CN1097759A - 含1-二环取代-3-喹诺酮羧酸衍生物的药物组合物制备方法 - Google Patents

含1-二环取代-3-喹诺酮羧酸衍生物的药物组合物制备方法 Download PDF

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CN1097759A
CN1097759A CN94100328A CN94100328A CN1097759A CN 1097759 A CN1097759 A CN 1097759A CN 94100328 A CN94100328 A CN 94100328A CN 94100328 A CN94100328 A CN 94100328A CN 1097759 A CN1097759 A CN 1097759A
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乌韦·彼得森
托马斯·申克
安德烈斯·克雷布斯
克劳斯·葛罗赫
迈克尔·施里瓦
英戈·霍勒
卡尔·格奥尔格·梅茨格
赖纳·恩达曼
汉斯-约阿希姆·蔡勒
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Abstract

本发明涉及下列式(I)的新的7-二环取代-3- 喹诺酮羧酸衍生物的药物组合物的制备方法。式 (I)中的取代基定义见说明书所述。该等组合物可 用作为抗菌剂和饲料添加剂。

Description

含7-二环取代-3-喹诺酮羧酸 衍生物的药物组合物制备方法
本发明涉及含新的7-二环取代-3-喹诺酮羧酸衍生物的药物组合物的制备方法。
德国专利申请3,318,145和欧洲专利申请106,489和153,826都已揭示了一些7位由吡咯烷基环取代的3-喹诺酮和1，5-二氮杂萘酮羧酸。
本发明的目的是提供制备含有上述化合物的药物组合物的方法。
业已发现如下式(I)的7-(1-吡咯烷基)-3-喹诺酮-和1，5-二氮杂萘酮羧酸衍生物，其药物上可用的水合物和酸加成盐，以及基础羧酸的碱金属，碱土金属，银和盐是具有高度抗菌活性，尤其对革兰氏阳性细菌。式I为：
Figure 9410032800041
式中：
X1为卤素，
X2为氢，氨基，具有1至4个碳原子的烷基氨基，每个烷基具有1至3个碳原子的二烷基氨基，羟基，具有1至4个碳原子的烷氧基，巯基，含有1至4个碳原子的烷硫基，芳硫基或卤素，
R1为具有1至4个碳原子的烷基，含有2至4个碳原子的链烯基，具有3至6个碳原子的环烷基，2-羟乙基，2-氟乙基，甲氧基，氨基，甲氨基，乙氨基，二甲氨基或任意可由1或2个氟原子取代的苯基，
R2为氢，具有1至4个碳原子的烷基或(5-甲基-2-氧代-1，3-间二氧杂环戊烯-4-基)甲基，
R3为下式结构的基团：
Figure 9410032800051
其中R4可表示H，C1-C4烷基，芳基或C1-C4酰基，
R5可表示H，C1-C4烷基，OH或OCH3，也可以是R4和R5一起为C1-C3链烯基桥，并可任意由甲基单或二取代，
R6可表示H，任意羟基取代的C1-C4烷基，芳基，杂芳基，苄基，C1-C4烷氧羰基，C1-C4酰基，(5-甲基-2-二氧代-1，3-间二氧杂环戊烯-4-基)-甲基或C3-C6环烷基，
R7可表示H或C1-C4烷基，
R′可表示H，CH3或苯基，
R″可表示H，CH3或苯基，
R_可表示H或CH3，
Y可表示O，CH2，CH2CH2或CH2-O，并且对于CH2-O基团，可通过O或CH2与氮原子连接，和
Z可表示O或S和
A为N或C-R8，其中R8表示H，卤素，甲基，氰基，硝基，羟基或甲氧基，或与R1一起形成具下列结构的桥键：
Figure 9410032800061
或
Figure 9410032800062
较佳化合物为下式(I)的那些化合物：式中：
X1为氟或氯，
X2为氢，氨基，具有1或2个碳原子的烷基氨基，二甲氨基，羟基，甲氧基，巯基，甲硫基，苯硫基，氟或氯，
R1为具有1至3个碳原子的烷基，具有2或3个碳原子的链烯基，具有3至5个碳原子的环烷基，2-羟乙基，2-氟乙基，甲氧基，氨基，甲氨基，乙氨基，二甲氨基或任意由1或2个氟原子取代的苯基，
R2为氢，具有1至3个碳原子的烷基或(5-甲基-1，3-二氧代-1，3-间二氧杂环戊烯-4-基)甲基，
R3为下列结构的基团：其中R4可表示H，C1-C3烷基或C1-C2酰基，
R5可表示H，C1-C3烷基，OH或OCH3，R4和R5还可以一起形成C1-C2链烯基桥键，并可以由甲基任意单或二取代，
R6可表示H，任意由羟基取代的C1-C3烷基，苯基，苄基，C1-C4烷氧羰基，C1-C2酰基，(5-甲基-2-氧代-1，3-间二氧杂环戊烯-4-基)-甲基或C3-C5环烷基，
R7可表示H或C1-C2烷基，
R′可表示H或CH3，
R″可表示H或CH3，
R_可表示H或CH3，
Y可表示O，CH2，CH2CH2或CH2-O，对于CH2-O基团来说，可通过O或CH2与氮连接，和
Z可表示O或S，和
A为N或C-R8，其中R8表示H，氟，氯，溴，甲基，硝基，羟基或甲氧基，或与R1一起形成下列结构的桥键：-O-CH2-CH-CH3。
更佳的化合物为下式(I)化合物式中：
X1为氟
X2为氢，氨基，甲氨基或氟，
R1为具有1或2个碳原子的烷基，乙烯基，环丙基，2-羟乙基，2-氟乙基，甲氧基，甲氨基，4-氟苯基或2，4-二氟苯基，
R2为氢或具有l或2个碳原子的烷基，
R3为下列结构的基团：
Figure 9410032800081
其中R4可表示H，C1-C2烷基或乙酰基，
R5可表示H或C1-C2烷基，R4和R5也可以一起形成可由甲基任意取代的C-C链烯基桥，
R6可表示H，CH3，C2H5，HOCH2CH2，苄基，C1-C4烷氧羰基或C1-C2乙酰基，
R7可表示H或CH3，
R′可表示H或CH3，
R″可表示H或CH3，
R_可表示H或CH3，
Y可表示O，CH2，CH2CH2或CH2-O，CH2-O基团可以通过O或CH2与氮连接，和
Z可表示O或S，和
A为N或CR8，其中R8表示H，氟或氯，或与R1一起形成具下列结构的桥键：
Figure 9410032800082
本发明进一步发现能按下面方法获得式(I)化合物，其中将下式(II)化合物与式(III)化合物反应，如合适的话可有酸夹带剂存在下和将R3中所含适当的保护基团移去(方法A)。式II为：
Figure 9410032800083
式中R1，R2，X1和X2定义如前，X3为卤，尤其为氟或氯，
式III为R3-H(III)，式中R3定义如前。
本发明的式(I)化合物能由下式(IV)化合物与式(V)化合物反应制得，如合适的话，可有酸夹带剂存在下进行(方法B)。式(I)化合物为：式中X1，R1，R2，R3和A定义如前，X2为氨基，具有1至4个碳原子的烷基氨基，每个烷基是有1至3个碳原子的二烷基氨基，羟基，具1至4个碳原子的烷氧基，巯基，具有1至4个碳原子的烷硫基或芳硫基，
式(IV)为：
Figure 9410032800092
式中X1，R1，R2，R3和A定义如前，式(II)化合物为X2-H(V)，式中X2定义如前。
也能通过下面方法获得本发明的式(Ia)化合物，
Figure 9410032800093
式中X1，X2，R1，R2和A定义如前，R3为下列结构的基团，
Figure 9410032800101
或 其中R4，R5，R6，R′，R″，R_，Y和Z定义如前。该方法中，将下式(VI)化合物与式(VII)化合物反应，如合适可在酸夹带剂存在下进行(方法C)，式(VI)化合物为：式中X1，X2，R1，R2和A定义如前，R3a为下式结构的基团：
Figure 9410032800104
或
Figure 9410032800105
式中R4，45，R′，R″，R_，Y和Z定义如前，式(VII)化合物为R6-Xa(VII)，其中R6定义如前，Xa为氯，溴，碘，羟基或乙酰氧基，
如果采用的起始原料例如为1-环丙基-6，7，8-三氟-1，4-二氢-4-氧代-3-喹啉羧酸和1-甲基八氢吡咯并〔3，4-b〕吡啶时，能按下面的反应方程式表示：
Figure 9410032800111
如起始原料例如为7-氯-6-氟-1-(4-氟苯基)-1，4-二氢-4-氧代-1，8-(1，5-二氮杂萘-3-羧酸和顺-3-叔丁氧羰氨基-4-甲氧基吡咯烷时，能按下面的反应方程式表示：
Figure 9410032800121
如果起始原料例如为1-环丙基-5，6，8-三氟-1，4-二氢-7-(2-甲基-2，7-二氮双环〔3.3.0〕辛-3-基)-4-氧代-3-喹啉酸和氨时，能用下面反应方程式表示：
Figure 9410032800131
如果起始原料例如为1-环丙基-7-(2，7-二氮双环〔3.3.0〕辛-7-基)-6-氟-1，4-二氢-4-氧代-3-喹啉羧酸和乙醇/氯化氢时，能用下面反应方程式表示：
Figure 9410032800132
用作为起始原料的式(II)化合物为已知物或能按已知方法制得。可提供的例子有：
7-氯-1-环丙基-6-氟-1，4-二氢-4-氧代-3-喹啉羧酸(德国专利申请3,142,854)，
1-环丙基-6，7-二氟-1，4-二氢-4-氧代-3-喹啉羧酸(欧洲专利申请113,091)，
6-氯-1-环丙基-7，8-二氟-1，4-二氢-4-氧代-3-喹啉羧酸(德国专利申请3,420,743)，
8-氯-1-环丙基-6，7-二氟-1，4-二氢-4-氧代-3-喹啉羧酸(德国专利申请3,420,743)，
1-环丙基-6，7，8-三氟-1，4-二氢-4-氧代-3-喹啉羧酸(德国专利申请3,318,145)，
6，8-二氯-1-环丙基-7-氟-1，4-二氢-4-氧代-3-喹啉羧酸(德国专利申请3,420,743)，
1-环丙基-6，7-二氟-1，4-二氢-8-甲基-4-氧代-3-喹啉羧酸，
1-环丙基-7-氯-6-氟-1，4-二氢-8-硝基-4-氧代-3-喹啉羧酸，
6，7-二氟-1-乙基-1，4-二氢-4-氧代-3-喹啉羧酸，
7-氯-6-氟-1-乙基-1，4-二氢-4-氧代-3-喹啉羧酸，
7-氯-6-氟-1，4-二氢-1-(2-羟乙基)-4-氧代-3-喹啉羧酸，
6，7-二氟-1-(2-氟乙基)-1，4-二氢-4-氧代-3-喹啉羧酸，
8-氯-1-(2，4-二氟苯基)-6，7-二氟-1，4-二氢-4-氧代-3-喹啉羧酸(欧洲专利申请235,762)，
7-氯-6-氟-1，4-二氢-1-甲氧基-4-氧代-3-喹啉羧酸，
7-氯-6-氟-1，4-二氢-1-甲氨基-4-氧代-3-喹啉羧酸，
6，7-二氟-1，4-二氢-4-氧代-3-喹啉羧酸，
7-氯-1-环丙基-6-氟-1，4-二氢-4-氧代1，8-二氮杂萘-3-羧酸，
6，7-二氟-1-环丙基-1，4-二氢-4-氧代-1，8-二氮杂萘-3-羧酸，
1-环丙基-6，7，8-三氟-1，4-二氢-4-氧代-3-喹啉羧酸乙酯(德国专利申请3,318,145)，
9，10-二氟-2，3-二氢-3-甲基-7-氧代-7H-吡啶并〔1，2，3-de〕〔1，4〕苯并噁嗪-6-羧酸(欧洲专利申请47,005)，
8，9-二氟-6，7-二氢-5-甲基-1-氧代-1H，5H-苯并〔i，j〕喹嗪-2-羧酸，
7-氯-6-氟-1-苯基-1，4-二氢-4-氧代-1，8-二氮杂萘-3-羧酸(欧洲专利申请153,580)，
7-氯-6-氟-1-(4-氟苯基)-1，4-二氢-4-氧代-1，8-二氮杂萘-3-羧酸(欧洲专利申请153,580)，
6，7，8-三氟-1，4-二氢-1-甲氨基-4-氧代-3-喹啉羧酸(德国专利申请3,409,922)，
1-氨基-6，7，8-三氟-1，4-二氢-4-氧代-3-喹啉羧酸(德国专利申请3,409,922)，
1-氨基-6，7，8-三氟-1，4-二氢-4-氧代-3-喹啉羧酸(德国专利申请3,409,922)，
6，7，8-三氟-1，4-二氢-1-二甲氨基-4-氧代-3-喹啉羧酸(德国专利申请3,409,922)，
7-氯-6-氟-1，4-二氢-8-硝基-4-氧代-1-苯基-3-喹啉羧酸，
7-氯-6-氟-1-(4-氟苯基)-1，4-二氢-8-硝基-4-氧代-3-喹啉羧酸，
6，7-二氟-1-(4-氟苯基)-1，4-二氢-8-甲基-4-氧代-3-喹啉羧酸，
6-氯-7-氟-1-(4-氟苯基)-1，4-二氢-4-氧代-3-喹啉羧酸(欧洲专利申请131,839)，
5，6，7，8-四氟-1-(2，4-二氟苯基-1，4-二氢-4-氧代-3-喹啉羧酸，
5，7-二氯-6-氟-1-(2，4-二氟苯基)-1，4-二氢-4-氧代-3-喹啉羧酸，
5，7-二氯-1-环丙基-6-氟-1，4-二氢-4-氧代-3-喹啉羧酸，
6-氯-7-氟-1-(2，4-二氟苯基)-1，4-二氢-4-氧代-3-喹啉羧酸(欧洲专利申请131,839)，
6，7，8-三氟-1-(4-氟苯基)-1，4-二氢-4-氧代-3-喹啉羧酸(欧洲专利申请申请154,780)，
6，7，8-三氟-1-(2，4-二氟苯基)-1，4-二氢-4-氧代-3-喹啉羧酸(欧洲专利申请154,780)
6，7，8-三氟-1，4-二氢-4-氧代-1-苯基-3-喹啉羧酸(欧洲专利申请154,780)，
7-氯-1-乙基-6-氟-1，4-二氢-4-氧代-1，8-二氮杂萘-3-羧酸
6，7-二氟-1，4-二氢-4-氧代-1-乙烯基-3-喹啉羧酸，
1-环丙基-5，6，7，8-四氟-1，4-二氢-4-氧代-3-喹啉羧酸，
5-氨基-1-环丙基-6，7，8-三氟-1，4二氢-4-氧代-3-喹啉羧酸，
1-环丙基-6，7，8-三氟-1，4-二氢-5-羟基-4-氧代-3-喹啉羧酸，和
1-环丙基-6，7-二氟-1，4-二氢-8-甲氧基-4-氧代-3-喹啉羧酸。
在某些例子中，用作起始化合物的式(III)化合物为新的。它们能按下面方法制备。
1.由N-保护的3，4-环氧吡咯烷(1)(German of fenlegungsschrift(德国公开申请)1,929,237和美国专利4,254,135)，并且其可以任意带有一个或二个甲基或苯基开始，制备式(IIIa)-(IIIe)的起始化合物。
Figure 9410032800171
R9＝苄基，乙酰基，烷氧羰基，苄氧羰基，三烷基甲硅烷基或磺酸基(保护基的例子)，
X3＝离去基团，例如卤，烷基或芳基磺酰氧基，
Figure 9410032800181
Figure 9410032800191
2.式(IIIf)起始化合物可按下面步骤由2-(1，2-二氯乙基)环氧乙烷制得：
Figure 9410032800201
3.通过在任意由一个或二个甲基或苯基取代的N-苄基马来酰亚胺中
Figure 9410032800211
4.按下述与亚硫酰氯进行环化，由3，4-环氧吡咯烷(1)制得式(IIIh)起始化合物：
Figure 9410032800212
5.由3，4-环氧吡咯烷(1)和乙醇胺的反应，经分子内醚化得到式(IIIi)起始化合物：
Figure 9410032800221
6.由氨基乙醛二甲基乙缩醛经分子内1，3-二极环加成反应制得式
Figure 9410032800222

Claims (2)

1.一种制备含有式(I)的7-二环取代-3-喹诺酮羧酸衍生物、其药物上可用的水合物和酸加成盐以及其基础酸的碱金属、碱土金属、银和鈲盐的药物组合物的方法：
Figure 9410032800021
式中X1为卤素，
X2为氢、氨基或卤素，
R1为具有1至4个碳原子的烷基、具有3至6个碳原子的环烷基或任选由1或2个氟原子取代的苯基，
R2为氢、具有1至4个碳原子的烷基，
R3为下式结构的基团
Figure 9410032800022
Figure 9410032800023
其中R4和R5一起表示1至3个碳原子的亚烷基桥，并任选由甲基单取代或二取代，
R6表示氢、任选由羟基取代的1至4个碳原子烷基、苯基、1至4个碳原子烷氧羰基、1至4个碳原子酰基，
R7表示氢或1至4个碳原子烷基，
R′、R″、R_各自表示氢或甲基，
Y表示O、CH2、CH2CH2、CH2O，其中CH2O基团可通过O或CH2与氮原子连接，
Z表示O，
A表示C-R8，R8表示氢或卤素，或R8与R1一起形成下式的桥基：
所述组合物中含有式(I)化合物0.1-99.5％(重量)，以及至少一种药物适用的辅料或赋形剂，
该方法的特征在于，将所述式(I)化合物与所述辅料或赋形剂混合到一起。
2.按权利要求1所述的方法，其中所述式(I)化合物的含量为0.5-95％(重量)。
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