CN111269218A - 三氟甲基取代的氨基吡喃环衍生物及其组合物和应用 - Google Patents
三氟甲基取代的氨基吡喃环衍生物及其组合物和应用 Download PDFInfo
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- CN111269218A CN111269218A CN201910887734.9A CN201910887734A CN111269218A CN 111269218 A CN111269218 A CN 111269218A CN 201910887734 A CN201910887734 A CN 201910887734A CN 111269218 A CN111269218 A CN 111269218A
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- Prior art keywords
- salt
- cycloalkyl
- heterocycloalkyl
- alkyl
- pharmaceutically acceptable
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 title claims abstract description 20
- FUHVVLMYNYHJPB-UHFFFAOYSA-N 2h-pyran-2-amine Chemical group NC1OC=CC=C1 FUHVVLMYNYHJPB-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 239000000203 mixture Substances 0.000 title claims abstract description 15
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- 125000001424 substituent group Chemical group 0.000 claims abstract description 44
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- 239000000651 prodrug Substances 0.000 claims abstract description 31
- 239000003112 inhibitor Substances 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- -1 aminopyranyl Chemical class 0.000 claims description 196
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 96
- 125000001072 heteroaryl group Chemical group 0.000 claims description 78
- 125000000217 alkyl group Chemical group 0.000 claims description 61
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- 125000003545 alkoxy group Chemical group 0.000 claims description 36
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- 229910052794 bromium Inorganic materials 0.000 claims description 30
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- 125000000304 alkynyl group Chemical group 0.000 claims description 10
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- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 claims description 9
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical class OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
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- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 5
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 5
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 4
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- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical group C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 claims description 4
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- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 4
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- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 4
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 claims description 4
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- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 claims description 4
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- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 claims description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical class CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 3
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- NKOHRVBBQISBSB-UHFFFAOYSA-N 5-[(4-hydroxyphenyl)methyl]-1,3-thiazolidine-2,4-dione Chemical compound C1=CC(O)=CC=C1CC1C(=O)NC(=O)S1 NKOHRVBBQISBSB-UHFFFAOYSA-N 0.000 claims description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 3
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229960003562 phentermine Drugs 0.000 description 1
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- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 1
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
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- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical class [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
本发明涉及一种三氟甲基取代的氨基吡喃环衍生物及其组合物和应用,具体而言涉及通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐、前药、含有该衍生物的药物组合物以及在制备二肽基肽酶IV(DPP‑IV)抑制剂的医药上的用途,
Description
技术领域
本发明涉及一种三氟甲基取代的氨基吡喃环衍生物及其组合物和应用,具体说涉及通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其可用药用的盐或其立体异构体及含有该衍生物或其可用药用的盐或其立体异构体的药物组合物,以及其作为治疗剂特别是作为二肽基肽酶IV(DPP-IV)抑制剂的用途。
背景技术
糖尿病是一个世界范围内的重大医疗问题,据国际糖尿病联盟(IDF)发布的最新报告,2017年全球约4.25亿成人患糖尿病,平均每11个人中就有1位患病。其中,中国患病人数达1.14亿人,糖尿病负担最重。庞大的患病人数还导致了巨大的医疗支出。据估算,2017年,全球20~79岁人群糖尿病医疗支出为7270亿美元,占所有医疗支出的12%,较2007年增长了4950亿美元。其中,美国的医疗支出最多,为3480亿美元;其次是中国,为1100亿美元。最常见的糖尿病类型是Ⅱ型糖尿病,在世界范围内,Ⅱ型糖尿病约占所有糖尿病的90%。由于现代不健康的生活方式,如锻炼减少和高热量饮食等原因,Ⅱ型糖尿病的发病率呈逐渐增加的趋势。
Ⅱ型糖尿病的特点是进展性的胰岛β细胞功能衰减与胰岛素抵抗。纠正糖代谢失调的药物治疗重点在于增强高血糖刺激下的胰岛素应答、增强胰岛素敏感性或通过肠道或尿液改变葡萄糖清除途径。二肽基肽酶-4(dipeptidyl peptidase-4,DPP-4)抑制剂能阻断胰高血糖素样肽-1(glucagon like peptide-1,GLP-1)的失活,刺激葡萄糖依赖的胰岛素分泌并抑制胰高血糖素分泌(药品评价,2018,15(13),8-10)。此外,DPP-4抑制剂可延迟胃排空、增强饱腹感、抑制摄食量,在使用GLP-1受体激动剂时这些效果更为显著。
目前全球已经上市的DPP-4抑制剂有西格列汀(Sitagliptin)、维格列汀(Vildagliptin)、沙格列汀(Saxagliptin)、阿格列汀(Alogliptin)、利格列汀(Linagliptin)、特力利汀(Teneligliptin)、奥格列汀(Omarigliptin)等。DPP-IV抑制剂最显著的特点是,由于肠促胰岛素只在机体进食后分泌,DPP-IV抑制剂不易在不适当的时候增加胰岛素水平,产生许多降糖药共同的副作用低血糖。近期的临床数据已经显示,抑制DPP-IV可使胰岛素分泌增加,降低血糖浓度并改善胰岛beta细胞功能(Diabetes,1998,47:1253-1258)。常见的DPP-IV抑制剂的副作用有呼吸道感染、喉咙痛、腹泻、感冒样症状、头痛头晕等。但总体具有较好的安全性和耐受性,目前还没有发现使用的病人有严重的体重增加或者潜在的体重减少以及水肿等症状。近几年,长效DPP-IV抑制剂特别引人注目。长效DPP-IV抑制剂使用更方便,同时具备理想的降糖效果,使其在Ⅱ型糖尿病患者中更受欢迎。
糖尿病(主要是Ⅱ型糖尿病)的发病率在全球范围内呈逐年增高趋势,成为继心血管疾病和肿瘤之后,第3位威胁人们健康和生命的非传染性疾病。糖尿病的治疗给家庭和社会带来了沉重的负担。因此,急需开发更多更新更好的DPP-IV抑制药物以满足广大患者临床用药的需要。
PCT/CN2015/078923专利申请公开了DPP-IV抑制剂如下结构的化合物用于治疗糖尿病,其中:
其中:
Ar为任选被0-5个独立地选自卤素、氰基、羟基等基团取代的苯基;
V选自以下基团:
且R2a和R2b各自独立选自H、F、Cl、Br、I、羟基、氰基、C1-8烷基等;R3a和R3b各自独立选自H、F、Cl、Br、I、羟基、氰基或C1-8烷基;R4选自H、氰基、C1-8烷基、C1-8烷氧基等;R5选自羟基、C1-8烷基、C1-8烷氧基等;R6、R7和R9各自独立选自H、C1-8烷基、C3-15环烷基等;R8选自C1-8烷基、C3-15环烷基、C6-10芳基、6至10杂芳基或3至15杂环基;不认为此专利中具体描述是本发明的一部分。
(2)US2007232676公布了如下结构的化合物作为DPP-IV抑制剂,其中:
Ar选自被1-5个选自卤素、羟基、C1-6烷基等取代基取代的苯基;
V选自等基团,且R3a、R3b独立地选自氢、被1-5个氟原子取代的C1-4烷基;R2选自氢、羟基、卤素、羧基等基团;R8选自氢、-(CH2)p-苯基等基团,但无甲基磺酰基;不认为此专利中具体描述是本发明的一部分。
(3)WO201731918公布了DPP-IV抑制剂如下结构的化合物用于治疗糖尿病,其中:
Ar是任选被1~5个选自烷基、卤素等取代基取代的C6-10芳基;
A3、A4、A5和A6各自独立选自碳原子或氮原子,并且A3、A4、A5和A6中至少2个是碳原子;不认为此专利中具体描述是本发明的一部分。
发明内容
本发明的目的是介绍一类新型DPP-IV抑制剂,具体而言具有通式(I)所示的化合物,经研究表明,此类结构的化合物具有良好的二肽基肽酶IV(DPP-IV)抑制活性和选择性,具有用于治疗或缓解II型糖尿病及类似疾病的前景。
本发明涉及一种通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药:
其中:
R1各自独立选自F、Cl、Br、I、羟基、氰基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、-(CH2)m-C3-15环烷基、-(CH2)m-3至15元杂环烷基、-(CH2)m-C6-10芳基、-(CH2)m-6至10元杂芳基、-(CH2)m-C(=O)-R5、-(CH2)m-NR6R7、-(CH2)m-C(=O)-NR6R7、-(CH2)m-O-C(=O)-NR6R7、-(CH2)m-S(=O)n-R8、-(CH2)m-NR9-S(=O)n-R8、-(CH2)m-NR9-C(=O)-NR6R7或-(CH2)m-NR9-C(=O)-R5,其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代,所述杂环烷基含有1至5个选自N、O或S(=O)n的原子或基团;
环A是饱和环或不饱和环;
R2各自独立选自氰基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、-(CH2)m-C3-15元环烷基、-(CH2)m-3至15元杂环烷基、-(CH2)m-C6-10芳基、-(CH2)m-6至10元杂芳基、-(CH2)m-C(=O)-R5、-(CH2)m-NR6R7、-(CH2)m-C(=O)-NR6R7、-(CH2)m-O-C(=O)-NR6R7、-(CH2)m-S(=O)n-R8、-(CH2)m-NR9-S(=O)n-R8、-(CH2)m-NR9-C(=O)-NR6R7或-(CH2)m-NR9-C(=O)-R5,其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至3个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代,所述杂环烷基含有1至5个选自N、O或S(=O)n的原子或基团;
R5选自羟基、C1-8烷基、C1-8烷氧基、C3-15环烷基、C6-10芳基、6至10杂芳基、-O-C3-15环烷基、-O-C6-10芳基或-O-(6至10元杂芳基);
R6、R7和R9各自独立选自H、C1-8烷基、C3-15环烷基、C6-10芳基、6至10元杂芳基或3至15元杂环烷基;
R8选自C1-8烷基、C3-15环烷基、C6-10芳基、6至10元杂芳基或3至15元杂环烷基;其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个F所取代,所述杂环烷基或杂芳基含有1至5个选自N、O或S(=O)n的原子或基团;
p选自0、1、2、3或4;
r选自0、1、2、3或4;
m选自0、1或2;
n选自0、1或2。
在一些实施方案中,R1选自F、Cl、Br、I、羟基、氰基或C1-8烷基;在一些实施方案中,R1选自F、Cl或Br;在一些实施方案中,R1选F。
在一些实施方案中,p选自0;在一些实施方案中,p选自1;在一些实施方案中,p选自2;在一些实施方案中,p选自3;在一些实施方案中,p选自4。
在一些实施方案中,r选自0;在一些实施方案中,r选自1;在一些实施方案中,p选自2;在一些实施方案中,r选自3;在一些实施方案中,r选自4。
在一些实施方案中,m选自0;在一些实施方案中,m选自1;在一些实施方案中,m选自2。
在一些实施方案中,n选自0;在一些实施方案中,n选自1;在一些实施方案中,n选自2。
本发明的一些实施例涉及一种通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药,其中:
R1各自独立选自F、Cl、Br、I、羟基、氰基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、-(CH2)m-C3-15环烷基、-(CH2)m-3至15元杂环烷基、-(CH2)m-C6-10芳基、-(CH2)m-6至10元杂芳基、-(CH2)m-C(=O)-R5、-(CH2)m-NR6R7、-(CH2)m-C(=O)-NR6R7、-(CH2)m-O-C(=O)-NR6R7、-(CH2)m-S(=O)n-R8、-(CH2)m-NR9-S(=O)n-R8、-(CH2)m-NR9-C(=O)-NR6R7或-(CH2)m-NR9-C(=O)-R5,优选F、Cl、Br、I、羟基、氰基、C1-8烷基、C1-8烷氧基或C1-8烷氧基,进一步优选F;其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代,优选任选进一步被0至5个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、甲基、乙基、甲氧基或乙氧基的取代基所取代,所述杂环烷基含有1至5个选自N、O或S(=O)n的原子或基团;
环A是饱和环或不饱和环,在一些实施方案中,环A是不饱和环;在一些实施方案中,环A是芳香环或者杂芳香环;在一些实施方案中,环A是苯环、嘧啶环、吡啶环、呋喃环、吡咯环、噻吩环、吡唑环、咪唑环、恶唑环、异恶唑环、噻唑环、异噻唑环、吡喃环、哒嗪环或吡嗪环;
R2各自独立选自氰基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、-(CH2)m-C3-15元环烷基、-(CH2)m-3至15元杂环烷基、-(CH2)m-C6-10芳基、-(CH2)m-6至10元杂芳基、-(CH2)m-C(=O)-R5、-(CH2)m-NR6R7、-(CH2)m-C(=O)-NR6R7、-(CH2)m-O-C(=O)-NR6R7、-(CH2)m-S(=O)n-R8、-(CH2)m-NR9-S(=O)n-R8、-(CH2)m-NR9-C(=O)-NR6R7或-(CH2)m-NR9-C(=O)-R5,优选氰基、C1-8烷基、C1-8烷氧基、-(CH2)m-C3-15元环烷基、-(CH2)m-C6-10芳基、-(CH2)m-C(=O)-R5、-(CH2)m-S(=O)n-R8或-(CH2)m-NR9-S(=O)n-R8,进一步优选-(CH2)m-S(=O)n-R8;其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至3个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代,优选任选进一步被0至3个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、甲基、乙基、甲氧基或乙氧基的取代基所取代,所述杂环烷基含有1至5个选自N、O或S(=O)n的原子或基团;
R5选自羟基、C1-8烷基、C1-8烷氧基、C3-15环烷基、C6-10芳基、6至10杂芳基、-O-C3-15环烷基、-O-C6-10芳基或-O-(6至10元杂芳基),优选羟基、C1-8烷基、C1-8烷氧基、C3-15环烷基,进一步优选羟基、甲基、乙基、甲氧基、乙氧基或环丙基;
R6、R7和R9各自独立选自H、C1-8烷基、C3-15环烷基、C6-10芳基、6至10元杂芳基或3至15元杂环烷基,优选H、C1-8烷基、C3-15环烷基,进一步优选H、甲基、乙基、甲氧基或乙氧基;
R8选自C1-8烷基、C3-15环烷基、C6-10芳基、6至10元杂芳基或3至15元杂环烷基,优选C1-2烷基、C3-6环烷基或3至6元杂环烷基,进一步优选甲基、乙基、环丙基或者环戊基,其中所述烷基、环烷基、杂环烷基、芳基或杂环芳基、甲基、乙基、 环丙基或者环戊基任选进一步被0至5个F所取代,所述杂环烷基或杂芳基含有1至5个选自N、O或S(=O)n的原子或基团;
p选自0、1、2、3或4,优选2或者3;
r选自0、1、2、3或4,优选1或2,进一步优选1;
m选自0、1或2,优选0;
n选自0、1或2,优选2。
在一些实施方案中,R1选自F,p选自2或者3。
在一些实施方案中,环A是不饱和环;在一些实施方案中,环A是芳香环或者杂芳香环;在一些实施方案中,环A是苯环、嘧啶环、吡啶环、呋喃环、吡咯环、噻吩环、吡唑环、咪唑环、恶唑环、异恶唑环、噻唑环、异噻唑环、吡喃环、哒嗪环或吡嗪环。
在一些实施方案中,
r选自1或2。
在一些实施方案中,R2选自C1-8烷基、C2-8烯基、C2-8炔基、-(CH2)m-C3-15元环烷基、-(CH2)m-3至15元杂环烷基、-(CH2)m-NR6R7、-(CH2)m-O-C(=O)-NR6R7、-(CH2)m-S(=O)n-R8、-(CH2)m-NR9-S(=O)n-R8、-(CH2)m-NR9-C(=O)-NR6R7或-(CH2)m-NR9-C(=O)-R5,其中所述烷基、烷氧基、烯基、炔基、环烷基或杂环烷基任选进一步被0至3个选自F、Cl、Br或I的取代基所取代,所述杂环烷基含有1至5个选自N、O或S(=O)n的原子或基团。
在一些实施方案中,R2选自-(CH2)m-C3-15元环烷基、-(CH2)m-3至15元杂环烷基或-(CH2)m-S(=O)n-R8,其中所述环烷基或杂环烷基任选进一步被0至3个选自F、Cl、Br或I的取代基所取代,所述杂环烷基含有1至5个选自N、O或S(=O)n的原子或基团。
在一些实施方案中,R2选自-(CH2)m-S(=O)n-R8。
在一些实施方案中,R8选自C1-8烷基、C3-15环烷基或3至15元杂环烷基;其中所述烷基、环烷基或杂环烷基任选进一步被0至5个F所取代,所述杂环烷基含有1至5个选自N、O或S(=O)n的原子或基团。
在一些实施方案中,R8选自C1-8烷基;其中所述烷基任选进一步被0至5个F所取代。
在一些实施方案中,R8选自C1-2烷基、C3-6环烷基或3至6元杂环烷基,其中所述烷基、环烷基、杂环烷基任选进一步被0至5个F所取代。
在一些实施方案中,R2选自-(CH2)m-S(=O)n-R8;
m选自0;
n选自2;
R8选自C1-8烷基、C3-15环烷基、C6-10芳基、6至10元杂芳基或3至15元杂环烷基;其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个F所取代,所述杂环烷基或杂芳基含有1至5个选自N、O或S(=O)n的原子或基团。
在一些实施方案中,
r选自1或2;
R2选自-(CH2)m-S(=O)n-R8;
m选自0;
n选自2;
R8选自C1-8烷基、C3-15环烷基、C6-10芳基、6至10元杂芳基或3至15元杂环烷基;其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个F所取代,所述杂环烷基或杂芳基含有1至5个选自N、O或S(=O)n的原子或基团。
在一些实施方案中,R8选自C1-2烷基、C3-6环烷基或3至6元杂环烷基,其中所述烷基、环烷基、杂环烷基任选进一步被0至5个F所取代;r选自1。
在一些实施方案中,
r选自1;
R2选自-(CH2)m-S(=O)n-R8;
m选自0;
n选自2;
R8选自C1-2烷基、C3-6环烷基或3至6元杂环烷基,其中所述烷基、环烷基、杂环烷基任选进一步被0至5个F所取代。
在一些实施方案中,R8选自甲基。
在一些实施方案中,通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药,其中该氨基吡喃环衍生物选自:
本发明的一些实施例涉及通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药,其中该氨基吡喃环衍生物选自:
本发明的一些实施例涉及通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药,其中该氨基吡喃环衍生物选自:
本发明的一些实施例涉及通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药化合物选自:
本发明还涉及通式(I)所示化合物或其立体异构体、水合物、溶剂化物、药学上可接受的盐或前药,其中所述的盐包括但不限于钠盐、钾盐、钙盐、镁盐、钡盐、铵盐、三甲胺盐、三乙胺盐、吡啶盐、甲基吡啶盐、2,6-二甲基吡啶盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、环己胺盐、二环己基铵盐、盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、三氟乙酸盐、乙酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、扁桃酸盐、富马酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、草酸盐、羟乙酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、门冬氨酸盐、谷氨酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐或它们的组合。
本发明还涉及一种药物组合物,所述的组合物包括:有效剂量的根据本发明前面任一项所述通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药,或进一步包括一种或多种其他治疗剂;以及药学上可接受的载体或赋形剂。
本发明还涉及一种药物组合物,其中所述的其他治疗剂包括:
(a)DPP-IV抑制剂或药学上可接受的盐,和/或
(b)SGLT-2抑制剂或药学上可接受的盐,和/或
(c)双胍类、噻唑烷二酮类、磺酰脲类、列奈类、α-葡萄糖苷酶抑制剂或胰高血糖素样肽-1类似物,或其药学上可接受的盐或前药。
本发明涉及的组合物,其中所述的SGLT-2抑制剂选自达格列净、坎格列净、阿格列净、恩帕列净、依帕列净、托伏列净、卢斯列净、瑞格列净、舍格列净或依托列净;DPP-IV抑制剂选自利拉列汀、西他列汀、维格列汀、阿格列汀、沙格列汀、地那列汀、卡格列汀、美格列汀、度格列汀、替格列汀、吉格列汀或曲格列汀;双胍类治疗剂选自二甲双胍或苯乙双胍;噻唑烷二酮类治疗剂选自环格列酮、吡咯列酮、罗格列酮、曲格列酮、发格列酮或达格列酮,磺酰脲类治疗剂选自格列美脲、甲苯磺丁脲、格列波脲、格列本脲、格列喹酮、格列吡嗪或格列齐特,列奈类治疗剂选自那格列奈、瑞格列奈或米格列奈,α-葡萄糖苷酶抑制剂选自阿卡波糖、伏格列波糖或米格列醇,胰高血糖素样肽-1类似物选自艾塞那肽或利拉鲁肽。
本发明还涉及通式(I)所述的化合物或其立体异构体、药学上可接受的盐及其组合物或其前药在制备二肽基肽酶-IV抑制剂中的应用。
根据本发明所述的应用,其中所述的二肽基肽酶-IV抑制剂用于制备治疗代谢性疾病的药物,其中所述的代谢性疾病选自糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高的水平、高脂血症、肥胖症、高甘油三脂血症、X综合症、动脉粥样硬化或高血压。
根据本发明所述的应用,所述的糖尿病为II型糖尿病。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素均包括它们的同位素,及本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或卤素任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又称为重氢)、氚(T,又称为超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“烷基”是指直链和支链的饱和脂肪族烃基团,主链包括1至20个碳原子,优选为1至12个碳原子,进一步优选为1至8个碳原子,更优选为1至6个碳原子,再进一步优选1至4个碳原子的直链与支链基团,最优选1至2个碳原子。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,2-二甲基己基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基和正癸基等。烷基可以是取代的或未取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(=O)-Ra、-O-(CH2)m-C(=O)-Ra、-(CH2)m-C(=O)-NRbRc、-(CH2)mS(=O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc,其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基、并环基。
“烷氧基”是指-O-烷基,其中烷基如本文上述定义。烷氧基可以是取代的或未取代的,烷氧基实施例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基和正己氧基等。当被取代时,取代基优选为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(=O)-Ra、-O-(CH2)m-C(=O)-Ra、-(CH2)m-C(=O)-NRbRc、-(CH2)mS(=O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc,其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,Rb与Rc可形成五或六元环烷基或杂环烷基Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“烯基”是指至少含一个碳-碳双键组成的如本文上述定义的烷基,优选含有2至20个碳原子,进一步优选2至12个碳原子,更优选在主链上有2至8个碳原子,烯基可以是取代的或未取代的。非限制性实施例包括乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1-戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯、1,4-己二烯、3-十一烯基、4-十二烯基和4,8,12-十四碳三烯基等。当被取代时,取代基为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(=O)-Ra、-O-(CH2)m-C(=O)-Ra、-(CH2)m-C(=O)-NRbRc、-(CH2)mS(=O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc,其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“炔基”是指包含至少一个碳-碳三键组成的如本文上述定义的烷基,优选含有2至20个碳原子,进一步优选2至8个碳原子,更优选在主链上有2至4个碳原子的炔基。炔基可以是取代的或未取代的。非限制性实施例包括乙炔基、1-丙炔基、2-丙炔基、丁炔基、2-丁炔基、3-丁炔基、1-甲基-2-丙炔基、4-戊炔基、3-戊炔基、1-甲基-2-丁炔基、2-己炔基、3-己炔基、2-庚炔基、3-庚炔基、4-庚炔基、3-辛炔基、3-壬炔基、4-癸炔基、3-十一炔基和4-十二炔基等;当被取代时,取代基优选为一个或多个以下基团,独立地选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(=O)-Ra、-O-(CH2)m-C(=O)-Ra、-(CH2)m-C(=O)-NRbRc、-(CH2)mS(=O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc,其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“卤素”是指氟、氯、溴、碘。
“羟基”是指-OH。
“氰基”是指-C≡N。
“环烷基”是指饱和或不饱和的非芳香环基,可以是取代的或未取代的,环碳原子包括3至20个碳原子,优选3至10个碳原子,进一步优选3至8个碳原子,非限制性实施例包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基、1,5-环辛二烯基、1,4-环己二烯基和环庚三烯基等。当被取代时,取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(=O)-Ra、-O-(CH2)m-C(=O)-Ra、-(CH2)m-C(=O)-NRbRc、-(CH2)mS(=O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团,其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“杂环烷基”是指取代的或未取代的饱和或者不饱和且至少含有1至5个选自N、O或S杂原子的非芳香环,非芳香环可以是3至10元的单环,4至20元的螺环、并环或桥环,杂环烷基环中选择性取代的N、S可被氧化成各种氧化态。优选3至12元杂环。非限制性实施例包括氧杂环丙烷基、氧杂环丁基、氧杂环戊基、氧杂环己基、氧杂环己基、氧杂环辛基、氮杂环丙烷基、氮杂环丁基、氮杂环戊基、氮杂环己基、氮杂环丙烯基、1,3二氧环戊基、1,4-二氧环戊基、1,3-二氧环戊基、1,3-二氧环己基、1,3-二硫环己基、氮杂环庚烯基、吗啉基、哌嗪基、吡啶基、呋喃基、噻吩基、吡咯基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、硫代吗啉基、二氢吡喃、噻二唑基、噁唑基、噁二唑基、吡唑基、1,4-二氧杂环己二烯基、
等。当被取代时,取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(=O)-Ra、-O-(CH2)m-C(=O)-Ra、-(CH2)m-C(=O)-NRbRc、-(CH2)mS(=O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团,其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“芳基”是指取代的或未取代的6至14元环状芳香基团,包括单环芳香基和稠环芳香基。优选6至14元芳香环,进一步优选6至10元芳香环,其非限制性实例包括苯基、萘基、蒽基和菲基等。所述芳基环可以稠合于杂芳基、杂环烷基或环烷基环上,其中与母体结构连接在一起的环为芳基环,非限制性实施例包含:
当被取代时,取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(=O)-Ra、-O-(CH2)m-C(=O)-Ra、-(CH2)m-C(=O)-NRbRc、-(CH2)mS(=O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团,其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“杂芳基”是指取代或未取代的5至14元芳香环,且含有1至5个选自N、O或S(=O)n杂原子或基团,优选5至10元杂芳香环,进一步优选5至6元。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉、硫代吗啉、1,3-二噻烷、苯并咪唑、哌叮基、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于芳基、杂环烷基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,非限制性实施例包含当被取代时,取代基可以为1至5个选自F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环烷基、桥环基、螺环基、并环基、羟基烷基、=O、羰基、醛、羧酸、羧酸酯、-(CH2)m-C(=O)-Ra、-O-(CH2)m-C(=O)-Ra、-(CH2)m-C(=O)-NRbRc、-(CH2)mS(=O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团,其中Rb与Rc独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环烷基、芳基、杂芳基、磺酰基、三氟甲磺酰基,作为选择,Rb与Rc可形成五或六元环烷基或杂环烷基。Ra与Rd各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环烷基、羰基、酯基、桥环基、螺环基或并环基。
“碳环”是指构成环骨架的原子全部是碳原子,可以是饱和的或不饱和的,可以被进一步取代。非限制性实施例包括环丙基、环丁基、环戊基、苯基、环戊二烯基或1-环己烯基。
“杂环”是指构成环骨架的原子包含杂原子,比如氮原子、硫原子、氧原子,可以是饱和的或不饱和的,也可以被进一步取代。非限制性实施例包含嘧啶环、吡啶环、呋喃环、吡咯环、噻吩环、吡唑环、咪唑环、恶唑环、异恶唑环、噻唑环、异噻唑环、吡喃环、哒嗪环或吡嗪环。
“饱和环”是指饱和的碳环或杂环,非限制性实施例包含环烷基或杂环烷基。
“不饱和环”是指不饱和碳环或不饱和杂环,非限制性实施例包含芳基及杂芳基。
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生,该说明包括该事件或环境发生或不发生的场合。如:“任选被F取代的烷基”指烷基可以但不必须被F取代,说明包括烷基被F取代的情形和烷基不被F取代的情形。
“药学上可接受的盐”或“其药学上可接受的盐”指的是保持游离酸或游离碱的生物有效性和特性,且所述的游离酸通过与无毒的无机碱或有机碱,或所述的游离酸通过与无毒的无机酸或有机酸反应获得的那些盐,包括碱金属盐,如钠盐、钾盐、锂盐等;碱土金属盐,如钙盐、镁盐等;其他金属盐,如铁盐、铜盐、钴盐等;有机碱盐,如铵盐、三乙胺盐、吡啶盐、甲基吡啶盐、2,6-二甲基吡啶盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、环己胺盐、乙二胺盐、胍盐、异丙基胺盐、三甲基胺盐、三丙基胺盐、三乙醇胺盐、二乙醇胺盐、乙醇胺盐、二甲基乙醇胺盐、二环己基胺盐、咖啡碱盐、普鲁卡因盐、胆碱盐、甜菜碱盐、苯明青霉素盐、葡萄糖胺盐、N-甲基葡糖胺盐、可可碱盐、氨丁三醇盐、嘌呤盐、哌嗪盐、吗啉盐、哌啶盐、N-乙基哌啶盐、四甲基胺盐、二苄基胺盐和苯基甘氨酸烷基酯盐等;氢卤酸盐,如氢氟酸盐、盐酸盐、氢碘酸盐、氢溴酸盐等;无机酸盐,如硝酸盐、硫酸盐、高氯酸盐、磷酸盐等;低级烷磺酸盐,如甲磺酸盐、三氟甲磺酸盐、乙磺酸盐等;芳基磺酸盐,如苯磺酸盐、对甲苯磺酸盐等;有机酸盐,如蚁酸盐、富马酸盐、甲酸盐、三氟乙酸盐、糠酸盐、葡萄糖酸盐、谷氨酸盐、乙醇酸盐、羟乙磺酸盐、乳酸盐、马来酸盐、苹果酸盐、扁桃酸盐、粘液酸盐、双羟萘酸盐、泛酸盐、硬脂酸盐、琥珀酸盐、磺胺酸盐、酒石酸盐、丙二酸盐、2-羟基丙酸盐、柠檬酸盐、水杨酸盐、草酸盐、羟乙酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、赖氨酸盐、精氨酸盐、门冬氨酸盐、肉桂酸盐等。
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐或前体药物的组合或/和临床上使用的用于治疗、预防糖尿病的药物或/和SGLT-2抑制剂或/和DPP-IV抑制剂与其他组成成分的混合物,其中其它组分包含生理学/药学上可接受的载体和赋形剂。临床上使用的用于治疗、预防糖尿病的药物包括双胍、噻唑烷二酮、磺酰脲、列奈、α-葡萄糖苷酶抑制剂、GLP-1类似物或其药学上可接受的盐,例如二甲双胍、苯乙双胍、环格列酮(Ciglitazone)、吡咯列酮(Pioglitazone)、罗格列酮(Rosiglitazone)、曲格列酮(Troglitazone)、发格列酮(Farglitazar)、达格列酮(Darglitazoan)、格列美脲(Glimepiride)、甲苯磺丁脲(Tolglybutamide)、格列波脲(Glibornuride)、格列本脲(Glibenclamide)、格列喹酮(Gliquidone)、格列吡嗪(glipizide)、格列齐特(gliclazi石油醚)、那格列奈(Nateglinide)、瑞格列奈(Repaglinide)、米格列奈(mitiglinide)、阿卡波糖(Acarbose)、伏格列波糖(Voglibose)、米格列醇(Miglitol)、艾塞那肽(Exenatide)或利拉鲁肽(Liraglutide),SGLT-2抑制剂例如达格列净(Dapagliflozin)、坎格列净(Canagliflozin)、恩帕列净(Empagliflozin)、依帕列净(Ipragliflozin)、托伏列净(Tofogliflozin)、卢斯列净(Luseogliflozin)、瑞格列净(Remogliflozin)、舍格列净(Sergliflozin)或依托列净(Ertugliflozin),DPP-IV抑制剂例如利拉列汀(Linagliptin)、西他列汀(Sitagliptin)、维格列汀(Vildagliptin)、阿格列汀(Alogliptin)、沙格列汀(Saxagliptin)、地那列汀(Denagliptin)、卡格列汀(Carmegliptin)、美格列汀(Melogliptin)、度格列汀(Dutogliptin)、替格列汀(Teneligliptin)、吉格列汀(Gemigliptin)或曲格列汀(Trelagliptin)。药物组合物的目的是促进化合物对生物体的给药。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
“前药”是指可以在生理条件下或通过溶剂解转化为具有生物活性的本发明化合物的化合物。本发明的前药通过修饰在该化合物中的酚基团来制备,该修饰可以按常规的操作或在体内被除去,而得到母体化合物。当本发明的前体药物被施予哺乳动物个体时,前体药物被割裂而分别形成游离的羟基。前药的例子包括,但不限于本发明化合物的酚羟基和磷酸成钠盐衍生物。
本文所述化合物可以含有一个或多个不对称中心,并且由此可以以外消旋物、外消旋混合物、单一对映异构体、非対映异构体混合物和单一非対映异构体存在。
本文所述某些化合物含有双键,除非另有说明,包含E和Z几何构体。
“共晶体”或“共晶”是指活性药物成分(active pharmaceutical ingredient,API)和共晶形成物(cocrystal former,CCF)在氢键或其他非共价键的作用下结合而成的晶体,其中API和CCF的纯态在室温下均为固体,并且各组分间存在固定的化学计量比。共晶是一种多组分晶体,既包含两种中性固体之间形成的二元共晶,也包含中性固体与盐或溶剂化物形成的多元共晶。所述“共晶形成物”包括但不限于各种药学上可接受的酸、碱、非离子化合物、水、氨基酸、醇或其他溶剂,其非限制性实例包括丙氨酸(Ala)、缬氨酸(Val)、亮氨酸(Leu)、异亮氨酸(Ile)、脯氨酸(Pro)、苯丙氨酸(Phe)、色氨酸(Trp)、蛋氨酸(Met)、甘氨酸(Gly)、丝氨酸(Ser)、苏氨酸(Thr)、半胱氨酸(Cys)、酪氨酸(Tyr)、天冬酰胺(Asn)、谷氨酰胺(Gln)、赖氨酸(Lys)、精氨酸(Arg)、组氨酸(His)、天冬氨酸(Asp)、谷氨酸(Glu)、焦谷氨酸、硫酸、磷酸、硝酸、氢溴酸、盐酸、甲酸、乙酸、丙酸、苯磺酸、苯甲酸、苯乙酸、水杨酸、褐藻酸、氨茴酸、樟脑酸、柠檬酸、乙烯磺酸、蚁酸、富马酸、糠酸、葡萄糖酸、葡萄糖醛酸、谷氨酸、乙醇酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、粘液酸、双羟萘酸、泛酸、硬脂酸、琥珀酸、磺胺酸、酒石酸、对甲苯磺酸、丙二酸、2-羟基丙酸、草酸、羟乙酸、葡萄糖醛酸、半乳糖醛酸、枸橼酸、赖氨酸、精氨酸、门冬氨酸、肉桂酸、对甲苯磺酸、甲磺酸、乙磺酸或三氟甲磺酸、氨、异丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、二乙醇胺、乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、甲基葡糖胺、可可碱、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、甲醇、乙醇、丁炔二醇、1,2-丙二醇、(R)1,2-丙二醇、(S)1,2-丙二醇或1-甲基-1,2-乙二醇。
“X综合症”是指代谢综合症的病症、疾病和疾患。详细描述见JohannssonJ.Clin.Endocrinol.Metab.,1997,82,727-734。
“有效剂量”指引起组织、系统或受试者生理或医学翻译的化合物的量,此量是所寻求的,包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
“溶剂化物”指本发明化合物或其盐,它们还包括以分子间非共价力结合的化学计量或非化学计量的溶剂。当溶剂为水时,则为水合物。
“IC50”指半数抑制浓度,指达到最大抑制效果一半时的浓度。
本发明化合物的合成方法:
为了完成本发明的目的,本发明化合物可以由以下方案制备而得:
通式I-a的化合物参考WO2017031918A1方法合成;通式I-b的化合物参考WO2015192701A1方法合成。
通式I-a的化合物与通式I-b的化合物通过还原胺化生成通式I-c的化合物,脱除氨基保护基后生成通式I的化合物。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果,旨在帮助阅读者更好地理解本发明的实质和特点,不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)和/或质谱(MS)来确定的。
NMR位移(δ)以10-6(ppm)的单位给出。
NMR的测定是用(Bruker ADVANCE III 400)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS),1HNMR信息以下列格式来列表:化学位移(多重峰(s,单峰;d,双重峰;t,三重峰;q,四重峰;m,多重峰),质子数)。
MS的测定用(Agilent 6120B(ESI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorba x SB-C18 100x 4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
无特殊说明,三乙胺、甲基叔丁基醚、水合联氨、四丁基溴化铵、二氯亚砜、咪唑、氢化钠、三苯基磷、三氟乙酸购买于成都市科龙化工试剂厂;二碳酸二叔丁基酯、N,N'-二羰基二咪唑、N,N-二甲基甲酰胺二甲基缩醛、N,O-二甲基羟氨盐酸盐、顺式-4-羟基-D-脯氨酸盐酸盐购买于爱斯特(成都)医药技术有限公司;碳酸铯、硼氢化锂、叔丁基二甲基氯硅烷、N-羟基丁二酰亚胺、二(三甲基硅基)氨基钠、二苯亚甲基甘氨酸乙酯、反式-L-羟基脯氨酸购买于安耐吉化学;戴斯马丁购买于上海泰坦科技股份有限公司;三氟甲磺酸甲酯、2,5-二氟溴苯、S-(三氟甲基)二苯并噻吩三氟甲基磺酸盐购买于上海德默医药科技有限公司;2-碘丙烷购买于上海毕得医药科技有限公司;异丙基氯化镁/氯化锂四氢呋喃溶液购买于百灵威科技有限公司;炔丙基苯磺酸酯、四丁基氟化铵、三(乙酰氧基)硼氢化钠、四丁基六氟磷酸胺购买于阿达玛斯试剂公司;环戊二烯基双(三苯基膦)氯化钌(II)购买于ACROSorgainics;硼烷二甲硫醚购买于韶远化学科技(上海)有限公司;四氢呋喃-3-磺酰基氯购买于南京康满林化工实业有限公司;过硼酸钠购买于天津光复精细化工研究所;氯{[(1R,2R)-(-)-2-氨基-1,2-二苯基乙基](五氟苯磺酰)氨基}(对伞花烃)钌(II)购买于Stremchemical;碘甲烷、甲基磺酰氯购买于国药集团药业股份有限公司。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。
氢气氛是指反应瓶连接一个约2L容积的氢气气球。
氢化反应通常抽真空,充入氢气,反复操作3次。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温。
室温为最适宜的反应温度,为20℃~30℃。
实施例1:
(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(5-甲磺酰异吲哚啉-2-基)-6-(三氟甲基)四氢吡喃-3-胺(化合物1)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(5-methylsulfonylisoindolin-2-yl)-6-(trifluoromethyl)te trahydropyran-3-amine.
第一步:N-[(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(5-甲基磺酰基异吲哚-2-基)-6-(三氟甲基)四氢吡喃-3-基]氨基甲酸叔丁酯(1c)
tert-butyl
N-[(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(5-methylsulfonylisoindolin-2-yl)-6-(trifluoromethyl)tetrahydropyran-3-yl]carbamate
化合物1a参考WO2017031918A1方法合成;化合物1b参考WO2015192701A1方法合成。
将化合物1a(340mg,1.7mmol)和化合物1b(680mg,1.7mmol)加入到20mL氯仿中,在90℃下反应1小时直至溶剂蒸干。剩余物重新溶解于1,2-二氯乙烷(15mL)中,在氮气氛围中,依次加入三(乙酰氧基)硼氢化钠(1.1g,5.2mmol)和乙酸(150mg,2.5mmol),室温下反应3小时。向反应液中加入饱和碳酸氢钠溶液(20mL)淬灭反应,分层,用乙酸乙酯(20mL×2)萃取水相,合并有机相,无水硫酸钠干燥,浓缩。硅胶柱层析(石油醚/乙酸乙酯=3/1-1/1)分离纯化,得到化合物1c,白色固体(500mg,产率50%)。
Ms m/z(ESI):577.2[M+1];
第二步:(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(5-甲磺酰异吲哚啉-2-基)-6-(三氟甲基)四氢吡喃-3-胺(化合物1)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(5-methylsulfonylisoindolin-2-yl)-6-(trifluoromethyl)tetrahydropyran-3-amine
将化合物1c(500mg,0.87mmol)溶于6mL二氯甲烷和2mL三氟乙酸中,室温下搅拌1小时。反应结束后加入饱和碳酸氢钠水溶液(30mL)淬灭反应,分层后用乙酸乙酯萃取水相(30mL×2),合并有机相,无水硫酸钠干燥,浓缩。硅胶柱层析分离纯化(二氯甲烷/甲醇=30:1),得到化合物1,淡黄色固体(230mg,产率56%)。
Ms m/z(ESI):477.1[M+1];
1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.80-7.77(m,1H),7.54(d,1H),7.33-7.19(m,3H),4.80-4.67(m,1H),4.50(d,1H),4.18-4.09(m,2H),4.04-3.97(m,2H),3.37-3.32(m,1H),3.19(s,3H),3.08-2.96(m,1H),2.31(d,1H),1.88-1.55(m,3H).
实施例2:
(2R,3S,5R,6S)-5-((5-甲基磺酰基异吲哚-2-基)-6-(三氟甲基)-2-(2,4,5-三氟苯基)四氢吡喃-3-胺(化合物2)
(2R,3S,5R,6S)-5-(5-methylsulfonylisoindolin-2-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydropyran-3-amine
第一步:N-[(2R,3S,5R,6S)-5-(5-甲基磺酰基异吲哚啉-2-基)-6-(三氟甲基)-2-(2,4,5-三氟苯基)四氢吡喃-3-基叔丁基]氨基甲酸酯(2b)
tert-butyl
N-[(2R,3S,5R,6S)-5-(5-methylsulfonylisoindolin-2-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydropyran-3-yl]carbamate
化合物2b参考WO2015192701A1方法合成。
将化合物1a(320mg,1.6mmol)和化合物2b(670mg,1.6mmol)加入到20mL氯仿中,在90℃下反应1小时直至溶剂蒸干。剩余物重新溶解于1,2-二氯乙烷(15mL)中,在氮气氛围中,依次加入三(乙酰氧基)硼氢化钠(1.0g,4.9mmol)和乙酸(150mg,2.5mmol),室温下反应3小时。向反应液中加入饱和碳酸氢钠溶液(20mL)淬灭反应,分层,用乙酸乙酯(20mL×2)萃取水相,合并有机相,无水硫酸钠干燥,浓缩。硅胶柱层析(石油醚/乙酸乙酯=3/1-1/1)分离纯化,得到化合物2c,白色固体(500mg,产率52%)。
Ms m/z(ESI):595.2[M+1]。
第二步:(2R,3S,5R,6S)-5-((5-甲基磺酰基异吲哚-2-基)-6-(三氟甲基)-2-(2,4,5-三氟苯基)四氢吡喃-3-胺(化合物2)
(2R,3S,5R,6S)-5-(5-methylsulfonylisoindolin-2-yl)-6-(trifluoromethyl)-2-(2,4,5-trifluorophenyl)tetrahydropyran-3-amine
将化合物1c(500mg,0.84mmol)溶于6mL二氯甲烷和2mL三氟乙酸中,室温下搅拌1小时。反应结束后加入饱和碳酸氢钠水溶液(30mL)淬灭反应,分层后用乙酸乙酯萃取水相(30mL×2),合并有机相,无水硫酸钠干燥,浓缩。硅胶柱层析分离纯化(二氯甲烷/甲醇=30:1),得到化合物2,浅粉色固体(220mg,产率50%)。
Ms m/z(ESI):495.1[M+1];
1H NMR(400MHz,DMSO-d6)δ7.83(s,1H),7.81-7.76(m,1H),7.62-7.48(m,3H),4.80-4.65(m,1H),4.47(d,1H),4.18-4.08(m,2H),4.05-3.95(m,2H),3.41-3.32(m,1H),3.19(s,3H),3.06-2.92(m,1H),2.36-2.22(m,1H),1.87-1.72(m,1H),1.54(br,2H).
生物测试
1、DPP-IV体外酶活测定
利用重组人DPP-IV和H-Ala-Pro-AFC的酶学反应测定本发明化合物的DPP-IV体外酶活。按照DPP-IV Fluorescent ActivityAssay Kit(BPS Bioscience)配制缓冲液、待测样品工作液、DPP-IV酶稀释液和AFC底物稀释液。
准备96孔板,每孔先加入80μL缓冲液,之后加入5μL DPP-AFC-底物。在加入不同浓度待测样工作液,每孔5μL,空白组加入5μL缓冲液。最后在测试组对照中加入10μL DPP-IV酶,空白对照组中加入10μL缓冲液。用Origin 7.5软件对数据进行统计学分析,得到各测试化合物的IC50值,结果见表1。
表1 DPP-IV体外酶活测定结果
序号 | 化合物编号 | IC50(nM) |
1 | 化合物1 | <20 |
2 | 化合物2 | <20 |
结论:本发明化合物具有明显的DPP-IV酶的抑制活性。
2、大鼠药代动力学评价
雄性SD大鼠(购于成都达硕实验动物有限公司),200g左右,6~8周龄,共15只。试验当天,15只SD大鼠按体重随机分为5组,每组3只。给药前1天禁食不禁水12~14h,给药后4h给食。口服给药剂量为3.0mg/kg,给药体积灌胃为10ml/kg。于给药前及给药后异氟烷麻醉经眼眶取血0.10ml,置于EDTAK2离心管中并放置冰浴上。5000rpm,4℃离心10min,收集血浆。口服给药后采血点:0min,15min,30min,1h,2h,4h,6h,8h,24h,48h,72h。分析检测前,所有血浆样品存于-80℃。经蛋白沉淀前处理后,用HPLC-MS/MS对样品进行检测。
表2大鼠药代动力学评估结果
Claims (17)
1.通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药:
其中:
R1各自独立选自F、Cl、Br、I、羟基、氰基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、-(CH2)m-C3-15环烷基、-(CH2)m-3至15元杂环烷基、-(CH2)m-C6-10芳基、-(CH2)m-6至10元杂芳基、-(CH2)m-C(=O)-R5、-(CH2)m-NR6R7、-(CH2)m-C(=O)-NR6R7、-(CH2)m-O-C(=O)-NR6R7、-(CH2)m-S(=O)n-R8、-(CH2)m-NR9-S(=O)n-R8、-(CH2)m-NR9-C(=O)-NR6R7或-(CH2)m-NR9-C(=O)-R5,其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代,所述杂环烷基含有1至5个选自N、O或S(=O)n的原子或基团;
环A是饱和环或不饱和环;
R2各自独立选自氰基、C1-8烷基、C1-8烷氧基、C2-8烯基、C2-8炔基、-(CH2)m-C3-15元环烷基、-(CH2)m-3至15元杂环烷基、-(CH2)m-C6-10芳基、-(CH2)m-6至10元杂芳基、-(CH2)m-C(=O)-R5、-(CH2)m-NR6R7、-(CH2)m-C(=O)-NR6R7、-(CH2)m-O-C(=O)-NR6R7、-(CH2)m-S(=O)n-R8、-(CH2)m-NR9-S(=O)n-R8、-(CH2)m-NR9-C(=O)-NR6R7或-(CH2)m-NR9-C(=O)-R5,其中所述烷基、烷氧基、烯基、炔基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至3个选自F、Cl、Br、I、-CH2F、-CHF2、-CF3、羟基、C1-4烷基或C1-4烷氧基的取代基所取代,所述杂环烷基含有1至5个选自N、O或S(=O)n的原子或基团;
R5选自羟基、C1-8烷基、C1-8烷氧基、C3-15环烷基、C6-10芳基、6至10杂芳基、-O-C3-15环烷基、-O-C6-10芳基或-O-(6至10元杂芳基);
R6、R7和R9各自独立选自H、C1-8烷基、C3-15环烷基、C6-10芳基、6至10元杂芳基或3至15元杂环烷基;
R8选自C1-8烷基、C3-15环烷基、C6-10芳基、6至10元杂芳基或3至15元杂环烷基,其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个F所取代,所述杂环烷基或杂芳基含有1至5个选自N、O或S(=O)n的原子或基团;
p选自0、1、2、3或4;
r选自0、1、2、3或4;
m选自0、1或2;
n选自0、1或2。
2.根据权利要求1所述通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药,其中:
R1选自F;
p选自2或者3。
4.根据权利要求3所述通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药,其中:
R2选自-(CH2)m-S(=O)n-R8;
m选自0;
n选自2;
R8选自C1-8烷基、C3-15环烷基、C6-10芳基、6至10元杂芳基或3至15元杂环烷基;其中所述烷基、环烷基、杂环烷基、芳基或杂芳基任选进一步被0至5个F所取代,所述杂环烷基或杂芳基含有1至5个选自N、O或S(=O)n的原子或基团。
5.根据权利要求4所述通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药,其中:
R8选自C1-2烷基、C3-6环烷基或3至6元杂环烷基,其中所述烷基、环烷基、杂环烷基任选进一步被0至5个F所取代;
r选自1。
11.根据权利要求1~10中任一项所述通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药,其中所述的盐选自钠盐、钾盐、钙盐、镁盐、钡盐、铵盐、三甲胺盐、三乙胺盐、吡啶盐、甲基吡啶盐、2,6-二甲基吡啶盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐、环己胺盐、二环己基铵盐、盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、三氟乙酸盐、乙酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、扁桃酸盐、富马酸盐、丙二酸盐、苹果酸盐、2-羟基丙酸盐、草酸盐、羟乙酸盐、水杨酸盐、葡萄糖醛酸盐、半乳糖醛酸盐、枸橼酸盐、门冬氨酸盐、谷氨酸盐、苯甲酸盐、肉桂酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、乙磺酸盐、三氟甲磺酸盐或它们的组合。
12.一种药物组合物,所述的组合物包括:有效剂量的根据权利要求1~11中任一项所述通式(I)所示的三氟甲基取代的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药,或进一步包括一种或多种其他治疗剂以及药学上可接受的载体或赋形剂。
13.根据权利要求12所述的组合物,其中所述的其他治疗剂包括:
(a)DPP-IV抑制剂或药学上可接受的盐,和/或
(b)SGLT-2抑制剂或药学上可接受的盐,和/或
(c)双胍类、噻唑烷二酮类、磺酰脲类、列奈类、α-葡萄糖苷酶抑制剂或胰高血糖素样肽-1类似物,或其药学上可接受的盐或前药。
14.根据权利要求13所述的组合物,其中所述的SGLT-2抑制剂选自达格列净、坎格列净、阿格列净、恩帕列净、依帕列净、托伏列净、卢斯列净、瑞格列净、舍格列净或依托列净;DPP-IV抑制剂选自利拉列汀、西他列汀、维格列汀、阿格列汀、沙格列汀、地那列汀、卡格列汀、美格列汀、度格列汀、替格列汀、吉格列汀或曲格列汀;双胍类治疗剂选自二甲双胍或苯乙双胍;噻唑烷二酮类治疗剂选自环格列酮、吡咯列酮、罗格列酮、曲格列酮、发格列酮或达格列酮;磺酰脲类治疗剂选自格列美脲、甲苯磺丁脲、格列波脲、格列本脲、格列喹酮、格列吡嗪或格列齐特;列奈类治疗剂选自那格列奈、瑞格列奈或米格列奈;α-葡萄糖苷酶抑制剂选自阿卡波糖、伏格列波糖或米格列醇;胰高血糖素样肽-1类似物选自艾塞那肽或利拉鲁肽。
15.权利要求1~11中任一项所述通式(I)所示的氨基吡喃环衍生物或其立体异构体、药学上可接受的盐或前药或者权利要求12~14中任一项所述的组合物在制备二肽基肽酶-IV抑制剂中的应用。
16.根据权利要求15中所述的应用,其中所述的二肽基肽酶-IV抑制剂用于制备治疗代谢性疾病的药物,其中所述的代谢性疾病包括糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高的水平、高脂血症、肥胖症、高甘油三脂血症、X综合症、动脉粥样硬化或高血压。
17.根据权利要求16中所述的应用,其中所述的糖尿病为II型糖尿病。
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