CN101300006B - 用于治疗肥胖的mao-b抑制剂 - Google Patents
用于治疗肥胖的mao-b抑制剂 Download PDFInfo
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- CN101300006B CN101300006B CN2006800273036A CN200680027303A CN101300006B CN 101300006 B CN101300006 B CN 101300006B CN 2006800273036 A CN2006800273036 A CN 2006800273036A CN 200680027303 A CN200680027303 A CN 200680027303A CN 101300006 B CN101300006 B CN 101300006B
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Abstract
本发明提供式(I)和(II)的新型化合物
Description
相关申请的交叉参考
本申请要求在2005年6月2日提交的正在审理的第60/686,585号美国临时申请的优先权,其在此被引入作为参考。
技术领域
本申请涉及化合物和其药物组合物及利用它们治疗肥胖的方法。更具体地,本发明涉及使用MAO-B抑制剂治疗肥胖的新方法。
背景技术
左旋司来吉兰(L-Selegiline)是单胺氧化酶(monoamine oxidase,MAO)抑制剂,其被开发用于治疗神经系统紊乱并且主要用于治疗帕金森病(Parkinson′s disease)。MAO是一种酶,负责代谢生物单胺,包括5-羟色胺、多巴胺、组胺和苯乙胺。通过抑制位于中枢神经系统(central nervous system,CNS)内的MAO,MAO抑制剂和其类似物增加了脑突触内存在的单胺的浓度。这增强了单胺调节的神经传递,有效地治疗神经系统紊乱,例如帕金森病和抑郁症。
MAO酶也位于许多周边(非CNC)组织内,其包括脂肪细胞,即包含人体脂肪的细胞。脂肪细胞内MAO酶的功能还没有被证实。目前,左旋司来吉兰和其它MAO抑制剂唯一批准的临床应用是治疗神经系统紊乱,例如帕金森病和抑郁症。
肥胖与脂肪细胞组织(即,人体脂肪)总量的增加有关,尤其是位于腹部区域的脂肪细胞组织。肥胖在美国已经达到流行病的比例。近年来肥胖流行程度在所有人种和种族间稳步上升。根据美国外科总署(United States SurgeonGeneral),61%的成年人和14%的儿童肥胖或超重。四千四百万美国人肥胖,其中还有八百万人在医学上被视为超重。在美国,肥胖每年导致超过300,00人死亡,并且将很快超过作为可预防死亡的主要原因的吸烟。肥胖是慢性病,其直接引起许多危险的共发病,包括2型糖尿病、心血管疾病、炎症、过早衰老和某些形式的癌症。2型糖尿病目前在美国是第七大死亡原因,它是一种严重的且危及生命的 疾病,其在成年人和儿童中的患病率呈增长趋势。因为80%以上的2型糖尿病患者超重,所以肥胖就成为发展2型糖尿病的最大危险因子。越来越多的临床证据表明,控制2型糖尿病的最佳途径是减轻体重。
由于安全方面的顾虑,治疗肥胖最受欢迎的非处方药——苯丙醇胺和麻黄素,以及最受欢迎的处方药——氟苯丙胺被退出市场。目前批准的长期治疗肥胖的药物分为两类:(a)中枢神经系统(CNS)食欲抑制剂,例如西布曲明(sibutramine),和(b)肠道脂肪酶抑制剂,如奥利司他(orlistat)。CNS食欲抑制剂通过激活脑内的“饱中枢”和/或抑制脑内的“饥饿中枢”来减少饮食行为。肠道脂肪酶抑制剂减少来自胃肠道(GI)的膳食脂肪的吸收。尽管西布曲明和奥利司他的工作机理非常不同,但它们共同具有相同的总目标,即降低体重,但首要的是减少到达体循环的卡路里量。遗憾的是,这些间接疗法产生的只是有限的初始体重下降(与使用安慰剂的大约2%相比,其为大约5%),其通常维持不下去。治疗一年或两年之后,大部分患者回到或超过他们原来的重量。此外,大部分被批准的抗肥胖疗法产生不期望的并且经常为危险的副作用,这可能使治疗复杂化并且影响了患者的生活质量。
缺乏治疗效果与螺旋上升的肥胖流行病一起使得“肥胖的治疗”成为最重大且最紧迫的未满足的医疗需要之一。因此真正且持续地需要开发治疗或预防肥胖的改进药物。
一般的MAO-B抑制剂如司来吉兰已经在临床上用于治疗CNS病症。现在出乎意料地发现它们也具有抗肥胖活性。甚至更令人惊讶的是,由这些药剂调节的抗肥胖活性在CNC之外。这个新发现为肥胖的预防或治疗提供了新方法。此外,如果这些化合物的CNS作用能够消除,它们周边调节的抗肥胖特性应当提供更安全的治疗药剂。因此,高度期望发现具有有限或没有CNS作用的MAO-B抑制剂。这种化合物有望用于治疗肥胖和及其引起的并发症种类。
发明内容
因此,一方面,本发明提供新型MAO-B抑制剂或制药上可接受的盐,其用于治疗肥胖、糖尿病和/或心脏代谢紊乱(例如过度紧张、血脂异常、高血压和胰岛素抗性)。
另一方面,本发明提供新型药物组合物,其包括:制药上可接受的载体和治疗上有效量的本发明所述的至少一种化合物或其制药上可接受的盐形式。
另一方面,本发明提供治疗肥胖、糖尿病和/或心脏代谢紊乱(例如过度紧张、血脂异常、高血压和胰岛素抗性)的新方法,其包括:给予需要的患者治疗上有效量的本发明所述的至少一种化合物或其制药上可接受的盐形式。
另一方面,本发明提供治疗CNS紊乱的新方法,其包括给予需要的患者治疗上有效量的本发明所述的至少一种化合物或其制药上可接受的盐形式。
另一方面,本发明提供新型化合物的制备方法。
另一方面,本发明提供用于治疗的新型化合物或制药上可接受的盐。
另一方面,本发明提供新型化合物在制备用于治疗肥胖、糖尿病和/或心脏代谢紊乱的药物上的用途。
本发明人的发现——目前要求保护的化合物或其制药上可接受的盐形式有望是有效的MAO-B抑制剂——已经实现了这些和其它目标,这在下面详述的描述中将变得明显。
发明详述
本发明是基于下述意想不到的发现:MAO-B抑制剂能够减少温血动物内脂肪细胞组织(即,人体脂肪)的量。这个发现是意想不到的,因为人体脂肪可以被减少,尽管很少,若有的话,要伴随着食物摄取的减少。
在一个实施方式中,本发明提供新型化合物A或其立体异构体或制药上可接受的盐:
其中,Q、R、R1、W、X、X1、X2和X3均独立地选自H和能够减少或限制化合物A的CNS活性的基团;并且
条件是:Q、R、R1、W、X、X1、X2和X3中至少一个不是H。
在另一个实施方式中,本发明提供式I或II的新型化合物或其立体异构体或制药上可接受的盐:
其中:
R,在各种情况下,独立地选自H、C1-6烷基、C2-6链烯基和C2-6炔基;
R1选自H、C1-6烷基、C2-6链烯基、C2-6炔基、(CH2)mCO2R、C2-6链烯基-CO2R、CH2CH(NHAc)CO2R、CH2CH(NHR)CO2R和(CH2)nPO(OR)2;
A-是抗衡离子;
V选自O-、C1-4烷基、C2-4链烯基和C2-4炔基;
X、X1、X2和X3独立地选自H、OR、C1-6烷基、C2-6链烯基、C2-6 炔基、卤素、CF3、硝基、-CN、N(R)2、(CH2)m-四唑、(CH2)nCO2R、(CH2)nCONR2、(CH2)nCN、O(CH2)nCN、O(CH2)n-四唑、O(CH2)nCO2R、O(CH2)nCON(R)2、O-C2-6 链烯基-CO2R、O(CH2)nPO(OR)2、NR-C2-4链烯基、NRSO2CH3、NR(CH2)nCO2R、NR(CH2)nCON(R)2、NR-C2-4链烯基-CO2R、NR(CH2)nPO(OR)2、NR(CH2)nSO2OR、NR(CH2)n-四唑、SO2NRCH3、OCH2CHMCONRCH2CO2R、CH2-芳基、O(CH2)nPO(OR)2、O(CH2)nSO2OR、OCH2(CH2)nN+(CH3)3A-、O(CH2)n-联苯基、O(CH2)n-联苯基-(CH2)mCO2R、O(CH2)n-联苯基-(CH2)m四唑、O(CH2)n-联苯基-(CH2)mCN、O(CH2)n-联苯基-(CH2)mCON(R)2、NR(CH2)n-联苯基、NR(CH2)n-联苯基-(CH2)mCO2R、NR(CH2)n-联苯基-(CH2)m四唑、NR(CH2)n-联苯基-(CH2)mCN、NR(CH2)n-联苯基-(CH2)mCON(R)2、O(CH2)n-芳基、O(CH2)n-杂芳基、NR(CH2)n-芳基、NR(CH2)n-杂芳基、O(CH2)n-芳基(CH2)mCO2R、O(CH2)n-芳基-C2-6链烯基-CO2R、O(CH2)n-芳基(CH2)m-四唑、O(CH2)n-芳基(CH2)mCN、O(CH2)n-芳基(CH2)mCON(R)2、 O(CH2)n-芳基(CH2)m-PO(OR)2、O(CH2)n-芳基-O(CH2)nCO2R、O(CH2)n-基-O-C2-6 链烯基-CO2R、O(CH2)n-芳基O(CH2)n-四唑、O(CH2)n-芳基O(CH2)nCN、O(CH2)n-芳基O(CH2)nCON(R)2、O(CH2)n-芳基O(CH2)n-PO(OR)2、O(CH2)n-芳基-NR(CH2)nCO2R、O(CH2)n-芳基-NRC2-6链烯基-CO2R、O(CH2)n-芳基-NR(CH2)n-四唑、O(CH2)n-芳基-NR(CH2)nCN、O(CH2)n-芳基-NR(CH2)nCON(R)2、O(CH2)n-芳基-NR(CH2)n-PO(OR)2、NR(CH2)n-芳基(CH2)mCO2R、NR(CH2)n-芳基-C2-6链烯基-CO2R、NR(CH2)n-芳基(CH2)m-四唑、NR(CH2)n-芳基(CH2)mCN、NR(CH2)n-芳基(CH2)mCON(R)2、NR(CH2)n-芳基(CH2)m-PO(OR)2、NR(CH2)n-芳基-NR(CH2)nCO2R、NR(CH2)n-芳基-NR-C2-6链烯基-CO2R、NR(CH2)n-芳基-NR(CH2)n-四唑、NR(CH2)n-芳基-NR(CH2)nCN、NR(CH2)n-芳基-NR(CH2)nCON(R)2、NR(CH2)n-芳基-NR(CH2)nPO(OR)2、NR(CH2)n-芳基O(CH2)nCO2R、NR(CH2)n-芳基-O-C2-6链烯基-CO2R、NR(CH2)n-芳基-O(CH2)n-四唑、NR(CH2)n-芳基O(CH2)nCN、NR(CH2)n-芳基-O(CH2)nCON(R)2、NR(CH2)n-芳基O(CH2)nPO(OR)2、O(CH2)n-杂芳基(CH2)mCO2R、O(CH2)n-杂芳基-C2-6链烯基-CO2R、O(CH2)n-杂芳基(CH2)m-四唑、O(CH2)n-杂芳基-O(CH2)mCN、O(CH2)n-杂芳基(CH2)mCON(R)2、O(CH2)n-杂芳基(CH2)m-PO(OR)2、O(CH2)n-杂芳基-O(CH2)nCO2R、O(CH2)n-杂芳基-O-C2-6链烯基-CO2R、O(CH2)n-杂芳基O(CH2)n-四唑、O(CH2)n-杂芳基O(CH2)nCN、O(CH2)n-杂芳基O(CH2)nCON(R)2、O(CH2)n-杂芳基O(CH2)n-PO(OR)2、O(CH2)n-杂芳基-NR(CH2)nCO2R、O(CH2)n-杂芳基-NR-C2-6链烯基-CO2R、O(CH2)n-杂芳基-NR(CH2)n-四唑、O(CH2)n-杂芳基-NR(CH2)nCN、O(CH2)n-杂芳基-NR(CH2)nCON(R)2、O(CH2)n-杂芳基-NR(CH2)n-PO(OR)2,、NR(CH2)n-杂芳基(CH2)mCO2R、NR(CH2)n-杂芳基-C2-6链烯基-CO2R、NR(CH2)n-杂芳基(CH2)m-四唑、NR(CH2)n-杂芳基(CH2)mCN、NR(CH2)n-杂芳基(CH2)mCON(R)2、NR(CH2)n-杂芳基(CH2)m-PO(OR)2、NR(CH2)n-杂芳基-NR(CH2)nCO2R、NR(CH2)n-杂芳基-NR-C2-6链烯基-CO2R、NR(CH2)n-杂芳基-NR(CH2)n-四唑、NR(CH2)n-杂芳基-NR(CH2)nCN、NR(CH2)n-杂芳基-NR(CH2)nCON(R)2、NR(CH2)n-杂芳基-NR(CH2)nPO(OR)2、NR(CH2)n-杂芳基-O(CH2)nCO2R、NR(CH2)n-杂芳基-O-C2-6链烯基-CO2R、NR(CH2)n-杂芳基-O(CH2)n-四唑、NR(CH2)n-杂芳基-O(CH2)nCN、NR(CH2)n-杂芳基-O(CH2)nCON(R)2、NR(CH2)n-杂芳基O(CH2)nPO(OR)2,其中杂芳基是5-12元环体系,该环体系由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S,并且其中芳基和杂芳基被1-2个X4取代和四唑被0-1个R取代;
X4选自H、OR、O-C2-6链烯基、C1-6烷基、C2-6链烯基、C2-6炔基、卤素、CF3、硝基、-CN、C(O)NR2、NRSO2CH3和SO2N(R)C1-6烷基;
Q选自H、OH、C1-6烷氧基、O(CH2)nCO2R、O(CH2)nCON(R)2、O-C2-6 链烯基、O-C2-6链烯基-CO2R、OCH2CH2CONRCH2CO2R、OCH2CHMCONRCH2CO2R、O(CH2)nPO(OR)2、O(CH2)nSO2OR、OCH2CH(NHAC)CO2R、OCH2CH(NHR)CO2R、O(CH2)n-芳基和O(CH2)n-5-12元杂芳基,所述杂芳基由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S;
W选自H、CO2R、CON(R)2、CH2OH、CH2OC1-6烷基、CH2OC2-6 链烯基、CH2O(CH2)nCO2R、CH2O(CH2)nCON(R)2、CH2O-C2-6链烯基-CO2R、CH2OCH2CH2CONRCH2CO2R、CH2OCH2CHMCONRCH2CO2R、CH2O(CH2)nPO(OR)2、CH2O(CH2)nSO2OR、CH2OCH2CH(NHAc)CO2R、CH2OCH2CH(NHR)CO2R、CH2O-C2-6链烯基和CH2O(CH2)nCONH2、CH2O(CH2)n-芳基和CH2O(CH2)n-5-12元杂芳基,所述杂芳基由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S,并且其中杂芳基被1-2个X4取代;
M独立地选自H、C1-6烷基、C3-8环烷基、C2-6链烯基、C2-6炔基、芳基、(CH2)n-芳基、杂芳基和(CH2)n-杂芳基,其中杂芳基是5-12元环体系,该环体系由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S,并且其中芳基和杂芳基被1-2个X4取代;
m独立地选自0、1、2、3和4;和
n独立地选自1、2、3和4;
条件是:X、X1、X2和X3中至少一个不是H、烷基、烷氧基、羟基和卤。
在另一变体中,本发明的化合物具有不大于一个的酸官能度。
在另一个实施方式中,本发明提供式I1或II1的新型化合物或其立体异构体或制药上可接受的盐:
在另一个实施方式中,本发明提供式I a的新型化合物或其立体异构体或制药上可接受的盐:
其中:
R,在各种情况下,独立地选自H和C1-4烷基;
R1选自H和C1-4烷基;
X和X1独立地选自H、OR、C1-4烷基、C2-4链烯基、C2-4炔基、卤素、CF3、硝基、-CN、O(CH2)nCON(R)2、O-C2-4链烯基、N(R)2、NRSO2CH3、SO2NRCH3、CH2N(C1-4烷基)2、CH2-芳基、CH2-杂芳基、O(CH2)n-芳基、O(CH2)n-杂芳基、NR(CH2)n-芳基、NR(CH2)n-杂芳基、O(CH2)n-芳基-(CH2)mCON(R)2、O(CH2)n-芳基-O(CH2)nCON(R)2、O(CH2)n-芳基-NR(CH2)nCON(R)2、O(CH2)n-杂芳基-(CH2)mCON(R)2、O(CH2)n-杂芳基-O(CH2)nCON(R)2、O(CH2)n-杂芳基-NR(CH2)nCON(R)2、NR(CH2)n-芳基-(CH2)mCON(R)2、NR(CH2)n-芳基-O(CH2)nCON(R)2、NR(CH2)n-芳基-NR(CH2)nCON(R)2、NR(CH2)n-杂芳基-O(CH2)nCON(R)2、NR(CH2)n-杂芳基-(CH2)mCON(R)2、NR(CH2)n-杂芳基-NR(CH2)nCON(R)2、O(CH2)n-联苯基、O(CH2)n-联苯基-CN、O(CH2)n-联苯基-CONH2、NR(CH2)n-联苯基、NR(CH2)n-联苯基-CN和NR(CH2)n-联苯基-CONH2,其中杂芳基是5-10元环体系,该环体系由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S,并且其中芳基和杂芳基被1-2个X4取代;
X4选自H、OH、C1-4烷氧基、C1-4烷基、C2-4链烯基、C2-4炔基、卤素、CF3、硝基、-CN、C(O)NR2、NRSO2CH3和SO2N(R)C1-6烷基;
n独立地选自1、2和3;
条件是:X和X1中至少一个不是H、烷基、烷氧基、羟基和卤。
[3a]在另一个实施方式中,本发明提供式Ia的新型化合物或其立体异构体或制药上可接受的盐,其中:
X和X1中一个是H并且另一个选自OH、C1-4烷基、C2-4链烯基、C2-4炔基、卤素、CF3、硝基、-CN、C1-4烷氧基、O(CH2)nCON(R)2、O-C2-4链烯基、N(R)2、NRSO2CH3、SO2NRCH3、CH2N(C1-4烷基)2、CH2-芳基、CH2-杂芳基、O(CH2)n-芳基、O(CH2)n-杂芳基、NR(CH2)n-芳基、NR(CH2)n-杂芳基、O(CH2)n-芳基-(CH2)mCON(R)2、O(CH2)n-芳基-O(CH2)nCON(R)2、O(CH2)n-芳基-NR(CH2)nCON(R)2、O(CH2)n-杂芳基-(CH2)mCON(R)2、O(CH2)n-杂芳基-O(CH2)nCON(R)2、O(CH2)n-杂芳基-NR(CH2)nCON(R)2、NR(CH2)n-芳基-(CH2)mCON(R)2、NR(CH2)n-芳基-O(CH2)nCON(R)2、NR(CH2)n-芳基-NR(CH2)nCON(R)2、NR(CH2)n-杂芳基-O(CH2)nCON(R)2、NR(CH2)n-杂芳基-(CH2)mCON(R)2、NR(CH2)n-杂芳基-NR(CH2)nCON(R)2、O(CH2)n-联苯基、O(CH2)n-联苯基-CN、O(CH2)n-联苯基-CONH2、NR(CH2)n-联苯基、NR(CH2)n-联苯基-CN和NR(CH2)n-联苯基-CONH2,其中杂芳基是5-10元环体系,该环体系由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S,并且其中芳基和杂芳基被1-2个X4 取代;
条件是:X和X1中至少一个不是H、烷基、烷氧基、羟基和卤。
在另一个实施方式中,本发明提供式Ia1的新型化合物或其立体异构体或制药上可接受的盐:
在另一个实施方式中,本发明提供式Ib的新型化合物或其立体异构体或制药上可接受的盐:
1b
其中:
R,在各种情况下,独立地选自H和C1-4烷基;
R1选自H、C1-4烷基、(CH2)mCO2R、C2-4链烯基-CO2R、CH2CH(NHAc)CO2R、CH2CH(NHR)CO2R和(CH2)nPO(OR)2;
X和X1独立地选自H、OR、C1-4烷基、C2-4链烯基、C2-4炔基、卤素、CF3、硝基、-CN、O(CH2)nCON(R)2、O-C2-4链烯基、N(R)2、NRSO2CH3、SO2NRCH3、CH2N(C1-4烷基)2、CH2-芳基、CH2-杂芳基、O(CH2)n-芳基、O(CH2)n-杂芳基、NR(CH2)n-芳基、NR(CH2)n-杂芳基、O(CH2)n-芳基-(CH2)mCON(R)2、O(CH2)n-芳基-O(CH2)nCON(R)2、O(CH2)n-芳基-NR(CH2)nCON(R)2、O(CH2)n-杂芳基-(CH2)mCON(R)2、O(CH2)n-杂芳基-O(CH2)nCON(R)2、O(CH2)n-杂芳基-NR(CH2)nCON(R)2、NR(CH2)n-芳基-(CH2)mCON(R)2、NR(CH2)n-芳基-O(CH2)nCON(R)2、NR(CH2)n-芳基-NR(CH2)nCON(R)2、NR(CH2)n-杂芳基-O(CH2)nCON(R)2、NR(CH2)n-杂芳基-(CH2)mCON(R)2、NR(CH2)n-杂芳基-NR(CH2)nCON(R)2、O(CH2)n-联苯基、O(CH2)n-联苯基-CN、O(CH2)n-联苯基-CONH2、NR(CH2)n-联苯基、NR(CH2)n-联苯基-CN和NR(CH2)n-联苯基-CONH2,其中杂芳基是5-10元环体系,该环体系由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S,并且其中芳基和杂芳基被1-2个X4取代;
X4选自H、OH、C1-4烷氧基、C1-4烷基、C2-4链烯基、C2-4炔基、卤素、CF3、硝基、-CN、C(O)NR2、NRSO2CH3和SO2N(R)C1-6烷基;
W选自H、CH2OH、CH2OC1-4烷基、CH2OC2-4链烯基、CH2O(CH2)nCO2R、CH2O-C2-4链烯基-CO2R、CH2O(CH2)nCON(R)2、CH2O(CH2)nPO(OR)2、CH2O(CH2)n-芳基和CH2O(CH2)n-5-10元杂芳基,所述杂芳基由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S;
m独立地选自0、1和2;和
n独立地选自1、2和3;
条件是:X和X1中至少一个不是H、烷基、烷氧基、羟基和卤。
[5a]在另一个实施方式中,本发明提供式Ib的新型化合物或其立体异构体或制药上可接受的盐,其中:
X和X1中一个是H并且另一个选自 OH、C1-4烷基、C2-4链烯基、C2-4炔基、卤素、CF3、硝基、-CN、C1-4烷氧基、O(CH2)nCON(R)2、O-C2-4链烯基、N(R)2、NRSO2CH3、SO2NRCH3、CH2N(C1-4烷基)2、CH2-芳基、CH2-杂芳基、O(CH2)n-芳基、O(CH2)n-杂芳基、NR(CH2)n-芳基、NR(CH2)n-杂芳基、O(CH2)n-芳基-(CH2)mCON(R)2、O(CH2)n-芳基-O(CH2)nCON(R)2、O(CH2)n-芳基-NR(CH2)nCON(R)2、O(CH2)n-杂芳基-(CH2)mCON(R)2、O(CH2)n-杂芳基-O(CH2)nCON(R)2、O(CH2)n-杂芳基-NR(CH2)nCON(R)2、NR(CH2)n-芳基-(CH2)mCON(R)2、NR(CH2)n-芳基-O(CH2)nCON(R)2、NR(CH2)n-芳基-NR(CH2)nCON(R)2、NR(CH2)n-杂芳基-O(CH2)nCON(R)2、NR(CH2)n-杂芳基-(CH2)mCON(R)2、NR(CH2)n-杂芳基-NR(CH2)nCON(R)2、O(CH2)n-联苯基、O(CH2)n-联苯基-CN、O(CH2)n-联苯基-CONH2、NR(CH2)n-联苯基、NR(CH2)n-联苯基-CN、NR(CH2)n-联苯基-CONH2,其中杂芳基是5-10元环体系,该环体系由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S,并且其中芳基和杂芳基被1-2个X4 取代;
条件是:X和X1中至少一个不是H、烷基、烷氧基、羟基和卤。
在另一个实施方式中,本发明提供式Ib1的新型化合物或其立体异构体或制药上可接受的盐:
在另一个实施方式中,本发明提供式Ic的新型化合物或其立体异构体或制药上可接受的盐:
Ic
其中:
在各种情况下,R独立地选自H、C1-4烷基、C2-4链烯基和C2-4炔基;
R1选自H和C1-4烷基;
X、X1、X2和X3独立地选自H、OR、C1-4烷基、C2-4链烯基、C2-4 炔基、卤素、CF3、硝基、-CN、N(R)2、(CH2)m-四唑、(CH2)nCO2R、(CH2)nCONR2、(CH2)nCN、O(CH2)nCN、O(CH2)n-四唑、O(CH2)nCO2R、O(CH2)nCON(R)2、O-C2-4 链烯基-CO2R、O(CH2)nPO(OR)2、NR-C2-4链烯基、NRSO2CH3、NR(CH2)nCO2R、NR(CH2)nCON(R)2、NR-C2-4链烯基-CO2R、NR(CH2)nPO(OR)2、NR(CH2)nSO2OR、NR(CH2)n-四唑、SO2NRCH3、OCH2CHMCONRCH2CO2R、CH2-芳基、O(CH2)nPO(OR)2、O(CH2)nSO2OR、OCH2(CH2)nN+(CH3)3A-、O(CH2)n-联苯基、O(CH2)n-联苯基-(CH2)mCO2R、O(CH2)n-联苯基-(CH2)m四唑、O(CH2)n-联苯基-(CH2)mCN、O(CH2)n-联苯基-(CH2)mCON(R)2、NR(CH2)n-联苯基、NR(CH2)n-联苯基-(CH2)mCO2R、NR(CH2)n-联苯基-(CH2)m四唑、NR(CH2)n-联苯基-(CH2)mCN、NR(CH2)n-联苯基-(CH2)mCON(R)2、O(CH2)n-芳基、O(CH2)n-杂芳基、NR(CH2)n-芳基、NR(CH2)n-杂芳基、O(CH2)n-芳基(CH2)mCO2R、O(CH2)n-芳基-C2-4链烯基-CO2R、O(CH2)n-芳基(CH2)m-四唑、O(CH2)n-芳基(CH2)mCN、O(CH2)n-芳基(CH2)mCON(R)2、O(CH2)n-芳基(CH2)m-PO(OR)2、O(CH2)n-芳基-O(CH2)nCO2R、O(CH2)n-芳基-O-C2-4 链烯基-CO2R、O(CH2)n-芳基O(CH2)n-四唑、O(CH2)n-芳基O(CH2)nCN、O(CH2)n-芳基O(CH2)nCON(R)2、O(CH2)n-芳基O(CH2)n-PO(OR)2、O(CH2)n-芳基-NR(CH2)nCO2R、O(CH2)n-芳基-NRC2-4链烯基-CO2R、O(CH2)n-芳基-NR(CH2)n-四唑、O(CH2)n-芳基-NR(CH2)nCN、O(CH2)n-芳基-NR(CH2)nCON(R)2、O(CH2)n-芳基-NR(CH2)n-PO(OR)2、NR(CH2)n-芳基(CH2)mCO2R、NR(CH2)n-芳基-C2-4链烯基-CO2R、NR(CH2)n-芳基(CH2)m-四唑、NR(CH2)n-芳基(CH2)mCN、NR(CH2)n-芳基(CH2)mCON(R)2、NR(CH2)n-芳基(CH2)m-PO(OR)2、NR(CH2)n-芳基-NR(CH2)nCO2R、NR(CH2)n-芳基-NR-C2-4链烯基-CO2R、NR(CH2)n-芳基-NR(CH2)n-四唑、NR(CH2)n-芳基-NR(CH2)nCN、NR(CH2)n-芳基-NR(CH2)nCON(R)2、NR(CH2)n-芳基-NR(CH2)nPO(OR)2、NR(CH2)n-芳基O(CH2)nCO2R、NR(CH2)n-芳基-O-C2-4链烯基-CO2R、NR(CH2)n-芳基-O(CH2)n-四唑、NR(CH2)n-芳基O(CH2)nCN、NR(CH2)n-芳基-O(CH2)nCON(R)2、NR(CH2)n-芳基O(CH2)nPO(OR)2、O(CH2)n-杂芳基(CH2)mCO2R、O(CH2)n-杂芳基-C2-4链烯基-CO2R、O(CH2)n-杂芳基(CH2)m-四唑、O(CH2)n-杂芳基-O(CH2)mCN、O(CH2)n-杂芳基(CH2)mCON(R)2、O(CH2)n-杂芳基(CH2)m-PO(OR)2、O(CH2)n-杂芳基-O(CH2)nCO2R、O(CH2)n-杂芳基-O-C2-4链烯基 -CO2R、O(CH2)n-杂芳基O(CH2)n-四唑、O(CH2)n-杂芳基O(CH2)nCN、O(CH2)n-杂芳基O(CH2)nCON(R)2、O(CH2)n-杂芳基O(CH2)n-PO(OR)2、O(CH2)n-杂芳基-NR(CH2)nCO2R、O(CH2)n-杂芳基-NR-C2-4链烯基-CO2R、O(CH2)n-杂芳基-NR(CH2)n-四唑、O(CH2)n-杂芳基-NR(CH2)nCN、O(CH2)n-杂芳基-NR(CH2)nCON(R)2、O(CH2)n-杂芳基-NR(CH2)n-PO(OR)2,、NR(CH2)n-杂芳基(CH2)mCO2R、NR(CH2)n-杂芳基-C2-4链烯基-CO2R、NR(CH2)n-杂芳基(CH2)m-四唑、NR(CH2)n-杂芳基(CH2)mCN、NR(CH2)n-杂芳基(CH2)mCON(R)2、NR(CH2)n-杂芳基(CH2)m-PO(OR)2、NR(CH2)n-杂芳基-NR(CH2)nCO2R、NR(CH2)n-杂芳基-NR-C2-4链烯基-CO2R、NR(CH2)n-杂芳基-NR(CH2)n-四唑、NR(CH2)n-杂芳基-NR(CH2)nCN、NR(CH2)n-杂芳基-NR(CH2)nCON(R)2、NR(CH2)n-杂芳基-NR(CH2)nPO(OR)2、NR(CH2)n-杂芳基-O(CH2)nCO2R、NR(CH2)n-杂芳基-O-C2-4链烯基-CO2R、NR(CH2)n-杂芳基-O(CH2)n-四唑、NR(CH2)n-杂芳基-O(CH2)nCN、NR(CH2)n-杂芳基-O(CH2)nCON(R)2、NR(CH2)n-杂芳基O(CH2)nPO(OR)2,其中杂芳基是5-10元环体系,该环体系由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S,并且其中芳基和杂芳基被1-2个X4取代和四唑被0-1个R取代;
X4选自H、OR、C1-4烷氧基、C1-4烷基、C2-4链烯基、C2-4炔基、卤素、CF3、硝基、-CN、C(O)NR2、NRSO2CH3和SO2N(R)C1-6烷基;
A-选自Cl和Br;
M独立地选自H、C1-4烷基、C3-6环烷基、C2-4链烯基、C2-4炔基、芳基、(CH2)n-芳基、杂芳基和(CH2)n-杂芳基,其中杂芳基是5-12元环体系,该环体系由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S;和
m独立地选自0、1和2;和
n独立地选自1、2和3;
条件是:X、X1、X2和X3中至少一个不是H、烷基、烷氧基、羟基和卤。
[7a]在另一个实施方式中,本发明提供式I c的新型化合物或其立体异构体或制药上可接受的盐,其中:
X、X1、X2和X3中的三个为H并且第四个选自OH、C1-4烷基、C2-4 链烯基、C2-4炔基、卤素、CF3、硝基、C1-4烷氧基、-CN、N(R)2、(CH2)m-四唑、 (CH2)nCO2R、(CH2)nCONR2、(CH2)nCN、O(CH2)nCN、O(CH2)n-四唑、O(CH2)nCO2R、O(CH2)nCON(R)2、O-C2-4链烯基-CO2R、O(CH2)nPO(OR)2、NR-C2-4链烯基、NRSO2CH3、NR(CH2)nCO2R、NR(CH2)nCON(R)2、NR-C2-4链烯基-CO2R、NR(CH2)nPO(OR)2、NR(CH2)nSO2OR、NR(CH2)n-四唑、SO2NRCH3、OCH2CHMCONRCH2CO2R、CH2-芳基、O(CH2)nPO(OR)2、O(CH2)nSO2OR、OCH2(CH2)nN+(CH3)3A-、O(CH2)n-联苯基、O(CH2)n-联苯基-(CH2)mCO2R、O(CH2)n-联苯基-(CH2)m四唑、O(CH2)n-联苯基-(CH2)mCN、O(CH2)n-联苯基-(CH2)mCON(R)2、NR(CH2)n-联苯基、NR(CH2)n-联苯基-(CH2)mCO2R、NR(CH2)n-联苯基-(CH2)m四唑、NR(CH2)n-联苯基-(CH2)mCN、NR(CH2)n-联苯基-(CH2)mCON(R)2、O(CH2)n-芳基、O(CH2)n-杂芳基、NR(CH2)n-芳基、NR(CH2)n-杂芳基、O(CH2)n-芳基(CH2)mCO2R、O(CH2)n-芳基-C2-4链烯基-CO2R、O(CH2)n-芳基(CH2)m-四唑、O(CH2)n-芳基(CH2)mCN、O(CH2)n-芳基(CH2)mCON(R)2、O(CH2)n-芳基(CH2)m-PO(OR)2、O(CH2)n-芳基-O(CH2)nCO2R、O(CH2)n-芳基-O-C2-4链烯基-CO2R、O(CH2)n-芳基O(CH2)n-四唑、O(CH2)n-芳基O(CH2)nCN、O(CH2)n-芳基O(CH2)nCON(R)2、O(CH2)n-芳基O(CH2)n-PO(OR)2、O(CH2)n-芳基-NR(CH2)nCO2R、O(CH2)n-芳基-NRC2-4链烯基-CO2R、O(CH2)n-芳基-NR(CH2)n-四唑、O(CH2)n-芳基-NR(CH2)nCN、O(CH2)n-芳基-NR(CH2)nCON(R)2、O(CH2)n-芳基-NR(CH2)n-PO(OR)2、NR(CH2)n-芳基(CH2)mCO2R、NR(CH2)n-芳基-C2-4链烯基-CO2R、NR(CH2)n-芳基(CH2)m-四唑、NR(CH2)n-芳基(CH2)mCN、NR(CH2)n-芳基(CH2)mCON(R)2、NR(CH2)n-芳基(CH2)m-PO(OR)2、NR(CH2)n-芳基-NR(CH2)nCO2R、NR(CH2)n-芳基-NR-C2-4链烯基-CO2R、NR(CH2)n-芳基-NR(CH2)n-四唑、NR(CH2)n-芳基-NR(CH2)nCN、NR(CH2)n-芳基-NR(CH2)nCON(R)2、NR(CH2)n-芳基-NR(CH2)nPO(OR)2、NR(CH2)n-芳基O(CH2)nCO2R、NR(CH2)n-芳基-O-C2-4链烯基-CO2R、NR(CH2)n-芳基-O(CH2)n-四唑、NR(CH2)n-芳基O(CH2)nCN、NR(CH2)n-芳基-O(CH2)nCON(R)2、NR(CH2)n-芳基O(CH2)nPO(OR)2、O(CH2)n-杂芳基(CH2)mCO2R、O(CH2)n-杂芳基-C2-4链烯基-CO2R、O(CH2)n-杂芳基(CH2)m-四唑、O(CH2)n-杂芳基-O(CH2)mCN、O(CH2)n-杂芳基(CH2)mCON(R)2、O(CH2)n-杂芳基(CH2)m-PO(OR)2、O(CH2)n-杂芳基-O(CH2)nCO2R、O(CH2)n-杂芳基-O-C2-4链烯基-CO2R、O(CH2)n-杂芳基O(CH2)n-四唑、O(CH2)n-杂芳基O(CH2)nCN、O(CH2)n-杂芳基O(CH2)nCON(R)2、O(CH2)n-杂芳基O(CH2)n-PO(OR)2、O(CH2)n-杂芳基-NR(CH2)nCO2R、O(CH2)n-杂芳基-NR-C2-4链烯基-CO2R、O(CH2)n-杂芳基-NR(CH2)n-四唑、O(CH2)n-杂芳基-NR(CH2)nCN、O(CH2)n-杂芳基-NR(CH2)nCON(R)2、O(CH2)n-杂芳基-NR(CH2)n-PO(OR)2,、NR(CH2)n-杂芳基(CH2)mCO2R、NR(CH2)n-杂芳基-C2-4链烯基-CO2R、NR(CH2)n-杂芳基(CH2)m-四唑、NR(CH2)n-杂芳基(CH2)mCN、NR(CH2)n-杂芳基(CH2)mCON(R)2、NR(CH2)n-杂芳基(CH2)m-PO(OR)2、NR(CH2)n-杂芳基-NR(CH2)nCO2R、NR(CH2)n-杂芳基-NR-C2-4 链烯基-CO2R、NR(CH2)n-杂芳基-NR(CH2)n-四唑、NR(CH2)n-杂芳基-NR(CH2)nCN、 NR(CH2)n-杂芳基-NR(CH2)nCON(R)2、NR(CH2)n-杂芳基-NR(CH2)nPO(OR)2、NR(CH2)n-杂芳基-O(CH2)nCO2R、NR(CH2)n-杂芳基-O-C2-4链烯基-CO2R、NR(CH2)n-杂芳基-O(CH2)n-四唑、NR(CH2)n-杂芳基-O(CH2)nCN、NR(CH2)n-杂芳基-O(CH2)nCON(R)2、NR(CH2)n-杂芳基O(CH2)nPO(OR)2,其中杂芳基是5-10元环体系,该环体系由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S,并且其中芳基和杂芳基被1-2个X4取代和四唑被0-1个R取代;
条件是:X、X1、X2和X3中至少一个不是H、烷基、烷氧基、羟基和卤。
在另一个实施方式中,本发明提供式I c1的新型化合物或其制药上可接受的盐:
在另一个实施方式中,本发明提供式I d的新型化合物或其立体异构体或制药上可接受的盐:
其中:
R,在各种情况下,独立地选自H、C1-4烷基、C2-4链烯基和C2-4炔基;
R1选自H、C1-4烷基、(CH2)mCO2R、(CH2)nPO(OR)2、C2-4链烯基和C2-4炔基;
X、X1和X2独立地选自H、OR、C1-4烷基、C2-4链烯基、C2-4炔基、卤素、CF3、硝基、O(CH2)nCON(R)2、O-C2-4链烯基、N(R)2、NRSO2CH3、SO2NRCH3、CH2N(C1-4烷基)2、CH2-芳基、CH2-杂芳基、O(CH2)n-芳基、O(CH2)n-杂芳基、O(CH2)n-芳基(CH2)mCN、O(CH2)n-芳基(CH2)mCON(R)2、O(CH2)n-芳基O(CH2)nCN、O(CH2)n-芳基O(CH2)nCON(R)2、NR(CH2)n-芳基(CH2)mCN、NR(CH2)n-芳基(CH2)mCON(R)2、NR(CH2)n-芳基O(CH2)nCN、NR(CH2)n-芳基O(CH2)nCON(R)2、NR(CH2)n-芳基-NR(CH2)nCN、NR(CH2)n-芳基-NR(CH2)nCON(R)2、O(CH2)n-联苯基、O(CH2)n-联苯基-CN、O(CH2)n-联苯基-CONH2、NR(CH2)n-联苯基、NR(CH2)n-联苯基-CN、NR(CH2)n-联苯基-CONH2、O(CH2)n-杂芳基、O(CH2)n-杂芳基-(CH2)mCON(R)2和NR(CH2)n-杂芳基-(CH2)mCON(R)2;其中杂芳基是5-12元环体系,其是由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S,并且其中芳基和杂芳基被1-2个X4取代;
X4选自H、OH、C1-6烷氧基、C1-6烷基、C2-6链烯基、C2-6炔基、卤素、CF3、硝基、-CN、C(O)NR2、NRSO2CH3和SO2N(R)C1-6烷基;
Q选自OH、C1-4烷氧基、O(CH2)nCO2R、O(CH2)nCON(R)2、O-C2-4 链烯基、O-C2-4链烯基-CO2R、OCH2CH2CONRCH2CO2R、OCH2CHMCONRCH2CO2R、O(CH2)nPO(OR)2、O(CH2)nSO2OR、OCH2CH(NHAc)CO2R、OCH2CH(NHR)CO2R、O(CH2)n-芳基和 O(CH2)n-5-10元杂芳基,该杂芳基由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S;
M独立地选自H、C1-4烷基、C3-6环烷基、C2-4链烯基、C2-4炔基、芳基、(CH2)n-芳基、杂芳基和(CH2)n-杂芳基,其中杂芳基是5-12元环体系,该环体系由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S;和
m独立地选自0、1和2;和
n独立地选自1、2和3;
条件是:X、X1和X2中至少一个不是H、烷基、烷氧基、羟基和卤。
[9a]在另一个实施方式中,本发明提供式Id的新型化合物或其立体异构体或制药上可接受的盐,其中:
X、X1和X2中的两个是H并且第三个选自OH、OR、C1-4烷基、C2-4 链烯基、C2-4炔基、卤素、CF3、硝基、C1-4烷氧基、O(CH2)nCON(R)2、O-C2-4链烯基、N(R)2、NRSO2CH3、SO2NRCH3、CH2N(C1-4烷基)2、CH2-芳基、CH2-杂芳基、O(CH2)n-芳基、O(CH2)n-杂芳基、O(CH2)n-芳基(CH2)mCN、O(CH2)n-芳基(CH2)mCON(R)2、O(CH2)n-芳基O(CH2)nCN、O(CH2)n-芳基O(CH2)nCON(R)2、NR(CH2)n-芳基(CH2)mCN、NR(CH2)n-芳基(CH2)mCON(R)2、NR(CH2)n-芳基O(CH2)nCN、NR(CH2)n-芳基-O(CH2)nCON(R)2、NR(CH2)n-芳基-NR(CH2)nCN、NR(CH2)n-芳基-NR(CH2)nCON(R)2、O(CH2)n-联苯基、O(CH2)n-联苯基-CN、O(CH2)n-联苯基-CONH2、NR(CH2)n-联苯基、NR(CH2)n-联苯基-CN、NR(CH2)n-联苯基-CONH2、O(CH2)n-杂芳基、O(CH2)n-杂芳基-(CH2)mCON(R)2和NR(CH2)n-杂芳基-(CH2)mCON(R)2;其中杂芳基是5-12元环体系,该环体系由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S,并且其中芳基和杂芳基被1-2个X4取代;
条件是:X、X1和X2中至少一个不是H、烷基、烷氧基、羟基和卤。
在另一个实施方式中,本发明提供式I d1的新型化合物或其立体异构体或制药上可接受的盐:
在另一个实施方式中,本发明提供式IIa的新型化合物或其立体异构体:
其中:
R,在各种情况下,独立地选自H、C1-4烷基、C2-4链烯基和C2-4炔基;
R1选自H和C1-4烷基;
A-选自Cl-和Br-;
V选自O-、C1-4烷基、C2-4链烯基和C2-4炔基;
X和X1独立地选自H、OR、C1-4烷基、C2-4链烯基、C2-4炔基、卤素、CF3、硝基、O(CH2)nCON(R)2、O-C2-4链烯基、NRSO2CH3、SO2NRCH3、CH2-芳基、CH2-杂芳基、O(CH2)n-芳基、O(CH2)n-杂芳基、O(CH2)n-芳基(CH2)mCN、O(CH2)n-芳基(CH2)mCON(R)2、O(CH2)n-芳基O(CH2)nCN、O(CH2)n-芳基O(CH2)nCON(R)2、NR(CH2)n-芳基(CH2)mCN、NR(CH2)n-芳基(CH2)mCON(R)2、NR(CH2)n-芳基O(CH2)nCN、NR(CH2)n-芳基O(CH2)nCON(R)2、NR(CH2)n-芳基-NR(CH2)nCN、NR(CH2)n-芳基-NR(CH2)nCON(R)2、O(CH2)n-联苯基、O(CH2)n-联苯基-CN、O(CH2)n-联苯基-CONH2、NR(CH2)n-联苯基、NR(CH2)n-联苯基-CN、NR(CH2)n-联苯基-CONH2、O(CH2)n-杂芳基、O(CH2)n-杂芳基-(CH2)mCON(R)2和NR(CH2)n-杂芳基-(CH2)mCON(R)2;其中杂芳基是5-12元环体系,该环体系由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S,并且其中芳基和杂芳基被1-2个X4取代;
X4选自H、OR、C1-6烷氧基、C1-6烷基、C2-6链烯基、C2-6炔基、卤素、CF3、硝基、-CN、C(O)NR2、NRSO2CH3和SO2N(R)C1-6烷基;
n独立地选自1、2和3;
条件是:X和X1中至少一个不是H、烷基、烷氧基、羟基和卤。
[11a]在另一个实施方式中,本发明提供式IIa的新型化合物或其立体异构体,其中:
X和X1中的一个是H并且另一个选自OH、C1-4烷基、C2-4链烯基、C2-4炔基、卤素、CF3、硝基、C1-4烷氧基、O(CH2)nCON(R)2、O-C2-4链烯基、NRSO2CH3、SO2NRCH3、CH2-芳基、CH2-杂芳基、O(CH2)n-芳基、O(CH2)n-杂芳基、O(CH2)n-芳基(CH2)mCN、O(CH2)n-芳基(CH2)mCON(R)2、O(CH2)n-芳基O(CH2)nCN、O(CH2)n-芳基O(CH2)nCON(R)2、NR(CH2)n-芳基(CH2)nCN、NR(CH2)n-芳基(CH2)mCON(R)2、NR(CH2)n-芳基O(CH2)nCN、NR(CH2)n-芳基O(CH2)nCON(R)2、NR(CH2)n-芳基-NR(CH2)nCN、NR(CH2)n-芳基-NR(CH2)nCON(R)2、O(CH2)n-联苯基、O(CH2)n-联苯基-CN、O(CH2)n-联苯基-CONH2、NR(CH2)n-联苯基、NR(CH2)n-联苯 基-CN、NR(CH2)n-联苯基-CONH2、O(CH2)n-杂芳基、O(CH2)n-杂芳基-(CH2)mCON(R)2和NR(CH2)n-杂芳基-(CH2)mCON(R)2,其中杂芳基是5-12元环体系,该环体系由碳原子和1-4个杂原子组成,所述杂原子选自N、O和S,并且其中芳基和杂芳基被1-2个X4取代;
条件是:X和X1中至少一个不是H、烷基、烷氧基、羟基和卤。
在另一个实施方式中,本发明提供式IIa1的新型化合物:
在另一个实施方式中,本发明提供新型药物组合物,其包括:制药上可接受的载体和治疗上有效量的本发明所述的化合物或其立体异构体或制药上可接受的盐形式。
在另一个实施方式中,本发明提供治疗疾病的新方法,其包括:给予需要它的患者治疗上有效量的本发明所述的化合物或其制药上可接受的盐形式,其中所述疾病选自肥胖、糖尿病、心脏代谢紊乱和其组合。
在另一个实施方式中,心脏代谢紊乱选自过度紧张、血脂异常(例如不期望的血脂水平、升高的胆固醇水平和降低的LDL水平)、高血压和胰岛素抗性。
在另一个实施方式中,本发明提供治疗肥胖并发症的新方法,其包括:给需要它的患者服用治疗上有效量的本发明所述的至少一种化合物或其制药上可接受的盐。
在另一个实施方式中,本发明提供治疗肥胖并发症(co-morbidity)的新方法,其包括:给予需要它的患者治疗上有效量的本发明所述的化合物或其制药上可接受的盐形式。
在另一个实施方式中,所述并发症选自糖尿病、代谢综合症、痴呆和心脏病。
在另一个实施方式中,所述并发症选自过度紧张;胆囊病;胃肠失调;月经无规律;退化性关节炎;静脉停滞溃疡;肺换气不足综合征;睡眠呼吸暂停;打鼾;冠状动脉疾病;动脉硬化性疾病;大脑假瘤;事故倾向性;增加的手术风险;骨关节炎;高胆固醇;和增加的卵巢、子宫颈、子宫、乳房、前列腺和胆囊的恶性肿瘤发病率。
在另一个实施方式中,本发明提供治疗CNS病症的新方法,其包括:给予需要它的患者治疗上有效量的本发明所述的化合物或其制药上可接受的盐形式。
在另一个实施方式中,CNS紊乱选自急性和慢性神经系统紊乱、认知紊乱和记忆减退。这些病症的实例包括神经系统的慢性或外伤性退化过程,其包括阿尔茨海默氏病(Alzheimer′s disease)、其它类型的老年痴呆症、轻度认知障碍和帕金森病。CNS紊乱的其它实例包括精神病,其包括抑郁症、忧虑症、恐慌发作、社交恐惧症、精神分裂症和食欲不振。CNS紊乱进一步的实例包括酒精、尼古丁和其它成瘾药物所引起的断除症状。CNS紊乱另外的实例包括神经性疼痛和神经性炎症(例如多发性硬化症)。
在另一个实施方式中,本发明也提供通过给予MAO-B抑制剂来预防或逆转脂肪组织在哺乳动物中的沉积的方法。通过预防或逆转脂肪组织的沉积,MAO-B抑制剂有望降低肥胖的发病率或严重度,因此减少了相关并发症的发病率或严重度。
在另一个实施方式中,本发明提供用于治疗的本发明所述的化合物。
在另一个实施方式中,本发明提供本发明在制备治疗肥胖、糖尿病、心脏代谢紊乱和其组合中的药物中的应用。
本发明可以体现为其它具体的形式,而不脱离其精神和基本特征。本发明包括本文所提到的本发明各方面的所有组合。应当理解的是,本发明所述的任意和所有的实施方式可以与任何其它的实施方式(一个或多个)结合起来描述另外的实施方式。还应当理解的是,优选实施方式的每个单个元素意欲单个地作为其自己独立的实施方式。此外,一个实施方式的任意元素意欲与来自任意实施方式的任意和所有其它的元素结合来描述另外的实施方式。
定义
除非另外指明,在本申请中出现的定义中提供的实例是非包括性的。它们非限定性地包括所引用的实例。
本文所述的化合物可以具有不对称中心、几何中心(例如双键)或两者兼有。除非具体说明具体的立体化学或异构体形式,意指结构的所有手性体、非对映异构体、外消旋形式和所有几何异构形式。本发明所述的含有不对称取代原子的化合物可以被分离为旋光或外消旋形式。如何制备旋光体是本领域众所周知的,例如通过外消旋形式的溶解、通过从旋光原材料中合成或通过使用手性助剂。烯烃、C=N双键或其它类型的双键的几何异构体可以出现在本文所述的化合物中,并且所有这样稳定的异构体都被包括在本发明中。具体而言,本发明所述化合物的顺式和反式几何异构体也可以存在并且可以被分离为异构体的混合物或单独的异构体形式。用于制备本发明所述化合物和其中所制备的中间体的所有方法都被认为是本发明的组成部分。所显示或描述的化合物的所有互变异构体也被认为是本发明的组成部分。
“烷基”包括具有特定数目碳原子的支链和直链饱和脂族烃基。举例来说,C1-6烷基包括C1、C2、C3、C4、C5和C6烷基基团。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基和仲戊基。
“链烯基”包括带有一个或多个不饱和碳碳键的直链或支链构型的特定数目的烃原子,所述不饱和碳碳键可以出现在链上的任何稳定点处,例如乙烯基和丙烯基。C2-6链烯基包括C2、C3、C4、C5和C6链烯基基团。
“炔基”包括带有一个或多个碳碳三键的直链或支链构型的特定数目的烃原子,所述碳碳三键可以出现在链上的任何稳定点处,例如乙炔基和丙炔基。C2-6炔基包括C2、C3、C4、C5和C6炔基基团。
“环烷基”包括饱和环中的特定数目的烃原子,例如环丙基、环丁基、环戊基、环己基、环庚基和环辛基。C3-8环烷基包括C3、C4、C5、C6、C7和C8环烷基基团。
“烷氧基”指的是如上述所定义的烷基基团,其具有通过氧桥连接的指定数目的烃原子。C1-6烷氧基包括C1、C2、C3、C4、C5和C6烷氧基基团。烷氧基的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和仲戊氧基。
“卤”或“卤素”指的是氟、氯、溴和碘。
“抗衡离子”用于指小的带负电的种类,例如氯离子、溴离子、氢氧根、醋酸根和硫酸根。
“芳基”指的是任何稳定的6、7、8、9、10、11、12或13元单环的、双环的或三环的环,其中至少一个环,如果一个以上的环存在的话,是芳香族的。芳基的实例包括芴基、苯基、萘基、2,3-二氢化茚基、金刚烷基和四氢化萘基。
“杂芳基”指的是任何稳定的5、6、7、8、9、10、11或12元单环的、双环的或三环的杂环,其是芳香族的,并且其是由碳原子和1、2、3或4个杂原子组成的,所述杂原子独立地选自N、O和S。如果杂芳基是双环或三环的,那么这两个或三个环中至少一个必须含有杂原子,尽管这两个或所有三个每个都可以含有一个或多个杂原子。如果杂芳基是双环或三环的,那么这些环中只有一个必须是芳香族的。该N基团可以是N、NH或N-取代基,这取决于所选择的环并且如果取代被叙述的话。该氮和硫杂原子可以任选地被氧化(例如S、S(O)、S(O)2和N-O)。该杂芳环可以在形成稳定结构的任意的杂原子或碳原子处被连接至其侧链基团上。如果得到的化合物是稳定的,本文所述的杂芳环可以在碳或氮原子上被取代。
杂芳基的实例包括吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并噻吩基(benzothiofuranyl)、苯并噻吩基(benzothiophenyl)、苯并唑基、苯并唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异唑基、苯并异噻唑基、苯并咪唑基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、苯并吡喃基、噌啉基、十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢氟[2,3-b]四氢呋喃、呋喃基、呋咱基、咪唑基、1H-吲唑基、indolenyl、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、靛红基、异苯并呋喃基、异苯并二氢吡喃基、异吲唑基、异二氢吲哚基、异吲哚基、异喹啉基、异噻唑基、异唑基、1,5-二氮杂萘基、二唑基、1,2,3-二唑基、1,2,4-二唑基、1,2,5-二唑基、1,3,4-二唑基、唑烷基、 唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪基、phenoxathinyl、吩嗪基、2,3-二氮杂萘基、喋啶基、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶并 唑、吡啶并咪唑、吡啶并噻唑、吡啶基(pyridinyl)、吡啶基(pyridyl)、嘧啶基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四唑基、6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、噻吩基、噻吩并噻唑基、噻吩并唑基、噻吩并咪唑基、噻吩基、三嗪基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基 和呫吨基。
预防脂肪组织沉积包含治疗方法,其中根据本发明所述,对象的脂肪组织水平与治疗之前(即其给药前的水平)保持大约相同,或者比给药前水平不超过约1、2、3、4、5、6、7、8、9、或10%(尤其当对象被预先处理以增加脂肪组织水平时)。
使脂肪组织沉积逆转包含治疗方法,其中根据本发明所述,对象的脂肪组织水平比治疗之前(即其给药前的水平)低。较低的实例包括比给药前水平低1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20%或更多。
哺乳动物和患者包含温血哺乳动物,其典型地处于医疗护理下(例如人和驯养的动物)。哺乳动物的实例包括(a)猫、犬、马、牛和人以及(b)人。
“治疗(treating)”或“治疗(treatment)”包含对哺乳动物疾病状态的治疗,并且包括:(a)预防在哺乳动物中出现疾病状态,尤其是当这样的哺乳动物易患此种疾病状态但还没有诊断出患病时;(b)抑制疾病状态,例如阻止其发展;和/或(c)减轻疾病状态,例如使疾病状态退化直到达到期望的终点。治疗也包括疾病症状的改善(例如减轻痛苦或不适),其中这样的改善可以直接或可以不直接影响疾病(例如促成、传播、表达等)。
“制药上可接受的盐”指的是所公开化合物的衍生物,其中母体化合物通过制备其酸式或碱式盐而被修饰。制药上可接受的盐的实例非限定性地包括碱性残基例如胺的无机或有机酸式盐;酸性残基例如羧酸的碱金属盐或有机盐;和其类似物。该制药上可接受的盐包括例如从无毒无机或有机酸中形成的母体化合物的传统无毒盐或季铵盐。举例来说,这样的传统无毒盐非限定性地包括那些衍生自下述无机酸和有机酸的盐:1,2-乙烷二磺酸、2-乙酸基苯甲酸、2-羟基乙烷磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、重碳酸、碳酸、柠檬酸、乙二胺四乙酸、乙烷二磺酸、乙磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、乙醇酸、乙醇酰阿散酸(glycollyarsanilic)、己基间苯二酚、哈胺(hydrabamic)、氢溴酸、盐酸、氢碘酸、羟基马来酸(hydroxymaleic)、羟基萘甲酸、羟乙磺酸、乳酸、乳糖酸、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲磺酸、萘磺酸、硝酸、草酸、扑酸(pamoic)、泛酸、苯乙酸、磷酸、聚半乳糖醛酸、丙酸、水杨酸、硬脂酸、碱式乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁酸、酒石酸和对甲苯磺酸。
本发明所述制药上可接受的盐可以通过传统的化学方法从含有碱性 或酸性部分的母体化合物中合成。一般地,通过在水或有机溶剂或两者的混合物中将这些化合物的游离酸或碱形式与化学计量量的合适碱或酸反应,可以制备这样的盐;一般地,非水性介质例如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。合适的盐的列表可在Remington′s Pharmaceutical Sciences,18th ed.,MackPublishing Company,Easton,PA,1990,p 1445中找到,其公开内容在此被引入作为参考。
“治疗上有效量”包括本发明所述化合物的量,其当单独或联合给药以治疗肥胖或本文所列出的另一种适应症时是有效的。“治疗上有效量”也包括所要求保护的化合物的组合物的量,其对于治疗期望的适应症是有效的。化合物的组合优选地是增效组合。举例来说,正如Chou和Talalay,Adv.Enzyme Regul.1984,22:27-55所述,当联合给药时这些化合物的效应大于作为单独药剂给药时这些化合物的加和效应时,就出现增效作用。一般地,增效作用在这些化合物的次最佳浓度时能最清楚地得到证实。增效作用可以表现在:与单个组分相比,这种组合物具有更低的细胞毒素、增强的效应和一些其它有益的作用。
效用
肥胖定义为身体质量指数(BMI)为30或以上。该指数是个体体重相对于身高的量度。BMI是通过体重(以千克计)除以身高(以米计)的平方而计算的。正常且健康的体重定义为BMI在20与24.9之间。超重定义为BMI为25或以上。肥胖在美国已经达到流行比例,存在四千四百万肥胖美国人,并且另外有八百万人被视为医学超重。
肥胖是一种疾病,其特征是由脂肪组织,尤其是位于腹部区域的脂肪组织的过量积累而导致的状况。期望这样治疗超重或肥胖患者:降低他们的脂肪组织的量,并且因此使他们的总体重降低至对于他们的性别和身高来说在正常的范围内。这样,他们患有并发症例如糖尿病和心血管病的风险将被降低。同样期望的是:防止正常重量的个体积累额外的、过量的脂肪组织,有效维持他们的体重在BMI<25,并且防止并发症的发展。还期望的是控制肥胖,有效地防止超重和肥胖个体积累额外的、过量的脂肪组织,降低进一步使其并发症恶化的危险。
存在两种形式的MAO,称为MAO-A和MAO-B。这两种形式的区别在于底物和抑制剂的专一性以及氨基酸的数目和序列。MAO-B优选的底物是β-苯乙胺。相反,MAO-A优选的底物是5-羟色胺。如果存在任何选择性的话,一些MAO抑制剂显示出对MAO-A或MAO-B的选择性,然而其它的MAO抑制剂则很少显示。举例来说,MAO抑制剂氯吉兰(clorgyline)优选地抑制MAO-A; MAO抑制剂左旋司来吉兰(L-selegiline)优选地抑制MAO-B;以及,MAO抑制剂异烟酰异丙肼(iproniazid)没有选择性(即对两者有相似的亲和力)。选择性的实例包括这样的化合物:其对一种形式的MAO的亲和力要比另一种形式高大约2、3、4、5、6、7、8、9、10、20、30、40、50、100、200、300、400、500、600、700、800、900、1000或更多倍。本领域普通技术人员认识到将MAO抑制剂分类可能有些困难。一些化合物可能在体外选择性地抑制一种形式的MAO而在体内则失去其选择性。同样,化合物的选择性可能在物种与物种之间或组织与组织之间不同。在本发明的背景下,在哺乳动物中体内抑制MAO-B的活性是期望的。因此,选择性和亲和力是根据MAO抑制剂的体内活性和正被给药或要被给药的哺乳动物物种。本发明所述MAO-B抑制剂的选择性的实例包括(a)在要被治疗的哺乳动物物种(例如人)中,对MAO-B的亲和力要比对MAO-A的高至少2、3、4、5、6、7、8、9、10、20、30、40、50至100倍,和(b)在要被治疗的哺乳动物物种(例如人)中,对MAO-B的亲和力要比对MAO-A的高至少100倍。
本发明所述的一些化合物已经被设计成具有降低的CNS暴露,依据的是它们没有能力或具有有限的能力穿透血-脑屏障(例如季铵盐或酸取代基)或者它们参与主动运输系统,因此降低了中枢调节的负作用,这是许多抗肥胖药剂存在的潜在问题。
本发明所述的其它化合物有望穿透血-脑屏障,因此有助于治疗CNS紊乱(例如帕金森病、抑郁症和阿尔海默氏病)。
MAO酶也位于许多周围(非CNS)组织中,包括脂肪细胞,即包含人体脂肪的细胞。为了治疗非CNS紊乱(例如肥胖、糖尿病和/或心脏代谢紊乱),必须给予足够的药物以抑制周围组织中的MAO。现在正使用的治疗各种精神病和神经系统疾病的MAO抑制剂,不论其给药途径如何,都是从体循环中进入CNS。尽管在体循环中存在,这样的药物进入周围组织,包括脂肪组织、肝脏和肌肉。本领域技术人员认识到,意欲从体循环进入CNS以治疗精神病和神经系统疾病的MAO抑制剂,也接触到包括脂肪组织、肝脏和肌肉在内的周围组织中的MAO。因此,用于治疗非CNS紊乱的MAO抑制剂也从体循环部分进入CNS。
药物通过穿过血-脑屏障(BBB)从体循环进入CNS。BBB是高度专一的“守门人”,其通过防止许多潜在的有害物质从体循环中进入CNS而保护大脑。关于BBB,许多是已知的,以及关于传递经过它的化合物所需的物理化学性质。
不穿过BBB进入CNS或通过传输机理容易被消除的药物(J Clin Invest.97,2517(1996))在文献中是已知的,并且由于它们不能发展药理作用必需的脑水平而具有低的CNS活性。在药物在CNS中积累之前,该BBB具有至少一种可除去所述药物的机理。位于BBB血浆膜中的P-糖蛋白(P-gp)能通过跨膜迁移影响许多药物的脑渗透和药理活性。一些药物在脑中缺乏累积可以由位于BBB的P-gp将其从脑中活性去除来解释。举例来说,典型的阿片样药物洛哌丁胺,其在临床上被用作止泻剂,被P-gp从脑中活性地去除,因此解释了其缺乏阿片样CNS效应。另一个实例是多潘立酮(domperidone),一种多巴胺受体阻断剂,其参与P-gp运输(J Clin Invest.97,2517(1996))。尽管穿越BBB的多巴胺受体阻断剂可用于治疗精神分裂症,易被消除的多潘立酮可被用于防止呕吐,而没有产生不利的CNS效应的可能性。
除了上述化合物之外,具有延缓或防止BBB渗透或有助于参与活性消除过程的结构特征的药剂已经在各种治疗中得到鉴定。这些药剂包括抗组胺剂(Drug Metab.Dispos.31,312(2003))、β-抗肾上腺素受体能拮抗剂(B-阻断剂)(Eur.J.Clin.Pharmacol.28,Suppl:21-3(1985);Br.J.Clin.Pharmacol.,11(6),549-553(1981))、非核苷反转录酶抑制剂(NNRTIs)(J.Pharm Sci.,88(10)950-954(1999))和阿片药物质拮抗剂。后面一组已经被测试与其在GI道内的活性相关。这些周围选择性的阿片样药物拮抗剂在各种美国专利中予以描述,其被用于治疗哺乳动物中的非CNS病理,尤其是GI道内的那些(参见US 5,260,542;US5,434,171;US 5,159,081;和US 5,270,238)。
其它类型的非脑渗透性化合物可以通过在分子内产生电荷而制备。因此,向药物莨菪胺或阿托品的叔胺官能度中添加甲基基团,与母体分子不同,通过正电荷的存在可防止它们穿过BBB。然而,新分子(甲基莨菪胺和甲基阿托品)保留了其全部的抗胆碱能药理特性。因此,这些药物也能用于治疗周围疾病,而不用担心不利的CNS效应。季铵化合物甲基纳曲酮(methylnaltrexone)也被用于防止和/或治疗与阿片样物质给药相关的阿片样物质和非阿片样物质诱导的副作用。
MAO-B抑制剂例如司来吉兰已经用于治疗CNS紊乱。意想不到的发现——由这些药剂调节的抗肥胖活性是由非CNS机理调节的,可使得本发明所述化合物受到周围限制是期望的,即当非CNS紊乱要被治疗时,所述化合物没有能力或具有有限的能力穿过BBB或通过主动运输系统从脑中容易地消除。可期望本发明所述化合物被从周围限制,这又将导致没有或非常有限的CNS效应。正如先前在较早的周围限制性药剂种类中所证实的,具有周围调节的抗肥胖特性的化合物应当产生具有更大安全性的治疗药剂。可以期望,当本发明所述化合物以治 疗上有效量给予时没有或具有非常有限的CNS效应。同样可以期望的是,缺乏CNS效应是当本发明所述化合物以治疗上有效量给予时具有最低脑浓度的结果。在这个背景下,最低脑浓度是指这样的水平:其太低而不能有效地治疗CNS适应症,或者太低而不能引起明显的或可测量的有害或不期望的副作用。应当注意,当试图治疗CNS紊乱时CNS活性是期望的。
当Q、R、R1、W、X、X1、X2和X3都为H时,化合物A是雷沙吉兰(Rasagiline)。雷沙吉兰是穿过BBB并且指示用于帕金森病的药物。在化合物A中,R、R1、R2、X、X1、Y和Z中是能降低或限制化合物A的CNS活性的基团。这种降低或限制通过R、R1、R2、X、X1、Y和Z中的至少一个为如下基团来实现:相对于雷沙吉兰,该基团限制了化合物A穿过BBB的能力,或者它能使其在高于雷沙吉兰的浓度时被活性地去除。化合物A的脑水平的实例包括下述水平:(a)当在同样剂量下给予时,其比雷沙吉兰低50、55、60、65、70、75、80、85、90、91、92、93、94、95、96、97、98、99至100%;(b)当在同样剂量下给予时,其比雷沙吉兰低90、91、92、93、94、95、96、97、98、99至100%;(c)当在同样剂量下给予时,其比雷沙吉兰低98、99至100%。
治疗肥胖的大部分方法依赖于能量吸收的大幅度减少,或者通过食物摄取的减少(例如西布曲明(sibutramine))或者通过抑制脂肪吸收(例如奥利司他(orlistat))。在本发明中,可以期望在不存在食物摄取明显减少时脂肪组织被显著减少。作为本发明的结果,重量减轻来源于MAO-B抑制剂的治疗,很大程度上不依赖于食欲和食物摄取。在脂肪组织降低期间食物摄取水平的实例包括:(a)食物摄取被保持、增加,或者低于根据本发明进行治疗前对象正常范围(即其给药前水平)的大约0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、或20%;(b)食物摄取被保持、增加,或者低于其给药前水平的大约0、1、2、3、4、5、6、7、8、9、10、11、12、13、14或15%;(c)食物摄取被保持、增加,或者低于其给药前水平的大约0、1、2、3、4、5、6、7、8、9或10%;和(d)食物摄取水平被保持、增加,或者低于其给药前水平的大约0、1、2、3、4或5%。
在一些情况下,脂肪组织的降低可能伴随着无脂肪体重(lean musclemass)的伴生损失。这在癌症患者身上特别明显,其显示出所有身体组织成分的损耗,包括脂肪组织和无脂肪体重。然而在本发明中,可以期望在不存在无脂肪体重明显减少的情况下身体脂肪被明显减少。脂肪组织的降低是由于MAO-B抑制剂的治疗,其不依赖于无脂肪体重的明显变化。在脂肪组织降低期间无脂肪体重水平的实例包括:(a)无脂肪体重被保持、增加,或低于根据本发明进行治疗前 对象正常范围(即其给药前水平)不超过大约1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30%;(b)无脂肪体重被保持、增加,或低于其给药前水平不超过大约1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15%;(c)无脂肪体重被保持、增加,或低于其给药前水平不超过大约1、2、3、4、5、6、7、8、9或10%;和(d)无脂肪体重被保持、增加,或低于其给药前水平不超过大约1、2、3、4或5%。
在一些情况下,脂肪组织的丧失可能伴随着水分的伴生损失。这对于促进脱水的饮食方案来说尤其明显。在本发明中,可以期望在不存在水分明显减少的情况下身体脂肪被明显减少。换句话说,脂肪组织的降低是由于MAO-B抑制剂的治疗,其不依赖于水分的明显变化。在脂肪组织降低期间水分水平的实例包括:(a)水分被保持、增加,或低于根据本发明进行治疗前对象正常范围(即其给药前水平)不超过大约1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30%;(b)水分被保持、增加,或低于其给药前水平不超过大约0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、或15%;(c)水分被保持、增加,或低于其给药前水平不超过大约0、1、2、3、4、5、6、7、8、9或10%;和(d)水分被保持、增加,或低于其给药前水平不超过大约0、1、2、3、4或5%。
西布曲明和奥利司他目前被销售用于治疗肥胖。这两个化合物通过完全不同的机理实现重量减轻。西布曲明,CNS食欲遏抑药,抑制5-羟色胺和去甲肾上腺素的神经元再摄取。奥利司他抑制负责分解摄取脂肪的肠道脂肪酶。
MAO-B抑制剂的作用机理被认为与食欲遏抑药、肠道脂肪酶抑制剂和其它具有相似适应症的药剂(例如5-羟色胺拮抗剂,瘦蛋白、脂肪酸合成酶抑制剂,单胺氧化酶(MAO)抑制剂)完全不同。通过产生例如相加或增效效应,MAO-B抑制剂与用于治疗上述适应症(例如肥胖、糖尿病、心脏代谢紊乱和其组合)的一种或多种其它药剂的共同给药有望是有利的。另外药剂的实例包括食欲遏抑药和脂肪酶抑制剂。因此,本发明提供治疗肥胖、糖尿病和/或心脏代谢紊乱的方法,其包括给予治疗上有效量的本发明所述化合物和第二成分,所述第二成分选自食欲遏抑药(例如西布曲明、芬特明(phentermine)、芬氟拉明(fenfluramine))和肠道脂肪酶抑制剂(例如奥利司他)。
MAO-B抑制剂有望促进体重减轻,而不会可感知地降低热量摄取。MAO-B抑制剂与食欲遏抑药共同给药有望对体重减轻产生相加或增效效应。类似地,MAO-B抑制剂与脂肪酶抑制剂共同给药有望对体重减轻产生相加或增效效 应。
化合物抑制MAO的能力可以采用R.Uebelhack等,Pharmacopsychiatry 31,1988,p187-192的方法(如下所述)进行测定。
富含血小板的血浆和血小板的制备。整夜禁食之后,在上午八点与八点半之间将来自健康对象的静脉血收集到含有EDTA采血管中(11.6mgEDTA/ml血液)。血液在20℃、250×g下离心过滤15分钟后,上清液富含血小板的血浆(PRP)被收集并且用细胞计数器(德国希尔敦的MOIAB)数出PRP中血小板的数目。2ml PRP在1500×g下被纺丝10分钟产生血小板小球。该小球用冰冷的盐水洗三次,在2ml、pH7.4的Soerensen磷酸盐缓冲液中再悬浮,并在-18℃下储存一天。
MAO试验。新鲜的PRP或冷冻的血小板悬浮液(100μl)一般分别在药物不存在或存在下、37℃下、100μl 0.9%的NaCl溶液或pH 7.4的磷酸盐缓冲液预温育10分钟。然后在37℃下加入50μl 2-苯基乙胺-[乙基-1-14C]盐酸盐(PEA)溶液(比活性为56 Ci/mol,Amersham)至终浓度为5μM,并且使该温育持续30分钟。通过加入50μl 4M的HClO4终止反应。MAO的反应产物苯乙醛被萃取到2ml正己烷中。将等分有机相加入到闪烁混合物中并用液体闪烁计数器测定放射能。具有合适血小板数目下,在至少60分钟内产物的形成与时间成线性关系。在温育混合物中加入2mM的巴吉林(pargyline)而得到空白值。所有试验重复进行一次。
化合物抑制MAO活性的能力也可以采用下述方法进行测定。编码人MAO-B的cDNA可以采用E.-J.Schlaeger和K.Christensen描述的方法(TransientGene Expression in Mammalian Cells Grown in Serum-free Suspension Culture;Cytotechnology,15:1-13,1998)被瞬时转染到EBNA细胞内。转染后,细胞通过Polytron匀浆器在20mM含有0.5mM EGTA和0.5mM苯甲基磺酰氯的pH8.0 TrisHCl(三(羟甲基)氨基甲烷盐酸盐)缓冲液中被匀浆化。通过在45,000×g下离心得到细胞膜,并且在用20mM含有0.5mM EGTA的pH8.0 Tris HCl缓冲液淋洗两次后,最后将膜在缓冲液中再悬浮并将等分式样在-80℃下储存直至使用。
MAO-B酶活性可以采用改编自M.Zhou和N.Panchuk-Voloshina所述方法(A One-Step Fluorometric Method for the Continuous Measurement ofMonoamine Oxidase Activity,Analytical Biochemistry,253:169-174,1997)的分光光度试验进行测定。简单地说,膜等分试样在0.1M磷酸钾缓冲溶液,pH 7.4,含有或不含各种浓度的所述化合物,于37℃下被温育30分钟。温育后,通过加入MAO 底物酪胺及1U/ml的辣根过氧化物酶(Roche Biochemicals)和80μM N-乙酰基-3,7-二羟基吩嗪(Amplex Red,Molecular Probes),开始酶反应。这些样品在终体积200μl,37℃下被进一步温育30分钟,并且用SpectraMax plate reader(MolecularDevices)在波长570nm下测定吸光度。对于MAO-B,在10μM盐酸司来吉兰的存在下测定背景(非特定的)吸光度。利用九个抑制剂浓度得到抑制曲线,各浓度测两次,通过将数据与四参数对数方程拟合,测定IC50值。
本发明所述化合物被期望是MAO-B抑制剂。如在本文所描述的试验中所测量,已经测试了代表性的化合物,并且已显示具有活性,因为发现它们的IC50值在≤10μM的范围内。如果本发明所述化合物具有小于或等于10μM的IC50 值,则它们被认为是MAO-B抑制剂。用于本发明的MAO-B抑制剂的期望活性水平的另外的实例包括:(a)1μM或以下的IC5O值,(b)0.1μM或以下的IC50值,(c)0.01μM或以下的IC50值,(d)0.001μM或以下的IC50值,和(e)0.0001μM或以下的IC50值。
在本发明中,MAO-B抑制剂(一个或多个)可以经肠、肠胃外、口服和经皮肤给药。本领域技术人员理解给予本发明化合物的途径可有明显不同。除了其它口服给药之外,缓释组合物可以是有利的。给药途径的其它实例包括注射(例如静脉内、肌肉内和腹膜内);皮下;皮下植入;口腔、舌下、局部、直肠、阴道和鼻内给药。也可采用生物侵蚀、非生物侵蚀、生物降解和非生物降解的给药系统。
如果制备片剂形式的固体组合物,主要活性成分可以与药物载体相混合,药物载体的实例包括硅石、淀粉、乳糖、硬脂酸镁和滑石。片剂可以包被上蔗糖或另一合适的物质或者它们可以被处理以具有持续的或延迟的活性并且持续释放预定量的活性成分。凝胶胶囊可以通过将活性成分与稀释剂混合并将得到的混合物结合到软或硬的凝胶胶囊中而得到。糖浆或酏剂可以含有活性成分以及甜味剂——其优选地是无热量的,防腐剂(例如对羟基苯甲酸甲酯和/或对羟基苯甲酸丙酯),调味剂和合适的色料。水可分散性粉末或颗粒可以含有活性成分,其混合有分散剂或润湿剂,或者混合有悬浮剂例如聚乙烯吡咯烷酮,以及混合有甜味剂或味道中和剂(taste corrector)。直肠给药可借助栓剂来实现,所述栓剂是利用在直肠温度下粘合剂融化(例如可可脂和/或聚乙二醇)制备的。肠胃外给药可使用含水悬浮液、等渗盐水溶液或可注射无菌溶液来实现,其含有药理上相容的分散剂和/或润湿剂(例如丙二醇和/或聚乙二醇)。活性成分任选地用一个或多个载体或添加剂配制成微胶囊或微球。活性成分也可以与环糊精形成的复合物的形式存在,例如α-环糊精、β-环糊精或γ-环糊精、2-羟丙基-β-环糊精和/或甲基-β-环 糊精。
MAO-B抑制剂每天给药的剂量将在个体基础上有所变化,并且在某种程度上可由所治疗的疾病(例如肥胖)的严重程度来决定。MAO-B抑制剂的剂量也将根据所给药的MAO-B抑制剂而变化。MAO-B抑制剂剂量范围的实例大约从0.001、0.002、0.003、0.004、0.005、0.006、0.007、0.008、0.009、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9、1.0、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、76、80、85、90、95至100mg/kg哺乳动物体重。MAO-B抑制剂可以以单剂量给药或在一段时期内以多个更小的剂量给药。MAO-B抑制剂被给予的时间长度根据个体基础而异,并且可持续直到达到期望的结果(即人体脂肪减少,或人体脂肪的增加被阻止)。因此,治疗可持续一天至几周、几个月甚或几年,这取决于被治疗对象、期望的结果、以及受体对本发明所述治疗的反应有多快。
本发明所述片剂的可能实例如下。
成分 mg/片
活性成分 100
粉末状乳糖 95
白玉米淀粉 35
聚乙烯吡咯烷酮 8
羧甲基淀粉钠 10
硬脂酸镁 2
药片重量 250
本发明所述胶囊的可能实例如下。
成分 mg/片
活性成分 50
结晶乳糖 60
微晶纤维素 34
滑石 5
硬脂酸镁 1
胶囊填充重量 150
在上述胶囊中,该活性成分具有合适的颗粒大小。结晶乳糖和微晶纤维素相互均匀混合,筛选,然后将滑石和硬脂酸镁混合其中。最终的混合物被装填入合适大小的硬凝胶胶囊里。
本发明所述注射溶液的可能实例如下。
成分 mg/片
活性物质 1.0mg
1 N HCl 20.0μl
乙酸 0.5mg
NaCl 8.0mg
苯酚 10.0mg
1N NaOH 足够量至pH5
H2O 足够量至1ml
合成
本发明所述化合物可采用有机合成领域普通技术人员所熟知的许多方法制备。本发明所述化合物可采用下述方法以及有机合成化学领域已知的合成方法,或通过如本领域普通技术人员所理解的在其上的变更来合成。优选的方法非限定性地包括下述那些方法。这些反应在这样的溶剂中进行,所述溶剂适合所应用的试剂和材料并且适合被实施的变化。有机合成领域普通技术人员应当理解的是,分子上存在的官能度应当与所提出的变化相容。这将有时需要判断是改变合成步骤的顺序还是选择一个特定的工艺方案而不是另一个,以便得到本发明期望的化合物。还有应当认识到,在本领域中设计任何合成路线中另一主要的考虑因素是对用于保护本发明所述化合物中存在的活性官能团的保护基团的明智选择。为专业实施者描述许多可选方案的权威人士是Greene和Wuts(ProtectiveGroups In Organic Synthesis,Wiley and Sons,1991)。本文所引用的所有参考文献在此以其全部引入作为参考。
方案1
在方案1中,酮酸可以用甲醇和硫酸酯化(步骤a),并且接着在弱酸性介质中用炔丙胺和氰基硼氢钠处理应当提供炔丙基氨基酯(步骤b)。对应的酸可以通过在含有共溶剂的水溶液中用氢氧化锂处理而产生(步骤c)。可选地,该氨基酯可以进一步用溴代甲烷烷基化,产生叔氨基酯(步骤d),并且随后的氢氧化锂处理应当产生叔氨基酸(步骤e)。
方案2
如方案2所示,羟基-2,3-二氢-1-茚酮可以在溶剂例如DMF或THF中低温下用一当量的氢化钠和苄基溴进行苄化,以产生苄氧基-2,3-二氢-1-茚酮(步骤a)。该酮在二氯乙烷中在乙酸的存在下用炔丙胺和氰基硼氢钠处理应当产生仲胺(步骤b)。该仲胺在吡啶溶液中用三苯甲基氯保护应当产生三苯甲基化的仲胺(步骤c)。该保护的炔丙胺用正丁基锂脱质子化,接着用溴乙酸乙酯处理,应当产生酯(步骤d)。在乙酸中用干溴化氢处理应当导致失去三苯甲基保护基团,产生苄氧基氨基酯(步骤e),接着暴露于三氟乙酸应当提供羟基-2,3-二氢化茚基氨基酯(步骤f)。氢氧化锂处理应当产生仲氨基酸(步骤g)。可选地,如上所述,步骤e的苄氧基-2,3-二氢-1-茚酮氨基酯也可以被水解,产生该苄氧基-2,3-二氢-1-茚酮氨基酸,在其苯环上任选地可以具有卤素、CF3、烷基或烷氧基取代基。
方案2’
如方案2’所示,羟基-2,3-二氢-1-茚酮可以在丙酮中大约60℃下在碳酸钾存在下用各种苄基溴进行苄化,所述苄基溴任选地用各种基团(例如酯、烷基酯、烷氧基酯腈、烷基腈、烷氧基腈、卤素、CF3等)取代,产生取代的苄氧基-2,3-二氢-1-茚酮(步骤a)。在苯基上的取代基是腈的情况下,在大约30℃下在乙腈和乙酸中用炔丙胺和氰基硼氢钠处理这些酮应当提供仲胺(步骤b)。在大约室温下在碳酸钾存在下在DMSO中用30%的过氧化氢对这些腈进行水合应当产生酰胺(步骤c)。可选地,通过在二甲苯中回流下用叠氮钠和三辛基氯化锡处理,该腈可以被转化成四唑,接着在甲苯/THF溶液中用无水HCl进行三烃甲锡烷基加合 物(trialkylstannyl adduct)的裂解(步骤f)。在2,3-二氢-1-茚酮含有带有酯取代基的苄基基团的情况下,在30-50℃下在乙腈和乙酸中用炔丙胺进行还原性氨基化可产生氨基酯(步骤d)。在含水的THF中用氢氧化锂进行酯的水解可产生酸(步骤e)。卤素、烷基、烷氧基和CF3-取代的苄氧基-1,2-二氢化茚可以通过如上所述的还原性氨基化从2,3-二氢-1-茚酮中产生。
方案3
方案3描述了如何用三苯甲基氯保护2,3-二氢化茚基炔丙胺(雷沙吉兰)以产生三苯甲基化的仲胺(步骤a)。用正丁基锂处理,接着用氯甲酸甲酯处理,应当产生三苯甲基保护的氨基酯(步骤b),其可以在乙酸中用溴化氢去保护(步骤c)。相应的酸可以通过用氢氧化锂水溶液处理而产生(步骤d)。
方案4
如方案4所示,酮酸可以用甲醇和硫酸进行酯化(步骤a),并且接着在弱酸性介质中用炔丙胺和氰基硼氢钠处理应当提供炔丙基氨基酯(步骤b)。该仲胺可以用三苯甲基氯或其它合适的保护基进行保护,以得到被保护的酯(步骤c)。该酯然后可以用氢化铝锂还原,得到伯醇(步骤d),其经过用氢化钠脱质子化和用溴丙酸乙酯烷基化后应当提供酯(步骤e)。在乙酸或其它合适的去保护试剂中用溴化氢去掉保护基团应当提供仲氨基酯(步骤f),并且在水溶液中用氢氧化锂进行酯的水解应当产生氨基酸(步骤g)。
方案5
如方案5所述,酮酸可以用甲醇和硫酸进行酯化(步骤a),并且接着在弱酸性介质中用炔丙胺和氰基硼氢钠处理应当提供炔丙基氨基酯(步骤b)。该仲胺可以用三苯甲基氯或其它合适的保护基团进行保护,以得到被保护的酯(步骤c)。该酯然后可以用氢化铝锂还原,得到伯醇(步骤d),其经过用氢化钠脱质子化和用溴代甲烷烷基化后应当提供醚(步骤e)。该甲基醚用正丁基锂处理接着用碘乙酸乙酯进行烷基化,应当提供酯(步骤f)。随后在乙酸或其它合适的去保护试剂中用溴化氢进行胺的去保护(步骤g),并且接着在水溶液中用氢氧化锂进行酯的水解,应当产生氨基酸(步骤h)。
方案6
方案6表明,在大约室温或以上的温度下用溴乙酸乙酯和在丙酮中的碳酸钾进行羟基-2,3-二氢-1-茚酮的烷基化可以产生2,3-二氢-1-茚酮酯(步骤a)。该酮酯在大约30℃下乙酸存在下在乙腈中用炔丙胺和氰基硼氢钠处理可以提供仲胺(步骤b)。在水溶液中用氢氧化锂进行该酯的水解应当提供氨基酸(步骤c)。可选地,该酯可以在乙酸存在下在二氯乙烷中用甲醛液和三乙酰氧基硼氢化钠进行烷基化,以产生N-甲基类似物,其如上所述能够水解成酸。该2,3-二氢-1-茚酮在大约室温或以上的温度下在碳酸钾存在下在丙酮中用溴乙腈进行烷基化可以产生酮-腈(步骤d)。该酮-睛在大约30℃下乙酸存在下在乙腈中用炔丙胺和氰基硼氢钠处理可以提供仲胺(步骤e)。接着该腈在碳酸钾存在下在DMSO中用30%的过氧化氢进行水合作用可以提供酰胺(步骤f)。
方案7
如方案7所示,氨基醇可以用STABASE(1,1,4,4-四甲基二甲硅烷基氮杂-环戊烷(1,1,4,4-tetramethydisilylaza-yclopentane))、芳基醛或其它合适的保护试剂处理,以得到被保护的氨基醇(步骤a)。然后该醇用氢化钠脱质子化并且用溴丁酸乙酯烷基化,以产生酯(步骤b)。利用在甲醇中的甲苯磺酸(STABASE)去除此保护基团或在适于其它保护基的其它合适的条件下去除保护基团,在中和后,应当提供伯氨基酯(步骤c)。该胺在弱酸性潮湿条件下用丙炔醛二乙基乙缩醛(propioaldehyde diethyl acetal)和氰基硼氢钠处理应当产生炔丙基氨基酯(步骤d)。该胺利用甲醛液和氰基硼氢钠进一步烷基化可以提供甲基化的叔氨基酯(步骤e)。接着在水溶液中用氢氧化锂处理仲氨基酯(步骤f)或叔氨基酯(步骤g)应当分别产生仲氨基酸和叔氨基酸。
方案8
方案8显示了在溶剂例如甲苯、乙醇或醚中当用卤代烷例如溴代甲烷或碘代甲烷处理时,叔氨基1,-二氢化茚如何能够得到对应的季铵盐,其中Z可以是H或O(CH2)n-苯基,并且苯基可任选地用卤素或CF3取代。在室温下这些叔胺在二氯甲烷中用Davis试剂(苯基氧氮丙啶苯-磺酰胺(phenyloxaziridinebenezene-sulfonamide))处理可得到对应的胺N-氧化物(步骤b)。
本发明所述化合物的一个立体异构体可以是比其对应物(一个或多个)更有效的MAO-B抑制剂。因此,立体异构体被包括在本发明中。这些立体异构体中的一些显示在下面的方案9-13中。当必需时,外消旋物质的分离可以通过使用手性柱的HPLC来实现,或者通过利用拆解试剂的拆分来实现,所述拆解试剂如在Wilen,S.H.Tables of Resolving Agents and Optical Resolutions 1972,308中所述,或者通过使用对映异构的纯酸和纯碱的拆分来实现。本发明所述手性化合物也可以直接合成,其使用手性催化剂或手性配体,例如Jacobsen,E.Ace.Chem.Res.2000,33,421-431,或者使用不对称合成领域普通技术人员所熟知的其它对映体或非对映体选择性反应和试剂。
方案9
方案10
方案11
方案12
方案13
本发明的其它特征在下述示例性实施方式的描述过程中将变得显而易见,所述实施方式被给出的目的是阐述本发明并且没有意欲对其进行限制。
实施例
下面的表A-C描述了本发明的实施例,其已经被合成并测试。这些化合物的活性如下。
+=IC50≤10μM;
++=IC50≤1μM;和
+++=IC50≤100nM。
根据每个实施例所提供的方案编号的方法,可以制备这些实施例。
表A
所有化合物是外消旋的:
表B
所有化合物是外消旋的:
表C
所有化合物是外消旋的:
N-CH2:3.51(s) N-CH:4.40(m) PhCH2O:5.06 芳香族H’s 6.85-7.45 | |||||
28 | CH2C6H5 | CH3 | + | 环-CH2:2.13(m) C≡CH:2.26(m) N-CH3:2.34(s) 环-CH:2.41(m) 环-CH:2.76(m) 环-CH:2.97(m) N-CH2:3.51(s) N-CH:4.46(m) PhCH2O:5.06 芳香族H’s 6.86-7.50 | 方案2 |
29 | CH2CH2C6H5 | H | + | 环-CH:1.92(m) C≡CH:2.27(m) 环-CH:2.41(m) 环-CH:2.75(m) 环-CH:3.00(m) PhOCH2:3.10(t) N-CH2:3.52(q) PhOCH2:4.19(t) N-CH:4.41(t) 芳香族H’s 6.77-7.37 | 方案2 |
30 | CH2CO2Et | CH3 | + | 酯-CH3:1.30(t) 环-CH2:2.13(m) C≡CH:2.26(m) N-CH3:2.32(s) 环-CH:2.74(m) 环-CH:2.89(m) N-CH2:3.51(s) 酯-CH2:4.27(q) N-CH:4.43(m) 芳香族H’s 6.81-7.28 | 方案6 |
31 | CH2CH=CHCO2Et | CH3 | ++ | 酯-CH3:1.30(t) 环-CH2:2.16(m) C≡CH:2.29(m) N-CH3:2.37(s) 环-CH:2.77(m) 环-CH:2.90(m) N-CH2:3.37(m) 酯-CH2:4.20(q) N-CH:4.48(m) OCH2-乙烯基:4.70(m) CH=:6.19 (dt) CH=:7.07 (dt) 芳香族H’s 6.80-7.15 | 方案6 |
32 | CH2CH=CHCO2Et | H | + | 酯-CH3:1.30(t) 环-CH:1.95(m) C≡CH:2.32(m) 环-CH:2.44(m) 环-CH:2.78(m) 环-CH:3.00(m) N-CH2:3.54(m) | 方案6 |
酯-CH2:4.21(q) N-CH:4.45(m) OCH2-乙烯基:4.70(m) CH=:6.19(dt) CH=:7.07(dt) 芳香族H’s 6.80-7.2 | |||||
33 | CH2C6H5CO2Me(4) | CH3 | + | 环-CH2:2.15(m) C≡CH:2.27(m) N-CH3:2.35(s) 环-CH:2.75(m) 环-CH:2.89(m) N-CH2:3.35(m) OCH3:3.92(s) N-CH:4.45(m) PhOCH2:5.13(q) 芳香族H’s 6.86-8.05 | 方案2’ |
34 | CH2C6H5CO2Me(4) | H | + | 环-CH:1.95(m) C≡CH:2.26(m) 环-CH:2.43(m) 环-CH:2.77(m) 环-CH:2.95(m) N-CH2:3.51(q) OCH3:3.92(s) N-CH:4.38(m) PhOCH2:5.12(s) 芳香族H’s 6.83-8.10 | 方案2’ |
35 | CH2C6H5CO2Me(3) | H | + | 环-CH:1.93(m) C≡CH:2.29(m) 环-CH:2.42(m) 环-CH:2.77(m) 环-CH:2.97(m) N-CH2:3.51(q) OCH3:3.93(s) N-CH:4.42(t) PhOCH2:5.10(s) 芳香族H’s 6.85-8.15 | 方案2’ |
36 | CH2C6H5OCH2CN(3) | H | ++ | (CDCl3) 环-CH:1.87(m) C≡CH:2.27(m) 环-CH:2.43(m) 环-CH:2.77(m) 环-CH:2.95(m) N-CH2:3.50(q) N-CH:4.37(t) O-CH2CN:4.78(s) PhCH2O:5.06(s) 芳香族H’s 6.83-7.38 | 方案2’ |
37 | CH2C6H5CN(3) | H | + | (CDCl3) 环-CH:1.87(m) C≡CH:2.28(m) 环-CH:2.44(m) 环-CH:2.78(m) 环-CH:2.95(m) N-CH2:3.51(q) N-CH:4.38(t) | 方案2’ |
PhCH2O:5.08(s) 芳香族H’s 6.82-7.73 | |||||
38 | CH2C6H5CONH2(3) | H | + | (CD3OD) 环-CH:1.88(m) 环-CH:2.37(m) C≡CH:2.67(m) 环-CH:2.75(m) 环-CH:2.94(m) N-CH2:3.43(q) N-CH:4.38(t) PhCH2O:5.13(s) 芳香族H’s 6.86-7.97 | 方案2’ |
表I-VI显示了本发明所述化合物的代表性实施例。在每个表中的每个实施例代表了本发明的单个种类。
表I
Ex.# | X | X1 | R | R1 |
1 | H | H | CH3 | H |
2 | H | H | H | H |
3 | H | H | CH3 | CH3 |
4 | H | H | H | CH3 |
5 | OH | H | CH3 | H |
6 | OH | H | H | H |
7 | OH | H | CH3 | CH3 |
8 | OH | H | H | CH3 |
9 | H | OH | CH3 | H |
10 | H | OH | H | H |
11 | H | OH | CH3 | CH3 |
12 | H | OH | H | CH3 |
13 | OCH3 | H | CH3 | H |
14 | OCH3 | H | H | H |
15 | OCH3 | H | CH3 | CH3 |
16 | OCH3 | H | H | CH3 |
17 | H | OCH3 | CH3 | H |
18 | H | OCH3 | H | H |
19 | H | OCH3 | CH3 | CH3 |
20 | H | OCH3 | H | CH3 |
21 | OCH2C6H5 | H | CH3 | H |
22 | OCH2C6H5 | H | H | H |
23 | OCH2C6H5 | H | CH3 | CH3 |
24 | OCH2C6H5 | H | H | CH3 |
25 | H | OCH2C6H5 | CH3 | H |
26 | H | OCH2C6H5 | H | H |
27 | H | OCH2C6H5 | CH3 | CH3 |
28 | H | OCH2C6H5 | H | CH3 |
29 | OCH2C6H5 | H | CH3 | H |
30 | OCH2C6H5 | H | H | H |
31 | OCH2C6H5 | H | CH3 | CH3 |
32 | OCH2C6H5 | H | H | CH3 |
33 | OCH2CH2C6H5 | H | CH3 | H |
34 | OCH2CH2C6H5 | H | H | H |
35 | OCH2CH2C6H5 | H | CH3 | CH3 |
36 | OCH2CH2C6H5 | H | H | CH3 |
37 | H | OCH2CH2C6H5 | CH3 | H |
38 | H | OCH2CH2C6H5 | H | H |
39 | H | OCH2CH2C6H5 | CH3 | CH3 |
40 | H | OCH2CH2C6H5 | H | CH3 |
41 | OCH2CH=CH2 | H | CH3 | H |
42 | OCH2CH=CH2 | H | H | H |
43 | OCH2CH=CH2 | H | CH3 | CH3 |
44 | OCH2CH=CH2 | H | H | CH3 |
45 | H | OCH2CH=CH2 | CH3 | H |
46 | H | OCH2CH=CH2 | H | H |
47 | H | OCH2CH=CH2 | CH3 | CH3 |
48 | H | OCH2CH=CH2 | H | CH3 |
49 | OCH2CONH2 | H | CH3 | H |
50 | OCH2CONH2 | H | H | H |
51 | OCH2CONH2 | H | CH3 | CH3 |
52 | OCH2CONH2 | H | H | CH3 |
53 | H | OCH2CONH2 | CH3 | H |
54 | H | OCH2CONH2 | H | H |
55 | H | OCH2CONH2 | CH3 | CH3 |
56 | H | OCH2CONH2 | H | CH3 |
57 | Br | H | CH3 | H |
58 | Br | H | H | H |
59 | Br | H | CH3 | CH3 |
60 | Br | H | H | CH3 |
61 | H | Cl | CH3 | H |
62 | H | Cl | H | H |
63 | H | Cl | CH3 | CH3 |
64 | H | Cl | H | CH3 |
65 | NO2 | H | CH3 | H |
66 | NO2 | H | H | H |
67 | NO2 | H | CH3 | CH3 |
68 | NO2 | H | H | CH3 |
69 | NH2 | H | CH3 | H |
70 | NH2 | H | H | H |
71 | NH2 | H | CH3 | CH3 |
72 | NH2 | H | H | CH3 |
73 | NHSO2CH3 | H | CH3 | H |
74 | NHSO2CH3 | H | H | H |
75 | NHSO2CH3 | H | CH3 | CH3 |
76 | NHSO2CH3 | H | H | CH3 |
77 | H | CH3 | CH3 | H |
78 | H | CH3 | H | H |
79 | H | CH3 | CH3 | CH3 |
80 | H | CH3 | H | CH3 |
表IIa
Ex.# | X | X1 | R1 |
1. | H | H | CO2CH2CH3 |
2. | H | H | CO2H |
3. | OH | H | CO2CH2CH3 |
4. | OH | H | CO2H |
5. | OCH3 | H | CO2CH2CH3 |
6. | OCH3 | H | CO2H |
7. | OCH2CH=CH2 | H | CO2CH2CH3 |
8. | OCH2CH=CH2 | H | CO2H |
9. | OCH2C6H5 | H | CO2CH2CH3 |
10. | OCH2C6H5 | H | CO2H |
11. | OCH2CH2C6H5 | H | CO2CH2CH3 |
12. | OCH2CH2C6H5 | H | CO2H |
13. | OCH2CONH2 | H | CO2CH2CH3 |
14. | OCH2CONH2 | H | CO2H |
15. | H | Cl | CO2CH2CH3 |
16. | H | Cl | CO2H |
17. | Br | H | CO2CH2CH3 |
18. | Br | H | CO2H |
19. | H | CH3 | CO2CH2CH3 |
20. | H | CH3 | CO2H |
21. | NO2 | H | CO2CH2CH3 |
22. | NO2 | H | CO2H |
23. | NH2 | H | CO2CH2CH3 |
24. | NH2 | H | CO2H |
25. | NHSO2CH3 | H | CO2CH2CH3 |
26. | NHSO2CH3 | H | CO2H |
27. | H | OH | CO2CH2CH3 |
28. | H | OH | CO2H |
29. | H | OCH3 | CO2CH2CH3 |
30. | H | OCH3 | CO2H |
31. | H | OCH2CH=CH2 | CO2CH2CH3 |
32. | H | OCH2CH=CH2 | CO2H |
33. | H | OCH2C6H5 | CO2CH2CH3 |
34. | H | OCH2C6H5 | CO2H |
35. | H | OCH2CH2C6H5 | CO2CH2CH3 |
36. | H | OCH2CH2C6H5 | CO2H |
37. | H | OCH2CONH2 | CO2CH2CH3 |
38. | H | OCH2CONH2 | CO2H |
39. | H | H | CH2CO2CH2CH3 |
40. | H | H | CH2CO2H |
41. | OH | H | CH2CO2CH2CH3 |
42. | OH | H | CH2CO2H |
43. | OCH3 | H | CH2CO2CH2CH3 |
44. | OCH3 | H | CH2CO2H |
45. | OCH2CH=CH2 | H | CH2CO2CH2CH3 |
46. | OCH2CH=CH2 | H | CH2CO2H |
47. | OCH2C6H5 | H | CH2CO2CH2CH3 |
48. | OCH2C6H5 | H | CH2CO2H |
49. | OCH2CH2C6H5 | H | CH2CO2CH2CH3 |
50. | OCH2CH2C6H5 | H | CH2CO2H |
51. | OCH2CONH2 | H | CH2CO2CH2CH3 |
52. | OCH2CONH2 | H | CH2CO2H |
53. | H | Cl | CH2CO2CH2CH3 |
54. | H | Cl | CH2CO2H |
55. | Br | H | CH2CO2CH2CH3 |
56. | Br | H | CH2CO2H |
57. | H | CH3 | CH2CO2CH2CH3 |
58. | H | CH3 | CH2CO2H |
59. | NO2 | H | CH2CO2CH2CH3 |
60. | NO2 | H | CH2CO2H |
61. | NH2 | H | CH2CO2CH2CH3 |
62. | NH2 | H | CH2CO2H |
63. | NHSO2CH3 | H | CH2CO2CH2CH3 |
64. | NHSO2CH3 | H | CH2CO2H |
65. | H | OH | CH2CO2CH2CH3 |
66. | H | OH | CH2CO2H |
67. | H | OCH3 | CH2CO2CH2CH3 |
68. | H | OCH3 | CH2CO2H |
69. | H | OCH2CH=CH2 | CH2CO2CH2CH3 |
70. | H | OCH2CH=CH2 | CH2CO2H |
71. | H | OCH2C6H5 | CH2CO2CH2CH3 |
72. | H | OCH2C6H5 | CH2CO2H |
73. | H | OCH2CH2C6H5 | CH2CO2CH2CH3 |
74. | H | OCH2CH2C6H5 | CH2CO2H |
75. | H | OCH2CONH2 | CH2CO2CH2CH3 |
76. | H | OCH2CONH2 | CH2CO2H |
77. | H | H | CH2CH2CO2CH2CH3 |
78. | H | H | CH2CH2CO2H |
79. | OH | H | CH2CO2CH2CH2CH3 |
80. | OH | H | CH2CH2CO2H |
81. | OCH3 | H | CH2CH2CO2CH2CH3 |
82. | OCH3 | H | CH2CH2CO2H |
83. | OCH2CH=CH2 | H | CH2CO2CH2CH2CH3 |
84. | OCH2CH=CH2 | H | CH2CH2CO2H |
85. | OCH2C6H5 | H | CH2CH2CO2CH2CH3 |
86. | OCH2C6H5 | H | CH2CH2CO2H |
87. | OCH2CH2C6H5 | H | CH2CO2CH2CH2CH3 |
88. | OCH2CH2C6H5 | H | CH2CH2CO2H |
89. | OCH2CONH2 | H | CH2CH2CO2CH2CH3 |
90. | OCH2CONH2 | H | CH2CH2CO2H |
91. | H | Cl | CH2CO2CH2CH2CH3 |
92. | H | Cl | CH2CH2CO2H |
93. | Br | H | CH2CH2CO2CH2CH3 |
94. | Br | H | CH2CH2CO2H |
95. | H | CH3 | CH2CO2CH2CH2CH3 |
96. | H | CH3 | CH2CH2CO2H |
97. | NO2 | H | CH2CH2CO2CH2CH3 |
98. | NO2 | H | CH2CH2CO2H |
99. | NH2 | H | CH2CO2CH2CH2CH3 |
100. | NH2 | H | CH2CH2CO2H |
101. | NHSO2CH3 | H | CH2CH2CO2CH2CH3 |
102. | NHSO2CH3 | H | CH2CH2CO2H |
103. | H | OH | CH2CO2CH2CH2CH3 |
104. | H | OH | CH2CH2CO2H |
105. | H | OCH3 | CH2CH2CO2CH2CH3 |
106. | H | OCH3 | CH2CH2CO2H |
107. | H | OCH2CH=CH2 | CH2CO2CH2CH2CH3 |
108. | H | OCH2CH=CH2 | CH2CH2CO2H |
109. | H | OCH2C6H5 | CH2CH2CO2CH2CH3 |
110. | H | OCH2C6H5 | CH2CH2CO2H |
111. | H | OCH2CH2C6H5 | C H2CO2CH2CH2CH3 |
112. | H | OCH2CH2C6H5 | CH2CH2CO2H |
113. | H | OCH2CONH2 | CH2CH2CO2CH2CH3 |
114. | H | OCH2CONH2 | CH2CH2CO2H |
115. | H | H | CH2CH2PO(OCH2CH3)2 |
116. | H | H | CH2CH2PO(OH)2 |
117. | OH | H | CH2CH2PO(OCH2CH3)2 |
118. | OH | H | CH2CH2PO(OH)2 |
119. | OCH3 | H | CH2CH2PO(OCH2CH3)2 |
120. | OCH3 | H | CH2CH2PO(OH)2 |
121. | OCH2CH=CH2 | H | CH2CH2PO(OCH2CH3)2 |
122. | OCH2CH=CH2 | H | CH2CH2PO(OH)2 |
123. | OCH2C6H5 | H | CH2CH2PO(OCH2CH3)2 |
124. | OCH2C6H5 | H | CH2CH2PO(OH)2 |
125. | OCH2CH2C6H5 | H | CH2CH2PO(OCH2CH3)2 |
126. | OCH2CH2C6H5 | H | CH2CH2PO(OH)2 |
127. | OCH2CONH2 | H | CH2CH2PO(OCH2CH3)2 |
128. | OCH2CONH2 | H | CH2CH2PO(OH)2 |
129. | H | Cl | CH2CH2PO(OCH2CH3)2 |
130. | H | Cl | CH2CH2PO(OH)2 |
131. | Br | H | CH2CH2PO(OCH2CH3)2 |
132. | Br | H | CH2CH2PO(OH)2 |
133. | H | CH3 | CH2CH2PO(OCH2CH3)2 |
134. | H | CH3 | CH2CH2PO(OH)2 |
135. | NO2 | H | CH2CH2PO(OCH2CH3)2 |
136. | NO2 | H | CH2CH2PO(OH)2 |
137. | NH2 | H | CH2CH2PO(OCH2CH3)2 |
138. | NH2 | H | CH2CH2PO(OH)2 |
139. | NHSO2CH3 | H | CH2CH2PO(OCH2CH3)2 |
140. | NHSO2CH3 | H | CH2CH2PO(OH)2 |
141. | H | OH | CH2CH2PO(OCH2CH3)2 |
142. | H | OH | CH2CH2PO(OH)2 |
143. | H | OCH3 | CH2CH2PO(OCH2CH3)2 |
144. | H | OCH3 | CH2CH2PO(OH)2 |
145. | H | OCH2CH=CH2 | CH2CH2PO(OCH2CH3)2 |
146. | H | OCH2CH=CH2 | CH2CH2PO(OH)2 |
147. | H | OCH2C6H5 | CH2CH2PO(OCH2CH3)2 |
148. | H | OCH2C6H5 | CH2CH2PO(OH)2 |
149. | H | OCH2CH2C6H5 | CH2CH2PO(OCH2CH3)2 |
150. | H | OCH2CH2C6H5 | CH2CH2PO(OH)2 |
151. | H | OCH2CONH2 | CH2CH2PO(OCH2CH3)2 |
152. | H | OCH2CONH2 | CH2CH2PO(OH)2 |
153. | H | H | CH2CH=CHCO2CH2CH3 |
154. | H | H | CH2CH=CHCO2H |
155. | OH | H | CH2CH=CHCO2CH2CH3 |
156. | OH | H | CH2CH=CHCO2H |
157. | OCH3 | H | CH2CH=CHCO2CH2CH3 |
158. | OCH3 | H | CH2CH=CHCO2H |
159. | OCH2CH=CH2 | H | CH2CH=CHCO2CH2CH3 |
160. | OCH2CH=CH2 | H | CH2CH=CHCO2H |
161. | OCH2C6H5 | H | CH2CH=CHCO2CH2CH3 |
162. | OCH2C6H5 | H | CH2CH=CHCO2H |
163. | OCH2CH2C6H5 | H | CH2CH=CHCO2CH2CH3 |
164. | OCH2CH2C6H5 | H | CH2CH=CHCO2H |
165. | OCH2CONH2 | H | CH2CH=CHCO2CH2CH3 |
166. | OCH2CONH2 | H | CH2CH=CHCO2H |
167. | H | Cl | CH2CH=CHCO2CH2CH3 |
168. | H | Cl | CH2CH=CHCO2H |
169. | Br | H | CH2CH=CHCO2CH2CH3 |
170. | Br | H | CH2CH=CHCO2H |
171. | H | CH3 | CH2CH=CHCO2CH2CH3 |
172. | H | CH3 | CH2CH=CHCO2H |
173. | NO2 | H | CH2CH=CHCO2CH2CH3 |
174. | NO2 | H | CH2CH=CHCO2H |
175. | NH2 | H | CH2CH=CHCO2CH2CH3 |
176. | NH2 | H | CH2CH=CHCO2H |
177. | NHSO2CH3 | H | CH2CH=CHCO2CH2CH3 |
178. | NHSO2CH3 | H | CH2CH=CHCO2H |
179. | H | OH | CH2CH=CHCO2CH2CH3 |
180. | H | OH | CH2CH=CHCO2H |
181. | H | OCH3 | CH2CH=CHCO2CH2CH3 |
182. | H | OCH3 | CH2CH=CHCO2H |
183. | H | OCH2CH=CH2 | CH2CH=CHCO2CH2CH3 |
184. | H | OCH2CH=CH2 | CH2CH=CHCO2H |
185. | H | OCH2C6H5 | CH2CH=CHCO2CH2CH3 |
186. | H | OCH2C6H5 | CH2CH=CHCO2H |
187. | H | OCH2CH2C6H5 | CH2CH=CHCO2CH2CH3 |
188. | H | OCH2CH2C6H5 | CH2CH=CHCO2H |
189. | H | OCH2CONH2 | CH2CH=CHCO2CH2CH3 |
190. | H | OCH2CONH2 | CH2CH=CHCO2H |
表IIb
Ex.# | X | X1 | R1 |
1. | H | H | CO2CH2CH3 |
2. | H | H | CO2H |
3. | OH | H | CO2CH2CH3 |
4. | OH | H | CO2H |
5. | OCH3 | H | CO2CH2CH3 |
6. | OCH3 | H | CO2H |
7. | OCH2CH=CH2 | H | CO2CH2CH3 |
8. | OCH2CH=CH2 | H | CO2H |
9. | OCH2C6H5 | H | CO2CH2CH3 |
10. | OCH2C6H5 | H | CO2H |
11. | OCH2CH2C6H5 | H | CO2CH2CH3 |
12. | OCH2CH2C6H5 | H | CO2H |
13. | OCH2CONH2 | H | CO2CH2CH3 |
14. | OCH2CONH2 | H | CO2H |
15. | H | Cl | CO2CH2CH3 |
16. | H | Cl | CO2H |
17. | Br | H | CO2CH2CH3 |
18. | Br | H | CO2H |
19. | H | CH3 | CO2CH2CH3 |
20. | H | CH3 | CO2H |
21. | NO2 | H | CO2CH2CH3 |
22. | NO2 | H | CO2H |
23. | NH2 | H | CO2CH2CH3 |
24. | NH2 | H | CO2H |
25. | NHSO2CH3 | H | CO2CH2CH3 |
26. | NHSO2CH3 | H | CO2H |
27. | H | OH | CO2CH2CH3 |
28. | H | OH | CO2H |
29. | H | OCH3 | CO2CH2CH3 |
30. | H | OCH3 | CO2H |
31. | H | OCH2CH=CH2 | CO2CH2CH3 |
32. | H | OCH2CH=CH2 | CO2H |
33. | H | OCH2C6H5 | CO2CH2CH3 |
34. | H | OCH2C6H5 | CO2H |
35. | H | OCH2CH2C6H5 | CO2CH2CH3 |
36. | H | OCH2CH2C6H5 | CO2H |
37. | H | OCH2CONH2 | CO2CH2CH3 |
38. | H | OCH2CONH2 | CO2H |
39. | H | H | CH2CO2CH2CH3 |
40. | H | H | CH2CO2H |
41. | OH | H | CH2CO2CH2CH3 |
42. | OH | H | CH2CO2H |
43. | OCH3 | H | CH2CO2CH2CH3 |
44. | OCH3 | H | CH2CO2H |
45. | OCH2CH=CH2 | H | CH2CO2CH2CH3 |
46. | OCH2CH=CH2 | H | CH2CO2H |
47. | OCH2C6H5 | H | CH2CO2CH2CH3 |
48. | OCH2C6H5 | H | CH2CO2H |
49. | OCH2CH2C6H5 | H | CH2CO2CH2CH3 |
50. | OCH2CH2C6H5 | H | CH2CO2H |
51. | OCH2CONH2 | H | CH2CO2CH2CH3 |
52. | OCH2CONH2 | H | CH2CO2H |
53. | H | Cl | CH2CO2CH2CH3 |
54. | H | Cl | CH2CO2H |
55. | Br | H | CH2CO2CH2CH3 |
56. | Br | H | CH2CO2H |
57. | H | CH3 | CH2CO2CH2CH3 |
58. | H | CH3 | CH2CO2H |
59. | NO2 | H | CH2CO2CH2CH3 |
60. | NO2 | H | CH2CO2H |
61. | NH2 | H | CH2CO2CH2CH3 |
62. | NH2 | H | CH2CO2H |
63. | NHSO2CH3 | H | CH2CO2CH2CH3 |
64. | NHSO2CH3 | H | CH2CO2H |
65. | H | OH | CH2CO2CH2CH3 |
66. | H | OH | CH2CO2H |
67. | H | OCH3 | CH2CO2CH2CH3 |
68. | H | OCH3 | CH2CO2H |
69. | H | OCH2CH=CH2 | CH2CO2CH2CH3 |
70. | H | OCH2CH=CH2 | CH2CO2H |
71. | H | OCH2C6H5 | CH2CO2CH2CH3 |
72. | H | OCH2C6H5 | CH2CO2H |
73. | H | OCH2CH2C6H5 | CH2CO2CH2CH3 |
74. | H | OCH2CH2C6H5 | CH2CO2H |
75. | H | OCH2CONH2 | CH2CO2CH2CH3 |
76. | H | OCH2CONH2 | CH2CO2H |
77. | H | H | CH2CH2CO2CH2CH3 |
78. | H | H | CH2CH2CO2H |
79. | OH | H | CH2CO2CH2CH2CH3 |
80. | OH | H | CH2CH2CO2H |
81. | OCH3 | H | CH2CH2CO2CH2CH3 |
82. | OCH3 | H | CH2CH2CO2H |
83. | OCH2CH=CH2 | H | CH2CO2CH2CH2CH3 |
84. | OCH2CH=CH2 | H | CH2CH2CO2H |
85. | OCH2C6H5 | H | CH2CH2CO2CH2CH3 |
86. | OCH2C6H5 | H | CH2CH2CO2H |
87. | OCH2CH2C6H5 | H | CH2CO2CH2CH2CH3 |
88. | OCH2CH2C6H5 | H | CH2CH2CO2H |
89. | OCH2CONH2 | H | CH2CH2CO2CH2CH3 |
90. | OCH2CONH2 | H | CH2CH2CO2H |
91. | H | Cl | CH2CO2CH2CH2CH3 |
92. | H | Cl | CH2CH2CO2H |
93. | Br | H | CH2CH2CO2CH2CH3 |
94. | Br | H | CH2CH2CO2H |
95. | H | CH3 | CH2CO2CH2CH2CH3 |
96. | H | CH3 | CH2CH2CO2H |
97. | NO2 | H | CH2CH2CO2CH2CH3 |
98. | NO2 | H | CH2CH2CO2H |
99. | NH2 | H | CH2CO2CH2CH2CH3 |
100. | NH2 | H | CH2CH2CO2H |
101. | NHSO2CH3 | H | CH2CH2CO2CH2CH3 |
102. | NHSO2CH3 | H | CH2CH2CO2H |
103. | H | OH | CH2CO2CH2CH2CH3 |
104. | H | OH | CH2CH2CO2H |
105. | H | OCH3 | CH2CH2CO2CH2CH3 |
106. | H | OCH3 | CH2CH2CO2H |
107. | H | OCH2CH=CH2 | CH2CO2CH2CH2CH3 |
108. | H | OCH2CH=CH2 | CH2CH2CO2H |
109. | H | OCH2C6H5 | CH2CH2CO2CH2CH3 |
110. | H | OCH2C6H5 | CH2CH2CO2H |
111. | H | OCH2CH2C6H5 | CH2CO2CH2CH2CH3 |
112. | H | OCH2CH2C6H5 | CH2CH2CO2H |
113. | H | OCH2CONH2 | CH2CH2CO2CH2CH3 |
114. | H | OCH2CONH2 | CH2CH2CO2H |
115. | H | H | CH2CH2PO(OCH2CH3)2 |
116. | H | H | CH2CH2PO(OH)2 |
117. | OH | H | CH2CH2PO(OCH2CH3)2 |
118. | OH | H | CH2CH2PO(OH)2 |
119. | OCH3 | H | CH2CH2PO(OCH2CH3)2 |
120. | OCH3 | H | CH2CH2PO(OH)2 |
121. | OCH2CH=CH2 | H | CH2CH2PO(OCH2CH3)2 |
122. | OCH2CH=CH2 | H | CH2CH2PO(OH)2 |
123. | OCH2C6H5 | H | CH2CH2PO(OCH2CH3)2 |
124. | OCH2C6H5 | H | CH2CH2PO(OH)2 |
125. | OCH2CH2C6H5 | H | CH2CH2PO(OCH2CH3)2 |
126. | OCH2CH2C6H5 | H | CH2CH2PO(OH)2 |
127. | OCH2CONH2 | H | CH2CH2PO(OCH2CH3)2 |
128. | OCH2CONH2 | H | CH2CH2PO(OH)2 |
129. | H | Cl | CH2CH2PO(OCH2CH3)2 |
130. | H | Cl | CH2CH2PO(OH)2 |
131. | Br | H | CH2CH2PO(OCH2CH3)2 |
132. | Br | H | CH2CH2PO(OH)2 |
133. | H | CH3 | CH2CH2PO(OCH2CH3)2 |
134. | H | CH3 | CH2CH2PO(OH)2 |
135. | NO2 | H | CH2CH2PO(OCH2CH3)2 |
136. | NO2 | H | CH2CH2PO(OH)2 |
137. | NH2 | H | CH2CH2PO(OCH2CH3)2 |
138. | NH2 | H | CH2CH2PO(OH)2 |
139. | NHSO2CH3 | H | CH2CH2PO(OCH2CH3)2 |
140. | NHSO2CH3 | H | CH2CH2PO(OH)2 |
141. | H | OH | CH2CH2PO(OCH2CH3)2 |
142. | H | OH | CH2CH2PO(OH)2 |
143. | H | OCH3 | CH2CH2PO(OCH2CH3)2 |
144. | H | OCH3 | CH2CH2PO(OH)2 |
145. | H | OCH2CH=CH2 | CH2CH2PO(OCH2CH3)2 |
146. | H | OCH2CH=CH2 | CH2CH2PO(OH)2 |
147. | H | OCH2C6H5 | CH2CH2PO(OCH2CH3)2 |
148. | H | OCH2C6H5 | CH2CH2PO(OH)2 |
149. | H | OCH2CH2C6H5 | CH2CH2PO(OCH2CH3)2 |
150. | H | OCH2CH2C6H5 | CH2CH2PO(OH)2 |
151. | H | OCH2CONH2 | CH2CH2PO(OCH2CH3)2 |
152. | H | OCH2CONH2 | CH2CH2PO(OH)2 |
153. | H | H | CH2CH=CHCO2CH2CH3 |
154. | H | H | CH2CH=CHCO2H |
155. | OH | H | CH2CH=CHCO2CH2CH3 |
156. | OH | H | CH2CH=CHCO2H |
157. | OCH3 | H | CH2CH=CHCO2CH2CH3 |
158. | OCH3 | H | CH2CH=CHCO2H |
159. | OCH2CH=CH2 | H | CH2CH=CHCO2CH2CH3 |
160. | OCH2CH=CH2 | H | CH2CH=CHCO2H |
161. | OCH2C6H5 | H | CH2CH=CHCO2CH2CH3 |
162. | OCH2C6H5 | H | CH2CH=CHCO2H |
163. | OCH2CH2C6H5 | H | CH2CH=CHCO2CH2CH3 |
164. | OCH2CH2C6H5 | H | CH2CH=CHCO2H |
165. | OCH2CONH2 | H | CH2CH=CHCO2CH2CH3 |
166. | OCH2CONH2 | H | CH2CH=CHCO2H |
167. | H | Cl | CH2CH=CHCO2CH2CH3 |
168. | H | Cl | CH2CH=CHCO2H |
169. | Br | H | CH2CH=CHCO2CH2CH3 |
170. | Br | H | CH2CH=CHCO2H |
171. | H | CH3 | CH2CH=CHCO2CH2CH3 |
172. | H | CH3 | CH2CH=CHCO2H |
173. | NO2 | H | CH2CH=CHCO2CH2CH3 |
174. | NO2 | H | CH2CH=CHCO2H |
175. | NH2 | H | CH2CH=CHCO2CH2CH3 |
176. | NH2 | H | CH2CH=CHCO2H |
177. | NHSO2CH3 | H | CH2CH=CHCO2CH2CH3 |
178. | NHSO2CH3 | H | CH2CH=CHCO2H |
179. | H | OH | CH2CH=CHCO2CH2CH3 |
180. | H | OH | CH2CH=CHCO2H |
181. | H | OCH3 | CH2CH=CHCO2CH2CH3 |
182. | H | OCH3 | CH2CH=CHCO2H |
183. | H | OCH2CH=CH2 | CH2CH=CHCO2CH2CH3 |
184. | H | OCH2CH=CH2 | CH2CH=CHCO2H |
185. | H | OCH2C6H5 | CH2CH=CHCO2CH2CH3 |
186. | H | OCH2C6H5 | CH2CH=CHCO2H |
187. | H | OCH2CH2C6H5 | CH2CH=CHCO2CH2CH3 |
188. | H | OCH2CH2C6H5 | CH2CH=CHCO2H |
189. | H | OCH2CONH2 | CH2CH=CHCO2CH2CH3 |
190. | H | OCH2CONH2 | CH2CH=CHCO2H |
表III
Ex.# | X | X1 | R1 | R” |
1. | H | H | H | CH2-CO2CH2CH3 |
2. | H | H | CH3 | CH2-CO2H |
3. | OH | H | H | CH2-CO2CH2CH3 |
4. | OH | H | CH3 | CH2-CO2H |
5. | OCH3 | H | H | CH2-CO2CH2CH3 |
6. | OCH3 | H | CH3 | CH2-CO2H |
7. | OCH2CH=CH2 | H | H | CH2-CO2CH2CH3 |
8. | OCH2CH=CH2 | H | CH3 | CH2-CO2H |
9. | OCH2C6H5 | H | H | CH2-CO2CH2CH3 |
10. | OCH2C6H5 | H | CH3 | CH2-CO2H |
11. | OCH2CH2C6H5 | H | H | CH2-CO2CH2CH3 |
12. | OCH2CH2C6H5 | H | CH3 | CH2-CO2H |
13. | OCH2-CONH2 | H | H | CH2-CO2CH2CH3 |
14. | OCH2-CONH2 | H | CH3 | CH2-CO2H |
15. | H | Cl | H | CH2-CO2CH2CH3 |
16. | H | Cl | CH3 | CH2-CO2H |
17. | Br | H | H | CH2-CO2CH2CH3 |
18. | Br | H | CH3 | CH2-CO2H |
19. | H | CH3 | H | CH2-CO2CH2CH3 |
20. | H | CH3 | CH3 | CH2-CO2H |
21. | NO2 | H | H | CH2-CO2CH2CH3 |
22. | NO2 | H | CH3 | CH2-CO2H |
23. | NH2 | H | H | CH2-CO2CH2CH3 |
24. | NH2 | H | CH3 | CH2-CO2H |
25. | NHSO2CH3 | H | H | CH2-CO2CH2CH3 |
26. | NHSO2CH3 | H | CH3 | CH2-CO2H |
27. | H | OH | H | CH2-CO2CH2CH3 |
28. | H | OH | CH3 | CH2-CO2H |
29. | H | OCH3 | H | CH2-CO2CH2CH3 |
30. | H | OCH3 | CH3 | CH2-CO2H |
31. | H | OCH2CH=CH2 | H | CH2-CO2CH2CH3 |
32. | H | OCH2CH=CH2 | CH3 | CH2-CO2H |
33. | H | OCH2C6H5 | H | CH2-CO2CH2CH3 |
34. | H | OCH2C6H5 | CH3 | CH2-CO2H |
35. | H | OCH2CH2C6H5 | H | CH2-CO2CH2CH3 |
36. | H | OCH2CH2C6H5 | CH3 | CH2-CO2H |
37. | H | OCH2-CONH2 | H | CH2-CO2CH2CH3 |
38. | H | OCH2-CONH2 | CH3 | CH2-CO2H |
39. | H | H | H | CH2CH2-CO2CH2C H3 |
40. | H | H | CH3 | CH2CH2-CO2H |
41. | OH | H | H | CH2CH2-CO2CH2C H3 |
42. | OH | H | CH3 | CH2CH2-CO2H |
43. | OCH3 | H | H | CH2CH2-CO2CH2C H3 |
44. | OCH3 | H | CH3 | CH2CH2-CO2H |
45. | OCH2CH=CH2 | H | H | CH2CH2-CO2CH2C H3 |
46. | OCH2CH=CH2 | H | CH3 | CH2CH2-CO2H |
47. | OCH2C6H5 | H | H | CH2CH2-CO2CH2C H3 |
48. | OCH2C6H5 | H | CH3 | CH2CH2-CO2H |
49. | OCH2CH2C6H5 | H | H | CH2CH2-CO2CH2C H3 |
50. | OCH2CH2C6H5 | H | CH3 | CH2CH2-CO2H |
51. | OCH2-CONH2 | H | H | CH2CH2-CO2CH2C H3 |
52. | OCH2-CONH2 | H | CH3 | CH2CH2-CO2H |
53. | H | Cl | H | CH2CH2-CO2CH2C H3 |
54. | H | Cl | CH3 | CH2CH2-CO2H |
55. | Br | H | H | CH2CH2-CO2CH2C H3 |
56. | Br | H | CH3 | CH2CH2-CO2H |
57. | H | CH3 | H | CH2CH2-CO2CH2C H3 |
58. | H | CH3 | CH3 | CH2CH2-CO2H |
59. | NO2 | H | H | CH2CH2-CO2CH2C H3 |
60. | NO2 | H | CH3 | CH2CH2-CO2H |
61. | NH2 | H | H | CH2CH2-CO2CH2C H3 |
62. | NH2 | H | CH3 | CH2CH2-CO2H |
63. | NHSO2CH3 | H | H | CH2CH2-CO2CH2C H3 |
64. | NHSO2CH3 | H | CH3 | CH2CH2-CO2H |
65. | H | OH | H | CH2CH2-CO2CH2C H3 |
66. | H | OH | CH3 | CH2CH2-CO2H |
67. | H | OCH3 | H | CH2CH2-CO2CH2C H3 |
68. | H | OCH3 | CH3 | CH2CH2-CO2H |
69. | H | OCH2CH=CH2 | H | CH2CH2-CO2CH2C H3 |
70. | H | OCH2CH=CH2 | CH3 | CH2CH2-CO2H |
71. | H | OCH2C6H5 | H | CH2CH2-CO2CH2C H3 |
72. | H | OCH2C6H5 | CH3 | CH2CH2-CO2H |
73. | H | OCH2CH2C6H5 | H | CH2CH2-CO2CH2C H3 |
74. | H | OCH2CH2C6H5 | CH3 | CH2CH2-CO2H |
75. | H | OCH2-CONH2 | H | CH2CH2-CO2CH2C |
H3 | ||||
76. | H | OCH2-CONH2 | CH3 | CH2CH2-CO2H |
77. | H | H | H | CH2CH2P-O(OCH2 CH3)2 |
78. | H | H | CH3 | CH2CH2P-O(OH)2 |
79. | OH | H | H | CH2CH2P-O(OCH2 CH3)2 |
80. | OH | H | CH3 | CH2CH2P-O(OH)2 |
81. | OCH3 | H | H | CH2CH2P-O(OCH2 CH3)2 |
82. | OCH3 | H | CH3 | CH2CH2P-O(OH)2 |
83. | OCH2CH=CH2 | H | H | CH2CH2P-O(OCH2 CH3)2 |
84. | OCH2CH=CH2 | H | CH3 | CH2CH2P-O(OH)2 |
85. | OCH2C6H5 | H | H | CH2CH2P-O(OCH2 CH3)2 |
86. | OCH2C6H5 | H | CH3 | CH2CH2P-O(OH)2 |
87. | OCH2CH2C6H5 | H | H | CH2CH2P-O(OCH2 CH3)2 |
88. | OCH2CH2C6H5 | H | CH3 | CH2CH2P-O(OH)2 |
89. | OCH2-CONH2 | H | H | CH2CH2P-O(OCH2 CH3)2 |
90. | OCH2-CONH2 | H | CH3 | CH2CH2P-O(OH)2 |
91. | H | Cl | H | CH2CH2P-O(OCH2 CH3)2 |
92. | H | Cl | CH3 | CH2CH2P-O(OH)2 |
93. | Br | H | H | CH2CH2P-O(OCH2 CH3)2 |
94. | Br | H | CH3 | CH2CH2P-O(OH)2 |
95. | H | CH3 | H | CH2CH2P-O(OCH2 CH3)2 |
96. | H | CH3 | CH3 | CH2CH2P-O(OH)2 |
97. | NO2 | H | H | CH2CH2P-O(OCH2 CH3)2 |
98. | NO2 | H | CH3 | CH2CH2P-O(OH)2 |
99. | NH2 | H | H | CH2CH2P-O(OCH2 CH3)2 |
100. | NH2 | H | CH3 | CH2CH2P-O(OH)2 |
101. | NHSO2CH3 | H | H | CH2CH2P-O(OCH2 CH3)2 |
102. | NHSO2CH3 | H | CH3 | CH2CH2P-O(OH)2 |
103. | H | OH | H | CH2CH2P-O(OCH2 CH3)2 |
104. | H | OH | CH3 | CH2CH2P-O(OH)2 |
105. | H | OCH3 | H | CH2CH2P-O(OCH2 CH3)2 |
106. | H | OCH3 | CH3 | CH2CH2P-O(OH)2 |
107. | H | OCH2CH=CH2 | H | CH2CH2P-O(OCH2 CH3)2 |
108. | H | OCH2CH=CH2 | CH3 | CH2CH2P-O(OH)2 |
109. | H | OCH2C6H5 | H | CH2CH2P-O(OCH2 CH3)2 |
110. | H | OCH2C6H5 | CH3 | CH2CH2P-O(OH)2 |
111. | H | OCH2CH2C6H5 | H | CH2CH2P-O(OCH2 CH3)2 |
112. | H | OCH2CH2C6H5 | CH3 | CH2CH2P-O(OH)2 |
113. | H | OCH2-CONH2 | H | CH2CH2P-O(OCH2 |
CH3)2 | ||||
114. | H | OCH2-CONH2 | CH3 | CH2CH2P-O(OH)2 |
115. | H | H | H | CH2CH=CH-CO2C H2CH3 |
116. | H | H | CH3 | CH2CH=CH-CO2H |
117. | OH | H | H | CH2CH=CH-CO2C H2CH3 |
118. | OH | H | CH3 | CH2CH=CH-CO2H |
119. | OCH3 | H | H | CH2CH=CH-CO2C H2CH3 |
120. | OCH3 | H | CH3 | CH2CH=CH-CO2H |
121. | OCH2CH=CH2 | H | H | CH2CH=CH-CO2C H2CH3 |
122. | OCH2CH=CH2 | H | CH3 | CH2CH=CH-CO2H |
123. | OCH2C6H5 | H | H | CH2CH=CH-CO2C H2CH3 |
124. | OCH2C6H5 | H | CH3 | CH2CH=CH-CO2H |
125. | OCH2CH2C6H5 | H | H | CH2CH=CH-CO2C H2CH3 |
126. | OCH2CH2C6H5 | H | CH3 | CH2CH=CH-CO2H |
127. | OCH2-CONH2 | H | H | CH2CH=CH-CO2C H2CH3 |
128. | OCH2-CONH2 | H | CH3 | CH2CH=CH-CO2H |
129. | H | Cl | H | CH2CH=CH-CO2C H2CH3 |
130. | H | Cl | CH3 | CH2CH=CH-CO2H |
131. | Br | H | H | CH2CH=CH-CO2C H2CH3 |
132. | Br | H | CH3 | CH2CH=CH-CO2H |
133. | H | CH3 | H | CH2CH=CH-CO2C H2CH3 |
134. | H | CH3 | CH3 | CH2CH=CH-CO2H |
135. | NO2 | H | H | CH2CH=CH-CO2C H2CH3 |
136. | NO2 | H | CH3 | CH2CH=CH-CO2H |
137. | NH2 | H | H | CH2CH=CH-CO2C H2CH3 |
138. | NH2 | H | CH3 | CH2CH=CH-CO2H |
139. | NHSO2CH3 | H | H | CH2CH=CH-CO2C H2CH3 |
140. | NHSO2CH3 | H | CH3 | CH2CH=CH-CO2H |
141. | H | OH | H | CH2CH=CH-CO2C H2CH3 |
142. | H | OH | CH3 | CH2CH=CH-CO2H |
143. | H | OCH3 | H | CH2CH=CH-CO2C H2CH3 |
144. | H | OCH3 | CH3 | CH2CH=CH-CO2H |
145. | H | OCH2CH=CH2 | H | CH2CH=CH-CO2C H2CH3 |
146. | H | OCH2CH=CH2 | CH3 | CH2CH=CH-CO2H |
147. | H | OCH2C6H5 | H | CH2CH=CH-CO2C H2CH3 |
148. | H | OCH2C6H5 | CH3 | CH2CH=CH-CO2H |
149. | H | OCH2CH2C6H5 | H | CH2CH=CH-CO2C H2CH3 |
150. | H | OCH2CH2C6H5 | CH3 | CH2CH=CH-CO2H |
151. | H | OCH2-CONH2 | H | CH2CH=CH-CO2C |
H2CH3 | ||||
152. | H | OCH2-CONH2 | CH3 | CH2CH=CH-CO2H |
153. | H | H | CH2-CO2CH2CH3 | CH3 |
154. | H | H | CH2-CO2H | CH3 |
155. | OH | H | CH2-CO2CH2CH3 | CH3 |
156. | OH | H | CH2-CO2H | CH3 |
157. | OCH3 | H | CH2-CO2CH2CH3 | CH3 |
158. | OCH3 | H | CH2-CO2H | CH3 |
159. | OCH2CH=CH2 | H | CH2-CO2CH2CH3 | CH3 |
160. | OCH2CH=CH2 | H | CH2-CO2H | CH3 |
161. | OCH2C6H5 | H | CH2-CO2CH2CH3 | CH3 |
162. | OCH2C6H5 | H | CH2-CO2H | CH3 |
163. | OCH2CH2C6H5 | H | CH2-CO2CH2CH3 | CH3 |
164. | OCH2CH2C6H5 | H | CH2-CO2H | CH3 |
165. | OCH2-CONH2 | H | CH2-CO2CH2CH3 | CH3 |
166. | OCH2-CONH2 | H | CH2-CO2H | CH3 |
167. | H | Cl | CH2-CO2CH2CH3 | CH3 |
168. | H | Cl | CH2-CO2H | CH3 |
169. | Br | H | CH2-CO2CH2CH3 | CH3 |
170. | Br | H | CH2-CO2H | CH3 |
171. | H | CH3 | CH2-CO2CH2CH3 | CH3 |
172. | H | CH3 | CH2-CO2H | CH3 |
173. | NO2 | H | CH2-CO2CH2CH3 | CH3 |
174. | NO2 | H | CH2-CO2H | CH3 |
175. | NH2 | H | CH2-CO2CH2CH3 | CH3 |
176. | NH2 | H | CH2-CO2H | CH3 |
177. | NHSO2CH3 | H | CH2-CO2CH2CH3 | CH3 |
178. | NHSO2CH3 | H | CH2-CO2H | CH3 |
179. | H | OH | CH2-CO2CH2CH3 | CH3 |
180. | H | OH | CH2-CO2H | CH3 |
181. | H | OCH3 | CH2-CO2CH2CH3 | CH3 |
182. | H | OCH3 | CH2-CO2H | CH3 |
183. | H | OCH2CH=CH2 | CH2-CO2CH2CH3 | CH3 |
184. | H | OCH2CH=CH2 | CH2-CO2H | CH3 |
185. | H | OCH2C6H5 | CH2-CO2CH2CH3 | CH3 |
186. | H | OCH2C6H5 | CH2-CO2H | CH3 |
187. | H | OCH2CH2C6H5 | CH2-CO2CH2CH3 | CH3 |
188. | H | OCH2CH2C6H5 | CH2-CO2H | CH3 |
189. | H | OCH2-CONH2 | CH2-CO2CH2CH3 | CH3 |
190. | H | OCH2-CONH2 | CH2-CO2H | CH3 |
191. | H | H | CH2CH2P-O(OCH 2CH3)2 | CH3 |
192. | H | H | CH2CH2P-O(OH)2 | CH3 |
193. | OH | H | CH2CH2P-O(OCH 2CH3)2 | CH3 |
194. | OH | H | CH2CH2P-O(OH)2 | CH3 |
195. | OCH3 | H | CH2CH2P-O(OCH 2CH3)2 | CH3 |
196. | OCH3 | H | CH2CH2P-O(OH)2 | CH3 |
197. | OCH2CH=CH2 | H | CH2CH2P-O(OCH 2CH3)2 | CH3 |
198. | OCH2CH=CH2 | H | CH2CH2P-O(OH)2 | CH3 |
199. | OCH2C6H5 | H | CH2CH2P-O(OCH 2CH3)2 | CH3 |
200. | OCH2C6H5 | H | CH2CH2P-O(OH)2 | CH3 |
201. | OCH2CH2C6H5 | H | CH2CH2P-O(OCH | CH3 |
2CH3)2 | ||||
202. | OCH2CH2C6H5 | H | CH2CH2P-O(OH)2 | CH3 |
203. | OCH2-CONH2 | H | CH2CH2P-O(OCH 2CH3)2 | CH3 |
204. | OCH2-CONH2 | H | CH2CH2P-O(OH)2 | CH3 |
205. | H | Cl | CH2CH2P-O(OCH 2CH3)2 | CH3 |
206. | H | Cl | CH2CH2P-O(OH)2 | CH3 |
207. | Br | H | CH2CH2P-O(OCH 2CH3)2 | CH3 |
208. | Br | H | CH2CH2P-O(OH)2 | CH3 |
209. | H | CH3 | CH2CH2P-O(OCH 2CH3)2 | CH3 |
210. | H | CH3 | CH2CH2P-O(OH)2 | CH3 |
211. | NO2 | H | CH2CH2P-O(OCH 2CH3)2 | CH3 |
212. | NO2 | H | CH2CH2P-O(OH)2 | CH3 |
213. | NH2 | H | CH2CH2P-O(OCH 2CH3)2 | CH3 |
214. | NH2 | H | CH2CH2P-O(OH)2 | CH3 |
215. | NHSO2CH3 | H | CH2CH2P-O(OCH 2CH3)2 | CH3 |
216. | NHSO2CH3 | H | CH2CH2P-O(OH)2 | CH3 |
217. | H | OH | CH2CH2P-O(OCH 2CH3)2 | CH3 |
218. | H | OH | CH2CH2P-O(OH)2 | CH3 |
219. | H | OCH3 | CH2CH2P-O(OCH 2CH3)2 | CH3 |
220. | H | OCH3 | CH2CH2P-O(OH)2 | CH3 |
221. | H | OCH2CH=CH2 | CH2CH2P-O(OCH 2CH3)2 | CH3 |
222. | H | OCH2CH=CH2 | CH2CH2P-O(OH)2 | CH3 |
223. | H | OCH2C6H5 | CH2CH2P-O(OCH 2CH3)2 | CH3 |
224. | H | OCH2C6H5 | CH2CH2P-O(OH)2 | CH3 |
225. | H | OCH2CH2C6H5 | CH2CH2P-O(OCH 2CH3)2 | CH3 |
226. | H | OCH2CH2C6H5 | CH2CH2P-O(OH)2 | CH3 |
227. | H | OCH2-CONH2 | CH2CH2P-O(OCH 2CH3)2 | CH3 |
228. | H | OCH2-CONH2 | CH2CH2P-O(OH)2 | CH3 |
229. | H | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
230. | H | H | CH2-CO2H | CH2CH=CH2 |
231. | OH | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
232. | OH | H | CH2-CO2H | CH2CH=CH2 |
233. | OCH3 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
234. | OCH3 | H | CH2-CO2H | CH2CH=CH2 |
235. | OCH2CH=CH2 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
236. | OCH2CH=CH2 | H | CH2-CO2H | CH2CH=CH2 |
237. | OCH2C6H5 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
238. | OCH2C6H5 | H | CH2-CO2H | CH2CH=CH2 |
239. | OCH2CH2C6H5 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
240. | OCH2CH2C6H5 | H | CH2-CO2H | CH2CH=CH2 |
241. | OCH2-CONH2 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
242. | OCH2-CONH2 | H | CH2-CO2H | CH2CH=CH2 |
243. | H | Cl | CH2-CO2CH2CH3 | CH2CH=CH2 |
244. | H | Cl | CH2-CO2H | CH2CH=CH2 |
245. | Br | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
246. | Br | H | CH2-CO2H | CH2CH=CH2 |
247. | H | CH3 | CH2-CO2CH2CH3 | CH2CH=CH2 |
248. | H | CH3 | CH2-CO2H | CH2CH=CH2 |
249. | NO2 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
250. | NO2 | H | CH2-CO2H | CH2CH=CH2 |
251. | NH2 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
252. | NH2 | H | CH2-CO2H | CH2CH=CH2 |
253. | NHSO2CH3 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
254. | NHSO2CH3 | H | CH2-CO2H | CH2CH=CH2 |
255. | H | OH | CH2-CO2CH2CH3 | CH2CH=CH2 |
256. | H | OH | CH2-CO2H | CH2CH=CH2 |
257. | H | OCH3 | CH2-CO2CH2CH3 | CH2CH=CH2 |
258. | H | OCH3 | CH2-CO2H | CH2CH=CH2 |
259. | H | OCH2CH=CH2 | CH2-CO2CH2CH3 | CH2CH=CH2 |
260. | H | OCH2CH=CH2 | CH2-CO2H | CH2CH=CH2 |
261. | H | OCH2C6H5 | CH2-CO2CH2CH3 | CH2CH=CH2 |
262. | H | OCH2C6H5 | CH2-CO2H | CH2CH=CH2 |
263. | H | OCH2CH2C6H5 | CH2-CO2CH2CH3 | CH2CH=CH2 |
264. | H | OCH2CH2C6H5 | CH2-CO2H | CH2CH=CH2 |
265. | H | OCH2-CONH2 | CH2-CO2CH2CH3 | CH2CH=CH2 |
266. | H | OCH2-CONH2 | CH2-CO2H | CH2CH=CH2 |
267. | H | H | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
268. | H | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
269. | OH | H | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
270. | OH | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
271. | OCH3 | H | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
272. | OCH3 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
273. | OCH2CH=CH2 | H | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
274. | OCH2CH=CH2 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
275. | OCH2C6H5 | H | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
276. | OCH2C6H5 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
277. | OCH2CH2C6H5 | H | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
278. | OCH2CH2C6H5 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
279. | OCH2-CONH2 | H | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
280. | OCH2-CONH2 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
281. | H | Cl | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
282. | H | Cl | CH2CH2P-O(OH)2 | CH2CH=CH2 |
283. | Br | H | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
284. | Br | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
285. | H | CH3 | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
286. | H | CH3 | CH2CH2P-O(OH)2 | CH2CH=CH2 |
287. | NO2 | H | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
288. | NO2 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
289. | NH2 | H | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
290. | NH2 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
291. | NHSO2CH3 | H | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
292. | NHSO2CH3 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
293. | H | OH | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
294. | H | OH | CH2CH2P-O(OH)2 | CH2CH=CH2 |
295. | H | OCH3 | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
296. | H | OCH3 | CH2CH2P-O(OH)2 | CH2CH=CH2 |
297. | H | OCH2CH=CH2 | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
298. | H | OCH2CH=CH2 | CH2CH2P-O(OH)2 | CH2CH=CH2 |
299. | H | OCH2C6H5 | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
300. | H | OCH2C6H5 | CH2CH2P-O(OH)2 | CH2CH=CH2 |
301. | H | OCH2CH2C6H5 | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
302. | H | OCH2CH2C6H5 | CH2CH2P-O(OH)2 | CH2CH=CH2 |
303. | H | OCH2-CONH2 | CH2CH2P-O(OCH 2CH3)2 | CH2CH=CH2 |
304. | H | OCH2-CONH2 | CH2CH2P-O(OH)2 | CH2CH=CH2 |
305. | H | H | CH2-CO2CH2CH3 | CH2-CONH2 |
306. | H | H | CH2-CO2H | CH2-CONH2 |
307. | OH | H | CH2-CO2CH2CH3 | CH2-CONH2 |
308. | OH | H | CH2-CO2H | CH2-CONH2 |
309. | OCH3 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
310. | OCH3 | H | CH2-CO2H | CH2-CONH2 |
311. | OCH2CH=CH2 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
312. | OCH2CH=CH2 | H | CH2-CO2H | CH2-CONH2 |
313. | OCH2C6H5 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
314. | OCH2C6H5 | H | CH2-CO2H | CH2-CONH2 |
315. | OCH2CH2C6H5 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
316. | OCH2CH2C6H5 | H | CH2-CO2H | CH2-CONH2 |
317. | OCH2-CONH2 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
318. | OCH2-CONH2 | H | CH2-CO2H | CH2-CONH2 |
319. | H | Cl | CH2-CO2CH2CH3 | CH2-CONH2 |
320. | H | Cl | CH2-CO2H | CH2-CONH2 |
321. | Br | H | CH2-CO2CH2CH3 | CH2-CONH2 |
322. | Br | H | CH2-CO2H | CH2-CONH2 |
323. | H | CH3 | CH2-CO2CH2CH3 | CH2-CONH2 |
324. | H | CH3 | CH2-CO2H | CH2-CONH2 |
325. | NO2 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
326. | NO2 | H | CH2-CO2H | CH2-CONH2 |
327. | NH2 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
328. | NH2 | H | CH2-CO2H | CH2-CONH2 |
329. | NHSO2CH3 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
330. | NHSO2CH3 | H | CH2-CO2H | CH2-CONH2 |
331. | H | OH | CH2-CO2CH2CH3 | CH2-CONH2 |
332. | H | OH | CH2-CO2H | CH2-CONH2 |
333. | H | OCH3 | CH2-CO2CH2CH3 | CH2-CONH2 |
334. | H | OCH3 | CH2-CO2H | CH2-CONH2 |
335. | H | OCH2CH=CH2 | CH2-CO2CH2CH3 | CH2-CONH2 |
336. | H | OCH2CH=CH2 | CH2-CO2H | CH2-CONH2 |
337. | H | OCH2C6H5 | CH2-CO2CH2CH3 | CH2-CONH2 |
338. | H | OCH2C6H5 | CH2-CO2H | CH2-CONH2 |
339. | H | OCH2CH2C6H5 | CH2-CO2CH2CH3 | CH2-CONH2 |
340. | H | OCH2CH2C6H5 | CH2-CO2H | CH2-CONH2 |
341. | H | OCH2-CONH2 | CH2-CO2CH2CH3 | CH2-CONH2 |
342. | H | OCH2-CONH2 | CH2-CO2H | CH2-CONH2 |
343. | H | H | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
344. | H | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
345. | OH | H | CH2CH2P-O(OCH 2CH3)2 | CH2-CON H2 |
346. | OH | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
347. | OCH3 | H | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
348. | OCH3 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
349. | OCH2CH=CH2 | H | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
350. | OCH2CH=CH2 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
351. | OCH2C6H5 | H | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
352. | OCH2C6H5 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
353. | OCH2CH2C6H5 | H | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
354. | OCH2CH2C6H5 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
355. | OCH2-CONH2 | H | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
356. | OCH2-CONH2 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
357. | H | Cl | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
358. | H | Cl | CH2CH2P-O(OH)2 | CH2-CONH2 |
359. | Br | H | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
360. | Br | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
361. | H | CH3 | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
362. | H | CH3 | CH2CH2P-O(OH)2 | CH2-CONH2 |
363. | NO2 | H | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
364. | NO2 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
365. | NH2 | H | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
366. | NH2 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
367. | NHSO2CH3 | H | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
368. | NHSO2CH3 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
369. | H | OH | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
370. | H | OH | CH2CH2P-O(OH)2 | CH2-CONH2 |
371. | H | OCH3 | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
372. | H | OCH3 | CH2CH2P-O(OH)2 | CH2-CONH2 |
373. | H | OCH2CH=CH2 | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
374. | H | OCH2CH=CH2 | CH2CH2P-O(OH)2 | CH2-CONH2 |
375. | H | OCH2C6H5 | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
376. | H | OCH2C6H5 | CH2CH2P-O(OH)2 | CH2-CONH2 |
377. | H | OCH2CH2C6H5 | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
378. | H | OCH2CH2C6H5 | CH2CH2P-O(OH)2 | CH2-CONH2 |
379. | H | OCH2-CONH2 | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
380. | H | OCH2-CONH2 | CH2CH2P-O(OH)2 | CH2-CONH2 |
381. | H | H | CH2-CO2CH2CH3 | CH2C6H5 |
382. | H | H | CH2-CO2H | CH2C6H5 |
383. | OH | H | CH2-CO2CH2CH3 | CH2C6H5 |
384. | OH | H | CH2-CO2H | CH2C6H5 |
385. | OCH3 | H | CH2-CO2CH2CH3 | CH2C6H5 |
386. | OCH3 | H | CH2-CO2H | CH2C6H5 |
387. | OCH2CH=CH2 | H | CH2-CO2CH2CH3 | CH2C6H5 |
388. | OCH2CH=CH2 | H | CH2-CO2H | CH2C6H5 |
389. | OCH2C6H5 | H | CH2-CO2CH2CH3 | CH2C6H5 |
390. | OCH2C6H5 | H | CH2-CO2H | CH2C6H5 |
391. | OCH2CH2C6H5 | H | CH2-CO2CH2CH3 | CH2C6H5 |
392. | OCH2CH2C6H5 | H | CH2-CO2H | CH2C6H5 |
393. | OCH2-CONH2 | H | CH2-CO2CH2CH3 | CH2C6H5 |
394. | OCH2-CONH2 | H | CH2-CO2H | CH2C6H5 |
395. | H | Cl | CH2-CO2CH2CH3 | CH2C6H5 |
396. | H | Cl | CH2-CO2H | CH2C6H5 |
397. | Br | H | CH2-CO2CH2CH3 | CH2C6H5 |
398. | Br | H | CH2-CO2H | CH2C6H5 |
399. | H | CH3 | CH2-CO2CH2CH3 | CH2C6H5 |
400. | H | CH3 | CH2-CO2H | CH2C6H5 |
401. | NO2 | H | CH2-CO2CH2CH3 | CH2C6H5 |
402. | NO2 | H | CH2-CO2H | CH2C6H5 |
403. | NH2 | H | CH2-CO2CH2CH3 | CH2C6H5 |
404. | NH2 | H | CH2-CO2H | CH2C6H5 |
405. | NHSO2CH3 | H | CH2-CO2CH2CH3 | CH2C6H5 |
406. | NHSO2CH3 | H | CH2-CO2H | CH2C6H5 |
407. | H | OH | CH2-CO2CH2CH3 | CH2C6H5 |
408. | H | OH | CH2-CO2H | CH2C6H5 |
409. | H | OCH3 | CH2-CO2CH2CH3 | CH2C6H5 |
410. | H | OCH3 | CH2-CO2H | CH2C6H5 |
411. | H | OCH2CH=CH2 | CH2-CO2CH2CH3 | CH2C6H5 |
412. | H | OCH2CH=CH2 | CH2-CO2H | CH2C6H5 |
413. | H | OCH2C6H5 | CH2-CO2CH2CH3 | CH2C6H5 |
414. | H | OCH2C6H5 | CH2-CO2H | CH2C6H5 |
415. | H | OCH2CH2C6H5 | CH2-CO2CH2CH3 | CH2C6H5 |
416. | H | OCH2CH2C6H5 | CH2-CO2H | CH2C6H5 |
417. | H | OCH2-CONH2 | CH2-CO2CH2CH3 | CH2C6H5 |
418. | H | OCH2-CONH2 | CH2-CO2H | CH2C6H5 |
419. | H | H | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
420. | H | H | CH2CH2P-O(OH)2 | CH2C6H5 |
421. | OH | H | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
422. | OH | H | CH2CH2P-O(OH)2 | CH2C6H5 |
423. | OCH3 | H | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
424. | OCH3 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
425. | OCH2CH=CH2 | H | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
426. | OCH2CH=CH2 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
427. | OCH2C6H5 | H | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
428. | OCH2C6H5 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
429. | OCH2CH2C6H5 | H | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
430. | OCH2CH2C6H5 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
431. | OCH2-CONH2 | H | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
432. | OCH2-CONH2 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
433. | H | Cl | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
434. | H | Cl | CH2CH2P-O(OH)2 | CH2C6H5 |
435. | Br | H | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
436. | Br | H | CH2CH2P-O(OH)2 | CH2C6H5 |
437. | H | CH3 | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
438. | H | CH3 | CH2CH2P-O(OH)2 | CH2C6H5 |
439. | NO2 | H | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
440. | NO2 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
441. | NH2 | H | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
442. | NH2 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
443. | NHSO2CH3 | H | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
444. | NHSO2CH3 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
445. | H | OH | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
446. | H | OH | CH2CH2P-O(OH)2 | CH2C6H5 |
447. | H | OCH3 | CH2CH2P-O(OCH 2CH3)2 | CH2C6H5 |
448. | H | OCH3 | CH2CH2P-O(OH)2 | CH2-CONH2 |
449. | H | OCH2CH=CH2 | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
450. | H | OCH2CH=CH2 | CH2CH2P-O(OH)2 | CH2-CONH2 |
451. | H | OCH2C6H5 | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
452. | H | OCH2C6H5 | CH2CH2P-O(OH)2 | CH2-CONH2 |
453. | H | OCH2CH2C6H5 | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
454. | H | OCH2CH2C6H5 | CH2CH2P-O(OH)2 | CH2-CONH2 |
455. | H | OCH2-CONH2 | CH2CH2P-O(OCH 2CH3)2 | CH2-CONH2 |
456. | H | OCH2-CONH2 | CH2CH2P-O(OH)2 | CH2-CONH2 |
表IV
Ex.# | X | X1 | R1 | R” |
1. | H | H | H | CH2-CO2CH2CH3 |
2. | H | H | CH3 | CH2-CO2H |
3. | OH | H | H | CH2-CO2CH2CH3 |
4. | OH | H | CH3 | CH2-CO2H |
5. | OCH3 | H | H | CH2-CO2CH2CH3 |
6. | OCH3 | H | CH3 | CH2-CO2H |
7. | OCH2CH=CH2 | H | H | CH2-CO2CH2CH3 |
8. | OCH2CH=CH2 | H | CH3 | CH2-CO2H |
9. | OCH2C6H5 | H | H | CH2-CO2CH2CH3 |
10. | OCH2C6H5 | H | CH3 | CH2-CO2H |
11. | OCH2CH2C6H5 | H | H | CH2-CO2CH2CH3 |
12. | OCH2CH2C6H5 | H | CH3 | CH2-CO2H |
13. | OCH2-CONH2 | H | H | CH2-CO2CH2CH3 |
14. | OCH2-CONH2 | H | CH3 | CH2-CO2H |
15. | H | Cl | H | CH2-CO2CH2CH3 |
16. | H | Cl | CH3 | CH2-CO2H |
17. | Br | H | H | CH2-CO2CH2CH3 |
18. | Br | H | CH3 | CH2-CO2H |
19. | H | CH3 | H | CH2-CO2CH2CH3 |
20. | H | CH3 | CH3 | CH2-CO2H |
21. | NO2 | H | H | CH2-CO2CH2CH3 |
22. | NO2 | H | CH3 | CH2-CO2H |
23. | NH2 | H | H | CH2-CO2CH2CH3 |
24. | NH2 | H | CH3 | CH2-CO2H |
25. | NHSO2CH3 | H | H | CH2-CO2CH2CH3 |
26. | NHSO2CH3 | H | CH3 | CH2-CO2H |
27. | H | OH | H | CH2-CO2CH2CH3 |
28. | H | OH | CH3 | CH2-CO2H |
29. | H | OCH3 | H | CH2-CO2CH2CH3 |
30. | H | OCH3 | CH3 | CH2-CO2H |
31. | H | OCH2CH=CH2 | H | CH2-CO2CH2CH3 |
32. | H | OCH2CH=CH2 | CH3 | CH2-CO2H |
33. | H | OCH2C6H5 | H | CH2-CO2CH2CH3 |
34. | H | OCH2C6H5 | CH3 | CH2-CO2H |
35. | H | OCH2CH2C6H5 | H | CH2-CO2CH2CH3 |
36. | H | OCH2CH2C6H5 | CH3 | CH2-CO2H |
37. | H | OCH2-CONH2 | H | CH2-CO2CH2CH3 |
38. | H | OCH2-CONH2 | CH3 | CH2-CO2H |
39. | H | H | H | CH2CH2-CO2CH2CH3 |
40. | H | H | CH3 | CH2CH2-CO2H |
41. | OH | H | H | CH2CH2-CO2CH2CH3 |
42. | OH | H | CH3 | CH2CH2-CO2H |
43. | OCH3 | H | H | CH2CH2-CO2CH2CH3 |
44. | OCH3 | H | CH3 | CH2CH2-CO2H |
45. | OCH2CH=CH2 | H | H | CH2CH2-CO2CH2CH3 |
46. | OCH2CH=CH2 | H | CH3 | CH2CH2-CO2H |
47. | OCH2C6H5 | H | H | CH2CH2-CO2CH2CH3 |
48. | OCH2C6H5 | H | CH3 | CH2CH2-CO2H |
49. | OCH2CH2C6H5 | H | H | CH2CH2-CO2CH2CH3 |
50. | OCH2CH2C6H5 | H | CH3 | CH2CH2-CO2H |
51. | OCH2-CONH2 | H | H | CH2CH2-CO2CH2CH3 |
52. | OCH2-CONH2 | H | CH3 | CH2CH2-CO2H |
53. | H | Cl | H | CH2CH2-CO2CH2CH3 |
54. | H | Cl | CH3 | CH2CH2-CO2H |
55. | Br | H | H | CH2CH2-CO2CH2CH3 |
56. | Br | H | CH3 | CH2CH2-CO2H |
57. | H | CH3 | H | CH2CH2-CO2CH2CH3 |
58. | H | CH3 | CH3 | CH2CH2-CO2H |
59. | NO2 | H | H | CH2CH2-CO2CH2CH3 |
60. | NO2 | H | CH3 | CH2CH2-CO2H |
61. | NH2 | H | H | CH2CH2-CO2CH2CH3 |
62. | NH2 | H | CH3 | CH2CH2-CO2H |
63. | NHSO2CH3 | H | H | CH2CH2-CO2CH2CH3 |
64. | NHSO2CH3 | H | CH3 | CH2CH2-CO2H |
65. | H | OH | H | CH2CH2-CO2CH2CH3 |
66. | H | OH | CH3 | CH2CH2-CO2H |
67. | H | OCH3 | H | CH2CH2-CO2CH2CH3 |
68. | H | OCH3 | CH3 | CH2CH2-CO2H |
69. | H | OCH2CH=CH2 | H | CH2CH2-CO2CH2CH3 |
70. | H | OCH2CH=CH2 | CH3 | CH2CH2-CO2H |
71. | H | OCH2C6H5 | H | CH2CH2-CO2CH2CH3 |
72. | H | OCH2C6H5 | CH3 | CH2CH2-CO2H |
73. | H | OCH2CH2C6H5 | H | CH2CH2-CO2CH2CH3 |
74. | H | OCH2CH2C6H5 | CH3 | CH2CH2-CO2H |
75. | H | OCH2-CONH2 | H | CH2CH2-CO2CH2CH3 |
76. | H | OCH2-CONH2 | CH3 | CH2CH2-CO2H |
77. | H | H | H | CH2CH2P-O(OCH2CH3)2 |
78. | H | H | CH3 | CH2CH2P-O(OH)2 |
79. | OH | H | H | CH2CH2P-O(OCH2CH3)2 |
80. | OH | H | CH3 | CH2CH2P-O(OH)2 |
81. | OCH3 | H | H | CH2CH2P-O(OCH2CH3)2 |
82. | OCH3 | H | CH3 | CH2CH2P-O(OH)2 |
83. | OCH2CH=CH2 | H | H | CH2CH2P-O(OCH2CH3)2 |
84. | OCH2CH=CH2 | H | CH3 | CH2CH2P-O(OH)2 |
85. | OCH2C6H5 | H | H | CH2CH2P-O(OCH2CH3)2 |
86. | OCH2C6H5 | H | CH3 | CH2CH2P-O(OH)2 |
87. | OCH2CH2C6H5 | H | H | CH2CH2P-O(OCH2CH3)2 |
88. | OCH2CH2C6H5 | H | CH3 | CH2CH2P-O(OH)2 |
89. | OCH2-CONH2 | H | H | CH2CH2P-O(OCH2CH3)2 |
90. | OCH2-CONH2 | H | CH3 | CH2CH2P-O(OH)2 |
91. | H | Cl | H | CH2CH2P-O(OCH2CH3)2 |
92. | H | Cl | CH3 | CH2CH2P-O(OH)2 |
93. | Br | H | H | CH2CH2P-O(OCH2CH3)2 |
94. | Br | H | CH3 | CH2CH2P-O(OH)2 |
95. | H | CH3 | H | CH2CH2P-O(OCH2CH3)2 |
96. | H | CH3 | CH3 | CH2CH2P-O(OH)2 |
97. | NO2 | H | H | CH2CH2P-O(OCH2CH3)2 |
98. | NO2 | H | CH3 | CH2CH2P-O(OH)2 |
99. | NH2 | H | H | CH2CH2P-O(OCH2CH3)2 |
100. | NH2 | H | CH3 | CH2CH2P-O(OH)2 |
101. | NHSO2CH3 | H | H | CH2CH2P-O(OCH2CH3)2 |
102. | NHSO2CH3 | H | CH3 | CH2CH2P-O(OH)2 |
103. | H | OH | H | CH2CH2P-O(OCH2CH3)2 |
104. | H | OH | CH3 | CH2CH2P-O(OH)2 |
105. | H | OCH3 | H | CH2CH2P-O(OCH2CH3)2 |
106. | H | OCH3 | CH3 | CH2CH2P-O(OH)2 |
107. | H | OCH2CH=CH2 | H | CH2CH2P-O(OCH2CH3)2 |
108. | H | OCH2CH=CH2 | CH3 | CH2CH2P-O(OH)2 |
109. | H | OCH2C6H5 | H | CH2CH2P-O(OCH2CH3)3 |
110. | H | OCH2C6H5 | CH3 | CH2CH2P-O(OH)2 |
111. | H | OCH2CH2C6H5 | H | CH2CH2P-O(OCH2CH3)2 |
112. | H | OCH2CH2C6H5 | CH3 | CH2CH2P-O(OH)2 |
113. | H | OCH2-CONH2 | H | CH2CH2P-O(OCH2CH3)2 |
114. | H | OCH2-CONH2 | CH3 | CH2CH2P-O(OH)2 |
115. | H | H | H | CH2CH=CH-CO2CH2CH3 |
116. | H | H | CH3 | CH2CH=CH-CO2H |
117. | OH | H | H | CH2CH=CH-CO2CH2CH3 |
118. | OH | H | CH3 | CH2CH=CH-CO2H |
119. | OCH3 | H | H | CH2CH=CH-CO2CH2CH3 |
120. | OCH3 | H | CH3 | CH2CH=CH-CO2H |
121. | OCH2CH=CH2 | H | H | CH2CH=CH-CO2CH2CH3 |
122. | OCH2CH=CH2 | H | CH3 | CH2CH=CH-CO2H |
123. | OCH2C6H5 | H | H | CH2CH=CH-CO2CH2CH3 |
124. | OCH2C6H5 | H | CH3 | CH2CH=CH-CO2H |
125. | OCH2CH2C6H5 | H | H | CH2CH=CH-CO2CH2CH3 |
126. | OCH2CH2C6H5 | H | CH3 | CH2CH=CH-CO2H |
127. | OCH2-CONH2 | H | H | CH2CH=CH-CO2CH2CH3 |
128. | OCH2-CONH2 | H | CH3 | CH2CH=CH-CO2H |
129. | H | Cl | H | CH2CH=CH-CO2CH2CH3 |
130. | H | Cl | CH3 | CH2CH=CH-CO2H |
131. | Br | H | H | CH2CH=CH-CO2CH2CH3 |
132. | Br | H | CH3 | CH2CH=CH-CO2H |
133. | H | CH3 | H | CH2CH=CH-CO2CH2CH3 |
134. | H | CH3 | CH3 | CH2CH=CH-CO2H |
135. | NO2 | H | H | CH2CH=CH-CO2CH2CH3 |
136. | NO2 | H | CH3 | CH2CH=CH-CO2H |
137. | NH2 | H | H | CH2CH=CH-CO2CH2CH3 |
138. | NH2 | H | CH3 | CH2CH=CH-CO2H |
139. | NHSO2CH3 | H | H | CH2CH=CH-CO2CH2CH3 |
140. | NHSO2CH3 | H | CH3 | CH2CH=CH-CO2H |
141. | H | OH | H | CH2CH=CH-CO2CH2CH3 |
142. | H | OH | CH3 | CH2CH=CH-CO2H |
143. | H | OCH3 | H | CH2CH=CH-CO2CH2CH3 |
144. | H | OCH3 | CH3 | CH2CH=CH-CO2H |
145. | H | OCH2CH=CH2 | H | CH2CH=CH-CO2CH2CH3 |
146. | H | OCH2CH=CH2 | CH3 | CH2CH=CH-CO2H |
147. | H | OCH2C6H5 | H | CH2CH=CH-CO2CH2CH3 |
148. | H | OCH2C6H5 | CH3 | CH2CH=CH-CO2H |
149. | H | OCH2CH2C6H5 | H | CH2CH=CH-CO2CH2CH3 |
150. | H | OCH2CH2C6H5 | CH3 | CH2CH=CH-CO2H |
151. | H | OCH2-CONH2 | H | CH2CH=CH-CO2CH2CH3 |
152. | H | OCH2-CONH2 | CH3 | CH2CH=CH-CO2H |
153. | H | H | CH2-CO2CH2CH3 | CH3 |
154. | H | H | CH2-CO2H | CH3 |
155. | OH | H | CH2-CO2CH2CH3 | CH3 |
156. | OH | H | CH2-CO2H | CH3 |
157. | OCH3 | H | CH2-CO2CH2CH3 | CH3 |
158. | OCH3 | H | CH2-CO2H | CH3 |
159. | OCH2CH=CH2 | H | CH2-CO2CH2CH3 | CH3 |
160. | OCH2CH=CH2 | H | CH2-CO2H | CH3 |
161. | OCH2C6H5 | H | CH2-CO2CH2CH3 | CH3 |
162. | OCH2C6H5 | H | CH2-CO2H | CH3 |
163. | OCH2CH2C6H5 | H | CH2-CO2CH2CH3 | CH3 |
164. | OCH2CH2C6H5 | H | CH2-CO2H | CH3 |
165. | OCH2-CONH2 | H | CH2-CO2CH2CH3 | CH3 |
166. | OCH2-CONH2 | H | CH2-CO2H | CH3 |
167. | H | Cl | CH2-CO2CH2CH3 | CH3 |
168. | H | Cl | CH2-CO2H | CH3 |
169. | Br | H | CH2-CO2CH2CH3 | CH3 |
170. | Br | H | CH2-CO2H | CH3 |
171. | H | CH3 | CH2-CO2CH2CH3 | CH3 |
172. | H | CH3 | CH2-CO2H | CH3 |
173. | NO2 | H | CH2-CO2CH2CH3 | CH3 |
174. | NO2 | H | CH2-CO2H | CH3 |
175. | NH2 | H | CH2-CO2CH2CH3 | CH3 |
176. | NH2 | H | CH2-CO2H | CH3 |
177. | NHSO2CH3 | H | CH2-CO2CH2CH3 | CH3 |
178. | NHSO2CH3 | H | CH2-CO2H | CH3 |
179. | H | OH | CH2-CO2CH2CH3 | CH3 |
180. | H | OH | CH2-CO2H | CH3 |
181. | H | OCH3 | CH2-CO2CH2CH3 | CH3 |
182. | H | OCH3 | CH2-CO2H | CH3 |
183. | H | OCH2CH=CH2 | CH2-CO2CH2CH3 | CH3 |
184. | H | OCH2CH=CH2 | CH2-CO2H | CH3 |
185. | H | OCH2C6H5 | CH2-CO2CH2CH3 | CH3 |
186. | H | OCH2C6H5 | CH2-CO2H | CH3 |
187. | H | OCH2CH2C6H5 | CH2-CO2CH2CH3 | CH3 |
188. | H | OCH2CH2C6H5 | CH2-CO2H | CH3 |
189. | H | OCH2-CONH2 | CH2-CO2CH2CH3 | CH3 |
190. | H | OCH2-CONH2 | CH2-CO2H | CH3 |
191. | H | H | CH2CH2P-O(OCH2CH3)2 | CH3 |
192. | H | H | CH2CH2P-O(OH)2 | CH3 |
193. | OH | H | CH2CH2P-O(OCH2CH3)2 | CH3 |
194. | OH | H | CH2CH2P-O(OH)2 | CH3 |
195. | OCH3 | H | CH2CH2P-O(OCH2CH3)2 | CH3 |
196. | OCH3 | H | CH2CH2P-O(OH)2 | CH3 |
197. | OCH2CH=CH2 | H | CH2CH2P-O(OCH2CH3)2 | CH3 |
198. | OCH2CH=CH2 | H | CH2CH2P-O(OH)2 | CH3 |
199. | OCH2C6H5 | H | CH2CH2P-O(OCH2CH3)2 | CH3 |
200. | OCH2C6H5 | H | CH2CH2P-O(OH)2 | CH3 |
201. | OCH2CH2C6H5 | H | CH2CH2P-O(OCH2CH3)2 | CH3 |
202. | OCH2CH2C6H5 | H | CH2CH2P-O(OH)2 | CH3 |
203. | OCH2-CONH2 | H | CH2CH2P-O(OCH2CH3)2 | CH3 |
204. | OCH2-CONH2 | H | CH2CH2P-O(OH)2 | CH3 |
205. | H | Cl | CH2CH2P-O(OCH2CH3)2 | CH3 |
206. | H | Cl | CH2CH2P-O(OH)2 | CH3 |
207. | Br | H | CH2CH2P-O(OCH2CH3)2 | CH3 |
208. | Br | H | CH2CH2P-O(OH)2 | CH3 |
209. | H | CH3 | CH2CH2P-O(OCH2CH3)2 | CH3 |
210. | H | CH3 | CH2CH2P-O(OH)2 | CH3 |
211. | NO2 | H | CH2CH2P-O(OCH2CH3)2 | CH3 |
212. | NO2 | H | CH2CH2P-O(OH)2 | CH3 |
213. | NH2 | H | CH2CH2P-O(OCH2CH3)2 | CH3 |
214. | NH2 | H | CH2CH2P-O(OH)2 | CH3 |
215. | NHSO2CH3 | H | CH2CH2P-O(OCH2CH3)2 | CH3 |
216. | NHSO2CH3 | H | CH2CH2P-O(OH)2 | CH3 |
217. | H | OH | CH2CH2P-O(OCH2CH3)2 | CH3 |
218. | H | OH | CH2CH2P-O(OH)2 | CH3 |
219. | H | OCH3 | CH2CH2P-O(OCH2CH3)2 | CH3 |
220. | H | OCH3 | CH2CH2P-O(OH)2 | CH3 |
221. | H | OCH2CH=CH2 | CH2CH2P-O(OCH2CH3)2 | CH3 |
222. | H | OCH2CH=CH2 | CH2CH2P-O(OH)2 | CH3 |
223. | H | OCH2C6H5 | CH2CH2P-O(OCH2CH3)2 | CH3 |
224. | H | OCH2C6H5 | CH2CH2P-O(OH)2 | CH3 |
225. | H | OCH2CH2C6H5 | CH2CH2P-O(OCH2CH3)2 | CH3 |
226. | H | OCH2CH2C6H5 | CH2CH2P-O(OH)2 | CH3 |
227. | H | OCH2-CONH2 | CH2CH2P-O(OCH2CH3)2 | CH3 |
228. | H | OCH2-CONH2 | CH2CH2P-O(OH)2 | CH3 |
229. | H | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
230. | H | H | CH2-CO2H | CH2CH=CH2 |
231. | OH | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
232. | OH | H | CH2-CO2H | CH2CH=CH2 |
233. | OCH3 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
234. | OCH3 | H | CH2-CO2H | CH2CH=CH2 |
235. | OCH2CH=CH2 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
236. | OCH2CH=CH2 | H | CH2-CO2H | CH2CH=CH2 |
237. | OCH2C6H5 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
238. | OCH2C6H5 | H | CH2-CO2H | CH2CH=CH2 |
239. | OCH2CH2C6H5 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
240. | OCH2CH2C6H5 | H | CH2-CO2H | CH2CH=CH2 |
241. | OCH2-CONH2 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
242. | OCH2-CONH2 | H | CH2-CO2H | CH2CH=CH2 |
243. | H | Cl | CH2-CO2CH2CH3 | CH2CH=CH2 |
244. | H | Cl | CH2-CO2H | CH2CH=CH2 |
245. | Br | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
246. | Br | H | CH2-CO2H | CH2CH=CH2 |
247. | H | CH3 | CH2-CO2CH2CH3 | CH2CH=CH2 |
248. | H | CH3 | CH2-CO2H | CH2CH=CH2 |
249. | NO2 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
250. | NO2 | H | CH2-CO2H | CH2CH=CH2 |
251. | NH2 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
252. | NH2 | H | CH2-CO2H | CH2CH=CH2 |
253. | NHSO2CH3 | H | CH2-CO2CH2CH3 | CH2CH=CH2 |
254. | NHSO2CH3 | H | CH2-CO2H | CH2CH=CH2 |
255. | H | OH | CH2-CO2CH2CH3 | CH2CH=CH2 |
256. | H | OH | CH2-CO2H | CH2CH=CH2 |
257. | H | OCH3 | CH2-CO2CH2CH3 | CH2CH=CH2 |
258. | H | OCH3 | CH2-CO2H | CH2CH=CH2 |
259. | H | OCH2CH=CH2 | CH2-CO2CH2CH3 | CH2CH=CH2 |
260. | H | OCH2CH=CH2 | CH2-CO2H | CH2CH=CH2 |
261. | H | OCH2C6H5 | CH2-CO2CH2CH3 | CH2CH=CH2 |
262. | H | OCH2C6H5 | CH2-CO2H | CH2CH=CH2 |
263. | H | OCH2CH2C6H5 | CH2-CO2CH2CH3 | CH2CH=CH2 |
264. | H | OCH2CH2C6H5 | CH2-CO2H | CH2CH=CH2 |
265. | H | OCH2-CONH2 | CH2-CO2CH2CH3 | CH2CH=CH2 |
266. | H | OCH2-CONH2 | CH2-CO2H | CH2CH=CH2 |
267. | H | H | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
268. | H | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
269. | OH | H | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
270. | OH | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
271. | OCH3 | H | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
272. | OCH3 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
273. | OCH2CH=CH2 | H | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
274. | OCH2CH=CH2 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
275. | OCH2C6H5 | H | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
276. | OCH2C6H5 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
277. | OCH2CH2C6H5 | H | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
278. | OCH2CH2C6H5 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
279. | OCH2-CONH2 | H | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
280. | OCH2-CONH2 | H | CH2CH2 P-O(OH)2 | CH2CH=CH2 |
281. | H | Cl | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
282. | H | Cl | CH2CH2P-O(OH)2 | CH2CH=CH2 |
283. | Br | H | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
284. | Br | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
285. | H | CH3 | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
286. | H | CH3 | CH2CH2P-O(OH)2 | CH2CH=CH2 |
287. | NO2 | H | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
288. | NO2 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
289. | NH2 | H | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
290. | NH2 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
291. | NHSO2CH3 | H | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
292. | NHSO2CH3 | H | CH2CH2P-O(OH)2 | CH2CH=CH2 |
293. | H | OH | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
294. | H | OH | CH2CH2P-O(OH)2 | CH2CH=CH2 |
295. | H | OCH3 | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
296. | H | OCH3 | CH2CH2P-O(OH)2 | CH2CH=CH2 |
297. | H | OCH2CH=CH2 | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
298. | H | OCH2CH=CH2 | CH2CH2P-O(OH)2 | CH2CH=CH2 |
299. | H | OCH2C6H5 | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
300. | H | OCH2C6H5 | CH2CH2P-O(OH)2 | CH2CH=CH2 |
301. | H | OCH2CH2C6H5 | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
302. | H | OCH2CH2C6H5 | CH2CH2P-O(OH)2 | CH2CH=CH2 |
303. | H | OCH2-CONH2 | CH2CH2P-O(OCH2CH3)2 | CH2CH=CH2 |
304. | H | OCH2-CONH2 | CH2CH2P-O(OH)2 | CH2CH=CH2 |
305. | H | H | CH2-CO2CH2CH3 | CH2-CONH2 |
306. | H | H | CH2-CO2H | CH2-CONH2 |
307. | OH | H | CH2-CO2CH2CH3 | CH2-CONH2 |
308. | OH | H | CH2-CO2H | CH2-CONH2 |
309. | OCH3 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
310. | OCH3 | H | CH2-CO2H | CH2-CONH2 |
311. | OCH2CH=CH2 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
312. | OCH2CH=CH2 | H | CH2-CO2H | CH2-CONH2 |
313. | OCH2C6H5 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
314. | OCH2C6H5 | H | CH2-CO2H | CH2-CONH2 |
315. | OCH2CH2C6H5 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
316. | OCH2CH2C6H5 | H | CH2-CO2H | CH2-CONH2 |
317. | OCH2-CONH2 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
318. | OCH2-CONH2 | H | CH2-CO2H | CH2-CONH2 |
319. | H | Cl | CH2-CO2CH2CH3 | CH2-CONH2 |
320. | H | Cl | CH2-CO2H | CH2-CONH2 |
321. | Br | H | CH2-CO2CH2CH3 | CH2-CONH2 |
322. | Br | H | CH2-CO2H | CH2-CONH2 |
323. | H | CH3 | CH2-CO2CH2CH3 | CH2-CONH2 |
324. | H | CH3 | CH2-CO2H | CH2-CONH2 |
325. | NO2 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
326. | NO2 | H | CH2-CO2H | CH2-CONH2 |
327. | NH2 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
328. | NH2 | H | CH2-CO2H | CH2-CONH2 |
329. | NHSO2CH3 | H | CH2-CO2CH2CH3 | CH2-CONH2 |
330. | NHSO2CH3 | H | CH2-CO2H | CH2-CONH2 |
331. | H | OH | CH2-CO2CH2CH3 | CH2-CONH2 |
332. | H | OH | CH2-CO2H | CH2-CONH2 |
333. | H | OCH3 | CH2-CO2CH2CH3 | CH2-CONH2 |
334. | H | OCH3 | CH2-CO2H | CH2-CONH2 |
335. | H | OCH2CH=CH2 | CH2-CO2CH2CH3 | CH2-CONH2 |
336. | H | OCH2CH=CH2 | CH2-CO2H | CH2-CONH2 |
337. | H | OCH2C6H5 | CH2-CO2CH2CH3 | CH2-CONH2 |
338. | H | OCH2C6H5 | CH2-CO2H | CH2-CONH2 |
339. | H | OCH2CH2C6H5 | CH2-CO2CH2CH3 | CH2-CONH2 |
340. | H | OCH2CH2C6H5 | CH2-CO2H | CH2-CONH2 |
341. | H | OCH2-CONH2 | CH2-CO2CH2CH3 | CH2-CONH2 |
342. | H | OCH2-CONH2 | CH2-CO2H | CH2-CONH2 |
343. | H | H | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
344. | H | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
345. | OH | H | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
346. | OH | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
347. | OCH3 | H | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
348. | OCH3 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
349. | OCH2CH=CH2 | H | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
350. | OCH2CH=CH2 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
351. | OCH2C6H5 | H | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
352. | OCH2C6H5 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
353. | OCH2CH2C6H5 | H | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
354. | OCH2CH2C6H5 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
355. | OCH2-CONH2 | H | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
356. | OCH2-CONH2 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
357. | H | Cl | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
358. | H | Cl | CH2CH2P-O(OH)2 | CH2-CONH2 |
359. | Br | H | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
360. | Br | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
361. | H | CH3 | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
362. | H | CH3 | CH2CH2P-O(OH)2 | CH2-CONH2 |
363. | NO2 | H | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
364. | NO2 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
365. | NH2 | H | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
366. | NH2 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
367. | NHSO2CH3 | H | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
368. | NHSO2CH3 | H | CH2CH2P-O(OH)2 | CH2-CONH2 |
369. | H | OH | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
370. | H | OH | CH2CH2P-O(OH)2 | CH2-CONH2 |
371. | H | OCH3 | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
372. | H | OCH3 | CH2CH2P-O(OH)2 | CH2-CONH2 |
373. | H | OCH2CH=CH2 | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
374. | H | OCH2CH=CH2 | CH2CH2P-O(OH)2 | CH2-CONH2 |
375. | H | OCH2C6H5 | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
376. | H | OCH2C6H5 | CH2CH2P-O(OH)2 | CH2-CONH2 |
377. | H | OCH2CH2C6H5 | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
378. | H | OCH2CH2C6H5 | CH2CH2P-O(OH)2 | CH2-CONH2 |
379. | H | OCH2-CONH2 | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
380. | H | OCH2-CONH2 | CH2CH2P-O(OH)2 | CH2-CONH2 |
381. | H | H | CH2-CO2CH2CH3 | CH2C6H5 |
382. | H | H | CH2-CO2H | CH2C6H5 |
383. | OH | H | CH2-CO2CH2CH3 | CH2C6H5 |
384. | OH | H | CH2-CO2H | CH2C6H5 |
385. | OCH3 | H | CH2-CO2CH2CH3 | CH2C6H5 |
386. | OCH3 | H | CH2-CO2H | CH2C6H5 |
387. | OCH2CH=CH2 | H | CH2-CO2CH2CH3 | CH2C6H5 |
388. | OCH2CH=CH2 | H | CH2-CO2H | CH2C6H5 |
389. | OCH2C6H5 | H | CH2-CO2CH2CH3 | CH2C6H5 |
390. | OCH2C6H5 | H | CH2-CO2H | CH2C6H5 |
391. | OCH2CH2C6H5 | H | CH2-CO2CH2CH3 | CH2C6H5 |
392. | OCH2CH2C6H5 | H | CH2-CO2H | CH2C6H5 |
393. | OCH2-CONH2 | H | CH2-CO2CH2CH3 | CH2C6H5 |
394. | OCH2-CONH2 | H | CH2-CO2H | CH2C6H5 |
395. | H | Cl | CH2-CO2CH2CH3 | CH2C6H5 |
396. | H | Cl | CH2-CO2H | CH2C6H5 |
397. | Br | H | CH2-CO2CH2CH3 | CH2C6H5 |
398. | Br | H | CH2-CO2H | CH2C6H5 |
399. | H | CH3 | CH2-CO2CH2CH3 | CH2C6H5 |
400. | H | CH3 | CH2-CO2H | CH2C6H5 |
401. | NO2 | H | CH2-CO2CH2CH3 | CH2C6H5 |
402. | NO2 | H | CH2-CO2H | CH2C6H5 |
403. | NH2 | H | CH2-CO2CH2CH3 | CH2C6H5 |
404. | NH2 | H | CH2-CO2H | CH2C6H5 |
405. | NHSO2CH3 | H | CH2-CO2CH2CH3 | CH2C6H5 |
406. | NHSO2CH3 | H | CH2-CO2H | CH2C6H5 |
407. | H | OH | CH2-CO2CH2CH3 | CH2C6H5 |
408. | H | OH | CH2-CO2H | CH2C6H5 |
409. | H | OCH3 | CH2-CO2CH2CH3 | CH2C6H5 |
410. | H | OCH3 | CH2-CO2H | CH2C6H5 |
411. | H | OCH2CH=CH2 | CH2-CO2CH2CH3 | CH2C6H5 |
412. | H | OCH2CH=CH2 | CH2-CO2H | CH2C6H5 |
413. | H | OCH2C6H5 | CH2-CO2CH2CH3 | CH2C6H5 |
414. | H | OCH2C6H5 | CH2-CO2H | CH2C6H5 |
415. | H | OCH2CH2C6H5 | CH2-CO2CH2CH3 | CH2C6H5 |
416. | H | OCH2CH2C6H5 | CH2-CO2H | CH2C6H5 |
417. | H | OCH2-CONH2 | CH2-CO2CH2CH3 | CH2C6H5 |
418. | H | OCH2-CONH2 | CH2-CO2H | CH2C6H5 |
419. | H | H | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
420. | H | H | CH2CH2P-O(OH)2 | CH2C6H5 |
421. | OH | H | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
422. | OH | H | CH2CH2P-O(OH)2 | CH2C6H5 |
423. | OCH3 | H | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
424. | OCH3 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
425. | OCH2CH=CH2 | H | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
426. | OCH2CH=CH2 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
427. | OCH2C6H5 | H | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
428. | OCH2C6H5 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
429. | OCH2CH2C6H5 | H | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
430. | OCH2CH2C6H5 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
431. | OCH2-CONH2 | H | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
432. | OCH2-CONH2 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
433. | H | Cl | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
434. | H | Cl | CH2CH2P-O(OH)2 | CH2C6H5 |
435. | Br | H | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
436. | Br | H | CH2CH2P-O(OH)2 | CH2C6H5 |
437. | H | CH3 | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
438. | H | CH3 | CH2CH2P-O(OH)2 | CH2C6H5 |
439. | NO2 | H | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
440. | NO2 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
441. | NH2 | H | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
442. | NH2 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
443. | NHSO2CH3 | H | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
444. | NHSO2CH3 | H | CH2CH2P-O(OH)2 | CH2C6H5 |
445. | H | OH | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
446. | H | OH | CH2CH2P-O(OH)2 | CH2C6H5 |
447. | H | OCH3 | CH2CH2P-O(OCH2CH3)2 | CH2C6H5 |
448. | H | OCH3 | CH2CH2P-O(OH)2 | CH2-CONH2 |
449. | H | OCH2CH=CH2 | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
450. | H | OCH2CH=CH2 | CH2CH2P-O(OH)2 | CH2-CONH2 |
451. | H | OCH2C6H5 | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
452. | H | OCH2C6H5 | CH2CH2P-O(OH)2 | CH2-CONH2 |
453. | H | OCH2CH2C6H5 | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
454. | H | OCH2CH2C6H5 | CH2CH2P-O(OH)2 | CH2-CONH2 |
455. | H | OCH2-CONH2 | CH2CH2P-O(OCH2CH3)2 | CH2-CONH2 |
456. | H | OCH2-CONH2 | CH2CH2P-O(OH)2 | CH2-CONH2 |
表Va
Ex. # | X | X1 | X2 | X3 | R1 |
1. | OCH2CO2-CH2CH3 | H | H | H | H |
2. | OCH2CO2-CH2CH3 | H | H | H | CH3 |
3. | OCH2CO2H | H | H | H | H |
4. | OCH2CO2H | H | H | H | CH3 |
5. | OCH2CH2-CO2CH2CH3 | H | H | H | H |
6. | OCH2CH2-CO2CH2CH3 | H | H | H | CH3 |
7. | OCH2CH2-CO2H | H | H | H | H |
8. | OCH2CH2-CO2H | H | H | H | CH3 |
9. | OCH2CH=CH-CO 2CH2CH3 | H | H | H | H |
10. | OCH2CH=CH-CO 2CH2CH3 | H | H | H | CH3 |
11. | OCH2CH=CH-CO 2H | H | H | H | H |
12. | OCH2CH=CH-CO 2H | H | H | H | CH3 |
13. | OCH2CH2-PO(OCH2CH3)2 | H | H | H | H |
14. | OCH2CH2-PO(OCH2CH3)2 | H | H | H | CH3 |
15. | OCH2CH2-PO(OH)2 | H | H | H | H |
16. | OCH2CH2-PO(OH)2 | H | H | H | CH3 |
17. | H | OCH2CO2-CH2CH3 | H | H | H |
18. | H | OCH2CO2-CH2CH3 | H | H | CH3 |
19. | H | OCH2CO2H | H | H | H |
20. | H | OCH2CO2H | H | H | CH3 |
21. | H | OCH2CH2CO2-CH2 | H | H | H |
CH3 | |||||
22. | H | OCH2CH2CO2-CH2 CH3 | H | H | CH3 |
23. | H | OCH2CH2CO2H | H | H | H |
24. | H | OCH2CH2CO2H | H | H | CH3 |
25. | H | OCH2CH=CH-CO2 CH2CH3 | H | H | H |
26. | H | OCH2CH=CH-CO2 CH2CH3 | H | H | CH3 |
27. | H | OCH2CH=CH-CO2 H | H | H | H |
28. | H | OCH2CH=CH-CO2 H | H | H | CH3 |
29. | H | OCH2CH2-PO(OCH 2CH3)2 | H | H | H |
30. | H | OCH2CH2-PO(OCH 2CH3)2 | H | H | CH3 |
31. | H | OCH2CH2-PO(OH)2 | H | H | H |
32. | H | OCH2CH2-PO(OH)2 | H | H | CH3 |
33. | H | H | OCH2CO2-CH2 CH3 | H | H |
34. | H | H | OCH2CO2-CH2 CH3 | H | CH3 |
35. | H | H | OCH2CO2H | H | H |
36. | H | H | OCH2CO2H | H | CH3 |
37. | H | H | OCH2CH2-CO2 CH2CH3 | H | H |
38. | H | H | OCH2CH2-CO2 CH2CH3 | H | CH3 |
39. | H | H | OCH2CH2-CO2 H | H | H |
40. | H | H | OCH2CH2-CO2 H | H | CH3 |
41. | H | H | OCH2-CH=CH- CO2CH2CH3 | H | H |
42. | H | H | OCH2-CH=CH- CO2CH2CH3 | H | CH3 |
43. | H | H | OCH2-CH=CH CO2H | H | H |
44. | H | H | OCH2-CH=CH CO2H | H | CH3 |
45. | H | H | OCH2CH2PO-( OCH2CH3)2 | H | H |
46. | H | H | OCH2CH2PO-( OCH2CH3)2 | H | CH3 |
47. | H | H | OCH2CH2-PO( OH)2 | H | H |
48. | H | H | OCH2CH2-PO( OH)2 | H | CH3 |
49. | H | H | H | OCH2CO2-CH2 CH3 | H |
50. | H | H | H | OCH2CO2-CH2 CH3 | CH3 |
51. | H | H | H | OCH2CO2H | H |
52. | H | H | H | OCH2CO2H | CH3 |
53. | H | H | H | OCH2CH2-CO2 CH2CH3 | H |
54. | H | H | H | OCH2CH2-CO2 CH2CH3 | CH3 |
55. | H | H | H | OCH2CH2-CO2 H | H |
56. | H | H | H | OCH2CH2-CO2 H | CH3 |
57. | H | H | H | OCH2-CH=CH- CO2CH2CH3 | H |
58. | H | H | H | OCH2-CH=CH- CO2CH2CH3 | CH3 |
59. | H | H | H | OCH2-CH=CH CO2H | H |
60. | H | H | H | OCH2-CH=CH CO2H | CH3 |
61. | H | H | H | OCH2CH2PO-( OCH2CH3)2 | H |
62. | H | H | H | OCH2CH2PO-( OCH2CH3)2 | CH3 |
63. | H | H | H | OCH2CH2-PO( OH)2 | H |
64. | H | H | H | OCH2CH2-PO( OH)2 | CH3 |
表Vb
Ex. # | X | X1 | X2 | X3 | R1 |
1. | OCH2CO2-CH2CH3 | H | H | H | H |
2. | OCH2CO2-CH2CH3 | H | H | H | CH3 |
3. | OCH2CO2H | H | H | H | H |
4. | OCH2CO2H | H | H | H | CH3 |
5. | OCH2CH2-CO2CH2CH3 | H | H | H | H |
6. | OCH2CH2-CO2CH2CH3 | H | H | H | CH3 |
7. | OCH2CH2-CO2H | H | H | H | H |
8. | OCH2CH2-CO2H | H | H | H | CH3 |
9. | OCH2CH=CH-CO 2CH2CH3 | H | H | H | H |
10. | OCH2CH=CH-CO 2CH2CH3 | H | H | H | CH3 |
11. | OCH2CH=CH-CO 2H | H | H | H | H |
12. | OCH2CH=CH-CO 2H | H | H | H | CH3 |
13. | OCH2CH2-PO(OC | H | H | H | H |
H2CH3)2 | |||||
14. | OCH2CH2-PO(OCH2CH3)2 | H | H | H | CH3 |
15. | OCH2CH2-PO(OH)2 | H | H | H | H |
16. | OCH2CH2-PO(OH)2 | H | H | H | CH3 |
17. | H | OCH2CO2-CH2CH3 | H | H | H |
18. | H | OCH2CO2-CH2CH3 | H | H | CH3 |
19. | H | OCH2CO2H | H | H | H |
20. | H | OCH2CO2H | H | H | CH3 |
21. | H | OCH2CH2CO2-CH2 CH3 | H | H | H |
22. | H | OCH2CH2CO2-CH2 CH3 | H | H | CH3 |
23. | H | OCH2CH2CO2H | H | H | H |
24. | H | OCH2CH2CO2H | H | H | CH3 |
25. | H | OCH2CH=CH-CO2 CH2CH3 | H | H | H |
26. | H | OCH2CH=CH-CO2 CH2CH3 | H | H | CH3 |
27. | H | OCH2CH=CH-CO2 H | H | H | H |
28. | H | OCH2CH=CH-CO2 H | H | H | CH3 |
29. | H | OCH2CH2-PO(OCH 2CH3)2 | H | H | H |
30. | H | OCH2CH2-PO(OCH 2CH3)2 | H | H | CH3 |
31. | H | OCH2CH2-PO(OH)2 | H | H | H |
32. | H | OCH2CH2-PO(OH)2 | H | H | CH3 |
33. | H | H | OCH2CO2-CH2 CH3 | H | H |
34. | H | H | OCH2CO2-CH2 CH3 | H | CH3 |
35. | H | H | OCH2CO2H | H | H |
36. | H | H | OCH2CO2H | H | CH3 |
37. | H | H | OCH2CH2-CO2 CH2CH3 | H | H |
38. | H | H | OCH2CH2-CO2 CH2CH3 | H | CH3 |
39. | H | H | OCH2CH2-CO2 H | H | H |
40. | H | H | OCH2CH2-CO2 H | H | CH3 |
41. | H | H | OCH2-CH=CH- CO2CH2CH3 | H | H |
42. | H | H | OCH2-CH=CH- CO2CH2CH3 | H | CH3 |
43. | H | H | OCH2-CH=CH CO2H | H | H |
44. | H | H | OCH2-CH=CH CO2H | H | CH3 |
45. | H | H | OCH2CH2PO-( OCH2CH3)2 | H | H |
46. | H | H | OCH2CH2PO-( OCH2CH3)2 | H | CH3 |
47. | H | H | OCH2CH2-PO( OH)2 | H | H |
48. | H | H | OCH2CH2-PO( OH)2 | H | CH3 |
49. | H | H | H | OCH2CO2-CH2 CH3 | H |
50. | H | H | H | OCH2CO2-CH2 CH3 | CH3 |
51. | H | H | H | OCH2CO2H | H |
52. | H | H | H | OCH2CO2H | CH3 |
53. | H | H | H | OCH2CH2-CO2 CH2CH3 | H |
54. | H | H | H | OCH2CH2-CO2 CH2CH3 | CH3 |
55. | H | H | H | OCH2CH2-CO2 H | H |
56. | H | H | H | OCH2CH2-CO2 H | CH3 |
57. | H | H | H | OCH2-CH=CH- CO2CH2CH3 | H |
58. | H | H | H | OCH2-CH=CH- CO2CH2CH3 | CH3 |
59. | H | H | H | OCH2-CH=CH CO2H | H |
60. | H | H | H | OCH2-CH=CH CO2H | CH3 |
61. | H | H | H | OCH2CH2PO-( OCH2CH3)2 | H |
62. | H | H | H | OCH2CH2PO-( OCH2CH3)2 | CH3 |
63. | H | H | H | OCH2CH2-PO( OH)2 | H |
64. | H | H | H | OCH2CH2-PO( OH)2 | CH3 |
表VIa
Ex.# | X | X1 | X2 | R | A- |
457. | H | H | H | CH3 | Cl- |
458. | H | H | H | CH2C≡CH | Cl- |
459. | H | OCH3 | H | CH3 | Cl- |
460. | H | OCH3 | H | CH2C≡CH | Cl- |
461. | H | H | OCH3 | CH3 | Cl- |
462. | H | H | OCH3 | CH2C≡CH | Cl- |
463. | OCH3 | H | H | CH3 | Cl- |
464. | OCH3 | H | H | CH2C≡CH | Cl- |
465. | H | OCH2C6H5 | H | CH3 | Cl- |
466. | H | OCH2C6H5 | H | CH2C≡CH | Cl- |
467. | H | H | OCH2C6H5 | CH3 | Cl- |
468. | H | H | OCH2C6H5 | CH2C≡CH | Cl- |
469. | OCH2C6H5 | H | H | CH3 | Cl- |
470. | OCH2C6H5 | H | H | CH2C≡CH | Cl- |
471. | H | Cl | H | CH3 | Cl- |
472. | H | Cl | H | CH2C≡CH | Cl- |
473. | H | H | Cl | CH3 | Cl- |
474. | H | H | Cl | CH2C≡CH | Cl- |
475. | Cl | H | H | CH3 | Cl- |
476. | Cl | H | H | CH2C≡CH | Cl- |
477. | H | OH | H | CH3 | Cl- |
478. | H | OH | H | CH2C≡CH | Cl- |
479. | H | H | OH | CH3 | Cl- |
480. | H | H | OH | CH2C≡CH | Cl- |
481. | OH | H | H | CH3 | Cl- |
482. | OH | H | H | CH2C≡CH | Cl- |
483. | H | OCH2CH=CH2 | H | CH3 | Cl- |
484. | H | OCH2CH=CH2 | H | CH2C≡CH | Cl- |
485. | H | H | OCH2CH=CH2 | CH3 | Cl- |
486. | H | H | OCH2CH=CH2 | CH2C≡CH | Cl- |
487. | OCH2CH=CH2 | H | H | CH3 | Cl- |
488. | OCH2CH=CH2 | H | H | CH2C≡CH | Cl- |
489. | H | NO2 | H | CH3 | Cl- |
490. | H | NO2 | H | CH2C≡CH | Cl- |
491. | H | H | NO2 | CH3 | Cl |
492. | H | H | NO2 | CH2C≡CH | Cl |
493. | NO2 | H | H | CH3 | Cl- |
494. | NO2 | H | H | CH2C≡CH | Cl- |
495. | H | NHSO2CH3 | H | CH3 | Cl- |
496. | H | NHSO2CH3 | H | CH2C≡CH | Cl- |
497. | H | H | NHSO2CH3 | CH3 | Cl |
498. | H | H | NHSO2CH3 | CH2C≡CH | Cl |
499. | NHSO2CH3 | H | H | CH3 | Cl- |
500. | NHSO2CH3 | H | H | CH2C≡CH | Cl- |
501. | H | H | OCH2CONH2 | CH3 | Cl- |
502. | H | H | OCH2CONH2 | CH2C≡CH | Cl- |
503. | H | OCH2CONH2 | H | CH3 | Cl- |
504. | H | OCH2CONH2 | H | CH2C≡CH | Cl- |
505. | OCH2CONH2 | H | H | CH3 | Cl- |
506. | OCH2CONH2 | H | H | CH2C≡CH | Cl- |
507. | H | OCH2CH2C6H5 | H | CH3 | Cl- |
508. | H | OCH2CH2C6H5 | H | CH2C≡CH | Cl- |
509. | H | H | OCH2CH2C6H5 | CH3 | Cl- |
510. | H | H | OCH2CH2C6H5 | CH2C≡CH | Cl |
511. | OCH2CH2 C6H5 | H | H | CH3 | Cl |
512. | OCH2CH2 C6H5 | H | H | CH2C≡CH | Cl |
513. | H | OCH2C6H4-Cl(3 ) | H | CH3 | Cl |
514. | H | OCH2C6H4-Cl(3 ) | H | CH2C≡CH | Cl |
515. | H | H | OCH2C6H4-Cl(3) | CH3 | Cl |
516. | H | H | OCH2C6H4-Cl(3) | CH2C≡CH | Cl |
517. | OCH2C6H4-Cl(3) | H | H | CH3 | Cl |
518. | OCH2C6H4-Cl(3) | H | H | CH2C≡CH | Cl |
519. | H | OCH2C6H4-Cl(4 ) | H | CH3 | Cl |
520. | H | OCH2C6H4-Cl(4 ) | H | CH2C≡CH | Cl |
521. | H | H | OCH2C6H4-Cl(4) | CH3 | Cl |
522. | H | H | OCH2C6H4-Cl(4) | CH2C≡CH | Cl |
523. | OCH2C6H4-Cl(4) | H | H | CH3 | Cl |
524. | OCH2C6H4-Cl(4) | H | H | CH2C≡CH | Cl |
525. | H | OCH2C6H4CF3( 3) | H | CH3 | Cl |
526. | H | OCH2C6H4CF3( 3) | H | CH2C≡CH | Cl |
527. | OCH2C6H4CF3(3) | H | H | CH3 | Cl |
528. | OCH2C6H4CF3(3) | H | H | CH2C≡CH | Cl |
529. | H | H | OCH2C6H4CF3(3) | CH3 | Cl |
530. | H | H | OCH2C6H4CF3(3) | CH2C≡CH | Cl |
531. | H | OCH2C6H4CF3( 4) | H | CH3 | Cl |
532. | H | OCH2C6H4CF3( 4) | H | CH2C≡CH | Cl |
533. | OCH2C6H4CF3(4) | H | H | CH3 | Cl |
534. | OCH2C6H4CF3(4) | H | H | CH2C≡CH | Cl |
535. | H | H | OCH2C6H4CF3(4) | CH3 | Cl |
536. | H | H | OCH2C6H4CF3(4) | CH2C≡CH | Cl |
表VIb
Ex.# | X | X1 | X2 | R1 |
537. | H | H | H | H |
538. | H | H | H | CH3 |
539. | H | OCH3 | H | H |
540. | H | OCH3 | H | CH3 |
541. | H | H | OCH3 | H |
542. | H | H | OCH3 | CH3 |
543. | OCH3 | H | H | H |
544. | OCH3 | H | H | CH3 |
545. | H | OCH2C6H5 | H | H |
546. | H | OCH2C6H5 | H | CH3 |
547. | H | H | OCH2C6H5 | H |
548. | H | H | OCH2C6H5 | CH3 |
549. | OCH2C6H5 | H | H | H |
550. | OCH2C6H5 | H | H | CH3 |
551. | H | Cl | H | H |
552. | H | Cl | H | CH3 |
553. | H | H | Cl | H |
554. | H | H | Cl | CH3 |
555. | Cl | H | H | H |
556. | Cl | H | H | CH3 |
557. | H | OH | H | H |
558. | H | OH | H | CH3 |
559. | H | H | OH | H |
560. | H | H | OH | CH3 |
561. | OH | H | H | H |
562. | OH | H | H | CH3 |
563. | H | OCH2CH=CH2 | H | H |
564. | H | OCH2CH=CH2 | H | CH3 |
565. | H | H | OCH2CH=CH2 | H |
566. | H | H | OCH2CH=CH2 | CH3 |
567. | OCH2CH=CH2 | H | H | H |
568. | OCH2CH=CH2 | H | H | CH3 |
569. | H | NO2 | H | H |
570. | H | NO2 | H | CH3 |
571. | H | H | NO2 | H |
572. | H | H | NO2 | CH3 |
573. | NO2 | H | H | H |
574. | NO2 | H | H | CH3 |
575. | H | NHSO2CH3 | H | H |
576. | H | NHSO2CH3 | H | CH3 |
577. | H | H | NHSO2CH3 | H |
578. | H | H | NHSO2CH3 | CH3 |
579. | NHSO2CH3 | H | H | H |
580. | NHSO2CH3 | H | H | CH3 |
581. | H | H | OCH2CONH2 | H |
582. | H | H | OCH2CONH2 | CH3 |
583. | H | OCH2CONH2 | H | H |
584. | H | OCH2CONH2 | H | CH3 |
585. | OCH2CONH2 | H | H | H |
586. | OCH2CONH2 | H | H | CH3 |
587. | H | OCH2CH2C6H5 | H | H |
588. | H | OCH2CH2C6H5 | H | CH3 |
589. | H | H | OCH2CH2C6H5 | H |
590. | H | H | OCH2CH2C6H5 | CH3 |
591. | OCH2CH2 C6H5 | H | H | H |
592. | OCH2CH2 C6H5 | H | H | CH3 |
593. | H | OCH2C6H4-Cl(3) | H | H |
594. | H | OCH2C6H4-Cl(3) | H | CH3 |
595. | H | H | OCH2C6H4-Cl(3) | H |
596. | H | H | OCH2C6H4-Cl(3) | CH3 |
597. | OCH2C6H4-Cl(3) | H | H | H |
598. | OCH2C6H4-Cl(3) | H | H | CH3 |
599. | H | OCH2C6H4-Cl(4) | H | H |
600. | H | OCH2C6H4-Cl(4) | H | CH3 |
601. | H | H | OCH2C6H4-Cl(4) | CH3 |
602. | H | H | OCH2C6H4-Cl(4) | H |
603. | OCH2C6H4-Cl(4) | H | H | CH3 |
604. | OCH2C6H4-Cl(4) | H | H | H |
605. | H | OCH2C6H4CF3(3) | H | H |
606. | H | OCH2C6H4CF3(3) | H | CH3 |
607. | OCH2C6H4CF3(3) | H | H | H |
608. | OCH2C6H4CF3(3) | H | H | CH3 |
609. | H | H | OCH2C6H4CF3(3) | H |
610. | H | H | OCH2C6H4CF3(3) | CH3 |
611. | H | OCH2C6H4CF3(4) | H | H |
612. | H | OCH2C6H4CF3(4) | H | CH3 |
613. | OCH2C6H4CF3(4) | H | H | H |
614. | OCH2C6H4CF3(4) | H | H | CH3 |
615. | H | H | OCH2C6H4CF3(4) | H |
616. | H | H | OCH2C6H4CF3(4) | CH3 |
表VIIa
Ex.# | X | X1 | X2 | R |
617. | OCH2CH=CH2 | H | H | H |
618. | OCH2CH=CH2 | H | H | CH3 |
619. | CF3 | H | H | H |
620. | CF3 | H | H | CH3 |
621. | NO2 | H | H | H |
622. | NO2 | H | H | CH3 |
623. | CH3 | H | H | H |
624. | CH3 | H | H | CH3 |
625. | NHSO2CH3 | H | H | H |
626. | NHSO2CH3 | H | H | CH3 |
627. | OCH2C6H5 | H | H | H |
628. | OCH2C6H5 | H | H | CH3 |
629. | OCH2C6H4-Cl(3) | H | H | H |
630. | OCH2C6H4-Cl(3) | H | H | CH3 |
631. | OCH2C6H4-Cl(4) | H | H | H |
632. | OCH2C6H4-Cl(4) | H | H | CH3 |
633. | OCH2C6H4-F(3) | H | H | H |
634. | OCH2C6H4-F(3) | H | H | CH3 |
635. | OCH2C6H4-F(4) | H | H | H |
636. | OCH2C6H4-F(4) | H | H | CH3 |
637. | OCH2C6H4-CF3(3) | H | H | H |
638. | OCH2C6H4-CF3(3) | H | H | CH3 |
639. | OCH2C6H4-CF3(4) | H | H | H |
640. | OCH2C6H4-CF3(4) | H | H | CH3 |
641. | OCH2C6H4-NO2(3) | H | H | H |
642. | OCH2C6H4-NO2(3) | H | H | CH3 |
643. | OCH2C6H4-NO2(4) | H | H | H |
644. | OCH2C6H4-NO2(4) | H | H | CH3 |
645. | OCH2C6H4-NHSO2CH3(3) | H | H | H |
646. | OCH2C6H4-NHSO2CH3(3) | H | H | CH3 |
647. | OCH2C6H4-NHSO2CH3(4) | H | H | H |
648. | OCH2C6H4-NHSO2CH3(4) | H | H | CH3 |
649. | OCH2C6H4-CN(3) | H | H | H |
650. | OCH2C6H4-CN(3) | H | H | CH3 |
651. | OCH2C6H4-CN(4) | H | H | H |
652. | OCH2C6H4-CN(4) | H | H | CH3 |
653. | OCH2C6H4-CON H2(3) | H | H | H |
654. | OCH2C6H4-CONH2(3) | H | H | CH3 |
655. | OCH2C6H4-CONH2(4) | H | H | H |
656. | OCH2C6H4-CONH2(4) | H | H | CH3 |
657. | OCH2C6H4-CH2CN(3) | H | H | H |
658. | OCH2C6H4-CH2CN(3) | H | H | CH3 |
659. | OCH2C6H4-CH2CN(4) | H | H | H |
660. | OCH2C6H4-CH2CN(4) | H | H | CH3 |
661. | OCH2C6H4-CH2CONH2(3) | H | H | H |
662. | OCH2C6H4-CH2CONH2(3) | H | H | CH3 |
663. | OCH2C6H4-CH2CONH2(4) | H | H | H |
664. | OCH2C6H4-CH2CONH2(4) | H | H | CH3 |
665. | OCH2C6H4-OCH2CN(3) | H | H | H |
666. | OCH2C6H4-OCH2CN(3) | H | H | CH3 |
667. | OCH2C6H4-OCH2CN(4) | H | H | H |
668. | OCH2C6H4-OCH2CN(4) | H | H | CH3 |
669. | OCH2C6H4-OCH2CONH2(3) | H | H | H |
670. | OCH2C6H4-OCH2CONH2(3) | H | H | CH3 |
671. | OCH2C6H4-OCH2CONH2(4) | H | H | H |
672. | OCH2C6H4-OCH2CONH2(4) | H | H | CH3 |
673. | OCH2C6H3-(CN)2(3 ,5) | H | H | H |
674. | OCH2C6H3-(CN)2(3,5) | H | H | CH3 |
675. | OCH2C6H3-(CN)2(3,5) | H | H | H |
676. | OCH2C6H3-(CN)2(3,5) | H | H | CH3 |
677. | OCH2C6H3-(CONH2)2(3,5) | H | H | H |
678. | OCH2C6H3-(CONH2)2(3,5) | H | H | CH3 |
679. | OCH2C6H3-(CONH2)2(3,5) | H | H | H |
680. | OCH2C6H3-(CONH2)2(3,5) | H | H | CH3 |
681. | OCH2CH2C6H5 | H | H | H |
682. | OCH2CH2C6H5 | H | H | CH3 |
683. | OCH2C6H4C6H4CN(2) | H | H | H |
684. | OCH2C6H4C6H4CN(2) | H | H | CH3 |
685. | OCH2C6H4C6H4CONH2(2) | H | H | H |
686. | OCH2C6H4C6H4CONH2(2) | H | H | CH3 |
表VIIIb
Ex.# | X1 | X | X2 | R |
687. | OCH2CH=CH2 | H | H | H |
688. | OCH2CH=CH2 | H | H | CH3 |
689. | CF3 | H | H | H |
690. | CF3 | H | H | CH3 |
691. | NO2 | H | H | H |
692. | NO2 | H | H | CH3 |
693. | CH3 | H | H | H |
694. | CH3 | H | H | CH3 |
695. | NHSO2CH3 | H | H | H |
696. | NHSO2CH3 | H | H | CH3 |
697. | OCH2C6H5 | H | H | H |
698. | OCH2C6H5 | H | H | CH3 |
699. | OCH2C6H4-Cl(3) | H | H | H |
700. | OCH2C6H4-Cl(3) | H | H | CH3 |
701. | OCH2C6H4-Cl(4) | H | H | H |
702. | OCH2C6H4-Cl(4) | H | H | CH3 |
703. | OCH2C6H4-F(3) | H | H | H |
704. | OCH2C6H4-F(3) | H | H | CH3 |
705. | OCH2C6H4-F(4) | H | H | H |
706. | OCH2C6H4-F(4) | H | H | CH3 |
707. | OCH2C6H4-CF3(3) | H | H | H |
708. | OCH2C6H4-CF3(3) | H | H | CH3 |
709. | OCH2C6H4-CF3(4) | H | H | H |
710. | OCH2C6H4-CF3(4) | H | H | CH3 |
711. | OCH2C6H4-NO2(3) | H | H | H |
712. | OCH2C6H4-NO2(3) | H | H | CH3 |
713. | OCH2C6H4-NO2(4) | H | H | H |
714. | OCH2C6H4-NO2(4) | H | H | CH3 |
715. | OCH2C6H4-NHSO2CH3(3) | H | H | H |
716. | OCH2C6H4-NHSO2CH3(3) | H | H | CH3 |
717. | OCH2C6H4-NHSO2CH3(4) | H | H | H |
718. | OCH2C6H4-NHSO2CH3(4) | H | H | CH3 |
719. | OCH2C6H4-CN(3) | H | H | H |
720. | OCH2C6H4-CN(3) | H | H | CH3 |
721. | OCH2C6H4-CN(4) | H | H | H |
722. | OCH2C6H4-CN(4) | H | H | CH3 |
723. | OCH2C6H4-CONH2(3) | H | H | H |
724. | OCH2C6H4-CONH2(3) | H | H | CH3 |
725. | OCH2C6H4-CONH2(4) | H | H | H |
726. | OCH2C6H4-CONH2(4) | H | H | CH3 |
727. | OCH2C6H4-CH2CN(3) | H | H | H |
728. | OCH2C6H4-CH2CN(3) | H | H | CH3 |
729. | OCH2C6H4-CH2CN(4) | H | H | H |
730. | OCH2C6H4-CH2CN(4) | H | H | CH3 |
731. | OCH2C6H4-CH2CONH2(3) | H | H | H |
732. | OCH2C6H4-CH2CONH2(3) | H | H | CH3 |
733. | OCH2C6H4-CH2CONH2(4) | H | H | H |
734. | OCH2C6H4-CH2CONH2(4) | H | H | CH3 |
735. | OCH2C6H4-OCH2CN(3) | H | H | H |
736. | OCH2C6H4-OCH2CN(3) | H | H | CH3 |
737. | OCH2C6H4-OCH2CN(4) | H | H | H |
738. | OCH2C6H4-OCH2CN(4) | H | H | CH3 |
739. | OCH2C6H4-OCH2CONH2(3) | H | H | H |
740. | OCH2C6H4-OCH2CONH2(3) | H | H | CH3 |
741. | OCH2C6H4-OCH2CONH2(4) | H | H | H |
742. | OCH2C6H4-OCH2CONH2(4) | H | H | CH3 |
743. | OCH2C6H3-(CN)2(3,5) | H | H | H |
744. | OCH2C6H3-(CN)2(3,5) | H | H | CH3 |
745. | OCH2C6H3-(CN)2(3,5) | H | H | H |
746. | OCH2C6H3-(CN)2(3,5) | H | H | CH3 |
747. | OCH2C6H3-(CONH2)2(3,5) | H | H | H |
748. | OCH2C6H3-(CONH2)2(3,5) | H | H | CH3 |
749. | OCH2C6H3-(CONH2)2(3,5) | H | H | H |
750. | OCH2C6H3-(CONH2)2(3,5) | H | H | CH3 |
751. | OCH2CH2C6H5 | H | H | H |
752. | OCH2CH2C6H5 | H | H | CH3 |
753. | OCH2C6H4C6H4CN(2) | H | H | H |
754. | OCH2C6H4C6H4CN(2) | H | H | CH3 |
755. | OCH2C6H4C6H4CONH2(2) | H | H | H |
756. | OCH2C6H4C6H4CONH2(2) | H | H | CH3 |
表VIIc
Ex.# | X2 | X | X1 | R |
757. | OCH2CH=CH2 | H | H | H |
758. | OCH2CH=CH2 | H | H | CH3 |
759. | CF3 | H | H | H |
760. | CF3 | H | H | CH3 |
761. | NO2 | H | H | H |
762. | NO2 | H | H | CH3 |
763. | CH3 | H | H | H |
764. | CH3 | H | H | CH3 |
765. | NHSO2CH3 | H | H | H |
766. | NHSO2CH3 | H | H | CH3 |
767. | OCH2C6H5 | H | H | H |
768. | OCH2C6H5 | H | H | CH3 |
769. | OCH2C6H4-Cl(3) | H | H | H |
770. | OCH2C6H4-Cl(3) | H | H | CH3 |
771. | OCH2C6H4-Cl(4) | H | H | H |
772. | OCH2C6H4-Cl(4) | H | H | CH3 |
773. | OCH2C6H4-F(3) | H | H | H |
774. | OCH2C6H4-F(3) | H | H | CH3 |
775. | OCH2C6H4-F(4) | H | H | H |
776. | OCH2C6H4-F(4) | H | H | CH3 |
777. | OCH2C6H4-CF3(3) | H | H | H |
778. | OCH2C6H4-CF3(3) | H | H | CH3 |
779. | OCH2C6H4-CF3(4) | H | H | H |
780. | OCH2C6H4-CF3(4) | H | H | CH3 |
781. | OCH2C6H4-NO2(3) | H | H | H |
782. | OCH2C6H4-NO2(3) | H | H | CH3 |
783. | OCH2C6H4-NO2(4) | H | H | H |
784. | OCH2C6H4-NO2(4) | H | H | CH3 |
785. | OCH2C6H4-NHSO2CH3(3) | H | H | H |
786. | OCH2C6H4-NHSO2CH3(3) | H | H | CH3 |
787. | OCH2C6H4-NHSO2CH3(4) | H | H | H |
788. | OCH2C6H4-NHSO2CH3(4) | H | H | CH3 |
789. | OCH2C6H4-CN(3) | H | H | H |
790. | OCH2C6H4-CN(3) | H | H | CH3 |
791. | OCH2C6H4-CN(4) | H | H | H |
792. | OCH2C6H4-CN(4) | H | H | CH3 |
793. | OCH2C6H4-CONH2(3) | H | H | H |
794. | OCH2C6H4-CONH2(3) | H | H | CH3 |
795. | OCH2C6H4-CONH2(4) | H | H | H |
796. | OCH2C6H4-CONH2(4) | H | H | CH3 |
797. | OCH2C6H4-CH2CN(3) | H | H | H |
798. | OCH2C6H4-CH2CN(3) | H | H | CH3 |
799. | OCH2C6H4-CH2CN(4) | H | H | H |
800. | OCH2C6H4-CH2CN(4) | H | H | CH3 |
801. | OCH2C6H4-CH2CONH2(3) | H | H | H |
802. | OCH2C6H4-CH2CONH2(3) | H | H | CH3 |
803. | OCH2C6H4-CH2CONH2(4) | H | H | H |
804. | OCH2C6H4-CH2CONH2(4) | H | H | CH3 |
805. | OCH2C6H4-OCH2CN(3) | H | H | H |
806. | OCH2C6H4-OCH2CN(3) | H | H | CH3 |
807. | OCH2C6H4-OCH2CN(4) | H | H | H |
808. | OCH2C6H4-OCH2CN(4) | H | H | CH3 |
809. | OCH2C6H4-OCH2CONH2(3) | H | H | H |
810. | OCH2C6H4-OCH2CONH2(3) | H | H | CH3 |
811. | OCH2C6H4-OCH2CONH2(4) | H | H | H |
812. | OCH2C6H4-OCH2CONH2(4) | H | H | CH3 |
813. | OCH2C6H3-(CN)2(3,5) | H | H | H |
814. | OCH2C6H3-(CN)2(3,5) | H | H | CH3 |
815. | OCH2C6H3-(CN)2(3,5) | H | H | H |
816. | OCH2C6H3-(CN)2(3,5) | H | H | CH3 |
817. | OCH2C6H3-(CONH2)2(3,5) | H | H | H |
818. | OCH2C6H3-(CONH2)2(3,5) | H | H | CH3 |
819. | OCH2C6H3-(CONH2)2(3,5) | H | H | H |
820. | OCH2C6H3-(CONH2)2(3,5) | H | H | CH3 |
821. | OCH2CH2C6H5 | H | H | H |
822. | OCH2CH2C6H5 | H | H | CH3 |
823. | OCH2C6H4C6H4CN(2) | H | H | H |
824. | OCH2C6H4C6H4CN(2) | H | H | CH3 |
825. | OCH2C6H4C6H4CONH2(2) | H | H | H |
826. | OCH2C6H4C6H4CONH2(2) | H | H | CH3 |
鉴于上述教导,本发明的许多修改和变化是可能的。因此应当理解的是,正如本文所述,在所附权利要求书的范围内,如本文所具体描述的本发明也可以以另外的方式实施。
Claims (10)
1.式I的化合物,或其制药上可接受的盐:
其中:
R,在各种情况下,独立地选自H和C1-6烷基;
R1是H;
X、X1和X2独立地选自H、O(CH2)nCO2R、O-C2-6链烯基-CO2R、O(CH2)nPO(OR)2、O(CH2)n-苯基、O(CH2)n-呋喃基、O(CH2)n-苯基(CH2)mCO2R、O(CH2)n-苯基(CH2)mCN、O(CH2)n-苯基(CH2)mCON(R)2、O(CH2)n-苯基-O(CH2)nCO2R、O(CH2)n-苯基O(CH2)nCN、O(CH2)n-苯基O(CH2)nCON(R)2、和O(CH2)n-呋喃基-(CH2)mCO2R;
X3是H;
Q是H;
W是H;
m独立地选自0、1、2、3和4;和
n独立地选自1、2、3和4;
条件是:X、X1和X2中至少一个不是H。
4.根据权利要求3所述的化合物,其中:
X和X1中的一个是H并且另一个选自O(CH2)n-苯基、O(CH2)n-呋喃基、O(CH2)n-苯基-(CH2)mCON(R)2、O(CH2)n-苯基-O(CH2)nCON(R)2。
6.根据权利要求1所述的化合物,其中所述化合物具有式I c,或为其制药上可接受的盐:
其中:
R在各种情况下独立地选自H和C1-4烷基;
R1是H;
X、X1和X2独立地选自H、O(CH2)nCO2R、O-C2-4链烯基-CO2R、O(CH2)nPO(OR)2、O(CH2)n-苯基、O(CH2)n-呋喃基、O(CH2)n-苯基(CH2)mCO2R、O(CH2)n-苯基(CH2)mCN、O(CH2)n-苯基(CH2)mCON(R)2、O(CH2)n-苯基-O(CH2)nCO2R、O(CH2)n-苯基O(CH2)nCN、O(CH2)n-苯基O(CH2)nCON(R)2、和O(CH2)n-呋喃基(CH2)mCO2R;
X3是H;
m独立地选自0、1和2;和
n独立地选自1、2和3;
条件是:X、X1和X2中的至少一个不是H。
7.根据权利要求6所述的化合物,其中:
X、X1和X2中的两个为H并且第三个选自O(CH2)nCO2R、O-C2-4链烯基-CO2R、O(CH2)nPO(OR)2、O(CH2)n-苯基、O(CH2)n-呋喃基、O(CH2)n-苯基(CH2)mCO2R、O(CH2)n-苯基(CH2)mCN、O(CH2)n-苯基(CH2)mCON(R)2、O(CH2)n-苯基-O(CH2)nCO2R、O(CH2)n-苯基O(CH2)nCN、O(CH2)n-苯基O(CH2)nCON(R)2、和O(CH2)n-呋喃基(CH2)mCO2R;和X3是H。
9.化合物,其选自表A、B和C,或其制药上可接受的盐;
表A
表B
表C
10.药物组合物,其包括:权利要求1-9中任一项所述的化合物和制药上可接受的载体。
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PCT/US2006/021142 WO2006130707A2 (en) | 2005-06-02 | 2006-06-01 | Mao-b inhibitors useful for treating obesity |
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TWI361075B (en) * | 2007-03-16 | 2012-04-01 | Brion Res Inst Of Taiwan | Pharmaceutical composition for inhibiting the syndrome of snore |
EP2053033A1 (en) * | 2007-10-26 | 2009-04-29 | Bayer Schering Pharma AG | Compounds for use in imaging, diagnosing and/or treatment of diseases of the central nervous system or of tumors |
IT1392914B1 (it) * | 2009-01-22 | 2012-04-02 | Dipharma Francis Srl | Procedimento per la preparazione di (r)-n-propargil-1-amminoindano e suoi sali |
KR102007633B1 (ko) | 2016-12-15 | 2019-08-06 | 일동제약(주) | 신규 페닐 프로피온 산 유도체 및 이의 용도 |
CN107056630B (zh) * | 2017-01-23 | 2020-01-17 | 合肥工业大学 | 一种茚满类衍生物及其合成方法和在医药上的用途 |
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DK3697785T3 (da) | 2017-10-18 | 2023-04-03 | Jubilant Epipad LLC | Imidazo-pyridine forbindelser som pad-inhibitorer |
AU2018362046B2 (en) | 2017-11-06 | 2023-04-13 | Jubilant Prodel LLC | Pyrimidine derivatives as inhibitors of PD1/PD-L1 activation |
CA3083374A1 (en) | 2017-11-24 | 2019-05-31 | Jubilant Episcribe Llc | Heterocyclic compounds as prmt5 inhibitors |
AU2019234185A1 (en) | 2018-03-13 | 2020-10-01 | Jubilant Prodel LLC. | Bicyclic compounds as inhibitors of PD1/PD-L1 interaction/activation |
CN117835981A (zh) * | 2021-06-21 | 2024-04-05 | 尹诺卫医药有限公司 | 控制血糖水平和治疗糖尿病及相关疾患的方法 |
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AU2006252540B2 (en) | 2011-12-01 |
JP5253155B2 (ja) | 2013-07-31 |
NZ564130A (en) | 2009-12-24 |
IL187825A (en) | 2012-08-30 |
EP1890690A2 (en) | 2008-02-27 |
CA2620476A1 (en) | 2006-12-07 |
ZA200800036B (en) | 2008-12-31 |
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US7649115B2 (en) | 2010-01-19 |
US20100168068A1 (en) | 2010-07-01 |
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