CN102526012A - Application of retinoic acid and derivatives thereof to preparation of medicines for treating hepatic fibrosis - Google Patents
Application of retinoic acid and derivatives thereof to preparation of medicines for treating hepatic fibrosis Download PDFInfo
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- CN102526012A CN102526012A CN2012100298651A CN201210029865A CN102526012A CN 102526012 A CN102526012 A CN 102526012A CN 2012100298651 A CN2012100298651 A CN 2012100298651A CN 201210029865 A CN201210029865 A CN 201210029865A CN 102526012 A CN102526012 A CN 102526012A
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- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 title claims abstract description 17
- 229960001727 tretinoin Drugs 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 229940079593 drug Drugs 0.000 title claims abstract description 12
- 206010019668 Hepatic fibrosis Diseases 0.000 title claims abstract description 8
- 229930002330 retinoic acid Natural products 0.000 title abstract description 13
- 238000000034 method Methods 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 description 36
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- -1 aromatic radical Chemical class 0.000 claims description 14
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 7
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 9
- 241001597008 Nomeidae Species 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 30
- 208000019425 cirrhosis of liver Diseases 0.000 abstract description 29
- 241001465754 Metazoa Species 0.000 abstract description 5
- 108010018242 Transcription Factor AP-1 Proteins 0.000 abstract description 4
- 102100023132 Transcription factor Jun Human genes 0.000 abstract description 4
- 230000008506 pathogenesis Effects 0.000 abstract description 3
- 230000002265 prevention Effects 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 2
- 229940126586 small molecule drug Drugs 0.000 abstract description 2
- 239000002253 acid Substances 0.000 description 39
- 241000699670 Mus sp. Species 0.000 description 14
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 12
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 12
- 229960002591 hydroxyproline Drugs 0.000 description 12
- YUKQRDCYNOVPGJ-UHFFFAOYSA-N thioacetamide Chemical compound CC(N)=S YUKQRDCYNOVPGJ-UHFFFAOYSA-N 0.000 description 12
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 12
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 11
- 150000001335 aliphatic alkanes Chemical group 0.000 description 9
- 210000004185 liver Anatomy 0.000 description 7
- 238000013246 thioacetic acid model Methods 0.000 description 7
- 0 CC1(C)C(C(*)=C(*)C(N)=C(*)C(*)=C(*)C(*)=C(*)*)=C(C)CCC1 Chemical compound CC1(C)C(C(*)=C(*)C(N)=C(*)C(*)=C(*)C(*)=C(*)*)=C(C)CCC1 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000002285 corn oil Substances 0.000 description 4
- 235000005687 corn oil Nutrition 0.000 description 4
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 4
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 4
- 210000004500 stellate cell Anatomy 0.000 description 4
- 125000003944 tolyl group Chemical class 0.000 description 4
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 2
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
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- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
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Abstract
本发明公开了一种视黄酸及其衍生物在制备治疗肝纤维化药物中的应用。本发明提供了一种可以有效阻断肝纤维化发作的转录因子AP-1的功能抑制剂小分子药物即视黄酸及其衍生物在制备治疗肝纤维化药物中的应用，本发明的应用实现了动物水平上对肝纤维化发病过程的抑制。本发明的有益效果是提供了一种新的预防治疗肝纤维化疾病的方法，通过给予视黄酸及其衍生化合物以及其制剂来抑制和阻断肝纤维化的发作，同时，本发明所使用的小分子药物易于获取，价格低廉，性质稳定，便于保存和运输。The invention discloses an application of retinoic acid and its derivatives in the preparation of medicines for treating liver fibrosis. The present invention provides a function inhibitor of transcription factor AP-1, which can effectively block the onset of hepatic fibrosis, and the application of retinoic acid and its derivatives in the preparation of drugs for treating hepatic fibrosis. The application of the present invention The inhibition of the pathogenesis of liver fibrosis at the animal level has been achieved. The beneficial effect of the present invention is to provide a new method for the prevention and treatment of liver fibrosis, by giving retinoic acid and its derivative compounds and its preparations to inhibit and block the onset of liver fibrosis, at the same time, the present invention uses High-quality small-molecule drugs are easy to obtain, low in price, stable in nature, and easy to store and transport.
Description
the
技术领域 technical field
本发明属于生物医药技术领域，具体涉及视黄酸及其衍生化合物在制备预防及治疗肝纤维化为主要病理特征的肝脏疾病药物中的应用。 The invention belongs to the technical field of biomedicine, and specifically relates to the application of retinoic acid and its derivative compounds in the preparation of liver disease medicines for the prevention and treatment of liver fibrosis as the main pathological feature.
the
背景技术 Background technique
肝纤维化是指肝脏内弥漫性细胞外基质(特别是胶原)过度沉积。它不是一个独立的疾病，许多慢性肝脏疾病均可引起肝纤维化，其病因大致可分为感染性（慢性乙型、丙型和丁型病毒性肝炎，血吸虫病等），先天性代谢缺陷（肝豆状核变性、血色病、α1-抗胰蛋白酶缺乏症等），化学代谢缺陷（慢性酒精性肝病、慢性药物性肝病）以及自身免疫性肝炎、原发性胆汁性肝硬化和原发性硬化性胆管炎等。其临床症状主要包括疲乏无力、食欲减退、消化不良、出血等，而且病程迁延不愈，甚至有癌变可能。针对肝纤维化治疗过去主要集中在糖皮质类固醇、秋水仙素、干扰素等，但是传统的治疗存在靶点尚不明确，副作用较大，停药后易复发，成本较高等缺点。 Liver fibrosis refers to the excessive deposition of diffuse extracellular matrix (especially collagen) in the liver. It is not an independent disease. Many chronic liver diseases can cause liver fibrosis. The etiology can be roughly divided into infectious (chronic hepatitis B, C and D viruses, schistosomiasis, etc.), Hepatolenticular degeneration, hemochromatosis, α1-antitrypsin deficiency, etc.), chemical metabolic defects (chronic alcoholic liver disease, chronic drug-induced liver disease) and autoimmune hepatitis, primary biliary cirrhosis and primary Sclerosing cholangitis, etc. Its clinical symptoms mainly include fatigue, loss of appetite, indigestion, bleeding, etc., and the course of the disease is protracted and may even become cancerous. In the past, the treatment of liver fibrosis mainly focused on glucocorticoids, colchicine, interferon, etc., but the traditional treatment has the disadvantages of unclear targets, large side effects, easy recurrence after drug withdrawal, and high cost.
肝纤维化的发病机制中最重要的一环是肝星状细胞的异常活化，活化的星状细胞通过大量表达分泌细胞外基质造成纤维化病变。星状细胞的活化一方面可由炎症系统的刺激诱导发生，同时也存在细胞内的引起和维持活化状态的分子生物学基质。在纤维化病变发生后，维持星状细胞活化的原因则主要是其内部的自激活分析生物学信号通路的持续活化。这些信号通路中，转录因子AP-1是一个极其关键的分子。AP-1的过度表达和功能的持续激活，是维持星状细胞活化状态的一个主要影响因素。 The most important link in the pathogenesis of liver fibrosis is the abnormal activation of hepatic stellate cells. Activated stellate cells cause fibrotic lesions by expressing and secreting extracellular matrix in large quantities. On the one hand, the activation of stellate cells can be induced by the stimulation of the inflammatory system, and at the same time, there are molecular biological substrates in the cells that cause and maintain the activated state. After the occurrence of fibrotic lesions, the reason for maintaining the activation of stellate cells is mainly the continuous activation of their internal self-activation analysis biological signaling pathways. In these signaling pathways, the transcription factor AP-1 is an extremely critical molecule. The overexpression and continuous activation of AP-1 is a main factor to maintain the activated state of stellate cells.
发明内容 Contents of the invention
本发明的目的即在于提供一种可以有效阻断肝纤维化发作的转录因子AP-1的功能抑制剂小分子药物即视黄酸及其衍生物在制备治疗肝纤维化药物中的应用，本发明的应用实现了动物水平上对肝纤维化发病过程的抑制。 The purpose of the present invention is to provide a small molecular drug that can effectively block the function inhibitor of the transcription factor AP-1 that can effectively block the onset of hepatic fibrosis, namely the application of retinoic acid and its derivatives in the preparation of drugs for the treatment of hepatic fibrosis. The application of the invention realizes the inhibition of the pathogenesis of liver fibrosis at the animal level.
本发明的具有下述结构式（Ⅰ）的视黄酸及其衍生物在制备治疗肝纤维化药物中的应用， The application of retinoic acid and its derivatives having the following structural formula (I) in the preparation of drugs for treating liver fibrosis of the present invention,
（Ⅰ） (I)
其中，R1为-COOH或-COH或 CH2OH；R2, R4, R5, R6, R8, R9各自为H或C1-C6烷烃基；R3, R7各自为H或C1-C6烷烃基或芳香基或卤素或硝基或烷氧基。此时结构式（Ⅰ）所示结构包括但不限于如下化合物： Among them, R1 is -COOH or -COH or CH2OH; R2, R4, R5, R6, R8, R9 are each H or C1-C6 alkane group; R3, R7 are each H or C1-C6 alkane group or aromatic group or halogen Or nitro or alkoxy. At this time, the structures shown in structural formula (I) include but are not limited to the following compounds:
化合物1：9-(2,6,6-三甲基环己烯)-2,4,6,8-全反式壬四烯酸 Compound 1: 9-(2,6,6-Trimethylcyclohexene)-2,4,6,8-all-trans-nonatraenoic acid
化合物11：6-乙基-9-甲基-9-(2,6,6-三甲基环己烯)壬四烯酸 Compound 11: 6-Ethyl-9-methyl-9-(2,6,6-trimethylcyclohexene)nonatetonic acid
化合物25：3-氯-9-(2,6,6-三甲基环己烯)壬四烯酸 Compound 25: 3-Chloro-9-(2,6,6-trimethylcyclohexene)nonadonic acid
化合物37：3-硝基-7-对甲基苯基-9-(2,6,6-三甲基环己烯)壬四烯酸 Compound 37: 3-nitro-7-p-methylphenyl-9-(2,6,6-trimethylcyclohexene)nonatetonic acid
所述R1优选为-COOH；所述芳香基优选为未取代或烷基取代的苯基。 The R1 is preferably -COOH; the aryl group is preferably an unsubstituted or alkyl-substituted phenyl group.
所述烷基取代苯基优选为单或多取代甲基苯基包括对甲基苯基或2-甲基苯基或2,4-二甲基苯基或2,6-二甲基苯基或2,4,6-三甲基苯基等。 The alkyl substituted phenyl is preferably mono- or multi-substituted methyl phenyl including p-methyl phenyl or 2-methyl phenyl or 2,4-dimethyl phenyl or 2,6- dimethyl phenyl Or 2,4,6-trimethylphenyl, etc.
结构式（Ⅰ）中，可优选当R1为-COOH；R2, R4, R5, R6, R8, R9均为H；R3为H或C1-C6烷烃基，R7为H或C1-C6烷烃基或未取代苯基或烷基取代苯基或卤素或硝基或烷氧基。 In the structural formula (I), it can be preferred that R1 is -COOH; R2, R4, R5, R6, R8, R9 are all H; R3 is H or C1-C6 alkane group, R7 is H or C1-C6 alkane group or not Substituted phenyl or alkyl substituted phenyl or halogen or nitro or alkoxy.
结构式（Ⅰ）中，也可优选当R1为-COOH；R2, R4, R5, R6, R7,R8, R9均为H；R3为未取代苯基或烷基取代苯基或卤素或硝基或烷氧基。 In the structural formula (I), it is also preferred when R1 is -COOH; R2, R4, R5, R6, R7, R8, R9 are all H; R3 is unsubstituted phenyl or alkyl substituted phenyl or halogen or nitro or alkoxy.
结构式（Ⅰ）中，也可优选当R1为-COOH；R2, R4, R5, R6, R8, R9均为H；R3为未取代苯基或烷基取代苯基或卤素或硝基或烷氧基，R7为未取代或烷基取代苯基。 In the structural formula (I), it is also preferred when R1 is -COOH; R2, R4, R5, R6, R8, R9 are all H; R3 is unsubstituted phenyl or alkyl substituted phenyl or halogen or nitro or alkoxy base, R7 is unsubstituted or alkyl-substituted phenyl.
所述烷基取代苯基优选为单或多取代甲基苯基包括对甲基苯基或2-甲基苯基或2,4-二甲基苯基或2,6-二甲基苯基或2,4,6-三甲基苯基等，最优选的烷基取代苯基为对甲基苯基。 The alkyl substituted phenyl is preferably mono- or multi-substituted methyl phenyl including p-methyl phenyl or 2-methyl phenyl or 2,4-dimethyl phenyl or 2,6- dimethyl phenyl or 2,4,6-trimethylphenyl, etc., and the most preferable alkyl-substituted phenyl group is p-methylphenyl group.
本发明的具有下述结构式（II）的视黄酸衍生物在制备治疗肝纤维化药物中的应用， The application of the retinoic acid derivatives of the present invention having the following structural formula (II) in the preparation of drugs for treating liver fibrosis,
（II） (II)
其中，R1’为-COOH或-COH或 CH2OH；R2’ ,R4’, R5’, R6’, R8’, R9’各自为H或C1-C6烷烃基；R3’, R7’各自为H或C1-C6烷烃基或芳香基或卤素或硝基或烷氧基，此时结构式（II）所示结构包括但不限于如下化合物： Wherein, R1 ' is -COOH or -COH or CH2OH; R2 ' , R4 ' , R5 ' , R6 ' , R8 ' , R9 ' are each H or C1-C6 alkane group; R3 ' , R7 ' are each H or C1 -C6 alkane group or aryl group or halogen or nitro group or alkoxy group, at this time the structure shown in the structural formula (II) includes but not limited to the following compounds:
化合物18：(2E,4E,6E,8E)-7-溴-9-(5,5,8,8-四甲基-5,6,7,8-四氢萘基-2-基) -2,4,6,8-四烯壬酸 Compound 18: (2E,4E,6E,8E)-7-bromo-9-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthyl-2-yl)- 2,4,6,8-tetraenoic acid
所述R1’优选为-COOH；所述芳香基优选为未取代或烷基取代的苯基； The R1 ' is preferably -COOH; the aryl is preferably an unsubstituted or alkyl-substituted phenyl group;
所述烷基取代苯基优选为单或多取代甲基苯基包括对甲基苯基或2-甲基苯基或2,4-二甲基苯基或2,6-二甲基苯基或2,4,6-三甲基苯基等。 The alkyl substituted phenyl is preferably mono- or multi-substituted methyl phenyl including p-methyl phenyl or 2-methyl phenyl or 2,4-dimethyl phenyl or 2,6- dimethyl phenyl Or 2,4,6-trimethylphenyl, etc.
结构式（II）中，优选的，当R1’为-COOH；R2’, R4’, R5’, R6’, R8’, R9’均为H；R3’为H或C1-C6烷烃基，R7’为H或C1-C6烷烃基或未取代苯基或烷基取代苯基或卤素或硝基或烷氧基。 In the structural formula (II), preferably, when R1 ' is -COOH; R2 ' , R4 ' , R5 ' , R6 ' , R8 ' , R9 ' are all H; R3 ' is H or C1-C6 alkane group, R7 ' It is H or C1-C6 alkane group or unsubstituted phenyl or alkyl substituted phenyl or halogen or nitro or alkoxy.
结构式（II）中，也可优选当R1’为-COOH；R2’, R4’, R5’, R6’, R7’,R8’, R9’均为H；R3’为未取代苯基或烷基取代苯基或卤素或硝基或烷氧基。 In the structural formula (II), it is also preferred when R1 ' is -COOH; R2 ' , R4 ' , R5 ' , R6 ' , R7 ' , R8 ' , R9 ' are all H; R3 ' is unsubstituted phenyl or alkyl Substituted phenyl or halogen or nitro or alkoxy.
结构式（II）中，也可优选R1’为-COOH；R2’, R4’, R5’, R6’, R8’, R9’均为H；R3’为H或C1-C6烷烃基或未取代苯基或烷基取代苯基或卤素或硝基或烷氧基，R7’为未取代或烷基取代苯基。 In the structural formula (II), it is also preferable that R1 ' is -COOH; R2 ' , R4 ' , R5 ' , R6 ' , R8 ' , R9 ' are all H; R3 ' is H or C1-C6 alkane group or unsubstituted benzene Base or alkyl substituted phenyl or halogen or nitro or alkoxy, R7 ' is unsubstituted or alkyl substituted phenyl.
所述烷基取代苯基优选为单或多取代甲基苯基包括对甲基苯基或2-甲基苯基或2,4-二甲基苯基或2,6-二甲基苯基或2,4,6-三甲基苯基等，最优选的烷基取代苯基为对甲基苯基。 The alkyl substituted phenyl is preferably mono- or multi-substituted methyl phenyl including p-methyl phenyl or 2-methyl phenyl or 2,4-dimethyl phenyl or 2,6- dimethyl phenyl or 2,4,6-trimethylphenyl, etc., and the most preferable alkyl-substituted phenyl group is p-methylphenyl group.
本发明的视黄酸及其衍生物可按照常规药物制剂的方法制成药学上可接受的各种剂型，然后按照药物剂型采用不同的给药方式。 The retinoic acid and its derivatives of the present invention can be prepared into various pharmaceutically acceptable dosage forms according to conventional pharmaceutical preparation methods, and then adopt different administration methods according to the pharmaceutical dosage forms.
本发明所述的化合物结构参考文献（Nature, 372: 107-110, 1994.）报道，可由专业的化合物合成服务机构提供，本发明使用的化合物来自上海药明康德新药开发有限公司。 The structure of the compound described in the present invention is reported in the reference literature (Nature, 372: 107-110, 1994.) and can be provided by a professional compound synthesis service organization. The compound used in the present invention comes from Shanghai WuXi Kangde New Drug Development Co., Ltd.
本发明的视黄酸及其衍生化合物可以通过口腔，静脉，鼻腔，直肠或其他任何可以输送有效剂量的活性物质的方式给药。合适的剂量是那些能得到所需要的最终量的剂量。而治疗不同的疾病也可能需要不同的剂量。该试剂的有效量是能导致肝纤维化程度明显降低的量。 The retinoic acid and its derivative compounds of the present invention can be administered orally, intravenously, nasally, rectally or in any other way that can deliver an effective dose of the active substance. Suitable dosages are those which give the desired end amount. Different diseases may require different doses. The effective amount of the agent is the amount that can cause a significant reduction in the degree of liver fibrosis.
具有常规技术的研究人员将能够确定本项发明所提供的试剂的最有效的给药剂量和时间考虑给药方式，药物代谢，以及其他一些药代动力学参数例如药物分布，清除率等。 A researcher with ordinary skill will be able to determine the most effective dosage and timing of administration of the agents provided by the present invention taking into account the mode of administration, drug metabolism, and other pharmacokinetic parameters such as drug distribution, clearance rate and the like.
活性的试剂可以通过一个药物载体或者稀释液给药。这项发明所提供的试剂还可以和其他试剂例如化疗或者免疫激活药物或者治疗药物联合给药。对这项发明适用的药物载体或者稀释液的实例包括任何溶有水溶性有机载体的生理缓冲液，例如环糊精磷酸盐缓冲液以及pH7.0到7.4的含有合适的水溶性有机载体其它缓冲液。合适的水溶性有机载体包括但是不限于环糊精，玉米油，DMSO，胶囊等。 The active agent can be administered via a pharmaceutical carrier or diluent. The agents provided by this invention can also be administered in combination with other agents such as chemotherapeutic or immunostimulatory drugs or therapeutic drugs. Examples of pharmaceutical carriers or diluents suitable for this invention include any physiological buffer solution containing a water-soluble organic carrier, such as cyclodextrin phosphate buffer and other buffers containing a suitable water-soluble organic carrier at pH 7.0 to 7.4 liquid. Suitable water-soluble organic carriers include, but are not limited to, cyclodextrin, corn oil, DMSO, capsules, and the like.
本发明通过体内对肝纤维化模型进行例证。此处的动物包括但是不限于：小鼠，大鼠，驯养动物包括但是不限于猫，狗，以及其它一些动物例如但是不限于牛，羊，猪，马，灵长类动物例如但是不限于猴子和人。小鼠肝纤维化模型的体内检测是被广泛认可和接受的体内药物活性检测的模型，同时也可以为其它生物例如人，但是不仅限于人提供参考。 The invention is exemplified in vivo on a model of liver fibrosis. Animals here include but are not limited to: mice, rats, domesticated animals including but not limited to cats, dogs, and other animals such as but not limited to cows, sheep, pigs, horses, primates such as but not limited to monkeys and people. The in vivo detection of the mouse liver fibrosis model is a widely recognized and accepted model for the detection of drug activity in vivo, and can also provide references for other organisms such as humans, but not limited to humans.
本发明的有益效果是提供了一种新的预防治疗肝纤维化疾病的方法，通过给予视黄酸及其衍生化合物以及其制剂来抑制和阻断肝纤维化的发作。同时，本发明所使用的小分子药物易于获取，价格低廉，性质稳定，便于保存和运输。 The beneficial effect of the present invention is to provide a new method for the prevention and treatment of liver fibrosis, which can inhibit and block the onset of liver fibrosis by administering retinoic acid and its derivative compounds and its preparations. At the same time, the small molecule drug used in the present invention is easy to obtain, low in price, stable in property, and convenient for storage and transportation.
the
具体实施方式 Detailed ways
下面的例子用以解释本发明，但是该相关技术领域的技术人员应当理解，其并不应被视作对本发明实质精神的限制。 The following examples are used to explain the present invention, but those skilled in the relevant technical field should understand that they should not be regarded as limiting the essence of the present invention.
实施例1Example 1
视黄酸及其衍生化合物的口服液体制剂对TAA导致的小鼠肝纤维化模型的治疗应用： Therapeutic application of oral liquid formulations of retinoic acid and its derivatives to TAA-induced liver fibrosis in mice:
1、使用硫代乙酰胺( thioacetamide，TAA)的磷酸缓冲溶液于ICR小鼠腹腔注射，建立TAA型肝纤维化模型。 1. The phosphate buffer solution of thioacetamide (TAA) was injected intraperitoneally into ICR mice to establish a TAA-type liver fibrosis model.
2、将化合物溶解到玉米油中，在建立TAA型肝纤维化模型同时进行灌胃，对肝纤维化进行治疗。实验中使用的化合物编号和结构如表1所示。 2. The compound is dissolved in corn oil, and the TAA-type liver fibrosis model is established, and the liver fibrosis is treated by intragastric administration. The compound numbers and structures used in the experiments are shown in Table 1.
3、TAA与化合物每周给药2次，给药4周后处死小鼠，取出肝脏分别做羟脯氨酸测定以及谷丙转氨酶测定。 3. TAA and the compound were administered twice a week. After 4 weeks of administration, the mice were sacrificed, and the livers were taken out for the determination of hydroxyproline and alanine aminotransferase.
材料及方法：将化合物用玉米油溶解，配成2.0mg/ml储液备用。建立小鼠TAA型肝纤维化模型，所用小鼠为雄性ICR小鼠，体重16-18g。将小鼠随机分为模型组和治疗组，模型组小鼠腹腔注射TAA的磷酸缓冲液（200mg/kg），每周给药两次。建立模型当周开始治疗，化合物治疗组按20mg/kg灌胃给药，TAA模型组给相应量的玉米油，每周给药两次。模型建立四周后处死，取病变肝脏组织匀浆后取上清，采用碱水解法测定羟脯氨酸含量。 Materials and methods: The compound was dissolved in corn oil and prepared as a 2.0 mg/ml stock solution for later use. A mouse model of TAA liver fibrosis was established, and the mice used were male ICR mice with a body weight of 16-18 g. The mice were randomly divided into a model group and a treatment group. The mice in the model group were intraperitoneally injected with TAA in phosphate buffer (200 mg/kg), twice a week. The treatment started on the week when the model was established, and the compound treatment group was given intragastric administration of 20 mg/kg, and the TAA model group was given the corresponding amount of corn oil, twice a week. The models were sacrificed four weeks after establishment, and the supernatant was obtained after the lesioned liver tissue was homogenized, and the content of hydroxyproline was determined by alkaline hydrolysis.
肝纤维化时，肝内主要增加的成分为胶原纤维，羟脯氨酸为胶原纤维所特有，为此肝羟脯氨酸的含量可直接反应肝纤维化的程度。由表1可以发现口服化合物治疗可以有效缓解小鼠肝纤维化发作，治疗组的羟脯氨酸值明显低于TAA模型组。 When hepatic fibrosis occurs, the main increase in the liver is collagen fibers, and hydroxyproline is unique to collagen fibers. Therefore, the content of hepatic hydroxyproline can directly reflect the degree of liver fibrosis. It can be found from Table 1 that oral compound treatment can effectively alleviate the onset of liver fibrosis in mice, and the hydroxyproline value in the treatment group was significantly lower than that in the TAA model group.
表1 肝脏羟脯氨酸含量测定 Table 1 Determination of liver hydroxyproline content
数据均以平均值±标准差的形式加以显示，显著性差异通过ANOVA检验加以确定，P≤0.05视为具有显著性差异。 The data are displayed in the form of mean ± standard deviation, and the significant difference is determined by ANOVA test, and P≤0.05 is considered to have a significant difference.
实施例2Example 2
视黄酸及其衍生化合物的水溶液注射制剂对TAA导致的小鼠肝纤维化模型的治疗应用： Therapeutic application of aqueous injection formulations of retinoic acid and its derivatives to TAA-induced liver fibrosis in mice:
1、使用硫代乙酰胺( thioacetamide，TAA)的磷酸缓冲溶液于ICR小鼠腹腔注射，建立TAA型肝纤维化模型。 1. The phosphate buffer solution of thioacetamide (TAA) was injected intraperitoneally into ICR mice to establish a TAA-type liver fibrosis model.
2、将配制好的化合物的水溶液注射制剂在建立TAA型纤维化模型同时进行注射，对肝纤维化进行治疗。 2. Injecting the prepared aqueous solution injection preparation of the compound while establishing the TAA fibrosis model to treat liver fibrosis.
3、TAA与化合物每周给药2次，给药4周后处死小鼠，取出肝脏分别做羟脯氨酸测定。 3. TAA and the compound were administered twice a week, and the mice were sacrificed 4 weeks after the administration, and the livers were taken out for the determination of hydroxyproline.
材料及方法：将化合物用环糊精和生理盐水配制成1.0mg/kg的储液备用。小鼠TAA肝纤维化模型建立参照实施1，建模当日，将小鼠随机分组即TAA模型组、化合物治疗组。建立模型当周开始治疗，化合物治疗组按20mg/kg注射动物，TAA模型组给同等量的生理盐水，每周给药两次。模型建立四周后处死，取病变肝脏组织，做羟脯氨酸测定。测定结果见表2，由表2可以发现视黄酸及其衍生物的水溶液注射剂可以有效缓解小鼠肝纤维化发作，治疗组的羟脯氨酸值明显低于TAA模型组。 Materials and methods: The compound was formulated with cyclodextrin and normal saline to prepare a 1.0 mg/kg stock solution for future use. The mouse TAA liver fibrosis model was established by referring to implementation 1. On the day of modeling, the mice were randomly divided into TAA model group and compound treatment group. The treatment started on the week when the model was established, the compound treatment group was injected with 20 mg/kg, and the TAA model group was given the same amount of normal saline twice a week. The model was sacrificed four weeks after establishment, and the diseased liver tissue was taken for the determination of hydroxyproline. The measurement results are shown in Table 2. From Table 2, it can be found that the aqueous injection of retinoic acid and its derivatives can effectively alleviate the onset of liver fibrosis in mice, and the hydroxyproline value of the treatment group is significantly lower than that of the TAA model group.
表2 羟脯氨酸含量测定 Table 2 Determination of hydroxyproline content
数据均以平均值±标准差的形式加以显示，显著性差异通过ANOVA检验加以确定，P≤0.05视为具有显著性差异。 The data are displayed in the form of mean ± standard deviation, and the significant difference is determined by ANOVA test, and P≤0.05 is considered to have a significant difference.
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| 张煜，张锦生，徐元鼎，曹华康，施建英，张月娥，朱虹光: "维甲酸对肝致癌剂引起的肝纤维化及癌前病变的影响", 《临床与实验病理学杂志》 * |
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