CN1085659C - 2-(4-取代)-苄基氨基-2-甲基-丙酰胺衍生物 - Google Patents
2-(4-取代)-苄基氨基-2-甲基-丙酰胺衍生物 Download PDFInfo
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Abstract
本发明公开了具有神经***活性的式(I)的新的2-(4-取代)-苄基氨基-2-甲基-丙酰胺化合物,其中:n为0,1,2或3;X为-O-,-S-,-CH2-或-NH-;每一个R及R1分别是氢,C1-C6烷基,卤素,C1-C4烷氧基或三氟甲基;每一个R2,R3和R4分别为氢,C1-C6烷基或C3-C7环烷基;及其药物可接受的盐。
Description
本发明涉及新的2-(4-取代)-苄基氨基-2-甲基-丙酰胺衍生物,它们作为治疗剂的应用,这些化合物的制备以及含有这些化合物的药物组合物。
WO90/14334公开了具有中枢神经***活性的N-苯基烷基取代α-氨基羧酰胺衍生物。
已经发现,本发明的新2-(4-取代)-苄基氨基-2-甲基-丙酰胺衍生物具有有价值的生物学活性,特别是用作抗癫痫,抗帕金森氏症,神经保护,抗抑郁,抗痉挛和/或催眠的药物。
式中:
n为0,1,2或3;
X为-O-,-S-,-CH2-,或-NH-;
每一个R和R1分别是氢,C1-C6烷基,卤素,羟基,C1-C4烷氧基或三氟甲基;
每一个R2,R3和R4分别是氢,C1-C6烷基或C3-C7环烷基;
式(I)的化合物的药物可接受的盐包括与无机酸如盐酸,氢溴酸,硫酸和磷酸所成的酸加成盐或与有机酸如乙酸,丙酸,乳酸,草酸,苹果酸,马来酸,酒石酸,枸橼酸,苯甲酸,苯乙醇酸,C1-C4烷基磺酸,水杨酸及富马酸所成的酸加成盐。
本发明的另一个内容是式(I)的化合物及其药物可接受的盐也可以形成药用的溶剂化物,如单-,双-或三水合物。
烷基和烷氧基可以是支链或直链的。
C1-C6烷基基团优先选自C1-C4的烷基,特别是甲基,乙基,正丙基和异丙基,正丁基,异丁基,仲丁基和叔丁基,最好是甲基或乙基。
典型的C1-C4烷氧基包括甲氧基或乙氧基。
卤原子可以是氯,氟或溴。
C3-C7环烷基可以是环丙基,环己基或环庚基,特别是环丙基。
本发明还包括所有式(I)化合物的可能的异构体及其混合物,它们的代谢产物以及式(I)化合物可药用的生物前体(又称为前体药物)。
本发明的优选化合物为式(I)的化合物及其药物可接受的盐,式中:
n为1或2;
X为-O-,-S-或-NH-;
R为氢;
R1为氢或卤素;
R2,R3和R4分别是氢或C1-C4的烷基;
本发明的更优选化合物为式(I)的化合物及其药物可接受的盐,式中:
n为1;
X为-O-,-S-或-NH-;
R1为氢或卤素;
R,R2,R3和R4是氢;
本发明具体的化合物例举如下:
2-[4-(3-氟苄基氧)苄基氨基]-2-甲基-丙酰胺;
2-[4-(3-氯苄基氧)苄基氨基]-2-甲基-丙酰胺;
2-[4-(4-氯苄基氧)苄基氨基]-2-甲基-丙酰胺;
2-[4-(3-溴苄基氧)苄基氨基]-2-甲基-丙酰胺;
2-[4-(4-氟苄基氧)苄基氨基]-2-甲基-丙酰胺;
2-[4-(2-氟苄基氧)苄基氨基]-2-甲基-丙酰胺;
2-[4-(3-氟苄基氨基)苄基氨基]-2-甲基-丙酰胺;
2-[4-(苄基硫烷基(sulfanyl))苄基氨基]-2-甲基-丙酰胺;
2-[4-(3-氟苄基氧)苄基甲基氨基]-2-甲基-丙酰胺;
2-{[4-(3-氟苄基氧)苄基]-基}-2-甲基-N-甲基-丙酰胺;
2-{[4-(3-氯苄基氧)苄基]甲基氨基}-2-甲基-丙酰胺;
2-{[4-(3-溴苄基氧)苄基]甲基氨基}-2-甲基-丙酰胺;
如需要,上述化合物可以是单独的(S)或(R)异构体或混合物,或其药物可接受的盐。
式中n,R,R1和X的定义同上,
式中R3和R4的定义同上,
得到式(I)中R2为氢原子的化合物;
或者
式中R1,R2,R3,R4,n和X的定义同上,
与式(V)或(VI)化合物反应,得到其中R2为C1-C6烷基的本发明化合物。
R′2W (V) R″2CHO (VI)
式中W为一个卤素原子;R′2为一个C1-C6的烷基,R″2为一个氢原子或C1-C5的烷基,如果需要,可以将一种本发明化合物转化成另一种本发明化合物和/或将一种本发明化合物转化成其药物可接受的盐和/或将盐转化成其游离形式。
上面所述的所有方法均可重复并可以按照有机化学中的已知方法操作。
式(IV)化合物是R2为氢原子的式(I)化合物。
式(II)化合物与式(III)化合物反应,生成式(I)或(IV)化合物的反应为一个还原胺化反应,其能够按照已知的方法操作。根据本发明的一个优选实施方案,反应可以在氮气氛下,在适宜有机溶剂中如醇如低级链烷醇如甲醇,或乙腈中,在反应温度为0℃-约40℃,在还原剂存在下,还原剂最好为氰基硼氢化钠,进行。为了加速反应,偶尔也可将分子筛加入到反应混合物中。
在式(V)化合物中,卤素W优选为碘。式(IV)化合物与式(V)化合物的烷基化反应可在适宜的有机溶剂如醇类如甲醇,乙醇或异丙醇,最好为乙醇,于温度为0℃-约50℃下进行。
式(IV)化合物与式(VI)醛类化合物的烷基化反应可在适宜的有机溶剂如醇类如甲醇,乙醇,或乙腈,在适宜的还原剂存下,如氰基硼氢化钠,于温度为0℃-约30℃下进行。
如上所述,可以运用已知的方法将一种本发明的化合物转化成另一种本发明化合物。上面的方法b)可以作为一种本发明化合物选择性的转化成另一种本发明化合物的例子。
用常规方法也可以进行本发明化合物的选择性成盐反应以及将盐转化成游离化合物的反应。
式(II),(III),(V)以及(VI)化合物为已知化合物或可通过已知方法获得。
当本发明化合物及其中间体中存在在进行上面反应之前需保护的基团时,可以按照众所周知的有机化学方法在反应前对它们进行保护,然后再去保护。
药理学:
本发明的化合物具有中枢神经***活性,可以用于疾病的治疗如:抗癫痫,抗帕金森氏症和用作神经保护剂如:可预防或治疗中风,供氧不足,局部缺血,中枢神经***外伤,血糖过少或外科手术引起的神经原缺失以及预防与治疗如阿尔茨海默氏症,肌萎缩性侧索硬化,Down氏症,Huntington氏症,由获得性免疫缺陷综合症引起的痴呆症,梗塞性痴呆,脑内感染或炎症等神经退化性疾病;它们也能够用作抗抑郁药,催眠药,抗痉挛药并可用于治疗眼部损伤及rethinopaty病。
本发明化合物的中枢神经***活性依据药理学方法进行了评价,所用方法诸如:拮抗小鼠静脉注射bicuculline所引起的惊厥以及致死率([抗惊厥药物],D.M.Woodbury et al.eds.,2nd edition,Raven Press,NewYork,1982),或拮抗最大电击引发的癫痫(MES)(Woodbury,L.A.andDavenport,V.D.,Arch.Int.Pharmacodyn.Ther.92;97-104,1952)。
下表是将一组具有代表性的本发明的化合物与相应的WO90/14334中已知的2-去甲基相关化合物进行MES比较试验后的结果概况,
其中:*代表前述的WO90/14334中已知2-去甲基化合物。
FCE 29088A代表2-(4-(3-氟苄基氧)苄基氨基)-2-甲基-丙酰胺,甲磺酸盐;
FCE 26743A*代表(S)-2-(4-(3-氟苄基氧)苄基氨基)丙酰胺,甲磺酸盐;
FCE 29482A代表2-(4-苄基硫烷基)苄基氨基)-2-甲基-丙酰胺,甲磺酸盐;
FCE 26727A*代表(S)-2-(4-苄基硫烷基)苄基氨基)丙酰胺,甲磺酸盐;
FCE 29484A代表2-(4-(2-氟苄基氧)苄基氨基)-2-甲基-丙酰胺,甲磺酸盐;
FCE 26742A*代表(S)-2-(4-(2-氟苄基氧)苄基氨基)丙酰胺,甲磺酸盐;
FCE 29644A代表2-(4-(3-氯苄基氧)苄基氨基)-2-甲基-丙酰胺,甲磺酸盐;
FCE 26193A*代表(S)-2-(4-(3-氯苄基氧)苄基氨基)丙酰胺,甲磺酸盐;
FCE 29645A代表2-(4-(4-氟苄基氧)苄基氨基)-2-甲基-丙酰胺,甲磺酸盐;
FCE 26998A*代表(S)-2-(4-(4-氟苄基氧)苄基氨基)丙酰胺,甲磺酸盐;
FCE 29647A代表2-(4-(3-氟苄基氧)苄基氨基)-2-甲基-N-甲基丙酰胺,甲磺酸盐;
FCE 28657A*代表(S)-2-(4-(3-氟苄基氧)苄基氨基)-N-甲基-丙酰胺,甲磺酸盐;
上表列出的比较活性试验数据显示,本发明的新化合物是前面提到的相似化合物活性的2到4倍。
根据本发明,治疗患者的方法包括给患者服用有效量的本发明化合物。依该方法本发明化合物可以用于治疗神经***异常,例如癫痫或帕金森氏症;可以用作神经保护剂,抗抑郁症药,催眠药或抗痉挛药。病人的症状由此可以得到改善。
本发明的化合物能够以不同的剂型给予病人服用,如以片剂,胶囊,糖衣片或薄膜衣片,液体溶液或悬浮液等剂型口服;以栓剂形式直肠给药;可以肌肉注射,静脉注射或以输注的形式胃肠外给药。
剂量的选择取决于病人的年龄,体重,病情以及给药途径;例如,成年人口服给予的本发明代表性药物2-[4-(3-氟苄基氧)苄基氨基]-2-甲基丙酰胺的剂量范围可以从约1到500毫克每剂量单位,每天1到5次。
本发明还包括作为活性成分的本发明化合物与可药用的赋形剂(作为载体或稀释剂)组成的药物组合物。
含有本发明化合物的药物组合物可依常规方法制备,以可药用的形式服用。
例如,固体口服剂型除含有活性化合物外,可以含有稀释剂如乳糖,右旋糖,蔗糖,纤维素,玉米淀粉或马铃薯淀粉;润滑剂如微粉硅胶,滑石粉,硬脂酸,硬脂酸镁或钙,和/或聚乙二醇类;粘合剂如淀粉类,***胶,明胶,甲基纤维素,羧甲基纤维素或聚乙烯吡咯烷酮;崩解剂如淀粉,藻酸,藻酸盐或葡糖酸淀粉钠;泡腾混合物;染料;甜味剂;润湿剂如卵磷脂,聚山梨酸酯,硫酸月桂酯;和无毒无药理活性且可用于药物配制的物质。药物制剂可以用已知的方法制备,如混合,制粒,压片,包糖衣或包薄膜衣的方法制备。
口服用的液体分散剂可以是糖浆剂,乳剂和悬浮剂。
糖浆剂中选用的载体如蔗糖或蔗糖与甘油和/或甘露糖醇和/或山梨醇。
悬浮剂和乳剂的载体可是,如天然胶,琼脂,藻酸钠,果胶,甲基纤维素,羧甲基纤维素或聚乙烯醇。
肌肉注射用悬浮液或溶液除了含有活性成分外,可含有可药用的载体,如注射用水,橄榄油,油酸乙酯,二元醇类如丙二醇,如果有必更还可加适量利多卡因盐酸盐。静脉注射或输注溶液可含有的载体如注射用水或最好为注射用等渗盐水溶液。
栓制除含有活性化合物外,还可含有可药用的载体,如可可脂,聚乙二醇,聚氧乙烯脱水山梨醇脂肪酸酯表面活性剂或卵磷脂。下面的例子描述但不限定本发明。
实施例1
2-[4-(3-氟苄基氧)苄基氨基]-2-甲基-丙酰胺,甲磺酸酯(FCE29088A)
在氮气氛下,边搅拌边向2-氨基-2-甲基丙酰胺盐酸盐(7.01克,0.051摩尔)的无水甲醇(160毫升)溶液中加入7.0克3A的分子筛,另外,单独加入氰基氢硼化钠(2.31克;0.037摩尔),10分钟后,加入含有10.6克(0.046摩尔)4-(3-氟苄基氧)苯甲醛的140毫升无水甲醇溶液。24小时后,反应完成,过滤混合物,蒸发溶液后的残余物直接用硅胶闪式色谱(洗脱剂∶氯仿98∶甲醇2∶30%氨水0.15),产生一白色固体(6.2克;43%)。由此获得的游离碱用化学计算量的甲磺酸处理,即得本发明化合物(熔点为209-213℃)。
与此类似,下列产品也能够通过相应的醛与适宜的酰胺反应获得:
2-[4-(3-氯苄基氧)苄基氨基]-2-甲基-丙酰胺,甲磺酸盐,熔点为202-206℃(FCE 29644A);
2-[4-(3-溴苄基氧)苄基氨基]-2-甲基-丙酰胺,甲磺酸盐,熔点为197-202℃(FCE 29494A);
2-[4-(4-氟苄基氧)苄基氨基]-2-甲基-丙酰胺,甲磺酸盐,熔点为233℃(FCE 29645A);
2-[4-(2-氟苄基氧)苄基氨基]-2-甲基-丙酰胺,甲磺酸盐,熔点为215-220℃(FCE 29484A);
2-[4-(3-氟苄基氨基)苄基氨基]-2-甲基-丙酰胺,甲磺酸盐,熔点为165℃ca(分解)(FCE 29822A);
2-[(4-苄基硫烷基)苄基氨基]-2-甲基-丙酰胺,甲磺酸盐,熔点为214-215℃(FCE 29482A);
2-[4-(3-氟苄基氧)苄基氨基]-2-甲基-N-甲基-丙酰胺,甲磺酸盐,熔点为213-218℃(FCE 29647A);
2-[4-(4-氯苄基氧)苄基氨基]-2-甲基-丙酰胺,甲磺酸盐,熔点为226-227℃(FCE 29485A);
实施例2
2-{[4-(3-氟苄基氧)苄基]甲基氨基}-2-甲基-丙酰胺(FCE 29486)
在氮气流下,将1克(0.00316摩尔)2-[4-(3-氟苄基氧)苄基氨基]-2-甲基-丙酰胺溶解于50毫升乙腈中。室温下向该混合液中加入3.16毫升(0.0389摩尔)37%的甲醛以及0.29克(0.00460摩尔)氰基硼氢化钠。20分钟后用冰醋酸调节溶液至中性。搅拌40分钟后蒸发至干。往残余物加入40毫升2N的氢氧化钾。用乙酸乙酯提取后,用N/2氢氧化钾冲洗,然后用水和盐水冲洗,有机层用硫酸钠干燥脱水,然后过滤,蒸发形成残余物,将其在硅胶进行闪式色谱(洗脱剂∶氯仿200∶甲醇3∶30%氨水0.2)得到0.75克(72%)的白色固体(熔点121-123℃)。
以此类推,下列的产品能够用相应的仲胺来制备:
2-{[4-(3-氯苄基氧)苄基]甲基基}-2-甲基-丙酰胺;以及
2-{[4-(3-溴苄基氧)苄基]甲基氨基}-2-甲基-丙酰胺。
例3
应用常规的制药技术能够制备含有下列组分的胶囊制剂:
2-[4-(3-氟苄基氧)苄基氨基]-2-甲基-丙酰胺甲磺酸盐50毫克
滑石粉 2毫克
玉米淀粉 2毫克
微晶纤维素 6毫克
硬脂酸镁 1毫克
Claims (10)
2.权利要求1的式(I)化合物及其药物可接受的盐,其中:
n为1或2;
X为-O-,-S-或-NH-;
R为氢;
R1为氢或卤素;
R2,R3及R4分别为氢或C1-C4烷基;
3.权利要求1的式(I)化合物及其药物可接受的盐,其中:
n为1;
X为-O-,-S-或-NH-;
R1为氢或卤素;
R,R2,R3及R4为氢;
4.权利要求1的化合物及其药用可接受盐,其选自下组的化合物:2-[4-(3-氟苄基氧)苄基氨基]-2-甲基-丙酰胺;2-[4-(3-氯苄基氧)苄基氨基]-2-甲基-丙酰胺;2-[4-(4-氯苄基氧)苄基氨基]-2-甲基-丙酰胺;2-[4-(3-溴苄基氧)苄基氨基]-2-甲基-丙酰胺;2-[4-(4-氟苄基氧)苄基氨基]-2-甲基-丙酰胺;2-[4-(2-氟苄基氧)苄基氨基]-2-甲基-丙酰胺;2-[4-(3-氟苄基氨基)苄基氨基]-2-甲基-丙酰胺;2-{[4-(3-氟苄基氧)苄基]-甲基氨基}-2-甲基-丙酰胺;2-[4-(3-氟苄基氧)苄基氨基]-2-甲基-N-甲基-丙酰胺;或它们的药物可接受的盐。
5.制备式(I)化合物及其药物可接受的盐的方法,其中,n为0,1,2或3;x为-O-, -S-, -CH2-或-NH-;R和R1分别为氢,C1-C6烷基,卤素,羟基,C1-C4烷氧基或三氟甲基;
R2为氢或C1-C6烷基;
R3和R4分别为氢,C1-C6烷基或C3-C7环烷基;其包括:
其中R,R1,R3,R4,n和X如权利要求1所定义,与式(V)或(VI)的化合物
R’2W (V) R”2CHO (VI)
其中W为卤素原子;R’2为C1-C6烷基,R”2为氢或C1-C5烷基,反应,在后者中需有还原剂存在,得R2为C1-C6烷基的式I化合物,选择性地,当所得式I化合物为游离碱时,将其转化成可药用的盐,和当所得式I化合物为盐时,将其转化成游离的化合物。
6.含有适宜载体和/或稀释剂以及如权利要求1-4任一项定义的作为活性成分的式(I)化合物或其药物可接受的盐的药物组合物。
7.权利要求1-4任一项所要求的式I化合物或其药物可接受的盐在制备药物中用途。
8.权利要求1-4任一项所定义的式(I)化合物或其药物可接受的盐在制备用于治疗帕金森氏症和用于治疗和预防神经退化性疾病的药物中用途。
9.权利要求1-4任一项所定义的式(I)的化合物或其药物可接受的盐在制备用于治疗眼部损伤以及视网膜病药物中用途。
10.权利要求1-4任一项所定义的式(I)化合物或其药物可接受的盐在制备抗抑郁药,催眠药以及抗痉挛药物中应用。
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TW544448B (en) * | 1997-07-11 | 2003-08-01 | Novartis Ag | Pyridine derivatives |
AU749214C (en) * | 1997-11-21 | 2006-03-30 | Purdue Neuroscience Company | Substituted 2-aminoacetamides and the use thereof |
GB9727523D0 (en) * | 1997-12-31 | 1998-02-25 | Pharmacia & Upjohn Spa | Alpha-aminoamide derivatives useful as analgesic agents |
US6281211B1 (en) | 1999-02-04 | 2001-08-28 | Euro-Celtique S.A. | Substituted semicarbazides and the use thereof |
JP2002541215A (ja) | 1999-04-09 | 2002-12-03 | ユーロ−セルティック エス. ア. | ナトリウムチャネル遮断薬組成物およびその使用 |
AU2001249610B2 (en) * | 2000-03-31 | 2005-03-24 | Euro-Celtique S.A. | Aminopyridines and their use as anticonvulsants and sodium channel blockers |
WO2003020273A2 (en) | 2001-09-03 | 2003-03-13 | Newron Pharmaceuticals Spa | Pharmaceutical composition comprising gabapentin or an analogue thereof and an $g(a)-aminoamide and its analgesic use |
US6667327B2 (en) | 2002-02-04 | 2003-12-23 | Hoffmann-La Roche Inc. | Pyridine amido derivatives |
EP1438956A1 (en) | 2003-01-16 | 2004-07-21 | Newron Pharmaceuticals S.p.A. | Alpha-aminoamide derivatives useful as antimigraine agents |
AR044007A1 (es) * | 2003-04-11 | 2005-08-24 | Newron Pharmaceuticals Inc | Metodos para el tratamiento de la enfermedad de parkinson |
EP1524267A1 (en) * | 2003-10-15 | 2005-04-20 | Newron Pharmaceuticals S.p.A. | Substituted benzylaminoalkylene heterocycles |
CN100441188C (zh) | 2003-10-23 | 2008-12-10 | 弗·哈夫曼-拉罗切有限公司 | 作为mao-b抑制剂的苯并氮杂衍生物 |
EP1557166A1 (en) * | 2004-01-21 | 2005-07-27 | Newron Pharmaceuticals S.p.A. | Alpha-aminoamide derivatives useful in the treatment of lower urinary tract disorders |
EP1588704A1 (en) * | 2004-04-22 | 2005-10-26 | Newron Pharmaceuticals S.p.A. | Alpha-aminoamide derivatives useful in the treatment of restless legs syndrome and addictive disorders |
AU2005282028B2 (en) * | 2004-09-10 | 2011-03-24 | Newron Pharmaceuticals S.P.A. | (halobenzyloxy) benzylamino-propanamides as sodium and/or calcium channel selective modulators |
AU2006307953A1 (en) * | 2005-10-26 | 2007-05-03 | Boehringer Ingelheim International Gmbh | (Hetero)aryl compounds with MCH antagonistic activity and medicaments comprising these compounds |
CA2629065C (en) | 2005-12-22 | 2013-08-06 | Newron Pharmaceuticals S.P.A. | 2 -phenylethylamino derivatives as calcium and/or sodium channel modulators |
EP1870097A1 (en) * | 2006-06-15 | 2007-12-26 | Newron Pharmaceuticals S.p.A. | Alpha-aminoamide derivatives useful in the treatment of cognitive disorders |
CA2658246A1 (en) * | 2006-07-28 | 2008-01-31 | Alcon Research Ltd. | Monoamine oxidase inhibitors useful for treating disorders of the outer retina |
SI2155663T1 (en) | 2007-06-15 | 2018-03-30 | Newron Pharmaceuticals S.P.A. | SUBSTITUTED 2- (2- (PHENYL) ETHYLAMINO) ALKANAMIDIC DERIVATIVES AND THEIR USE AS SODIUM AND / OR CALCIUM CHANNEL MODULATORS |
ME02509B (me) * | 2010-04-27 | 2017-02-20 | Newron Pharm Spa | Proces za proizvodnju metansulfonatnih soli ralfinamida ili njihovih r-enantiomera |
CN107709314A (zh) | 2015-06-11 | 2018-02-16 | 巴斯利尔药物国际股份公司 | 外排泵抑制剂及其治疗性用途 |
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GB9306899D0 (en) * | 1993-04-01 | 1993-05-26 | Erba Carlo Spa | Substituted (arylalkylaminobenzyl) aminopropionamide derivatives and process for their preparation |
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CN1047496A (zh) * | 1989-05-25 | 1990-12-05 | 法米塔利亚·卡洛·埃巴有限责任公司 | N-苯烷基取代的α-氨基羧基酰胺衍生物的制备方法 |
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