CN107759588B - 一类苯基-(吡唑并[1,5-a]吡啶-3-基)甲酮衍生物 - Google Patents
一类苯基-(吡唑并[1,5-a]吡啶-3-基)甲酮衍生物 Download PDFInfo
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- CN107759588B CN107759588B CN201710713936.2A CN201710713936A CN107759588B CN 107759588 B CN107759588 B CN 107759588B CN 201710713936 A CN201710713936 A CN 201710713936A CN 107759588 B CN107759588 B CN 107759588B
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- Prior art keywords
- pyridin
- methanone
- hydroxyphenyl
- halogen
- cyano
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- KMSWJHBCYGDQIE-UHFFFAOYSA-N phenyl(pyrazolo[1,5-a]pyridin-3-yl)methanone Chemical class C1=NN2C=CC=CC2=C1C(=O)C1=CC=CC=C1 KMSWJHBCYGDQIE-UHFFFAOYSA-N 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 201000005569 Gout Diseases 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 25
- 201000001431 Hyperuricemia Diseases 0.000 claims abstract description 16
- 230000001737 promoting effect Effects 0.000 claims abstract description 3
- -1 cyano, hydroxy Chemical group 0.000 claims description 140
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 29
- 239000001257 hydrogen Substances 0.000 claims description 29
- 150000002431 hydrogen Chemical class 0.000 claims description 26
- 125000004414 alkyl thio group Chemical group 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- VODRKJSPZSDAOT-UHFFFAOYSA-N (2-ethylpyrazolo[1,5-a]pyridin-3-yl)-(4-hydroxyphenyl)methanone Chemical compound C(C)C1=NN2C(C=CC=C2)=C1C(=O)C1=CC=C(C=C1)O VODRKJSPZSDAOT-UHFFFAOYSA-N 0.000 claims description 6
- ZQSNSOKRCBQASV-UHFFFAOYSA-N (3,5-dibromo-4-hydroxyphenyl)-(2-ethylpyrazolo[1,5-a]pyridin-3-yl)methanone Chemical compound CCc1nn2ccccc2c1C(=O)c1cc(Br)c(O)c(Br)c1 ZQSNSOKRCBQASV-UHFFFAOYSA-N 0.000 claims description 5
- 125000001153 fluoro group Chemical group F* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 208000017169 kidney disease Diseases 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 2
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 claims 4
- 125000001188 haloalkyl group Chemical group 0.000 claims 3
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims 2
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 claims 2
- 239000000463 material Substances 0.000 claims 1
- 230000003424 uricosuric effect Effects 0.000 claims 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 abstract description 40
- 229940116269 uric acid Drugs 0.000 abstract description 35
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 abstract description 34
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 abstract description 14
- 230000029142 excretion Effects 0.000 abstract description 9
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical class O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
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- WHQCHUCQKNIQEC-UHFFFAOYSA-N benzbromarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC(Br)=C(O)C(Br)=C1 WHQCHUCQKNIQEC-UHFFFAOYSA-N 0.000 description 23
- 102100030431 Fatty acid-binding protein, adipocyte Human genes 0.000 description 20
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
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- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 8
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- 125000001424 substituent group Chemical group 0.000 description 8
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 7
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- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 description 6
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类苯基‑(吡唑并[1,5‑a]吡啶‑3‑基)甲酮衍生物,其为通式(I)所示的化合物或其药学上可接受的盐。本发明的化合物或其药学上可接受的盐可应用于促尿酸排泄治疗或预防高尿酸血症和痛风,或治疗糖尿病。
Description
技术领域
本发明属于药物化学领域,具体涉及一类苯基-(吡唑并[1,5-a]吡啶-3-基)甲酮类化合物及其组合物和在药物方面的用途。
背景技术
痛风(Gout)是由人体内长期高尿酸血症所引起的慢性代谢性疾病。尿酸是人类嘌呤代谢的终产物,溶解于血液中,绝大部分尿酸经肾脏排泄。当人体内嘌呤代谢紊乱,导致尿酸生成增加,或摄取过多的高嘌呤食物,而尿酸排泄不畅(患者占80-85%),使其在血液中大量积蓄达到饱和,出现尿酸盐结晶,沉积在关节和软组织等部位,从而诱发痛风(Richette P,Bardin T.Gout.Lancet.2010,375(9711):318-328)。因此,血尿酸水平是检测罹患痛风可能性的临床辨别指标,一般认为37℃时血清尿酸水平男性>7mg/dL,女性>6mg/dL时为高尿酸血症。
痛风是继糖尿病之后的第二大代谢性疾病,己被联合国列为21世纪二十大顽症之一。西方发达国家(包括英国、德国和美国)痛风患病率较高,为1.4-3.9%(Annemans L,Spaepen E,Gaskin M,et al.Gout in UK and Germany:prevalence,comorbidities andmanagement in general practice 2000-2005.Annals of the rheumaticdiseases.2008,67(7):960-966;Zhu Y,Pandya BJ,Choi HK.Prevalence of gout andhyperuricemia in the US general population:the National Health and NutritionExamination Survey 2007-2008.Arthritis and rheumatism,2011,63(10):3136-3141)。一般认为,痛风与人们的饮食结构和生活习惯密切相关。2007-2008年的一份调查报道称,美国痛风病人已达830万。随着中国经济的飞速发展,近年来痛风发病率也直线上升,有报道称中国痛风患者人数已超5000万,且男性痛风患者人数远高于女性。2010年进行的一项针对3978名40-74岁上海城市人口的流行病学研究表明,约有25%的男性患高尿酸血症(Raquel Villegas,Xiang YB,Cai QY,et al.Prevalence and determinants ofhyperuricemia in middle-aged,urban Chinese men.Metabolic Syndrome and RelatedDisorders.2010,8(3):263-270)。
目前痛风治疗主要分为急性发作期和间歇期/慢性期的治疗。急性期治疗主要使用消炎止痛药来控制痛风症状,减轻患者疼痛,但无法降低体内血尿酸浓度;间歇期或慢性期痛风的治疗,旨在长期有效地降低和控制体内血尿酸水平。抗痛风药物的作用机理主要分为抑制尿酸生成和促进尿酸排泄。抑制尿酸生成药物主要是黄嘌呤氧化酶(Xanthineoxidase)抑制剂,其通过抑制嘌呤代谢中所需的黄嘌呤氧化酶,从而抑制嘌呤向尿酸的转化,减少尿酸的生成。该类药物主要有:别嘌呤醇和非布索坦。但别嘌呤醇使用剂量大,且有过敏性皮疹、肝功能损伤等副作用,这种过敏性皮疹有时是致命性的。而于2009年欧美上市的非布索坦也有十分严重的心血管并发症和胃肠道副作用,同时会导致头疼及一定的肝损伤。
人体约70%的尿酸经由肾脏排泄,而高尿酸血症患者中约有80-85%是由尿酸排泄障碍所致(Cheeseman C.Solute carrier family 2,member 9and uric acidhomeostasis.Current Opinion in Nephrology and Hypertension.2009,18(5):428-432)。故促尿酸排泄在痛风和高尿酸血症的治疗中具有十分重要的地位。其作用机理为抑制尿酸盐在近曲小管的重吸收,增加尿酸盐的排泄而降低体内血尿酸浓度。尿酸盐阴离子转运体1(urate anion transporter1,URAT1)在肾脏近曲小管上皮细胞刷状缘膜上特异性的表达,是肾脏中负责人体尿酸重吸收最主要的蛋白,控制着约90%以上的肾小球滤过后尿酸的重吸收。因此,抑制URAT1转运作用可降低尿酸重吸收,促进尿酸在肾脏的排泄,而达到降低体内血尿酸水平的效果(Michael FW,Jutabha P,Quada B.Developing potenthuman uric acid transporter 1(hURAT1)inhibitors.Journal of MedicinalChemistry.2011,54,2701-2713)。目前市场主要使用的URAT1抑制剂为苯溴马隆(Benzbromarone)、Zurampic、丙磺舒和苯磺唑酮。苯溴马隆对人体有严重的肝脏毒性,没能进入美国市场,2003年也从部分欧洲国家退出市场;Zurampic刚于2015年12月美国获批上市,其具有严重的肾脏和心血管毒副作用,且疗效远不如苯溴马隆,需要跟别嘌醇合用;丙磺舒和苯磺唑酮疗效十分差、且使用剂量大,副作用大。
苯溴马隆为一种苯并呋喃衍生物,其化学名称为3,5-二溴-4-羟苯基-2-乙基-3-苯并呋喃基-甲酮。60年代由法国Labaz公司开发,为典型的促尿酸排泄剂,于1971年在德国上市。虽然苯溴马隆有严重的肝脏毒副作用,但其仍为目前世界上疗效最好的治疗痛风药物。本专利涉及的一类化合物为苯溴马隆类似物,其促尿酸排泄能力优于苯溴马隆,且毒性低于苯溴马隆。
近期王贺瑶等人报道了苯溴马隆的新用途,他们发现苯溴马隆对FABP4(A-FABP或aP2)有抑制活性,IC50=14.8μM;并且苯溴马隆以25或50mg/kg口服剂量给药db/db小鼠4周,能显著降低该糖尿病小鼠的血糖水平和增加胰岛素敏感性。通过模拟分子对接研究发现,苯溴马隆能与FABP4上多个残基位点作用而抑制其活性,表明苯溴马隆是FABP4的特异性抑制剂(Cai H-Y,Wang T,Zhao J-C,et al.Benzbromarone,an old uricosuric drug,inhibits human fatty acid binding protein 4in vitro and lowers the bloodglucose level in db/db mice.Acta Pharmacologica Sinica,2013,34:1397-1402)。
FABP4是脂肪细胞型脂肪酸结合蛋白,主要存在于脂肪组织和巨噬细胞中。在脂质代谢紊乱性疾病的发生发展中发挥重要作用。有研究称FABP4基因缺陷但饮食或基因肥胖的小鼠,它的高胰岛素血症明显降低,且能减轻胰岛素抵抗(Uysal KT,Scheja L,Wiesbrochk SM,et al.Improved glucose and lipid metabolism in geneticallyobese mice lacking aP2.Endocrinology.2000,141,3388-3396)。Annette等人对544例中国非糖尿病受试者进行长达10年的流行病学跟踪,发现糖耐量受损和空腹血糖增高受试者FABP4的血清水平显著升高,10年后患有Ⅱ型糖尿病的受试者循环FABP4基线水平显著高于非糖尿病受试者,表明血清FABP4可预测糖尿病的发展(Tso AW,Xu A,Sham PC,etal.Serum adipocyte fatty acid binding protein as a new biomarker predictingthe development of type 2diabetes:a 10-year prospective study in a Chinesecohort.Diabetes Care,2007,30:2667-2672)。FABP4抑制剂可提高胰岛素敏感性,降低血清甘油三酯水平,从而降低罹患Ⅱ型糖尿病的风险。据报道FABP4的小分子抑制剂BMS309403,能有效的改善肥胖和糖尿病小鼠的糖代谢,增强胰岛素敏感性,提高胰岛素耐量和葡萄糖耐量,同时改善动脉硬化症(Furuhashi M,Tuncman G,Gorgun CZ,etal.Treatment of diabetes and atherosclerosis by inhibiting fatty-acid-bindingprotein aP2.Nature,2007,447:959–965)。
糖尿病与痛风同属慢性代谢性综合症,威胁着人类的生活健康和生命质量。目前全球糖尿病患病人数已达3.8亿(Ⅱ型糖尿病约占90%),每年又以6%的速度增长(Van DS,Beulens JW,van der Schouw YT,et al.The global burden of diabetes and itscomplications:an emerging pandemic.European Journal of CardiovascularPrevention and Rehabilitation,2010,17:S3-8),国际糖尿病联盟(IDF)预计到2030年糖尿病总人数将激增至5.5亿。据IDF2014年最新报告表明我国糖尿病人数已达9629万人,居全球首位,其次为印度的6685万人和再次为美国的2580万人。糖尿病与包括痛风在内的其他代谢综合症密切相关。Gentile等人发现Ⅱ型糖尿病患者的血尿酸水平明显高于正常人群,而且高尿酸血症对Ⅱ型糖尿病患者糖尿病肾病的发生和发展具有加速作用(Bo S,Cavallo-Perin P,Gentile L,et al.Hypouricemia and hyperuicemia in type2diabetes:two different phenotypes.European Journal of ClinicalInvestigation.2001,31(4):318-321)。2011年美国风湿病学会也发布了研究成果,称痛风患者尿酸水平控制不佳会明显增加患糖尿病和肾病的风险。
苯溴马隆是促尿酸排泄的老药,已沿用至今近40年,虽然有严重的肝脏毒副作用,但其临床表现依旧优异,仍有包括中国、日本、德国、巴西、新西兰在内的20多个国家在广泛使用。最近的研究发现了苯溴马隆具有抑制FABP4活性、降低糖尿病小鼠血糖、和增加胰岛素敏感性的新作用。研究也证明有许多痛风病人也同时患有糖尿病。本发明专利涉及的化合物为苯溴马隆结构类似物,具有更优的促尿酸排泄能力和相似的抑制FABP4活性效果,且毒副作用小,有望替代苯溴马隆成为新一代高效、低毒的抗痛风药物,以及同时具有治疗糖尿病的双重药效。
发明内容
本发明的目的是在现有技术的基础上,设计并提供一类具有抑制URAT1转运尿酸盐能力的苯基-(吡唑并[1,5-a]吡啶-3-基)甲酮类化合物,其不仅能够提高对URAT1的抑制效果,还可通过改变化合物在体内的代谢途径,有效的防止被P450s代谢成毒性产物,从而使此类化合物具有低肝毒性,提高其在痛风等相关高尿酸血症疾病临床治疗的应用安全。同时,此类化合物具有抑制FABP4的作用,可用于降低血糖和增加胰岛素敏感性而用于治疗或预防糖尿病。本发明属于药物化学领域,涉及一类化合物或其药学上可接受的盐在制备治疗或预防高尿酸血症、肾病、痛风或糖尿病药物方面的应用。
本发明的另一目的是提供一种含有苯基-(吡唑并[1,5-a]吡啶-3-基)甲酮类衍生物的药物组合物。
本发明的第三个目的是提供上述苯基-(吡唑并[1,5-a]吡啶-3-基)甲酮类衍生物在预防或治疗高尿酸症、痛风或糖尿病肾病方面的用途。
本发明的目的可以通过以下措施达到:
一类通式(I)所示的化合物或其药学上可接受的盐,
其中,
R1或R2分别独立地选自氢、氘、卤素、氰基、羟基、硝基、氨基、羧基、取代氨基或者取代或非取代的下述基团:C1-5烷基或C1-3烷氧基;
R3独立地选自氢、卤素、氰基、取代或非取代的下述基团:C1-4烷基、C3-4环烷基、或C1-3烷氧基;
R4、R5或R6分别独立地选自氢、氘、卤素、氰基、羟基、硝基、取代氨基、C2-3烯基、C2-3炔基或者取代或非取代的下述基团:C1-5烷基、C1-5烷氧基或C1-5烷硫基;
R1、R2、R4、R5或R6中的取代基选自氘、卤素、氰基、羟基、硝基、氨基、羧基、C1-3烷基、C3-4环烷基或C1-3烷氧基;
R3中的取代基选自氘、卤素、氰基、羟基、硝基、氨基、羧基、C1-3烷基或C1-3烷氧基。
在一种优选方案中,本发明的化合物或其药学上可接受的盐,其中化合物具有通式(II)所示结构,
其中,
R1或R2分别独立地选自氢、氘、卤素、氰基、羟基、硝基、氨基、取代氨基或者取代或非取代的下述基团:C1-3烷基、C1-3烷氧基或C1-3烷硫基;
R3选自氢、C1-4烷基、C3-4环烷基、卤素、氰基或C1-3烷氧基;
R4或R5分别独立地选自氢、氘、卤素、氰基、羟基、硝基、取代氨基、C2-3烯基、C2-3炔基或者取代或非取代的下述基团:C1-2烷基、C1-2烷氧基或C1-2烷硫基;
R1或R2中的取代基选自C1-3烷基、羟基、卤素或C1-3烷氧基;
R4或R5中的取代基选自C1-3烷基或卤素。
本发明的式(I)和(II)化合物,在一种优选方案中,R1或R2分别独立地选自氢、氟、氯、溴、氰基、羟基或者取代或非取代的下述基团:C1-3烷基、C1-3烷氧基或C1-2烷硫基;其取代基选自卤素、羟基、C1-3烷基、C3-4环烷基或C1-3烷氧基。
本发明的式(I)和(II)化合物,在另一种优选方案中,R1或R2分别独立地选自氢、卤素、氰基、羟基、C1-5烷基、C1-5羟基烷基、C1-5烷氧基或C1-5烷硫基。
本发明的式(I)和(II)化合物,在一种更优选方案中,R1或R2分别独立地选自氢、氟、氯、溴、甲基、乙基、正丙基、异丙基、羟甲基、甲氧基、乙氧基、正丙氧基、异丙氧基、甲硫基、乙硫基、正丙硫基或异丙硫基。
本发明的式(I)和(II)化合物,在一种优选方案中,R4或R5分别独立地选自氢、氘、卤素、氰基、硝基、取代氨基、C2-3烯基、C2-3炔基或者取代或非取代的下述基团:C1-3烷基、C1-3烷氧基或C1-2烷硫基。
本发明的式(I)和(II)化合物,在另一种优选方案中,R4或R5分别独立地选自氢、卤素、氰基、乙烯基、乙炔基或者取代或非取代的下述基团:C1-2烷基、C1-2烷氧基或C1-2烷硫基;其取代基选自卤素、C1-2烷基、C3-4环烷基或C1-3烷氧基。
本发明的式(I)和(II)化合物,在一种更优选方案中,R4或R5分别独立地选自氢、氟、氯、溴、碘、氰基、甲基、乙基、正丙基、异丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、甲硫基、乙硫基、正丙硫基、异丙硫基。
本发明的式(I)和(II)化合物,在一种优选方案中,R3选自氢、卤素、氰基或者取代或非取代的下述基团:C1-3烷基或C3-4环烷基;取代基选自氘、卤素、氰基、羟基、硝基、氨基、羧基、C1-3烷基、C3-4环烷基或C1-3烷氧基。
本发明的式(I)和(II)化合物,在另一种优选方案中,R3选自氢或C1-4烷基。
本发明的化合物或其药学上可接受的盐,其中化合物选自:
(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基苯基)甲酮,
(3,5-二溴-4-羟基苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮,
(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基-3,5-二碘苯基)甲酮,
5-(2-乙基吡唑并[1,5-a]吡啶-3-羰基)-2-羟基-3-碘苯甲腈,
(3-溴-4-羟基-5-甲基苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮,
(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基-3-碘-5-甲基苯基)甲酮,
5-(2-乙基吡唑并[1,5-a]吡啶-3-羰基)-2-羟基-3-甲基苯甲腈,
(3-氯-4-羟基-5-碘苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮,
(3,5-二碘-4-羟基苯基)(2-乙基-4-甲基吡唑并[1,5-a]吡啶-3-基)甲酮,
(3,5-二溴-4-羟基苯基){2-乙基-6-(乙硫基)吡唑并[1,5-a]吡啶-3-基}甲酮,
(3,5-二溴-4-羟基苯基)(2-乙基-5-甲基吡唑并[1,5-a]吡啶-3-基)甲酮,
(3-溴-4-羟基-5-碘苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮,
(3,5-二溴-4-羟基苯基){2-乙基-4-(乙硫基)吡唑并[1,5-a]吡啶-3-基}甲酮,
(3,5-二溴-4-羟基苯基)(2-乙基-6-氟吡唑并[1,5-a]吡啶-3-基)甲酮,
(2-乙基吡唑并[1,5-a]吡啶-3-基)(2-乙硫基-4-羟基苯基)甲酮,
(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基-3-碘苯基)甲酮,
(3,5-二溴-4-羟基苯基)(2-丙基吡唑并[1,5-a]吡啶-3-基)甲酮,
(3,5-二溴-4-羟基苯基)(2-乙基-6-甲氧基吡唑并[1,5-a]吡啶-3-基)甲酮,
(3,5-二溴-4-羟基苯基)(吡唑并[1,5-a]吡啶-3-基)甲酮,
(3,5-二溴-4-羟基苯基)[5-(羟甲基)吡唑并[1,5-a]吡啶-3-基]甲酮。
本发明的化合物,可以通过如下通式制备:
通式吡啶化合物在一定条件下制成氨基吡啶盐(IA)后跟炔进行关环反应,得到相应的吡唑并[1,5-a]吡啶化合物(IB),然后依次进行水解和脱羧,得到化合物(ID)。化合物(ID)跟酰氯在路易斯酸催化下反应,得到二芳基酮类化合物(IE)。经过不同化学反应得到相应的目标产物(I)。R1、R2、R3、R4和R5基团的定义如上所述。
除非另有说明,下列用在权利要求书和说明书中的术语有如下含义:
“氢”,是指氕(1H),它是氢元素的主要稳定同位素。
“卤素”,是指氟原子,氯原子,溴原子或碘原子。
“烷基”,表示1-20个碳原子的饱和的脂烃基,包括直链和支链基团(本申请书中提到的数字范围,例如“1-20”,是指该基团,此时为烷基,可以含1个碳原子、2个碳原子、3个碳原子等,直至包括20个碳原子)。含1-4个碳原子的烷基称为低级烷基。当低级烷基没有取代基时,称其为未取代的低级烷基。更优选的是,烷基是有2-5个碳原子的中等大小的烷基。本发明中的烷基例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。最好是,烷基为有2-4个碳原子的低级烷基,例如乙基、丙基、2-丙基、正丁基、异丁基或叔丁基等。烷基可以是取代的或未取代的。
“烷氧基”,表示-O-(未取代的烷基)和-O-(未取代的环烷基)基团,其进一步表示-O-(未取代的烷基)。代表性实施例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
“烷硫基”,表示-S-(未取代的烷基)和-S-(未取代的环烷基)基团,其进一步表示-S-(未取代的烷基)。代表性实施例包括但不限于甲硫基、乙硫基、丙硫基、丁硫基、环丙硫基、环丁硫基、环戊硫基、环己硫基等。
“烯基”,表示具有C=C双键的不饱和的脂烃基,包括直链和支链基团;本发明中的烯基优选采用C2-7烯基,进一步优选C2-6烯基或C2-4烯基,例如乙烯基、丙烯基、烯丙基、丙-1-烯-2-基等。
“炔基”,表示具有C≡C叁键的不饱和的脂烃基,包括直链和支链基团;本发明中的炔基优选采用C2-7炔基,进一步优选C2-6炔基或C2-4炔基,例如乙炔基、丙炔基、炔丙基、丙-1-炔-2-基等。
“环烷基”表示具有3个以上C原子的单环或双环烷基,包括但不限于环丙基、环戊基、环己基、二环庚基。
“氰基”,表示-CN基团。
“硝基”,表示-NO2基团。
“氨基”,表示-NH2基团。
“药学上可接受的盐”,是包含通式(I)的化合物与有机酸或无机酸形成的盐,表示保留母体化合物的生物有效性和性质的那些盐。这类盐包括:
(1)与酸成盐,通过母体化合物的游离碱与无机酸或有机酸的反应而得,无机酸例如(但不限于)盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等,有机酸例如(但不限于)乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐,金属离子例如碱金属离子、碱土金属离子或铝离子,有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等。
“药物组合物”,指的是在此描述的一种或多种化合物或者它们的药学上可接受的盐和前药与其它的化学成分,例如药学上可接受的载体和赋形剂的混合物。药物组合物的目的是促进化合物对生物体的给药。
在下文中,除非特别地限制,作为治疗剂活性成分的式(I)化合物包括它们的所有药学上可接受的盐,它们应当理解为落入本发明的范围内。在本说明书中,仅仅为了方便,将它们简称为“式(I)的化合物”。
根据本发明的上述的式(I)化合物在下面的实施例中已证实,它们对与通风有关的黄嘌呤氧化酶表现出强烈的抑制作用。因此,它们可以用于预防和治疗与黄嘌呤氧化酶相关的疾病,例如,高尿酸血症、心力衰竭、心血管疾病、高血压、糖尿病、肾疾病、炎症、关节病等。本发明的化合物还可应用于糖尿病。
本发明包括一种药物组合物,其包含本发明中任一所述化合物、其药学上可接受的盐或其易水解的前药酯作为活性成分。
本发明的化合物、其药学上可接受的盐或其易水解的前药酯可应用于制备黄嘌呤氧化酶抑制剂药物方面。
本发明的化合物、其药学上可接受的盐或其易水解的前药酯可应用于制备预防或治疗高尿酸症、痛风、肾病、糖尿病肾病、炎性疾病、神经性系统疾病的药物方面。
具体实施方式
实施例1:(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基苯基)甲酮(5)和(3,5-二溴-4-羟基苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮(6)的合成
步骤A:将1-氨基碘化吡啶(15.54g,70.0mmol)、2-戊炔酸乙酯(9.72g,77.1mmol)、碳酸钾(21.26g,154mmol)和DMF(150mL)的混合物在室温下搅拌4.5小时。加入水(450mL),过滤,滤饼用水(100mL)洗涤,得2-乙基吡唑并[1,5-a]吡啶-3-甲酸乙酯(1)。该化合物不经纯化直接用于下一步反应。
步骤B:化合物1的全部粗品、乙醇(30mL)、THF(30mL)和2M氢氧化钠水溶液(70mL)的混合物在60℃搅拌过夜。减压蒸除约一半溶剂,加入水(150mL),用2M盐酸调节pH值至5~6。过滤,得2-乙基吡唑并[1,5-a]吡啶-3-甲酸(2)(10.0g)。该化合物不经纯化直接用于下一步反应。
步骤C:将化合物2粗品(5.6g)悬浮在水(100mL)中,加入浓硫酸(4mL),所得混合物在80℃搅拌3小时。冷却到室温,用2M氢氧化钠水溶液调节pH值至8~9。用乙酸乙酯(40mL×3)萃取,合并的有机相依次用水(30mL)和饱和食盐水(20mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,得2-乙基吡唑并[1,5-a]吡啶(3)(3.18g)。步骤A、B和C三步反应总收率为55.5%。
步骤D:化合物3(584mg,3.99mmol)、4-甲氧基苯甲酰氯(680mg,3.99mmol)和三氯化铝(800mg,6.0mmol)的混合物在100℃搅拌过夜。稍微冷却后,加入乙酸乙酯(30mL)和水(30mL),用2M氢氧化钠水溶液调节pH值至9~10。分层,收集有机相。水相用乙酸乙酯(30mL×2)萃取,合并的有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:30~1:10洗脱),得(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-甲氧基苯基)甲酮(4)(305mg)。收率为27.3%。1H NMR(DMSO-d6,300MHz)δ8.79(d,J=6.9Hz,1H),7.66(d,J=8.7Hz,2H),7.44-7.39(m,1H),7.33-7.30(m,1H),7.08-7.03(m,3H),3.86(s,3H),2.84(q,J=7.5Hz,2H),1.21(t,J=7.5Hz,3H)。
步骤E:将60%氢化钠(218mg,5.45mmol)分批加到乙硫醇(338mg,5.44mmol)的DMF(3mL)溶液中,搅拌约5分钟后将化合物4(305mg,1.09mmol)的DMF(3mL)溶液加入上述反应混合物中,所得混合物在120℃搅拌2小时。冷却到室温,加入水(30mL),用2M盐酸调节pH值至7~8。然后用乙酸乙酯(30mL×3)萃取,合并的有机相依次用水(20mL×3)和饱和食盐水(20mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,得(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基苯基)甲酮(5)(420mg)。取少量化合物用硅胶柱纯化来做相关分析测试,其余化合物不经纯化直接用于下一步反应。1H NMR(DMSO-d6,300MHz)δ10.22(s,1H),8.76(d,J=6.6Hz,1H),7.56(d,J=8.4Hz,2H),7.42-7.31(m,2H),7.05-7.01(m,1H),6.87(d,J=8.4Hz,2H),2.84(q,J=7.5Hz,2H),1.20(t,J=7.5Hz,3H)。MS(EI,m/z):265.1[M-H]-。
步骤F:将溴(67mg,0.419mmol)的醋酸(1mL)溶液滴加到化合物5(73mg)和无水乙酸钠(46.3mg,0.564mmol)的醋酸(5mL)溶液中,所得混合物在室温下搅拌过夜。向反应混合物中滴加饱和亚硫酸氢钠水溶液,直到颜色褪去。减压蒸除溶剂,加入水(25mL),用饱和碳酸氢钠水溶液调节pH值至7~8。用乙酸乙酯(40mL×2)萃取,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:20~1:1洗脱),得(3,5-二溴-4-羟基苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮(6)(60mg)。步骤E和F两步反应总收率为74.7%。1H NMR(DMSO-d6,300MHz)δ10.77(s,1H),8.81(d,J=6.9Hz,1H),7.80(s,2H),7.50-7.40(m,2H),7.12-7.07(m,1H),2.82(q,J=7.5Hz,2H),1.23(t,J=7.5Hz,3H)。MS(EI,m/z):420.9[M-H]-。
实施例2:(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基-3,5-二碘苯基)甲酮(7)的合成
向化合物5(233mg,0.875mmol)的甲醇(10mL)溶液中加入无水乙酸钠(158mg,1.93mmol)和碘(489mg,1.93mmol),所得混合物在回流下搅拌1小时。然后加入含有氢氧化钠(63mg,1.58mmol)的水(15mL)溶液,继续回流1小时。冷却到室温,向反应混合物中滴加饱和亚硫酸氢钠水溶液,直到颜色褪去。加入水(30mL),用乙酸乙酯(40mL×2)萃取,合并的有机相用饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:20~1:1洗脱),得(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基-3,5-二碘苯基)甲酮(7)(300mg)。收率为66.2%。1H NMR(DMSO-d6,300MHz)δ10.26(s,1H),8.80(d,J=6.9Hz,1H),7.98(s,2H),7.50-7.40(m,2H),7.11-7.06(m,1H),2.80(q,J=7.5Hz,2H),1.22(t,J=7.5Hz,3H)。MS(EI,m/z):516.9[M-H]-。
实施例3:5-(2-乙基吡唑并[1,5-a]吡啶-3-羰基)-2-羟基-3-碘苯甲腈(8)的合成
将化合物7(280mg,0.540mmol)、氰化亚铜(58mg,0.648mmol)和DMF(6mL)的混合物在100℃搅拌过夜。冷却到室温,加入水(30mL),用乙酸乙酯(30mL×3)萃取,合并的有机相依次用水(20mL×2)和饱和食盐水(10mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:10~20:1洗脱),得5-(2-乙基吡唑并[1,5-a]吡啶-3-羰基)-2-羟基-3-碘苯甲腈(8)。1H NMR(DMSO-d6,300MHz)δ8.71(d,J=6.9Hz,1H),8.05(d,J=2.1Hz,1H),7.52(d,J=2.1Hz,1H),7.45-7.33(m,2H),6.99-6.95(m,1H),2.83(q,J=7.5Hz,2H),1.22(t,J=7.5Hz,3H)。MS(EI,m/z):416.0[M-H]-。
实施例4:(3-溴-4-羟基-5-甲基苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮(11)的合成
步骤A:将3-甲基-4-甲氧基苯甲酸(500mg,3.0mmol)悬浮在氯化亚砜(6mL)中,加入DMF(2滴),所得混合物在回流下搅拌5小时。减压蒸除溶剂,加入化合物3(419mg,2.87mmol)和三氯化铝(573mg,4.30mmol),所得混合物在100℃搅拌过夜。加入乙酸乙酯(30mL)和水(30mL),用2M氢氧化钠水溶液调节pH值至9~10。分层,收集有机相。水相用乙酸乙酯(30mL×2)萃取,合并的有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:30~1:10洗脱),得(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-甲氧基-3-甲基苯基)甲酮(9)(330mg)。收率为39.1%。
步骤B:将60%氢化钠(210mg,5.25mmol)分批加到乙硫醇(327mg,5.26mmol)的DMF(3mL)溶液中,搅拌约5分钟后将化合物9(310mg,1.05mmol)的DMF(3mL)溶液加入上述反应混合物中,所得混合物在120℃搅拌2小时。冷却到室温,加入水(30mL),用2M盐酸调节pH值至7~8。然后用乙酸乙酯(30mL×3)萃取,合并的有机相依次用水(20mL×3)和饱和食盐水(20mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:15~1:5洗脱),得(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基-3-甲基苯基)甲酮(10)(220mg)。收率为74.7%。
步骤C:将NBS(58mg,0.326mmol)加入到化合物10(70mg,0.250mmol)的DMF(5mL)溶液中,所得混合物在室温下搅拌1小时。加入水(25mL),用乙酸乙酯(20mL×3)萃取,合并的有机相用饱和食盐水(10mL×5)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:10~1:8洗脱),得(3-溴-4-羟基-5-甲基苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮(11)。1H NMR(DMSO-d6,300MHz)δ9.86(s,1H),8.78(d,J=6.9Hz,1H),7.63(s,1H),7.49-7.36(m,3H),7.08-7.04(m,1H),2.82(q,J=7.5Hz,2H),2.27(s,3H),1.22(t,J=7.5Hz,3H)。MS(EI,m/z):357.0[M-H]-。
实施例5:(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基-3-碘-5-甲基苯基)甲酮(12)和5-(2-乙基吡唑并[1,5-a]吡啶-3-羰基)-2-羟基-3-甲基苯甲腈(13)的合成
步骤A:向化合物10(125mg,0.446mmol)的甲醇(15mL)溶液中加入无水乙酸钠(40mg,0.488mmol)和碘(125mg,0.492mmol),所得混合物在回流下搅拌1小时。然后加入含有氢氧化钠(16mg,0.40mmol)的水(6mL)溶液,继续回流1小时。冷却到室温,向反应混合物中滴加饱和亚硫酸氢钠水溶液,直到颜色褪去。加入水(45mL),用乙酸乙酯(20mL×3)萃取,合并的有机相用饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:20~1:1洗脱),得(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基-3-碘-5-甲基苯基)甲酮(12)。1H NMR(DMSO-d6,300MHz)δ9.85(s,1H),8.78(d,J=6.0Hz,1H),7.82(s,1H),7.45-7.36(m,3H),7.08-7.04(m,1H),2.81(q,J=7.5Hz,2H),2.27(s,3H),1.21(t,J=7.5Hz,3H)。MS(EI,m/z):405.0[M-H]-。
步骤B:将含有化合物12(142mg,0.350mmol)、氰化亚铜(47mg,0.525mmol)和DMF(10mL)的混合物在100℃搅拌过夜。冷却到室温,加入水(40mL),用乙酸乙酯(30mL×3)萃取,合并的有机相依次用水(20mL×2)和饱和食盐水(10mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:15~1:2洗脱),得5-(2-乙基吡唑并[1,5-a]吡啶-3-羰基)-2-羟基-3-甲基苯甲腈(13)。1H NMR(DMSO-d6,300MHz)δ10.62(s,1H),8.81(d,J=6.6Hz,1H),7.97(s,1H),7.80(s,1H),7.50-7.40(m,2H),7.11-7.07(m,1H),2.81(q,J=7.5Hz,2H),2.50(s,3H),1.22(t,J=7.5Hz,3H)。MS(EI,m/z):304.1[M-H]-。
实施例6:(3-氯-4-羟基-5-碘苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮(16)的合成
步骤A和B的实验操作分别参见实施例4中的步骤A和B,其中实施例4步骤A中的3-甲基-4-甲氧基苯甲酸用3-氯-4-甲氧基苯甲酸替代。
步骤C:将化合物15跟碘在甲醇中进行碘代反应,得(3-氯-4-羟基-5-碘苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮(16),具体实验操作参见实施例5中的步骤A。1H NMR(DMSO-d6,300MHz)δ10.87(s,1H),8.80(d,J=6.6Hz,1H),7.93(s,1H),7.67(s,1H),7.50-7.39(m,2H),7.11-7.06(m,1H),2.81(q,J=7.5Hz,2H),1.22(t,J=7.5Hz,3H)。MS(EI,m/z):425.0[M-H]-。
实施例7:(3,5-二碘-4-羟基苯基)(2-乙基-4-甲基吡唑并[1,5-a]吡啶-3-基)甲酮(21)的合成
步骤A:将羟胺磺酸(7.91g,69.9mmol)溶解于水(35mL),加入3-甲基吡啶(19.5g,209mmol),所得混合物在90℃搅拌1小时。在65℃下减压蒸除液体,然后用甲苯(50mL×3)在减压下带除水。将反应混合物溶解于DMF(100mL),在冰水浴下分批加入碳酸钾(40.0g,290mmol),然后加入2-戊炔酸乙酯(8.8g,69.8mmol)。所得混合物在室温下搅拌3小时,再升温到50℃搅拌过夜。加入水(500mL),用乙酸乙酯(200mL×3)萃取,合并的有机相依次用水(100mL×2)和饱和食盐水(100mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:100洗脱),得2-乙基-4-甲基吡唑并[1,5-a]吡啶-3-甲酸乙酯(17)(2.06g)。收率为12.7%。1H NMR(DMSO-d6,300MHz)δ8.57(d,J=6.9Hz,1H),7.24(d,J=6.9Hz,1H),6.98-6.32(m,1H),4.28(q,J=7.2Hz,2H),2.96(q,J=7.5Hz,2H),2.60(s,3H),1.32(t,J=7.5Hz,3H),1.25(t,J=7.5Hz,3H)。
步骤B:将化合物17(2.32g,9.99mmol)溶解于甲醇(15mL),加入3M氢氧化钠水溶液(50mL),所得混合物在80℃搅拌3小时。稍微冷却后,用浓盐酸调节pH值至5~6,再加入浓硫酸(2mL),然后升温到80℃搅拌3小时。冷却到室温,用2M氢氧化钠水溶液调节pH值至9~10。用乙酸乙酯(100mL×3)萃取,合并的有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,得2-乙基-4-甲基吡唑并[1,5-a]吡啶(18)(1.44g)。收率为90.0%。
步骤C和D的实验操作分别参见实施例1中的步骤D和E。
步骤E:将化合物20跟碘在甲醇中反应,得(3,5-二碘-4-羟基苯基)(2-乙基-4-甲基吡唑并[1,5-a]吡啶-3-基)甲酮(21),具体实验操作参见实施例2。1H NMR(CDCl3,300MHz)δ8.45-8.43(m,1H),8.19(s,2H),7.09-7.07(m,1H),6.85-6.83(m,1H),6.17(s,1H),2.65(q,J=7.5Hz,2H),2.50(s,3H),1.23(t,J=7.5Hz,3H)。MS(EI,m/z):530.9[M-H]-。
实施例8:(3,5-二溴-4-羟基苯基){2-乙基-6-(乙硫基)吡唑并[1,5-a]吡啶-3-基}甲酮(27)的合成
步骤A的实验操作参见实施例7中的步骤A,其中实施例7步骤A中的3-甲基吡啶用3-氟吡啶替代。
化合物22:1H NMR(DMSO-d6,300MHz)δ9.12(s,1H),8.06-8.01(m,1H),7.69-7.63(m,1H),4.30(q,J=6.9Hz,2H),3.02(q,J=7.2Hz,2H),1.37-1.24(m,6H)。
化合物23:1H NMR(DMSO-d6,300MHz)δ8.65(d,J=6.9Hz,1H),7.41-7.34(m,1H),7.08-7.02(m,1H),4.27(q,J=7.2Hz,2H),3.01(q,J=7.5Hz,2H),1.37-1.24(m,6H)。
步骤B和C的实验操作分别参见实施例7中的步骤B和C。
步骤D:将60%氢化钠(106mg,2.65mmol)分批加到乙硫醇(165mg,2.65mmol)的DMF(5mL)溶液中,搅拌约5分钟后再将化合物25(158mg,0.530mmol)的DMF(3mL)溶液加入上述反应混合物中,所得混合物在120℃搅拌1.5小时。冷却到室温,加入水(40mL),用2M盐酸调节pH值至7~8。然后用乙酸乙酯(30mL×3)萃取,合并的有机相依次用水(20mL×3)和饱和食盐水(20mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,得{2-乙基-6-(乙硫基)吡唑并[1,5-a]吡啶-3-基}(4-羟基苯基)甲酮(26)(210mg)。该化合物不经纯化直接用于下一步反应。MS(EI,m/z):325.1[M-H]-。
步骤E:将溴(99mg,0.619mmol)的醋酸(2mL)溶液滴加到化合物26粗品(112mg)和无水乙酸钠(69mg,0.841mmol)的醋酸(8mL)溶液中,所得混合物在室温下搅拌5小时。向反应混合物中滴加饱和亚硫酸氢钠水溶液,直到颜色褪去。减压蒸除溶剂,加入水(30mL),用饱和碳酸氢钠水溶液调节pH值至7~8。用乙酸乙酯(30mL×3)萃取,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:20~1:5洗脱),得(3,5-二溴-4-羟基苯基){2-乙基-6-(乙硫基)吡唑并[1,5-a]吡啶-3-基}甲酮(27)(78mg)。步骤D和E两步反应总收率为62.4%。1H NMR(DMSO-d6,300MHz)δ10.78(s,1H),8.81(s,1H),7.81(s,2H),7.48(dd,J=1.5,9.3Hz,1H),7.35(d,J=9.3Hz,1H),3.03(q,J=7.5Hz,2H),2.80(q,J=7.5Hz,2H),1.22(t,J=7.2Hz,6H)。MS(EI,m/z):483.0[M-H]-。
实施例9:(3,5-二溴-4-羟基苯基)(2-乙基-5-甲基吡唑并[1,5-a]吡啶-3-基)甲酮(28)的合成
制备化合物28的实验操作依次参见实施例7中的步骤A、B、C和D以及实施例1中的步骤F,其中实施例7步骤A中的3-甲基吡啶用4-甲基吡啶替代。1H NMR(DMSO-d6,300MHz)δ8.68(d,J=6.9Hz,1H),7.77(s,2H),7.29(s,1H),6.94(d,J=6.9Hz,1H),2.74(q,J=7.5Hz,2H),2.34(s,3H),1.19(t,J=7.5Hz,3H)。MS(EI,m/z):437.0[M-H]-。
实施例10:(3-溴-4-羟基-5-碘苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮(31)的合成
步骤A和B的实验操作分别参见实施例4中的步骤A和B,其中实施例4步骤A中的3-甲基-4-甲氧基苯甲酸用3-溴-4-甲氧基苯甲酸替代。
步骤C:将化合物30跟碘在甲醇中进行碘代反应,得(3-溴-4-羟基-5-碘苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮(31),具体实验操作参见实施例5中的步骤A。1H NMR(DMSO-d6,300MHz)δ10.63(s,1H),8.81(d,J=6.9Hz,1H),7.98-7.97(m,1H),7.80(d,J=1.8Hz,1H),7.50-7.39(m,2H),7.11-7.07(m,1H),2.81(q,J=7.5Hz,2H),1.22(t,J=7.5Hz,3H)。MS(EI,m/z):468.9[M-H]-。
实施例11:(3,5-二溴-4-羟基苯基){2-乙基-4-(乙硫基)吡唑并[1,5-a]吡啶-3-基}甲酮(32)的合成
以2-乙基-4-氟吡唑并[1,5-a]吡啶-3-甲酸乙酯(23)为起始原料,制备化合物32的实验操作依次参见实施例8中的步骤B、C、D和E。1H NMR(DMSO-d6,300MHz)δ8.63(d,J=6.0Hz,1H),7.77(s,2H),7.35(d,J=6.6Hz,1H),7.05-7.00(m,1H),2.90(q,J=7.2Hz,2H),2.64(q,J=7.5Hz,2H),1.17(t,J=7.5Hz,3H),1.06(t,J=7.2Hz,3H)。MS(EI,m/z):482.9[M-H]-。
实施例12:(3,5-二溴-4-羟基苯基)(2-乙基-6-氟吡唑并[1,5-a]吡啶-3-基)甲酮(34)的合成
步骤A:在冰水浴下将1.0M三溴化硼甲苯溶液(5mL)滴加到化合物25(493mg,1.65mmol)的无水二氯甲烷(15mL)溶液中,所得混合物在室温下搅拌过夜。将反应混合物倒入冰水(30mL)中,用饱和碳酸氢钠水溶液调节pH值至7~8。用乙酸乙酯(30mL×3)萃取,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:30~1:5洗脱),得(2-乙基-6-氟吡唑并[1,5-a]吡啶-3-基)(4-羟基苯基)甲酮(33)(438mg)。收率为93.4%。MS(EI,m/z):283.1[M-H]-。
步骤B:将溴(62mg,0.388mmol)的醋酸(3mL)溶液滴加到化合物33(50mg,0.176mmol)和无水乙酸钠(43mg,0.524mmol)的醋酸(7mL)溶液中,所得混合物在室温下搅拌过夜。向反应混合物中滴加饱和亚硫酸氢钠水溶液,直到颜色褪去。减压蒸除溶剂,然后加入水(30mL),用饱和碳酸氢钠水溶液调节pH值至7~8。用乙酸乙酯(25mL×3)萃取,无水硫酸钠干燥。减压蒸除溶剂,产物用二氯甲烷/石油醚重结晶,得(3,5-二溴-4-羟基苯基)(2-乙基-6-氟吡唑并[1,5-a]吡啶-3-基)甲酮(34)(63mg)。收率为81.0%。1H NMR(DMSO-d6,300MHz)δ9.17-9.15(m,1H),7.81(s,2H),7.62-7.56(m,1H),7.51-7.46(m,1H),2.79(q,J=7.5Hz,2H),1.22(t,J=7.2Hz,3H)。MS(EI,m/z):440.9[M-H]-。
实施例13:(2-乙基吡唑并[1,5-a]吡啶-3-基)(2-乙硫基-4-羟基苯基)甲酮(36)的合成
化合物36的制备方法依次参见实施例4中的步骤A和B,其中实施例4步骤A中的3-甲基-4-甲氧基苯甲酸用2-氟-4-甲氧基苯甲酸替代。1H NMR(DMSO-d6,500MHz)δ10.03(s,1H),8.76(d,J=6.0Hz,1H),7.45-7.41(m,1H),7.19-7.14(m,2H),7.07-7.04(m,1H),6.87(s,1H),6.65(d,J=6.0Hz,1H),2.84(q,J=7.0Hz,2H),2.77(q,J=7.5Hz,2H),1.20-1.13(m,6H)。MS(EI,m/z):325.1[M-H]-。
实施例14:(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基-3-碘苯基)甲酮(38)的合成
化合物38的制备方法依次参见实施例4中的步骤A和实施例12中的步骤A,其中实施例4步骤A中的3-甲基-4-甲氧基苯甲酸用3-碘-4-甲氧基苯甲酸替代。1H NMR(DMSO-d6,500MHz)δ11.14(s,1H),8.78(d,J=7.0Hz,1H),7.98(d,J=2.0Hz,1H),7.57-7.55(m,1H),7.45-7.41(m,1H),7.38-7.36(m,1H),7.07-7.04(m,1H),6.97(d,J=8.5Hz,1H),2.83(q,J=7.5Hz,2H),1.21(t,J=7.5Hz,3H)。MS(EI,m/z):391.0[M-H]-。
实施例15:(3,5-二溴-4-羟基苯基)(2-丙基吡唑并[1,5-a]吡啶-3-基)甲酮(39)的合成
化合物39的制备方法依次参见实施例4中的步骤A、B、C、D、E和F,其中实施例1步骤A中的2-戊炔酸乙酯用2-己炔酸乙酯替代。1H NMR(DMSO-d6,500MHz)δ10.75(s,1H),8.80(d,J=7.0Hz,1H),7.80(s,2H),7.48-7.41(m,2H),7.10-7.07(m,1H),2.77(t,J=7.5Hz,2H),1.70-1.76(m,2H),0.87(t,J=7.5Hz,3H)。MS(EI,m/z):437.0[M-H]-。
实施例16:(3,5-二溴-4-羟基苯基)(2-乙基-6-甲氧基吡唑并[1,5-a]吡啶-3-基)甲酮(41)的合成
步骤A:将化合物33(160mg,0.563mmol)、甲醇钠(304mg,5.63mmol)和DMF(10mL)的混合物在120℃搅拌过夜。加入水(40mL),用柠檬酸调节pH值至5~6,然后用乙酸乙酯(30mL×3)萃取,合并的有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:10~1:4洗脱),得(2-乙基-6-甲氧基吡唑并[1,5-a]吡啶-3-基)(4-羟基苯基)甲酮(40)(89mg)。收率为53.3%。1H NMR(DMSO-d6,500MHz)δ10.18(s,1H),8.50(s,1H),7.53(d,J=8.5Hz,2H),7.26-7.20(m,2H),6.86(d,J=8.5Hz,2H),3.84(s,3H),2.80(q,J=7.5Hz,2H),1.19(t,J=7.5Hz,3H)。
步骤B:将溴(101mg,0.632mmol)的醋酸(2mL)溶液滴加到化合物40(85mg,0.287mmol)和无水乙酸钠(71mg,0.865mmol)的醋酸(8mL)溶液中,所得混合物在室温下搅拌过夜。向反应混合物中滴加饱和亚硫酸氢钠水溶液,直到颜色褪去。减压蒸除溶剂,加入水(30mL),用饱和碳酸氢钠水溶液调节pH值至7~8。用乙酸乙酯(30mL×3)萃取,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,乙酸乙酯:石油醚=1:20~1:10洗脱),得(3,5-二溴-4-羟基苯基)(2-乙基-6-甲氧基吡唑并[1,5-a]吡啶-3-基)甲酮(41)。1H NMR(DMSO-d6,500MHz)δ10.68(s,1H),8.56(d,J=1.5Hz,1H),7.78(s,2H),7.36-7.34(m,1H),7.29-7.27(m,1H),3.85(s,3H),2.77(q,J=7.5Hz,2H),1.21(t,J=7.5Hz,3H)。MS(EI,m/z):453.0[M-H]-。
实施例17:(3,5-二溴-4-羟基苯基)(吡唑并[1,5-a]吡啶-3-基)甲酮(42)的合成
化合物42的制备方法参见实施例1,其中实施例1步骤A中的2-戊炔酸乙酯用丙炔酸乙酯替代。1H NMR(DMSO-d6,400MHz)δ10.71(s,1H),8.98(d,J=7.2Hz,1H),8.51(s,1H),8.29-8.27(m,1H),7.98(s,2H),7.73-7.70(m,1H),7.30-7.26(m,1H)。MS(EI,m/z):394.9[M-H]-。
实施例18:(3,5-二溴-4-羟基苯基)[5-(羟甲基)吡唑并[1,5-a]吡啶-3-基]甲酮(48)的合成
步骤A、B和C的实验操作参见实施例7中的步骤A、B和C,其中实施例7步骤A中的3-甲基吡啶和2-戊炔酸乙酯分别用4-甲基吡啶和丙炔酸乙酯替代,得(4-甲氧基苯基)[5-甲吡唑并[1,5-a]吡啶-3-基)甲酮(45)。
步骤D:将含有化合物45(165mg,0.620mmol)、NBS(121mg,0.680mmol)、偶氮二异丁腈(31mg,0.189mmol)、醋酸(11mg,0.183mmol)和四氯化碳(15mL)的混合物在氮气下回流搅拌过夜。冷却到室温,加入水(20mL),用二氯甲烷(20mL×2)萃取,无水硫酸钠干燥。减压蒸除溶剂,产物经柱层析纯化(200~300目硅胶,二氯甲烷:石油醚=1:10~1:2洗脱),得(46)(130mg)。收率为60.9%。
步骤E和F的实验操作参见实施例12中的步骤A和B,得(3,5-二溴-4-羟基苯基)[5-(羟甲基)吡唑并[1,5-a]吡啶-3-基]甲酮(48)。1H NMR(DMSO-d6,500MHz)δ8.98-8.96(m,1H),8.43(s,1H),8.38(s,1H),7.98(s,2H),7.74-7.67(m,2H),7.31-7.20(m,1H),4.92(s,2H)。MS(EI,m/z):453.0[M+Na]+。
实施例19:化合物对HEK293转染细胞株中hURAT1转运尿酸的抑制试验
试剂名称及来源:
苯溴马隆购自Sigma-Aldrich Co.LLC;质粒pCMV6-hURAT1购自OrigeneTechnologies,Inc;G418购自生工生物工程股份有限公司;HEK293细胞株购自中国科学院上海生命科学研究院细胞资源中心;多聚赖氨酸购自Sigma-Aldrich Co.LLC;14C-尿酸购自美国American Radiolabeled Chemicals,Inc;葡萄糖酸钠、葡萄糖酸钾、葡萄糖酸钙、KH2PO4、MgSO4、葡萄糖和HEPES购自国药集团化学试剂有限公司。
试验方法和结果:
1.构建高表达hURAT1的HEK293稳转细胞株:采用质粒pCMV6-hURAT1转染进入HEK293细胞内,再经过G418(终浓度500μg/ml)抗性筛选获得稳转细胞株,其高表达hURAT1转运膜蛋白,可用于体外hURAT1转运尿酸的抑制试验(具体步骤可见文献:Yi M.Weaver,David J.Ehresman,John L.Butenhoff,Bruno Hagenbuch.Roles of rat renal organicanion transporters in transporting perfluorinated carboxylates with differentchain lengths.Toxicological Sciences,2009,113(2):305-314)。
2.包被24孔板:按200μl/孔加入0.1mg/ml多聚赖氨酸,放置过夜。移去多聚赖氨酸,用无菌水清洗并彻底晾干,待用。
3.将HEK293-hURAT1稳转细胞按2×105个/孔接入包被过的24孔板中,37℃,5%CO2的条件下培养3天。
4.实验当天,用37℃温浴过的HBSS(125mM葡萄糖酸钠、4.8mM葡萄糖酸钾、1.3mM葡萄糖酸钙、1.2mM KH2PO4、1.2mM MgSO4、5.6mM葡萄糖、25mM HEPES,pH 7.4)清洗2遍细胞并吸净,再按160μl/孔加入HBSS,并按20μl/孔加入终浓度为500nM试验化合物,做为试验化合物孔;按180μl/孔加入HBSS但不加试验化合物,做为空白对照孔。放置室温下10min。
5.按20μl/孔加入终浓度为50μM的14C尿酸,放置室温下20min。
6.吸净每孔溶液,用预冷的HBSS清洗细胞并吸净。最后加入0.2M NaOH溶解细胞,收集细胞碎片并加入适量闪烁液,然后置PerkinElmer MicroBeta Trilux 1450液体闪烁分析仪上检测同位素14C尿酸的放射强度(CPM值)。
7.在HEK293转染细胞株中,化合物对hURAT1转运尿酸的抑制率计算公式如下所示,试验化合物的CPM值以CPM(试验化合物)表示;空白对照的CPM值以CPM(空白对照)表示。试验化合物均设三次重复,试验结果取平均值,并计算标准偏差SD。试验结果见表1。
表1.试验化合物对HEK293转染细胞株中hURAT1转运尿酸的抑制率
实施例20:化合物对FABP4体外抑制试验:
试剂名称及来源:
FABP4Inhibitor/Ligand Screening Assay Kit购自美国Cayman ChemicalCompany
试验方法和结果:
1.取出96孔板(黑色),每孔加入40μl FABP检测缓冲液。
2.每孔加入25μl FABP4蛋白溶液。空白对照孔加入25μl FABP检测缓冲液。
3.再每孔加入25μl检测试剂(注意需要避光)。
4.最后每孔加入10μl终浓度20μM的试验化合物;100%对照孔加入10μl试验化合物的溶剂。
5.用封条密封96孔板,放置于室温下反应10min。
6.移去封条,把96孔板置于酶标仪上,以Em:475nm/Ex:370nm的波长检测读数。
化合物对FABP4体外抑制率计算公式如下所示。空白对照荧光强度值以F(空白对照)表示;试验化合物荧光强度值以F(试验化合物)表示;100%对照荧光强度值以F(100%对照)表示。试验均设三次重复,结果取平均值,并计算标准偏差SD。具体试验操作也可参见本试剂盒说明书。试验结果见表2。
表2.试验化合物对FABP4体外抑制率
Claims (10)
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中,
R1或R2分别独立地选自氢、卤素、氰基、羟基、C1-3烷基、C1-3羟基烷基、C1-3卤代烷基、C1-3烷氧基或C1-3烷硫基;
R3选自氢、卤素、C1-4烷基、C1-4羟基烷基或C1-4卤代烷基;
R4选自氢、卤素、氰基、C1-2烷基、C1-2卤代烷基、C1-2烷氧基或C1-2烷硫基;
R5选自卤素、氰基、C1-2烷基、C1-2卤代烷基、C1-2烷氧基或C1-2烷硫基。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其中
R1或R2分别独立地选自氢、氟、氯、溴、氰基、羟基、C1-3烷基、C1-3羟基烷基、C1-3卤代烷基、C1-3烷氧基或C1-3烷硫基;
R4选自氢、卤素、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基或C1-2烷硫基;
R5选自卤素、氰基、C1-3烷基、C1-3卤代烷基、C1-3烷氧基或C1-2烷硫基。
4.根据权利要求1或2所述的化合物或其药学上可接受的盐,其中,
R3选自氢、卤素、C1-3烷基、C1-3羟基烷基或C1-3卤代烷基。
5.根据权利要求1所述的化合物或其药学上可接受的盐,其中,
R1或R2分别独立地选自氢、卤素、氰基、羟基、C1-5烷基、C1-5羟基烷基、C1-5烷氧基或C1-5烷硫基;
R4选自氢、卤素、氰基、C1-2烷基、C1-2卤代烷基、C1-2烷氧基或C1-2烷硫基;
R5选自卤素、氰基、C1-2烷基、C1-2卤代烷基、C1-2烷氧基或C1-2烷硫基。
6.根据权利要求1所述的化合物或其药学上可接受的盐,其中,
R1或R2分别独立地选自氢、氟、氯、溴、甲基、乙基、正丙基、异丙基、羟甲基、甲氧基、乙氧基、正丙氧基、异丙氧基、甲硫基、乙硫基、正丙硫基或异丙硫基;
R4选自氟、氯、溴、碘、氰基、甲基、乙基、正丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、甲硫基或乙硫基;
R5选自氢、氟、氯、溴、碘、氰基、甲基、乙基、正丙基、甲氧基、乙氧基、正丙氧基、异丙氧基、甲硫基或乙硫基。
7.根据权利要求1所述的化合物或其药学上可接受的盐,其中化合物选自:
(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基苯基)甲酮,
(3,5-二溴-4-羟基苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮,
(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基-3,5-二碘苯基)甲酮,
5-(2-乙基吡唑并[1,5-a]吡啶-3-羰基)-2-羟基-3-碘苯甲腈,
(3-溴-4-羟基-5-甲基苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮,
(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基-3-碘-5-甲基苯基)甲酮,
5-(2-乙基吡唑并[1,5-a]吡啶-3-羰基)-2-羟基-3-甲基苯甲腈,
(3-氯-4-羟基-5-碘苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮,
(3,5-二碘-4-羟基苯基)(2-乙基-4-甲基吡唑并[1,5-a]吡啶-3-基)甲酮,
(3,5-二溴-4-羟基苯基){2-乙基-6-(乙硫基)吡唑并[1,5-a]吡啶-3-基}甲酮,
(3,5-二溴-4-羟基苯基)(2-乙基-5-甲基吡唑并[1,5-a]吡啶-3-基)甲酮,
(3-溴-4-羟基-5-碘苯基)(2-乙基吡唑并[1,5-a]吡啶-3-基)甲酮,
(3,5-二溴-4-羟基苯基){2-乙基-4-(乙硫基)吡唑并[1,5-a]吡啶-3-基}甲酮,
(3,5-二溴-4-羟基苯基)(2-乙基-6-氟吡唑并[1,5-a]吡啶-3-基)甲酮,
(2-乙基吡唑并[1,5-a]吡啶-3-基)(2-乙硫基-4-羟基苯基)甲酮,
(2-乙基吡唑并[1,5-a]吡啶-3-基)(4-羟基-3-碘苯基)甲酮,
(3,5-二溴-4-羟基苯基)(2-丙基吡唑并[1,5-a]吡啶-3-基)甲酮,
(3,5-二溴-4-羟基苯基)(2-乙基-6-甲氧基吡唑并[1,5-a]吡啶-3-基)甲酮,
(3,5-二溴-4-羟基苯基)(吡唑并[1,5-a]吡啶-3-基)甲酮,
(3,5-二溴-4-羟基苯基)[5-(羟甲基)吡唑并[1,5-a]吡啶-3-基]甲酮。
8.一种药物组合物,其以权利要求1~7中任一项所述的化合物或其药学上可接受的盐为活性成分或主要活性成分,辅以药学上可接受的辅料。
9.权利要求1~7中任一项所述的化合物或其药学上可接受的盐在制备促尿酸排泄药物或治疗糖尿病药物方面的应用。
10.权利要求1~7中任一项所述的化合物或其药学上可接受的盐在制备治疗或预防高尿酸血症、肾病、痛风或糖尿病药物方面的应用。
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