CN1525972A - 杂双环crf拮抗剂 - Google Patents
杂双环crf拮抗剂 Download PDFInfo
- Publication number
- CN1525972A CN1525972A CNA02813866XA CN02813866A CN1525972A CN 1525972 A CN1525972 A CN 1525972A CN A02813866X A CNA02813866X A CN A02813866XA CN 02813866 A CN02813866 A CN 02813866A CN 1525972 A CN1525972 A CN 1525972A
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- Prior art keywords
- group
- alkyl
- methyl
- compound according
- alkoxy
- Prior art date
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- 239000005557 antagonist Substances 0.000 title description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 158
- -1 -NR6R7 Chemical group 0.000 claims abstract description 109
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 37
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 claims abstract description 36
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 claims abstract description 34
- 102000012289 Corticotropin-Releasing Hormone Human genes 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 24
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 22
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 18
- 150000002367 halogens Chemical class 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 229910052757 nitrogen Chemical group 0.000 claims abstract description 14
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 13
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims abstract description 13
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 13
- 238000002360 preparation method Methods 0.000 claims abstract description 13
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 12
- 125000003118 aryl group Chemical group 0.000 claims abstract description 10
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 10
- 239000012453 solvate Substances 0.000 claims abstract description 10
- 229940002612 prodrug Drugs 0.000 claims abstract description 9
- 239000000651 prodrug Substances 0.000 claims abstract description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 8
- 230000001404 mediated effect Effects 0.000 claims abstract description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 3
- 230000008569 process Effects 0.000 claims abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 17
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- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 8
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 5
- 208000019901 Anxiety disease Diseases 0.000 claims description 5
- 230000036506 anxiety Effects 0.000 claims description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
- ZVTDJFCIQSZODD-UHFFFAOYSA-N 2-[1-[1-[2,4-bis(trifluoromethyl)phenyl]-6-methyl-2,3-dihydropyrrolo[2,3-b]pyridin-4-yl]pyrazol-3-yl]-1,3-thiazole Chemical compound C12=NC(C)=CC(N3N=C(C=C3)C=3SC=CN=3)=C2CCN1C1=CC=C(C(F)(F)F)C=C1C(F)(F)F ZVTDJFCIQSZODD-UHFFFAOYSA-N 0.000 claims description 4
- 208000020401 Depressive disease Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- BISOKIVPXCKTDB-UHFFFAOYSA-N 1-[2,4-bis(trifluoromethyl)phenyl]-6-methyl-4-(3-pyridin-2-ylpyrazol-1-yl)-2,3-dihydropyrrolo[2,3-b]pyridine Chemical compound C12=NC(C)=CC(N3N=C(C=C3)C=3N=CC=CC=3)=C2CCN1C1=CC=C(C(F)(F)F)C=C1C(F)(F)F BISOKIVPXCKTDB-UHFFFAOYSA-N 0.000 claims description 2
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 2
- OWDRGDIMOGRUBC-UHFFFAOYSA-N 2-[1-[1-(4-methoxy-2-methylphenyl)-6-methyl-2,3-dihydropyrrolo[2,3-b]pyridin-4-yl]pyrazol-3-yl]-1,3-thiazole Chemical compound CC1=CC(OC)=CC=C1N1C(N=C(C)C=C2N3N=C(C=C3)C=3SC=CN=3)=C2CC1 OWDRGDIMOGRUBC-UHFFFAOYSA-N 0.000 claims description 2
- JYFKCJUYMDDGNO-UHFFFAOYSA-N 2-[1-[6-methyl-1-[2-methyl-4-(trifluoromethoxy)phenyl]-2,3-dihydropyrrolo[2,3-b]pyridin-4-yl]pyrazol-3-yl]-1,3-thiazole Chemical compound C12=NC(C)=CC(N3N=C(C=C3)C=3SC=CN=3)=C2CCN1C1=CC=C(OC(F)(F)F)C=C1C JYFKCJUYMDDGNO-UHFFFAOYSA-N 0.000 claims description 2
- JYNDEXCIODLBHK-UHFFFAOYSA-N 2-[1-[8-[2,4-bis(trifluoromethyl)phenyl]-2-methyl-6,7-dihydro-5h-1,8-naphthyridin-4-yl]pyrazol-3-yl]-1,3-thiazole Chemical compound C12=NC(C)=CC(N3N=C(C=C3)C=3SC=CN=3)=C2CCCN1C1=CC=C(C(F)(F)F)C=C1C(F)(F)F JYNDEXCIODLBHK-UHFFFAOYSA-N 0.000 claims description 2
- PILQTHJQQVUSEV-UHFFFAOYSA-N 3-methyl-4-[6-methyl-4-[3-(1,3-thiazol-2-yl)pyrazol-1-yl]-2,3-dihydropyrrolo[2,3-b]pyridin-1-yl]benzonitrile Chemical compound C12=NC(C)=CC(N3N=C(C=C3)C=3SC=CN=3)=C2CCN1C1=CC=C(C#N)C=C1C PILQTHJQQVUSEV-UHFFFAOYSA-N 0.000 claims description 2
- KGKXRTIQVIDWRO-UHFFFAOYSA-N 4-[1-[1-[2,4-bis(trifluoromethyl)phenyl]-6-methyl-2,3-dihydropyrrolo[2,3-b]pyridin-4-yl]pyrazol-3-yl]morpholine Chemical compound C12=NC(C)=CC(N3N=C(C=C3)N3CCOCC3)=C2CCN1C1=CC=C(C(F)(F)F)C=C1C(F)(F)F KGKXRTIQVIDWRO-UHFFFAOYSA-N 0.000 claims description 2
- IUDHIXABFWMKSO-UHFFFAOYSA-N 4-[6-methyl-4-[3-(1,3-thiazol-2-yl)pyrazol-1-yl]-2,3-dihydropyrrolo[2,3-b]pyridin-1-yl]-3-(trifluoromethyl)benzonitrile Chemical compound C12=NC(C)=CC(N3N=C(C=C3)C=3SC=CN=3)=C2CCN1C1=CC=C(C#N)C=C1C(F)(F)F IUDHIXABFWMKSO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 3
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 122
- 239000000543 intermediate Substances 0.000 description 62
- 235000019439 ethyl acetate Nutrition 0.000 description 60
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 50
- 238000006243 chemical reaction Methods 0.000 description 44
- 239000011541 reaction mixture Substances 0.000 description 43
- 239000000243 solution Substances 0.000 description 39
- 239000007832 Na2SO4 Substances 0.000 description 32
- 229910052938 sodium sulfate Inorganic materials 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 239000000741 silica gel Substances 0.000 description 28
- 229910002027 silica gel Inorganic materials 0.000 description 28
- 238000003818 flash chromatography Methods 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 26
- 108010056643 Corticotropin-Releasing Hormone Receptors Proteins 0.000 description 22
- 239000000047 product Substances 0.000 description 22
- 239000000284 extract Substances 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- 239000012267 brine Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- 239000007787 solid Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000012298 atmosphere Substances 0.000 description 16
- 239000002464 receptor antagonist Substances 0.000 description 14
- 229940044551 receptor antagonist Drugs 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 208000002193 Pain Diseases 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 206010047700 Vomiting Diseases 0.000 description 8
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- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 201000006549 dyspepsia Diseases 0.000 description 6
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000007796 conventional method Methods 0.000 description 5
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- 208000024714 major depressive disease Diseases 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- UZOGLHNKDHOSGA-UHFFFAOYSA-N 2-(1h-pyrazol-5-yl)-1,3-thiazole Chemical compound N1N=CC=C1C1=NC=CS1 UZOGLHNKDHOSGA-UHFFFAOYSA-N 0.000 description 4
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 4
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- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 4
- GPVWUKXZFDHGMZ-UHFFFAOYSA-N dicyclohexyl-[2-(2-methylphenyl)phenyl]phosphane Chemical group CC1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 GPVWUKXZFDHGMZ-UHFFFAOYSA-N 0.000 description 4
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- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 3
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Abstract
本发明提供了包括立体异构体、前药和其可药用盐或溶剂化物的式(I)化合物、其制备方法、含有所述式(I)化合物的药物组合物及其在治疗促肾上腺皮质激素释放因子(CRF)介导的疾病中的用途,其中,R是芳基或杂芳基,各自可被1-4个下述基团取代:卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、-C(O)R5、硝基、-NR6R7、氰基和R8;R1是氢、C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤素、NR6R7或氰基;R2是氢、C3-C7环烷基或R9;R3是C3-C7环烷基或R9;或R2和R3与N一起形成5-14元杂环,且该杂环可以被1-3个R10取代;R4是氢、C1-C6烷基、卤素或卤代C1-C6烷基;R5是C1-C4烷基、-OR6或-NR6R7;R6是氢或C1-C6烷基;R7是氢或C1-C6烷基;R8是5-6元杂环,该杂环可以是饱和杂环或可以含有1-3个双键,且可被一个或多个R11取代;R9是C1-C6烷基,其可以被一个或多个下述基团取代:C3-C7环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、羟基、卤代C1-C6烷基;R10是R8、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、羟基、卤素、硝基、氰基、C(O)NR6R7、可以被1-4个R11取代的苯基;R11是C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、羟基、卤素、硝基、氰基或C(O)NR6R7;X是碳或氮;n是1或2。
Description
本发明涉及双环衍生物、其制备方法,含有所述双环衍生物的药物组合物及其在治疗中的用途。
第一促肾上腺皮质激素释放因子(CRF)已从羊下丘脑中分离出来,并确认为41-氨基酸肽(Vale等人,Science 213:1394-1397,1981)。现已发现,CRF会在内分泌、神经和免疫系统机能中产生深刻变化。CRF被认为是源自垂体前叶的促肾上腺皮质激素(″ACTH″)、B内啡呔和其它阿黑皮素原(″POMC″)衍生肽的基础释放和应激释放的主要生理调节剂(Vale等人,Science 213:1394-1397,1981)。
除了刺激产生ACTH和POMC的作用之外,CRF可能是关键中枢神经系统神经递质之一,且在整合身体对应激的总应答中起决定性作用。
用CRF直接对脑给药引起行为、生理和内分泌应答,该应答与处于应激环境之下的动物的应答相同。
相应地,临床数据表明CRF受体拮抗剂可以代表新的抗抑郁剂和/或抗焦虑药物,所述药物可用于治疗表现形式为CRF分泌过多的神经精神病障碍。
第一CRF受体拮抗剂是肽(参见,例如,Rivier等,US 4605642;Rivier等,Science 224:889,1984)。尽管这些肽确定了CRF受体拮抗剂能减少对CRF的药理学应答,但是,肽CRF受体拮抗剂具有肽疗法的常规缺点,包括缺乏稳定性且口服活性有限。最近,报道了小分子CRF受体拮抗剂。
WO 95/10506特别公开了具有一般CRF拮抗活性的通式(A)化合物,
其中,Y可以是CR29;V可以是氮,Z可以是碳,R3可以表示胺衍生物和R4可以与R29一起形成5-元环,且当R29是-CH(R30)时,R4是CH(R28)。但没有具体公开对应于上述定义的化合物。
WO95/33750也描述了具有CRF拮抗活性的通式(B)化合物,
其中A和Y可以是氮和碳,且B可以表示胺衍生物。但没有具体公开对应于上述定义的化合物。
WO98/08846描述了具有CRF拮抗活性的通式(C)化合物,
其中,A可以是碳,G可以是氮或碳,B可以是氨基衍生物且其它基团具有所定义的含义。
鉴于CRF的生理重要性,因此,研究出具有显著CRF受体结合活性且能拮抗CRF受体生物学活性的小分子仍然是期望的目标。上述CRF受体拮抗剂可用于治疗内分泌、精神和神经病症或疾病,一般包括应激相关疾病。
虽然通过给药CRF受体拮抗剂来实现CRF调节已取得重大进步,但本领域仍需要有效的小分子CRF受体拮抗剂。还需要含有所述CRF受体拮抗剂的药物组合物以及与其用于治疗诸如应激相关疾病的用途有关的方法。本发明满足上述需要并具有其它相关优点。
本发明尤其涉及新化合物,该新化合物是促肾上腺皮质激素释放因子(CRF)受体的有效和特异的拮抗剂。
本发明提供了包括立体异构体、前药和其可药用盐或溶剂化物的式(I)化合物,
其中,
R是芳基或杂芳基,各自可被1-4个下述基团取代:卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、-C(O)R5、硝基、-NR6R7、氰基和R8;
R1是氢、C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤素、NR6R7或氰基;
R2是氢、C3-C7环烷基或R9;
R3是C3-C7环烷基或R9;或
R2和R3与N一起形成5-14元杂环,且该杂环可以被1-3个R10取代;
R4是氢、C1-C6烷基、卤素或卤代C1-C6烷基;
R5是C1-C4烷基、-OR6或-NR6R7;
R6是氢或C1-C6烷基;
R7是氢或C1-C6烷基;
R8是5-6元杂环,该杂环可以是饱和杂环或可以含有1-3个双键,且可被一个或多个R11取代;
R9是C1-C6烷基,其可以被一个或多个下述基团取代:C3-C7环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、羟基、卤代C1-C6烷基;
R10是R8、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、羟基、卤素、硝基、氰基、C(O)NR6R7、可以被1-4个R11取代的苯基;
R11是C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、
C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、羟基、卤素、硝基、氰基或C(O)NR6R7;
X是碳或氮;
n是1或2。
采用本领域已知方法可制备本发明游离碱氨基化合物的酸加成盐,且酸加成盐可以由有机和无机酸形成。合适的有机酸包括马来酸、苹果酸、富马酸、苯甲酸、抗坏血酸、丁二酸、甲磺酸、对甲苯磺酸、乙酸、草酸、丙酸、酒石酸、水杨酸、柠檬酸、葡糖酸、乳酸、苦杏仁酸、肉桂酸、天冬氨酸、硬脂酸、软脂酸、乙醇酸、谷氨酸和苯磺酸。合适的无机酸包括盐酸、氢溴酸、硫酸、磷酸和硝酸。因此,术语式(I)的“可药用盐”包括任一和所有的可药用盐形式。
溶剂化物可以是,例如,水合物。
参照下文,本发明化合物包括式(I)化合物和其可药用酸加成盐以及其可药用溶剂化物。
另外,前药也包括在本发明范围内。前药是任何共价键连接的载体,当对患者给药前药时,前药可以在体内释放式(I)化合物。一般通过修饰官能团来制备前药,并且,这种修饰可以通过通过常规操作裂解或在体内裂解,从而得到母体化合物。前药包括例如其中羟基、氨基或巯基与任何基团连接的本发明化合物,当对患者给药时,所连接的这些基团断裂进而形成羟基、氨基或巯基。因此,具有代表性的前药实例包括(但不限于)式(I)化合物的醇、巯基和胺官能团的乙酸酯、甲酸酯和苯甲酸酯衍生物。而且,对于羧酸(-COOH)而言,可以使用其酯,例如,甲酯、乙酯等。
关于立体异构体,式(I)化合物可以具有手性中心,并可以外消旋化物、外消旋混合物和单一对映体或非对映体的形式存在。本发明包括所有这些异构形式,包括其混合物。而且,式(I)化合物的某些结晶形式可以以多晶型物的形式存在,所述多晶型物包括在本发明中。
本发明中作为一个基团或作为基团的一部分使用的术语C1-C6烷基是指含有1-6个碳原子的直链或支链烷基,所述基团的实例包括甲基、乙基、丙基、异丙基、正丁基、异丁基、戊基或己基。
术语C3-C7环烷基是指3-7个碳原子的非芳香单环烃环,例如,环丙基、环丁基、环戊基、环己基或环庚基;而不饱和环烷基包括环戊烯基和环己烯基等。
术语卤素指氟、氯、溴或碘原子。
术语卤代C1-C6烷基或卤代C1-C2烷基指具有一个或多个碳原子的烷基,且其中至少一个氢原子被卤素取代,例如,三氟甲基等。
术语C2-C6链烯基定义为含有一个或多个双键且具有2-6个碳原子的直链或支链烃基,例如,乙烯基、2-丙烯基、3-丁烯基、2-丁烯基、2-戊烯基、3-戊烯基、3-甲基-2-丁烯基或3-己烯基等。
术语C1-C6烷氧基可以是直链或支链烷氧基,例如,甲氧基、乙氧基、丙氧基、丙-2-氧基、丁氧基、丁-2-氧基或甲基丙-2-氧基等。
术语卤代C1-C6烷氧基可以是被至少一个卤素原子,优选被氟取代的上文定义的C1-C6烷氧基,例如,OCHF2或OCF3。
术语C2-C6炔基定义为含有一个或多个三键且具有2-6个碳原子的直链或支链烃基,包括乙炔基、丙炔基、1-丁炔基、1-戊炔基、3-甲基-1-丁炔基等。
术语芳基是指芳香碳环基团,例如,苯基、联苯基或萘基。
术语杂芳基是指具有至少一个选自氮、氧和硫的杂原子并含有至少一个碳原子的5-10元芳香杂环,包括单和双环体系。
具有代表性的杂芳基包括(但不限于)呋喃基、苯并呋喃基、噻吩基、苯并噻吩基、吡咯基、吲哚基、异氮杂茚基、吖吲哚基、吡啶基、喹啉基、异喹啉基、噁唑基、异噁唑基、苯并噁唑基、吡唑基、咪唑基、苯并咪唑基、噻唑基、苯并噻唑基、异噻唑基、哒嗪基、嘧啶基、吡嗪基、三嗪基、肉啉基、2,3-二氮杂萘基、三唑基、四唑基和喹唑啉基。
术语5-14元杂环是指饱和、不饱和或芳香5-7元单环杂环或7-14元多环杂环,所述杂环含有1-4个独立选自氮、氧和硫的杂原子,其中,氮和硫杂原子可以任选被氧化,且氮杂原子可以任选被季铵化,所述杂环包括双环杂环(其中上述任一杂环与苯环稠合)以及三环(和更高环)杂环。杂环可通过任何杂原子或碳原子连接。杂环包括上文定义的杂芳基。因此,除上文列举的芳香杂芳基外,杂环还包括(但不限于)吗啉基、吡咯烷酮基、吡咯烷基、哌啶基、乙内酰脲基、戊内酰胺基、环氧乙烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、四氢吡啶基、四氢嘧啶基、四氢噻吩基、四氢噻喃基、四氢嘧啶基、四氢噻吩基和四氢噻喃基等。
根据上述定义,术语5-6元杂环是指饱和、不饱和或芳香5-6元单环杂环,所述杂环含有1-4个独立选自氮、氧和硫的杂原子,其中,氮和硫杂原子可以任选被氧化,且氮杂原子可以任选被季铵化。杂环包括上文定义的杂芳基。杂环可通过任何杂原子或碳原子连接。因此,该术语包括(但不限于)吗啉基、吡啶基、吡嗪基、吡唑基、噻唑基、三唑基、咪唑基、噁二唑基、噁唑基、吡咯烷酮基、吡咯烷基、哌啶基、乙内酰脲基、戊内酰胺基、环氧乙烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、四氢吡啶基、四氢嘧啶基、四氢噻吩基、四氢噻喃基、四氢嘧啶基、四氢噻吩基和四氢噻喃基等。
本发明具有代表性的化合物包括下式(Ia)和(Ib)化合物,
在一个优选实施方案中,其中根据上述式(I)化合物的定义n=1,本发明CRF受体拮抗剂具有式(Ia)结构,且当n=2时,本发明CRF受体拮抗剂具有式(Ib)结构,其中R、R1、R2和R3的定义同上。
本发明其它具有代表性的化合物包括通式(I)化合物,其中,R2和R3与N一起形成可被1-3个R10取代的5-14元杂环基团;所述R10定义同上。
根据所选择的X,本发明CRF受体拮抗剂包括式(IIa)和(IIb)化合物,
其中,NR2R3表示可被1-3个R8取代的5-6元杂环基团。
尤其包括下式(IIIa)和(IIIb)化合物,
其中,R1、R和R8定义同上。
所述化合物的实例将在实验部分提出。
本发明更优选的实施方案包括,但不限于,式(I)、(Ia)、(Ib)、(IIa)、(IIb)、(IIIa)、(IIIb)的化合物,其中,
R1是C1-C3烷基或卤代C1-C3烷基,优选甲基或三氟甲基;
R4是氢;和
R是芳基,选自:2,4-二氯苯基、2-氯-4-甲基苯基、2-氯-4-三氟甲基、2-氯-4-甲氧基苯基、2,4,5-三甲基苯基、2,4-二甲基苯基、2-甲基-4-甲氧基苯基、2-甲基-4-氯苯基、2-甲基-4-三氟甲基、2,4-二甲氧基苯基、2-甲氧基-4-三氟甲基苯基、2-甲氧基-4-氯苯基、3-甲氧基-4-氯苯基、2,5-二甲氧基-4-氯苯基、2-甲氧基-4-异丙基苯基、2-甲氧基-4-三氟甲基苯基、2-甲氧基-4-异丙基苯基、2-甲氧基-4-甲基苯基、2-三氟甲基4-氯苯基、2,4-三氟甲基苯基、2-三氟甲基-4-甲基苯基、2-三氟甲基-4-甲氧基苯基、2-溴-4-异丙基苯基、2-甲基-4-氰基苯基、2-氯-4-氰基苯基、4-甲基-6-二甲基氨基吡啶-3-基、3,5-二氯-吡啶-2-基、2,6-二甲氧基-吡啶-3-基和3-氯-5-三氯甲基-吡啶-2-基。
本发明优选的化合物是:
1-(2,4-二-三氟甲基-苯基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶;
1-(2,4-二-三氟甲基-苯基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶;
3-甲基-4-[6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基]苄腈;
4-[6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基]-3-三氟甲基-苄腈;
6-甲基-1-(2-甲基-4-三氟甲氧基-苯基)-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶;
1-(2,4-二-三氟甲基-苯基)-7-甲基-5-(3-噻唑-2-基-吡唑-1-基)-1,2,3,4-四氢-[1,8]萘啶;
1-(4-甲氧基-2-甲基-苯基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1 H-吡咯并[2,3-b]吡啶;
1-(2,4-二-三氟甲基-苯基)-6-甲基-4-(3-吗啉-4-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶;
1-(2,4-二-三氟甲基-苯基)-6-甲基-4-(3-吡啶-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶;和
4-[1,3’]联吡唑-1’-基-1-(2,4-二-三氟甲基-苯基)-6-甲基-2,3-二氢-IH-吡咯并[2,3-b]吡啶。
一般,通过本领域技术人员已知的有机合成技术和本发明实施例中陈述的具有代表性的方法,可以制备式(I)化合物。
采用下文概述的一般方法,可以制备式(I)化合物、其盐和其溶剂化物。在下文中,除非另有说明,基团R、R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11和n同上文式(I)化合物中的定义。
根据下述反应图解1可以方便地制备式(IIa)化合物:
反应图解1
其中,
步骤a表示:在碱性条件下,通过与合适的胺NR2R3反应,将离去基团L转化成式(III)化合物的氨基基团,L选自卤素或磺酸(例如,甲磺酸、甲苯磺酸)的反应性残基,优选是氯;
步骤b表示:用合适的还原剂(例如,DIBAI-H)将酯基还原成式(IV)化合物的羟基;
步骤c表示:用合适的氧化剂(例如,Dess-Martin periodinane)将羟基氧化成式(V)化合物的醛基;
步骤d表示:在一般条件下,通过维蒂希反应,形成烯醇醚,然后通过酸解(步骤e),形成式(VII)化合物的醛基;
步骤f表示:用合适的还原剂(例如,NaBH4)将醛基还原成式(VIII)化合物的羟基;
步骤g表示:将羟基转化成化合物(IX)的合适保护基团(例如,TBS:叔丁基二甲基甲硅烷基);
步骤h表示:与合适的胺RNH2进行偶合的Buchwald反应;
步骤i表示:脱保护反应,得到式(XI)化合物的羟基;
步骤1表示:在将式(XI)化合物的羟基转化成合适的离去基团(例如,溴化物,通过与CBr4和PPh3反应)后,加热进行分子内环化,得到最终的式(IIa)化合物。
用另一种方法,通过下述反应图解2可方便地制备式(IIa)化合物:
反应图解2
其中,
步骤a’表示:将羟基转化成式(XII)化合物的合适离去基团L’,L’独立于L,并与L具有相同的定义(例如,甲磺酸,通过在Et3N中与MsCl反应);
步骤b’表示:在诸如DMF的无质子偶极溶剂中,通过与例如KCN反应,将L’转化成式(XIII)化合物的氰基衍生物;
步骤c’表示:用合适的还原剂(例如,BH3-THF)将氰基还原成式(XIV)化合物的氨基;
步骤d’表示:在合适溶剂(例如,NMP)中,在高温下,通过加热进行式(XIV)化合物的分子内环化;
步骤e’表示:用合适还原剂(例如NaBH4)将醛基还原成式(VIII)化合物的羟基;
步骤f’:对应于上述步骤h。
根据下述反应图解3可方便地制备式(IIb)化合物:
反应图解3:
其中,
步骤a”:对应于上述步骤d;
步骤b”:对应于上述步骤e;
步骤c”:对应于上述步骤f;
步骤d”:对应于上述步骤g;
步骤e”:对应于上述步骤h;
步骤f”:对应于上述步骤i;
步骤g”:对应于上述步骤l。
式(II)化合物是已知化合物或可以根据文献中的已知方法制备。
在根据本领域技术人员已知的方法制备杂环活性残基后,可通过上述反应图解1、2和3制备式(IIIa)和(IIIb)化合物。
合适的羟基保护基团的实例包括三烃基甲硅烷基醚,例如,三甲基甲硅烷基醚和叔丁基二甲基甲硅烷基醚。采用公知的标准方法(例如,在ProtectiveGroups in Organic Chemistry,pages 46-119,Edited by J F W McOmie(PlenumPress,1973)中描述的方法),可以除去羟基保护基。例如,当Pg是叔丁基二甲基甲硅烷基时,通过用三乙胺三氢氟酸盐处理,可除去羟基保护基。
也可以使用常规方法,由式(I)化合物的其它盐,包括式(I)化合物的其它可药用盐制备可药用盐。
通过合适溶剂的结晶或蒸发,能容易地分离出带有溶剂分子的式(I)化合物,进而得到相应的溶剂化物。
如果需要式(I)化合物的特定对映体,则使用常规方法拆分式(I)化合物相应的对映体混合物,可以制备该对映体。因此,通过使用手性HPLC法,从式(I)的外消旋化合物可制备所需对映体。
本发明还包括同位素标记化合物,同位素标记化合物与式I和下文列举的化合物相同,只不过同位素标记化合物一个或多个原子被原子质量或质量数与通常在自然界发现的原子质量或质量数不同的原子代替。可引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟、碘和氯的同位素,例如,3H、11C、14C、18F、123I和125I。含有上述同位素和/或其它原子的其它同位素的本发明化合物和其可药用盐包括在本发明范围内。本发明的同位素标记化合物,例如,引入了诸如3H、14C的放射性同位素的本发明化合物可用于药物和/或底物组织分布测定。由于易于制备和具有可检测性,因此,特别优选氚(即,3H)和碳-14(即,14C)的同位素。11C和18F同位素特别适用于PET(正电子发射断层显像),125I特别适用于SPECT(单光子发射计算机化断层显像),它们都可用于脑成象。而且,用诸如氘(即,2H)的重同位素取代,能够获得由更高代谢稳定性带来的某些治疗优点,例如,增加的体内半衰期或降低的剂量需求,因此,在某些情况下是优选的。一般,通过实行反应图解和/或下述实施例中公开的方法,用易于获得的同位素标记试剂代替非同位素标记试剂,可以制备本发明式I和式I之后的结构式所示的同位素标记化合物。
本发明的CRF受体拮抗剂已证明在包括CRF1和CRF2受体的CRF受体部位具有活性,并且可用于治疗CRF或CRF受体介导的病症。
用作CRF受体拮抗剂的化合物效力可以用各种测定方法测定。本发明的合适CRF拮抗剂能抑制CRF与其受体的特异性结合并拮抗与CRF相关活性。作为CRF受体拮抗剂的式(I)化合物的活性可以通过一种或多种能用于测定CRF受体拮抗剂活性的公认测定法来测定,所述测定法包括(但不限于)DeSouza等人(J.Neuroscience 7:88;1978)和Battaglia等人(Synapse 1:572,1987)公开的测定方法。
用闪烁亲近同质技术(SPA)进行CRF受体结合测定。配体与表达CRF受体的重组膜制品结合,所述CRF受体本身又与涂布了麦胚凝集素的SPA珠结合。在实施例部分将对实验进行详细描述。
关于CRF受体结合亲和性,本发明CRF受体拮抗剂的Ki小于10μm。
本发明化合物用于治疗与CRF受体有关的中枢神经系统疾病。尤其用于治疗或预防重性抑郁症,包括两相性抑郁症,单相性抑郁症,带有或不带有精神病特征、紧张症特征、忧郁症特征、非典型特征或产后发作的单发或复发重性抑郁发作,并用于治疗焦虑症和治疗急性焦虑症。包括在上述重性抑郁症之内的其它心境障碍包括带有或不带有非典型特征的早发性或迟发性精神抑郁症,官能性抑郁症,创伤后精神紧张性障碍和社会恐怖症;带有抑郁心境的早发性或迟发性阿耳茨海默氏痴呆;带有抑郁心境的血管性痴呆;由酒精、安非他明、可卡因、致幻剂、吸入剂、阿片样物质、苯环利定、镇静剂、安眠剂、抗焦虑药和其它物质诱发的心境障碍;抑郁型分裂情感性精神障碍和带有抑郁心情的适应性障碍。普通医学病症,包括,但不限于,心肌梗死、糖尿病、流产或小产等,也可导致重性抑郁症。
本发明化合物也可用于治疗或预防精神分裂症样精神障碍,包括类偏执型精神分裂症、错乱型精神分裂症、紧张型精神分裂症、未分化型精神分裂症和残余精神分裂症。
本发明化合物可用作止痛剂。尤其可用于治疗创伤性疼痛(例如,术后疼痛);例如臂丛的创伤性撕脱疼痛;慢性疼痛(例如,在诸如在骨关节炎、类风湿性关节炎或牛皮癣性关节炎中存在的关节炎疼痛);神经病性疼痛(例如,带状疱疹后神经痛、三叉神经神经痛、节性或肋间神经痛、纤维肌痛、灼痛、外周神经病、糖尿病性神经病、化疗导致的神经病、AIDS相关神经病、枕骨神经痛、膝状神经痛、舌咽神经痛、反射交感性营养不良和幻肢疼痛);诸如偏头疼、急性或慢性紧张性头疼、颞下颌疼痛、上颌窦疼痛和丛集性头疼的各种头疼;牙痛;恶性肿瘤疼痛;源自内脏的疼痛;胃肠痛;神经陷夹疼痛;运动损失疼痛;痛经;月经痛;脑膜炎;蛛网膜炎;肌骨骼疼;诸如脊柱狭窄的下腰背疼痛;子宫脱垂(prolapsed disc);坐骨神经痛;咽痛;强硬性脊椎炎;痛风;烧伤;瘢痕疼痛;痒病和丘脑疼痛(例如,中风后的丘脑疼痛)。
本发明化合物还可用于治疗食欲和食物摄取机能障碍以及诸如厌食、神经性厌食和食欲过盛的病症。
本发明化合物还可用于治疗睡眠障碍,包括Dysomnia、失眠症、睡眠窒息、嗜眠发作和昼夜节律紊乱(Circadian ritmic)。
本发明化合物还可用于治疗或预防认知障碍。认知障碍包括痴呆、健忘症和未另作说明的认知障碍。
而且,本发明化合物还可用作没有认知和/或记忆缺失的健康人的记忆和/或认知增强剂
本发明化合物还可用于治疗对许多物质的耐药性和依赖性。例如,本发明化合物可用于治疗对尼古丁、酒精、咖啡因和苯环利定(类苯环利定化合物)的依赖性或用于治疗对阿片制剂(例如,大麻、海洛因和吗啡)或苯并二氮杂庚因的耐药性和依赖性或用于治疗对可卡因、镇静剂、安眠药、安非他明或安非他明相关药物(例如,右旋苯异丙胺、甲基苯异丙胺)或其混合物成瘾。
本发明化合物也可用作抗炎药。尤其可用于治疗哮喘、流行性感冒、慢性支气管炎和类风湿性关节炎中的炎症;用于治疗胃肠道炎性疾病,例如,局限性回肠炎、溃疡性结肠炎、炎性肠病(IBD)和非甾类抗炎药诱发的损害;诸如疱疹和湿疹的皮肤炎性疾病;诸如膀胱炎和压迫性失禁的膀胱炎性疾病以及眼和牙齿炎症。
本发明化合物还可用于治疗变应性疾病,尤其是诸如荨麻疹的皮肤变应性疾病和诸如鼻炎的气道变应性疾病。
本发明化合物还用于治疗呕吐,即,恶心、干呕和呕吐。呕吐包括急性呕吐、迟发性呕吐和早发性呕吐。本发明化合物可用于治疗引发的呕吐。例如,呕吐可以由下列因素诱发:药物(例如,诸如烷化剂的肿瘤化疗剂,例如,环磷酰胺、卡莫司汀、环己亚硝脲和苯丁酸氮芥);细胞毒素抗生素(例如,放线菌素D、阿霉素、丝裂霉素C和争光霉素);抗代谢物(例如,阿糖胞苷、氨甲蝶呤和5-氟尿嘧啶);长春花生物碱(例如,依托泊甙、长春花硷和长春新硷)和其它药物(例如,顺铂、达卡巴嗪、盐酸丙卡巴肼和羟基脲)以及上述药物的混合物;辐射病;放射治疗(例如,在诸如肿瘤治疗中进行的胸或腹放射治疗);毒物;毒素,例如,由代谢性疾病或感染(例如,胃炎)导致的毒素或在细菌或病毒性胃肠感染中释放的毒素;妊娠;前庭疾病(例如,晕动病、眩晕、头晕和梅尼埃尔氏病);手术后疾病;胃肠梗阻;胃肠能动性降低;内脏疼痛(例如,心肌梗死或腹膜炎);偏头痛;颅内压力增加;颅内压力降低(例如,高空病);诸如吗啡的阿片样镇痛剂;胃食管反流疾病;胃酸过多性消化不良;嗜食或酗酒;胃酸过多;酸性胃(sour stomach);反酸/反胃;胃灼热,例如,发作性胃灼热、夜发性胃灼热和进餐导致的胃灼热;和消化不良。
本发明化合物尤其可用于治疗诸如过敏性肠并发症(IBS)的胃肠疾病;诸如牛皮癣、瘙痒症和晒斑的皮肤疾病;诸如心绞痛、血管性头痛和雷诺氏疾病的血管痉挛疾病;脑局部缺血,如随蛛网膜下出血引起的脑血管痉挛;诸如硬皮病和嗜酸性片吸虫病的纤维组织形成疾病和胶原疾病;免疫增强或抑制相关疾病,例如,全身性红斑狼疮和诸如肌风湿病的风湿性疾病;以及咳嗽。
本发明化合物用于治疗由脑中风、血栓栓塞中风、出血性中风、脑缺血、脑血管痉挛、低血糖、低氧症、缺氧症和产期窒息心动停止引起的神经中毒性损伤。
因此本发明提供了一种用于治疗,特别是用于给人类用药的式(I)化合物或其可药用盐或其溶剂化物。
作为本发明的另一方面,还提供了式(I)化合物或其可药用盐或其溶剂化物在制备用于治疗CRF介导的病症的药物中的用途。
在另一方面,本发明提供了治疗包括人类在内的哺乳动物的方法,特别是治疗CRF介导的病症的方法,该方法包括给药有效量的式(I)化合物或其可药用盐或其溶剂化物。
不用说,所提及的治疗包括预防和缓减已存在的症状。
可以给药式(I)化合物原化学药品,但是,活性组分优选以药物制剂的形式存在。
因此,本发明还提供了一种药物组合物,所述药物组合物含有至少一种式(I)化合物或其可药用盐,并配制成可通过任何适宜的途径给药的制剂。所述组合物优选以适合药物的剂型,尤其是适合人类用药物的剂型存在,而且,可以通过常规方法,使用一种或多种可药用载体或赋型剂方便地配制。
因此,式(I)化合物可配制成经口、口含、肠胃外、局部(包括眼和鼻)、长效或直肠给药的制剂或配制成适于经吸入或吹入(经口或鼻)给药的制剂。
对于口服给药,药物组合物可以是,例如,片剂或胶囊剂型,该剂型通过常规方法制备,并使用诸如粘合剂(例如,预先凝胶化的玉米淀粉、聚乙烯吡咯烷酮或羟丙基甲基纤维素)、填料(例如,乳糖、微晶纤维素或磷酸氢钙)、润滑剂(例如,硬脂酸镁、滑石或硅石)、崩解剂(例如,马铃薯淀粉或淀粉乙醇酸钠)或湿润剂(例如,十二烷基硫酸钠)的可药用赋形剂。用本领域的已知方法可以将片剂包衣。口服给药液体制剂可以是,例如,溶液、糖浆剂或悬浮剂,或者,它们以干品存在,使用前与水或其它合适载体一起混配成口服液体制剂。所述液体制剂可以通过常规方法制备,其中使用诸如悬浮剂(例如,山梨糖醇糖浆剂、纤维素衍生物或氢化可食用脂肪)、乳化剂(例如,卵磷脂或阿拉伯胶)、非水载体(例如,杏仁油、油质酯、乙醇或分馏的植物油)和防腐剂(例如,对羟基苯甲酸甲酯或丙酯或山梨酸)的可药用添加剂。所述制剂中还可酌情含有缓冲盐、调味剂、着色剂和甜味剂。
口服给药制剂可以配制成能缓释活性化合物的制剂。
对于口含给药,组合物可以配制成片剂或按常规方法配制。
本发明化合物可以配制成快速浓注或连续输注的肠胃外给药制剂。注射制剂可以单位剂型的形式存在,例如,存在于加入防腐剂的安瓿或多剂量容器中。例如,该组合物可以是在油性或水性载体中的悬浮剂、溶液或乳剂,并可含有诸如悬浮剂、稳定剂和/或分散剂的配方试剂。或者,活性组分可以是粉末的形式,其在使用前与合适的载体(如,无致热原的无菌水)混配。
本发明化合物可配制成软膏、霜剂、凝胶、洗剂、栓剂、气雾剂或滴剂(例如,滴眼剂、滴耳剂或滴鼻剂)用于局部给药。例如,可以用加入了适当增稠剂和/或胶凝剂的水性或油性基质来配制软膏和霜剂。,使用无菌组分通过无菌方法可制备眼药软膏。
洗剂可以使用水性或油性基质来配制,且一般还含有一种或多种乳化剂、稳定剂、分散剂、悬浮剂、增稠剂或着色剂。滴剂可以用水性或非水性基质来配制,并且也含有一种或多种分散剂、稳定剂、增溶剂或悬浮剂。它们还可以含有防腐剂。
本发明化合物还可配制成经直肠给药组合物,例如,含有诸如可可脂或其它甘油酯的常规栓剂基质的栓剂或潴留灌肠剂。
本发明化合物还可配制成长效制剂。这种长效制剂可通过埋入(例如,皮下或肌内埋入)或肌内注射给药。因此,例如,可将本发明化合物与合适的聚合物或疏水材料(例如,在可药用油中的乳液)或离子交换树脂一起配制,或将本发明化合物配制成微溶的衍生物,例如,微溶的盐。
对于鼻内给药,可将本发明化合物配制成通过合适的计量或单剂量装置给药的溶液,或者,配制成与合适载体混合的粉末,该粉末制剂使用合适的输送装置给药。
本发明化合物的建议剂量为1-约1000mg/天。可理解的是,根据患者的年龄和病情,有必要对剂量作一些常规改变,且准确剂量最终由主治医师或兽医来确定。剂量还取决于给药途径和所选择的具体化合物。
因此,肠胃外给药日剂量一般为1-约100mg,优选为1-80mg。口服给药日剂量一般在1-300mg的范围内,例如,1-100mg。
实施例
除非另有说明,在中间体和实施例中:
熔点(m.p.)是在Gallenkamp熔点测定器上测定,且未校正。所有温度均为℃。在FT-IR仪上测定红外光谱。在400MHz记录质子核磁共振(1H-NMR)谱,化学位移以ppm为单位并表示为距离Me4Si内标峰的低磁场位移,峰形表示如下:s,单峰;d,双峰;dd;双二重峰;t,三重峰;q,四重峰或m,多重峰。在硅胶(Merck AG Darmstaadt,Germany)上进行柱色谱分离。在本发明中使用了下述缩写:EtOAc=乙酸乙酯、cHex=环己烷、CH2Cl2=二氯甲烷、Et2O=乙醚、DMF=N,N’-二甲基甲酰胺、DIPEA=N,N-二异丙基乙胺、DME=乙二醇二甲醚、MeOH=甲醇,Et3N=三乙胺、TFA=三氟乙酸、THF=四氢呋喃、DIBAL-H=氢化二异丁基铝、DMAP=二甲基氨基吡啶、LHMDS=六甲基二硅氮烷锂、Tlc是指在硅胶色谱板上的薄层色谱,干燥的是指用无水硫酸钠干燥的溶液;r.t.(RT)指室温。
中间体1
2,4-二氯-6-甲基-烟酸乙酯
根据已公开的方法(Mittelkbach,Martin;Synthesis,1988,
6,p.479-80)制备标题化合物。
中间体2
2-氯-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-烟酸乙酯
在0℃和N2气氛下,向2-(1H-吡唑-3-基)-1,3-噻唑(7.71g,1.05eq)的无水DMF(61ml)溶液中加入60%的NaH矿物油(2.03g,1.05eq)分散体,并在0℃搅拌反应混合物10分钟,然后在室温搅拌1小时。在0℃加入
中间体1(11.34g,48.0mmol)的无水DMF(35ml)溶液,并将所得溶液在110℃加热3小时。用水淬灭反应,用EtOAc萃取,盐水洗涤,用无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 7∶3)提纯粗产物,得到7.02g白色固体标题化合物。
NMR(1H,CDCl3):δ7.91(d,1H),7.91(d,1H),7.41(d,1H),7.31(s,1H),7.18(d,1H),4.50(q,2H),2.78(s,3H),1.25(t,3H)。
MS(m/z):349[MH]+。
中间体3
[2-氯-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶-3-基]-甲醇
在-78℃和N2气氛下,向
中间体2(1.5g,4.3mmol)的无水CH2Cl2(30ml)溶液中加入1.0M DIBAl-H的环己烷(12.9ml,3.0eq)溶液。在-78℃搅拌反应混合物10小时,然后在室温搅拌1小时。然后用饱和罗谢尔盐溶液淬灭反应,用EtOAc萃取,盐水洗涤,用无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 1∶1)提纯粗产物,得到1.02g白色固体
标题化合物。
NMR(1H,CDCl3):δ8.05(d,1H),7.90(d,1H),7.40(d,1H),7.25(s,1H),7.10(d,1H),4.65
(S,2H),4.0(bs,1H),2.60(s,3H)。
MS(m/z):307[M]+。
中间体4
2-氯-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶-3-甲醛
在室温和N2气氛下,向
中间体3(150mg,0.5mmol)的无水CH2Cl2(5ml)溶液中加入Dess-Martin periodinane(273mg,1.12eq)。并在室温搅拌反应混合物1小时。然后用溶解在碳酸氢钠饱和溶液中的0.5g硫代硫酸钠溶液淬灭反应,用EtOAc萃取,盐水洗涤,无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 1∶1)提纯粗产物,得到124mg白色固体
标题化合物。
NMR(1H,CDCl3):δ10.4(s,1H),8.0-7.9(2d,2H),7.40(2d,2H),7.10(s,1H),2.70(s,3H)。
MS(m/z):305[MH]+。
中间体5
2-氯-3-(2-甲氧基-乙烯基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶
在0℃和N2气氛下,向氯化(甲氧基甲基)-三苯基鏻(4.24g,3eq)的无水THF(20ml)溶液中加入1.6M正丁基锂的环己烷(7.73ml,12.37mmol)溶液,将反应混合物升温至室温,并搅拌15分钟。然后加入
中间体4(1.25g,4.1mmol)的无水THF(15ml)溶液,并在室温搅拌反应1.5小时。用水淬灭反应,用EtOAc萃取,盐水洗涤,无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 4∶1)提纯粗产物,得到961mg白色固体
标题化合物(E∶Z=3∶2,直接用于下一步反应)。
NMR(1H,CDCl3)principal E product:δ7.90(m,1H),7.83(m,1H),7.38(m,1H),7.05(m,1H),7.00(m,1H),6.51(d,1H),5.63(d,1H),3.64(s,3H),2.60(s,3H)。
MS(m/z):333 [MH]+。
中间体6
[2-氯-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶-3-基]-乙醛
向
中间体5(936mg,2.8mmol)的无水THF(15ml)溶液中加入6N HCl(21ml,45eq),并在室温搅拌反应混合物15小时。然后用饱和NaHCO3水溶液淬灭反应,直至pH=7,用EtOAc萃取,盐水洗涤,无水Na2SO4干燥,过滤并真空浓缩,得到893mg白色固体
标题化合物,该产物无需进一步提纯,可直接用于下一步反应。
NMR(1H,CDCl3):δ9.80(s,1H),7.90-7.80(2d,2H),7.70(d,1H),7.20(d,1H),7.0(s,1H),4.25(s,2H),2.70(s,3H)。
MS(m/z):319[MH]+。
中间体7
2-[2-氯-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶-3-基]-乙醇
向
中间体6(903mg,2.84mmol)的无水MeOH(10ml)溶液中加入CeCl3(700mg,1eq)和NaBH4(107mg,1eq),在室温搅拌反应混合物5分钟。用水淬灭反应,用乙酸乙酯萃取,盐水洗涤,无水Na2SO4干燥,过滤并真空浓缩,得到848mg白色固体
标题化合物,该产物无需进一步提纯,可直接用于下一步反应。
NMR(1H,CDCl3):δ8.00(m,2H),7.50(d,1H),7.20(m,2H),4.25(t,2H),3.20(t,2H),2.70(s,3H)。
MS(m/z):321[MH]+。
中间体8
3-[2-(叔丁基-二甲基-甲硅烷氧基)-乙基]-2-氯-6-甲基-4-(3-噻唑-2-基-吡
唑-1-基)-吡啶
向
中间体7(840mg,2.6mmol)的无水CH2CL2(10ml)溶液中加入2,6-二甲基吡啶(0.67ml,2.2eq)和三氟甲磺酸叔丁基二甲基甲硅烷基酯(0.89ml,1.5eq),并在室温搅拌反应混合物15小时。然后用饱和NH4Cl水溶液淬灭反应,用EtOAc萃取,盐水洗涤,无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 3∶2)提纯产物,得到950mg无色油状
标题化合物。
NMR(1H,CDCl3):δ8.20(d,1H),7.75(d,1H),7.35(d,1H),7.00(m,2H),4.00(t,2H),3.05(t,2H),2.55(s,3H),0.80(s,9H),-0.10(s,6H)。
MS(m/z):435[MH]+。
中间体9
(2,4-二-三氟甲基-苯基)-[3-[2-(叔丁基-二甲基-甲硅烷氧基)-乙基]-6-甲基
-4-(3-噻唑-2-基-吡唑-1-基)-吡啶-2-基]-胺
向
中间体8(240mg,0.553mmol)的无水DME(1ml)溶液中加入Pd2(dba)3(51mg,0.1eq)、2-(二环己基膦基)-2’-甲基联苯(60mg,0.3eq)、K3PO4(317mg,3eq)和2,4-二(三氟甲基)苯胺(0.17ml,2eq),并微波照射反应混合物(150W,100℃,60psi)20分钟。用饱和NH4Cl水溶液淬灭反应,用EtOAc萃取,盐水洗涤,无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 9∶1)提纯产物,得到180mg无色油状
标题化合物。
NMR(1H,CDCl3):δ8.55(d,1H),8.20(bs,1H),7.90(d,1H),7.80(m,2H),7.65(dd,1H),7.40(d,1H),7.05(d,1H),6.85(s,1H),4.20(t,2H),2.90(t,2H),2.60(s,3H),0.80(s,9H),0.10(s,6H)。
MS(m/z):628[MH]+。
中间体10
2-[2-(2,4-二-三氟甲基-苯基氨基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶
-3-基]-乙醇
向中间体9(240mg,0.38mmol)的无水THF(5ml)溶液中加入Et3N·3HF(0.187ml,2eq),在室温搅拌反应混合物15小时。用饱和NH4Cl水溶液淬灭反应,用EtOAc萃取,盐水洗涤,无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 1∶1)提纯产物,得到180mg无色油状
标 题化合物。
NMR(1H,CDCl3):δ8.45(bs,1H),8.20(d,1H),7.85(d,1H),7.85(2d,2H),7.65(dd,1H),7.30(d,1H),7.05(d,1H),6.85(s,1H),4.20(t,2H),2.85(t,2H),2.50(s,3H)。
MS(m/z):514[MH]+。
中间体11
甲磺酸2-氯-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶-3-基甲酯
在-25℃和N2气氛下,
向中间体3(308mg,1.01mmol)的无水CH2Cl2(2.5ml)溶液中加入Et3N(280μl,2eq)和CH3SO2Cl(120μl,1.5eq)。在-25℃搅拌反应混合物2小时,然后在-5℃再搅拌2小时。用水稀释反应混合物,并用CH2Cl2萃取。用无水Na2SO4干燥合并的有机萃取液,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 6∶4→1∶1)提纯粗产物,得到88mg无色油状
标题化合物。
NMR(1H,CDCl3):δ7.90(d,1H),7.87(d,1H),7.39(d,1H),7 34(s,1H),7.14(d,1H),5.5(s,2H),3.0(s,3H),2.78(s,3H)。
MS(m/z):385[MH]+,Cl。
中间体12
[2-氯-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶-3-基]-乙腈
在0℃和N2气氛下,
向中间体11(88mg,0.229mmol)的无水DMF(2.5ml)溶液中加入KCN(15mg,1eq)。在室温搅拌反应混合物5小时。用水和1MNaOH稀释反应混合物,用Et2O萃取。用无水Na2SO4干燥合并的有机萃取液,过滤并真空浓缩,得到黄色固体
标题化合物(60mg),该产物无需进一步提纯,可直接用于下一步反应。
NMR(1H,CDCl3):δ7.92(d,1H),7.91(d,1H),7.41(d,1H),7.31(s,1H),7.18(d,1H),3.99(s,2H),2.78(s,3H)。
MS(m/z):316[MH]+,Cl。
中间体13
2-[2-氯-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶-3-基]-乙胺
在室温和N2气氛下,
向中间体12(810mg,2.571mmol)的无水THF(6ml)溶液中加入BH3·THF(10.3ml,4eq)。回流搅拌反应混合物2小时。真空浓缩反应混合物,并用MeOH稀释。在室温加入1M HCl的Et2O(7.7μl,3eq)溶液,回流搅拌反应2小时。用水稀释反应混合物,并用1M NaOH碱化至pH=12。用快速色谱法(硅胶,CH2Cl2/MeOH 6∶4)提纯粗产物,得到浅黄色固体
标题化 合物(690mg)。
NMR(1H,CDCl3):δ8.42(d,1H),7.94(d,1H),7.79(d,1H),7.48(s,1H),7.07(d,1H),2.81(m,4H),2.51(s,3H),2.0(bs,2H)。
MS(m/z):320 [MH]+,Cl。
中间体14
6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶
在室温和N2气氛下,
向中间体13(640mg,2.01mmol)的无水N-甲基吡咯烷酮(13ml)溶液中加入Et3N(1.12ml,4eq)。在110℃搅拌反应混合物7小时。用水稀释反应混合物,用EtOAc萃取。用无水Na2SO4干燥合并的有机萃取液,过滤并真空浓缩。用快速色谱法(硅胶,CH2Cl2/MeOH 98∶2)提纯粗产物,得到白色固体
标题化合物(187mg)。
NMR(1H,CDCl3):δ7.98(d,1H),7.89(d,1H),7.35(d,1H),7.06(d,1H),4.65(bs,1H),3.72(t,2H),3.48(t,2H),2.42(s,3H)。
MS(m/z):284[MH]+。
中间体15
2-氯-3-(3-甲氧基-烯丙基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)吡啶
在0℃和N2气氛下,向搅拌的氯化(甲氧基甲基)三苯基鏻(833mg,3eq)的无水THF(4ml)悬浮液中滴加1.6M正丁基锂的环己烷(1.50ml,3eq)溶液。室温搅拌反应混合物15分钟,然后加入
中间体6(258mg,1eq)的无水THF(3ml)溶液。将反应混合物搅拌1.5小时。用水淬灭反应,用EtOAc萃取,无水Na2SO4干燥合并的有机萃取液,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc8∶2)提纯粗产物,得到220mg
标题化合物(黄色油状,78%),该化合物是反式和顺式(60/40)乙烯基醚的未分离混合物。
NMR(1H,CDCl3):δ7.88(d,1H),7.79(d,1H),7.36(d,1H),7.19(s,1H),7.08(d,1H),6.31(d,1H),4.90(m,1H),3.44(d,2H),3.48(s,3H),2.57(s,3H)。
MS(m/z):347[MH]+,1Cl。
中间体16
3-[2-氯-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶-3-基]-丙醛
向
中间体15(370mg,1.07mmol)的THF(15ml)溶液中加入6N HCl(12ml,67.5eq),并在室温搅拌反应混合物13小时。向反应混合物中加入NaHCO3溶液,直至pH=7,用EtOAc萃取水相。用无水Na2SO4干燥合并的有机萃取液,过滤并真空浓缩至干。得到粗
标题化合物(335mg)无需进一步提纯直接用于下一步反应。
NMR(1H,CDCl3):δ9.84(s,1H),7.84(d,1H),7.75(d,1H),7.30(d,1H),7.06(d,1H),7.05(s,1H),3.10-3.30(m,4H),2.55(s,3H)。
MS(m/z):333[M+1]+,1Cl。
中间体17
3-[2-氯-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶-3-基]-丙-1-醇
在室温和N2气氛下,
向中间体16(335mg,1mmol)的无水CH3OH(5ml)溶液中加入CeCl3(247mg,1eq)和NaBH4(38mg,1eq)。搅拌反应混合物20分钟。真空除去溶剂,将残余物重新溶解在EtOAc/H2O中并分层。水层用EtOAc萃取,用无水Na2SO4干燥合并的有机萃取液,过滤并真空浓缩。提纯(硅胶,cHex/EtOAc 8∶2)粗产物,得到277.4mg澄清油状
标题化合物。
NMR(1H,CDCl3):δ7.90(d,1H),7.76(d,1H),7.36(d,1H),7.12 (s,1H),7.07(d,1H),3.70(m,2H),2.90(t,2H),2.58(s,3H),2.20(bt,1H),2.04(m,2H)。
MS(m/z):335[M+1]+,1Cl。
中间体18
3-[3-(叔丁基-二甲基-甲硅烷氧基)-丙基]-2-氯-6-甲基-4-(3-噻唑-2-基-吡
唑-1-基)-吡啶
在0℃和N2气氛下,
向中间体17(277.4mg,0.83mmol)的无水DMF(7ml)溶液中加入咪唑(621mg,11eq)、叔丁基二甲基甲硅烷基氯(350mg,2.8eq)和催化量的DMAP。在室温搅拌反应混合物2小时。然后向反应混合物中加入饱和NH4Cl水溶液,用EtOAc萃取。用无水Na2SO4干燥合并的有机萃取液,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 7∶3)提纯粗产物,得到347mg黄色油状
标题化合物。
NMR(1H,CDCl3):δ7.89(d,1H),7.81(d,1H),7.34(d,1H),7.20(s,1H),7.08 (d,1H),3.66(t,2H),2.86 (m,2H),2.57(s,3H),1.89(m,2H),0.86(s,9H),-0.006(s,6H)。
MS(m/z):449[M]+,1Cl。
中间体19
(2,4-二-三氟甲基-苯基)-[3-[3-(叔丁基-二甲基-甲硅烷氧基)-丙基]-6-甲基
-4-(3-噻唑-2-基-吡唑-1-基)-吡啶-2-基]-胺
在室温和N2气氛下,向含有Pd2(dba)3(17mg,0.1eq)、2-(二环己基膦基)-2’-甲基联苯(20mg,0.3eq)和K3PO4(103mg,2.7eq)的管形瓶中加入
中间体18(80mg,0.18mmol)的无水DME(0.5ml)溶液和2,4-二(三氟甲基)苯胺(82ml,2eq)的无水DME(0.5ml)溶液。在P=110W,T=100℃和p=18psi的试验参数下,将反应混合物微波照射五次(3×10分钟+30分钟+60分钟)。用水稀释溶液,用EtOAc萃取,用无水Na2SO4干燥合并的有机萃取液,过滤并真空浓缩至干。用快速色谱法(硅胶,cHex/EtOAc 7∶3)提纯粗产物,得到49mg黄色油状
标题化合物。
NMR(1H,CDCl3):δ8.58(d,1H),7.89(d,1H),7.85(d,1H),7.77(dd,1H),7.76(d,1H),7.34(d,1H),7.23(bs,1H),7.08(d,1H),6.86(s,1H),3.67(t,2H),2.69(m,2H),2.3(s,3H),1.90(m,2H),0.8(s,9H),-0.02(s,6H)。
MS(m/z):642[M+1]+。
中间体20
3-[2-(2,4-二-三氟甲基-苯基氨基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶
-3-基]-丙-1-醇
向
中间体19(60mg,0.094mmol)的无水THF(2ml)溶液中加入
TEA·3HF(0.046ml,3eq)。在室温搅拌反应混合物12小时。然后向反应混合物中加入饱和NH4Cl溶液,用EtOAc萃取。用无水Na2SO4干燥合并的有机萃取液,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 1∶1)提纯粗产物,得到36.4mg白色固体标题化合物。
NMR(1H,CDCl3):δ8.62(d,1H),7.90(d,1H),7.85(bs,1H),7.76(dd,1H),7.7(d,1H),7.37(bs,1H),7.36(d,1H),7.07(d,1H),6.83(s,1H),3.73(t,2H),2.73(t,2H),2.52(s,3H),2.04(m,2H)。
MS(m/z):528[M+1]+。
中间体21
2,4-二-三氟甲基-苯基-[3-(3-溴-丙基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-
吡啶-2-基]-胺
向
中间体20(36.4mg,0.066mmol)的无水CH2Cl2(1ml)溶液中加入CBr4(44mg,2eq)和PPh3(34mg,2eq)。在室温搅拌反应混合物1小时。然后向反应混合物中加入饱和NaHCO3水溶液,用EtOAc萃取,用无水Na2SO4干燥合并的有机萃取液,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 7∶3)提纯粗产物,得到25.7mg白色固体
标题化合物。
NMR(1H,CDCl3):δ8.6(d,1H),7.90(d,1H),7.87(d,1H),7.77(m,1H),7.37(d,1H),7.15(bs,1H),7.10(d,1H),6.84(s,1H),3.47(t,2H),2.78(m,2H),2.52(s,3H),2.3(m,2H)。
MS(m/z):590 [M]+,1Br;510[M-Br]+。
中间体22
4-[3-[2-(叔丁基-二甲基-硅烷氧基)-乙基]-6-甲基-4-(3-噻唑-2-基-吡唑-1-
基)-吡啶-2-基氨基]-3-甲基-苄腈
向
中间体8(186mg,0.43mmol)的无水DME(1ml)溶液中加入Pd2(dba)3(39mg,0.1eq)、2-(二环己基膦基)-2’-甲基联苯(47mg,0.3eq)、K3PO4(246mg,2.6eq)和3-甲基-4-氨基苄腈(113mg,2eq),并微波照射反应混合物(150W,100℃,60psi)20分钟。用饱和NH4Cl水溶液淬灭反应,用EtOAc萃取,盐水洗涤,用无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 8∶2)提纯产物,得到61mg白色固体
标题化合物。
NMR(1H,CDCl3):δ8.30(d,1H),8.06(bs,1H),7.89(d,1H),7.78(d,1H),7.46(dd,1H),7.44(d,1H),7.36(d,1H),7.09(d,1H),6.81(s,1H),4.34(m,2H),2.82(t,2H),2.56(s,3H),2.36(s,3H),0.85(s,9H),0.02(s,6H)。
MS(m/z):531[MH]+。
中间体23
4-[3-(2-羟基-乙基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶-2-基氨基]-3-
甲基-苄腈
向
中间体22(61mg,0.115mmol)的无水THF(2ml)溶液中加入Et3N·3HF(0.056ml,3eq),并在室温搅拌反应混合物15小时。用饱和NH4Cl水溶液淬灭反应,用EtOAc萃取,盐水洗涤,用无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 1∶1)提纯产物,得到46mg白色固体
标题化 合物。
NMR(1H,CDCl3):δ8.39(bs,1H),8.14(d,1H),7.90(d,1H),7.79(d,1H),7.46(m,2H),7.36(d,1H),7.09(d,1H),6.82(s,1H),4.34(m,2H),2.83(t,2H),2.54(s,3H),2.34(s,3H)。
MS(m/z):417[MH]+。
中间体24
4-[3-(2-羟基-乙基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-吡啶-2-基氨基]-3-
三氟甲基-苄腈
向
中间体8(106mg,0.244mmol)的无水DME(1ml)溶液中加入Pd2(dba)3(22mg,0.1eq)、2-(二环己基膦基)-2’-甲基联苯(27mg,0.3eq)、K3PO4(140mg,2.7eq)和3-三氟甲基-4-氨基苄腈(91mg,2eq),并微波照射反应混合物(150W,100℃,60psi)20分钟。用饱和NH4Cl水溶液淬灭反应,用EtOAc萃取,盐水洗涤,用无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 8∶2)提纯产物,所分离的产物含有一些未反应苯胺,该产物无需进一步提纯,可直接用于下一步反应。
向上述制得的混合物(120mg)的无水THF(5ml)溶液中加入Et3N·3HF(0.063ml,2eq),并在室温搅拌反应混合物15小时。用饱和NH4Cl水溶液淬灭反应,用EtOAc萃取,盐水洗涤,用无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 1∶1)提纯产物,得到40mg白色固体
标题化合物。
NMR(1H,CDCl3):δ8.81(bs,1H),8.22(d,1H),7.90(d,1H),7.87(d,1H),7.79(d,1H),7.68(dd,1H),7.37(d,1H),7.17(d,1H),6.92(s,1H),4.26(q,2H),2.87(t,2H),2.54(s,3H),2.63(t,1H)。
MS(m/z):471[MH]+。
中间体25
[3-[2-(叔丁基-二甲基-甲硅烷氧基)-乙基]-6-甲基-4-(3-噻唑-2-基-吡唑-1-
基)-吡啶-2-基]-(2-甲基-4-三氟甲氧基-苯基)-胺
在室温和N2气氛下,向
中间体8(110mg,0.253mmol)的无水DME(1ml)溶液中加入Pd2(dba)3(23mg,0.1eq)、2-(二环己基膦基)-2’-甲基联苯(28mg,0.3eq)、K3PO4(145mg,2.7eq)和2-甲基-4-三氟甲基苯胺(97mg,2eq),并微波照射反应混合物20分钟(150W,100℃,60psi)。用饱和NH4Cl水溶液淬灭反应,用EtOAc萃取,盐水洗涤,无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 7∶3)提纯产物,得到80mg黄色油状标题化合物。
NMR(1H,CDCl3):δ8.05(d,1H),7.83(bs,1H),7.78 (d,1H),7.7(d,1H),7.46(dd,1H),7.44(d,1H),7.36(d,1H),7.09(d,1H),6.81(s,1H),4.34(m,2H),2.82(t,2H),2.56(s,3H),2.36(s,3H),0.85(s,9H),0.023(s,6H)。
MS(m/z):590[MH]+。
中间体26
2-[6-甲基-2-(2-甲基-4-三氟甲氧基-苯基氨基)-4-(3-噻唑-2-基-吡唑-1-基)-
吡啶-3-基]-乙醇
向
中间体25(80mg,0.135mmol)的无水THF(2ml)溶液中加入Et3N·3HF(66μl,8eq),并在室温搅拌反应混合物15小时。用饱和NH4Cl水溶液淬灭反应,用EtOAc萃取,盐水洗涤,无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 1∶1)提纯产物,得到48mg无色油状
标 题化合物。
NMR(1H,CDCl3):δ7.91(bs,1H),7.85(d,1H),7.7(d,1H),7.65(d,1H),7.30(d,1H),7.15-6.95(m,3H),6.65(s,1H),4.34(m,2H),2.83(t,2H),2.54(s,3H),2.34(s,3H)。
实施例1
具有代表性的式(IIIa)化合物的合成
实施例1-1
1-(2,4-二-三氟甲基-苯基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-
吡咯并[2,3-b]吡啶
在室温和N2气氛下,向
中间体10(40mg,0.078mmol)的无水CH2Cl2(2ml)溶液中加入CBr4(52mg,2eq)和PPh3(41mgl,2eq),并搅拌反应混合物3小时。用饱和NaHCO3水溶液淬灭反应,用EtOAc萃取,盐水洗涤,无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 2∶1)提纯产物,得到18mg白色固体
标题化合物。
用另一种方法:
实施例1-1
1-(2,4-二-三氟甲基-苯基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-
吡咯并[2,3-b]吡啶
在N2气氛下,向压卷曲盖的微波管形瓶中的三(二亚苄基丙酮)合钯(0)(3.2mg,0.1eq)、2-(二环己基膦基)-2’-甲基联苯(3.8mg,0.3eq)和K3PO4(20mg,2.8eq)的混合物中加入
中间体14(10mg,0.035mmol)和2,4-二(三氟甲基)-溴苯(6μl,1eq)的无水DME(1ml)溶液。在P=150W、T=100℃和p=60psi的试验参数下,微波照射反应混合物2个周期(2×10分钟)。然后加入水(1ml),用EtOAc萃取产物。用饱和NaCl水溶液(5ml)洗涤合并的有机萃取液,并用无水Na2SO4干燥。滤除固体,蒸发溶剂,得到粗产物,用快速色谱法(硅胶,cHex/EtOAc7∶3)提纯粗产物,得到无色油状
标题化合物(1mg,0.002mmol)。
实施例1-2
3-甲基-4-[6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡
啶-1-基]苄腈
向
中间体23(44mg,0.106mmol)的无水CH2Cl2(1ml)溶液中加入CBr4(71mg,2eq)和PPh3(60mg,2eq)。在室温搅拌反应混合物3小时。用饱和NaHCO3水溶液淬灭反应,用EtOAc萃取,盐水洗涤,用无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 4∶1)提纯产物,得到18mg白色固体
标题化合物。
实施例1-3
4-[6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-
基]-3-三氟甲基-苄腈
向
中间体24(40mg,0.085mmol)的无水CH2Cl2(2ml)溶液中加入CBr4(56mg,2eq)和PPh3(45mg,2eq)。在室温搅拌反应混合物3小时。用饱和NaHCO3水溶液淬灭反应,用EtOAc萃取,盐水洗涤,用无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 2∶1)提纯产物,得到13mg白色固体
标题化合物。
实施例1-4
6-甲基-1-(2-甲基-4-三氟甲氧基苯基)-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢
-1H-吡咯并[2,3-b]吡啶
向
中间体26(48mg,0.101mmol)的无水CH2Cl2(2ml)溶液中加入CBr4(66mg,2eq)和PPh3(53mg,2eq)。在室温搅拌反应混合物3小时。用饱和NaHCO3水溶液淬灭反应,用EtOAc萃取,盐水洗涤,用无水Na2SO4干燥,过滤并真空浓缩。用快速色谱法(硅胶,cHex/EtOAc 8∶2)提纯产物,得到10mg白色固体
标题化合物。
实施例1-5
1-(4-甲氧基-2-甲基-苯基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢
-1H-吡咯并[2,3-b]吡啶
在N2气氛下,向
中间体28(31mg,0.075mmol,1eq)的无水DCM(5ml)溶液中加入CBr4(53mg,0.16mmol,2eq)和三苯基膦(42mg,0.16mmol,2.1eq)。在室温搅拌反应混合物15小时。然后加入水(10ml),水相用EtOAc(20ml)萃取,用无水Na2SO4干燥有机层,过滤并真空浓缩。用快速色谱法(洗脱液:cHex/EtOAc7∶3)提纯粗产物,得到5.2mg无色油状VSAF/6274/4/1。
实施例1-6
1-(2,4-二-三氟甲基-苯基)-6-甲基-4-(3-吗啉-4-基-吡唑-1-基)-2,3-二氢-1H-
吡咯并[2,3-b]吡啶
用4-(1-H-吡唑-3-基)-吗啉(J.Org.Chem.,1984,269-276)代替在
中间体2制备中的2-(1-H-吡唑-3-基)-噻唑,按类似于实施例1-1的方法制备标题化合物。
实施例1-7
1-(2,4-二-三氟甲基-苯基)-6-甲基-4-(3-吡啶-2-基-吡唑-1-基)-2,3-二氢-1H-
吡咯并[2,3-b]吡啶
用2-(1-H-吡唑-3-基)-吡啶(市售)代替在
中间体2制备中的2-(1-H-吡唑-3-基)-噻唑,按类似于实施例1-1的方法制备标题化合物。
实施例1-8
4-[1,3’]联吡唑-1’-基-1-(2,4-二-三氟甲基-苯基)-6-甲基-2,3-二氢-1H-吡咯
并[2,3-b]吡啶
用1’H-[1,3’]联吡唑(由1H-吡唑-3-基胺制备:J.Heterocyl.Chem.,1983,1629-1639;J.Heterocyl.Chem.,1983,733-738)代替
中间体2制备中的2-(1H-吡唑-3-基)-噻唑,按类似于实施例1-1的方法制备标题化合物。
所有的分析数据列于下表1-1。
表1-1
实施例2
具有代表性的式(IIIb)化合物的合成
所有分析数据列于下表2-1。
实施例2-1
1-(2,4-二-三氟甲基-苯基)-7-甲基-5-(3-噻唑-2-基-吡唑-1-基)-1,2,3,4-四氢
-[1,8]萘啶
在N2气氛下,
向中间体21(24.8mg,0.042mmol)的无水N-甲基吡咯烷酮(2ml)溶液中加入Et3N(12μl,4eq)。在P=90W、T=99℃和p=6psi的试验参数下,微波照射反应混合物10分钟。然后向反应混合物中加入饱和NH4Cl水溶液,水相用EtOAc萃取。合并的有机萃取液用饱和NH4Cl溶液(3x)洗涤,Na2SO4干燥,过滤并真空浓缩。粗产物用SCX柱(洗脱液:CH2Cl2、MeOH和浓NH4OH的MeOH溶液(25%),洗脱出所需产物)提纯,得到18.4mg白色泡沫状标题化合物。
表2-1
实施例3
CRF结合活性
通过化合物替代125I-oCRF和1251-蛙皮降压肽分别结合CRF1和CRF2SPA的能力,体外测定CRF结合亲和力,所述CRF1和CRF2 SPA来自在中国仓鼠卵巢(CHO)细胞膜中表达的重组人类CRF受体。对于膜的制备,将由铺满细胞的T-瓶得到的CHO细胞收集在50mL离心管中的SPA缓冲液(HEPES/KOH 50mM、EDTA2mM;MgCl2 10mM,pH7.4)中,用Polytron均化并离心(4℃,50′000g 5分钟:带有JA20转子的Beckman离心机)。如上所述,将沉淀再次悬浮、均化和离心。
向每孔1μl化合物稀释液(100%DMSO溶液)中加入100μl试剂混合物,在Optiplate中进行SPA实验。通过混合SPA缓冲液、WGA SPA珠(2.5mg/mL)、BSA(1mg/mL)和膜(对于每毫升CRF1和CRF2,分别为50和5ug蛋白质)以及50pM放射性配体来制备试验混合物。
将孔板在室温培养过夜(>18小时),并用带有WGA-SPA125I计数程序的Packard Topcount阅读。
实施例4
CRF功能试验
在用于测定其抑制效力的功能试验中测定本发明化合物的特性。用CRF刺激人类CRF-CHO细胞,并通过测定cAMP累积来评估受体激活。
将由铺满细胞的T-瓶得到的CHO细胞再次悬浮在不带有G418的培养介质中,并分散在96-孔板中,25′000c/孔,100μl/孔,培养过夜。培养后,将介质用37℃100μLcAMP IBMX缓冲液(5mM KCl、5mM NaHCO3、154mMNaCl、5mM HEPES、2.3mM CaCl2、1mM MgCl2;1g/L葡萄糖,通过加入1mg/mLBSA和1mM IBMX调节pH至7.4)和在纯DMSO中的1μL拮抗剂稀释液代替。在37℃,在没有CO2的平板培养器中再培养10分钟后,加入1μL在纯DMSO中的激动剂稀释液。如上所述,将板培养10分钟,并用AmershamRPA538试剂盒测定cAMP细胞浓度。
正如上文详细列举的那样,每篇公开文献被具体和单独指出在本发明中引作参考,同样,说明书中引用的所有公开文献,包括但不限于专利和专利申请,在本发明中都引作参考。
当然本发明包括上文所述的具体和优选基团的所有组合情况。
包括说明书和权利要求书的本申请可以作为任何后续申请的优先权基础。所述后续申请的权利要求可以涉及本发明中描述的任一特征或特征的组合。它们可以是产物、组合物、方法或用途权利要求,并可以包括下述权利要求(仅仅是作为举例,而不仅限于此)。
Claims (22)
1.包括立体异构体、前药和其可药用盐或溶剂化物的式(I)化合物,
其中,
R是芳基或杂芳基,各自可被1-4个下述基团取代:卤素、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、-C(O)R5、硝基、-NR6R7、氰基和R8;
R1是氢、C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤素、NR6R7或氰基;
R2是氢、C3-C7环烷基或R9;
R3是C3-C7环烷基或R9;或
R2和R3与N一起形成5-14元杂环,且该杂环可以被1-3个R10取代;
R4是氢、C1-C6烷基、卤素或卤代C1-C6烷基;
R5是C1-C4烷基、-OR6或-NR6R7;
R6是氢或C1-C6烷基;
R7是氢或C1-C6烷基;
R8是5-6元杂环,该杂环可以是饱和杂环或可以含有1-3个双键,且可被一个或多个R11取代;
R9是C1-C6烷基,其可以被一个或多个下述基团取代:C3-C7环烷基、C1-C6烷氧基、卤代C1-C6烷氧基、羟基、卤代C1-C6烷基;
R10是R8、C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、羟基、卤素、硝基、氰基、C(O)NR6R7、可以被1-4个R11取代的苯基;
R11是C3-C7环烷基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、C2-C6链烯基、C2-C6炔基、卤代C1-C6烷氧基、羟基、卤素、硝基、氰基或C(O)NR6R7;
X是碳或氮;
n是1或2。
2.根据权利要求1的化合物,其中,R2和R3与N一起形成5-14元杂环,且该杂环可以被1-3个R10取代。
3.根据权利要求1的化合物,其为通式(Ia)所示的化合物,
其中R、R1、R2、R3、R4和X同权利要求1中的定义。
4.根据权利要求3的化合物,其为通式(IIa)所示的化合物,
其中R、R1、R2、R3和R4同权利要求1中的定义。
5.根据权利要求4的化合物,其中基团NR2R3表示可以被1-3个R8基团取代的5-6元杂环基团。
8.根据权利要求7的化合物,其为通式(IIIb)所示的化合物,
其中R、R1、R2、R4和R3同权利要求1中的定义。
9.根据权利要求1-8中任一权利要求的化合物,其中R1是C1-C3烷基或卤代C1-C3烷基,R4是氢。
10.根据权利要求1-9中任一权利要求的化合物,其中R是芳基,选自:2,4-二氯苯基、2-氯-4-甲基苯基、2-氯-4-三氟甲基、2-氯-4-甲氧基苯基、2,4,5-三甲基苯基、2,4-二甲基苯基、2-甲基-4-甲氧基苯基、2-甲基-4-氯苯基、2-甲基-4-三氟甲基、2,4-二甲氧基苯基、2-甲氧基-4-三氟甲基苯基、2-甲氧基-4-氯苯基、3-甲氧基-4-氯苯基、2,5-二甲氧基-4-氯苯基、2-甲氧基-4-异丙基苯基、2-甲氧基-4-三氟甲基苯基、2-甲氧基-4-异丙基苯基、2-甲氧基-4-甲基苯基、2-三氟甲基4-氯苯基、2,4-三氟甲基苯基、2-三氟甲基-4-甲基苯基、2-三氟甲基-4-甲氧基苯基、2-溴-4-异丙基苯基、2-甲基-4-氰基苯基、2-氯-4-氰基苯基、4-甲基-6-二甲基氨基吡啶-3-基、3,5-二氯-吡啶-2-基、2,6-二甲氧基-吡啶-3-基和3-氯-5-三氯甲基-吡啶-2-基。
11.根据权利要求1-10中任一权利要求的化合物,选自:
1-(2,4-二-三氟甲基-苯基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶;
1-(2,4-二-三氟甲基-苯基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶;
3-甲基-4-[6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基]苄腈;
4-[6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶-1-基]-3-三氟甲基-苄腈;
6-甲基-1-(2-甲基-4-三氟甲氧基-苯基)-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶;
1-(2,4-二-三氟甲基-苯基)-7-甲基-5-(3-噻唑-2-基-吡唑-1-基)-1,2,3,4-四氢-[1,8]萘啶;
1-(4-甲氧基-2-甲基-苯基)-6-甲基-4-(3-噻唑-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶;
1-(2,4-二-三氟甲基-苯基)-6-甲基-4-(3-吗啉-4-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶;
1-(2,4-二-三氟甲基-苯基)-6-甲基-4-(3-吡啶-2-基-吡唑-1-基)-2,3-二氢-1H-吡咯并[2,3-b]吡啶;和
4-[1,3’]联吡唑-1’-基-1-(2,4-二-三氟甲基-苯基)-6-甲基-2,3-二氢-1H-吡咯并[2,3-b]吡啶。
12.制备权利要求1中式(I)化合物的方法,包括
13.权利要求1-11中任一权利要求的化合物在制备用于治疗CRF(促肾上腺皮质激素释放因子)介导的疾病的药物中的用途。
14.根据权利要求13的用途,用于制备治疗抑郁症和焦虑症的药物。
15.根据权利要求14的用途,用于制备治疗IBS(过敏性肠病)和IBD(炎性肠病)的药物。
16.根据权利要求1-11中任一权利要求的化合物,用于治疗CRF(促肾上腺皮质激素释放因子)介导的疾病。
17.根据权利要求16的化合物,用于治疗抑郁症和焦虑症。
18.根据权利要求17的化合物,用于治疗IBS(过敏性肠病)和IBD(炎性肠病)。
19.含有权利要求1-11中任一权利要求的化合物和一种或多种可药用载体或赋型剂的药物组合物。
20.治疗哺乳动物,包括人类,尤其是治疗CRF(促肾上腺皮质激素释放因子)介导的疾病的方法,包括给药有效量的权利要求1-11中任一权利要求的化合物。
21.根据权利要求20的方法,用于治疗抑郁症和焦虑症,包括给药有效量的权利要求1-11中任一权利要求的化合物。
22.根据权利要求21的方法,用于治疗IBS(过敏性肠病)和IBD(炎性肠病),包括给药有效量的权利要求1-11中任一权利要求的化合物。
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