CN1090480C - 用于治疗多巴胺系统紊乱疾病的苯氧哌嗪衍生物 - Google Patents
用于治疗多巴胺系统紊乱疾病的苯氧哌嗪衍生物 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Bioinformatics & Cheminformatics (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
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- Neurosurgery (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及通式I所示的化合物的应用，其中：R1和R3分别独立地表示氢，芳基，氨基甲酰基，低级烷基羰基，低级烷基，卤素，低级烷基羰氨基，低级链烯基羰基，氨基，芳氨基，芳氧基，硝基，芳乙酰基，低级链烷酰基低级烷基，烷基磺酰氨基，脲基或呋喃-2-羰氨基，和R2表示氢，低级烷基，三氟甲基，卤素，低级烷氧基，低级烷羰基或低级烷基羰氨基；或R1和R2共同表示-OCH2O-，-O(CH2)2O-或-O(CH2)3-；R4表示氢，卤素，羟基，低级烷基，低级烷氧基或硝基；R5表示氢，卤素或低级烷氧基；R6表示氢，低级烷基，卤素，羟基，氨基，低级烷氧基，三氟甲基，硝基或低级烷基羰氨基和R7表示氢，低级烷基羰基。也包括其在药剂学上可接受的盐的应用。这些化合物可以用以控制和阻止由于多巴胺系统紊乱所引起的疾病，也可以用于生产相应药物。
Description
本发明涉及芳香醚，特别是通式I所示的苯氧哌嗪衍生物，也包括其在药剂学上可接受的盐。
其中R1和R3分别独立地表示氢，芳基，氨基甲酰基，低级烷基羰基，
低级烷基，卤素，低级烷基羰氨基，低级链烯基羰氨基，
氨基，芳氨基，芳氧基，硝基，芳乙酰基，低级链烷酰基
低级烷基，烷基磺酰氨基，脲基或呋喃-2-羰胺基，和R2 表示氢，低级烷基，三氟甲基，卤素，低级烷氧基，低级
烷基羰基或低级烷基羰氨基，或R1和R2 可以在一起表示
-OCH2O-，-O(CH2)2O-或-(CH2)3-，R4 可以是氢，卤素，羟基，低级烷基，低级烷氧基或硝基R5 表示氢，卤素或低级烷氧基，R6 表示氢，低级烷基，卤素，羟基，氨基，低级烷氧基，三
氟甲基，硝基或低级烷基羰氨基以及R7 表示氢，低级烷基羰基。
这些化合物和它们的盐是已知的。它们的制备和它们作为抗高血压剂的应用已在DE-OS 1964423中描述过。
在本文中，“低级烷基”表示直链或支链的1～6个碳原子的低级烷基，如，甲基、乙基、异丙基、丁基、戊基以及类似基团。“低级烷氧基”表示低级烷基醚基团，其中低级烷基如前所述。例如，甲氧基、乙氧基、异丙氧基以及类似基团。“卤素”指氯，溴、氟和碘。在上述卤素原子中，优选氟和氯。
如有要求，氨基基团可被有1-6个碳原子的低级烷基基团取代，如甲基-，乙基-，丙基-，丁基-或戊-氨基等。“低级链烯基”表示直链或支链的烯型的2-6个碳原子的不饱和碳氢基团。“芳基”表示苯基或含有1-4个碳原子的低级烷基的苯基。其中，优选对-甲苯基。
目前，人们惊奇地发现这些化合物可以用以控制和防止由于多巴胺系统紊乱所引起的疾病。此时它们属于精神病治疗药物，如用于精神分裂症。本发明的目的是分子式I的化合物用于治疗和抑制由多巴胺系统紊乱所引发的疾病的用途和这些化合物作为有效成分用于生产上述治疗的药物的应用以及包含这些化合物的药物。
这些化合物的新型药理学性质是由于对神经受体有高度选择性亲和力，特别是对多巴胺D4受体。因此，当使用它们时，人们可以期望它们比已知的传统的中枢抗精神病药如氟哌啶醇有更为轻微的副作用。氟哌啶醇是公认地结合于D2和D3受体的药物。人们发现它在治疗精神分裂症时，D2和D3受体浓度增加大约10％，而与此同时D4受体浓度的增加大于600％(TiPS，July 1994，vol.15，p.264-70)。试验说明
这些化合物以结合D4受体的能力来定义其特征。
此外，相对于D2受体活性，这些化合物可期望有好的结合于D4受体的选择性。
在实验中使用的是CHO细胞(中国仓鼠卵巢细胞)。
用超速离心法从D4-CHO和D2-CHO细胞分离到粗制的膜，储存在-80℃。在解冻后与缓冲液(50mM Tris，1mM EDTA，5nM KCl，1.5mM CaCl2，4mMMgCl2，PH7.4)匀浆化，在室温下与200pM[3H]-史匹哌酮和浓度逐渐增加的受试化合物(1×10-11M-1×10-4M)共孵90分钟，非特异的结合通过与1×10-5M(+)-布他拉莫共孵来建立。用一个GF/C玻璃过滤器过滤掉未结合的配体，结合物的放射活性在Parkard TopCount液闪计数器中通过闪烁作用来测得。
下面的表显示了选择的一些结合D4受体的化合物的结合情况。Ki值为结合常数，表示化合物与D4受体的亲和力。通过[3H]-史匹哌酮方法确定。该计算值可用配体实现。表1
表一所示为特定的活性化合物，它们是下列化合物：1 1-苯氧基-3-(4-苯基哌嗪-1-基)-丙-2-醇2 1-(2-氨基苯氧基)-3-(4-苯基哌嗪-1-基)-丙-2-醇3 1-[2-[2-羟基-3-(4-苯基哌嗪-1-基)-丙氧基]-苯基]-乙酮4 2-[2-羟基-3-(4-苯基哌嗪-1-基)-丙氧基]-苯甲酰胺5 1-[4-(4-氯苯基)-哌嗪-1-基]-3-(3-三氟甲基苯氧基)-丙-2-醇6 N-[2-[2-羟基-3-(4-邻-甲苯基哌嗪-1-基)-丙氧基]-苯基]-乙酰胺7 N-[2-[2-羟基-3-[4-(2-三氟甲基苯基)-哌嗪-1-基]-丙氧基]-苯
基]-乙酰胺8 N-[2-[2-羟基-3-(4-(2-羟基苯基)-哌嗪-1-基)-丙氧基]-苯基]-乙
酰胺9 [+]-1-(2-氨基苯氧基)-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙-2-醇10 N-[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯基]乙
酰胺11 [+]-N-[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯
基]乙酰胺12 [-]-N-[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯
基]乙酰胺13 N-[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯基]丙
酰胺14 己酸[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯
基]-酰胺15 N-[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯基]-
2，2-二甲基-丙酰胺16 [+]-(E)-丁-2-烯醇酸[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-
基]-丙氧基]-苯基]-酰胺17 呋喃-2-羧酸[2-[2-羟基-3-[4-(2-甲氧基-苯基)-哌嗪-1-基]-丙氧
基]-苯基]-酰胺18 [2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-苯基]-脲19 N-[2-[2-羟基-3-[4-(2-甲氧基-苯基)-哌嗪-1-基]-丙氧基]-5-甲基
-苯基]-乙酰胺20 N-[2-[2-羟基-3-[4-(2-甲氧基苯基)-哌嗪-1-基]-丙氧基]-4-甲基-
苯基]-乙酰胺21 N-[2-[3-[4-(2-乙氧基苯基)-哌嗪-1-基]-2-羟基-丙氧基]-苯基]-
丙酰胺22 1-(2-氨基苯氧基)-3-[4-(2-硝基苯基)-哌嗪-1-基]-丙-2-醇30 2-(2-乙酰氨基苯氧基)-1-[4-(2-甲氧基-苯基)-哌嗪-1-基-甲基]-
乙酸乙酯31 [+]-2-(2-乙酰氨基苯氧基)-1-[4-(2-甲氧基苯基)-哌嗪-1-基-甲
基]-乙酸乙酯
下表2清楚地表明了一些化合物对D2受体的选择性，以D4受体和D2受体的Ki比值来表示。
表2
| 化合物号 | R1 | R2 | R3 | R4 | R5 | R6 | R7 | Kiat D4[nM] | 选择性，对D2 |
| 23242526272829 | HHHHNO2HH | CH3HHHHBrH | H-NHCOCH2CH3-NHCOCH3-NHSO2CH3-NHCOCH3-NHCOCH3-NHCOCH3 | HHOHHHHH | HHHHHHH | HH-OCH3-OCH3-OCH3-OCH3NO2 | HHHHHHH | 9.62910.23.2155.88.7 | 3002331370177112135360 |
式I的化合物及其在药剂学上可接受的盐可以作为药物使用。例如，以药物制剂的形式。药物制剂可以是口服的，如片剂，包衣片剂，糖丸，硬和软明胶胶囊，溶液剂，乳剂或混浮剂。此外，也可以直肠给药，如以栓剂的方式给药，或可以是经肠外给药，如以注射液的方式给药。
可以在生产符合分子式I的化合物和其在药剂学上可接受的盐的药物制剂时使用药剂学惰性的、无机的或有机的载体。如乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或硬脂酸盐等可以用作为片剂、包衣片剂、糖丸和硬明胶胶囊的赋形剂。软明胶胶囊的合适的赋形剂是，比如，植物油，蜡，动物脂肪，半固态和液态多元醇等；然而取决于活性成分的性质。通常制做软胶囊时不需要载体。生产溶液剂和糖浆剂的赋形剂有如，水，多元醇，蔗糖，转化蔗糖，葡萄糖等。制备分子式I中的化合物的水溶性的盐的水性注射液时可以应用乙醇，多元醇，甘油，植物油等辅料。但是这并不是一个既定的规则。栓剂的适合的赋形剂，如天然的或硬化油，蜡，动物油脂，半固态和液态多元醇等。
此外，药学制剂还可以含有防腐剂，增溶剂，稳定剂，湿润剂，乳化剂，甜味剂，着色剂，增香剂，改变渗透压的盐，缓冲液，包衣剂或抗氧化剂。还可以含有其他有治疗价值的物质。
如前所述，本发明的目的还是含有符合分子式I的化合物或其在药剂学上可接受的盐和在治疗上为惰性的赋形剂的药剂，以及生产上述药剂的方法，该方法包括符合分子式I的一种或多种化合物或其在药剂学上可接受的盐以及如果必要，与一种或多种有治疗价值的物质组成复方，并含有一种或多种治疗惰性的载体。剂量可以在很宽的范围内进行变化，并根据各个具体情况而变化。总之，每日1-1000mg左右的剂量应是适宜的。
最后，如前所述，本发明的目的还在于采用符合分子式I的化合物及其在药剂学上可以接受的盐生产药物，特别是用于控制和预防由于多巴胺系统紊乱引起的疾病的药物的用途。
实施例A
以通用的方式生产包含下列成分的片剂：
mg/片活性成分 100乳糖粉末 95白色玉米淀粉 35聚乙烯吡咯烷 8羧甲基淀粉钠 10硬脂酸镁 2
片重250
实施例B
以通用的方式生产包含下列成分的片剂：
mg/片活性成分 200乳糖粉末 100白色玉米淀粉 64聚乙烯吡咯烷酮 12羧甲基淀粉钠 20硬脂酸镁 4
片重400
实施例C
制备包含下列成分的胶囊剂：
mg/片活性成分 50乳糖结晶 60微晶纤维素 34滑石 5硬脂酸镁 1
胶囊全重150颗粒尺寸合适的活性成分，结晶乳糖和微晶纤维素，混合均匀，过筛后，加入滑石和硬脂酸镁混匀，最后将混合物填入合适尺寸的硬胶囊制成。
Claims (4)
1.通式I所示的化合物，及其在药剂学上可接受的盐在生产用于治疗和预防由于多巴胺系统紊乱所引起的疾病的药物的用途，
其中R1和R3 分别独立地表示氢，芳基，氨基甲酰基，低级烷基羰基，低
级烷基，卤素，低级烷基羰氨基，低级链烯基羰氨基，氨基，
芳氨基，芳氧基，硝基，芳乙酰基，低级链烷酰基低级烷基，
烷基磺酰氨基，脲基或呋喃-2-羰氨基，和R2 表示氢，低级烷基，三氟甲基，卤素，低级烷氧基，低级烷
羰基或低级烷基羰氨基；或R1和R2 共同表示
-OCH2O-，-O(CH2)2O-或-(CH2)3-；R4 表示氢，卤素，羟基，低级烷基，低级烷氧基或硝基；R5 表示氢，卤素或低级烷氧基；R6 表示氢，低级烷基，卤素，羟基，氨基，低级烷氧基，三氟
甲基，硝基或低级烷基羰氨基和R7 表示氢，低级烷基羰基。
2.根据权利要求1的符合通式I的化合物的用途，其中R1表示氢或甲基，R2表示氢，三氟甲基或甲基，R4表示氢，羟基或卤素，R5表示氢，R3、R6和R7与权利要求1中的相同。
3.根据权利要求1或2的用途，其用在精神疾病方面。
4.根据权利要求3的用途，其用在抗精神分裂症方面。
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| US7071204B2 (en) * | 2003-06-30 | 2006-07-04 | Research Triangle Institute | Camptothecin analogs having an E-ring ketone |
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