CN1649875A - 作为肿瘤坏死因子产生抑制剂的2-硫杂-二苯并薁及用于其制备的中间体 - Google Patents
作为肿瘤坏死因子产生抑制剂的2-硫杂-二苯并薁及用于其制备的中间体 Download PDFInfo
- Publication number
- CN1649875A CN1649875A CNA038094932A CN03809493A CN1649875A CN 1649875 A CN1649875 A CN 1649875A CN A038094932 A CNA038094932 A CN A038094932A CN 03809493 A CN03809493 A CN 03809493A CN 1649875 A CN1649875 A CN 1649875A
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- Prior art keywords
- alkyl
- dibenzo
- compound
- azulene
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000003112 inhibitor Substances 0.000 title claims description 8
- 239000000543 intermediate Substances 0.000 title abstract description 6
- ZOJHYZMNGGBPBV-UHFFFAOYSA-N 4-thiatetracyclo[12.4.0.02,6.08,13]octadeca-1(18),2,6,8,10,12,14,16-octaene Chemical class C1SC=C2C3=C(C4=C(C=C12)C=CC=C4)C=CC=C3 ZOJHYZMNGGBPBV-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000004519 manufacturing process Methods 0.000 title abstract 3
- 102000018594 Tumour necrosis factor Human genes 0.000 title description 2
- 108050007852 Tumour necrosis factor Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 101
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 239000012453 solvate Substances 0.000 claims abstract description 6
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 5
- -1 sulphinyl Chemical group 0.000 claims description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 11
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N methyl alcohol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 125000003435 aroyl group Chemical group 0.000 claims description 7
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- 125000006239 protecting group Chemical group 0.000 claims description 7
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- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 6
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 6
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
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- JMURFHVEGWDZAG-UHFFFAOYSA-N C(=O)OCC.C=1SC=C2C3=C(OC4=C(C12)C=CC=C4)C=CC=C3 Chemical compound C(=O)OCC.C=1SC=C2C3=C(OC4=C(C12)C=CC=C4)C=CC=C3 JMURFHVEGWDZAG-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
- 125000004494 ethyl ester group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 3
- HQFPRWNUTIWUBQ-UHFFFAOYSA-N 13-oxa-4-thiatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2,5,7,9,11,14,16-octaene Chemical compound O1C2=CC=CC=C2C2=CSC=C2C2=CC=CC=C12 HQFPRWNUTIWUBQ-UHFFFAOYSA-N 0.000 claims description 3
- ZRKMWZCUSSWZRH-UHFFFAOYSA-N 2,8-dithia-dibenzo[e,h]azulene Chemical compound S1C2=CC=CC=C2C2=CSC=C2C2=CC=CC=C12 ZRKMWZCUSSWZRH-UHFFFAOYSA-N 0.000 claims description 3
- SSKKEXIASNDAHS-UHFFFAOYSA-N 9-chloro-13-oxa-4-thiatetracyclo[12.4.0.02,6.07,12]octadeca-1(18),2,5,7(12),8,10,14,16-octaene Chemical compound O1C2=CC=CC=C2C2=CSC=C2C2=CC(Cl)=CC=C21 SSKKEXIASNDAHS-UHFFFAOYSA-N 0.000 claims description 3
- PEYUMWICYYIKGW-UHFFFAOYSA-N C(=O)OCC.C=1SC=C2C3=C(SC4=C(C12)C=CC=C4)C=CC=C3 Chemical compound C(=O)OCC.C=1SC=C2C3=C(SC4=C(C12)C=CC=C4)C=CC=C3 PEYUMWICYYIKGW-UHFFFAOYSA-N 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 3
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 239000011574 phosphorus Substances 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- RSPCKAHMRANGJZ-UHFFFAOYSA-N thiohydroxylamine Chemical compound SN RSPCKAHMRANGJZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- HKMMNIAKTVDNRY-UHFFFAOYSA-N 2,8-dithia-dibenzo[e,h]azulene-1-carbaldehyde Chemical compound S1C2=CC=CC=C2C2=CSC(C=O)=C2C2=CC=CC=C21 HKMMNIAKTVDNRY-UHFFFAOYSA-N 0.000 claims description 2
- BTPFNAIDNNKPGG-UHFFFAOYSA-N [2-(11-chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-ethyl]-dimethyl-amine Chemical compound O1C2=CC=CC=C2C2=CSC(COCCN(C)C)=C2C2=CC(Cl)=CC=C21 BTPFNAIDNNKPGG-UHFFFAOYSA-N 0.000 claims description 2
- FIPUYFYYUGAKNL-UHFFFAOYSA-N [2-(2,8-dithia-dibenzo[e,h]azulene-1-ylmethoxy)-ethyl]-dimethyl-amine Chemical compound S1C2=CC=CC=C2C2=CSC(COCCN(C)C)=C2C2=CC=CC=C21 FIPUYFYYUGAKNL-UHFFFAOYSA-N 0.000 claims description 2
- XLIZITKPNHJCPA-UHFFFAOYSA-N [2-(5-chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-ethyl]-dimethyl-amine Chemical compound O1C2=CC=C(Cl)C=C2C2=CSC(COCCN(C)C)=C2C2=CC=CC=C21 XLIZITKPNHJCPA-UHFFFAOYSA-N 0.000 claims description 2
- 235000010357 aspartame Nutrition 0.000 claims description 2
- RMCAUKPOUZTMOV-UHFFFAOYSA-N cyclohepta[d][1,3]thiazol-2-one Chemical compound C1=CC=CC=C2SC(=O)N=C21 RMCAUKPOUZTMOV-UHFFFAOYSA-N 0.000 claims description 2
- NHNBYPVXKPUXFU-UHFFFAOYSA-N dimethyl-[2-(8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-ethyl]-amine Chemical compound O1C2=CC=CC=C2C2=CSC(COCCN(C)C)=C2C2=CC=CC=C21 NHNBYPVXKPUXFU-UHFFFAOYSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 238000011200 topical administration Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 37
- 230000005764 inhibitory process Effects 0.000 abstract description 7
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- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- 239000000203 mixture Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 5
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- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 4
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
- C07D333/80—Seven-membered rings
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Abstract
本发明涉及2-硫杂-二苯并薁类化合物,它们的药理学上可接受的盐和溶剂化物,它们的制备方法和中间体以及它们的抗炎效果,特别是它们的肿瘤坏死因子-α(TNF-α)的产生抑制作用和白介素-1(IL-1)的产生抑制作用以及镇痛作用。
Description
技术领域
本发明涉及2-硫杂-二苯并薁类化合物,它们的药理学上可接受的盐和溶剂化物,它们的制备方法和中间体以及它们的抗炎效果,特别是它们的肿瘤坏死因子-α(TNF-α)的产生抑制作用和白介素-1(IL-1)的产生抑制作用以及镇痛作用。
现有技术
迄今,在文献中已经描述过在2位被甲基、甲基酮、硝基或羧基衍生物取代的1-硫杂-二苯并薁(Cagniant PG,C.R.Hebd.Sceances Acad.Sci.,1976,283:683-686)。已知某些1,3-二氮杂-二苯并薁衍生物及其盐是新的具有抗炎作用的化合物种类(US3,711,489、US 4,198,421和CA 967,573)。在2位具有烷氧基取代基的1-硫杂-二苯并薁衍生物(WO 01/878990)也具有强抗炎作用。不过根据我们的知识和可以得到的文献数据,迄今一般还不知道2-硫杂二苯并薁结构,因此也不知道由此结构衍生的衍生物或它们作为TNF-α分泌抑制剂和IL-1分泌抑制剂的抗炎作用和它们的镇痛作用。
1975年,TNF-α被定义为体外与体内由内毒素诱导并导致肿瘤坏死的内毒素诱导的血清因子(Carswell EA等人,Proc.Natl.Acad.Sci.U.S.A.,1975,72:3666-3670)。除了抗肿瘤活性以外,TNP-α还具有若干其他生物活性,它们在生物体内平衡以及病理生理学条件中都是重要的。TNF-α的主要来源是单核细胞-巨噬细胞、T-淋巴细胞和肥大细胞。
抗TNFa抗体(cAZ)在类风湿性关节炎(RA)患者的治疗中有效这一发现(Elliott M等人,Lancet(柳叶刀),1994,344:1105-1110)增强了人们找到新的TNF-α抑制剂作为可能的有效的RA药物的兴趣。类风湿性关节炎是以不可逆的关节病理改变为特征的自体免疫性慢性炎性疾病。除了RA以外,TNF-α拮抗剂还可应用于若干病理条件和疾病,例如脊椎炎、骨关节炎、痛风与其他关节炎症、脓毒病、脓毒性休克、中毒性休克综合征、特应性皮炎、接触性皮炎、牛皮癣、肾小球性肾炎、红斑狼疮、硬皮病、哮喘、恶病质、慢性阻塞性肺疾病、充血性心力衰竭、胰岛素抗性、肺纤维变性、多发性硬化、克罗恩氏病、溃疡性结肠炎、病毒感染和AIDS。
在TNF-α或其受体基因灭活的小鼠体内实验中得到了TNF-α的生物学重要性证据。这样的动物耐受胶原诱导的关节炎(Mori L等人,J.Immunol.,1996,157:3178-3182)和内毒素诱导的休克(PfefferK等人,Cell,1993,73:457-467)。在TNF-α水平增加的动物实验中,出现慢性炎性多关节炎(Georgopoulos S等人,J.Inflamm.,1996,46:86-97;Keffer J等人,EMBO J.,1991,10:4025-4031),这被TNF-α的产生抑制剂所减轻。这类炎性与病理条件的治疗通常包括非固醇类抗炎药物的应用,不过在严重情况下给以金盐、D-青霉胺或甲氨蝶呤。所述药物对症治疗不会终止病理过程。已经建立起类风湿性关节炎治疗中的新方法,例如基于替尼达鲁、来氟米特、环孢菌素、FK-506和中和TNF-α作用的生物分子。目前,市场上可以得到名为etanercept(Enbrel,Immunex/Wyeth)的可溶性TNF-α受体的融合蛋白和名为Infliximab(Remicade,Centocor)的小鼠与人嵌合单克隆抗体。除了RA疗法以外,etanercept和Infliximab也被证实用于克罗恩氏病的治疗(Exp.Opin.Invest.Drugs,2000,9:103)。
在RA疗法中,除了TNF-α分泌的抑制作用以外,抑制IL-1分泌也是重要的,因为IL-1代表细胞调节、免疫调节和病理生理条件,例如炎症中的重要细胞因子(Dinarello CA等人,Rev.Infect.Disease,1984,6:51)。已知IL-1的生物活性是:T细胞的活化、体温上升的诱导、前列腺素或胶原酶分泌的刺激、嗜中性白细胞的趋化性和血浆铁水平的降低(Dinarello CA,J.ClinicalImmunology,1985,5:287)。已知IL-1可以与两种受体结合:IL-1RI和IL-1RII。IL-1RI在细胞内传递信号,而IL-1RII存在于细胞表面,在细胞内不传递信号。由于IL1-RII与IL-1和IL1-RI都结合,固此它能够充当IL-1作用的负性调节剂。除了所提到的信号传递调节机理以外,细胞内存在另一种天然的IL-1受体桔抗剂(IL-1ra)。这种蛋白质与IL-1RI结合,但是不传递任何信号。它在信号传递抑制中的效力不大,因此它的浓度必须比IL-1高500倍,才能中断信号传递。临床上试验了重组人IL-1ra(Amgen)(Bresnihan B等人,Arthrit.Rheum.,1996,39:73),所得结果证明472名RA患者症状相对于安慰剂而言有所改善。这些结果说明IL-1活性抑制在疾病治疗中的重要性,例如RA,其中IL-1的产生被干扰了。由于存在TNF-α与IL-1的协同作用,2-硫杂-二苯并薁可以用于治疗与TNF-α和IL-1分泌增加有关的病症与疾病。
技术问题的解决方案
本发明涉及式I的2-硫杂-二苯并薁及其药理学上可接受的盐和溶剂化物:
其中
X可以是CH2或者杂原子如O、S、S(=O)、S(=O)2或NRa,其中Ra为氢或保护基;
Y和Z彼此独立地表示一个或多个相同或不同的与任何可用的碳原子连接的取代基,并可以是卤素、C1-C4烷基、C2-C4链烯基、C2-C4炔基、三氟甲基、卤代C1-C4烷基、羟基、C1-C4烷氧基、三氟甲氧基、C1-C4烷酰基、氨基、氨基-C1-C4烷基、C1-C4烷基氨基、N-(C1-C4-烷基)氨基、N,N-二(C1-C4-烷基)氨基、硫醇、C1-C4烷硫基、磺酰基、C1-C4烷基磺酰基、亚磺酰基、C1-C4烷基亚磺酰基、羧基、C1-C4烷氧基羰基、氰基、硝基;
R1可以是氢、卤素、任选取代的C1-C7烷基或C2-C7链烯基、C2-C7炔基、任选取代的芳基或杂芳基和杂环、羟基、羟基-C2-C7链烯基、羟基-C2-C7炔基、C1-C7烷氧基、硫醇、硫代C2-C7链烯基、硫代C2-C7炔基、C1-C7烷硫基、氨基、N-(C1-C7烷基)氨基、N,N-二(C1-C7烷基)氨基、C1-C7烷基氨基、氨基-C2-C7链烯基,氨基-C2-C7炔基、氨基-C1-C7烷氧基、C1-C7烷酰基、芳酰基、氧代C1-C7烷基、C1-C7烷酰氧基、羧基、任选取代的C1-C7烷氧基羰基或芳氧基羰基、氨基甲酰基、N-(C1-C7-烷基)氨基甲酰基、N,N-二(C1-C7-烷基)氨基甲酰基、氰基、氰基-C1-C7烷基、磺酰基、C1-C7烷基磺酰基、亚磺酰基、C1-C7烷基亚磺酰基、硝基或式II的取代基:
其中
R3和R4可以同时或彼此独立地为氢、C1-C4烷基、芳基或与N一起意指任选取代的杂环或杂芳基;
m和n代表0-3的整数;
Q1和Q2彼此独立地代表氧、硫或基团:
其中取代基
y1和y2可以彼此独立地为氢、卤素、任选取代的C1-C4烷基或芳基、羟基、C1-C4烷氧基、C1-C4烷酰基、硫醇、C1-C4烷硫基、磺酰基、C1-C4烷基磺酰基、亚磺酰基、C1-C4烷基亚磺酰基、氰基、硝基或者一起形成羰基或亚氨基;
R2可以为氢、羧基或烷氧基羰基。
术语“卤代”、“hal”或“卤素”指卤原子,它可以是氟、氯、溴或碘。
术语“烷基”意指烷烃,由此衍生出基团,它可以是直链或支链或环基团或者直链与环基团和支链与环基团的组合。例如,优选的直链或支链烷基为甲基、乙基、丙基、异丙基、丁基、仲丁基和叔丁基。优选的环烷基例如为环戊基或环己基。
术语“卤代烷基”指必须被至少一个卤原子取代的烷基。最常见的卤代烷基例如为氯甲基、二氯甲基、三氟甲基或1,2-二氯丙基。
术语“链烯基”指具有烃基团含义的链烯基,它可以是直链或支链或环基团,或者是直链与环基团或支链与环基团的组合,但它具有至少一个碳-碳双键。最常见的链烯基为乙烯基、丙烯基、丁烯基或环己烯基。
术语“炔基”指具有烃基团含义的炔基,它是直链或支链,并包含至少一个和至多二个碳-碳叁键。最常见的炔基例如为乙炔基、丙炔基或丁炔基。
术语“烷氧基”指直链或支链烷氧基。这些基团的实例为甲氧基、丙氧基、丙-2-氧基、丁氧基、丁-2-氧基或甲基丙-2-氧基。
术语“芳基”意指芳环基团如苯基和稠合芳环基团。芳基包含一个具有至少6个碳原子的环或者二个总共有10个碳原子并在碳原子之间有交替双(共振)键的环。最常用的芳基例如为苯基或萘基。一般地,芳基可以通过任何可用碳原子经直接的键或经C1-C4亚烷基如亚甲基或亚乙基连接到分子剩余部分。
术语“杂芳基”意指具有4-12个碳原子的单环或双环芳香和部分芳香基团,其中至少一个为杂原子如O、S或N,且可用氮原子或碳原子是所述基团与分子的剩余部分经直接的键或以上定义的C1-C4烷基结合的部位。此类的实例为噻吩基、吡咯基、咪唑基、吡啶基、噁唑基、噻唑基、吡唑基、四唑基、嘧啶基、吡嗪基、喹啉基或三嗪基。
术语“杂环”指5元或6元、完全饱和或部分不饱和的杂环基团,其包含至少一个杂原子如O、S或N,且可用氮原子或碳原子是所述基团与分子的剩余部分经直接的键或以上定义的C1-C4烷基结合的部位。最常见的实例为吗啉基、哌啶基、哌嗪基、吡咯烷基、吡嗪基或咪唑基。
术语“烷酰基”涉及直链酰基,例如甲酰基、乙酰基或丙酰基。
术语“芳酰基”指芳香酰基,例如苯甲酰基。
术语“任选取代的烷基”指可以任选附加地被一、二、三或更多个取代基取代的烷基。这些取代基可以是卤原子(优选氟或氯)、羟基、C1-C4烷氧基(优选甲氧基或乙氧基)、硫醇、C1-C4烷硫基(优选甲硫基或乙硫基),氨基、N-(C1-C4)烷基氨基(优选N-甲基氨基或N-乙基氨基),N,N-二(C1-C4-烷基)-氨基(优选二甲基氨基或二乙基氨基)、磺酰基、C1-C4烷基磺酰基(优选甲基磺酰基或乙基磺酰基)、亚磺酰基、C1-C4烷基亚磺酰基(优选甲基亚磺酰基)。
术语“任选取代的链烯基”指任选附加地被一、二或三个卤原子取代的链烯基。这些取代基可以例如是2-氯乙烯基、1,2-二氯乙烯基或2-溴-丙烯-1-基。
术语“任选取代的芳基、杂芳基或杂环”指任选附加地被一个或二个取代基取代的芳基、杂芳基或杂环基。取代基可以是卤素(优选氯或氟)、C1-C4烷基(优选甲基,乙基或异丙基)、氰基、硝基、羟基、C1-C4烷氧基(优选甲氧基或乙氧基)、硫醇、C1-C4烷硫基(优选甲硫基或乙硫基),氨基、N-(C1-C4)烷基氨基(优选N-甲基氨基或N-乙基氨基)、N,N-二(C1-C4-烷基)-氨基(优选N,N-二甲基氨基或N,N-二乙基氨基)、磺酰基、C1-C4烷基磺酰基(优选甲基磺酰基或乙基磺酰基)、亚磺酰基、C1-C4烷基亚磺酰基(优选甲基亚磺酰基)。
当X意指NRa而Ra意指保护基时,Ra指如下的基团:烷基(优选甲基或乙基)、烷酰基(优选乙酰基)、烷氧基羰基(优选甲氧基羰基或叔丁氧基羰基)、芳基甲氧基羰基(优选苄氧基羰基)、芳酰基(优选苯甲酰基)、芳基烷基(优选苄基)、烷基甲硅烷基(优选三甲基甲硅烷基)或烷基甲硅烷基烷氧基烷基(优选三甲基甲硅烷基乙氧基甲基)。
当R2和R3与N一起意指杂芳基或杂环时,它意指这些杂芳基或杂环具有至少一个被氮原子取代的碳原子,通过该原子所述基团与分子的剩余部分连接。这些基团的实例为吗啉-4-基、哌啶-1-基、吡咯烷-1-基、咪唑-1-基或哌嗪-1-基。
术语“药学上适宜的盐”指式I的化合物的盐,例如包括含C1-C4烷基卤(优选溴甲烷、氯甲烷)(季铵盐)的盐、含无机酸(盐酸、氢溴酸、磷酸、偏磷酸、硝酸或硫酸)的盐或者含有机酸(酒石酸、乙酸、柠檬酸、马来酸、乳酸、富马酸、苯甲酸、琥珀酸、甲磺酸或对甲苯磺酸)的盐。
某些式I的化合物可以与无机或有机酸或碱形成盐,这些也包括在本发明之内。
可以形成式I的化合物或其盐的溶剂化物(最常见的水合物)也是本发明的目的。
根据特定的取代基,式I的化合物可以具有几何异构体和一个或多个手性中心,因而可以存在旋光对映体或非对映异构体。本发明还涉及这种异构体及其混合物,包括外消旋体。
本发明还涉及式I的特定化合物的所有可能的互变异构形式。
本发明的其它目的涉及根据以下方法制备式I的化合物,所述方法包括:
a)对于式I的化合物,其中R1和R2彼此独立地代表羧基、C1-C6烷氧基羰基、芳氧基羰基或芳基烷氧基羰基,
用式IV的化合物将式III的α-二酮环化
b)对于式I的化合物,其中Q1意指-O-,
使式V的醇
与式VI的化合物反应
其中R5意指离去基团;
c)对于式I的化合物,其中Q1意指-O-、-NH-、-S-或-C≡C-,
使式Va的化合物与式VIa的化合物反应
其中L1意指离去基团
d)对于式I的化合物,其中Q1意指-O-、-NH-或-S-,
使式Vb的化合物
与式VI的化合物反应,其中R5意指离去基团;
e)对于式I的化合物,其中Q1意指-C=C-,使其中的Q1意指羰基的式Vb的化合物与磷内鎓盐反应。
制备方法:
a)式III的α-二酮和式IV的化合物(其中R1和R2同时或彼此独立地代表C1-C6-烷氧基羰基、芳氧基羰基或芳基烷氧基羰基)的环化是通过公开的制备类似化合物的方法(Chadwick DJ等人,J.Chem.Soc.Perkin Trans.I,1972,2079-81)来完成。环化反应在醇(最常见在叔丁醇中)中,在醇化物(优选叔丁醇钾)存在下完成。
此反应的原料化合物是已知的,或者可以由用于制备类似化合物的方法制备:例如对于式III的α-二酮,采用Leonard N.J.等人,J.Am.Chem.Soc.,1955,77:5078,US 3,711,489或LombardinoJ.G,J.杂cyclic Chem.,1974,11:17-21的方法;或者例如对于式IV的硫醚,采用Overberger C.G.等人,J.Am.Chem.Soc.,1950,72:4958-61的方法。可以将所得的化合物纯化、分离和表征,或者可以将其不经分离而进一步转化。
b)根据本发明方法的式I的化合物可以通过式V的醇与式VI的化合物反应制备,其中R5意指离去基团,它可以是卤原子(最常见溴、碘或氯)或磺酰氧基(最常见三氟甲基磺酰氧基或对甲苯磺酰氧基)。缩合反应可以根据公开的类似化合物的制备方法完成(Menozzi G等人,J.Heterocyclic Chem.,1997,34:963-968或WO 01/87890)。所述反应在20℃至100℃的温度下,在1-24小时内,在两相系统(优选含50%NaOH/甲苯),在相转移催化剂(优选苄基三乙基氯化铵,苄基三乙基溴化铵、鲸蜡基三溴甲烷)存在下完成。在处理反应混合物之后,通过重结晶法或硅胶柱色谱法分离形成的产物。
制备式V的醇的原料化合物为式I的化合物,其中R1和R2彼此独立地意指羧基或酯基(乙氧基羰基、甲氧基羰基),通过脱羧得到式I的化合物,其中R2意指氢,而R1意指酯基,通过将该化合物还原得到式V的醇。脱羧通过在250-300℃下,在金属,优选铜存在下进行热解来完成。还原反应通过使用金属氢化物如氢化锂铝或氢化钠来完成。而且,式V的醇可以通过水解对应的酯(在碱性或酸性介质中)来制备。
式VI的原料化合物是已知的,或者根据公开的制备类似化合物的方法制备。
c)式I的化合物可以根据本发明的方法,通过式Va的化合物(其中L1意指以上关于R5定义的离去基团)和式VIa的化合物(其中Q1意指氧、氮、硫或-C≡C-)反应来制备。最适宜的缩合反应是文献中公开的饱和碳原子上的亲核取代反应。
式Va的原料化合物(最常见卤化物)可以通过用常规卤化剂(例如氢溴酸、PBr3、SOCl2或PCl5),采用文献公开的方法将式V的醇卤化(例如溴化或氯化)得到。所得的化合物可以分离或不经分离而用作制备式I的化合物的适宜中间体。
式VIa的原料化合物是已知的,或者根据公开的制备类似化合物的方法制备。
d)式I的化合物(其中Q1意指杂原子-O-、-NH-或-S-)可以通过缩合式Vb的化合物和式VI的化合物来制备,其中R5意指以上定义的离去基团。反应可以在方法b)中公开的反应条件下或者在文献中公开的亲核取代反应条件下完成。原料醇、胺和硫醇可以通过水、胺或硫化氢与化合物Va根据文献公开的方法反应得到。
e)可以将结构V的醇氧化成对应的式Vb的化合物,其中Q1意指羰基,所述化合物可以进一步通过与对应的内鎓盐试剂反应导致延长链并形成如在HR专利申请20000310中公开的含有羰基或酯基的链烯基取代基。
除了上述反应之外,式I的化合物可以通过其它式I的化合物转化来制备。应该理解本发明还包括这些化合物和方法。官能团改变的特定实例是醛基团与所选择的磷内鎓盐反应导致延长链并形成如在HR专利申请20000310中公开的含有羰基或酯基的链烯基取代基。这些反应在溶剂如苯、甲苯或己烷中,在高温(最常见沸腾温度)下完成。
通过式Va的化合物与1-炔烃在碱性介质(例如在氨水中的酰胺钠)反应得到式I的化合物,其中Q1为-C≡C-。此方法的反应条件公开在文献中。在类似的反应条件(亲核取代)下,可以制备不同的醚、硫醚或胺衍生物。
通过诸如Vilsmeier酰化或n-BuLi和二甲基甲酰反应形成式I的化合物是另一个常规的转化实例。这些方法的反应条件在文献中是已知的。
通过水解具有腈、酰胺或酯基团的式I的化合物可以制备具有羧基的化合物,它是制备其它具有新的官能团的化合物如酯、酰胺、卤化物、醛、醇或胺的合适的中间体。
氧化或还原反应还可以改变式I的化合物的取代基。最常用的氧化剂是过氧化物(过氧化氢、间氯过苯甲酸或苯甲酰基过氧化物)或高锰酸盐、铬酸盐或高氯酸盐离子。因此,例如通过用吡啶基重铬酸盐或吡啶基氯铬酸盐氧化醇形成醛基团,可以通过进一步氧化将此基团转化成羧基。通过用在乙酸中的四乙酸铅或者用N-溴琥珀酰亚胺,使用催化量的苯甲酰氯将其中的R1意指烷基的式I的化合物氧化得到对应的羰基衍生物。
通过选择性氧化烷硫基可以制备烷基亚磺酰基或烷基磺酰基。
通过用硝基还原化合物可以制备氨基化合物。所述反应在常规催化氢化条件下完成或采用电化学法完成。通过使用担载在碳上的钯进行催化氢化可以将链烯基取代基转化成烷基酮或者将腈基转化成氨基烷基。
可以通过标准的取代反应或者常规的单独官能团的改变在式I的化合物中引入不同的芳香结构的取代基。这些反应的实例是取代基的芳香取代、烷基化、卤化、羟基化以及氧化或还原。
试剂和反应条件根据文献是已知的。因此,例如在浓硝酸和硫酸存在下通过芳香取代引入硝基。通过使用酰基卤或烷基卤可以引入酰基或烷基。反应在路易斯酸如三氯化铝或铁存在下,在弗瑞德-克来福特反应条件下完成。通过将硝基还原得到氨基,通过重氮化反应将氨基转化成适宜的起始基团,此基团可以用以下一种基团取代:H、CN、OH、Hal。
为了防止化学反应中不期望的相互作用,通常有必要保护某些基团,例如羟基、氨基、硫或羧基。为此目的,可以使用许多保护基[Green TW,Wuts PGH,Protective Groups in Organic Synthesis,John Wiley and Sons,1999],且它们的选择、使用和除去是化学合成中的常规方法。
氨基或烷基氨基的常规保护基是诸如以下的基团:烷酰基(乙酰基)、烷氧基羰基(甲氧基羰基、乙氧基羰基或叔丁氧基羰基);芳基甲氧基羰基(苄氧基羰基)、芳酰基(苯甲酰基)或烷基甲硅烷基(三甲基甲硅烷基或三甲基甲硅烷基乙氧基甲基)基团。除去保护基的条件取决于这种基团的选择和特性。因此,例如酰基如烷酰基、烷氧基羰基或芳酰基可以通过在碱(氢氧化钠或氢氧化钾)存在下水解除去,叔丁氧基羰基或烷基甲硅烷基(三甲基甲硅烷基)可以通过用适宜的酸(盐酸、硫酸、磷酸或三氟乙酸)处理除去,而芳基甲氧基羰基(苄氧基羰基)可以通过使用催化剂如担载在碳上的钯进行氢化来除去。
式I的化合物的盐可以通过已知的方法,例如使式I的化合物与对应的碱或酸在适宜的溶剂或溶剂混合物如醚(乙醚)或醇(乙醇、丙醇或异丙醇)存在下反应来制备。
本发明的另一目的涉及本发明的化合物在炎性疾病和症状,例如所有由TNF-α和IL-1的过度分泌诱导的疾病和症状的治疗中的应用。
作为本发明的目的细胞因子或炎症介质的产生抑制剂或其药理学上可接受的盐可以用于制备治疗和预防任何由细胞因子或炎症介质的过度未调节生产诱发的病理性症状或疾病的药物,所述药物应该包含有效剂量的该抑制剂。
本发明具体涉及TNF-α抑制剂的有效剂量,它可以通过常规方法测定。
而且,本发明涉及一种包含有效的无毒剂量的本发明的化合物和药学上可接受的载体或溶剂的药物组合物。
药物组合物的制备可以包括将成分混合、制粒、制片和溶解。化学载体可以是固体或液体。固体载体可以是乳糖、蔗糖、滑石、明胶、琼脂、果胶、硬脂酸镁、脂肪酸等。液体载体可以是糖浆、油如橄榄油、向日葵油或豆油、水等。类似地,载体还可以包含用于延时释放活性成分的组分,例如一硬脂酸甘油酯或二硬脂酸甘油酯。可以使用不同剂型的药物制剂。因此,如果使用固体载体,这些剂型可以是片剂、硬明胶胶囊、可以在胶囊中口服的粉末或颗粒。固体载体的数量可以变化,但大体上为25mg-1g。如果使用液体载体,则制剂的剂型为糖浆、乳剂、软明胶胶囊、无菌注射液如安瓿或非水液体悬浮液。
根据本发明的化合物可以进行口、肠胃外、局部、鼻内、直肠内和阴道内给药。这里的肠胃外途径表示静脉内、肌内和皮下应用。本发明的适宜制剂可以用于预防和治疗多种由细胞因子或炎症介质(主要为TNF-α)的过度未调节生产诱发的疾病和病理性炎症。它们包括类风湿性关节炎、类风湿性脊椎炎、骨关节炎与其它关节病症与疾病、湿疹、牛皮癣生其它皮肤炎症(例如由UV辐射(太阳照射和类似的UV光源)诱发的灼伤)、炎性眼疾病、克罗恩氏病、溃疡性结肠炎和哮喘。
通过下列体外和体内实验测定本发明化合物对TNF-α和IL-1分泌的抑制作用。
体外人外周血液单核细胞中TNF-α和IL-1分泌的测定
人外周血液单核细胞(PMBC)是在Ficoll-PaqueTMPlus(Amersham-Pharmacia)上分离PMBC后从肝素化全血制备的。为测定TNF-α水平,在微量滴定平底平板(96孔,Falcon)上,将3.5-5×104细胞在200μl PRMI1640培养基中培养18至24小时,向培养基中加入先前在54℃/30分钟条件下灭活的10%FBS(牛胎儿血清,Biowhittaker)、100单位/ml青霉素、100mg/ml链霉素和20mM HEPES(GIBCO)。在37℃下,在含5%CO2的大气中,在90%湿度下培养细胞。将阴性对照细胞仅在培养基(NC)中培养,而在阳性对照中加入1ng/ml脂多糖(LPS,大肠杆菌血清型0111:B4,SIGMA)(PC)刺激TNF-α的分泌。向用LPS刺激的细胞培养物加入供试物质后研究它们对TNF-α分泌的作用(TS)。按照厂商(R&D Systems)的建议,用ELISA法测定细胞上清液中的TNF-α水平。试验敏感度为<3pg/ml TNF-α。在相同的条件下。用相同数量的细胞和相同浓度的刺激物,通过ELISA法(R&D Systems)测定IL-1水平。通过下列方程计算TNF-α或IL-1产生的抑制百分率:
抑制%=[1-(TS-NC)/(PC-NC)]×100
IC50被定义为抑制50%TNF-α产生的物质浓度。
IC50为20μM或更低的化合物被视为活性的。
体外小鼠腹膜巨噬细胞分泌TNF-α和IL-1的测定
为了得到腹膜巨噬细胞,向8至12周龄的雄性Balb/C小鼠腹膜内注射300μg母多糖(SIGMA)的磷酸盐缓冲溶液(PBS),总体积为0.1ml/小鼠。24小时后,按照Laboratory Animals Welfare Act(实验室动物福利法案)使小鼠安乐死。腹腔用无菌盐水(5ml)洗涤。将所得腹膜巨噬细胞用无菌盐水洗涤两次,最后一次离心(350g/10分)后,将它们再次悬浮在RPMI1640中,向其中加入10%FBS部分。为了测定TNF-α分泌,在微量滴定平底平板(96孔,Falcon)上,将5×104细胞/孔在总体积为200μl的RPMI1640培养基中培养18至24小时,向培养基中加入热灭活的10%FBS(牛胎儿血清,Biowhittaker)、100单位/ml青霉素、100单位/ml链霉素、20mM HEPES和50μM2-巯基乙醇(均来自GIBCO)。在37℃下,在含5%CO2的大气中,在90%湿度下培养细胞。将阴性对照细胞仅在培养基(NC)中培养,而在阳性对照中加入10ng/ml脂多糖(LPS,大肠杆菌血清型0111:B4,SIGMA)(PC)刺激TNF-α的分泌。向用LPS刺激的细胞培养物加入供试物质后研究它们对TNF-α分泌的作用(TS)。用ELISA法(R&DSystems,Biosource)测定细胞上清液中的TNF-α水平。在与TNF-α试验相同的试验中用ELISA法(R&D Systems)测定IL-1水平。通过下列方程计算TNF-α或IL-1产生的抑制百分率:
抑制%=[1-(TS-NC)/(PC-NC)]×100
IC50被定义为抑制50%TNF-α产生的物质浓度。
IC50为10μM或更低的化合物被视为活性的。
LPS诱导的小鼠TNF-α或IL-1过度分泌的体内模型
按照前人所述方法诱导小鼠中的TNF-α或IL-1分泌(BadgerAM等人,J.Pharmac.Env.Therap.,1996,279:1453-1461)。试验使用8至12周龄的雄性Balb/c小鼠,每组6-10只动物。将动物仅用溶剂口服处理(阴性和阳性对照),或者用供试物溶液口服处理,30分钟后用LPS(大肠杆菌血清型0111:B4,Sigma)腹膜内处理,剂量为25μg/动物。2小时后,借助腹膜内注射Roumpun(Bayer)和Ketanest(Parke-Davis)使动物安乐死。在Vacutainer试管(BectonDickinson)内采集每只动物的血样,按照厂商的建议分离血浆。按照厂商教导用ELISA法(Biosource,R&D Systems)测定血浆中的TNF-α水平。试验敏感度为<3pg/ml TNF-α。用ELISA法测定IL-1水平(R&D Systems)。通过下列方程计算TNF-α或IL-1产生的抑制百分率:
抑制%=[1-(TS-NC)/(PC-NC)]×100
在10mg/kg剂量下抑制30%或更多TNF-α产生的化合物被视为活性的。
关于止痛活性的扭曲试验
本试验中,向小鼠腹腔注射刺激物,最常见为乙酸,诱发疼痛。动物反应为特征性扭曲,因此而得到试验名称(Collier HOJ等人,Pharmac.Chemother.,1968,32:295-310;Fukawa K等人,J.Pharmacol.Meth.,1980,4:251-259;Schweizer A等人,AgentsActions,1988,23:29-31)。本试验适合于测定化合物的止痛活性。方法:使用8至12周龄的雄性Balb/c小鼠(Charles River,Italy)。向对照组口服给予甲基纤维素,30分钟后腹膜内给予浓度0.6%的乙酸,而向试验组口服给予标准物质(乙酰水杨酸)或供试物质的甲基纤维素溶液。30分钟后腹膜内给予0.6%乙酸(体积0.1ml/10g)。将小鼠单独放置在玻璃漏斗下,在20分钟内记录每只动物扭曲的次数。按照下列方程计算扭曲的抑制百分率:
抑制%=(对照组扭曲的平均次数-试验组扭曲的次数)/对照组扭曲的次数×100
止痛活性等于或好于乙酰水杨酸的化合物被视为活性的。
LPS诱导小鼠休克的体内模型
使用8至12周龄的雄性Balb/C小鼠(Charles River,Italy)。在无菌盐水中稀释从粘质沙雷氏菌(Serratie marcessans)分离的LPS(Sigma,L-6136)。第一次LPS注射是真皮内给药的,剂量为4μg/小鼠。18至24小时后,静脉内给予LPS,剂量为200μg/小鼠。按上述方式向对照组给以两次LPS注射。在每次LPS给药之前半小时,向试验组口服给予供试物。观察24小时后的存活率。
在30mg/kg剂量下导致40%或更好存活率的化合物被视为活性的。
实施例14的化合物在至少两项研究试验中证明有活性。不过,这些结果仅供例示化合物的生物活性,决不以任何方式限制本发明。
制备方法和实施例
通过以下实施例例示本发明,这些实施例不是以任何方式限定本发明。
实施例1
8-氧杂-2-硫杂-二苯并[e,h]薁-1,3-二甲酸一乙酯(1)
将在叔丁醇中的二苯并[b,f]氧杂环庚烯(oxepin)-10,11-二酮(III;X=O,Y=Z=H)(0.004mole)和硫醚(IV;R5=Et)(0.008mole)的溶液加到在5ml叔丁醇(10ml)中的丁醇钾溶液(0.013mole),加热至60℃。在60℃下搅拌30分钟后,冷却反应混合物,并用5M HCl水溶液(10ml)酸化,然后在30℃的温度和30hPa的压力下蒸发大部分的溶剂。将乙醚(20ml)加到残余物,然后用2M NH4OH(10ml)萃取溶液。用稀HCl将合并的萃取物酸化至酸反应物,并得到褐色结晶形式的二羧酸酯。
实施例2
5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1,3-二甲酸1-甲酯(2)
5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1,3-二甲酸3-甲酯(3)
根据实施例1的方法,从2-氯-二苯并[b,f]氧杂环庚烯-10,11-二酮(III;X=O,Y=2-Cl,Z=H)和硫醚(IV;R5=Me)开始,得到褐色油形式的二羧酸酯的混合物。
实施例3
2,8-二硫杂-二苯并[e,h]薁-1,3-二甲酸一乙酯(4)
根据实施例1的方法,从二苯并[b,f]硫杂环庚烯(tiepin)-10,11-二酮(III;X=S,Y=Z=H)和硫醚(IV;R=Et)开始,得到褐色结晶形式的二羧酸酯。
实施例4
8-氧杂-2-硫杂-二苯并[e,h]薁-1-甲酸乙酯(5)
8-氧杂-2-硫杂-二苯并[e,h]薁(9)
将二羧酸酯1(200mg)和铜(150mg)的均匀混合物在30℃下加热2小时。冷却反应混合物后,向其中加入乙醚,并滤出不溶的氧化铜。减压蒸发滤液,并用柱色谱法分离产物混合物。分离结晶形式的化合物5和9。
实施例5
5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-甲酸甲酯(6)
11-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-甲酸甲酯(7)
5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁(10)
根据实施例4的方法,从二羧酸酯2和3的混合物开始,得到化合物10的二种一羧酸酯,6和7的混合物。用柱色谱法从一羧酸酯混合物中分离化合物10。分离羧酸酯6和7,并用GC-MS测定为二个接近的峰,且m/z=314(MH+)。
实施例6
2,8-二硫杂-二苯并[e,h]薁-1-甲酸乙酯(8)
2,8-二硫杂-二苯并[e,h]薁(11)
根据实施例4的方法,从二羧酸酯4开始制备化合物8和11。用柱色谱法分离化合物的混合物得到二种结晶形式的产物。
实施例7
1,3-二溴-2,8-二硫杂-二苯并[e,h]薁(12)
向冷却至0℃的化合物11的二氯甲烷溶液(0.38mmole,在2ml二氯甲烷中)逐滴加入溴(100μl)。在相同的温度下将反应混合物再搅拌45分钟。通过加入10%Na2S2O3水溶液(10ml)使过量的溴反应。用二氯甲烷萃取产物,减压蒸发溶剂后用柱色谱法纯化得到白色结晶形式的二溴衍生物。
实施例8
(8-氧杂-2-硫杂-二苯并[e,h]薁-1-基)-甲醇(13)
向在无水醚(10mmoles,在15ml无水醚中)中的LiALH4的悬浮液逐滴加入酯5(2mmoles,在15ml无水醚中)的醚溶液。将反应混合物于室温下搅拌4小时。在全部数量的酯已反应(反应过程用薄层色谱法跟踪)后,通过加入二乙醚和水分解过量的LiAIH4。滤出所得的白色沉淀,并在用无水Na2SO4干燥之后减压蒸发滤液。粗产物用柱色谱法纯化得到黄色结晶形式的纯产物。
实施例9
(5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基)-甲醇(14)
(11-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基)-甲醇(15)
根据实施例8的方法,从酯6和7的混合物开始制备标题化合物的混合物,用柱色谱法分离混合物得到黄色结晶形式的纯物质。
实施例10
(2,8-二硫杂-二苯并[e,h]薁-1-基)-甲醇(16)
根据实施例8的方法,从对应的酯8开始制备褐色结晶形式的醇。
表1
化合物 | X | Y | Z | R1 | R2 | 1H NMR(ppm) |
1 | O | H | H | CO2H | CO2Et | 1.33(t,3H);4.32(m,2H);7.14-7.19(m,2H);7.31-7.42(m,7.54-7.64(m, |
2H)(CDCl3) | ||||||
2 | O | 5-Cl | H | CO2H | CO2Me | |
3 | O | H | 11-Cl | CO2H | CO2Me | |
4 | S | H | H | CO2H | CO2Et | 1.15(t,3H);4.22(m,2H);7.29-7.40(m,4H);7.54-7.58(m,7.63-7.66(m,2H);13.5(bs,1H)(DMSO-d6) |
5 | O | H | H | H | CO2Et | 1.32(t,3H);4.33(m,2H);7.17-7.67(m,9H)(CDCl3) |
6 | O | 5-Cl | H | H | CO2Me | |
7 | O | H | 11-Cl | H | CO2Me | |
8 | S | H | H | H | CO2Et | 1.25(t,3H);4.26(m,2H);7.24-7.35(m,4H);7.50-7.54(m,2H);7.58(s,1H);7.62-7.67(m,2H)(CDCl3) |
9 | O | H | H | H | H | 7.24-7.30(m,2H);7.37-7.41(m,4H);7.66-7.69(m,2H);7.97(s,2H)(DMSO-d6) |
10 | O | 5-Cl | H | H | H | 7.19-7.58(m,9H)(CDCl3) |
11 | S | H | H | H | H | 7.25-7.37(m,4H);7.49(s,2H);7.53-7.57(m,2H);7.64-7.68(m,2H)(CDCl3) |
12 | S | H | H | Br | Br | 7.28-7.40(m,4H);7.61-7.68(m,4H)(CDCl3) |
13 | O | H | H | H | CHOH | 1.76(bs,1H);4.97(bd,2H);7.17-7.38(m,6H);7.46(s,1H);7.54-7.60(m,2H)(CDCl3) |
14 | O | 5-Cl | H | H | CH2OH | 4.88(bs,1H);4.93(s,2H);7.27-7.43(m,5H);7.67-7.70(m,2H);7.80(s,1H)(CD3COCD3) |
15 | O | H | 11-Cl | H | CH2OH | 4.93(bs,3H);7.23-7.29(m,1H);7.36-7.46(m,4H);7.65-7.68(m,1H);7.73(s,1H);7.82(d,1H)(CD3COCD3) |
16 | S | H | H | H | CHOH | 1.84(bs,1H);4.13(m,2H);7.23-7.38(m,4H);7.40(s,1H);7.48-7.50(m,2H);7.62-7.72(m,2H)(CDCl3) |
实施例11
a)二甲基-[3-(8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基]-胺
向在50%氢氧化钠(3ml)中的3-二甲基氨基丙基氯化物-盐酸盐溶液(2.5mmoles)加入苄基三乙基氯化铵(0.3mmole)和醇13(0.25mmole)的甲苯溶液。在剧烈搅拌下加热反应混合物并回流4小时。然后将其冷却至室温,用水稀释并用二氯甲烷萃取。用柱色谱法纯化后得到一种油产物。
1H NMR(ppm,CDCl3):2.08(m,2H);2.58(s,6H);2.84(m,2H);3.69(m,2H);4.75(bd,2H);7.16-7.36(m,6H),7.46(s,1H);7.47-7.56(m,2H)。
b)二甲基-[2-(8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-乙基]-胺
从醇13(0.25mmole)和2-二甲基氨基乙基氯化物-盐酸盐(2.5mmoles)开始,得到一种油产物。
1H NMR(ppm,CDCl3):2.52(s,6H);2.86(bs,2H);3.85(bs,2H);4.80(bd,2H);7.16-7.36(m,6H);7.46(s,1H);7.49-7.56(m,2H)。
c)3-(8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基胺
从醇13(0.25mmole)和3-氯丙基胺-盐酸盐(2.5mmoles)开始,得到一种油产物。
1H NMR(ppm,CDCl3):1.99(m,2H);3.05(t,2H);3.70(bs,2H);4.3-4.5(b,2H);4.72(bs,2H);7.15-7.60(m,9H)。
实施例12
a)3-(5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基胺
向在50%氢氧化钠(3ml)中的3-氯丙基胺-盐酸盐(2.2mmoles)的溶液加入苄基三乙基氯化铵(0.3mmole)和醇14(0.22mmole)的甲苯溶液。在剧烈搅拌下加热反应混合物并回流5小时。然后将其冷却至室温,用水稀释并用二氯甲烷萃取。用柱色谱法纯化后得到一种油产物。
MS(m/z):372(MH+)。
b)[2-(5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-乙基]-二甲基-胺
从醇14(0.29mmole)和2-二甲基氨基乙基氯化物-盐酸盐(2.9mmoles)开始,得到一种油产物。
MS(m/z):386(MH+)。
c)[3-(5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基]-二甲基-胺
从醇14(0.22mmole)和3-二甲基氨基丙基氯化物-盐酸盐(2.2mmoles)开始,得到一种油产物。
MS(m/z):400(MH+);
实施例13
a)[2-(11-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-乙基]-二甲基-胺
向在50%氢氧化钠(3ml)中的2-二甲基氨基乙基氯化物-盐酸盐(1.8mmoles)的溶液加入苄基三乙基氯化铵(0.3mmole)和醇15(0.18mmole)的甲苯溶液。在剧烈搅拌下加热反应混合物并回流5小时。然后将其冷却至室温,用水稀释并用二氯甲烷萃取。柱色谱法纯化后得到一种油产物。
MS(m/z):386(MH+)。
b)3-(11-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基胺
从醇15(0.18mmole)和3-氯丙基胺-盐酸盐(1.8mmoles)开始,得到一种油产物。
1H NMR(ppm,CD3COCD3):1.82(s,2H);1.97(t,2H);3.36(t,2H);3.76(bs,2H);4.74(s,2H);7.26-7.82(m,8H);
MS(m/z):372(MH+)。
实施例14
a)[3-(2,8-二硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基]-二甲基-胺
向在50%氢氧化钠(5ml)中的3-二甲基氨基丙基氯化物-盐酸盐(6.7mmoles)的溶液加入苄基三乙基氯化铵(0.88mmole)和醇16(0.67mmole)的甲苯溶液。在剧烈搅拌下加热反应混合物并回流5小时。然后将其冷却至室温,用水稀释并用二氯甲烷萃取。柱色谱法纯化后得到一种油产物。
1H NMR(ppm,CDCl3):2.04(p,2H);2.57(s,6H);2.82(bs,2H);3.61(m,2H);4.67(m,2H);7.27-7.71(m,8H);7.40(s,1H)。
b)[2-(2,8-二硫杂-二苯并[e,h]薁-1-基甲氧基)-乙基]-二甲基-胺
从醇16(0.67mmole)和2-二甲基氨基乙基氯化物-盐酸盐(6.7mmoles)开始,得到一种油产物;
1H NMR(ppm,CDCl3):2.49(s,6H);2.86(bs,2H);3.78(m,2H);4.72(m,2H);7.23-7.70(m,8H);7.40(s,1H)。
c) 3-(2,8-二硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基胺
从醇16(0.27mmole)和3-氯丙基胺-盐酸盐(2.7mmoles)开始,得到一种油产物。
MS(m/z):354(MH+)。
实施例15
2,8-二硫杂-二苯并[e,h]薁-1-甲醛
向醇16(3.0mmoles,在40ml中)的二氯甲烷溶液加入二吡啶-铬-(VI)-氧化物(吡啶基重铬酸盐,PDC,0.006mole)。将反应混合物于室温下搅拌18小时。将乙醚(50ml)加到反应混合物,用Florisil柱纯化如此稀释的反应混合物得到黄色结晶产物。
1H NMR(ppm,CDCl3):7.29-7.45(m,5H);7.53-7.56(m,1H);7.65-7.68(m,1H);7.72-7.75(m,1H);7.81(d,1H);9.84(s,1H)。
Claims (14)
1.一种式I的化合物及其药理学上可接受的盐和溶剂化物:
其特征在于
X可以是CH2或者杂原子如O、S、S(=O)、S(=O)2或NRa,其中Ra为氢或保护基;
Y和Z彼此独立地表示一个或多个相同或不同的与任何可用的碳原子连接的取代基,并可以是卤素、C1-C4烷基、C2-C4链烯基、C2-C4炔基、三氟甲基、卤代C1-C4烷基、羟基、C1-C4烷氧基、三氟甲氧基、C1-C4烷酰基、氨基、氨基-C1-C4烷基、C1-C4烷基氨基、N-(C1-C4-烷基)氨基、N,N-二(C1-C4-烷基)氨基、硫醇、C1-C4烷硫基、磺酰基、C1-C4烷基磺酰基、亚磺酰基、C1-C4烷基亚磺酰基、羧基、C1-C4烷氧基羰基、氰基、硝基;
R1可以是氢、卤素、任选取代的C1-C7烷基或C2-C7链烯基、C2-C7炔基、任选取代的芳基或杂芳基和杂环、羟基、羟基-C2-C7链烯基、羟基-C2-C7炔基、C1-C7烷氧基、硫醇、硫代C2-C7链烯基、硫代C2-C7炔基、C1-C7烷硫基、氨基、N-(C1-C7烷基)氨基、N,N-二(C1-C7烷基)氨基、C1-C7烷基氨基、氨基-C2-C7链烯基,氨基-C2-C7炔基、氨基-C1-C7烷氧基、C1-C7烷酰基、芳酰基、氧代C1-C7烷基、C1-C7烷酰氧基、羧基、任选取代的C1-C7烷氧基羰基或芳氧基羰基、氨基甲酰基、N-(C1-C7-烷基)氨基甲酰基、N,N-二(C1-C7-烷基)氨基甲酰基、氰基、氰基-C1-C7烷基、磺酰基、C1-C7烷基磺酰基、亚磺酰基、C1-C7烷基亚磺酰基、硝基或式II的取代基:
其中
R3和R4同时或可以彼此独立地为氢、C1-C4烷基、芳基或与N一起意指任选取代的杂环或杂芳基;
m和n代表0-3的整数;
Q1和Q2彼此独立地代表氧、硫或基团:
其中取代基
y1和y2可以彼此独立地为氢、卤素、任选取代的C1-C4烷基或芳基、羟基、C1-C4烷氧基、C1-C4烷酰基、硫醇、C1-C4烷硫基、磺酰基、C1-C4烷基磺酰基、亚磺酰基、C1-C4烷基亚磺酰基、氰基、硝基或者一起形成羰基或亚氨基;
R2可以为氢、羧基或烷氧基羰基。
2.根据权利要求1的化合物,其特征在于X代表S或O。
3.根据权利要求2的化合物,其特征在于Y和/或Z代表H或Cl。
4.根据权利要求3的化合物和盐,其特征在于R1和/或R2代表H、Br、COOH、COOMe、COOEt。
5.根据权利要求3的化合物,其特征在于R1代表H,而R2代表COOMe、COOEt、CHO、CH2OH。
6.根据权利要求3的化合物和盐,其特征在于R1代表H,而R2具有式II的含义。
7.根据权利要求6的化合物和盐,其特征在于m意指1,符号n意指1或2,Q1代表O,而Q2代表CH2。
8.根据权利要求7的化合物和盐,其特征在于R3和R4代表H或Me。
9.根据权利要求4所选择的化合物:
8-氧杂-2-硫杂-二苯并[e,h]薁;
2,8-二硫杂-二苯并[e,h]薁;
5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁;
1,3-二溴-2,8-二硫杂-二苯并[e,h]薁;
8-氧杂-2-硫杂-二苯并[e,h]薁-1,3-二甲酸一乙酯;
5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1,3-二甲酸1-甲酯;
5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1,3-二甲酸3-甲酯;
2,8-二硫杂-二苯并[e,h]薁-1,3-二甲酸一乙酯。
10.根据权利要求5所选择的化合物:
8-氧杂-2-硫杂-二苯并[e,h]薁-1-甲酸乙酯;
5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-甲酸甲酯;
11-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-甲酸甲酯;
2,8-二硫杂-二苯并[e,h]薁-1-甲酸乙酯;
2,8-二硫杂-二苯并[e,h]薁-1-甲醛;
(8-氧杂-2-硫杂-二苯并[e,h]薁-1-基)-甲醇;
(5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基)-甲醇;
(11-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基)-甲醇;
(2,8-二硫杂-二苯并[e,h]薁-1-基)-甲醇。
11.根据权利要求8所选择的化合物:
二甲基-[3-(8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基]-胺;
二甲基-[2-(8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-乙基]-胺;
3-(8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基胺;
3-(5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基胺;
[2-(5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-乙基]-二甲基-胺;
[3-(5-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基]-二甲基-胺;
[2-(11-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-乙基]-二甲基-胺;
3-(11-氯-8-氧杂-2-硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基胺;
[3-(2,8-二硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基]-二甲基-胺;
[2-(2,8-二硫杂-二苯并[e,h]薁-1-基甲氧基)-乙基]-二甲基-胺;
3-(2,8-二硫杂-二苯并[e,h]薁-1-基甲氧基)-丙基胺。
12.一种式I的化合物及其药理学上可接受的盐和溶剂化物的制备方法:
其中
X可以是CH2或者杂原子如O、S、S(=O)、S(=O)2或NRa,其中Ra为氢或保护基;
Y和Z彼此独立地表示一个或多个相同或不同的与任何可用的碳原子连接的取代基,并可以是卤素、C1-C4烷基、C2-C4链烯基、C2-C4炔基、三氟甲基、卤代C1-C4烷基、羟基、C1-C4烷氧基、三氟甲氧基、C1-C4烷酰基、氨基、氨基-C1-C4烷基、C1-C4烷基氨基、N-(C1-C4-烷基)氨基、N,N-二(C1-C4-烷基)氨基、硫醇、C1-C4烷硫基、磺酰基、C1-C4烷基磺酰基、亚磺酰基、C1-C4烷基亚磺酰基、羧基、C1-C4烷氧基羰基、氰基、硝基;
R1可以是氢、卤素、任选取代的C1-C7烷基或C2-C7链烯基、C2-C7炔基、任选取代的芳基或杂芳基和杂环、羟基、羟基-C2-C7链烯基、羟基-C2-C7炔基、C1-C7烷氧基、硫醇、硫代C2-C7链烯基、硫代C2-C7炔基、C1-C7烷硫基、氨基、N-(C1-C7烷基)氨基、N,N-二(C1-C7烷基)氨基、C1-C7烷基氨基、氨基-C2-C7链烯基,氨基-C2-C7炔基、氨基-C1-C7烷氧基、C1-C7烷酰基、芳酰基、氧代C1-C7烷基、C1-C7烷酰氧基、羧基、任选取代的C1-C7烷氧基羰基或芳氧基羰基、氨基甲酰基、N-(C1-C7-烷基)氨基甲酰基、N,N-二(C1-C7-烷基)氨基甲酰基、氰基、氰基-C1-C7烷基、磺酰基、C1-C7烷基磺酰基、亚磺酰基、C1-C7烷基亚磺酰基、硝基或式II的取代基:
其中
R3和R4同时或可以彼此独立地为氢、C1-C4烷基、芳基或与N一起意指任选取代的杂环或杂芳基;
m和n代表0-3的整数;
Q1和Q2彼此独立地代表氧、硫或基团:
其中取代基
y1和y2可以彼此独立地为氢、卤素、任选取代的C1-C4烷基或芳基、羟基、C1-C4烷氧基、C1-C4烷酰基、硫醇、C1-C4烷硫基、磺酰基、C1-C4烷基磺酰基、亚磺酰基、C1-C4烷基亚磺酰基、氰基、硝基或者一起形成羰基或亚氨基;
R2可以为氢、羧基或烷氧基羰基,
其特征在于所述制备方法包括:
a)对于式I的化合物,其中R1和R2彼此独立地代表羧基、C1-C6烷氧基羰基、芳氧基羰基或芳基烷氧基羰基,
用式IV的化合物将式III的α-二酮环化
b)对于式I的化合物,其中Q1意指-O-,使式V的醇
与式VI的化合物反应
其中R5意指离去基团;
c)对于式I的化合物,其中Q1意指-O-、-NH-、-S-或-C≡C-,使式Va的化合物与式VIa的化合物反应
其中L1意指离去基团
d)对于式I的化合物,其中Q1意指-O-、-NH-或-S-,使式Vb的化合物
与式VI的化合物反应,其中R5意指离去基团;
e)对于式I的化合物,其中Q1意指-C=C-,使其中的Q1意指羰基的式Vb的化合物与磷内鎓盐反应。
13.根据权利要求4和5的式I的化合物用作制备具有抗炎作用的新的2-硫杂-二苯并薁类化合物的中间体的用途。
14.根据权利要求6的式I的化合物作为细胞因子或炎症介质的产生抑制剂,用于通过口、肠胃外或局部给予无毒剂量的适宜的药物制剂来治疗和预防任何由细胞因子或炎症介质的过度未调节生产诱导的病理症状或疾病的用途。
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HRP20020305A8 (en) | 2002-04-10 | 2009-03-31 | GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. | 2-thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof |
HRP20020304B1 (en) * | 2002-04-10 | 2008-04-30 | GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. | 1-oxa-3-aza-dibenzoazulenes as inhibitors of tumor necrosis factor production and intermediates for the production thereof |
HRP20020452A2 (en) * | 2002-05-23 | 2004-02-29 | Pliva D D | 1,2-diaza-dibenzoazulen as inhibitor of production of tumor necrosis factors and intermediates for preparation thereof |
HRP20030885A2 (en) * | 2003-11-03 | 2005-08-31 | Pliva-Istra�iva�ki institut d.o.o. | USE OF 2-THIA-DIBENZO[e,h]AZULENES FOR THE MANUFACTURE OF PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT AND PREVENTION OF CENTRAL NERVOUS SYYTEM DISEASES AND DISORDERS |
HRP20030956A2 (en) * | 2003-11-21 | 2005-08-31 | Pliva-Istra�iva�ki institut d.o.o. | USE OF 1,2-DIAZA-DIBENZO[e,h]AZULENES FOR THE MANU |
JP2009521454A (ja) * | 2005-12-20 | 2009-06-04 | プレジデント・アンド・フエローズ・オブ・ハーバード・カレツジ | 化合物、スクリーニング、および処置方法 |
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US3711489A (en) | 1971-03-31 | 1973-01-16 | Pfizer | Certain 8,9-dihydro(3,4,7,8)cycloocta(1,2-d)imidazoles |
CA967573A (en) | 1972-12-22 | 1975-05-13 | Joseph G. Lombardino | Tetracyclic anti-inflammatory agents |
NL7605526A (nl) | 1976-05-24 | 1977-11-28 | Akzo Nv | Nieuwe tetracyclische derivaten. |
US4198421A (en) | 1978-11-30 | 1980-04-15 | E. I. Du Pont De Nemours And Company | Antiinflammatory 2-substituted-dibenzo[2,3:6,7]oxepino[4,5-d]imidazoles |
FR2504140A1 (fr) | 1981-04-16 | 1982-10-22 | Centre Nat Rech Scient | Nouveaux derives tetracycliques de la dibenzazepine, leur procede de preparation et les compositions pharmaceutiques en renfermant |
FI841399A (fi) | 1983-04-12 | 1984-10-13 | Ciba Geigy Ag | Polycykliska karboxylsyrafoereningar, foerfarande foer deras framstaellning och dessa karboxylsyrafoereningar innehaollande preparat samt deras anvaendning. |
IE62754B1 (en) | 1988-08-26 | 1995-02-22 | Akzo Nv | Tetracyclic antidepressants |
IT1227527B (it) | 1988-12-05 | 1991-04-12 | Ciatti Maurizio | Spazzolino da denti a setole rotanti |
ATE199088T1 (de) | 1994-11-02 | 2001-02-15 | Janssen Pharmaceutica Nv | Substituierte tetracyclische oxazepine- und thiazepinederivate mit 5-ht2 rezeptoraffinität |
US5552399A (en) | 1994-11-02 | 1996-09-03 | Janssen Pharmaceutica N.V. | Substituted tetracyclic azepine derivatives |
EE03612B1 (et) | 1996-04-12 | 2002-02-15 | Janssen Pharmaceutica N.V. | Asendatud tetratsüklilised tetrahüdrofuraanderivaadid |
UA52778C2 (uk) | 1997-10-10 | 2003-01-15 | Янссен Фармацевтика Н.В. | Галогенозаміщені тетрациклічні похідні тетрагідрофурану, спосіб їх отримання та композиція на їх основі |
HRP20000310A2 (en) * | 2000-05-17 | 2002-02-28 | Pliva Farmaceutska Ind Dioniko | New dibenzoazulene compounds as tumor necrosis factor inhibitors |
HRP20020305A8 (en) | 2002-04-10 | 2009-03-31 | GlaxoSmithKline istra�iva�ki centar Zagreb d.o.o. | 2-thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof |
HRP20030957A2 (en) | 2003-11-21 | 2005-08-31 | Pliva-Istra�iva�ki institut d.o.o. | USE OF 1-THIA-3-AZA-DIBENZO[e,h]AZULENES FOR THE MANUFACTURE OF PHARMACEUTICAL FORMULATIONS FOR THE TREATMENT AND PREVENTION OF CENTRAL NERVOUS SYSTEM DISEASES AND DISORDERS |
HRP20040104A2 (en) | 2004-01-30 | 2005-10-31 | Pliva-Istra�iva�ki institut d.o.o. | Use of benzonaphthoazulenes for the manufacture of pharmaceutical formulations for the treatment and prevention of central nervous system diseases and disorders |
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IL164396A0 (en) | 2005-12-18 |
DE60304048T2 (de) | 2006-10-19 |
ATE320433T1 (de) | 2006-04-15 |
MXPA04009943A (es) | 2005-09-30 |
US7435834B2 (en) | 2008-10-14 |
IS7474A (is) | 2004-09-27 |
JP2005526828A (ja) | 2005-09-08 |
EP1509530B1 (en) | 2006-03-15 |
RU2334749C2 (ru) | 2008-09-27 |
DK1509530T3 (da) | 2006-07-17 |
CA2481514A1 (en) | 2003-10-16 |
DE60304048D1 (de) | 2006-05-11 |
ZA200408063B (en) | 2006-07-26 |
NZ535620A (en) | 2006-03-31 |
PT1509530E (pt) | 2006-07-31 |
RU2004132868A (ru) | 2005-06-10 |
AU2003259963A1 (en) | 2003-10-20 |
EP1509530A1 (en) | 2005-03-02 |
BR0309094A (pt) | 2005-02-09 |
US20050182126A1 (en) | 2005-08-18 |
SI1509530T1 (sl) | 2006-08-31 |
NO20044506L (no) | 2004-11-09 |
HRP20020305A2 (en) | 2003-10-31 |
UA79277C2 (en) | 2007-06-11 |
CY1105036T1 (el) | 2010-03-03 |
ES2260637T3 (es) | 2006-11-01 |
WO2003084962A1 (en) | 2003-10-16 |
HRP20020305A8 (en) | 2009-03-31 |
PL372748A1 (en) | 2005-08-08 |
YU88304A (sh) | 2006-08-17 |
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