CN1511029A - 4-(2-氟苯基)-6-甲基-2-(1-哌嗪基)噻吩并[2,3-d]嘧啶用于治疗疼痛的应用 - Google Patents

4-(2-氟苯基)-6-甲基-2-(1-哌嗪基)噻吩并[2,3-d]嘧啶用于治疗疼痛的应用 Download PDF

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CN1511029A
CN1511029A CNA028103785A CN02810378A CN1511029A CN 1511029 A CN1511029 A CN 1511029A CN A028103785 A CNA028103785 A CN A028103785A CN 02810378 A CN02810378 A CN 02810378A CN 1511029 A CN1511029 A CN 1511029A
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pain
treatment
thieno
piperazinyl
fluorophenyl
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CN1230176C (zh
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H��J��ʩ�͵�
H·J·巴德斯雷
R·W·格里斯特伍德
D·卡瓦拉
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Dynogen Pharmaceuticals Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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

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Abstract

4－(2－氟苯基)－6－甲基－2－(1－哌嗪基)噻吩并[2，3－D]嘧啶或其盐用于治疗疼痛。

Description

4-(2-氟苯基)-6-甲基-2-(1-哌嗪基)噻吩并 [2，3-D]嘧啶用于治疗疼痛的应用
发明领域
本发明涉及已知化合物的一种新的治疗应用。
发明背景
4-(2-氟苯基)-6-甲基-2-(1-哌嗪基)噻吩并[2，3-D]嘧啶一水合物盐酸盐是已知的(参见US-A-4695568)并表现出作为抗抑郁剂的活性。它具有血清素和去甲肾上腺素能再摄入-阻断性质，且这些性质可能是其用作抗抑郁剂的机理。该化合物还具有5HT-3阻断活性。
疼痛可以表征为轻度、中度或严重疼痛。它在性质上可以是急性或慢性的。急性疼痛趋于在数分钟或数天内消失，但如果它持续大约两周以上，则通常称其为慢性疼痛。疼痛可以是外伤或炎症导致，这经常被称为感受伤害的疼痛。但是，非简单地由这些原因导致而主要由感觉脉冲的神经功能异常或者功能异常的过程导致的疼痛通常称为神经病性疼痛或神经原性疼痛。
急性感受伤害的疼痛可较好地被非甾类抗炎药(NSAID)如布洛芬控制，如果疼痛轻微则用阿斯匹林控制。对于中度疼痛，曲马朵和可卡因是有用的。对于严重疼痛，鸦片制剂如吗啡很奏效。
通常用NSAID和COX-2抑制剂良好地控制由于炎症导致的轻度至中度慢性感受伤害的疼痛，虽然这些药物可能导致严重的胃溃疡和出血。曲马朵也是非常有效的，但可能导致恶心、呕吐和便秘。对于中度感受伤害的疼痛，鸦片制剂如羟考酮和可待因是有用的，但它们导致便秘。对于严重感受伤害的疼痛，尽管存在呼吸抑制和成瘾的风险，鸦片制剂如吗啡是主流的治疗。
对于神经病性疼痛缺乏充足的治疗，且仅加巴喷丁许可用于此目的。神经病性疼痛急需新的药物。还需要更为安全和强劲的感受伤害的疼痛的止痛剂。
发明概述
令人惊奇的是，已发现以上鉴定的已知化合物(这里称为MCI-225)具有治疗疼痛的活性。其血清素和去甲肾上腺素能再摄入阻断和5HT-3受体阻断的结合在以前未被确认为疼痛活性的原因。可以理解可以使用任何适宜形式的活性成分，例如其它盐形式，或者前药或活性代谢产物。
发明描述
通过本发明可以治疗，例如控制或预防疼痛。为此目的，以任何适宜的方法将活性化合物与常规的稀释剂或载体一起制备。所述活性化合物优选通过口途径给药；其它适宜的给药途径包括舌下/颊、透皮、肌内、鼻内、直肠、肠胃外、皮下、肺和局部给药。活性试剂的有效剂量取决于疾病的性质和程度、患者的年龄和症状和其它本领域技术人员已知的因素。典型的日剂量可以为0.1mg-5mg。
含有活性成分的药物组合物可以是舌下片剂或贴剂的形式。适宜的口用组合物包括片剂、锭剂、糖锭、含水或含油悬浮液、可分散的粉末或颗粒剂、乳剂、硬或软胶囊、糖浆和酏剂。适宜的添加剂包括甜味剂、调味剂、着色剂和防腐剂。片剂包含与以下物质混合的活性成分：无毒的药学上可接受的赋形剂，例如惰性稀释剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如玉米淀粉或海藻酸；粘合剂，例如淀粉、明胶或阿拉伯胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石。片剂可以是未包衣的或者它们可以用已知的技术包衣以延迟在胃肠道中的崩解和吸收，从而提供长期的持续作用。例如，可以使用一种延时材料如一硬脂酸甘油酯或二硬脂酸甘油酯。还可以将它们包衣形成用于控释的渗透性治疗片剂。硬明胶胶囊可以包括惰性固体稀释剂，例如碳酸钙、磷酸钙或高岭土；软明胶胶襄可以包括水或油介质，例如花生油、液体石蜡或橄榄油。
以下的研究已表明了30mg/kg的口服剂量的MCI-225在体内炎性疼痛模型中的止痛活性。所述作用相当于吲哚美辛(1mg/kg)，一种广泛用于慢性疼痛如关节炎疼痛的NSAID的作用。
研究
三组大鼠接受赋形剂、吲哚美辛或MCI-225。每组13只大鼠。根据改良的Randal1 Selitto法诱导炎性疼痛，并使用爪压力痛觉计(analgesiometer)测定发炎爪的痛阈。在给药后1和3小时测定以克为单位的爪后撤的阈值，以克为单位。结果如下表所示。
  组   治疗   剂量(mg/kg)                    发炎爪的组平均(±sd)痛阈(g)
  给药前1小时   给药前2小时   给药后1小时   给药后3小时
  1   赋形剂   0   191.5±88.56   146.5±28.82   135.0±36.23   135.0±34.10
  2   MCI-225   30   147.7±65.91   138.5±34.72   170.8*±39.47   205.4**±68.30
  3   吲哚美辛   1   166.2±68.32   144.2±41.32   200.8*±82.96   210.0*±107.12
  组   治疗  剂量(mg/kg)     给药前读取的痛阈(g)的组平均值变化(±sd)
    给药后1小时     给药后3小时
  1   赋形剂     0     -11.5±50.56     -11.5±38.32
  2   MCI-225     30     32.3*±56.41     66.9**±65.85
  3   消炎痛     1     56.5**±56.18     65.8*±95.17
sd＝标准偏差
与赋形剂治疗组差异的统计学上的显著性：*p＜0.05，**p＜0.0 1。
结果表明MCI-225能够将痛阈在1小时时增加32.3g，在3小时时增加66.9g。在相同的时间间隔内在这些值和赋形剂的值之间存在统计学上显著的差异。据此MCI-225可用于治疗炎性疼痛和其它疼痛。

Claims (4)

1.4-(2-氟苯基)-6-甲基-2-(1-哌嗪基)噻吩并[2，3-D]嘧啶或其盐用于制备治疗疼痛的药物的应用。
2.根据权利要求1的应用，其中所述该盐为一水合物盐酸盐。
3.根据权利要求1或2的应用，其中所述疼痛为感受伤害疼痛。
4.根据权利要求1或2的应用，其中所述疼痛为神经病性疼痛。
CNB028103785A 2001-05-22 2002-05-21 4－(2－氟苯基)－6－甲基－2－(1－哌嗪基)噻吩并[2,3－d]嘧啶用于制备治疗疼痛的药物的应用 Expired - Fee Related CN1230176C (zh)

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GBGB0112494.0A GB0112494D0 (en) 2001-05-22 2001-05-22 New therapeutic use

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JP (1) JP3749519B2 (zh)
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AT (1) ATE359769T1 (zh)
AU (1) AU2002307872B2 (zh)
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CA (1) CA2447465A1 (zh)
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GB0216027D0 (en) 2002-07-10 2002-08-21 Arachnova Therapeutics Ltd New therapeutic use
US20040087642A1 (en) * 2002-10-24 2004-05-06 Zeldis Jerome B. Methods of using and compositions comprising a JNK inhibitor for the treatment, prevention, management and/or modification of pain
DE602004005814T2 (de) 2003-01-13 2008-01-10 Dynogen Pharmaceuticals Inc., Waltham Verfahren zur behandlung von übelkeit, erbrechen, würgereiz oder jede kombination daraus
WO2004062623A2 (en) * 2003-01-13 2004-07-29 Dynogen Pharmaceuticals, Inc. Method of treating functional bowel disorders
EP1539181B1 (en) 2003-04-04 2007-06-27 Dynogen Pharmaceuticals Inc. Method of treating lower urinary tract disorders
EP1795196A3 (en) * 2003-04-04 2008-02-06 Dynogen Pharmaceuticals, Inc. Method of treating lower urinary tract disorders

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WO2002094249A1 (en) 2002-11-28
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BR0209956A (pt) 2004-04-20
JP2004531557A (ja) 2004-10-14
ES2283598T3 (es) 2007-11-01
ATE359769T1 (de) 2007-05-15
CN1230176C (zh) 2005-12-07
GB0112494D0 (en) 2001-07-11
CA2447465A1 (en) 2002-11-28
EP1390022A1 (en) 2004-02-25
JP3749519B2 (ja) 2006-03-01
DE60219616T2 (de) 2008-01-31
KR20040012808A (ko) 2004-02-11
DE60219616D1 (de) 2007-05-31
SI1390022T1 (sl) 2007-08-31
PT1390022E (pt) 2007-05-31
EP1390022B1 (en) 2007-04-18

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