CN1201455A - 制备1－(2－[2－异噁唑-3-基苯并呋喃－5－基氧基]乙基氨基)－3－苯氧基－2(s)－醇的方法和中间体 - Google Patents
制备1－(2－[2－异噁唑-3-基苯并呋喃－5－基氧基]乙基氨基)－3－苯氧基－2(s)－醇的方法和中间体 Download PDFInfo
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Abstract
一种通过用含水无机酸处理式(Ⅳ)化合物来制备式(Ⅰ)化合物的方法。一种式(Ⅱ)化合物,其中R1为氢且R2和R3一起形成单键或R1和R2一起形成单键且R3为氢或式(Ⅲ)基团。式(Ⅰ)化合物,其可药用盐和前药用作降血糖药和减肥药。它们也用于增加可食动物即有蹄动物和家禽的瘦肉积累和/或改善瘦肉与脂肪比。
Description
本发明涉及下述式I的一些化合物。更详细地说，本发明涉及用于制备式I化合物的方法和中间体。式(I)化合物，其可药用盐和前药用作降血糖药和减肥药。它们也用于增加可食动物即有蹄动物和家禽的瘦肉积累和/或改善瘦肉与脂肪比。
式I化合物及其可药用盐和前药当口服给予高血糖或糖尿病哺乳动物时可有效地降低血液葡萄糖水平。
式I化合物当给予哺乳动物时也减缓体重增长。这些化合物影响体重增加的能力是由于刺激脂肪组织代谢的β-肾上腺素能受体的活化作用。糖尿病的特征在于生产和利用碳水化合物的代谢缺陷，导致不能维持适当的血糖水平。这些缺陷的结果是升高血糖或血糖过多。治疗糖尿病的研究集中在使禁食和饭后血糖水平正常化的努力上。目前治疗包括给予外源性胰岛素，口服给药和饮食治疗。
目前公认两种主要形式的糖尿病。I型糖尿病，或胰岛素依赖性糖尿病，是因绝对缺乏胰岛素(调节碳水化合物利用的激素)引起的。II型糖尿病，或非胰岛素依赖性糖尿病，通常伴有正常或甚至升高的胰岛蓄素水平，并且看起来是组织不能对胰岛素适当反应引起的。大多数II型糖尿病人也是过度肥胖的。
β-肾上腺素能受体可分为β1、β2和β3-亚型。β1受体的活化可引起心率加快，而β2受体活化诱发平滑肌组织松弛，这引起血压下降及平滑肌震颤。β3-受体的活化刺激脂肪分解(肥胖组织甘油三酯分解成甘油和游离脂肪酸)，因此促进胀肪质损失。刺激β3-受体的化合物将具有减肥活性。另外，作为β3-肾上腺素能受体激动剂的化合物有降血糖或抗糖尿病活性，但这种作用机制不清楚。选择性刺激β3-受体，即没有或几乎没有β1或β2活性的化合物将具有抗糖尿病和/或减肥活性，但没有不需要的增加心率(β1-作用)作用或肌肉震颤(β2-作用)作用。然而，因这些药物缺乏对β3-肾上腺素能受体与另两种肾上腺素能受体β1和β2的选择性，β3-肾上腺素能受体激动剂用作抗糖尿病药、降血糖药和减肥药的用途受到限制。式I化合物，其可药用盐和前药是选择性的β3肾上腺素能受体激动剂。式I化合物，其可药用盐和前药记载于未决美国专利申请08/076026中，其转让给本申请受让人并在这里全部并入本文。
本发明涉及用于制备式I化合物的方法和中间体
这里所用的术语“卤”，除非另有指示，包括氯、氟、溴和碘。
这里所用的术语“烷基”，除非另有指示，包括具有直链，支链或环部分或其结合的饱和单价烃基。
这里所用的术语“一种或多种取代基”包括基于可键合部位的数目从一种到最大可能数目的取代基。
这里所用的术语“治疗”包括预防性治疗。
本发明的方法和产物在下面反应路线中举例说明。
路线
路线(续)
参照路线，在碱存在下用苯酚处理化合物1，生成化合物2。用于该步的碱选自碱金属氢化物NaH，和碱金属烷氧化物如叔丁醇钠。在极性非质子溶剂如DMF或THF中实现该反应。优选在DMF中用NaH进行该反应。
在(C1-C6)链烷醇中用C6H5CH2NH(CH2)2处理化合物2，生成化合物3。优选的链烷醇为乙醇。在(C1-C6)链烷醇如乙醇或丙醇中用氢化催化剂如Pd(OH)2/C或Pd/C存在下用氢处理化合物3，生成化合物4。化合物4与羰基化合物如醛或酮反应生成化合物5和6的混合物。用于本发明这部分实施的醛包括脂肪族醛如乙醛和芳香醛如苯甲醛。
使用的酮可举例为脂肪族酮如丙酮和甲乙酮；环烷酮如环己酮和芳烷酮如苯乙酮。优选的羰基化合物为环己酮。在溶剂如(C1-C6)链烷醇，优选甲醇中进行反应。
在适当的三烷基膦或三芳基膦如(C4H9)3P或(C6H5)3P，或承载于聚合物上的(C6H5)3P(例如承载的(C6H5)3P聚合物，Aldich Cat.No36,645-5，其为每克树脂含3mmol亚磷的2％二乙烯基苯交联聚苯乙烯)存在下用化合物7和偶氮二羰基二烷氧化物如偶氮二羰基二丙氧化物或二乙氧化物，或二胺如偶氮二羰基二哌啶分别处理化合物5或6，或其混合物，生成化合物8。在溶剂如苯，甲苯或THF中进行反应。优选的溶剂为甲苯。按照美国申请序列号08/076026中的方法制备化合物7。
用含水无机酸处理化合物8，生成化合物1。使用的无机酸包括HCL，H2SO4，NaHSO4，HBr和H4PO4。优选的无机酸为NaHSO4。
当式I化合物和其可药用盐(此后称为“活性化合物”)经口服或非肠道给予哺乳动物(包括人)时，对于治疗糖尿病和/或高血糖症一般得到满意效果。为更方便且避免注射可能引起的疼痛与刺激，口服给药是优选的。然而，因疾病或其它异常，在病人不能吞咽药物，或口服给药后吸收减少时，非肠道给药也是必要的。无论哪种给药途径，单剂量或多剂量给药的剂量范围为大约0.01-约50mg/kg患者体重/天，优选约0.1-25mg/kg体重/天。然而，被治疗个体患者的最佳剂量由负责治疗的医生决定，一般最初给予小剂量，随后增加以决定最合适剂量。这将根据所用特定化合物及待治疗患者变化。
当单独治疗肥胖或治疗结合糖尿病和/或高血糖症的肥胖时，以日剂量0.01毫克-约50毫克/千克动物体重，优选每天分四次给药，或以持续释放形式，给予活性化合物时，一般得到满意效果。对大多数哺乳动物来说，日总剂量为约0.1毫克-约6000毫克，优选约1毫克-约1500毫克。对于体重70千克成人，日总剂量一般为约0.1毫克-约1500毫克。可调节该剂量方案以达到最佳治疗反应。
活性化合物与可药用载体或稀释剂一起使用。适当的可药用载体包括惰性固体填充剂或稀释剂和灭菌水溶液或有机溶液。活性化合物以足以提供所需的上述范围剂量存在于药物组合物中。这样，对口服给药来说，化合物可与适当的固体或液体载体或稀释剂结合形成胶囊，片剂，粉末剂，糖浆，溶液，悬浮液等。如果需要，药物组合物可含其它成分如调味剂，增甜剂、赋形剂等。
片剂，丸剂，胶囊等也可含有粘合剂如黄著胶，阿拉伯胶，玉米淀粉或明胶；赋形剂如磷酸二钙；崩解剂如玉米淀粉，马铃薯淀粉，藻酸，润滑剂如玉米淀粉，马铃薯淀粉，藻酸，润滑剂如硬脂酸镁；甜味剂如蔗糖，乳糖或糖精。当剂型为胶囊时，除上述类型材料外，也可含液体载体如脂肪油。
其它不同材料可以作为包衣或为改变剂量单位的物理形式而存在。例如，可用虫胶，糖或两者包衣片剂。糖浆或酏剂除含上述活性成分外，可含作为甜味剂的蔗糖，作为防腐剂的对羟基苯甲羧甲酯和丙酯，染料和调味剂如樱桃味或橙味调味剂。
活性化合物也可经非肠道给药。对非肠道给药来说，活性化合物可与灭菌水或有机介质结合形成可注射溶液或悬浮液。在适当混有表面活性剂如羟基丙基纤维素的水中可制备这些活性化合物的溶液或悬浮液。也可在芝麻油或花生油，乙醇，水，多元醇(如甘油，丙二醇和液态聚乙二醇)，其适当混合物哦，植物油，N-甲基葡萄胺，聚乙烯基吡咯烷酮和其在油中的混合物以及化合物水溶性药用盐的水溶液中制备分散液。在一般贮存和使用条件下，这些制剂含有防腐剂以防止微生物生长。按这种方式制备的可注射溶液然后可经静脉内、腹膜内、皮下或肌内给药，肌内给药是人优选的人类非肠道给药途径。
适于注射使用的药物剂型包括灭菌水溶液或分散液和当场制备可注射灭菌溶液或分散液的灭菌粉末。无论如何，剂型必须灭菌并且必须有一定的流动性以便容易注射。在生产和贮存条件下它必须稳定且必须耐微生物如细菌和真菌的污染。
所用活性成分的有效剂量可根据所用特定化合物，给药方式，待治疗的疾病以及待治疗疾病的病情而变化。
活性化合物也用于增加瘦肉积累和/或改善可食动物即有蹄动物和家禽的瘦肉与脂肪比。
一般通过混合本发明化合物和足量动物饲料使饲料中化合物占约10-3-500ppm来制备有效提高家禽，猪，羊，山羊，家庭宠物和牛的瘦肉积累和改善瘦肉与脂肪比的动物饲料组合物。
通过将约75％-95％重量份的活性化合物和约5％-约25％重量份的适当载体或稀释剂混合可制备动物饲料添加剂。适用于组成饲料添加剂组合物的载体包括下面：菌蓿粉、大豆粉、棉籽油粉、亚麻子油饼粉、氯化钠、玉米粉、罐糖蜜、脲素、骨粉、玉米穗轴粉等。载体促使活性成分均匀分散在混入添加剂的最终饲料中。因此，它对保证活性成分适当分散在饲料中起了重要作用。
如果添加剂用作饲料的顶肥，它同样有助于保证活性物质均匀分布在顶肥饲料中。
优选的含有药物的猪、牛、羊和山羊饲料一般每吨饲料含0.01-400克活性成分，对这些动物来说最佳量通常为每吨饲料含大约50-300克。
优选的家禽和家庭宠物饲料通常每吨饲料含约0.01-400克，优选10-400克活性成分。
对于动物的非肠道给药来说，可以糊剂或丸剂形式制备活性化合物并以植入物形式给药，通常在寻求瘦肉积累增加且瘦肉与脂肪比改善的动物的头或耳部的皮肤下给药。
一般来说，非肠道给药包括注射足量的活性化合物以供给动物0.01-100毫克/千克体重/天的活性成分。猪、牛、羊和山羊的优选剂量为0.01-50毫克/千克体重/天活性成分；而家禽和家庭宠物的优选剂量水平范围通常为0.01-35毫克/千克体重/天。
可通过将活性成分分散在可药用油如花生油、芝麻油，玉米油等中来制备糊剂。
可通过将有效量活性成分和稀释剂如聚乙二醇，巴西棕榈蜡等混合制备含有效量活性成分的丸剂，润滑剂如硬脂酸镁或硬脂酸钙可加入以改善成丸过程。
当然可给动物不只一粒丸剂以达到所需剂量水平，它将使瘦肉积累增加并改善所需的瘦肉与脂肪比。而且，已发现为了维持动物体内适当的药物水平在动物治疗期间也可定期放入植入物。
活性化合物有几个有利特征。对于希望增加瘦肉且减少宠物多余胆肪的所有者或兽医来说，活性化合物提供了可实现这个目的的手段。对于家禽饲养者和养猪人来说，活性化合物和使用生产出较瘦的动物，它控制肉食工业较高的价格。
在Hewlett packard 5890 GC连接Hewltt Packard Model 5971 AMass Selective Detector上用HP-112米毛细管柱上进行GC MS’S。柱条件如下：初温，133℃；升温速率19℃/分；终温310℃。
在Bruker AM-250MHz分光计上进行NMR’s。
在Hewlett Packard 5989质谱仪上进行MS，粒子束(Cl)+，捕获离子为(M+1)+。
实施例1
(S)-1，2-环氧-3-苯氧基丙烷
向0℃ 80.0克(0.85mol)苯酚的150mIDMF中分批加入37.4克(0.94mol，1.1当量)氢化钠(按重量计60％矿物油分散液)。1.5小时后向反应浆液中分二批加入220克(0.85mol)3-硝基苯磺酸(S)-缩水甘油酯〔(3-硝基苯磺酸(2S)-缩水甘油酯)，从Seprachem(Marisborogh，MA01762)购得〕。室温下搅拌反应混合物过夜。均一反应混合物的TLC分析表示反应实质上已进行完全。将反应混合物冷却至0℃，用500ml饱和氯化铵水溶液使反应停止。然后用2升乙酸乙酯和500ml水稀释混合物。分离有机相，用1升乙酸乙酯萃取水相三次。用盐水洗合并的有机物，然后用硫酸钠干燥。然后在室温下真空除去挥发物，在约45℃同时保持真空下除去DMF。粗品油无需另外纯化即可直接用于下一步(假设理论产率)。
TLC(硅胶)R9＝0.80(60∶40％己烷/乙酯乙酯)
GCMS C9H10O2(M+)＝150，t1＝1.46min.
1HNMR(CDCl3)δ7.26-7.33(m，2H)，6.91-7.00(m，3H)，4.18-4.24(m，1H)，3.91-3.87(m，1H)，3.31-3.38(m，1H)，2.87-2.91(m，1H)，2.73-2.77(m，1H).
实施例2
(S)-1-〔苄基-2-羟基-乙基)-氨基〕-3-苯氧基-丙-2-醇
用300ml乙醇稀释前述的粗品油(0.85mol)，然后用125ml(0.88mol，1.04当量)N-苄基乙醇胺处理。于50℃加热反应混合物过夜，期间TLC分析表明反应进行完全。溶液直接用于下一步(假定理论产率)。
此时浓缩样品，用于分析：
TLC(硅胶)Rf＝0.50(95∶5二氯甲烷/甲醇)GCMS：C18H23NO3(M+)＝301，t1＝7.29min.1H NMR(CD3OD)δ7.17-7.36(m，7H)，6.85-6.93(m，3H)，3.93-4.03(m，2H)，3.80-3.87(m，1H)，3.70(s，2H)，3.55-3.65(m，2H)，2.60-2.77(m，4H).
实施例3
(S)-1-〔2-羟基-乙基)-氨基〕-3-苯氧基-丙-乙醇
向0.85mol上述制备的实施例2的标题产品的乙醇溶液中加入(0.0克20％氢氧化钯/C。在Parr仪中于50PSI氢化后，TLC分析表明原料已消耗掉。通过Celite床过滤除去催化剂。然后用1升乙腈稀释反应混合物，用250ml己烷洗三次以除去在实施例1中随氢化钠一起加入的矿物油。真空除去挥发物，残余物溶于1升乙酸乙酯中。冷却至0℃时，固体沉淀。从700ml4：3己烷/乙酸乙酯中第二次收获得到共148克标题化合物，其为白色固体(以实施例1中所用的3-硝基苯磺酸(S)-缩水甘油酯计共83％)。TLC(硅胶)Rf＝0.50(80∶20二氯甲烷/甲醇)。
GCMS：C11H17NO3(M+)＝211，t1＝4.32min.
1H NMR(CD3OD)δ7.21-7.28(m，2H)，6.91-6.94(m，3H)，4.02-4.18(m，1H)3.93-3.95(m，2H)，3.61-3.76(m，2H)，2.68-2.92(m，4H).
实施例4
(S)-2-(2-苯氧基甲基-1-氧杂-4-氮杂-螺〔4，5〕癸-4-基)乙醇(1)和(S)-1-(1-氧杂-4-氮杂-螺〔4，5〕癸-4-基)-3-苯氧基-丙-2-醇(2)
向3.0克(14.2mmol)实施例3的标题产品在35ml甲醇中的溶液中加入2.95ml(28.6ml，2.0当量)环巳酮。搅拌过夜后，GCMS分析表明原料已消耗掉。真空除去挥发物，随后用甲苯共沸除去痕量甲醇。1H NMR表明(1)与(2)的比大约为2.5∶1。粗产物(含痕量环己酮)无需纯化而直接用于下步。
GCMS：C17H25NO3(M+)＝291，t1＝6.51min(两个化合物).
(1)鉴定信号
1H NMR(CD3OD)δ4.30-4.42(m，1H)，3.59-3.67(m，2H)，3.16-3.26(m，1H)2.95-3.02(m，1H)，2.61-2.69(m，2H).
(2)鉴定信号
1H NMR(CD3OD)δ3.80-3.89(m，2H)，3.05-3.13(m，2H).
实施例5
1-(2-〔2-异噁唑-3-基苯并呋喃-5-基氧基〕乙基氨基)-3-苯氧基-2(S)-醇
向685mg(2.35mmol，2.0当量)实施例4标题产物的混合物(来自上步)在15ml甲苯中的溶液中加入238mg(1.18mmol，1.0当量)5-羟基-2-〔1，2，4〕噁二唑-3-基苯并尿甾(benzouran)(按照美国专利申请序列号08/076026中方法制备)，600mg(2.35mmol，2.0当量)偶氮二羰基二哌啶，随后加入616mg(2.35mmol，2.0当量)三苯基膦。搅拌反应混合过夜。滤出固体(还原的偶氮衍生物)，真空从滤液中除去挥发物。然后用15ml3：1己烷/乙酸乙酯研磨残余物，滤出固体(三苯基膦)。然后真空除去滤液中挥发物，用15ml 10％硫酸氢钠水溶液处理含(S)-4-〔2-(2-[1，2，4]噁二唑-3-基苯并尿甾-5基氧基)-乙基〕-苯氧基甲基-1-氧杂-4-氮杂-螺〔4.5〕癸烷的残余物以裂开噁唑烷基并形成标题化合物。用饱和碳酸氢钠水溶液中和，随后用15ml乙酸乙酯萃取3次，用硫酸钠干燥，真空除去挥发物。用硅胶色谱分离残余物，用95∶5乙酸乙酯/甲醇洗脱。合并并真空蒸发含产物的馏分，得到310mg(66％)标题产物，其为白色固体。
TLC(硅胶Rf＝0.20(95∶5乙酸乙酯/甲醇)
MS：C21H21N3O5(M+1)+＝396
1H NMR(DMSO-d6)δ9.79(s，1H)，7.62-7.66(m，2H)，7.22-7.29(m，3H)，7.06-7.10(m，1H)，6.90-6.93(m，3H)，4.05-4.09(m，2H)，3.86-3.96(m，3H)，2.91-2.96(m，2H)，2.60-2.82(m，2H).
实施例6
(S)-4-〔2-(2-[1，2，4]噁二唑-3-基苯并尿甾-5-基氧基)-乙基〕-苯氧基甲基-1-氧杂-4-氮杂-螺〔4，5〕癸烷
由于标题化合物固有的不稳定及在未纯化的反应混合物中不能彻底地定义它，通过用甲醇中1.0当量环己酮处理上面制备的实施例5标题化合物制备较纯样品。真空蒸发挥发物，得到标题产物，用于进一步分析。
MS：C27H29N3O5(M+1)+＝476
Claims (8)
1.式II化合物
其中R1为氢且R2和R3一起构成单键或R1和R2一起构成单键且R3为氢或式III的基团
2.权利要求1的化合物，其中R1和R2一起构成单键，R3为式III的基团。
3.权利要求1的化合物，其中R1和R2一起构成单键，R3为氢。
4.权利要求1的化合物，其中R2和R3一起构成单键，R1为式III的基团。
5.一种制备式I化合物的方法，
其包括用含水无机酸处理式IV化合物
6.权利要求5的方法，其中在氮杂二羰基二哌啶及三苯基磷存在下通过用式VII化合物
处理式V或VI的化合物或其混合物来制备式IV化合物
7.权利要求6的方法，其中通过用环己酮处理式VIII化合物
来制备式V和VI化合物的混合物。
8.一种制备式I化合物的方法，
其包括下面步骤：
a)用环己酮处理式VIII化合物
生成式V和VI化合物的混合物；
b)用式VII化合物
处理式V或VI化合物或其混合物，得到式IV化合物
和c)用含水无机酸处理式IV化合物得到式I化合物。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US815395P | 1995-10-31 | 1995-10-31 | |
| US60/008,153 | 1995-10-31 |
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| Publication Number | Publication Date |
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| CN1201455A true CN1201455A (zh) | 1998-12-09 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN96198046A Pending CN1201455A (zh) | 1995-10-31 | 1996-08-15 | 制备1－(2－[2－异噁唑-3-基苯并呋喃－5－基氧基]乙基氨基)－3－苯氧基－2(s)－醇的方法和中间体 |
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| EP (1) | EP0861240A1 (zh) |
| JP (1) | JPH10513480A (zh) |
| KR (1) | KR19990067172A (zh) |
| CN (1) | CN1201455A (zh) |
| AU (1) | AU6628596A (zh) |
| BR (1) | BR9611217A (zh) |
| CA (1) | CA2234081A1 (zh) |
| CZ (1) | CZ130898A3 (zh) |
| HR (1) | HRP960502A2 (zh) |
| HU (1) | HUP9900090A3 (zh) |
| IL (1) | IL123623A0 (zh) |
| PL (1) | PL327997A1 (zh) |
| TR (1) | TR199800710T2 (zh) |
| WO (1) | WO1997016432A1 (zh) |
| YU (1) | YU57396A (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102736513A (zh) * | 2011-03-29 | 2012-10-17 | 通用电气公司 | 包括冗余性的hart信道接口部件 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2653464B1 (en) | 2012-04-20 | 2017-09-27 | Rohm and Haas Company | Benzylamine hydrophobe |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| PL312005A1 (en) * | 1993-06-14 | 1996-04-01 | Pfizer | Binary amines as antidiabetic and antiobesitic agents |
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1996
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- 1996-08-15 JP JP9506054A patent/JPH10513480A/ja active Pending
- 1996-08-15 KR KR1019980703123A patent/KR19990067172A/ko not_active Application Discontinuation
- 1996-08-15 EP EP96925934A patent/EP0861240A1/en not_active Withdrawn
- 1996-08-15 WO PCT/IB1996/000803 patent/WO1997016432A1/en not_active Application Discontinuation
- 1996-08-15 AU AU66285/96A patent/AU6628596A/en not_active Abandoned
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- 1996-08-15 HU HU9900090A patent/HUP9900090A3/hu unknown
- 1996-08-15 CA CA002234081A patent/CA2234081A1/en not_active Abandoned
- 1996-08-15 PL PL96327997A patent/PL327997A1/xx unknown
- 1996-08-15 CN CN96198046A patent/CN1201455A/zh active Pending
- 1996-10-29 HR HR60/008,153A patent/HRP960502A2/hr not_active Application Discontinuation
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102736513A (zh) * | 2011-03-29 | 2012-10-17 | 通用电气公司 | 包括冗余性的hart信道接口部件 |
Also Published As
| Publication number | Publication date |
|---|---|
| YU57396A (sh) | 1998-11-05 |
| HUP9900090A2 (hu) | 1999-10-28 |
| IL123623A0 (en) | 1998-10-30 |
| AU6628596A (en) | 1997-05-22 |
| MX9803497A (es) | 1998-09-30 |
| WO1997016432A1 (en) | 1997-05-09 |
| HUP9900090A3 (en) | 1999-11-29 |
| KR19990067172A (ko) | 1999-08-16 |
| EP0861240A1 (en) | 1998-09-02 |
| HRP960502A2 (en) | 1998-04-30 |
| CA2234081A1 (en) | 1997-05-09 |
| CZ130898A3 (cs) | 1999-03-17 |
| TR199800710T2 (xx) | 1998-08-21 |
| BR9611217A (pt) | 1999-04-06 |
| PL327997A1 (en) | 1999-01-04 |
| JPH10513480A (ja) | 1998-12-22 |
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