CN1234800A - 二氮杂萘衍生物 - Google Patents
二氮杂萘衍生物 Download PDFInfo
- Publication number
- CN1234800A CN1234800A CN97199186A CN97199186A CN1234800A CN 1234800 A CN1234800 A CN 1234800A CN 97199186 A CN97199186 A CN 97199186A CN 97199186 A CN97199186 A CN 97199186A CN 1234800 A CN1234800 A CN 1234800A
- Authority
- CN
- China
- Prior art keywords
- compound
- phenyl
- formula
- naphthyridine
- group
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
本发明公开了一种新的游离形式或盐形式的8－芳基－1,7－二氮杂萘,其是PDEⅣ抑制剂,因而可用作药物,如用于治疗气喘。优选的化合物包括式Ⅰ和Ⅱ的化合物,其中,R基团如说明书定义。本发明还公开了包含所述化合物的药物组合物,化合物的制备方法及用于该方法的新的中间体。
Description
本发明涉及新的8-芳基-1,7-二氮杂萘类化合物及其生产方法，包含所述化合物的药物组合物及所述化合物作为药物的用途。
本发明提供了游离形式或药用盐形式的8-芳基-1,7-二氮杂萘。“芳基”是指具有至多10个芳族非氢原子的单环或双环芳环或杂芳环基团，该基团直接连接至1,7-二氮杂萘上(如苯基、吡啶基、四唑基、苯并呋咱基或苯并硫代呋咱基)，或经亚甲基桥基连接至1,7-二氮杂萘上(如苄基或吡啶甲基)；优选具有至多六个芳族碳原子的单环芳基，至多两个碳原子可被氮原子代替，例如苯基、苄基、4-吡啶基或4-吡啶甲基，选择性地带有羧基、羧基酯或羟基。8-芳基基团可选择性地再次被取代，特别是被吸电子基团取代，如硝基、次氮基、亚氨基、卤素或含卤取代基(如三氟甲基)或氰基，取代基优选在间位。例如，8-芳基可以是氰基苯基、硝基苯基、四唑基苯基(如四唑-1-基苯基)或氯代苯基。选择性地，分子的二氮杂萘双环也可进一步被取代或二取代，特别是6-取代，取代基可以是羟基、烷基、链烯基、链炔基、烷氧基、芳基、芳氧基、氨基、芳氨基、二芳氨基、烷氨基、二烷氨基、芳基酰氨基或烷基酰氨基，其中“烷基”是指至多8个碳原子的脂族基团，其选择性地带有羧基或羧基酯或羟基和/或选择性地包含醚键和/或酯键。
具体而言，本发明提供了新的8-苯基-和8-苄基-1,7-二氮杂萘，其中，1,7-二氮杂萘双环选择性地被6位-取代，例如，如以下举例的那样，苯环被吸电子取代基如硝基选择性地取代；例如，式Ⅰ的化合物和其酯，和其酰胺；游离形式或药用盐形式；
其中R1为苯基、苄基、3-硝基苯基、3-氯苯基、3-氰基苯基、3-(四唑基)苯基、苯并呋咱基或苯并硫代呋咱基；R2为羟基、氨基、三氟甲磺酰基、烯丙基、烷基、链烯基、链炔基、烷氧基、芳基、芳烷基、芳氧基、氨基、芳基氨基、二芳基氨基、烷氨基、二烷基氨基、烷基芳基、芳基酰氨基或烷基酰氨基。
在式Ⅰ中及在本发明的说明书中，“烷基”和“芳基”与本发明中上述对8-苄基-1,7-二氮杂萘的定义相同。
优选R2选自羟基、氨基、芳基氨基(如苯氨基)、芳基(如苯基)、烷芳基(如低级烷基苯基)、链烯基(如乙烯基)、链炔基(如乙炔基)、含醚键和/或酯键的烷氧基(如甲氧羰基甲氧基)和烷基酰氨基(如乙酰氨基)。
特别是令人惊奇地发现，所有新发现的6,8-芳基-1,7-二氮杂萘类化合物均可用作药物，特别是口服的活性PDE4抑制剂，例如，用于治疗气喘。
因而，在本发明优选的实施方案中，提供了6-(羧基苯基或羧基甲基苯基)-8-(苯基，苯并[c]噻二唑基或苯并[c]呋咱基)-1,7-二氮杂萘，和其酯和其酰胺，游离形式或可药用盐形式。
更优选的是，本发明提供了6-(4-羧基苯基或4-羧基甲基苯基)-8-(苯基，4-苯并[c]噻二唑基或4-苯并[c]呋咱基)-1,7-二氮杂萘，和其酯和其酰胺，游离形式或可药用盐形式。
所谓苯并[c]噻二唑基或苯并[c]呋咱基分别是指下式A和B的基团：因此，在本发明的特别优选的实施方案中，提供了下式Ⅱ的化合物
其中n为0或1；R7为羟基、氨基、C1-4烷氨基或C1-4烷氧基，优选羟基或氨基；而R3为H,R4为硝基、卤素(如氯)、氰基或四唑基(如1-四唑基)，R5和R6一起形成另一个键，或者R3、R4、R5和R6一起为=N-O=或=N-S-N=；和其酯和酰胺；游离形式或可成药形式。
用于药物的适宜药用盐形式的8-芳基-1,7-二氮杂萘如式Ⅰ或式Ⅱ的化合物可按照常规方式制备。例如，具有游离羧酸基团的化合物，如其中R7为OH的式Ⅱ化合物可与适宜的碱如氨基糖，例如N-甲基-葡糖胺进行接触，得到相应的碱加成盐。通常，这种碱加成盐为水溶性盐。
本发明的8-芳基-1,7-二氮杂萘如式Ⅰ化合物可通过使2-氰基-3-吡啶基乙腈与下述化合物反应制备：
a)与-种酸反应，如H-A，其中，A为卤素，如溴，得到式Ⅲ的化合物：
式Ⅲ化合物可进一步衍生得到本发明的化合物，例如，式Ⅲ化合物在钯或镍催化剂存在下，采用金属试剂，进行交联偶合反应，以形成碳-碳键，例如进行Stille、Suzuki或Heck反应，即，使式Ⅲ化合物与Y-R8化合物反应，其中，Y为金属离去基团，如，B(OH)2-、(CH2)3Sn-(CH3(CH2)3)3Sn-,R8为如前定义的8-芳基部分，如苄基或3-硝基苯基，得到相应的式Ⅳ化合物
或者
b)与Grignard试剂如R8-MgBr反应，其中，R8为如前定义的8-芳基部分，如苄基或3-硝基苯基，得到相应的式Ⅳ化合物；或者
c)与碱金属醇盐如甲醇钠混合，反应得到式Ⅲ′的化合物
其中，Alk代表C1-C8烷基，如甲基。-O-Alk取代基可被转化成卤素A，从而，该化合物如上所述在8位上衍生得到式Ⅲ化合物。
在式Ⅲ、Ⅲ′或Ⅳ中的氨基可进一步反应，例如
(ⅰ)采用适宜的活化试剂进行活化反应，如采用三氟甲磺酸和NaNO2，得到式Ⅴ的三氟甲磺酸酯：其中，Q为如前定义的卤素A、如前对式Ⅲ′化合物上述定义的-O-Alk取代基或8-苄基部分，R8如前定义，式Ⅴ化合物为一种新的并非常有用的制备本发明化合物的中间体，例如当式Ⅰ中R2与分子的其它部分经碳-碳键连接，取代反应可如下进行，例如在钯或镍催化剂存在下，采用金属试剂，进行交联偶合反应，以形成碳-碳键，例如进行Stille、Suzuki或Heck反应，例如，使式Q为R8的Ⅴ化合物与Y-R2化合物反应，其中，Y为如前定义的金属离去基团，R2为所需的碳取代基，例如如前对式Ⅰ定义的烷基、链烯基、链炔基、芳基或烷芳基，选择性地以被保护形式进行，随后，如果需要的话进行脱保护反应；或
(ⅱ)进行烷基或苄基取代反应(如通过与相应的烷基卤或有机金属化合物反应)得到所需的仲胺或叔胺；或
(ⅲ)进行酰化反应(例如，通过与羧酸或酸酐反应)得到相应的酰胺，采用常规过程；或
(ⅳ)例如通过在稀酸如硫酸存在下，与NaNO2反应转化成羟基，并且选择性地再进行衍生如通过与烷基卤在适宜的反应条件下反应进行O-烷基化反应。
优选6-(羧基-，或羧基甲基-苯基)-8-(苯基，苯并[c]噻二唑基或苯并[c]呋咱基)-1,7-二氮杂萘，或其酯或酰胺，如式Ⅱ的化合物，通常采用下述方法制备：
(A)为了制备6-(羧基-，或羧基甲基-苯基)-8-(苯基，苯并[c]噻二唑基或苯并[c]呋咱基)-1,7-二氮杂萘或其酯或酰胺，使6-X-8-(苯基，苯并[c]噻二唑基或苯并[c]呋咱基)-1,7-二氮杂萘与X＇-(羧基-，或羧基甲基-苯基)或其酯或酰胺反应，或者，使6-(羧基-，或羧基甲基-苯基)-8-X-1,7-二氮杂萘或其酯或酰胺与X′-(苯基，苯并[c]噻二唑基或苯并[c]呋咱基)反应，其中，X和X′为能够参与交联偶合反应的离去基团；例如，当X为三氟甲磺酰基或卤素如溴或氯时，X′为金属离去基团如取代的硼(如，-B(OH)2、-B(OAlk)2或-BAlk2，其中，Alk为烷基，如甲基或乙基)或三烷基锡烷基(如，(CH3(CH2)3)3Sn-或(CH3)3Sn-)或Grignard基(例如MgBr)；和/或
(B)选择性地使6-(羧基-，或羧基甲基-苯基)-8-(苯基，苯并[c]噻二唑基或苯并[c]呋咱基)-1,7-二氮杂萘与适宜的胺如氨或(C1-4)烷基胺反应，得到相应的酰胺；和/或
(C)选择性地使6-(羧基-，或羧基甲基-苯基)-8-(苯基，苯并[c]噻二唑基或苯并[c]呋咱基)-1,7-二氮杂萘与适宜的醇如(C1-4)醇反应，得到相应的酯；和
回收形成的游离或盐形式的6-(羧基-，或羧基甲基-苯基)-8-(苯基，苯并[c]噻二唑基或苯并[c]呋咱基)-1,7-二氮杂萘，或其酯或酰胺。
步骤(A)的反应条件在本领域中是公知的，在交联偶合反应中采用金属试剂，如在钯或镍催化剂存在下进行，以形成碳-碳键；例如，如在Stille、Suzuki或Heck反应中。步骤(B)和(C)的反应条件是用于从羧酸和胺的反应制备酰胺及从羧酸与醇反应制备酯的领域中是公知的，例如，在酸性或碱性条件下进行。回收和纯化方法也采用常规方法，例如色谱法或结晶法。
因此，在本发明的优选实施方案中，提供了一种制备如前定义的式Ⅱ化合物的方法，该方法包括使式Ⅵ化合物与式Ⅶ化合物反应，回收所获得的游离形式或盐形式的式Ⅱ化合物，
其中，R3、R4、R5、R6和X与前述对式Ⅶ定义相同
其中，R7和X′定义如前。
用于上述反应的6-X-8-(苯基，苯并[c]噻二唑基或苯并[c]呋咱基)-1,7-二氮杂萘和6-(羧基-或羧基甲基-苯基)-8-X-1,7-二氮杂萘或其酯或酰胺可适宜地以2-氰基-3-吡啶基乙腈与一种酸如H-A反应，其中，A为卤素，如溴，得到一种式Ⅲ的化合物，以后根据需要，按照上述再进行衍生。
上述制备本发明8-芳基-1,7-二氮杂萘的方法，特别是制备6-(羧基-或羧基甲基-苯基)-8-(苯基，苯并[c]噻二唑基或苯并[c]呋咱基)-1,7-二氮杂萘或其酯或酰胺的方法均是新的，并且式Ⅳ,Ⅴ和Ⅵ中间体也是新的，本发明的保护范围也包含这些新的方法和中间体。可以理解，其中Q为R8的式Ⅴ化合物以及式Ⅳ化合物均在本发明的8-芳基-1,7-二氮杂萘范围之内。
因此，本发明还提供了式Ⅴ′中间体其中，Q ′为卤素，或-O-Alk，其中Alk代表C1-C8烷基，和式Ⅵ中间体
其中，R3、R4、R5、R6和X如前定义。
下述实施例用于说明本发明。
实施例实施例1：6-氨基-8-(3-硝基苯基)-1,7-二氮杂萘A．2-氰基-3-吡啶基乙腈
向搅拌中的3-氰基甲基吡啶-N-氧化物(30g,0.22mol；合成参见Shigenobu Okuda,Michael M.Robison,J.Am.Chem.Soc.81,740(1959))的二氯甲烷(200mL)悬浮液中加入三甲基硅烷甲腈(26g,0.26mol)。向悬浮液中加入二甲基氨基甲酰氯(28g,0.26mol)。将混合物搅拌45小时。除去溶剂，将残余物溶解于乙酸乙酯中。溶液用1N氢氧化钠和水洗涤，真空浓缩。产物用快速硅胶柱色谱纯化(15∶2甲苯/丙酮)，得到标题化合物。质量M+H 144.1。熔点62-63℃。B．6-氨基-8-溴-1,7-二氮杂萘
在充分搅拌下，使HBr鼓泡通过2-氰基-3-吡啶基乙腈(3.6g,0.025mol)的甲苯(80mL)溶液，持续5小时。然后，小心地加入4N的氢氧化钠，再将悬浮液剧烈搅拌。对混合物过滤，产物用水洗涤，干燥。用甲苯进行结晶，得到标题化合物。质量M+H 225。熔点188℃，分解。C．6-氨基-8-(3-硝基苯基)-1,7-二氮杂萘
向于四氢呋喃(80mL)与碳酸钠水溶液(34mL,2N)混合物中的6-氨基-8-溴-1,7-二氮杂萘(4g,0.018mol)的搅拌下的溶液中加入双(二亚苄基丙酮)钯(0.40g,0.0007mol)、三苯膦(0.37g,0.0014mol)和3-硝基苯基硼酸(3.7g,0.022mol)。将混合物在80℃下搅拌16小时。将混合物过滤，加入乙酸乙酯，混合物再用2N氢氧化钠和水洗涤。除去有机溶剂，将残余物悬浮于乙醚中。过滤，得到标题化合物。质量M+H 267。熔点221-223℃。实施例2：6-氨基-8-(4-苯并[c]呋咱基)-1,7-二氮杂萘
向搅拌中的6-氨基-8-溴-1,7-二氮杂萘(3.0g,13.4mmol)的DMF(50mL)溶液中加入双(二亚苄基丙酮)钯(308mg,0.54mmol)、三苯膦(565mg,2.15mmol)和4-甲基甲锡烷基苯并[c]呋咱(4.92g,16.0mmol)。将混合物在125℃下保持4小时。加入乙酸乙酯(500mL)，再加入KF水溶液(40％,100mL)。将混合物剧烈搅拌45分钟，过滤。分离出有机相，用水洗涤，浓缩。在30分钟内及0℃下，将残余物溶入搅拌中的乙醚(20mL)中，过滤，得到标题化合物(2.8g)。质量M+H264。熔点244-250℃。实施例3：6-羟基-8-(3-硝基苯基)-1,7-二氮杂萘
在4℃下，向6-氨基-8-(3-硝基苯基)-1,7-二氮杂萘(500mg,1.87mmol；按实施例1制备)的浓硫酸和水(3mL,2∶1)的溶液中加入硝酸钠(155mg,2.25mmol)。30分钟后，除去冰浴，将混合物升温至70℃30分钟。将反应混合物倒入冰中，溶液用加入的碳酸氢钠中和。滤出沉淀，用水洗涤，得到标题化合物。熔点为262-265℃。实施例4：6-甲氧羰基甲氧基-8-(3-硝基苯基)-1,7-二氮杂萘
在室温下，将6-羟基-8-(3-硝基苯基)-1,7-二氮杂萘(107mg,0.40mmol，按前实施例生产，选择性地不经纯化)、碳酸钾(55mg,0.40mmol)和溴乙酸甲酯(37μL,0.4mmol)的悬浮液在丙酮-二甲基甲酰胺(2mL,1∶1)中搅拌2小时。加入乙酸乙酯，有机相用2N氢氧化钠洗涤。真空除去溶剂，粗产物用制备薄层色谱法纯化，得到标题化合物。质量M+H 340。熔点160-162℃。实施例5：6-乙酰氨基-8-(3-硝基苯基)-1,7-二氮杂萘盐酸盐
将于吡啶(1mL)和二甲基甲酰胺(3mL)中6-氨基-8-(3-硝基苯基)-1,7-二氮杂萘(300mg,1.1mmol；按实施例1制备)与乙酸酐(0.12mL,1.2mmol)的悬浮液在80℃下保持3小时。加入水，滤出沉淀，用水充分洗涤。过滤，得到标题产物。质量M+H 308。熔点235-238℃。实施例6：6-氨基-8-苄基-1,7-二氮杂萘
在室温下，向2-氰基-3-吡啶基乙腈(2g,0.014mol)的甲苯(20mL)溶液中加入苄基溴化镁(8.4mL,2M的四氢呋喃溶液，0.17mol)。1小时后，用饱和氯化铵溶液使反应停止。产物用乙酸乙酯萃取，有机层用2N氢氧化钠及水洗涤。产物用快速硅胶柱色谱纯化(10∶3甲苯/丙酮)，得到标题化合物。质量M+H 236。熔点113-116℃。实施例7：6-苯基氨基-8-(3-硝基苯基)-1,7-二氮杂萘
向三苯基铋(182mg,0.41mmol)的二氯甲烷(0.5mL)与四氢呋喃(0.5mL)溶液中加入过乙酸(0.083mL,40％)。将混合物搅拌1小时。然后，加入6-氨基-8-(3-硝基苯基)-1,7-二氮杂萘(100mg,0.37mmol；实施例1制备)的二氯甲烷(0.5mL)与THF(0.5mL)溶液。加入铜(30mg,0.47mmol)，将悬浮液搅拌40小时。用乙酸乙酯稀释悬浮液，过滤。滤液用2N碳酸氢钠及水洗涤，有机层进行真空浓缩。经制备薄层色谱处理(8∶2二氯甲烷/正己烷)，得到标题化合物。质量M+H 343.1。熔点158-160℃。实施例8：6-三氟甲磺酰基-8-(3-硝基苯基)-1,7-二氮杂萘
向6-氨基-8-(3-硝基苯基)-1,7-二氮杂萘(1.24g,0.0047mol；实施例1制备)的三氟甲磺酸(12mL)溶液中分几批加入亚硝酸钠(0.64g,0.0093mol)。将溶液加热至60℃，搅拌过夜。将混合物倒入乙酸乙酯与冰的混合物中。然后，加入2N氢氧化钠，直至水相呈碱性。有机相用水洗涤，真空浓缩。产物用快速硅胶柱色谱纯化(7∶3己烷/乙酸乙酯)，得到标题化合物。质量M+H 400。熔点106-108℃。实施例9：6-苯基-8-(3-硝基苯基)-1,7-二氮杂萘
向6-三氟甲磺酰基-8-(3-硝基苯基)-1,7-二氮杂萘(300mg,0.75mmol；实施例8制备)的四氢呋喃(5mL)溶液中加入苯基硼酸(118mg,0.97mmol)、双(二亚苄基丙酮)钯(18mg,0.03mmol)、三苯膦(16mg,0.06mmol)和碳酸钠水溶液(2N,1.44mL)。将溶液在60℃下保持20小时。溶液用乙酸乙酯稀释，过滤，再用1N氢氧化钠及水洗涤。真空除去溶剂，得到纯产物。质量M+H 328。熔点172-175℃。实施例10：6-乙烯基-8-(3-硝基苯基)-1,7-二氮杂萘
向6-三氟甲磺酰基-8-(3-硝基苯基)-1,7-二氮杂萘(250mg,0.62mmol；实施例8制备)的四氢呋喃(3mL)溶液中加入乙烯基三丁基锡烷(218mg,0.68mmol)、双(二亚苄基丙酮)钯(14mg,0.025mmol)、三苯膦(13mg,0.049mmol)和氯化锂(78mL,1.86mmol)。将混合物在70℃下过夜放置。溶液用乙酸乙酯稀释，过滤，用水洗涤。经制备薄层色谱处理(8∶2二氯甲烷/正己烷)，得到标题化合物。质量M+H 278。熔点145-151℃。实施例11：6-乙炔基-8-(3-硝基苯基)-1,7-二氮杂萘A．按照下述过程制备6-三甲基甲硅烷基乙炔基-8-(3-硝基苯基)-
1,7-二氮杂萘
向6-三氟甲磺酰基-8-(3-硝基苯基)-1,7-二氮杂萘(200mg,0.50mmol；实施例8制备)的二甲基甲酰胺(1mL)与三乙胺(0.5mL)溶液中加入乙炔基三甲基硅烷(0.078mL,0.56mmol)、双(二亚苄基丙酮)钯(5.8mg,0.020mmol)、三苯膦(5.3mg,0.020mmol)和碘化铜(3.8mg,0.020mmol)。将混合物在60℃下放置2小时。溶液用乙酸乙酯稀释，用水洗涤。产物通过快速硅胶柱色谱纯化(20∶0.2甲苯/丙酮)，得到6-三甲基甲硅烷基乙炔基-8-(3-硝基苯基)-1,7-二氮杂萘。质量M+H 348。熔点160-163℃。B．向6-三甲基甲硅烷基乙炔基-8-(3-硝基苯基)-1,7-二氮杂萘(77mg,0.22mmol)的甲醇(0.5mL)与甲苯(0.5mL)溶液中加入1N氢氧化钾(0.22mL)。将混合物搅拌2小时。对悬浮液过滤，产物用水和乙醚洗涤，得到标题化合物。质量M+H 276。熔点215℃，分解。实施例12：6-(4-羧基苯基)-8-(3-氰基苯基)-1,7-二氮杂萘
向6-三氟甲磺酰基-8-(3-氰基苯基)-1,7-二氮杂萘(2.15g,5.67mmol)的DMF(21.5mL)溶液中加入4-羧基苯基硼酸(1.13g,6.81mmol)、双(二亚苄基丙酮)钯(131mg,0.23mmol)、三苯膦(95mg,0.36mmol)和碳酸钾水溶液(2N,17mL)。将反应混合物在80℃下搅拌2.5小时。通过硅藻土对热的溶液过滤，通过小心地加入水(10mL)和盐酸水溶液(2N,8mL)，沉淀出粗产物。对悬浮液过滤，粗产物在热THF(30mL)中搅拌。再次对冷的悬浮液进行过滤，得到标题化合物(1.12g)。M+H 352。熔点大于300℃。保留时间HPLC=7.58分钟(柱：LiChroCart 125-4,Supersphere 60 RP-select B,40°；洗脱：乙腈-水(0.1％TFA)=45∶55；1mL/分钟；在254nm下检测)。实施例13：6-(4-氨基甲酰基苯基)-8-(3-硝基苯基)-1,7-二氮杂萘
向6-(4-羧基苯基)-8-(3-硝基苯基)-1,7-二氮杂萘(100mg,0.28mmol)的甲苯(2mL)悬浮液中加入亚硫酰氯(0.1mL,1.37mmol)。将反应混合物回流3小时。蒸出溶剂，将残余物溶入THF(2mL)中。加入氨水，将溶液在室温下再搅拌2小时。加入乙酸乙酯，有机层用水洗涤，得到纯的标题化合物，其熔点为237-240℃。实施例14：6-(4-羧基苯基)-8-(4-苯并[c]呋咱基)-1,7-二氮杂萘A．6-氨基-8-甲氧基-1,7-二氮杂萘
向钠(3.2g,0.139mol)的甲醇(1400mL)溶液中加入2-氰基-3-吡啶基乙腈(20g,0.139mol)，将反应混合物在室温下搅拌17小时。然后，加入水(700mL)，蒸出大多数的甲醇，结晶得到标题化合物，熔点为178-180℃。B．6-三氟甲磺酰基-8-甲氧基-1,7-二氮杂萘
0℃下，向6-氨基-8-甲氧基-1,7-二氮杂萘(19g,0.108mol)于1∶1水与三氟甲磺酸(380mL)的溶液中小心地加入亚硝酸钠(11.2g,0.162mol)的水(40mL)溶液。1小时后，除去冷却浴，再于室温下将反应混合物搅拌1小时。然后，加入乙酸乙酯(500mL)，加入碳酸氢钠(4N,1L)将溶液中和。水相再用乙酸乙酯萃取(3×500mL)。蒸出有机相，粗产物用快速硅胶柱色谱纯化(20∶3甲苯/丙酮)，得到标题化合物。M+308；熔点99-101℃。C．6-(4-羧基苯基)-8-甲氧基-1,7-二氮杂萘
向6-三氟甲磺酰基-8-甲氧基-1,7-二氮杂萘(1.5g,4.86mmol)的DMF(40mL)溶液中加入4-羧基苯基硼酸(0.866g,5.34mmol)、双(二亚苄基丙酮)钯(112mg,0.167mmol)、三邻甲苯膦(96mg,0.32mmol)和碳酸钠水溶液(2N,14.6mL)。将反应混合物在110℃下搅拌3小时。通过硅藻土对热的溶液过滤，将溶液蒸发至干。将粗产物溶解于热水(60mL)中，水相用乙酸乙酯(3×50mL)洗涤。通过小心地加入盐酸水溶液(2N,6mL)，沉淀出产物。对悬浮液过滤，粗产物在热乙酸乙酯(50mL)中搅拌。再次对冷的悬浮液进行过滤，得到标题化合物(1.10g)。M+280。熔点大于300℃。D．6-(4-羧基苯基)-8-溴-1,7-二氮杂萘
向6-(4-羧基苯基)-8-甲氧基-1,7-二氮杂萘(250mg,0.892mmol)的DMF(10mL)溶液中加入PBr3(0.63mL,6.63mmol)。将反应混合物加热至100℃，加热30分钟。然后，将悬浮液倒入水(50mL)中，溶液用乙酸乙酯洗涤(2×50mL)。分去有机相，粗产物在乙醚中搅拌。对悬浮液过滤，得到标题化合物(215mg)。熔点248-250℃，分解。E．4-苯并[c]呋咱基硼酸
向4-苯并[c]呋咱基溴(4g,0.020mol)的四氢呋喃(80mL)与正戊烷(20mL)溶液中加入硼酸三乙酯(3.8mL,0.022mol)和N,N,N,N-四亚乙基二胺(3mL,0.02mol)。然后，在-100℃下滴加入正丁基锂(8.8mL,2.5N己烷溶液，0.022mol)，将溶液再搅拌5分钟。将反应混合物倒入饱合氯化铵水溶液中，水相用乙酸乙酯萃取。分出有机相，粗产物溶入二氯甲烷/正己烷(5∶6)中。对悬浮液过滤，得到标题化合物(1.05g)，即可不经纯化使用。F．6-(4-羧基苯基)-8-(4-苯并[c]呋咱基)-1,7-二氮杂萘
向6-(4-羧基苯基)-8-溴-1,7-二氮杂萘(100mg,0.304mmol)的DMF(2.5mL)溶液中加入4-苯并[c]呋咱基硼酸(60mg,0.36mmol)、双(二亚苄基丙酮)钯(7mg,0.0122mmol)、三邻甲苯膦(7.4mg,0.024mmol)和碳酸钠水溶液(2N,0.9mL)。将反应混合物在80℃下搅拌2小时。通过硅藻土对热的溶液过滤，将溶液蒸发至干。将粗产物溶解于乙酸乙酯(20mL)中，过滤悬浮液，分出有机相。将残余物溶解于热DMF(7mL)中，通过小心地加入盐酸水溶液(2N,1mL)沉淀出粗产物。粗产物再用热DMF重结晶,得到标题化合物(68mg)。M+H 369；熔点大于300℃。保留时间HPLC=10.40分钟(柱：LiChroCart 125-4,Supersphere 60 RP-select B,40°；洗脱：乙腈-水(0.1％TFA)=45∶55；1mL/分钟；在254nm下检测)。
通过重复上述各实施例所述过程，采用适宜的原料，可制得下述式Ⅰ的化合物，如表1所确认。
表1 
具有游离羧基的化合物碱加成盐(如前面所述)可通过使化合物与适宜的氨基糖如N-甲基-D-葡糖胺接触制得。下述实施例用于说明这种碱加成盐的制备。实施例34：6-(4-羧基苯基)-8-(4-苯并[c]呋咱基)-1,7-二氮杂萘：
与N-甲基-D-葡糖胺的盐
向6-(4-羧基苯基)-8-(4-苯并[c]呋咱基)-1,7-二氮杂萘(1g,2.72mmol)的DMF(100mL)热溶液中加入N-甲基-D-葡糖胺(0.53g,2.72mmol)。减压除去溶剂，将残余物用热甲醇(约50mL)进行重结晶，得到纯产物(1.11g)。熔点230℃，分解。保留时间HPLC=6.65分钟(柱：LiChroCart 125-4,Supersphere 60 RP-select B,50°；洗脱：15分钟内梯度0％B/100％A-70％B/30％A；A:900mL水/100mL丙酮中的2.7gKHPO4/0.027g NaHPO4；和B:100mL水/900mL乙腈；在220nm下测量)。产物溶于水。
本发明的8-芳基-1,7-二氮杂萘，如式Ⅰ化合物，特别是优选的6-(羧基苯基或羧基甲基苯基)-8-(苯基，苯并[c]噻二唑基或苯并[c]呋咱基)-1,7-二氮杂萘，和其酯和酰胺，游离形式或盐形式(以下称之为本发明的试剂)显示出药物活性，可用作药物，如用于治疗以下所述的疾病。
具体而言，本发明的试剂显示出周期性核苷酸磷酸二酯酶(PDE)同工酶抑制活性，对4型同工酶的选择性。
本发明的试剂具有抗炎作用、抗呼吸道高反应性和支气管扩张性。它们还具有免疫抑制性、THFα分泌抑制作用及其它药理学活性，如下面标准试验方法所述：A．PDE4抑制作用：重组PDE4A、PDE4B、PDE4C和PDE4D同工酶抑制试验克隆和表达：
PDE4cDNA对四种同工酶进行编码，人PDE4A(如下文所述：Sullivan等，Cell Signal 1994；6:793-812)、大鼠PDE4B(如下文所述：Colicelli等，Proc.Natl.Acad.Sci.USA 1989；86:3599-3903)、人PDE4C(如下文所述：Engel等，FEBS Lett.1995；458:305-310)和人PDE4D(如下文所述：Baecker等，Gene 1994；138:253-256)被分别克隆成染色体外酵母表达载体(PDE4C、PDE4D)或整合在均缺乏野生型酵母PDE基因的酿酒酵母菌株的pep4基因座上。将酵母菌株表达的PDE4同工酶在1L的培养介质中于30℃下培养，沉淀，匀浆前冷冻。
匀浆：将沉淀的酵母(5mL)悬浮于50mL缓冲液(10mM Tris-羟甲基氨基甲烷，1mM乙二胺四乙酸，1mg/mL亮异蛋白酶肽和胃蛋白酶抑制剂A,175mg/mL苯基甲基磺酰基氟，1mM二硫苏糖醇，用盐酸调节pH7.4)。在离心后，向沉淀物中加入用缓冲液洗涤过的15g玻璃珠(425-600mm，酸洗过，Sigma Chemical Co.)。向此浆液中加入1mL的缓冲液和60mg的胆酰氨基丙烷磺酸，将浆液在4℃下剧烈搅拌4小时。酵母细胞分裂，如黑细胞那样进行显微镜观察(相差光学)，大于30％(通常为50％)。将浆液转移至粗玻璃漏斗中，通过抽吸收集匀浆，用总共15mL缓冲液洗涤玻璃珠。通过离心(2000xg,10min,4℃)从细胞溶浆中分离出细胞片段。再将沉淀物悬浮于15mL的缓冲液中，并与细胞溶浆一起进行PDE活性试验。
其它同工酶制备也由人体得到。类型3和4的制备是利用3型同工酶在血小板中很明显的优势及4型同工酶在嗜中性白细胞中很明显的优势得到的，使用了下列技术。
细胞和组织在冰上于Tris-HCl 10mM pH7.4中进行匀浆，所述溶液包含蔗糖(250mM)、EDTA 1mM、二硫苏糖醇(1mM)、亮异蛋白酶肽和胃蛋白酶抑制剂A(均为1μg/mL)，以及苯基-甲基-磺酰基氟(PMSF,0.17mg/mL，匀浆前加入)。从人血中得到嗜中性白细胞(4型)和血小板(2型和3型)，用超声波进行处理(Branson probe,4×15秒)。从患者进行外科手术时获得人肺(1型和5型)，采用Polytron匀浆机进行匀浆(30秒两次)。
同工酶制剂：PDE3和4(底物cAMP 1μM)制剂分别由血小板的低速上层清液和嗜中性白细胞匀浆组成。通过阴离子交换色谱法(Q琼脂糖)分离出1型(底物cAMP 1μM,Ca2+0.5mM，钙调蛋白125nM)、2型(cAMP100μM)和5型(cGMP 1μM)，所述色谱法采用匀浆缓冲液的氯化钠梯率，缓冲液中不含蔗糖和PMSF(0-0.1M氯化钠在2.5柱体积中，0.1-0.45M在24柱体积中)。PDEl：其中通过Ca2++钙调蛋白(分别为0.5mM和125nM)可刺激cAMP 1μM水解的级分；在0.17-0.18M氯化钠中洗脱。PDE2：显示在100μM时而非1μM时实质性cAMP水解活性的级分；在0.31-0.32M氯化钠中洗脱。PDE5：选择性水解cGMP 1μM而非cAMP 1μM的级分；在0.20-24M氯化钠中洗脱。PDE试验
试验方法基于Thompson等的两步法(Adv.Second MessengerPhosphoprotein Res.1979；10:69-92)，对96孔微量滴定板进行了改进。简而言之，酶用匀浆缓冲液(见前述)稀释以在试验中使10-30％全部底物水解。为使反应开始，将25mL的稀释后的酶加至25mL底物([3H]-cAMP,1.25mM,740Bq)和75mL抑制剂溶液(见下面)中。37℃下30分钟后，在热水浴中反应停止(65℃,5分钟)。将板在冰上冷却，并在37℃的25mL 5＇-核苷酸酶(Snake Venom，来自oiophaghus hannah,Sigma Chemical Co.,0.1mg/mL水溶液)中培养。通过随后加入30％(v/v)Dowex 1×2浆液(乙酸盐形式)在0.2％(v/v)乙酸中的等分试样(100+50+50mL,5分钟间隔)，从[3H]-腺苷中分离出未反应的底物。通过离心对Dowex沉淀。采用自动移液管装置(HamiltonMicroLab 2200)将上清液的等分试样转移至96-孔固相闪烁板(LumaPlate,Canberra Packard)上，干燥(50℃下至少4小时)，计数(Canberra Packard TopCount)。
抑制剂：在二甲基亚砜(DMSO)中制备抑制剂的储备液，用水/DMSO稀释得到7种浓度，覆盖30-70％抑制率。DMSO的浓度在整个试验中保持恒定在50mL/mL。
抑制参数测定：通过非线性最小二乘法拟合两个参数对数方程，由浓度-抑制曲线测量50％最大抑制率处的浓度(IC50)及剂量-反应曲线的斜率(Hill系数)。结果表示为观察到50％最大抑制处抑制剂浓度(IC50)的负对数值(mol/L；pIC50)。估计95％置信区间，并表示为pL和pU(分别为在上下限置信限度的负对数值)。在试验中引起可视沉淀的浓度排除于分析之外。
在试验方法中，本发明的试剂主要抑制4型PDE同工酶，其对1、2、3和7型PDE同工酶的作用相当小。而就4型PDE同工酶(即4A-D型PDE)而言，与4A、4B和4C型PDE同工酶相比，本发明的试剂通常显示出对4D型PDE同工酶具有抑制选择性。抗炎活性：通过甲酰基-MetLeuPhe(fMLP)抑制嗜酸性细胞活性
在双-N-甲基吖啶(25μM)存在下，用fMLP(1μM)刺激纯化的人嗜酸性细胞(在0.2mLHBSS中，104/孔)。采用对数方程由剂量响应曲线测量氧化爆发的抑制率(以化学发光的变化进行测量)。
本发明的试剂在上述测试方法中于0.0001-5μM浓度下，通过在低nM范围内具有活性。例如，实施例2的化合物在该试验中IC50为0.006μM。
由于本发明的试剂具有抗炎活性、对呼吸道高活性作用以及它们与PDE同工酶抑制性相关的特性，特别是作为选择性4型抑制剂的特性，本发明的试剂可用于治疗特别是预防性治疗阻塞性或炎性呼吸道疾病。因此，通过长期连续和经常给药，本发明的试剂可防止支气管收缩或其它随阻塞性或炎性呼吸道疾病发生的症状发作，或用于控制、改善或逆转这种疾病的基本状态。
由于本发明的试剂具有支气管舒张剂活性，因此，本发明的试剂可用作支气管舒张剂，例如用于治疗急性或慢性支气管收缩，例如对阻塞性或炎性呼吸道疾病进行症状治疗。
本发明中与阻塞性或炎性呼吸道疾病相关的术语“治疗”是指包括预防和对症治疗。
按照本发明，还提供了一种在需要的患者中进行治疗的方法，
a)用于治疗呼吸道高反应性的方法，
b)进行支气管扩张的方法，特别是
c)治疗阻塞性或炎性呼吸道疾病的方法，所述方法包括向患者施用有效量的本发明的试剂。
本发明可治疗的阻塞性或炎性呼吸道疾病包括气喘、尘肺、慢性阻塞性呼吸道或或肺疾病(COAD或COPD)和成人呼吸窘迫症(ARDS)，以及由于其它药物治疗如阿斯匹林或β-激动剂治疗引起的呼吸道高反应性加重。
本发明可用于治疗各种类型或病因的气喘，包括内因性气喘，特别是外因性气喘。可用于治疗过敏性(变应性/IgE介导的)气喘。同样可用于治疗非变应性气喘，例如，包括支气管性气喘、运动引起的气喘和职业性气喘，由细菌感染引起的气喘和其它非过敏性气喘。还可用于治疗气喘性婴儿综合征(婴儿初期气喘)。
本发明可用于治疗各种类型或病因的尘肺病，例如包括肺矾土沉着病、炭末沉着病、石棉沉着病、石末沉着病、驼鸟毛尘肺、肺铁末沉着病、硅肺、烟草沉着病和棉屑沉着病。
本发明还可用于治疗COPD或COAD，包括慢性支气管炎、肺气肿或与之相关的呼吸困难。
本发明也可用于治疗各种类型或病因的支气管炎，例如，包括急性支气管炎、花生仁吸入性支气管炎、卡他性支气管炎、慢性支气管炎、格鲁布性支气管炎或结核性支气管炎等。
由于本发明的试剂作为TNF-α释放选择性抑制剂具有活性，因而，其可用于下调或抑制TNF-α释放，例如，用于治疗涉及TNF-α释放或TNF-α释放起介导作用的疾病，例如，其病原学涉及或包含致病的，例如不希望出现的、过量的或未调节的TNF-α释放的的疾病，特别是用于治疗恶病质或内毒素休克和治疗AIDS[参见，Sharief等，Mediators of Inflammation,I,323-338(1992)]。
本发明的方法可用于治疗与各种病因的与致病的TNF-α释放或TNF-α血清水平有关的恶病质，包括例如由细菌、病毒或寄生虫引起的恶病质，由于感染或体液或其它器官如肾功能缺乏或衰退引起的恶病质。例如，本发明的方法可用于治疗癌性、疟疾性和vermal恶病质，由于脑垂体机能障碍引起的恶质病，甲状腺恶质病、胸腺恶质病以及尿毒症。特别是用于治疗与AIDS有关的恶质病，即由HIV感染引起或相关的恶质病。
本发明的方法还可用于治疗脓毒性休克，例如由于细菌感染引起的休克病。在这点上，需要注意的是，本发明给出了治疗脓毒性休克本身以及由脓毒性休克引起的或以脓毒性休克为症状的疾病的治疗方法，例如治疗ARDS(成人呼吸窘迫综合征)的方法。
本发明的方法还可用于治疗由HIV感染引起的疾病，如AIDS，例如，控制或缓解这种疾病的发展。
由于本发明的试剂具有抑制PDE同工酶和/或TNF-α释放抑制特性及其免疫抑制活性，本发明的试剂也可用作免疫抑制剂，例如，用于治疗自身免疫性疾病，特别是用于治疗涉及炎性过程的自身免疫性疾病，或具有炎性原因或病因的自身免疫性疾病，或用作用于治疗炎性疾病的抗炎剂，特别是用于治疗涉及自身免疫反应或具有自身免疫原因或病因的炎性疾病。
本发明可以适用的疾病的实例包括：自身免疫性血液紊乱(如，溶血性贫血症、再生障碍性贫血、纯红细胞贫血和自发性血小板减少症)、系统性红斑狼疮、多软骨炎、硬皮病、韦格内氏肉芽肿病、皮肤肌炎、慢性活动性肝炎、重症肌无力、斯约二氏综合征、自发性口炎性腹泻、自身免疫性炎性肠疾病(如，溃疡性结肠炎和节段性回肠炎)、内分泌性眼病、突眼性甲状腺肿、肉样瘤病、牙槽炎、慢性过敏症肺炎、多发性硬化症、原发性胆肝硬化、少年糖尿病(糖尿病Ⅰ型)、眼色素层炎(前和后眼色素层炎)、干性角膜结膜炎、春天性角膜结膜炎、间隙性肺纤维化、牛皮癣性关节病和肾小球性肾炎(带有或不带有肾病综合征，如包括自发性肾病综合征或最小变化肾病)、以及炎性和/或过度增生性皮肤疾病如牛皮癣、特应性皮炎、天疱疮，特别是接触性皮炎，如，过敏性接触性皮炎。
本发明的试剂特别适用于治疗关节炎，其它风湿性或炎性疾病，特别是用于治疗类风湿性关节炎。
作为一种免疫抑制剂，本发明的试剂还可用于防止移植排斥，例如，用于维持过敏性器官移植等，例如肾、肝、肺、心、心-肺、肠、骨髓、皮肤或角膜移植。
由于本发明的试剂具有抗炎活性，特别是可抑制嗜酸性细胞激活，本发明也可用于治疗与嗜酸性细胞有关的疾病，例如，嗜酸性细胞减少，特别是与嗜酸性细胞相关的呼吸道紊乱(如，涉及致病的肺组织嗜酸性浸润)，包括嗜酸性细胞过多，这是由于其会影响呼吸道和/或肺，以及，例如，与嗜酸性细胞有关的伴随或共生吕弗勒氏综合征的呼吸道疾病，嗜酸性肺炎、寄生虫(特别是后生动物)感染(包括热带的嗜酸性细胞增多)、支气管肺性曲霉病、结节性多动脉炎(包括丘-施综合征)、嗜酸性肉芽瘤和由药物反应引起影响呼吸道的与嗜酸性细胞相关的病症。
由于本发明的试剂具有与抑制同工酶相关的特性，特别是作为选择性4型抑制剂的特性，因而，本发明的试剂可用作4型PDE抑制剂，例如用于治疗与组织钙缺乏有关的疾病，特别是与钙缺乏有关的骨和关节变性疾病，特别是骨质疏松症。从而，它们可进一步用于治疗过敏性炎性疾病，如鼻炎、结膜炎、特应性皮炎、荨麻疹和胃肠变应性变态反应；用作血管舒张药，使用用于治疗咽峡炎、高血压、充血性心脏衰竭和多梗死性痴呆；以及用于治疗表明PDE抑制的其它疾病，例如，抑郁症和以认知功能损害为特征的疾病，包括老年性痴呆、帕金森氏病和中风。
由于本发明的试剂能够与免疫抑制药和/或消炎药协同作用，因而，本发明的试剂也可用作辅助治疗剂与这类药物同时使用，例如作为这类药治疗活性的增效剂作用，或者作为减少这类药物所需剂量或潜在副作用的手段。可与本发明的试剂一起共同给药的药物的实例包括：环肽(cyclopeptide)、环胨(cyclopeptolide)或大环内酯免疫抑制剂或抗炎药，例如，属于环孢菌素类的药物，如环孢菌素A或G,tacrolimus药物(也称之为FK 506)，子囊霉素和纳巴霉素和其各种公知的协同剂及衍生物，以及糖皮质激素药。可进行联合治疗的疾病包括，例如，任一种需要进行免疫抑制药或抗炎药治疗的疾病，例如，如前所述的那些。具体而言，本发明的试剂适用于作为前述药物进行联合治疗，例如，用于免疫抑制治疗、抗炎治疗或抗气喘治疗，例如，达到环孢菌素如环孢菌素A-、大环内酯-或甾族化合物减量作用。
按照前述内容，本发明也提供了：B．一种在需要的患者中进行治疗的方法
a)一种用于下调或抑制TNF-α释放的方法，
b)一种用于抑制PDE 4同工酶活性的方法，
c)一种进行免疫抑制的方法，
d)一种用于治疗炎性疾病的方法，或
e)一种用于治疗如前所述具体疾病的方法，所述方法包括向患者施用有效量的本发明的试剂。
本发明也提供了：C．一种用作药物的本发明的试剂，例如用于如前所述疾病的治疗或任一种方法中，例如，如前定义的方法A或B。
当然，用于实施本发明的剂量可根据具体施治的疾病、具体采用的本发明的试剂、给药方式及所需治疗而改变。但是，一般而言，要治疗前述疾病达到满意的结果，口服给药时的剂量大约为0.01-2.0mg/kg。对于较大的哺乳动物如人而言，口服的每日剂量相应地为约0.75-150mg，可方便地以缓释剂形式每日给药1次或2-4次。因而，口服的单位剂量形式为约0.2-75或150mg，例如为约0.2或20-50、75或100mg本发明的试剂，以及可药用稀释剂或载体。
对用于治疗慢性或阻塞性呼吸道疾病如气喘而言，本发明的试剂也可通过吸入法给药。剂量也根据具体施治的疾病、具体采用的本发明的试剂、具体的给药方式改变(例如是否为干粉吸入)以及所需的治疗效果。但是，一般而言，吸入式每日给药剂量大约为2.5-130.0μg/kg/天，如约13.0-60.0μg/kg/天。对于较大的哺乳动物如人而言，吸入给药的每日剂量，如用于治疗气喘，为约0.2-10.0mg，例如，约1-5mg，可方便地每日1次给药或分2或3次给药。每次给药的适宜剂量大约为200μg至3.3mg，每日至多给药3次，适宜通过干粉吸入传送装置给药，每次给药时，喷2-8次。
本发明的试剂也可通过其它任一种适宜的方式给药，例如通过浸剂给药，如用于治疗内毒素休克；鼻给药，如用于治疗鼻炎；眼给药，如用于治疗眼睛的自身免疫性疾病；透皮给药，即局部涂敷于皮肤上，如用于治疗皮肤病或牛皮癣；或直肠给药，即以灌肠剂或栓剂给药，如用于治疗炎性肠病。通过这些方式的适宜剂量通常为小于口服给药所需剂量的10-100倍。
包含本发明试剂的药物组合物可采用常规的稀释剂或赋形剂以及药剂领域公知的技术制备。因此，口服给药剂量形式可包括片剂、胶囊剂等。用于透皮给药的制剂可为霜剂、软膏剂、凝胶剂或透皮传送系统，如贴剂，除了包含稀释剂或载体外，还适当包含皮肤增透剂，其也是本领域已知的。
用于吸入的组合物可包括气溶胶或其它可雾化制剂以及可吸入干粉制剂，可采用稀释剂或无稀释剂，以用于本领域公知的任一种适宜的干粉吸入系统。为制备吸入用干粉形式，本发明的试剂适宜以可成药酸加成盐形式使用。所述盐被适当地粉碎，如使其平均粒径为约203μm。至少约90％的该物质平均粒径小于7.8μm，优选小于4.8μm。为了确保得到一种适宜并均匀的颗粒状产品以用于以干粉形式给药，优选在降温条件下，将活性成分与适用于吸入的载体介质如乳糖预混后进行粉碎。
因而，本发明也提供了一种包含本发明试剂与可药用稀释剂或载体的药物组合物，如，用于前述任一种方法的药物组合物。
Claims (11)
1、一种游离形式或盐形式的8-芳基-1,7-二氮杂萘或其N-氧化物。
2、根据权利要求1的式Ⅰ化合物，
其中R1为苯基、苄基、3-硝基苯基、3-氯苯基、3-氰基苯基、3-(四唑基)苯基、苯并呋咱基或苯并硫代呋咱基；R2为羟基、氨基、三氟甲磺酰基、烯丙基、烷基、链烯基、链炔基、烷氧基、芳基、芳烷基、芳氧基、氨基、芳基氨基、二芳基氨基、烷氨基、二烷基氨基、烷基芳基、芳基酰氨基或烷基酰氨基；和其酯，和其酰胺；为游离形式或盐形式。
3、根据权利要求1的化合物，该化合物为6-(羧基苯基或羧基甲基苯基)-8-(苯基，苯并[c]噻二唑基或苯并[c]呋咱基)-1,7-二氮杂萘，和其酯和其酰胺，为游离形式或可药用盐形式。
4、根据权利要求3的化合物，结构为式Ⅱ
其中n为0或1；R7为羟基、氨基、C1-4烷氨基或C1-4烷氧基，优选羟基或氨基；而R3为H,R4为硝基、卤素(如氯)、氰基或四唑基(如1-四唑基)，R5和R6一起形成另一个键，或者R3、R4、R5和R6一起为=N-O=或=N-S-N=；和其酯和酰胺；为游离形式或药用盐形式。
5、根据权利要求1或3的化合物，该化合物为实施例1-33的任一种化合物。
6、根据权利要求1的化合物，用作药物。
7、包含权利要求1化合物的药物组合物。
8、权利要求1的化合物在生产用于治疗炎症，特别是呼吸道阻塞性疾病如气喘的药物中的用途。
9、一种如权利要求4定义的式Ⅱ化合物的制备方法，该方法包括使式Ⅵ的化合物其中，R3、R4、R5和R6如权利要求4定义，X为离去基团与式Ⅶ的化合物反应
其中，R7如权利要求4定义，X′为离去基团，回收以游离形式或盐形式得到的式Ⅱ化合物。
10、式Ⅴ′的化合物
其中，Q′为卤素或-O-Alk，其中Alk代表C1-C8烷基。
11、式Ⅵ的化合物
其中，R3、R4、R5和R6如权利要求4定义，X为离去基团。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9622386.2 | 1996-10-28 | ||
| GBGB9622386.2A GB9622386D0 (en) | 1996-10-28 | 1996-10-28 | Organic compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1234800A true CN1234800A (zh) | 1999-11-10 |
| CN1103773C CN1103773C (zh) | 2003-03-26 |
Family
ID=10802050
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN97199186A Expired - Fee Related CN1103773C (zh) | 1996-10-28 | 1997-10-24 | 二氮杂萘衍生物 |
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| Country | Link |
|---|---|
| US (1) | US6136821A (zh) |
| EP (1) | EP0934320B1 (zh) |
| JP (1) | JP4451496B2 (zh) |
| KR (1) | KR100524329B1 (zh) |
| CN (1) | CN1103773C (zh) |
| AR (1) | AR009128A1 (zh) |
| AT (1) | ATE236155T1 (zh) |
| AU (1) | AU724471B2 (zh) |
| BR (1) | BR9713280B1 (zh) |
| CA (1) | CA2269946C (zh) |
| CO (1) | CO4910164A1 (zh) |
| CZ (1) | CZ146699A3 (zh) |
| DE (1) | DE69720493T2 (zh) |
| DK (1) | DK0934320T3 (zh) |
| ES (1) | ES2196377T3 (zh) |
| GB (1) | GB9622386D0 (zh) |
| HK (1) | HK1022305A1 (zh) |
| HU (1) | HUP9904204A3 (zh) |
| ID (1) | ID18623A (zh) |
| IL (2) | IL129502A0 (zh) |
| MY (1) | MY132642A (zh) |
| NO (1) | NO312677B1 (zh) |
| NZ (1) | NZ335363A (zh) |
| PE (1) | PE10899A1 (zh) |
| PL (1) | PL189280B1 (zh) |
| PT (1) | PT934320E (zh) |
| SI (1) | SI0934320T1 (zh) |
| SK (1) | SK283562B6 (zh) |
| TR (1) | TR199900920T2 (zh) |
| TW (1) | TW399052B (zh) |
| WO (1) | WO1998018796A1 (zh) |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298324C (zh) * | 2001-11-05 | 2007-02-07 | 诺瓦提斯公司 | 萘啶衍生物、其制备方法及其作为磷酸二酯酶同功酶4(pde4)抑制剂的应用 |
| CN100413864C (zh) * | 2002-12-16 | 2008-08-27 | 诺瓦提斯公司 | 作为pde4抑制剂的[1,7]二氮杂萘 |
Families Citing this family (95)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003502278A (ja) * | 1999-01-15 | 2003-01-21 | ビイク グルデン ロンベルク ヒエーミツシエ フアブリーク ゲゼルシヤフト ミツト ベシユレンクテル ハフツング | 新規のｎ−オキシド |
| PT1147087E (pt) * | 1999-01-15 | 2005-09-30 | Altana Pharma Ag | Feantridina-n-oxidos com actividade de inibicao de pde-iv |
| ATE320800T1 (de) | 1999-08-21 | 2006-04-15 | Altana Pharma Ag | Synergistische kombination von roflumilast und salmeterol |
| US6953774B2 (en) | 2000-08-11 | 2005-10-11 | Applied Research Systems Ars Holding N.V. | Methods of inducing ovulation |
| HUP0400637A2 (hu) | 2001-01-31 | 2004-06-28 | Pfizer Products Inc. | Nikotinamid-biaril-származékok, amelyek PDE4 izozimek inhibitoraiként alkalmazhatók és ezeket tartalmazó gyógyszerkészítmények |
| CA2436551A1 (en) | 2001-01-31 | 2002-08-08 | Pfizer Products Inc. | Thiazolyl-, oxazolyl-, pyrrolyl-, and imidazolyl-acid amide derivatives useful as inhibitors of pde4 isozymes |
| ES2248231T3 (es) | 2001-01-31 | 2006-03-16 | Pfizer Products Inc. | Derivados de eteres utiles como inhibidores de las isozimas pde4. |
| US7250518B2 (en) | 2001-01-31 | 2007-07-31 | Pfizer Inc. | Nicotinamide acids, amides, and their mimetics active as inhibitors of PDE4 isozymes |
| MXPA03010672A (es) * | 2001-05-23 | 2004-03-02 | Tanabe Seiyaku Co | Composicion para el tratamiento regenerativo de enfermedades del cartilago. |
| JP4484515B2 (ja) | 2001-10-16 | 2010-06-16 | メモリ ファーマセチカル コーポレーション | 神経病症候群の治療の為のｐｄｅ−４阻害剤としての、４−（４−アルコキシ−３−ヒドロキシフェニル）−２−ピロリディン誘導体。 |
| DK1908463T3 (da) | 2001-12-14 | 2011-11-28 | Merck Serono Sa | Fremgangsmåder til at inducere ægløsning ved anvendelse af en ikke polypeptid-CAMP-niveaumodulator |
| EP1569908B1 (en) | 2002-11-19 | 2010-09-15 | Memory Pharmaceuticals Corporation | Pyridine n-oxide compounds as phosphodiesterase 4 inhibitors |
| EP1624893A2 (en) | 2003-04-01 | 2006-02-15 | Applied Research Systems ARS Holding N.V. | Inhibitors of phosphodiesterases in infertility |
| CN1805929A (zh) * | 2003-04-16 | 2006-07-19 | 记忆药物公司 | 磷酸二酯酶4抑制剂 |
| US7226930B2 (en) * | 2003-04-18 | 2007-06-05 | Memory Pharmaceutical Corporation | Phosphodiesterase 4 inhibitors |
| TW200519106A (en) | 2003-05-02 | 2005-06-16 | Novartis Ag | Organic compounds |
| MY141255A (en) | 2003-12-11 | 2010-03-31 | Memory Pharm Corp | Phosphodiesterase 4 inhibitors, including n-substituted diarylamine analogs |
| GB0401334D0 (en) | 2004-01-21 | 2004-02-25 | Novartis Ag | Organic compounds |
| US20090042951A1 (en) * | 2004-02-20 | 2009-02-12 | Robert Danziger | Blood Pressure Reduction in Salt-Sensitive Hypertension |
| GB0411056D0 (en) | 2004-05-18 | 2004-06-23 | Novartis Ag | Organic compounds |
| EP1758873A1 (en) * | 2004-06-22 | 2007-03-07 | Rigel Pharmaceuticals, Inc. | Ubiquitin ligase inhibitors |
| BRPI0515307A (pt) * | 2004-09-14 | 2008-07-15 | Novartis Ag | compostos orgánicos |
| CN101166733A (zh) * | 2004-10-15 | 2008-04-23 | 记忆药物公司 | 作为磷酸二酯酶4抑制剂的吡唑衍生物 |
| AU2005295350A1 (en) * | 2004-10-20 | 2006-04-27 | Memory Pharmaceuticals Corporation | Phosphodiesterase 4 inhibitors |
| GT200500281A (es) | 2004-10-22 | 2006-04-24 | Novartis Ag | Compuestos organicos. |
| GB0424284D0 (en) | 2004-11-02 | 2004-12-01 | Novartis Ag | Organic compounds |
| GB0426164D0 (en) | 2004-11-29 | 2004-12-29 | Novartis Ag | Organic compounds |
| JP2006241111A (ja) * | 2005-03-04 | 2006-09-14 | Univ Nihon | 新規ベンゾフロキサン及びその合成法 |
| GB0507577D0 (en) | 2005-04-14 | 2005-05-18 | Novartis Ag | Organic compounds |
| GB0510390D0 (en) | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
| EP2258359A3 (en) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation with sabcomelin |
| EP1928437A2 (en) | 2005-08-26 | 2008-06-11 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation |
| JP2009512711A (ja) | 2005-10-21 | 2009-03-26 | ブレインセルス，インコーポレイティド | Ｐｄｅ阻害による神経新生の調節 |
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| BRPI0617467A2 (pt) * | 2005-10-21 | 2011-07-26 | Glaxo Group Limided | compostos e seus usos como antibacterianos |
| AU2006308889A1 (en) | 2005-10-31 | 2007-05-10 | Braincells, Inc. | GABA receptor mediated modulation of neurogenesis |
| GB0526244D0 (en) | 2005-12-22 | 2006-02-01 | Novartis Ag | Organic compounds |
| EP1963324B1 (en) | 2005-12-22 | 2010-04-21 | Glaxo Group Limited | Heterocyclic compounds, their preparation and their use as antibacterials |
| GB0601951D0 (en) * | 2006-01-31 | 2006-03-15 | Novartis Ag | Organic compounds |
| US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
| BRPI0710573A2 (pt) | 2006-04-21 | 2012-02-28 | Novartis Ag | compostos orgánicos, usos e processos para a preparação dos referidos compostos, bem como composição farmacêutica compreendendo os mesmos |
| EP2021000A2 (en) | 2006-05-09 | 2009-02-11 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
| MX2008014320A (es) | 2006-05-09 | 2009-03-25 | Braincells Inc | Neurogenesis mediada por el receptor de 5-hidroxitriptamina. |
| MX2009002496A (es) | 2006-09-08 | 2009-07-10 | Braincells Inc | Combinaciones que contienen un derivado de 4-acilaminopiridina. |
| US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
| CN101516885A (zh) | 2006-09-29 | 2009-08-26 | 诺瓦提斯公司 | 作为pi3k脂质激酶抑制剂的吡唑并嘧啶类化合物 |
| WO2008052734A1 (en) | 2006-10-30 | 2008-05-08 | Novartis Ag | Heterocyclic compounds as antiinflammatory agents |
| AU2007342223B2 (en) | 2007-01-10 | 2011-02-24 | Irm Llc | Compounds and compositions as channel activating protease inhibitors |
| KR20100005730A (ko) | 2007-05-07 | 2010-01-15 | 노파르티스 아게 | 유기 화합물 |
| PT2444120T (pt) | 2007-12-10 | 2018-01-03 | Novartis Ag | Análogos da amilorida espirocíclicos como bloqueadores de enac |
| EP2231642B1 (en) | 2008-01-11 | 2013-10-23 | Novartis AG | Pyrimidines as kinase inhibitors |
| US8268834B2 (en) | 2008-03-19 | 2012-09-18 | Novartis Ag | Pyrazine derivatives that inhibit phosphatidylinositol 3-kinase enzyme |
| EP2300010B1 (en) | 2008-06-10 | 2015-03-04 | Novartis AG | Pyrazine derivatives as epithelial sodium channel blockers |
| JP2012516345A (ja) | 2009-01-29 | 2012-07-19 | ノバルティス アーゲー | 星細胞腫治療用置換ベンゾイミダゾール |
| WO2010099217A1 (en) | 2009-02-25 | 2010-09-02 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
| US8389526B2 (en) | 2009-08-07 | 2013-03-05 | Novartis Ag | 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives |
| CA2770873A1 (en) | 2009-08-12 | 2011-02-17 | Novartis Ag | Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation |
| SG10201404886PA (en) | 2009-08-17 | 2014-10-30 | Intellikine Llc | Heterocyclic compounds and uses thereof |
| BR112012008061A2 (pt) | 2009-08-20 | 2016-03-01 | Novartis Ag | compostos de oxima heterocíclica |
| AU2010310449A1 (en) | 2009-10-22 | 2012-05-03 | Vertex Pharmaceuticals Incorporated | Compositions for treatment of cystic fibrosis and other chronic diseases |
| US8247436B2 (en) | 2010-03-19 | 2012-08-21 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF |
| BR112013000946B1 (pt) | 2010-07-14 | 2020-09-08 | Novartis Ag | Compostos heterocíclicos agonistas de receptor de ip, seus usos, composição e combinação farmacêuticas |
| WO2012034095A1 (en) | 2010-09-09 | 2012-03-15 | Irm Llc | Compounds and compositions as trk inhibitors |
| US8637516B2 (en) | 2010-09-09 | 2014-01-28 | Irm Llc | Compounds and compositions as TRK inhibitors |
| US8372845B2 (en) | 2010-09-17 | 2013-02-12 | Novartis Ag | Pyrazine derivatives as enac blockers |
| EP2673277A1 (en) | 2011-02-10 | 2013-12-18 | Novartis AG | [1, 2, 4]triazolo [4, 3 -b]pyridazine compounds as inhibitors of the c-met tyrosine kinase |
| JP5808826B2 (ja) | 2011-02-23 | 2015-11-10 | インテリカイン， エルエルシー | 複素環化合物およびその使用 |
| PH12013501758A1 (en) | 2011-02-25 | 2013-10-14 | Irm Llc | Pyrazolo [1,5-a] pyridines as trk inhibitors |
| US8883819B2 (en) | 2011-09-01 | 2014-11-11 | Irm Llc | Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension |
| CA2848809A1 (en) | 2011-09-15 | 2013-03-21 | Novartis Ag | 6-substituted 3-(quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyradines as c-met tyrosine kinase |
| US9034879B2 (en) | 2011-09-16 | 2015-05-19 | Novartis Ag | Heterocyclic compounds for the treatment of CF |
| WO2013038381A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine/pyrazine amide derivatives |
| WO2013038378A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
| JP6165733B2 (ja) | 2011-09-16 | 2017-07-19 | ノバルティス アーゲー | Ｎ−置換ヘテロシクリルカルボキサミド類 |
| WO2013038373A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
| US9174994B2 (en) | 2011-11-23 | 2015-11-03 | Intellikine, Llc | Enhanced treatment regimens using mTor inhibitors |
| US20150119399A1 (en) | 2012-01-10 | 2015-04-30 | President And Fellows Of Harvard College | Beta-cell replication promoting compounds and methods of their use |
| EP2802589B1 (en) | 2012-01-13 | 2016-01-06 | Novartis AG | Fused pyrroles as ip receptor agonists for the treatment of pulmonary arterial hypertension (pah) and related disorders |
| US8809340B2 (en) | 2012-03-19 | 2014-08-19 | Novartis Ag | Crystalline form |
| AU2013243097A1 (en) | 2012-04-03 | 2014-10-09 | Novartis Ag | Combination products with tyrosine kinase inhibitors and their use |
| JP5907006B2 (ja) * | 2012-09-04 | 2016-04-20 | エヌ・イーケムキャット株式会社 | ビフェニル化合物の合成方法 |
| JP5907005B2 (ja) * | 2012-09-04 | 2016-04-20 | エヌ・イーケムキャット株式会社 | ビフェニル化合物の合成方法 |
| EP2956455B1 (en) | 2013-02-13 | 2017-05-17 | Novartis AG | Ip receptor agonist heterocyclic compounds |
| US9073921B2 (en) | 2013-03-01 | 2015-07-07 | Novartis Ag | Salt forms of bicyclic heterocyclic derivatives |
| EP2968340A4 (en) | 2013-03-15 | 2016-08-10 | Intellikine Llc | COMBINING KINASE INHIBITORS AND USES THEREOF |
| TW201605450A (zh) | 2013-12-03 | 2016-02-16 | 諾華公司 | Ｍｄｍ２抑制劑與ＢＲＡＦ抑制劑之組合及其用途 |
| CN106458966B (zh) | 2014-04-24 | 2019-05-07 | 诺华股份有限公司 | 作为磷脂酰肌醇3-激酶抑制剂的吡嗪衍生物 |
| PT3134396T (pt) | 2014-04-24 | 2019-12-16 | Novartis Ag | Derivados de amino piridina como inibidores da fosfatidilinositol 3-quinase |
| CA2945212A1 (en) | 2014-04-24 | 2015-10-29 | Novartis Ag | Amino pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors |
| US9741941B2 (en) | 2014-04-29 | 2017-08-22 | Universal Display Corporation | Organic electroluminescent materials and devices |
| WO2016011658A1 (en) | 2014-07-25 | 2016-01-28 | Novartis Ag | Combination therapy |
| AU2015294889B2 (en) | 2014-07-31 | 2018-03-15 | Novartis Ag | Combination therapy |
| KR20220019015A (ko) | 2019-06-10 | 2022-02-15 | 노파르티스 아게 | Cf, copd, 및 기관지확장증 치료를 위한 피리딘 및 피라진 유도체 |
| CA3146109A1 (en) | 2019-08-28 | 2021-03-04 | Novartis Ag | Substituted 1,3-phenyl heteroaryl derivatives and their use in the treatment of disease |
| TW202140550A (zh) | 2020-01-29 | 2021-11-01 | 瑞士商諾華公司 | 使用抗ｔｓｌｐ抗體治療炎性或阻塞性氣道疾病之方法 |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS54138572A (en) * | 1978-04-17 | 1979-10-27 | Kyowa Hakko Kogyo Co Ltd | Novel isoquinoline derivative |
| JPS57203068A (en) * | 1981-06-08 | 1982-12-13 | Teikoku Hormone Mfg Co Ltd | Novel 1-phenylisoquinoline derivative |
| FR2567520B1 (fr) * | 1984-07-11 | 1987-01-02 | Carpibem | Nouvelles phenyl-naphthyridines, leur procede de preparation, medicaments les contenant, notamment anti-ulceres |
| JPS6230780A (ja) * | 1985-04-17 | 1987-02-09 | Ss Pharmaceut Co Ltd | １，７−ナフチリジン誘導体及びこれを含有する薬剤 |
| JPS6348277A (ja) * | 1986-08-19 | 1988-02-29 | Ss Pharmaceut Co Ltd | ８−ピペラジニル−１，７−ナフチリジン誘導体 |
| GB8800397D0 (en) * | 1988-01-08 | 1988-02-10 | Sandoz Ltd | Improvements in/relating to organic compounds |
| US4956371A (en) * | 1989-09-19 | 1990-09-11 | Euroceltique, S.A. | Substituted isoquinolines and methods of using same |
| US5466697A (en) * | 1994-07-13 | 1995-11-14 | Syntex (U.S.A.) Inc. | 8-phenyl-1,6-naphthyridin-5-ones |
| JP2001511813A (ja) * | 1997-02-18 | 2001-08-14 | ニューロクライン バイオサイエンシーズ，インコーポレイテッド | Ｃｒｆレセプターアンタゴニストおよびそれらに関連する方法 |
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1996
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- 1997-10-24 CN CN97199186A patent/CN1103773C/zh not_active Expired - Fee Related
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- 1997-10-24 AU AU69084/98A patent/AU724471B2/en not_active Ceased
- 1997-10-24 AT AT97948803T patent/ATE236155T1/de not_active IP Right Cessation
- 1997-10-24 PT PT97948803T patent/PT934320E/pt unknown
- 1997-10-27 ID IDP973530A patent/ID18623A/id unknown
- 1997-10-27 MY MYPI97005054A patent/MY132642A/en unknown
- 1997-10-27 ZA ZA9709593A patent/ZA979593B/xx unknown
- 1997-10-28 CO CO97063263A patent/CO4910164A1/es unknown
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1999
- 1999-04-19 IL IL129502A patent/IL129502A/en unknown
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1298324C (zh) * | 2001-11-05 | 2007-02-07 | 诺瓦提斯公司 | 萘啶衍生物、其制备方法及其作为磷酸二酯酶同功酶4(pde4)抑制剂的应用 |
| CN100413864C (zh) * | 2002-12-16 | 2008-08-27 | 诺瓦提斯公司 | 作为pde4抑制剂的[1,7]二氮杂萘 |
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