CN1764635A - 羧酸化合物 - Google Patents
羧酸化合物 Download PDFInfo
- Publication number
- CN1764635A CN1764635A CNA2004800079145A CN200480007914A CN1764635A CN 1764635 A CN1764635 A CN 1764635A CN A2004800079145 A CNA2004800079145 A CN A2004800079145A CN 200480007914 A CN200480007914 A CN 200480007914A CN 1764635 A CN1764635 A CN 1764635A
- Authority
- CN
- China
- Prior art keywords
- amino
- phenyl
- carbonyl
- propionic acid
- pyrans
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- -1 carboxylic acid compounds Chemical class 0.000 title abstract description 55
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 316
- 239000003814 drug Substances 0.000 claims abstract description 43
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
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- 230000036407 pain Effects 0.000 claims abstract description 20
- 201000010099 disease Diseases 0.000 claims abstract description 17
- 208000003251 Pruritus Diseases 0.000 claims abstract description 14
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000002485 urinary effect Effects 0.000 claims abstract description 10
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 564
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 317
- 235000019260 propionic acid Nutrition 0.000 claims description 282
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 282
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 241
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 57
- 238000002360 preparation method Methods 0.000 claims description 51
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 44
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- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 10
- 230000004913 activation Effects 0.000 claims description 8
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- OHCQJHSOBUTRHG-KGGHGJDLSA-N FORSKOLIN Chemical compound O=C([C@@]12O)C[C@](C)(C=C)O[C@]1(C)[C@@H](OC(=O)C)[C@@H](O)[C@@H]1[C@]2(C)[C@@H](O)CCC1(C)C OHCQJHSOBUTRHG-KGGHGJDLSA-N 0.000 claims description 6
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- GSGGGWKJETXHBZ-GOSISDBHSA-N 3-[4-[(2,5-difluorophenoxy)methyl]-2-[[(1r)-1-naphthalen-1-ylethyl]carbamoyl]phenyl]propanoic acid Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)C(=O)C(C(=CC=1)CCC(O)=O)=CC=1COC1=CC(F)=CC=C1F GSGGGWKJETXHBZ-GOSISDBHSA-N 0.000 claims description 3
- YAHQKIFKHUOWKP-GOSISDBHSA-N 3-[4-[(2,5-difluorophenoxy)methyl]-2-[[(1r)-1-naphthalen-2-ylethyl]carbamoyl]phenyl]propanoic acid Chemical compound N([C@H](C)C=1C=C2C=CC=CC2=CC=1)C(=O)C(C(=CC=1)CCC(O)=O)=CC=1COC1=CC(F)=CC=C1F YAHQKIFKHUOWKP-GOSISDBHSA-N 0.000 claims description 3
- GYPCCLWXKCELLX-GOSISDBHSA-N 4-[4-(3,5-difluoroanilino)-2-[[(1r)-1-naphthalen-1-ylethyl]carbamoyl]phenyl]butanoic acid Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)C(=O)C(C(=CC=1)CCCC(O)=O)=CC=1NC1=CC(F)=CC(F)=C1 GYPCCLWXKCELLX-GOSISDBHSA-N 0.000 claims description 3
- ZPCTWPISNWMESA-HXUWFJFHSA-N 4-[4-(3-cyanoanilino)-2-[[(1r)-1-naphthalen-1-ylethyl]carbamoyl]phenyl]butanoic acid Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)C(=O)C(C(=CC=1)CCCC(O)=O)=CC=1NC1=CC=CC(C#N)=C1 ZPCTWPISNWMESA-HXUWFJFHSA-N 0.000 claims description 3
- YUXPZJVJIGXPRR-LJQANCHMSA-N 4-[4-(3-fluoroanilino)-2-[[(1r)-1-naphthalen-1-ylethyl]carbamoyl]phenyl]butanoic acid Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)C(=O)C(C(=CC=1)CCCC(O)=O)=CC=1NC1=CC=CC(F)=C1 YUXPZJVJIGXPRR-LJQANCHMSA-N 0.000 claims description 3
- ILHMLIDSFQXERT-OAQYLSRUSA-N 4-[4-(3-methylphenoxy)-2-[[(1r)-1-naphthalen-1-ylethyl]carbamoyl]phenyl]butanoic acid Chemical compound N([C@H](C)C=1C2=CC=CC=C2C=CC=1)C(=O)C(C(=CC=1)CCCC(O)=O)=CC=1OC1=CC=CC(C)=C1 ILHMLIDSFQXERT-OAQYLSRUSA-N 0.000 claims description 3
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- PEKDQOJCERRHBF-HXUWFJFHSA-N NCC=1C=C(C=CC1)NC1=CC(=C(C=C1)CCCC(=O)O)C(=O)N[C@H](C)C1=CC=CC2=CC=CC=C12 Chemical compound NCC=1C=C(C=CC1)NC1=CC(=C(C=C1)CCCC(=O)O)C(=O)N[C@H](C)C1=CC=CC2=CC=CC=C12 PEKDQOJCERRHBF-HXUWFJFHSA-N 0.000 claims description 3
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Classifications
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
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- C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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Abstract
本发明涉及式(I)的羧酸化合物:其中R1是H或烷基;m是2或3;n是0-2的整数;R2是苯基、萘基、苯并呋喃或苯并噻吩;Q是-CH2-O-Cyc1、-CH2-Cyc2或-L-Cyc3;并且R3a和R3b各自独立是氢或烷基,或R3a和R3b一起形成四氢-2H-吡喃;其药学上可接受的盐、其制备方法和包含这样的化合物作为活性成分的药物。由于具有特异地拮抗PGE2受体(尤其是其亚型-EP3受体)的活性,式(I)化合物可用于预防和/活治疗搔痒症、疼痛、排尿紊乱或应激反应诱导的疾病。
Description
技术领域
本发明涉及羧酸化合物。更具体地,本发明涉及式(I)羧酸化合物:
其中所有符号具有如下所述的含义;其盐、其溶剂合物或其前药、其制备方法以及包含其作为活性成分的药物。
发明背景
前列腺素E2(PGE2)被认为是花生四烯酸级联中的代谢产物。已知PGE2具有细胞-保护活性、子宫收缩活性、疼痛-诱导作用、对消化性蠕动的促进作用、觉醒作用、对胃酸分泌的抑制作用、降血压活性以及利尿活性。
在最近的研究中发现,PGE2受体分为几种亚型,其相互之间具有不同的生理作用。目前已知四种受体亚型且分别被称为EP1、EP2、EP3和EP4[J.Lipid Mediators Cell Signaling,
12,379-391(1995)]。
在这些亚型中,EP3受体被认为涉及外周神经的信号转导、控制中枢神经中的放热反应、通过在脑神经元中表达形成记忆、血管化作用、以及通过在肾小管中表达重吸收尿、子宫收缩、ACTH的生成、血小板聚集。此外,它还在血管平滑肌、心脏和胃肠道中表达。
因此,可与EP3受体强烈结合并显示拮抗活性的化合物可用于预防和/或治疗由于EP3受体过度表达而诱导的疾病。
WO 02/16311的说明书中描述了一种具有EP3和/或EP4受体拮抗剂活性的化合物-式(IA)的羧酸化合物:
其中R1A是COOH、COOR6A;R6A是C1-6烷基等;AA是C1-6亚烷基等;R2A是C1-6烷基、C2-6链烯基、C2-6炔基、C1-6烷氧基、卤原子、CF3、氰基、硝基、羟基、NR11AR12A、CONR11AR12A、SO2NR11AR12A或-S(O)xA-(C1-6)烷基;mA是0、1或2;R11A和R12A各自独立是氢或C1-4烷基;XA是0、1或2;BA环是C5-7元单-碳环;R3A是氢或C1-4烷基;R4A是C1-8烷基、C2-8链烯基;R5A是C5-10单-或二-碳环或包括至少一个选自氮、氧或硫杂原子的5-10元单-或二-杂环,各环被1-2个R13A取代或未取代;R13A是C1-6烷基、C1-6烷氧基、卤原子、CF3、氰基、C1-4烷氧基(C1-4)烷基、苯基、苯基(C1-6)烷基、-(C1-4亚烷基)yA-J-(C1-8亚烷基)ZA-R14A、苯甲酰基或噻吩羰基;或其无毒的盐。
发明内容
为了发现了与PGE2受体、EP3受体特异性结合并显示了对其拮抗活性的化合物,本发明人进行了积极的研究,并发现式(I)的羧酸化合物可实现该目的并完成了本发明。
本发明涉及如下方面:
1)式(I)的羧酸化合物:
其中R1是氢或C1-4烷基;
R2是苯基、萘基、苯并呋喃基或苯并噻吩基(benzothionyl),其未被取代或被1-2个C1-4烷基和/或卤素取代;
Q是(i)-CH2-O-Cyc1、(ii)-CH2-Cyc2或(iii)-L-Cyc3;
Cyc1是苯基或吡啶基,其未被取代或被1-2个R4取代;
Cyc2是吲哚基,其未被取代或被1-2个R4取代;
Cyc3是被1-2个R4取代的苯基;
L是-O-或-NH-;
R3a和R3b各自独立是氢或C1-4烷基或
R3a和R3b,与它们所连接的碳原子一起形成四氢-2H-吡喃;
m是2或3;
n是0、1或2;
R4是C1-4烷基、C1-4烷硫基、卤素或氰基或当Cyc3是被2个R4取代的苯基时,两个R4与苯基一起可以形成
其盐、其溶剂合物或其前药。
2)根据上述1)的羧酸化合物,其是
(1)3-(4-(2,5-二氟苯氧基甲基)-2-((((1R)-1-(萘-2-基)乙基)氨基)羰基)苯基)丙酸,
(2)3-(4-(2,5-二氯苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(3)3-(4-(2-氯-5-甲基苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(4)3-(4-(2-氯-5-氟苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(5)3-(4-(2,5-二氟苯氧基甲基)-2-(((4-苯基四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(6)3-(4-(2,5-二氯苯氧基甲基)-2-(((4-苯基四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(7)3-(4-(2-氯-5-氟苯氧基甲基)-2-(((4-苯基四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(8)3-(4-(2,5-二氟苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸,
(9)3-(4-(3-氰基苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸,
(10)3-(4-(2,5-二甲基苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸,
(11)3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(12)3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(13)3-(4-(3-氰基苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(14)3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(15)3-(4-(5-氟吲哚-1-基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(16)3-(4-(2,4-二甲基苯氧基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(17)3-(2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-苯氧基甲基苯基)丙酸,
(18)3-(2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3-吡啶基氧基甲基)苯基)丙酸,
(19)3-(4-(3-氯苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(20)3-(4-(3,4-二甲基苯氧基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(21)3-(4-(2-氯-5-氟苯氧基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(22)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(3-甲基吲哚-1-基甲基)苯基)丙酸,
(23)3-(4-(2,5-二氟苯氧基甲基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丙酸,
(24)3-(4-(2-氟-5-甲基苯氧基甲基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丙酸,
(25)3-(2-(((4-(3,5-二甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2-氟-5-甲基苯氧基甲基)苯基)丙酸,
(26)3-(4-(2-氟-5-甲基苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(27)3-(2-(((4-(苯并呋喃-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2,5-二氟苯氧基甲基)苯基)丙酸,
(28)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(4-氟-2-甲基苯氧基甲基)苯基)丙酸,
(29)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-((2-甲基吡啶-3-基)氧基甲基)苯基)丙酸,
(30)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-((2-甲基吡啶-5-基)氧基甲基)苯基)丙酸,
(31)3-(4-(3-氟苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(32)3-(4-(3-甲基苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(33)3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(34)3-(2-(((4-(苯并呋喃-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2,5-二甲基苯氧基甲基)苯基)丙酸,
(35)3-(2-(((4-(苯并噻吩-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2,5-二甲基苯氧基甲基)苯基)丙酸,
(36)3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(2-(2-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(37)3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(2-(2-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(38)3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(2-(4-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(39)3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(40)3-(4-(6-氟吲哚-1-基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(41)3-(4-(6-氟吲哚-3-基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(42)3-(4-(3-甲基吲哚-1-基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(43)3-(4-(3-氰基苯氧基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(44)3-(4-(6-氟吲哚-1-基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(45)3-(4-(6-氟吲哚-3-基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(46)3-(4-(3-甲基吲哚-1-基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(47)3-(4-(6-氟吲哚-1-基甲基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(48)3-(2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3-甲基吲哚-1-基甲基)苯基)丙酸,
(49)3-(4-(3-氰基苯氧基甲基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(50)4-(4-(1,3-二氧杂茚满-5-基氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(51)4-(4-(3-甲基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(52)4-(4-(3-氰基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(53)4-(4-(3,4-二甲基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(54)4-(4-(茚满-5-基氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(55)4-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(56)4-(4-(3-甲硫基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(57)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(3-氟苯基氨基)苯基)丙酸,
(58)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(3-甲基苯基氨基)苯基)丙酸,
(59)3-(4-(3-氰基苯基氨基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(60)3-(4-(3,5-二氟苯基氨基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(61)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(1,3-二氧杂茚满-5-基氨基)苯基)丙酸,
(62)3-(4-(3,5-二氟苯氧基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(63)3-(4-(3-氰基苯氧基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(64)4-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(萘-2-基)乙基)氨基)羰基)苯基)丁酸,
(65)3-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丙酸,
(66)3-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(萘-2-基)乙基)氨基)羰基)苯基)丙酸,
(67)3-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(3-甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(68)3-(4-(3-甲基苯基氨基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(69)4-(4-(3-氟苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(70)4-(4-(3-甲基苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(71)4-(4-(3,5-二氟苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(72)4-(4-(1,3-二氧杂茚满-5-基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(73)4-(4-(3-氰基苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(74)3-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丙酸,
(75)3-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(萘-2-基)乙基)氨基)羰基)苯基)丙酸,
(76)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(3,5-二甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(77)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(78)3-(4-(3,5-二甲基苯氧基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(79)3-(2-(((4-(苯并呋喃-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3,5-二甲基苯氧基)苯基)丙酸,
(80)3-(2-(((4-(苯并呋喃-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3,5-二甲基苯基氨基)苯基)丙酸,
(81)3-(4-(3,5-二甲基苯氧基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(82)3-(4-(3,5-二甲基苯氧基)-2-(((4-(3,5-二甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(83)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(84)3-(2-(((4-(3,5-二甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3-甲基苯基氨基)苯基)丙酸,
(85)3-(2-(((4-(苯并噻吩-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3,5-二甲基苯基氨基)苯基)丙酸,
(86)3-(4-(3,5-二甲基苯氧基)-2-(((4-(2-(4-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(87)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(2-(4-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(88)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(2-(2-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(89)3-(4-(3,5-二甲基苯氧基)-2-(((4-(2-(2-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,或
(90)3-(4-(3,5-二甲基苯氧基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
其盐、其溶剂化物或其前药。
3)根据上述1)的羧酸化合物,其是
(1)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(5-氟-2-甲基苯氧基甲基)苯基)丙酸,
(2)3-(2-(((4-(苯并噻吩-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2,5-二氟苯氧基甲基)苯基)丙酸,
(3)3-(4-(2-氟-5-甲基苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸,
(4)3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(5)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(6)3-(2-(((4-(苯并噻吩-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3,5-二甲基苯氧基)苯基)丙酸,
(7)3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(8)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(3-吡啶基氧基甲基)苯基)丙酸,
(9)3-(4-(2-氟-5-甲基苯氧基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(10)3-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(11)3-(4-(6-氟吲哚-1-基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(12)3-(4-(3,5-二甲基苯氧基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(13)4-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(14)3-(4-(2-氯-5-甲基苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸,
(15)3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(2-(4-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(16)3-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(3-甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(17)3-(4-(2-氟-5-甲基苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(18)3-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,或
(19)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
其盐、其溶剂化物或其前药。
4)一种药物组合物,其包含根据上述1)的羧酸化合物、其盐、其溶剂化物或其前药。
5)根据上述4)的药物组合物,其是EP3受体拮抗剂。
6)根据上述5)的药物组合物,其是用于因EP3受体过度激活而诱导的疾病的预防和/或治疗药物。
7)根据上述6)的药物组合物,其中因EP3受体过度激活而诱导的疾病选自搔痒症、疼痛、泌尿紊乱和应激反应-相关疾病中的一种或多种。
8)根据上述7)的药物组合物,其中疼痛是关节炎疼痛或神经性疼痛。
9)根据上述7)的药物组合物,其中泌尿紊乱是尿频。
10)一种药物组合物,其包含根据上述1)的羧酸化合物、其盐、其溶剂化物或其前药,以及一种或多种选自甾类药物、非甾类抗炎药、免疫抑制剂、抗过敏药、中介蛋白释放抑制剂、白细胞三烯受体拮抗剂、抗组胺药、福斯高林制剂、磷酸二酯酶抑制剂、氧化氮合酶抑制剂、大麻素-2受体兴奋剂、非阿片类镇痛剂、非类固醇类消炎剂药、环氧合酶抑制剂、阿片类镇痛剂、前列腺素、N-型钙通道阻滞剂、α1肾上腺素受体阻滞剂、黄体酮制剂、抗胆碱能药物、毒蕈碱受体拮抗剂、5-HT1A受体激动剂、σ1受体激动剂、5-羟色胺神经系统激动剂、促肾上腺皮质激素释放因子受体拮抗剂、质子泵抑制剂、M1受体拮抗剂、细胞保护剂、三环类抗抑郁药和四环类抗抑郁剂的药物。
11)一种预防和/或治疗哺乳动物体内因EP3受体过度激活而诱导的疾病的方法,包括给予哺乳动物有效量的根据上述1)的羧酸化合物、其盐、其溶剂化物或其前药。
12)根据上述1)的羧酸化合物其盐、其溶剂化物或其前药在制备用于预防和/或治疗因EP3受体过度激活而诱导的疾病的药物中的用途。
在本发明中,C1-4烷基包括甲基、乙基、丙基、丁基及其异构体。
在本发明中,C1-4烷硫基包括甲硫基、乙硫基、丙硫基、丁硫基及其异构体。
在本发明中,卤素包括氟、氯、溴和碘。
在本发明中,优选的R1是氢、甲基或乙基。
在本发明中,优选的n是0或2。
在本发明中,优选的由R2代表的环取代基是甲基或氟。
在本发明中,优选的R3a和R3b各自独立是氢、甲基、异丁基或由R3a和R3b以及与它们所连接的碳原子所代表的四氢-2H-吡喃。更具体地,优选如下基团:
在本发明中,优选R4是甲基、硫基甲基、氟、氯或氰基。
除非另有指定,本发明包括所有异构体。例如,烷基包括直链的或支链的。此外,本发明还包括双键、环系、稠合环的异构体(E-,Z-,顺-,反-),由不对称碳原子形成的异构体(R-,S-,α-,β-构型,对映体,非对映体),光学活性异构体(D-,L-,d-,l-),通过色谱分离形成的极性化合物(较高极性化合物、较低极性化合物)、平衡化合物(equilibrium compounds)、旋光异构体(rotational isomer)、其任意比例的混合物以及消旋混合物。
在本发明中,具体化合物是描述于实施例中的化合物以及药学上可接受的盐。
盐:
本发明的化合物可通过已知方法转化为相应的药学上可接受的盐。优选无毒和水溶性盐。在本发明中,盐是碱金属盐比如钾盐、钠盐等,碱土金属盐比如钙盐、镁盐等,铵盐,药学上可接受的有机胺比如四甲基铵、三乙基胺、甲胺、二甲基胺、环戊基胺、苄胺、苯乙基胺、哌啶、单乙醇胺、二乙醇胺、三(羟基甲基)甲胺、赖氨酸、精氨酸、N-甲基-D-葡糖胺等。
在本发明中,优选的酸加成盐是无毒和水溶性盐。在本发明中,酸加成盐是无机酸盐比如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐,有机酸盐例如醋酸盐、乳酸盐、洒石酸盐、草酸盐、富马酸盐、马来酸盐、柠檬酸盐、苯甲酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、甲苯磺酸盐、羟乙基磺酸盐、葡糖醛酸、葡糖酸盐。
本发明的化合物及其药学上可接受的盐可通过常规方法转化为相应的水合物。
本发明化合物的制备:
可通过例如如下方法制备本发明式(I)化合物。
(1)在(I)化合物中,其中R1是氢,即,式(Ia)化合物:
其中所有符号具有与前述相同的含义;
可以在碱性条件下对式(Ib)化合物脱保护而制备:
其中R1b是C1-4烷基且其它符号具有与前述相同的含义。
在碱性条件下脱保护的方法是已知的,例如,可以在水混溶有机溶剂(例如,甲醇、乙醇、四氢呋喃、二噁烷或其混合物)中使用碱(例如,氢氧化钠、氢氧化钾和碳酸钾)的水溶液在-10至90℃下完成。
式(Ib)代表的化合物可通过例如根据下面反应路线A-D的方法制备。
反应路线A
反应路线B
反应路线C-1
反应路线C-2
反应路线D
在这些路线中,
Q1是(i)-CH2-O-Cyc1或(ii)-CH2-Cyc2;
Q2是(iii-1)-O-Cyc3;
Q3是(iii-2)-NH-Cyc3;
Q4是(iii)-L-Cyc3;
Y1是羟基保护基;
Y2是氨基保护基;
Ms是甲磺酰基;
Tf是三氟甲基磺酰基;
X是卤素;
其它符号具有与上述相同的含义。
毒性:
已证明本发明化合物的毒性足够低并因此用作药物时足够安全。
工业应用性
药物应用:
本发明化合物显示了结合PGE2受体特别是亚型EP3的拮抗活性,并因此,它们被认为适用于预防和/或治疗例如疼痛(例如,关节炎疼痛、癌性疼痛、骨折时疼痛、手术时疼痛、拔牙后疼痛、神经性疼痛、异常性疼痛、痛觉过敏、疱疹后疼痛等等)、搔痒、荨麻疹、异位性皮炎、接触性皮炎、变应性结膜炎、透析时的各种症状、哮喘、鼻炎、打喷嚏、尿频、膀胱炎、神经原性膀胱、排尿紊乱、射精紊乱、退热、全身性炎症反应、学习能力缺失、阿尔茨海默氏病、癌症的生成、癌扩散、癌扩散至器官、视网膜病、皮肤红斑、温度损伤、灼伤、类固醇性灼伤(steroidal burn)、肾机能不全、肾病、急性肾炎、慢性肾炎、血液电解质异常、先兆性早产(threatened earlydelivery)、先兆流产、月经过多、痛经、子宫内膜异位、经前期综合征、生殖紊乱、应激反应病、焦虑、忧郁症、躁狂-抑郁症、心身障碍、恐慌紊乱、精神错乱、血栓形成、栓塞、暂时性缺血性发作、脑梗塞、动脉粥样硬化、器官移植、心肌梗塞、心功能不全、高血压、动脉硬化、循环紊乱和由此伴随的溃疡、神经病、血管性痴呆、水肿、各种关节炎疾病、滑膜炎、风湿病、骨关节炎、腹泻、便秘、胆汁流出紊乱、溃疡性结肠炎和克罗恩氏病。
优选地,认为它们对于预防和/或治疗疼痛(关节炎疼痛、神经性疼痛)、搔痒、排尿紊乱或应激性疾病时更加有效。
关节炎疼痛的例子包括风湿病、骨关节炎和伴随滑膜炎的疼痛。
神经性疼痛的例子包括带状疱疹神经痛、治疗后神经痛、反射性交感神经萎缩、灼性神经痛、胸廓切开术后疼痛、假肢痛、丘脑疼痛、癌性疼痛、骨折后疼痛、外部损伤或灼伤、舌痛(口内灼伤综合症)和三叉神经痛。
排尿紊乱的例子包括尿频例如与神经性膀胱、神经原性膀胱、受刺激的膀胱、不稳定的膀胱以及与前列腺病态有关的尿频。
应激性疾病的例子包括精神创伤后的应激反应紊乱、应激性胃炎、应激性溃疡、过敏性肠综合征、应激性哮喘、应激性脱发、应激性精神紊乱、忧郁症、心身障碍、恐慌紊乱、应激性失眠症、应激性高血压、应激性头痛、应激性无月经、应激性便秘、应激性过食疾病或拒食以及应激性生殖功能缺乏。
可以给予通过组合本化合物或其盐与其它药物而获得的组合药物实现下列目的:
1)补充和/或增强本化合物的预防和/或治疗效果;
2)改善本化合物的动力学和/或吸收并减少剂量;和/或
3)消除本化合物的副作用。
本化合物与其它药物的组合物可以以并入一个制剂的形式给药,或者可以以单独制剂给药。当这些药物以单独制剂给药时,它们可以同时或在不同时间给药。就后者而言,本化合物可以在另一药物之前给药。或者,另一药物可以在本化合物之前给药。这些药物的给药方法相同或不同。
上述组合制剂起预防和/或治疗效果的疾病并未被具体地限制,但可以是补充和/或增强本化合物的预防和/或治疗效果的那些疾病。
用于补充和/或增强本化合物对于搔痒、荨麻疹、异位性皮炎、接触性皮炎、变应性结膜炎、透析时各种症状的预防和/或治疗效果的其它药物包括甾类药物、非甾族消炎药、免疫抑制剂、抗变应性的药物、介质释放抑制剂、白细胞三烯受体拮抗剂、抗组胺剂、福斯高林制剂、磷酸二酯酶抑制剂、氧化氮合酶抑制剂、大麻素-2受体刺激剂等等。
用于补充和/或增强本化合物对于疼痛的预防和/或治疗效果的其它药物包括非阿片类镇痛剂比如非甾类消炎药、环加氧酶(COX)抑制剂;阿片类镇痛剂,前列腺素,N-型钙通道阻滞剂,氧化氮合酶抑制剂,大麻素-2受体刺激物等等。
用于补充和/或增强本化合物对于神经性疼痛的预防和/或治疗效果的其它药物包括三环类抗忧郁药和四环类抗忧郁药等等。
用于补充和/或增强本化合物对于排尿紊乱的预防和/或治疗效果的其它药物包括用于排尿紊乱的其它药物,比如α1肾上腺素受体阻滞剂、黄体酮制剂、抗胆碱能剂和毒蕈碱受体拮抗剂等等。
用于补充和/或增强本化合物对于应激性疾病的预防和/或治疗效果的其它化合物包括用于应激性疾病的其它药物,比如5-HT1A受体激动剂、σ1受体激动剂、5-羟色胺神经系统激动剂、促皮质释放因子(CRF)受体拮抗剂、质子泵抑制剂、M1受体拮抗剂和细胞保护剂等等。
用于补充和/或增强本化合物对于癌症生成、癌扩散、癌扩散至器官的预防和/或治疗效果的其它药物包括抗癌剂、止痛药、金属蛋白酶抑制剂等等。
非甾类抗炎药的例子包括水杨酰水杨酸、水杨酸钠、阿司匹林、阿司匹林·二铝酸盐掺合物、双氟尼酸、吲哚美辛、sprofen、乌芬那酯、愈创蓝油烃、丁苯羟酸、联苯乙酸、双氯芬酸、甲苯酰吡啶乙酸钠、奇诺力、联苯丁酮酸、萘丁美酮、丙谷美辛、吲哚美辛法呢醇、阿西美辛、丙谷美辛马来酸盐、氨芬酸钠、莫苯唑酸、依托度酸、布洛芬、布洛芬吡啶甲醇、萘普生、氟吡洛芬、醋氧乙基氟吡洛芬、酮洛芬、非诺洛芬钙、噻洛酚酸、噁丙嗪、pyranoprofen、环氧洛芬钠、阿明洛芬、扎托洛芬、甲灭酸、甲灭酸铝、托灭酸、弗洛非宁、酮保泰松、oxyfenbutazone、吡罗昔康、替诺昔康、安吡昔康、联苯乙酸软膏、依匹唑、羟哌苯酮盐酸盐、替诺立定盐酸盐、依莫法宗、sulpirin、米格来宁、散利痛、塞德G、散利痛N、索邦、基于菌毛素的感冒药物、退热净、羟非那西丁、二甲替嗪甲磺酸盐、美洛昔康、塞来考昔、罗非考昔、伐地考昔、西美曲特-包含剂、非基于菌毛素的感冒药等等。
甾类药物的例子包括,例如,作为外用药的丙酸氯氟美松、醋酸二氟拉松、醋酸氟轻松、呋喃羧酸莫米松、二丙酸倍他米松、丁酸丙酸倍他米松、戊酸倍他米松、醋丁二氟龙、布地缩松、戊酸二氟可龙、安西缩松、哈西缩松、地塞米松、丙酸地塞米松、戊酸地塞米松、醋酸氟美松、醋酸氢化可的松、丁酸氢化可的松、丁酸丙酸氢可的松、丙酸地泼罗酮、戊酸醋酸强的松龙、肤轻松、丙酸倍氯米松、醋酸去炎松、特戊酸二氟美松、丙酸阿氯米松、丁酸氯倍他松(clobethasone butyrate)、氢化泼尼松、倍氯米松丙酸酯、氟氢缩松等等。
体内使用的药物和注射剂包括醋酸可的松、氢化可的松、氢化可的松磷酸钠、氢化可的松琥珀酸钠、醋酸氟氢可的松、氢化泼尼松、醋酸氢化泼尼松、强的松龙琥珀酸钠、氢化泼尼松丁基乙酸酯、强的松龙磷酸钠、醋酸卤泼尼松、甲基强的松龙、醋酸甲基强的松龙、甲基泼尼松龙琥珀酸钠、氟羟脱氢皮醇、醋酸氟羟脱氢皮醇、醋酸去炎松、地塞米松、醋酸氟美松、地塞米松磷酸钠、地塞米松棕榈酸、泼拉米松醋酸、倍他米松等等。
吸入剂包括倍丙酸氯米松、丙酸氟替卡松、布地缩松、氟尼缩松、氟羟脱氢皮醇、ST-126P、环索奈德、软脂酸地塞米松(dexamethasonepalomithionate)、糠酸莫米松、磺酸普拉睾酮、地夫可特、甲基强的松龙sleptanate、甲基泼尼松龙琥珀酸酯钠等等。
免疫抑制剂包括普托品(FK-506)、氨甲喋呤、环孢子菌素、子囊霉素、来氟米特、布西拉明、柳氮磺吡啶等等。
介质释放抑制剂包括曲尼司特,色甘酸二钠,氨来占诺,瑞吡司特,异丁司特,他扎司特,吡嘧司特钾等等。
白细胞三烯受体拮抗剂包括普仑司特水合物、孟鲁司特、扎鲁司特、MCC-847、KCA-757、CS-615、YM-158、L-740515、CP-195494、LM-1484、RS-635、A-93178、S-36496、BIIL-284、ONO-4057等等。
抗组胺剂包括富马酸甲哌噻庚酮、美喹他嗪、盐酸氮卓斯汀、奥沙米特、特非那定、富马酸依美斯汀、盐酸依匹斯汀、阿司咪唑、依巴斯汀、盐酸西替立嗪、贝他斯汀、非索非那定、氯雷他定、地氯雷他定、盐酸奥洛他定、TAK-427、ZCR-2060、NIP-530、糠酸莫米松、咪唑斯汀、BP-294、安多司特、金诺芬、阿伐斯汀等等。
抗癌症剂包括烷基化剂(例如,盐酸氮芥N-氧化物、环磷酰胺、异环磷酰胺、美法仑、硫替派、卡巴醌、白消安等等)、亚硝基脲衍生物(例如,嘧啶亚硝脲盐酸盐、雷莫司汀等等)、抗代谢药(例如,氨甲喋呤、巯基嘌呤、6-巯基嘌呤核糖核苷、氟尿嘧啶、替加氟、UFT、卡莫氟、doxyfluridine、阿糖胞苷、依诺他滨等等)、抗癌症抗生素(放线菌素D、自力霉素、柔红霉素盐酸盐、亚德利亚霉素盐酸盐、阿柔比星盐酸盐、新制癌菌素、吡柔比星、表柔比星、依达比星、色霉素A3、博来霉素、硫酸培洛霉素等等)、植物生物碱(例如,硫酸vunblastin、硫酸长春新碱、硫酸长春地辛等等)、激素剂(例如,雌氮芥硫酸钠、美雄烷、表硫雄醇、枸橼酸它莫西芬、磷酸己烯雌酚、6α-甲基-17α-乙酸基孕甾酮、阿那曲唑、法倔唑、醋酸亮丙瑞林等等)、免疫强化剂(例如,香菇多糖、溶链菌制剂、云芝多糖、裂裥菌素、乌苯美司、干扰素等等)(例如等、左旋天冬醯胺、盐酸甲基下肼、盐酸米托蒽醌、顺铂、卡铂等等)。
磷酸二酯酶抑制剂包括PDE4抑制剂比如咯利普兰、西洛司特(商品名:Ariflo)、Bay 19-8004、NIK-616、罗氟司特(BY-217)、西潘茶碱(BRL-61063)、atizoram(CP-80633)、SCH-351591、YM-976、V-11294A、PD-168787、D-4396、IC-485等等。
阿片类镇痛剂包括非甾类抗炎药止痛药(例如,阿斯匹林、阿明洛芬、醋氧乙基氟吡洛芬、舒洛芬、氯苯扎利二钠、替诺昔康、环氧洛芬钠、perbiprofen、氟吡洛芬、吡罗昔康、法奈基吲哚美辛、吡喃洛芬、舒林酸、消炎痛、萘丁美酮、依托度酸、非那西汀、萘普生、双氯灭痛等等)、环加氧酶(COX)抑制剂(例如,扎托洛芬、尼美舒利、扎托洛芬、唑利洛芬、噁丙嗪、咪洛芬、酮洛芬、amtolmetin guacil、莫苯唑酸、氯诺昔康、美洛昔康、安吡昔康、醋氯芬酸、塞来考昔、帕瑞考昔、艾托考昔等等)、甾体类止痛药(例如,双甲丙酰龙、氢化泼尼松等等)、透明质酸钠、金诺芬、依普黄酮、铜锌协同质、阿克他利、subreum、柳氮磺吡啶和来氟米特等等。
阿片样物质类的止痛剂包括磷酸可待因、盐酸丁丙诺啡、盐酸镇痛新、吗啡(盐酸吗啡和硫酸吗啡)、芬太尼、盐酸哌替啶和利富吩等等。
该三环抗忧郁药的实例包括盐酸丙咪嗪、盐酸地昔帕明、盐酸氯丙咪嗪、马来酸三甲丙咪嗪、盐酸阿米替林、盐酸去甲替林、盐酸洛非帕明、阿莫沙平、盐酸度硫平、加巴喷丁、美西律、可乐宁和氯胺酮等等。
四环类抗忧郁药包括马普替林和米塞林等等。
用于排尿紊乱的其它药物是盐酸特拉唑嗪、呱胺甲尿啶、氟氧前列素、盐酸他苏洛辛、盐酸哌唑嗪、烯丙雌烯醇、盐酸羟丁宁、盐酸双苯丁胺、盐酸丙哌维林、萘哌地尔、氯地孕酮、巯乙磺酸钠、阿夫唑嗪、NC-1800、托特罗定、silodosin、非度索嗪、氯化托斯必姆、TF-505、R-701、R-1554、R-802和solifenacin等等。
用于应激性疾病的其它药物是坦度螺酮柠檬酸盐、来索吡琼、伊格美新、AP-521、PLD-116、ilaprazole、ME-3412、DMP-696、ME-3412、YJA-20379-8、盐酸哌仑西平、兰索拉唑、多司马酯和osemozotan等等。
本化合物与其它药物的重量比并没有特别的限制。
可以给予任何两种或多种其它药物的组合。
此外,用于补充和/或增强本化合物的预防和/或治疗效果的其它药物不仅包括迄今为止已发现的那些药物还包括基于上述机理发现的那些药物。
为了上述目的,本化合物或本化合物与其它药物的组合通常可以全身地或局部地给药,一般经口腔或肠胃外给药。
给药剂量取决于例如年龄、体重、症状、期望的疗效、给药途径和治疗的持续时间。对于成年人,每人的口服剂量一般从1μg至10g,每天可给药若干次;胃肠外给药剂量从0.1μg至1g,每天可给药若干次,或每天经静脉持续给药1至24小时。
如上所述,所用剂量取决于各种条件。因此,有时可以使用较上述指定范围更低或更高的剂量。
为了给予本化合物或本化合物与其它药物的组合,用法包括由用于口服给药的内用固体制剂和内用液体药剂以及用于肠胃外给药的注射制剂、外用制剂、栓剂、滴眼液、吸入剂等等。
用于口服给药的内用固体制剂包括片剂、丸剂、胶囊、粉剂、颗粒剂等等。胶囊包括硬胶囊和软胶囊。
这样的内用固体制剂通过常规应用的配制方法制备,使用了一种或两种或多种活性物质或者其与下列物质的混合物:赋形剂(乳糖、甘露糖醇、葡萄糖、微晶纤维素、淀粉等等)、粘合剂(羟丙基纤维素、聚乙烯吡咯烷酮、硅铝酸镁等等)、崩解剂(纤维素乙醇酸钙等等)、润滑剂(硬脂酸镁等等)、稳定剂和助溶剂(谷氨酸、天冬氨酸等等)。如果必要的话、可涂有涂层剂(蔗糖、明胶、羟丙基纤维素、邻苯二甲酸羟丙基甲基纤维素等等)。其可涂有两层或更多层。此外,由可吸收材料比如明胶制备的胶囊包括在其范围内。
用于口服给药的内用液体药剂包括药学上可接受的水溶液、悬浮液、乳剂、糖浆、酏剂等等。这些液体药剂通过在常规应用的稀释剂(净化水、乙醇或其混合物等等)中溶解、悬浮或乳化一种或多种活性物质而制备。这些液体形式还可进一步包含一些添加剂比如湿润剂、悬浮剂、乳化剂、甜味剂、调味剂、芳香剂、防腐剂、缓冲剂等等。
外用的肠胃外给药制剂的剂型包括软膏、凝胶剂、乳剂、热敷剂、贴片、搽剂、雾化剂、吸入剂、喷雾剂、气雾剂、滴鼻剂等等。这样的制剂包含一种或两种或多种活性物质并通过公知的方法或通常使用的配方制备。
根据公知的配方或通常使用的配方制备软膏剂。例如,通过在基质中软化或熔融一种或两种活性物质而制备。软膏基质选自公知的或通常使用的基质。例如,可以由一种基质或其两种或多种的混合物制备,这些基质选自较高级脂肪酸或高级脂肪酸酯(己二酸、肉豆蔻酸、棕榈酸、硬脂酸、油酸、己二酸酯、肉豆蔻酸酯、棕榈酸酯、硬脂酸酯、油酸酯等等)、石蜡(蜂蜡、鲸石蜡、地蜡等等)、表面活性剂(聚氧乙烯烷基醚磷酸酯等等)、高级醇(鲸蜡醇、硬脂醇、十八醇十六醇混合物等等)、硅氧烷油类(二甲聚硅氧烷等等)、烃(亲水性凡士林、白凡士林、精制羊毛脂、液体石蜡等等)、乙二醇(乙二醇、二乙二醇、丙二醇、聚乙二醇、聚乙二醇等等)、植物油(蓖麻油、橄榄油、芝麻油、松节油等等)、动物油类(貂油、蛋黄油、角鲨烷、角鲨烯等等)、水、吸收促进剂和皮肤刺激性抑制剂。软膏剂还可包含湿润剂、防腐剂、稳定剂、抗氧化剂、调味剂等等。
根据公知的配方或通常使用的配方制备凝胶剂。例如,通过在基质中熔融一种或多种活性物质而制备。凝胶基质基质选自公知的或通常使用的基质。例如,可以由一种基质或其两种或多种的混合物制备,这些基质选自低级醇(乙醇、异丙醇等等)、胶凝剂(羧甲基纤维素、羟乙基纤维素、羟丙基纤维素、乙基纤维素等等)、中和剂(三乙醇胺、二异丙醇胺等等)、表面活性剂(聚乙二醇一硬脂酸等等),树胶、水、吸附促进剂和皮肤刺激性抑制剂。凝胶剂还可包含防腐剂,抗氧化剂,调味剂等等。
例如,通过在基质中熔融或乳化一种或多种活性物质而制备。膏基选自公知的或通常使用的基质。例如,可以由一种基质或其两种或多种的混合物制备,这些基质选自高级脂肪酸酯、低级醇、烃、多元醇(丙二醇、1,3-丁二醇等等)、高级醇(2-十六醇、鲸蜡醇等等)、乳化剂(聚氧乙烯烷基醚,脂肪酸酯等等)、水、吸收促进剂和皮肤刺激性抑制剂。乳剂还可包含防腐剂、抗氧化剂、调味剂等等。
根据公知的配方或通常使用的配方制备热敷剂。例如,通过在基质中熔融一种或多种活性物质,捏和然后在底物上应用并散布该捏和物质而制备。热敷剂基质选自公知的或通常使用的基质。例如,可以由一种基质或其两种或多种的混合物而制备,这些基质选择增稠剂(聚丙烯酸、聚乙烯吡咯烷酮、阿拉伯胶、淀粉、明胶、甲基纤维素等等)、润湿剂(脲、甘油、丙二醇等等)、填料(高岭土、氧化锌、滑石粉、钙、镁等等)、水、助溶剂、增粘剂和皮肤刺激性抑制剂。热敷剂还可包含防腐剂、抗氧化剂、调味剂等等。
根据公知的配方或通常使用的配方制备贴片。例如,通过在基质中熔融一种或多种活性物质碱然后在一种底物上应用并散布而制备。贴片基质选自公知的或通常使用的基质。例如,可以由一种基质或其两种或多种的混合物制备,这些基质选自聚合物基质、油脂、较高级脂肪酸、增粘剂和皮肤刺激性抑制剂。贴片还可包含防腐剂、抗氧化剂、调味剂等等。
根据公知的配方或通常使用的配方制备搽剂。例如,通过在一种或多种选择水、醇(乙醇、聚乙二醇等等)、较高级脂肪酸、甘油、脂肪酸、乳化剂、悬浮剂等的媒介中溶解、悬浮或乳化一种或两种活性物质而制备。搽剂还可包含防腐剂、抗氧化剂、调味剂等等。
除通常使用的稀释剂外,雾化剂、吸入剂和喷雾剂可包含稳定剂比如亚硫酸氢钠,用于提供等渗性的缓冲剂例如等渗剂比如氯化钠、柠檬酸钠或柠檬酸。制备喷雾剂的方法详细描述于例如US 2,868,691和US 3,095,355中。
用于肠胃外给药的注射剂包括溶液、悬浮液、乳剂和将会在使用之前溶解或混悬的固体注射剂。这样的注射剂通过在溶液中溶解、悬浮或乳化一种或多种活性物质而使用。该溶剂包括例如注射用蒸馏水、生理盐水、植物油、醇比如丙二醇、聚乙二醇和乙醇及其混合物。该注射剂可以进一步包含稳定剂、助溶剂(谷氨酸、天冬氨酸、Polysorbate 80(注册商标)等等),悬浮剂、乳化剂、安抚剂、缓冲剂、防腐剂等等。这样的注射剂可以通过在最终步骤灭菌或使用防腐剂过程而制备。或者,还可制备无菌的固态产物比如冷冻干燥产品并在使用之前灭菌或溶于无菌的注射用蒸馏水或其它溶剂。
用于肠胃外给药的吸入剂包括气雾剂、用于吸入的粉剂和用于吸入的液体。这些吸入剂可溶解或悬浮在水或其它合适的媒介中备用。
根据公知的方法可以制备该吸入剂。
例如,用于吸入的液体药剂可以,如果必要的话,通过适当地选择下列物质而制备:防腐剂(苯扎氯铵、帕拉贝等等)、着色剂、缓冲剂(磷酸钠、醋酸钠等等)、等渗剂(氯化钠、浓缩甘油等等)、增稠剂(聚羧乙烯等等)、吸收促进剂等等。
用于吸入的粉剂可以,如果必要的话,通过适当地选择下面的物质而制备:润滑剂(硬脂酸及其盐等等)、粘合剂(淀粉、糊精等等)、赋形剂(乳糖、纤维素等等)、着色剂、防腐剂(苯扎氯铵、帕拉贝等等)、吸收促进剂等等。
当给予该用于吸入的液体时,通常使用喷雾器(雾化器、喷雾器)。当使用该用于吸入的粉剂时,通常使用一种粉剂吸入给药装置。
用于肠胃外给药的其它组合物包括栓剂和用于阴道给药的子宫托,其包含一种或多种活性物质并且根据普通的配方制备。
完成本发明的最佳方式
现在,参考下面的参考实施例、实施例、制剂实施例和测试实施例更加详细地描述本发明,尽管本发明不被解释为受限于此。
用于本发明中的化合物名称是根据IUPAC规则命名的。
在括号中给出的关于色谱分离和TLC的溶剂说明了所用的各洗脱剂或展开剂而且比值表示体积比。
在括号中给出的关于NMR的溶剂说明了在测量中所应用的各种溶剂。
参考实施例1
7-溴甲基香豆素
向7-甲基香豆素(50g)的乙腈(1.2L)溶液中加入N-溴代丁二酰亚胺(56g)和α,α′-偶氮二异丁基腈(510mg),于内温78℃下搅拌该混合物30分钟。浓缩反应混合物并加入水。过滤收集结晶得到具有下列物理参数的标题化合物(76g)。
NMR(300MHz,CDCl3):δ7.69(d,9.6Hz,1H),7.46(d,J=8.1Hz,1H),7.34(d,J=1.8Hz,1H),7.30(dd,J=8.1,1.8Hz,1H),6.43(d,9.6Hz,1H),4.52(s,2H)。
参考实施例2
7-(2,5-二氟苯氧基甲基)香豆素:
将参考实施例1中制备的化合物(40g)、2,5-二氟苯酚(21.8g)和碳酸钾(46.4g)溶于二甲基甲酰胺(DMF;250mL)中,于60℃加热该混合物50分钟。该反应混合物冷却至室温后,向该混合物中加入水。过滤收集固体。干燥该固体得到具有下列物理参数的标题化合物(43.9g)。
NMR(300MHz,DMSO-d6):δ8.05(d,J=9.6Hz,1H),7.74(d,J=7.8Hz,1H),7.46(brs,1H),7.41(brd,J=7.8Hz,1H),7.32-7.18(m,2H),6.78(m,1H),6.49(d,J=9.6Hz,1H),5.30(s,2H)。
参考实施例3
3-(4-(2,5-二氟苯氧基甲基)-2-羟基苯基)丙烯酸甲酯:
在氩氛中,室温下,向氢化钠(18.2g,60%油)的四氢呋喃(THF;150mL)溶液中加入甲醇(24.6mL)。于50℃搅拌该混合物30分钟。冷却该混合物至室温,将参考实施例2中制备的化合物(43.9g)的DMF(750mL)溶液滴加入该混合物中。于50℃搅拌该混合物30分钟。冷却该混合物至室温。冰浴中向该混合物中加入1N盐酸。使用乙酸乙酯提取该混合物。有机层经水和饱和氯化钠水溶液洗涤,无水硫酸镁干燥并浓缩。所得固体经叔丁基甲基醚/己烷混合溶剂结晶得到具有下列物理参数的标题化合物(46.5g)。
NMR(300MHz,DMSO-d6):δ10.4(s,1H),7.84(d,J=16.2Hz,1H),7.64(d,J=7.8Hz,1H),7.26(m,1H),7.16(m,1H),6.98(s,1H),6.89(d,J=7.8Hz,1H),6.77(m,1H),6.61(d,J=16.2Hz,1H),5.15(s,2H),3.70(s,3H)。
参考实施例4
3-(4-(2,5-二氟苯氧基甲基)-2-羟基苯基)丙酸甲酯:
向参考实施例3中制备的化合物(46.5g)的THF(400mL)/甲醇(100mL)溶液中缓慢加入六水二氯化镍(41.3g)和硼氢化钠(21.9g)。搅拌该混合物2.5小时。反应溶液经叔丁基甲基醚稀释并通过celite(商标)过滤。滤液经乙酸乙酯稀释,用水和饱和氯化钠水溶液洗涤,硫酸镁干燥并浓缩。残留物经硅胶柱色谱(乙酸乙酯∶己烷=1∶1)纯化得到具有下列物理参数的标题化合物(23.6g)。
NMR(300MHz,CDCl3):δ7.20(s,1H),7.10(d,J=7.8Hz,1H),7.01(ddd,J=10.5,9.0,5.4Hz,1H),6.96-6.91(m,2H),6.71(m,1H),6.58(m,1H),5.03(s,2H),3.70(s,3H),2.92-2.88(m,2H),2.74-2.70(m,2H)。
参考实施例5
3-(2-羧基-4-(2,5-二氟苯氧基甲基)苯基)丙酸甲酯:
在氩氛中,0℃下,向参考实施例4中制备的化合物(250mg)的吡啶(1.55mL)溶液中加入三氟甲磺酸酯(144μL)。室温下搅拌该混合物60分钟。反应混合物经乙酸乙酯稀释。稀释液相继经水、1N盐酸、水和饱和氯化钠水溶液洗涤,硫酸镁干燥并浓缩。
在氩氛中,向所得化合物的DMF(2.5mL)溶液中继续加入乙酸钾(380mg)、双(二苯基膦基)二茂铁(41mg)和乙酸钯(II)(8.7mg)。该混合物在一氧化碳气体中于90℃搅拌过夜。反应混合物经叔丁基甲基醚稀释并通过celite(商标)过滤。滤液相继经饱和氯化铵溶液、水和饱和氯化钠水溶液洗涤,硫酸镁干燥并浓缩。残留物经硅胶柱色谱(乙酸乙酯∶己烷=1∶1)纯化得到具有下列物理参数的标题化合物(193mg)。
NMR(300MHz,CDCl3):δ8.11(d,J=1.8Hz,1H),7.59(dd,J=8.1,1.8Hz,1H),7.38(d,J=8.1Hz,1H),7.04(m,1H),6.74(m,1H),6.62(m,1H),5.11(s,2H),3.67(s,3H),3.38-3.33(m,2H),2.74-2.69(m,2H)。
参考实施例6
4-羟基-4-(3,5-二甲基苯基)四氢-2H-吡喃:
在氩氛中,-78℃下,向5-溴-间-二甲苯(5.55g)的THF(60mL)溶液中加入正丁基锂(17.8mL)。搅拌该混合物1小时。向反应混合物中加入四氢呋喃-4-酮(2.0g),并搅拌该混合物3小时。向该反应混合物中加入水并用乙酸乙酯稀释该溶液。有机层经水和饱和氯化钠水溶液洗涤,硫酸镁干燥并浓缩。残留物经硅胶柱色谱(乙酸乙酯∶己烷=1∶3)纯化得到具有下列物理参数的标题化合物(2.6g)。
TLC:Rf 0.51(乙酸乙酯∶己烷=1∶1);
NMR(300MHz,CDCl3):δ7.10(s,2H),6.93(s,1H),3.99-3.82(m,5H),2.34(s,6H),2.23-2.11(m,2H),1.72-1.63(m,2H)。
参考实施例7
N-(4-(3,5-二甲基苯基)四氢-2H-吡喃-4-基)氯乙酰胺:
在冰浴下,向参考实施例6中制备的化合物(1.51g)的氯乙腈(5mL)和乙酸(10mL)溶液中缓慢滴加硫酸(3滴)。室温搅拌该混合物过夜。将该混合物倾入冰水中并加入5N氢氧化钠水溶液碱化。用叔丁基甲基醚提取该混合物。有机层经水和饱和氯化钠水溶液洗涤,硫酸镁干燥并浓缩。残留物经硅胶柱色谱(乙酸乙酯∶己烷=1∶3)纯化得到具有下列物理参数的标题化合物(288mg)。
TLC:Rf 0.54(乙酸乙酯∶己烷=1∶1);
NMR(300MHz,CDCl3):δ6.98(s,2H),6.90(s,1H),6.76(bs,1H),4.02(s,2H),3.89(dt,J=12.0,3.3Hz,2H),3.72(dt,J=12.0,2.1Hz,2H),2.42-2.34(m,2H),2.32(s,6H),2.29-2.13(m,2H)。
参考实施例8
4-氨基-4-(3,5-二甲基苯基)四氢-2H-吡喃:
向参考实施例7制备的化合物(250mg)的乙醇(2mL)和乙酸(0.4mL)溶液中加入硫脲(81.2mg)。于70℃搅拌该混合物过夜。反应混合物经叔丁基甲基醚稀释,加入2N氢氧化钠水溶液碱化并分离有机层。该有机层经水和饱和氯化钠水溶液洗涤,硫酸镁干燥并浓缩得到具有下列物理参数的标题化合物(160mg)。
TLC:Rf 0.54(甲醇∶氯仿=1∶5);
NMR(300MHz,CDCl3):δ7.07(s,2H),6.90(s,1H),3.92(dt,J=11.4,2.4Hz,2H),3.79(dt,J=11.4,4.2Hz,2H),2.34(s,6H),2.24-2.13(m,2H),1.68-1.60(m,2H)。
参考实施例9
(2R)-3-氮杂-4-(3,5-二甲基苯基)-2-苯基-3-丁烯-1-醇:
将3,5-二甲基苯甲醛(30.0g)和(R)-苯基甘氨醇(30.7g)的甲苯溶液(200mL)回流3小时同时蒸除与水共沸的混合物。浓缩反应混合物得到具有下列物理参数的标题化合物(59.7g)
TLC:Rf 0.69(己烷∶乙酸乙酯=4∶1)。
参考实施例10
(2R,4R)-3-氮杂-6-甲基-4-(3,5-二甲基苯基)-2-苯基-6-庚烯-1-醇盐酸盐:
在氩氛中,于氯化钠冰浴中,向镁(40.8g)的无水THF(800mL)溶液中滴加3-氯-2-甲基-1-丙烯(60.8g)的无水THF(450mL)溶液。冰浴中搅拌该混合物1.5小时然后室温下搅拌1小时制得格氏试剂。
在氩氛中,于氯化钠冰浴中,用3小时向参考实施例9中制备的化合物的无水甲苯(300mL)溶液中滴加该格氏试剂(1120mL),并在氯化钠冰浴中搅拌该混合物30分钟。将饱和氯化铵溶液和水加入该反应混合物中并分离有机层。水层经乙酸乙酯提取并合并上面的有机层。所合并的有机层经饱和氯化钠水溶液洗涤,无水氯化镁干燥并浓缩。冰浴下向残留物的乙酸乙酯(500mL)溶液中加入4N盐酸/二噁烷(100mL)。浓缩该溶液并使用异丙醇-己烷重结晶得到具有下列物理参数的标题化合物(60.9g)。
TLC:Rf 0.80(己烷∶乙酸乙酯=1∶2);
NMR(300MHz,CDCl3):δ9.52(brs,2H),7.39-7.20(m,5H),6.94(s,2H),6.81(s,1H),5.44(brs,1H),4.70(s,1H),4.63(s,1H),4.40-4.20(m,2H),4.14(m,1H),3.83(m,1H),3.11(dd,J=14,4.4Hz,1H),2.94(dd,J=14,11Hz,1H),2.17(s,6H),1.49(s,3H)。
参考实施例11
(1R)-3-甲基-1-(3,5-二甲基苯基)丁胺盐酸盐:
氢氛中,于60℃搅拌参考实施例10中制备的化合物(33.0g)和氧化铂(IV)(4.60g)的乙醇(330mL)溶液40小时。反应混合物经celite(商标)过滤并浓缩滤液。残留物经乙醇/乙酸乙酯重结晶得到具有下列物理参数的标题化合物(7.30g)。
TLC:Rf 0.30(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ8.41(brs,3H),7.11(s,2H),7.01(s,1H),4.10(m,1H),2.27(s,6H),1.82-1.66(m,2H),1.31(m,1H),0.86(d,J=6.6Hz,3H),0.82(d,J=6.6Hz,3H)。
实施例1
3-(4-(2,5-二氟苯氧基甲基)-2-((((1R)-1-(萘-2-基)乙基)氨基)羰基)苯基)丙酸甲酯
在氩氛中,于室温下搅拌参考实施例5中制备的化合物(80mg)、(1R)-1-(萘-2-基)乙胺(47mg)、1-乙基-3-[3-(二甲基氨基)丙基]碳二酰亚胺(66mg)和1-羟基苯并三唑(46mg)的DMF(1mL)溶液过夜。反应混合物经乙酸乙酯稀释。稀释液相继经1N盐酸、碳酸氢钠水溶液洗涤,经水和饱和氯化钠水溶液洗涤,硫酸镁干燥并浓缩得到具有下列物理参数的标题化合物。
TLC:Rf 0.35(己烷∶乙酸乙酯=1∶1);
NMR(300MHz,CDCl3):δ7.87-7.58(m,4H),7.55-7.39(m,5H),7.27(m,1H),7.02(m,1H),6.80-6.68(m,2H),6.64-6.55(m,1H),5.50(m,1H),5.05(s,2H),3.59(s,3H),3.06(t,J=7.2Hz,2H),2.70(m,2H),1.70(d,J=6.6Hz,3H)。
实施例2
3-(4-(2,5-二氟苯氧基甲基)-2-((((1R)-1-(萘-2-基)乙基)氨基)羰基)苯基)丙酸:
向实施例1中制备的化合物的甲醇(1mL)/THF(1mL)溶液中加入1N氢氧化钠水溶液(1mL),搅拌该混合物过夜。加入1N盐酸酸化该反应混合物并使用乙酸乙酯提取。有机层经水和饱和氯化钠水溶液洗涤,硫酸镁干燥并浓缩。残留物经乙酸乙酯/己烷重结晶得到具有下列物理参数的标题化合物(83mg)。
TLC:Rf 0.47(氯仿∶甲醇=10∶1);
NMR(300MHz,CDCl3):δ1.70(d,J=6.96Hz,3H),2.76(t,J=7.51Hz,2H),3.07(t,J=7.51Hz,2H),5.05(s,2H),5.49(m,1H),6.59(m,2H),6.72(m,1H),7.02(m,1H),7.30(d,J=7.87Hz,1H),7.49(m,5H),7.83(m,4H)。
实施例2(1)至2(59)
经如参考实施例1→参考实施例2→参考实施例3→参考实施例4→参考实施例5→实施例1→实施例2一系列反应相同的过程使用相应的化合物得到下列化合物。
实施例2(1)
3-(4-(2,5-二氯苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.57(氯仿∶甲醇=10∶1);
NMR(300MHz,DMSO-d6):δ1.93(m,2H),2.30(s,3H),2.41(m,2H),2.48(m,2H),2.86(t,J=7.83Hz,2H),3.76(m,4H),5.27(s,2H)7.05(m,2H),7.22(m,3H),7.34(d,J=7.69Hz,1H),7.42(m,2H),7.50(m,2H),8.64(s,1H)。
实施例2(2)
3-(4-(2-氯-5-甲基苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.60(氯仿∶甲醇=10∶1);
NMR(300MHz,DMSO-d6):δ1.93(m,2H),2.30(s,3H),2.30(s,3H),2.42(m,4H),2.86(t,J=7.83Hz,2H),3.76(m,4H),5.21(s,2H),6.79(dd,J=7.97,1.10Hz,1H),7.02(d,J=6.87Hz,1H),7.13(d,J=1.65Hz,1H),7.21(m,3H),7.32(m,2H)7.44(m,1H),7.53(d,J=1.65Hz,1H),8.62(s,1H),12.10(s,1H)。
实施例2(3)
3-(4-(2-氯-5-氟苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.59(氯仿∶甲醇=10∶1);
NMR(300MHz,DMSO-d6):δ1.92(m,2H),2.30(s,3H),2.44(m,4H),2.86(t,J=7.83Hz,2H),3.76(m,4H),5.25(s,2H),6.84(m,1H),7.02(d,J=6.87Hz,1H),7.23(m,4H),7.34(m,1H),7.47(m,3H),8.64(s,1H)。
实施例2(4)
3-(4-(2,5-二氟苯氧基甲基)-2-(((4-苯基四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.23(己烷∶乙酸乙酯∶乙酸=50∶50∶1);
NMR(300MHz,CDCl3):δ2.26(m,2H),2.52(m,2H),2.69(t,J=7.28Hz,2H),3.00(t,J=7.28Hz,2H),3.82(m,2H),3.93(m,2H),5.08(s,2H),6.63(m,2H),6.75(m,1H),7.05(m,1H)7.27(m,2H),7.39(m,3H),7.50(m,3H)。
实施例2(5)
3-(4-(2,5-二氯苯氧基甲基)-2-(((4-苯基四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.35(己烷∶乙酸乙酯∶乙酸=50∶50∶1);
NMR(300MHz,CDCl3):δ2.26(m,2H),2.51(m,2H),2.69(t,J=7.28Hz,2H),3.00(t,J=7.28Hz,2H),3.83(m,2H),3.93(m,2H),5.11(s,2H),6.57(s,1H),6.94(dd,J=8.52,2.20Hz,1H)6.99(d,J=2.20Hz,1H),7.28(m,3H),7.41(m,3H),7.50(m,2H),7.60(d,J=1.65Hz,1H)。
实施例2(6)
3-(4-(2-氯-5-氟苯氧基甲基)-2-(((4-苯基四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.36(己烷∶乙酸乙酯∶乙酸=50∶50∶1);
NMR(300MHz,CDCl3):δ2.26(m,2H),2.51(m,2H),2.70(t,J=7.28Hz,2H),3.01(t,J=7.28Hz,2H),3.84(m,2H),3.94(m,2H),5.11(s,2H),6.55(s,1H),6.70(m,2H),7.34(m,6H)7.51(m,2H),7.61(d,J=1.65Hz,1H)。
实施例2(7)
3-(4-(2,5-二氟苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.52(己烷∶乙酸乙酯=1∶1);
NMR(300MHz,CDCl3):δ0.99(d,J=6.41Hz,6H),1.71(m,3H),2.35(s,3H),2.71(m,2H),3.02(m,2H),5.06(s,2H),5.20(m,1H),6.40(d,J=8.79Hz,1H),6.62(m,1H),6.73(m,1H),7.05(m,2H),7.14(m,2H),7.23(d,J=7.69Hz,1H),7.29(d,J=8.42Hz,1H),7.41(m,2H)。
实施例2(8)
3-(4-(2-氯-5-甲基苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.31(己烷∶乙酸乙酯=1∶1);
NMR(300MHz,CDCl3):δ0.98(d,J=6.41Hz,3H),0.99(d,J=6.41Hz,3H),1.75(m,3H)2.31(s,3H),2.35(s,3H),2.72(m,2H),3.04(m,2H),5.09(s,2H),5.20(m,1H),6.37(d,J=8.79Hz,1H),6.75(m,1H),6.79(m,1H),7.08(m,1H),7.15(m,2H),7.26(m,3H),7.42(m,1H),7.53(d,J=1.65Hz,1H)。
实施例2(9)
3-(4-(3-氰基苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.32(己烷∶乙酸乙酯=1∶1);
NMR(300MHz,CDCl3):δ0.99(d,J=6.59Hz,6H),1.72(m,3H),2.35(s,3H),2.73(m,2H),3.03(m,2H),5.03(s,2H),5.21(m,1H),6.37(d,J=8.60Hz,1H),7.09(brd,J=7.87Hz,1H)7.17(m,4H),7.27(m,3H),7.38(m,3H)。
实施例2(10)
3-(4-(2,5-二甲基苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.39(己烷∶乙酸乙酯=1∶1);
NMR(300MHz,CDCl3):δ0.98(d,J=6.41Hz,3H),0.99(d,J=6.41Hz,3H),1.72(m,3H)2.22(s,3H),2.32(s,3H),2.35(s,3H),2.73(m,2H),3.04(m,2H),5.02(s,2H),5.21(m,1H)6.28(d,J=8.79Hz,1H),6.71(m,2H),7.06(m,2H)7.14(m,2H),7.23(d,J=7.69Hz,1H),7.28(m,1H),7.42(m,2H)。
实施例2(11)
3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.60(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ2.37(m,2H),2.64(m,4H),3.00(t,J=7.14Hz,2H),3.87(m,2H)3.97(m,2H),5.07(s,2H),6.62(m,1H),6.75(m,2H),7.05(m,1H),7.28(d,J=8.06Hz,1H)7.44(m,3H),7.53(d,J=1.65Hz,1H),7.63(dd,J=8.70,1.92Hz,1H),7.83(m,3H),7.93(d,J=1.83Hz,1H)。
实施例2(12)
3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.52(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ2.24(m,5H),2.32(s,3H),2.36(s,3H),2.48(m,2H),2.70(t,J=7.32Hz,2H),3.02(t,J=7.32Hz,2H),3.87(m,4H),5.05(s,2H),6.47(s,1H),6.72(m,2H),7.07(m,2H),7.27(m,4H),7.43(dd,J=7.87,1.65Hz,1H),7.54(s,1H)。
实施例2(13)
3-(4-(3-氰基苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.13(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ2.37(m,2H),2.63(m,2H),2.71(t,J=7.14Hz,2H),3.00(t,J=7.14Hz,2H),3.92(m,4H),5.04(s,2H),6.83(s,1H),7.19(m,2H),7.29(m,2H),7.43(m,5H)7.63(dd,J=8.70,1.74Hz,1H),7.83(m,3H),7.94(s,1H)。
实施例2(14)
3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.33(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ2.26(s,3H),2.32(s,3H),2.38(m,2H),2.59(m,2H),2.69(t,J=7.32Hz,2H),3.01(t,J=7.32Hz,2H),3.86(m,2H)3.98(m,2H),5.05(s,2H),6.59(s,1H)6.73(m,2H),7.06(d,J=7.87Hz,1H),7.28(d,J=8.06Hz,1H),7.45(m,3H),7.56(d,J=1.46Hz,1H),7.62(dd,J=8.60,1.83Hz,1H),7.83(m,3H),7.93(d,J=1.83Hz,1H)。
实施例2(15)
3-(4-(5-氟吲哚-1-基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.42(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ0.93(d,J=6.41Hz,6H),1.60(m,3H),2.28(s,6H),2.65(m,2H),2.95(m,2H),5.09(m,1H),5.25(s,2H),6.15(d,J=8.60Hz,1H),6.50(dd,J=3.11,0.73Hz,1H),6.90(m,4H),7.00(m,2H),7.12(m,3H),7.28(dd,J=9.52,2.56Hz,1H)。
实施例2(16)
3-(4-(6-氟吲哚-1-基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.44(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ0.93(d,J=6.59Hz,6H),1.60(m,3H),2.28(s,6H),2.65(m,2H),2.95(m,2H),5.08(m,1H),5.22(s,2H),6.14(d,J=8.42Hz,1H),6.53(d,J=3.30Hz,1H),6.88(m,5H),7.02(m,2H),7.08(d,J=3.11Hz,1H)7.16(d,J=8.42Hz,1H),7.55(dd,J=8.42,5.31Hz,1H)。
实施例2(17)
3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(3-吡啶基氧基甲基)苯基)丙酸:
TLC:Rf 0.49(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ0.91(m,6H),1.42(m,1H),1.71(m,2H),2.24(s,6H),2.43(m,2H),2.83(m,2H),4.96(m,1H),5.17(s,2H),6.84(s,1H),6.95(s,2H),7.39(m,5H),8.17(d,J=4.03Hz,1H),8.35(s,1H),8.76(d,J=8.42Hz,1H),12.08(s,1H)。
实施例2(18)
3-(4-(2,4-二甲基苯氧基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.61(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ0.98(d,J=6.31Hz,3H),0.99(d,J=6.31Hz,3H),1.70(m,3H),2.23(s,3H),2.26(s,3H),2.31(s,6H),2.72(m,2H),3.03(m,2H),5.01(s,2H),5.15(m,1H),6.24(d,J=8.79Hz,1H),6.75(d,J=8.24Hz,1H),6.94(m,5H),7.27(m,1H),7.41(m,2H)。
实施例2(19)
3-(2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-苯氧基甲基苯基)丙酸:
TLC:Rf 0.26(氯仿∶甲醇=19∶1);
NMR(300MHz,CDCl3):δ2.35(m,2H),2.64(m,4H),2.99(t,J=7.14Hz,2H),3.91(m,4H),5.04(s,2H),6.70(s,1H),6.96(m,3H),7.30(m,3H),7.45(m,4H),7.61(dd,J=8.60,2.01Hz,1H),7.82(m,3H),7.92(d,J=1.46Hz,1H)。
实施例2(20)
3-(2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3-吡啶基氧基甲基)苯基)丙酸:
TLC:Rf 0.43(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,DMSO-d6):δ2.06(m,2H),2.49(m,4H),2.85(t,J=7.78Hz,2H),3.81(d,J=7.87Hz,4H),5.21(s,2H),7.34(m,2H),7.48(m,5H),7.65(dd,J=8.70,1.74Hz,1H),7.88(m,4H),8.18(dd,J=4.58,1.28Hz,1H),8.37(d,J=2.75Hz,1H),8.81(brs,1H)。
实施例2(21)
3-(4-(3-氯苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.60(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ2.37(m,2H),2.62(d,J=12.63Hz,2H),2.70(t,J=7.14Hz,2H),3.00(t,J=7.60Hz,2H),3.85(m,2H),3.97(m,2H)5.03(s,2H),6.68(s,1H),6.85(m,1H),6.97(m,2H),7.22(t,J=7.96Hz,1H),7.29(d,J=7.87Hz,1H),7.45(m,4H),7.62(m,1H),7.83(m,3H),7.93(s,1H)。
实施例2(22)
3-(4-(2-氟-5-甲基苯氧基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.59(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ0.98(d,J=6.32Hz,3H),0.99(d,J=6.32Hz,3H),1.72(m,3H)2.29(s,3H),2.31(s,6H),2.72(m,2H),3.03(m,2H),5.07(s,2H),5.16(m,1H),6.31(d,J=8.42Hz,1H),6.72(m,1H),6.81(dd,J=7.87,1.83Hz,1H),6.91(s,1H),6.97(m,3H),7.28(d,J=7.69Hz,1H),7.42(m,2H)。
实施例2(23)
3-(4-(3,4-二甲基苯氧基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.59(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ0.97(d,J=6.41Hz,3H),0.98(d,J=6.41Hz,3H),1.69(m,3H)2.20(s,3H),2.24(s,3H),2.31(s,6H),2.71(m,2H),3.03(m,2H),4.98(s,2H),5.16(m,1H)6.28(d,J=8.42Hz,1H),6.69(dd,J=8.15,2.84Hz,1H),6.78(d,J=2.56Hz,1H),6.90(s,1H),6.95(s,2H),7.04(d,J=8.42Hz,1H),7.27(m,1H),7.41(m,2H)。
实施例2(24)
3-(4-(2-氯-5-氟苯氧基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.59(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ0.98(d,J=6.32Hz,3H),0.99(d,J=6.32Hz,3H),1.73(m,3H)2.31(s,6H),2.72(m,2H),3.04(m,2H),5.08(s,2H),5.16(m,1H),6.30(d,J=8.60Hz,1H),6.67(m,2H),6.91(s,1H),6.96(s,2H),7.32(m,2H),7.42(m,1H),7.49(d,J=1.65Hz,1H)。
实施例2(25)
3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(3-甲基吲哚-1-基甲基)苯基)丙酸:
TLC:Rf 0.45(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ0.93(d,J=6.59Hz,6H),1.58(m,3H),2.28(s,6H),2.33(d,J=0.73Hz,3H),2.66(t,J=7.32Hz,2H),2.95(m,2H),5.07(m,1H),5.22(s,2H),6.10(d,J=8.79Hz,1H),6.87(s,4H),7.04(m,2H),7.14(m,4H),7.58(m,1H)。
实施例2(26)
3-(4-(2,5-二氟苯氧基甲基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.47(氯仿∶甲醇=10∶1);
NMR(300MHz,CDCl3):δ1.80(d,J=6.77Hz,3H),2.77(t,J=7.32Hz,2H),3.09(t,J=7.32Hz,2H),5.00(s,2H),6.14(m,1H),6.37(d,J=8.06Hz,1H),6.63(m,2H),7.00(m,1H),7.28(d,J=7.69Hz,1H),7.50(m,6H),7.82(d,J=8.24Hz,1H),7.88(d,J=7.69Hz,1H),8.22(d,J=8.24Hz,1H)。
实施例2(27)
3-(4-(2-氟-5-甲基苯氧基甲基)-2-((((1R)-1-(萘-1-基))氨基)羰基)苯基)丙酸:
TLC:Rf 0.41(氯仿∶甲醇=10∶1);
NMR(300MHz,CDCl3):δ1.80(d,J=6.77Hz,3H),2.25(s,3H),2.77(t,J=7.05Hz,2H),3.09(t,J=7.05Hz,2H),5.01(s,2H),6.14(m,1H),6.37(d,J=8.06Hz,1H),6.69(m,1H),6.75(m,1H),6.93(dd,J=11.26,8.15Hz,1H),7.27(m,1H),7.51(m,6H),7.82(d,J=8.42Hz,1H)7.88(d,J=6.96Hz,1H),8.22(d,J=8.60Hz,1H)。
实施例2(28)
3-(4-(2-氟-5-甲基苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.41(氯仿∶甲醇=10∶1);
NMR(300MHz,CDCl3):δ0.99(d,J=6.41Hz,6H),1.74(m,3H),2.29(s,3H),2.35(s,3H),2.72(t,J=7.69Hz,2H),3.03(m,2H),5.07(s,2H),5.20(m,1H),6.35(d,J=8.60Hz,1H)6.74(m,1H),6.81(dd,J=7.96,2.11Hz,1H),6.97(dd,J=11.26,8.15Hz,1H),7.23(m,5H),7.42(m,2H)。
实施例2(29)
3-(4-(2-氟-5-甲基苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.41(氯仿∶甲醇=10∶1);
NMR(300MHz,CDCl3):δ2.30(s,3H),2.38(m,2H),2.61(m,2H),2.68(t,J=7.20Hz,2H)2.99(t,J=7.20Hz,2H),3.91(m,4H),5.09(s,2H),6.68(m,2H),6.83(d,J=8.06Hz,1H),6.98(dd,J=11.26,8.15Hz,1H),7.27(d,J=7.20Hz,1H)7.51(m,5H),7.87(m,4H)。
实施例2(30)
3-(2-(((4-(3,5-二甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2-氟-5-甲基苯氧基甲基)苯基)丙酸:
TLC:Rf 0.41(氯仿∶甲醇=10∶1);
NMR(300MHz,CDCl3):δ2.23(m,2H),2.30(s,3H),2.32(s,6H),2.45(m,2H),2.70(t,J=7.23Hz,2H),3.03(t,J=7.23Hz,2H),3.86(m,4H)5.10(s,2H),6.46(s,1H),6.73(m,1H)6.83(m,1H),6.91(s,1H),6.98(dd,J=11.17,8.24Hz,1H),7.08(s,2H),7.29(d,J=8.06Hz,1H),7.43(dd,J=7.87,1.83Hz,1H),7.56(s,1H)。
实施例2(31)
3-(4-(2-氟-5-甲基苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.41(氯仿∶甲醇=10∶1);
NMR(300MHz,CDCl3):δ2.23(m,2H),2.30(s,3H),2.36(s,3H),2.49(m,2H),2.69(t,J=7.32Hz,2H),3.01(t,J=7.32Hz,2H),3.89(m,4H)5.09(s,2H),6.51(s,1H),6.73(m,1H)6.84(dd,J=7.96,1.92Hz,1H),6.98(dd,J=11.17,8.24Hz,1H),7.08(m,1H),7.27(m,4H),7.43(m,1H),7.55(d,J=1.65Hz,1H)。
实施例2(32)
3-(2-(((4-(苯并呋喃-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2,5-二氟苯氧基甲基)苯基)丙酸:
TLC:Rf 0.52(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ2.48(m,4H),2.72(t,J=7.14Hz,2H),3.03(t,J=7.14Hz,2H),3.86(m,4H),5.07(s,2H),6.62(m,1H),6.74(m,3H),7.04(m,1H),7.24(m,3H),7.42(m,2H),7.54(m,2H)。
实施例2(33)
3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.49(氯仿∶甲醇=10∶1);
NMR(300MHz,DMSO-d6):δ1.53(m,2H),2.05(m,2H),2.26(d,J=13.73Hz,2H),2.57(m,4H),2.97(m,2H),3.63(m,4H),5.20(s,2H),6.78(m,1H),7.22(m,7H),7.35(d,J=8.42Hz,1H),7.43(m,2H),8.06(s,1H)。
实施例2(34)
3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(4-氟-2-甲基苯氧基甲基)苯基)丙酸:
TLC:Rf 0.57(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ0.98(d,J=6.32Hz,3H),0.99(d,J=6.32Hz,3H),1.69(m,3H)2.24(s,3H),2.31(s,6H),2.75(t,J=7.51Hz,2H),3.04(m,2H),4.99(s,2H),5.17(m,1H),6.27(d,J=7.69Hz,1H),6.82(m,4H),6.95(s,2H),7.29(d,J=8.42Hz,1H),7.41(s,2H)。
实施例2(35)
3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-((2-甲基吡啶-3-基)氧基甲基)苯基)丙酸:
TLC:Rf 0.57(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ0.89(d,J=6.22Hz,3H),0.93(d,J=6.22Hz,3H),1.40(m,1H),1.72(m,2H),2.25(m,6H),2.39(s,3H),2.44(d,J=6.96Hz,2H),2.84(t,J=7.87Hz,2H),4.96(m,1H)5.15(s,2H),6.84(s,1H),6.95(s,2H),7.17(dd,J=8.06,4.76Hz,1H),7.38(m,4H),8.01(m,1H)8.79(d,J=8.79Hz,1H)。
实施例2(36)
3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-((2-甲基吡啶-5-基)氧基甲基)苯基)丙酸:
TLC:Rf 0.57(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ0.89(d,J=6.41Hz,3H),0.93(d,J=6.41Hz,3H),1.38(m,1H),1.69(m,2H),2.24(s,6H),2.39(s,3H),2.43(m,2H),2.84(t,J=7.87Hz,2H),4.97(m,1H),5.15(s,2H)6.84(s,1H),6.95(s,2H),7.17(dd,J=8.42,4.76Hz,1H),7.31(d,J=8.06Hz,1H),7.40(m,3H)8.00(d,J=4.76Hz,1H),8.80(d,J=8.06Hz,1H)。
实施例2(37)
3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(5-氟-2-甲基苯氧基甲基)苯基)丙酸(此后,化合物(I)):
TLC:Rf 0.57(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ0.90(d,J=6.68Hz,3H),0.92(d,J=6.68Hz,3H),1.39(m,1H),1.70(m,2H),2.13(s,3H),2.24(s,6H),2.42(t,J=7.32Hz,2H),2.81(t,J=7.05Hz,2H),4.97(m,1H),5.09(s,2H),6.66(m,1H),6.83(s,1H),6.92(dd,J=11.44,2.47Hz,1H),6.97(s,2H),7.15(t,J=7.60Hz,1H),7.31(m,2H),7.38(m,1H)。
实施例2(38)
3-(4-(3-氟苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.54(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ2.06(m,2H),2.53(m,4H),2.85(t,J=7.69Hz,2H),3.81(d,J=8.79Hz,4H),5.15(s,2H),6.78(m,1H),6.90(m,2H),7.33(m,2H),7.46(m,4H),7.65(dd,J=8.79,1.65Hz,1H),7.88(m,4H),8.79(s,1H)。
实施例2(39)
3-(4-(3-甲基苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.59(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ2.06(m,2H),2.28(s,3H),2.54(m,4H),2.85(t,J=7.32Hz,2H),3.81(d,J=8.97Hz,4H),5.10(s,2H),6.80(m,3H),7.17(t,J=7.78Hz,1H),7.31(d,J=7.51Hz,1H),7.46(m,4H),7.65(dd,J=8.79,1.83Hz,1H),7.88(m,4H),8.78(s,1H)。
实施例2(40)
3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.53(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ1.51(m,2H),2.05(m,2H),2.12(s,3H),2.28(m,5H),2.58(m,4H),2.98(t,J=8.24Hz,2H),3.62(m,4H),5.10(s,2H),6.64(m,1H),6.88(s,1H),7.00(d,J=7.69Hz,1H),7.17(m,3H),7.26(m,2H),7.34(d,J=8.06Hz,1H),7.43(m,1H),7.48(s,1H),8.09(s,1H)。
实施例2(41)
3-(2-(((4-(苯并呋喃-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2,5-二甲基苯氧基甲基)苯基)丙酸:
TLC:Rf 0.53(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ2.09(m,2H),2.15(s,3H),2.26(s,3H),2.44(m,2H),2.52(m,2H),2.90(t,J=7.69Hz,2H),3.76(d,J=6.59Hz,4H),5.10(s,2H),6.66(d,J=7.32Hz,1H),6.76(s,1H),6.88(s,1H),7.03(d,J=7.32Hz,1H),7.22(m,2H),7.33(d,J=7.69Hz,1H),7.47(m,3H),7.57(m,1H),8.82(s,1H)。
实施例2(42)
3-(2-(((4-(苯并噻吩-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2,5-二氟苯氧基甲基)苯基)丙酸:
TLC:Rf 0.48(氯仿∶甲醇=10∶1);
NMR(300MHz,DMSO-d6):δ2.06(m,2H),2.58(m,4H),2.91(t,J=7.96Hz,2H),3.77(m,4H),5.22(s,2H),6.78(m,1H),7.31(m,6H),7.46(m,2H),7.77(d,J=6.96Hz,1H),7.86(d,J=7.51Hz,1H),8.90(s,1H)。
实施例2(43)
3-(2-(((4-(苯并噻吩-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2,5-二甲基苯氧基甲基)苯基)丙酸:
TLC:Rf 0.48(氯仿∶甲醇=10∶1);
NMR(300MHz,DMSO-d6):δ2.07(m,2H),2.18(s,3H),2.26(s,3H),2.57(m,4H),2.92(t,J=8.06Hz,2H),3.77(m,4H),5.12(s,2H),6.67(d,J=7.51Hz,1H),6.89(s,1H),7.04(d,J=7.32Hz,1H),7.32(m,4H),7.45(m,1H),7.53(s,1H),7.77(d,J=6.77Hz,1H),7.85(d,J=7.32Hz,1H),8.91(s,1H)。
实施例2(44)
3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(2-(2-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.35(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ1.83(m,2H),2.26(m,4H),2.70(m,2H),2.87(t,J=7.41Hz,2H),3.14(t,J=7.51Hz,2H),3.70(m,2H),3.85(m,2H),5.10(s,2H),6.07(s,1H),6.62(m,1H),6.76(m,1H),7.02(m,3H),7.17(m,2H),7.34(d,J=7.69Hz,1H),7.46(m,1H),7.51(d,J=1.83Hz,1H)。
实施例2(45)
3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(2-(2-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.40(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ1.82(m,2H),2.26(m,7H),2.32(s,3H),2.70(m,2H),2.87(t,J=7.14Hz,2H),3.14(t,J=7.14Hz,2H),3.69(m,2H),3.85(m,2H),5.06(s,2H),5.98(s,1H),6.71(d,J=6.22Hz,2H),7.01(m,3H),7.18(m,2H),7.33(d,J=7.87Hz,1H),7.47(m,1H),7.54(m,1H)。
实施例2(46)
3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(2-(4-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.80(m,2H),2.26(m,7H),2.32(s,3H),2.63(m,2H),2.86(t,J=7.37Hz,2H),3.13(t,J=7.37Hz,2H),3.68(m,2H),3.84(m,2H),5.06(s,2H),5.95(s,1H),6.72(m,2H),6.95(m,2H),7.04(d,J=7.87Hz,1H),7.15(m,2H),7.33(d,J=7.87Hz,1H),7.46(dd,J=8.10,1.50Hz,1H),7.51(d,J=1.28Hz,1H)。
实施例2(47)
3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.80(m,2H),2.27(m,4H),2.67(m,2H),2.85(t,J=7.23Hz,2H),3.13(t,J=7.23Hz,2H),3.69(m,2H),3.85(m,2H),5.09(s,2H),6.11(s,1H),6.62(m,1H),6.75(m,1H),6.98(m,4H),7.21(m,1H),7.33(d,J=8.06Hz,1H),7.46(m,2H)。
实施例2(48):
3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.80(m,2H),2.27(m,10H),2.66(m,2H),2.86(t,J=7.14Hz,2H),3.14(t,J=7.14Hz,2H),3.68(m,2H),3.86(m,2H),5.06(s,2H),5.98(s,1H),6.71(m,2H),6.94(m,4H),7.21(m,1H),7.33(d,J=7.69Hz,1H),7.47(d,J=8.06Hz,1H),7.51(s,1H)。
实施例2(49)
3-(4-(6-氟吲哚-1-基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
NMR(300MHz,CDCl3):δ1.72(m,2H),2.16(m,4H),2.53(m,2H),2.81(t,J=7.14Hz,2H),3.07(t,J=7.32Hz,2H),3.43(m,2H),3.76(m,2H),5.28(s,2H),5.75(s,1H),6.54(dd,J=3.20,0.82Hz,1H),6.87(m,3H),7.20(m,8H),7.54(dd,J=8.88,5.58Hz,1H)。
实施例2(50)
3-(4-(6-氟吲哚-3-基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
NMR(300MHz,CDCl3):δ1.73(m,2H),2.18(m,4H),2.56(m,2H),2.83(t,J=7.56Hz,2H),3.08(t,J=7.56Hz,2H),3.50(m,2H),3.78(m,2H),4.09(s,1H),5.76(s,1H),6.83(m,1H),6.93(d,J=2.75Hz,1H),7.03(dd,J=9.61,2.29Hz,1H),7.26(m,10H),8.03(s,1H)。
实施例2(51)
3-(4-(3-甲基吲哚-1-基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
NMR(300MHz,CDCl3):δ1.69(m,2H),2.07(m,2H),2.18(m,2H),2.31(d,J=1.10Hz,3H),2.50(m,2H),2.80(t,J=7.23Hz,2H),3.06(t,J=7.23Hz,2H),3.38(m,2H),3.75(m,2H),5.28(s,2H),5.62(s,1H),6.84(d,J=1.46Hz,1H),6.90(d,J=1.10Hz,1H),7.18(m,10H),7.59(m,1H)。
实施例2(52)
3-(4-(3-氰基苯氧基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
NMR(300MHz,CDCl3):δ1.82(m,2H),2.28(m,4H),2.67(m,2H),2.87(t,J=7.18Hz,2H),3.14(t,J=7.18Hz,2H),3.68(m,2H),3.85(m,2H),5.06(s,2H),6.16(s,1H),7.30(m,12H)。
实施例2(53)
3-(4-(6-氟吲哚-1-基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
NMR(300MHz,CDCl3):δ2.28(m,2H),2.47(m,2H),2.64(t,J=7.18Hz,2H),2.94(t,J=7.18Hz,2H),3.60(m,2H),3.89(m,2H),5.27(s,2H),6.38(s,1H),6.58(d,J=3.11Hz,1H),6.90(m,3H),7.10(m,2H),7.19(m,1H),7.47(m,3H),7.59(dd,J=8.60,5.31Hz,1H),7.81(m,4H)。
实施例2(54)
3-(4-(6-氟吲哚-3-基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
NMR(300MHz,CDCl3):δ2.32(m,2H),2.51(m,2H),2.67(t,J=7.28Hz,2H),2.96(t,J=7.28Hz,2H),3.69(m,2H),3.91(m,2H),4.10(s,2H),6.40(s,1H),6.85(m,1H),6.92(d,J=1.83Hz,1H),7.06(m,1H),7.18(d,J=8.42Hz,1H),7.29(m,2H),7.37(dd,J=8.88,5.03Hz,1H),7.47(m,2H),7.53(dd,J=8.97,1.83Hz,1H),7.80(m,3H),7.86(m,1H),8.04(s,1H)。
实施例2(55)
3-(4-(3-甲基吲哚-1-基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
NMR(300MHz,CDCl3):δ2.25(m,2H),2.37(d,J=1.10Hz,3H),2.42(m,2H),2.62(t,J=7.23Hz,2H),2.93(t,J=7.23Hz,2H),3.56(m,2H),3.87(m,2H),5.28(s,2H),6.27(s,1H),6.90(dd,J=6.68,1.19Hz,2H),7.17(m,5H),7.44(m,3H),7.63(m,1H),7.80(m,4H)。
实施例2(56)
3-(4-(6-氟吲哚-1-基甲基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
NMR(300MHz,CDCl3):δ1.70(m,2H),2.16(m,4H),2.51(m,2H),2.80(t,J=7.32Hz,2H),3.07(t,J=7.32Hz,2H),3.42(m,2H),3.76(m,2H),5.29(s,2H),5.76(s,1H),6.54(d,J=3.30Hz,1H),6.89(m,6H),7.11(m,2H),7.22(m,2H),7.54(dd,J=8.61,5.31Hz,1H)。
实施例2(57):
3-(2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3-甲基吲哚-1-基甲基)苯基)丙酸
NMR(300MHz,CDCl3):δ1.67(m,2H),2.11(m,4H),2.30(s,3H),2.47(m,2H),2.78(t,J=7.32Hz,2H),3.05(t,J=7.32Hz,2H),3.37(m,2H),3.74(m,2H),5.28(s,2H),5.62(s,1H),6.88(m,5H),7.15(m,6H),7.58(d,J=6.96Hz,1H)。
实施例2(58)
3-(4-(3-氰基苯氧基甲基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
NMR(300MHz,CDCl3):δ1.80(m,2H),2.29(m,4H),2.66(m,2H),2.87(t,J=7.28Hz,2H),3.13(t,J=7.28Hz,2H),3.68(m,2H),3.83(s,2H),5.07(s,2H),6.21(s,1H),6.92(m,3H),7.30(m,8H)。
实施例2(59)
3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(2-(4-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
NMR(300MHz,CDCl3):δ1.82(m,2H),2.25(m,4H),2.64(m,2H),2.84(t,J=7.32Hz,2H),3.13(t,J=7.32Hz,2H),3.68(m,2H),3.83(m,2H),5.08(s,2H),6.09(s,1H),6.62(m,1H),6.75(m,1H),6.99(m,3H),7.15(m,2H),7.32(d,J=7.87Hz,1H),7.45(m,2H)。
参考实施例12
7-甲氧基甲氧基香豆素:
在氩氛中,于0℃向7-羟基香豆素(100g)、异丙基乙基胺(161mL)的无水DMF(500mL)溶液中加入甲氧基甲基氯(70.3mL)。室温搅拌该混合物4小时。向该反应混合物中加入己烷/乙酸乙酯(2/1)和饱和碳酸氢钠水溶液的混合物,并使用乙酸乙酯提取。有机层经水和饱和氯化钠水溶液洗涤,无水硫酸镁干燥并浓缩得到具有下列物理数据的标题化合物(74.1g)。
TLC:Rf 0.50(己烷∶乙酸乙酯=3∶2);
NMR(300MHz,CDCl3):δ7.64(d,J=9.6Hz,1H),7.39(d,J=8.7Hz,1H),7.01(d,J=2.4Hz,1H),6.96(dd,J=8.7,2.4Hz,1H),6.28(d,J=9.6Hz,1H),5.24(s,2H),3.49(s,3H)。
参考实施例13
3-(4-甲氧基甲氧基-2-羟基苯基)丙烯酸甲酯:
使用参考实施例12中制备的化合物(74.1g)经与参考实施例3的一系列反应相同的过程获得具有下列物理数据的标题化合物(100g)。
TLC:Rf 0.38(己烷∶乙酸乙酯=2∶1);
NMR(300MHz,CDCl3):δ7.92(d,J=16Hz,1H),7.39(d,J=8.5Hz,1H),6.62(dd,J=8.5,2.2Hz,1H),6.54(d,J=2.2Hz,1H),6.51(d,J=16Hz,1H),6.01(s,1H),5.17(s,2H),3.81(s,3H),3.47(s,3H)。
参考实施例14
3-(4-甲氧基甲氧基-2-羟基苯基)丙酸甲酯:
在氢氛中室温搅拌参考实施例13中制备的化合物(90g)和10%钯碳(8.4g)的甲醇(1000mL)溶液。反应混合物经celite(商标)过滤。浓缩滤液得到具有下列物理数据的标题化合物(92.1g)。
TLC:Rf 0.47(己烷∶乙酸乙酯=3∶2);
NMR(300MHz,CDCl3):δ7.24(s,1H),6.97(d,J=8.2Hz,1H),6.61(d,J=2.5Hz,1H),6.57(dd,J=8.2,2.5Hz,1H),5.13(s,2H),3.69(s,3H),3.46(s,3H),2.84(t,J=6.1Hz,2H),2.69(t,J=6.1Hz,2H)。
参考实施例15
3-(4-甲氧基甲氧基-2-羧基苯基)丙酸甲酯:
使用参考实施例14中制备的化合物(82.8g)经与参考实施例5的一系列反应相同的过程获得具有下列物理数据的标题化合物(51.4g)。
TLC:Rf 0.34(己烷∶乙酸乙酯=1∶1);
NMR(300MHz,CDCl3):δ7.71(d,J=2.7Hz,1H),7.24(d,J=8.7Hz,1H),7.17(dd,J=8.7,2.7Hz,1H),5.20(s,2H),3.67(s,3H),3.49(s,3H),3.27(t,J=7.6Hz,2H),2.68(t,J=7.6Hz,2H)。
参考实施例16
3-(2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)-4-甲氧基甲氧基苯基)丙酸甲酯:
使用参考实施例15中制备的化合物(82.8g)经与参考实施例1的一系列反应相同的过程获得具有下列物理数据的标题化合物(15.9g)。
TLC:Rf 0.69(己烷∶乙酸乙酯=1∶1);
NMR(300MHz,CDCl3):δ8.23(d,J=8.7Hz,1H),7.92-7.78(m,2H),7.63-7.43(m,4H),7.12(d,J=8.1Hz,1H),7.03-6.95(m,2H),6.45(d,J=8.4Hz,1H),6.12(m,1H),5.10(s,2H),3.61(s,3H),3.41(s,3H),3.00(t,J=7.5Hz,2H),2.74-2.56(m,2H),1.80(d,J=6.6Hz,3H)。
参考实施例17
3-(2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)-4-甲氧基甲氧基苯基)丙醇:
在氮氛中,于冰浴中,向参考实施例16中制备的化合物(15.9g)的无水四氢呋喃(100mL)溶液中加入硼氢化锂(2.03g)。于60℃搅拌该混合物4小时。向该反应混合物中加入水和饱和氯化铵溶液。该混合物经乙酸乙酯提取。有机层经水和饱和氯化钠水溶液洗涤,无水硫酸镁干燥并浓缩得到具有下列物理数据的标题化合物(13.2g)。
TLC:Rf 0.32(己烷∶乙酸乙酯=1∶1);
NMR(300MHz,CDCl3):δ8.21(d,J=8.4Hz,1H),7.91-7.80(m,2H),7.63-7.43(m,4H),7.15(d,J=8.5Hz,1H),7.02(dd,J=8.5,2.8Hz,1H),6.91(d,J=2.8Hz,1H),6.23-6.04(m,2H),5.09(s,2H),3.59-3.43(m,3H),3.41(s,3H),2.88-2.71(m,2H),1.92-1.82(m,2H),1.79(d,J=6.6Hz,3H)。
参考实施例18
3-(2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)-4-甲氧基甲氧基苯基)丙基甲磺酸酯:
在氩氛中,于冰浴中向参考实施例17中制备的化合物(13.2g)和三乙胺(7.80mL)的无水THF(80mL)溶液中滴加甲磺酰氯(3.18mL)。搅拌该混合物10分钟。反应混合物经乙酸乙酯稀释。稀释液经水和饱和氯化钠水溶液洗涤,无水硫酸镁干燥并浓缩得到具有下列物理数据的标题化合物(22.3g)。
TLC:Rf 0.50(己烷∶乙酸乙酯=1∶1)。
参考实施例19
4-(2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)-4-甲氧基甲氧基苯基)丁腈:
在氩氛中,于80℃搅拌参考实施例18中制备的化合物(22.3g)和氰化钠(2.01g)的无水二甲亚砜(100mL)溶液5小时。冰浴中,向该反应混合物加入水。该混合物经乙酸乙酯提取。有机层经水和饱和氯化钠水溶液洗涤,无水硫酸镁干燥并浓缩。残留物经叔丁基甲基醚/己烷结晶得到具有下列物理数据的标题化合物(10.2g)。
TLC:Rf 0.32(己烷∶乙酸乙酯=1∶1);
NMR(300MHz,CDCl3):δ8.22(d,J=8.7Hz,1H),7.92-7.80(m,2H),7.64-7.44(m,4H),7.12(d,J=8.1Hz,1H),7.01(dd,J=8.1,2.5Hz,1H),6.95(d,J=2.5Hz,1H),6.18-5.99(m,2H),5.11(s,2H),3.42(s,3H),2.79(t,J=7.5Hz,2H),2.30-2.12(m,2H),2.00-1.86(m,2H),1.80(d,J=6.6Hz,3H)。
参考实施例20
4-(2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)-4-甲氧基甲氧基苯基)丁酸:
向参考实施例19中制备的化合物(7.13g)的乙醇(30mL)溶液中加入33%氢氧化钾水溶液(10mL)。于80℃搅拌该混合物过夜。向该反应混合物中加入6N盐酸并用乙酸乙酯提取该混合物。有机层经水和饱和氯化钠水溶液洗涤,无水硫酸镁干燥并浓缩得到具有下列物理数据的标题化合物(9.39g)。
TLC:Rf 0.33(氯仿∶甲醇=19∶1);
NMR(300MHz,CDCl3):δ8.23(d,J=8.4Hz,1H),7.91-7.78(m,2H),7.63-7.42(m,4H),7.11(d,J=8.1Hz,1H),6.98(dd,J=8.2,2.5Hz,1H),6.92(d,J=2.5Hz,1H),6.19-6.02(m,2H),5.08(s,2H),3.41(s,3H),2.83-2.64(m,2H),2.37-2.17(m,2H),1.97-1.82(m,2H),1.78(d,J=6.6Hz,3H)。
参考实施例21
4-(2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)-4-羟基苯基)丁酸甲酯:
向参考实施例20中制备的化合物(9.39g)的甲醇(40mL)溶液中加入浓硫酸(1mL)。于60℃搅拌该混合物过夜。冰浴中,向该反应混合物中加入水并用乙酸乙酯提取该混合物。有机层经水和饱和氯化钠水溶液洗涤,无水硫酸镁干燥并浓缩。残留物经己烷结晶得到具有下列物理数据的标题化合物(6.45g)。
TLC:Rf 0.45(己烷∶乙酸乙酯=1∶1);
NMR(300MHz,CDCl3):δ8.20(d,J=8.4Hz,1H),7.90-7.76(m,2H),7.59-7.40(m,4H),6.96(m,1H),6.74-6.66(m,2H),6.27-6.04(m,3H),3.57(s,3H),2.75-2.54(m,2H),2.28-2.07(m,2H),1.87-1.67(m,2H),1.76(d,J=6.6Hz,3H)。
参考实施例22
2-溴-5-硝基苯甲酸苄酯:
在氩氛中,向2-溴-5-硝基苯甲酸(5.14g)的DMF溶液中加入溴苄(2.73mL)和碳酸钾(4.33g)。室温搅拌该混合物30分钟。向该反应混合物中加入水并用乙酸乙酯提取该混合物。有机层经水和饱和氯化钠水溶液洗涤,无水硫酸镁干燥并浓缩。残留物经己烷/乙酸乙酯洗涤得到具有下列物理数据的标题化合物(6.59g)。
TLC:Rf 0.62(己烷∶乙酸乙酯=4∶1);
NMR(300MHz,CDCl3):δ8.64(d,J=2.7Hz,1H),8.16(dd,J=8.7,2.7Hz,1H),7.86(d,J=8.7Hz,1H),7.49-7.39(m,5H),5.42(s,2H)。
参考实施例23
2-(2-乙氧基羰基乙烯基)-5-硝基苯甲酸苄酯:
在氩氛中,向参考实施例22中制备的化合物(5.57g)的二甲亚砜(30mL)溶液中加入丙烯酸乙酯(3.6mL)、乙酸钯(II)(186mg)、1,1′-双(二苯基膦基)二茂铁(460mg)和三乙胺(11.6mL)。于80℃搅拌该混合物4小时。向该反应混合物中加入乙酸乙酯和水,该混合物经celite(商标)过滤。滤液经乙酸乙酯提取。有机层经水和饱和氯化钠水溶液洗涤,无水硫酸镁干燥并浓缩。残留经硅胶柱色谱纯化得到具有下列物理数据的标题化合物(5.33g)。
TLC:Rf 0.45(己烷∶乙酸乙酯=6∶1);
NMR(300MHz,CDCl3):δ8.82(d,J=2.1Hz,1H),8.45(d,J=15.9Hz,1H),8.36(dd,J=8.7,2.1Hz,1H),7.75(d,J=8.7Hz,1H),7.49-7.39(m,5H),6.38(d,J=15.9Hz,1H),5.42(s,2H),4.29(q,J=7.2Hz,2H),1.35(t,J=7.2Hz,3H)。
参考实施例24
2-(2-乙氧基羰基乙基)-5-氨基苯甲酸:
向参考实施例23中制备的化合物(5.33g)的乙醇(40mL)/乙酸乙酯(10mL)溶液中加入10%钯碳(500mg)。氢氛中室温搅拌该混合物4小时。反应混合物经celite(商标)过滤。浓缩滤液。残留物经己烷/乙酸乙酯洗涤得到具有下列物理数据的标题化合物(2.72g)。
TLC:Rf 0.70(乙酸乙酯);
NMR(300MHz,CDCl3):δ7.35(d,J=2.7Hz,1H),7.10(d,J=8.1Hz,1H),6.81(dd,J=8.1,2.7Hz,1H),4.11(q,J=7.2Hz,2H),3.20(t,J=7.5Hz,2H),2.64(t,J=7.5Hz,2H),1.23(t,J=7.2Hz,3H)。
参考实施例25
2-(2-乙氧基羰基乙基)-5-(叔丁氧基羰基氨基)苯甲酸:
于65℃搅拌参考实施例24中制备的化合物(4.00g)和叔丁基焦碳酸酯(5.52g)的THF(8mL)溶液2小时。浓缩反应混合物。残留经叔丁基甲基醚/己烷结晶得到具有下列物理数据的标题化合物(4.86g)。
TLC:Rf 0.38(己烷∶乙酸乙酯=1∶2);
NMR(300MHz,CDCl3):δ7.94(d,J=2.1Hz,1H),7.58(d,J=7.4Hz,1H),7.25(d,J=7.4Hz,1H),6.63(brs,1H),4.12(q,J=7.2Hz,2H),3.26(t,J=7.5Hz,2H),2.67(t,J=7.5Hz,2H),1.53(s,9H),1.23(t,J=7.2Hz,3H)。
实施例3
4-(4-(1,3-二氧杂茚满-5-基氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸甲酯:
室温下搅拌参考实施例21中制备的化合物(250mg)、3,4-(亚甲基二氧基)苯基硼酸(318mg)、乙酸铜(II)(116mg)、三乙胺(445μL)和4分子筛(63mg)的无水二氯甲烷溶液3天。反应混合物经celite(商标)过滤并使用乙酸乙酯稀释滤液。稀释液相继经饱和氯化铵溶液、水和饱和氯化钠水溶液洗涤,无水硫酸镁干燥并浓缩。残留物经硅胶柱色谱(己烷∶乙酸乙酯=3∶1)纯化得到具有下列物理数据的标题化合物(85mg)。
TLC:Rf 0.44(己烷∶乙酸乙酯=2∶1);
NMR(300MHz,CDCl3):δ8.20(m,1H),7.91-7.79(m,2H),7.59-7.42(m,4H),7.12(m,1H),6.90-6.83(m,2H),6.72(d,J=8.4Hz,1H),6.50(d,J=2.4Hz,1H),6.41(dd,J=8.4,2.4Hz,1H),6.16-6.02(m,2H),5.99-5.95(m,2H),3.62(s,3H),2.84-2.63(m,2H),2.33-2.12(m,2H),1.96-1.83(m,2H),1.78(d,J=6.6Hz,3H)。
实施例4
4-(4-(1,3-二氧杂茚满-5-基氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸:
使用实施例3中制备的化合物(80mg)经与参考实施例2的一系列反应相同的过程获得具有下列物理数据的标题化合物(74mg)。
TLC:Rf 0.56(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.77(d,J=6.32Hz,3H),1.89(m,2H),2.28(m,2H),2.75(m,2H),5.96(d,J=1.37Hz,2H),6.07(m,2H),6.40(dd,J=8.45,2.40Hz,1H),6.49(d,J=2.40Hz,1H),6.71(d,J=8.45Hz,1H),6.85(m,2H),7.12(d,J=8.52Hz,1H),7.51(m,4H),7.84(m,2H),8.18(d,J=7.97Hz,1H)。
实施例4(1)-4(48)
使用参考实施例15制备的化合物和相应的化合物经与参考实施例16→参考实施例21→实施例3→实施例4一系列反应相同的过程,或者使用参考实施例24制备的化合物和相应的化合物经与参考实施例16→实施例3→实施例4一系列反应相同的过程,或者使用参考实施例15或参考实施例25制备的化合物和相应的化合物经与参考实施例16→参考实施例17→参考实施例18→参考实施例19→参考实施例20→参考实施例21→实施例3→实施例4一系列反应相同的过程获得下列化合物。
实施例4(1)
4-(4-(3-甲基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸:
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.77(d,J=6.59Hz,3H),1.90(m,2H),2.30(s,3H),2.29(m,2H),2.77(m,2H),6.08(m,2H),6.73(m,2H),6.91(m,3H),7.16(m,2H),7.50(m,4H),7.81(m,1H),7.86(m,1H),8.19(m,1H)。
实施例4(2)
4-(4-(3-氰基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸:
TLC:Rf 0.25(己烷∶乙酸乙酯=1∶1);
NMR(300MHz,CDCl3):δ1.79(d,J=6.59Hz,3H),1.93(m,2H),2.31(m,2H),2.78(m,2H),6.03(d,J=8.52Hz,1H),6.12(m,1H),6.95(m,2H),7.14(m,2H),7.23(d,J=8.79Hz,1H)7.45(m,6H),7.82(d,J=8.24Hz,1H),7.87(m,1H)8.20(m,1H)。
实施例4(3)
4-(4-(3,4-二甲基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸:
TLC:Rf 0.44(己烷∶乙酸乙酯=1∶1);
NMR(300MHz,CDCl3):δ1.76(d,J=6.41Hz,3H),1.91(m,2H),2.20(s,3H),2.23(s,3H),2.30(m,2H),2.76(m,2H),6.08(m,2H),6.67(dd,J=8.24,2.56Hz,1H),6.74(d,J=2.56Hz,1H),6.88(m,2H),7.05(d,J=8.06Hz,1H),7.12(d,J=8.24Hz,1H),7.50(m,4H),7.80(d,J=8.06Hz,1H),7.86(m,1H),8.19(m,1H)。
实施例4(4)
4-(4-(茚满-5-基氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸:
TLC:Rf 0.42(己烷∶乙酸乙酯=1∶1);
NMR(300MHz,CDCl3):δ1.77(d,J=6.41Hz,3H),1.91(m,2H),2.09(m,2H),2.30(m,2H),2.76(m,2H),2.86(q,J=7.38Hz,4H),6.06(m,2H),6.72(dd,J=8.06,2.38Hz,1H),6.79(m,1H),6.89(m,2H),7.13(d,J=8.24Hz,2H),7.51(m,4H),7.80(d,J=8.24Hz,1H),7.87(m,1H),8.19(m,1H)。
实施例4(5)
4-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸:
TLC:Rf 0.39(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ1.77(d,J=6.59Hz,3H),1.92(m,2H),2.25(s,6H),2.31(m,2H),2.78(m,2H),6.00(d,J=8.42Hz,1H),6.10(m,1H),6.55(s,2H),6.73(s,1H),6.90(m,2H),7.15(m,1H),7.51(m,4H),7.81(d,J=8.06Hz,1H),7.87(m,1H),8.20(m,1H)。
实施例4(6)
4-(4-(3-甲硫基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸:
TLC:Rf 0.35(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ1.78(d,J=6.59Hz,3H),1.92(m,2H),2.31(m,2H),2.43(s,3H),2.77(m,2H),6.01(m,1H),6.11(m,1H),6.67(dd,J=8.42,2.20Hz,1H),6.83(t,J=1.83Hz,1H),6.94(m,3H),7.19(m,2H),7.50(m,4H),7.81(d,J=8.06Hz,1H),7.87(m,1H),8.20(d,J=8.06Hz,1H)。
实施例4(7)
3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(3-氟苯基氨基)苯基)丙酸:
TLC:Rf 0.53(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ0.89(d,J=6.41Hz,3H),0.92(d,J=6.41Hz,3H),1.38(m,1H),1.72(m,2H),2.23(s,6H),2.42(m,2H),2.77(t,J=7.78Hz,2H),4.96(m,1H),6.58(m,1H),6.86(m,3H),6.93(s,2H),7.04(m,2H),7.20(m,2H),8.48(s,1H),8.73(d,J=7.51Hz,1H),12.04(s,1H)。
实施例4(8)
3-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.37(氯仿∶甲醇=19∶1);
NMR(300MHz,CDCl3):δ0.96(d,J=6.22Hz,3H),0.97(d,J=6.22Hz,3H),1.68(m,3H),2.26(s,6H),2.29(s,6H),2.70(t,J=7.14Hz,2H),2.95(m,2H),5.14(m,1H),6.23(d,J=8.79Hz,1H),6.61(s,1H),6.67(s,2H),6.89(s,1H),6.93(s,2H),7.02(m,2H),7.12(m,1H)。
实施例4(9)
3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(3-甲基苯基氨基)苯基)丙酸:
TLC:Rf 0.33(氯仿∶甲醇=19∶1);
NMR(300MHz,CDCl3):δ0.96(d,J=6.41Hz,3H),0.97(d,J=6.41Hz,3H),1.67(m,3H),2.29(s,6H),2.30(s,3H),2.70(t,J=7.69Hz,2H),2.95(m,2H),5.14(m,1H),6.24(d,J=8.42Hz,1H),6.85(m,6H),7.02(m,2H),7.15(m,2H)。
实施例4(10)
3-(4-(3-氰基苯基氨基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.61(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,DMSO-d6):δ0.91(m,6H),1.38(m,1H),1.69(m,2H),2.23(s,6H),2.42(t,J=7.78Hz,2H),2.78(t,J=8.06Hz,2H),4.95(m,1H),6.83(s,1H),6.93(s,2H),7.00(d,J=2.38Hz,1H),7.08(m,1H),7.20(d,J=8.24Hz,2H),7.37(m,3H),8.62(s,1H),8.77(d,J=8.79Hz,1H)。
实施例4(11)
3-(4-(3,5-二氟苯基氨基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.76(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,DMSO-d6):δ0.90(d,J=6.41Hz,3H),0.92(d,J=6.41Hz,3H),1.37(m,1H),1.69(m,2H),2.23(s,6H),2.43(m,2H),2.78(t,J=7.87Hz,2H),4.95(m,1H),6.53(m,1H),6.67(dd,J=10.25,2.20Hz,2H),6.83(s,1H),6.94(s,2H),7.02(d,J=2.20Hz,1H),7.08(m,1H),7.21(d,J=8.24Hz,1H),8.72(s,1H),8.80(m,1H)。
实施例4(12)
3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(1,3-二氧杂茚满-5-基氨基)苯基)丙酸:
TLC:Rf 0.52(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ0.96(d,J=6.31Hz,3H),0.97(d,J=6.31Hz,3H),1.68(m,3H),2.29(s,6H),2.68(m,2H),2.92(m,2H),5.12(m,1H),5.94(s,2H),6.27(d,J=8.42Hz,1H),6.53(dd,J=8.24,2.20Hz,1H),6.64(d,J=2.20Hz,1H),6.73(d,J=8.24Hz,1H),6.89(m,5H),7.08(d,J=8.24Hz,1H)。
实施例4(13)
3-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.47(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ0.95(d,J=6.32Hz,3H),0.96(d,J=6.32Hz,3H),1.67(m,3H)2.28(s,6H),2.29(s,6H),2.72(m,2H),3.00(m,2H),5.13(m,1H),6.19(d,J=8.60Hz,1H),6.61(s,2H),6.77(s,1H),6.93(m,4H),7.00(d,J=2.56Hz,1H),7.20(d,J=8.42Hz,1H)。
实施例4(14)
3-(4-(3,5-二氟苯氧基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.47(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ0.97(d,J=6.41Hz,6H),1.67(m,3H),2.30(s,6H),2.72(m,2H),3.01(m,2H),5.15(m,1H),6.28(d,J=8.97Hz,1H),6.52(m,3H),6.90(s,1H),6.94(s,2H),7.02(m,2H),7.27(m,1H)。
实施例4(15)
3-(4-(3-氰基苯氧基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.44(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ0.97(d,J=6.59Hz,6H),1.69(m,3H),2.29(s,6H),2.73(m,2H),3.01(m,2H),5.15(m,1H),6.32(d,J=8.79Hz,1H),6.90(s,1H),6.94(s,2H),7.00(m,2H),7.21(m,2H),7.27(m,1H),7.41(m,2H)。
实施例4(16)
4-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(萘-2-基)乙基)氨基)羰基)苯基)丁酸:
TLC:Rf 0.47(氯仿∶甲醇=10∶1);
NMR(300MHz,CDCl3):δ1.67(d,J=6.77Hz,3H),1.92(m,2H),2.27(s,6H),2.31(t,J=7.20Hz,2H),2.77(t,J=8.10Hz,2H),5.45(m,1H),6.11(d,J=7.69Hz,1H),6.59(s,2H),6.75(s,1H),6.94(dd,J=8.42,2.56Hz,1H),7.02(d,J=2.56Hz,1H),7.17(d,J=8.42Hz,1H),7.48(m,3H),7.82(m,4H)。
实施例4(17)
3-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.47(氯仿∶甲醇=10∶1);
NMR(300MHz,CDCl3):δ1.78(d,J=6.77Hz,3H),2.26(s,6H),2.77(t,J=7.78Hz,2H)3.06(t,J=7.78Hz,2H),6.12(m,1H),6.27(d,J=8.06Hz,1H),6.55(s,2H),6.74(s,1H),6.93(m,2H),7.19(d,J=8.24Hz,1H),7.51(m,4H),7.81(d,J=8.06Hz,1H),7.87(m,1H),8.17(d,J=8.60Hz,1H)。
实施例4(18)
3-(4-(3,5-二甲基苯氧基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.45(氯仿∶甲醇=10∶1);
NMR(300MHz,CDCl3):δ2.29(s,6H),2.38(m,2H),2.58(m,2H),2.67(t,J=7.23Hz,2H)2.96(t,J=7.23Hz,2H),3.83(m,2H),3.95(m,2H),6.55(s,1H),6.63(s,2H),6.79(s,1H)6.95(dd,J=8.42,2.56Hz,1H),7.11(d,J=2.56Hz,1H),7.19(d,J=8.42Hz,1H),7.46(m,2H),7.59(dd,J=8.60,1.83Hz,1H),7.82(m,3H),7.91(d,J=1.65Hz,1H)。
实施例4(19)
3-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(萘-2-基)乙基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.47(氯仿∶甲醇=10∶1);
NMR(300MHz,CDCl3):δ1.68(d,J=6.96Hz,3H),2.27(s,6H),2.75(m,J=7.41,7.41Hz,2H),3.03(t,J=7.41Hz,2H),5.45(m,1H),6.43(d,J=7.87Hz,1H),6.60(s,2H),6.76(s,1H),6.95(dd,J=8.60,2.75Hz,1H),7.06(d,J=2.75Hz,1H),7.21(d,J=8.60Hz,1H),7.48(m,3H),7.83(m,4H)。
实施例4(20)
3-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(3-甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.47(氯仿∶甲醇=10∶1);
NMR(300MHz,CDCl3):δ0.96(d,J=6.30Hz,6H),1.68(m,3H),2.28(s,6H),2.34(s,3H),2.72(t,J=7.60Hz,2H),2.98(m,2H),5.17(m,1H),6.23(d,J=8.60Hz,1H),6.61(s,2H)6.77(s,1H),6.94(dd,J=8.42,2.56Hz,1H),7.00(d,J=2.56Hz,1H),7.17(m,5H)。
实施例4(21)
3-(4-(3-甲基苯基氨基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.48(氯仿∶甲醇=10∶1);
NMR(300MHz,DMSO-d6):δ2.05(m,2H),2.25(s,3H),2.44(m,4H),2.77(t,J=7.69Hz,2H),3.79(m,4H),6.67(d,J=7.32Hz,1H),6.90(d,J=8.06Hz,1H),7.02(m,2H),7.14(m,3H),7.49(m,2H),7.64(dd,J=8.60,1.65Hz,1H),7.87(m,4H)8.21(s,1H),8.71(s,1H),12.06(s,1H)。
实施例4(22)
3-(4-(3,5-二甲基苯基氨基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.49(氯仿∶甲醇=10∶1);
NMR(300MHz,DMSO-d6):δ2.05(m,2H),2.21(s,6H),2.47(m,4H),2.76(t,J=7.87Hz,2H),3.80(m,4H),6.50(s,1H),6.77(s,2H),6.99(dd,J=8.42,2.20Hz,1H),7.13(d,J=8.42Hz,1H),7.18(d,J=2.20Hz,1H),7.48(m,2H),7.64(dd,J=8.79,1.83Hz,1H),7.87(m,4H),8.13(s,1H),8.71(s,1H),12.06(s,1H)。
实施例4(23)
4-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸:
TLC:Rf 0.52(二氯甲烷∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.76(d,J=6.59Hz,3H),1.90(m,2H),2.22(s,6H),2.29(m,2H),2.72(m,2H),6.07(m,2H),6.57(s,1H),6.60(s,2H),6.91(d,J=2.40Hz,1H),6.99(dd,J=8.40,2.40Hz,1H),7.07(d,J=8.40Hz,1H),7.51(m,4H),7.84(m,2H),8.22(d,J=8.42Hz,1H)。
实施例4(24)
4-(4-(3-氟苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸:
TLC:Rf 0.48(二氯甲烷∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.77(d,J=6.59Hz,3H),1.90(m,2H),2.28(m,2H),2.73(m,2H),5.70(s,1H),6.09(m,2H),6.61(m,3H),6.94(d,J=2.20Hz,1H),7.10(m,3H),7.53(m,4H),7.84(m,2H),8.21(d,J=8.42Hz,1H)。
实施例4(25)
4-(4-(3-甲基苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸:
TLC:Rf0.44(二氯甲烷∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.76(d,J=6.59Hz,3H),1.90(m,2H),2.26(s,3H),2.29(m,2H),2.72(m,2H),6.08(m,2H),6.75(m,3H),6.91(d,J=2.20Hz,1H),7.06(m,3H),7.51(m,4H),7.84(m,2H),8.22(d,J=8.42Hz,1H)。
实施例4(26)
4-(4-(3,5-二氟苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸:
TLC:Rf 0.44(二氯甲烷∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.77(d,J=6.22Hz,3H),1.89(m,2H),2.26(m,2H),2.73(m,2H),5.87(s,1H),6.10(m,2H),6.34(m,3H),6.94(d,J=2.40Hz,1H),7.06(dd,J=8.40,2.40Hz,1H),7.13(d,J=8.10Hz,1H),7.51(m,4H),7.83(m,2H),8.21(d,J=8.42Hz,1H)。
实施例4(27)
4-(4-(1,3-二氧杂茚满-5-基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸:
TLC:Rf 0.52(二氯甲烷∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.76(d,J=6.59Hz,3H),1.89(m,2H),2.27(m,2H),2.69(m,2H),5.92(s,2H),6.06(m,2H),6.45(dd,J=8.06,2.20Hz,1H),6.57(d,J=1.83Hz,1H),6.68(d,J=8.40Hz,1H),6.77(d,J=2.56Hz,1H),6.86(dd,J=8.40,2.10Hz,1H),7.02(d,J=8.06Hz,1H),7.50(m,4H),7.84(m,2H),8.20(d,J=8.42Hz,1H)。
实施例4(28)
4-(4-(3-氰基苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸:
TLC:Rf 0.54(二氯甲烷∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.77(d,J=6.22Hz,3H),1.89(m,2H),2.27(m,2H),2.73(m,2H),5.94(s,1H),6.12(m,2H),6.93(d,J=2.20Hz,1H),7.16(m,6H),7.49(m,4H),7.84(m,2H),8.21(d,J=8.42Hz,1H)。
实施例4(29)
3-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(3-甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.56(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ0.91(dd,J=10.25,6.41Hz,6H),1.38(m,1H),1.70(m,2H),2.19(s,6H),2.27(s,3H),2.41(dd,J=8.97,6.77Hz,2H),2.74(t,J=7.78Hz,2H),4.98(m,1H),6.46(s,1H)6.71(s,2H),6.98(m,3H),7.13(m,4H),8.07(s,1H),8.74(d,J=8.97Hz,1H)。
实施例4(30)
3-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.51(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ1.54(d,J=6.96Hz,3H),2.17(s,6H),2.45(m,2H),2.79(t,J=7.69Hz,2H),5.91(m,1H),6.46(s,1H),6.68(s,2H),7.00(m,2H),7.11(m,1H),7.54(m,4H),7.82(d,J=8.06Hz,1H),7.94(dd,J=7.87,1.28Hz,1H)8.05(s,1H),8.22(d,J=8.06Hz,1H),8.99(m,1H)。
实施例4(31)
3-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(萘-2-基)乙基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.53(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ1.50(d,J=6.96Hz,3H),2.18(s,6H),2.44(m,2H),2.79(t,J=7.69Hz,2H),5.28(m,1H),6.47(s,1H),6.70(s,2H),7.01(m,2H),7.12(m,1H),7.47(m,2H),7.57(dd,J=8.42,1.65Hz,1H),7.86(m,4H),8.06(s,1H),8.91(d,J=8.06Hz,1H)。
实施例4(32)
3-(4-(3,5-二甲基苯基氨基)-2-(((4-(3,5-二甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.53(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ1.89(m,2H),2.20(s,6H),2.24(s,6H),2.40(m,4H),2.75(m,2H),3.73(m,4H),6.48(s,1H),6.77(s,2H),6.83(s,1H),6.98(dd,J=8.33,2.29Hz,1H),7.03(s,2H),7.12(d,J=8.24Hz,1H),7.19(d,J=2.20Hz,1H),8.12(s,1H),8.54(s,1H)。
实施例4(33)
3-(4-(3,5-二甲基苯基氨基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.44(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ1.92(m,2H),2.20(s,6H),2.28(s,3H),2.41(m,4H),2.76(m,2H),3.75(m,4H),6.48(s,1H),6.76(s,2H),6.99(m,2H),7.12(d,J=8.42Hz,1H),7.21(m,5H),8.12(s,1H)。
实施例4(34)
3-(4-(3,5-二甲基苯氧基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.49(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ2.22(m,2H),2.30(s,6H),2.35(s,3H),2.47(m,2H),2.69(t,J=7.14Hz,2H),2.97(t,J=7.23Hz,2H),3.77(m,2H)3.91(m,2H),6.40(s,1H),6.63(m,2H)6.78(m,1H),6.95(dd,J=8.51,2.65Hz,1H),7.08(m,2H)7.20(d,J=8.42Hz,1H),7.26(m,3H)。
实施例4(35)
3-(2-(((4-(苯并呋喃-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3,5-二甲基苯氧基)苯基)丙酸:
TLC:Rf 0.52(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ2.28(s,6H),2.48(m,4H),2.69(t,J=7.14Hz,2H),2.98(t,J=7.14Hz,2H),3.83(m,4H),6.61(m,3H),6.76(m,2H),6.95(dd,J=8.42,2.56Hz,1H),7.09(d,J=2.56Hz,1H),7.22(m,3H),7.38(m,1H),7.55(m,1H)。
实施例4(36)
3-(2-(((4-(苯并呋喃-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3,5-二甲基苯基氨基)苯基)丙酸:
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ2.27(s,6H),2.48(m,4H),2.69(t,J=7.10Hz,2H),2.94(t,J=7.10Hz,2H),3.84(m,4H),6.63(m,2H),6.69(s,2H),6.74(d,J=0.73Hz,1H),7.07(m,3H),7.21(m,2H),7.39(m,1H),7.55(m,1H)。
实施例4(37)
3-(4-(3,5-二甲基苯氧基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
NMR(300MHz,DMSO-d6):δ1.50(m,2H),2.00(m,2H),2.22(s,6H),2.26(m,2H),2.48(m,2H),2.58(m,2H),2.93(m,2H),3.52(m,2H),3.65(m,2H),6.68(s,2H),6.78(s,1H),6.92(d,J=2.56Hz,1H),6.97(dd,J=8.40,2.56Hz,1H),7.14(m,3H),7.26(m,3H),8.01(s,1H)。
实施例4(38)
3-(4-(3,5-二甲基苯氧基)-2-(((4-(3,5-二甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.50(氯仿∶甲醇=10∶1);
NMR(300MHz,DMSO-d6):δ1.89(m,2H),2.21(s,6H),2.25(s,6H),2.35(d,J=12.63Hz,2H),2.44(m,2H),2.84(t,J=7.96Hz,2H),3.69(m,4H)6.69(s,2H),6.81(m,2H),6.89(d,J=2.75Hz,1H),6.98(m,3H),7.29(d,J=8.42Hz,1H),8.54(s,1H)。
实施例4(39)
3-(4-(3,5-二甲基苯基氨基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.48(氯仿∶甲醇=10∶1);
NMR(300MHz,DMSO-d6):δ1.49(m,2H),2.01(m,2H),2.16(s,6H),2.27(d,J=14.10Hz,2H),2.57(m,4H),2.88(t,J=7.87Hz,2H),3.62(m,4H),6.44(s,1H),6.75(s,2H),6.98(dd,J=8.42,2.38Hz,1H),7.15(m,5H),7.24(m,2H)7.99(s,1H),8.11(s,1H)。
实施例4(40)
3-(2-(((4-(3,5-二甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3-甲基苯基氨基)苯基)丙酸:
TLC:Rf 0.49(氯仿∶甲醇=9∶1);
NMR(300MHz,DMSO-d6):δ1.90(m,2H),2.24(s,9H),2.41(m,4H),2.78(t,J=8.06Hz,2H),3.74(m,4H),6.65(d,J=6.96Hz,1H),6.83(s,1H),6.90(d,J=9.15Hz,1H),7.01(m,4H),7.12(m,3H),8.20(s,1H),8.53(s,1H)。
实施例4(41)
3-(2-(((4-(苯并噻吩-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3,5-二甲基苯氧基)苯基)丙酸:
TLC:Rf 0.49(氯仿∶甲醇=10∶1);
NMR(300MHz,DMSO-d6):δ2.05(m,2H),2.25(s,6H),2.54(m,4H),2.87(t,J=7.87Hz,2H),3.73(m,4H),6.68(s,2H),6.82(s,1H),6.97(m,2H),7.32(m,4H),7.75(m,1H),7.84(dd,J=8.06,0.92Hz,1H),8.85(s,1H)。
实施例4(42)
3-(2-(((4-(苯并噻吩-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3,5-二甲基苯基氨基)苯基)丙酸:
TLC:Rf 0.47(氯仿∶甲醇=10∶1);
NMR(300MHz,DMSO-d6):δ2.04(m,2H),2.20(s,6H),2.59(m,4H),2.81(m,2H),3.75(m,4H),6.49(s,1H),6.76(s,2H),7.00(dd,J=8.33,2.29Hz,1H),7.13(d,J=8.42Hz,1H),7.19(d,J=2.38Hz,1H),7.32(m,3H),7.76(dd,J=6.96,1.65Hz,1H),7.82(d,J=8.42Hz,1H),8.14(s,1H),8.82(s,1H)。
实施例4(43)
3-(4-(3,5-二甲基苯氧基)-2-(((4-(2-(4-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.52(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.79(m,2H),2.23(m,4H),2.28(s,6H),2.60(m,2H),2.83(t,J=7.40Hz,2H),3.08(t,J=7.40Hz,2H),3.65(m,2H),3.82(m,2H),5.96(s,1H),6.64(s,2H),6.78(s,1H),6.95(m,3H),7.06(d,J=2.56Hz,1H),7.12(m,2H),7.22(d,J=8.60Hz,1H)。
实施例4(44)
3-(4-(3,5-二甲基苯基氨基)-2-(((4-(2-(4-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.50(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.78(m,2H),2.24(m,10H),2.60(m,2H),2.81(t,J=7.32Hz,2H),3.04(t,J=7.32Hz,2H),3.63(m,2H),3.81(m,2H),5.98(s,1H),6.62(s,1H),6.70(s,2H),6.94(m,2H),7.10(m,5H)。
实施例4(45)
3-(4-(3,5-二甲基苯基氨基)-2-(((4-(2-(2-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.36(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,CDCl3):δ1.80(m,2H),2.24(m,10H),2.68(m,2H),2.83(t,J=7.28Hz,2H),3.05(t,J=7.28Hz,2H),3.66(m,2H),3.84(m,2H),5.96(s,1H),6.63(s,1H),6.71(s,2H),7.09(m,7H)。
实施例4(46)
3-(4-(3,5-二甲基苯氧基)-2-(((4-(2-(2-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.39(己烷∶乙酸乙酯=1∶1,1%乙酸);
NMR(300MHz,DMSO-d6):δ1.50(m,2H),1.98(m,2H),2.25(m,8H),2.56(m,4H),2.92(t,J=7.78Hz,2H),3.52(m,2H),3.66(m,2H),6.67(d,J=0.73Hz,2H),6.77(s,1H),6.95(m,2H),7.09(m,2H),7.20(m,2H),7.30(d,J=8.42Hz,1H),8.03(s,1H)。
实施例4(47)
3-(4-(3,5-二甲基苯氧基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.52(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.78(m,2H),2.24(m,4H),2.28(s,6H),2.63(m,2H),2.83(t,J=6.99Hz,2H),3.08(t,J=6.99Hz,2H),3.64(m,2H),3.82(m,2H),5.96(s,1H),6.64(s,2H),6.78(s,1H),6.91(m,4H),7.05(d,J=2.56Hz,1H),7.22(m,2H)。
实施例4(48)
3-(4-(3,5-二甲基苯基氨基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸:
TLC:Rf 0.52(氯仿∶甲醇=9∶1);
NMR(300MHz,CDCl3):δ1.77(m,2H),2.24(m,10H),2.61(m,2H),2.82(t,J=7.36Hz,2H),3.04(t,J=7.36Hz,2H),3.65(m,2H),3.81(m,2H),5.99(s,1H),6.62(s,1H),6.70(s,2H),7.05(m,7H)。
制剂实施例1
下列组分经常规方法混合并冲压成100片各自包含5mg活性成分的片剂。
本发明的化合物 500mg
羧基甲基纤维素钙(崩解剂) 200mg
硬脂酸镁(润滑剂) 100mg
微晶纤维素 9.2g
制剂实施例2
下列组分经常规方法混合。溶液经常规方法灭菌,将5ml溶液置于安瓿中并冷冻干燥得到100个各自包含20mg活性成分的安瓿。
本发明的化合物 2.0g
甘露醇 20g
蒸馏水 500ml
测试实施例1
通过例如下面的试验证明了本发明的化合物与PGE2受体尤其是EP3受体强烈结合并显示拮抗活性。
(i)使用表达前列腺素类受体亚型的细胞的结合测定
使用表达前列腺素类受体亚型(小鼠EP1、EP2、EP3α和EP4)的CHO细胞,根据Sugimoto等的方法[J.Biol.Chem.,
267,6463-6466(1992)]完成了膜级分的制备。
包含膜级分(50μL)、[3H]-PGE2的终体积为150μL的标准测定混合物于室温孵化1小时。通过加入3mL冰冷缓冲液终止该反应。减压下使该混合物快速通过玻璃过滤器(GF/B)。通过液体闪烁计数仪测量与过滤器有关的放射活性。
根据Scatchard曲线[Ann.N.Y.Acad.Sci.,
51,660(1949)]测定Kd和Bmax值。存在过量(10μM)未标记的PGE2时,测定了非特异性结合的结合量。在竞争特异性[3H]-PGE2结合测定试验中,以2.5nM的浓度加入[3H]-PGE2且以各种浓度加入本发明的化合物。在所有反应中使用下面的缓冲液。
缓冲液:10mM磷酸钾(pH 6.0),1mM EDTA,10mM MgCl2,0.1M NaCl.[C]是[3H]-PGE2的浓度。
通过下面的等式计算各化合物的抑制常数(Ki):
Ki=IC50/(1+([C]/Kd))
结果表明,本发明化合物的Ki低于100nM,强烈结合于EP3受体上。
(ii)使用表达前列腺素类受体亚型的细胞的EP3拮抗活性测定
根据Sugimoto等的方法[J.Biol.Chem.,
267,6463-6466(1992)]完成了表达小鼠EP3受体亚型的CHO细胞的制备。试验前将该细胞培养于96-孔微板(104细胞/孔)中两天。使用100μL的PBS洗涤各孔后,加入Fura-2AM,细胞吸收60分钟。使用HEPES洗涤各孔后,于37℃加入测试化合物和PGE2(10nM)。测量细胞内钙浓度的变化。即,进行340/380nm波长的激发并测量510nm的荧光,然后计算荧光强度的比值。顺便地,在使用PGE2(10nM)作为激动剂的情况下,测试计算为抑制率的化合物的拮抗活性并计算IC50值。
结果表明,本发明化合物的IC50低于100nM,强烈结合于EP3受体上。
测试实施例2
下面使用尖叫反应作为指数研究了本发明化合物对于佐剂-诱发的关节炎模型的疼痛反应的抑制作用,该模型是慢性关节炎疼痛模型。
使用了七周龄的Lewis雄性大鼠。测量各大鼠左后腿的体积后,向右后腿的爪皮中注射悬浮于液体石蜡中的600μg/100μL的乳酪分枝杆菌(Difco)死细胞,以产生佐剂-关节炎大鼠。注射该佐剂22天后,在口服给予测试物前弯曲伸展左后腿膝关节五次,并使用在这五次中均尖叫的大鼠进行试验。按照前一天左后腿浮肿的体积进行分组,每组包括10只大鼠。本发明的各化合物(1、3、10和30mg/kg)和作为对照的0.5%甲基纤维素水溶液(5mL/kg)口服给药。给药1、2、3和4小时后观察尖叫反应。其中尖叫反应用作指数的止痛效果判断按下面方式进行,在各观察期,弯曲伸展左后腿膝关节五次,五次中均未观察到尖叫的情况定义为尖叫反应阴性,而在一个或多个评价点处尖叫反应为阴性的个体被定义为尖叫反应阳性。
结果,在对照组中没有观察到止痛作用阳性的个体,而在给予化合物(I)的组中,例如自10mg/kg或更低组中观察到了止痛作用阳性的个体,因此观察到EP3受体拮抗剂对佐剂-诱发关节炎模型疼痛的止痛作用。
测试实施例3
使用逃避潜伏期(escape latency)作为指数按照下述方法研究了本发明化合物对于角叉胶-诱发的痛觉过敏模型的止痛作用,该模型是急性炎症疼痛模型。
使用七周龄SD种雄性大鼠。使用用于足底测试的测量装置向各大鼠右后腿辐射热刺激,测量直至抬腿逃避的时间并作为逃避潜伏期。取决于逃避潜伏期进行分组,各组包含7至8只大鼠,且本发明的各化合物(3、10和30mg/kg)和作为对照的0.5%甲基纤维素水溶液(5mL/kg)口服给药。口服给予测试物1小时后,将溶于生理盐水中的角叉胶(2mg/100μL)经皮下注射到大鼠右后腿。测量注射角叉胶后3小时内的逃避潜伏期。
结果,在注射角叉胶的对照组中观察到逃避潜伏期降低且诱发了痛觉过敏,但在给予化合物(I)的组中,例如,与对照组相比,从不高于10mg/kg组中观察到其逃避潜伏期显著升高,因此观察到EP3受体拮抗剂对角叉胶-诱发痛觉过敏的改善作用。
测试实施例4
下面研究了本发明化合物对硫前列酮诱发的尿频模型的抑制作用。
使用体重大约300g的雄性Crj:CD(SD)IGS大鼠。本发明的各化合物(3、10、30和100mg/kg)和作为对照的0.5%甲基纤维素水溶液(5mL/kg)口服给药。口服给予测试物0.5小时后,皮下给予硫前列酮(0.2mg/4mL/kg)。作为未诱发组,口服给予0.5%甲基纤维素水溶液,且在y小时后,皮下给予生理盐水。给予硫前列酮之后立即开始测量排尿直至此后3小时。测量排尿时既不供给食物也不供给水,将动物置于装有尿液测量装置的代谢笼中,并使用数据采集系统记录随着时间流逝收集到的尿液重。顺便提及地,各组的案例数为3至4例。
结果观察到对照组中通过皮下给予硫前列酮增加了排尿频率,但在给予化合物(I)的组中,例如,从不高于30mg/kg组中显示了低的排尿频率值。其结果指出EP3受体拮抗剂对硫前列酮诱发的尿频具有抑制作用。
测试实施例5
研究本发明化合物对由硫前列酮诱发的ACTH和皮质酮提高的抑制作用。
使用雄性Crj:CD(SD)IGS大鼠。本发明化合物或作为对照的NaOH水溶液口服给药,1小时后,硫前列酮皮下给药。作为未诱发组,口服给予NaOH水溶液,1小时后,皮下给予生理盐水。给予硫前列酮1小时后,大鼠被断头并收集血液。向血液中加入EDTA和抑肽酶后离心并测量其上清液中的ACTH或皮质酮浓度。
测试实施例6
研究了本发明化合物对自发出现皮炎的NC小鼠的自发性搔痒行为的抑制作用。
使用自发出现皮炎的雄性NC小鼠。将小鼠置于观察笼中并使其适应环境30分钟,在无人情况下使用录像带记录1小时内的搔痒行为。回放录像带,小鼠使用其后腿搔脸、耳、后颈及其周边的行为判断为搔痒并计算其频率。每30分钟,口服给予本发明的各化合物和作为对照的0.5%甲基纤维素水溶液(5mL/kg),共给药3至5次。第二次给药后立即通过录像记录1至3小时,并计算小鼠的搔痒时间。
测试实施例7
当0.3%二硝基氟苯(DNFB)重复施用于Brown Norway(BN)大鼠头皮以诱发皮炎时,施用后24至27小时内观察到自发性搔痒行为增加。研究本发明化合物对搔痒行为的抑制作用。
对于切割的雄性BN大鼠头皮,将溶解于丙酮与橄榄油中的0.3%DNFB可用作半抗原。作为未诱发组,应用丙酮与橄榄油的混合物。一周后,再次施用于头皮,此后,每隔1天重复施用三次。第四次施用后24至27小时内,在无人环境下对大鼠录像。回放录像带,大鼠用其后腿搔施用半抗原处周边区域的一系列行为被判断为搔痒行为,并计算其频率。从第三次至第六次施用12至48小时后,口服给予本发明的各化合物和作为对照的0.5%甲基纤维素水溶液。对于未诱发组,口服给予0.5%甲基纤维素水溶液。给药后通过录像记录30分钟至3小时,并计算大鼠的搔痒时间。
Claims (12)
1.式(I)的羧酸化合物:
其中R1是氢或C1-4烷基;
R2是苯基、萘基、苯并呋喃基或苯并噻吩基,其未被取代或被1-2个C1-4烷基和/或卤素取代;
Q是(i)-CH2-O-Cyc1、(ii)-CH2-Cyc2或(iii)-L-Cyc3;
Cyc1是苯基或吡啶基,其未被取代或被1-2个R4取代;
Cyc2是吲哚基,其未被取代或被1-2个R4取代;
Cyc3是被1-2个R4取代的苯基;
L是-O-或-NH-;
R3a和R3b各自独立是氢或C1-4烷基或
R3a和R3b,与它们所连接的碳原子一起形成四氢-2H-吡喃;
m是2或3;
n是0、1或2;
R4是C1-4烷基、C1-4烷硫基、卤素或氰基,或当Cyc3是被2个R4取代的苯基时,两个R4与苯基一起可以形成
其盐、其溶剂合物或其前药。
2.根据权利要求1的羧酸化合物,其是
(1)3-(4-(2,5-二氟苯氧基甲基)-2-((((1R)-1-(萘-2-基)乙基)氨基)羰基)苯基)丙酸,
(2)3-(4-(2,5-二氯苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(3)3-(4-(2-氯-5-甲基苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(4)3-(4-(2-氯-5-氟苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(5)3-(4-(2,5-二氟苯氧基甲基)-2-(((4-苯基四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(6)3-(4-(2,5-二氯苯氧基甲基)-2-(((4-苯基四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(7)3-(4-(2-氯-5-氟苯氧基甲基)-2-(((4-苯基四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(8)3-(4-(2-氯-5-氟苯氧基甲基)-2-(((4-苯基四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(9)3-(4-(3-氰基苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸,
(10)3-(4-(2,5-二甲基苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸,
(11)3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(12)3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(13)3-(4-(3-氰基苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(14)3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(15)3-(4-(5-氟吲哚-1-基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(16)3-(4-(2,4-二甲基苯氧基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(17)3-(2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-苯氧基甲基苯基)丙酸,
(18)3-(2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3-吡啶基氧基甲基)苯基)丙酸,
(19)3-(4-(3-氯苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(20)3-(4-(3,4-二甲基苯氧基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(21)3-(4-(2-氯-5-氟苯氧基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(22)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(3-甲基吲哚-1-基甲基)苯基)丙酸,
(23)3-(4-(2,5-二氟苯氧基甲基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丙酸,
(24)3-(4-(2-氟-5-甲基苯氧基甲基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丙酸,
(25)3-(2-(((4-(3,5-二甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2-氟-5-甲基苯氧基甲基)苯基)丙酸,
(26)3-(4-(2-氟-5-甲基苯氧基甲基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(27)3-(2-(((4-(苯并呋喃-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2,5-二氟苯氧基甲基)苯基)丙酸,
(28)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(4-氟-2-甲基苯氧基甲基)苯基)丙酸,
(29)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-((2-甲基吡啶-3-基)氧基甲基)苯基)丙酸,
(30)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-((2-甲基吡啶-5-基)氧基甲基)苯基)丙酸,
(31)3-(4-(3-氟苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(32)3-(4-(3-甲基苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(33)3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(34)3-(2-(((4-(苯并呋喃-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2,5-二甲基苯氧基甲基)苯基)丙酸,
(35)3-(2-(((4-(苯并噻吩-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2,5-二甲基苯氧基甲基)苯基)丙酸,
(36)3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(2-(2-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(37)3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(2-(2-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(38)3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(2-(4-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(39)3-(4-(2,5-二甲基苯氧基甲基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(40)3-(4-(6-氟吲哚-1-基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(41)3-(4-(6-氟吲哚-3-基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(42)3-(4-(3-甲基吲哚-1-基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(43)3-(4-(3-氰基苯氧基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(44)3-(4-(6-氟吲哚-1-基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(45)3-(4-(6-氟吲哚-3-基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(46)3-(4-(3-甲基吲哚-1-基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(47)3-(4-(6-氟吲哚-1-基甲基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(48)3-(2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3-甲基吲哚-1-基甲基)苯基)丙酸,
(49)3-(4-(3-氰基苯氧基甲基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(50)4-(4-(1,3-二氧杂茚满-5-基氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(51)4-(4-(3-甲基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(52)4-(4-(3-氰基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(53)4-(4-(3,4-二甲基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(54)4-(4-(茚满-5-基氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(55)4-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(56)4-(4-(3-甲硫基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(57)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(3-氟苯基氨基)苯基)丙酸,
(58)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(3-甲基苯基氨基)苯基)丙酸,
(59)3-(4-(3-氰基苯基氨基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(60)3-(4-(3,5-二氟苯基氨基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(61)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(1,3-二氧杂茚满-5-基氨基)苯基)丙酸,
(62)3-(4-(3,5-二氟苯氧基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(63)3-(4-(3-氰基苯氧基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(64)4-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(萘-2-基)乙基)氨基)羰基)苯基)丁酸,
(65)3-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丙酸,
(66)3-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(萘-2-基)乙基)氨基)羰基)苯基)丙酸,
(67)3-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(3-甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(68)3-(4-(3-甲基苯基氨基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(69)4-(4-(3-氟苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(70)4-(4-(3-甲基苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(71)4-(4-(3,5-二氟苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(72)4-(4-(1,3-二氧杂茚满-5-基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(73)4-(4-(3-氰基苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(74)3-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丙酸,
(75)3-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(萘-2-基)乙基)氨基)羰基)苯基)丙酸,
(76)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(3,5-二甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(77)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(78)3-(4-(3,5-二甲基苯氧基)-2-(((4-(3-甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(79)3-(2-(((4-(苯并呋喃-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3,5-二甲基苯氧基)苯基)丙酸,
(80)3-(2-(((4-(苯并呋喃-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3,5-二甲基苯基氨基)苯基)丙酸,
(81)3-(4-(3,5-二甲基苯氧基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(82)3-(4-(3,5-二甲基苯氧基)-2-(((4-(3,5-二甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(83)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(84)3-(2-(((4-(3,5-二甲基苯基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3-甲基苯基氨基)苯基)丙酸,
(85)3-(2-(((4-(苯并噻吩-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3,5-二甲基苯基氨基)苯基)丙酸,
(86)3-(4-(3,5-二甲基苯氧基)-2-(((4-(2-(4-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(87)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(2-(4-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(88)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(2-(2-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(89)3-(4-(3,5-二甲基苯氧基)-2-(((4-(2-(2-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,或
(90)3-(4-(3,5-二甲基苯氧基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
其盐、其溶剂化物或其前药。
3.根据权利要求1的羧酸化合物,其是
(1)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(5-氟-2-甲基苯氧基甲基)苯基)丙酸,
(2)3-(2-(((4-(苯并噻吩-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(2,5-二氟苯氧基甲基)苯基)丙酸,
(3)3-(4-(2-氟-5-甲基苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸,
(4)3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(5)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(6)3-(2-(((4-(苯并噻吩-2-基)四氢-2H-吡喃-4-基)氨基)羰基)-4-(3,5-二甲基苯氧基)苯基)丙酸,
(7)3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(2-苯基乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(8)3-(2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)-4-(3-吡啶基氧基甲基)苯基)丙酸,
(9)3-(4-(2-氟-5-甲基苯氧基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(10)3-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(11)3-(4-(6-氟吲哚-1-基甲基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(12)3-(4-(3,5-二甲基苯氧基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(13)4-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(萘-1-基)乙基)氨基)羰基)苯基)丁酸,
(14)3-(4-(2-氯-5-甲基苯氧基甲基)-2-((((1R)-3-甲基-1-(3-甲基苯基)丁基)氨基)羰基)苯基)丙酸,
(15)3-(4-(2,5-二氟苯氧基甲基)-2-(((4-(2-(4-氟苯基)乙基)四氢-2H-吡喃4-基)氨基)羰基)苯基)丙酸,
(16)3-(4-(3,5-二甲基苯基氨基)-2-((((1R)-1-(3-甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸,
(17)3-(4-(2-氟-5-甲基苯氧基甲基)-2-(((4-(萘-2-基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
(18)3-(4-(3,5-二甲基苯氧基)-2-((((1R)-1-(3,5-二甲基苯基)-3-甲基丁基)氨基)羰基)苯基)丙酸或
(19)3-(4-(3,5-二甲基苯基氨基)-2-(((4-(2-(3-氟苯基)乙基)四氢-2H-吡喃-4-基)氨基)羰基)苯基)丙酸,
其盐、其溶剂化物或其前药。
4.一种药物组合物,其包含根据权利要求1的羧酸化合物、其盐、其溶剂化物或其前药。
5.根据权利要求4的药物组合物,其是EP3受体拮抗剂。
6.根据权利要求5的药物组合物,其是用于因EP3受体过度激活而诱导的疾病的预防和/或治疗药物。
7.根据权利要求6的药物组合物,其中因EP3受体过度激活而诱导的疾病选自搔痒症、疼痛、泌尿紊乱和与应激反应-相关疾病中的一种或多种。
8.根据权利要求7的药物组合物,其中疼痛是关节炎疼痛或神经性疼痛。
9.根据权利要求7的药物组合物,其中泌尿紊乱是尿频。
10.一种药物组合物,其包含根据权利要求1的羧酸化合物、其盐、其溶剂化物或其前药,以及一种或多种选自甾类药物、非甾类抗炎药、免疫抑制剂、抗过敏药、中介蛋白释放抑制剂、白细胞三烯受体拮抗剂、抗组胺药、福斯高林制剂、磷酸二酯酶抑制剂、氧化氮合酶抑制剂、大麻素-2受体兴奋剂、非阿片类镇痛剂、非类固醇类消炎剂药、环氧合酶抑制剂、阿片类镇痛剂、前列腺素、N-型钙通道阻滞剂、α1肾上腺素受体阻滞剂、黄体酮制剂、抗胆碱能药物、毒蕈碱受体拮抗剂、5-HT1A受体激动剂、σ1受体激动剂、5-羟色胺神经系统激动剂、促肾上腺皮质激素释放因子受体拮抗剂、质子泵抑制剂、M1受体拮抗剂、细胞保护剂、三环类抗抑郁药和四环类抗抑郁剂的药物。
11.一种预防和/或治疗哺乳动物体内因EP3受体过度激活而诱导的疾病的方法,包括给予哺乳动物有效量的根据权利要求1的羧酸化合物、其盐、其溶剂化物或其前药。
12.根据权利要求1的羧酸化合物、其盐、其溶剂化物或其前药在制备用于因EP3受体过度激活而诱导的疾病的预防和/或治疗药物中的用途。
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EP (1) | EP1591441A4 (zh) |
JP (1) | JPWO2004069788A1 (zh) |
KR (1) | KR20050106421A (zh) |
CN (2) | CN1764635A (zh) |
AU (1) | AU2004209496A1 (zh) |
BR (1) | BRPI0407258A (zh) |
CA (1) | CA2515516A1 (zh) |
MX (1) | MXPA05008307A (zh) |
NO (1) | NO20053753L (zh) |
NZ (1) | NZ541603A (zh) |
PL (1) | PL378119A1 (zh) |
RU (1) | RU2335490C2 (zh) |
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BRPI0414487A (pt) * | 2003-09-17 | 2006-11-14 | Ono Pharmaceutical Co | composto de ácido carboxìlico e composições medicinais contendo os mesmos como o ingrediente ativo |
ES2350452T3 (es) * | 2004-11-22 | 2011-01-24 | Venus Remedies Limited | Formulación parenteral de aceclofenaco líquido no acuoso. |
SI1988085T1 (sl) * | 2006-02-21 | 2015-03-31 | Toyama Chemical Co., Ltd. | Postopek za izdelavo 3-(5-(4-(ciklopentiloksi)-2-hidroksibenzoil)-2-((3 -hidroksi-1,2-benzizoksazol-6-il)metoksi)fenil)propionat estra in intermediata za ta postopek |
ITMI20061368A1 (it) * | 2006-07-14 | 2008-01-15 | Acraf | Composto 2-arilindolico sostituito in posizione 5, composizione farmaceutica che lo comprende nonche' composti intermedi e procedimento per prepararlo |
SI2848610T1 (en) * | 2006-11-15 | 2018-02-28 | Ym Biosciences Australia Pty Ltd | Inhibitors of kinase activity |
US7662858B2 (en) | 2008-05-23 | 2010-02-16 | Aaipharma, Inc. | Method of treating post-surgical acute pain |
WO2011017346A2 (en) * | 2009-08-03 | 2011-02-10 | Emisphere Technologies, Inc. | Fast-acting naproxen composition with reduced gastrointestinal effects |
US20140155419A1 (en) * | 2011-07-29 | 2014-06-05 | Erkan Baloglu | Compounds and methods |
AU2015269064B2 (en) | 2014-06-06 | 2020-02-13 | Allergan, Inc. | Novel EP4 agonists as therapeutic compounds |
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PH12617A (en) * | 1973-04-13 | 1979-07-05 | Thomae Gmbh Dr K | Aminobenzyl-amides and salts thereof |
KR100189863B1 (ko) * | 1993-12-27 | 1999-06-01 | 나이또 하루오 | 안트라닐산 유도체 |
JP3909864B2 (ja) * | 1995-07-26 | 2007-04-25 | 小野薬品工業株式会社 | ナフチルオキシ酢酸誘導体およびそれらを有効成分として含有する薬剤 |
US6043275A (en) * | 1998-04-16 | 2000-03-28 | Ono Pharmaceutical Co., Ltd. | 3,7-dithiaprostanoic acid derivative |
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JP2005502600A (ja) | 2001-06-07 | 2005-01-27 | イーライ・リリー・アンド・カンパニー | ペルオキシソーム増殖因子活性化受容体(ppar)のモジュレーター |
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JPWO2004069788A1 (ja) | 2006-05-25 |
AU2004209496A1 (en) | 2004-08-19 |
ZA200506258B (en) | 2006-04-26 |
PL378119A1 (pl) | 2006-03-06 |
KR20050106421A (ko) | 2005-11-09 |
US7576129B2 (en) | 2009-08-18 |
CN101328135A (zh) | 2008-12-24 |
MXPA05008307A (es) | 2005-09-20 |
NO20053753L (no) | 2005-11-07 |
US20070167498A1 (en) | 2007-07-19 |
RU2005125047A (ru) | 2006-02-10 |
CA2515516A1 (en) | 2004-08-19 |
RU2335490C2 (ru) | 2008-10-10 |
WO2004069788A1 (ja) | 2004-08-19 |
NO20053753D0 (no) | 2005-08-04 |
EP1591441A4 (en) | 2007-10-31 |
NZ541603A (en) | 2008-03-28 |
EP1591441A1 (en) | 2005-11-02 |
BRPI0407258A (pt) | 2006-01-31 |
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