CN1092961C - 具有抗高血糖作用的药物 - Google Patents

具有抗高血糖作用的药物 Download PDF

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CN1092961C
CN1092961C CN95107767A CN95107767A CN1092961C CN 1092961 C CN1092961 C CN 1092961C CN 95107767 A CN95107767 A CN 95107767A CN 95107767 A CN95107767 A CN 95107767A CN 1092961 C CN1092961 C CN 1092961C
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moxonidine
blood
hyperglycemia
acid
pharmaceutical
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CN1122224A (zh
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E·坎
D·兹格勒
R·布略克诺
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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
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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Abstract

本文叙述了莫索尼定及其药用酸加合盐用于制备治疗和(或)预防高血糖症的药物制剂。

Description

具有抗高血糖作用的药物
本发明涉及4-氯-5-[(4，5-二氢-1H-咪唑-2-基)-氨基]-6-甲氧基-2-甲基嘧啶(莫索尼定)及其药用酸加合盐的应用，用于治疗和(或)预防高血糖症，也涉及治疗这种疾病的适宜药物的制备。
本发明目的是开发新的用于治疗可导致高血糖症的代谢失调的新的药物制剂。
按本发明，式I的4-氯-5-[(4，5-二氢-1H-咪唑-2-基)-氨基]-6-甲氧基-2-甲基嘧啶及其药用酸加合盐用于制备药物制剂，以治疗高血糖症。
Figure C9510776700031
作为莫索尼定的药用酸加合盐，适宜的盐是与无机酸形成的盐例如氢卤酸盐，或与有机酸成盐例如与低碳脂族一元或二元羧酸，如乙酸、富马酸或酒石酸，或芳香羧酸，如水杨酸所成的盐。
用于治疗高血糖状态的、本发明提及的化合物处在德国专利NO.2849537叙述的具有降压性质的5-[(2-咪唑啉-2-基)-氨基]-嘧啶衍生物的范围内，并从此专利中是已知的。含有莫索尼定的药剂作为降血压药以商品名Physiotens出售，医药上作为降压药而应用。这类化合物可按已知方式，按照上述德国专利所述的方法或类似的方法制备。
现在意外地发现，莫索尼定及其药用酸加合盐对于人及大哺乳类具有抗高血糖作用，并且适于治疗各种遗传代谢障碍所伴随的高血糖症，例如由于提高了葡萄糖的释放和(或)降低了葡萄糖的代谢利用，而出现的血浆中提高的葡萄糖水平，这些都与高血压、胰岛素抗性、葡萄糖非耐受性，II型糖尿病和(或)肥胖症有关。
按照本发明，为了治疗高血糖状态，莫索尼定及其药用酸加合盐可以常规药用剂型口服、静脉注射或透皮吸收。
为此，本发明化合物的有效抗高血糖剂量与常规的药用助剂和(或)载体制成固体或液态药物剂型。作为固体制剂的例子是口服制剂，如片剂、包衣剂、胶囊剂、粉剂或颗粒剂，或用栓剂。这些固体制剂除药用常规助剂例如润滑剂或片剂崩解到外，还可含有药用无机和(或)有机载体如乳糖、滑石粉或淀粉，液态制剂如有效成分的溶液、悬浮液、乳剂，可含有常规的稀释剂如水，油类，和(或)悬浮剂如聚乙二醇等等。此外还可含有其它助剂，如防腐剂、矫味剂等等。
该有效成分可与药用助剂和(或)载体按常规方法混合，制成制剂。为了制备固体药剂，有效成分可与例如助剂和(或)载体按常规方法混合并制成湿颗粒或干颗粒。颗粒或粉末可直接装入胶囊中，或按常规方法打成片核。还可根据需要按已知方法加以包衣。
莫索尼定的抗高血糖作用是用动物试验和不同级别的高血糖症患者的临床研究加以确证的。
临床研究是用双盲法总教228患者六周时间进行的。
患者随机分成四组。所有患者服用片剂，每日2次，每次1片。预试验期的4周，所有患者服用安慰剂片剂。在特定的试验期，设一对照组(K组)服用安慰剂片。第1试验组(1组)服用的片剂，每片含0.1mg莫索尼定，第2试验组(2组)服用量为每片含莫索尼定0.2mg，第3试验组(3组)服用的每片含莫索尼定0.4mg。每个患者在开始试验的第1天空腹取血，6周后的最后一天空腹取血。测定血浆中糖含量，按每1/10升葡萄糖mg数计算。
为了评价测定结果，将4个组的每个组再分成2个亚组：A)具有初始血浆葡萄糖正常值的先证者，范围为≤115mg/dlB)具有初始血浆葡萄糖病理学高水平的先证者，范围为＞115mg/dl。这个亚组包括的患者是略提高的初始血浆葡萄糖值，范围为115～139mg/dl和明显提高的初始血浆葡萄糖值，为糖尿病范围(≥140mg/dl)。糖尿病患者亚组B1)的测定结果还要逐个地评价。
下表列出了所有研究组的血浆葡萄糖测定的统计学计算的平均值(±标准误差)：
血浆葡萄糖值的变化
给药 患者分组 患者人数           血浆葡萄糖水平(mg/dl)(平均值±标准误差)
        初值       终值
安慰剂      KAKBKB1     4991        94(±1)134(±5)172      93(±2)129(±6)174
0.1mg莫索尼定每日二片      1A1B1B1     5271        95(±1)131(±8)183      93(±2)117(±4)103
0.2mg莫索尼定每日二片      2A2B2B1     45106        93(±2)170(±17)198(±21)      95(±2)134(±8)144(±12)
0.4mg莫索尼定每日二片      3A3B3B1     46102        92(±2)130(±5)158(±7)      91(±2)120(±10)139(±28)
上表清楚地表明，在受试期间，只有那些服用安慰剂的所有患者初始血浆葡萄糖值实际上没有变化。不同剂量莫索尼定治疗患者结果表明，具有正常的初始血浆葡萄糖值的患者实际没有变化，而初始血浆葡萄糖值高的患者，经莫索尼定治疗后血浆葡萄糖值明显回降，初始血浆葡萄糖值越高，回降值越大。
以上试验结果表明，莫索尼定呈现有抗高血糖作用，使提高的血糖值下降，但不影响正常的血糖值。该试验结果作为指标还表明，莫索尼定对胰岛素抗性有良好作用。因此，莫索尼定及其酸加合盐适于治疗高血糖症。
应用剂量可依具体情况而不同，并可依待处理的状态的性质和给药形式而变化。通常对人体口服给药来治疗高血糖状态而言，日剂量处于0.2-0.8mg，优选0.4-0.8mg的范围是适宜的。
以下实施例对用于处理高血糖状态的、含莫索尼定的药物制剂的制备进行详细解释，但不限制本发明的范围。
实施例1含莫索尼定的膜包衣片剂组成：片芯：莫索尼定                                        0.020份乳糖                                            9.580份聚乙烯吡咯烷酮USP                               0.070份交联聚乙烯吡咯烷酮USP(Cros-                     0.300份povidone USP)硬脂酸镁                                        0.030份(水                                             0.750份)总固体物质                                      10.000份膜包衣物组成：羟丙基甲基纤维素                                0.156份30％乙基纤维素水分散体                          0.480份(△固体物质)                                    (0.144)份聚乙二醇6000                                    0.030份二氧化钛                                        0.150份滑石                                            0.1197份红色氧化铁                                      0.0003份(水                                             3.864份)总固体物质                                      0.600份膜包衣悬浮物总量                                4.800份使用4.8kg前述膜包衣悬浮物使10,000片芯涂敷至每片100mg重量。片芯制备：
将莫索尼定和乳糖混合，用粘结剂聚乙烯吡咯烷酮在水中的一种溶液使该混合物彻底润湿，充分捏合，得到的产物摊于架上，并在约50℃的温度下干燥至湿份含量最高为0.5％。干燥后的产品经过0.75mm筛(Frewitt-机)。在得到的颗粒与交联聚乙烯吡咯烷酮和硬脂酸镁混合后，将其压成重量为100mg的片芯，这样，各个片芯含0.2mg有效成分。膜包衣悬浮物的制备：
羟丙基甲基纤维素和聚乙二醇6000溶解于部份水中。在搅拌下向该溶液中加入由滑石、二氧化钛和氧化铁于其余水中形成的悬浮液。得到的悬浮物在轻度搅拌下用30％乙基纤维素水分散体稀释。片芯的膜包衣：
在用约70℃的热空气使这种片芯加热到约45℃的情况下，在一个涂膜设备中，将上述膜包衣悬浮物喷涂于片芯上。随后在约45℃下将膜包衣了的片芯干燥16个小时。

Claims (1)

1.式I的4-氯-5-[(4，5-二氢-1H-咪唑-2-基)-氨基]-6-甲氧基-2-甲基嘧啶及其药用酸加合盐的应用，
Figure C9510776700021
用于制备治疗高血糖症的药剂。
CN95107767A 1994-07-01 1995-06-30 具有抗高血糖作用的药物 Expired - Fee Related CN1092961C (zh)

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US5977121A (en) * 1995-02-28 1999-11-02 Eli Lilly And Company Use of moxonidine for the treatment of atherosclerosis
PL330637A1 (en) * 1996-06-06 1999-05-24 Lilly Co Eli Agent for and method of treating hypostatic cardiac insufficiency
CA2229123A1 (en) * 1997-02-11 1998-08-11 Mitchell Irvin Steinberg Pharmaceutical agents
DE19722322A1 (de) * 1997-05-28 1998-12-03 Solvay Pharm Gmbh Nephroprotektives Arzneimittel
EP0919234A3 (en) * 1997-10-17 1999-08-25 Eli Lilly And Company Potentiation of pharmaceuticals by moxonidine
US6897019B1 (en) * 1998-04-17 2005-05-24 Tufts College Methods for treating and preventing insulin resistance and related disorders
AU2727400A (en) * 1999-01-29 2000-08-18 Eli Lilly And Company Moxonidine salts
DE19911371A1 (de) 1999-03-15 2000-09-21 Solvay Pharm Gmbh Arzneimittel zur Behandlung von funktionellen Störungen und Erkrankungen der unteren Darmwege, insbesondere von damit einhergehenden abdominalen visceralen Schmerzen
AU2003257418A1 (en) * 2002-06-19 2004-01-06 Solvay Pharmaceuticals Gmbh Medicament for the treatment of diseases requiring inhibition or a reduction in the activity of ph value-regulating bicarbonate transporter proteins
BRPI0415198A (pt) * 2003-10-10 2006-12-05 Solvay Pharm Gmbh composição farmacêutica compreendendo um agonista seletivo do receptor da imidazolina i1 e um bloqueador do receptor da angiotensina ii
RU2542462C2 (ru) * 2013-06-28 2015-02-20 Андрей Владиславович Струтынский Способ коррекции кризового течения гипертонической болезни и абдоминального ожирения

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DE2849537A1 (de) * 1978-11-15 1980-05-22 Beiersdorf Ag Substituierte 5-(2-imidazolin-2-yl)- aminopyrimidine und verfahren zu deren herstellung

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US4323570A (en) * 1978-11-15 1982-04-06 Beiersdorf Aktiengesellschaft Substituted aminopyrimidines
FR2669927B1 (fr) * 1990-11-29 1994-04-08 Adir Cie Nouveaux derives de guanidine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.

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DE2849537A1 (de) * 1978-11-15 1980-05-22 Beiersdorf Ag Substituierte 5-(2-imidazolin-2-yl)- aminopyrimidine und verfahren zu deren herstellung

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DE4423177A1 (de) 1996-01-04
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IL113411A0 (en) 1995-07-31
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ATE210444T1 (de) 2001-12-15
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JP3841846B2 (ja) 2006-11-08
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US5712283A (en) 1998-01-27
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AU1775795A (en) 1996-01-18
IL113411A (en) 1999-07-14
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ZA954691B (en) 1996-01-29
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CN1122224A (zh) 1996-05-15
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