CN1146415C - 取代的3,5-二苯基-1,2,4-三唑及其作为药用金属螯合剂的用途 - Google Patents
取代的3,5-二苯基-1,2,4-三唑及其作为药用金属螯合剂的用途 Download PDFInfo
- Publication number
- CN1146415C CN1146415C CNB971958319A CN97195831A CN1146415C CN 1146415 C CN1146415 C CN 1146415C CN B971958319 A CNB971958319 A CN B971958319A CN 97195831 A CN97195831 A CN 97195831A CN 1146415 C CN1146415 C CN 1146415C
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- Prior art keywords
- alkyl group
- low alkyl
- hydroxyphenyl
- low
- amino
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- 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.)
- Expired - Lifetime
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- 229910052751 metal Inorganic materials 0.000 title claims description 15
- 239000002184 metal Substances 0.000 title claims description 15
- KPKQWXGFEKRQQA-UHFFFAOYSA-N 3,5-diphenyl-1h-1,2,4-triazole Chemical class C1=CC=CC=C1C1=NNC(C=2C=CC=CC=2)=N1 KPKQWXGFEKRQQA-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000002738 chelating agent Substances 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims abstract description 22
- 241001465754 Metazoa Species 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 244
- 150000003839 salts Chemical class 0.000 claims description 73
- -1 nitro, carboxyl Chemical group 0.000 claims description 56
- 229910052739 hydrogen Inorganic materials 0.000 claims description 54
- 239000001257 hydrogen Substances 0.000 claims description 54
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 45
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 42
- 238000000034 method Methods 0.000 claims description 38
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 35
- 125000003545 alkoxy group Chemical group 0.000 claims description 34
- 150000002367 halogens Chemical class 0.000 claims description 34
- 229910052757 nitrogen Inorganic materials 0.000 claims description 32
- 125000003282 alkyl amino group Chemical group 0.000 claims description 30
- 150000002431 hydrogen Chemical class 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 24
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 12
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 12
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 12
- 239000005711 Benzoic acid Substances 0.000 claims description 11
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
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- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 150000001450 anions Chemical class 0.000 claims description 3
- MFSUKOCGNJOMDD-UHFFFAOYSA-N n-ethoxyacetamide Chemical class CCONC(C)=O MFSUKOCGNJOMDD-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 claims 1
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- 206010065973 Iron Overload Diseases 0.000 abstract 1
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- 238000003810 ethyl acetate extraction Methods 0.000 description 24
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 24
- 235000011152 sodium sulphate Nutrition 0.000 description 24
- 239000002585 base Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
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- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 14
- 150000003973 alkyl amines Chemical class 0.000 description 13
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 239000008101 lactose Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229920002261 Corn starch Polymers 0.000 description 7
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- 150000002825 nitriles Chemical class 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
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- 235000012222 talc Nutrition 0.000 description 7
- 229910052623 talc Inorganic materials 0.000 description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
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- 125000003435 aroyl group Chemical group 0.000 description 5
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 5
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
公开了式I的3,5-二苯基-1,2,4-三唑的用途,其中R1-R5定义见说明书。该化合物具有有用的药学性质,特别是具有铁螯合剂活性。它们可用于治疗温血动物体内的铁过载。
Description
大量温血动物的病症与机体组织中存在过量的金属有关,特别是三价金属。例如透析脑病与骨软化症、以及阿尔茨海默病中的铝。在其他疾病中,特别是人,过量的铁存在于多种组织中。这被叫作铁过载(以前称之为含铁血黄素沉积症)。例如可见于铁的胃肠外给药(尤其是反复输血)以后或来自胃肠道的铁摄取量增加以后。反复输血法对严重的贫血来说是必要的,尤其是重型地中海贫血,这是β-地中海贫血的严重形式,以及其他贫血症。来自胃肠道的铁吸收量增加既可以首先发生,例如由于基因缺陷(所谓的血色素沉着),也可以其次发生,例如在贫血以后,输血法对该贫血来说不是必要的,例如中度地中海贫血,这是β-地中海贫血的缓和形式。
铁过载如果不进行治疗,会导致严重的器官损伤,特别是肝、心和内分泌器官,并可引起死亡。铁螯合剂能够动员和排泄沉积在器官中的铁,从而降低与铁有关的发病率和死亡率。
铁(III)浓度的降低对由铁(III)依赖的微生物与寄生虫所引起的病症的治疗也有重要意义,不仅在人类医学、例如特别是疟疾,而且在兽医学中都具有至关重要的意义。与其他金属、特别是三价金属配合,也能用于将其从机体中排泄出去。文献中也描述了许多进一步的应用,例如G.Kontoghiorghes,《毒理学快报》80,1-18(1995)。
去铁胺B是早已为人所知的用于这些目的的治疗药物(H.Bickel,H.Keberle和E.Vischer,《瑞士化学学报》46,1385-9(1963))。不过该制剂的一个缺点却是去铁胺及其盐口服给药仅具有低而不足的活性,因此在所有上述应用的可能性中需要一种胃肠外给药剂型。例如作为特别有效的方法,建议将活性物质通过缓慢(8至12小时)皮下输注的方式进行给药,不过该方法需要使用一种便携式机械装置,例如电动驱动的注射器。除了笨拙以外,该方案治疗成本高,严重限制了其用途;特别是不可能实现地中海地区国家、中东国家、印度与东南亚的地中海贫血、世界范围的疟疾和非洲国家的镰状细胞性贫血的综合治疗.而且这些广泛流传的疾病严重威胁着这些国家的卫生事业,因此寻找一种更为简单和更为廉价的疗法,优选以口服活性制剂的方式,是本领域的迫切目标。
大量3,5-二苯基-1,2,4-三唑早已为人所知,其用途被描述为除草剂、例如EP 0185401,作为血管紧张素II受体拮抗剂、见EP 0480659,或非常普遍地作为精细化学品的中间体与原料化合物,例如见JP06345728。
现已发现,某些取代的3,5-二苯基-1,2,4-三唑在用于治疗导致人或动物机体中金属过量的病症或由金属过量导致的病症时,具有重要的药理学性质,主要是显著地与三价金属离子结合,特别是其中的铁(A.E.Martell和R.J.Motekaitis,“稳定常数的测定和使用”,纽约VCH出版公司1992)。例如在使用非铁过载的cholodocostomized大鼠的动物模型中(R.J.Bergeron等《医药化学杂志》34,2072-2078(1991))或铁过载的猴的动物模型中(R.J.Bergeron等《血液》81,2166-2173(1993)),在剂量约为5μmol/kg时,它们能够防止含铁色素的沉积,在机体中已有铁沉积的情况下,可促使铁排泄。
本发明涉及式I化合物及其盐的用途,
其中
R1与R5彼此同时或独立为氢、卤素、羟基、低级烷基、卤代-低级烷基、低级烷氧基、卤代-低级烷氧基、羧基、氨基甲酰基、N-低级烷基氨基甲酰基、N,N-二-低级烷基氨基甲酰基或腈;R2与R4彼此同时或独立为氢、未取代或取代的低级链烷酰基或芳酰基、或一种在生理条件下可被除去的基团;R3为氢、低级烷基、羟基-低级烷基、卤代-低级烷基、羧基-低级烷基、低级烷氧基羰基-低级烷基、R6R7N-C(O)-低级烷基、未取代或取代的芳基或芳基-低级烷基、或未取代或取代的杂芳基或杂芳烷基;R6与R7彼此同时或独立为氢、低级烷基、羟基-低级烷基、烷氧基-低级烷基、羟基烷氧基-低级烷基、氨基-低级烷基、N-低级烷基氨基-低级烷基、N,N-二-低级烷基氨基-低级烷基、N-(羟基-低级烷基)氨基-低级烷基、N,N-二(羟基-低级烷基)氨基-低级烷基、或与它们所结合的氮原子共同构成一个氮杂脂环;
所述用途是治疗导致人或动物机体中金属过量的疾病或由金属过量导致的疾病;优选为以药学上可接受的剂型,特别是在用于人体治疗的方法中;还涉及该类型的治疗方法。
卤素例如是氯、溴或氟,不过也可以是碘。
前缀“低级”指的是具有不超过7个碳原子、特别是不超过4个碳原子的基团。
烷基是直链或支链的。本身例如低级烷基,或作为其他基团的成分,例如低级烷氧基、低级烷基胺、低级链烷酰基、低级烷基氨基羰基,它可以是未取代的,或例如被卤素、羟基、低级烷氧基、三氟甲基、环-低级烷基、氮杂脂环基或苯基取代,优选为未取代的或被羟基取代。
低级烷基例如为正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、新戊基、正己基或正庚基,优选为甲基、乙基和正丙基。卤代-低级烷基是被卤素,优选氯或氟取代的低级烷基,特别是被至多三个氯原子或氟原子取代。
低级烷氧基例如为正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、正戊氧基、异戊氧基,优选为甲氧基和乙氧基。卤代-低级烷氧基是被卤素,优选氯或氟取代的低级烷氧基,特别是被至多三个氯原子或氟原子取代。
氨基甲酰基是H2N-C(O)-基团,N-低级烷基氨基甲酰基是低级烷基-HN-C(O)-,N,N-二-低级烷基氨基甲酰基是二-低级烷基-N-C(O)-。
低级链烷酰基是HC(O)-和低级烷基-C(O)-,例如乙酰基、丙酰基、丁酰基或新戊酰基。
低级烷氧基羰基指的是低级烷基-O-C(O)-基团,例如正丙氧基羰基、异丙氧基羰基、正丁氧基羰基、异丁氧基羰基、仲丁氧基羰基、叔丁氧基羰基、正戊氧基羰基、异戊氧基羰基,优选为甲氧基羰基和乙氧基羰基。
芳基例如芳基本身,或作为芳基-低级烷基或芳酰基等其他基团的成分,例如为苯基或萘基,是取代的或未取代的。芳基优选为苯基,该苯基是未取代的或被一或多个、特别是一或两个取代基取代,例如低级烷基、低级烷氧基、羟基、硝基、氨基、卤素、三氟甲基、羧基、低级烷氧基羰基、氨基、N-低级烷基氨基、N,N-二-低级烷基氨基、氨基羰基、低级烷基氨基羰基、二-低级烷基氨基羰基、杂环烷基、杂芳基或氰基。芳基主要为未取代的苯基或萘基,或被低级烷基、低级烷氧基、羟基、卤素、羧基、低级烷氧基羰基、N,N-二-低级烷基氨基或杂环烷基羰基取代的苯基。
芳酰基是芳基-C(O)-基团,例如苯甲酰基、甲苯甲酰基、萘甲酰基或对甲氧基苯甲酰基。
芳基-低级烷基例如苯甲基、对氯苯甲基、邻氟苯甲基、苯乙基、对甲苯甲基、对二甲氨基苯甲基、对二乙氨基苯甲基、对氰基苯甲基、对吡咯烷代(pyrrolidino)苯甲基。
杂环烷基指的是具有3至8个环原子、特别是具有5至不超过7个环原子的环烷基,至少一个环原子是杂原子;氧、氮和硫是优选的。氮杂脂环基是具有3-8个环原子、特别是5-7个环原子的饱和环烷基,其中至少一个环原子是氮原子。氮杂脂环基也可进一步含有环杂原子,例如氧、氮或硫;例如哌啶基、哌嗪基、吗啉基或吡咯烷基。氮杂脂环基可以是未取代的或被卤素或低级烷基取代。优选的通过一个环氮原子结合的氮杂脂环基已知被叫作哌啶子基、哌嗪代(piperazino)、吗啉代、吡咯烷代等。
杂芳基例如杂芳基本身,或作为杂芳基-低级烷基等其他取代基的成分,是具有3至不超过7个环原子、特别是5至不超过7个环原子的芳族基团,其中至少一个环原子为杂原子,例如吡咯基、咪唑基、三唑基、四唑基、噁唑基、噻唑基、呋喃基、噻吩基、吡啶基、吡嗪基、噁嗪基、噻嗪基、吡喃基或嘧啶基。杂芳基可以是取代的或未取代的。优选的杂芳基是未取代的,或被一或多个、特别是一或两个取代基取代,例如低级烷基、卤素、三氟甲基、羧基或低级烷氧基羰基。
杂芳基-低级烷基指的是一种低级烷基,其中至少一个优选位于末端C原子上的氢原子被一个杂芳基置换,如果烷基链含有两个或更多碳原子的话。
N-低级烷基氨基例如正丙氨基、正丁氨基、异丙氨基、异丁氨基、羟基乙氨基,优选为甲氨基和乙氨基。在N,N-二-低级烷基氨基中,烷基取代基可以相同或不同。因此N,N-二-低级烷基氨基例如N,N-二甲氨基、N,N-二乙氨基、N,N-甲乙氨基、N-甲基-N-吗啉代乙氨基、N-甲基-N-羟基乙氨基、N-甲基-N-苯甲氨基。
式I化合物的盐特别是药学上可接受的盐,尤其是与碱所形成的盐,诸如适当的碱金属或碱土金属盐,例如钠盐、钾盐或镁盐;药学上可接受的过渡金属盐,诸如锌盐;或与有机胺所形成的盐,诸如环状胺,诸如单-、二-或三-低级烷基胺,诸如羟基-低级烷基胺,例如单-、二-或三羟基-低级烷基胺、羟基-低级烷基-低级烷基胺或多羟基-低级烷基胺。环状胺例如为吗啉、硫代吗啉、哌啶或吡咯烷。适当的单-低级烷基胺例如为乙胺和叔丁胺;二-低级烷基胺例如为二乙胺和二异丙胺;三-低级烷基胺例如为三甲胺和三乙胺。适当的羟基-低级烷基胺例如为单-、二-与三乙醇胺;羟基-低级烷基-低级烷基胺例如为N,N-二甲氨基乙醇和N,N-二乙氨基乙醇;适当的多羟基-低级烷基胺例如葡糖胺。在其他情况下,也有可能生成酸加成盐,例如与强的无机酸,诸如矿物酸,例如硫酸、磷酸或氢卤酸;与强的有机羧酸,诸如低级链烷羧酸,例如乙酸,诸如饱和或不饱和的二元羧酸,例如丙二酸、马来酸或富马酸,或诸如羟基羧酸,例如酒石酸或柠檬酸;或与磺酸,诸如低级链烷磺酸或取代或未取代的苯磺酸,例如甲磺酸或对甲苯磺酸。具有一个酸性基团(例如羧基)和一个碱性基团(例如氨基)的式I化合物也可以以内盐的形式存在,也就是两性离子的形式,或者分子的一部分以内盐的形式存在,另一部分以正常盐的形式存在。
本发明特别涉及式I化合物的用途,用于治疗导致人或动物机体中金属过量的疾病或由金属过量导致的疾病,优选为以药学上可接受的剂型,特别是在用于人体治疗的方法中,还涉及该类型的治疗方法。
此外,本发明涉及新颖的制剂,该制剂含有至少一种式I化合物及其盐,其中
R1与R5彼此同时或独立为氢、卤素、羟基、低级烷基、卤代-低级烷基、低级烷氧基、卤代-低级烷氧基、羧基、氨基甲酰基、N-低级烷基氨基甲酰基、N,N-二-低级烷基氨基甲酰基或腈;R2与R4彼此同时或独立为氢、未取代或取代的低级链烷酰基或芳酰基、或一种在生理条件下可被除去的基团;R3为氢、低级烷基、羟基-低级烷基、卤代-低级烷基、羧基-低级烷基、低级烷氧基羰基-低级烷基、R6R7N-C(O)-低级烷基、未取代或取代的芳基、被N-低级烷基氨基、N,N-二-低级烷基氨基或吡咯烷代取代的芳基-低级烷基、或未取代或取代的杂芳基或杂芳烷基;R6与R7彼此同时或独立为氢、低级烷基、羟基-低级烷基、烷氧基-低级烷基、羟基烷氧基-低级烷基、氨基-低级烷基、N-低级烷基氨基-低级烷基、N,N-二-低级烷基氨基-低级烷基、N-(羟基-低级烷基)氨基-低级烷基、N,N-二(羟基-低级烷基)氨基-低级烷基、或与它们所结合的氮原子共同构成一个氮杂脂环;
和至少一种药学上可接受的载体;还涉及该制剂的制备方法。这些药物制剂是针对温血动物、尤其是人的肠内给药制剂,特别是口服给药,进一步为直肠给药,以及胃肠外给药制剂,其中所含有的药理活性成分是独立的或与常规药物助剂结合。药物制剂例如含有(以重量百分比计)大约0.001%至100%、优选为约0.1%至约100%的活性成分。
肠内或胃肠外给药的药物制剂例如为单位剂量形式,诸如糖衣片、片剂、可分散片剂、泡腾片、胶囊、可悬浮药粉、悬浮液或栓剂、或安瓿。它们按照本身为已知的方法制备,例如通过常规的平底锅包衣、混合、造粒或冷冻干燥的方法。于是,通过使活性成分与固体载体混合,如果需要的话将所得混合物造粒,如果需要或必要的话,加入适当的助剂后加工该混合物或颗粒,得到片剂或糖衣片的片芯,可以制得口服给药的药物制剂。
适当的载体特别是填充剂,诸如糖类,例如乳糖、蔗糖、甘露糖醇或山梨糖醇,纤维素制剂和/或磷酸钙,例如磷酸三钙或磷酸氢钙;还有粘合剂,诸如淀粉糊,例如使用玉米淀粉、小麦淀粉、稻米淀粉或马铃薯淀粉的淀粉糊,明胶,黄蓍胶,甲基纤维素和/或聚乙烯吡咯烷酮;如果需要的话,还有崩解剂,诸如上述的淀粉,还有羧甲基淀粉,交联聚乙烯吡咯烷酮,琼脂或藻酸或其盐、诸如藻酸钠。助剂主要为流动调节剂和润滑剂,例如水杨酸,滑石,硬脂酸或其盐、诸如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。糖衣片芯涂以适当的包衣,如果需要的话为肠衣,包衣尤其用浓缩的糖溶液制得,该溶液如果需要的话含有阿拉伯胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛,包衣溶液使用适当的有机溶剂或溶剂混合物,或者在肠衣的制备中为适当的纤维素制剂的溶液,诸如乙酰纤维素邻苯二甲酸酯或羟丙甲基纤维素邻苯二甲酸酯。例如为了识别或标记活性成分的不同剂量,可以向片剂或糖衣片包衣中加入着色剂或颜料。
可分散片剂是在较少量的液体、如水中迅速崩解的片剂,如果需要的话,其中可含有矫味剂或掩蔽活性成分味道的物质。将它们用于较大个体剂量的口服给药是很方便的,其中所要给药的活性成分的量多到药片在给药后被完整地吞下或未经咀嚼,特别是对儿童来说,不再能被便利地吸收。进一步的可口服给药的药剂是硬明胶胶囊以及包封了明胶和一种增塑剂如甘油或山梨糖醇的软胶囊。硬明胶胶囊可含有颗粒形式的活性成分,例如其与乳糖等填充剂,淀粉等粘合剂,和/或滑石或硬脂酸镁等助流剂(glidant),以及稳定剂(如果需要的话)的混合物。在软胶囊中,活性成分优选是溶于或悬浮于适当的液体中的,例如脂肪油、液体石蜡或液体聚乙二醇,加入稳定剂也是可以的。
而且,可悬浮药粉也是适用于口服的剂型,例如被称为“瓶装药粉”、简记为“PIB”,或即饮悬浮液。对这种剂型来说,活性成分例如与药学上可接受的月桂基硫酸钠或多乙氧基醚等表面活性剂、羟丙基纤维素、羟丙甲基纤维素或另一种在先技术已知和以前被描述过的(例如《药物赋型剂手册》)助悬剂、柠檬酸或酒石酸及其盐等pH调节剂或一种USP缓冲剂混合,如果需要的话再与乳糖等填充剂以及进一步的助剂混合,分装在适当的容器中,单剂量瓶或安瓿较为方便。临使用前加入一定量的水,振摇制得悬浮液。另外也可在分装之前加入水。
可直肠给药的药剂例如为栓剂,由活性成分与一种栓剂基质的组合组成。适当的栓剂基质例如为天然或合成的甘油三酯、石蜡族烃、聚乙二醇或高级链烷醇。也可使用直肠用明胶胶囊,其中含有活性成分与一种基质物质的组合。可能的基质物质例如为液态甘油三酯、聚乙二醇或石蜡族烃。
对胃肠外给药来说,首先,水溶性形式的活性成分、例如水溶性盐的水溶液是适用的;进一步地,可用活性成分的悬浮液,例如适当的油性注射悬浮液、适当的亲脂性溶剂或赋型剂、如芝麻油等脂肪油或者油酸乙酯或甘油三酯等合成的脂肪酸酯,或者可用含水注射悬浮液,其中含有提高粘度的物质,例如羧甲基纤维素钠、山梨糖醇和/或葡聚糖,如果需要的话还含有稳定剂。
活性成分的剂量取决于多种因素,例如活性成分的活性与作用持续时间、所治疗疾病或其症状的严重程度、给药方式、温血动物的种类、性别、年龄、体重和/或温血动物的个体条件。在口服给药的情况下,每日给药的剂量在10与大约120mg/kg之间,特别是在20与大约80mg/kg之间,对一个体重大约40kg的温血动物来说,优选在大约400mg与大约4800mg之间,特别是大约800mg至3200mg,最好将该每日剂量分成2至12次个体剂量。
优选地,本发明涉及新颖的制剂,该制剂含有至少一种式I化合物及其盐,其中
R1与R5彼此同时或独立为氢、卤素、羟基、低级烷基、卤代-低级烷基、低级烷氧基或卤代-低级烷氧基;R2与R4彼此同时或独立为氢或一种在生理条件下可被除去的基团;R3为低级烷基、羟基-低级烷基、羧基-低级烷基、低级烷氧基羰基-低级烷基、R6R7N-C(O)-低级烷基、取代的芳基、被N-低级烷基氨基、N,N-二-低级烷基氨基或吡咯烷代取代的芳基-低级烷基、或未取代或取代的杂芳基或杂芳烷基;R6与R7彼此同时或独立为氢、低级烷基、羟基-低级烷基、烷氧基-低级烷基、羟基烷氧基-低级烷基、氨基-低级烷基、N-低级烷基氨基-低级烷基、N,N-二-低级烷基氨基-低级烷基、N-(羟基-低级烷基)氨基-低级烷基、N,N-二(羟基-低级烷基)氨基-低级烷基、或与它们所结合的氮原子共同构成一个氮杂脂环;
和至少一种药学上可接受的载体,还涉及该制剂的制备方法。这些药物制剂是针对温血动物、尤其是人的肠内给药制剂,特别是口服给药,进一步为直肠给药,以及胃肠外给药制剂,其中所含有的药理活性成分是独立的或与常规药物助剂结合。药物制剂例如含有(以重量百分比计)大约0.001%至100%、优选为约0.1%至约50%的活性成分。
本发明也制得有用的新颖的通式II化合物及其盐
其中
R1与R5彼此同时或独立为氢、卤素、低级烷基、卤代-低级烷基、低级烷氧基、卤代-低级烷氧基、羧基、氨基甲酰基、N-低级烷基氨基甲酰基、N,N-二-低级烷基氨基甲酰基或腈;R2与R1彼此同时或独立为氢、未取代或取代的低级链烷酰基或芳酰基、或一种在生理条件下可被除去的基团;R3为R6R7N-C(O)-低级烷基、未取代或取代的芳基、被N-低级烷基氨基、N,N-二-低级烷基氨基或吡咯烷代取代的芳基-低级烷基、或未取代或取代的杂芳基或杂芳烷基,其条件是若R2与R4是氢,且R1与R5是氢、卤素、低级烷基、卤代-低级烷基、低级烷氧基或腈,则R3不是苯基或被卤素、硝基、腈、羟基、低级烷基、卤代-低级烷基、低级烷氧基或低级烷氧基羰基取代的苯基;R6与R7彼此同时或独立为氢、低级烷基、羟基-低级烷基、烷氧基-低级烷基、羟基烷氧基-低级烷基、氨基-低级烷基、N-低级烷基氨基-低级烷基、N,N-二-低级烷基氨基-低级烷基、N-(羟基-低级烷基)氨基-低级烷基、N,N-二(羟基-低级烷基)氨基-低级烷基、或与它们所结合的氮原子共同构成一个氮杂脂环。
本发明主要涉及式II化合物及其盐,其中
R1与R5彼此同时或独立为氢、卤素、低级烷基、卤代-低级烷基、低级烷氧基或卤代-低级烷氧基;R2与R4彼此同时或独立为氢或一种在生理条件下可被除去的基团;R3为R6R7N-C(O)-低级烷基、取代的芳基、被N-低级烷基氨基、N,N-二-低级烷基氨基或吡咯烷代取代的芳基-低级烷基、或未取代或取代的杂芳烷基,其条件是若R2与R4是氢,且R1与R5是氢、卤素、低级烷基、卤代-低级烷基或低级烷氧基,则R3不是被卤素、硝基、腈、羟基、低级烷基、卤代-低级烷基、低级烷氧基或低级烷氧基羰基取代的苯基;R6与R7彼此同时或独立为氢、低级烷基、羟基-低级烷基、烷氧基-低级烷基、羟基烷氧基-低级烷基、氨基-低级烷基、N-低级烷基氨基-低级烷基、N,N-二-低级烷基氨基-低级烷基、N-(羟基-低级烷基)氨基-低级烷基、N,N-二(羟基-低级烷基)氨基-低级烷基、或与它们所结合的氮原子共同构成一个氮杂脂环。
本发明特别是要涉及式II化合物及其药学上可接受的盐,其中R1与R5彼此同时或独立为氢、卤素或低级烷基;R2与R4为氢;R3为R6R7N-C(O)-低级烷基、被羧基或R8R9N-C(O)-取代的芳基、被N-低级烷基氨基、N,N-二-低级烷基氨基或吡咯烷代取代的芳基-低级烷基、或未取代或取代的杂芳烷基;R6与R7彼此同时或独立为氢、低级烷基、羟基-低级烷基、烷氧基-低级烷基、羟基烷氧基-低级烷基、氨基-低级烷基、N-低级烷基氨基-低级烷基、N,N-二-低级烷基氨基-低级烷基、N-(羟基-低级烷基)氨基-低级烷基、N,N-二(羟基-低级烷基)氨基-低级烷基、或与它们所结合的氮原子共同构成一个氮杂脂环;R8与R9彼此同时或独立为氢或低级烷基,或与它们所结合的氮原子共同构成一个氮杂脂环。
本发明尤其涉及如实施例所述的具体的式II化合物及其盐,特别是其药学上可接受的盐。
这些化合物可按照本身已知的方法进行制备,例如,
a)使一种式III化合物
其中R1、R2、R4和R5定义同上,X-是一种阴离子,
与一种式IV化合物或其盐反应
R3-NH-NH2 (IV)
其中R3定义同上;或者
b)使一种式V化合物或其盐
其中R1、R4和R5定义同上,
与一种式IV化合物或其盐反应,其中R3定义同上;或者
c)使一种式VI化合物
其中R1、R2、R4和R5定义同上,
与一种式IV化合物或其盐反应,其中R3定义同上;
然后如果必要的话,通过除去保护基团使该化合物转化为一种式II化合物,如果需要的话,再转化为另一种式II化合物,和/或如果需要的话,使所得的盐转化为游离化合物或另一种盐,和/或如果需要的话,使所得游离的且具有成盐性质的式II化合物转化为盐。
在该方法的下列详细说明中,除非另有声明,符号R1-R5定义同式II、III、IV、V和VI。
方法(a):按照方法(a)的反应相当于1,2,4-二噻唑烷与肼进行的环重排反应,得到本身为已知的1,2,4-三唑(Wagner,G.等《药物(Pharmazie)》35,48-49(1980))。X-可以是任意所需的阴离子,优选为卤素阴离子,特别是溴阴离子。有无溶剂的存在均能进行反应,不过更为有利的是反应在一种极性溶剂或混合溶剂中进行,在这种情况下,化合物IV是可以作为本身或一种溶剂化物存在的,特别是作为一种水合物。反应可在冷却、室温或高达反应混合物回流温度的高温条件下进行。反应优选在室温或高温下进行。
方法(b):按照方法(b)的反应相当于苯并噁嗪酮与肼的反应,该反应本身是已知的(Wagner,G.等《化学杂志》21,261(1981)和Ryabukhin,Y.等《Khim.Geterotsiklicheskikh Soed.》1983(3),406-410)。反应在一种极性溶剂或混合溶剂中进行,优选在一种低级链烷醇中进行,特别是甲醇或乙醇,如果需要的话加入一种碱,例如一种叔胺,特别是三低级烷基胺,如果化合物III和/或IV是作为一种盐存在的话,例如作为一种氢卤酸盐。反应可在冷却、室温或高达反应混合物回流温度的高温条件下进行。在一个特别优选的实施方式中,反应是在乙醇中回流的条件下进行的。
原料化合物V是可以得到的,例如在亚硫酰氯的存在下,借助于适当取代的水杨酸与适当取代的水杨酰胺的反应(Brunetti,H.等CH388252和Brunetti,H.与Lüthi,C.《瑞士化学学报》55,1566(1972))。此外,将适当取代的水杨酰氯与适当取代的水杨酰胺的混合物加热,也能制得原料化合物V。
方法(c):方法(c)相当于二酰胺与肼的反应,该反应本身是已知的(Einhorn,A.等《李比希化学记事》343,229(1905),Brunner,K.《德国化学协会报告(Ber.dtsch.chem.Ges.)》47,2671(1914)和《化学月刊》36,509(1915))。反应发生的条件为极性、质子溶剂,弱酸催化、优选在含水乙酸中,和高温条件。
式II化合物也可以按照其它方法进行制备,这些方法本身是已知的,例如按照Temple,C.《杂环化合物化学》37卷,John Wiley &Sons,纽约1981所述的方法。
保护基团、它们的引入和除去例如描述在J.F.W.McOmie《有机化学中的保护基团》,Plenum出版社,伦敦,纽约1973,和《有机化学的方法》,Houben-Weyl,第4版,1571卷,Georg-Thieme-Verlag,Stuttgart 1974,还有Theodora W.Greene《有机合成中的保护基团》,John Wiley & Sons,纽约1981。保护基团的特征在于它们能被容易地除去,也就是说不会发生所不需要的副反应,例如溶剂化反应、还原反应、光解反应或在生理条件下的反应。
羟基例如可以以易于裂解的酯或醚基的形式存在,优选为链烷酰或芳烷酰酯基,或者环杂烷基、芳烷基或烷氧基烷基醚基,不过也可以是甲硅烷基酯或甲硅烷基醚基,特别是乙酰基或苯甲酰基酯,或者四氢吡喃基、苯甲基或甲氧基甲基醚。
式III、IV、V和VI的原料在某些情况下是新颖的,同样是本发明的主题。如果必要的话,按照已知方法可以引入适当的保护基团,或者进行进一步的衍生作用。
由于不是所需最终的式II产物的成分,保护基团用本身已知的方法除去,例如通过溶剂分解作用,特别是水解、醇解或酸解,或者通过还原反应,任选逐步或同时。
式II化合物也可以转化为其他式II或式I化合物。
因此,例如可能将一种其中R3为芳基羧酸酯基团的式II化合物水解为对应的芳基羧酸,所得的式II化合物中R3为羧酸基团。该反应例如在一种环状醚与一种链烷醇的极性混合溶剂中进行,溶剂中加入了一种碱金属氢氧化物。
若式I原料化合物或任意的中间体中含有干扰性反应基团,例如羧基、羟基或氨基,可以用容易除去的保护基团临时将它们保护起来。
为了加工可得到的式II化合物或其盐以及必要时的中间体,使用常规的方法,例如过量试剂的溶剂分解作用;重结晶,色谱法,例如分配、离子或凝胶色谱,在无机溶剂相与有机溶剂相之间分配;单次或多次萃取,特别是在酸化或提高碱性或盐分含量之后,用吸潮盐或在高温下干燥,如果需要的话使其通过或通以气流;消化;过滤;洗涤;溶解;蒸发(如果必要的话在真空或高真空中进行);蒸馏;沉淀;离心;结晶,例如对所得油形式的化合物进行结晶或从母液中结晶,也可能用晶体对最终产物进行种子结晶;冷冻干燥;或者两种或多种上述加工步骤的组合,这些步骤也可以重复进行;等等。
原料和中间体可以使用其纯品形式,例如经过上述的加工步骤后的形式,部分纯化形式,或者例如直接使用其粗产物。
所得化合物、包括它们的盐,也可以是水合物或溶剂化物的形式,或者它们的晶体中例如可以含有结晶所用的溶剂。
溶剂和稀释剂例如为水;醇类,例如低级链烷醇,如甲醇、乙醇、丙醇、丁醇或乙二醇一甲基醚(甲基溶纤剂);二醇类,例如乙二醇;三醇或多元醇类,例如甘油或二甘醇;或芳醇类,例如苯酚或苯甲醇;酰胺类,例如羧酰胺,如N,N-二甲基甲酰胺或N,N-二甲基乙酰胺;无机酸的酰胺,例如六甲基磷酰胺;醚类,例如环状醚,如四氢呋喃或二噁烷,或无环醚,如二乙醚或乙二醇二甲醚;卤代烃类,例如卤代低级链烷烃类,如二氯甲烷或氯仿;酮类,例如丙酮;腈类,例如乙腈;酯类,例如乙酸乙酯;二烷基亚砜类,例如二甲基亚砜;氮杂环类,例如N-甲基吡咯烷酮或吡啶;烃类,例如低级链烷烃类,如己烷或庚烷;或芳族化合物,例如苯、甲苯或二甲苯;或这些溶剂的混合物,对上述反应和加工步骤可以在每种情况下选择合适的溶剂。
本发明方法中,游离形式或盐形式的原料物质和中间体优选用来制得起先所描述的特别有价值的化合物II或其盐。用于制备化合物II或其盐的游离形式或盐形式的新颖的原料物质和中间体、它们的用途和它们的制备方法也构成了本发明的主题。
本发明也涉及该方法的这样一些实施方式,其中将在可在任意所需方法步骤中作为中间体得到的化合物用作原料,进行剩下的方法步骤,或者在反应条件下生成一种原料物质,或者使用其衍生物的形式,例如其一种盐的形式。
化合物II的盐可以以一种本身已知的方式进行制备。因此例如通过用一种适当的酸或一种适当的离子交换试剂进行处理,可以得到化合物II的酸加成盐,通过用一种适当的碱或一种适当的离子交换试剂进行处理,可以得到其碱盐。用一种常规方法可将式II化合物的盐转化为游离的化合物II;例如通过一种适当的碱性试剂或一种适当的离子交换试剂的处理,可将酸加成盐转化;通过一种适当的酸或一种适当的离子交换试剂的处理,可将碱盐转化。
用一种本身已知的方法可将化合物II的盐转化为化合物II的其他盐;例如在一种适当的溶剂中,通过用另一种酸的适当的金属盐、如钠、钡或银盐,例如乙酸银处理一种无机酸的盐、如盐酸盐,可将酸加成盐转化为其他酸加成盐,其中所生成的无机盐、如氯化银,是不溶性的,于是从反应混合物中沉淀出来。
根据程序或反应条件的不同,所得具有成盐性质的化合物II可以是游离形式或盐形式。
作为化合物II的游离形式与盐形式之间的密切联系的结果,如果合适,也可将游离的化合物II或其盐近似和方便地理解为其对应的盐或游离的化合物II,这一点已如上述,下文还将涉及。
包括其成盐化合物的盐在内的化合物II也能得到其水合物的形式和/或包括其他溶剂,例如如果合适,包括以固体形式存在的化合物结晶所用的溶剂。
根据原料物质和加工程序的不同选择,化合物II及其盐可以以可能的异构体之一的形式存在,例如立体异构体或互变异构体,或者作为其混合物。关于这一点,可得到的纯异构体例如纯对映体、纯非对映体或纯互变异构体。相应地,可能存在的异构体混合物例如外消旋物或非对映体混合物。按照本方法或以其他方式可得到的游离形式或盐形式的化合物II的异构体混合物可用常规方法将各成分分离,例如以各成分的物理化学差异为基础,采用已知的分步结晶、蒸馏和/或色谱分离的方法。可有利地分离活性更强的异构体。
下列实施例将对上述发明进行说明,但对本发明没有限制。(上文和下文中使用下列缩写-除非另有规定-h:小时;m.p.:熔点;DMSO-d6:六氘二甲基亚砜)
实施例1:3,5-双(2-羟苯基)-1-(2-羟乙基)-1H-[1,2,4]三唑
将12.0g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮悬浮在100ml甲醇中并用7.6g的2-羟乙基肼处理。使混合物在回流下沸腾1h,冷却并加入100ml水。滤出在此过程中沉淀出来的晶体,用甲醇/水洗涤。干燥后,目标化合物呈无色晶体,m.p.145-147℃。
原料的制备方法例如下述:
a)2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮:将106.0g水杨酰氯与93.0g水杨酰胺混合,并在170℃下加热30分钟,直至氯化氢不再逸出。混合物冷却,残余物从乙醇中结晶。干燥后,所得2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮为淡黄色晶体,m.p.206-208℃。
实施例2:[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯
将51.5g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮、30.5ml三乙胺和33.4g盐酸肼基乙酸乙酯在450ml乙醇中在回流下沸腾0.5h。冷却时,产物以结晶形式沉淀出来。将其滤出并用乙醇洗涤。干燥后,[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯呈无色晶体,m.p.172-174℃。
实施例3:3,5-双(2-羟苯基)-1-(2,2,2-三氟乙基)-1H-[1,2,4]三唑
将1.38g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮与1.6ml的2,2,2-三氟乙基肼在20ml乙醇中在回流下沸腾0.5h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥,并在旋转蒸发器中浓缩。残余物从甲醇/水中结晶。干燥后,3,5-双(2-羟苯基)-1-(2,2,2-三氟乙基)-1H-[1,2,4]三唑呈无色晶体,m.p.154-156℃。
实施例4:3,5-双(2-羟苯基)-1-(4-硝基苯基)-1H-[1,2,4]三唑
将1.0g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮、0.5ml三乙胺和0.7g的盐酸4-硝基苯基肼在10ml乙醇中在回流下沸腾1h。冷却时,产物以结晶形式沉淀出来。将其滤出并用乙醇洗涤。干燥后,3,5-双(2-羟苯基)-1-(4-硝基苯基)-1H-[1,2,4]三唑呈无色晶体,m.p.180-183℃。
实施例5:4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸
将5.0g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮和3.5g的4-肼基苯甲酸在75ml乙醇中在回流下沸腾2h。将冷却时沉淀出来的晶体用乙醇洗涤。干燥后,4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸呈无色晶体,m.p.264-265℃。
实施例6:{4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯基}吗啉-4-基甲酮
将3.0g的4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸(实施例5)和1.25ml的1-氯-N,N,2-三甲基-1-丙烯-1-胺(CAS登记号26189-59-3)在50ml四氢呋喃中搅拌2h。加入2.2ml三乙胺和0.8ml吗啉,混合物在室温下搅拌18h。将其倾入水中并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从异丙醇中结晶。干燥后,{4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯基}吗啉-4-基甲酮呈无色晶体,m.p.157-160℃。
实施例7:{4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯基}-(4-甲基哌嗪-1-基)甲酮
将3g的4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸(实施例5)和1.25ml的1-氯-N,N,2-三甲基-1-丙烯-1-胺在50ml四氢呋喃中搅拌2h。加入2.2ml三乙胺和1ml的N-甲基哌嗪,混合物在室温下搅拌48h。将其倾入水中并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从异丙醇中结晶。干燥后,{4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯基}-(4-甲基哌嗪-1-基)甲酮呈无色晶体,m.p.226-229℃。
实施例8:3,5-双(2-羟苯基)-1-(4-甲氧基苯基)-1H-[1,2,4]三唑
将5g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮、3.7g盐酸4-甲氧苯基肼和3ml三乙胺在75ml乙醇中在回流下沸腾2h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从异丙醇中结晶。干燥后,3,5-双(2-羟苯基)-1-(4-甲氧基苯基)-1H-[1,2,4]三唑呈无色晶体,m.p.179-181℃。
实施例9:3,5-双(2-羟苯基)-1-(2,4-二氟苯基)-1H-[1,2,4]三唑
将5.0g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮、3.9g盐酸2,4-二氟苯基肼和3ml三乙胺在25ml乙醇中在回流下沸腾2h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从乙醇中结晶。干燥后,3,5-双(2-羟苯基)-1-(2,4-二氟苯基)-1H-[1,2,4]三唑呈无色晶体,m.p.144-146℃。
实施例10:3,5-双(2-羟苯基)-1-苄基-1H-[1,2,4]三唑
将5.0g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮和3.4g盐酸苄肼与5.9ml三乙胺在50ml乙醇中在回流下沸腾4h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从异丙醇中结晶。干燥后,3,5-双(2-羟苯基)-1-苄基-1H-[1,2,4]三唑呈无色晶体,m.p.166-168℃。
实施例11:4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基甲基]苄腈
将5.0g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮、3.9g盐酸4-氰基苄肼和6ml三乙胺在50ml乙醇中在回流下沸腾3h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从乙醇/水中结晶。干燥后,4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基甲基]苄腈呈无色晶体,m.p.147-149℃。
实施例12:3,5-双(2-羟苯基)-1-(4-二乙氨基苄基)-1H-[1,2,4]三唑
将5.0g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮和5.4g盐酸4-二乙氨基苄肼与6.7ml三乙胺在50ml乙醇中在回流下沸腾18h。混合物倾入水中并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从异丙醇中结晶。干燥后,3,5-双(2-羟苯基)-1-(4-二乙氨基苄基)-1H-[1,2,4]三唑呈无色晶体,m.p.125-127℃。
实施例13:3,5-双(2-羟苯基)-1-(4-吡咯烷-1-基苄基)-1H-[1,2,4]三唑
将5.0g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮和5.2g盐酸(4-吡咯烷-1-基苄基)肼与6.7ml三乙胺在50ml乙醇中在回流下沸腾18h。混合物倾入水中并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从乙酸乙酯/己烷中结晶。干燥后,3,5-双(2-羟苯基)-1-(4-吡咯烷-1-基苄基)-1H-[1,2,4]三唑呈无色晶体,m.p.153-155℃。
原料的制备方法例如下述:
a)盐酸(4-吡咯烷-1-基苄基)肼:将7.0g的4-吡咯烷基苯甲醛和5.3g肼基甲酸叔丁酯在50ml乙醇中在回流下沸腾5h。混合物冷却,用乙醇稀释至250ml,加入1.0g钯/碳(10%),使混合物进行氢化反应,直至每摩尔原料吸收了1摩尔氢。滤出催化剂,将滤液在旋转蒸发器中浓缩至干。残余物溶于90ml的4M氯化氢/二噁烷中并在室温下保持20h。冷冻干燥后,所得盐酸(4-吡咯烷-1-基苄基)肼为一浅黄色固体。MS:192(M++H)
实施例14:3,5-双(2-羟苯基)-1-(吡啶-4-基甲基)-1H-[1,2,4]三唑
将5.0g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮和5.9g盐酸4-肼基甲基吡啶(CAS登记号89598-56-1)与10ml三乙胺在50ml乙醇中在回流下沸腾4h。混合物冷却,倾入水中并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从异丙醇中结晶。干燥后,3,5-双(2-羟苯基)-1-(吡啶-4-基甲基)-1H-[1,2,4]三唑呈无色晶体,m.p.197-199℃。
实施例15:3,5-双(2-羟苯基)-1-(吡啶-3-基甲基)-1H-[1,2,4]三唑
将5.0g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮和6.2g盐酸3-肼基甲基吡啶(57616-01-0)与13ml三乙胺在50ml乙醇中在回流下沸腾5h。混合物冷却,倾入水中并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从异丙醇中结晶。干燥后,3,5-双(2-羟苯基)-1-(吡啶-3-基甲基)-1H-[1,2,4]三唑呈无色晶体,m.p.174-176℃。
实施例16:3,5-双(5-氯-2-羟苯基)-1-(2-羟乙基)-1H-[1,2,4]三唑
将15.0g的6-氯-2-(5-氯-2-羟苯基)苯并[e][1,3]噁嗪-4-酮和4ml羟乙基肼在50ml乙醇中在回流下沸腾2h。冷却时沉淀出来的晶体从乙醇/水中结晶。干燥后,3,5-双(5-氯-2-羟苯基)-1-(2-羟乙基)-1H-[1,2,4]三唑呈无色晶体,m.p.166-170℃。
原料的制备方法例如下述:
a)6-氯-2-(5-氯-2-羟苯基)苯并[e][1,3]噁嗪-4-酮:向40.0g的5-氯水杨酰胺与54.0g的5-氯水杨酸在400ml二甲苯中的混合物中加入2.5ml吡啶后,在回流下沸腾。在2h过程中加入38ml亚硫酰氯,混合物进一步搅拌1h,然后在减压下蒸馏除去溶剂。将残余物悬浮在200ml乙醇中,滤出并用乙醇洗涤。干燥后,所得6-氯-2-(5-氯-2-羟苯基)苯并[e][1,3]噁嗪-4-酮为淡黄色晶体,m.p.246-248℃。
实施例17:4-[3,5-双(5-氯-2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸
将3.0g的6-氯-2-(5-氯-2-羟苯基)苯并[e][1,3]噁嗪-4-酮和1.7g的4-肼基苯甲酸在40ml乙醇中在回流下沸腾2h。冷却时沉淀出来的晶体从异丙醇中结晶。干燥后,4-[3,5-双(5-氯-2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸呈无色晶体,m.p.275-278℃。
实施例18:3,5-双(5-氯-2-羟苯基)-1-(吡啶-2-基甲基)-1H-[1,2,4]三唑
将3.0g的6-氯-2-(5-氯-2-羟苯基)苯并[e][1,3]噁嗪-4-酮和1.7g的盐酸2-肼基甲基吡啶与3ml三乙胺在50ml乙醇中在回流下沸腾5h。冷却时沉淀出来的晶体用乙醇洗涤。干燥后,3,5-双(5-氯-2-羟苯基)-1-(吡啶-2-基甲基)-1H-[1,2,4]三唑呈无色晶体,m.p.227-229℃。
实施例19:3,5-双(5-氯-2-羟苯基)-1-(4-二甲氨基苄基)-1H-[1,2,4]三唑
将3.0g的6-氯-2-(5-氯-2-羟苯基)苯并[e][1,3]噁嗪-4-酮和2.2g盐酸4-二甲氨基苄肼与3ml三乙胺在50ml乙醇中在回流下沸腾4h。冷却时沉淀出来的晶体用乙醇洗涤。干燥后,3,5-双(5-氯-2-羟苯基)-1-(4-二甲氨基苄基)-1H-[1,2,4]三唑呈无色晶体,m.p.205-207℃。
实施例20:4-[3,5-双(5-氟-2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸
将2.5g的6-氟-2-(5-氟-2-羟苯基)苯并[e][1,3]噁嗪-4-酮和1.6g的4-肼基苯甲酸在25ml乙醇中在回流下沸腾3h。混合物冷却,倾入水中并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从乙酸乙酯/己烷中结晶。干燥后,4-[3,5-双(5-氟-2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸呈无色晶体,m.p.252-255℃。
原料的制备方法例如下述:
a)6-氟-2-(5-氟-2-羟苯基)苯并[e][1,3]噁嗪-4-酮:向4.3g的5-氟水杨酰胺与4.7g的5-氟水杨酸在50ml二甲苯中的混合物中加入0.3ml吡啶后,在回流下沸腾。在2h过程中加入4.4ml亚硫酰氯,混合物进一步搅拌1h,然后在减压下蒸馏除去溶剂。将残余物悬浮在30ml乙醇中,滤出并用乙醇洗涤。干燥后,所得6-氟-2-(5-氟-2-羟苯基)苯并[e][1,3]噁嗪-4-酮为淡黄色晶体,m.p.250-252℃。
实施例21:4-[3,5-双(2-羟基-5-甲基苯基)-[1,2,4]三唑-1-基]苯甲酸
将1.15g的2-(6-羟基间甲苯基)-6-甲基-4H-[1,3]苯并噁嗪-4-酮(CAS登记号24798-62-7)和0.6g的4-肼基苯甲酸在15ml乙醇中在回流下沸腾2h。冷却时沉淀出来的晶体从异丙醇中结晶。干燥后,4-[3,5-双(2-羟基-5-甲基苯基)-[1,2,4]三唑-1-基]苯甲酸呈无色晶体,m.p.268-269℃。
实施例22:[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸
将0.6g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)和0.4g氢氧化钠溶于20ml甲醇,混合物在室温下搅拌2h。将其用0.1N盐酸酸化,滤出沉淀出来的晶体。用水洗涤并干燥后,[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸呈无色晶体,m.p.231-233℃。
实施例23:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-甲基乙酰胺
将2.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)溶于15ml乙醇,并用0.8ml的8M甲胺乙醇溶液处理。混合物60℃下搅拌3h,然后冷却。滤出在此过程中沉淀出来的晶体并用乙醇洗涤。干燥后,2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-甲基乙酰胺呈无色晶体,m.p.247-249℃。
实施例24:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-羟乙基)乙酰胺
将2.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)溶于10ml乙醇胺,并在室温下搅拌2h。混合物在真空中浓缩至干,残余物从异丙醇中结晶。干燥后,2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-羟乙基)乙酰胺呈无色晶体,m.p.208-211℃。
实施例25:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-甲氧基乙基)乙酰胺
将4.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)溶于30ml的2-甲氧基乙胺,混合物在室温下搅拌2h。将其在真空中浓缩至干,残余物从异丙醇中结晶。干燥后,2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-甲氧基乙基)乙酰胺呈无色晶体,m.p.184-186℃。
实施例26:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2,3-二羟丙基)乙酰胺
将2.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)和2.4g的(+/-)3-氨基-1,2-丙二醇在10ml乙醇中在60℃下加热2h。滤出在冷却时沉淀出来的晶体并用乙醇洗涤。干燥后,2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2,3-二羟丙基)乙酰胺呈无色晶体,m.p.180-181℃。
实施例27:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-吗啉-4-基乙基)乙酰胺
将5.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)和2.9m1的4-(2-氨乙基)吗啉在50ml四氢呋喃中在回流下沸腾18h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从异丙醇中结晶。干燥后,2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-吗啉-4-基乙基)乙酰胺呈无色晶体,m.p.180-182℃。
实施例28:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-羟乙基)-N-甲基乙酰胺
将2.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)和8ml的N-甲基乙醇胺在60℃下加热1h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从异丙醇中结晶。干燥后,2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-羟乙基)-N-甲基乙酰胺呈无色晶体,m.p.101-104℃。
实施例29:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-[2-(2-羟乙氧基)乙基]乙酰胺
将2.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)和10ml的2-(2-氨乙氧基)乙醇在室温下搅拌2h。混合物倾入水中并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从异丙醇中结晶。干燥后,2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-[2-(2-羟乙氧基)乙基]乙酰胺呈无色晶体,m.p.173-174℃。
实施例30:N-{2-[双(2-羟乙基)氨基]乙基}-2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酰胺
将2.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)和1.0g的N,N-双(2-羟乙基)乙二胺在8ml乙醇中在回流下沸腾24h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物在硅胶上层析。浓缩并干燥后,N-{2-[双(2-羟乙基)氨基]乙基}-2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酰胺呈无色泡沫。Rf值:0.35(硅胶60,二氯甲烷/甲醇=9/1)。
1H-NMR(DMSO-d6):2.5(m,6H),3.1(m,2H),3.4(m,4H),4.2(bs,2H),4.9(s,2H),7.0(m,4H),7.4(m,3H),7.95(d,1H),8.1(t,1H),11.0ppm(s,1H)。
实施例31:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-羟基-1-羟甲基乙基)乙酰胺
将2.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)和2.0g的2-氨基-1,3-丙二醇在8ml乙醇中在回流下沸腾3h。冷却时沉淀出来的晶体从异丙醇中结晶。干燥后,2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-羟基-1-羟甲基乙基)乙酰胺呈无色晶体,m.p.212-214℃。
实施例32:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-[2-(4-甲基哌嗪-1-基)乙基]乙酰胺
将3g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)和2.5g的2-(4-甲基哌嗪-1-基)乙胺在40ml乙醇中在回流下沸腾20h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物在硅胶上层析。浓缩并干燥后,所得2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-[2-(4-甲基哌嗪-1-基)乙基]乙酰胺为无色泡沫。Rf值:0.17(硅胶60,二氯甲烷/甲醇=9/1)。
1H-NMR(DMSO-d6):2.1(s,3H),2.3(m,10H),3.15(m,2H),4.9(s,2H),7.0(m,4H),7.4(m,3H),8.0(m,2H),11.0ppm(s,1H)。
实施例33:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N,N-二甲基乙酰胺
将2.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)溶于15ml二甲胺乙醇溶液(33%),并将该溶液在60℃下搅拌20h。冷却时沉淀出来的晶体从异丙醇中结晶。干燥后,2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N,N-二甲基乙酰胺呈无色晶体,m.p.196-197℃。
实施例34:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-1-吗啉-4-基乙酮
将2.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)和8ml吗啉在回流下沸腾1h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从乙酸乙酯/己烷中结晶。干燥后,2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-1-吗啉-4-基乙酮呈无色晶体,m.p.149-151℃。
实施例35:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-1-(4-甲基哌嗪-1-基)乙酮
将2.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)和8ml的1-甲基哌嗪在80℃下搅拌3h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从乙醇中结晶。干燥后,2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-1-(4-甲基哌嗪-1-基)乙酮呈无色晶体,m.p.199-201℃。
实施例36:N-苄基-2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-甲基乙酰胺
将2.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)和9ml的N-甲基苯甲胺在80℃下搅拌16h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从乙醇/水中结晶。干燥后,N-苄基-2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-甲基乙酰胺呈无色晶体,m.p.179-180℃。
实施例37:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N,N-双(2-羟乙基)乙酰胺
将2.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)和6.5g二乙醇胺在5ml乙醇中在回流下沸腾2h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物在硅胶上层析。浓缩并干燥后,所得2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N,N-双(2-羟乙基)乙酰胺为无色泡沫。Rf值:0.28(硅胶60,二氯甲烷/甲醇=9/1)。1H-NMR(DMSO-d6):3.2-3.6(m,8H),4.4-5.1(b,2H),5.35(s,2H),7.0(m,4H),7.4(m,3H),7.95(d,1H),10.4(bs,1H),11.05ppm(s,1H).
实施例38:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-二甲氨基乙基)-N-甲基乙酰胺
将2.0g的[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例2)和9ml的N,N,N’-三甲基乙二胺在80℃下搅拌5h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从异丙醇中结晶。干燥后,2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-二甲氨基乙基)-N-甲基乙酰胺呈无色晶体,m.p.172-174℃。
实施例39:2-[3,5-双(5-氯-2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-吗啉-4-基乙基)乙酰胺
将4g的[3,5-双(5-氯-2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯(实施例40)和2.6g的4-(2-氨乙基)吗啉在50ml乙醇中在回流下沸腾18h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从异丙醇中结晶。干燥后,2-[3,5-双(5-氯-2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-吗啉-4-基乙基)乙酰胺呈无色晶体,m.p.224-226℃。
实施例40:[3,5-双(5-氯-2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯
将6.0g氯-2-(5-氯-2-羟苯基)苯并[e][1,3]噁嗪-4-酮(实施例16)、3.0ml三乙胺和3.3g盐酸肼基乙酸乙酯在60ml乙醇中在回流下沸腾2h。冷却时,产物以晶体的形式沉淀出来。将其滤出并用乙醇洗涤。干燥后,所得[3,5-双(5-氯-2-羟苯基)-[1,2,4]三唑-1-基]乙酸乙酯为无色晶体,m.p.195-200℃。
实施例41:2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸
将4.8g的2-(2-羟苯基)苯并[e][1,3]噁嗪-4-酮和3.5g的2-肼基苯甲酸在10ml乙醇中在回流下沸腾4h。混合物冷却,倾入水中,并用乙酸乙酯萃取。合并的有机相经硫酸钠干燥并在旋转蒸发器中浓缩。残余物从乙酸乙酯/己烷中结晶。干燥后,所得2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸为无色晶体,m.p.132-138℃。
实施例42:4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸乙酯
将10g的4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸(实施例5)和0.5ml硫酸在200ml乙醇中在回流下沸腾20h。冷却时沉淀出来的晶体从异丙醇/水中结晶。干燥后,所得4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸乙酯为无色晶体,m.p.148-149℃。
实施例A至D:药物制剂
对下文中“活性成分”这一表达方式应理解为指的是以游离形式或药学上可接受的盐的形式存在的式I化合物,特别是上述实施例之一所述产物类型的化合物。
实施例A:按如下可制得片剂,每片含有200mg活性成分:
组成(10000片)
活性成分 2000.0g
乳糖 500.0g
马铃薯淀粉 352.0g
明胶 8.0g
滑石 60.0g
硬脂酸镁 10.0g
二氧化硅(高分散) 20.0g
乙醇 适量
将活性成分与乳糖和292g马铃薯淀粉混合,混合物用明胶的乙醇溶液湿润,过筛造粒。干燥后,与其余的马铃薯淀粉、硬脂酸镁、滑石和二氧化硅混合,将混合物压制成片,片重295.0mg,活性成分含量为200mg,如果需要的话,刻以断裂凹槽,用来对剂量进行更为精确的调整。
实施例B:按如下可制得包衣片,每片含有400mg活性成分:
组成(1000片)
活性成分 400.0g
乳糖 100.0g
玉米淀粉 70.0g
滑石 8.5g
硬脂酸钙 1.5g
羟丙甲基纤维素 2.36g
片胶 0.64g
水 适量
二氯甲烷 适量
将活性成分、乳糖和40g玉米淀粉混合,并用由15g玉米淀粉和水(加热)制得的糊状物湿润、造粒。将颗粒干燥,加入其余的玉米淀粉、滑石和硬脂酸钙并与颗粒混合。混合物压制成片,用羟丙甲基纤维素与片胶的二氯甲烷溶液进行包衣;包衣片的最终重量为583mg。
实施例C:例如按照下列方法可制得硬明胶胶囊,含有500mg活性成分:
组成(1000粒胶囊)
活性成分 500.0g
乳糖 250.0g
微晶纤维素 30.0g
月桂基硫酸钠 2.0g
硬脂酸镁 8.0g
将月桂基硫酸钠通过网孔宽度0.2mm的筛网,筛入到冷冻干燥的活性成分中。两种成分紧密混合。然后先通过网孔宽度0.6mm的筛网筛入乳糖,再通过网孔宽度0.9mm的筛网筛入微晶纤维素。之后再将各成分紧密混合10分钟。最后通过网孔宽度0.8mm的筛网筛入硬脂酸镁。进一步混合3分钟后,每粒适当大小的硬明胶胶囊中分装790mg所得配方。
实施例D:例如按下述可制得口服悬浮粉末,含有300mg活性成分:
组成(1次给药)
活性成分 300mg
羟丙基纤维素(Klucel HF) 50mg
酒石酸 100mg
月桂基硫酸钠 100mg
将月桂基硫酸钠通过网孔宽度0.2mm的筛网,筛入到冷冻干燥的活性成分中。两种成分紧密混合。然后通过网孔宽度0.9mm的筛网筛入微晶纤维素。之后,再次将各成分紧密混合10分钟。最后,通过网孔宽度0.8mm的筛网筛入酒石酸。进一步混合3分钟后,将混合物分装在容积至少为10ml的容器中。使用时,将混合物用水加至10ml并剧烈振摇。
Claims (13)
1·式I化合物及其药学上可接受的盐用于制备治疗导致人或动物机体中金属过量的疾病或由金属过量导致的疾病的药物的用途:
其中
R1与R5彼此同时或独立为氢、卤素或低级烷基;
R2与R4彼此均为氢;
R3为羟基-低级烷基、卤代-低级烷基、羧基-低级烷基、低级烷氧基羰基-低级烷基、R6R7N-C(O)-低级烷基、被硝基、羧基、低级烷氧基、低级烷氧羰基、卤素或R8R9N-C(O)-取代的苯基,未取代的或被氰基、N-低级烷基氨基、N,N-二低级烷基氨基或吡咯烷基取代的芳基-低级烷基、或未取代的杂芳烷基;
R6与R7彼此同时或独立为氢、低级烷基、羟基-低级烷基、烷氧基-低级烷基、羟基烷氧基-低级烷基、氨基-低级烷基、N,N-二-低级烷基氨基-低级烷基、N-(羟基-低级烷基)氨基-低级烷基、N,N-二(羟基-低级烷基)氨基-低级烷基、或与它们所结合的氮原子共同构成一个氮杂脂环;
R8和R9彼此独立地为氢或低级烷基或与它们相联的氮原子一起形成氮杂脂环。
2·根据权利要求1的用途,所述药物用于治疗导致人或动物机体中铁过量的疾病或由铁过量导致的疾病。
3·一种药物制剂,含有至少一种根据权利要求1的式I化合物或其药学上可接受的盐,其中
R1与R5彼此同时或独立为氢、卤素或低级烷基;
R2与R4均为氢;
R3为羟基-低级烷基、卤代-低级烷基、羧基-低级烷基、低级烷氧基羰基-低级烷基、R6R7N-C(O)-低级烷基、被硝基、羧基、低级烷氧基、低级烷氧羰基、卤素或R8R9N-C(O)-取代的苯基、被N-低级烷氨基、N,N-二低级烷氨基或吡咯烷代取代的芳基-低级烷基、或未取代的杂芳烷基;
R6与R7彼此同时或独立为氢、低级烷基、羟基-低级烷基、烷氧基-低级烷基、羟基烷氧基-低级烷基、氨基-低级烷基、N,N-二(羟基-低级烷基)氨基-低级烷基、或与它们所结合的氮原子共同构成一个氮杂脂环;
R8和R9彼此独立地为氢或低级烷基或与它们相联的氮原子一起形成氮杂脂环;
和至少一种药学上可接受的载体。
4·权利要求3的药物制剂,含有至少一种根据权利要求1的式I化合物或药学上可接受的盐,其中
R1与R5彼此同时或独立为氢、卤素或低级烷基;
R2与R4均为氢;
R3为羟基-低级烷基、羧基-低级烷基、低级烷氧基羰基-低级烷基、R6R7N-C(O)-低级烷基、被硝基、羧基、低级烷氧基、低级烷氧羰基、卤素或R8R9N-C(O)-取代的苯基、被N-低级烷基氨基、N,N-二-低级烷基氨基或吡咯烷代取代的芳基-低级烷基、或未取代的杂芳烷基;
R6与R7彼此同时或独立为氢、低级烷基、羟基-低级烷基、烷氧基-低级烷基、羟基烷氧基-低级烷基、氨基-低级烷基、N,N-二-低级烷基氨基-低级烷基、N-(羟基-低级烷基)氨基-低级烷基、N,N-二(羟基-低级烷基)氨基-低级烷基、或与它们所结合的氮原子共同构成一个氮杂脂环;
R8和R9彼此独立地为氢或低级烷基或与它们相联的氮原子一起形成氮杂脂环;
和至少一种药学上可接受的载体。
5·一种式I化合物及其盐
其中
R1与R5彼此同时或独立为氢、卤素或低级烷基;
R2与R4均为氢;
R3为R6R7N-C(O)-低级烷基、被硝基、羧基、低级烷氧基、低级烷氧羰基、卤素或R8R9N-C(O)-取代的苯基、被N-低级烷基氨基、N,N-二-低级烷基氨基或吡咯烷代取代的芳基-低级烷基、或未取代的杂芳烷基,其条件是
若R2与R4是氢,且R1与R5是氢、卤素或低级烷基,则R3不是被卤素、硝基、低级烷氧基或低级烷氧基羰基取代的苯基;
R6与R7彼此同时或独立为氢、低级烷基、羟基-低级烷基、烷氧基-低级烷基、羟基烷氧基-低级烷基、氨基-低级烷基、N,N-二-低级烷基氨基-低级烷基、N-(羟基-低级烷基)氨基-低级烷基、N,N-二(羟基-低级烷基)氨基-低级烷基、或与它们所结合的氮原子共同构成-个氮杂脂环;
R8和R9彼此独立地为氢或低级烷基或与它们相联的氮原子一起形成氮杂脂环。
6·一种根据权利要求5的式I化合物及其盐,其中
R1与R5彼此同时或独立为氢、卤素、低级烷基;
R2与R4均为氢;
R3为R6R7N-C(O)-低级烷基、被硝基、羧基、低级烷氧基、低级烷氧羰基、卤素或R8R9N-C(O)-取代的苯基、被N-低级烷基氨基、N,N-二-低级烷基氨基或吡咯烷代取代的芳基-低级烷基、或未取代的杂芳烷基,其条件是若R2与R4是氢,且R1与R5是氢、卤素或低级烷基,则R3不是被卤素、硝基、低级烷氧基或低级烷氧基羰基取代的苯基;
R6与R7彼此同时或独立为氢、低级烷基、羟基-低级烷基、烷氧基-低级烷基、羟基烷氧基-低级烷基、氨基-低级烷基、N,N-二-低级烷基氨基-低级烷基、N-(羟基-低级烷基)氨基-低级烷基、N,N-二(羟基-低级烷基)氨基-低级烷基、或与它们所结合的氮原子共同构成一个氮杂脂环;
R8和R9彼此独立地为氢或低级烷基或与它们相联的氮原子一起形成氮杂脂环。
7·一种根据权利要求5的式I化合物及其药学上可接受的盐,其中
R1与R5彼此同时或独立为氢、卤素或低级烷基;
R2与R4为氢;
R3为R6R7N-C(O)-低级烷基、被羧基或R8R9N-C(O)-取代的芳基、被N-低级烷基氨基、N,N-二-低级烷基氨基或吡咯烷代取代的芳基-低级烷基、或未取代的杂芳烷基;
R6与R7彼此同时或独立为氢、低级烷基、羟基-低级烷基、烷氧基-低级烷基、羟基烷氧基-低级烷基、氨基-低级烷基、N,N-二-低级烷基氨基-低级烷基、N-(羟基-低级烷基)氨基-低级烷基、N,N-二(羟基-低级烷基)氨基-低级烷基、或与它们所结合的氮原子共同构成一个氮杂脂环;
R8与R9彼此同时或独立为氢或低级烷基,或与它们所结合的氮原子共同构成一个氮杂脂环。
8·权利要求5的化合物,选自由下列化合物组成的组:
{4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯基}-(4-甲基哌嗪-1-基)甲酮;
{4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯基}吗啉-4-基甲酮;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-1-(4-甲基哌嗪-1-基)乙酮;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-1-吗啉-4-基乙酮;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N,N-双(2-羟乙基)乙酰胺;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N,N-二甲基乙酰胺;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2,3-二羟丙基)乙酰胺;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-二甲氨基乙基)-N-甲乙酰胺;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-羟基-1-羟甲基乙基)乙酰胺;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-羟乙基)乙酰胺;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-羟乙基)-N-甲基乙酰胺;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-甲氧基乙基)乙酰胺;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-吗啉-4-基乙基)乙酰胺;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-[2-(2-羟乙氧基)乙基]乙酰胺;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-[2-(4-甲基哌嗪-1-基)乙基]乙酰胺;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-甲基乙酰胺;
2-[3,5-双(5-氯-2-羟苯基)-[1,2,4]三唑-1-基]-N-(2-吗啉-4-基乙基)乙酰胺;
3,5-双(2-羟苯基)-1-(4-二乙氨基苄基)-1H-[1,2,4]三唑;
3,5-双(2-羟苯基)-1-(4-吡咯烷-1-基苄基)-1H-[1,2,4]三唑;
3,5-双(2-羟苯基)-1-(吡啶-3-基甲基)-1H-[1,2,4]三唑;
3,5-双(2-羟苯基)-1-(吡啶-4-基甲基)-1H-[1,2,4]三唑;
3,5-双(5-氯-2-羟苯基)-1-(4-二甲氨基苄基)-1H-[1,2,4]三唑;
3,5-双(5-氯-2-羟苯基)-1-(吡啶-2-基甲基)-1H-[1,2,4]三唑;
4-[3,5-双(2-羟基-5-甲基苯基)-[1,2,4]三唑-1-基]苯甲酸;
2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸;
4-[3,5-双(5-氯-2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸;
4-[3,5-双(5-氟-2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸;
N-{2-[双(2-羟乙基)氨基]乙基}-2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]乙酰胺;
N-苄基-2-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]-N-甲基乙酰胺;
及其药学上可接受的盐。
9·根据权利要求5的化合物,它是4-[3,5-双(2-羟苯基)-[1,2,4]三唑-1-基]苯甲酸及其药学上可接受的盐。
10·一种药物制剂,含有根据权利要求5-9任一项的至少一种化合物或其药学上可接受的盐,以及至少一种药学上可接受的载体。
11·根据权利要求5至9中任一项的化合物在药物制剂制备中的用途。
12·根据权利要求11的用途,其中所述药物制剂用于治疗人或动物机体中铁过量。
13·一种制备根据权利要求5的式I化合物及其盐的方法,该方法包括
a)使一种式III化合物
其中R1、R2、R4和R5定义同权利要求5,X-是一种阴离子,
与一种式IV化合物或其盐反应
R3-NH-NH2 (IV)
其中R3定义同权利要求5中所述;或者
b)使一种式V化合物或其盐
其中R1、R4和R5定义同权利要求5,
与一种式IV化合物或其盐反应,其中R3定义同权利要求5;或者
c)使一种式VI化合物
其中R1、R2、R4和R5定义同权利要求5,
与一种式IV化合物或其盐反应,其中R3定义同权利要求5;
然后如果必要的话,通过除去保护基团使该化合物转化为一种权利要求5所述的式I化合物,如果需要的话,再转化为另一种权利要求5所述的式I化合物,和/或如果需要的话,使所得的盐转化为游离化合物或另一种盐,和/或如果需要的话,使所得游离的且具有成盐性质的权利要求5所述的式I化合物转化为盐。
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EP3489692A1 (de) | 2017-11-28 | 2019-05-29 | Siemens Healthcare Diagnostics Products GmbH | Prothrombinzeit-reagenz enthaltend einen eisenchelator |
TR201722910A2 (tr) | 2017-12-29 | 2019-07-22 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Deferasi̇roks i̇çeren suda dağilabi̇len tablet formülasyonlari |
KR20190110771A (ko) | 2018-03-21 | 2019-10-01 | 주식회사 한국팜비오 | 데페라시록스를 함유하는 소형 분산성 정제 |
CN108727287B (zh) * | 2018-05-10 | 2020-10-27 | 东南大学 | 1,2,4-三唑类化合物及其盐和应用 |
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GR1009592B (el) * | 2018-07-03 | 2019-09-11 | Φαρματεν Α.Β.Ε.Ε. | Φαρμακευτικο σκευασμα που περιλαμβανει εναν χηλικο παραγοντα συμπλεκτικο του σιδηρου και μεθοδος για την παρασκευη αυτου |
KR20200113116A (ko) | 2019-03-22 | 2020-10-06 | 주식회사 한국팜비오 | 데페라시록스를 포함하는 필름코팅정제 |
TW202102478A (zh) | 2019-04-01 | 2021-01-16 | 瑞士商威佛(國際)股份有限公司 | 新穎的鐵螯合物 |
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IT202000000922A1 (it) | 2020-01-20 | 2021-07-20 | Cage Chemicals S R L | Complessi di ferro e relativi sali come agenti di contrasto per MRI |
WO2022186809A1 (en) | 2021-03-05 | 2022-09-09 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | The film coated tablet comprising deferasirox |
CN114276305B (zh) * | 2021-12-28 | 2023-11-17 | 中山大学 | 一种三取代苯基-1,2,4-三氮唑衍生物及其制备和治疗神经元损伤的应用 |
CN114591254B (zh) * | 2022-03-31 | 2023-10-13 | 中山大学 | 一种3,5-二取代苯基-1,2,4-三氮唑衍生物及其制备方法和应用 |
CN114478410B (zh) * | 2022-03-31 | 2022-11-29 | 中山大学 | 一种二取代苯基-1,2,4-三氮唑衍生物及其制备和应用 |
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CH84663A4 (zh) | 1963-01-24 | 1964-11-14 | ||
DE2628152C2 (de) | 1976-06-23 | 1985-03-28 | Bayer Ag, 5090 Leverkusen | Fungizide und nematizide Mittel |
US4528196A (en) * | 1981-02-23 | 1985-07-09 | The United States Of America As Represented By The Department Of Health And Human Services | Chelating agents for the treatment of iron overload |
GB8429307D0 (en) | 1984-11-20 | 1984-12-27 | Shell Int Research | Heterocyclic herbicides |
IL84331A0 (en) * | 1987-11-02 | 1988-04-29 | Yissum Res Dev Co | Pyridoxyl hydrazone derivatives and pharmaceutical compositions containing the same |
US5260322A (en) | 1990-10-08 | 1993-11-09 | Merck & Co., Inc. | Angiotension II antagonists in the treatment of hyperuricemia |
DE4320801A1 (de) * | 1993-06-23 | 1995-01-05 | Fahlberg List Pharma Gmbh | 2-Hydroxyphenylsubstituierte 1,2,4-Triazole und 1,2,4-Oxadiazole, ihre Verwendung als pharmazeutische Wirkstoffe und sie enthaltende Arzneimittel |
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