,例如舒马曲坦和利扎曲普坦;(20)阿仑膦酸和其它骨质疏松症治疗药;(21)其它化合物,例如5-氨基水杨酸及其前药、抗代谢药,例如硫唑嘌呤和6-巯基嘌呤、细胞毒癌化疗药、缓激肽(BK2或BK1)拮抗剂、塞曲司特、神经激肽拮抗剂(NK1/NK2)等TP受体拮抗剂、美国专利5,510,332、WO97/03094、WO97/02289、WO96/40781、WO96/22966、WO96/20216、WO96/01644、WO96/06108、WO95/15973和WO96/31206等叙述的VLA-4拮抗剂。
此外,本发明所包括的治疗前列腺素D2介导疾病的方法,该方法包括给予需要这种治疗的患者治疗有效量的式I的化合物,并且与一种或多种以上刚列出的成分共同给予。当单独给予活性成分时,其用量可为各个活性成分常规用量,或者在一些情况下,活性成分合用可导致一种或多种活性成分的较低剂量。
合成方法
本发明式I的化合物可根据流程图A-F概述的合成路线,并按照本文提供的实施例描述的方法制备。本文提供的流程图和具体实施例以说明为目的,本领域技术人员会意识到其它本发明化合物可以类似方法用说明性步骤制备,或通过本领域熟知的官能团相互转换步骤得到,或用有机合成领域技术人员已知的其它其它步骤制备。
方法A
吡啶1可进行甲酰化作用得到醛2,其步骤描述于J.HeterocyclicChem.,第81页,(1988),Heterocycles第151页,1993或Synthesis,第306页(1999)。卤素用甲硫醇钠或甲醇钠替代,然后与叠氮乙酸甲酯缩合产生叠氮烯烃4,在热环境下环化得到吲哚5(参见例如,Tetrahedron Lett.,2000,41:4777-4780)。为得到稠合的5元环系列,在KOtBu存在下用丙烯酸甲酯处理化合物5,然后用HCl/EtOH脱羧基得到6(m=1)。为得到稠合的6-7元环系列,用NaH/DMF和合适的溴代酯处理化合物5,然后用KOtBu/THF进行环化,最后用HCl/EtOH实现脱羧得到6(m=2、3)。酯7的形成用Reformatsky条件进行,然后用TMSCl/NaI脱氧,或者通过Horner-Emmonds反应然后经PtO2或Pd(OH)2氢化。或者,通过还原作用用乙醇-THF中的NaBH4将6转化成7,然后用NaHMDS作为碱与氯磷酸二苯酯反应。所得磷酸酯用丙二酸二甲酯和NaHMDS处理。将该双酯在DMSO中与NaCl一起加热得到7。
流程图A
NaH/DMF
2)H2/PtO2 m=1,2,3
MeOH/THF R=Me,Et
或H2/Pd(OH)2/MeOH Y=Cl,o
或 Z=O或S
1)NaBH4/EtOH
2)(PhO)2POCl/NaHMDS
3)MeO2CCH2CO2Me/NaHMDS
4)NaCl/DMSO
方法B
化合物7与合适的酰氯在1,2二氯乙烷中进行的Friedel-Crafts反应,得到相应的酮8。接着用氢氧化钠使酯裂开,得到酸9。为制备硫醚11,用SO2Cl2在1,2二氯乙烷中处理合适的二硫化物,得到相应的亚磺酰氯,然后将其与化合物7反应,得到硫醚酯10。用氢氧化钠水溶液水解10得到酸11。
流程图B
方法C
硫醚化合物8a可用Na2WO4/H2O2氧化,得到相应的砜酯,将其水解得到砜酸12。化合物7a可同样被氧化,所得砜13可按照流程图B中所述步骤合成为硫醚14。
流程图C
方法D
将溴吡啶醛2a用方法A所述反应步骤合成为化合物15。酯和异丙基部分的引入见下述。Reformatsky反应后,用TMSCl/NaI脱氧,然后用钯介导与2-溴丙烯偶合,接着氢化得到16。或者,Horner-Emmonds反应后用钯介导与2-溴丙烯偶合,最后氢化两个烯烃,得到16,按照流程图B所述将其合成为化合物17。也可将异丙基在合成早期引入。化合物2a可如方法A化合物5的制备中所示被转化成吖吲哚酯。将异丙基如所述用钯介导与2-溴丙烯偶合,从而引入。
流程图D
方法E
吖吲哚18可按照J.Heterocyclic Chem.359(1992)中步骤制备。用碱处理18,然后通过CO2和重氮甲烷得到酯19,接着通过方法A和B中所述化学过程将其进一步官能化,得到酸23。或者,缩合2-吡啶甲醛与叠氮基乙酸甲酯得到叠氮基烯烃25,将其在热条件下环化得到酯19,将其继续进行得到酸23。
流程图E
可供选择的方法:
方法F
按照方法A所述通用方法从2-氯吡啶制备化合物26。然后用三丁基异丙稀基锡烷(J.Org.Chem.1988,第3218页)和三(二亚苄基丙酮)合二钯在三苯基砷存在下,将酮26转化成甲基乙烯基化合物27。酮27的Wittig Horner反应后,氢化得到酯28。酯28被转化成化合物29。将对映体在手性HPLC OD柱上分离,然后水解得到30和31。
生物学活性测定试验
式I化合物可通过用下述试验测定其体外和体内前列腺素类拮抗剂或激动剂活性及其选择性而得到检验。得到证明的前列腺素受体活性为DP、EP1、EP2、EP3、EP4、FP、IP和TP。
人胚肾(HEK)293(ebna)细胞系中前列腺素类受体的稳定表达
将全长编码序列的前列腺素类受体cDNA亚克隆到哺乳动物表达载体的合适位点中,并转染到HEK 293(ebna)细胞中。表达个体cDNA的HEK 293(ebna)细胞在选择条件下生长,生长2-3周后用接种克隆环法分离单菌落并随后扩展成克隆细胞系。
前列腺素类受体结合试验
培养并收获HEK 293(ebna)细胞,在蛋白酶抑制剂存在下裂解细胞,接着通过差速离心制备膜,供受体结合试验使用。前列腺素类受体结合试验在含有1mM EDTA、10mM二价阳离子和合适放射性配体的10mM MES/KOH(pH6.0)(EP、FP和TP)或10mMHEPES/KOH(pH7.4)(DP和IP)中进行。反应自加入膜蛋白开始。将配体加入二甲亚砜中,在所有孵育(体系)中保持恒定在1%(v/v)。在1μM相应非放射性前列腺素类存在下测定非特异性结合。在室温下或30℃保温60分钟,然后快滤。用总结合减去非特异性结合来计算特异性结合。在各个配体浓度的剩余特异性结合以配体浓度的函数来计算和表示,以绘制用于测定配体亲和性的S形浓度-反应曲线。
前列腺素类受体激动剂和拮抗剂试验
进行测量刺激(HEK 293(ebna)细胞中EP2、EP4、DP和IP)或抑制(人红白血病(HEL)细胞中EP3)细胞内cAMP蓄积或细胞内钙活动化(用脱辅基-水母发光蛋白稳定转染的HEK 293(ebna)细胞中EP1、FP和TP)的全细胞第二信使试验,以确定受体配体是激动剂还是拮抗剂。就cAMP试验而言,收获细胞并将其重悬于含有25mM HEPES,pH7.4的HBSS中。孵育(体系)含有100μM RO-20-1724(IV型磷酸二酯酶抑制剂,购自Biomol),在仅仅EP3抑制试验情况下,还含有15μM毛喉素以刺激cAMP产生。样品于37℃保温10分钟,终止反应并测定cAMP水平。对于钙活动化试验,细胞带有辅因子还原型谷胱甘肽和腔肠素,收获并重悬于Ham′s F12培养基。通过监测由钙与细胞内发光蛋白水母发光蛋白结合而激发的发光来测定钙活动化。将配体加入到二甲亚砜中,在所有孵育(体系)中保持恒定在1%(v/v)。对于激动剂,第二信使反应表示为配体浓度的函数,计算相对于前列腺素类标准的EC50值和最大反应。对于拮抗剂,配体抑制激动剂反应的能力通过Schild分析测定,计算KB和斜率值。
预防PGD2或变应原诱导的过敏性绵羊的鼻充血
动物准备:使用健康成年绵羊(18-50kg)。这些动物基于对皮内注射猪蛔虫(Ascaris suum)提取物自然阳性皮肤反应挑选。
鼻充血的测量:实验用意识清醒的动物进行。将动物置于手推车中,俯卧位,头部固定。鼻腔导气管阻力(NAR)用修改的面具鼻测量技术测量。为插入鼻气管插管对鼻通道进行局部麻醉(2%利多卡因)。将管最大端与呼吸速率计连接,血流和血压信号记录在用于联机计算NAR的计算机的示波器上。通过给予雾化溶液来完成(10揿/鼻孔)进行鼻攻击试验。记录攻击前和攻击后60-120分钟后的NAR充血的变化。
预防PGD2和变应原诱导的短尾猴的鼻塞
动物准备:使用健康成年雄性短尾猴(4-10kg)。这些动物基于对皮内注射猪蛔虫提取物天然阳性皮肤反应挑选。每个实验前,选用来研究的猴子禁食过夜,随意饮水。第二天早晨,从其居住的笼子移出前,用氯胺酮镇静(10-15mg/kg肌注)。将其置于加热台上(36℃),大剂量注射(5-12mg/kg静脉注射)丙泊酚。将动物用具套囊气管(4-6mm直径)进行插管,并通过连续静脉内输入丙泊酚(25-30mg/kg/h)维持麻醉。在实验全程监测生命体征(心率、血压、呼吸频率、体温)。
鼻充血的测量:通过与气管相连的呼吸速度描记器测量动物呼吸阻力,以确保其正常。用Ecovision accoustic量鼻器评价鼻充血。该技术给出非侵入性2D鼻内超声波回声图。用配备有客户定制软件(Hood Laboratories,Mass,U.S.A.)的膝上型计算机,在10秒钟内计算出鼻容积和沿着鼻腔长度的最小横断面面积。鼻攻击试验直接针对动物鼻腔(50μl容量)。记录攻击前和攻击后60-120分钟后的鼻充血变化。如果鼻充血发生,会将其换算成鼻体积的减少。
受过训练的意识清醒的松鼠猴的肺力学
试验步骤包括将训练过的松鼠猴放在气溶胶暴露房间的座椅中。就对照而言,记录约30分钟的呼吸参数的肺结构测量值,以建立每只猴当天的正常对照值。就口服给药而言,将化合物溶解或悬浮于1%甲基纤维素溶液(甲基纤维素,65HG,400cps)中,并以1mL/kg体重的体积给予。对于用气雾剂给予化合物,使用DeVilbiss超声喷雾器。在用1∶25稀释的PGD2气雾剂或猪蛔虫抗原气雾剂攻击猴之前,预处理周期变动范围从5分钟到4小时。
攻击后,通过计算机计算每分钟的数据,格式为包括空气阻力(RL)和动力顺应性(Cdyn)在内的每个呼吸参数对照值的百分比变化。每个试验化合物的结果在攻击后60分钟的最短时间里随后获得,然后将其与先前记录的该猴基线对照值相比较。此外,每个猴的60分钟攻击后总体值(之前的基线值和测试值)分别求平均值,并用于计算由试验化合物引起的介质或蛔虫抗原反应总体百分抑制。为统计分析,使用配对t检验。(参考:McFarlane,C.S.等,Prostaglandins,28,173-182(1984)和McFarlane,C.S.等,Agents Actions,22,63-68(1987))。
过敏性绵羊中诱导的支气管收缩的预防
动物准备:使用平均体重为35kg(范围18-50kg)成年绵羊。所有使用的动物要满足两个条件:a)它们对1∶1,000或1∶10,000稀释的猪蛔虫提取物有天然皮肤反应(Greer Diagnostics,Lenois,NC);和b)它们已经预先对用猪蛔虫吸入剂攻击起免疫反应,伴有急性支气管收缩和晚期支气管梗阻(W.M.Abraham等,Am.Rev.Resp.Dis.,128,839-44(1983))。
气道力学的测量:将未镇静的绵羊限制在手推车中,俯卧位,头部固定。鼻道用2%利多卡因溶液表面麻醉后,将气囊式导管通过一个鼻孔插入食管下段。接着将带套囊的气管导管用柔韧的纤维光学支气管镜导向通过另一鼻孔插入动物。用食管气囊式导管(充有1mL空气)评价胸膜腔压力,放置该装置以使吸气产生负压与清晰可辨的心源性振荡区分。用带边孔导管(内径2.5mm)进入并放置在鼻气管插管远端以测量气管中侧压。
跨肺压,作为气管压和胸膜腔压的差值,用压差换能器(DP45;Validyne Corp.,Northridge,CA)测量。为测量肺阻力(RL),将鼻气管插管的最大端与呼吸速率计(Fleisch,Dyna Sciences,Blue Bell,PA)连接。血流和跨肺压的信号记录在与PDP-11数字计算机(DigitalEquipment Corp.,Maynard,MA)相连的示波器(DR-12型;Electronicsfor Medicine,White Plains,NY)上,根据通过积分和血流获得的跨肺压、呼吸量在线计算肺阻力。分析10-15次呼吸以确定肺阻力。胸腔气体量(Vtg)用身体体积描记器测量,以获得具体的肺阻力(SRL=RL-Vtg)。
提供以下实施例以说明本发明,不能以任何方式解释为限制本发明的范围。除非另有说明,实施例中,
-所有式I的终产物用NMR、TLC和元素分析或质谱进行分析;
-中间体用NMR和TLC进行分析;
-大多数化合物用快速色谱法在硅胶上纯化,重结晶和/或swish(悬浮于溶剂然后过滤固体);
-反应过程用薄层色谱法(TLC)跟踪,给出的反应时间仅用于说明;
对映体过量用正相HPLC手性柱:ChiralPak AD;250×4.6mm测量。
实施例1
[5-[(4-氯苯基)硫基]-4-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-6-基]
乙酸
步骤1
4-氯烟碱醛
如F.Marsais等,J.Heterocyclic Chem.,25,81(1988)所述,制备标题化合物。
步骤2
4-(甲硫基)烟碱醛
向NaSMe(9.5g,135mmol)的MeOH(250mL)溶液中加入步骤1的4-氯烟碱醛(13.5g,94.4mmol)/MeOH(250mL)。将反应混合物在60℃维持15min。将反应混合物倒在NH4Cl和EtOAc上。分离有机相,用H2O洗涤并经Na2SO4干燥。然后将所述化合物通过硅胶用50%EtOAc/己烷纯化,得到标题化合物。
步骤3
(2Z)-2-叠氮基-3-[4-(甲硫基)吡啶-3-基]丙-2-烯酸甲酯
将4-(甲硫基)烟碱醛(4.8g,31mmol)和叠氮乙酸甲酯(9.0g,78mmol)的MeOH(50mL)溶液于-12℃加入到25%NaOMe的MeOH(16.9mL,78mmol)溶液中。在30分钟加入过程中,监测内部温度并使其保持在-10℃至-12℃。然后将所得混合物在冰浴中搅拌几小时,然后在低温房冰浴中过夜。然后将悬浮液倒在冰和NH4Cl的混合物上,搅拌10分钟后将浆状物过滤。将产物用冷H2O洗涤,然后真空干燥,得到标题化合物含有少许盐的淡棕色固体(7.4g)。然后将所述化合物通过硅胶用EtOAc纯化。
步骤4
4-(甲硫基)-1H-吡咯并[2,3-b]吡啶-2-甲酸甲酯
将步骤3化合物(0.40g,1.6mmol)的二甲苯(16mL)悬浮液缓慢加热到140℃。在140℃15分钟后,让黄色溶液冷却至室温。必须小心操作,因为氮的形成有放热的可能。然后将悬浮液冷却至0℃,过滤并用二甲苯洗涤,得到标题化合物。
步骤5
4-(甲硫基)-6-氧代-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-7-甲酸乙酯
在0℃,向步骤4化合物(0.35g,1.6mmol)的DMF(20mL)溶液中加入NaH(1.2当量)。5分钟后,加入nBu4NI(0.10g)和4-溴丁酸乙酯(0.40mL)。在室温下1小时后,将反应混合物倒在饱和NH4Cl和EtOAc上。分离有机相,用H2O洗涤并经NaSO4干燥。蒸发后,用快速色谱法纯化粗产物。将二酯溶于THF(7.0mL),并于0℃加入1.06M叔丁醇钾(2.2mL)的THF溶液。在室温下1小时后,将反应混合物倒在饱和NH4Cl和EtOAc上。分离有机相,经NaSO4干燥,并减压蒸发,得到标题化合物的乙酯和甲酯混合物。
步骤6
4-(甲硫基)-8,9-二氢吡咯并[3,2-b]吲嗪-6(7H)-酮
向步骤5的化合物(0.32g)中加入EtOH(8.0mL)和浓HCl(2.0mL)。将所得悬浮液回流5小时。让反应混合物在EtOAc和Na2CO3之间分配。分离有机相,蒸发后得到标题化合物。
步骤7
(2E,2Z)-[4-(甲硫基)-8,9-二氢吡啶并[3,2-b]吲嗪-6(7H)-亚基] 乙酸乙酯
向膦酰乙酸三乙酯(0.45g,2.17mmol)的DMF(12mL)溶液中加入80%NaH(0.06g,2.00mmol)和步骤6的化合物(0.22g,1.00mmole)。在55℃4小时后,将反应混合物倒在饱和NH4Cl和EtOAc上。分离有机相并减压蒸发。粗产物通过快速色谱纯化,得到标题化合物。
步骤8
[4-(甲硫基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-6-基]乙酸乙酯
将步骤7的化合物加热溶解于MeOH-THF中。室温下,向预冷溶液中加入PtO2,将所得混合物在1大气压氢气下保持18小时。将反应混合物在硅藻土上用CH2Cl2小心过滤。减压蒸发滤液,得到标题化合物。或者,步骤7的化合物可用Pd(OH)2在EtOAc中于40PSI的H2下氢化18小时。
步骤9
[4-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-6-基]乙酸乙酯
将步骤8的化合物(0.08g,0.27mmol)置于MeOH(3.0mL)中,向其中加入Na2WO4(0.10g)和30%H2O2(600μL)。1小时后,让反应混合物在H2O和EtOAc之间分配。有机相用H2O洗涤,分离并蒸发。标题化合物用快速色谱法进行纯化。
步骤10
[5-[(4-氯苯基)硫基]-4-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,2-b]吲 嗪-6-基]乙酸乙酯
向4,4′-二氯二苯基二硫化物(0.24g)的1,2-二氯乙烷溶液(2.0mL)中加入SO2Cl2(50μL)。将步骤9的化合物(0.05g)置于DMF(2.0mL)中,向其中加入上述混合物(≈180μl)。用1H NMR跟踪反应,并维持在室温下直到原料没有剩余。将反应混合物倒在饱和NaHCO3和EtOAc上。分离有机相,蒸发,标题化合物用快速色谱法进行纯化。
步骤11
[5-[(4-氯苯基)硫基]-4-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,2-b] 吲嗪-6-基]乙酸
将步骤10的化合物溶于1/1混合的THF-MeOH中,向其中加入1N NaOH。在室温下18小时后,让反应混合物在NH4Cl和EtOAc之间分配。分离有机相,经Na2SO4干燥,蒸发,得到标题化合物。1H NMR(500MHz,丙酮-d6)δ11.00(bs,1H),8.60(d,1H),7.80(d,1H),7.20(d,2H),7.00(d,2H),4.65(m,1H),4.20(m,1H),3.75(m,1H),3.35(s,3H),2.80 to 2.10(m,6H).
实施例2
[5-[(4-氯苯基)硫基]-4-(甲硫基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-6-基]乙
酸
按照类似于实施例1步骤10和11所描述的方法,可从实施例1中步骤8的化合物制备标题化合物。
m/z 418。
实施例3
[5-[(3,4-二氯苯基)硫基]-4-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-
6-基]乙酸(对映体A和对映体B)
如实施例1所述,用步骤10中双(3,4-二氯苯基)二硫化物制备标题化合物。
1H NMR(500MHz,丙酮-d6)δ8.55(d,1H),7.85(d,1H),7.35(d,1H),7.15(s,1H),6.95(d,1H),4.60(m,1H),4.15(m,1H),3.80(m,1H),3.40(s,3H),2.80 to 2.10(m,6H).
m/z 484.
将所述对映体在Chiralecel OD柱25cm×20mm上分离,条件:30%异丙醇,7%乙醇,0.2%乙酸/己烷,流速8ml/min。其纯度用Chiralecel OD柱25cm×4.6mm加以证实,条件:35%异丙醇0.2%乙酸/己烷,流速1.0ml/分钟。流动性较强的对映体Tr=9.7分钟,流动性较弱的对映体Tr 11.1分钟。
实施例4
[5-(4-氯苯甲酰基)-4-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-6-基]
乙酸
步骤1
[5-(4-氯苯甲酰基)-4-(甲硫基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪- 6-基]乙酸乙酯
向4-氯苯甲酰氯(0.30g,1.7mmol)的1,2-二氯乙烷(6.0mL)溶液中加入AlCl3(0.24g,1.8mmole)。5分钟后,将实施例1步骤8的[4-(甲硫基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-6-基]乙酸乙酯(0.15g,0.47mmole)的1,2-二氯乙烷(6.0mL)溶液加入到上述混合物中。4小时后,在80℃,让反应混合物在EtOAc和NaHCO3之间分配。分离有机相,经Na2SO4干燥,蒸发。标题化合物用快速色谱法进行纯化。
步骤2
[5-(4-氯苯甲酰基)-4-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,2-b]吲 嗪-6-基]乙酸乙酯
向[5-(4-氯苯甲酰基)-4-(甲硫基)-6,7,8-9-四氢吡啶并[3,2-b]吲嗪-6基]乙酸乙酯(0.12g,0.27mmole)的MeOH(5.0mL)溶液中加入Na2WO4(0.1g)和30%H2O2(300μL)。将反应混合物于55℃搅拌1小时。然后让反应混合物在H2O和EtOAc之间分配。将有机相用H2O洗涤,经Na2SO4干燥并蒸发。标题化合物用快速色谱法进行纯化。
步骤3
[5-(4-氯苯甲酰基)-4-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,2-b]吲 嗪-6-基]乙酸
将[5-(4-氯苯甲酰基)-4-(甲磺酰基)-6,7-8,9-四氢吡啶并[3,2-b]吲嗪-6基]乙酸乙酯如实施例1步骤11所描述进行处理,得到标题化合物。
1H NMR(500MHz,丙酮-d6)δ8.55(d,1H),7.90(d,2H),7.65(d,1H),7.45(d,2H),4.55(m,1H),4.25(m,1H),3.45(m,1H),3.20(s,3H),2.05 to 3.00(m,6H).
m/z 446
实施例5
[5-(4-溴苯基)硫基]-4-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-6-基]
乙酸
按照实施例1描述的方法,用4,4′-二溴二苯基二硫化物制备标题化合物。
1H NMR(500MHz,丙酮-d6)δ8.60(d,1H),7.80(d,1H),7.35(d,2H),7.00(d,2H),4.65(m,1H),4.20(m,1H),3.80(m,1H),3.35(s,3H),2.80 to 2.10(m,6H).
实施例6方法-1
[9-[(3,4-二氯苯基)硫基]-1-(甲磺酰基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯
里嗪-8-基]乙酸
步骤1
2-(甲硫基)烟碱醛
除将溶液在55℃加热2小时外,其它如实施例1步骤2所述,由2-溴代烟碱醛(A.Numata Synthesis 1999,第306页)制备标题化合物。
步骤2
(2Z)-2-叠氮基-3-[2-(甲硫基)吡啶-3-基]丙-2-烯酸甲酯
如实施例1步骤3所述,制备标题化合物。
步骤3
4-(甲硫基)-1H-吡咯并[3,2-c]吡啶-2-甲酸甲酯
将(2Z)-2-叠氮基-3-[2-(甲硫基)吡啶-3-基]丙-2-烯酸甲酯(1.00g,4.00mmol)的均三甲苯(50mL)溶液在160℃加热1小时。将反应混合物冷却至室温,然后冷却至0℃,将沉淀过滤并用冷的均三甲苯洗涤,得到标题化合物。
步骤4
1-(甲硫基)-8-氢代-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-7-甲 酸甲酯
向4-(甲硫基)-1H-吡咯并[3,2-c]吡啶-2-甲酸甲酯(0.30g,1.35mmol)的THF(3mL)-甲苯(12.0mL)悬浮液中加入1.06M叔丁醇钾(1.42mL/1.41mmol)和丙烯酸甲酯(300μL)的THF溶液。将所得混合物在80℃加热18小时。让所得混合物在EtOAc和NH4Cl之间分配,通过硅藻土过滤。分离有机相,经Na2SO4干燥并过滤,得到标题化合物。
步骤5
1-(甲硫基)-6,7-二氢-8H-吡啶并[3,4-b]吡咯里嗪-8-酮
如实施例1步骤6所述,将1-(甲硫基)-8-氧代-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-7-甲酸甲酯转化成标题化合物。
步骤6
[8-羟基-1-(甲硫基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8-基] 乙酸甲酯
将1-(甲硫基)-6,7-二氢-8H-吡啶并[3,4-b]吡咯里嗪-8-酮(0.15g,0.68nmol)、溴乙酸甲酯(0.34mL)、Zn-Cu(0.226g)的混合物在THF(3.0mL)中超声处理2小时。然后将混合物在60℃加热5分钟,直到反应完成。让反应混合物在EtOAc和NH4Cl之间分配。分离有机相,经Na2SO4干燥,过滤并减压蒸发,得到标题化合物。将所述化合物通过快速色谱纯化。
步骤7
[1-(甲硫基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8-基]乙酸甲 酯
将NaI(0.300g)置于CH3CN(3.2mL)中,向其中加入TMSCl(0.266mL)。将该混合物在水浴中加入到[8-羟基-1-(甲硫基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8-基]乙酸甲酯(0.15g,0.515mmol)的CH3CN(1.5mL)悬浮液中。0.5小时后,让反应混合物在EtOAc和NaHCO3之间分配。分离有机相,经硫代硫酸钠洗涤,经MgSO4干燥并蒸发。标题化合物用快速色谱法进行纯化。
步骤8
[1-(甲磺酰基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8-基]乙酸 甲酯
如实施例1步骤9所述,将[1-(甲硫基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8-基]乙酸甲酯转化成标题化合物。
步骤9
[9-[(3,4-二氯苯基)硫基]-1-(甲磺酰基)-7,8-二氢-6H-吡啶并 [3,4-b]吡咯里嗪-8-基]乙酸
如实施例1步骤10和11所描述,用步骤10中双(3,4-二氯苯基)二硫化物将[1-(甲磺酰基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8-基]乙酸甲酯转化成标题化合物。
1H NMR(500MHz,丙酮-d6)δ8.35(d,1H)7.80(d,1H),7.35(d,1H),7.15(s,1H),6.95(d,1H),4.55(m,1H),4.35(m,1H),3.90(m,1H),3.30(s,3H),3.15(m,1H),3.05(m,1H),2.80(m,1H),2.50(m,1H)。
实施例6方法-2
[9-[(3,4-二氯苯基)硫基]-1-(甲磺酰基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯
里嗪-8-基]乙酸
步骤1
1-(甲硫基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8-醇
在0℃,向实施例6方法-1步骤5中1-(甲硫基)-6,7-二氢-8H-吡啶并[3,4-b]吡咯里嗪-8-酮(0.55g,2.2mmol)的EtOH(10mL)-THF(1mL)悬浮液中加入NaBH4(0.10g,2.6mmol)。在室温下30分钟后,加入丙酮猝灭反应。减压蒸去溶剂,将EtOAC和H2O加入残余物。分离有机相,经MgSO4干燥并蒸发。标题化合物用EtOAc/己烷洗涤并过滤。
步骤2
2-[1-(甲硫基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8-基]丙二 酸二甲酯
在-78℃,向1-(甲硫基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8-醇(0.54g,2.1mmol)的THF(10mL)悬浮液中加入1M NaHMDS/THF(2.35mL,2.4mmol)和氯磷酸二苯酯(0.53mL,2.6mmol)。30分钟后,加入丙二酸二甲酯(0.73mL,6.4mmol)和1M NaHMDS置于THF(6.8mL,6.8mmol)溶液中。使反应混合物到0℃,然后到室温。然后让所得混合物在ETOAc和NH4Cl之间分配。有机相经MgSO4干燥,过滤并蒸发。标题化合物用快速色谱法进行纯化。
步骤3
[1-(甲硫基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8-基]-乙酸甲 酯
向2-[1-(甲硫基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8-基]丙二酸二甲酯(0.59g,2.17mmol)和DMSO(4mL)的混合物中加入NaCl(0.45g)的H2O(0.45mL)溶液。在150℃18小时后,让反应混合物在ETOAc和H2O之间分配。分离有机相,经Na2SO4干燥,并蒸发。然后标题化合物用快速色谱法进行纯化。
步骤4
[9-[(3,4-二氯苯基)硫基]-1-(甲磺酰基)-7,8-二氢-6H-吡啶并 [3,4-b]吡咯里嗪-8-基]乙酸
如实施例6方法-1步骤8-9所描述,由[1-(甲硫基)-7,8-二氢-6H-吡啶并-[3,4-b]吡咯里嗪-8基]乙酸甲酯获得标题化合物。
实施例7
[10-[(3,4-二氯苯基)硫基]-1-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,4-b]吲嗪-
9-基]乙酸
步骤1
[1-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,4-b]吲嗪-9-基]乙酸乙酯
按照与实施例1步骤5-9中描述的方法相同的方法,由实施例6步骤3的产物制备标题化合物。
步骤2
[10-[(3,4-二氯苯基)硫基]-1-(甲磺酰基)-6,7,8,9-四氢吡啶并 [3,4-b]吲嗪-9-基]乙酸
按照与实施例1步骤10-11相同的方法,用步骤10中双(3,4-二氯苯基)二硫化物将步骤1的产物转化成标题化合物。
MS M+1=485。
实施例8
(4-(甲磺酰基)-5-{[4-(三氟甲基)苯基]硫基}-6,7,8,9-四氢吡啶并[3,2-b]-
吲嗪-6-基)乙酸
如实施例1所述,用双[4-(三氟甲基)苯基]二硫化物制备标题化合物。
1H NMR(500MHz,丙酮-d6)δ8.55(d,1H),7.75(d,1H),7.45(d,2H),7.15(d,2H),4.55(m,1H),4.15(m,1H),3.80(m,1H),3.30(s,3H),2.80 to 2.10(m,6H).
m/z 513(M+1)
实施例9
[5-[(2-氯-4-氟苯基)硫基]-4-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-
6-基]乙酸
如实施例1所述,用双(2-氯-4-氟苯基)二硫化物制备标题化合物。
m/z 469(M+1)。
实施例10
[4-(甲磺酰基)-5-(2-萘硫基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-6-基]乙酸
如实施例1所述,用二(2-萘基)二硫化物制备标题化合物。
M/z 467(M+1)。
实施例11
[5-[(2,3-二氯苯基)硫基]-4-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-
6-基]乙酸
如实施例1所述,用双(2,3-二氯苯基)二氯化物制备标题化合物。
1H NMR(500MHz,丙酮-d6)δ8.85(d,1H),7.80(d,1H),7.30(d,1H),7.00(t,1H),6.60(d,1H),4.60(m,1H),4.20(m,1H),3.80(m,1H),3.40(s,3H),2.80 to 2.10(m,6H).
实施例12
[5-[(4-甲基苯基)硫基]-4-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-6-
基]乙酸
如实施例1所述,用对甲苯基二硫化物制备标题化合物。
1H NMR(500MHz,丙酮-d6)δ8.55(d,1H),7.80(d,1H),6.95(m,4H),4.60(m,1H),4.15(m,1H),3.80(m,1H),3.35(s,3H),2.80 to 2.10(m,6H).
实施例13
[4-(甲磺酰基)-5-(苯硫基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-6-基]乙酸
如实施例1所述,用二苯基二硫化物制备标题化合物。
1H NMR(500MHz,丙酮-d6)δ8.55(d,1H),7.80(d,1H),7.15 to 6.90(m,5H),4.60(m,1H),4.15(m,1H),3.75(m,1H),3.30(s,3H),2.80 to 2.10(m,6H).
实施例14
[5-[(2,4-二氯苯基)硫基]-4-(甲磺酰基)-6,7,8,9-四氢吡啶并[3,2-b]吲嗪-
6-基]乙酸
如实施例1所述,用双(2,4-二氯苯基)二硫化物制备标题化合物。在乙醚中用Br2由2,4-二氯噻吩基制备二硫化物。
1H NMR(500MHz,丙酮-d6)δ8.55(d,1H),7.85(d,1H),7.35(s,1H),7.00(d,1H),6.65(d,1H),4.55(m,1H),4.15(m,1H),3.80(m,1H),3.35(s,3H),2.80 to 2.10(m,6H).
实施例15
[5-[(4-氯苯基)硫基]-4-(甲磺酰基)-6,7,8,9-四氢吡啶并[4,3-b]吲嗪-6-基]
乙酸
如实施例1所述,由3-氯烟碱醛(Heterocycles,第151页,1993)
制备标题化合物,仅仅末端环化通过回流时在萘烷上添加叠氮化物来完成。
1H NMR(500MHz,丙酮-d6)δ9.20(s,1H),8.85(s,1H),7.20(d,2H),7.00(d,2H),4.70(m,1H),4.30(m,1H),3.75(m,1H),3.35(s,3H),2.80 to 2.10(m,6H).
实施例16
[9-[(4-氯苯基)硫基]-1-(甲磺酰基)-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪
-8-基]乙酸
如实施例1步骤10和11概述的方法所述,用步骤10中的双(4-氯苯基)二硫化物由实施例6方法1步骤8的产物制备标题化合物。
1H NMR(500MHz,丙酮-d6)δ8.25-8.3(m,1H),7.71-7.75(m,1H),7.12-7.17(m,2H),6.97-7.04(m,2H),4.45-4.51(m,1H),4.32-4.39(m,1H),3.73-3.80(m,1H),3.29(s,3H),3.15-3.21(m,1H),2.99-3.08(m,1H),2.66-2.73(m,1H),2.46-2.54(m,1H).
实施例17
{9-[(3,4-二氯苯基)硫基]-1-异丙基-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪
-8-基}乙酸(对映体A和对映体B)
步骤1
2-氯烟碱醛
在-40℃,向二异丙基胺(110mL,780mmol)的THF(500mL)溶液中加入2.5M n-BuLi(300mL,750mmol)的己烷溶液。5分钟后,将反应混合物冷却至-95℃,然后依次加入DMPU(15mL)和2-氯吡啶(50mL,532mmol)。然后将所得混合物升温,于-78℃搅拌4小时。之后,在加入DMF(70mL)之前将黄色悬浮液再次冷却至-95℃。将最终反应混合物升温至-78℃,并在该温度下搅拌1.5小时。将反应混合物倒进冷HCl水溶液(3N,800mL)中,并搅拌5分钟。加入浓NH4OH水溶液调节pH至7.5。用EtOAc萃取水层三次。合并有机层,用NH4Cl水溶液和盐水洗涤,经无水Na2SO4干燥,过滤并浓缩。粗产物用硅胶板进一步纯化,用从100%己烷到100%EtOAc梯度洗脱,并将产物在冷己烷中结晶得到标题化合物淡黄色固体。
步骤2
(2Z)-2-叠氮基-3-(2-氯吡啶-3-基)丙-2-烯酸甲酯
如实施例1步骤3所述,制备标题化合物。
步骤3
4-氯-1H-吡咯并[3,2-c]吡啶-2-甲酸甲酯
按照类似于实施例6方法-1步骤3的方法,制备标题化合物。
步骤4
1-氯-8-氧代-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-7-甲酸甲酯
向4-氯-1H-吡咯并[3,2-c]吡啶-2-甲酸甲酯(12.5g,59mmol)的THF(116mL)-甲苯(460mL)的悬浮液中加入1.0M叔丁醇钾(64mL,64mmol)和丙烯酸甲酯(55mL,611mmol)的THF溶液。将所得混合物在100℃加热18小时。之后,将悬浮液冷却至室温,将其倒入饱和NH4Cl水溶液(400mL)和己烷(400mL)混合物中。滗析固体,过滤并用H2O和己烷洗涤,得到标题化合物。
步骤5
1-氯-6,7-二氢-8H-吡啶并[3,4-b]吡咯里嗪-8-酮
以实施例1步骤6所述类似方式用异丙醇替代乙醇,并在100℃加热1小时来制备标题化合物。
步骤6
1-异丙稀基-6,7-二氢-8H-吡啶并[3,4-b]吡咯里嗪-8-酮
向1-氯-6,7-二氢-8H-吡啶并[3,4-b]吡咯里嗪-8-酮(5.0g,24.3mmol)、三(二亚苄基丙酮)合二钯(O)(1.0g,1.09mmol)和三苯基砷(2.70g,8.82mmol)的DMF(100mL)混合溶液中加入三丁基异丙稀基锡烷(9.60g,29.00mmol)。将所得混合物脱气,并在78℃加热18小时。减压蒸去溶剂。将CH2Cl2和硅藻土加入到所得混合物中,然后经硅藻土过滤。标题化合物用快速色谱法进行纯化(50%→100%EtOAc/己烷)。
步骤7
(2E)-(1-异丙烯基-6,7-二氢-8H-吡啶并[3,4-b]吡咯里嗪-8-亚基) 乙酸乙酯
在-78℃,向1-异丙烯基-6,7-二氢-8H-吡啶并[3,4-b]吡咯里嗪-8-酮(0.60g,2.8mmol)和膦酰乙酸三乙酯(1.00g,4.46mmol)的THF(24mL)溶液中加入80%NaH(0.12g,4.00mmol),使反应混合物升温至0℃,然后升至室温。将反应混合物倒在饱和NH4Cl和EtOAc上。分离有机相,经Na2SO4干燥,并蒸发。标题化合物用快速色谱法进行纯化(40%EtOAc/己烷)。
步骤8
(1-异丙基-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8-基)乙酸乙酯
向(2E)-(1-异丙烯基-6.7-二氢-8H-吡啶并[3,4-b]吡咯里嗪-8-亚基)乙酸乙酯(0.40g,1.4mmol)的MeOH(20mL)溶液中加入Pd(OH)2(0.20g)。将混合物在1个大气压H2下搅拌3小时。将混合物在硅藻土上过滤,并蒸发,得到标题化合物。
步骤9
{9-[(3,4-二氯苯基)硫基]-1-异丙基-7,8-二氢-6H-吡啶并[3,4-b] 吡咯里嗪-8-基}乙酸乙酯
向双(3,4-二氯苯基)二硫化物(0.24g,0.67mmol)的CH2Cl2(5.6mL)溶液中加入SO2Cl2(0.036mL)。将所得黄色混合物在室温下搅拌1小时。在0℃,将该溶液加入(1-异丙基-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8-基)乙酸乙酯(0.15g,0.52mmol)的DMF(5.6mL)溶液中。在0℃,1.5小时后,将反应混合物倒在饱和NaHCO3和EtOAc上。分离有机相,经Na2SO4干燥,过滤并蒸发。标题化合物用快速色谱法进行纯化(30%→40%EtOAc/己烷)。
步骤10
{9-[(3,4-二氯苯基)硫基]-1-异丙基-7,8-二氢-6H-吡啶并[3,4-b] 吡咯里嗪-8-基}乙酸
向{9-[(3,4-二氯苯基)硫基]-1-异丙基-7,8-二氢-6H-吡啶并[3,4-b]吡咯里嗪-8基}乙酸乙酯(0.23g,0.50mmol)的THF(5mL和MeOH(2.5mL)溶液中加入1.0M NaOH(1.5mL,1.5mmol)。室温搅拌18小时后,加入HOAc(0.25mL),并蒸去溶剂。将残余物溶于EtOAc/H2O中,有机层用H2O和盐水洗涤。干燥(Na2SO4)后,过滤并蒸发溶液。将残余物和1∶1的EtOAc∶己烷一起搅拌,过滤后得到化合物的白色固体。
1H NMR(MeOH-d4)δ1.14-1.26(m,6H),2.47-2.56(m,1H),2.56-2.64(m,1H),2.94-3.05(m,2H),3.81-3.89(m,1H),4.22-4.30(m,1H),4.33-4.44(m,2H),6.93-6.99(m,1H),7.14-7.19(m,1H),7.33-7.39(m,1H),7.54-7.59(m,1H),8.16-8.21(m,1H).
将步骤10的产物用CH2N2转化成其甲酯,并将该酯用HPLC柱在手性固定相(chiralcel OD柱2×25cm)上分离,用12%2-丙醇/己烷洗脱,流速为6mL/min。对映体A(较弱极性)保留时间为31.9分钟,对映体B(较强极性)保留时间为35.5分钟。将A和B如实施例17步骤10所述水解,得到标题化合物的A和B对映体。
Claims (30)
1.一种具有下式I的化合物及其药学上可接受的盐和水合物,
其中:
A选自任选被1-4个卤原子、O(CH2)1-2和S(CH2)1-2取代的C1-3烷基;
Ar为各自任选被1-4个独立选自Rg的基团取代的芳基或杂芳基;
Q选自:
(1)COOH,
(2)CONRaRb,
(3)C(O)NHSO2Rc,
(4)SO2NHRa,
(5)SO3H,
(6)PO3H2,和
(7)四唑基;
X1、X2、X3或X4之一为氮原子,其余的独立选自CH和C-Rg;
Y1选自-(CRdRe)a-X-(CRdRe)b-、亚苯基、C3-6环烷叉基和C3-6亚环烷基,其中a和b为0-1的整数,以使a和b的和等于0、1或2,X为化学键、O、S、NRa、C(O)、CH(ORa)、OC(O)、C(O)O、C(O)NRa、OC(O)NRa、NRaC(O)、CRd=CRe或C≡C;
Y2选自(CRdRe)m和CRd=CRe;
R1选自H、CN、ORa、S(O)nC1-6烷基和任选被1-6个独立选自卤素、ORa和S(O)nC1-6烷基的基团取代的C1-6烷基;
R2选自H和任选被1-6个卤素取代的C1-6烷基;或
R1和R2一起表示氧代基;或
R1和R2结合在一起形成3元环或4元环,该环含有0个或1个选自NRf、S、和O的杂原子并且任选被1个或2个选自F、CF3和CH3的基团取代;
R3选自H和任选被1-6个独立选自ORa和卤素的基团取代的C1-6烷基;
R3和Rb独立选自H、C1-10烷基、C2-10烯基、C2-10炔基、Cy和CyC1-10烷基,其中所述烷基、烯基、炔基和Cy任选被1-6个独立选自以下的取代基取代:卤素、氨基、羧基、C1-4烷基、C1-4烷氧基、芳基、杂芳基、芳基C1-4烷基、羟基、CF3、OC(O)C1-4烷基、OC(O)NRiRj和芳氧基;或者Ra和Rb与连接它们的原子一起形成含有0-2个独立选自氧、硫和N-Rf等额外杂原子的4-7元杂环;
Rc选自任选被1-6个卤素、芳基和杂芳基取代的C1-6烷基,其中所述芳基和杂芳基任选被1-3个选自卤素、OC1-6烷基、O-卤代C1-6烷基、C1-6烷基和卤代C1-6烷基的基团取代;
Rd和Re独立地为H、卤素、芳基、杂芳基、C1-6烷基或卤代C1-6烷基;
Rf选自H、C1-6烷基、卤代C1-6烷基、Cy、C(O)C1-6烷基、C(O)卤代C1-6烷基和C(O)-Cy;
Rg选自:
(1)卤素,
(2)CN,
(3)任选被1-8个独立选自芳基、杂芳基、卤素、NRaRb、C(O)Ra、C(ORa)RaRb、SRa和ORa的基团取代的C1-6烷基,其中芳基、杂芳基和烷基各自任选被1-6个独立选自卤素、CF3和COOH的基团取代,
(4)任选被1-6个独立选自卤素和ORa的基团取代的C2-6烯基,
(5)Cy,
(6)C(O)Ra,
(7)C(O)ORa,
(8)CONRaRb,
(9)OCONRaRb,
(10)OC1-6烷基,其中烷基任选被1-6个选自卤素、芳基、杂芳基、OH和OC(O)Ra的取代基取代,
(11)O-Cy,
(12)S(O)nC1-6烷基,其中烷基任选被1-6个选自卤素、芳基、杂芳基、OH、和OC(O)Ra的取代基取代,
(13)S(O)n-Cy,
(14)-NRaS(O)nRb,
(15)-NRaRb,
(16)-NRaC(O)Rb,
(17)-NRaC(O)ORb,
(18)-NRaC(O)NRaRb,
(19)S(O)nNRaRb,
(20)NO2,
(21)C5-8环烯基,
其中Cy任选被1-8个独立选自卤素、C(O)Ra、ORa、C1-3烷基、芳基、杂芳基和CF3的基团取代;
Ri和Rj独立选自H、C1-10烷基、Cy和Cy-C1-10烷基;或
Ri和Rj与连接它们的氮原子一起形成含有0-2个独立选自O、S和N-Rf的额外杂原子的5-7元环;
Cy选自杂环基、芳基和杂芳基;
m为1、2或3;且
n为0、1或2。
2.权利要求1的化合物,其中A-Q为CH2CO2H。
3.权利要求1的化合物,其中Ar为萘基或任选取代的苯基,其中所述取代基为1-2个独立选自Rg的基团。
4.权利要求1的化合物,其中Y1选自C(O)和S。
5.权利要求1的化合物,其中X1、X2和X3之一为氮原子,其余的独立地为CH或CRg,X4为CRg。
6.权利要求1的化合物,其中X1、X2和X3之一为氮原子,其余的为CH,X4为任选被ORa取代的C-S(O)n-C1-6烷基或C-C1-6烷基。
7.权利要求1的化合物,其中R1、R2和R3各自为氢。
8.权利要求1的化合物,其中Y2选自CH2和CH2CH2。
9.权利要求1的化合物,所述化合物由式Ia表示:
其中X2和X3独立地为CH或C-Rg,A、Ar、Q、Y1、R1、R2、m和Rg如权利要求1中所定义。
10.权利要求9的化合物,其中X2和X3各自为CH,R1和R2各自为H,A-Q为CH2CO2H。
11.权利要求9的化合物,其中Y1-Ar为任选被1-2个独立选自卤素、C1-6烷基和三氟甲基的基团取代的S-苯基。
12.权利要求1的化合物,所述化合物由式Ib表示:
其中X1和X2独立地为CH或C-Rg,A、Ar、Q、Y1、R1、R2、m和Rg如权利要求1中所定义。
13.权利要求12的化合物,其中X1和X2各自为CH,R1和R2各自为H,A-Q为CH2CO2H。
14.权利要求13的化合物,其中Y1-Ar为任选被1-2个独立选自卤素、C1-6烷基和三氟甲基的基团取代的S-苯基。
16.权利要求15的化合物,其中Ar为任选被1个或2个独立选自卤素、C1-3烷基和三氟甲基的基团取代的苯基。
17.权利要求15的化合物,其中Y1为S或C(O)。
18.权利要求15的化合物,其中X4选自任选被ORa取代的C-S(O)n-C1-6烷基和C-C1-6烷基。
19.权利要求15的化合物,其中Y1-Ar为任选被1个或2个独立选自卤素、C1-6烷基和三氟甲基的基团取代的S-苯基;X1和X2各自为CH,X3为N,m为1或2,X4为C-SO2C1-6烷基或C1-6烷基。
20.权利要求1的化合物,所述化合物选自:
21.一种药用组合物,所述组合物包含如权利要求1-20中任一项所定义的式I化合物或其药学上可接受的盐或水合物,以及药学上可接受的载体。
22.权利要求21的组合物,所述组合物还包含选自以下的第二活性成分:抗组胺药、白三烯拮抗剂和白三烯生物合成抑制剂。
23.一种治疗前列腺素D2介导疾病的方法,所述方法包括给予需要这种治疗的患者治疗有效量的权利要求1的化合物。
24.一种治疗鼻充血的方法,所述方法包括给予需要这种治疗的患者治疗有效量的权利要求1的化合物。
25.一种治疗过敏性哮喘的方法,所述方法包括给予需要这种治疗的患者治疗有效量的权利要求1的化合物。
26.一种治疗过敏性鼻炎的方法,所述方法包括给予需要这种治疗的患者治疗有效量的权利要求1的化合物。
27.权利要求1-20中任一项所定义的式I化合物或其药学上可接受的盐或溶剂合物,其适用于药物疗法。
28.权利要求27的化合物的盐或水合物,其适用于治疗前列腺素D2介导的疾病。
29.权利要求1-20中任一项所定义的式I化合物或其药学上可接受的盐或溶剂合物在制备用于治疗鼻充血、过敏性哮喘或过敏性鼻炎的药物中的用途。
30.一种前列腺素受体拮抗剂药用组合物,所述组合物包含可接受拮抗量的权利要求1-20中任一项所定义的式I化合物或其药学上可接受的盐或溶剂合物,及其药学上可接受的载体。
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CN101896178B (zh) * | 2007-10-10 | 2013-11-20 | 北京赛林泰医药技术有限公司 | 作为crth2受体拮抗剂的杂环化合物 |
CN105925004A (zh) * | 2016-05-04 | 2016-09-07 | 三峡大学 | 一种氟硼吡咯里嗪荧光染料及其合成方法 |
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CN105925004A (zh) * | 2016-05-04 | 2016-09-07 | 三峡大学 | 一种氟硼吡咯里嗪荧光染料及其合成方法 |
CN105925004B (zh) * | 2016-05-04 | 2017-06-06 | 三峡大学 | 一种氟硼吡咯里嗪荧光染料及其合成方法 |
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