CN1035179C - 新的吲哚衍生物 - Google Patents
新的吲哚衍生物 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D209/16—Tryptamines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Processing Of Solid Wastes (AREA)
- Fertilizers (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrane Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
式(I)化合物及其药学上可接受的盐可用于偏头痛和其它疾病的治疗，它们可由相应的吲哚基-2-羧酸脱羧而制备。
Description
本发明涉及新的吲哚衍生物、其制备方法、包含它们的药用组合物及其医疗用途。
发生偏头痛的机制尚不清楚，但已经证实，头痛时颅内大血管出现扩张。一些像麦角胺和5-羟色胺(5-HT)之类的化合物通过对″类5-HT，″受体的兴奋作用而对颈动脉血管床具有血管收缩作用。但是这些化合物选择性差，从而引起不期望的和具有潜在危险的副作用。
在英国专利2124210A和2162532A中，公开了新的抗偏头痛化合物，它似乎更具选择性地激发″类5-羟色胺″受体的亚群体。其中Samatriptan
是可得到的治疗偏头痛药。该化合物对5HT1D受体有很高的亲合性，但是它对5-HT1A受体也有很高的亲合性。对5-HT1A的这一亲合性通过中枢神经系统作用而引起低血压和其它副作用。
我们现在发现，在甲基磺酰基中引入氮环能提供新的抗偏头痛化合物，它对5-HT1D受体比对5-HT1A受体有较大的亲合性，因此副作用小。
因此，本发明提供下式化合物及其药学上可接受的盐式中R1和R2各自代表氢原子或直链或支链的C1-6烷基，Z代表选自下列基团的环：
其中n代表4、5或6；R3代表氢或直链或支链的C1-6烷基，R4代表直链或支链的C1-6烷基、甲氧基、苄基或R5NHCO基，R5是直链或支链的C1-6烷基；R6代表直链或支链的C1-6烷基。
本发明化合物中R1、R2、R3、R4、R5和R6定义中的烷基优选的是直链或支链的C1-4烷基。
优选R1和R2是烷基且Z是II或V的通式I化合物。
本发明的特征之一是通式I吲哚衍生物可通过将通式VI羧酸脱羧制得。式(VI)如下：(式中各代号如上文定义)。该反应通常在铜粉、氧化铜、氧化亚或其它铜衍生物之类的催化剂存在下，在像喹啉、三正丁胺、N，N-二甲基乙酰胺或吡啶之类的有机溶剂中进行，反应温度在100-200℃之间。
本发明化合物制备用中间体VI是按照文献所述方法制备的(参见
A.Gonzalez，Synth.Commun.′(1991)，21，669；B.A.Howell，J.chem.Ed.176(1984)；H.Plieninger，Ber.(1950)，83，268).
通式I吲哚衍生物可以按已知的方法在适当溶剂(例如丙酮、乙醇、二氧六环或四氢呋喃)中以酸使其转变为酸加成盐。适当的酸加成盐是那些衍生自无机酸如盐酸和硫酸的盐。
用常用试验动物按下述方法进行实验和评估：狗隐静脉
按照基本上与Humphrey等人(1988)所述相同的方法进行等长记录。简而言之，从麻醉的比哥猎狗身上取出外侧隐静脉环标本(3mm宽)，于37℃和2g的平衡张力下悬浮于30ml含有Krebs的器官浴中，实验在5-HT2，H1和蕈毒碱拮抗剂的存在下进行，1M的5-羟色胺用作标准定量参比。(Humphrey P.P.A.；Feniuk W.；Perren M.J.；Connor H.E.；Oxford A.W.；Coates I.H.and Butina D.(1988).GR 43175，aselective agonist for the 5-HT1-like receptor in dog isolatedsaphenous vein.Br.J.Pharmac.94，1123-1132).与5HTID受体的结合
按照与Bruinevls等人所述的基本相同的方法进行了评估。将不同量的受试药物加到0.25ml最终体积反应液中，该反应液包含100μg腓肠有尾核膜蛋白，100pM(5-羟色胺-5-O-羧甲基-甘氨酰基[125I]酪氨酰胺(125I-GTI)，4mM CaCl2和50mM TrisHCl缓冲剂，其pH＝7.4。于37℃下保温30分钟后，用玻璃纤维过滤器将试样减压过滤，用冰冷的缓冲液洗涤过滤器并干燥。非特异性结合定义为在10μM5 HT存在下获得的结合。用γ计数器将捕获的放射活性定量。绘制置换曲线，用线性回归法计算每种受试化合物置换50％放射性配体的浓度。数据为至少3次不同试验(每次两个平行试验)的平均值。(Bruinvels A.T.；Lery H.； Palacios J.M.and Hoyer D.5-HT1Dbinding sites in various species：similar pharmacologicalprofile in dog，monkey，calf，guinea-pig and human brainmembranes.Naunyn-Schmiedeberg′s Arch. Pharmacol.(in press)).与5HT1A受体的结合
按照与Gozlan等人(1983)所述的基本相同的方法进行了评估。将不同量的受试药物加到1ml最终体积反应液中，该反应液包含100μg(大鼠海马)膜蛋白，0.5nM 3H-8-OH-DPAT，4mM CaCl2 0.1％抗环血酸，10μl巴吉林和50mM Tris HCl缓冲剂，其pH＝7.4。于25℃下保温30分钟后，用玻璃纤维过滤器将试样减压过滤，用冰冷的缓冲液洗涤过滤器并干燥。非特异性结合定义为在10μM 5HT存在下获得的结合。用闪烁计数器将放射活性定量。数据处理按5 HT1D结合评估的方法进行。
(Gozlan H.；El Mestikawy S.；Pichat L.；Glowinski J.and Hamon M.(1983). Identification ofpresynaptic serotonin autoreceptors using a new ligand：3H-PAT.Nature 305，140-142).
用本发明化合物(见下文实施例)进行的上述试验结果以及用于比较的Sumatriptan的结果见表1所示：
表1 不同药理学试验结果
| 狗隐静脉pD2 | 结合 IC50nM | |||
| 125I-GTI | 3H-8-OH-DPAT | 5HT1A/5HT1D | ||
| Sumatriptan1211 | 6.06±0.016.06±0.035.92±0.106.47±0.03 | 10.4±110.7±0.46.9±0.43.2±0.3 | 460±67825±69340±0.5850±40 | 44.277.149.3265.6 |
由上述结果可以断定：本发明化合物通过对5 HT1D受体的兴奋作用而表现出对5-HT1D受体的选择性结合和血管收缩能力。根据该结果，本发明提供通过给药和停药对防治偏头痛和其它由血管疾病引起的头痛(例如集聚性头痛和慢性陈发性偏头痛)具有潜在用途的化合物。并可用来防治紧张性头疼、运动性疾病、抑郁症和焦虑症。
因而，本发明提供式I吲哚衍生物及其药学上可接受的盐以及包含该衍生物及其盐的药用组合物，用来治疗人体疾病。
因此，式I吲哚衍生物及其药学上可按受的盐以及包含该衍生物及其盐的药用组合物可用于人体疾病的治疗方法中，该方法包括给予需要治疗的患者以有效量的所述衍生物或其盐或所述组合物。
本发明还提供包含至少一种通式I化合物或药学上可接受的盐(活性成分)和药学上可接受的载体或稀释剂。活性成分可占组合物的0.001-99％(重量)，最好占0.01-90％(重量)，这取决于制剂的性质和用药前是否还需进一步稀释。该组合物最好制成适合于口服、局部、经皮或非肠道给药的形式。
与活性化合物或其盐混合而形成本发明组合物的药学上可接受的载体本身是公知的，实际所用的赋形剂尤其取决于计划的给药方法和组合物。本发明组合物最好制成适于非肠道和口服给药的形式，口服给药用组合物可以是片剂、胶囊或液体制剂，如混合物、酏剂、糖浆或混悬剂的形式，它们都含一种或多种本发明化合物。上述制剂可按本领域熟知的方法制得。
可用于组合物的制备的稀释剂包括那些与活性成分以及着色剂或矫味剂(如果必要的话)可配伍的液体和固体稀释剂。片剂以含有1-200mg活性成分或等量的其盐为宜。
用于口服的液体组合物可以是溶液和混悬剂的形式。溶液可以是可溶性盐或活性化合物的其它衍生物与例如蔗糖形成糖浆的水性溶液。混悬剂可包括本发明活性化合物或其药学上可接受的盐与水以及助悬剂或矫味剂。
用于非肠道注射的组合物可从可溶性盐制备，该盐可以是经过或末经过冷冻干燥的，可溶于水或适当的非肠道注射流体。
有效剂量通常为每天10-600mg活性成分。
下述实施例说明本发明化合物的制备。
实施例1
将氧化铜(160mg；0.0011mol)于氮气氛中加到预先干燥的1-[[2-羧基-3-(2-二甲基氨乙基)-5-吲哚基]甲磺酰基]吡咯烷(1.6g；0.0442mol)的无水喹啉(75ml)溶液中。将反应混合物加热至190℃，保持15分钟。搅拌至室温，倒入1N盐酸(150ml)和乙酸乙酯(50ml)的混合物中，振荡、滗析。水溶液用乙酸乙酯洗数次，然后加入固体碳酸氢钠至pH＝7.8，用正已烷洗涤以消除喹啉。用固体碳酸钠将水溶液碱化，用乙酸乙酯提取。将有机溶液干燥(硫酸钠)，减压除去溶剂，得深色油(1.3g；收率92％)。该产物用硅胶柱色谱提纯，用二氯甲烷∶乙醇∶氢氧化铵(60∶8∶1)洗脱，得白色泡沫状1-[[3-(2-二甲基氨乙基)-5-吲哚基]吡咯烷(0.8g)。
向上述产物(0.8g)的丙酮(30ml)溶液中加数滴盐酸饱和二氧六环溶液。滤集沉淀的固体，用丙酮洗涤、干燥得1-[[3-(2-二甲基氨乙基)-5-吲哚基]甲磺酰基]吡咯烷盐酸盐(0.75g)，m.p.218-220℃。
按照实施例1所公开的方法，用适当取代的反应物VI可制得其它通式I吲哚衍生物，见下表2。
表2
| 化合物序号 | R1，R2 | Z | 衍生物 | M.P.℃ |
| 1234567891011 | R1＝R2＝CH3R1＝R2＝CH3R1＝R2＝CH3R1＝H；R2＝CH3R1＝R2＝CH3R1＝R2＝CH3R1＝R2＝CH3R1＝R2＝CH3R1＝R2＝CH3R1＝R2＝CH3R1＝R2＝CH3 | II；n＝4II；n＝5II；n＝6II；n＝4IIIIV；R3＝H；R4＝4-CH3IV；R3＝R4＝4-CH3IV；R3＝H；R4＝甲氧基IV；R3＝H；R4＝苄基IV；R3＝H；R4＝H3CNHCOV；R6＝C2H5 | HClHCl琥珀酸氢盐HClHCl琥珀酸氢盐琥珀酸氢盐琥珀酸氢盐HCl碱碱 | 218-220225-227(d)127-130(d)177-178231-232(d)151-153170-172143-145225-227161-163170-171 |
实施例2
按下列配方制得各含10mg 1-[[3-(2-二甲基氨乙基)-5-吲哚基]甲磺酰基]哌啶盐酸盐(活性成分)的20,000个安瓿。
活性成分 200g
氯化钠 200g
足量注射级水 40升方法
将活性成分和氯化钠溶于40升水中，通过滤菌器，灭菌条件下按已知方式装入2ml玻璃安瓿中。
Claims (6)
1.式(I)化合物或其药学上可接受的盐，式(I)为：
式中R1和R2各自代表氢原子或直链或支链的C1-6烷基，Z代表选自下列基团的环：其中n代表4、5或6；R3代表氢或直链或支链的C1-6烷基，R4代表直链或支链的C1-6烷基、甲氧基、苄基或R5NHCO基，R5是直链或支链的C1-6烷基；R6代表直链或支链的C1-6烷基。
2.根据权利要求1的化合物，其中R4是直链或支链的C1-6烷基。
3.根据权利要求1的化合物，其中R1和R2是相同或不同，各自为直链或支链的C1-4烷基；Z是式II基团。
4.根据权利要求1的化合物，其中式(I)表示下列化合物或其盐酸盐：
1-[[3-(2-二甲基氨乙基)-5-吲哚基]甲磺酰基吡咯烷；
1-[[3-(2-二甲基氨乙基)-5-吲哚基]甲磺酰基哌啶；或
1-[[3-(2-二甲基氨乙基)-5-吲哚基]甲磺酰基-4-乙氧羰基哌嗪。
5.式(I)化合物或其药学上可接受的盐的制备方法，它包括将式(VI)羧酸脱羧；式I和式VI如下：式中R1、R2和Z与其在权利要求1中的定义相同；
任选地以酸使生成的式(I)所示的吲哚衍生物转变为酸加成盐。
6.一种药物组合物，该药物组合物包括权利要求1的化合物和药学上可接受的载体或稀释剂。
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| FR2731224B1 (fr) * | 1995-03-02 | 1997-05-30 | Pf Medicament | Nouveaux derives bi-tryptaminiques sulfonamides, leur procede de preparation et leur utilisation a titre de medicaments |
| GB9523462D0 (en) * | 1995-11-16 | 1996-01-17 | Merck Sharp & Dohme | Therapeutic agents |
| US8022095B2 (en) | 1996-08-16 | 2011-09-20 | Pozen, Inc. | Methods of treating headaches using 5-HT agonists in combination with long-acting NSAIDs |
| US6310066B1 (en) | 1998-04-29 | 2001-10-30 | American Home Products Corp. | Antipsychotic indolyl derivatives |
| US6204274B1 (en) | 1998-04-29 | 2001-03-20 | American Home Products Corporation | Indolyl derivatives as serotonergic agents |
| US6066637A (en) * | 1998-06-19 | 2000-05-23 | American Home Products Corporation | Indolyl derivatives as serotonergic agents |
| GB0302094D0 (en) | 2003-01-29 | 2003-02-26 | Pharmagene Lab Ltd | EP4 receptor antagonists |
| GB0324269D0 (en) | 2003-10-16 | 2003-11-19 | Pharmagene Lab Ltd | EP4 receptor antagonists |
| WO2006129190A1 (en) * | 2005-06-03 | 2006-12-07 | Glenmark Pharmaceuticals Limited | Process for the preparation of almotriptan |
| US20070112055A1 (en) * | 2005-09-30 | 2007-05-17 | Glenmark Pharmaceuticals Limited | Crystalline forms of almotriptan and processes for their preparation |
| DE102006027229A1 (de) * | 2006-06-09 | 2007-12-20 | Grünenthal GmbH | 1,3-Disubstituierte 4-Methyl-1H-pyrrol-2-carbonsäureamide und ihre Verwendung zur Herstellung von Arzneimitteln |
| AU2007310949A1 (en) | 2006-10-19 | 2008-04-24 | Auspex Pharmaceuticals, Inc. | Substituted indoles |
| TWI321616B (en) | 2007-03-27 | 2010-03-11 | Coretronic Corp | Centrifugal blower |
| CZ302424B6 (cs) * | 2007-06-13 | 2011-05-11 | Zentiva, A. S. | Zpusob prípravy almotriptanu o vysoké cistote |
| CN101842352A (zh) * | 2007-08-02 | 2010-09-22 | 基因里克斯(英国)有限公司 | 新方法 |
| CN103724252A (zh) * | 2012-10-12 | 2014-04-16 | 苏州四同医药科技有限公司 | 一种阿莫曲坦的制备方法 |
| EP3766483A1 (en) | 2019-07-19 | 2021-01-20 | BioPharma Synergies, S. L. | Orodispersible powder composition comprising a triptan |
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