CN1117492A - 幽门螺杆菌感染的治疗 - Google Patents

幽门螺杆菌感染的治疗 Download PDF

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CN1117492A
CN1117492A CN95103628A CN95103628A CN1117492A CN 1117492 A CN1117492 A CN 1117492A CN 95103628 A CN95103628 A CN 95103628A CN 95103628 A CN95103628 A CN 95103628A CN 1117492 A CN1117492 A CN 1117492A
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A·E·吉拉德
T·D·古茨
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Abstract

分子式I的一种化合物及其药物可接受的酸加成盐可成功地治疗螺杆菌感染，其中R1为氢或者甲基，R2为氢或者L-丙氨酸-L-丙氨酰。该类化合物可用来治疗胃及十二指肠溃疡。

Description

幽门螺杆菌感染的治疗
本发明涉及一种新的螺杆菌感染的治疗方法，即使用已知的二氮杂萘羧酸抗菌化合物治疗螺杆菌感染；以及一种新的胃及十二指肠溃疡的治疗方法，即以上述已知的化合物治疗胃及十二指肠溃疡。
1982年发现的致病菌幽门螺杆菌目前认为是导致人类胃及十二指肠溃疡的原因所在。临床实验表明清除该菌可使溃疡愈合并且降低复发率。虽然离体情况下许多抗菌制剂可独自抑制螺杆菌生长，但人及动物的体内实验表明当这些制剂单独使用时通常不能达到抑菌作用。
相应的细菌可引起动物感染。例如貂科螺杆菌为雪貂的病原菌，而猫科螺杆菌为猫的病原菌。
本发明所用的化合物披露于美国专利NO.5,164,402。
本发明涉及一种幽门螺杆菌感染的治疗方法，即给患者服用有效剂量的下式化合物及其药物可接受的酸加成盐活性化合物。
Figure A9510362800051
其中R1为氢或者甲基，R2为氢或者L—丙氨酸—L—丙氨酰。
在本发明具体实施方案中，活性化合物为7—([1a，5a，6a]—6—氨基—3—氮杂双环[3.1.0]己—3—基)—1—(2，4—二氟苯基)—6—氟—1，4—二氢—4—氧—1，8—二氮杂萘—3—羧酸甲磺酸盐。
本发明还涉及一种胃及十二指肠溃疡的治疗方法，即给患者服用有效剂量的活性化合物。更具体的讲，所用化合物为7—([1a，5a，6a]—6—氨基—3—氮杂双环[3.1.0]己—3—基)—1—(2，4—二氟苯基)—6—氟—1，4—二氢—4—氧—1，8—二氮杂萘—3—羧酸甲磺酸盐。
该活性化合物及其制备可参见美国专利号，5,164,402。
根据美国专利号5,164,402披露，式I的化合物形成药物可接受的酸加成盐。所有这些盐都在本发明范围内，并可按美国专利号5,164,402中描述的那样制备。适合的酸如下：乙酸，乳酸，琥珀酸，马来酸，酒石酸，柠檬酸，葡糖酸，抗坏血酸，苯甲酸，甲磺酸，对甲苯磺酸，肉桂酸，富马酸，磷酸，盐酸，氢溴酸，氢碘酸，氨基磺酸，及磺酸。
根据本发明，该活性化合物还可与一种附加的抗微生物制剂结合，例如硝基咪唑类抗生素，如硝基砜咪唑及灭滴灵；四环素类，如四环素，强力霉素及二甲胺四环素；青霉素类，如羟氨苄青霉素，氨苄青霉素及磺唑氨苄青霉素；头孢菌素类，如头孢氯，羟氨苄头孢菌素，头孢拉定(Cephadrine)，头孢氨呋肟，头抱呋新酯，头孢氨苄，头孢波肟酯，头孢噻甲羧肟及头抱三嗪噻肟；羧苄青霉素类，如伊米配能及麦罗派南；氨基糖甙类，如巴龙霉素；大环内酯类抗生素，如红霉素，甲氧基红霉素及阿泽红霉素；林可霉素类抗生素，如氯洁霉素；利福霉素类，如利福平；以及呋喃
Figure A9510362800061
啶。本发明还包括该有效化合物与治疗有关酸紊乱的药用化合物结合，例如酸泵抑制剂包括奥美拉唑及郎素那唑，或者Hz受体拮抗剂包括雷尼替丁，西咪替丁及法莫替丁。
根据本发明较好的结合为7—([1a，5a，6a]—6—氨基—3—氮杂双环[3.1.0]己—3—基)—1—(2，4—二氟苯基)—6—氟—1，4—二氢—4—氧基—1，8—二氮杂萘—3—羧酸甲磺酸盐与羟氨苄青霉素。
根据本发明第二种结合为7—([1a，5a，6a]—6—氨基—3—氮杂双环[3.1.0]己—3—基)—1—(2，4—二氟苯基)—6—氟—1，4—二氢—4—氧基—1，8—二氮杂萘—3—羧酸甲磺酸盐和四环素。
根据本发明第三种优选的结合为7—([1a，5a，6a]—6—氨基—3—氮杂双环[3.1.0]己—3—基)—1—(2，4—二氟苯基)—6—氟—1，4—二氢—4—氧基—1，8—二氮杂萘—3—羧酸甲磺酸盐和奥美拉唑。
该类活性化合物在治疗人类幽门螺杆菌及动物相应的螺杆菌感染中是有用的。这些活性化合物也用于治疗胃及十二指肠溃疡。这里“治疗”的意思包括灭除螺杆菌微生物及缓解胃及十二指肠溃疡。
本发明中的该类活性化合物可以单独服用，但通常将以与一种药剂载体混合物的形式服用，而载体的选择则根据拟服用的途径及标准的药剂做法而定。例如口服该类活性化合物或以片剂的形式口服，其中片剂含赋形剂如淀粉或乳糖，或以胶囊的形式单独或与赋形剂混合物的形式口服，或以酏剂或混悬液的形式(其中含有调味剂及着色剂)给药。该类活性化合物用于动物时，最好将其掺入动物的食品及饮水中，浓度范围为5—5000ppm，最好在25—500ppm之间。
该类活性化合物中的R2为L—丙氨酸—L—丙氨酰时可以注射非肠道给药，例如肌内，静脉或皮下注射给药。非胃肠途径给药时，最好以无菌溶液的形式使用，其中可含一些溶质例如足够量的盐或者葡萄糖以使溶液等渗。给动物使用时，可以从肌肉或者皮下给药，剂量范围控制在0.1—50mg/kg/天，最好在1—5mg/kg/天，可每天1次给予或分3次给予。
本发明的该类化合物给人服用时，即可口服，也可采用非胃肠途径给药，口服给药时剂量范围控制在0.1—50mg/kg/天，最好1—5mg/kg/天1次或分3次给予。肌肉或静脉途径给药时，剂量范围控制在0.1—50mg/kg/天，最好1—5mg/kg/天。肌肉注射给药时，可1次或分3次给予，静脉给药时可以连续静点。根据服用者的体重和情况可做必要的变化，给药途径也应由本领域技术人员选择。
该类化合物的活性在体外可通过以下程序测得。抗菌剂的琼脂稀释液
将待评价的化合物6mg溶于0.6ml100％的二甲亚砜(DMSO)中，然后将其加入6ml的无菌布氏肉汤中并注意其溶解性。DMSO的最终浓度为总体积的10％。然后在无菌的布氏肉汤中进行系列的倍比稀释(3ml化合物+3布氏肉汤)。各取上述系列稀释液2ml分别加入到无菌的佩特里培养盘中，再向其中加入18ml熔化后冷却(约50℃)的含有7％马血的布鲁氏菌琼脂。最后在琼脂中化合物的稀释度为1∶10。例如，如果最高浓度(第1个液体培养稀释液)含有1000μg/ml，并且在琼脂中以1∶10稀释，琼脂中药物的最后浓度为100μg/ml。琼脂盘可在接种前的1天制备，但需冷冻过夜。接种物的制备
幽门螺杆菌可在含有胰蛋白酶大豆—5％羊血琼脂盘内持续培养，每48小时转种1次。貂科螺杆菌也可在同样的琼脂上持续培养，且根据前1次转种时的生长程度每48—60小时转种1次。培养盘与水激活的(10ml)CampyPak Plus(BBL Microbio.Systems)及钯催化剂一起放入密封的GasPak罐中在37℃温度下培养。
螺杆菌可在10ml含有10％的小牛血清的布鲁菌液体培养液在一种深的佩特里培养盘中培养。可将这些培养盘与水激活的CampyPak Plus及钯催化剂一起放入GasPak罐内封存并置于一震荡器(50rpm)上37℃温度条件下培养18—20小时。
将过夜的培养物(约108CFU/ml)在一带有螺帽的试管内以布氏肉汤稀释10倍(没有FCS)并以此做为标准接种物。将稀释的细菌0.8ml加入Steere复制板的孔内，并将0.002ml约含2×104个细菌的菌液置于琼脂表面。将已接种的盘子与水激活的(10ml)CampyPakPlus及钯催化剂一起放入一GasPak罐中37℃封存孵育48小时。结果的解释
孵育后，所有测试的盘子与不含化合物的生长对照盘比较。MIC即是与对照盘比较抑制生长的浓度。在较高浓度时可见一生长薄膜，但这并不算数，不能做为真正的MIC。对照细菌也在每个盘子内孵育，并且将其稀释1000倍以做为接种物使用。对照细菌包括空肠弯曲菌(#6686)，大肠杆菌的筛选培养物(#51A266和#51A470)，产气肠杆菌(#67A040)，阴沟肠杆菌(#678009)，斯徒普罗威登氏菌(#77A013)，及雷极普罗威登氏菌(#77C025)。盘子和/或接种物离开微量需氧的环境不能超过2小时。此外还建议包括螺杆菌培养在内的所有操作应在一层流动通风橱内进行，以减少霉菌污染培养物的机会。
Lee等人的小鼠模型，胃肠病学，99，1315—23(1990)可用来预测一种化合物在人体内对抗幽门螺杆菌的活性。
猫科螺杆菌可生长在含有10％的小牛血清的布氏肉汤内。很快地解冻已冻结的培养液；检查细菌的机能性，并将0.5cc解冻的培养液接种在含有9.5cc的布鲁氏菌/血清混合液的一种深的组织培养盘内，将盘子放入一Campy Pak罐[BBL]内以确保一个微需氧的环境。将此罐置于转速为60RPM的旋转混匀器上在37℃的条件下孵育。18小时后应见到混浊。以一(相)显微镜检查细菌的纯度及机动性，然后倒入一烧瓶中。在感染之前使Swiss—Webster雌鼠(18—20g)禁食18小时。在1周内隔日3次感染小鼠。在最后1次感染小鼠2周后开始服药。治疗为每日服药1次连续服用14天。治疗结束后约3周处死动物。将胃切下并沿胃大弯切开。从胃窦区取一组织块(3mm，组织块)。冲洗组织块表面，切碎并放入含有100微升脲酶的试管中。脲酶试剂为Hazell等人制备的，美国胃肠病学杂志，82，292—296(1982)。脲酶试剂(pH6.3—6.5)含尿素及酚红。如果有螺杆菌存在，脲酶可分解尿素引起pH改变。紫色(碱性)为螺杆菌阳性；红/黄(无变化)为阴性。18小时后记录颜色变化。一般每个治疗组20只小鼠；记录每组阳性的百分比。
在临床上有多种方法可确定人体内是否有幽门螺杆菌存在。这些方法用来在治疗前进行感染的初始诊断，还用来确定灭除病人体内的细菌的治疗是否成功。
尿素呼吸试验包括消化同位素标记的尿素。幽门螺杆菌产生可降解尿素的脲酶；而哺乳类胃细胞中不含此酶。因此可通过标记二氧化碳的产生(根据所采用的同位素，经质谱仪或放射性分析)确定幽门螺杆菌的存在。
也可用血清学检查来确定是否有幽门螺杆菌感染。可采用酶连免疫分析法(ELISA)测出幽门螺杆菌的血清抗体，如1gG和1gA。有许多种不同的幽门螺杆菌蛋白质可做为抗原。
病人的内窥镜检查可提供组织标本，这些标本在微需氧环境中培养可诊断是否为幽门螺杆菌感染。也可将标本吉姆萨或苏木精—伊红染色进行组织学检查。还可以采用尿素试验，该试验也是利用了幽门螺杆菌可产生脲酶这一点。该试验主要是依据尿素水解后形成氨气，导致pH改变而出现可观察到的变化。

Claims (6)

1.将式(I)化合物用于制备治疗(i)幽门螺杆菌感染或(ii)胃及十二指肠溃疡的药物的方法，其包括有效治疗量的式I化合物及药用酸加成盐，
Figure A9510362800021
其中R1为氢或者甲基，R2为氢或者L—丙氨酸—L—丙氨酰。
2.权利要求1用途，其中所述的化合物为7—([1a，5a，6a]—6—氨基—3—氮杂双环[3.1.0]己—3—基)—1—(2，4—二氟苯基)—6—氟—1，4—二氢—4—氧基—1，8—二氮杂萘—3—羧酸甲磺酸盐。
3.权利要求1所述的用途，其中R2为L—丙氨酸—L—丙氨酰，所述的化合物为非胃肠道途径服用。
4.根据权利要求1到3的用途，其中I的化合物与一种附加的抗菌制剂结合在一起服用。
5.依据权利要求4所述用途，其中所述的附加抗菌制剂为羟氨苄青霉素。
6.依据权利要求4所述的用途，其中所述的附加抗菌制剂为奥美拉唑。
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