CN1068878C - 唑酮类氨磺酰衍生物抗螺杆菌剂 - Google Patents
唑酮类氨磺酰衍生物抗螺杆菌剂 Download PDFInfo
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- CN1068878C CN1068878C CN95194022A CN95194022A CN1068878C CN 1068878 C CN1068878 C CN 1068878C CN 95194022 A CN95194022 A CN 95194022A CN 95194022 A CN95194022 A CN 95194022A CN 1068878 C CN1068878 C CN 1068878C
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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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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Abstract
本发明涉及通式(Ⅰ)化合物，其药学上可接受的加成盐和其立体化学异构体，通式(Ⅰ)中的Y，R1，R2，R3，R4，R5，R6Z和式的含义如说明书所述；还涉及通式(Ⅰ)化合物的制备方法，这些化合物作为药物的应用和含通式(Ⅰ)化合物的药物组合物。
Description
本发明涉及作为有效抗螺杆菌剂(Helicobacter)的取代的唑酮(azolone)衍生物。
US-4,791,111公开了具有类似于本发明化合物结构的唑酮类化合物。这类化合物是制备[[4-[4-(4-苯基-1-哌嗪基)苯氧甲基)-1,3-二氧戊环-2-基]甲基]-1H-咪唑和-1H-1,2,4-三唑的中间体。
在US-4,931,444中记载了具有抑制5-脂氧合酶活性的取代的唑酮衍生物。这些化合物以其有益的抗螺杆菌活性为特征。
在根除螺杆菌方面，包括分别给予两种抗菌药物的二重治疗并不是满意的，这是由于下述的一种或多种原因：低的根除速度，众多的副作用和螺杆菌产生抗菌性。包括给予两种抗菌剂和铋化合物的三重治疗虽然是有效的，但对患者有诸多要求而且也有副作用。本发明的化合物在用于Helicobacter pylori及相关种的单一治疗方面是有效的。
本发明涉及通式(Ⅰ)的化合物及其药学上可接受的加成盐和立体化学异构体，
其中Y是CH或N；R1,R2和R3各自为H或C1-4烷基；R4和R5各自为H，卤素，C1-4烷基，C1-4烷氧基，羟基，三氟甲基，三氟甲氧基或二氟甲氧基；R6是C1-4烷基；或任意取代有卤素，C1-4烷基羰基氨基，C1-4烷氧基，C1-4烷基或硝基的苯基；Z是C=0或CHOH；和是如下的基团：
上面所说的卤素是指氟，氯，溴和碘；C1-4烷基是指有1-4个碳原子的直链和支链饱和烃基，例如甲基，乙基，丙基，1-甲基乙基，丁基，1-甲基丙基，2-甲基丙基和1,1-二甲基乙基；C1-6烷基类似上面定义的C1-4烷基和包括有5-6个碳原子的较高级的同类物如戊基和己基。
术语药学上可接受的加成盐是指通式(Ⅰ)化合物可以形成的无毒的有治疗活性的加成盐形式。具有碱性的通式(Ⅰ)化合物的游离碱形式以常规方法用适当量的合适酸处理，可以转化成相应的有治疗活性的、无毒的酸加成盐形式。合适的酸包括，例如无机酸如氢卤素如盐酸或氢溴酸；硫酸；硝酸；磷酸等；或有机酸如乙酸，丙酸，羟基乙酸，乳酸，丙酮酸，草酸，丙二酸，丁二酸，马来酸，富马酸，苹果酸，酒石酸，柠檬酸，甲磺酸，乙磺酸，苯磺酸，对甲苯磺酸，环己烷氨基磺酸，水杨酸，对氨基水杨酸，双羟萘酸等。上面所述的加成盐也包括稳定形式的通式(Ⅰ)化合物及其盐的溶剂化物。这样的溶剂化物例如是水合物，醇合物等。
术语立体化学异构体形式是指通式(Ⅰ)化合物可以具有的不同的异构体以及构象异构体。除非另有说明或指定，化合物的化学名称是指所有可能的立体化学异构体和构象异构体形式的混合物，该混合物含有基本分子结构的所有非对映体，对映体和/或构象体。通式(Ⅰ)化合物的所有立体化学异构体形式不论是纯的形式或者彼此的混合物形式都包括在本发明范围之内。
每个手征中心的绝对构型可以用立体化学描述符R和S表示。有两个手征中心的化合物，按照化学文摘规定用R*和S*表示相对立体描述符(Chemical Substance Name Selection Manual(CA),1982Edition,Vol.Ⅲ,Chapter 20)。
本发明的某些化合物可以存在不同的互变形式，所有这些互变形式都包括在本发明的范围内。
第一组有趣的化合物是其中R4为卤素和R5为氢的通式(Ⅰ)化合物。第二组有趣的化合物是其中
为通式(a-1)或(a-2)的通式(Ⅰ)化合物。
第三组有趣的化合物是其中Y为N和R1为氢的通式(Ⅰ)化合物。
第四组有趣的化合物是其中R2为C1-4烷基和R3为氢的通式(Ⅰ)化合物。
第五组有趣的化合物是其中R6为C1-4烷基的通式(Ⅰ)化合物。
优选的化合物是其中R1,R3和R5是氢；R2是C1-4烷基；R4是卤素和Y是N的通式(Ⅰ)化合物。
更优选的化合物是其中R1,R3和R5是氢；R2是乙基；R4是卤素；Y是N；R6是C1-4烷基；和是通式(a-1)或(a-2)基团的通式(Ⅰ)化合物。
最优选的化合物是(R*,R*)-1-[5-[2-[1-[(4-氯苯基)羟甲基]丙基]-2,3-二氢-3-氧-4H-1,2,4-三唑-4-基]-2-吡啶基]-4-(甲磺酰基)哌嗪，其药学上可接受的加成盐和立体化学异构体。
制备与本发明通式(Ⅰ)化合物类似的化合物的方法叙述于US-4,791,111和US-4,931,444中。
特别是，通式(Ⅰ)化合物可以在反应惰性溶剂如二氯甲烷，N,N-二甲基甲酰胺等中和任意地在碱如三乙胺存在下，以通式(Ⅱ)的中间体与通式(Ⅲ)的试剂反应来制备。
通式(Ⅰ)化合物也可以在适宜的溶剂中和适宜的碱存在下通过以通式(Ⅵ)的试剂N-烷基化通式(Ⅴ)的中间体来制备。
通式(Ⅰ)化合物也可以通过已知的官能基转移过程互相转化。
例如，其中Z为C=O的通式(Ⅰ)化合物可以按已知还原反应转化为其中Z为CHOH的通式(Ⅰ)化合物。例如，该还原反应可以通过与金属氢化物或复合金属氢化物如氢硼化钠，氰基氢硼化钠等，在水，1-甲基-吡咯烷酮，乙腈，醇介质如甲醇、乙醇，或醚如四氢呋喃，1,4-二噁烷，或这样的溶剂的混合物中反应方便地进行。
该还原反应也可以通过与三(1-甲基乙氧基)氢硼化钾，三(1-甲基丙基)氢硼化钠或三(1-甲基丙基)氢硼化钾，在惰性溶剂如四氢呋喃或N,N’-二甲基甲酰胺中反应来进行。
任意地，通式(Ⅱ)的中间体与通式(Ⅲ)试剂的反应和上述还原反应，可以在单独反应器中进行。
通式(Ⅰ)化合物的纯异构体形式可以通过常规的分离方法从混合物中分出。特别是，可以利用手征固定相如适宜的衍生纤维素，例如三(二甲基氨基甲酰基)纤维素(Cbiralcel OD)和类似的手征固定相，通过柱色谱分离对映体。
在所有上述和下述制备中，反应产物可以从反应混合物中分离，如果需要，进一步的提纯可以按本领域已知的方法进行。
通式(Ⅱ)的中间体可以通过通式(Ⅳ)的化合物与酸如氢溴酸等反应来制备。
通式(Ⅴ)的中间体可以按照上述从通式(Ⅱ)中间体制备通式(Ⅰ)化合物的方法来制备。
通式(Ⅰ)的化合物及其药学上可接受的加成盐和立体化学异构体形式对于Helicobacter species，如Helicobacter pylori,Helicobactermustelae,Helicobacter felis等，特别是Helicobacter pylori呈现有效的药物活性。
特别重要的发现是，该主题化合物对于螺杆菌的生长以及对于该菌的细菌活性显示抑制活性。对螺杆菌的细菌效力按照Antimicrob、Agents Chemother1991,Vol.35,pp 869-872所述方法以悬浮培养测定。
本发明化合物的有趣特征涉及其对螺杆菌的高度专一活性。本发明的通式(Ⅰ)化合物，于直至10-5M浓度对于下述任何细菌不显示抑制活性：
Campylobactor jejuni,Campylobactor coli,campylobactor fetus,Campylobactor sputorum,vibrio spp.,Staphylococcus aureus 和Escherichia coli。
本发明化合物的一个重要优点是在中性pH以下，其对H.pylori的持续活性。在体外的低pH下的活性可以表明，在体内胃的酸环境下该化合物无有害作用。
因此，本发明的主题化合物被认为是治疗温血动物特别是人免受螺杆菌病及其痛苦的有价值的治疗药物。所说的疾病或痛苦例如是胃炎，胃溃疡，十二支肠溃疡和胃癌。
由于本发明化合物的有用的抗螺杆菌性质，它们可配制成为了不同给药用目的的各种药剂形式。为了制备本发明的药物组合物，碱形式或其加成盐形式的有效量的特定化合物作为活性组分，与药学上可接受的载体以紧密的混合物形式结合，取决于给药要求的制剂形式可以采取广泛不同的形式。这些药物组合物以单剂量形式经口腔、直肠或肠胃外注射给药是较合适的，例如在口服剂型的制剂组合物中，可以应用任何常用的药用介质，例如水，甘油，油醇等在口服液体制剂如悬液，糖浆，驰剂和溶液中；或固体载体如淀粉，糖，高岭土，润滑剂，粘合剂，崩解剂等在粉剂，丸剂，胶囊剂和片剂中。对于胃肠外用组合物，载体通常包括至少大部分为消毒水，和其它成分例如助溶剂。注射溶液，例如其中载体可以含有盐水溶液，葡萄糖溶液或盐水和葡萄糖混合溶液。注射悬液中也可以含有合适的液体载体，悬浮剂等。
当该药物组合物采取水溶液形式时，显示低溶解性的通式(Ⅰ)化合物可以依其盐形式配制，或加入水可混溶的和药物学上可接受的助溶剂，如二甲基亚砜等，或者以适宜的载体例如环糊精(CD)或特别是环糊精衍生物增溶通式(Ⅰ)化合物，例如US-3,459,731,EP-A-149,197(July 24,1 985),EP-A-1 97,571(October 15,1986),US-4,535,152或WO90/12035(October 18,1990)中所述的环糊精衍生物。合适的环糊精衍生物是α-,β-,γ-环糊精或醚和其混合醚，其中环糊精的葡糖酐单元的一个或多个羟基被C1-6烷基，特别是甲基、乙基或异丙基；羟基C1-6烷基，特别是羟乙基、羟丙基或羟丁基；羧基C1-6烷基，特别是羧甲基或羧乙基；C1-6烷基羰基，特别是乙酰基；C1-6烷氧基羰基C1-6烷基或羧基C1-6烷基-氧-C1-6烷基，特别是羧基甲氧基丙基或羧基乙氧基丙基；C1-6烷基羰基氧C1-6烷基，特别是2-乙酰氧基丙基所取代。特别值得提出的配位剂和/或增溶剂是β-CD,2,6-二-甲基-β-CD,2-羟乙基-β-CD,2-羟乙基-γ-CD,2-羟丙基-γ-CD和(2-羧基甲氧基)丙基-β-CD，和特别是2-羟丙基-β-CD。
术语混合醚是指其中至少两个环糊精羟基被不同的基团如羟丙基和羟乙基醚化后的环糊精衍生物。
平均摩尔取代(M.S.)用于表示每摩尔葡糖酐中烷氧基单元的平均摩尔值。M.S.值可以由不同的分析技术如核磁共振(NMR)，质谱(MS)和红外光谱(IR)测定。取决于所用技术，对于每一给定的环糊精衍生物可能得到稍微不同的值。在本发明组合物中使用的环糊精羟烷基衍生物，由质谱测得的M.S.值是在0.125-10范围内，特别是0.3-3或0.3-1.5范围内。优选的M.S.范围是大约0.3-0.8，特别是大约0.35-0.5和更特别是大约0.4。由NMR或IR测是的M.S.值优选为0.3-1，特别是0.55-0.75。
平均取代度(D.S.)是指每个葡糖酐单元的平均取代羟基值。D.S.值可由各种分析技术如核磁共振(NMR)，质谱(MS)和红外光谱(IR)测定。取决于所用技术，对于每一给定的环糊精衍生物可能得到稍微不同的值。本发明组合物中所用环糊精衍生物，由MS测得的D.S.值在0.125-3范围内，特别是0.2-2或0.2-1.5。优选的D.S.值是大约0.2-0.7，特别是大约0.35-0.5和更特别是大约0.4。由NMR或IR测得的D.S.值是0.3-1，特别是0.55-0.75。本发明组合物中所用的较特殊的β-和γ-环糊精羟烷基衍生物是部分取代的环糊精衍生物，其中在葡糖酐单元不同位置的羟基的平均烷基化度是在3-位为大约0％-20％，在2-位为大约2％-70％和6-位为大约5％-90％。优选的未取代的β-或γ-环糊精的量小于总环糊精含量的5％，特别是小于1.5％。另一种特别有趣的环糊精衍生物是任意甲基化的β-环糊精。
用于本发明的最优选的环糊精衍生物是那些部分取代的β-环糊精醚或有羟基丙基，羟基乙基和特别是2-羟基丙基和/或2-(1-羟基丙基)取代基的混合醚。
用于本发明组合物的最优选的环糊精衍生物是M.S.值为0.35-0.50的羟基丙基-β-环糊精并含有少于1.5％未取代的β-环糊精。由NMR或IR测定的M.S.值优选范围是0.55-0.75。
为了便于用药和剂量均匀，将上述药物组合物配制成剂量单位形式是特别有益的。说明书和权利要求书中所用剂量单位形式涉及适合作单位剂量的实际的独立单位，每个单位含有由要求的治疗效果决定的预定量的活性组分和所需的药物载体。这样的剂量单位形式的例子是片剂(包括刻痕片剂或包衣片剂)，胶囊剂，丸剂，粉剂包，糯米纸囊剂，注射溶液或悬液等及其分离的多单元结合形式。
鉴于主题化合物在治疗螺杆菌相关疾病方面的效力，证实了本发明提供了治疗温血动物特别是人免遭螺杆菌相关疾病的方法。该方法包括以与药物载体的混合物形式系统给药药学上有效量的通式(Ⅰ)化合物，其药学上可接受的加成盐或其立体化学异构体。本发明的另一方面涉及主题化合物作为药物而施用。
一般预料，日用有效量为0.05-50mg/kg体重，优选0.1-30mg/kg体重和更优选0.5-10mg/kg体重。根据治疗主体的反应和/或根据医生规定的本发明化合物的评价该有效日用剂量可以降低或增加。因此，上述有效剂量范围仅仅是指导性的和不打算限制本发明的范围或应用至任何程度。
任意地，用于根除螺杆菌的其它活性化合物可以与本发明化合物结合给药。给药可以是分开的(即同时的或顺序的)或不同药物可以结合于一个剂量形式中。结合治疗的适宜化合物是铋化合物如碱式柠檬酸铋，碱式水杨酸铋等；抗菌素如氨苄青霉素，羟氨苄青霉素，Clarithromycin等；H2受体拮抗剂如甲腈咪胺，雷尼替丁等；和特别是质子泵抑制剂如奥美拉唑，Iansoprazole,pantoprozole等。与本发明的通式(Ⅰ)化合物结合治疗有效的所述化合物的有效日用量是0.05-50mg/kg体重。
实验部分
下面“DMSO”是指二甲基亚砜。
实施例1
a)(±)4-[5-[2-[1-(4-氯苯甲酰基)丙基]-1,5-二氢-5-氧-4H-1,2,4-三唑-4-基]-2-吡啶基]-1-哌嗪羧酸乙酯(24g)在48％氢溴酸水溶液(250ml)中的混合物，搅拌和回流过夜，蒸发溶剂，将残留物溶于CH2Cl2中，以NH4OH/H2O中和。以CH2Cl2提取。有机层用水洗，干燥，过滤和蒸发。残留物(总共18g)的样品(3.5g)以硅胶柱色谱提纯(洗脱剂：CH2Cl2/(CH3OH/NH3)99/1)。收集纯流分，蒸发。将残留物溶于2-丙醇并在2-丙醇中结晶成其盐酸盐(1∶1)。滤出沉淀，用2-丙醇洗，于150℃下干燥。将产物溶于2-丙醇中，滴加吡啶直至所有产物溶解，接着结晶。滤出沉淀，干燥，得到1.7g(±)-2-[1-(4-氯苯甲酰基)丙基]-2,4-二氢-4-[6-(1-哌嗪基)-3-吡啶基]-3H-1,2,4-三唑-3-酮单盐酸盐(39.4％)；m.p.209.8℃(中间体1)。
b)苯磺酰氯(0.044g)和中间体1(0.1g)在CH2Cl2(10ml)和N,N-二乙胺(1ml)中的混合物于室温下搅拌过夜。混合物在硅胶上经HPLC提纯(洗脱剂：CH2Cl2 100至CH2Cl2/CH3OH 90/10 20分钟和120ml/分钟)。收集所要流分，蒸发，得到在DMSO(10.5ml)中的0.119g(85％)(±)-1-[5-[2-[1-(4-氯苯甲酰基)丙基]-2,3-二氢-3-氧-4H-1,2,4-三唑-4-基]-2-吡啶基]-4-(苯磺酰基)哌嗪(化合物1)的溶液。
以类似的方法制备：
| 化合物号 | R6 | A |
| 23456789101112131415161718 | 4-甲基苯基4-甲氧基苯基4-溴苯基4-硝基苯基4-(甲基羰基氨基)苯基甲基4-氟苯基4-氟苯基苯基4-甲基苯基4-甲氧基苯基4-溴苯基4-硝基苯基4-(甲基羰基氨基)苯基甲基4-氯苯基4-氟苯基 | NNNNNNNNCHCHCHCHCHCHCHCHCH |
实施例2
将N,N-二乙胺(1ml)和苯磺酰氯(过量；0.06g)加到中间体l(0.1g)在N,N-二甲基甲酰胺(2ml)中的溶液中。加入在四氢呋喃(1.5ml)中的K[OCH(CH3)2]3BH,1M。在室温下搅拌反应混合物过夜。加两滴水并继续搅拌2小时。加CH2Cl2直至总体积达到20ml。离心分离混合物并过滤。加MgSO4,在硅胶上以高效液相色谱分离混合物(洗脱剂A:CH2Cl2；洗脱剂B:CH2Cl2/CH3OH 90/10；从90％A和10％B,2分钟(125ml/分钟)，到90％A和10％B；升级，18分钟(125ml/分钟，至100％B)。收集纯流分，蒸发溶剂，得到0.054g(±)-(R*,R*)-1-[5-[2-[1-[(4-氯苯基)羟甲基]丙基]-2,3-二氢-3-氧-4H-1,2,4-三唑-4-基]-2-吡啶基]-4-(苯磺酰基)哌嗪(化合物19)。
以类似方法制备：
| 化合物号 | R6 | A | 物理数据 |
| 20212223242526272829303132333435 | 4-甲基苯基4-甲氧基苯基4-溴苯基4-硝基苯基4-(甲基羰基氨基)苯基甲基4-氯苯基4-氟苯基苯基4-甲基苯基4-甲氧基苯基4-溴苯基4-(甲基羰基基)苯基甲基4-氯苯基4-氟苯基 | NNNNNNNNCHCHCHCHCHCHCHCH | (R*,R*)(R*,R*)(R*,R*)(R*,R*)(R*,R*)(R*,R*)(R*,R*)(R*,R*)(R*,R*)(R*,R*)(R*,R*)(R*,R*)(R*,R*)(R*,R*)(R*,R*)(R*,R*) |
药物实施例
主题化合物的抗螺杆菌活性以下述体外试验程序被评价。
实施例3
试验化合物对螺杆菌的活性
试验化合物对Helicobacter pylori的活性是由从临床材料所得一组标准5H.Pylori菌株测定。通过测定用抗菌剂处理细菌的培养物后H.pylori脲酶的活性来确定最小抑制浓度(MICs)。
以10-3M浓度溶解试验化合物于DMSO中，同时以DMSO稀释至10-4M。移10μl体积的不同试验液于Repli-Dish井中(Sterilin)。每个Repli-Dish壁上都移有纯DMSO作对照。在每批试验中都包括作为参考化合物的氯苄青霉素((+)-6-[(2-氨基-2-苯基乙酰基)氨基]-3,3-二甲基-7-氧-4-硫-1-氮杂双环[3.2.0]庚烷-2-羧酸三水合物)和甲硝哒唑(2-甲基-5-硝基-1H-咪唑-1-乙醇)。(这些试验化合物以最终浓度为10-5,10-6,10-7和10-8M被试验)。试板在使用前一直贮存于4℃。H.pylori的五种离析物以10％血液琼脂再次培养2或3天。细菌在含5％氧，10％CO2和85％氮的大气下于37℃生长。接种Helicobactor pylori的悬液在Brain-Heart浸剂肉汤中制备并调节至在530nM处1.5±0.3的吸收率。
保持于45℃的新制备的10％血液琼脂以1ml体积加到试板井中，稀释试验化合物至10-5和10-6M。冷却介质，然后移10μl体积细菌悬液于琼脂表面。这些试板在上述微氧气氛下于37℃孵化48小时。为了便于板的计数和确保介质上的任何生长是真正的H.pylori，使用只对该样品有活性的高效尿素。孵化48小时后，1ml体积的脲酶肉汤慢慢加到每个Repli-Dish井中并于37℃下孵化试板2小时。以每个井移取100μl液体样品至96孔微稀释板的井中。紫色解释为H.pylori生长，橙黄色为H.pylori不生长。这表明可以获得清楚的边界点，由此可以确定抑制作用。于两个试验浓度均显示活性的所有化合物，以进一步烯释液再试验以确定MIC和作为靶生物的更宽细菌样品谱。至此，发现化合物25的MIC值等于或低于10μM。
组合物实施例
这些实施例中使用的“活性组分”(A.I.)涉及通式(Ⅰ)的化合物，其药学上可接受的酸加成盐或其立体化学异构形式。
实施例4
口服滴剂
于60-80℃下将500gA.I.溶于0.5升2-羟基丙酸和1.5升聚乙二醇中。冷至30-40℃后再加35升聚乙二醇并均匀地搅拌混合物。向其中加1750g糖精钠在2.5升纯水中的溶液。在搅拌下加2.5升可可香料和加聚乙二醇至50升体积，得到含有10g/mlA.I.的口服滴剂。将所得溶液装入适宜的容器中。
实施例5
胶囊剂
20g A.I6g十二烷基硫酸钠，56g淀粉，56g乳糖，0.8g胶体二氧化硅和1.2g硬脂酸镁一起激烈搅拌。所得混合物接着装入1000个适宜的硬明胶胶囊，每个胶囊中含有20mgA.I.。
实施例6
涂膜片剂
片芯的制备
100gA.I570g乳糖和200g淀粉的混合物均匀混合后，用5g十二烷基硫酸钠和l0g聚乙烯吡咯烷酮在200ml水中的溶液弄湿。湿粉混合物过筛，干燥，再过筛。加100g微晶纤维素和15g氢化植物油。很好地混合并压成片，得到10,000个片，每片含有10mg A.I.。
涂膜
向10g甲基纤维素在75ml变性乙醇中的溶液中加入5g乙基纤维素在150ml二氯甲烷中的溶液。然后，再加75ml二氯甲烷和2.5ml1,2,3-丙三醇。10g聚乙二醇被熔融并溶于75ml二氯甲烷中。将后一溶液加到前一溶液中，然后，加2.5g硬脂酸镁，5g聚乙烯吡咯烷酮和30ml浓色悬液并混合均匀。用所得混合物在涂覆设备中涂覆上面所得片芯。
实施例7
栓剂
将3g A.I.溶于3g 2,3-二羟基丁二酸在25ml聚乙二醇400中的溶液中。12g表面活性剂和足量至300g的甘油三酸酯一起熔融。后一混合物与前一溶液很好混合。将所得混合物倾入37-38℃的模中，形成每个含有30mg/ml A.I.的100个栓剂。
Claims (8)
1．通式(Ⅰ)的化合物及其药物上可接受的加成盐或立体化学异构体，
其中Y是CH或N；R1,R2和R3各自为H或C1-4烷基；R4和R5各自为H，卤素，C1-4烷基，C1-4烷氧基，羟基，三氟甲基，三氟甲氧基或二氟甲氧基；R6是C1-4烷基；或任意取代有卤素，C1-4烷基羰基氨基，C1-4烷氧基，C1-4烷基或硝基的苯基；Z是C=O或CHOH；和
是如下的基团：
2．权利要求1的化合物，其中R1,R3和R5是氢；R2是C1-4烷基；R4是卤素；和Y是N。
3．权利要求2的化合物，其中R2是乙基；R6是C1-4烷基；和是通式(a-1)或(a-2)的基团。
4．权利要求1的化合物，该化合物是(R*,R*)-1-[5-[2-[1-[(4-氯苯基)羟甲基]丙基]-2,3-二氢-3-氧-4H-l,2,4-三唑-4-基]-2-吡啶基]-4-(甲磺酰基)哌嗪；或其药学上可接受的加成盐或其立体化学异构体。
5．一种药物组合物，其中含有药物上有效量的权利要求1-4任一项要求的化合物和药物上可接受的载体。
6．权利要求1-4任一项要求的化合物在制备治疗螺杆菌相关疾病、胃炎、胃溃疡、十二指肠和胃癌的药物中的应用。
7．一种治疗性结合物，包括权利要求1-4任一项要求的化合物，药物上可接受的铋化合物和/或质子泵抑制剂。
8．通式(Ⅰ)化合物的制备方法，其中R1,R2,R3,R4,R5,R6,Y,Z和的定义与权利要求1中同样，
该方法的特征是，
a)在适当的反应惰性溶剂中和任意地在碱存在下，以通式(Ⅱ)的中间体与通式(Ⅲ)的试剂反应；
b)在适当的溶剂中和适宜的碱存在下，以通式(Ⅵ)的试剂N-烷基化通式(Ⅴ)的中间体；
和如果需要，按照已知官能团转换程序，相互转化通式(Ⅰ)化合物；用药学上可接受的酸处理使通式(Ⅰ)化合物转化为其酸加成盐；或相反地，用碱处理将其盐形式转化为游离碱形式；和/或制备其化学立体异构体形式。
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| Application Number | Priority Date | Filing Date | Title |
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| EP94202015.7 | 1994-07-12 | ||
| EP94202015 | 1994-07-12 |
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| US (2) | US5571811A (zh) |
| EP (1) | EP0770071B1 (zh) |
| JP (1) | JPH10502386A (zh) |
| CN (1) | CN1068878C (zh) |
| AT (1) | ATE206706T1 (zh) |
| AU (1) | AU684981B2 (zh) |
| BR (1) | BR9508376A (zh) |
| CA (1) | CA2194562A1 (zh) |
| CZ (1) | CZ2997A3 (zh) |
| DE (1) | DE69523159T2 (zh) |
| FI (1) | FI970113A0 (zh) |
| HU (1) | HUT76636A (zh) |
| IL (1) | IL114537A (zh) |
| MX (1) | MX9700340A (zh) |
| NO (1) | NO970089L (zh) |
| NZ (1) | NZ289853A (zh) |
| PL (1) | PL318149A1 (zh) |
| SK (1) | SK4497A3 (zh) |
| TW (1) | TW341571B (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5637592A (en) * | 1994-07-12 | 1997-06-10 | Janssen Pharmaceutica N.V. | Acyl derivatives of azolones |
| US5571811A (en) * | 1994-07-12 | 1996-11-05 | Janssen Pharmaceutica N.V. | Sulfonamide derivatives of azolones |
| US5639754A (en) * | 1994-07-12 | 1997-06-17 | Janssen Pharmaceutica N.V. | Urea and thiourea derivatives of azolones |
| CN1262281C (zh) | 1999-03-17 | 2006-07-05 | 森永制果株式会社 | 含有可可组分的药品、饮食品和饲料 |
| US6780880B1 (en) | 1999-08-26 | 2004-08-24 | Robert R. Whittle | FT-Raman spectroscopic measurement |
| US6316020B1 (en) | 1999-08-26 | 2001-11-13 | Robert R. Whittle | Pharmaceutical formulations |
| US6312712B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Method of improving bioavailability |
| US6262085B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6369087B1 (en) | 1999-08-26 | 2002-04-09 | Robert R. Whittle | Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same |
| US6312723B1 (en) | 1999-08-26 | 2001-11-06 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US6262086B1 (en) | 1999-08-26 | 2001-07-17 | Robert R. Whittle | Pharmaceutical unit dosage form |
| US6326384B1 (en) | 1999-08-26 | 2001-12-04 | Robert R. Whittle | Dry blend pharmaceutical unit dosage form |
| US6268385B1 (en) | 1999-08-26 | 2001-07-31 | Robert R. Whittle | Dry blend pharmaceutical formulations |
| US20050119251A1 (en) * | 2001-12-21 | 2005-06-02 | Jian-Min Fu | Nicotinamide derivatives and their use as therapeutic agents |
| AU2003282244B2 (en) * | 2002-11-14 | 2008-11-20 | Aderans Research Institute, Inc. | Cultivation of hair inductive cells |
| JP4960085B2 (ja) * | 2003-03-19 | 2012-06-27 | エクセリクシス， インク． | Ｔｉｅ−２モジュレータと使用方法 |
| AU2005286728A1 (en) * | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase |
| AU2005286731A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase |
| EP1804799B1 (en) * | 2004-09-20 | 2013-08-21 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
| US7777036B2 (en) | 2004-09-20 | 2010-08-17 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as therapeutic agents |
| AR051095A1 (es) * | 2004-09-20 | 2006-12-20 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso comoinhibidores de la estearoil-coa desaturasa |
| CA2580856A1 (en) * | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors |
| AU2005286790A1 (en) * | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Bicyclic heterocyclic derivatives and their use as inhibitors of stearoyl-CoA-desaturase (SCD) |
| MX2007003325A (es) | 2004-09-20 | 2007-06-05 | Xenon Pharmaceuticals Inc | Derivados heterociclicos y su uso como inhibidores estearoil-coa-desaturasa. |
| AU2005286793A1 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives for the treatment of diseases mediated by stearoyl-CoA desaturase enzymes |
| EP2029138A1 (en) | 2005-06-03 | 2009-03-04 | Xenon Pharmaceuticals Inc. | Aminothiazole derivatives as human stearoyl-coa desaturase inhibitors |
| KR20210113648A (ko) * | 2019-01-06 | 2021-09-16 | 소마젠 인크 | Ｈｔｒａ 저해제 및 ｃａｇａ 저해제 및 이의 용도 |
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| CA1292472C (en) * | 1985-12-03 | 1991-11-26 | Alfonsus Guilielmus Knaeps | Derivatives of ¬¬4-¬4-(4-phenyl-1-piperazinyl)- phenoxymethyl|-1,3-dioxolan-2-yl|methyl|-1h-imidazoles and 1h-1,2,4-triazoles |
| US4791111A (en) * | 1985-12-23 | 1988-12-13 | Janssen Pharmaceutica, N.V. | [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles having anti-microbial properties |
| CA1331757C (en) * | 1988-02-29 | 1994-08-30 | Janssen Pharmaceutica Naamloze Vennootschap | 5-lipoxygenase inhibiting 4-(4-phenyl-1-piperazinyl)phenols |
| CA2076257A1 (en) * | 1991-09-13 | 1993-03-14 | Jan Heeres | 4-¬4-¬4-(4-hydroxyphenyl)-1- piperazinyl|phenyl|-5-methyl-3h -1,2,4-triazol-3-one derivatives |
| US5571811A (en) * | 1994-07-12 | 1996-11-05 | Janssen Pharmaceutica N.V. | Sulfonamide derivatives of azolones |
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Also Published As
| Publication number | Publication date |
|---|---|
| NO970089L (no) | 1997-03-10 |
| AU684981B2 (en) | 1998-01-08 |
| BR9508376A (pt) | 1997-10-28 |
| NO970089D0 (no) | 1997-01-09 |
| ZA955760B (en) | 1997-01-13 |
| CA2194562A1 (en) | 1996-01-25 |
| HUT76636A (en) | 1997-10-28 |
| FI970113A (fi) | 1997-01-10 |
| DE69523159T2 (de) | 2002-06-20 |
| EP0770071B1 (en) | 2001-10-10 |
| EP0770071A1 (en) | 1997-05-02 |
| MX9700340A (es) | 1997-05-31 |
| FI970113A0 (fi) | 1997-01-10 |
| US5728700A (en) | 1998-03-17 |
| HU9700080D0 (en) | 1997-02-28 |
| JPH10502386A (ja) | 1998-03-03 |
| DE69523159D1 (de) | 2001-11-15 |
| ATE206706T1 (de) | 2001-10-15 |
| US5571811A (en) | 1996-11-05 |
| TW341571B (en) | 1998-10-01 |
| CN1152308A (zh) | 1997-06-18 |
| NZ289853A (en) | 1997-11-24 |
| PL318149A1 (en) | 1997-05-12 |
| WO1996001818A1 (en) | 1996-01-25 |
| CZ2997A3 (en) | 1997-09-17 |
| IL114537A (en) | 1999-04-11 |
| IL114537A0 (en) | 1995-11-27 |
| AU2981995A (en) | 1996-02-09 |
| SK4497A3 (en) | 1997-12-10 |
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