CN1105858A - 治疗休克的嘧啶酮和咪唑啉酮 - Google Patents

治疗休克的嘧啶酮和咪唑啉酮 Download PDF

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CN1105858A
CN1105858A CN94108290A CN94108290A CN1105858A CN 1105858 A CN1105858 A CN 1105858A CN 94108290 A CN94108290 A CN 94108290A CN 94108290 A CN94108290 A CN 94108290A CN 1105858 A CN1105858 A CN 1105858A
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维多利亚·L·科汉
埃里克·R·佩蒂弗
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    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Abstract

分子式如Ⅰ的化合物及其药用酸加成盐，在治疗 休克和其它与TNFα有关的病症中是有效的，其中X、m、n、R1、R2、R3和R4如本文所定义。

Description

本发明涉及一种用某些嘧啶酮和咪唑啉酮治疗休克和抑制哺乳动物体内α肿瘤坏死因子（TNFα）生成的方法。
本发明所用的嘧啶酮和咪唑啉酮作为抗抑郁剂已在专利文献US5，128，358中公开，该专利文献一并作为参考文献。文献WO    91/07178公开了这些化合物在治疗气喘、炎症和皮肤病中的用途。但它们在治疗休克和TNFα方面的作用没有在上述文献中公开过。
按照本发明，通过供给需抑制TNFα生成的受试者如下分子式的化合物或含一个碱性N原子的该化合物的药用酸加成盐，可以抑制TNFα的生成，用量要足以满足上述治疗的需要。
Figure 941082903_IMG4
上述分子式中
X是O或NH；
m是0、1或2；
n是0、1或2；
m和n是1或2；
R1是C7～C11三环烷基或C7～C11二环烷基；
R2是甲基或乙基；
R3是H、C1～C3烷基、C2～C3链烯基、苄基或苯乙基；
R4是H、C1～C3烷基或C2～C3链烷酰基；条件是当m+n为1时，m为0，n为1，当m+n为2时，则R3和R4分别为H原子。
在一优选方案中，所用化合物为5-（3-[（2S）-外双环[2，2，1]庚-2-基氧]-4-甲氧苯基）-3，4，5，6-四氢嘧啶-2（1H）-酮。
在本发明的一个更具体的实施例中，按上述定义分子式Ⅰ的化合物用于治疗休克。
分子式Ⅰ化合物及其可药用的酸加成盐（活性化合物）和这些化合物的制备已在专利US 5，128，358中公开。如该专利所述，手性中心存在于几个多环烷基基团R1和嘧啶酮或咪唑啉酮基团中。本发明方法所用的分子式Ⅰ化合物也包括外消旋非对映的结构和各个光学异构体。
上述活性化合物抑制TNFα的生成，因而可用于过量或无规律的TNFα生成导致疾病的治疗，如脓毒性休克、出血性休克、风湿性关节炎、HIV感染、2型糖尿病的抗胰岛素性、炎性疾病、成人呼吸窘迫症、肾透析后综合症及骨髓移植后的移植性抗宿主病。
此处所指的治疗包括对疾病的预防和缓解。
该活性化合物可通过各种常规给药途径给到需要治疗的受试者，包括口服、肠胃外投药和局部给药。一般情况下，该活性化合物的口服或肠胃外给药剂量为每天按受治疗者体重计每公斤给药0.1到25毫克之间，最佳量为0.3到5mg/kg。然而，根据受治疗者条件的不同，给药剂量会有某些变化。任何情况下，负责给药的人将为个别的病人确定合适的剂量。
活性化合物可以单独施用，或以单剂量或复合剂量与药用可接受的载体结合施用。合适的药用载体包括惰性固体稀释剂或填充剂、无菌水溶液及不同的有机溶剂。活性化合物与药用载体形成的药物组合物可方便地以各种不同的剂型给药。如片剂、粉剂、糖衣片、糖浆、注射液等等。
如果需要，这些药物组合物可包含其它添加成分如调味剂、结合剂、赋形剂等。因此，为了口服给药的目的，含不同赋形剂的片剂可与不同的崩解剂及不同的结合剂一起使用，其中赋形剂如柠檬酸钠、碳酸钙和磷酸钙，崩解剂如淀粉、藻酸和某些复合硅酸盐，结合剂如聚乙烯吡咯烷酮、蔗糖、凝胶和金合欢胶。另外，制片剂时，润滑剂常常是有用的，如硬脂酸镁、十二烷基硫酸钠和滑石。同类的固体成分也可用作软和硬填充凝胶胶囊的填充物。用于此目的的最佳材料包括乳糖和高分子量的聚乙二醇。当口服给药需用液体悬浮液或酏剂时，其中的基本活性成分可与各种甜味剂或调味剂、色素或染料、及如果需要与乳化剂或悬浮剂结合，同时与稀释剂如水、乙醇、丙烯基乙二醇、丙三醇及其组合一起使用。
对于肠胃外给药，可使用活性化合物在芝麻油或花生油、或含水丙烯基乙二醇、或无菌水溶液中的溶液。这样的水溶液应该在必要时适于缓冲，液体稀释剂应先变成与盐或葡萄糖等渗的。这些特殊的水溶液特别适于静脉、肌肉、皮下和腹腔内给药。所用的无菌水溶液介质都能用标准技术制得。
活性化合物抑制TNFα生成的能力如下所述。
实施例
通过腹膜内注射0.3mg脂多糖（E.coli，0111：B4）在雌性Balb/c小鼠（20～25g）身上诱发内毒素休克，不时进行存活观察直到72小时。在诱导内毒素休克前0.5小时，以0.5%羧甲基纤维素为载体，用口服管饲法喂药。
腹膜内给予0.3mg脂多糖（E.coli，0111：B4）1小时后，从Balb/c鼠内抽取血清并用ELISA法检测TNFα。在注射脂多糖前0.5小时，以0.5%羧甲基纤维素为载体，用口服管饲法喂药。
用Ficoll/Hypaque法从人体外周血中分离出单核细胞，并粘着到聚苯乙烯板上。粘附细胞在用LPS（10ng/ml）刺激18小时以前，与5-（3-[（2S）-外双环[2，2，1]庚-2-基氧]-4-甲氧苯基）-3，4，5，6-四氢嘧啶-2（1H）-酮在37℃下培养1小时。TNFα的释出在稀释的培养上清液中用夹心ELISA法（R    &    D，Minneapolis    MN）检测。
可以发现，5-（3-[（2S）-外双环[2，2，1]庚-2-基氧]-4-甲氧苯基）-3，4，5，6-四氢嘧啶-2（1H）-酮抑制了（1）鼠内毒素休克的死亡率和TNFα生成（ED50=4.1mg/kg    口服），及（2）体外人体单核细胞的TNFα释出（IC50=0.12±0.05μm，n=4）。

Claims (4)

1、一种抑制肿瘤坏死因子α生成的方法，包括对需要这种抑制的受治疗者提供一种以下分子式的化合物：
Figure 941082903_IMG2
或含一个碱性N原子的该化合物的药用酸加成盐，用量要足以满足上述治疗的需要，
其中
X是O或NH；
m是0、1或2；
n是0、1或2；
m和n是1或2；
R1为C7～C11三环烷基或C7～C11二环烷基；
R2是甲基或乙基；
R3是H、C1～C3烷基、C2～C3链烯基、苄基或苯乙基；
R4是H、C1～C3烷基或C2～C3链烷酰基；条件是当m+n为1时，m为0，n为1，当m+n为2时，则R3和R4分别为H。
2、根据权利要求1所述的方法，其中所述的化合物是5-（3-[（2S）-外双环[2，2，1]庚-2-基氧]-4-甲氧苯基）-3，4，5，6-四氢嘧啶-2（1H）-酮。
3、一种治疗休克的方法，包括对需要这种受治疗者提供一种以下分子式的化合物：
Figure 941082903_IMG3
或含一个碱性N原子的该化合物的药用酸加成盐，用量足以满足该治疗所需的量，
其中
X是O或NH；
m是0、1或2；
n是0、1或2；
m和n是1或2；
R1是C7～C11三环烷基或C7～C11二环烷基；
R2是甲基或乙基；
R3是H、C1～C3烷基、C2～C3链烯基、苄基或苯乙基；
R4是H、C1～C3烷基或C2～C3链烷酰基；条件是当m+n为1时，m为0，n为1，当m+n为2时，则R3和R4分别为H。
4、根据权利要求3所述的方法，其中所述化合物为5-（3-[（2S）-外双环[2，2，1]庚-2-基氧]-4-甲氧苯基）-3，4，5，6-四氢嘧啶-2（1H）-酮。
CN94108290A 1993-07-13 1994-07-13 治疗休克的嘧啶酮和咪唑啉酮 Pending CN1105858A (zh)

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US08/091,693 US5482944A (en) 1993-07-13 1993-07-13 Pyrimidones and imidazolinones for treatment of shock
US08/091,693 1993-07-13

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CA (1) CA2127735A1 (zh)
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US5563143A (en) * 1994-09-21 1996-10-08 Pfizer Inc. Catechol diether compounds as inhibitors of TNF release

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DE3315797A1 (de) * 1983-04-30 1984-10-31 Beiersdorf Ag, 2000 Hamburg Substituierte phenyl-2-(1h)-pyrimidinone, verfahren zu ihrer herstellung und ihre verwendung sowie diese verbindungen enthaltende zubereitungen
US4971959A (en) * 1987-04-14 1990-11-20 Warner-Lambert Company Trisubstituted phenyl analogs having activity for congestive heart failure
RU2104306C1 (ru) * 1989-11-13 1998-02-10 Пфайзер Инк. Способ получения оптически активного (2s)- или (2r)-эндо-бицикло[2.2.1]гептан-2-ола, способ получения 5-(3-[(2r)-экзо-бицикло[2.2.1]гепт-2-илокси]-4-метоксифенил)-3,4,5,6-тетрагидропиримидин-2(1н)-она, оптически активный 5-(3-[экзо-бицикло[2.2.1]гепт-2-илокси]4-метоксифенил)-3,4,5,6-тетрагидропиримидин-2(1н)-он, оптически активные промежуточные соединения и способ их получения
WO1991007177A1 (en) * 1989-11-13 1991-05-30 Pfizer Inc. Pyrimidone derivatives and analogs in the treatment of asthma or certain skin disorders
KR930703262A (ko) * 1990-11-06 1993-11-29 스튜어트 알. 슈터 이미다졸리디논 화합물

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