CN1124486A - 含有杂环基团的脒衍生物及其制备和应用 - Google Patents

含有杂环基团的脒衍生物及其制备和应用 Download PDF

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CN1124486A
CN1124486A CN94192207A CN94192207A CN1124486A CN 1124486 A CN1124486 A CN 1124486A CN 94192207 A CN94192207 A CN 94192207A CN 94192207 A CN94192207 A CN 94192207A CN 1124486 A CN1124486 A CN 1124486A
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欧斯特-奥托·伦斯
库尔特·施罗姆
拉尔夫·安德斯凯维兹
弗朗兹·伯克
阿明·富格纳
赫伯特·霍耶尔
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Boehringer Ingelheim GmbH
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Abstract

式(I)的化合物(该化合物在说明书中有更全面的解释)，可通过常规方法制备及可用于药用的常规的盖仑(galenic)制剂中。

Description

含有杂环基团的脒衍生 物及其制备和应用
本发明涉及含有杂环基团的新的脒衍生物、其常规制备方法和其在药用组合物中作为活性物质的应用。
所述的新的脒衍生物具有下列通式
Figure A9419220700141
其中A代表下述基团之一
X1-A1-X2    (II)
X2-A1-X1    (III)
其中A1代表直链或支链的二价脂肪族C2-6基团，其中也可以含有一个双键或三键，或代表下述基团之一X1    代表O，S，SO，SO2，CH2，NH或 X2    代表O，S，CH2或
Figure A9419220700153
B     代表CH＝CH，CH＝N，S或
Figure A9419220700154
Het代表一个杂环基团或一个杂环系统，该杂环系统由带有1至3个取代基的两个或三个缩合环组成，
式I的手性化合物可以外消旋物的形式存在，或以纯的或集中的对映体的形式，以及以碱或以与无机酸或有机酸，特别是生理上可接受的酸成盐的形式存在。
下述基团是上述定义中杂环基或缩合体系的一些实例：
Figure A9419220700171
(X3＝O，S，CH2，SO，SO2，NR10，CH2-CH2，CH＝CH)
Figure A9419220700181
Figure A9419220700201
在这些结构式中：
R1和R2，可以相同也可以不同，代表CF3、卤素、R5、OR5、COR6、SR6、SOR6、SO2R6、SO2NR5R7、C(OH)R5R7或一起代表与苯环的相邻C原子相连的二价基团-CR8＝CR9-CH＝CH-、-CH＝CR8-CR9＝CH-、-CR8＝CH-CR9＝CH-、-O-CHR10-CH2-、-O-CH2-O-、-O-CH2-CH2-O-、-(CH2)3-4-、-NH-CO-O-、-NH-CO-CH2-O-、-CO-CH2-O-或-CO-CH2CH2-O-，这些基团反过来可被C1-4-烷基取代，
R3代表卤素、OH、CF3、R5、OR6、COR6、CONR5R7、CH2OH、CH2-O-(C1-4-烷基)、SR6、SOR6、SO2R6、SO2NR5R7、NH-CO-(C1-4-烷基)、NH-SO2-(C1-4-烷基)、NR5R7或C(OH)R5R7、或具有1至3个杂原子的五元杂环和下式基团，
Figure A9419220700202
或
Figure A9419220700203
或
Figure A9419220700204
(其中D、E和G，可以相同或不同，代表CH、N、C-(C1-4-烷基)、或C-苯基，L代表O或S)，
R4代表H、卤素、NH2、NH-(C1-4-烷基)、C1-4-烷基、N(C1-4-烷基)2、OH、C1-4-烷氧基、苯基，
R5代表H、C1-12-烷基、吡啶基、苯基、被卤素、C1-4-烷基、C1-4-烷氧基或C2-5-酰基任选取代的苯基、或苯基-(C1-4-烷基)，
R6代表C1-12-烷基、苯基、或被卤素、C1-4-烷基、C1-4-烷氧基或C2-5-酰基任选取代的苯基，
R7代表H或C1-12-烷基、
R8、R9(可以相同或不同)，代表H、OH、C1-4-烷基、C1-4-烷氧基或C2-5-酰基，
R10代表H或C1-4-烷基，
R11、R12可以相同或不同，代表H、OH、卤素、CF3、C1-4-烷基或C1-4-烷氧基，
R13、R14可以相同或不同，代表H、C1-4-烷基、C1-4-烷氧基、苯基、萘基、同时这些环系可以被相同或不同的基团单取代或多取代，所述基团选自氟、氯、溴、C1-4-烷基、C1-4-烷氧基、或假卤素(比如CN或CF3)、或R13和R14代表吡啶基，
如果A1含有双键或三键，通常不与杂原子相邻。A1在这种情况下，优选代表CH2-CH＝CH-CH2(顺式或反式)或CH2-C≡C-CH2。如果A1代表
Figure A9419220700211
则X1不会是该基团。如果A与Het中的氮原子相连(例如在基团j至O中)，A是通过碳原子与该氮原子相连。在本说明书中，在任何情况下，基团A以插入式I中的形式来表示，如果R1、R2和R3一起出现，当至少R1和R2之一不是氢时，R3通常只代表氢。
在上述定义范围内的优选化合物，被式Ia所包括：
Figure A9419220700221
其中A1′、X1′、X2′和Het′具有下述含义：
A1′代表(CH2)2-6、CH2-C6H4-CH2、Z或E、CH2-CH＝CH-CH2、CH2-C≡C-CH2；
X1′代表O、S；
X2′代表O、S；
Het′代表上述式a、b、e、f、g、k、n中的一个，其中R1、R2和R3可以相同或不同，代表H、R5、OR5或COR5和R1与R2一起也可以代表稠合环。
式I的化合物可以通过已知方法制备，优选下述方法：
1、将式V的化合物与氨在醇溶剂中(比如，甲醇、乙醇、正丙醇、异丙醇)，或在惰性溶剂中(例如二氯甲烷、四氢呋喃、二噁烷中)反应，反应温度在约0和50℃之间，优选20℃。
Figure A9419220700231
(其中Het、R4、A和B定义如上，R优选代表C1-4-烷基或苄基)
2、将式(VI)的偕胺肟与氢，在催化剂，比如Raney镍、钯、铂存在下进行还原反应。
Figure A9419220700232
(其中Het、R4、A和B定义如上)
3、其中X1或X2代表O或S的式I化合物，可以通过下述方法制得：
Figure A9419220700233
或
Figure A9419220700241
(其中A、B、Het、X1、X2和R4定义如上，L代表亲核离去基团，Z代表OH或SH)
该反应在碱存在下(金属碳酸盐、金属氢氧化物、金属氢化物)，于下述溶剂比如二甲基亚砜、二甲基甲酰胺、乙腈或醇溶剂比如，甲醇、乙醇或丙醇中进行，反应温度在约0和140℃之间，或在反应混合物的沸腾温度。
苯酚类或噻吩类也可以其盐的形式，例如碱金属盐的形式来使用。合适的亲核离去基团是卤素，例如，Br、Cl或磺酸基团，比如甲磺酸基或苯磺酸基。
起始物V和VI优选从通式(XI)的相应的腈来制备，也可以根据方法3的类似反应依次得到。
Figure A9419220700242
(其中A、B、Het和R4定义如上)，其它的合成方法包括将相应的腈与HCl通过偕氯代亚胺阶段反应，或直接与，例如，C1-6醇或苄醇在酸(比如盐酸)存在下进行反应。所述的腈与H2S在溶剂(比如吡啶或二甲基甲酰胺)中，在碱(比如三乙胺)存在下进行反应，然后烷基化或苄基化，结果得到式V的化合物。从相应于式V化合物另一方面的羧酸酰胺开始反应，也可以得到式V化合物。该反应是与三烷基氧鎓盐，比如，三乙氧鎓四氟硼酸盐反应，溶剂为二氯甲烷、四氢呋喃或二噁烷，反应温度在0和50℃之间，优选室温。
通过腈XI与羟胺在醇中，例如，甲醇、乙醇、丙醇、异丙醇中进行反应，也可以得到相应的式VI偕胺肟。
式VII、VIII、IX和X的起始物可通过常规方法制备。
根据本发明的化合物有治疗用途，特别是其LTB4-拮抗活性。因而，这类化合物特别适用于与炎症和/或过敏过程相关的疾病，例如，IBD(肠炎疾病)，过敏性鼻炎；ARDS(成人呼吸困难综合症)、哮喘、溃疡性结肠炎、牛皮癣和由非甾体抗炎药物(NSAID)诱导的胃病的治疗。所述的新化合物也可以与其它活性物质结合使用，例如，抗过敏药、内分泌调节剂、β2-肾上腺素能药物、用作吸入剂的甾体、抗组织胺药和/或PAF拮抗剂。给药方式可以是局部、口服、透皮、滴鼻或肠胃外途径或吸入施用。
所述的治疗或预防剂量取决于疾病的性质和严重程度，以及单个化合物的效能和患者的体重。
所述的新化合物可以通过局部、口服、透皮、肠胃外给药或吸入的方式施用。所述的化合物在常规制剂中，即在含有惰性药用载体和有效量的活性物质的组合物中，是以活性成分的形式存在的。所述的常规制剂包括素片或包衣片、胶囊、锭剂、粉剂、溶液剂、混悬剂、用于吸入的气雾剂、膏剂、乳剂、糖浆剂、栓剂等。根据本发明化合物的有效剂量，口服时是在20和200mg/剂之间。作为吸入剂时，应使用含有0.5％至5％活性物质的粉剂或溶液剂，每一剂量中含有约2至20mg的活性物质。
所述的新化合物可以与下述物质结合使用，如抗过敏剂、内分泌调节剂、β2-肾上腺素能药物、用作吸入剂的甾体或抗组织胺药。
下述实施例给出所述制剂的可能配方：1、片剂组成：根据本发明的活性物质    20份(重量)硬脂酸                   6份(重量)葡萄糖                 474份(重量)
将上述成分按照常规方法制成重500mg的片剂。如果需要，活性物质的含量可以增加或减少，相应地减少或增加葡萄糖的用量。2、栓剂组成：根据本发明的活性物质   100份(重量)乳糖粉                  45份(重量)可可油                1555份(重量)
将上述成分按常规方法制成重1.79的栓剂。3、用于吸入的粉剂
将微粉化的活性物质(式I的化合物；颗粒大小约0.5至7μm)装入硬胶囊中，每个重5mg，任选加入微粉化乳糖。上述的粉剂用常规吸入装置，例如：根据DE-A 3345722进行吸入。
用下述试验方法，对本发明化合物的活性进行测定。a)LTB4-受体结合试验
3H-LTB4对活体U937细胞的结合(具有自然表达的LTB4受体的分化的人单核细胞系)受到抑制，且随着受试物质(在0℃培养2小时)浓度的增加呈剂量依赖关系。用膜过滤除去未结合的3H-LTB4，用闪烁记数器对LTB4受体/3H-LTB4复合体的放射活性进行定量分析。通过置换曲线对测得值的重复适应来确定亲和值(抑制常数Ki)。(程序：王氏电脑“coupled mass equilibria”)b)豚鼠体中的中性粒细胞凝聚
体外用LTB4指示(在凝聚仪中测定透光度的增加，以mm记录；每个实验重复两次)：与受试物质在聚二醇(poldiol)/DMSO中培养后，抑制2分钟。c)鼠耳中由白细胞三烯(leukotrien)-B4指示的中性白细胞的凝聚中性白细胞在鼠耳皮肤中的流量，通过髓过氧化物酶活性的光密度测定(mOD/分钟)来评估(Bradley等：J.Invest.Dermatol.78，206，1982)。左耳经LTB4(每面250ng)局部处理后，比右耳(2×5μl丙醇作溶剂)增加6小时。
在LTB4刺激前30分钟，口服施用于1％纤基乙酸钠300溶液中的活性物质。
试验a)的本发明化合物的Ki值在1和20nmol/l之间，优选低于10nmol/l。特别应提到的是所述新化合物的优良的口服效用。
下述实施例详细叙述了本发明化合物可能的制备方法。表中，BS代表碱，含在盐中的酸用下述缩写符号表示：1、AC，2、MS，3、FU，4、FU1对应的阴离子是：1.CH3COO(-)，2.CH3SO3 (-)，       
Figure A9419220700282
方法1：实施例1
Figure A9419220700283
将9.6g的4-[2-(2-苯并噻唑基氧)乙氧基]-苄腈溶于100ml的无水二氯甲烷和100ml的无水乙醇中。在约-15℃下，通HCl气4小时。然后，将该混合物室温放置过夜，加入约800ml乙醚，倾去溶剂后，得到结晶产物。将该残留物溶于50ml的乙醇中，加入50ml的氨饱和的乙醇后，将该混合物回流1.5小时。减压蒸去溶剂，残留物用乙醇/乙醚重结晶。得到2.5g的4-[2-(2-苯并噻唑基氧)-乙氧基]-苄脒的盐酸盐，熔点205-207℃。方法2：实施例2
Figure A9419220700291
                      CH3SO3H
将3.85g的4-[5-(5-甲基-2-苯并噁唑基-巯基]-戊氧-苄胺肟的甲磺酸盐溶于200ml的甲醇中。加入Raney镍，该混合物在通常条件于50℃进行氢化，直至计算量的氢气全部用完(约5小时)。抽滤除去催化剂，蒸去溶剂，残留物用异丙醇重结晶。4-[5-(5-甲基-2-苯并噁唑基-巯基]-戊氧-苄脒甲磺酸盐的熔点为129-130℃。方法3：实施例3
Figure A9419220700292
                            HCl.H2O
将1.6g的2-巯基-5-苯基-1，2，4-噁二唑溶于40ml的无水二甲基甲酰胺中。加入270mg的80％氢化钠分散体后，将该混合物先在室温搅拌半小时。然后加热至50℃，向其中逐滴加入2g溶于40ml无水二甲基甲酰胺中4-溴乙氧基苄脒的溶液。将该混合物在50℃继续反应2小时。冷却后，倾入冰水中。将该混合物抽滤，悬浮于乙醇中，加入带醚的盐酸，直到酸化反应完成。同时已被溶解的所述化合物，以其盐酸盐的形式沉淀出来。抽滤，用水重结晶。干燥后，得0.6g的2-[2-(4-脒基-苯氧基)-乙基巯基]-5-苯基-1，3，4-噁二唑的盐酸盐(熔点237-8℃)。
下述的化合物可以通过与实施例类似的方法制备：表I下式化合物
Figure A9419220700301
No.    A                    碱或成盐酸熔点[℃]1    -S-(CH2)3-O-HCl-H2O    157-82    -S-(CH2)5-O-HCl          95-63    -S-(CH2)6-O-HCl-H2O     98-94    -S-(CH2)4-O-HCl         143-45    -S-(CH2)2-O-HCl         218-9
                          表II下式化合物No.        A          Ra     Rb  碱或成盐酸  熔点[℃]
1    -S-(CH2)3-O  C6H5  C6H5  HCl       219-20
2
   -N  N-(CH2)2-O-H       H        HCl       211
3    -O-(CH2)2-O- H       H        HCl       222
4    -S-(CH2)2-O- C6H5  H        HCl.H2O 102-3
5    -S-(CH2)3-O- C6H5  H        HCl       108-9
6    -S-(CH2)4-O- C6H5  C6H5   HCl       187-8
7    -S-(CH2)5-O- H       C6H5   HCl       164
8    -S-(CH2)3-O- H       C6H5   HCl       172
9    -S-(CH2)4-O  H       C6H5   HCl       183
10    -S-(CH2)4-O- C6H5  H       HCl.H2O  110-1
No.      A             Ra     Rb 碱或成盐酸 熔点[℃]
11    -S-(CH2)2-O-  C6H5  C6H5  HCl      258-9
12    -S-(CH2)4-O-  H        H       HCl      156-7
                         表III下式化合物No.    A                    Ra         Rb 碱或成盐酸 熔点[℃]1    S-(CH2)5-O           CH3        H    MS       129-302
Figure A9419220700332
H           H    HCl      244-53    S-(CH2)5-O        叔-C4H9      H    BS       65-70
                                         H2O4
Figure A9419220700333
H          H    3MS      207-95    O-(CH2)2-O            H          H    HCl      218-206    S-(CH2)6-O            H          H    HCl      140-17    S-(CH2)5-O            H          H    HCl      184-58    S-(CH2)6-O            H          H    BS       130-19    S-(CH2)5-O            Cl         H    MS       160-210   S-(CH2)5-O            H          CH3 MS       160-1No.        A            Ra    Rb 碱或成盐酸  熔点[℃]11    S-(CH2)3-O      H      H     HCl       128-30
                                 .H2O12    S-(CH2)4-O      H      H     HCl       20313    S-(CH2)2-O      H      H     HCl       18714    S-(CH2)5-O      H      H     HCl-      104-515    O-(CH2)3-O      H      H     HCl       114-5
                                 .H2O16    O-(CH2)4-O      H      H     HCl       180-1
                                .H2O17    S-(CH2)5-O      OCH3 H     MS        142-418    S-(CH2)4-O      OCH3 H     MS        163-419    S-(CH2)2-O      CH3  H     MS        177-820    S-(CH2)5-O      F     H     MS        145-721    S-(CH2)4-O      F     H     HCl       177-922    NH-(CH2)4-O     H     H     FUl       238
                           表IV下式化合物No.     A          Ra    Rb  碱或成盐酸  熔点[℃]1    (CH2)5-O   C6H5  H       HCl      161-22    S-(CH2)2-O  H     C6H5   HCl      190-13    S-(CH2)5-O  H     C6H5   HCl      1604    S-(CH2)6-O  H     C6H5   HCl      166-75    S-(CH2)4-O C6H5 C6H5   HCl      170-16    S-(CH2)5-O C6H5  H       HCl      109
                               1/2 H2O7    S(CH2)4-O  C6H5  H       HCl      1428    S-(CH2)4-O   H     C6H5   HCl      146
                    表V下式化合物
Figure A9419220700361
No.       A                    Ra 碱或成盐酸  熔点[℃]
1    -S-(CH2)4-O-            H      HCl      172-3
2    -S-(CH2)3-O-            H      HCl      156-7
3    -S-(CH2)2-O-            H      HCl      177-8
4    -S-(CH2)5-O-            H      HCl      110-2
5    -O-(CH2)2-O-            H      HCl      205-7
6    -S-(CH2)6-O-            H      HCl      148，5
                                                50，5
7
Figure A9419220700362
     H      MS       220-2
No.     A                   Ra   碱或成盐酸  熔点[℃]
8    S-(CH2)5-O          OC2H5  HCl       142-3
9  H      MS        165
                     表VI下式化合物
Figure A9419220700381
No.    A               Ra  Rb Rc碱或成盐酸 熔点[℃]1    (CH2)4-O         H    H    H    HCl      1702    (CH2)4-O         H    H    CH3 HCl      813    CH2-CH＝CH        H    H    H    HCl      145-55
      CH2-O4    CH2-C＝C-CH2-O   H    H    H    HCl      148-52
                                -异-C3H7OH5    (CH2)4-O         Cl   Cl   H    HCl      185-76
Figure A9419220700382
H    H    H    HCl      180-907
Figure A9419220700383
   H     H    H    HCl      259-64
                     表VII下式化合物
Figure A9419220700391
No.     A          Ra Rb  X    碱或成盐酸  熔点[℃]1    S-(CH2)3-O  H   H    S     HCl.H2O   1702    S-(CH2)4-O  H   H    S     HCl        186-73    O-(CH2)2-O  H   H    S     HCl        209-10
                     NH4    O-(CH2)4-O  H   C    S     2HCl       274-5
                     NH25    O-(CH2)4-O OCH3OCH3S     HCl        181-26    S-(CH2)2-O  H   H    S     HCl.H2O   188-97    S-(CH2)2-O  H   H    O     HCl.H2O   237-88    S-(CH2)3-O  H   H    O     HCl        1759    S-(CH2)4-O  H   H    O     HCl        182
                      表VIII下式化合物No.       A             Ra          碱或成盐酸 熔点[℃]1    -S-(CH2)2-O-    CH3             2HCl   162-42    -S-(CH2)3-O-    C6H5           HCl    207-83    -S-(CH2)4-O-    C6H5           HCl    1644    -S-(CH2)5-O-    C6H5           BS     121-25    -S-(CH2)4-O-    CH3             HCl    158-96    -S-(CH2)6-O-    C6H5           FUl    221-27    -S-(CH2)4-O-    4-(CH3O)-C6H4 HCl    157-88    -S-(CH2)5-O-    4-(CH3O)-C6H4 HCl    119-219    -S-(CH2)5-O-    3-(CH3O)-C6H4 HCl    92-410   -S-(CH2)4-O-    3-(CH3O)-C6H4 HCl    100-211   -S-(CH2)5-O-    2-(CH3O)-C6H4 HCl    45-912   -S-(CH2)4-O-    2-(CF3)-C6H4  FU     211 No.        A                   Ra     碱或成盐酸  熔点[℃]13    -S-(CH2)4-O-    3-(CF3)-C6H4    FU     21014    -S-(CH2)5-O-    3-(CF3)-C6H4    FU     202-315    -S-(CH2)4-O-    2-萘基              HCl    112-316
Figure A9419220700411
C6H5        FUl    229-3017    -S-(CH2)5-O-    2-萘基              FU1    220-118    -S-(CH2)5-O-    2-(CF3)-C6H4    FUl    21319    -S-(CH2)4-O-    1-萘基              FUl    226-720    -S-(CH2)5-O-    1-萘基              FUl    218-921    -SO-(CH2)5-O-   C6H5             FU     23222    -S-(CH2)2-O-    C6H5             FU     239-4023    -S-(CH2)3-O-    2-(CF3)-C6H4    FUl    222-324    -S-(CH2)6-O-    2-(CF3)-C6H4    FUl    226-725    -SO-(CH2)5-O-   C6H5             FUl    215-626    -S-(CH2)5-O-    2-(CH3)-C6H4    FUl    22727    -S-(CH2)5-O-    4-(CF3)-C6H4    FUl    228-928    -S-(CH2)5-O-    2-(C2H5)-C6H4  FUl    22529    -S-(CH2)5-O-    2-(正C3H7)-C6H4FUl    224 No.        A                  Ra                 碱或成盐酸  熔点[℃]30  -S-(CH2)5-O-    2-(n-C3H7)-3-(CH3O)-C6H3 FUl      223-431  -S-(CH2)5-O-    2-(CH3O)-4-(CH3O)-C6H3    FUl      211-232  -S-(CH2)5-O-    3-(CH3O)-4-(CH3O)-C6H3    FUl      21333  -S-(CH2)5-O-    2-(CH3O)-5-(CH3O)-C6H3    FUl      21934  -S-(CH2)5-O-    3-(CH3O)-5-(CH3O)-C6H3    FUl      21535  -S-(CH2)5-O-    2-(n-C3H7)-3-OH-C6H3      HCl      154-736
Figure A9419220700421
2-(CF3)-C6H5          FUl      228，5-937  -S-(CH2)5-O-    2-(CH3O)-6-(CH3O)-C6H3    FUl      21238  -S-(CH2)5-O-    2-(CH3O)-3-(CH3O)-C6H3    FUl      225
                   表IX下式化合物
Figure A9419220700431
No.            Het                     A   碱或成盐酸 熔点[℃]1
Figure A9419220700432
       (CH2)4-O  HCl       1812
Figure A9419220700433
       (CH2)4-O  HCl       2193
Figure A9419220700434
 (CH2)4-O  HCl       213-44
Figure A9419220700435
(CH2)4-O  HCl       213-4
                                           2，5
                                           H2O5
Figure A9419220700436
   (CH2)4-O  HCl       228-30No.     Het                                  A    碱或成盐酸  熔点[℃]6
Figure A9419220700441
        (CH2)4-O    HCl      189-907
Figure A9419220700442
    (CH2)4-O    HCl      248-508
Figure A9419220700443
                S-(CH2)3-O  HCl      143-5
                                                 H2O9
Figure A9419220700444
                S-(CH2)2-O  2HCl     233-510
Figure A9419220700445
        S-(CH2)2-O  HCl      145
                                                 H2ONo.      Het.                       A    碱或成盐酸  熔点[℃]11
Figure A9419220700451
     (CH2)2-O    HCl       23512
Figure A9419220700452
S-(CH2)2-O  2HCl      271
                                         H2O13 (CH2)2-O     HCl       174-4
                                          H2O14
Figure A9419220700454
         (CH2)2-O     HCl       278-9
                                           1/2
                                           H2O15
Figure A9419220700455
         S-(CH2)2-O   HCl       293No.       Het                       A      碱或成盐酸  熔点[℃]16       S-(CH2)2-O    BS      161-217
Figure A9419220700462
(CH2)2-O       HCl     257
                                             H2O18
Figure A9419220700463
        S-(CH2)2-O     HCl     253-4
                                             H2ONo.      Het                           A    碱或成盐酸  熔点[℃]19
Figure A9419220700471
            -(CH2)5-O     FUl      233-520              -(CH2)4-O     FUl      227-821
Figure A9419220700473
           S-(CH2)4-O   HCl      26322 S-(CH2)4-O   HCl      148-923       -(CH2)4-O    FUl      226-7No.       Het                      A        碱或成盐酸  熔点[℃]24        O-(CH2)5-O    FUl      234
                                                  (分解)25        O-(CH2)4-O    HCl     120-226
Figure A9419220700483
         O-(CH2)5-O    FUl     237-8
                                                  (分解)27
Figure A9419220700484
        O-(CH2)4-O    HCl     17828
Figure A9419220700485
           O-(CH2)5-O    FUl     223-4
                                                  (分解)29 O-(CH2)5-O    FUl     219-20
                                                  (分解)No.      Het                           A     碱或成盐酸  熔点[℃]30
Figure A9419220700491
O-(CH2)4-O    FUl      229-30
                                                      (分解)31
Figure A9419220700492
            O-(CH2)4-O    HCl      15732
Figure A9419220700493
                S-(CH2)5-O    HCl      148-933          O-(CH2)5-O    HCl      130-234             O-(CH2)2-O    HCl      188-935
Figure A9419220700496
              S-(CH2)5-O    HCl      149-50No.      Het                       A     碱或成盐酸  熔点[℃]36
Figure A9419220700501
         -(CH2)5-O     HCl      150-137           S-(CH2)5-O    HCl      174-538     O-(CH2)5-O    FUl      236-739  S-(CH2)4-O    HCl      150-140
Figure A9419220700505
   S-(CH2)5-O    HCl      119-2141
Figure A9419220700506
   S-(CH2)4-O    HCl      154-5No.      Het                            A    碱或成盐酸  熔点[℃]42
Figure A9419220700511
    S-(CH2)5-O    MS      105-343
Figure A9419220700512
 S-(CH2)5-O    AC      206-8
                      表X下式化合物
Figure A9419220700521
No.    Ra         Rb     Rc     A         碱或   熔点[℃]
                                           成盐酸1    C6H5        H       H  -(CH2)4-O    HCl      215-82    C6H5        H       H  -(CH2)5-O    BS       129-303    C6H5      C6H5    H  -(CH2)4-O    FU       244-54    C6H5      C6H5    H  -(CH2)5-O    FU       249-505     H             H    C6H5-(CH2)4-O   FUl      226-76 2-(CH3O)-C6H5 H       H  -(CH2)5-O    2HCl     246-77     C6H5       H       H  -CH2-  -CH2O FU       231-28 3-(CH3O)-C6H5 H       H  -(CH2)5-O    FUl      235
 No.   Ra  Rb    Rc           A       碱或   熔点[℃]
                                         成盐酸
 9     H     H    C6H5  -(CH2)5-O    FUl    220-1
 10    H     H    C6H5  -CH2-  -CH2O FUl    223

Claims (9)

1、式I的脒衍生物或其与无机酸或有机酸形成的盐
Figure A9419220700021
其中A代表下述基团之一
   X1-A1-X2    (II)
   X2-A1-X1    (III)其中A1代表直链或支链的二价脂肪族C2-6基团，它可以含有一个双键或三键，或代表下述基团之一X1    代表    O，S，SO，SO2，CH2，NH或
Figure A9419220700032
X2    代表    O，S，CH2或 B     代表    CH＝CH，CH＝N，S或
Figure A9419220700034
Het   代表一个杂环基团或一个杂环系统，该杂环系统由可带有1至3个取代基的两个或三个缩合环组成，R4    代表H、F、Cl、Br、I、NH2、NH-(C1-4-烷基)、N(C1-4烷基)2、OH、C1-4-烷氧基、C1-4-烷基、苯基，R11和R12，可以相同或不同，代表H、OH、F、Cl、Br、I、CF3、C1-4-烷基或-烷氧基，
(该手性化合物可以外消旋体的形式存在，或以纯的或集中的对映体的形式存在)，它们以碱的形式，或与无机或有机酸形成盐的形式存在。
2、根据权利要求1的化合物，其中Het代表下述(a)至(z)的基团：
Figure A9419220700061
Figure A9419220700062
(X3＝O，S，CH2，SO，SO2，NR10，CH2-CH2，CH＝CH)
Figure A9419220700063
Figure A9419220700071
Figure A9419220700081
Figure A9419220700091
R1和R2，可以相同也可以不同，代表CF3、卤素、R5、OR5、COR6、SR6、SOR6、SO2R6、SO2NR5R7、C(OH)R5R7或一起代表与苯环的相邻C原子相连的二价基团-CR8＝CR9-CH＝CH-、-CH＝CR8-CR9＝CH-、-CR8＝CH-CR9＝CH-、-O-CHR10-CH2-、-O-CH2-O-、-O-CH2-CH2-O-、-(CH2)3-4-、-NH-CO-O-、-NH-CO-CH2-O-、-CO-CH2-O-或-CO-CH2CH2-O-，这些基团反过来可以被C1-4-烷基取代，R3   代表卤素、OH、CF3、R5、OR6、COR6、CONR5R7、CH2OH、CH2-O-(C1-4-烷基)、SR6、SOR6、SO2R6、SO2NR5R7、NH-CO-(C1-4-烷基)、NH-SO2-(C1-4-烷基)、NR5R7或C(OH)R5R7、或具有1至3个杂原子的五元杂环和下式基团，或 或
Figure A9419220700103
(其中D、E和G，可以相同或不同，代表CH、N、C-(C1-4-烷基)、或C-苯基，L代表O或S)，R4   代表H、卤素、NH2、NH-(C1-4-烷基)、C1-4-烷基、N(C1-4-烷基)2、OH、C1-4-烷氧基或苯基，R5   代表H、C1-12-烷基、吡啶基、苯基、被卤素、C1-4-烷基、C1-4-烷氧基或C2-5酰基任选取代的苯基、或苯基-(C1-4-烷基)，R6   代表C1-12-烷基、苯基、或被卤素、C1-4-烷基、C1-4-烷氧基或C2-5酰基任选取代的苯基，R7   代表H或C1-12-烷基，R8、R9(可以相同或不同)代表H、OH、C1-4-烷基、C1-4-烷氧基或C2-5-酰基，R10  代表H或C1-4-烷基，R11、R12可以相同或不同，代表H、OH、卤素、CF3、C1-4-烷基或C1-4-烷氧基，R13、R14可以相同或不同，代表H、C1-4-烷基、C1-4-烷氧基、苯基、萘基，这些环系可以被相同或不同的基团单取代或多取代，所述基团选自氟、氯、溴、C1-4-烷基、C1-4-烷氧基或假卤素(比如CN或CF3)、或R13和R14代表吡啶基。
3、式Ia的根据权利要求1或2的化合物
其中A1′、X1′、X2′和Het′具有下述含义：
A1′代表(CH2)2-6、CH2-C6H4-CH2、Z或E CH2-CH＝CH-CH2、CH2-C≡C-CH2；
X1′代表O、S；
X2′代表O、S；
Het′代表上述公式a、b、e、f、g、k、n中的一个基团，其中R1、R2和R3可以相同或不同，代表H、R5、OR5或COR5，R1和R2一起可以代表稠合环。
4、下式的化合物及其酸加成盐， 其中Rx代表
Figure A9419220700122
5、药用组合物，其特征在于它们含有根据权利要求1至4的化合物。
6、根据权利要求1至4的化合物，在制备药物组合物中的应用，该药用组合物用于治疗与炎症和/或过敏过程相关的疾病，特别是哮喘、溃疡性结肠炎、牛皮癣和由非甾体抗炎药物引发的胃病的治疗。
7、有效剂量的根据权利要求1至4的化合物的应用，用于治疗可使用LTB4-拮抗药物的疾病。
8、有效剂量的根据权利要求1至4的化合物的应用，用于治疗与炎症和/或过敏过程相关的疾病，特别是哮喘、溃疡性结肠炎、牛皮癣和由非甾体抗炎药物引发的胃病的治疗。
9、按已知方式制备根据权利要求1至4的化合物的方法，其特征在于：
a)式(V)的化合物与氨在惰性溶剂中反应
(其中Het、R4、A和B定义如上，R优选代表C1-4-烷基或苄基)或
b)式(VI)的偕胺肟在催化剂存在的条件下进行氢化还原
Figure A9419220700132
(其中Het、R4、A和B定义如上)
或
c)式VII的化合物与式VIII的化合物反应或式IX的化合物与式X的化合物反应。
CN94192207A 1993-03-23 1994-03-18 含有杂环基团的脒衍生物及其制备和应用 Pending CN1124486A (zh)

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AU2915892A (en) * 1991-11-14 1993-06-15 Glaxo Group Limited Piperidine acetic acid derivatives as inhibitors of fibrinogen-dependent blood platelet aggregation
EP0625138B1 (de) * 1992-02-05 1999-06-02 BOEHRINGER INGELHEIM INTERNATIONAL GmbH Neue amidinderivate, ihre herstellung und verwendung als arzneimittel mit ltb4-antagonistischer wirkung

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FI954491A (fi) 1995-09-22
CZ246695A3 (en) 1996-02-14
WO1994021616A1 (de) 1994-09-29
ZA941993B (en) 1994-09-23
LV11465B (en) 1996-12-20
AU6378094A (en) 1994-10-11
DE4309285A1 (de) 1994-09-29
FI954491A0 (fi) 1995-09-22
EP0690849A1 (de) 1996-01-10
KR960701026A (ko) 1996-02-24
HUT73968A (en) 1996-10-28
BG100069A (en) 1996-04-30
JPH08508467A (ja) 1996-09-10
SK117495A3 (en) 1996-01-10
IL109073A0 (en) 1994-06-24
LV11465A (lv) 1996-08-20
HU9502778D0 (en) 1995-11-28
CA2158994A1 (en) 1994-09-29
NO953763D0 (no) 1995-09-22
PL310806A1 (en) 1996-01-08
NO953763L (no) 1995-09-25

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