CN110392679B - 可用作双重atx/ca抑制剂的杂环化合物 - Google Patents
可用作双重atx/ca抑制剂的杂环化合物 Download PDFInfo
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- CN110392679B CN110392679B CN201880017056.4A CN201880017056A CN110392679B CN 110392679 B CN110392679 B CN 110392679B CN 201880017056 A CN201880017056 A CN 201880017056A CN 110392679 B CN110392679 B CN 110392679B
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- China
- Prior art keywords
- methyl
- phenyl
- methyltetrazol
- trifluoromethyl
- propanoyl
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title description 6
- 230000009977 dual effect Effects 0.000 title description 5
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 166
- -1 aminosulfonylphenyl Chemical group 0.000 claims abstract description 164
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 68
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 22
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 13
- 208000022873 Ocular disease Diseases 0.000 claims abstract description 11
- 238000011282 treatment Methods 0.000 claims abstract description 11
- 230000002265 prevention Effects 0.000 claims abstract description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 67
- 125000000217 alkyl group Chemical group 0.000 claims description 53
- 125000003545 alkoxy group Chemical group 0.000 claims description 46
- 238000006243 chemical reaction Methods 0.000 claims description 46
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 40
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 36
- 150000003839 salts Chemical class 0.000 claims description 36
- 238000006467 substitution reaction Methods 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 32
- 150000002367 halogens Chemical class 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 29
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 16
- ATIOZSZEDIGMIS-UHFFFAOYSA-N n-sulfonylbenzenesulfonamide Chemical compound O=S(=O)=NS(=O)(=O)C1=CC=CC=C1 ATIOZSZEDIGMIS-UHFFFAOYSA-N 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- VLYBPTDSUCQKGI-UHFFFAOYSA-N S(=O)(=O)=NS(=O)(=O)C1=CC(=CC=C1)F Chemical compound S(=O)(=O)=NS(=O)(=O)C1=CC(=CC=C1)F VLYBPTDSUCQKGI-UHFFFAOYSA-N 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 12
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 229940124530 sulfonamide Drugs 0.000 claims description 7
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- BTUNHNFBTGHBRC-UHFFFAOYSA-N n-sulfinylbenzenesulfonamide Chemical compound O=S=NS(=O)(=O)C1=CC=CC=C1 BTUNHNFBTGHBRC-UHFFFAOYSA-N 0.000 claims description 6
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- URMLBQNMIHBWHG-UHFFFAOYSA-N S(=O)(=O)=NS(=O)(=O)C1=C(C(=CC=C1)F)F Chemical compound S(=O)(=O)=NS(=O)(=O)C1=C(C(=CC=C1)F)F URMLBQNMIHBWHG-UHFFFAOYSA-N 0.000 claims description 4
- 125000005169 cycloalkylcarbonylamino group Chemical group 0.000 claims description 4
- FMZIUIFYMJWAEE-UHFFFAOYSA-N 2-[2-[1-[3-[2-[(5-methyltetrazol-2-yl)methyl]-4-(trifluoromethyl)phenyl]propanoyl]piperidin-4-yl]ethylsulfinyl]-1,3-thiazole-5-sulfonamide Chemical compound Cc1nnn(Cc2cc(ccc2CCC(=O)N2CCC(CCS(=O)c3ncc(s3)S(N)(=O)=O)CC2)C(F)(F)F)n1 FMZIUIFYMJWAEE-UHFFFAOYSA-N 0.000 claims description 2
- YIKJMTFIKWVVDM-UHFFFAOYSA-N 2-[2-[1-[3-[2-[(5-methyltetrazol-2-yl)methyl]-4-(trifluoromethyl)phenyl]propanoyl]piperidin-4-yl]ethylsulfonyl]-1,3-thiazole-5-sulfonamide Chemical compound CC=1N=NN(N=1)CC1=C(C=CC(=C1)C(F)(F)F)CCC(=O)N1CCC(CC1)CCS(=O)(=O)C=1SC(=CN=1)S(=O)(=O)N YIKJMTFIKWVVDM-UHFFFAOYSA-N 0.000 claims description 2
- BMWATXAZEMMJEK-UHFFFAOYSA-N 2-[2-[1-[3-[4-(difluoromethoxy)-2-[(5-methyltetrazol-2-yl)methyl]phenyl]propanoyl]piperidin-4-yl]ethylsulfinyl]-1,3-thiazole-5-sulfonamide Chemical compound CC1=NN(CC2=C(CCC(=O)N3CCC(CCS(=O)C4=NC=C(S4)S(N)(=O)=O)CC3)C=CC(OC(F)F)=C2)N=N1 BMWATXAZEMMJEK-UHFFFAOYSA-N 0.000 claims description 2
- ZOMCHNZMVMLDPJ-UHFFFAOYSA-N 3-[[1-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]piperidin-4-yl]methyl]-4-fluorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC(CC2CCN(CC2)C(=O)C2=CC(=NC(OCC3CCOCC3)=C2)C2CC2)=C(F)C=C1 ZOMCHNZMVMLDPJ-UHFFFAOYSA-N 0.000 claims description 2
- ZRYCTQBOQQJWNH-UHFFFAOYSA-N 4-[2-[1-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]piperidin-4-yl]ethylsulfinyl]-3-fluorobenzenesulfonamide Chemical compound C1(CC1)C1=NC(=CC(=C1)C(=O)N1CCC(CC1)CCS(=O)C1=C(C=C(C=C1)S(=O)(=O)N)F)OCC1CCOCC1 ZRYCTQBOQQJWNH-UHFFFAOYSA-N 0.000 claims description 2
- GEOBGFDHUGCISJ-UHFFFAOYSA-N 4-[2-[1-[3-[4-(difluoromethoxy)-2-[(5-methyltetrazol-2-yl)methyl]phenyl]propanoyl]piperidin-4-yl]ethylsulfinyl]-2,3-difluorobenzenesulfonamide Chemical compound CC1=NN(CC2=C(CCC(=O)N3CCC(CCS(=O)C4=C(F)C(F)=C(C=C4)S(N)(=O)=O)CC3)C=CC(OC(F)F)=C2)N=N1 GEOBGFDHUGCISJ-UHFFFAOYSA-N 0.000 claims description 2
- XGHTXOLGJNRNKS-UHFFFAOYSA-N 4-[2-[1-[5-cyclopropyl-6-(cyclopropylmethoxy)pyridine-3-carbonyl]piperidin-4-yl]ethylsulfonyl]-3-fluorobenzenesulfonamide Chemical compound C1(=CC=C(C=C1F)S(=O)(=O)N)S(=O)(=O)CCC1CCN(CC1)C(=O)C1=CN=C(OCC2CC2)C(=C1)C1CC1 XGHTXOLGJNRNKS-UHFFFAOYSA-N 0.000 claims description 2
- KXVQTJOSXSHGSM-UHFFFAOYSA-N 4-[[1-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]piperidin-4-yl]methylsulfinyl]-3-fluorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC(F)=C(C=C1)S(=O)CC1CCN(CC1)C(=O)C1=CC(=NC(OCC2CCOCC2)=C1)C1CC1 KXVQTJOSXSHGSM-UHFFFAOYSA-N 0.000 claims description 2
- NCLCDYLVTWCGLV-UHFFFAOYSA-N 4-[[4-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]piperazin-1-yl]methyl]-3-fluorobenzenesulfonamide Chemical compound C1(CC1)C1=NC(=CC(=C1)C(=O)N1CCN(CC1)CC1=C(C=C(C=C1)S(=O)(=O)N)F)OCC1CCOCC1 NCLCDYLVTWCGLV-UHFFFAOYSA-N 0.000 claims description 2
- NSLABQLZHYCEND-UHFFFAOYSA-N N-sulfonyl-1,3-thiazole-5-sulfonamide Chemical compound S(=O)(=O)=NS(=O)(=O)C1=CN=CS1 NSLABQLZHYCEND-UHFFFAOYSA-N 0.000 claims description 2
- YBLMHUSIWXKLGD-UHFFFAOYSA-N S(=O)=NS(=O)(=O)C1=CC(=CC=C1)F Chemical compound S(=O)=NS(=O)(=O)C1=CC(=CC=C1)F YBLMHUSIWXKLGD-UHFFFAOYSA-N 0.000 claims description 2
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 2
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
- 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 2
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims 16
- AVGVXNKQACEGBG-UHFFFAOYSA-N 2-sulfanylbenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1S AVGVXNKQACEGBG-UHFFFAOYSA-N 0.000 claims 1
- OHJCFUHWDONOCM-UHFFFAOYSA-N 4-[1-(6-cyclobutyloxy-5-cyclopropylpyridine-3-carbonyl)piperidin-4-yl]sulfonyl-3-fluorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC(F)=C(C=C1)S(=O)(=O)C1CCN(CC1)C(=O)C1=CC(C2CC2)=C(OC2CCC2)N=C1 OHJCFUHWDONOCM-UHFFFAOYSA-N 0.000 claims 1
- UOACMELVYDGMSF-UHFFFAOYSA-N 4-[2-[1-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]piperidin-4-yl]ethylsulfanyl]-3-fluorobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC(F)=C(SCCC2CCN(CC2)C(=O)C2=CC(=NC(OCC3CCOCC3)=C2)C2CC2)C=C1 UOACMELVYDGMSF-UHFFFAOYSA-N 0.000 claims 1
- LZXUVWUXKWKZOC-UHFFFAOYSA-N 4-[2-[1-[2-cyclopropyl-6-(oxan-4-ylmethoxy)pyridine-4-carbonyl]piperidin-4-yl]ethylsulfonyl]-3-fluorobenzenesulfonamide Chemical compound C1(S(=O)(=O)CCC2CCN(CC2)C(=O)C2=CC(C3CC3)=NC(=C2)OCC2CCOCC2)=C(F)C=C(S(=O)(=O)N)C=C1 LZXUVWUXKWKZOC-UHFFFAOYSA-N 0.000 claims 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 33
- 229910052799 carbon Chemical group 0.000 abstract description 13
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 6
- 125000005647 linker group Chemical group 0.000 abstract 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 174
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- 239000000543 intermediate Substances 0.000 description 64
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- 239000000243 solution Substances 0.000 description 55
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 52
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
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- 150000001412 amines Chemical class 0.000 description 30
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- DJWUNCQRNNEAKC-UHFFFAOYSA-L zinc acetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O DJWUNCQRNNEAKC-UHFFFAOYSA-L 0.000 description 1
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Abstract
本发明提供具有通式(I)的新型化合物、包含所述化合物的组合物以及所述化合物在治疗或预防眼病症中的用途,其中R1选自取代的苯基、吡啶基或噻吩基,R2选自任选取代的氨基磺酰基苯基、氨基磺酰基吡啶基、氨基磺酰基噻吩基或氨基磺酰基噻唑基,X是氮或碳,Y是连接基团,Z是直接键或连接基团,m=0‑5,n=0‑5,条件是m+n为2‑5。
Description
本发明涉及可用于哺乳动物中的治疗或预防的有机化合物,并且特别涉及双重的自分泌运动因子(autotaxin)(ATX)/碳酸酐酶抑制剂,其是溶血磷脂酸(LPA)生产的抑制剂,并且因此是LPA水平和相关信号传导的调节剂,用于炎性病症、神经系统病症、血管和心血管病症、癌症和眼病症的治疗或预防。
本发明提供新型的式(I)的化合物
其中
R1选自
i)被R3、R4和R5取代的苯基,
ii)被R3、R4和R5取代的吡啶基,和
iii)被R3、R4和R5取代的噻吩基;
X选自
i)N,和
ii)CH;
Y选自
i)-CH2-OC(O)-,
ii)-(CH2)qC(O)-,
iii)-(CH=CH)r-C(O)-,和
iv)-(CH≡CH)r-C(O)-;
W选自
i)-(CR9R10)p-,
ii)-(CR9R10)p-C(O)-,
iii)-(CR9R10)p-O-,
iv)-(CR9R10)p-S-,
v)-(CR9R10)p-S(O)-,和
vi)-(CR9R10)p-S(O)2-;
R2选自
i)取代的苯基,其中所述苯基的环被R6、R7和R8取代,
ii)取代的吡啶基,其中所述吡啶基的环被R6、R7和R8取代,
iii)取代的噻吩基,其中所述噻吩基的环被R6、R7和R8取代,
和
iv)取代的噻唑基,其中所述噻唑基的环被R6、R7和R8取代;
R3选自
i)卤代-C1-6-烷氧基,
ii)C3-8-环烷基,
iii)C3-8-环烷基-C1-6-烷基,
iv)C3-8-环烷基-C1-6-烷氧基,
v)C3-8-环烷氧基,
vi)C3-8-环烷氧基-C1-6-烷基,
vii)四唑基甲基,
viii)三唑基甲基,
ix)吡唑基甲基,
x)C1-6-烷基四唑基甲基,
xi)C1-6-烷基三唑基甲基,
xii)C1-6-烷基吡唑基甲基,
xiii)杂环烷基-C1-6-烷氧基;
R4选自
i)卤素,
ii)羟基,
iii)氰基,
iv)C1-6-烷基,
v)C1-6-烷氧基,
vi)C1-6-烷氧基-C1-6-烷基,
vii)卤代-C1-6-烷氧基,
viii)卤代-C1-6-烷基,
ix)羟基-C1-6-烷基,
x)C3-8-环烷基,
xi)C3-8-环烷基-C1-6-烷基,
xii)C3-8-环烷基-C1-6-烷氧基,
xiii)C3-8-环烷氧基,
xiv)C3-8-环烷氧基-C1-6-烷基,
xv)C1-6-烷基羰基氨基,
xvi)C3-8-环烷基羰基氨基,
R5选自
i)H,
ii)卤素,
iii)羟基,
iv)氰基,
v)C1-6-烷基,
vi)C1-6-烷氧基,
vii)C1-6-烷氧基-C1-6-烷基,
viii)卤代-C1-6-烷氧基,
ix)卤代-C1-6-烷基,
x)羟基-C1-6-烷基,
xi)C3-8-环烷基,
xii)C3-8-环烷基-C1-6-烷基,
xiii)C3-8-环烷基-C1-6-烷氧基,
xiv)C3-8-环烷氧基,
xv)C3-8-环烷氧基-C1-6-烷基,
xvi)C1-6-烷基羰基氨基,
xvii)C3-8-环烷基羰基氨基,
R6是氨基磺酰基;
R7和R8独立地选自
i)H,
ii)卤素,
iii)羟基,
iv)氰基,
v)C1-6-烷基,
vi)C1-6-烷氧基,
vii)C1-6-烷氧基-C1-6-烷基,
viii)卤代-C1-6-烷氧基,
ix)卤代-C1-6-烷基,
x)羟基-C1-6-烷基,
xi)C3-8-环烷基,
xii)C3-8-环烷基-C1-6-烷基,
xiii)C3-8-环烷基-C1-6-烷氧基,
xiv)C3-8-环烷氧基,和
xv)C3-8-环烷氧基-C1-6-烷基;
R9和R10独立地选自
i)H,
ii)C1-6-烷基,和
iii)C3-8-环烷基;
m和n独立地选自0、1、2、3、4或5,条件是m和n的和是2、3、4或5;
p选自0、1或2;
q选自0或2;
r选自0和1;
或药用盐。
自分泌运动因子(ATX)是一种也称作外核苷酸焦磷酸酶/磷酸二酯酶2或溶血磷脂酶D的分泌型酶,其对于将溶血磷脂酰胆碱(LPC)转化为生物活性的信号传导分子溶血磷脂酸(LPA)而言是重要的。已经表明,血浆LPA水平与ATX活性良好地相关,并且因此相信ATX是胞外LPA的重要来源。早期用原型ATX抑制剂的实验已经证实了,这样的化合物能够抑制在小鼠血浆中的LPA合成活性。在1970年代和1980年代早期进行的工作证明了,LPA可以引起各种各样的细胞响应;包括平滑肌细胞收缩、血小板活化、细胞增殖、趋化性等等。LPA经由向若干G蛋白偶联受体(GPCR)发出信号来介导它的效果;第一批成员最初被表示为Edg(内皮细胞分化基因)受体或心室区基因-1(vzg-1),但现在称为LPA受体。现在,原型群由LPA1/Edg-2/VZG-1、LPA2/Edg-4和LPA3/Edg-7组成。最近,已有人描述了三种另外的LPA受体LPA4/p2y9/GPR23、LPA5/GPR92和LPA6/p2Y5,它们与原型LPA1-3受体相比,更加紧密地与核苷酸选择性嘌呤能受体相关。ATX-LPA信号传导轴涉及多种多样的生理和病理生理功能,包括例如,神经系统功能、血管发育、心血管生理学、繁殖、免疫系统功能、慢性炎症、肿瘤转移和进展、器官纤维变性及肥胖症(obesity)和/或其他代谢疾病如糖尿病(diabetesmellitus)。因此,提高的ATX活性和/或提高的LPA水平、改变的LPA受体表达和改变的对LPA的响应可以有助于与ATX/LPA轴相关的大量不同的病理生理病症的引发、进展和/或结果。
碳酸酐酶(CA)是锌依赖性酶的家族,其催化二氧化碳和水以及碳酸氢盐和质子之间的平衡。CA反应涉及许多生理和病理过程。碳酸酐酶抑制可用于治疗眼病症、血流量减少的病症、癌症、水肿和炎性病症(包括细菌感染)。
预期双重作用ATX/CA抑制剂通过促进两个独立的途径,诸如通过在睫状体处的CA抑制来抑制房水(AH)产生并且通过AH排水系统内的ATX抑制来促进AH流出,来降低眼内压。在诸如糖尿病性视网膜病、年龄相关性黄斑病或视网膜静脉阻塞的眼内血管渗漏的情况下,已显示出或可预期CA水平在眼中增加并且促进pH增加。预期其活化许多可以促进疾病进展的水解酶,包括通过改变pH最佳值而展现额外ATX抑制的ATX。
按照本发明,可以将式(I)的化合物或它们的药用盐和酯用于治疗或预防与自分泌运动因子的活性和/或溶血磷脂酸(LPA)的生物活性相关的疾病、障碍或病症。
本文的式(I)的化合物或它们的药用盐和酯抑制自分泌运动因子和碳酸酐酶活性,并且因此抑制LPA生产和调节LPA水平及相关的信号传导。本文所述的双重ATX/CA-II抑制剂可用作用于治疗或预防疾病或病症的药剂:在所述疾病或病症中,ATX活性和/或LPA信号传导参与、涉及所述疾病的病原学或病理学,或者以其他方式与所述疾病的至少一种症状相关。ATX-LPA轴已经牵连于例如血管发生、慢性炎症、自体免疫疾病、纤维变性疾病、癌症和肿瘤转移和进展、眼病症、代谢病症如肥胖症和/或糖尿病、病症如胆汁淤积性或其他形式的慢性瘙痒症以及急性和慢性器官移植排斥反应中。
本发明的目的是式(I)的化合物和它们的上述的盐和酯,以及它们作为治疗活性物质的用途,用于制备所述化合物的方法,中间体,药物组合物,含有所述化合物的药物,它们的药用盐或酯,所述化合物、盐或酯用于治疗或预防与ATX活性和/或溶血磷脂酸(LPA)的生物活性相关的障碍或病症的用途,特别是治疗或预防炎性病症、神经系统病症、呼吸系统病症、血管和心血管病症、纤维变性疾病、癌症、眼病症、代谢病症、胆汁淤积性及其他形式的慢性瘙痒症以及急性和慢性器官移植排斥反应,以及所述化合物、盐或酯用于制备药物的用途,所述药物用于治疗或预防炎性病症、神经系统病症、呼吸系统病症、血管和心血管病症、纤维变性疾病、癌症、眼病症、代谢病症、胆汁淤积性及其他形式的慢性瘙痒症以及急性和慢性器官移植排斥反应。更特别地,本发明的目的是式(I)的化合物和它们的上述的盐和酯,以及它们作为治疗活性物质的用途,制备所述化合物的方法,中间体,药物组合物,含有所述化合物的药物,它们的药用盐或酯,所述化合物、盐或酯用于治疗或预防眼病症(另外特别是青光眼)的用途。
术语“C1-C6-烷氧基”表示式-O-R’的基团,其中R’是C1-C6-烷基。C1-C6-烷氧基的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基和叔丁氧基。
术语“C1-C6-烷氧基-C1-6-烷基”表示这样的C1-C6-烷基,其中该C1-C6-烷基的氢原子中的至少一个被C1-C6-烷氧基代替。特别的实例是甲氧基甲基、甲氧基乙基、乙氧基甲基、乙氧基乙基、异丙氧基甲基和异丙氧基乙基。
术语“C1-C6-烷基”表示1至6个碳原子的一价直链或支链饱和烃基。C1-C6-烷基的实例包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基和戊基。特别的烷基包括甲基、异丙基和叔丁基。
术语“C1-C6-烷基羰基”表示式-C(O)-R’的基团,其中R’是C1-C6-烷基。C1-C6-烷基羰基的实例包括这样的基团,其中R’是甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基和叔丁氧基。
术语“C1-C6-烷基羰基氨基”表示这样的氨基,其中氮原子被一个H原子并且被C1-C6-烷基羰基取代。特别的实例这样的氨基,其中氮原子被H和叔丁基羰基取代。
术语“C1-C6-烷基吡唑基”表示这样的吡唑基,其中氮原子之一被C1-C6-烷基取代。特别的实例是这样的吡唑基,其中氮原子之一被甲基取代。
术语“C1-C6-烷基吡唑基-C1-C6-烷基”表示这样的C1-C6-烷基,其中H原子之一被C1-C6-烷基吡唑基替代。特别的实例是这样的甲基或乙基,其中氢原子之一被甲基吡唑基取代。
术语“C1-C6-烷基四唑基”表示这样的四唑基,其中氮原子之一被C1-C6-烷基取代。特别的实例是这样的四唑基,其中氮原子之一被甲基取代。
术语“C1-C6-烷基四唑基-C1-C6-烷基”表示这样的C1-C6-烷基,其中H原子之一被C1-C6-烷基四唑基替代。特别的实例是这样的甲基或乙基,其中氢原子之一被甲基四唑基取代。
术语“C1-C6-烷基三唑基”表示这样的三唑基,其中氮原子之一被C1-C6-烷基取代。特别的实例是这样的三唑基,其中氮原子之一被甲基取代。
术语“C1-C6-烷基三唑基-C1-C6-烷基”表示这样的C1-C6-烷基,其中H原子之一被C1-C6-烷基三唑基替代。特别的实例是这样的甲基或乙基,其中氢原子之一被甲基三唑基取代。
术语“氨基”表示-NH2基团。
术语“氰基”表示-C≡N基团。
术语“C3-C8-环烷氧基”表示式-O-R’的基团,其中R’是C3-C8-环烷基。特别的实例是其中R’是环丙基的基团。
术语“C3-C8-环烷氧基-C1-C6-烷基”表示这样的C1-C6-烷基,其中该C1-C6-烷基的氢原子中的至少一个被C3-C8-环烷氧基取代。特别是实例是这样的甲基或乙基,其中该C3-C8-环烷氧基是环丙氧基。
术语“C3-C8-环烷基”表示3至8个环碳原子的一价饱和单环或二环烃基。二环表示由具有两个共同碳原子的两个饱和碳环组成的环系统。单环环烷基的实例是环丙基、环丁基、环戊基、环己基或环庚基。二环C3-C8-环烷基的实例是二环[2.2.1]庚基或二环[2.2.2]辛基。特别的C3-8-环烷基是环丙基。
术语“C3-C8-环烷基-C1-C6-烷氧基”表示这样的C1-C6-烷氧基,其中该C1-C6-烷氧基的氢原子中的至少一个被C3-C8-环烷基取代。特别的实例是这样的甲氧基或乙氧基,其中其氢原子中的至少一个被环丙基替代。
术语“C3-C8-环烷基-C1-C6-烷基”表示这样的C1-C6-烷基,其中该C1-C6-烷基的氢原子中的至少一个被C3-C8-环烷基取代。特别的实例是这样的甲基或乙基,其中其氢原子中的至少一个被环丙基替代。
术语“C3-C8-环烷基羰基”表示式-C(O)-R’的基团,其中R’是C3-C8-环烷基。C3-C8-环烷基羰基的实例是这样的基团,其中R’是环丙基。
术语“C3-C8-环烷基羰基氨基”表示这样的氨基,其中氮原子被一个H原子并且被C3-C8-环烷基羰基取代。特别的实例是这样的氨基,其中氮原子被H和环丙基取代。
术语“卤代-C1-C6-烷氧基”表示这样的C1-C6-烷氧基,其中该C1-C6-烷氧基的氢原子中的至少一个已被相同或不同的卤素原子替代。特别的实例是二氟甲氧基、三氟甲氧基、二氟乙氧基和三氟乙氧基。更特别的实例是三氟甲氧基。
术语“卤素”和“卤代”在本文中可互换使用,并且表示氟、氯、溴或碘。特别的卤素是氯。
术语“卤代-C1-C6-烷基”表示这样的C1-C6-烷基,其中该C1-C6-烷基的氢原子中的至少一个已被相同或不同卤素原子替代。特别的实例是二氟甲基、三氟甲基、二氟乙基和三氟乙基。更特别的实例三氟甲基。
术语“杂环烷基”,单独或组合地,表示4至9个环原子的一价饱和或部分不饱和的单环或二环环系统,其包含1、2或3个选自N、O和S的环杂原子,其余的环原子是碳。二环表示由具有两个共同环原子的两个环组成的,即,将两个环分开的桥是单键或者是一个或两个环原子的链。单环饱和杂环烷基的实例是4,5-二氢-唑基、氧杂环丁基、氮杂环丁基、吡咯烷基、2-氧代-吡咯烷-3-基、四氢呋喃基、四氢-噻吩基、吡唑烷基、咪唑烷基、唑烷基、异唑烷基、噻唑烷基、哌啶基、四氢吡喃基、四氢噻喃基、哌嗪基、吗啉基、硫代吗啉基、1,1-二氧代-硫代吗啉-4-基、氮杂环庚基、二氮杂环庚基、高哌嗪基或氧杂氮杂环庚基。二环饱和杂环烷基的实例是8-氮杂-二环[3.2.1]辛基、奎宁环基、8-氧杂-3-氮杂-二环[3.2.1]辛基、9-氮杂-二环[3.3.1]壬基、3-氧杂-9-氮杂-二环[3.3.1]壬基或3-硫杂-9-氮杂-二环[3.3.1]壬基。部分不饱和杂环烷基的实例是二氢呋喃基、咪唑啉基、二氢-唑基、四氢-吡啶基或二氢吡喃基。特别的实例是四氢吡喃基。
术语“杂环烷基-C1-C6-烷氧基”表示这样的C1-C6-烷氧基,其中该烷氧基的氢原子中的至少一个被杂环烷基替代。特别的实例是四氢吡喃基甲氧基。
术语“羟基”表示-OH基团。
术语“羟基-C1-C6-烷氧基”表示这样的C1-C6-烷氧基,其中该C1-C6-烷氧基的氢原子之一被羟基替代。特别的实例是羟基乙氧基和羟基丙氧基。
术语“羟基-C1-C6-烷基”表示这样的C1-C6-烷基,其中该C1-C6-烷基的氢原子之一被羟基取代。特别的实例是羟基甲基和羟基乙基。
术语“苯基-C1-C6-烷基”表示这样的C1-C6-烷基,其中该C1-C6-烷基的氢原子之一被苯基取代。特别的实例苯基甲基。
术语“吡唑基-C1-C6-烷基”表示这样的C1-C6-烷基,其中H原子之一被吡唑基替代。特别的实例是这样的甲基或乙基,其中氢原子之一被吡唑基取代。
术语“四唑基-C1-C6-烷基”表示这样的C1-C6-烷基,其中H原子之一被四唑基替代。特别的实例是这样的甲基或乙基,其中氢原子之一被四唑基取代。
术语“三唑基-C1-C6-烷基”表示这样的C1-C6-烷基,其中H原子之一被三唑基替代。特别的实例是这样的甲基或乙基,其中氢原子之一被三唑基取代。
术语“药用盐”是指保持游离碱或游离酸的生物学效用和性质的那些盐,它们不是在生物学或其他方面不适宜的。所述盐与采用以下的酸形成:无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等,特别是盐酸,以及有机酸如乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸、N-乙酰半胱氨酸等。此外,可以通过向游离酸中加入无机碱或有机碱来制备这些盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐等。衍生自有机碱的盐包括但不限于以下各项的盐:伯、仲和叔胺,取代的胺,包括天然存在的取代的胺、环胺和碱性离子交换树脂,如异丙胺,三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、赖氨酸、精氨酸、N-乙基哌啶、哌啶、聚亚胺树脂等。特别的式(I)的化合物的药用盐是盐酸盐、甲磺酸盐和柠檬酸盐。
“药用酯”是指通式(I)的化合物可以在官能团处衍生以提供能够在体内转化回母体化合物的衍生物。这样的化合物的实例包括生理学上可接受的且在代谢上不稳定的酯衍生物,如甲氧基甲酯,甲硫基甲酯和新戊酰氧基甲酯。另外,类似于在代谢上不稳定的酯,能够在体内生成通式(I)的母体化合物的通式(I)的化合物的任何生理上可接受的等效物都在本发明的范围内。
术语“保护基团”(PG)表示这样的基团:在与其在合成化学中相关的传统含义中选择性地阻挡多官能化合物中的反应性位点以使得化学反应可以在另一个未保护的反应性位点选择性地进行的基团。可以将保护基团在合适的点移除。示例性保护基团是氨基-保护基团、羧基-保护基团或羟基-保护基团。特别的保护基团是叔丁氧基羰基(Boc)、苄氧基羰基(Cbz)、芴基甲氧基羰基(Fmoc)和苄基(Bn)基团。进一步特别的保护基团是叔丁氧基羰基(Boc)和芴基甲氧基羰基(Fmoc)基团。更特别的保护基团是叔丁氧基羰基(Boc)基团。
缩写uM表示微摩尔浓度且等价于符号μM。
缩写uL表示微升且等价于符号μL。
缩写ug表示微克且等价于符号μg。
式(I)的化合物可以含有数个不对称中心,并且能够以以下形式存在:光学纯的对映异构体,对映异构体的混合物(诸如例如外消旋体),光学纯的非对映异构体,非对映异构体的混合物,非对映异构体的外消旋体或非对映异构体的外消旋体的混合物。
根据Cahn-Ingold-Prelog Convention,不对称碳原子可以为“R”或“S”构型。
本发明的另一个实施方案是根据本文所述的式(I)化合物及其药用盐或酯,特别是根据本文所述的式(I)化合物及其药用盐,更特别是根据本文所述的式(I)化合物。
本发明的另一个实施方案是根据如本文所述的式(I)的化合物,其中
R1选自
i)被R3、R4和R5取代的苯基,和
ii)被R3、R4和R5取代的吡啶基;
X选自
iii)N,和
iv)CH;
Y选自
v)-CH2-OC(O)-,和
vi)-(CH2)qC(O)-;
W选自
vii)-(CR9R10)p-,
viii)-(CR9R10)p-C(O)-,
ix)-(CR9R10)p-O-,
x)-(CR9R10)p-S-,
xi)-(CR9R10)p-S(O)-,和
xii)-(CR9R10)p-S(O)2-;
R2选自
xiii)取代的苯基,其中所述苯基的环被R6、R7和R8取代,
xiv)取代的吡啶基,其中所述吡啶基的环被R6、R7和R8取代,
xv)取代的噻吩基,其中所述噻吩基的环被R6、R7和R8取代,
和
xvi)取代的噻唑基,其中所述噻唑基的环被R6、R7和R8取代;
R3选自
xvii)卤代-C1-6-烷氧基,
xviii)氰基,
xix)C3-8-环烷基-C1-6-烷氧基,
xx)C3-8-环烷氧基,
xxi)C1-6烷基四唑基甲基,和
xxii)四氢吡喃基-C1-6-烷氧基;
R4选自
xxiii)卤素,
xxiv)氰基,
xxv)卤代-C1-6-烷氧基,
xxvi)卤代-C1-6-烷基,
xxvii)C3-8-环烷基,和
xxviii)C1-6-烷基羰基氨基;
R5是H;
R6是氨基磺酰基;
R7和R8独立地选自
xxix)H,和
xxx)卤素;
R9和R10都是H;
m选自0、1和2并且n选自1、2和3,条件是m和n的和是2、3、4或5;
p选自0、1和2;
q选自0和2;
或药用盐。
本发明的一个特别的实施方案是根据如本文所述的式(I)的化合物,其中R1选自
xxxi)被R3、R4和R5取代的苯基,和
xxxii)被R3、R4和R5取代的吡啶基。
本发明的一个进一步特别的实施方案是根据如本文所述的式(I)的化合物,其中R1是被R3、R4和R5取代的苯基。
本发明的一个特别的实施方案是根据如本文所述的式(I)的化合物,其中Y选自
xxxiii)-CH2-OC(O)-,和
xxxiv)-(CH2)qC(O)-。
本发明的一个特别的实施方案是根据如本文所述的式(I)的化合物,其中Y是-(CH2)qC(O)-。
本发明的一个特别的实施方案是根据如本文所述的式(I)的化合物,其中W选自
xxxv)-(CR9R10)p-,
xxxvi)-(CR9R10)p-S-,和
xxxvii)-(CR9R10)p-S(O)2-。
本发明的一个进一步特别的实施方案是根据如本文所述的式(I)的化合物,其中R2选自
xxxviii)取代的苯基,其中所述苯基的环被R6、R7和R8取代,
和
xxxix)取代的吡啶基,其中所述吡啶基的环被R6、R7和R8取代。
本发明的一个特别的实施方案是根据如本文所述的式(I)的化合物,其中R3选自
xl)卤代-C1-6-烷氧基,
xli)氰基,
xlii)C3-8-环烷基-C1-6-烷氧基,
xliii)C3-8-环烷氧基,
xliv)C1-6-烷基四唑基甲基,和
xlv)四氢吡喃基-C1-6-烷氧基。
本发明的一个进一步特别的实施方案是根据如本文所述的式(I)的化合物,其中R3选自
xlvi)C1-6-烷基四唑基甲基,和
xlvii)四氢吡喃基-C1-6-烷氧基。
本发明的一个特别的实施方案是根据如本文所述的式(I)的化合物,其中R4选自
xlviii)卤素,
xlix)氰基,
1)卤代-C1-6-烷氧基,
li)卤代-C1-6-烷基,
lii)C3-8-环烷基,和
liii)C1-6-烷基羰基氨基。
本发明的一个特别的实施方案是根据如本文所述的式(I)的化合物,其中R4选自
liv)卤代-C1-6-烷基,和
lv)C3-8-环烷基。
本发明的一个进一步特别的实施方案是根据如本文所述的式(I)的化合物,其中R5是H。
本发明的一个进一步特别的实施方案是根据如本文所述的式(I)的化合物,其中R7和R8独立地选自
lvi)H,和
lvii)卤素。
本发明的一个特别的实施方案是根据如本文所述的式(I)的化合物,其中R7是卤素。
本发明的一个特别的实施方案是根据如本文所述的式(I)的化合物,其中R8选自
lviii)H,和
lix)卤素。
本发明的一个更特别的实施方案是根据如本文所述的式(I)的化合物,其中R9和R10都是H。
本发明的一个特别的实施方案是根据如本文所述的式(Ia)的化合物,其中m选自0、1和2并且n选自1、2和3,条件是m和n的和是2、3、4或5。
本发明的一个特别的实施方案是根据如本文所述的式(Ia)的化合物,其中p选自0和1。
本发明的一个特别的实施方案是根据如本文所述的式(Ia)的化合物,其中p是0。
本发明的一个特别的实施方案是根据如本文所述的式(Ia)的化合物,其中q是2。
本发明的一个特别的实施方案是根据如本文所述的式(Ia)的化合物,其中
R1选自
i)被R3、R4和R5取代的苯基,和
ii)被R3、R4和R5取代的吡啶基;
X选自
iii)N,和
iv)CH;
Y选自
v)-CH2-OC(O)-,和
vi)-(CH2)qC(O)-;
W选自
vii)-(CR9R10)p-,
viii)-(CR9R10)p-C(O)-,
ix)-(CR9R10)p-O-,
x)-(CR9R10)p-S-,
xi)-(CR9R10)p-S(O)-,和
xii)-(CR9R10)p-S(O)2-;
R2选自
xiii)取代的苯基,其中所述苯基的环被R6、R7和R8取代,
xiv)取代的吡啶基,其中所述吡啶基的环被R6、R7和R8取代,
xv)取代的噻吩基,其中所述噻吩基的环被R6、R7和R8取代,
和
xvi)取代的噻唑基,其中所述噻唑基的环被R6、R7和R8取代;
R3选自
xvii)卤代-C1-6-烷氧基,
xviii)氰基,
xix)C3-8-环烷基-C1-6-烷氧基,
xx)C3-8-环烷氧基,
xxi)C1-6-烷基四唑基甲基,和
xxii)四氢吡喃基-C1-6-烷氧基;
R4选自
xxiii)卤素,
xxiv)氰基,
xxv)卤代-C1-6-烷氧基,
xxvi)卤代-C1-6-烷基,
xxvii)C3-8-环烷基,和
xxviii)C1-6-烷基羰基氨基;
R5是H;
R6是氨基磺酰基;
R7和R8独立地选自
xxix)H,和
xxx)卤素;
R9和R10都是H;
m选自0、1和2并且n选自1、2和3,条件是m和n的和是2、3、4或5;
p选自0、1和2;
q选自0和2;
或药用盐。
如本文所述的式(I)的化合物的特别实例选自
4-(2-氟-4-氨磺酰基苯基)哌嗪-1-甲酸2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苄酯
4-[(4-氨磺酰基苯基)甲基]哌啶-1-甲酸[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-基]甲酯
4-[(4-氨磺酰基苯基)甲基]哌啶-1-甲酸[5-氰基-3-(2,2-二甲基丙酰基氨基)吡啶-2-基]甲酯
4-(2-氟-4-氨磺酰基苯基)磺酰基哌啶-1-甲酸[5-氯-3-[(5-甲基四唑-2-基)甲基]吡啶-2-基]甲酯
4-(2-氟-4-氨磺酰基苯基)磺酰基哌啶-1-甲酸[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]甲酯;
2-氟-4-[[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]甲基]苯磺酰胺;
3-氟-4-[[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]甲基]苯磺酰胺;
4-[[4-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌嗪-1-基]甲基]-3-氟苯磺酰胺;
3-氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-羰基]苯磺酰胺;
2-氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-羰基]苯磺酰胺;
3,5-二氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-羰基]苯磺酰胺;
3-氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-羰基]苯磺酰胺;
4-(4-(3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙酰基)哌嗪-1-羰基)苯磺酰胺;
3-[[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]甲基]-4-氟苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]硫基苯磺酰胺;
3-氟-4-(4-(3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙酰基)哌嗪-1-基)苯磺酰胺;
4-[[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]甲基]苯磺酰胺;
4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]甲基]苯磺酰胺;
4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]吡咯烷-2-基]甲氧基]苯磺酰胺;
4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]吡咯烷-3-基]甲氧基]苯磺酰胺;
4-(1-(3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙酰基)哌啶-4-基)苯磺酰胺;
4-(4-(3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙酰基)哌嗪-1-基)苯磺酰胺;
4-氟-3-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]甲基]苯磺酰胺;
2,3-二氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]硫基苯磺酰胺;
2,3-二氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]亚磺酰基苯磺酰胺;
2,3-二氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]磺酰基苯磺酰胺;
2,3-二氟-4-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基磺酰基]苯磺酰胺;
2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]硫基-1,3-噻唑-5-磺酰胺;
2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]磺酰基-1,3-噻唑-5-磺酰胺;
2-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基亚磺酰基]-1,3-噻唑-5-磺酰胺;
3-氟-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]甲基硫基]苯磺酰胺;
3-氟-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]甲基亚磺酰基]苯磺酰胺;
3-氟-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]甲基磺酰基]苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]氮杂环丁-3-基]硫基苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]氮杂环丁-3-基]亚磺酰基苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]氮杂环丁-3-基]磺酰基苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]亚磺酰基苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]磺酰基苯磺酰胺;
3-氟-4-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基硫基]苯磺酰胺;
3-氟-4-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基亚磺酰基]苯磺酰胺;
3-氟-4-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基磺酰基]苯磺酰胺;
3-氟-4-[2-[1-[6-(2,2,2-三氟乙氧基)-5-(三氟甲基)吡啶-3-羰基]哌啶-4-基]乙基磺酰基]苯磺酰胺;
3-氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]磺酰基苯磺酰胺;
4-[[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]甲基硫基]-3-氟苯磺酰胺;
4-[[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]甲基亚磺酰基]-3-氟苯磺酰胺;
4-[[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]甲基磺酰基]-3-氟苯磺酰胺;
4-[1-(6-环丁氧基-5-环丙基吡啶-3-羰基)哌啶-4-基]磺酰基-3-氟苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]氮杂环丁-3-基]硫基-3-氟苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]氮杂环丁-3-基]亚磺酰基-3-氟苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]氮杂环丁-3-基]磺酰基-3-氟苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]磺酰基-2,3-二氟苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]磺酰基-3-氟苯磺酰胺;
4-[1-[3-[4-氯-2-[(5-甲基四唑-2-基)甲基]苯基]丙酰基]哌啶-4-基]磺酰基-3-氟苯磺酰胺;
4-[1-[3-[4-氰基-2-[(5-甲基四唑-2-基)甲基]苯基]丙酰基]哌啶-4-基]磺酰基-3-氟苯磺酰胺;
4-[2-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]乙基硫基]-3-氟苯磺酰胺;
4-[2-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]乙基亚磺酰基]-3-氟苯磺酰胺;
4-[2-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]乙基磺酰基]-3-氟苯磺酰胺;
4-[2-[1-[5-环丙基-6-(环丙基甲氧基)吡啶-3-羰基]哌啶-4-基]乙基磺酰基]-3-氟苯磺酰胺;
4-[4-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌嗪-1-基]磺酰基-3-氟苯磺酰胺;
4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]磺酰基苯磺酰胺;
5-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]硫基噻吩-2-磺酰胺;
5-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基磺酰基]噻吩-2-磺酰胺;
5-氟-6-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]硫基吡啶-3-磺酰胺;
6-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]硫基-5-氟吡啶-3-磺酰胺;
4-[1-[3-[4-(二氟甲氧基)-2-[(5-甲基四唑-2-基)甲基]苯基]丙酰基]哌啶-4-基]磺酰基-3-氟苯磺酰胺;
4-[2-[1-[3-[4-(二氟甲氧基)-2-[(5-甲基四唑-2-基)甲基]苯基]丙酰基]哌啶-4-基]乙基亚磺酰基]-2,3-二氟苯磺酰胺;
2,3-二氟-4-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基亚磺酰基]苯磺酰胺;
2-[2-[1-[3-[4-(二氟甲氧基)-2-[(5-甲基四唑-2-基)甲基]苯基]丙酰基]哌啶-4-基]乙基亚磺酰基]-1,3-噻唑-5-磺酰胺;
2-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基磺酰基]-1,3-噻唑-5-磺酰胺;
(+)-3-氟-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]亚磺酰基]苯磺酰胺;
(+)-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]吡咯烷-2-基]甲氧基]苯磺酰胺;
(+)-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]吡咯烷-3-基]甲氧基]苯磺酰胺;
(-)-3-氟-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]亚磺酰基]苯磺酰胺;
(-)-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]吡咯烷-2-基]甲氧基]苯磺酰胺;
(-)-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]吡咯烷-3-基]甲氧基]苯磺酰胺;
4-((4-(3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙酰基)哌嗪-1-基)甲基)苯磺酰胺;
及其药用盐。
如本文所述的式(I)的化合物的进一步特别的实例选自
3-氟-4-[[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]甲基]苯磺酰胺;
2,3-二氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]磺酰基苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]磺酰基苯磺酰胺;
3-氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]磺酰基苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]磺酰基-2,3-二氟苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]磺酰基-3-氟苯磺酰胺;
5-氟-6-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]硫基吡啶-3-磺酰胺;
及其药用盐。
用于制备如本文所述的式(I)的化合物的方法是本发明的一个目的。
本发明的式(I)的化合物的制备可以以顺序的或汇集的合成路线进行。本发明的合成显示在以下通用方案中。进行反应和所得产物的纯化所需的技能是本领域技术人员已知的。在反应过程中产生对映异构体或非对映异构体的混合物的情况下,可以通过本文描述的方法或者本领域技术人员已知的方法例如(手性)层析法或结晶法分离这些对映异构体或非对映异构体。以下方法的描述中使用的取代基和标志具有本文给出的含义。
通式(I)的化合物可以使用本领域中熟知的方法合成自胺前体1和合适的试剂。
例如,使胺1与合适的式R1-Y-OH(2)的羧酸反应,得到式(I)化合物,其中Y是-(CH2)qC(O)-、-(CH=CH)r-C(O)-或-(CH≡CH)r-C(O)-。该反应在偶联剂如1,1′-羰基二咪唑、N,N’-二环己基碳二亚胺、1-(3-二甲基氨基丙基)-3-乙基-碳二亚胺盐酸盐、O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲(uronium)六氟-磷酸盐、O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐或溴-三-吡咯烷基-鏻六氟磷酸盐的存在下,在非质子溶剂如二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、N-甲基吡咯烷酮和它们的混合物中,在-40℃至80℃的温度,在存在或不存在碱如三乙胺、二异丙基乙胺、4-甲基吗啉和/或4-(二甲基氨基)吡啶的情况下进行。
也可以使胺1与合适的酰化试剂如式R1-Y-Cl(3)的酰氯反应,以得到式(I)化合物,其中Y是-(CH2)qC(O)-、-(CH=CH)r-C(O)-或-(CH≡CH)r-C(O)-。该反应在溶剂如二氯甲烷、四氢呋喃或N,N-二甲基甲酰胺中,在碱如三乙胺或4-甲基吗啉存在下,在0℃至80℃的温度进行。
备选地,使胺1与合适的式R1-CH2-O-C(O)-Cl(4)的氯甲酸酯或式(5)的咪唑-1-甲酸酯反应,得到式(I)的化合物,其中Y是-CH2-OC(O)-。
该反应在合适的溶剂如二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、乙腈、丙酮、水或其混合物中,在碱例如三乙胺、二异丙基乙胺、吡啶、碳酸氢钾、碳酸钾的存在下,在0℃至溶剂或溶剂混合物的沸点的温度进行。
氯甲酸酯4是商购可得的,或可以通过与光气或光气等效物(例如二光气、三光气)反应由相应的式R1-CH2-OH(6)的醇合成,这如文献中所述。
由相应的式R1-CH2-OH(6)的醇通过与1,1′-羰基二咪唑反应来合成咪唑-1-甲酸酯5。该反应在溶剂如二氯甲烷、四氢呋喃或乙腈中在室温进行。典型地,咪唑-1-甲酸酯5不分离而是直接与胺1如上所述反应。
式R1-CH2-OH(6)的醇是商购可得的,或可以通过本文所述或本领域已知的方法制备。
羧酸(2)和酰卤(3)是商购可得的,或可以如本文中或文献中所述制备。
通式1的胺合成自适当保护的前体7。
合适的保护基(PG)是叔丁氧基羰基、苄氧基羰基或乙酰基。中间体7的去保护可以使用本领域中已知的方法和试剂进行。
例如,在PG是苄氧基羰基的情况中,去保护可以通过在1巴至100巴的压力下,在合适的催化剂如活性炭载钯的存在下,在20℃至150℃的温度,在溶剂如甲醇或乙醇中的氢化进行。
备选地,在其中PG是乙酰基的情况下,去保护可以在合适酸例如盐酸水溶液存在下在0℃至100℃的温度进行。
其中X是N,W是-(CR9R10)p-C(O)-并且p是0的中间体7可以由通式结构7A表示。PG是合适的保护基,例如,叔丁氧基羰基、苄氧基羰基或乙酰基,R2、m和n如上所定义。
使用本领域中已知的方法,酰胺7A可以由通式8的胺前体通过与合适的试剂反应而制备。
例如,使胺8与合适的式R2-COOH(9)的羧酸反应,得到式8A的化合物。该反应在偶联剂如1,1′-羰基二咪唑、N,N’-二环己基碳二亚胺、1-(3-二甲基氨基丙基)-3-乙基-碳二亚胺盐酸盐、O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐、O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐或溴-三-吡咯烷基-鏻六氟磷酸盐的存在下,在非质子溶剂如二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、N-甲基吡咯烷酮和它们的混合物中,在-40℃至80℃的温度,在存在或不存在碱如三乙胺、二异丙基乙胺、4-甲基吗啉和/或4-(二甲基氨基)吡啶的情况下进行。
其中X是N,W是-(CR9R10)p-S(O)2-并且p是0的中间体7可以由通式结构7B表示。PG是合适的保护基,例如,叔丁氧基羰基、苄氧基羰基或乙酰基,R2、m和n如上所定义。
利用本领域已知的方法,磺酰胺7B可以由通式8的胺前体通过与适当试剂的反应制备。例如,使胺8与合适的式R2-SO2Cl(10)的磺酰氯反应,得到式7B的化合物。该反应在合适溶剂如二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、乙腈、丙酮、水或其混合物中,在碱,例如三乙胺、二异丙基乙胺、吡啶、碳酸氢钾、碳酸钾的存在下,在0℃至溶剂或溶剂混合物的沸点的温度下进行。
胺8、羧酸9和磺酰氯10可商购获得或者可以如本文或文献中所述合成。
其中W是-(CR9R10)p-的中间体7可以由通式结构7C表示。中间体7C可商购获得或者可以如本文所述或利用本领域已知的方法制备。PG是合适的保护基,例如,叔丁氧基羰基、苄氧基羰基或乙酰基,R2、R9、R10、m、n和p如上所定义。
其中R2是取代的苯基的中间体7C可以由通式结构7CA表示,并且可以由通式结构7CA表示。PG是合适的保护基,例如,叔丁氧基羰基、苄氧基羰基或乙酰基,R2、R7、R8、R9、R10、m、n和p如上所定义。
利用本领域已知的方法,中间体7CA可以由化合物11制备。
例如,化合物11的氯磺化得到磺酰氯12。该反应可以利用适当的试剂例如氯磺酸,在没有溶剂或者在合适的溶剂例如二氯甲烷中,在0℃至100℃的温度下进行。
在第二步骤中,磺酰氯12与氨的反应得到7CA。此反应可以在合适的溶剂例如水、乙醇、四氢呋喃或其混合物中,在0℃至50℃的温度下进行。
化合物11可商购获得或者可以如本文或文献中所述合成。
其中X是CH并且W是-(CR9R10)p-S-或-(CR9R10)p-O--的中间体7可以由通式结构7D表示。V是氧或硫,R2、R9、R10、m、n和p如上所述,PG是保护基,例如,苄氧基羰基、叔丁氧基羰基或乙酰基。
利用本领域已知的方法和试剂,式7D的化合物可以由醇或硫醇合成。
例如,使醇或硫醇13与合适的卤化物R2-Hal(14)反应。Hal是F(优选的)、Cl、Br或I。该反应在碱例如氢化钠、碳酸铯或碳酸钾的存在下,在合适的溶剂例如四氢呋喃或N,N-二甲基乙酰胺中,在-78℃至+100℃的温度下进行。可能有必要卤化物14中的氨基磺酰基。合适的磺酰胺保护基是磺酰基甲脒基团,如本文或文献中所述的,其可以通过伯磺酰胺与二甲基酰胺二甲基缩醛的反应获得。
备选地,使用本领域已知的试剂和方法,式7D的化合物可以由醇13A和酚R2-OH(15)或苯硫酚R2-SH(16)合成。
此反应可以利用膦,例如,三苯基膦,偶氮二羧酸酯例如偶氮二甲酸二乙酯或偶氮甲酸二异丙酯,在溶剂如二氯甲烷、甲苯或四氢呋喃中,并且在0℃至40℃的温度进行。可能有必要保护酚15或苯硫酚16中的氨基磺酰基。合适的磺酰胺保护基是磺酰基甲脒基团,如本文或文献中所述的,其可以通过伯磺酰胺与N,N-二甲基酰胺二甲基缩醛的反应获得。
醇和硫醇13可商购获得,可以如本文所述制备或利用本领域已知的方法制备。
其中V是硫的中间体7D可以由通式结构7DA表示。R2、R9、R10、m和n如上所述,PG是保护基,例如,苄氧基羰基、叔丁氧基羰基或乙酰基。
其中X是CH并且W是-(CR9R10)p-S(O)-的中间体7可以由通式结构7E表示。R2、R9、R10、m、n和p如上所述,PG是保护基,例如,苄氧基羰基、叔丁氧基羰基或乙酰基。
利用本领域已知的方法和试剂,亚砜7E可以由硫化物7DA制备。例如,该反应可以在过氧化物试剂例如过氧化氢或3-氯过苯甲酸的存在下,在溶剂例如二氯甲烷、乙酸或甲酸中,在0℃至+50℃的温度下进行。
其中X是CH并且W是-(CR9R10)p-S(O)2-的中间体7可以由通式结构7F表示。R2、R9、R10、m、n和p如上所述,PG是保护基,例如,苄氧基羰基、叔丁氧基羰基或乙酰基。
利用合适的过氧化物试剂例如过氧化氢或3-氯过苯甲酸,在溶剂例如二氯甲烷、乙酸或甲酸中,在0℃至+50℃的温度下,砜7F可以由中间体硫化物7DA或亚砜7D制备。
其中X是N、W是-(CR9R10)p-C(O)-或-(CR9R10)p-S(O)2-并且p是0的式(I)的化合物可以由通式结构17表示。Z是C(O)或S(O)2,R1、R2、m和n如上所述。
其中Z是C(O)的式17的化合物可以由通式结构17A表示。R1、R2、m和n如上所述。
利用本领域已知的方法,酰胺17A可以由通式8的胺前体通过与适当试剂的反应制备。
例如,胺18与合适的式R2-COOH(9)的羧酸反应,得到式17A的化合物。该反应在偶联剂如1,1′-羰基二咪唑、N,N’-二环己基碳二亚胺、1-(3-二甲基氨基丙基)-3-乙基-碳二亚胺盐酸盐、O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐、O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐或溴-三-吡咯烷基-鏻六氟磷酸盐的存在下,在非质子溶剂如二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、N-甲基吡咯烷酮和它们的混合物中,在-40℃至80℃的温度,在存在或不存在碱如三乙胺、二异丙基乙胺、4-甲基吗啉和/或4-(二甲基氨基)吡啶的情况下进行。
其中Z是S(O)2的式17的化合物可以由通式结构17B表示。R1、R2、m和n如上所述。
利用本领域已知的方法,磺酰胺17B可以由通式18的胺前体通过与适当试剂的反应制备。例如,使胺18与合适的式R2-SO2Cl(10)的磺酰氯反应,得到式17B的化合物。该反应在合适的溶剂如二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、乙腈、丙酮、水或其混合物中,在碱,例如三乙胺、二异丙基乙胺、吡啶、碳酸氢钾、碳酸钾的存在下,在0℃至溶剂或溶剂混合物的沸点的温度下进行。
其中X是N、W是-(CR9R10)p-、R10是H并且p是1的式(I)的化合物可以由通式结构17C表示。R1、R2、m和n如上所述。
利用本领域已知的方法,式17C的化合物可以由胺前体18通过与适当试剂的反应制备。
例如,使胺18与醛或酮R2-C(O)-R9(21)在合适的还原剂,例如三乙酰基硼氢化钠、硼氢化钠或氰基硼氢化钠的存在下反应。该反应在合适的溶剂,例如,二氯甲烷、1,2-二氯乙烷、乙酸、甲醇或其混合物中,在0℃至溶剂的沸点的温度下进行。
备选地,使胺18与卤化物R2-CH(R9)-Hal(22)(Hal是Cl、Br或I)在合适的碱,例如,碳酸钾、碳酸铯或三乙胺的存在下反应。该反应在合适的溶剂,例如,甲醇、丙酮、乙腈或N,N,二甲基甲酰胺,在0℃至溶剂的沸点的温度下进行。
醛或酮(21)和卤化物(22)可商购获得或者可以如本文或文献中所述制备。
式18的胺可以由适当保护的前体19制备。
合适的保护基(PG)是叔丁氧基羰基或苄氧基羰基。中间体19的去保护可以利用本领域已知的方法和试剂进行。
例如,在PG是苄氧基羰基的情况中,去保护可以通过在1巴至100巴的压力下,在合适的催化剂如活性炭载钯的存在下,在20℃至150℃的温度,在溶剂如甲醇或乙醇中的氢化而进行。
使用本领域中熟知的方法,式19的化合物可以由胺前体20和合适的试剂合成。
例如,将胺20与合适的式R1-Y-OH(2)的羧酸反应,从而产生式(I)的化合物,其中Y是-(CH2)qC(O)-、-(CH=CH)r-C(O)-或-(CH≡CH)r-C(O)-。该反应在偶联剂如1,1′-羰基二咪唑、N,N’-二环己基碳二亚胺、1-(3-二甲基氨基丙基)-3-乙基-碳二亚胺盐酸盐、O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐、O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐或溴-三-吡咯烷基-鏻六氟磷酸盐的存在下,在非质子溶剂如二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、N-甲基吡咯烷酮和它们的混合物中,在-40℃至80℃的温度,在存在或不存在碱如三乙胺、二异丙基乙胺、4-甲基吗啉和/或4-(二甲基氨基)吡啶的情况下进行。
也可以将胺20与合适的酰化剂如式R1-Y-Cl(3)的酰基氯反应,以得到式(I)的化合物,其中Y是-(CH2)qC(O)-、-(CH=CH)r-C(O)-或-(CH≡CH)r-C(O)-。该反应在溶剂如二氯甲烷、四氢呋喃或N,N-二甲基甲酰胺中,在碱如三乙胺或4-甲基吗啉存在下,在0℃至80℃的温度进行。
备选地,使胺20与合适的式R1-CH2-O-C(O)-Cl(4)的氯甲酸酯或式(5)的咪唑-1-甲酸酯反应,得到式(I)的化合物,其中Y是-CH2-OC(O)-。该反应在合适的溶剂如二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、乙腈、丙酮、水或其混合物中,在碱例如三乙胺、二异丙基乙胺、吡啶、碳酸氢钾、碳酸钾的存在下,在0℃至溶剂或溶剂混合物的沸点的温度进行。
式20的胺是商购可得的,或可以如本文中或文献中所述制备。
此外,本发明的一个实施方案是用于制备如上所限定的式(I)的化合物的方法,所述方法包括式(II)的化合物在式(III)的化合物存在下的反应;
其中R1、R2、Y、W、X、m和n如本文所定义,并且在Y是-(CH2)qC(O)-、-(CH=CH)r-C(O)-或-(CH≡CH)r-C(O)-的情况下,则G是卤素或羟基,并且在Y是-OC(O)-的情况下,则G是氯。
特别地,在偶联剂如1,1′-羰基二咪唑、N,N’-二环己基碳二亚胺、1-(3-二甲基氨基丙基)-3-乙基-碳二亚胺盐酸盐、O-(苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐、O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐或溴-三-吡咯烷基-鏻六氟磷酸盐,特别是O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐的存在下,在非质子溶剂如二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、N-甲基吡咯烷酮和它们的混合物中,特别是在N,N-二甲基甲酰胺中,在存在或不存在碱如三乙胺、二异丙基乙胺、4-甲基吗啉和/或4-(二甲基氨基)吡啶的情况下,特别是在4-甲基吗啉存在下,并且在-78℃至回流,特别是在-10℃至室温的温度下进行。
此外,本发明的一个目的是如本文所述的根据式(I)化合物,所述化合物用作治疗活性物质。
本发明的又一个目的是一种药物组合物,所述药物组合物包含如本文所述的根据式(I)化合物和治疗惰性载体。
本发明的一个特别的实施方案是根据如本文中所述的式(I)的化合物,其用于治疗或预防眼病症、特别是青光眼。
本发明还涉及根据如本文中所述的式(I)的化合物用于制备药物的用途,所述药物用于治疗或预防眼病症、特别是青光眼。
本发明的还一个目的是用于治疗或预防眼病症、特别是青光眼的方法,所述方法包括施用有效量的根据如本文中所述的式(I)的化合物。
炎性病症包括,但是不限于,关节炎(arthritis),骨关节炎(osteoarthritis),多发性硬化(multiple sclerosis),全身性红斑狼疮(systemic lupus erythematodes),炎性肠病(inflammatory bowel disease),反常排泄紊乱(abnormal evacuation disorder)等,以及炎性气道疾病如特发性肺纤维变性(idiopathic pulmonary fibrosis)(IPF),慢性阻塞性肺病(chronic obstructive pulmonary disease)(COPD)或慢性支气管哮喘(asthma bronchiale)。
其他呼吸系统病症包括,但是不限于,其他不同病因的弥散性实质性肺疾病(diffuse parenchymal lung diseases),包括医源性药物引起的纤维变性,职业和/或环境引起的纤维变性,系统性疾病和血管炎,肉芽肿疾病(granulomatous diseases)(结节病(sarcoidosis)、超敏性肺炎(hypersensitivity pneumonia)),胶原血管疾病(collagenvascular disease),肺泡蛋白沉积症(alveolar proteinosis),朗格汉斯细胞肉芽肿病(Langerhans cell granulomatosis),淋巴管平滑肌瘤病(lymphangioleiomyomatosis),遗传疾病(赫曼斯基-普德拉克综合征(Hermansky-Pudlak Syndrome)、结节性硬化(tuberous sclerosis)、纤维神经瘤(neurofibromatosis)、代谢存储障碍(metabolicstorage disorders)、家族性间质性肺病(familial interstitial lung disease)),辐射引起的纤维变性,矽肺病,石棉引起的肺纤维变性(pulmonary fibrosis)或急性呼吸窘迫综合征(acute respiratory distress syndrome)(ARDS)。
神经系统病症包括,但是不限于,神经痛(neuropathic pain),精神分裂症(schizophrenia),神经炎症(neuro-inflammation)(例如星形胶质细胞增生(astrogliosis)),外部和/或自发的(糖尿病)神经病(neuropathies)等。
血管病症包括,但是不限于,动脉粥样硬化(atherosclerosis),血栓形成性血管疾病(thrombotic vascular disease)以及血栓形成性微血管病(thromboticmicroangiopathies),增生性动脉病(proliferative arteriopathy)(如被粘蛋白的细胞外基质包围的肿胀肌内膜细胞和小结增厚),动脉粥样硬化(atherosclerosis),降低的血管顺应性(如刚性、降低的腔室顺应性和降低的血管顺应性),内皮机能障碍(endothelialdysfunction)等。
心血管病症包括,但是不限于,急性冠状动脉综合征(acute coronarysyndrome),冠心病(coronary heart disease),心肌梗死(myocardial infarction),动脉的和肺部的高血压(hypertension),心率失常(cardiac arrhythmia)如心房颤动(atrialfibrillation),卒中(stroke)及其他血管损伤。
纤维变性疾病包括,但是不限于心肌和血管纤维变性,肺纤维变性,皮肤纤维变性,硬皮病(scleroderma)和被囊性腹膜炎(encapsulating peritonitis)。
癌症和癌症转移包括,但是不限于,乳腺癌、卵巢癌、肺癌、前列腺癌、间皮瘤(mesothelioma)、神经胶质瘤(glioma)、肠胃癌和它们的进展和转移性侵占(metastaticaggressiveness)。
眼病症包括,但是不限于,增殖性和非增殖性(糖尿病)视网膜病(retinopathy)、干性和湿性老年黄斑退化(age-related macular degeneration)(AMD)、黄斑水肿(macular edema)、主动脉/静脉闭塞(central arterial/venous occlusion)、外伤性损伤、青光眼(glaucoma)等。特别地,所述眼病症是青光眼。
代谢病症包括,但是不限于,肥胖症和糖尿病。
此外,本发明的一个实施方案是根据所述方法中任一种制备的如本文所述的式(I)化合物。
测定步骤
具有和不具有HIS标记的人全长ATX的制备
自分泌运动因子(ATX-ENPP2)克隆:cDNA由商用人造血细胞总RNA制备,并且在重叠PCR中用作模板以产生具有或不具有3’-6xHis标记的全长人ENPP2 ORF。将这些全长插入物克隆到pcDNA3.1V5-His TOPO(Invitrogen)载体中。检验若干个单克隆的DNA序列。来自正确全长克隆的DNA用于转染Hek293细胞以检验蛋白表达。编码ENPP2的序列符合Swissprot条目Q13822,具有或不具有额外的C-末端6xHis标记。
ATX发酵:通过在20L受控的搅拌槽生物反应器(Sartorius)中大规模瞬时转染制备重组的蛋白。在细胞生长和转染期间,将温度、搅拌速度、pH和溶解氧浓度分别保持在37℃、120rpm、7.1和30%DO。在FreeStyle 293培养基(Invitrogen)中悬浮培养FreeStyle293-F细胞(Invitrogen),并使用X-tremeGENE Ro-1539(商品,Roche Diagnostics)作为复合剂以约1-1.5x 10E6细胞/mL用上述质粒DNAs转染。将细胞进料至浓缩的营养液(JImmunol Methods 194(1996),19,1-199(第193页))并在转染后72h由丁酸钠(2mM)诱导及在转染后96h收获。表达通过Western Blot酶测定和/或分析型IMAC层析分析。在将细胞悬浮液在流通式热交换器中冷却至4℃之后,通过经过Zeta Plus 60M02E16(Cuno)和Sartopore 2XLG(Sartorius)过滤单元的过滤,进行细胞分离和上清液的无菌过滤。在纯化之前,将上清液在4℃储存。
ATX纯化:通过添加Brij 35至0.02%的最终浓度和通过使用1MHCl来调节pH至7.0,由此调节20升的培养物上清液用于超滤。随后首先将上清液经过0.2μm Ultran-PilotOpen Channel PES过滤器(Whatman)微过滤,随后通过具有30kDa MWCO的Ultran-PilotScreen Channel PES过滤器(Whatman)浓缩至1升。在IMAC层析之前,加入NiSO4至1mM的最终浓度。随后将清澈了的上清液施加至预先在50mM Na2HPO4 pH 7.0、0.5M NaCl、10%甘油、0.3%CHAPS、0.02%NaN3中平衡的HisTrap柱(GE Healthcare)。分别用相同的含有20mM、40mM和50mM咪唑的缓冲液分步洗涤该柱。随后使用线性梯度至0.5M咪唑,以15柱体积洗脱蛋白。使用配备有30kDa PES过滤膜的Amicon池将含有ATX的级分汇集并浓缩。随后在Superdex S-200制备级(XK 26/100)(GE Healthcare)上,在20mM BICINE pH 8.5、0.15MNaCl、10%甘油、0.3%CHAPS、0.02%NaN3中,通过尺寸排阻色谱将蛋白进一步纯化。在纯化后蛋白的最终收率为5-10mg ATX/升培养物上清液。将蛋白在-80℃储存。
人ATX酶抑制测定
使用特别标记的底物模拟物(MR121底物),通过荧光猝灭测定,测量ATX抑制。为了获得此MR121底物,用MR121荧光团(CAS 185308-24-1,1-(3-羧基丙基)-11-乙基-1,2,3,4,8,9,10,11-八氢-二吡啶并[3,2-b:2’,3’-i]吩嗪-13-)在乙醇胺侧的游离胺上标记BOC和TBS保护的6-氨基-己酸(R)-3-({2-[3-(2-{2-[2-(2-氨基-乙氧基)-乙氧基]-乙氧基}-乙氧基)-丙酰氨基]-乙氧基}-羟基-磷酰氧基)-2-羟基-丙酯(Ferguson等,Org Lett2006,8(10),2023),并随后,在脱保护后,接着用色氨酸在氨基己酸侧上标记。
测定工作溶液按如下制备:
测定缓冲液(50mM Tris-HCl、140mM NaCl、5mM KCl、1mM CaCl2、1mM MgCl2、0.01%Triton-X-100、pH 8.0:
ATX溶液:ATX(人His-标记的)储备溶液(1.08mg/mL,在20mMN-二(羟乙基)甘氨酸中,pH 8.5、0.15M NaCl、10%甘油、0.3%CHAPS、0.02%NaN3),在测定缓冲液中稀释至1.4-2.5x最终浓度;
MR121底物溶液:MR121底物储备溶液(800μM MR121底物,在DMSO中),在测定缓冲液中稀释至2-5x最终浓度。
在384孔样品板(Corning Costar#3655)中获得测试化合物(10mM储备,在DMSO中,8μL),并用8μL DMSO稀释。通过将8μL的cpd化合物溶液转移至下一行直至第O行,进行逐行地连续稀释。将化合物和对照溶液混合五次,并将2μL转移至384孔测定板(CorningCostar#3702)。随后,添加15μL的41.7nMATX溶液(30nM最终浓度),混合五次并随后在30℃温育15分钟。添加10μL的MR121底物溶液(1μM最终浓度),混合30次,随后在30℃温育15分钟。随后每2分钟测定荧光,持续1小时(Perkin Elmer板:视觉多模态读出装置);光强度:2.5%;exp.时间:1.4秒,过滤器:Fluo_630/690nm),且从这些读数计算IC50值。
人碳酸酐酶-II抑制测定
使用4-硝基苯基乙酸酯(4-NPA)作为底物,通过吸光度法测量人碳酸酐酶II(hCA-II)抑制。4-NPA可以通过氢氧化锌机制由活性hCA II催化。产物中的硝基苯酚盐可以被离子化以在348至400nm处产生具有高吸光度的亮黄色阴离子,如文献(Armstrong等人,J.Biol.Chem.1966,241,5137-5149)中所报道的。选择OD340 nm用于检测hCAII底物转化。
测定工作溶液按如下制备:
测定缓冲液:50mM MOPS、33mM Na2SO4、1mM EDTA、0.5mg/mL BSA、pH 7.5;
酶溶液:hCA-II(人、全长)储备溶液(1.0mg/mL,在20mM HEPES中,50mM NaCl,pH7.4),在测定缓冲液中稀释至2133x最终浓度;
4-NPA底物溶液:4-NPA底物储备溶液(250mM,在DMSO中,储存于-20℃),在去离子水中稀释至50x最终浓度。
在96-孔样品板(Corning Costar#3655)中获得测试化合物(10mM储备,在DMSO中,100μL),并稀释至0.5mM。通过将20μL化合物溶液转移至下一列(从第3列直至第22列),进行逐列地连续稀释。在此之后,将1.2μL转移至384孔测定板(Corning Costar#3701)。随后,添加30μL的16nM hCA II溶液(8nM最终浓度),混合五次。添加30μL的4-NPA底物溶液(2.5mM最终浓度),混合五次。然后在0时间立即测量340nm处的吸光度。将测定板在室温温育1小时,然后作为1小时时间测量(Perkin Elmer EnVision 2103;过滤器:Photometric 340;光强度60%;闪光数目:10)。从这些读数计算IC50值和Ki值。
本文所述的式(I)化合物和它们的药用盐或酯具有0.00001μM至1000μM之间的IC50值,特别的化合物具有0.0005μM至500μM之间的IC50值,进一步特别的化合物具有0.0005μM至50μM之间的IC50值,更特别的化合物具有0.0005μM至5μM的IC50值。这些结果已经通过使用上述酶测定获得。
式(I)化合物及其药用盐可以用作药物(例如以药物制剂的形式)。药物制剂可以以下列方式内部给药:如经口(例如以片剂,包衣片剂,糖衣丸,硬和软明胶胶囊,溶液剂,乳剂或混悬剂的形式),经鼻(例如以鼻喷雾的形式)或经直肠(例如以栓剂的形式)或局部经眼部(例如以溶液,软膏,凝胶或水溶性聚合物插入物的形式)。然而,给药也可以在肠胃外实现,如肌肉内、静脉内或眼内(例如以无菌注射液的形式)。
式(I)化合物及其药用盐可以用药物惰性的、无机或有机辅料处理,用于制备片剂、包衣片剂、糖衣丸、硬明胶胶囊、注射液或局部制剂。例如可以使用乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等作为这样的用于片剂、糖衣丸和硬明胶胶囊的辅料。
合适的用于软明胶胶囊的辅料是例如植物油、蜡、脂肪、半固体物质和液体多元醇、等等。
合适的用于制备溶液剂和糖浆剂的辅料是例如水、多元醇、蔗糖、转化糖、葡萄糖、等等。
合适的用于注射液的辅料是例如水、醇、多元醇、甘油、植物油、等等。
合适的用于栓剂的辅料是例如天然或硬化油、蜡、脂肪、半固体或液体多元醇、等等。
合适的用于局部眼部制剂的辅料是例如环糊精、甘露醇或本领域中已知的许多其他载体和赋形剂。
此外,药物制剂可以含有防腐剂、增溶剂、增粘物质、稳定剂、润湿剂、乳化剂、增甜剂、着色剂、香料、用于调节渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们还可以含有其它有治疗价值的物质。
剂量可以在宽范围内变化,并且当然将适合每种特定情况下的个体需求。通常,在经口给药的情况下,每kg体重为约0.1mg至20mg、优选每kg体重为约0.5mg至4mg(例如每人约300mg)的每日剂量,优选分成1-3个可以例如由相同量组成的单个剂量,这应当是适合的。在局部给药的情况中,制剂可以包含0.001重量%至15重量%的药物,并且所需剂量(可以为0.1至25mg)可以通过每天或每周单次剂量给药,或通过每天多次剂量(2至4次)给药,或通过每周多次剂量给药。然而,将清楚的是,当明确指示时,可以超过本文给出的上限或下限。
以下通过非限制性的实施例阐明本发明。
在制备实施例是作为对映异构体混合物的形式获得的情况下,可以通过本文中描述的方法或本领域技术人员已知的方法诸如例如手性层析法或结晶来获得纯的对映异构体。
实施例
如果不另外规定,所有实施例和中间体都在氮气氛下制备。
缩写:aq.=水性的;CAS-RN=化学文摘服务注册号;HPLC=高效液相色谱;MS=质谱;PS-BEMP=聚苯乙烯结合的2-叔丁基亚氨基-2-二乙氨基-1,3-二甲基全氢-1,3,2-二氮杂磷杂苯;sat.=饱和的。
实施例1
4-(2-氟-4-氨磺酰基苯基)哌嗪-1-甲酸[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]甲酯
在室温向[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]甲醇(中间体1;30mg,110μmol)在乙腈(2mL)中的溶液中加入1,1′-羰基二咪唑(17.9mg,110μmol)。将反应混合物加热至50℃并搅拌2h,然后加入3-氟-4-哌嗪-1-基苯磺酰胺(CAS-RN 847971-84-0;28.6mg,110μmol)和三乙胺(55.8mg,551μmol)在乙腈(2mL)中的悬浮液,并将反应混合物加热至回流。在15h小时之后,将反应混合物在饱和氯化铵水溶液和乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,二氯甲烷至90∶10∶0.25的二氯甲烷/甲醇/25%氨水溶液的梯度)制得标题化合物(15mg,24%)。白色固体,MS:558.1(M+H)+。
将3-氟-4-哌嗪-1-基苯磺酰胺用适当的胺或氨基甲酸酯替代并且将[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]甲醇用适当的醇替代,根据实施例1制备以下实施例。在其中将胺的氨基甲酸叔丁酯衍生物用作起始材料的情况下(实施例1.03和1.04),类似于实施例6,将氨基甲酸酯首先用三氟乙酸去保护。
实施例2
2-氟-4-[[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]甲基]苯磺酰胺
在室温向4-(3-氟-4-氨磺酰基苯甲酰基)哌嗪-1-甲酸叔丁酯(CAS-RN1395398-34-1;150mg,387μmol)在四氢呋喃(3mL)中的溶液中,加入硼烷四氢呋喃配合物(1M,在四氢呋喃中;1.16mL,1.16mmol),然后在14h之后,将反应混合物加热至60℃持续4h,然后逐滴加入2M盐酸水溶液(2mL)和另外的盐酸(25%,在水中;1.0mL,8.2mmol)。将混合物在60℃搅拌45min,然后将混合物直接在高真空蒸发并将剩余物与N,N-二甲基甲酰胺(3mL)和N-甲基吗啉(392mg,3.87mmol)、3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酸(CAS-RN1646783-83-6;122mg,387μmol)和O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐(147mg,387μmol)合并,然后在48h之后,在室温将反应混合物在饱和氯化铵水溶液和乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,二氯甲烷至90∶10∶0.25的二氯甲烷/甲醇/25%氨水溶液的梯度)制得标题化合物(87mg,40%)。无色胶状物,MS:570.3(M+H)+。
将4-(3-氟-4-氨磺酰基苯甲酰基)哌嗪-1-甲酸叔丁酯用适当的氨基甲酸酯替代并且将3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酸用适当的羧酸替代,根据实施例2制备以下实施例。
实施例3
2-氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-羰基]苯磺酰胺
作为制备实施例2中的副产物获得标题化合物(48mg,21%)。白色固体,MS:584.3(M+H)+。
实施例4
3,5-二氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-羰基]苯磺酰胺
向3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]-1-哌嗪-1-基丙-1-酮(中间体2;40mg,100μmol)在N,N-二甲基甲酰胺(3mL)中的溶液中,加入N-甲基吗啉(40.6mg,402μmol)、2,6-二氟-4-氨磺酰基苯甲酸(中间体3;26.2mg,110μmol)和O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐(42mg,110μmol),然后在室温18h之后,将反应混合物在饱和氯化铵水溶液和乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,二氯甲烷至90∶10∶0.25的二氯甲烷/甲醇/25%氨水溶液的梯度)制得标题化合物(51mg,84%)。白色固体,MS:602.3(M+H)+。
将2,6-二氟-4-氨磺酰基苯甲酸(中间体3)用适当的羧酸替代,根据实施例4制备以下实施例。
实施例5
3-[[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]甲基]-4-氟苯磺酰胺
向4-氟-3-(哌啶-4-基甲基)苯磺酰胺盐酸盐(中间体7;51.6mg,159μmol)在N,N-二甲基甲酰胺(3mL)中的溶液中,加入N-甲基吗啉(72.9mg,721μmol)、2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-甲酸(CAS-RN1810776-23-8;40mg,144μmol)和O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐(60.3mg,159μmol),然后在室温18h之后,将反应混合物在饱和氯化铵水溶液和乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,二氯甲烷至90∶10∶0.25的二氯甲烷/甲醇/25%氨水溶液的梯度)制得标题化合物(75mg,98%)。白色固体,MS:532.3(M+H)+。
将4-氟-3-(哌啶-4-基甲基)苯磺酰胺盐酸盐用适当的胺替代并且将2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-甲酸用适当的羧酸替代,根据实施例5制备以下实施例。
实施例6
2,3-二氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]硫基苯磺酰胺
在室温向4-(2,3-二氟-4-氨磺酰基苯基)硫基哌啶-1-甲酸叔丁酯(中间体9.2;31mg,60μmol)在二氯甲烷(3mL)中的溶液中,加入三氟乙酸(137mg,1.2mmol)。将反应混合物在40℃搅拌80min,然后将混合物直接蒸发并将剩余物放入N,N-二甲基甲酰胺(3mL)和N-甲基吗啉(61.9mg,600μmol)中,加入3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酸(CAS-RN 1646783-83-6;20.7mg,65.9μmol)和O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐(25.3mg,65.9μmol)。在室温18h之后,将反应混合物在饱和氯化铵水溶液和乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,二氯甲烷至90∶10∶0.25的二氯甲烷/甲醇/25%氨水溶液的梯度)制得标题化合物(27mg,74%)。白色固体,MS:605.2(M+H)+。
将4-(2,3-二氟-4-氨磺酰基苯基)硫基哌啶-1-甲酸叔丁酯(中间体9.2)用适当的氨基甲酸酯替代并且将3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酸(CAS-RN1646783-83-6)用适当的羧酸替代,根据实施例6制备以下实施例。
实施例7和8
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]亚磺酰基苯磺酰胺对映体1和对映体2
利用Reprosil Chiral-NR柱作为固定相并且庚烷/乙醇3∶2作为流动相,通过制备型HPLC分离外消旋的3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]亚磺酰基苯磺酰胺(实施例6.13;40mg,66.4μmol)。这产生较快速洗脱的(+)-对映体1(实施例7;17mg,43%;白色胶状物,MS:601.3(M-H)-)和较慢洗脱的(-)-对映体2(实施例8;14mg,35%;白色固体,MS:601.4(M-H)-)。
类似于实施例7和8,通过手性HPLC分离其外消旋物,制备以下实施例。
实施例9
4-[[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]甲基]苯磺酰胺
在室温向3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]-1-哌嗪-1-基丙-1-酮(中间体2;40mg,105μmol)在二氯甲烷(2mL)中的溶液中,加入4-甲酰基苯磺酰胺(CAS-RN 3240-35-5;23.2mg,126μmol)、三乙酰氧基硼氢化钠(28.8mg,136μmol)和乙酸(12.6mg,209μmol)。将混合物在室温搅拌16h,然后在50℃搅拌24h,然后将反应混合物在饱和碳酸氢钠水溶液和乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,二氯甲烷至90∶10∶0.25的二氯甲烷/甲醇/25%氨水溶液的梯度)制得标题化合物(6mg,10%)。白色固体,MS:552.2(M+H)+。
中间体
中间体1
[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]甲醇
步骤1:2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯甲酸乙酯
向2-[[2-溴-5-(三氟甲基)苯基]甲基]-5-甲基四唑(CAS-RN 1646389-14-1;209mg,651μmol)在乙醇(3mL)中的溶液中,加入1,1-双(二苯基膦基)二茂铁二氯钯(II)(CAS-RN 95464-05-4;21.3mg,26μmol)、三乙胺(98.8mg,976μmol)并放入到一氧化碳气氛中。在110℃在一氧化碳气氛(70巴)下将反应混合物搅拌18h。将反应混合物过滤并直接蒸发。层析法(硅胶,纯庚烷至庚烷∶乙酸乙酯=2∶1的梯度)制得标题化合物(186mg,91%),无色油状物,MS:315.1(M+H)+。
步骤2:[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]甲醇
向2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯甲酸乙酯(182mg,579μmol)在四氢呋喃(5mL)中的浅黄色溶液中,加入氯化钙(129mg,1.16mmol)在乙醇(5mL)中的溶液。将硼氢化钠(CAS-RN 16940-66-2;65.7mg,1.74mmol)在30min时间内分3份加入,得到白色悬浮液。在室温3h之后将反应混合物在饱和氯化铵水溶液和乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发而产生标题化合物,纯度为96%(NMR)(164mg,定量)。浅黄色油状物,MS:273.1(M+H)+。
中间体2
3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]-1-哌嗪-1-基丙-1-酮
步骤1:4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-
甲酸叔丁酯
在室温向3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酸(101mg,309μmol)、4-甲基吗啉(156mg,1.54mmol)、哌嗪-1-甲酸叔丁酯(57.5mg,309μmol)在N,N-二甲基甲酰胺(3mL)中的无色溶液中,加入O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟磷酸盐(117mg,309μmol),然后在18h之后将反应混合物在饱和氯化铵水溶液和乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,二氯甲烷至90∶10∶0.25的二氯甲烷/甲醇/25%氨水溶液的梯度)制得标题化合物(149mg,定量)。无色油状物,MS:483.2(M+H)+。
步骤2:3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]-1-哌嗪-1-基丙-1-
酮
向4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-甲酸叔丁酯(140mg,290μmol)在二氯甲烷(3mL)中的溶液中,加入三氟乙酸(496mg,4.35mmol)。将反应混合物在室温搅拌18h。将混合物直接蒸发并将剩余物在2M氢氧化钠水溶液和二氯甲烷之间分配。水相用二氯甲烷洗涤两次以上,然后有机相用硫酸镁干燥,过滤并蒸发而得到标题化合物(90mg,81%)。白色固体,MS:383.2(M+H)+。
中间体3
2,6-二氟-4-氨磺酰基苯甲酸
在回流下向3,5-二氟-4-甲基-苯磺酰胺(CAS-RN 1239964-24-9;500mg,2.41mmol)在水(25mL)中的搅拌悬浮液中,在1h内分批加入高锰酸钾(1.72g,10.9mmol),然后将悬浮液过滤并用水洗涤。将母液用乙酸乙酯萃取两次以分离杂质。水层用浓盐酸溶液酸化至pH1并用乙酸乙酯萃取3次。合并的有机层用硫酸镁干燥并蒸发至干而得到标题化合物(356mg,62%)。浅黄色固体,MS:235.9(M-H)-。
中间体4
4-(4-氨磺酰基苯基)磺酰基哌嗪-1-甲酸叔丁酯
在室温向哌嗪-1-甲酸叔丁酯(CAS-RN 57260-71-6;50mg,263μmol)在吡啶(208mg,2.63mmol)和四氢呋喃(1mL)中的浅黄色溶液中,加入4-氨磺酰基苯磺酰氯(CAS-RN46249-41-6;80.7mg,316μmol)在四氢呋喃(1mL)中的溶液。将反应混合物在室温搅拌18h并且转变成白色悬浮液,然后在饱和氯化铵水溶液和乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,二氯甲烷至90∶10∶0.25的二氯甲烷/甲醇/25%氨水溶液的梯度)制得标题化合物(64mg,60%)。白色固体,MS:404.3(M-H)-。
中间体4.1
4-(2-氟-4-氨磺酰基苯基)磺酰基哌嗪-1-甲酸叔丁酯
将4-氨磺酰基苯磺酰氯用2-氟-4-氨磺酰基苯磺酰氯(CAS-RN 52295-72-4)替代,类似于中间体4制备标题化合物。白色固体,MS:422.3(M-H)-。
中间体5
4-(2-氟-4-氨磺酰基苯甲酰基)哌嗪-1-甲酸叔丁酯
在室温向2-氟-4-氨磺酰基苯甲酸(CAS-RN 714968-42-0;69.4mg,301μmol)在N,N-二甲基甲酰胺(3mL)中的无色溶液中,加入4-甲基吗啉(111mg,1.09mmol)、哌嗪-1-甲酸叔丁酯(CAS-RN 57260-71-6;52mg,274μmol)和O-(7-氮杂苯并三唑-1-基)-N,N,N’,N’-四甲基脲六氟-磷酸盐(114mg,301μmol),然后在18h之后将反应混合物在饱和氯化铵水溶液和乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,二氯甲烷至90∶10∶0.25的二氯甲烷/甲醇/25%氨水溶液的梯度)制得标题化合物(107mg,定量)。白色泡沫,MS:386.3(M-H)-。
中间体6
[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-基]甲醇
在室温向2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-甲酸(CAS-RN 1810776-23-8;300mg,1.08mmol)在四氢呋喃(5mL)中的溶液中,缓慢地加入硼烷四氢呋喃配合物溶液(CAS-RN 14044-65-6;1M,在四氢呋喃中;2.7mL,2.7mmol)。将反应混合物在室温搅拌18h。加入更多的硼烷四氢呋喃配合物溶液(1.62mL,1.62mmol)并且继续搅拌6h。将反应谨慎地用3mL甲醇处理,在室温保持搅拌10min,然后完全蒸发。将剩余物在乙酸乙酯和1M氢氧化钠水溶液之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发,制得标题化合物(239mg,84%)。无色油状物,MS:264.3(M+H)+。
中间体7
4-氟-3-(哌啶-4-基甲基)苯磺酰胺盐酸盐
步骤1∶1-[4-[(2-氟苯基)甲基]-1-哌啶基]乙酮
将4-[(2-氟苯基)甲基]哌啶盐酸盐(CAS-RN 193357-26-5;350mg,1.48mmol)与二氯甲烷(5mL)合并并加入N-甲基吗啉(149mg,162μl,1.48mmol,然后在搅拌下在0℃逐滴加入乙酸酐(317mg,3.1mmol),并将混合物在室温搅拌1h。将混合物直接在真空中浓缩。将剩余物在乙酸乙酯和饱和碳酸氢钠水溶液之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发而得到标题化合物,其纯度为大约90%(NMR)(388mg,定量)。浅黄色油状物,MS:236.2(M+H)+。
步骤2:3-[(1-乙酰基-4-哌啶基)甲基]-4-氟-苯磺酰胺
在搅拌下在0℃将1-[4-[(2-氟苯基)甲基]-1-哌啶基]乙酮(384mg,1.47mmol)在二氯甲烷(5mL)中的溶液逐滴加入至磺氯酸(sulfurochloridic acid)(856mg,7.34mmol),然后在0℃搅拌30min并且在室温搅拌2h。将反应混合物直接在高真空下蒸发。将剩余物与四氢呋喃(5mL)合并并冷却至0℃,然后逐滴加入25%氨水溶液(3mL)。将反应混合物在0℃搅拌30min,然后在室温搅拌18h,然后直接蒸发以除去四氢呋喃。将含水剩余物在乙酸乙酯和1M盐酸水溶液之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,庚烷:乙酸乙酯=4∶1至9∶1的梯度,然后乙酸乙酯并且最后采用纯乙酸酯至纯甲醇的梯度)制得标题化合物(353mg,76%)。白色泡沫,MS:315.2(M+H)+。
步骤3:4-氟-3-(哌啶-4-基甲基)苯磺酰胺盐酸盐
将3-[(1-乙酰基-4-哌啶基)甲基]-4-氟-苯磺酰胺(345mg,1.1mmol)与盐酸水溶液(25%,在水中;4.8g,32.9mmol)合并并在回流下搅拌6h。将反应混合物直接蒸发并在高真空下干燥,得到标题化合物,其纯度为大约95%(NMR)(305mg,86%)。白色泡沫,MS:273.2(M+H)+。
中间体8
3-氟-4-哌啶-4-基硫基苯磺酰胺盐酸盐
步骤1:N′-(4-溴-3-氟-苯基)磺酰基-N,N-二甲基-甲脒
在室温将1,1-二甲氧基-N,N-二甲基-甲酰胺(CAS-RN 4637-24-5;170mg,1.38mmol)在乙腈(1mL)中的溶液逐滴加入至4-溴-3-氟苯磺酰胺(CAS-RN 263349-73-1;302mg,1.15mmol)在乙腈(3mL)中的搅拌溶液中。在1h后,将混合物在高真空直接蒸发,得到标题化合物(369mg,定量)。白色固体,MS:309.0(M+H)+。
步骤2:3-氟-4-哌啶-4-基硫基苯磺酰胺盐酸盐
将4-硫基哌啶-1-甲酸叔丁酯(CAS-RN 134464-79-2;244mg,1.1mmol)在N,N-二甲基甲酰胺(2mL)中的溶液逐滴加入至氢化钠(50%油分散液;52.9mg,1.1mmol)和N,N-二甲基甲酰胺(2mL)的搅拌混合物。在室温30min后,气体逸出完成并逐滴加入另一个N′-(4-溴-3-氟-苯基)磺酰基-N,N-二甲基-甲脒(351mg,1.1mmol)在N,N-二甲基甲酰胺(2mL)中的溶液。将反应混合物在60℃搅拌3h,然后直接蒸发以除去N,N-二甲基甲酰胺。将剩余物与甲醇(4mL)和2.5M氢氧化钠水溶液(4.4mL,11mmol)合并,然后在100℃搅拌1h。将混合物再次直接蒸发以除去甲醇,然后加入盐酸溶液(5M,在异丙醇中;4.4mL,22mmol)并在50℃搅拌1.5h。将白色悬浮液过滤,并将母液蒸发,得到标题化合物,为大约1∶1(溴化物异构体)的混合物,其纯度为80%(440mg,49%)。灰白色泡沫,MS:291.1(M+H)+。
中间体9
4-[(2-氟-4-氨磺酰基苯基)硫基甲基]哌啶-1-甲酸叔丁酯
步骤1:N′-(3,4-二氟苯基)磺酰基-N,N-二甲基-甲脒
类似于中间体8的步骤1,由3,4-二氟苯磺酰胺(CAS-RN 108966-71-8)和1,1-二甲氧基-N,N-二甲基-甲酰胺(CAS-RN 4637-24-5)制备标题化合物。白色固体,MS:249.1.0(M+H)+。
步骤2:4-[(2-氟-4-氨磺酰基苯基)硫基甲基]哌啶-1-甲酸叔丁酯
在室温将N′-(3,4-二氟苯基)磺酰基-N,N-二甲基-甲脒(315mg,1.27mmol)添加至氢化钠(50%油悬浮液;60.9mg,1.27mmol)和N,N-二甲基甲酰胺(2mL)的搅拌混合物中。5min后,加入4-(硫基甲基)哌啶-1-甲酸叔丁酯(CAS-RN 581060-27-7;281mg,1.27mmol)。可以观察到强烈气体逸出和放热反应。将反应混合物在室温搅拌1h,然后直接蒸发以除去N,N-二甲基甲酰胺。将剩余物与甲醇(4mL)和2.5M氢氧化钠水溶液(5.08mL,12.7mmol)合并,并将白色悬浮液在室温搅拌3h。将混合物在冰和1M盐酸水溶液与乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。剩余物的层析法(硅胶,二氯甲烷至90∶10∶0.25的二氯甲烷/甲醇/25%氨水溶液的梯度)制得标题化合物,其纯度为大约95%(NMR)(463mg,89%)。无色胶状物,MS:389.3(M-H)-。
将4-(硫基甲基)哌啶-1-甲酸叔丁酯(CAS-RN 581060-27-7)用适当的硫醇替代并且将3,4-二氟苯磺酰胺(CAS-RN 108966-71-8)用适当的磺酰胺替代,根据中间体9制备以下中间体。
中间体10
4-(2-氟-4-氨磺酰基苯基)亚磺酰基哌啶-1-甲酸叔丁酯
向4-(2-氟-4-氨磺酰基苯基)硫基哌啶-1-甲酸叔丁酯(中间体9.9;459mg,1.12mmol)在冰乙酸(2mL)中的溶液中,加入过氧化氢(35%,在水中;369mg,3.8mmol)。将所得的溶液在室温搅拌4h,然后在冰和乙酸乙酯之间分配。有机层用水和盐水洗涤,用硫酸镁干燥,过滤并在高真空蒸发,得到标题化合物(428mg,94%)。白色泡沫,MS:405.3(M-H)-。
将4-(2-氟-4-氨磺酰基苯基)硫基哌啶-1-甲酸叔丁酯(中间体9.9)用适当的硫醚替代,根据中间体10制备以下中间体。
中间体11
4-(2-氟-4-氨磺酰基苯基)磺酰基哌啶-1-甲酸叔丁酯
在室温向4-(2-氟-4-氨磺酰基苯基)亚磺酰基哌啶-1-甲酸叔丁酯(中间体10;374mg,920μmol)在二氯甲烷(4mL)中的无色溶液中,加入3-氯过苯甲酸(CAS-RN 937-14-4;318mg,1.84mmol)。将反应混合物在室温搅拌18h,然后在1M碳酸钠水溶液和乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发而得到标题化合物,其e纯度为大约90%(NMR)。
将此材料从2mL的二氯甲烷(286mg,74%)沉淀。白色固体,MS:421.3(M-H)-。
将4-(2-氟-4-氨磺酰基苯基)亚磺酰基哌啶-1-甲酸叔丁酯用适当的亚砜替代,根据中间体11制得以下中间体。
中间体12
N-[5-氰基-2-(羟基甲基)吡啶-3-基]-2,2-二甲基丙酰胺
步骤1:5-溴-3-(2,2-二甲基丙酰基氨基)吡啶-2-甲酸甲酯
向3-氨基-5-溴吡啶-2-甲酸甲酯(CAS-RN 1072448-08-8;900mg,3.7mmol)在吡啶(15mL)中的浅黄色悬浮液中,加入2,2-二甲基丙酰氯(CAS-RN 3282-30-2;546mg,4.44mmol)。颜色变成浅红色。加入更多的2,2-二甲基丙酰氯(1.092g,8.88mmol),并将反应在室温搅拌18h,然后在冰和1M盐酸水溶液与乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,二氯甲烷/庚烷1∶1至二氯甲烷的梯度)制得标题化合物(385mg,99%)。白色固体,MS:317.0(M+H)+。
步骤2:5-氰基-3-(2,2-二甲基丙酰基氨基)吡啶-2-甲酸甲酯
向含有5-溴-3-(2,2-二甲基丙酰基氨基)吡啶-2-甲酸甲酯(1.13g,3.59mmol)在N,N-二甲基甲酰胺(14.9mL)和水(119μl)中的溶液的微波小瓶中,加入三(二亚苄基丙酮)二钯(CAS-RN 51364-51-3;32.8mg,35.9μmol)、1,1′-双(二苯基膦基)二茂铁(CAS-RN12150-46-8;59.6mg,108μmol)、氰化锌(CAS-RN 557-21-1;232mg,1.97mmol)、锌(CAS-RN7440-66-6;9.38mg,143μmol)和乙酸锌(CAS-RN 557-34-6;26.3mg,143μmol)。将小瓶盖上盖并在微波中在140℃加热30min。将反应混合物过滤并将母液蒸发。将剩余物用50%碳酸氢钠水溶液稀释并用乙酸乙酯萃取。有机层用水和盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,二氯甲烷至二氯甲烷/甲醇50∶1的梯度)制得标题化合物(468mg,50%)。黄色固体,MS:262.2(M+H)+。
步骤3:N-[5-氰基-2-(羟基甲基)吡啶-3-基]-2,2-二甲基丙酰胺
向5-氰基-3-(2,2-二甲基丙酰基氨基)吡啶-2-甲酸甲酯(453mg,1.73mmol)在四氢呋喃(5mL)和乙醇(5mL)中的透明黄色溶液中,将硼氢化钠(262mg,6.94mmol)在30min时间内分3部分加入。将反应混合物在饱和氯化铵水溶液和乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,二氯甲烷至90∶10∶0.25的二氯甲烷/甲醇/25%氨水溶液的梯度)制得标题化合物(378mg,94%)。浅黄色粘性油状物,MS:234.2(M+H)+。
中间体13
3-[4-氰基-2-[(5-甲基四唑-2-基)甲基]苯基]丙酸
步骤1:(E)-3-[4-氰基-2-[(5-甲基四唑-2-基)甲基]苯基]丙-2-烯酸乙酯
向4-溴-3-[(5-甲基四唑-2-基)甲基]苯甲腈(CAS-RN 1646784-84-0;450mg,1.62mmol)在N,N-二甲基甲酰胺(6mL)中的无色溶液中,加入丙烯酸乙酯(194mg,1.94mmol)、三乙胺(491mg,4.85mmol)、乙酸钯(II)(7.27mg,32.4μmol)和三-O-甲苯基膦(39.4mg,129μmol)。将反应用氩气充气并在120℃搅拌18h,然后在饱和氯化铵水溶液和二氯甲烷之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,二氯甲烷至90∶10∶0.25的二氯甲烷/甲醇/25%氨水溶液的梯度)制得标题化合物(431mg,90%)。浅黄色固体。MS:296.2(M+H)+。
步骤2:3-[4-氰基-2-[(5-甲基四唑-2-基)甲基]苯基]丙酸乙酯
向(E)-3-[4-氰基-2-[(5-甲基四唑-2-基)甲基]苯基]丙-2-烯酸乙酯(431mg,1.45mmol)在甲醇(6mL)中的浅褐色悬浮液中,加入钯(CAS-RN7440-05-3;89.4mg,840μmol),并且引入氢气气氛。在室温17h后,将反应用氩气充气,用硅藻土助滤剂过滤并用甲醇漂洗。将母液全部蒸发,得到粗制标题化合物(286mg,66%)。灰色粘性油状物,MS:300.2(M+H)+。
步骤3:3-[4-氰基-2-[(5-甲基四唑-2-基)甲基]苯基]丙酸
向3-[4-氰基-2-[(5-甲基四唑-2-基)甲基]苯基]丙酸乙酯(79.1mg,264μmol)在四氢呋喃(1mL)和乙醇(0.5mL)中的无色溶液中,加入1M氢氧化锂一水合物水溶液(CAS-RN1310-66-3;793μl,793μmol)。将反应在室温搅拌4h,然后倒入冰中并用2M盐酸水溶液酸化至pH1。水相用乙酸乙酯萃取,然后有机相用盐水洗涤,用硫酸镁干燥,过滤并蒸发,制得标题化合物(66mg,92%)。白色固体。MS:270.3(M-H)-。
将4-溴-3-[(5-甲基四唑-2-基)甲基]苯甲腈用适当的起始材料替代,根据中间体13制备以下中间体。
中间体14
[5-氯-3-[(5-甲基四唑-2-基)甲基]吡啶-2-基]甲醇
步骤1:5-氯-3-[(5-甲基四唑-2-基)甲基]吡啶-2-甲酸甲酯
在室温将3-(溴甲基)-5-氯吡啶-2-甲酸甲酯(CAS-RN 1260667-62-6;500mg,1.51mmol)溶解在丙酮(10mL)中并加入碳酸钾(209mg,1.51mmol)和5-甲基-2H-四唑(CAS-RN 4076-36-2;130mg,1.51mmol)。将所得的悬浮液在回流(60℃)下搅拌2h,然后在冰水和乙酸乙酯之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,纯庚烷至庚烷∶乙酸乙酯=2∶1的梯度)制得标题化合物(185mg,46%)。白色固体,MS:268.1(M+H)+。
步骤2:[5-氯-3-[(5-甲基四唑-2-基)甲基]吡啶-2-基]甲醇
将2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯甲酸乙酯由5-氯-3-[(5-甲基四唑-2-基)甲基]吡啶-2-甲酸甲酯替代,类似于中间体1的步骤2制备标题化合物。灰白色半固体,MS:240.1(M+H)+。
中间体15
4-(2,3-二氟-4-氨磺酰基苯基)磺酰基哌啶-1-甲酸叔丁酯
向4-(2,3-二氟-4-氨磺酰基苯基)硫基哌啶-1-甲酸叔丁酯(中间体9.2;94mg,230μmol)在冰乙酸(3mL)中的溶液中,加入过氧化氢(35%,在水中;76mg,782μmol)。将所得的溶液在室温搅拌96h,然后在冰和乙酸乙酯之间分配。有机层用水和盐水洗涤,用硫酸镁干燥,过滤并蒸发。层析法(硅胶,纯庚烷至庚烷:乙酸乙酯=1∶2的梯度)制得标题化合物(94mg,74%)。白色固体,MS:439.2(M-H)-。
将4-(2,3-二氟-4-氨磺酰基苯基)硫基哌啶-1-甲酸叔丁酯(中间体9.2)用适当的硫醚替代,根据中间体15制备以下中间体。
中间体16
4-[2-(2-氟-4-氨磺酰基苯基)磺酰基乙基]哌啶-1-甲酸叔丁酯
将4-(2,3-二氟-4-氨磺酰基苯基)硫基哌啶-1-甲酸叔丁酯(中间体9.2)用4-[2-(2-氟-4-氨磺酰基苯基)亚磺酰基乙基]哌啶-1-甲酸叔丁酯(中间体10.4)替代,类似于中间体15制备标题化合物。白色固体,MS:449.3(M-H)-。
中间体17
6-环丁氧基-5-环丙基吡啶-3-甲酸
向5-溴-6-环丁氧基吡啶-3-甲酸(CAS-RN 1364678-46-5;1g,3.68mmol)在甲苯(25mL)和水(2.8mL)的无色溶液中,加入碳酸铯(3.59g,11.0mmol)、乙酸钯(II)(16.5mg,73.5μmol)、环丙基三氟硼酸钾(CAS-RN 1065010-87-8;598mg,4.04mmol)和丁基二-1-金刚烷基膦(CAS-RN 321921-71-5;79.1mg,221μmol)。将反应混合物脱气并用氩气充气三次,然后在120℃搅拌16h。将混合物在冰和1M氢氧化钠水溶液与二氯甲烷之间分配。有机层用盐水洗涤,用硫酸镁干燥,过滤并蒸发。从乙酸乙酯重结晶制得标题化合物(610mg,71%)。灰白色固体,234.4(M+H)+。
实施例A
式(I)的化合物可以以本身已知的方式作为活性成分用于制备以下组合物的片剂:
实施例B
式(I)的化合物可以以本身已知的方式作为活性成分用于制备以下组合物的胶囊:
Claims (26)
1.式(I)的化合物
其中
R1选自
i)被R3、R4和R5取代的苯基,
ii)被R3、R4和R5取代的吡啶基,和
iii)被R3、R4和R5取代的噻吩基;
X选自
i)N,和
ii)CH;
Y选自
i)-CH2-OC(O)-,和
ii)-(CH2)qC(O)-;
W选自
i)-(CR9R10)p-,
ii)-(CR9R10)p-C(O)-,
iii)-(CR9R10)p-O-,
iv)-(CR9R10)p-S-,
v)-(CR9R10)p-S(O)-,和
vi)-(CR9R10)p-S(O)2-;
R2选自
i)取代的苯基,其中所述苯基的环被R6、R7和R8取代,
ii)取代的吡啶基,其中所述吡啶基的环被R6、R7和R8取代,
iii)取代的噻吩基,其中所述噻吩基的环被R6、R7和R8取代,
和
iv)取代的噻唑基,其中所述噻唑基的环被R6、R7和R8取代;
R3选自
i)卤代-C1-6-烷氧基,
ii)C3-8-环烷基,
iii)C3-8-环烷基-C1-6-烷基,
iv)C3-8-环烷基-C1-6-烷氧基,
v)C3-8-环烷氧基,
vi)C3-8-环烷氧基-C1-6-烷基,
vii)四唑基甲基,
viii)三唑基甲基,
ix)吡唑基甲基,
x)C1-6-烷基四唑基甲基,
xi)C1-6-烷基三唑基甲基,
xii)C1-6-烷基吡唑基甲基,
xiii)四氢吡喃基-C1-6-烷氧基;
R4选自
i)卤素,
ii)羟基,
iii)氰基,
iv)C1-6-烷基,
v)C1-6-烷氧基,
vi)C1-6-烷氧基-C1-6-烷基,
vii)卤代-C1-6-烷氧基,
viii)卤代-C1-6-烷基,
ix)羟基-C1-6-烷基,
x)C3-8-环烷基,
xi)C3-8-环烷基-C1-6-烷基,
xii)C3-8-环烷基-C1-6-烷氧基,
xiii)C3-8-环烷氧基,
xiv)C3-8-环烷氧基-C1-6-烷基,
xv)C1-6-烷基羰基氨基,
xvi)C3-8-环烷基羰基氨基,
R5选自
i)H,
ii)卤素,
iii)羟基,
iv)氰基,
v)C1-6-烷基,
vi)C1-6-烷氧基,
vii)C1-6-烷氧基-C1-6-烷基,
viii)卤代-C1-6-烷氧基,
ix)卤代-C1-6-烷基,
x)羟基-C1-6-烷基,
xi)C3-8-环烷基,
xii)C3-8-环烷基-C1-6-烷基,
xiii)C3-8-环烷基-C1-6-烷氧基,
xiv)C3-8-环烷氧基,
xv)C3-8-环烷氧基-C1-6-烷基,
xvi)C1-6-烷基羰基氨基,
xvii)C3-8-环烷基羰基氨基,
R6是氨基磺酰基;
R7和R8独立地选自
i)H,
ii)卤素,
iii)羟基,
iv)氰基,
v)C1-6-烷基,
vi)C1-6-烷氧基,
vii)C1-6-烷氧基-C1-6-烷基,
viii)卤代-C1-6-烷氧基,
ix)卤代-C1-6-烷基,和
x)羟基-C1-6-烷基;
R9和R10独立地选自
i)H,和
ii)C1-6-烷基;
m和n独立地选自0、1、2、3、4或5,条件是m和n的和是2、3、4或5;
p选自0、1或2;
q选自0或2;
r选自0和1;
或药用盐。
2.根据权利要求1所述的化合物,其中
R1选自
i)被R3、R4和R5取代的苯基,和
ii)被R3、R4和R5取代的吡啶基;
X选自
i)N,和
ii)CH;
Y选自
i)-CH2-OC(O)-,和
ii)-(CH2)qC(O)-;
W选自
i)-(CR9R10)p-,
ii)-(CR9R10)p-C(O)-,
iii)-(CR9R10)p-O-,
iv)-(CR9R10)p-S-,
v)-(CR9R10)p-S(O)-,和
vi)-(CR9R10)p-S(O)2-;
R2选自
i)取代的苯基,其中所述苯基的环被R6、R7和R8取代,
ii)取代的吡啶基,其中所述吡啶基的环被R6、R7和R8取代,
iii)取代的噻吩基,其中所述噻吩基的环被R6、R7和R8取代,
和
iv)取代的噻唑基,其中所述噻唑基的环被R6、R7和R8取代;
R3选自
i)卤代-C1-6-烷氧基,
ii)C3-8-环烷基-C1-6-烷氧基,
iii)C3-8-环烷氧基,
iv)C1-6-烷基四唑基甲基,和
v)四氢吡喃基-C1-6-烷氧基;
R4选自
i)卤素,
ii)氰基,
iii)卤代-C1-6-烷氧基,
iv)卤代-C1-6-烷基,
v)C3-8-环烷基,和
vi)C1-6-烷基羰基氨基;
R5是H;
R6是氨基磺酰基;
R7和R8独立地选自
i)H,和
ii)卤素;
R9和R10都是H;
m选自0、1和2并且n选自1、2和3,条件是m和n的和是2、3、4或5;
p选自0、1和2;
q选自0和2;
或药用盐。
3.根据权利要求1所述的化合物,其中R1选自
i)被R3、R4和R5取代的苯基,和
ii)被R3、R4和R5取代的吡啶基。
4.根据权利要求1或2所述的化合物,其中R1是被R3、R4和R5取代的苯基。
5.根据权利要求1或2所述的化合物,其中Y是-(CH2)qC(O)-。
6.根据权利要求1或2所述的化合物,其中W选自
i)-(CR9R10)p-,
ii)-(CR9R10)p-S-,和
iii)-(CR9R10)p-S(O)2-。
7.根据权利要求1或2所述的化合物,其中R2选自
i)取代的苯基,其中所述苯基的环被R6、R7和R8取代,和
ii)取代的吡啶基,其中所述吡啶基的环被R6、R7和R8取代。
8.根据权利要求1所述的化合物,其中R3选自
i)卤代-C1-6-烷氧基,
ii)C3-8-环烷基-C1-6-烷氧基,
iii)C3-8-环烷氧基,
iv)C1-6-烷基四唑基甲基,和
v)四氢吡喃基-C1-6-烷氧基。
9.根据权利要求1或2所述的化合物,其中R3选自
i)C1-6-烷基四唑基甲基,和
ii)四氢吡喃基-C1-6-烷氧基。
10.根据权利要求1所述的化合物,其中R4选自
i)卤素,
ii)氰基,
iii)卤代-C1-6-烷氧基,
iv)卤代-C1-6-烷基,
v)C3-8-环烷基,和
vi)C1-6-烷基羰基氨基。
11.根据权利要求1或2所述的化合物,其中R4选自
i)卤代-C1-6-烷基,和
ii)C3-8-环烷基。
12.根据权利要求1所述的化合物,其中R5是H。
13.根据权利要求1所述的化合物,其中R7和R8独立地选自
i)H,和
ii)卤素。
14.根据权利要求1或2所述的化合物,其中R7是卤素。
15.根据权利要求1所述的化合物,其中R8选自
i)H,和
ii)卤素。
16.根据权利要求1所述的化合物,其中R9和R10都是H。
17.根据权利要求1所述的化合物,其中m选自0、1和2并且n选自1、2和3,条件是m和n的和是2、3、4或5。
18.根据权利要求1或2所述的化合物,其中m和n都是2。
19.根据权利要求1或2所述的化合物,其中p选自0和1。
20.根据权利要求1或2所述的化合物,其中p是0。
21.根据权利要求1或2所述的化合物,其中q是2。
22.根据权利要求1所述的化合物,所述化合物选自
4-(2-氟-4-氨磺酰基苯基)哌嗪-1-甲酸2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苄酯;
4-[(4-氨磺酰基苯基)甲基]哌啶-1-甲酸[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-基]甲酯;
4-[(4-氨磺酰基苯基)甲基]哌啶-1-甲酸[5-氰基-3-(2,2-二甲基丙酰基氨基)吡啶-2-基]甲酯;
4-(2-氟-4-氨磺酰基苯基)磺酰基哌啶-1-甲酸[5-氯-3-[(5-甲基四唑-2-基)甲基]吡啶-2-基]甲酯;
4-(2-氟-4-氨磺酰基苯基)磺酰基哌啶-1-甲酸[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]甲酯
2-氟-4-[[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]甲基]苯磺酰胺;
3-氟-4-[[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]甲基]苯磺酰胺;
4-[[4-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌嗪-1-基]甲基]-3-氟苯磺酰胺;
3-氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-羰基]苯磺酰胺;
2-氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-羰基]苯磺酰胺;
3,5-二氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-羰基]苯磺酰胺;
3-氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-羰基]苯磺酰胺;
4-(4-(3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙酰基)哌嗪-1-羰基)苯磺酰胺;
3-[[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]甲基]-4-氟苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]硫基苯磺酰胺;
3-氟-4-(4-(3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙酰基)哌嗪-1-基)苯磺酰胺;
4-[[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]甲基]苯磺酰胺;
4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]甲基]苯磺酰胺;
4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]吡咯烷-2-基]甲氧基]苯磺酰胺;
4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]吡咯烷-3-基]甲氧基]苯磺酰胺;
4-(1-(3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙酰基)哌啶-4-基)苯磺酰胺;
4-(4-(3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙酰基)哌嗪-1-基)苯磺酰胺;
4-氟-3-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]甲基]苯磺酰胺;
2,3-二氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]硫基苯磺酰胺;
2,3-二氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]亚磺酰基苯磺酰胺;
2,3-二氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]磺酰基苯磺酰胺;
2,3-二氟-4-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基磺酰基]苯磺酰胺;
2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]硫基-1,3-噻唑-5-磺酰胺;
2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]磺酰基-1,3-噻唑-5-磺酰胺;
2-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基亚磺酰基]-1,3-噻唑-5-磺酰胺;
3-氟-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]甲基硫基]苯磺酰胺;
3-氟-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]甲基亚磺酰基]苯磺酰胺;
3-氟-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]甲基磺酰基]苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]氮杂环丁-3-基]硫基苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]氮杂环丁-3-基]亚磺酰基苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]氮杂环丁-3-基]磺酰基苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]亚磺酰基苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]磺酰基苯磺酰胺;
3-氟-4-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基硫基]苯磺酰胺;
3-氟-4-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基亚磺酰基]苯磺酰胺;
3-氟-4-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基磺酰基]苯磺酰胺;
3-氟-4-[2-[1-[6-(2,2,2-三氟乙氧基)-5-(三氟甲基)吡啶-3-羰基]哌啶-4-基]乙基磺酰基]苯磺酰胺;
3-氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]磺酰基苯磺酰胺;
4-[[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]甲基硫基]-3-氟苯磺酰胺;
4-[[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]甲基亚磺酰基]-3-氟苯磺酰胺;
4-[[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]甲基磺酰基]-3-氟苯磺酰胺;
4-[1-(6-环丁基氧基-5-环丙基吡啶-3-羰基)哌啶-4-基]磺酰基-3-氟苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]氮杂环丁-3-基]硫基-3-氟苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]氮杂环丁-3-基]亚磺酰基-3-氟苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]氮杂环丁-3-基]磺酰基-3-氟苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]磺酰基-2,3-二氟苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]磺酰基-3-氟苯磺酰胺;
4-[1-[3-[4-氯-2-[(5-甲基四唑-2-基)甲基]苯基]丙酰基]哌啶-4-基]磺酰基-3-氟苯磺酰胺;
4-[1-[3-[4-氰基-2-[(5-甲基四唑-2-基)甲基]苯基]丙酰基]哌啶-4-基]磺酰基-3-氟苯磺酰胺;
4-[2-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]乙基硫基]-3-氟苯磺酰胺;
4-[2-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]乙基亚磺酰基]-3-氟苯磺酰胺;
4-[2-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]乙基磺酰基]-3-氟苯磺酰胺;
4-[2-[1-[5-环丙基-6-(环丙基甲氧基)吡啶-3-羰基]哌啶-4-基]乙基磺酰基]-3-氟苯磺酰胺;
4-[4-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌嗪-1-基]磺酰基-3-氟苯磺酰胺;
4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]磺酰基苯磺酰胺;
5-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]硫基噻吩-2-磺酰胺;
5-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基磺酰基]噻吩-2-磺酰胺;
5-氟-6-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]硫基吡啶-3-磺酰胺;
6-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]硫基-5-氟吡啶-3-磺酰胺;
4-[1-[3-[4-(二氟甲氧基)-2-[(5-甲基四唑-2-基)甲基]苯基]丙酰基]哌啶-4-基]磺酰基-3-氟苯磺酰胺;
4-[2-[1-[3-[4-(二氟甲氧基)-2-[(5-甲基四唑-2-基)甲基]苯基]丙酰基]哌啶-4-基]乙基亚磺酰基]-2,3-二氟苯磺酰胺;
2,3-二氟-4-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基亚磺酰基]苯磺酰胺;
2-[2-[1-[3-[4-(二氟甲氧基)-2-[(5-甲基四唑-2-基)甲基]苯基]丙酰基]哌啶-4-基]乙基亚磺酰基]-1,3-噻唑-5-磺酰胺;
2-[2-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]乙基磺酰基]-1,3-噻唑-5-磺酰胺;
(+)-3-氟-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]亚磺酰基]苯磺酰胺;
(+)-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]吡咯烷-2-基]甲氧基]苯磺酰胺;
(+)-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]吡咯烷-3-基]甲氧基]苯磺酰胺;
(-)-3-氟-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]亚磺酰基]苯磺酰胺;
(-)-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]吡咯烷-2-基]甲氧基]苯磺酰胺;
(-)-4-[[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]吡咯烷-3-基]甲氧基]苯磺酰胺;
4-((4-(3-(2-((5-甲基-2H-四唑-2-基)甲基)-4-(三氟甲基)苯基)丙酰基)哌嗪-1-基)甲基)苯磺酰胺;
及其药用盐。
23.根据权利要求1所述的化合物,所述化合物选自
3-氟-4-[[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]甲基]苯磺酰胺;
2,3-二氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]磺酰基苯磺酰胺;
3-氟-4-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]磺酰基苯磺酰胺;
3-氟-4-[4-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌嗪-1-基]磺酰基苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]磺酰基-2,3-二氟苯磺酰胺;
4-[1-[2-环丙基-6-(氧杂环己烷-4-基甲氧基)吡啶-4-羰基]哌啶-4-基]磺酰基-3-氟苯磺酰胺;
5-氟-6-[1-[3-[2-[(5-甲基四唑-2-基)甲基]-4-(三氟甲基)苯基]丙酰基]哌啶-4-基]硫基吡啶-3-磺酰胺;
及其药用盐。
25.一种药物组合物,所述药物组合物包含根据权利要求1至21中任一项所述的化合物和治疗惰性载体。
26.根据权利要求1至21中任一项所述的化合物用于制备药物的用途,所述药物用于治疗或预防眼病症。
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IL269188B (en) | 2021-12-01 |
CO2019009373A2 (es) | 2019-09-09 |
SG11201908560SA (en) | 2019-10-30 |
CR20190423A (es) | 2019-11-01 |
WO2018167001A1 (en) | 2018-09-20 |
CA3053329A1 (en) | 2018-09-20 |
CN110392679A (zh) | 2019-10-29 |
MA49879A (fr) | 2020-06-24 |
MX2019010772A (es) | 2019-12-16 |
RU2019132254A (ru) | 2021-04-16 |
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TW201838982A (zh) | 2018-11-01 |
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PH12019502118A1 (en) | 2020-07-06 |
CL2019002609A1 (es) | 2020-02-14 |
JP7157755B2 (ja) | 2022-10-20 |
US20200002297A1 (en) | 2020-01-02 |
EP3596059A1 (en) | 2020-01-22 |
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