CN1911928A - 5－(吡啶－3－基)－1－氮杂二环[3.2.1]辛烷衍生物,其制备及其治疗应用 - Google Patents
5－(吡啶－3－基)－1－氮杂二环[3.2.1]辛烷衍生物,其制备及其治疗应用 Download PDFInfo
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- CN1911928A CN1911928A CNA2006101091747A CN200610109174A CN1911928A CN 1911928 A CN1911928 A CN 1911928A CN A2006101091747 A CNA2006101091747 A CN A2006101091747A CN 200610109174 A CN200610109174 A CN 200610109174A CN 1911928 A CN1911928 A CN 1911928A
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- azabicyclic
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- halogen atom
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Abstract
本发明涉及通式(I)的化合物，式中：R表示卤素原子、被一或多个选自卤素原子和(C1－C6)烷基、(C1－C6)烷氧基、硝基、氨基、三氟甲基、氰基、羟基、乙酰基或亚甲二氧基取代的苯基、被一或多个(C1－C6)烷氧基任意取代的吡啶基、噻吩基、吲哚基、或者嘧啶基。此外，对于以表示的两个碳－碳键来说，一个是单键，另一个可以是单键或双键。本发明的化合物是烟碱受体配体。
Description
本发明专利申请是申请日为2003年1月3日，申请号为03801987.6，发明名称为“5-(吡啶-3-基)-1-氮杂二环[3.2.1]辛烷衍生物，其制备及其治疗应用”的发明专利申请的分案申请。
技术领域
本发明涉及一些化合物，它们是烟碱受体配体，可用于治疗或预防烟碱受体功能障碍相关性疾病，特别是在中枢神经系统水平上。
背景技术
现有技术文献先前已提及了显示出对烟碱受体具有高亲和性的化合物。在这些文献中，WO 134279涉及1，4-二氮杂二环[3.2.2]壬烷衍生物，以及二环[2.2.1]庚烷和庚烷的衍生物。
本发明的发明者现已证实，1-氮杂二环[3.2.1]辛烷衍生物对烟碱受体具有高亲和性。
发明内容
本发明的化合物以通式(I)表示，
式中，
R表示卤素原子或者(C3-C6)环烷基或者被一或多个选自卤素原子、或(C1-C6)烷基、(C1-C6)烷氧基、硝基、氨基、(C1-C3)二烷基氨基、三氟甲基、三氟甲氧基、氰基、羟基、乙酰基或亚甲二氧基的基团取代的苯基，
或者表示哌啶基、或吗啉-4-基、或吡咯烷-1-基、或氮杂环丁烷-1-基、或吖庚因-1-基、或吡啶基、或喹啉基、或噻吩基、或吡嗪基、或呋喃基、或苯并呋喃基、或苯并噻吩基、或吲哚基、或嘧啶基、或异噁唑基、或吩噁嗪基、或吩氧硫杂环己烯基、或联苯并噻吩基、或联苯并呋喃基、或吡咯基、或萘基，其中这些基团中的每一个可被一或多个选自卤素原子、(C1-C6)烷基、(C1-C6)烷氧基、三氟甲氧基、三氟甲基、硝基、氰基、羟基、氨基、(C1-C3)二烷基氨基、或者(C3-C8)环烷基氨基的基团任意取代，
条件是所述化合物不包括5-(2-溴吡啶-5-基)-1-氮杂二环[3.2.1]辛-3-烷、5-(2-氯吡啶-5-基)-1-氮杂二环[3.2.1]辛-3-烷和5-(2-氟吡啶-5-基)-1-氮杂二环[3.2.1]辛-3-烷。
对于以
表示的两个碳-碳键来说，一个是单键，另一个可以是单键或双键。此外，5位上的碳原子是不对称的，因此化合物可以两种对映体或对映体混合物形式存在。
本发明的化合物可以碱形式或酸加成盐形式存在。
优选化合物的子集是这样一些通式(I)化合物的子集，式中R表示卤素原子或者被一或多个选自卤素原子和(C1-C6)烷基、(C1-C6)烷氧基、硝基、氨基、三氟甲基、氰基、羟基、乙酰基或亚甲二氧基的基团取代的苯基、或者表示被一或多个(C1-C6)烷氧基任意取代的吡啶基、或噻吩基、或吲哚基、或嘧啶基。
通式(I)化合物可按下列方案所示的方法制备。使通式(II)表示的3-氧-1，4-氮杂二环[2.2.2]辛烷与通式(III)表示的吡啶衍生物反应，式(III)中R如上所限定，W表示卤素原子。
也可以在3-氧-1-氮杂二环[2.2.2]辛烷与通过用烷基锂衍生物置换卤金属而得到的通式(III)化合物的锂化衍生物之间进行缩合反应。
这可以生成通式(IV)表示的化合物，该化合物在酸性介质中受热处理，生成通式(I)化合物，其中以
表示的两个碳-碳键之一是双键。对该双键进行催化加氢处理，得到通式(I)化合物，其中氮杂二环辛烷环上的全部键都是饱和键。
3-氧-1-氮杂二环[2.2.2]辛烷可通过商业途径获得。
通式(III)化合物可通过商业途径获得或者参照文献所述的方法制成。
方案
某些化合物的取代基R不存在于起始化合物通式(III)表示的化合物中；取决于这些取代基的性质，它们可被引入通式(I)表示的最终化合物中。例如，式中R表示芳基的通式(I)化合物可这样制成：以相应的化合物(R表示卤素原子)为起始化合物，采用任何一种公知方法，例如在硼酸和钯催化剂，如四(三苯基膦)钯存在下进行Suzuki偶联，或者与适当反应物进行Stille偶联。
以下，结合实施例对本发明一些化合物的制备进行说明。
用元素微分析、红外光谱及核磁共振光谱确认所得化合物的结构。
实施例标题括号中的数字对应下表第一栏的数字。
在化合物的命名中，连字符“-”是命名的一部分，而下划线“”仅用作一行字结束的停顿，若无停顿就会省略该符号，不能用标准连字符或空格代替。
具体实施方式
实施例1(1号化合物)
5-(2-苯基吡啶-5-基)-1-氮杂二环[3.2.1]辛-3-烯氢溴酸盐(2∶1)
1.1 5-溴-2-苯基吡啶
在500毫升三颈烧瓶中依次加入30克(0.127mol)2，5-二溴吡啶在100毫升甲苯中的悬浮液、15.4克(0.127mol)苯基硼酸、4.4克(0.0038mol)四(三苯基膦)钯、90毫升2M碳酸钠水溶液和4毫升乙醇，该混合物在90℃加热22小时。
把混合物轻轻倒出，有机相用100毫升水洗涤，干燥，减压浓缩，残余物经硅胶柱层析纯化，洗脱液是环己烷和二氯甲烷的30/70混合物。得到22.4克晶体。
熔点：69-72℃。
1.2 3-羟基-3-(2-苯基吡啶-5-基)-1-氮杂二环[2.2.2]辛烷
在100毫升三颈烧瓶中加入2.5克(0.0107mol)5-溴-2-苯基吡啶在40毫升乙醚中的溶液，该反应混合物冷却至-60℃，然后在10分钟内逐滴滴入5.6毫升(0.0139mol)正丁基锂在己烷中的2M溶液，温度保持在-70℃1小时。
在10分钟内加入1.34克(0.0107mol)1-氮杂二环[2.2.2]辛-3-酮在20毫升四氢呋喃中的溶液，该混合物在-70℃搅拌30分钟，然后室温保持4小时。
加入100毫升甲醇使反应混合物水解，再减压浓缩。残余物用100毫升氯化铵饱和水溶液溶解，水相用氯仿萃取。有机相干燥，减压浓缩，残余物经硅胶柱层析纯化，洗脱液是氯仿、甲醇和氨水的90/10/1混合物。得到0.8克晶体。
熔点：214℃。
1.3 5-(2-苯基吡啶-5-基)-1-氮杂二环[3.2.1]辛-3-烯氢溴酸盐(2∶1)
在25毫升三颈烧瓶中加入0.8克(2.85mmol)3-羟基-3-(2-苯基吡啶-5-基)-1-氮杂二环[2.2.2]辛烷，再加入10毫升甲烷磺酸，该混合物在180℃加热24小时。
把混合物倒入冰中，加入浓氢氧化钠水溶液碱化，水相用氯仿萃取，有机相干燥，减压浓缩。残余物经硅胶柱层析纯化，洗脱液是氯仿、甲醇和氨水的98/2/0.2混合物。
得到0.25克产物，加入氢溴酸在乙酸中的5.7M溶液，生成二氢溴酸盐。得到0.22克二氢溴酸盐。
熔点：273-274℃。
实施例2(2号化合物)
5-(2-苯基吡啶-5-基)-1-氮杂二环[3.2.1]辛烷氢溴酸盐(2∶1)
在250帕尔瓶中加入0.14克(0.33mmol)5-(2-苯基吡啶-5-基)-1-氮杂二环[3.2.1]辛-3-烯在20毫升甲醇中的溶液，并加入0.14克10％钯/炭。再将该反应混合物置于0.35MPa氢气下，搅拌5小时。
用硅藻土过滤回收催化剂，溶剂减压浓缩。得到0.058克产物。
熔点：272-277℃。
实施例3(8号化合物)
5-[2-(3-甲基苯基)吡啶-5-基]-1-氮杂二环[3.2.1]辛烷草酸盐(1∶1)
3.1 3-羟基-3-(2-溴吡啶-5-基)-1-氮杂二环[2.2.2]辛烷
在2000毫升三颈烧瓶中加入27.6克(0.116mol)2，5-二溴吡啶在1000毫升乙醚中的溶液，将该反应混合物冷却至-67℃，在10分钟内逐滴滴入56毫升(0.140mol)丁基锂在己烷中的2.5M溶液。混合物在-67℃搅拌45分钟，然后在45分钟内加入14.5克(0.116mol)1-氮杂二环[2.2.2]辛-3-酮在150毫升乙醚中的溶液，该混合物在-67℃搅拌3小时。
加入300毫升氯化铵饱和水溶液，然后加入200毫升浓氢氧化钠水溶液，水相用氯仿萃取，有机相干燥，减压浓缩。残余物经硅胶柱层析纯化，洗脱液开始是氯仿、甲醇和氨水的95/5/0.5混合物，然后是氯仿、甲醇和氨水的80/15/1.5混合物。得到19.7克非晶质固体产物。
3.2 5-(2-溴吡啶-5-基)-1-氮杂二环[3.2.1]辛-3-烯
在100毫升三颈烧瓶中加入9.4克(0.033mol)3-羟基-3-(2-溴吡啶-5-基)-1-氮杂二环[2.2.2]辛烷和35毫升浓硫酸，该混合物在190℃加热1小时45分钟。
待混合物冷却，倒入400毫升冰-氢氧化钠冷却水溶液中，水相用氯仿萃取，有机相干燥，减压蒸发。残余物经硅胶柱层析纯化，洗脱液是氯仿、甲醇和氨水的90/10/1混合物。得到3.9克浅黄色固体产物。
熔点：73-75℃。
3.3 5-[2-(3-甲基苯基)吡啶-5-基]-1-氮杂二环[3.2.1]辛-3-烯草酸盐(1∶1)
在10毫升试管中依次加入0.2克(0.75mmol)5-(2-溴吡啶-5-基)-1-氮杂二环[3.2.1]辛-3-烯、3毫升甲苯、0.7毫升2M碳酸钠水溶液、0.147克(1.05mmol)3-甲基苯硼酸、0.042克(0.04mmol)四(三苯基膦)钯和0.7毫升乙醇，该混合物在100℃加热15小时。
轻轻倒出水相，粗产物先依次用甲醇和氯仿洗涤，再用Dowex树脂柱提取，洗脱液是氨水溶液。残余物经硅胶柱层析纯化，洗脱液是氯仿、甲醇和氨水的90/10/1混合物。得到0.167克油状产物，该产物溶解在2毫升异丙醇中，加入0.051克(0.057mmol)草酸在异丙醇中的溶液，形成草酸盐。得到0.188克晶体产物。
熔点：173-174℃。
实施例4(26号化合物)
5-[2-(3-氟苯基)吡啶-5-基]-1-氮杂二环[3.2.1]辛烷氢溴酸盐(2∶1)
在250毫升帕尔瓶中加入0.18克(0.51mmol)5-[2-(3-氟苯基)吡啶-5-基]-1-氮杂二环[3.2.1]辛-3-烯在20毫升甲醇中的溶液，并加入0.36克10％钯/炭，再将该反应混合物置于0.42MPa氢气下，45℃搅拌6小时。
用硅藻土过滤回收催化剂，滤液减压浓缩，将残余物溶解在10毫升1N氢氧化钠水溶液，水相用氯仿萃取，粗产物经硅胶柱层析纯化，洗脱液是氯仿、甲醇和氨水的80/20/2混合物。得到0.085克产物，在该产物中加入0.107毫升33％氢溴酸在乙酸中的溶液，形成二氢溴酸盐。得到0.097克晶体。
熔点：98-100℃。
下表列出本发明一些化合物的化学结构和物理性质。在“R”栏中，“(+)”表示右旋对映体，“(-)”表示左旋对映体；在该栏中无注解的是外消旋物。在“＝”栏中，若是1-氮杂二环辛烯，则标注的数字对应于双键的位置，“-”表示饱和杂环。在“盐”栏中，“-”表示碱形式化合物，“HBr”表示氢溴酸盐，“ox.”表示草酸盐。该栏中还给出相应的酸：碱摩尔比。在“熔点(℃)”栏中，“d”表示分解熔点。
表
| 编号 | R | ＝ | 盐 | 熔点(℃) |
| 1 | C6H5 | 3 | HBr 2∶1 | 273-274 |
| 2 | C6H5 | - | HBr 2∶1 | 272-277 |
| 3 | C6H5 | 2 | HBr 2∶1 | 297-305 |
| 4 | 2，4-(OCH3)2-5-嘧啶基 | 2 | HBr 2∶1 | 340(d) |
| 5 | 3，4-(OCH3)2-C6H3 | 3 | HBr 2∶1 | 261-262 |
| 6 | 3，4-(OCH3)2-C6H3 | - | HBr 2∶1 | 234-236 |
| 7 | 2-F-C6H4 | 3 | ox.1∶1 | 157-158 |
| 8 | 3-CH3-C6H4 | 3 | ox.1∶1 | 173-174 |
| 9 | 3-F-C6H4 | 3 | ox.1∶1 | 163-164 |
| 10 | 3-NO2-C6H4 | 3 | ox.1∶1 | 183-184 |
| 11 | 3-CF3-C6H4 | 3 | ox.1∶1 | 156-157 |
| 12 | 4-CH3-C6H4 | 3 | ox.1∶1 | 213-215 |
| 13 | 3-噻吩基 | 3 | ox.1∶1 | 189-190 |
| 14 | 3，4-OCH2O-C6H3 | 3 | ox.1∶1 | 201-202 |
| 15 | 4-Cl-C6H4 | 3 | ox.1∶1 | 201-203 |
| 16 | 3-CH3CO-C6H4 | 3 | ox.1∶1 | 155-156 |
| 17 | 3-吡啶基 | 3 | ox.1∶1 | 183-184 |
| 18 | 5-吲哚基 | 3 | ox.1∶1 | 253-254 |
| 19 | 4-CH3O-C6H4 | 3 | ox.1∶1 | 205-207 |
| 20 | 3，5-(CH3)2-C6H3 | 3 | ox.1∶1 | 192-193 |
| 21 | 4-吡啶基 | 3 | ox.1∶1 | 172-174 |
| 22 | 4-CH3O-C6H4 | - | HBr 2∶1 | 246-247 |
| 编号 | R | ＝ | 盐 | 熔点(℃) |
| 23 | 4-CH3-C6H4 | - | HBr 2∶1 | 295-297 |
| 24 | 3-CH3-C6H4 | - | HBr 2∶1 | 284-287 |
| 25 | 3，5-(CH3)2-C6H3 | - | HBr 2∶1 | 250-254 |
| 26 | 3-F-C6H4 | - | HBr 2∶1 | 98-100 |
| 27 | 3-噻吩基 | - | HBr 2∶1 | 193-196 |
| 28 | 3，4-OCH2O-C6H3 | - | HBr 2∶1 | 260-263 |
| 29 | 2-F-C6H4 | - | HBr 2∶1 | 266-269 |
| 30 | 3-吡啶基 | - | HBr 3∶1 | 256-260 |
| 31 | 4-吡啶基 | - | HBr 2∶1 | 249-253 |
| 32 | 3-NO2-C6H4 | - | HBr 3∶1 | 264-267 |
| 33 | 3-CF3-C6H4 | - | HBr 2∶1 | 218-221 |
| 34 | Br | 3 | HBr 2∶1 | 234-236 |
| 35 | Br | 2 | HBr 2∶1 | ＞350 |
| 36 | 4-哌啶基 | - | HBr 3∶1 | 289-292 |
| 37 | 3-哌啶基 | - | HBr 3∶1 | 261-265 |
| 38 | 4-CH3O-C6H4(+) | - | - | 125-129 |
| 39 | 4-CH3O-C6H4(-) | - | - | 125-129 |
| 40 | 3-F-C6H4(+) | - | - | 68-70 |
| 41 | 3-F-C6H4(-) | - | - | 68-70 |
| 42 | 2-噻吩基 | - | HBr 2∶1 | 251(d) |
| 43 | 2-噻吩基 | 3 | HBr 2∶1 | 246-247 |
| 44 | 5-CH3-2-噻吩基 | 3 | HBr 2∶1 | 237-238 |
| 45 | 5-CH3-2-噻吩基 | 3 | HBr 2∶1 | 210-211 |
| 46 | 5-Cl-2-噻吩基 | 3 | HBr 2∶1 | 248-250 |
| 47 | 5-Cl-2-噻吩基 | 3 | HBr 2∶1 | 258-259 |
| 48 | 2-呋喃基 | 3 | HBr 2∶1 | 262-264 |
| 49 | 2-呋喃基 | - | HBr 2∶1 | 182(d) |
| 50 | 5-吲哚基 | - | ox.1∶1 | 268-269 |
| 51 | 2-苯并呋喃基 | 3 | - | 145-146 |
| 52 | 2-苯并呋喃基 | - | HBr 2∶1 | 303-305 |
| 53 | 2-吡咯基 | 3 | HBr 2∶1 | 265-266 |
| 54 | 2-吡咯基 | - | ox.1∶1 | 95-97 |
| 编号 | R | ＝ | 盐 | 熔点(℃) |
| 55 | 2-苯并噻吩基 | 3 | - | 165-166 |
| 56 | 2-苯并噻吩基 | - | HBr 2∶1 | 311-313 |
| 57 | 3-呋喃基 | 3 | HBr 2∶1 | 291-294 |
| 58 | 3-呋哺基 | - | HBr 2∶1 | 313-315 |
| 59 | 4-CH3-3-吡啶基 | - | HBr 2∶1 | 268-270 |
| 60 | 3，5-(CH3)2-1，2-噁唑 | - | HBr 2∶1 | 116-117 |
| 61 | 3，5-(CH3)2-1，2-噁唑 | 3 | HBr 2∶1 | 250-252 |
| 62 | 2，4-(CH3O)2-嘧啶-5-基 | - | ox. | 70-72 |
| 63 | 4-CH3-2-噻吩基 | - | HBr 2∶1 | 336-338 |
| 64 | 4-CH3-2-噻吩基 | 3 | HBr 2∶1 | 284-285 |
| 65 | 1-联苯并呋喃基 | - | HBr 2∶1 | 188-189 |
| 66 | 1-联苯并呋喃基 | 3 | HBr 2∶1 | 302-304 |
| 67 | 1-吩氧硫杂环己烯基 | 3 | HBr 2∶1 | 292-293 |
| 68 | 1-吩氧硫杂环己烯基 | - | HBr 1∶1 | 200-203 |
| 69 | 8-喹啉基 | - | HBr 2∶1 | 206-208 |
| 70 | 8-喹啉基 | 3 | HBr 2∶1 | 309-310 |
| 71 | 3-苯并噻吩基 | - | HBr 2∶1 | 222-223 |
| 72 | 3-苯并噻吩基 | 3 | ox.1∶1 | 80-82 |
采用Anderson和Americ在Eur.J.Pharmacol.(1994，253，261)和Hall等人在Brain Res.(1993，600，127)中描述的方法，研究本发明的化合物对含有α4β2亚基的烟碱受体的亲和力。切除重150至200克的雄性Sprague Dawley大鼠头部，快速摘除整个脑部，4℃下在15体积的0.32M蔗糖溶液中均浆，再以1,000g离心10分钟。去除沉淀物，上清液在4℃下20,000g离心20分钟。回收沉淀物，借助PolyteonTM均浆机4℃下在15体积的二次蒸馏水中均浆，再以8,000g离心20分钟。去除沉淀物，上清液和皮层(血沉棕黄层)40,000g离心20分钟，回收沉淀物，悬于15毫升二次蒸馏水中，-80℃储存之前再次40,000g离心。在进行实验当天，慢慢解冻组织，悬于3体积的缓冲液中。取150微升该膜悬浮液，4℃下在500微升终体积缓冲液中加入100微升1nM[3H]-野靛碱，在测试化合物存在或不存下培养120分钟。用聚乙烯亚胺预处理的Whatman GF/BTM过滤器过滤，终止反应，过滤器在4℃洗二次，每次用5毫升缓冲液，通过液体闪烁成像法测定留在过滤器上的放射活性。在10μM(-)-烟碱存在下测定非特异性结合；非特异性结合占过滤器上回收的总结合的75-85％。测定研究化合物每种浓度与[3H]-野靛碱特异性结合的抑制百分比，再计算IC50值，其表示抑制一半特异性结合的化合物浓度。
还用Mark和Collins在J.Pharmacol.Exp.Ther.(1982，22，564)和Marks等人在Mol.Pharmacol.(1986，30，427)中描述的方法，测定本发明的化合物对含有α7亚基的烟碱受体的亲和力。切除重150至200克的雄性OFA大鼠头部，快速摘除整个脑部，4℃下在15体积的0.32M蔗糖溶液中均浆，再以1,000g离心10分钟。去除沉淀物，上清液在4℃下8,000g离心20分钟。回收沉淀物，借助PolyteonTM均浆机4℃下在15体积的二次蒸馏水中均浆，再以8,000g离心20分钟。去除沉淀物，上清液和皮层(血沉棕黄层)40,000g离心20分钟，回收沉淀物，悬于15毫升二次蒸馏水中，-80℃储存之前再次40,000g离心。在进行实验当天，慢慢解冻组织，悬于5体积的缓冲液中。取150微升该膜悬浮液，37℃下在测试化合物存在或不存下在黑暗中预培养30分钟。37℃下在250微升终体积20mM HEPES缓冲液和0.05％聚乙烯亚胺中加入50微升1nM[3H]α-银环蛇毒素，在黑暗中培养该膜60分钟。用0.05％聚乙烯亚胺预处理3小时的Whatman GF/BTM过滤器过滤，终止反应。过滤器在4℃洗二次，每次用5毫升缓冲液，通过液体闪烁成像法测定留在过滤器上的放射活性。在1μMα-银环蛇毒素存在下测定非特异性结合；非特异性结合占过滤器上回收的总结合的约60％。测定研究化合物每种浓度与[3H]α-银环蛇毒素特异性结合的抑制百分比，再计算IC50值，其表示抑制一半特异性结合的化合物浓度。
本发明具有最高亲和力的化合物的IC50值在0.005至20μM之间。
上述结果显示，本发明的化合物是烟碱受体的配体。它们中一些对含有α7亚基的受体有选择性，其他化合物具有对α4β2和α7型受体的混合性质。
测试结果提示，这些化合物可用于治疗或预防烟碱受体功能障碍相关性疾病，特别是在中枢神经系统水平上。
这些疾病包括损害认知能力的改变，更具体地说，是损害记忆的改变，以及损害注意力的改变，与阿耳茨海默病、病理性老化(老年性记忆衰退，AAMI)、帕金森综合症、21三体(唐氏综合症)、科尔萨科夫氏酒精性综合症或血管性痴呆(多发性硬化性痴呆，MDI)有关。
本发明的化合物还可用于治疗帕金森氏病中的运动障碍或其他神经系统疾病，例如杭廷顿氏舞蹈病、图雷特氏综合症、迟发性运动障碍和运动过度。
本发明的化合物还可以治愈或症状性治疗急性神经系统变性病理，例如中风和脑缺氧，慢性神经系统变性病理，例如阿耳茨海默氏病和帕金森氏病。它们可用于以下精神病病理中：精神分裂症、抑郁、焦虑、恐慌发作或者强迫性行为。
它们可预防由于戒烟或戒酒，或者戒除非成瘾物质例如可卡因、摇脚丸(LSD)、苯并二氮杂草引起的综合症。
所以，本发明提供一些药物组合物，其含有有效剂量的至少一种本发明的碱或盐形式化合物或药学上可接受的溶剂化物或者混合物以及合适的赋形剂。
根据药物形式和所希望的给药方法选择所述赋形剂。
所以，本发明的药物组合物可用于口服、舌下、皮下、肌内、静脉内、局部、气管内、鼻内、透皮、直肠或眼内给药。
例如，可能的单位给药形式是片剂、凝胶胶囊、丸剂、粉末、口服或注射溶液或悬浮液、透皮贴剂或栓剂。药膏、洗液和洗眼剂用于局部给药。
根据药物剂量形式，所述单位形式允许每日给予每千克体重0.01至20毫克活性成分。
当制备片剂时，在微粉化或未微粉化的活性成分中加入药物赋形剂，该赋形剂可以由乳糖、微晶纤维素或淀粉等稀释剂，或者诸如粘合剂(聚乙烯吡咯烷酮、羟基丙基甲基纤维素等)、二氧化硅等助流剂、硬脂酸镁、硬脂酸、三山萮酸甘油酯或硬脂酰富马酸钠等滑润剂的配制佐剂组成。还可加入湿润剂或表面活性剂，如十二烷基硫酸钠。
可能的制造技术是直接压片、干法制粒、湿法制粒或热熔。
片剂可以是纯片剂，或带有糖衣(例如用蔗糖制成糖衣)或带有各种聚合物或其他合适材料的包衣。借助聚合物基质或在薄膜中使用特定的聚合物，可将片剂的活性成分制成快速释放、延迟释放或缓释型式。
当制备凝胶胶囊时，可将活性成分与干燥药物赋形剂(简单混合、干或湿法制粒或热熔)，或者与液体或半固体药物赋形剂混合。凝胶胶囊可以是硬胶囊或软胶囊，不带薄膜或带薄膜，以便(例如，通过肠形式)具有快速、持续或延迟活性。
糖浆或酏剂形式或者以滴剂形式给予的组合物可含有活性成分与甜味剂，优选不含卡路里的甜味剂，对羟基苯甲酸甲酯或对羟基苯甲酸丙酯等防腐剂以及香味剂和着色剂。
水分散性粒剂或粉末可含有活性成分与由分散剂或湿润剂或聚乙烯吡咯烷酮等悬浮剂以及甜味剂或矫味剂组成的混合物。
直肠型给药必须借助栓剂，而栓剂是与在肠温下熔化的粘合剂如可可脂或聚乙二醇制成。
肠胃外给药型可采用含有药理学上相容的分散剂和/或湿润剂如丙二醇或丁二醇的水悬浮液、等渗盐水溶液或无菌注射溶液。
活性成分还可以配制成微胶囊形式，任选地与一或多种赋形剂或添加剂，或者与聚合物基质或者与环糊精一起配制(透皮贴剂或缓释形式)。
本发明的局部组合物含有与皮肤相容的介质。它们特别以水溶液、酒精溶液或水/酒精溶液、凝胶、呈乳霜或凝胶状的油包水或水包油乳液、微乳液或气溶胶形式，或者以含有离子型和/或非离子型脂质的泡沫分散剂形式提供。这些药物剂量形式按照本领域所采用的常规方法制备。
最后，本发明的药物组合物除了含有通式(I)化合物外，还可含有其他可用来治疗上述各种障碍和疾病的活性成分。
Claims (4)
1.纯对映体或对映体混合物形式的化合物，其特征在于：所述化合物以通式(I)表示，
式中，
R表示卤素原子或者(C3-C6)环烷基或者被一或多个选自卤素原子、或(C1-C6)烷基、(C1-C6)烷氧基、硝基、氨基、(C1-C3)二烷基氨基、三氟甲基、三氟甲氧基、氰基、羟基、乙酰基或亚甲二氧基的基团取代的苯基，
或者表示哌啶基、或吗啉-4-基、或吡咯烷-1-基、或氮杂环丁烷-1-基、或吖庚因-1-基、或吡啶基、或喹啉基、或噻吩基、或吡嗪基、或呋喃基、或苯并呋喃基、或苯并噻吩基、或吲哚基、或嘧啶基、或异噁唑基、或吩噁嗪基、或吩氧硫杂环己烯基、或联苯并噻吩基、或联苯并呋喃基、或吡咯基、或萘基，其中这些基团中的每一个可被一或多个选自卤素原子、(C1-C6)烷基、(C1-C6)烷氧基、三氟甲氧基、三氟甲基、硝基、氰基、羟基、氨基、(C1-C3)二烷基氨基、或者(C3-C8)环烷基氨基的基团任意取代，
其中对于以
表示的两个碳-碳键来说，一个是单键，另一个可以是单键或双键，
所述化合物可以碱形式或酸加成盐形式存在，
条件是所述化合物不包括5-(2-溴吡啶-5-基)-1-氮杂二环[3.2.1]辛-3-烷、5-(2-氯吡啶-5-基)-1-氮杂二环[3.2.1]辛-3-烷和5-(2-氟吡啶-5-基)-1-氮杂二环[3.2.1]辛-3-烷。
2.如权利要求1所述的化合物，其特征在于：R表示卤素原子或者被一或多个选自卤素原子和(C1-C6)烷基、(C1-C6)烷氧基、硝基、氨基、三氟甲基、氰基、羟基、乙酰基或亚甲二氧基的基团取代的苯基，或者表示被一或多个(C1-C6)烷氧基任意取代的吡啶基、或噻吩基、或吲哚基、或嘧啶基。
3.一种药物，其特征在于：所述的药物由如权利要求1所述的化合物组成。
4.一种药物组合物，其特征在于：所述的药物组合物含有如权利要求1所述的化合物和赋形剂。
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| Country | Link |
|---|---|
| US (2) | US7223750B2 (zh) |
| EP (1) | EP1465893B1 (zh) |
| JP (1) | JP4402957B2 (zh) |
| KR (1) | KR100977332B1 (zh) |
| CN (2) | CN1276921C (zh) |
| AR (2) | AR038098A1 (zh) |
| AT (1) | ATE355290T1 (zh) |
| AU (1) | AU2003216777B2 (zh) |
| BR (1) | BR0306707A (zh) |
| CA (1) | CA2471628C (zh) |
| CO (1) | CO5590914A2 (zh) |
| CY (1) | CY1106580T1 (zh) |
| DE (1) | DE60312123T2 (zh) |
| DK (1) | DK1465893T3 (zh) |
| EA (1) | EA007793B1 (zh) |
| EC (1) | ECSP045176A (zh) |
| ES (1) | ES2281631T3 (zh) |
| FR (1) | FR2834511B1 (zh) |
| HR (1) | HRP20040617B1 (zh) |
| IL (2) | IL162524A0 (zh) |
| IS (1) | IS2470B (zh) |
| MA (1) | MA27165A1 (zh) |
| ME (2) | ME00213B (zh) |
| MX (1) | MXPA04006630A (zh) |
| NO (1) | NO329309B1 (zh) |
| NZ (1) | NZ533793A (zh) |
| PL (1) | PL216665B1 (zh) |
| PT (1) | PT1465893E (zh) |
| RS (1) | RS50921B (zh) |
| SI (1) | SI1465893T1 (zh) |
| TN (1) | TNSN04120A1 (zh) |
| TW (1) | TWI336703B (zh) |
| UA (1) | UA77229C2 (zh) |
| WO (1) | WO2003057697A1 (zh) |
| ZA (1) | ZA200405002B (zh) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9902007D0 (en) * | 1999-01-30 | 1999-03-17 | Thomas Carpentry Services Limi | Improvements relating to door frames |
| FR2834511B1 (fr) * | 2002-01-07 | 2004-02-13 | Sanofi Synthelabo | Derives de 5-(pyridin-3-yl)-1-azabicyclo[3.2.1]octane, leur preparation et leur application en therapeutique |
| FR2889701B1 (fr) * | 2005-08-12 | 2007-10-05 | Sanofi Aventis Sa | Derives de 5-pyridinyl-1-azabicyclo[3.2.1]octane, leur preparation en therapeutique. |
| FR2889847B1 (fr) * | 2005-08-18 | 2007-10-05 | Sanofi Aventis Sa | Derives de 5-pyridazinyl-1-azabicyclo[3.2.1]octave, leur preparation en therapeutique. |
| FR2912404B1 (fr) | 2007-02-09 | 2009-04-10 | Sanofi Aventis Sa | Derives d'azabicycloalkane,leur preparation et leur application en therapeutique. |
| KR101925971B1 (ko) * | 2011-01-28 | 2018-12-06 | 에스케이바이오팜 주식회사 | 피리돈 유도체 및 이를 포함하는 약학적 조성물 |
| KR101928505B1 (ko) | 2011-01-28 | 2018-12-12 | 에스케이바이오팜 주식회사 | 피리돈 유도체 및 이를 포함하는 약학적 조성물 |
| WO2019087146A1 (en) | 2017-11-03 | 2019-05-09 | Novartis Ag | Azabicyclo and diazepine derivatives for treating ocular disorders |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5817679A (en) * | 1993-04-01 | 1998-10-06 | University Of Virginia | 7-Azabicyclo 2.2.1!-heptane and -heptene derivatives as cholinergic receptor ligands |
| AU7474794A (en) | 1993-07-22 | 1995-02-20 | E.I. Du Pont De Nemours And Company | Arthropodicidal azacyclic heterocycles |
| FR2786770B1 (fr) | 1998-12-04 | 2001-01-19 | Synthelabo | Derives de 1,4-diazabicyclo[3.2.2.]nonane, leur preparation et leur application en therapeutique |
| FR2786769B1 (fr) * | 1998-12-04 | 2002-10-25 | Synthelabo | Derives de 2,5-diazabicyclo[2.2.1]heptane, leur preparation et leur application en therapeutique |
| FR2834511B1 (fr) * | 2002-01-07 | 2004-02-13 | Sanofi Synthelabo | Derives de 5-(pyridin-3-yl)-1-azabicyclo[3.2.1]octane, leur preparation et leur application en therapeutique |
-
2002
- 2002-01-07 FR FR0200109A patent/FR2834511B1/fr not_active Expired - Fee Related
- 2002-12-31 TW TW091138055A patent/TWI336703B/zh not_active IP Right Cessation
-
2003
- 2003-01-03 CA CA2471628A patent/CA2471628C/en not_active Expired - Fee Related
- 2003-01-03 CN CNB038019876A patent/CN1276921C/zh not_active Expired - Fee Related
- 2003-01-03 ME MEP-2008-244A patent/ME00213B/me unknown
- 2003-01-03 NZ NZ533793A patent/NZ533793A/en not_active IP Right Cessation
- 2003-01-03 EP EP03712202A patent/EP1465893B1/fr not_active Expired - Lifetime
- 2003-01-03 BR BR0306707-6A patent/BR0306707A/pt not_active Application Discontinuation
- 2003-01-03 WO PCT/FR2003/000004 patent/WO2003057697A1/fr not_active Ceased
- 2003-01-03 ES ES03712202T patent/ES2281631T3/es not_active Expired - Lifetime
- 2003-01-03 EA EA200400770A patent/EA007793B1/ru not_active IP Right Cessation
- 2003-01-03 ME MEP-244/08A patent/MEP24408A/xx unknown
- 2003-01-03 CN CNA2006101091747A patent/CN1911928A/zh active Pending
- 2003-01-03 IL IL16252403A patent/IL162524A0/xx unknown
- 2003-01-03 AR ARP030100009A patent/AR038098A1/es not_active Application Discontinuation
- 2003-01-03 MX MXPA04006630A patent/MXPA04006630A/es active IP Right Grant
- 2003-01-03 SI SI200330774T patent/SI1465893T1/sl unknown
- 2003-01-03 KR KR1020047010566A patent/KR100977332B1/ko not_active Expired - Fee Related
- 2003-01-03 AU AU2003216777A patent/AU2003216777B2/en not_active Ceased
- 2003-01-03 HR HRP20040617AA patent/HRP20040617B1/hr not_active IP Right Cessation
- 2003-01-03 PL PL370065A patent/PL216665B1/pl unknown
- 2003-01-03 JP JP2003558012A patent/JP4402957B2/ja not_active Expired - Fee Related
- 2003-01-03 RS YUP-599/04A patent/RS50921B/sr unknown
- 2003-01-03 DE DE60312123T patent/DE60312123T2/de not_active Expired - Lifetime
- 2003-01-03 DK DK03712202T patent/DK1465893T3/da active
- 2003-01-03 PT PT03712202T patent/PT1465893E/pt unknown
- 2003-01-03 AT AT03712202T patent/ATE355290T1/de active
- 2003-01-03 US US10/500,015 patent/US7223750B2/en not_active Expired - Lifetime
- 2003-03-01 UA UA20040605056A patent/UA77229C2/uk unknown
-
2004
- 2004-06-14 IL IL162524A patent/IL162524A/en not_active IP Right Cessation
- 2004-06-16 IS IS7322A patent/IS2470B/is unknown
- 2004-06-24 ZA ZA200405002A patent/ZA200405002B/en unknown
- 2004-06-29 EC EC2004005176A patent/ECSP045176A/es unknown
- 2004-06-30 TN TNP2004000120A patent/TNSN04120A1/fr unknown
- 2004-07-01 CO CO04062934A patent/CO5590914A2/es active IP Right Grant
- 2004-07-01 MA MA27759A patent/MA27165A1/fr unknown
- 2004-07-05 NO NO20042846A patent/NO329309B1/no not_active IP Right Cessation
-
2007
- 2007-04-05 US US11/696,993 patent/US7585974B2/en not_active Expired - Fee Related
- 2007-05-10 CY CY20071100641T patent/CY1106580T1/el unknown
-
2012
- 2012-05-28 AR ARP120101864A patent/AR086573A2/es not_active Application Discontinuation
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