CN1060655A - 4-或5-取代吡啶-2-羧酸、它们的制备方法及药用 - Google Patents
4-或5-取代吡啶-2-羧酸、它们的制备方法及药用 Download PDFInfo
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- CN1060655A CN1060655A CN91109400A CN91109400A CN1060655A CN 1060655 A CN1060655 A CN 1060655A CN 91109400 A CN91109400 A CN 91109400A CN 91109400 A CN91109400 A CN 91109400A CN 1060655 A CN1060655 A CN 1060655A
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- carbon atom
- alkyl
- phenyl
- hydrogen
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Abstract
本发明涉及4位或5位氨基取代的吡啶-2-羧
酸及其药用。特别描述了这类化合物的抑制脯氨酸
羟化酶和赖氨酸羟化酶作用,以及在治疗胶原物和类
胶原物的生物合成障碍中的效用。
Description
抑制脯氨酸羟化酶和赖氨酸羟化酶的化合物,由于影响胶原专属羟化反应,对胶原生物合成产生非常选择性的抑制作用。在胶原生物合成的过程中,蛋白键合的脯氨酸或赖氨酸分别被脯氨酸羟化酶或赖氨酸羟化酶羟基化。如果该反应被抑制剂抑制,那么形成的胶原分子就无能发挥功效,同时胶原分子的羟基化就不充分,而且只有极少量的胶原分子被细胞释放到细胞外空间。另外,羟基化不充分的胶原不能插入到胶原基体之中,因而极易通过蛋白水解而破裂。这些影响的结果是沉积在细胞外空间的胶原的量在整体上下降。
已经知道,脯氨酸羟化酶被已知的抑制剂,例如α,α′-联吡啶抑制,就可以造成由巨噬细胞进行的CIg生物合成的抑制(W.Muller et al.,FEBS Lett.90(1978),218;Immunobiology 155(1978),47)。这导致补充活化的经典途径成为无效。所以,脯氨酸羟化酶抑制剂亦可作为例如免疫复合疾病中的免疫抑制剂起作用。
已经知道,吡啶-2,4-和-2,5-二羧酸能够有效地抑制脯氨酸羟化酶(K.Mazamaa et al.,Eur.J.Biochem.138(1984)239-245)。然而,在细胞培养中,这些化合物仅仅在很高的浓度下,才是有效的抑制剂(Tschank,G.el at.,Biochem.J.248(1987)625-633)。DE-A 34 32 094描述吡啶-2,4-和-2,5-二羧酸二酯,其中酯的烷基含1至6个碳原子,为脯氨酸羟化酶和赖氨酸羟化酶的抑制药物。
然而这些低级烷基二酯具有不利之处,这就是它们在体内过分迅速地分解为羧酸,并不能以充分高的浓度到达细胞中的作用部位,因而作为有可能施用的药物,相对来说就不大合适。
DE-A 37 03 959、DE-A 37 03 962和DE-A 37 03 963描述了酯/酰胺的普通混合剂形,这就是吡啶-2,4-和-2,5-二羧酸的高级烷基二酯和二酰胺,在动物模型上,它们是胶原生物合成的有效抑制剂。于是,DE-A 37 03 959特别描述了N,N′-双(2-甲氧乙基吡啶-2,4-二羧酸酰胺和N,N′-双(3-异丙氧丙基)吡啶-2,4-二羧酸酰胺的合成。
德国专利(申请书P 38 26 471.4和P 38 28 140.6描述了制备N,N′-双(2-甲氧乙基)吡啶-2,4-二羧酸酰胺的改进方法。
德国专利申请书P 39 24 093.2中设计了新型N,N′-双(烷氧烷基)吡啶-2,4-二羧酸酰胺类化合物。
德国专利申请书P 40 01 002.3描述了吡啶-2,4-和-2,5-二羧酸的二(硝酰烷基)酰胺,在制备脯氨酸羟化酶和赖氨酸羟化酶的抑制药中的应用。
吡啶-2,4-和-2,5-二羧酸酰胺(Hirakata etal.,J.Pharm.Soc.Japan 77(1957)219和Haring et al.,Helv.37(1954)147,153及吡啶-2,4-和-2,5-二羧酸酰肼(Itai et al.,Bl.Nation.Hyg.Labor.Tokyo,74(1956)115,117和Shinohara et al.,Chem.High Polymers Japan,15(1958)839)二者都被发现为抗结核剂。
JP53/28175(78/28175)报道N,N′-双(2-硝酰乙基)吡啶-2,4-和-2,5-二羧酸酰胺是具有扩张血管作用的化合物。
德国专利申请书P……(HOE 90/F 192)描述了2,4-和-2,5-取代吡啶的N-氧化物,在制备脯氨酸羟化酶和赖氨酸羟化酶抑制药中的应用。
现在令人惊奇地发现,下面指明的通式Ⅰ的4-或5-取代吡啶-2-羧酸及其生理上可以接受的盐类,在动物模型上有效地抑制赖氨酸羟化酶和脯氨酸羟化酶。
这样一来,本发明对通式Ⅰ的化合物提出权利要求:
其中R1和R2各自独立地为氢、含1至12个碳原子的烷基、含2至12个碳原子的烯基,含2至12个碳原子的炔基、非苯并或苯并的含5至7个碳原子的环烷基、芳基或杂芳基,这里作为R1和R2提到的这些基为非取代或被1个或多个相同或不同的R3基取代;其中R3为卤素,羟基、氰基、硝基、硝酰基、氨基、羧基、含1至4个碳原子的烷氧基、含1至4个碳原子的烷氧羰基、含1至4个碳原子的烷基氨基或二烷基氨基、吲哚基或苯基;其中吲哚基和苯基为非取代或被卤素、硝基、含1至4个碳原子的烷基或含1至4个碳原子的烷氧基取代一次、两次、或三次、在多取代的情形中,取代基可以相同或不同;或者,若R1为氢,则R2为-NCR4)(R5)基,其中R4和R5相同或不同,并且为氢、含1至4个碳原子的烷基、含1至3个碳原子的烷羰基或苯基;或者,若R2为α氨基酸,α氨基酸烷基酯、α氨基酰胺、α氨基烷基或二烷基酰胺的残基,它们通过N端键合而且其中所说的烷基含1至4个碳原子,并随意地被苯基单取代,当烷基含3至4个碳原子时,烷基也可以是链的;或者,若R1为氢,则R2为二肽或三肽残基,它们通过N端键合,这里的“残基”意指特定的氨基酸和它们的衍生物,或二肽或三肽,每种情形中都缺少N端;以及R1具有R2的含义,其中R1和R2相同或不同或者R1和R2一块键合到氮原子上,或为通式Ⅱ的基,
其中n的取值范围为1至3,A为O、S、CH2或-N(R6)-;在-N(R6)-中,R6为氢、苯基、含1至6个碳原子的烷基、含2至6个碳原子的烯基或含2至6个碳原子的炔基;这些所说的基为非取代或被苯基取代;该苯基反过来又是非取代的或被一个或多个相同的或不同的取代基取代一次或一次以上,这些取代基从卤素、硝基、氰基、羧基、羟基、甲基、乙基、甲氧基、乙氧基或三氟甲基中选择,或从-N(R7)2中选择,其中R7为氢或含1至3个碳原子的烷基,或从-COOR7、-CON(R8)2或-CONHR6中选择,其中R8具有R7的含义,或其中的(R8)2为含4至6个碳原子的烯链,在烯链中不直接连到氮原子上的零个或1个CH2基被O、S或N-R7取代,或其中R6为含1至4个碳原子的烷氧羰基或含3至7个碳原子的环烷基,和生理上可以接受的盐类,其中吡啶-4和5-羧酸酰胺-2-羧酸除外。
通式Ⅰ的特别优选的化合物是下述化合物,在这些化合物中,R1和R2各自独立地为氢、含1至6个碳原子的烷基、含2至6个碳原子的烯基、含2至6个碳原子的炔基、含5至7个碳原子的环烷基、芳基或杂芳基;这里作为R1和R2提到的基团为非取代的或被一个或两个相同的或不同的R3基取代;其中R3为卤素、羟基、氰基、氨基、羧基、含1至4个碳原子的烷氧基、含1至4个碳原子的烷氧羰基、含1至4个碳原子的烷基氨基或二烷基氨基、或苯基;其中苯基为非取代或被卤素,含1至2个碳原子的烷基或含1至2个碳原子的烷氧基取代一次;或者,若R1为氢,则R2为-N(R4)(R5)基,其中R4和R5相同或不同,并为氢或含1至3个碳原子的烷基;或者,若R1为氢,则R2为α氨基酸或α氨基酸烷基酯的残基,这些残基通过N端键合,而其中的烷基含1至3个碳原子,并随意地被苯基单取代,而且其中含3个碳原子的烷基也可以是支链的;以及
R1具有R2的含义,R1和R2可以相同也可以不同;或者
R1和R2一块连接到氮原子上,形成通式Ⅱ的基团,
在通式Ⅱ中,n在1至3中取值,A为O、CH2或-N(R6)-;其中R6为氢、苯基、含1至6个碳原子的烷基,这里所说的这些基为非取代的基或被含1至4个碳原子的烷氧羰基或含3至7个碳原子的环烷基取代,和生理上可接受的盐类,其中吡啶-4-和-5-羧酸酰胺-2-羧酸除外。
通式Ⅰ的特别优选的化合物是下述化合物,在这些化合物中,R1和R2各自独立地为氢,含1至6个碳原子的烷基、特别是含1至3个碳原子的烷基、含6个碳原子的环烷基、苯基或吡啶基,这里作为R1和R2所提到的基团为非取代或被1个或2个相同的R3基取代;其中R3为羟基、氨基、羧基、含1至4个碳原子的烷氧基,特别是甲氧基、含1至4个碳原子的烷氧羰基、或苯基,该苯基为非取代或被甲基或甲氧基取代一次;和
R1具有R2的含义,R1和R2可以相同,也可以不同;或者
R1和R2一块连接到氮原子上,形成通式Ⅱ的基团,
(Ⅱ)
在通式Ⅱ中,n为2,A为O或CH2;
在特别优选的通式Ⅰ的化合物中,还有它的生理上可以接受的盐类,其中吡啶-4-和-5-羧酸酰胺-2-羧酸除外。
所说的化合物,吡啶-4-和-5-羧酸酰胺-2-羧酸已由Thums,L.J.在Pharm.Belg.24(1-2),3-21(1969)中和Delarge,J.在Pharm.Acta.Helv.44(10),637-43(1969)中报道过。
卤素意指氟、氯、溴、碘;芳基意指苯基和萘基;杂芳基意指含1、2或3个氮和/或氧和/或硫原子的五元和六元芳环,它们也可以随意地是苯并杂芳基;杂芳基特别指吡啶基、哒嗪基、嘧啶基、吡嗪基,1,3,5-三嗪基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、噻嗯基、噁唑基、和噻唑基、并可随意地是它们的苯并化合物。
“一次以上的取代”在上文和下文中意指大多数存在于烷基中的氢原子至少有2个被所说的取代基取代。在这一点上,最好每个甲基或亚甲基上有一个取代基。
在多取代的情形中,取代基也可以是各自独立的。
本发明也涉及通式Ⅰ的化合物的应用,涉及生理上可接受的盐类加上吡啶-4-和5-羧酸酰胺-2-羧酸用于制备抑制脯氨酸羟化酶和赖氨酸羟化酶的药物。
最后,本发明涉及通式Ⅰ的化合物加上吡啶-4-和-5-羧酸酰胺-2-羧酸作为药用。
本发明特别涉及通式Ⅰ的化合物加上吡啶-4-和-5-羧酸酰胺-2-羧酸,用作纤维抑制和免疫抑制剂,用作脯氨酸羟化酶和赖氨酸羟化酶抑制剂,用来影响胶原和类胶原物的代谢和CIg的生物合成。
所有所说的含2个以上碳原子的烷基既可以是直链的,也可以是支链的。
本发明也涉及制备通式Ⅰ的化合物加上吡啶-4-或-5-羧酸酰胺-2-羧酸的程序。
根据本发明所述的方法,取吡啶-2,4-二羧酸为例,在下文中加以阐明。根据本发明,按制备2,5-取代的化合物的方法类似方式进行。
在步骤1中,可以买得的吡啶-2,4-二羧酸转变为它的二酰卤,最好是它的二酰氯,并随意地与取代的苄醇反应,制得吡啶-24-二羧酸的二苄酯。
在步骤2中,例如象Delarge,J.在Phar.Aeta.Helv.44(10),637(1969)中描述的,在铜催化剂的存在下,在二酯的2位选择性水解。
在步骤3中,2位的游离酸功能基转变为对应的酰氯,并与醇例如甲醇或乙醇反应,生成对应的2-羧酸酯。
在步骤4中,保留在4位的苄基保护基通过氢化(例如用H2/Pd,Houben-Weyl:Vol.IY/IC(1980),PP 381-82)脱去,并将4位的游离酸转变成它的酰氯。
然后所说得酰氯用通式Ⅲ的胺(其中R1和R2具有在通式Ⅰ的化合物中的含义)转变成混合的吡啶-4-羧酸酰胺-2-羧酸酯。
最后(步骤6)所得的2-羧酸酯用醇性碱(例如氢氧化钠的乙醇溶液)先转变为2-羧酸盐,该盐再用矿酸(例如盐酸)转变成根据本发明所述的通式Ⅰ′的化合物。
所说的在4位取代的化合物的反应图解中已经描述的反应方法,也可用于对应的5位取代的化合物。
通式Ⅰ的化合物加上吡啶-4-和-5-羧酸酰胺-2-羧酸具有有价值的药理活性,并特别显示作为纤维抑制剂和免疫制剂的活性和对脯氨酸羟化酶和赖氨酸羟化酶的抑制活性。
纤维酶活性能通过血浆中的Ⅲ型胶原的N端前肽或Ⅳ型胶原的N或C端交联区域(7S胶原或Ⅳ型胶原NC1)的放射免疫测定来确定。
为了此目的,经脯氨酸、前胶原Ⅲ肽、7S胶原和Ⅳ型胶原NC1的浓度,在
a)非治疗鼠(对照)
b)给过四氯化碳的鼠(CCl4对照)
c)先给四氯化碳,再给按照本发明所述的化合物的鼠,肝中测定。
(本试验方法由Rouiller,C.,experimental toxic injury of the liver;in the Liver,C.Rouiller,Vol.2,pp 335-476,New York,Academic Press,1964描述过)。
通式Ⅰ的化合物加上吡啶-4-和-5-羧酸酰胺-2-羧酸,能以含有它们和适宜的可以接受的药物赋形剂的药品的形式,作为药用。例如,这些化合物能够以含有与适合于肠内、皮内或注射给药的药物的、有机的或无机的赋形剂混合的形式,作为药用。这些赋形剂包括例如,水,阿拉伯胶、明胶、乳糖、淀粉、硬脂酸镁,滑石粉,植物油、聚二醇油、凡士林等等。
它们能为此目的口服给药,剂量为0.01-25.0mg/kg/天,最好是0.01-5.0mg/kg/天,或注射给药,剂量为0.001-5mg/kg/天,最好是0.001-2.5mg/kg/天,特别是0.005-1.0mg/kg/天。严重病例,亦可能增大剂量。不过,在许多病例中,较低的剂量已经充足。这些数据涉及到大约75公斤体重的成人。
本发明还包括使用本发明所述的化合物,制备用于治疗和预防前面提到的代谢失调。
另外,本发明还涉及含一种或多种按本发明所述的通式Ⅰ化合物和/或者它们的生理上可以接受的盐类,加上吡啶-4-和-5-羧酸酰胺-2-羧酸的药物。
这些药物通过本质上已知的或专业技术人员熟悉的方法来制备。作为药物,本发明所述的药理活性化合物(二活性物质)或者以原始形态使用,或者最好是与适宜的药物辅加剂或赋形剂结合,以片剂,糖衣片、胶囊、栓剂、乳化剂,悬浮剂或溶液的形式使用,其中活性化合物的含量高达大约95%,而在10%至75%之间有利。
所需的药物配方的合适的辅剂和赋形剂,除溶剂以外包括例如凝胶形成剂、栓剂基质,片剂赋形剂和其它活性物质赋形剂,还有抗氧化剂、分散剂、乳化剂、泡沫抑制剂、香料、防腐剂、助溶剂或着色剂。
活性化合物能口服、注射或直肠给药。活性化合物与适合于此目标的附加剂,例如赋形剂,稳定剂或惰性稀释剂混合,并通过常用的方法转变为适当的剂型,例如片剂、糖衣片、硬质胶囊、水性、醇性或油性悬浮液,或水性或油性溶液。
能被使用的惰性赋形剂的例子有,阿拉伯胶、氧化镁、碳酸镁、磷酸钾、乳糖、葡萄糖或淀粉,特别是玉米淀粉。能使用湿的或干的颗粒进行制备。合适的油性赋形剂或溶剂的例子有,植物油或动物油例如葵花油或鱼肝油。
对于皮下或静脉给药,若需要的话,使用适合于此目标的化合物例如助溶剂、乳化剂或其它辅助剂,将活性化合物转变成溶液、悬浮剂或乳化剂。适宜的溶剂的例子是,生理盐水或醇,例如乙醇、丙醇、甘油,以及糖溶液,例如葡萄糖或甘露糖醇溶液,或各种提到的溶剂的混合物。
下文通过实例更详细地解释本发明。
实例1
吡啶-2,4-二羧酸二苄酯(步骤1):
30g吡啶-2,4-二羧酸用30ml亚硫酰氯转变成酰氯,并与43.8g苄醇反应。产物用二异丙基醚重结晶。
产率:42.1g 熔点63-65℃
实例2
吡啶-2,4-二羧酸4苄酯(步骤2)
40g来自实例1的吡啶-2,4-二羧酸二苄酯加到700ml甲醇和27.8g硝酸铜的混悬液中。混合物在回流温度下沸腾1小时,冷却之后,过滤取出铜络合物。该络合物悬浮到二氧六环中,并通入硫化氢。滤去硫化铜沉淀,有机层浓缩。产物用石油醚搅拌。
产率:25.3g 熔点:113-115℃
实例3
吡啶-2,4-二羧酸-4-苄酯-2-甲酯(步骤3)
34g来自实例2的化合物加到1升四氢呋喃之中。混合物冷至0℃,在此温度下往里缓慢滴加250ml重氮甲烷溶液。混合物使升温至室温,并搅拌12小时。浓缩溶液,粗产品经层析(硅胶),乙酸乙酯作流动相)纯制。
产率:26g 熔点:58℃
实例4
吡啶-2,4-二羧酸-2-甲酯(步骤4)
26g来自实例3的化合物于室温下溶入1升二氧六环中。往该溶液中加入500mg钯/碳(10%)催化剂,在大气压下,氢化4小时。停止吸氢气后,减压滤去催化剂并除去溶剂。
产率:15.3g 熔点241-243℃
实例5a
吡啶-2,4-二羧酸-2-甲酯-4-(2-甲氧乙基)酰胺(步骤5)
11g来自实例4的化合物用4.8ml氧化亚砜,按实例1的类似途径转变成酰氯,后者与517ml 2-甲氧乙基胺反应,生成所需的酰胺。粗产品用二异丙基醚磨,减压滤出产物。
产率:915g 熔点:74-76℃
实例5b
吡啶-2,4-二羧酸-2-甲酯-4-(3-甲氧丙基)酰胺(步骤5)
3g来自实例4的化合物按实例5a类似的途径,用1.2ml氯化亚砜转变成酰氯,后者与117ml 3-甲氧基丙胺反应,生成所需的酰胺。粗产品经层析(乙酸乙酯/甲醇15/l展开)纯化。
产率:2.6g 油状物
实例6a
吡啶-2,4-二羧酸-4-(2-甲氧乙基)酰胺(步骤6)
2.3g氢氧化钠(小球)在室温下溶入70ml乙醇中。在此温度下,往里滴加9g来自实例5a的化合物与30ml乙醇制成的溶液。4小时后,该混合物蒸发至干,残留物用少量水萃出,所得的溶液用浓盐酸缓慢酸化。溶液蒸发,产物用热乙醇重结晶。
产率:8g 熔点:130-135℃
实例6b
吡啶-2,4-二羧酸-4-(3-甲氧丙基)酰胺(步骤6)
用3g来自于实例5b的酯,按与实例6a类似的途径制备该化合物。
产率:2.6g 熔点:118-122℃
Claims (7)
1、制备通式Ⅰ的4-或5-取代的吡啶-2-羧酸或其生理可接受盐的方法,
(Ⅰ)
在通式Ⅰ中,R1和R2各自独立地为氢,含1至12个碳原子的烷基,含2至12个碳原子的烯基、含2至12个碳原子的炔基,含5至7个碳原子的苯并或非苯并环烷基,芳基或杂芳基,这里提到的作为R1和R2的基,可以是非取代的,也可以被一个或多个相同或不同的R3基取代;其中R3为卤素、羟基、氰基、硝基、硝酰基、氨基、羧基,含1至4个碳原子的烷氧基、含1至4个碳原子的烷氧羰基,含1至4个碳原子的烷基氨基或二烷基氨基,吲哚基或苯基,其中吲哚基或苯基是非取代的,或者被卤素、硝基、含1至4个碳原子的烷基或1至4个碳原子的烷氧基取代一次、二次或三次,在多取代的情况下,取代基可以相同或不同。
或者,如果
R1为氢,则R2为-N(R4)(R5)基,其中R4和R5可以相同,也可以不同,并为氢,含1至4个碳原子的烷基、含1至3个碳原子的烷基、含1至3个碳原子的烷基羰基或苯基;
或者,如果
R1为氢,则R2为α氨基酸、α氨基醇烷基酯、α氨基酰胺、α氨基烷基酰胺或α氨基二烷基酰胺残基,它们通过N端键合;这里所说的烷基含1至4个碳原子,并随意地被苯基单取代,并且其中含3个和4个碳原子的烷基也可以是支链的;
或者,如果
R1为氢,则R2为二肽或三肽残基,它们经N端键合,这里的“残基”意味着在特殊的氨基酸和它们的衍生物,或二肽或三肽,等每种场合下,都缺少N端;和
R1具有R2的含义,其中R1和R2基可以相同,也可以不同;或者
R1和R2一块结合到氮原子上,形成通式Ⅱ的基团,
在通式Ⅱ中,n在1至3中取值,A为O、S、CH;或
-N(R6)-,其中R6为氢、苯基、含1至6个碳原子的烷基、含2至6个碳原子的烯基或含2至6个碳原子的炔基,这里所说的这些基是非取代的,或被苯基取代,而苯基反过来又可以是非取代的或被选自卤素、硝基、氰基、羧基、羟基、甲基、乙基、甲氧基、乙氧基和三氟甲基的一个或多个相同的或不同的取代基取代一次或多次;或为选自-N(R7)2(其中R7为氢或含1至3个碳原子的烷基)和-COOR7、-CON(R8)2或-CONHR6(其中R8具有R7的含义,或其中(R8)2是含4至6个碳原子的烯链,在该烯链中非直接连到氮原子上的零或一个CH2基被O、S,或N-R7取代,等基团的一个或多个相同或不同的取代一次或多次;或其中R6为含1至4个碳原子的烷氧羰基或含3至7个碳原子的环烷基;其中
-吡啶-2,4-二羧酸被转化为它们二酰卤,
-所得的二酰卤被转化为二苄酯,
-二苄酯在2位选择性水解
-这样生成的单苄酯在其游离羧基上转变为对应的酰氯,然后与除苄醇在外的醇反应使转化为对应的2-羧酸酯,
-4位或5位的苄基保护基通过氢化脱去,生成的4位或5位的游离酸被转化为对应的酰氯,
-来自上步的酰氯与通式Ⅲ的胺反应,
HNR1R2(Ⅲ)
在通式Ⅲ中的R1和R2具有通式Ⅰ中指出的含义,通过反应转变为混合的吡啶二羧酸-4-或-5-酰胺-2-酯,
-最后,用矿酸将所说的2-羧酸酯转变为2位的游离酸。
2、权利要求1中要求的方法,在该方法中,R1和R2各自独自地为氢、含1至6个碳原子的烷基、含2至6个碳原子的烯基、含2至6个碳原子的炔基、含5至7个碳原子的环烷基、芳基或杂芳基,这里作为R1和R2提到的这些基为非取代或被一个或两个相同或不同的R3基取代,其中R3为卤素、羟基、氰基、氨基、羧基、含1至4个碳原子的烷氧基、含1至4个碳原子的烷氧羰基、含1至4个碳原子的烷基氨基或二烷基氨基、或苯基;这里的苯基为非取代或被卤素、含1至2个碳原子的烷基或含1至2个碳原子的烷氧基取代一次,
或者,如果
R1为氢,则R2为-N(R4)(R5)基,其中R4和R5可以相同,也可以不同,并为氢或含1至3个碳原子的烷基,
或者,如果
R1为氢,则R2为通过N端键合的α氨基酸或α氨基酸烷基酯的残基,其中的烷基含1至3个碳原子,并随意地被苯基单取代,而且含3个碳原子的烷基也可以是支链,和
R1具有R2的含义,其中R1和R2可以相同或不同,或者
R1和R2一块键合到氮原子上,生成通式Ⅱ的基,
(Ⅱ)
在通式Ⅱ中,n的取值范围为1至3,A为O、CH2或-N(R6)-,其中R6为氢、苄基、含1至6个碳原子的烷基,这里所说的这些基为非取代的,或被含1至4个碳原子的烷氧羰基或含3至7个碳原子的环烷基取代;以及生理上可以接受的盐类,其中吡啶-4-和-5-羧酸酰胺-2-羧酸除外。
3、权利要求1中要求的化合物,其中R1和R2各自独立地为氢、含1至5个碳原子的烷基、特别是含1至3个碳原子的烷基、含6个碳原子的环烷基、苯基、或吡啶基,这里作为R1和R2提到的这些基为非取代的,或被一个或两个相同的R3基取代;其中R3基为羟基、氨基、羧基、含1至4个碳原子的烷氧基、特别是甲氧基、含1至4个碳原子的烷氧羰基、或苯基、其中苯基为非取代或被甲基或甲氧基取代一次;
和R1具有R2的含义,其中R1和R2基可以相同或不同;或者
R1和R2一块键合到氮原子上,形成通式Ⅱ的基团,
在通式Ⅱ中,n为2,A为O或CH2;以及R1和R2为生理上可以接受的盐类,其中吡啶-4-和-5-羧酸酰胺-2-羧酸除外。
4、权利要求1要求的化合物,该化合物用于抑制脯氨酸羟化酶和赖氨酸羟化酶。
5、权利要求1中要求的化合物,该化合物用作纤维抑制剂和免疫抑制剂。
6、含权利要求1中要求的化合物和/或其生理上可接受的盐类的药物,该药物用于治疗胶原和类胶原物生物合成障碍以及CIg的生物合成障碍。
7、制备能影响胶原和类胶原物的生理合成和CIg生物合成的药物的方法,该方法包括把权利要求1中要求的通式Ⅰ的化合物和/或该化合物的生理上可以接受的盐类结合到药物之中。
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DE4031000A DE4031000A1 (de) | 1990-10-01 | 1990-10-01 | 4- oder 5-substituierte pyridin-2-carbonsaeuren, verfahren zu deren herstellung sowie deren verwendung als arzneimittel |
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WO2006034341A2 (en) | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Pyridazine derivatives for inhibiting human stearoyl-coa-desaturase |
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- 1991-09-30 EP EP19910116632 patent/EP0479177A3/de not_active Withdrawn
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- 1991-09-30 JP JP3250719A patent/JPH04247070A/ja active Pending
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BG95162A (bg) | 1993-12-24 |
EP0479177A2 (de) | 1992-04-08 |
KR920007999A (ko) | 1992-05-27 |
AU8485291A (en) | 1992-04-02 |
FI914556A0 (fi) | 1991-09-27 |
ZA917805B (en) | 1992-05-27 |
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EP0479177A3 (en) | 1992-10-28 |
PL291881A1 (en) | 1992-06-15 |
JPH04247070A (ja) | 1992-09-03 |
NO913834L (no) | 1992-04-02 |
PT99132A (pt) | 1992-09-30 |
CS299191A3 (en) | 1992-06-17 |
DE4031000A1 (de) | 1992-04-09 |
CA2052510A1 (en) | 1992-04-02 |
FI914556A (fi) | 1992-04-02 |
MA22313A1 (fr) | 1992-07-01 |
IL99605A0 (en) | 1992-08-18 |
NO913834D0 (no) | 1991-09-30 |
BR9104205A (pt) | 1992-06-02 |
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