CN1211381C - 用于治疗炎性疾病的取代咪唑 - Google Patents
用于治疗炎性疾病的取代咪唑 Download PDFInfo
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- CN1211381C CN1211381C CNB988045230A CN98804523A CN1211381C CN 1211381 C CN1211381 C CN 1211381C CN B988045230 A CNB988045230 A CN B988045230A CN 98804523 A CN98804523 A CN 98804523A CN 1211381 C CN1211381 C CN 1211381C
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- compound
- phenyl
- fluorophenyl
- pyridyl
- imidazoles
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
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- 229940050411 fumarate Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
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- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
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- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 1
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- 238000001471 micro-filtration Methods 0.000 description 1
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- 235000010446 mineral oil Nutrition 0.000 description 1
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- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 229940039748 oxalate Drugs 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 125000005429 oxyalkyl group Chemical group 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
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- LJZPPWWHKPGCHS-UHFFFAOYSA-N propargyl chloride Chemical compound ClCC#C LJZPPWWHKPGCHS-UHFFFAOYSA-N 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- SDKPSXWGRWWLKR-UHFFFAOYSA-M sodium;9,10-dioxoanthracene-1-sulfonate Chemical compound [Na+].O=C1C2=CC=CC=C2C(=O)C2=C1C=CC=C2S(=O)(=O)[O-] SDKPSXWGRWWLKR-UHFFFAOYSA-M 0.000 description 1
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- 239000008107 starch Substances 0.000 description 1
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- 150000003431 steroids Chemical class 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
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- 229950004288 tosilate Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
本发明涉及式I的一系列取代的咪唑类、含有这些咪唑的药物组合物,以及制造它们使用的中间体。本发明的化合物抑制多种炎性细胞素的产生,可以用于治疗与炎性细胞素过度产生有关的疾病。
Description
本发明涉及一系列取代咪唑类、含有这些咪唑的药物组合物,以及制造它们使用的中间体。本发明的化合物抑制多种炎性细胞素,特别是TNF-α和IL-1β的产生。本发明的化合物使用于治疗与炎性细胞素过度产生有关的疾病,比如类风湿性关节炎、炎性肠道疾病、败血性休克、骨质疏松症和骨性关节炎。
发明的背景
炎性细胞素,如IL-1β和TNF-α在许多疾病如类风湿性关节炎中起着重要的作用。请见C.Dinarello等人的文章《炎性细胞素:白细胞介素和肿瘤坏死因子作为自体免疫疾病的效应物分子》(Inflammatory cytokines:Interleukin-1 and Tumor NecrosisFactor as Effector Molecules in Autoimmune Diseases)载Curr.Opin.Immunol.1991,3,941-48。关节炎是一种影响数百万人和侵袭人体任何处关节的炎性疾病。其症状从受影响关节轻微的疼痛和发炎到严重的和令人虚弱的疼痛和炎症。虽然这种疾病主要和上年纪的成人有关,但又不局限于成年人。最普通的关节炎治疗方法包括使用非类固醇类药物(NSAID),以减轻症状。然而,尽管该类药物得到广泛的应用,但许多个体不能耐受长时间治疗该疾病所需的剂量。此外,NSAID类药物只能治疗该疾病的症状而不能影响根本的病因。当病人对NSAID类药物缺乏响应时,经常使用其它的药物,如甲氮蝶呤、金盐、D-青霉胺和波尼松。这些药物也具有明显的毒性,而且它们的作用机理仍然是未知的。
IL-1β的受体拮抗物和TNF-α的单克隆抗体在小规模的人体临床试验中已经显示出能够减轻类风湿性关节炎的症状。除了基于蛋白质的治疗以外,也还有抑制这些细胞素产生,并在动物关节炎模型中显示出活性的小分子药剂。请见J.C.Boehm等人的《1-取代的4-芳基-5-吡啶基咪唑:一类具有低5-脂氧合酶和细胞氧合酶抑制药效的新型的细胞素抑制药物》(1-Substituted 4-Aryl-5-pyridinylimidazoles:A New Class of Cytokine Suppressive DrugWith Low 5-Lipoxygenase and Cyclooxygenase InhibitoryPotency)载J.Med.Chem.,1996,39,3929-37。在这些小分子的药剂当中,已经证实,SB 203580在LPS激发的人单细胞系中具有减缓TNF-α和IL-1β产生的效果,IC50值是50~100Nm。又请见Adams等人的《咪唑衍生物及其作为细胞素抑制剂的应用》(ImidazolDerivatives and Their Use as Cytokine Inhibitor)载国际专利申请WO 93/14081,1993年7月23日。除了这些活体外的试验以外,SB 204580在大鼠和小白鼠中抑制了炎性细胞素的产生,IC50值是15-25mg/kg.A.M.Badger等人的《SB203580的药理学特性,在关节炎、骨吸收的动物模型中对细胞素抑制结合蛋白质/p38激酶的选择性抑制,内毒素休克和免疫功能》(Pharmacological Profile of SB203580,A Selective Inhibitor of Cytokine Suppressive BindingProtein/p38 Kinase,in Animal Models of Arthritis,BoneResorption,Endotoxin Shock and Immune Function)载The Journalof Pharmacology and Experimental Thrapeutics,1996,279,1453-61.虽然现在还没有得到SB 203580的人体数据,已经证实在治疗类风湿性关节炎时TNF-α的单克隆抗体是有效的。请见M.J.Elliot等人的《用肿瘤坏死因子α的嵌合性单克隆抗体治疗类风湿性关节炎》(Treatment of Rheumatoid Arthritis with ChimericMonoclonal Antibodies to Tumor Necrosis Factor α)载ArthritisRheum.1993,36,1681-90。因为SB 203580具有口服的活性和在动物模型中具有药效,研究人员认为,具有此特征的化合物作为治疗类风湿性关节炎具有活力的药物是有潜力的。请见A.M.Badger等人《SB203580的药理学特性,在关节炎、骨吸收的动物模型中对细胞素抑制结合蛋白质/p38激酶的选择性抑制,内毒素休克和免疫功能》载The Journal of Pharmacology and Experimental Thrapeutics,1996,279,1453-61。
SB 203580和其它的小分子药物通过抑制丝氨酸/苏氨酸激酶p38来减缓炎性细胞素的产生(请注意,其它在一些研究人员把这个酶称作CSBP),IC50值是200nm。请见D.Griswold等人的《细胞素抑制抗炎药物结合蛋白质(CSPB),一种新型应激诱导激酶的药理学》(Pharmacology of Cytokine Suppressive Anti-inflammatory DrugBinding Protein(CSPB),A Novel Stress-Induced Kinase)载Parmatcology Communications,1996,7,323-29。虽然此激酶的确切机理还是未知的,但它和TNF-α的产生和与TNF-α受体相关的信号响应都是有关的。
发明概述
本发明的新型化合物在活体外可以抑制nmol级的p-38的活性。此外,该化合物在活体外抑制nmol级TNF-α和IL-1β的分泌。动物模型显示了LPS诱发的TNF-α的抑制,以及对类风湿性关节炎的抑制。在这样的活性范围内,本发明的化合物可用于治疗各种与细胞素有关的疾病,这包括:类风湿性关节炎、炎性肠道疾病、败血性休克、骨质疏松症、骨性关节炎、神经性疼痛、HIV复制、HIV痴呆、病毒性心肌炎、胰岛素依赖型糖尿病、非胰岛素依赖型糖尿病、牙周病、心瓣再狭窄、脱发、areta、HIV感染T细胞排空,即爱滋病、牛皮癣、急性胰腺炎、同种移植排斥、过敏性肺炎、动脉粥样硬化、多发性硬化、恶病质、早老性痴呆、中风、节段性回肠炎、炎性肠道疾病、局部缺血、充血性心力衰竭、肺纤维病变、肝炎、恶性胶质病、急性感染性多神经炎和全身性红斑狼疮。
本发明涉及通式I的化合物及其可药用的盐
其中:
R1是苯基、取代的苯基(这里的取代基选自C1-5烷基、卤素、硝基、三氟甲基和腈基),或者杂芳基,这里的杂芳基含有5-6个环原子;
R2是苯基、取代的苯基(这里的取代基选自C1-5烷基、卤素、硝基、三氟甲基和腈基),或者杂芳基,这里的杂芳基含有5-6个环原子,任选是取代的C1-4烷基;
R3是氢、SEM、C1-5烷氧基羰基、芳氧基羰基、芳基C1-5烷氧基羰基、芳基C1-5烷基、取代的芳基C1-5烷基(这里的芳基取代基独立地选自C1-5烷基、C1-5烷氧基、卤素、氨基、C1-5烷基氨基和二C1-5烷基氨基中的一个或几个成员)、苯二甲酰亚氨基C1-5烷基、氨基C1-5烷基、二氨基C1-5烷基、琥珀酰亚氨基C1-5烷基、C1-5烷基羰基、芳基羰基、C1-5烷基羰基C1-5烷基、芳氧基羰基C1-5烷基、杂芳基C1-5烷基,这里的杂芳基含有5~6个环原子;
R4是-(A)-(CH2)q-X其中:
Q是0~9;
X选自氢、羟基、乙烯基、取代的乙烯基(这里的一个或几个取代基选自氟、溴、氯和碘)、乙炔基、取代的乙炔基(这里的取代基选自氟、溴、氯和碘中的一个或几个)、C1-5烷基、取代的C1-5烷基(这里的烷基取代基选自一个或几个C1-5烷氧基、三卤代烷基、苯二甲酰亚氨基和氨基)、C3-7环烷基、C1-5烷氧基、取代的C1-5烷氧基(这里的烷基取代基选自苯二甲酰亚氨基和氨基)、苯二甲酰亚氨氧基、苯氧基、取代的苯氧基(这里的苯基取代基选自C1-5烷基、卤素和C1-5烷氧基)、苯基、取代的苯基(这里的苯基取代基选自C1-5烷基、卤素和C1-5烷氧基)、芳基C1-5烷基、取代的芳基C1-5烷基(这里的芳基取代基选自C1-5烷基、卤素和C1-5烷氧基)、芳基羟基C1-5烷基氨基、C1-5烷基氨基、二C1-5烷基氨基、腈基、肟基、苄氧基亚氨基、C1-5烷氧基亚氨基、苯二甲酰亚氨基、琥珀酰亚氨基、C1-5烷基羰氧基、苯基羰氧基、取代的苯基羰氧基、(这里的苯基取代基选自C1-5烷基、卤素和C1-5烷氧基)、苯基C1-5烷基羰氧基(这里的苯基取代基选自C1-5烷基、卤素和C1-5烷氧基)、氨基羰氧基、C1-5烷基氨基羰氧基、二C1-5烷基氨基羰氧基、C1-5烷氧基羰氧基、取代的C1-5烷氧基羰氧基(这里的烷基取代基选自甲基、乙基、异丙基和己基)、苯氧基羰氧基、取代的苯氧基羰氧基(这里的苯基取代基选自C1-5烷基、C1-5烷氧基和卤素)、C1-5烷硫基、取代的C1-5烷硫基(这里的烷基取代基选自羟基和苯二甲酰亚氨基)、C1-5烷基磺酰基、苯基磺酰基、取代的苯基磺酰基(这里的苯基取代基选自溴、氟、氯、C1-5烷氧基和三氟甲基);
只是要求:
如果A是
则q是0,以及X是H,R3可以不是SEM。
此外,本发明预期含有式I化合物的药物组合物,以及用式I化合物来治疗与细胞素有关疾病的方法。
除了式I的化合物以外,本发明还预期式II的中间体化合物。这些中间体用于制备式I的化合物,它们是如下的化合物:
其中:
R1是苯基、取代的苯基(这里的取代基选自C1-5烷基、卤素、硝基、三氟甲基和腈基),或者杂芳基,这里的杂芳基含有5-6个环原子;
R2是杂芳基,这里的杂芳基含有5-6个环原子,任选是取代的C1-4烷基;
R3是氢、SEM、C1-5烷氧基羰基、芳氧基羰基、芳基C1-5烷氧基羰基、芳基C1-5烷基、取代的芳基C1-5烷基(这里的芳基取代基独立地选自C1-5烷基、C1-5烷氧基、卤素、氨基、C1-5烷基氨基和二C1-5烷基氨基中的一个或几个成员)、苯二甲酰亚氨基C1-5烷基、氨基C1-5烷基、二氨基C1-5烷基、琥珀酰亚氨基C1-5烷基、C1-5烷基羰基、芳基羰基、C1-5烷基羰基C1-5烷基、芳氧基羰基C1-5烷基、杂芳基C1-5烷基,这里的杂芳基含有5~6个环原子;
R6是碘、氯或溴;
以及它们的可药用盐。
此外,本发明还涉及式I化合物的制备方法。
这些方法包括在钯偶联剂、适当的溶剂和有机碱存在下,在可以制备式I化合物的反应条件下,将式III的化合物与式IV的化合物接触
其中:
R1是苯基、取代的苯基(这里的取代基选自C1-5烷基、卤素、硝基、三氟甲基和腈基),或者杂芳基,这里的杂芳基含有5-6个环原子;
R2是苯基、取代的苯基(这里的取代基选自C1-5烷基、卤素、硝基、三氟甲基和腈基),杂芳基,这里的杂芳基含有5-6个环原子,任选是取代的C1-4烷基;
R3是氢、SEM、C1-5烷氧基羰基、芳氧基羰基、芳基C1-5烷氧基羰基、芳基C1-5烷基、取代的芳基C1-5烷基(这里的芳基取代基独立地选自C1-5烷基、C1-5烷氧基、卤素、氨基、C1-5烷基氨基和二C1-5烷基氨基中的一个或几个成员)、苯二甲酰亚氨基C1-5烷基、氨基C1-5烷基、二氨基C1-5烷基、琥珀酰亚氨基C1-5烷基、C1-5烷基羰基、芳基羰基、C1-5烷基羰基C1-5烷基、芳氧基羰基C1-5烷基、杂芳基C1-5烷基,这里的杂芳基含有5~6个环原子;
R6是碘、氯或溴;
C(C)-(CH2)q-X
IV
其中
q是0~9
以及
X是氢、C1-5烷基、取代的C1-5烷基、羟基、苯基、取代的苯基、氨基、C1-5烷基氨基、腈基、乙烯基、乙炔基芳基C1-5烷基、琥珀酰亚氨基、苯二甲酰亚氨氧基和卤素。
发明详述
在叙述本发明时使用的术语是一般通用的,而且被先有技术的专业人员所熟知。然而,也定义了可以具有其它意义的术语。术语FCS表示胎牛血清,TCA表示三氯乙酸,而RPMI表示由Roswell ParkMemoria Inst.(Sigma cat#R0833)得到的培养基。“独立地”表示当有一个以上的取代基时,这些取代基可以是不同的。术语“烷基”指的是直链的、环状的和分支链的烷基,而“烷氧基”指的是氧烷基,这里的烷基如上所定义。术语“杂芳基”指的是5元或6元芳香环,其中至少有一个元是杂原子。适当的杂原子包括氮、氧和硫。在5元环的情况下,该杂芳基将含有一个硫、氧或氮原子,此外还可以再含有直至3个氮。对于6元环,杂芳基可以含有直至3个氮。这样的杂芳基的例子包括吡啶-2-基、吡啶-3-基、吡啶-4-基、嘧啶-3-基、呋喃-2-基、呋喃-3-基、噻吩-2-基、噻吩-3-基、哒嗪、三嗪、噻唑、噁唑、吡唑等。SEM指的是2-(三甲基甲硅基)乙氧基甲基,而LDA指的是二异丙基氮化锂。符号Ph指的是苯基,PHT指的是苯二甲酰亚氨基,此外“芳基”包括单芳香环和稠合芳香环,如苯基和萘基。符号C(C)表示亚乙炔基:
而符号(CH2)表示亚乙烯基:术语“反应条件”包括如温度的物理参数。
如在本发明中使用的术语“细胞素”指的是蛋白质TNF-α和IL-1β。与细胞素有关的疾病是人和其它哺乳类动物由于细胞素过度产生所引起的疾病。细胞素,即TNF-α和IL-1β的过度产生与许多疾病有关。这些细胞素相关疾病包括,但不限于类风湿性关节炎、炎性肠道疾病、败血性休克、骨质疏松症、骨性关节炎、神经性疼痛、HIV复制、HIV痴呆、病毒性心肌炎、胰岛素依赖型糖尿病、非胰岛素依赖型糖尿病、牙周病、心瓣再狭窄、脱发、areta、HIV感染T细胞排空,或爱滋病、牛皮癣、急性胰腺炎、同种移植排斥、过敏性肺炎、动脉粥样硬化、多发性硬化、恶病质、早老性痴呆、中风、节段性回肠炎、炎性肠道疾病、局部缺血、充血性心力衰竭、肺纤维病变、肝炎、恶性胶质病、急性感染性多神经炎和全身性红斑狼疮。术语“有效剂量”指的是降低可以在患有细胞素相关疾病的哺乳类动物身上检出的TNF-α和/或IL-1β数量的式I化合物的数量。此外,术语“有效剂量”指的是减轻细胞素相关疾病的症状的式I化合物的数量。
本发明的化合物可以按照下面的方案来制备,其中某些方案得到本发明的多于一种的实施方案。在这些情况下,方案的选择是在先有技术的专业人员的能力范围内的判断。
为了得到分子中A是亚乙炔基的本发明化合物,可以使用1。该方案的原料是
1a类的4,5-二取代咪唑。取代的咪唑可以按照已知的方法制备,该本发明化合物的取代基R1和R2由中间体
1a的取代基决定。中间体
1a用碱,如NaH和惰性溶剂如四氢呋喃在室温下处理大约30分钟至1个小时。一旦完全形成了阴离子,加入烷基化试剂,如苯乙基氯,在大约60~100下搅拌反应混合物大约2~4小时,得到中间体
1b1
和
1b2
。在这一步骤中分离这些中间体,以具有一种优势异构体的方式形成最终的产物。另外,用在WO 96/21452,《某些1,4,5-三取代咪唑化合物用作细胞素》中叙述的方法可以制备中间体
1b1
和1b2
。
用强碱如LDA在惰性溶剂如四氢呋喃中,在-78下处理
1b2
约30分钟。在形成的阴离子中加入如碘或溴的卤素源,在30分钟至1小时之间将此混合物温热至环境温度,得到中间体W为碘的
1c。用钯偶联剂如二(acetatato)二(三苯基膦)钯II、取代的乙炔基化合物如3-丁基卡因-1-醇和有机碱如三乙胺,在惰性溶剂如回流的二氯甲烷中处理1c,得到
1d类的本发明化合物。另外,可以用其它的钯偶联剂处理1c。该偶联剂必须是钯II的化合物,它包括但不限于二(三苯基膦)二氯化钯、二(乙腈基)氯化钯(II)、二(乙腈基)二氯化钯(II)和二(苯并腈基)二氯化钯(II)。此外,可以加入催化数量的铜催化剂如碘化铜,以加大反应速度和/或将反应温度从回流温度降低到室温。
虽然用方案1来制备分子中A为亚乙炔基、n是1,q是2,x是羟基、R1是1,3-嘧啶-4-基、R2是4-氯苯基、R3是苯乙基的本发明化合物,但可以用该方案制备其它的产物。比如,为了改变R3,可以用另外的烷基化试剂或者酰基化试剂代替此烷基化试剂。为了制备分子中R3是C1-5烷氧基羰基、芳氧基羰基、芳基C1-5烷氧基羰基、C1-5烷基羰基和芳基羰基的化合物,在方案1中用一种酰基化试剂代替苄基氯。比如,为了制备分子中R3是苯甲酰基的化合物,用苯甲酰氯代替苄基氯。如果希望要分子中的R3是取代的芳基C1-5烷基、氨基C1-5烷基、取代的氨基C1-5烷基和C1-5烷基的化合物,可以用任何多种烷基化试剂代替苄基氯。比如,为了制备分子中R3是取代的氨基C1-5烷基的化合物,可以用1-溴-3-二甲基氨基丙烷代替苯乙基氯。
为了改变X和q,可以使用各种已知取代的亚乙炔基化合物。比如,如果我们用炔丙基氯代替3-丁基卡因-1-醇,可以制备分子中q是1,而X是Cl的化合物。用这样的方法完全可以制备分子中q是0~9,X是C1-5烷基、取代的C1-5烷基、苯基、取代的苯基、氨基、C1-5烷基氨基、腈基、乙烯基、乙炔基芳基C1-5烷基、琥珀酰亚氨基、苯二甲酰亚氨氧基和卤素的化合物。
方案1
可以用方案2制备分子中A是亚乙烯基的本发明化合物。中间体1a是此方案的原料,在室温下用碱如NaH和惰性溶剂如二甲基甲酰胺处理此原料约30分钟至1小时。一旦完全形成阴离子,在室温下加入2-(三甲基甲硅基)乙氧基氯甲烷,搅拌大约3~5小时,得到中间体2a1
和
2a2
。如同在方案1中一样,在此步骤中分离异构体。在-78℃下,用强碱如正丁基锂在惰性溶剂如四氢呋喃中处理中间体
2a2
大约1小时。加入卤素源如碘,在环境温度下搅拌该混合物约1小时,得到中间体
2b。在大约70℃下,用钯偶联剂如二(acetatato)二(三苯基膦)钯II、三甲基甲硅基乙炔和三乙胺处理
2b18~24小时,得到中间体2c。在含醇的溶剂如回流乙醇中,用HBr水溶液处理此中间体大约3~6小时,得到分子中A是乙烯基、X是Br的式1的化合物。
方案2
方案3说明制备分子中A是亚乙烯基的化合物的另一种方法。此方案的起点是在大约-78℃的温度下,在惰性溶剂如四氢呋喃中和在惰性气氛下,用碱如正丁基锂处理中间体
2a2
大约15~30分钟。加入二甲基甲酰胺,在环境温度下将此混合物搅拌大约1~5小时得到醛类中间体
3a。用由三苯基膦和四溴化碳形成的Wittig试剂、三乙胺和惰性溶剂如二氯甲烷处理
3a,得到乙烯基化合物
3b。可以在室温附近,用含水酸如盐酸处理此化合物几个小时,得到2-取代的衍生物3c。
由于有许多种已知的Wittig试剂,可以通过方案3制备许多种分子中A是乙烯基的本发明化合物。比如,为了得到分子中A是亚乙烯基、q是1,而X是乙烯基的本发明化合物,由三苯基膦和烯丙基溴得到的Wittig试剂代替了在方案3中使用的Wittig试剂。通过此方案可以制备分子中q是1~9,X是乙炔基、乙烯基、取代的乙烯基、C1-5烷基、取代的C1-5烷基、环烷基、苯基、ara-C1-5烷基、C1-5烷基氨基和腈基的化合物。
除了分子中A是亚乙烯基的化合物以外,可以用方案3制备分子中A是亚乙炔基,X是羟基取代的芳烷基的化合物。在-78℃下,在惰性溶剂如四氢呋喃中用碱如正丁基锂处理
3c,然后后苯甲醛处理,得到所需的产物
3d。
方案3
为了制备分子中A是
的本发明化合物,这里R5是氢,可以使用方案4。在室温下,在惰性溶剂如甲醇中,用羟基胺处理中间体
3a 3~6个小时,得到中间体
4a。可以用含水酸和回流的醇溶剂处理大约4小时,除去
4a的SEM基团,得到所需的产物
4b。为了制备分子中R5是C1-5烷基、苯基、苯基C1-5烷基的本发明化合物,可以用已知的相应的邻-取代的羟基胺类如邻-苄基羟基胺代替羟胺。
方案4
用方案5可以制备分子中X是C1-5烷硫基、取代的C1-5烷硫基、C1-5烷基磺酰基、苯基磺酰基和取代的苯基磺酰基的本发明化合物。如前所述的用5-氯-1-戊炔和钯偶联剂处理
1c,得到化合物
5a。在惰性溶剂如乙腈中,在室温下用亲核试剂如2-硫代乙醇代替氯化物,得到硫醇
5b。用过硫酸氢钾制剂水溶液和惰性溶剂如甲醇在环境温度下处理5b 3~6个小时,得到砜化合物
5c。
方案5
为了制备分子中X是C1-5烷氧基羰氧基的化合物,可以如方案6所示,使用化合物
1d。在室温下和在惰性溶剂和缓和碱中,用乙酰化试剂如氯甲酸甲酯处理化合物
1d,得到化合物6a。用已知的乙酰化试剂如氯甲酸甲酯,此方法可以用来制备分子中X是C1-5烷基羰氧基、苯基羰氧基、苯基C1-5烷基羰氧基、氨基羰氧基、C1-5烷基氨基羰氧基、二C1-5烷基氨基羰氧基、C1-5烷氧基羰氧基、取代的C1-5烷氧基羰氧基、苯氧基羰氧基和取代的苯氧基羰氧基的本发明化合物。比如,为了制备分子中X是甲基氨基羰氧基的化合物,用异氰酸甲酯代替氯甲酸甲酯。
如方案6所示,使用
1d可以合成分子中X是卤素的化合物。在室温下用三苯基膦和卤素源如四氯化碳处理化合物
1d,得到化合物
6b。在室温下用亲核试剂如二乙胺处理
6b,得到化合物
6c。
方案6
虽然请求保护的化合物被用作TNF-α和IL-1β的抑制剂,某些化合物的活性比另一些更高,它们是优选的或特别优选的。
优选的式I化合物包括如下的化合物:
和
以及
特别优选的R1是苯基或取代的苯基,其中的苯基取代基是卤素或腈基。
特别优选的R2是吡啶-4-基、嘧啶-4-基和2-丁基吡啶-4-基。
特别优选的R3是氢、(CH2)3Ph和(CH2)3PHT。
特别优选的A是亚乙烯基和亚乙炔基。
特别优选的q是0-6。
特别优选的X是氢、羟基、氯、腈基、环戊基、C1-5烷基羰氧基、苯基羰氧基、苯基C1-5烷基羰氧基、氨基羰氧基、C1-5烷基氨基羰氧基和二C1-5烷基氨基羰氧基。
可以将式I的化合物用于药物组合物,以治疗患有与炎性细胞素,特别是TNF-α过度产生有关疾病的患者(人和其他的灵长目动物)。优选的途径是口服,然而,可以通过静脉内、灌注或局部给药来施用该化合物。口服的剂量是每天大约0.05~100mg/kg。某些本发明化合物的口服剂量可以是每天大约0.05~约50mg/kg,而另外一些可以是每天大约0.05~约20mg/kg。灌注的剂量可以是大约1.0~10×104μg/kg/min的抑制剂与药物载体混合,时间是几分钟到几天。式I化合物局部给药可以与药物载体混合,药物在载体中的浓度大约是0.1~对10%。
用通常的药物赋形剂和制剂技术可以制备药物组合物。口服剂型可以是酏剂、糖浆、胶囊和片剂等。这里典型的固体载体是惰性物质,如孔糖、淀粉、葡萄糖、甲基纤维素、硬脂酸镁、磷酸氢二钙、甘露醇等,而典型的液体口服赋形剂包括乙醇、甘油、水等。所有的赋形剂按照要求可以用制备剂型的先有技术专业人员所公知的技术与崩解剂、稀释剂、制粒剂、润滑剂、粘合剂等相混合。使用水或其它的灭菌载体可以制备肠道外的剂型。
一般说来,将式I的化合物分离,以游离碱的形式使用,然而可以分离该化合物,以其药用盐的形式使用。这些盐的例子包括氢溴酸盐、氢碘酸盐、盐酸盐、过氯酸盐、硫酸盐、马来酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、苯甲酸盐、扁桃酸盐、甲磺酸盐、氢化乙磺酸盐、苯磺酸盐、草酸盐、双羟水杨酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己烷氨基磺酸盐和葡糖二酸盐。
具体地说,本发明涉及以下方面:
1.通式I的化合物及其可药用的盐
其中:
R1是卤代苯基、吡啶-2-基、吡啶-3-基或吡啶-4-基;
R2是卤代苯基、吡啶-2-基、吡啶-3-基或吡啶-4-基;
R3是氢、SEM或苯基C1-5烷基;
R4是-(A)-(CH2)q-X其中:
基C1-5烷基;
q是0~5;
X选自氢、羟基、C1-5烷基、C3-7环烷基、C1-5烷氧基、苯二甲酰亚氨氧基、苯基、二C1-5烷基氨基、腈基、苯二甲酰亚氨基、琥珀酰亚氨基、C1-5烷基羰氧基、苯基羰氧基、卤素、C1-5烷硫基或C1-5烷基磺酰基;
只是要求:
如果A是
则q是0,以及X是H,R3可以不是SEM。
2.第1项的化合物,其中R1是卤代苯基,R2是吡啶-2-基、吡啶-3-基或吡啶-4-基。
3.第2项的化合物,其中R1是4-氟苯基,R2是吡啶-4-基。
4.第3项的化合物,其中R3是氢或苯基C1-5烷基。
5.第4项的化合物,其中A是亚乙炔基,q是0~5。
6.第5项的化合物,其中X是琥珀酰亚氨基、羟基、苯基、C3-6环烷基、C1-5烷氧基、苯基羰氧基、二C1-5烷基氨基或腈基。
7.第1项的化合物及其可药用的盐,其选自4-(4-氟苯基)-2-(4-羟基丁炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(3-羟基丙炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(5-羟基戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑或4-(4-氟苯基)-2-(6-羟基己炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑。
8.第1项的化合物,其选自4-(4-氟苯基)-2-(4-羟基丁炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑及其可药用的盐。
9.第1项的化合物及其可药用的盐,其选自4-(4-氟苯基)-2-(5-氰基戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(4-二甲基氨基丁炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(4-(苯基羰氧基)丁炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(4-(甲基羰氧基)丁炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(3-环戊基丙炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑或4-(4-氟苯基)-2-(5-(丁基磺酰基)戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑。
10.第1项的化合物及其可药用的盐,其选自4-(4-氟苯基)-2-(辛炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(5-丁硫基戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(5-苯基戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(5-氯戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑或4-(4-氟苯基)2-(5-N-琥珀酰亚氨基戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑。
11.一种含有第1项的化合物和可药用的载体或稀释剂的药用组合物。
12.第11项的药用组合物,其中所述化合物如第6项的定义。
13.第11项的药用组合物,其中所述化合物如第7项的定义。
14.第11项的药用组合物,其中所述化合物如第8项的定义。
15.第1项的化合物在制备用于治疗与细胞素有关疾病的药物中的用途。
16.有效剂量的第11项的组合物在制备用于治疗与细胞素有关疾病的药物中的用途。
17.第15项的用途,其中口服该化合物,有效剂量是每天0.1~100mg/kg。
18.第17项的用途,其中该剂量是每天0.1~50mg/kg。
19.有效剂量的第1项的化合物在制备用于治疗关节炎的药物中的用途。
20.式II的化合物及其可药用的盐
其中:
R1是卤代苯基、吡啶-2-基、吡啶-3-基或吡啶-4-基;
R2是卤代苯基、吡啶-2-基、吡啶-3-基或吡啶-4-基;
R3是氢、SEM或苯基C1-5烷基;
R6是碘。
21.第20项的化合物,其中R1是4-氟苯基,R2是4-吡啶基。
22.第20项的化合物,其选自4-(4-氟苯基)-2-碘-1-(3-苯基丙基)-5-(4-吡啶基)咪唑。
23.制备如第1项定义的通式I化合物的方法,该方法包括在钯偶联剂、有机碱和适当的溶剂碱存在下,在可以制备通式I化合物的反应条件下,将通式III的化合物与通式IV的化合物接触
其中:
R1是卤代苯基、吡啶-2-基、吡啶-3-基或吡啶-4-基;
R2是卤代苯基、吡啶-2-基、吡啶-3-基或吡啶-4-基;
R3是氢、SEM或苯基C1-5烷基;
R6是碘、氯或溴;
-C≡C-(CH2)q-X
IV
其中
q是0~5
以及
X是氢、C1-5烷基、羟基、苯基、氨基、C1-5烷基氨基、腈基、乙烯基、乙炔基芳基C1-5烷基、琥珀酰亚氨基、苯二甲酰亚氨氧基或卤素。
24.根据第23项的方法,其中钯偶联剂选自二(乙酰)二(三苯基膦)钯(II)、二(三苯基膦)二氯化钯、二(乙腈基)氯化钯(II)、二(乙腈基)二氯硝基钯(II)和二(苯并腈基)二氯化钯(II)。
25.根据第23项的方法,其中的有机碱是三乙胺。
26.根据第23项的方法,其中式III的化合物是4-(4-氟苯基)-2-碘-1-(3-苯基丙基)-5-(4-吡啶基)咪唑,而式IV的化合物是3-丁基卡因-1-醇。
27.第23项的方法,其中适当的溶剂是二氯甲烷,反应条件是使二氯甲烷回流。
28.式II的化合物及其可药用的盐
其中:
R1是卤代苯基、吡啶-2-基、吡啶-3-基或吡啶-4-基;
R2是卤代苯基、吡啶-2-基、吡啶-3-基或吡啶-4-基;
R3是SEM或苯基C1-5烷基;
R6是碘、氯或溴。
生理学实施例
用
体外和
体内试验显示本发明化合物的生理活性。正如在前面所讨论的,抑制酶p38的抑制剂抑制TNF-α和IL-1β的产生。通过如下的体外试验测定本发明化合物抑制p38活性的能力。
将纯重组体p38(在这里,考虑到试验的线性范围和可接受的信噪比从经验测定酶的含量;以
E.coli表示6xHis-p38)、髓磷脂基础蛋白质基质(也进行实验测定)和pH值7.5的缓冲液(Hepes:25Mm;MgCl2:10Mm;MnCl2:10mM)的溶液(38μL)加入到96穴的圆底聚丙烯板中的92个穴中。其余的穴用作对照(CTRL)和背景(BKG)。用酶、基质、缓冲液和2%的二甲基亚砜(DMSO)准备CTRL,用基质、缓冲液和2%的DMSO制备BKG。将测试化合物在DMSO中的溶液(12μL)(化合物在10%的DSMO/H2O中被稀释到125μL,用25μL进行试验,这时最终的DMSO浓度为2%)加入到测试穴中。将ATP/33P-ATP溶液(10L:含有50μM未标记的ATP和1μCi33P-ATP)加入到所有的穴中,将完成的板进行混合,在30℃下培养30分钟。在每个穴中加入冰冷的50%TCA/10mM磷酸钠(60μL),将这些板放在冰上15分钟。将每个穴中的内容物转移到96穴过滤板(Millipore,MultiScreen-DP)的穴中,将该过滤板放在配有废物收集盘的真空集管上。用10%的TCA/10mM磷酸钠(200μL)在真空下洗涤5次。加入MicroScint-20闪烁剂,用Topseal-S片密封这些板,用具有颜色抑制修正的33P液体程序在Packard TopCount闪烁计数器中进行计数,这里的输出是进行了颜色抑制修正的cpm。通过下面的公式计算出该测试化合物的%抑制值:
%抑制值=[1-(试样-BKG)/(CTRL-BKG)]×100
虽然开始时化合物是以20μM进行测试,如果认为合适,可以在上述的浓度增加4倍进行测试。此外,对于某些化合物,用Deltagraph4-参数曲线拟合程序计算出IC50。
除了酶试验以外,还用按照如下的方法取自人血的外周血单核细胞(PBMC)在体外的整细胞试验中测试了本发明化合物的许多种。用肝素将刚刚得到的静脉血进行抗凝处理,用等体积的磷酸盐缓冲盐水(PBS)稀释,放在灭菌的管或其它容器中。将此混合物中的一份(30mL)转移到装在Ficoll-Hypaque(15mL)上离心试管中。在室温下将制备好的离心试管不加制动地在400g下离心30分钟。用移液管取出在单核细胞带状物上方血小板层的大约1/2到2/3。用移液管小心地除去大部分单核细胞层,用PBS稀释这些PBMC,并在600g下旋转15分钟。用另外一部分PBS洗涤得到的PBMC,在室温下在400g下旋转10分钟。在低内毒素RPMI/1%FCS培养介质中稀释回收的小粒,得到的细胞浓度0.5~2.0×106PMBC/ml。取出少量的悬浮液在血细胞计数器中进行计数,在室温下,在200g下将剩下的制剂离心15分钟。将回收的呈颗粒的PMBC重新悬浮在RPMI/1%FCS中达到浓度1.67×106/ml。
为了进行试验,将PBMC悬浮液(180μL)转移到96穴平底微过滤板的双连穴中,在37℃下培养1小时。在每个穴中加入测试化合物的溶液(10μL:在20x所需的最终浓度制备),在37℃下培养该板1小时。加入LPS在RPMI/1%FCS(200ng/mL)溶液(200μL),在37℃下培养该穴过夜。从每个穴中取出上清液(100μL),用RPMI/1%FCS(400μL)稀释。用商品ELISA工具(Genzyme)分析试样的TNF-α。
通过下面的
体外试验测定选择的本发明化合物的IL-1β活性。从PBMC制备塑料粘附细胞。简单地说,如上所述将PBMC加入到96穴板的穴中,在37℃下培养1小时,缓和地重新悬浮非粘附细胞,用移液管将其取出和弃去,用200μL培养介质缓和地洗涤穴3次来制备粘附细胞。在最后一次洗涤后,再在穴中加入培养介质(180μL)。化合物添加、LPS刺激、培养和收集上清液都如TNF-α。用商用的ELISA(Genzyme)试验上清液的白细胞介素-1β。
化合物4和36以分别为7和13nM的IC50抑制IL-1β的产生。
在下面的体内啮齿动物试验显示通式I化合物抑制LPS诱导TNF-α产生的能力。在以5~50mg/kg测试化合物的剂量口服5~10mL/kg之前,喂养小鼠(BALB/cJ雌鼠,Jackson试验室)或大鼠(Lewis雄鼠,Charles River)。在给药后三十分钟,腹膜内注射1mg/kg的LPS,将其放回饲养箱1小时。用CO2将动物麻醉,用心脏穿刺放血,收集全部血液(0.1~0.7mL)。让血结块,血清被转移去离心。将试样离心处理,收集血清,分成数份在-80冻结。用商用的ELISA测试试样的TNF-α(小鼠TNF-α测试内源的,大鼠TNF-α测试biosource的)。
除了其体内TNF-α活性以外,按照下面的方式,式I化合物还抑制大鼠模型生体内的多关节炎。在第0天,在Lewis雄鼠靠近尾部的皮下注射100μL浓度为7.5mg/mL的热杀酪酸分支杆菌在矿物油中的悬浮液。一组大鼠口服给药,从第0天到试验结束每天一次,用盐酸作为消极对照组,或者用20或50mg/kg的化合物4。作为抑制的积极对照组,一组在第0~9天用盐酸给药,然后从第10天到试验结束给药20mg/kg(或50mg/kg)的环孢菌素A(Cys)。在这些条件下,在第11~12天,消极对照组动物的爪子开始肿胀。根据试验的不同,在第8~10天用汞体积描记仪测量的两个后爪的体积,再在第14、17天以及19或21天进行测量。按照爪体积比第8~10天基线测量的增加情况分析数据。在4次试验得到的数据列在表A中。
表A
试验号 | 剂量(mg/kg) | 爪肿胀平均降低% |
1 | 20 | 79 |
2 | 20 | 4 |
3 | 50 | 71 |
4 | 50 | 20 |
本发明的选择化合物列在表B。大多数化合物测试了其抑制p38和TNF-α的能力,不过某些化合物是在一次试验中筛选的。列出了大多数化合物的IC50,如果得不到计算结果,就列出对于给定浓度的%抑制值。除了生理学数据以外,还列出了该化合物的合成示意式。因为在1-位置未取代的咪唑会发生互变异构,当R3是氢的时候,列出的R1和R2可以互相变化。
表B
p-38 TNF-α
化合物 R1 R2 R3 R4 IC50μm IC50μm 方案
4 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)2OH 0.65 3.0 1
8 4-F-Ph 4-pyr H (CH)2Cl 1.5 2
10 4-pyr 4-F-Ph SEM (CH)2Br2 16%@5μm 3
11 4-F-Ph 4-pyr H C(C)CH(OH)-Ph 400 3
13 4-F-Ph 4-pyr H CH(N)OH 45 4
14 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)3Cl 4 6
15 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)2- 38 6
-OC(O)NHPh
16 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)2Cl 6 6
17 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)2N(CH3)2 3
18 4-F-Ph 4-pyr SEM (CH)2Br2 1500 3
19 4-F-Ph 4-pyr H C(C)(CH2)3OH 85 1
20 4-pyr 4-F-Ph SEM C(C)(CH2)2OH >10,000 1
21 4-F-Ph 4-pyr H C(C)(CH2)2OH 80 1
22 4-F-Ph 4-pyr H C(C)(CH2)3PHT 700 6
23 4-pyr 4-F-Ph SEM C(C)(CH2)4OH >2,000 1
24 4-F-Ph 4-pyr H C(C)(CH2)4OH 100 1
25 4-pyr 4-F-Ph SEM C(C)(CH2)3CN >2,000 1
26 4-pyr 4-F-Ph SEM C(C)(CH2)2CH3 >2,000 1
27 4-pyr 4-F-Ph H C(C)(CH2)3CN 55 1
28 4-pyr 4-F-Ph H C(C)(CH2)2CH3 80 1
29 4-pyr 4-F-Ph H C(C)(CH2)3PHT 200 1
30 4-F-Ph 4-pyr H C(C)H 150 6
31 4-F-Ph 4-pyr H C(C)Br 250 1
32 4-F-Ph 4-pyr H CH(N)OCH2Ph 80 2
33 4-F-Ph 4-pyr H CH(N)O- 150 4
CH2(4-NO2Ph)
34 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)2CH3 10.0 1
35 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)3OH 99%@20μm 8.0 1
36 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)3CN 1.5 9.0 1
37 4-F-Ph 4-pyr (CH2)3PHT C(C)(CH2)2OH 160 1
38 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)3Ph 40 1
39 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)3 200 5
S(CH2)3CH3
40 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)3 6.5 5
-SO2(CH2)3CH3
41 4-F-Ph 4-pyr (CH2)3Ph C(C)CH2环戊基 28 1
42 4-F-Ph 4-pry (CH2)3Ph C(C)(CH2)5CH3 90 1
43 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)4OH 98%@20μm 5.2 1
44 4-F-Ph 4-pyr H (CH)2Br2 93%@20μm 200 2
45 4-F-Ph 4-pyr SEM C(C)(CH2)3- 850 1
-N-琥珀酰亚胺
46 4-F-Ph 4-pyr H (CH)2CN 250 1
47 4-F-Ph 4-pyr (CH2)3Ph C(C)CH2OH 7.2 1
48 4-F-Ph 4-pyr (CH2)3Ph C(C)CH2OPHT 85 1
49 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)2OCH3 3 6
50 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)2OCOPh 2 6
51 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH)2H 5.5 1
52 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)2OCOCH3 2.6 6
对于选择的本发明化合物的生体内测试结果列在表C中。用小鼠和/或大鼠测量了这些化合物的抑制TNF-α产生能力,列出的数据是在25mg/kg时的%抑制值。
表C
%抑制值 TNF-α
化合物 R1 R2 R3 R4 小鼠 大鼠
4 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)2OH 49.6 91
19 4-F-Ph 4-pyr H C(C)(CH2)3OH 29
24 4-F-Ph 4-pyr H C(C)(CH2)4OH 73
26 4-pyr 4-F-Ph SEM C(C)(CH2)2CH3 0
27 4-pyr 4-F-Ph H C(C)(CH2)3CN 95
28 4-pyr 4-F-Ph H C(C)(CH2)2CH3 88
34 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)2CH3 53
35 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)3OH 68
36 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)3CN 69.3
43 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)4OH 53
制备实施例
为了说明本发明,包括了下面的各实施例。这些实施例不限制本发明。它们只是提出实施本发明的方法。先有技术的专业人员可以找到其它的方法来实施本发明,这对他们是显而易见的。然而相信这些方法都在本发明的范围之内。
实施例1
5-(4)-(4-氟苯基)-4(5)-(4-吡啶基)咪唑
化合物1
将二氧化硒(4.82g,43.4mmol)在水(20mL)中的溶液加入到1-(4-氟苯基)-2-(4-吡啶基)-2-乙酮(9.33g,43.4mmol)在二(噁)烷(100mL)中的溶液里,将得到的混合物回流加热2小时。将此混合物真空浓缩,用乙酸乙酯研制并过滤。用乙酸乙酯/己烷(1∶1)作为洗脱剂将残渣进行柱状色谱提纯,得到1-(4-氟苯基)-2-(4-吡啶基)-1,2-乙烷二酮。在分离出的二酮在醋酸(150mL)中的溶液里加入醋酸铵(25.25g,0.328mol)和六亚甲基四胺(9.18g,65.5mmol)的混合物。在80℃下搅拌此混合物2小时,倒入浓氢氧化铵(200mL)中,过滤得到的沉淀,用水洗涤和干燥,得到固体状标题化合物:mp:242~244.3℃;MS 240(MH+)。
实施例2
4-(4-氟苯基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑
化合物2a
5-(4-氟苯基)-1-(3-苯基丙基)-4-(4-吡啶基)咪唑
化合物2b
在化合物1(7.15g,29.9mmol)在二甲基甲酰胺(70mL)的混合物中加入60%的氢化钠(1.32g,33mmol),搅拌30分钟。加入3-溴苯基丙烷(5.05mL,33mmol),在60℃和氮气下搅拌反应混合物2小时。将混合物倒入水中,用几份乙酸乙酯萃取。将合并的有机层用水洗涤,真空浓缩和用乙酸乙酯作为洗脱剂在二氧化硅上进行柱色谱提纯。化合物2a是极性较大的化合物,分离出成为固体:mp 70~74℃;MS 358(MH+)。化合物2b是极性较小的化合物,分离出成为固体:mp107.5~112.5℃。
实施例3
4-(4-氟苯基)-2-碘-1-(3-苯基丙基)-5-(4-吡啶基)咪唑
化合物3
在-78℃在化合物2a(9.69g,27.1mmol)的溶液里加入2M的二异丙基氮化锂/四氢呋喃(17mL),在-78℃下搅拌此混合物15分钟。加入碘(10.0g,39.4mmol),让得到的混合物在30分钟内温热至环境温度。加入亚硫酸钠水溶液和乙酸乙酯,分离有机层,用水洗涤并真空浓缩。用乙酸乙酯∶己烷(1∶1)作为洗脱剂,在二氧化硅凝胶上进行柱色谱提纯,得到固体化合物3:mp 117~119℃;MS 484(MH+)。
实施例4
4-(4-氟苯基)-2-(4-羟基丁炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑
化合物4
在化合物3(9.10g,18.8mmol)在二氯甲烷(40mL)的溶液里加入三乙胺(80mL)、二(acetato)二(三苯基膦)钯II(0.71g,0.95mmol)和3-丁基卡因-1-醇(2.90ml,37.6mmol)。回流搅拌反应混合物4小时,真空浓缩并在水和乙酸乙酯之间进行分配。真空浓缩有机层,用乙酸乙酯作为洗脱剂进行柱色谱提纯,得到固体化合物4:mp 125-126.5℃;MS 426(MH+)。
除了化合物4以外,通过此实施例的方法还制备另外一些通式I的化合物。使用适当取代的乙炔基衍生物代替3-丁基卡因-1-醇,得到在表D中列出的各种化合物及其质谱数据。
表D
化合物 R1 R2 R3 R4 (MH+)
34 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)2CH3 424
35 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)3OH 440
36 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)3CN 449
38 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)3Ph 500
39 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2S(CH2)CH3 512
41 4-F-Ph 4-pry (CH2)3Ph C(C)(CH2)5CH3 466
42 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)4OH 454
43 4-F-Ph 4-pyr (CH2)3Ph C(C)CH2环戊基 464
47 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)OH 412
48 4-F-Ph 4-pyr (CH2)3Ph C(C)(CH2)OPHT 557
实施例5
化合物5a 化合物5b
4-(4-氟苯基)-5-(4-吡啶基)-1-(2-(三甲基甲硅基)乙氧基甲基)咪唑
化合物5a
5-(4-氟苯基)-4-(4-吡啶基)-1-(2-(三甲基甲硅基)乙氧基甲基)咪唑
化合物5b
在氮气和搅拌下,在5-(4)-(4-氟苯基)-4(5)-(4-吡啶基)咪唑(5.50g,23mmol)在二甲基甲酰胺的溶液里加入60%的氢化钠(0.92g,23mmol)。15分钟后加入2-(三甲基甲硅基)乙氧基甲基氯(4.07mL,23mmol),将得到的混合物搅拌3小时,倒入水中,用硫酸镁干燥和真空浓缩。用乙酸乙酯作为洗脱剂,在二氧化硅凝胶上将得到的油状物进行柱色谱提纯。将第一种异构物结晶,得到化合物5a:mp 111~113℃;MS 370(MH+)。第二种异构物结晶,得到化合物5b;mp 62~64℃;MS 370(MH+)。
实施例6
5-(4-氟苯基)-2-碘-4-(4-吡啶基)-1-(2-(三甲基甲硅基)乙氧基甲基)咪唑
化合物6
在-78下在搅拌的化合物5b(2.35g,6.40mmol)在乙醚(150mL)的溶液里加入2N的正丁基锂/四氢呋喃(3.2mL)。1小时以后,加入碘(2.16g,8.50mmol),在环境温度下搅拌反应混合物1小时。加入亚硫酸钠水溶液(100mL),用水洗涤得到的有机层,用硫酸镁干燥,用柱色谱提纯,得到油状的化合物6:MS 496(MH+)。
实施例7
5-(4-氟苯基)-4-(4-吡啶基)-2-(三甲基甲硅基)乙炔基-1-(2-(三甲基甲硅基)乙氧基甲基)咪唑
化合物7
在化合物2(0.60g,1.20mmol)在三乙胺(15mL)的溶液里加入三甲基甲硅基乙炔(0.31mL)、二(acetato)二(三苯基膦)钯II(5mol%),在70℃下搅拌得到的混合物18小时。将得到的混合物冷却到室温,分离固体和滤液。用三乙胺洗涤固体,真空浓缩合并的有机层。用乙酸乙酯∶己烷(1∶1)作为洗脱剂,在柱色谱上将残渣提纯,得到固体化合物7:mp 128.3~129℃;MS 466(MH+)。
实施例8
2-(2-氯乙烯基)-5-(4-氟苯基)-4-(4-吡啶基)咪唑
化合物8
在化合物7的乙醇溶液中加入3N的盐酸,回流加热混合物5小时。真空浓缩得到的反应混合物,用碳酸氢钠中和,用乙酸乙酯萃取。真空浓缩有机层,用乙酸乙酯作为洗脱剂在柱色谱上提纯,得到固体化合物8:mp 185~187℃;MS 300(MH+)。
实施例9
5-(4-氟苯基)-4-(4-吡啶基)-1-(2-(三甲基甲硅基)乙氧基甲基)咪唑-2-甲醛
化合物9
在-78℃下在搅拌的化合物5b(7.10g,19.2mmol)四氢呋喃溶液中加入1.6N的正丁基锂(13mL,21mmol)。15分钟以后,加入二甲基甲酰胺(2.0mL,26mmol),在环境温度下搅拌混合物1小时,用水终止反应。用乙酸乙酯萃取此混合物,真空浓缩合并的有机萃取液。用乙酸乙酯∶己烷(1∶1)作为洗脱剂,在二氧化硅凝胶柱色谱上提纯残渣,得到固体化合物9:mp 42~45℃;MS 398(MH+)。
实施例10
2-[2,2-二溴乙烷-1-基]-5-(4-氟苯基)-4-(4-吡啶基)-1-(2-(三甲基甲硅基)乙氧基甲基)咪唑
化合物10
将三苯基膦(13.40g,51.1mmol)溶解于二氯甲烷(300mL)中并冷却到-10℃。滴加四溴化碳溶液(8.50g,25.6mmol),然后滴加化合物9(6.85g,17.2mmol)和三乙胺(2.79mL,20mmol的二氯甲烷溶液,将此混合物搅拌30分钟,倒入乙醚(500mL)中并过滤。真空浓缩过滤液,用乙酸乙酯∶己烷(1∶1)作为洗脱剂,在二氧化硅凝胶上进行柱色谱提纯,得到固体化合物10:mp 128~131℃;MS 554(MH+)。
实施例11
5-(4)-(4-氟苯基)-2-(3-羟基-3-苯基-丙炔-1-基)-4(5)-(4-吡啶基)咪唑
化合物11
在-78℃下在搅拌的化合物10(2.20g,3.80mmol)的四氢呋喃(50mL)溶液中加入1.6N的正丁基锂(5.0mL,8.0mmol)。30分钟以后,加入苯甲醛(0.40mL,3.94mmol),在环境温度下让混合物搅拌30分钟。加入水,真空浓缩得到的有机层并溶解于甲醇(20mL)和1N盐酸(20mL)中。在50℃下搅拌混合物2小时,用碳酸氢钠中和得到的混合物和要乙酸乙酯萃取。合并有机层并用硫酸镁干燥,用乙酸乙酯作为洗脱剂在二氧化硅凝胶上提纯,得到固体化合物11:mp 193~194℃;MS 370(MH+)。
实施例12
5-(4)-(4-氟苯基)-4(4-吡啶基)-1-(2-(三甲基甲硅基)乙氧基甲基)-2-肟基咪唑
化合物12
在室温下在搅拌的化合物9(0.50g,1.2mmol)在甲醇(5mL)的溶液里加入羟基胺盐酸盐(0.09g,1.3mmol)、碳酸氢钠(0.11g,1.3mmol)和水(5mL)。将此混合物搅拌3小时,倒入水中。过滤出固体沉淀,在真空下干燥,得到固体标题化合物∷mp 212~213℃;MS 413(MH+)。
实施例13
5-(4-氟苯基)-4-(4-吡啶基)-2-咪唑肟
化合物13
在化合物12在甲醇(5mL)的溶液中加入0.5M的盐酸(3mL)。回流加热此混合物2小时,用碳酸氢钠中和,过滤出得到的沉淀。用甲醇/水重结晶该固体,得到固体标题化合物;mp 318~320℃;MS 283(MH+)。
实施例14
2-(5-氯戊炔-1-基)-(4-氟苯基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑
化合物14
在回流下搅拌三乙胺(50mL)、二(acetato)二(三苯基膦)钯II(0.71g,0.95mmol)和5-氯-1-戊炔(0.71mL,6.70mmpl)以及化合物3(1.62g,3.35mmol)16小时。加入乙酸乙酯,过滤除去固体沉淀。真空浓缩过滤液层,用乙酸乙酯∶己烷(1∶2)作为洗脱液,在柱色谱上提纯,得到固体化合物14∷mp 102~104℃。
实施例15
4-(4-氟苯基)-2-(4-N-苯基氨基甲酰基丁炔-1-)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑
化合物15
在搅拌的化合物4(200mg,0.50mmol)在吡啶的溶液里加入异氰酸苯酯(11mL,1.0mmol)。搅拌混合物4小时,倒入冰中。用水洗涤固体沉淀并干燥,得到固体化合物15:mp 120~124℃。
实施例16
2-(4氯丁炔-1-基)-4-(4-氟苯基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑
化合物16
在室温下在化合物4(0.9g,2.12mmol)的溶液里加入三苯基膦(1.11g,4.23mmol)和四氯化碳(0.41mL,4.23mmol)。将混合物搅拌22小时,真空浓缩和用乙酸乙酯∶己烷(1∶1)作为洗脱剂进行柱色谱提纯,得到固体标题化合物:mp 132~134℃。
实施例17
2-(4-二甲基氨基丁炔-1-基)-4-(4-氟苯基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑
化合物17
在室温下搅拌化合物16(208mg,0.47mmol)在2N的二甲胺/甲醇(10mL)中的溶液并真空浓缩18小时。用二氯甲烷∶甲醇(19∶1)作为洗脱剂将残渣进行柱色谱提纯,得到固体标题化合物:mp 115~117℃。
Claims (28)
1.通式I的化合物及其可药用的盐
其中:
R1是卤代苯基、吡啶-2-基、吡啶-3-基或吡啶-4-基;
R2是卤代苯基、吡啶-2-基、吡啶-3-基或吡啶-4-基;
R3是氢、SEM或苯基C1-5烷基;
R4是-(A)-(CH2)q-X其中:
q是0~5;
X选自氢、羟基、C1-5烷基、C3-7环烷基、C1-5烷氧基、苯二甲酰亚氨氧基、苯基、二C1-5烷基氨基、腈基、苯二甲酰亚氨基、琥珀酰亚氨基、C1-5烷基羰氧基、苯基羰氧基、卤素、C1-5烷硫基或C1-5烷基磺酰基;
只是要求:
如果A是
则q是0,以及X是H,R3可以不是SEM。
2.权利要求1的化合物,其中R1是卤代苯基,R2是吡啶-2-基、吡啶-3-基或吡啶-4-基。
3.权利要求2的化合物,其中R1是4-氟苯基,R2是吡啶-4-基。
4.权利要求3的化合物,其中R3是氢或苯基C1-5烷基。
5.权利要求4的化合物,其中A是亚乙炔基,q是0~5。
6.权利要求5的化合物,其中X是琥珀酰亚氨基、羟基、苯基、C3-6环烷基、C1-5烷氧基、苯基羰氧基、二C1-5烷基氨基或腈基。
7.权利要求1的化合物及其可药用的盐,其选自4-(4-氟苯基)-2-(4-羟基丁炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(3-羟基丙炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(5-羟基戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑或4-(4-氟苯基)-2-(6-羟基己炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑。
8.权利要求1的化合物,其选自4-(4-氟苯基)-2-(4-羟基丁炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑及其可药用的盐。
9.权利要求1的化合物及其可药用的盐,其选自4-(4-氟苯基)-2-(5-氰基戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(4-二甲基氨基丁炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(4-(苯基羰氧基)丁炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(4-(甲基羰氧基)丁炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(3-环戊基丙炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑或4-(4-氟苯基)-2-(5-(丁基磺酰基)戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑。
10.权利要求1的化合物及其可药用的盐,其选自4-(4-氟苯基)-2-(辛炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(5-丁硫基戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(5-苯基戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(5-氯戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑、4-(4-氟苯基)-2-(戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑或4-(4-氟苯基)2-(5-N-琥珀酰亚氨基戊炔-1-基)-1-(3-苯基丙基)-5-(4-吡啶基)咪唑。
11.一种含有权利要求1的化合物和可药用的载体或稀释剂的药用组合物。
12.权利要求11的药用组合物,其中所述化合物如权利要求6的定义。
13.权利要求11的药用组合物,其中所述化合物如权利要求7的定义。
14.权利要求11的药用组合物,其中所述化合物如权利要求8的定义。
15.权利要求1的化合物在制备用于治疗与细胞素有关疾病的药物中的用途。
16.有效剂量的权利要求11的组合物在制备用于治疗与细胞素有关疾病的药物中的用途。
17.权利要求15的用途,其中口服该化合物,有效剂量是每天0.1~100mg/kg。
18.权利要求17的用途,其中该剂量是每天0.1~50mg/kg。
19.有效剂量的权利要求1的化合物在制备用于治疗关节炎的药物中的用途。
21.权利要求20的化合物,其中R1是4-氟苯基,R2是4-吡啶基。
22.权利要求20的化合物,其选自4-(4-氟苯基)-2-碘-1-(3-苯基丙基)-5-(4-吡啶基)咪唑。
24.根据权利要求23的方法,其中钯偶联剂选自二(乙酰)二(三苯基膦)钯(II)、二(三苯基膦)二氯化钯、二(乙腈基)氯化钯(II)、二(乙腈基)二氯硝基钯(II)和二(苯并腈基)二氯化钯(II)。
25.根据权利要求23的方法,其中的有机碱是三乙胺。
26.根据权利要求23的方法,其中式III的化合物是4-(4-氟苯基)-2-碘-1-(3-苯基丙基)-5-(4-吡啶基)咪唑,而式IV的化合物是3-丁基卡因-1-醇。
27.权利要求23的方法,其中适当的溶剂是二氯甲烷,反应条件是使二氯甲烷回流。
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US5965583A (en) | 1999-10-12 |
DE69816109T2 (de) | 2004-04-22 |
UA65572C2 (en) | 2004-04-15 |
PT1028954E (pt) | 2003-11-28 |
WO1998047892A1 (en) | 1998-10-29 |
KR20010020204A (ko) | 2001-03-15 |
PL191111B1 (pl) | 2006-03-31 |
NO995095D0 (no) | 1999-10-19 |
KR100568438B1 (ko) | 2006-04-07 |
ATE244234T1 (de) | 2003-07-15 |
EP1028954B1 (en) | 2003-07-02 |
RU2222534C2 (ru) | 2004-01-27 |
DK1028954T3 (da) | 2003-10-27 |
CN1253558A (zh) | 2000-05-17 |
US6521655B1 (en) | 2003-02-18 |
BR9808998A (pt) | 2000-08-08 |
ZA983451B (en) | 1999-10-25 |
ES2202840T3 (es) | 2004-04-01 |
HUP0002842A3 (en) | 2002-01-28 |
JP2001522357A (ja) | 2001-11-13 |
CA2297176A1 (en) | 1998-10-29 |
IL132318A0 (en) | 2001-03-19 |
TR199902622T2 (xx) | 2000-05-22 |
DE69816109D1 (de) | 2003-08-07 |
AR012594A1 (es) | 2000-11-08 |
EP1028954A1 (en) | 2000-08-23 |
NO995095L (no) | 1999-12-09 |
HUP0002842A2 (hu) | 2001-06-28 |
PL336758A1 (en) | 2000-07-17 |
US6214830B1 (en) | 2001-04-10 |
NO318937B1 (no) | 2005-05-30 |
NZ500447A (en) | 2001-09-28 |
AU7138298A (en) | 1998-11-13 |
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