CN1582269A - 羟基二十碳烯酸类似物 - Google Patents
羟基二十碳烯酸类似物 Download PDFInfo
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- CN1582269A CN1582269A CNA028221532A CN02822153A CN1582269A CN 1582269 A CN1582269 A CN 1582269A CN A028221532 A CNA028221532 A CN A028221532A CN 02822153 A CN02822153 A CN 02822153A CN 1582269 A CN1582269 A CN 1582269A
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- Prior art keywords
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- acid
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- WREJOFLDSZJEDV-UHFFFAOYSA-N 2-hydroxyicos-2-enoic acid Chemical class CCCCCCCCCCCCCCCCCC=C(O)C(O)=O WREJOFLDSZJEDV-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 209
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 11
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical group O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- 125000005843 halogen group Chemical group 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical group 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 4
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 239000002253 acid Substances 0.000 claims description 49
- -1 carbon olefin Chemical class 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 9
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 8
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
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- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 7
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- 238000006243 chemical reaction Methods 0.000 description 50
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 21
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- 238000000605 extraction Methods 0.000 description 18
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- 229910052786 argon Inorganic materials 0.000 description 11
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- 125000004494 ethyl ester group Chemical group 0.000 description 11
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 9
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- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 8
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
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- PRQROPMIIGLWRP-UHFFFAOYSA-N N-formyl-methionyl-leucyl-phenylalanin Chemical compound CSCCC(NC=O)C(=O)NC(CC(C)C)C(=O)NC(C(O)=O)CC1=CC=CC=C1 PRQROPMIIGLWRP-UHFFFAOYSA-N 0.000 description 6
- 241000700159 Rattus Species 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 6
- 230000007574 infarction Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- HXLVDKGPVGFXTH-UHFFFAOYSA-N butyl(dimethyl)silane Chemical group CCCC[SiH](C)C HXLVDKGPVGFXTH-UHFFFAOYSA-N 0.000 description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
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- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
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- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 4
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- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
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- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 2
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000002444 silanisation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
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- 229960001866 silicon dioxide Drugs 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 229940126703 systemic medication Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
Classifications
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Abstract
一种下式(I)表示的羟基二十碳烯酸类似物或其药物学上可接受的盐或水合物,化学键代表顺式亚乙烯基或亚乙炔基;Y代表CH2、O或S(O)p,其中p为0、1或2;m代表包括1和4在内的整数1-4;n代表包括0和3在内的整数0-3;m和n之和为包括3和7在内的整数3-7;R1代表C1-4烷基或C3-8环烷基;R2代表氢原子或甲基;R3代表COR4、腈基、卤素原子、四唑基或噻唑烷二酮基;R4代表OR6、NHR6、N(OH)R6、NHSO2R5、丙三醇或官能化丙三醇;R5代表C1-15烷基、C6-10芳基或C7-14被以下基团取代的芳基:烷基、卤素或氨基;R6代表氢原子、C1-10烷基或羟基取代的C1-10烷基。本发明化合物可用作弹性蛋白酶释放抑制剂。
Description
本申请基于2001年9月14日申请的美国临时专利申请60/318874并要求该申请的优先权,所述申请通过引用整体结合到本文中。
技术领域
本发明涉及具有弹性蛋白酶释放抑制活性的新型羟基二十碳烯酸类似物、其药物学上可接受的盐或其水合物。
本发明还涉及弹性蛋白酶释放抑制组合物,该组合物包含作为活性成分的羟基二十碳烯酸类似物。
背景技术
蛋白酶由一种淋巴细胞—中性白细胞产生,其作用主要是降解入侵的微生物如细菌或破坏性细胞,因此在生物防御反应中起重要作用。中性白细胞弹性蛋白酶是一种丝氨酸蛋白酶(下文简称弹性蛋白酶),中性白细胞颗粒大量释放这种弹性蛋白酶,感染或炎症性疾病情况下出现大量中性白细胞。弹性蛋白酶是一种能够分解以下蛋白质的酶:弹性蛋白、胶原蛋白、蛋白聚糖、纤连蛋白等,它们构成体内结缔组织基质,如肺、软骨、血管壁、皮肤、韧带等。此外,已经阐明这种酶也可作用于其它蛋白质和细胞。
弹性蛋白酶保持活体体内平衡,而它的作用通过内在的抑制剂蛋白质受到控制,通常为α1-蛋白酶抑制剂、α2-巨球蛋白、分泌性白细胞蛋白酶抑制剂等。然而,由于在炎症位置弹性蛋白酶产生过多或抑制水平过低,弹性蛋白酶和内在抑制剂失去平衡,弹性蛋白酶的释放活性可因失控而导致组织受损。
已知弹性蛋白酶与某些疾病的病理有关,如:肺气肿、成人呼吸窘迫综合症、特发性肺纤维化、囊性肺纤维化、慢性间质性肺炎、慢性支气管炎、慢性窦肺感染、弥漫性泛支气管炎、支气管扩张、哮喘、胰腺炎、肾炎、肝功能不全,慢性风湿病、关节硬化、骨关节炎、牛皮癣、牙周炎、动脉粥样硬化、器官移植排斥、早产儿羊膜破裂、水疱病、休克、脓毒症、系统性红斑狼疮、节段性回肠炎、播散性静脉内凝固、脑梗塞、心脏病、肾病中观测到的局部缺血再灌注障碍、角膜组织瘢痕形成、脊椎炎等。
鉴于前述,弹性蛋白酶释放抑制剂可用作治疗上述疾病的治疗剂或预防剂,最近预测性地进行了深入研究,已经有各种各样的弹性蛋白酶释放抑制剂报道。然而,它们的活性不是很令人满意,此外还未找到一种临床适用的含有羟基二十碳烯酸的弹性蛋白酶释放抑制剂。
发明公示
本发明物目的之一是提供一种新型化合物,该化合物具有显著的弹性蛋白酶释放抑制活性。
本发明的另一目的是提供一种弹性蛋白酶释放抑制组合物,该组合物包含羟基二十碳烯酸类似物或其药物学上可接受的盐或其水合物以及药物学上可接受的载体。
附图简要说明
图1图示在小鼠t-MCAo模型中,化合物50对梗塞体积的影响。再灌注后71小时测定整体(实心条)、皮质层(立体条)、皮质下(空心条)梗塞体积。数据为平均数±SEM。*p<0.05(与赋形剂处理组相比)(Dunnett检验)。
发明详述
本发明人深入研究发现:一种新型的用下面的结构式表示的羟基二十碳烯酸类似物,其表现出弹性蛋白酶释放抑制活性,本发明在此基础上完成。
更具体地说,本发明涉及下式(I)(I)表示的羟基二十碳烯酸类似物或其药物学上可接受的盐或其水合物:
其中
化学键
代表顺式亚乙烯基或亚乙炔基;
Y代表CH2、O或S(O)p,p为0、1或2;
m代表1-4的整数(包括1和4),n代表0-3的整数,m和n之和为3-7的整数(包括3和7);
R1代表C1-4烷基或C3-8环烷基;
R2代表氢原子或甲基;
R3代表COR4、腈基、卤素原子、四唑基或噻唑烷二酮基,其中R4是OR6、NHR6、N(OH)R6、NHSO2R5(其中R5是C1-15烷基、C6-10芳基或C7-14被以下基团取代的芳基:烷基、卤素或氨基,且R6是卤素原子、C1-10烷基或羟基取代的C1-10烷基)、丙三醇和官能化丙三醇(例如二酰基丙三醇和磷酸丙三醇酯)。特别优选的化合物是(R)-16-羟基二十-14-炔酸、(R)-17-羟基二十一-15-炔酸,(R)-(Z)-16-羟基二十-14-烯酸和(R)-(Z)-15-羟基十九-13-烯酸。
本文使用的术语“C1-4烷基”指的是直链或支链烷基,包括例如甲基、乙基、丙基、异丙基、丁基、异丁基和叔丁基。
符号m代表1-4的整数(包括1和4),n代表0-3的整数,且m和n之和为3-7(包括3和7),优选3、4或5。
本文使用的术语“C3-8环烷基”包括例如环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
本文使用的术语“C1-15烷基”包括例如甲基、丁基、叔丁基、辛基、癸基和十五烷基。
本文使用的术语“C6-10芳基”包括例如苯基、1-萘基和2-萘基。
本文使用的术语“被烷基、卤素或氨基取代的C7-14芳基”包括例如对甲苯基、邻甲苯基、2,4,6-三甲苯基和间异丙苯基、间氯苯基和对氨基苯基。
本文使用的术语“C1-10烷基”意指直链或支链烷基,包括例如甲基、乙基、丁基、异丁基、戊基、己基、庚基、辛基、2-甲基-1-己基、2,4-二甲基-1-戊基、壬基和癸基。
本文使用的术语“羟基取代的C1-10烷基”意指直链或支链烷基被羟基取代,包括例如:2-羟基乙基、6-羟基己基、1-羟基-2-丙基或1-羟基-2-甲基-2-丙基。
本文使用的术语“药物学上可接受的盐”包括例如碱金属(例如钠和钾)的盐、碱土金属(例如钙和镁)的盐、或以下物质的盐:氨、甲胺、二甲胺、二乙胺、环戊胺、苄胺、哌啶、单乙醇胺、二乙醇胺、三乙醇胺、单甲基单乙醇胺、环甲胺(toromethamine)、赖氨酸、鸟氨酸、哌嗪、苄星青霉素G、3-氨基吡啶、普鲁卡因、胆碱、2-氨基-4-甲基吡啶、四烷基铵、三(羟基甲基)氨基甲烷和乙二胺。
I式(I)化合物可用例如下面的反应流程所示方法制备。
在反应流程中,Z和Z2可以相同或不同,分别代表卤素原子或离去基团如甲磺酰氧基和对甲苯磺酰氧基;R7代表羟基的保护基,其对碱是稳定的,例如三甲基甲硅烷基、三乙基甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基、甲氧基甲基、乙氧基乙基、四氢吡喃基、苄基和对甲氧基苄基;R31代表CO2H、OR6、CONHR6或卤素原子;R61与R6相同,氢原子除外;R32代表CO2R61、OR6或CONHR6;p1是整数1或2;R1、R2、R3、R4、R5、R6、
Y、m、n和p的定义同前。
反应流程1
(1)在存在碱(例如n-Buli、LiNH2或NaNH2)、-78℃至室温下,式(II)的化合物与式(III)的化合物在适宜的有机溶剂(例如四氢呋喃、六甲基磷酰三胺、N,N′-二甲基亚丙基脲、NH3、二甲亚砜或二甲基甲酰胺、或其混合物)中反应,,生成式(IV)的化合物。
(2)在适宜的有机溶剂(例如R61OH表示的醇溶剂或醚类溶剂(例如四氢呋喃或乙醚))中,在0℃-60℃、优选室温至40℃条件下,用有机酸(例如对甲苯磺酸或醋酸、或它们的胺盐(例如对甲苯磺酸吡啶鎓))或无机酸(例如盐酸或硫酸)处理式(IV)化合物,由此除去羟基的保护基团得到式(Ia)化合物。
(3)还原式(Ia)的化合物产生式(Ib)化合物,一种还原方法例如为在氢气氛下使用含Pd催化剂(例如Pd-CaCO3、Pd(OAc)2)或含Ni催化剂(例如Ni(OAc)2和NaBH4);一种方法是在MeOH或AcOH及其它中用Zn作为还原剂。
(4)R32是CO2R61的式(Ia2)化合物而R32是CO2R61的式(Ib2)化合物用常规水解使用的碱处理,例如NaOH、LiOH或KOH,在适宜有机溶剂如醇溶剂(如MeOH或EtOH)、或水混溶性溶剂(如四氢呋喃或二噁烷)与水的混合溶剂中进行所述处理,得到式(I)中R3是CO2H的式(Ic)的化合物。
反应流程3
(5)使式(II)的化合物和式(III2)的化合物以与上述(1)相同的方法反应,接着用与上述(2)相同的方法进行脱保护反应,生成式(IV2)的化合物。
(6)使式(IV2)的化合物以与上述(3)相同的方法进行还原反应,生成式(IV3)的化合物。
(7)式(IV2)或(IV3)的化合物与式(V)或(V2)的化合物在适宜的有机溶剂如MeOH、EtOH、t-BuOH、丙酮、二甲基甲酰胺、四氢呋喃或CH3CN中反应,其中存在适宜的碱例如Et3N、NaH、KH、NaHCO3、K2CO3、NaOH、CaCO3或季铵盐(如Et4NBr),必要时,加入NaI等,得到式(Id)的化合物。
(8)使式(Id)的化合物以与上述(4)相同的方法水解,生成式(Ie)的化合物。
(9)式(Id)或(Ie)的化合物用氧化剂如NaIO4、H2O2、AcOOH、间氯过苯甲酸或t-BuOOH、在适宜的有机溶剂如二氯甲烷、MeOH、EtOH、二乙醚或水、或其混合物中处理,温度为-20℃-50℃,分别生成式(Id2)或(Ie2)的化合物。用与(4)相同的方法水解式(Id2)的化合物也可制得式(Ie2)的化合物。
反应流程4
(10)使式(II)和式(III3)的化合物以与(1)相同的方法反应,得到式(IV4)的化合物。
(11)使式(IV4)的化合物与式(III4)的化合物在适宜的有机溶剂如苯、甲苯、二甲基甲酰胺、二甲亚砜、六甲基磷酰三胺或CH3CN中、在适宜的碱如NaOH、KOH、NaH、KH或K2CO3或Ag2O存在下反应,若有必要,添加如n-Bu4NI或n-Bu4NHSO4等,得到式(IV5)的化合物。
(12)使式(IV5)的化合物以与(2)相同的方法反应,得到式(If)的化合物。
(13)使式(If)的化合物以与(3)相同的方法反应,得到式(Ig)的化合物。
(14)使式(If)或(Ig)的化合物以与(4)相同的方法反应,得到式(Ih)的化合物。
(15)使式(Ic),(Ie),(Ie2)或(Ih)的化合物转化为具有N-羟基-琥珀酰亚胺和1-(3-二甲基氨基丙基)-3-乙基-碳二亚胺盐酸盐或N,N’-羰基二咪唑的相应活性酯或转化为具有相应SOCl2或(COCl)2的相应酰氯,然后与HR4反应,若有需要,在存在碱如1,8-二氮杂双环[5.4.0]十一-7-烯、1,5-二氮杂双环[4.3.0]壬(non)-5-烯或Et3N下反应,得到式(Ii)的化合物。
反应流程6
(16)式(IV2)或(IV3)的化合物与式(VI)的化合物进行反应,方法与(7)相同,接着用与(2)相同的方法进行脱保护反应,然后用CCl4-PPh3、PBr3、CBr4-PPh3、I2-PPh3或类似物直接卤化,或用甲磺酰氯、对甲苯磺酰氯或类似物转化成离去基团,得到式(VII)的化合物。
(17)式(VII)的化合物与氰化剂如NaCN、KCN、LiCN或CuCN在适宜的有机溶剂如二甲亚砜、二甲基甲酰胺、四氢呋喃、CH3CN、甲苯或苯、或它们与水的混合溶剂中反应,若有需要,反应在存在添加剂如15-冠醚或n-Bu4NI条件下进行,得到式(Ij)的化合物。式(Ij)的化合物进一步与氮化物形成剂如NaN3或Me3SiN3反应得到式(Ik)的化合物。
(18)式(VII)的化合物与四氢噻唑二酮反应得到式(Im)的化合物。
本发明化合物可通过口服或胃肠外进行系统性用药或口服用药,例如直肠、皮下、肌间、静脉内、透皮给药和鼻/肺吸入或经皮途径用药。
本发明化合物可为口服用药剂型,例如片剂、粉剂、颗粒剂、细粉剂、胶囊剂、溶液剂、乳剂、悬浮剂或用常规方法制备的类似制剂。静脉途径用的药物学制剂可为水性溶液剂或非水性溶液剂、乳剂、悬浮液、固体制剂(其在使用前溶于可注射溶剂后使用)等。本发明的化合物可用α-,β-或γ-环糊精或取代的环糊精形成包合物制成药用制剂。此外,例如通过注射可给予本发明化合物的水性溶液剂或非水性溶液剂、乳剂或悬浮剂。用药剂量可根据患者的年龄、体重和其它因素而不同,成人给药剂量可为1ng/kg/天-1000mg/kg/天,每天用药1次或数次。
式(I)表示的代表性化合物举例说明如下:
化合物编号R1 R2
Y m n R2 *
1 nBu H C≡C CH2 4 3 CO2H R
2 nBu H C≡C CH2 3 3 CO2H R
3 nBu H C≡C CH2 2 3 CO2Et R
4 nBu H C≡C CH2 2 3 CO2H R
5 Me H C≡C CH2 2 3 CO2H R
6 Me H C≡C CH2 1 3 CO2H RS
7 Et H C≡C CH2 1 3 CO2Et RS
8 Et H C≡C CH2 1 3 CO2H RS
9 nPr H C≡C CH2 1 3 CO2Et RS
10 nPr H C≡C CH2 1 3 CO2H RS
11 nBu H C≡C CH2 1 3 CO2Et R
12 nBu H C≡C CH2 1 3 CO2H R
13 nBu H C≡C CH2 1 3 CO2H S
14 iBu H C≡C CH2 1 3 CO2H R
15 sBu H C≡C CH2 1 3 CO2nHex R
16 sBu H C≡C CH2 1 3 CO2H R
17 cPent H C≡C CH2 1 3 CO2H R
18 cHep H C≡C CH2 1 3 CO2tBu R
19 cPent H C≡C CH2 1 3 CO2H R
20 cOct H C≡C CH2 1 3 CO2H R
21 nBu H C≡C CH2 1 3 CO2Na R
22 nPr H C≡C CH2 1 3 CONH2 RS
23 nBu H C≡C CH2 1 3 CONH2 RS
24 Et Me C≡C CH2 1 3 CONHOH RS
25 nPr H C≡C CH2 1 3 CONHOH R
26 nBu H C≡C CH2 1 3 CONHOH RS
27 nBu H C≡C CH2 1 2 CO2Et R
28 nBu H C≡C CH2 1 2 CO2H R
29 Et Me C≡C CH2 1 2 CO2H RS
30 Me H C≡C CH2 1 2 CO2H R
31 nBu H C≡C CH2 1 2 CONH2 R
32 nBu H C≡C CH2 1 2 CONHOH R
33 nBu H C≡C CH2 1 2 噻唑烷二酮 R
34 nBu H C≡C CH2 1 3 Cl R
35 nBu H C≡C CH2 1 3 OH R
36 nBu H C≡C CH2 1 3 四唑 R
37 nBu H C≡C CH2 1 3 CN R
38 nBu H C≡C CH2 3 3 CN R
39 nBu H C≡C CH2 2 3 OH R
40 nBu H C≡C CH2 2 3 OMe R
41 nBu H (Z)CH=CH CH2 4 3 CO2H R
42 nPr Me (Z)CH=CH CH2 3 3 CO2H RS
43 nBu H (Z)CH=CH CH2 3 3 CO2H R
44 nBu H (Z)CH=CH CH2 2 3 CO2Et R
45 nBu H (Z)CH=CH CH2 2 3 CO2iPr R
46 nBu H (Z)CH=CH CH2 2 3 CO2H R
47 nBu H (Z)CH=CH CH2 1 3 CO2Et R
48 Et H (Z)CH=CH CH2 1 3 CO2H RS
49 nPr H (Z)CH=CH CH2 1 3 CO2H RS
50 nBu H (Z)CH=CH CH2 1 3 CO2H R
51 sBu H (Z)CH=CH CH2 1 3 CO2H R
52 nBu H (Z)CH=CH CH2 1 3 CONH(CH2)2OH R
53 nBu H (Z)CH=CH CH2 1 3 CONHTs R
54 nBu Me (Z)CH=CH CH2 1 3 CO2H RS
55 nBu H (Z)CH=CH CH2 1 3 CONHOH R
56 nBu H (Z)CH=CH CH2 1 3 CO2H S
57 nBu H (Z)CH=CH CH2 1 3 CONH2 R
58 nBu H (Z)CH=CH CH2 1 3 CONHSO2nPentadec R
59 nBu H (Z)CH=CH CH2 1 3 四唑 R
60 nBu H (Z)CH=CH CH2 1 3 噻唑烷二酮 R
61 cPr H (Z)CH=CH CH2 1 3 CONHSO2nOct R
62 cHex H (Z)CH=CH CH2 1 3 CO2H R
63 iBu H (Z)CH=CH CH2 1 3 CO2H RS
64 nBu H (Z)CH=CH CH2 1 2 CO2Et R
65 nBu H (Z)CH=CH CH2 1 2 CO2H R
66 nBu H (Z)CH=CH CH2 1 2 CO2Na R
67 nBu H (Z)CH=CH CH2 1 2 四唑 R
68 nBu H (Z)CH=CH CH2 1 2 噻唑烷二酮 R
69 nBu H (Z)CH=CH CH2 1 2 CONHEt RS
70 nBu H (Z)CH=CH CH2 1 2 CONHMe R
71 sBu H (Z)CH=CH CH2 1 2 CO2H R
72 nPr H (Z)CH=CH CH2 1 2 CO2H RS
73 nBu H C≡C S 1 3 CO2H R
74 nBu H C≡C S 4 0 CO2Me R
75 nBu H C≡C S 4 0 CO2H R
76 sBu H C≡C S 4 0 CO2Me R
77 nBu H C≡C S 3 0 CO2Me R
78 nBu H C≡C S 3 0 CO2H R
79 nBu H C≡C S(O) 3 0 CO2H R
80 nBu H C≡C S(O)2 3 0 CO2H R
81 nBu H C≡C S 3 0 CO2H S
82 nBu Me C≡C S 3 0 CO2H RS
83 cHex H C≡C S 3 0 CO2H R
84 nBu H C≡C S 4 0 CONHMs RS
85 nBu H C≡C O 1 3 CO2Me R
86 nBu H C≡C O 1 3 CO2H R
87 nBu H C≡C O 1 3 CONHTs R
88 iBu H C≡C O 3 0 CO2H RS
89 nBu H C≡C O 3 0 CONHSO2nOct RS
90 nBu H (Z)CH=CH S 4 0 CO2Me R
91 nBu H (Z)CH=CH S 4 0 CO2H R
92 nBu H (Z)CH=CH S 1 3 CO2H R
93 nBu H (Z)CH=CH S 3 0 CO2Me R
94 nBu H (Z)CH=CH S 3 0 CO2H R
95 nBu H (Z)CH=CH S(O) 3 0 CO2H R
96 nBu H (Z)CH=CH S(O)2 3 0 CO2H R
97 nBu H (Z)CH=CH S 4 1 CO2Et R
98 nBu H (Z)CH=CH S 4 1 CO2H R
99 nBu H (Z)CH=CH S 3 2 CO2H R
100 nPr H (Z)CH=CH S 3 0 CONH2 R
101 nBu H (Z)CH=CH O 1 3 CO2Me R
102 nBu H (Z)CH=CH O 1 3 CO2H R
103 cHep H (Z)CH=CH O 1 3 CO2H R
104 cPr H (Z)CH=CH O 1 3 CO2H R
105 nBu H (Z)CH=CH O 3 0 CO2H R
106 iPr H (Z)CH=CH O 3 0 CO2H RS
107 nBu H (Z)CH=CH O 4 0 CONH2 RS
108 nBu H (Z)CH=CH O 3 0 CONH2 R
109 nBu H C≡C CH2 1 3 Br R
110 nBu H (Z)CH=CH CH2 1 3 Br R
111 nBu H (Z)CH=CH CH2 1 3 CN R
iPr:异丙基,iBu:异丁基,sBu:仲丁基,tBu:叔丁基,cPr:环丙基,cPent:环戊基,cHex:环己基,cHep:环庚基,cOct:环辛基,nOct:正辛基,nPentadec:正十五烷基。
*:连接R1和R2的不对称碳原子。
本发明化合物具有强效的弹性蛋白酶释放抑制活性,因此可用于治疗和预防有关弹性蛋白酶的疾病。
实施本发明的最佳模式
实施例
通过下列实施例和测试实施例将更具体地说明本发明。
实施例1
(R)-16-羟基二十-14-炔酸(化合物编号12)
(1)在-50℃、氩气流下,n-BuLi(4.0ml,2.47M的己烷溶液,9.9mmol)滴加入(R)-3-叔丁基二甲基甲硅烷氧基-1-庚炔(1.02g,4.5mmol)溶液中,后一溶液在THF(四氢呋喃)(20ml)和HMPA(六甲基磷酰三胺)(2.5ml)的混合溶剂中,(R)-1-庚炔-3-醇和13-溴十三烷酸(1.32g,4.5mmol)进行常规硅烷化反应制得。然后在约2.5小时内将反应液温度上升至室温,然后在室温下搅拌2小时。在获得的溶液中加入盐酸水溶液(150ml,1.0M),用Et2O(100ml×2)萃取混合物。用盐水(100ml)冲洗有机层,无水硫酸镁干燥并浓缩。将获得的粗产物溶于EtOH(22.5ml)中,加入浓硫酸(0.5ml)后,在室温下搅拌混合物3天。在反应液中加入饱和碳酸氢钠水溶液(150ml),用Et2O(100ml×2)萃取。用饱和碳酸氢钠水溶液(150ml)冲洗有机层,用无水硫酸镁干燥并浓缩。生成的粗产物用硅胶柱色层法提纯获得(R)-16-羟基二十-14-炔酸乙酯(667mg)。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.20-1.75(m,26H),1.25(t,J=7.1Hz,3H),2.20(dt,J=1.9,7.0Hz,2H),2.29(t,J=7.5Hz,2H),4.12(q,J=7.1Hz,2H),4.30-4.40(m,1H)
IR(直接压片):3436,2928,2855,1737,1466,1375,1180,1102,1036,723cm-1
(2)在室温下将NaOH水溶液(1.3ml,1.0M,1.3mmol)加入上述(1)获得的化合物(115mg,0.33mmol)在THF(12.2ml)和水(4.1ml)的混合溶剂中的溶液中,在室温下搅拌混合物3天。反应溶液用草酸水溶液(1.0M)制成酸性,加水(100ml)并用AcOEt(100ml×2)萃取混合物。用盐水(100ml)冲洗有机层,无水硫酸镁干燥并浓缩。生成的粗产物用硅胶柱色层法提纯获得标题化合物(102mg)。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.2Hz,3H),1.18-1.78(m,26H),2.20(dt,J=1.8,7.0Hz,2H),2.35(t,J=7.5Hz,2H),4.30-4.38(m,1H)
IR(KBr):3403,2920,2852,1698,1472,1434,1413,1279,1256,1232,1209,1188,1147,1113,1051,940,718,602,472,418cm-1
实施例2
(R)-(Z)-16-羟基二十-14-烯酸(化合物编号50)
(1)在氢气氛下将NaBH4(8.0mg,0.21mmol)的EtOH(1.0ml)悬浮液体滴加到Ni(OAc)2·4H2O(30mg,0.105mmol)的EtOH(5ml)溶液中,在室温下搅拌混合物30分钟。室温下在反应液中滴加入乙二胺(0.06ml,1.05mmol),然后滴加实施例1(1)获得的化合物(370mg,1.05mmol)的EtOH(2.0ml)溶液,在室温下搅拌混合物约5小时,直到氢气吸收终止。给反应溶液加入Et2O(50ml),搅拌混合物10分钟后,通过硅胶垫过滤并浓缩。生成的粗产物用硅胶柱色层法提纯,获得(R)-(Z)-16-羟基二十-14-烯酸乙酯(265mg)。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.8Hz,3H),1.23-1.48(m,27H),1.55-1.66(m,2H),2.04-2.12(m,2H),2.29(t,J=7.5Hz,2H),4.12(q,J=7.2Hz,2H),4.37-4.48(m,1H),5.32-5.40(m,1H),5.44-5.53(m,1H)。
IR(直接压片):3427,2926,2854,1739,1466,1375,1180,1100,1030,724cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,从而获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.8Hz,3H),1.23-1.49(m,24H),1.54-1.70(m,2H),2.04-2.12(m,2H),2.35(t,J=7.5Hz,2H),4.44(dt,J=6.4,8.5Hz,1H),5.32-5.41(m,1H),5.44-5.54(m,1H).
IR(直接压片):3369,2925,2845,1712,1466,1412,1384,1281,1119,1003,722cm-1
实施例3
(R)-17-羟基二十一-15-炔酸(化合物编号4)
(1)进行反应的方法与实施例1(1)大体上相同,只是用14-溴十四烷酸代替13-溴十三烷酸,获得(R)-17-羟基二十一-15-炔酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.2Hz,3H),1.19-1.74(m,31H),2.20(d t,J=1.9,7.0Hz,2H),2.29(t,J=7.5Hz,2H),4.12(q,J=7.2Hz,2H),4.28-4.41(m,1H)。
IR(直接压片):3436,2927,2855,1737,1466,1375,1180,1104,1036,722cm-1.
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,从而获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.2Hz,3H),1.20-1.80(m,28H),2.20(dt,J=1.9,7.0Hz,2H),2.35(t,J=7.5Hz,2H),4.35(tt,J=6.6,1.9Hz,1H)。
IR(KBr):3371,3281,2922,2849,1702,1465,1438,1412,1316,1274,1228,1206,1188,1150,1111,1051,1012,889,725,491cm-1
实施例4
(R)-(Z)-17-羟基二十一-15-烯酸(化合物编号46)
(1)用实施例3(1)获得的化合物进行反应,方法与实施例2(1)相同,获得(R)-(Z)-17-羟基二十一-15-烯酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.8Hz,3H),1.18-1.70(m,31H),1.98-2.18(m,2H),2.29(t,J=7.5Hz,2H),4.12(q,J=7.2Hz,2H),4.37-4.48(m,1H),5.32-5.54(m,2H)。
IR(直接压片):3428,2925,2854,2360,1739,1466,1374,1180,1100,1031,723,430cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.8Hz,3H),1.19-1.72(m,28H),1.95-2.16(m,2H),2.35(t,J=7.5Hz,2H),4.38-4.49(m,1H),5.30-5.55(m,2H)。
IR(直接压片):3400,2925,2854,1712,1466,1412,1200,1002,970,723,430cm-1
实施例5
(R)-15-羟基十九-13-炔酸(化合物编号28)
(1)进行反应的方法与实施例1(1)大体上相同,只是用12-溴十二烷酸代替13-溴十三烷酸,生成(R)-15-羟基十九-13-炔酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.2Hz,3H),1.19-1.79(m,27H),2.20(dt,J=2.0,7.0Hz,2H),2.29(t,J=7.5Hz,2H),4.12(q,J=7.2Hz,2H),4.29-4.40(m,1H)。
IR(直接压片):3436,2929,2856,2361,1737,1466,1375,1180,1100,1036,722cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.2Hz,3H),1.20-1.80(m,24H),2.20(dt,J=2.0,7.0Hz,2H),2.35(t,J=7.5Hz,2H),4.35(tt,J=6.6,2.0Hz,1H)
IR(KBr):3373,3279,2922,2850,1707,1464,1414,1330,1288,1264,1236,1210,1190,1150,1108,1051,1012,962,888,726,588cm-1
实施例6
(R)-(Z)-15-羟基十九-13-烯酸(化合物编号65)
(1)用实施例5(1)获得的化合物进行反应,方法与实施例2(1)相同,获得(R)-(Z)-15-羟基十九-13-烯酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.85-0.98(m,3H),1.20-1.68(m,27H),1.97-2.16(m,2H),2.29(t,J=7.5Hz,2H),4.12(q,J=7.2Hz,2H),4.43(dt,J=8.5,6.3Hz,1H),5.31-5.55(m,2H)。
IR(直接压片):3426,2927,2855,1740,1466,1375,1248,1181,1099,723,1030,724cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.91(t,J=6.8Hz,3H),1.16-1.70(m,24H),1.97-2.17(m,2H),2.35(t,J=7.5Hz,2H),4.38-4.49(m,1H),5.30-5.54(m,2H)。
IR(直接压片):3368,2925,2854,1712,1466,1413,1275,1100,1002,724cm-1
实施例7
(RS)-(Z)-16-羟基-16-甲基二十-14-烯酸(化合物编号54)
(1)进行反应的方法与实施例1(1)大体上相同,只是用(RS)-3-叔丁基二甲基甲硅烷氧基-3-甲基-1-庚炔代替(R)-3-叔丁基二甲基甲硅烷氧基-1-庚炔,生成(RS)-16-羟基-16-甲基二十-14-炔酸乙酯,然后用与实施例2(1)相同的方法进行反应,获得(RS)-(Z)-16-羟基-16-甲基二十-14-烯酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.91(t,J=7.0Hz,3H),1.20-1.68(m,32H),2.24-2.35(m,4H),4.12(q,J=7.2Hz,2H),5.28-5.42(m,2H)。
IR(直接压片):3436,2926,2854,2361,1739,1644,1466,1372,1303,1180,1101,1034,942,724cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.91(t,J=7.0Hz,3H),1.19-1.70(m,29H),2.25-2.39(m,4H),5.28-5.41(m,2H)
IR(直接压片):3400,2926,2854,1712,1466,1412,1371,1223,1048,940,724cm-1
实施例8
(RS)-(Z)-16-羟基-18-甲基十九-14-烯酸(化合物编号63)
(1)进行反应的方法与实施例1(1)大体上相同,只是用(RS)-3-叔丁基二甲基甲硅烷氧基-5-甲基-1-己炔代替(R)-3-叔丁基二甲基甲硅烷氧基-1-庚炔,生成(RS)-16-羟基-18-甲基十九-14-炔酸乙酯,然后用与实施例2(1)相同的方法进行反应生成(RS)-(Z)-16-羟基-18-甲基十九-14-烯酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.92(d,J=6.5Hz,3H),0.94(d,J=6.5Hz,3H),1.18-1.80(m,26H),2.02-2.15(m,2H)2.29(t,J=7.5Hz,2H),4.12(q,J=7.2Hz,2H),4.47-4.56(m,1H)5.31-5.57(m,26H)。
IR(直接压片):3436,2926,2854,1739,1466,1369,1180,1034,722cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.92(d,J=6.7Hz,3H),0.94(d,J=6.5Hz,3H),1.19-1.77(m,23H),2.00-2.19(m,2H),2.35(t,J=7.5Hz,2H),4.47-4.57(m,1H),5.30-5.40(m,1H),5.42-5.52(m,1H)。
IR(KBr):3370,2924,2852,1714,1472,1384,1370,1350,1318,1277,1259,1236,1210,1104,1081,1009,994,974,823,751,720,629,556,460cm-1
实施例9
(RS)-16-羟基十九-14-炔酸(化合物编号10)
(1)进行反应的方法与实施例1(1)大体上相同,只是用(RS)-3-叔丁基二甲基甲硅烷氧基-1-己炔代替(R)-3-叔丁基二甲基甲硅烷氧基-1-庚炔,生成(RS)-16-羟基十九-14-炔酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.91-0.99(m,3H),1.20-1.78(m,27H),2.20(dt,J=2.0,7.1Hz,2H),2.29(t,J=7.5Hz,2H),4.12(q,J=7.1Hz,2H),4.31-4.43(m,1H)。
IR(直接压片):3448,2929,2855,1737,1466,1374,1245,1180,1101,1029,854,723cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.95(t,J=7.3Hz,3H),1.22-1.73(m,24H),2.20(dt,J=1.9,7.0Hz,2H),2.35(t,J=7.5Hz,2H),4.36(tt,J=6.6,1.9Hz,1H)
IR(KBr):3358,2920,2852,1698,1472,1413,1320,1296,1254,1243,1230,1207,1188,1150,1106,1067,1027,942,718,474,416cm-1
实施例10
(RS)-16-羟基十八-14-炔酸(化合物编号8)
(1)进行反应的方法与实施例1(1)大体上相同,只是用(RS)-3-叔丁基二甲基甲硅烷氧基-1-戊炔代替(R)-3-叔丁基二甲基甲硅烷氧基-1-庚炔,生成(RS)-16-羟基十八-14-炔酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:1.00(t,J=7.4Hz,3H),1.18-1.78(m,25H),2.20(dt,J=1.9,7.0Hz,2H),2.29(t,J=7.5Hz,2H),4.12(q,J=7.2Hz,2H),4.26-4.36(m,1H)。
IR(直接压片):3436,2928,2854,1737,1465,1374,1180,1099,1035,965,722cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:1.00(t,J=7.4Hz,3H),1.20-1.75(m,22H),2.20(dt,J=2.0,7.0Hz,2H),2.35(t,J=7.5Hz,2H),4.31(tt,J=6.4,1.9Hz,1H)。
IR(KBr):3357,2921,2852,1698,1472,1439,1413,1341,1324,1279,1256,1232,1209,1188,1148,1088,1072,1035,1007,965,718,625cm-1
实施例11
4-((R)-10-羟基十四-8-炔基硫基)丁酸(化合物编号78)
(1)在0℃、氩气流下将正-BuLi(19.7ml,2.47M的己烷溶液,48.7mmol)滴加到(R)-3-叔丁基二甲基甲硅烷氧基-1-庚炔(10.0g,44.3mmol)的THF(179ml)溶液中。然后在室温下搅拌反应液30分钟,使反应溶液冷却到-40℃,向其中滴加入1,7-二溴庚烷(22.9g,88.6mmol)的DMPU(N,N’-二甲基丙烯脲)(22.4ml),在约2小时内将反应液的温度升至室温,然后在室温下搅拌2小时。向生成的溶液中加入饱和氯化铵水溶液(500ml),混合物用己烷(300ml×2)萃取。用盐水(500ml)冲洗有机层,无水硫酸镁干燥并浓缩。生成的粗产物用蒸馏法提纯获得((R)-10-溴-1-丁基癸-2-炔基氧基)-叔丁基二甲基甲硅烷(12.6g)。
1H-NMR(CDCl3,300MHz)δppm:0.10(s,3H),0.12(s,3H),0.84-0.96(m,3H),0.91(s,9H),1.24-1.68(m,14H),1.80-1.92(m,2H),2.19(dt,J=1.9,6.9Hz,2H),3.41(t,J=6.4Hz,2H),4.32(tt,J=6.5,1.9Hz,1H)。
IR(直接压片):2930,2858,2233,1463,1407,1389,1361,1341,1251,1217,1152,1110,1083,1006,938,837,778,725,667,565cm-1
(2)在室温下将HCl水溶液(0.5ml,1.0M,1.3mmol)加入上述(1)获得的化合物(910mg,2.24mmol)的MeOH(15ml)溶液中,在室温下搅拌混合物1小时。反应溶液中加入饱和碳酸氢钠溶液(100ml),然后用AcOEt(100ml×2)萃取混合物。用盐水(100ml)冲洗有机层,无水硫酸镁干燥并浓缩。生成的粗产物用硅胶柱色层法提纯获得(R)-14-溴十四-6-炔-5-醇(628mg).
1H-NMR(CDCl3,300MHz)δppm:0.88-0.96(m,3H),1.22-1.77(m,14H),1.79-1.93(m,2H),2.21(dt,J=2.0,6.9Hz,2H),3.41(t,J=6.8Hz,2H),4.29-4.40(m,1H)。
IR(直接压片):3368,2930,2858,2231,1465,1379,1333,1250,1148,1104,1038,1008,876,726,646,563cm-1
(3)在氩气流下将NaOMe(79mg,1.47mmol)加入上述(2)获得化合物(250mg,0.864mmol)的MeOH(6ml)溶液中,向其中滴加γ-硫代丁内酯(132mg,1.30mmol)的MeOH(3ml)溶液,然后加入NaI(15mg),在室温下搅拌混合物14小时,再在45℃温度下搅拌1小时。冷却反应溶液至室温,加入饱和的氯化铵水溶液(50ml),然后用Et2O(50ml×2)萃取混合物。用盐水(50ml)冲洗有机层,无水硫酸镁干燥并浓缩。生成的粗产物用硅胶柱色层法提纯获得4-((R)-10-羟基十四-8-炔基硫基)丁酸甲酯(0.23g)。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.23-1.77(m,16H),1.85-1.97(m,2H),2.20(dt,J=1.9,7.0Hz,2H),2.41-2.59(m,6H),3.68(s,3H),4.35(tt,J=6.6,1.9Hz,1H)。
IR(直接压片):3453,2930,2858,2230,1740,1437,1366,1315,1212,1175,1145,1037,1008,888,727cm-1
(4)用上述(3)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.22-1.75(m,18H),1.86-1.98(m,2H),2.21(dt,J=1.9,6.9Hz,2H),2.51(t,J=7.2Hz,4H),2.57(t,J=7.2Hz,2H),4.36(tt,J=6.5,1.9Hz,1H)。
IR(直接压片):3340,2930,2858,2231,1708,1456,1293,1236,1147,1036,1003,889,728cm-1
实施例12
4-((R)-(Z)-10-羟基十四-8-烯基硫基)丁酸(化合物编号94)
(1)用实施例11(2)获得的化合物进行反应,方法与实施例2(1)相同,获得(R)-(Z)-14-溴十四-6-烯-5-醇。
1H-NMR(CDCl3,300MHz)δppm:0.84-0.96(m,3H),1.20-1.67(m,14H),1.79-1.92(m,2H),1.98-2.16(m,2H),3.41(t,J=6.8Hz,2H),4.37-4.47(m,1H),5.32-5.54(m,2H)。
IR(直接压片):3351,3006,2930,2856,1656,1466,1378,1252,1121,1007,878,727,646,564cm-1
(2)进行反应的方法与实施例11(3)大体上相同,只是用上述(1)获得的化合物代替(R)-14-溴十四-6-炔-5-醇,生成4-((R)-(Z)-10-羟基十四-8-烯基硫基)丁酸甲酯。
1H-NMR(CDCl3,300MHz)δppm:0.91(t,J=6.9Hz,3H),1.20-1.68(m,16H),1.85-2.18(m,4H),1.98-2.18(m,2H),2.40-2.60(m,6H),3.68(s,3H),4.37-4.58(m,1H),5.31-5.53(m,2H)。
IR(直接压片):3436,3004,2928,2855,1740,1438,1366,1314,1211,1174,1140,1006,887,749cm-1
(3)用上述(2)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.86-0.95(m,3H),1.21-1.67(m,16H),1.85-2.21(m,4H),2.50(2t,J=7.2Hz,4H),2.57(t,J=7.2Hz,2H),4.40-4.50(m,1H),5.31-5.54(m,2H)
IR(直接压片):3368,2929,2856,1708,1457,1293,1235,1138,1000,753cm-1
实施例13
5-((R)-10-羟基十四-8-炔基硫基)戊酸(化合物编号75)
(1)进行反应的方法与实施例11(3)大体上相同,只是用δ-硫代戊内酯代替γ-硫代丁内酯,生成5-((R)-10-羟基十四-8-炔基硫基)戊酸甲酯。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.22-1.80(m,20H),2.21(dt,J=1.9,7.0Hz,2H),2.34(t,J=7.3Hz,2H),2.50(t,J=7.1Hz,2H),2.52(t,J=7.2Hz,2H),3.68(s,3H),4.30-4.40(m,1H)
IR(直接压片):3436,2931,2858,2230,1740,1459,1437,1378,1271,1206,1174,1039,888,729,504cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.22-1.82(m,20H),2.21(dt,J=2.0,6.9Hz,2H),2.39(t,J=7.2Hz,2H),2.51(t,J=7.1Hz,2H),2.53(t,J=7.1Hz,2H),4.35(tt,J=6.5,2.0Hz,1H)。
IR(直接压片):3350,2930,2858,1712,1708,1460,1282,1229,1149,1037,1004,892,727cm-1
实施例14
5-((R)-(Z)-10-羟基十四-8-烯基硫基)戊酸(化合物编号91)
(1)进行反应的方法与实施例11(3)大体上相同,只是用实施例12(1)获得的化合物和δ-硫代戊内酯分别代替(R)-14-溴十四-6-炔-5-醇和γ-硫代丁内酯,生成5-((R)-(Z)-10-羟基十四-8-烯基硫基)戊酸甲酯。
1H-NMR(CDCl3,300MHz)δppm:0.86-0.95(m,3H),1.21-1.79(m,20H),1.98-2.18(m,2H),2.34(t,J=7.3Hz,2H),2.50(t,J=7.3Hz,2H),2.52(t,J=7.1Hz,2H),3.67(s,3H),4.37-4.47(m,1H),5.32-5.53(m,2H)。
IR(直接压片):3436,2928,2855,2360,2343,1740,1437,1384,1271,1205,1174,1009,886,750,669cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.86-0.95(m,3H),1.21-1.81(m,20H),1.97-2.20(m,2H),2.38(t,J=7.2Hz,2H),2.44-2.58(m,4H),4.44(dt,J=8.2,6.6Hz,1H),5.31-5.54(m,2H)
IR(直接压片):3367,3006,2930,2855,1712,1708,1461,1418,1278,1228,1124,1001,897,752cm-1
实施例15
4-((R)-10-羟基十四-8-炔-1-磺酰基)丁酸(化合物编号80)
在室温下将间氯过苯甲酸(35mg,0.274mmol)加入实施例11获得的化合物(30mg,0.0913mmol)的CHCl3(3ml)液中,在室温下搅拌混合物4小时。加入饱和硫代硫酸钠水溶液(30ml)),然后用AcOEt(30ml×2)萃取混合物。用盐水(30ml)冲洗有机层,无水硫酸镁干燥并浓缩,生成的粗产物用硅胶柱色层法提纯,获得标题化合物(17mg)。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.21-1.92(m,16H),2.10-2.27(m,4H),2.60(t,J=6.7Hz,2H),2.94-3.13(m,4H),4.28-4.46(m,1H)。
IR(KBr):3485,3370,2932,2860,1692,1470,1446,1420,1328,1274,1242,1217,1200,1124,1083,1056,1016,912,776,750,728,613,575,510,473,420cm-1
实施例16
4-((R)-10-羟基十四-8-炔-1-亚磺酰基)丁酸(化合物编号79)
在室温下将NaIO4(74mg,0.34mmol)的水(0.9ml)溶液加入到实施例11获得的化合物(30mg,0.0913mmol)的MeOH(2.3ml)溶液中,在室温温度下搅拌混合物4小时。向反应溶液中加入盐水(30ml)后,用AcOEt(30ml×2)萃取混合物。用盐水(30ml)冲洗有机层,无水硫酸镁干燥并浓缩。生成的粗产物用硅胶柱色层法提纯,获得标题化合物(28mg)。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.29-1.86(m,16H),2.08-2.26(m,4H),2.46-2.96(m,6H),4.30-4.40(m,1H)。
IR(直接压片):3368,2933,2859,1724,1456,1412,1291,1225,1144,1034,1003,847,727cm-1
实施例17
(RS)-16-羟基二十-14-炔酰胺(化合物编号23)
(1)将乙腈(0.263ml,5.0mmol)的THF(5ml)溶液冷却至-65℃后,滴加n-BuLi(2.23ml,2.46M的己烷溶液,5.5mmol),同时在氩气流下搅拌。然后将反应液在此温度下搅拌1小时。在0℃下于10分钟内将反应液滴加到1,11-二溴十一烷(3.14g,10mmol)的THF(10ml)液中。在室温下搅拌混合物15分钟。向生成的溶液中加入水(10ml)和乙酸乙酯(30ml),分离出有机层。用无水硫酸镁干燥并浓缩。生成的粗产物用柱色层法提纯,获得13-溴十三腈(800mg)。
1H-NMR(CDCl3,200MHz)δppm:1.20-1.96(m,20H),2.35(t,J=7.0Hz,2H),3.43(t,J=6.8Hz,2H)。
IR(直接压片):3400,2927,2854,2246,1636,1466,1384,1251,1068,722,644,562cm-1
(2)上述(1)获得的化合物(800mg)的70硫酸(0.5ml)水溶液在70℃加热、氩气流下搅拌2小时。冷却反应液至室温,加入冰水(30ml),滤除由此分离的结晶状粗产物。将分离物溶解于乙酸乙酯(100ml)中,用氢氧化钠水溶液(2.0M)中和后萃取。用盐水(100ml)冲洗有机层,无水硫酸镁干燥并浓缩。获得的晶体物质减压干燥获得13-溴十三酰胺(790mg)。
1H-NMR(CDCl3,300MHz)δppm:1.20-1.71(m,18H),1.79-1.91(m,2H),2.22(t,J=7.6Hz,2H),3.41(t,J=6.9Hz,2H),5.34(bs,2H)。
IR(KBr):3395,3191,2922,2851,1647,1471,1420,1330,1281,1281,1254,1228,1204,1123,801,721,648,565,520,472,421cm-1
(3)用上述(2)获得的化合物和(RS)-3-叔丁基二甲基甲硅烷氧基-1-庚炔分别代替13-溴十三酸和(R)-3-叔丁基二甲基甲硅烷氧基-1-庚炔反应,进行反应的方法大体上与实施例1(1)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.20-1.80(m,26H),2.16-2.27(m,4H),4.35(tt,J=6.5,1.9Hz,1H),5.28(bs,1H),5.38(bs,1H)。
IR(KBr):3360,3188,2920,2850,1663,1633,1472,1426,1411,1334,1268,1241,1216,1191,1139,1105,1041,882,811,721,641,530cm-1
实施例18
(RS)-16-羟基十九-14-炔酰胺(化合物编号22)
进行反应的方法大体上与实施例1(1)相同,只是用实施例17(2)获得的化合物和(RS)-3-叔丁基二甲基甲硅烷氧基-1-己炔分别代替13-溴十三酸和(R)-3-叔丁基二甲基甲硅烷氧基-1-庚炔,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.95(t,J=7.2Hz,3H),1.20-1.71(m,24H),2.16-2.26(m,4H),4.32-4.40(m,1H),5.10-5.45(m,2H)。
IR(KBr):3359,3187,2920,2850,1662,1633,1471,1426,1412,1334,1316,1242,1216,1139,1103,1066,1027,946,880,814,704,643,530cm-1
实施例19
(R)-(Z)-16-羟基-16-环己基十六-14-烯酸(化合物编号62)
(1)进行反应的方法大体上与实施例1(1)相同,只是用(R)-3-叔丁基二甲基甲硅烷氧基-3-环己基-1-丙炔代替(R)-3-叔丁基二甲基甲硅烷氧基-1-庚炔,生成(R)-16-羟基-16-环己基十六-14-炔酸乙酯,然后以与实施例2(1)相同的方法进行反应,生成(R)-(Z)-16-羟基-16-环己基-十六-14-烯酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.84-2.16(m,36H),2.29(t,J=7.5Hz,2H),4.08-4.18(m,3H),5.32-5.42(m,1H),5.47-5.59(m,1H)。
IR(直接压片):3400,2924,2853,1739,1450,1373,1183,1100,1031,973,892,722cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.84-1.43(m,24H),1.57-1.81(m,6H),1.86-2.17(m,3H),2.35(t,J=7.4Hz,2H),4.15(dd,J=9.2,7.3Hz,1H),5.32-5.42(m,1H),5.48-5.59(m,1H)。
IR(KBr):3290,2924,2850,1702,1467,1449,1383,1288,1262,1234,1184,1105,1083,1058,1002,929,802,729,640,572,468,444,432,418cm-1
实施例20
(RS)-(Z)-16-羟基十九-14-烯酸(化合物编号49)
(1)用实施例9(1)获得的化合物进行反应,方法与实施例2(1)相同,生成(RS)-(Z)-16-羟基十九-14-烯酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.93(t,J=7.1Hz,3H),1.18-1.68(m,27H),2.00-2.16(m,2H),2.29(t,J=7.5Hz,2H),4.12(q,J=7.2Hz,2H),4.40-4.49(m,1H),5.31-5.45(m,2H)。
IR(直接压片):3400,2925,2854,2361,1737,1646,1465,1384,1318,1179,1098,1026,757cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.93(t,J=7.2Hz,3H),1.19-1.69(m,24H),1.98-2.16(m,2H),2.35(t,J=7.5Hz,2H),4.40-4.49(m,1H),5.31-5.40(m,1H),5.42-5.54(m,1H)。
IR(KBr):3389,3011,2957,2920,2851,1718,1464,1435,1324,1305,1282,1260,1230,1207,1188,1126,1070,1032,959,925,898,842,720,699,544,472,429cm-1
实施例21
(RS)-(Z)-16-羟基十八-14-烯酸(化合物编号48)
(1)用实施例10(1)获得的化合物进行反应,方法与实施例2(1)相同,生成(RS)-(Z)-16-羟基十八-14-烯酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.91(t,J=7.5Hz,3H),1.18-1.68(m,25H),1.97-2.16(m,2H),2.29(t,J=7.5Hz,2H),4.12(q,J=7.2Hz,2H),4.31-4.41(m,1H),5.31-5.56(m,2H)。
IR(直接压片):3428,2925,2854,1739,1465,1374,1246,1180,1110,1034,966,722cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例1(2)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.91(t,J=7.5Hz,3H),1.18-1.70(m,22H),1.95-2.18(m,2H),2.35(t,J=7.5Hz,2H),4.31-4.41(m,1H),5.29-5.70(m,2H)。
IR(KBr):3284,2922,2852,1698,1472,1433,1412,1302,1278,1255,1230,1208,1188,1121,1072,962,856,793,742,718,684,529cm-1
实施例22
(R)-16-羟基二十-14-炔腈(化合物编号37)
(1)进行反应的方法与实施例11(1)相同,只是用1,12-二溴十二烷代替1,7-二溴庚烷,生成化合物((R)-15-溴-1-丁基十五-2-炔基氧基)-叔丁基二甲基硅烷。
1H-NMR(CDCl3,300MHz)δppm:0.10(s,3H),0.12(s,3H),0.88-0.92(m,12H),1.24-1.52(m,22H),1.58-1.67(m,2H),1.80-1.93(m,2H),2.18(dt,J=2.0,6.9Hz,2H),3.41(t,J=6.8Hz,2H),4.31(ddt,J=1.9,1.9,6.5Hz,1H)。
IR(直接压片):2930,2856,1464,1361,1341,1251,1152,1110,1083,1005,938,838,778,667,566cm-1
(2)在10分钟内向氰化钠(735mg,15mmol)的DMSO(二甲亚砜)(20ml)(干燥后蒸馏)溶液中滴加上述(1)获得的化合物(4.74g,10mmol),同时在80℃时边加热边搅拌,然后搅拌混合物2小时。使反应溶液降至室温,倒进水中,用己烷(200ml)萃取混合物,然后用水(50ml)冲洗,用无水硫酸镁干燥并浓缩。生成的粗产物用硅胶柱色层法提纯,获得(R)-16-(叔丁基二甲基甲硅烷氧基)二十-14-炔腈(3.73g)。
1H-NMR(CDCl3,300MHz)δppm:0.10(s,3H),0.12(s,3H),0.84-0.92(m,12H),1.19-1.52(m,22H),1.58-1.72(m,4H),2.18(dt,J=2.0,7.0Hz,2H),2.33(t,J=7.1Hz,2H),4.27-4.36(m,1H)。
(3)进行反应的方法与实施例11(2)相同,只是用上述(2)获得的化合物代替实施例11(1)获得的化合物,从而获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.20-1.74(m,26H),2.20(dt,J=1.9,7.0Hz,2H),2.33(t,J=7.2Hz,2H),4.28-4.39(m,1H)。
IR(直接压片):3436,2929,2856,2247,1466,1147,1104,1038,1008,723cm-1
实施例23
(R)19-(1H-四唑-5-基)十九-6-炔-5-醇(化合物编号36)
向实施例22得到的化合物(1.0g,3.3mmol)的DMF(二甲基甲酰胺)(30ml)溶液中加入叠氮化钠(644mg,9.9mmol)和氯化铵(530mg,9.9mmol),在125℃下回流加热混合物39小时后。反应完成后,将反应液倒入水(100ml)中,用AcOEt(200ml)萃取混合物。用水(50ml)冲洗有机层后,再用盐水(50ml)冲洗,无水硫酸镁干燥并浓缩。生成的粗产物用硅胶柱色层法提纯,并用Et2O/石油醚重结晶,从而获得标题化合物(442mg)。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.17-1.54(m,22H),1.62-1.92(m,4H),2.14-2.24(m,2H),2.97-3.11(m,2H),4.38-4.47(m,1H)。
IR(KBr):3208,2920,2852,1546,1472,1408,1378,1292,1261,1246,1228,1214,1147,1107,1066,1047,1008,825,758,718,608cm-1
实施例24
(R)-19-溴十九-6-炔-5-醇(化合物编号109)
进行反应的方法与实施例11(2)相同,只是用实施例22(1)获得的化合物代替实施例11(1)获得的化合物,从而获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.23-1.58(m,22H),1.60-1.74(m,2H),1.79-1.92(m,2H),2.20(dt,J=2.0,7.0Hz,2H),3.41(t,J=6.8Hz,2H),4.30-4.39(m,1H)。
IR(直接压片):3368,2927,2855,2230,1466,1148,1037,722,646,563cm-1
实施例25
(R)-(Z)-19-溴十九-6-烯-5-醇(化合物编号110)
进行反应的方法与实施例2(1)相同,只是用实施例24获得的化合物代替实施例1(1)获得的化合物,从而获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.91(t,J=6.9Hz,3H),1.20-1.65(m,24H),1.79-1.92(m,2H),2.01-2.15(m,2H),3.41(t,J=6.8Hz,2H),4.37-4.47(m,1H),5.31(m,2H)。
IR(直接压片):3368,3005,2925,2854,1656,1466,1378,1251,1008,722,647,564cm-1
实施例26
(R)-(Z)-19-羟基二十-14-烯腈(化合物编号111)
进行反应的方法与实施例22(2)相同,只是用实施例25获得的化合物代替实施例22(1)获得的化合物,从而获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.91(t,J=7.0Hz,3H),1.20-1.72(m,26H),2.00-2.14(m,2H),2.33(t,J=7.1Hz,2H),4.37-4.48(m,1H),5.31-5.54(m,2H)。
IR(直接压片):3436,2926,2854,2247,1466,1007,723,500cm-1
实施例27
(R)-(Z)-19-(1H-四唑-5-基)十九-6-烯-5-醇(化合物编号59)
进行反应的方法与实施例23相同,只是用实施例26获得的化合物代替实施例22获得的化合物,从而获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.8Hz,3H),1.16-1.56(m,23H),1.58-1.72(m,1H),1.76-1.90(m,2H),1.96-2.20(m,2H),3.02(t,J=7.7Hz,2H),4.46-4.58(m,1H),5.34-5.58(m,2H)。
IR(直接压片):3292,3006,2925,2854,2627,2098,1656,1558,1466,1378,1251,1103,1054,1001,897,724cm-1
实施例28
(RS)-(Z)-15-羟基十八-13-烯酸(化合物编号72)
(1)进行反应的方法大体上与实施例1(1)相同,只是用12-溴十二烷酸和(RS)-3-叔丁基二甲基甲硅烷氧基-1-己炔分别代替13-溴十三酸和(R)-3-叔丁基二甲基甲硅烷氧基-1-庚炔,生成(RS)-15-羟基十八-13-炔酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.95(t,J=7.2Hz,3H),1.21-1.74(m,25H),2.20(dt,J=1.9,7.0Hz,2H),2.29(t,J=7.5Hz,2H),4.13(q,J=7.2Hz,2H),4.32-4.40(m,1H)。
IR(直接压片):3436,2929,2855,1737,1466,1374,1248,1180,1100,1029,854,723cm-1
(2)用上述(1)获得的化合物进行反应,方法与实施例2(1)相同,生成(RS)-(Z)-15-羟基十八-13-烯酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.93(t,J=7.2Hz,3H),1.20-1.68(m,25H),2.02-2.13(m,2H),2.28(t,J=7.5Hz,2H),4.12(q,J=7.2Hz,2H),5.31-5.40(m,1H),5.43-5.54(m,1H)。
IR(直接压片):3428,2926,2854,2360,1739,1466,1374,1350,1247,1180,1098,1063,1033,848,723cm-1
(3)用上述(2)获得的化合物进行反应,方法与实施例1(2)相同,从而获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.93(t,J=7.2Hz,3H),1.20-1.75(m,22H),1.93-2.20(m,2H),2.35(t,J=7.5Hz,2H),4.40-4.49(m,1H),5.36(dt,J=8.7,1.4Hz,1H),5.43-5.53(m,1H)。
IR(直接压片):3368,2926,2854,1711,1466,1384,1247,1098,1064,1004,756cm-1
实施例29
(S)-(Z)-16-羟基二十-14-烯酸(化合物编号56)
(1)在实施例2获得的化合物(1)(250mg,0.71mmol)中加入苯甲酸(130mg,1.06mmol)、三苯磷(278mg,1.06mmol)和偶氮二羧酸二乙酯(0.46ml,1.06mmol),在0℃、氩气流下搅拌该混合物1小时,同时升温至室温。向反应液中加入己烷(5ml),过滤混合物并用硅胶柱色层法提纯获得苯甲酸(S)-(Z)-1-丁基-15-乙氧基羰基十五-2-烯酯(149mg)。
1H-NMR(CDCl3,300MHz)δppm:0.91(t,J=7.1Hz,3H),1.19-1.43(m,25H),1.50-1.86(m,4H),2.13-2.33(m,4H),4.12(q,J=7.1Hz,2H),5.36-5.48(m,1H),5.50-5.63(m,1H),5.72-5.83(m,1H),7.38-7.47(m,2H),7.50-7.57(m,1H),7.99-8.07(m,2H)。
IR(直接压片):2928,2855,1736,1718,1603,1585,1466,1452,1372,1315,1271,1177,1110,1070,1027,945,712,688cm-1
(2)向上述(1)获得的化合物(149mg,0.325mmol)的EtOH(1ml)溶液中加入20%的乙醇钠的乙醇溶液(0.17ml,0.488mmol),在室温下搅拌混合物过夜后,将由此获得的反应液倒入饱和的盐酸溶液(10ml)中,用乙酸乙酯(20ml×2)萃取,盐水(30ml)冲洗有机层,用无水硫酸镁干燥。生成的粗产物用硅胶柱色层法提纯得(S)-(Z)-16-羟基二十-14-烯酸乙酯(53mg)。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.6Hz,3H),1.21-1.68(m,29H),2.02-2.12(m,2H),2.28(t,J=7.5Hz,2H),4.12(q,J=7.1Hz,2H),4.37-4.49(m,1H),5.31-5.40(m,1H)5.43-5.57(m,1H)。
IR(直接压片):3428,2926,2855,1739,1466,1375,1180,1100,1031,723cm-1
(3)用上述(2)获得的化合物(48mg,0.135mmol)进行反应,方法与实施例1(2)相同,从而获得标题化合物(40mg)。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.8Hz,3H),1.20-1.51(m,22H),1.54-1.70(m,4H),2.00-2.16(m,2H),2.35(t,J=7.5Hz,2H),4.43(dt,J=8.5,6.4Hz,1H),5.31-5.41(m,1H),5.43-5.55(m,1H)。
IR(KBr):3277,2922,2852,1703,1468,1438,1302,1105,1047,1017,972,791,721,638,466cm-1
实施例30
(R)-(Z)-(13-羟基十七-11-烯氧基)乙酸(化合物编号102)
(1)在-50℃、氩气流下向丙基-2-炔氧基乙酸(1.14g,10mmol)的混合溶剂THF(10ml)和HMPA(5ml)的溶液中滴加n-BuLi(9.23ml,2.46M的己烷溶液,24mmol)。然后在约30分钟内升温到-30℃,然后向反应液中滴加2-(7-溴庚氧基)-四氢吡喃(4.19g,15mmol)的THF(10ml)溶液。然后在约2小时内搅拌下升温到室温。加入盐酸(3.0M)水溶液使反应液呈酸性,用AcOEt(60ml×2)萃取。盐水(100ml)冲洗有机层,无水硫酸镁干燥并在减压条件下蒸馏除去溶剂。对获得的粗产物的乙醇溶液(50ml)加入浓硫酸(0.5ml),获得的混合物在室温下搅拌过夜,将反应液倒入饱和碳酸氢钠水溶液中,用乙酸乙酯(100×2)萃取。盐水冲洗有机层,无水硫酸镁干燥并浓缩。生成的粗产物用硅胶柱色层法提纯,获得(10-羟基癸-2-炔氧基)乙酸乙酯(0.92g)。
1H-NMR(CDCl3,300MHz)δppm:1.20-1.64(m,13H),2.22(tt,J=7.0,2.2Hz,2H),3.65(t,J=6.5Hz,2H),4.18(s,2H),4.24(q,J=7.2Hz,2H),4.29(t,J=2.2Hz,2H)。
IR(直接压片):3400,2933,2858,2221,1752,1639,1450,1384,1278,1208,1137,1114,1027,936,858,722,595,500cm-1
(2)在冰冷却、氩气流下向上述(1)获得的化合物(0.92g,3.59mmol)和四溴化碳(1.55g,4.7mmol)的二氯甲烷(30ml)溶液中加入三苯膦(1.32g,4.7mmol)的二氯甲烷(10ml)溶液。搅拌1小时后,减压条件下减压蒸馏除去二氯甲烷,用硅胶柱色层法提纯,获得10-溴癸-2-炔氧基)乙酸乙酯(1.05g)。
1H-NMR(CDCl3,300MHz)δppm:1.22-1.58(m,11H),1.81-1.93(m,2H),2.22(tt,J=7.0,2.2Hz,2H),3.41(t,J=6.8Hz,2H),4.17(s,2H),4.24(q,J=7.2Hz,2H),4.29(t,J=2.2Hz,2H)。
IR(直接压片):2934,2858,2220,1752,1450,1380,1249,1205,1138,1113,1028,937,859,723,644,561cm-1
(3)向上述(2)获得的化合物(1.0g,3.13mmol)的乙醇(20ml)溶液中加入Pd-C(5%,50mg),在室温、氢气下搅拌混合物1小时。反应溶液用C盐过滤并浓缩,所得粗产物用硅胶柱色层法提纯,获得(10-溴癸氧基)乙酸乙酯(0.76g)。
1H-NMR(CDCl3,300MHz)δppm:1.17-1.49(m,15H),1.54-1.69(m,2H),1.79-1.92(m,2H),3.41(t,J=6.9Hz,2H),3.52(t,J=6.7Hz,2H),4.06(s,2H),4.22(q,J=7.2Hz,2H)。
IR(直接压片):2929,2855,1757,1736,1466,1376,1273,1201,1139,1032,723,646,564cm-1
(4)向上述(3)获得的化合物的THF(30ml)溶液中加入氢氧化钠(8.9ml,1.0M)的水溶液,生成的混合物在30℃下搅拌3天后。将反应液倒入饱和氯化铵水溶液中,用乙酸乙酯(75ml×2)萃取。用盐水冲洗有机层,无水硫酸镁干燥并浓缩。用硅胶柱色层法提纯获得的粗产物,获得(10-溴癸氧基)乙酸(415mg)。
1H-NMR(CDCl3,300MHz)δppm:1.22-1.50(m,12H),1.57-1.70(m,2H),1.80-1.92(m,2H),3.41(t,J=6.8Hz,2H),3.58(t,J=6.7Hz,2H),4.09(s,2H)。
IR(直接压片):2928,2855,2284,1734,1431,1245,1134,723,677,562cm-1
(5)进行反应的方法大体上与实施例1(1)相同,只是用上述(4)获得的化合物代替13-溴十三酸,生成(R)-(13-羟基十七-11-炔氧基)乙酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.20-1.75(m,25H),2.20(dt,J=2.0,7.0Hz,2H),3.52(t,J=6.7Hz,2H),4.06(s,2H),4.22(q,J=7.1Hz,2H),4.30-4.39(m,1H)。
IR(直接压片):3468,2930,2857,1756,1466,1377,1275,1202,1138,1034,723cm-1
(6)进行反应的方法大体上与实施例2(1)相同,只是使用上述(5)获得的化合物,生成(R)-(Z)-(13-羟基十七-11-烯氧基)乙酸乙酯。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.8Hz,3H),1.20-1.70(m,25H),2.00-2.15(m,2H),3.52(t,J=6.7Hz,2H),4.06(s,2H),4.22(q,J=7.2Hz,2H),4.38-4.47(m,1H),5.32-5.41(m,1H),5.43-5.53(m,1H)。
IR(直接压片):3436,2927,2855,2361,1757,1656,1466,1377,1275,1202,1139,1027,723cm-1
(7)进行反应的方法大体上与实施例1(2)相同,只是用上述(6)获得的化合物,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.9Hz,3H),1.18-1.50(m,22H),1.54-1.69(m,2H),1.99-2.17(m,2H),3.57(t,J=6.6Hz,2H),4.09(s,2H),4.39-4.49(m,1H),5.32-5.41(m,1H),5.44-5.45(m,1H)。
IR(直接压片):3400,2927,2855,2361,1734,1466,1384,1240,1136,1021,756,670,571cm-1
实施例31
(R)-5-(14-羟基十八-12-炔基)噻唑烷-2,4-二酮(化合物编号33)
(1)在0℃、氩气流下向(R)-叔丁基二甲基甲硅烷氧基-1-庚炔(3.01g,13.3mmol)的THF(20ml)溶液中滴加n-BuLi(5.95ml,2.46M己烷溶液,14.6mmol),然后冷却反应溶液到-40℃给反应液,随后滴加1,11-二溴十一烷(6.87g,21.9mmol)的混合溶剂THF(50ml)和DMPU(20ml)的溶液,然后在1.5小时内将反应液升温到室温。向生成的溶液中加入盐酸水溶液(10ml,3.0M),用己烷(100ml×2)萃取混合物。用盐水(200ml)冲洗有机层,无水硫酸镁干燥并浓缩。获得的粗产物用蒸馏法提纯,获得(R)-(14-溴-1-丁基十四-2-炔氧基)-叔丁基二甲基硅烷(3.39g)。
1H-NMR(CDCl3,300MHz)δppm:0.10(s,3H),0.12(s,3H),0.84-0.96(m,12H),1.20-1.68(m,26H),1.80-1.91(m,2H),2.18(dt,J=1.9,6.9Hz,2H),3.41(t,J=6.8Hz,2H),4.27-4.35(m,1H)。
IR(直接压片):2929,2856,1464,1361,1341,1251,1110,1083,1006,938,837,778,667,565cm-1
(2)在-60℃、氩气流下向2,4-噻唑烷二酮(141mg,1.2mmol)的混合溶剂THF(5ml)和HMPA(3ml)溶液中滴加n-BuLi(1.17ml,2.46M己烷溶液,2.88mmol)。在该温度下搅拌30分钟,再在室温下搅拌混合物30分钟,随后将混合物降温至-60℃,之后滴加上述(1)获得的化合物(460mg,1.0mmol)的THF(5ml)溶液,然后使混合物在4小时内升温至0℃。向溶液中加入盐酸(5ml,3.0M)水溶液,用己烷(100ml×2)萃取混合物。盐水(200ml)冲洗有机层,无水硫酸镁干燥并浓缩。获得的粗产物用硅胶柱色层法提纯,获得(R)-5-[14-(叔丁基二甲基甲硅烷氧基)十八-12-炔基]噻唑烷-2,4-二酮(175mg)。
1H-NMR(CDCl3,300MHz)δppm:0.10(s,3H),0.12(s,3H),0.84-0.96(m,12H),1.20-1.68(m,26H),2.18(dt,J=2.0,6.9Hz,2H),4.24-4.36(m,2H),7.26(bs,1H)。
IR(直接压片):3216,3067,2928,2855,2231,1758,1702,1464,1385,1333,1250,1152,1110,1084,1005,937,837,777,668,605,536cm-1
(3)向上述(2)获得的化合物(170mg,0.35mmol)的MeOH(5ml)溶液中加入盐酸(0.5ml,3.0M)水溶液,在室温下搅拌混合物1小时。将溶液倒入饱和碳酸氢钠水溶液(5ml),之后用乙酸乙酯(20ml×2)萃取。盐水(30ml)冲洗有机层,无水硫酸镁干燥并浓缩。所得粗产物用硅胶柱色层法提纯,获得标题化合物(104mg)。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.18-2.24(m,28H),4.27(dd,J=9.2,4.3Hz,1H),4.35(ddt,J=1.9,1.9,6.6Hz,1H),8.56(bs,1H)。
IR(直接压片):3346,3160,3053,2921,2850,2229,1753,1724,1468,1329,1209,1164,1107,1046,889,774,739,722,671,610,546,465,428cm-1
实施例32
(R)-(Z)-5-(14-羟基十八-12-烯基)噻唑烷-2,4-二酮
(化合物编号68)
(1)向实施例31(1)获得的化合物(4.28g,9.31mmol)的MeOH(50ml)溶液中加入盐酸(0.5ml,3.0M)水溶液,在室温下搅拌混合物1小时。将该反应溶液倒入饱和碳酸氢钠水溶液(10ml),用乙酸乙酯(30ml×2)萃取。盐水(50ml)冲洗有机层,无水硫酸镁干燥并浓缩。所得粗产物用硅胶柱色层法提纯,获得(R)-18-溴十八-6-炔-5-醇(1.59g)。
1H-NMR(CDCl3,300MHz)δppm:0.92(t,J=7.1Hz,3H),1.21-1.57(m,20H),1.60-1.74(m,2H),1.80-1.92(m,2H),2.20(dt,J=2.0,7.0Hz,2H),3.41(t,J=6.9Hz,2H),4.30-4.40(m,1H)。
IR(直接压片):3368,2929,2855,2215,1672,1466,1384,1148,1039,723,646,564cm-1
(2)进行反应的方法大体上与实施例2(1)相同,只是用上述(1)获得的化合物,生成(R)-(Z)-18-溴十八-6-烯-5-醇。
1H-NMR(CDCl3,300MHz)δppm:0.91(t,J=6.9Hz,3H),1.20-1.68(m,22H),1.80-1.92(m,2H),1.99-2.15(m,2H),3.41(t,J=6.9Hz,2H),4.38-4.48(m,1H),5.32-5.42(m,1H),5.43-5.54(m,1H)。
IR(直接压片):3368,3005,2926,2854,1466,1378,1251,1008,723,646,564cm-1
(3)向上述(2)获得的化合物(500mg,1.38mmol)的DMF(25ml)溶液中加入叔丁基二甲基甲硅烷氯化物(230mg,1.52mmol)和咪唑(188mg,2.76mmol)。在室温下搅拌混合物过夜。将反应液倒入饱和碳酸氢钠水溶液(10ml)中,用乙酸乙酯(30ml×2)萃取。盐水(50ml)冲洗有机层,无水硫酸镁干燥并浓缩。所得粗产物用硅胶柱色层法提纯,获得(R)-(Z)-(14-溴-1-丁基十四-2-烯氧基)-叔丁基二甲基硅烷(650mg)。
1H-NMR(CDCl3,300MHz)δppm:0.02(s,3H),0.04(s,3H),0.81-0.94(m,12H),1.18-1.60(m,22H),1.71-1.82(m,2H),1.94-2.09(m,2H),3.53(t,J=6.8Hz,2H),4.33-4.43(m,1H),5.29-5.37(m,2H)。
IR(直接压片):2956,2928,2856,1464,1361,1253,1078,1006,939,836,775,723,668cm-1
(4)用上述(3)获得的化合物进行反应,方法与实施例31(2)相同,生成5-[(R)-(Z)-14-(叔丁基二甲基甲硅烷氧基)十八-12-烯基]噻唑烷-2,4-二酮。
1H-NMR(CDCl3,300MHz)δppm:0.02(s,3H),0.04(s,3H),0.89-0.96(m,12H),1.20-1.62(m,22H),1.84-2.08(m,4H),2.09-2.25(m,2H),4.28(dd,J=9.2,4.21Hz,1H),4.33-4.43(m,1H),5.24-5.37(m,2H),7.88(bs,1H)。
IR(直接压片):3216,3011,2927,2855,1758,1702,1464,1385,1361,1330,1253,1152,1006,939,836,775,669,605,536cm-1
(5)用上述(4)获得的化合物进行反应,方法与实施例31(3)相同,获得标题化合物。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.8Hz,3H),1.20-1.71(m,24H),1.84-2.24(m,4H),4.27(dd,J=9.0,4.2Hz,1H),4.38-4.48(m,1H),5.31-5.54(m,1H),5.43-5.54(m,1H),8.51(bs,1H)。
IR(直接压片):3348,3167,3060,2921,2850,1753,1753,1720,1656,1561,1542,1509,1468,1330,1212,1164,1054,739,671,610,546,466,438cm-1
实施例33
N-((R)-(Z)-16-羟基二十-14-烯酰基)-4-甲苯磺酰胺(化合物编号53)
(1)在0℃下,向实施例2获得化合物的(150mg,0.46mmol)的THF(5ml)溶液中加入N-羟基琥珀酰亚胺(159mg,1.38mmol)和1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(265mg,1.38mmol),在该温度下搅拌混合物2天。在反应溶液中加入水(50ml),用乙酸乙酯(50ml×2)萃取混合物。用盐水(100ml)冲洗有机层,无水硫酸镁干燥并浓缩,生成的粗产物用硅胶色层法提纯,获得(R)-(Z)-16-羟基二十-14-烯酸2,5-二氧代吡咯烷-1-基乙酯(163mg)。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.8Hz,3H),1.18-1.80(m,26H),2.02-2.15(m,2H),2.60(t,J=7.5Hz,2H),2.83(s,4H),4.38-4.48(m,1H),5.31-5.41(m,1H),5.43-5.53(m,1H)。
IR(KBr):3349,2923,2853,1827,1790,1728,1470,1407,1381,1211,1150,1072,996,869,814,722,655,582,553,420cm-1
(2)在上述(1)获得的化合物(70mg,0.165mmol)的THF(3ml)溶液中加入对甲苯磺酰胺(283mg,1.65mmol)和DBU(1,8-二氮杂二环[5.4.0]十一-7-烯)(0.027ml,0.182mmol)中,在室温下搅拌混合物过夜。将反应溶液倒入饱和氯化铵溶液(30ml)中,用乙酸乙酯(50ml×2)萃取。用盐水(50ml)冲洗有机层,无水硫酸镁干燥并浓缩,生成的粗产物用硅胶柱色层法提纯,获得标题化合物(36mg)。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.9Hz,3H),1.16-1.66(m,26H),2.00-2.14(m,2H),2.22(t,J=7.5Hz,2H),2.44(s,3H),4.38-4.48(m,1H),5.32-5.42(m,1H),5.44-5.54(m,1H),7.30-7.37(m,2H),7.90-8.00(m,3H)。
IR(KBr):3311,3008,2927,2852,1726,1598,1472,1427,1410,1387,1337,1305,1188,1174,1124,1085,1068,1022,1004,861,850,816,720,671,550cm-1
实施例34
(R)-(Z)-16-羟基二十-14-烯酸羟基酰胺(化合物编号55)
在温度0℃下,在给实施例2获得的化合物(80mg,0.245mmol)的Et2O(2ml)溶液中加入氯甲酸乙酯(28μL,0.294mmol)和N-甲基吗啉(35μL,0.319mmol)。在该温度下搅拌混合物30分钟后,过滤反应溶液,向滤出液中加入无盐羟胺(60mg),室温下搅拌生成的混合物30分钟并浓缩,获得的粗产物用硅胶柱色层法提纯,获得标题化合物(12mg)。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.8Hz,3H),1.15-1.75(m,26H),1.96-2.28(m,4H),4.38-4.48(m,1H),5.31-5.42(m,1H),5.44-5.54(m,1H)。
IR(直接压片):3255,2917,2848,2286,1656,1467,1384,1076,722,503cm-1
实施例35
(R)-(Z)-16-羟基二十-14-烯酸(2-羟基乙基)酰胺(化合物编号52)
在室温、氩气流下,向实施例2获得的化合物(300mg,0.92mmol)的CH2Cl2(10ml)溶液中加入草酰氯(1.01ml,2M CH2Cl2溶液,2.02mmol),搅拌混合物2小时。减压蒸馏反应液,将由此获得的螯合物溶于CH2Cl2(10ml)中,加入乙醇胺(0.45ml,7.36mmol),然后在室温下搅拌混合物2小时。向溶液中加入水,用Et2O(50ml×2)萃取。用盐水(50ml)冲洗有机层,无水硫酸镁干燥并浓缩,生成的粗产物用硅胶柱色层法提纯,获得标题化合物(132mg)。
1H-NMR(CDCl3,300MHz)δppm:0.90(t,J=6.9Hz,3H),1.21-1.72(m,26H),2.00-2.15(m,2H),2.21(t,J=7.7Hz,2H),3.39-3.47(m,2H),3.70-3.76(m,2H),4.37-4.38(m,1H),5.32-5.41(m,2H),5.43-5.54(m,1H),5.89(bs,1H)。
IR(KBr):3296,3089,3014,2920,2851,1642,1555,1464,1441,1379,1319,1280,1216,1181,1126,1060,1040,1004,876,730,688,610,540cm-1
测试实施例1
测试fMLP(N-甲酰-Met-Leu-Phe)刺激产生弹性蛋白酶
腹膜内注射1%无菌酪蛋白盐水溶液(120ml/kg)后15-18小时获取大鼠中性白细胞。在断头术后,用腹腔灌洗法获得细胞。灌洗溶液为冰冷PBS(磷酸缓冲盐溶液)。混合腹膜渗出溶液,离心分离后将其以1×107细胞/ml悬浮在HBSS(Hanks’Balanced Salt Solution)中。加入细胞松弛素B(最终浓度:5μg/ml)刺激细胞,将细胞加入孔培养板(190μl/孔),然后加入不同浓度(10-7-3×10-5)的本发明化合物,在37℃、5%的CO2中孵育10分钟后,加入fMLP(20μM,10μL),同时在没有加入fMLP的一组中加入含0.4%乙醇的HBSS溶液10μL。轻轻地搅拌后,再孵育细胞10分钟。在冰上中止反应,通过离心回收孵育后的上清液。
孵育上清液中的弹性蛋白酶活性鉴定
采用0.12mM特异性弹性蛋白酶底物N-琥珀酰-L-丙氨酰-L-丙氨酰-L-脯氨酸-缬氨酸-MCA(Peptide Institute,Inc.,Osaka)在50mMTris-HCl中(pH8.0)检测孵育的上清液中的弹性蛋白酶活性。加入50微升孵育上清液到底物溶液(50μL)中,在37℃时孵育30分钟。以激发波长360nm和发射波长480nm测得弹性蛋白酶活性。
弹性蛋白酶释放抑制活性(抑制率)根据以下公式计算:
抑制率(%)={1-(A-C)/(B-C)}×100
其中A代表加入fMLP(1μM)时的荧光强度;B代表加入fMLP(1μM)和本发明化合物时的荧光强度;C代表没有fMLP(1μM)时的荧光强度。
采用浓度抑制比曲线计算本发明化合物的50%抑制浓度(IC50值),结果见表1。
表1
受试化合物 | IC50值(μM) |
化合物12 | 9.18 |
化合物4 | 10.3 |
化合物50 | 8.29 |
化合物65 | 17.5 |
在上表中,化合物12、4、50和65对应于相应实施例化合物。上述结果表明本发明化合物具有抑制弹性蛋白酶产生的活性。
测试实施例2
化合物50对大鼠暂时性MCA闭塞(t-MCAo)模型梗塞体积的影响方法
用2%的氟烷麻醉成年雄性Wistar大鼠(200-250g),小心解剖右内颈动脉(ICA),在ICA下插入硅包被缝合线(18mm长),采用加热板保持体温在37℃。手术后,中止麻醉,大鼠局部缺血表现为上肢末端严重的偏瘫。在MCA闭塞1小时后,移除线使得局部缺血区域得到再灌注。小鼠接受1小时静脉内输注溶媒(10%的HP-β-CD)或再灌注后立即静脉内输注溶于溶媒的化合物50。
为了测定梗塞体积,在再灌注71小时后处死大鼠,用生理盐水经心脏灌注大脑,切除头颅骨,切成2-mm冠状切片,将切片浸入37℃、2%的氯化三苯基四唑盐(TTC)溶液中30分钟。
本发明所有值为平均值±SEM。为便于统计分析,使用了Dunnett’s multiple-range检验方法。
结果
化合物50对大鼠暂时性MCAo模型的梗塞体积的影响呈剂量依赖
性
溶于10%的HP-β-CD溶液的本发明化合物0.001、0.01和0.1mg/kg/min在再灌注后立即连续给药1小时,化合物在0.001mg/kg/min剂量时就降低梗塞体积,并且在0.01mg/kg/min的剂量时显著降低梗塞总体大小35.3%(与溶媒处理组相比)(图1)。该结果表明化合物50对局部缺血的脑损伤有保护作用。
工业应用性
本发明的羟基二十碳烯酸类似物具有强效的弹性蛋白酶释放抑制活性,因此可用作弹性蛋白酶释放抑制剂。
已知弹性蛋白酶与某些疾病的病理有关,例如:肺气肿、成人呼吸窘迫综合症、特发性肺纤维化、囊性肺纤维化、慢性间质性肺炎、慢性支气管炎、慢性窦肺性感染、弥漫性泛支气管炎、支气管扩张、哮喘、胰腺炎、肾炎、肝功能不全、慢性风湿病、关节硬化、骨关节炎、牛皮癣、牙周炎、动脉粥样硬化、器官移植排斥、早产儿羊膜破裂、水疱病、休克、脓毒症、系统性红斑狼疮、节段性回肠炎、播散性静脉内凝固、脑梗塞、心脏病、肾病时观测到的局部缺血血再灌注障碍、角膜组织瘢痕形成、脊椎炎等。
所以,本发明的弹性蛋白酶释放抑制剂可用作上述疾病治疗剂或预防剂。
现有技术文献列表
1.WO 01/34548
2.WO 01/34550
3.WO 01/34551
Claims (4)
1.一种下式(I)表示的羟基二十碳烯酸类似物或其药物学上可接受的盐或水合物:
其中化学键
代表顺式亚乙烯基或亚乙炔基;
Y代表CH2、O或S(O)p,其中p为0、1或2;
m代表包括1和4在内的整数1-4;
n代表包括0和3在内的整数0-3;
m和n之和为包括3和7在内的整数3-7;
R1代表C1-4烷基或C3-8环烷基;
R2代表氢原子或甲基;
R3代表COR4、腈基、卤素原子、四唑基或噻唑烷二酮基;
R4代表OR6、NHR6、N(OH)R6、NHSO2R5、丙三醇或官能化丙三醇;R5代表C1-15烷基、C6-10芳基或C7-14被以下基团取代的芳基:烷基、卤素或氨基;
R6代表氢原子、C1-10烷基或羟基取代的C1-10烷基。
2.权利要求1的式(I)羟基二十碳烯酸类似物,其中m和n之和为3、4或5,R1是C1-4烷基,R2是氢,R3是COR4、四唑基或噻唑烷二酮基,Y是CH2。
3.权利要求1的式(I)羟基二十碳烯酸类似物,其中所述化合物是(R)-16-羟基二十-14-炔酸、(R)-17-羟基二十一-15-炔酸、(R)-(Z)-16-羟基二十-14-烯酸或(R)-(Z)-15-羟基十九-13-烯酸。
4.一种弹性蛋白酶释放抑制组合物,其包含下式(I)表示的羟基二十碳烯酸类似物或其药物学上可接受的盐或水合物和药物学上可接受的载体:
Y代表CH2、O或S(O)p,其中p为0、1或2;
m代表包括1和4的整数1-4;
n代表包括0和3在内的整数0-3;
m和n之和为包括3和7在内的整数3-7;
R1代表C1-4烷基或C3-8环烷基;
R2代表氢原子或甲基;
R3代表COR4、腈基、卤素原子、四唑基或噻唑烷二酮基;
R4代表OR6、NHR6、N(OH)R6、NHSO2R5、丙三醇或官能化丙三醇;R5代表C1-15烷基、C6-10芳基或被以下基团取代的C7-14芳基:烷基、卤素或氨基;
R6代表氢、C1-10烷基或羟基取代的C1-10烷基。
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- 2002-09-09 CN CNA028221532A patent/CN1582269A/zh active Pending
- 2002-09-09 JP JP2003528770A patent/JP2005503412A/ja not_active Withdrawn
- 2002-09-09 EP EP02761383A patent/EP1425258A4/en not_active Withdrawn
- 2002-09-09 PL PL02366978A patent/PL366978A1/xx unknown
- 2002-09-09 PL PL02366980A patent/PL366980A1/xx unknown
- 2002-09-09 WO PCT/US2002/025970 patent/WO2003024922A1/en not_active Application Discontinuation
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2004
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- 2004-03-12 NO NO20041065A patent/NO20041065L/no unknown
Also Published As
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PL366980A1 (en) | 2005-02-07 |
MXPA04002336A (es) | 2005-10-05 |
MXPA04002390A (es) | 2004-11-22 |
KR20040047826A (ko) | 2004-06-05 |
CA2460263A1 (en) | 2003-03-27 |
EP1425258A2 (en) | 2004-06-09 |
NO20041065L (no) | 2004-06-14 |
WO2003024390A2 (en) | 2003-03-27 |
EP1436252A4 (en) | 2005-02-09 |
EP1436252A1 (en) | 2004-07-14 |
KR20040047829A (ko) | 2004-06-05 |
JP2005508317A (ja) | 2005-03-31 |
CA2460358A1 (en) | 2003-03-27 |
NO20041066L (no) | 2004-06-14 |
US20050038259A1 (en) | 2005-02-17 |
JP2005503412A (ja) | 2005-02-03 |
CN1585745A (zh) | 2005-02-23 |
WO2003024922A1 (en) | 2003-03-27 |
EP1425258A4 (en) | 2005-02-16 |
WO2003024390A3 (en) | 2004-01-22 |
PL366978A1 (en) | 2005-02-07 |
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