CN103857682A - 用于治疗黑色素相关疾病的氮杂环丁烷衍生物 - Google Patents
用于治疗黑色素相关疾病的氮杂环丁烷衍生物 Download PDFInfo
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- CN103857682A CN103857682A CN201280034899.8A CN201280034899A CN103857682A CN 103857682 A CN103857682 A CN 103857682A CN 201280034899 A CN201280034899 A CN 201280034899A CN 103857682 A CN103857682 A CN 103857682A
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- Prior art keywords
- phenyl
- azetidine
- azaspiro
- oxa
- oxadiazole
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- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Abstract
本发明公开的是如本文所述的式I的氮杂环丁基化合物,
Description
发明领域
本发明涉及某些式I化合物(3-(4-(螺杂环)甲基)苯氧基)氮杂环丁烷-1-基)(5-(苯基)-1,3,4-噁二唑-2-基)甲酮、此类化合物的制备方法、它们在治疗黑色素聚集激素相关疾病或病症(例如肥胖症、肥胖症相关病症、焦虑症和抑郁症)中的用途、以及涉及含有它们的药物组合物。
发明背景
黑色素聚集激素(MCH)的作用被认为牵涉焦虑症、抑郁症、肥胖症和肥胖症相关病症。已经发现,MCH是进食行为和能量稳态的主要调节剂并且是353-氨基酸孤儿G蛋白偶联受体(GPCR)(称为SLC-1(也称为GPR24))的天然配体。SLC-1与促生长素抑制素受体为序列同源性的,并且通常被称作"黑色素聚集激素受体"(MCH受体1型、MCH1受体、或MCHR1)。
在缺少MCH1受体的小鼠中,没有提高的对MCH的摄食应答,并且可见到消瘦表型,这表明该受体负责介导MCH的摄食效应。MCH受体拮抗剂也已被证明阻断MCH的摄食效应,并减少饮食诱导的肥胖小鼠的体重和肥胖。MCH1受体的分布及序列的保守性表明该受体在人和啮齿类动物中的作用相似。因此,MCH受体拮抗剂已被建议作为肥胖症和特征为摄食过度和超重的其它病症的治疗。
正在涌现的证据也表明,MCHR1在情绪和应激的调节中发挥作用。在中枢神经系统中,MCHR1mRNA和蛋白质分布在各种下丘脑核(包括例如室旁核(PVN)和伏核壳)以及边缘结构(包括例如海马、隔膜(septum)、扁桃体、蓝斑和中缝背核)中,所有这些都被认为牵涉对情绪和应激的调节。
据报道,在视前内侧区内引入MCH诱导了焦虑症,但也报道了MCH注射的相反的抗焦虑剂样效应。将MCH注射入MCHR1丰富的伏核壳内,降低了大鼠在强制游泳试验中的活动能力,这表明抑郁效应。另外,已经报道,MCHR1拮抗剂在啮齿动物试验中显示抗抑郁药和抗焦虑剂样的效应,这表明MCHR1在抑郁症和焦虑症中的作用。
因此,认为MCH拮抗剂可能为许多人提供益处,并且可能具有缓解焦虑症和抑郁症的潜力,且可用于治疗肥胖症和肥胖症相关病症。
具有双环中央核的MCH受体拮抗剂公开于WO2006/066173(苯并噻唑或苯并噁唑中央核)和US2005/0222161(苯并咪唑核)中。
我们共同未决的申请WO2010/125390公开了式A化合物
或其药学上可接受的盐,其中
R1表示H、氟、氯、溴、氰基、任选被一个或更多个氟取代的C1-3烷基、或任选被一个或更多个氟取代的C1-2烷氧基;
A表示O或S;
R2和R3独立地表示H、氟、氯、溴、任选被一个或更多个氟取代的C1-4烷基、或任选被一个或更多个氟取代的C1-4烷氧基;条件是R2和R3彼此不位于间位;
R4和R5独立地表示H或C1-4烷基;且
X和Y独立地表示O或CH2,条件是X和Y不同;以及此类化合物在治疗黑色素聚集激素相关疾病或病症(例如肥胖症、肥胖症相关病症、焦虑症和抑郁症)中的用途。公开于WO2010/125390中的化合物是具有两个彼此稠合的四元环的螺环化合物。本申请不包括此类化合物,因为本申请涉及具有至少一个五元环的螺环化合物。
我们的共同未决的申请WO2012/004588公开了式B化合物
或其药学上可接受的盐,其中
R1表示H、氟、氯、溴、氰基、任选被一个或更多个氟取代的C1-4烷基、任选被一个或更多个氟取代的C1-2烷氧基、或任选被一个或更多个氟取代的C1-3烷基硫基;
R2表示H或氟;
R4表示式–NRaRb的基团,其中
a)Ra和Rb独立地表示:1)H2)任选被以下基团中的一个或更多个取代的C1-4烷基:氟、羟基、C1-4烷氧基、或C3-6环烷基,其中C3-6环烷基任选被以下基团中的一个或更多个取代:羟基、C1-4烷氧基或氟,3)任选被以下基团中的一个或更多个取代的C3-6环烷基:羟基、C1-4烷氧基或氟,4)C1-4烷氧基C2-4亚烷基,其中亚烷基链任选被一个或更多个C1-4烷基取代或,5)Ra表示H、C1-4烷基或C3-6环烷基且Rb表示基团–L-R8,其中L表示键或任选被一个或更多个C1-4烷基取代的C1-4亚烷基链且R8表示任选被以下基团中的一个或更多个取代的含有1或2个选自氧和氮的杂原子的碳连接的4-7元饱和单环杂环:羟基、C1-4烷基、C1-4烷氧基或C1-4烷酰基;或
b)Ra和Rb与它们所连接的氮原子一起表示任选含有额外的氧、硫、SO或SO2的饱和的4至7元单环杂环,条件是该额外原子或基团总与氮原子间隔至少两个碳原子并且其中所述环任选被以下基团中的一个或更多个取代:氟、羟基、C1-4烷氧基、C1-4烷氧基羰基、C3-6环烷基、或任选被羟基或C1-4烷氧基或一个或更多个氟取代的C1-4烷基,条件是通过杂原子连接到环的取代基不位于与任何环杂原子相邻的碳原子上;或
c)Ra和Rb与它们所连接的氮原子一起表示含有额外氮的饱和的4至7元单环杂环,其任选在额外氮原子上被以下基团取代:C1-4烷酰基、苯酰基、C1-4烷氧基羰基、C1- 4烷基磺酰基;氨基甲酰基、N-C1-4烷基氨基甲酰基、N,N-二C1-4烷基氨基甲酰基或C1-4烷基;
R5表示H或任选被一个或更多个氟或以下基团中的一个取代的C1-3烷基:羟基或C1-4烷氧基;
R6和R7独立地表示H、氟、氯、溴、任选被一个或更多个氟取代的C1-4烷基、任选被一个或更多个氟取代的C1-4烷氧基;条件是R6和R7彼此不位于间位;且
A表示O或S;以及此类化合物在治疗黑色素聚集激素相关疾病或病症(例如肥胖症、肥胖症相关病症、焦虑症和抑郁症)中的用途。
发明概述
本发明提供为MCH受体拮抗剂且因此有可能用于治疗焦虑症、抑郁症、肥胖症和肥胖症相关病症的化合物。
发明描述
本发明提供式I化合物
或其药学上可接受的盐,其中
R1表示H、任选被一个或更多个氟取代的C1-3烷氧基
或任选被一个或更多个氟取代的C1-3烷基;
R2和R3独立地表示H、氟、氯、溴、任选被一个或更多个氟取代的C1-3烷基、或任选被一个或更多个氟取代的C1-3烷氧基,条件是R2和R3彼此不位于间位;
A1表示键、CH2或CH2-CH2;
A2表示键、CH2、CH2-CH2或CH2-CH2-CH2;条件是A1和A2中的碳的总数一起为2或3;
X表示键、CH2或O;且
Y表示键、CH2或O;
前体条件是1)X和Y中的一个且仅一个总是O且2)当A1和A2各自表示CH2时则X和Y中的一个为CH2。
本发明提供式IA化合物
或其药学上可接受的盐,其中
R1表示H、任选被一个或更多个氟取代的C1-3烷氧基
或任选被一个或更多个氟取代的C1-3烷基;
R2和R3独立地表示H、氟、氯、溴、任选被一个或更多个氟取代的C1-3烷基、或任选被一个或更多个氟取代的C1-3烷氧基;
A表示CH2或CH2-CH2;
X表示键、CH2或O;且
Y表示键、CH2或O;
前体条件是1)X和Y中的一个且仅一个总是O且2)当A为CH2且X和Y中的一个为O时,则X和Y中的另一个为CH2。
在另一方面,本发明提供由式II表示的式I化合物
或其药学上可接受的盐,其中
R1表示H、甲氧基或二氟甲基;且
R2表示H、甲基或甲氧基。
在另一方面,本发明提供由式IIA表示的式I化合物
或其药学上可接受的盐,其中
R1表示H、甲氧基或二氟甲基;且
R2表示H、甲基或甲氧基。
在进一步的实施方案中,本发明提供式IIB的化合物
或其药学上可接受的盐,其中
R1表示H、甲氧基或二氟甲基;且
R2表示H、甲基或甲氧基。
在进一步的实施方案中,本发明提供式IIC的化合物
或其药学上可接受的盐,其中
R1表示H、甲氧基或二氟甲基;且
R2表示H、甲基或甲氧基。
在进一步的实施方案中,本发明提供式IID的化合物
或其药学上可接受的盐,其中
R1表示H、甲氧基或二氟甲基;且
R2表示H、甲基或甲氧基。
在进一步的实施方案中,本发明提供式IIE的化合物
或其药学上可接受的盐,其中
R1表示H、甲氧基或二氟甲基;且
R2表示H、甲基或甲氧基。
各个变量组的优选值如下。此类值在适当时可与上文或下文中界定的值、定义、权利要求、方面或实施方案中任一种一起使用。特别是,每一个可用作式(I)(包括式II、IIA、IIB、IIC、IID和IIE)的最宽定义上的个体限制。此外,下列值中的每一个可与其它下列值中的一个或更多个组合使用以限制式(I)(包括式II、IIA、IIB、IIC、IID和IIE)的最宽定义、或任何子定义。然而,应理解,将在应用这些组合中观察到对前提条件的限制。
1)R1表示任选被一个或更多个氟取代的C1-2烷氧基。
2)R1表示任选被一个或更多个氟取代的C1-2烷基。
3)R1表示H、甲氧基或二氟甲基。
4)R1表示H或甲氧基。
5)R1表示H.
6)R1表示甲氧基。
7)R2表示H.
8)R2表示甲基。
9)R2表示甲氧基。
10)R2和R3独立地表示H、氟、任选被一个或更多个氟取代的C1-2烷基、或任选被一个或更多个氟取代的C1-2烷氧基;
11)a)R2和R3独立地表示氟、氯、溴、任选被一个或更多个氟取代的C1-3烷基、或任选被一个或更多个氟取代的C1-3烷氧基或特别是b)R2和R3独立地表示氟、任选被一个或更多个氟取代的C1-2烷基、或任选被一个或更多个氟取代的C1-2烷氧基和在a)或b)情况下R2和R3彼此不位于间位;
12)a)R2和R3独立地表示氟、氯、溴、任选被一个或更多个氟取代的C1-3烷基、或任选被一个或更多个氟取代的C1-3烷氧基或特别是b)R2和R3独立地表示氟、任选被一个或更多个氟取代的C1-2烷基、或任选被一个或更多个氟取代的C1-2烷氧基和在a)或b)情况下R2和R3彼此位于邻位:
13)R2和R3是相同的。
14)A1表示CH2。
15)A1表示CH2-CH2。
16)A2表示CH2。
17)A2表示CH2-CH2。
18)A2表示CH2-CH2-CH2。
19)A表示CH2。
20)A表示CH2-CH2。
21)X表示键。
22)X表示CH2。
23)X表示O。
24)Y表示键。
25)Y表示CH2。
26)Y表示O。
术语"C1-3烷基"是指含有1至3个碳原子直链或支链烷烃基团。示例性基团包括甲基;乙基;和丙基;异丙基。
术语“C1-3烷氧基”是指通式–ORa的基团,其中Ra选自C1-3烷基。示例性基团包括甲氧基、乙氧基、丙氧基和异丙氧基。
在另一方面,本发明提供下列化合物或其药学上可接受的盐中的一种或更多种:
(-)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-二唑-2-基)甲酮;
(3-(4-(6-氧杂-2-氮杂螺[3.4]辛-2-基甲基)-3-甲基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-二唑-2-基)甲酮;
(3-(4-(5-氧杂-2-氮杂螺[3.4]辛-2-基甲基)-3-甲基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-二唑-2-基)甲酮;
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-二唑-2-基)甲酮;
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)-3-甲氧基苯氧基)氮杂环丁烷-1-基)(5-(4-(二氟甲基)苯基)-1,3,4-二唑-2-基)甲酮;
本发明还提供任何一种来自上述列表的化合物或1至29中任何数目的上述化合物。在另一方面,本发明提供如在上述任意定义中定义的式I化合物(包括式II、IIA、IIB、IIC、IID和IIE),但排除上文即刻所列的化合物的列表中任意一种或更多种的化合物。
接着在描述中,式I化合物可选地包括下列式:II、IIA、IIB、IIC、IID和IIE中的每一个的化合物。
本文进一步描述的是药物组合物,其包含式I化合物、或其药学上可接受的盐、以及药学上可接受的载体和/或稀释剂。
本文还进一步描述的是用于治疗或预防其中调节MCH1受体是有益的的疾病或病症的方法,其包括对需要此类治疗或预防的温血动物施用治疗有效量的式I化合物、或其药学上可接受的盐。
本文更进一步描述的是根据式I的化合物、或其药学上可接受的盐、或其混合物用于治疗或预防其中调节MCH1受体是有益的的疾病或病症的用途。
本文甚至进一步描述的是根据式I的化合物、或其药学上可接受的盐、或其混合物在用于治疗或预防其中调节MCH1受体是有益的的疾病或病症的药物的制备中的用途。
本文再进一步描述的是式I化合物、或其药学上可接受的盐作为药物的用途。
除非另有说明,否则术语"MCHR"是指黑色素聚集激素受体蛋白1(MCHR1)。
术语“治疗(treat)”、“治疗(treating)”和“治疗(treatment)”是指调节疾病和/或其伴随症状。
术语“预防(prevent)”、“预防(preventing)”和“预防(prevention)”是指减少或消除疾病和/或其伴随症状。
本文所使用的术语“调节(modulate)”、“调节(modulates)”、“调节(modulating)”或“调节(modulation)”是指例如激活(例如,激动剂活性)或抑制(例如,拮抗剂活性)至少一个MCHR。
本文所采用的术语“药学上可接受的”表明,被识别是“药学上可接受的”主题对于向患者/受试者施用是适合的且生理学上可接受的。例如,术语“(一种或更多种)药学上可接受的盐”表示(一种或更多种)适合的且生理学上可接受的盐。
本文所使用的术语“预防(prophylaxis)″指(i)防止疾病和/或病症的发展;和/或(ii)在疾病和/或病症已经发展的状态中防止疾病和/或病症恶化。
本文所使用的术语"MCHR介导的病症和/或疾病"是指服从通过MCHR活性剂调节的病症和/或疾病。
术语"治疗有效量"是指足以调节所治疗的病症或疾病的一种或更多种症状的化合物的量。
另一个实施方案涉及本文所描述的化合物,其中一个或更多个原子是相同元素的同位素,例如11C、13C、14C或氘。在特定实施方案中,用氚标记化合物。通过并入标记的原料或者在氚的情况下通过已知方法用氚交换氢合成此类同位素标记的化合物。已知方法包括(1)亲电卤化,然后在氚源的存在下还原卤素,例如在钯催化剂的存在下用氚气氢化;或(2)在氚气和合适的有机金属(例如钯)催化剂的存在下,实施用氚交换氢。
用氚标记的化合物可用于识别新颖的药物化合物,所述药物化合物能与MCH1受体结合并通过激动、部分激动或拮抗MCH1受体来调节活性。此类氚标记的化合物可用于测定中,所述测定测量此类化合物的置换,以评价与MCH1受体结合的配体的结合。
在甚至进一步的实施方案中,本文公开的化合物可额外包含一个或更多个同位素原子。在该实施方案的一个特定形式中,化合物包含同位素卤素。通过已知方法并入标记的原料来合成此类标记的化合物。在一个特定实施方案中,所述同位素选自18F、123I、125I、131I、75Br、76Br、77Br或82Br。在更特别的实施方案中,同位素是18F。
应理解,当本发明化合物含有一个或更多个手性中心时,例如式I、II或IIC化合物,本发明化合物可以对映体形式或非对映体形式存在,以及被分离为对映体形式或非对映体形式,或作为外消旋混合物。本发明包括式I化合物的任何可能的对映体、非对映体、外消旋体或其混合物。本发明化合物的光学活性形式可通过例如以下方式制备:例如使用IA柱(由ChiralTechnologiesEurope供应)或OJ柱(由ChiralTechnologiesEurope供应)手性色谱分离外消旋体、通过由光学活性原料合成或通过基于下文所述的程序进行非对称合成。
应进一步理解,本发明涵盖式I化合物的互变异构体。
应理解,本发明的某些化合物可以溶剂化形式(例如水合形式)和非溶剂化形式存在。应进一步理解,本发明涵盖式I化合物的所有此类溶剂化形式。应进一步理解,本发明涵盖此类溶剂化物的所有晶形。
式I化合物也可形成盐。因此,当本文提及式I化合物时,除非另有说明,否则此类提及包括其盐。在一个实施方案中,式I化合物形成药学上可接受的盐。在另一个实施方案中,式I化合物形成可例如用于分离和/或纯化式I化合物的盐。应理解,本发明涵盖此类盐和此类盐的溶剂化物的任意和所有晶形以及这些盐的任意溶剂化物的任意晶形。
通常,可通过使用本领域众所周知的标准程序来获得根据式I的化合物的药学上可接受的盐。这些标准程序包括但不限于例如使足够碱性的化合物(例如烷基胺)与合适的酸(例如盐酸或乙酸)反应,以得到生理学上可接受的阴离子。
在一个实施方案中,可将根据式I的化合物转化成其药学上可接受的盐或溶剂化物,特别是酸加成盐,例如盐酸盐、氢溴酸盐、磷酸盐、乙酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、甲烷磺酸盐(甲磺酸盐)和对甲苯磺酸盐。特别优选的盐是盐酸盐和甲磺酸盐。
通常,可根据以下方法和本领域技术人员的常识和/或根据随后实施例中陈述的方法来制备式I化合物。溶剂、温度、压力和其它反应条件可由本领域普通技术人员容易地选择。原料为市售的或由本领域技术人员容易地制备。可在化合物的制备中采用组合技术,例如当中间体具有适合于这些技术的基团时。
可通过以下方法制备式I化合物:
a)在还原剂诸如三乙酰氧基硼氢化钠的存在下、在适当溶剂诸如二氯甲烷中、以及任选地在碱例如三乙胺或N,N-二异丙基乙基胺的存在下(如果使用IV的盐)、在0至150℃范围内(特别是在5至30℃范围内)的温度下,使式III化合物与式IV化合物或其盐反应,
其中R1、R2和R3如前文定义
其中A1、A2、X和Y如前文定义;或
b)在适当溶剂诸如醇(例如甲醇)中、在0至150℃范围内(特别是在5至30℃范围内)的温度下和任选地在催化剂例如氰化钠的存在下,使式V化合物与式VI化合物反应
其中R2、R3、A1、A2、X和Y如前文定义
其中R1如前文所定义且L1表示离去基团(例如C1-4烷氧基)。
式III化合物可通过如下制备:在碱例如Cs2CO3的存在下、任选在溶剂例如DMF或优选DMA的存在下,以及在0至150℃范围内(特别是在50至120℃范围内)的温度下使式VII化合物与式VIII反应
Ⅶ中R2和R3如前文定义
式V化合物可通过如下制备:在0至150℃范围内(特别在5至30℃范围内)的温度下使式IX化合物
(其中R2、R3、A1、A2、X和Y如前文定义且PG表示胺保护基诸如烷氧基羰基、例如叔丁氧基羰基)与脱保护剂诸如酸(例如三氟乙酸)反应。
式IX化合物可通过如下制备:使式X化合物
(其中A1、A2、X和Y如前文定义)与式XI化合物
(其中R2、R3、A1和A2如前文定义且PG表示胺保护基例如烷氧基羰基、例如叔丁氧基羰基)反应。
某些化合物或式III、IV、V和IX的化合物是新颖的,并在本文中作为本发明的进一步方面而要求保护。在本发明的优选方面,这些化合物为基本纯形式,例如大于50%纯,特别是大于95%纯,更特别是大于99%纯。
进一步的实施方案涉及用于治疗或预防其中调节MCH1受体是有益的疾病或病症的方法,其包括对需要此类治疗或预防的温血动物施用治疗有效量的式I化合物或其药学上可接受的盐。
更特别的实施方案涉及用于治疗或预防其中调节MCH1受体是有益的疾病或病症的方法,其包括对需要此类治疗或预防的温血动物施用治疗有效量的拮抗性的式I化合物。
进一步的实施方案涉及根据式I的化合物或其药学上可接受的盐、或其混合物用于治疗或预防其中调节MCH1受体是有益的的疾病或病症的用途。
更特别的实施方案涉及式I拮抗剂化合物或其药学上可接受的盐用于治疗或预防其中调节MCH1受体是有益的的疾病或病症的用途。
又一个实施方案涉及根据式I的化合物、或其药学上可接受的盐在制造用于治疗或预防其中调节MCH1受体是有益的的疾病或病症的药物中的用途。
再一个实施方案涉及用作药物的根据式I的化合物、或其药学上可接受的盐。
另一个实施方案涉及药物组合物,其包含根据式I的化合物、或其药学上可接受的盐以及药学上可接受的载体和/或稀释剂。
进一步的实施方案涉及药物组合物,其可用于治疗或预防本文提及的由温血动物中MCH1受体功能障碍所引起的疾病或病症,所述组合物包含治疗有效量的用于治疗或预防此类疾病或病症的式I化合物、或其药学上可接受的盐、和至少一种药学上可接受的载体和/或稀释剂。
在一个实施方案中,所述温血动物是哺乳动物物种,包括但不限于例如人和家养动物,例如狗、猫和马。
在进一步的实施方案中,所述温血动物为人。
在一个实施方案中,可使用根据式I的化合物来治疗或预防的疾病和/或病症包括但不限于,例如心境障碍、焦虑症和进食障碍。
示例性心境障碍包括但不限于,例如抑郁症,例如重症抑郁障碍和心境恶劣障碍、双相型抑郁症和/或双相型躁狂症(如双相I型障碍(bipolarI),包括但不限于具有狂躁发作、抑郁发作或混合发作的那些;以及双相II型障碍(bipolarII));环性气质障碍(cyclothymiac’sdisorder(s));焦虑性抑郁症;和由于一般医学状况引起的心境障碍。
示例性焦虑症包括但不限于例如无广场恐怖症的惊恐症、具有广场恐怖症的惊恐症、无惊恐症史的广场恐怖症、特定恐怖症、社交恐怖症、强迫症、应激相关障碍、创伤后应激障碍、急性应激障碍、一种或更多种广泛性焦虑障碍、由于一般医学状况引起的广泛性焦虑障碍。
示例性进食障碍包括但不限于例如肥胖症。
上述病症和障碍中的许多例如在AmericanPsychiatricAssociation:DiagnosticandStatisticalManualofMentalDisorders,第四版,TextRevision,Washington,DC,AmericanPsychiatricAssociation,2000中定义。
另一个实施方案涉及用于治疗或预防心境障碍、焦虑症、或进食障碍的方法,其包括对需要此类治疗或预防的温血动物施用治疗有效量的根据式I的化合物、或其药学上可接受的盐。
又一个实施方案涉及用于治疗或预防至少一种心境障碍的方法,其包括对需要此类治疗或预防的温血动物施用治疗有效量的根据式I的化合物、或其药学上可接受的盐。
再一个实施方案涉及用于治疗或预防至少一种焦虑症的方法,其包括对需要此类治疗或预防的温血动物施用治疗有效量的根据式I的化合物、或其药学上可接受的盐。
甚至进一步的实施方案涉及用于治疗或预防至少一种进食障碍的方法,其包括对需要此类治疗或预防的温血动物施用治疗有效量的根据式I的化合物、或其药学上可接受的盐。
另一个实施方案提供用于治疗或预防温血动物中的至少一种选自焦虑症、抑郁症和肥胖症的疾病或病症的方法,其包括对需要此类治疗或预防的所述动物施用治疗有效量的根据式I的化合物。
又一个实施方案提供用于治疗或预防温血动物中的焦虑症的方法,其包括对需要此类治疗或预防的所述动物施用治疗有效量的根据式I的化合物。
进一步的实施方案提供用于治疗或预防温血动物中的广泛性焦虑障碍的方法,其包括对需要此类治疗或预防的所述动物施用治疗有效量的根据式I的化合物。
再一个实施方案提供用于治疗或预防温血动物中的抑郁症的方法,其包括对需要此类治疗或预防的所述动物施用治疗有效量的根据式I的化合物。
甚至又一的实施方案提供用于治疗或预防温血动物中的肥胖症的方法,其包括对需要此类治疗或预防的所述动物施用治疗有效量的根据式I的化合物。
更特别的实施方案涉及用于治疗或预防其中调节MCH1受体是有益的疾病或病症的方法,其包括对需要此类治疗或预防的温血动物施用治疗有效量的拮抗性的式I化合物。
进一步的实施方案涉及用于治疗或预防温血动物中的选自焦虑症、抑郁症和肥胖症的疾病或病症的方法,其包括对需要此类治疗或预防的所述动物施用治疗有效量的式I化合物或其药学上可接受的盐。
进一步的实施方案涉及用于治疗或预防温血动物中的焦虑症的方法,其包括对需要此类治疗或预防的所述动物施用治疗有效量的式I化合物或其药学上可接受的盐。
进一步的实施方案涉及用于治疗或预防温血动物中的一般性焦虑障碍的方法,其包括对需要此类治疗或预防的所述动物施用治疗有效量的式I化合物或其药学上可接受的盐。
进一步的实施方案涉及用于治疗或预防温血动物中的抑郁症的方法,其包括对需要此类治疗或预防的所述动物施用治疗有效量的式I化合物或其药学上可接受的盐。
进一步的实施方案涉及治疗或预防温血动物中的肥胖症的方法,其包括对需要此类治疗或预防的所述动物施用治疗有效量的式I化合物或其药学上可接受的盐。
甚至进一步的实施方案涉及式I化合物、或其药学上可接受的盐用于治疗或预防其中调节MCH1受体是有益的的疾病或病症。
更特别的实施方案涉及式I拮抗性的化合物、或其药学上可接受的盐用于治疗或预防其中调节MCH1受体是有益的的疾病或病症。
进一步的实施方案涉及式I化合物、或其药学上可接受的盐用于治疗或预防选自心境障碍、焦虑症和进食障碍的疾病或病症。
再一个实施方案涉及用于治疗或预防心境障碍的式I化合物、或其药学上可接受的盐。
甚至进一步的实施方案涉及用于治疗或预防焦虑症的式I化合物、或其药学上可接受的盐。
甚至进一步的实施方案涉及用于治疗或预防进食障碍的式I化合物、或其药学上可接受的盐。
另外再一个实施方案涉及用于治疗或预防选自焦虑症、抑郁症和肥胖症的疾病或病症的式I化合物、或其药学上可接受的盐。
另外又一个实施方案涉及用于治疗或预防焦虑症的式I化合物、或其药学上可接受的盐。
另外再一个实施方案涉及用于治疗或预防一般性焦虑障碍的式I化合物、或其药学上可接受的盐。
甚至另外又一个实施方案涉及用于治疗或预防抑郁症的式I化合物、或其药学上可接受的盐、或其混合物。
又一个实施方案涉及用于治疗或预防肥胖症的式I化合物、或其药学上可接受的盐。
又一个实施方案涉及式I化合物、或其药学上可接受的盐在制造用于治疗或预防其中调节MCH1受体是有益的的疾病或病症的药物中的用途。
进一步的实施方案涉及式I化合物、或其药学上可接受的盐在制造用于治疗或预防选自心境障碍、焦虑症和进食障碍的疾病或病症的药物中的用途。
进一步的实施方案涉及在制造用于治疗或预防心境障碍的药物中使用式I化合物、或其药学上可接受的盐。
进一步的实施方案涉及在制造用于治疗或预防焦虑症的药物中使用式I化合物、或其药学上可接受的盐。
另外又一个实施方案涉及在制造用于治疗或预防进食障碍的药物中使用式I化合物、或其药学上可接受的盐。
甚至进一步的实施方案涉及在制造用于治疗或预防选自焦虑症、抑郁症和肥胖症的疾病或病症的药物中使用式I化合物、或其药学上可接受的盐。
甚至再进一步的实施方案涉及在制造用于治疗或预防焦虑症的药物中使用式I化合物、或其药学上可接受的盐。
甚至又进一步的实施方案涉及在制造用于治疗或预防一般性焦虑障碍的药物中使用式I化合物、或其药学上可接受的盐,
甚至又再进一步的实施方案涉及在制造用于治疗或预防抑郁症的药物中使用式I化合物、或其药学上可接受的盐。
另一个实施方案涉及式I化合物、或其药学上可接受的盐在制造用于治疗或预防肥胖症的药物中的用途。
进一步的实施方案涉及使用式I化合物、或其药学上可接受的盐用于治疗或预防胰岛素耐性、肝脏脂肪变性(包括NASH)、脂肪肝、或睡眠呼吸暂停。
另外又一个实施方案涉及使用式I化合物、或其药学上可接受的盐作为药物。
另一个实施方案涉及药物组合物,其包含式I化合物、或其药学上可接受的盐和药学上可接受的载体和/或稀释剂。
另一个实施方案涉及药物组合物,其可用于治疗或预防本文提及的由温血动物中MCH1受体功能障碍所引起的疾病或病症,所述组合物包含治疗有效量的有效用于治疗或预防此类疾病或病症的式I化合物、或其药学上可接受的盐、和至少一种药学上可接受的载体和/或稀释剂。
在一个实施方案中,所述温血动物是哺乳动物物种,包括但不限于例如人和家养动物,例如狗、猫和马。
在进一步的实施方案中,所述温血动物为人。
又一个实施方案提供至少一种用于制备式I化合物的方法。
在另外又一个实施方案中,可将式I化合物或其药学上可接受的盐和/或包含式I化合物或其药学上可接受的盐的药物组合物或制剂与至少一种选自以下的其它药学活性化合物并行(concurrently)、同时、按序或分开施用:
(i)抗抑郁药,包括但不限于例如阿戈美拉汀(agomelatine)、阿米替林(amitriptyline)、阿莫沙平(amoxapine)、安非他酮(bupropion)、西酞普兰(citalopram)、氯米帕明(clomipramine)、地昔帕明(desipramine)、多塞平(doxepin)、度洛西汀(duloxetine)、艾扎索南(elzasonan)、依他普仑(escitalopram)、氟伏沙明(fluvoxamine)、氟西汀(fluoxetine)、吉哌隆(gepirone)、丙米嗪(imipramine)、伊沙匹隆(ipsapirone)、马普替林(maprotiline)、去甲替林(nortriptyline)、萘法唑酮(nefazodone)、帕罗西汀(paroxetine)、苯乙肼(phenelzine)、普罗替林(protriptyline)、雷美替胺(ramelteon)、瑞波西汀(reboxetine)、罗巴佐坦(robalzotan)、舍曲林(sertraline)、西布曲明(sibutramine)、硫代尼索西汀(thionisoxetine)、反苯环丙胺(tranylcypromaine)、曲唑酮(trazodone)、三甲丙咪嗪(trimipramine)、文拉法辛(venlafaxine)及它们的等同物和一种或更多种药学活性异构体和一种或更多种代谢物;
(ii)非典型抗精神病药,包括但不限于例如喹硫平(quetiapine)及其一种或更多种药学活性异构体和一种或更多种代谢物;
(iii)抗精神病药,包括但不限于例如氨磺必利(amisulpride)、阿立哌唑(aripiprazole)、阿塞那平(asenapine)、benzisoxidil、联苯芦诺(bifeprunox)、卡马西平(carbamazepine)、氯氮平(clozapine)、氯丙嗪(chlorpromazine)、debenzapine、双丙戊酸钠(divalproex)、度洛西汀(duloxetine)、艾司佐匹克隆(eszopiclone)、氟哌啶醇(haloperidol)、伊潘立酮(iloperidone)、拉莫三嗪(lamotrigine)、洛沙平(loxapine)、美索达嗪(mesoridazine)、奥氮平(olanzapine)、帕潘立酮(paliperidone)、哌拉平(perlapine)、奋乃静(perphenazine)、吩噻嗪(phenothiazine)、苯基丁基哌啶(phenylbutylpiperidine)、匹莫齐特(pimozide)、丙氯拉嗪(prochlorperazine)、利培酮(risperidone)、舍吲哚(sertindole)、舒必利(sulpiride)、舒普罗酮(suproclone)、舒立克隆(suriclone)、硫利达嗪(thioridazine)、三氟拉嗪(trifluoperazine)、曲美托嗪(trimetozine)、丙戊酸盐(valproate)、丙戊酸(valproicacid)、佐匹克隆(zopiclone)、佐替平(zotepine)、齐拉西酮(ziprasidone)及它们的等价物和一种或更多种药学活性异构体和一种或更多种代谢物;
(iv)抗焦虑药,包括但不限于例如阿奈螺酮(alnespirone)、阿扎哌隆(azapirones)、苯并二氮杂(benzodiazepines)、巴比妥酸盐(barbiturates)例如阿地唑仑(adinazolam)、阿普唑仑(alprazolam)、balezepam、苯他西泮(bentazepam)、溴西泮(bromazepam)、溴替唑仑(brotizolam)、丁螺环酮(buspirone)、氯硝西泮(clonazepam)、氯氮(clorazepate)、氯氮(chlordiazepoxide)、环丙西泮(cyprazepam)、地西泮(diazepam)、苯海拉明(diphenhydramine)、艾司唑仑(estazolam)、非诺班(fenobam)、氟硝西泮(flunitrazepam)、氟西泮(flurazepam)、膦西泮(fosazepam)、劳拉西泮(lorazepam)、氯甲西泮(lormetazepam)、甲丙氨酯(meprobamate)、咪达唑仑(midazolam)、硝西泮(nitrazepam)、奥沙西泮(oxazepam)、普拉西泮(prazepam)、夸西泮(quazepam)、瑞氯西泮(reclazepam)、曲卡唑酯(tracazolate)、曲匹泮(trepipam)、替马西泮(temazepam)、三唑仑(triazolam)、乌达西泮(uldazepam)、唑拉西泮(zolazepam)及它们的等价物和一种或更多种药学活性异构体和一种或更多种代谢物;
(v)抗惊厥药(anticonvulsants),包括但不限于例如卡马西平(carbamazepine)、丙戊酸盐(valproate)、拉莫三嗪(lamotrogine)、加巴喷丁(gabapentin)及它们的等价物和一种或更多种药学活性异构体和一种或更多种代谢物;
(vi)阿尔茨海默氏病治疗剂(Alzheimer'stherapies),包括但不限于例如多奈哌齐(donepezil)、美金刚(memantine)、他克林(tacrine)及它们的等价物和一种或更多种药学活性异构体和一种或更多种代谢物;
(vii)帕金森病治疗剂(Parkinson’stherapies),包括但不限于例如得普尼林(deprenyl)、L-多巴(L-dopa)、莱奎普(Requip)、米拉帕(Mirapex)、MAOB抑制剂例如司来吉兰(selegeline)和雷沙吉兰(rasagiline)、comP抑制剂如答是美(Tasmar)、A-2抑制剂、多巴胺再摄取抑制剂、NMDA拮抗剂、尼古丁激动剂、多巴胺激动剂、神经元型一氧化氮合酶的抑制剂及它们的等价物和一种或更多种药学活性异构体和一种或更多种代谢物;
(viii)偏头痛治疗剂(migrainetherapies),包括但不限于例如阿莫曲坦(almotriptan)、金刚烷胺(amantadine)、溴隐亭(bromocriptine)、布他比妥(butalbital)、卡麦角林(cabergoline)、氯醛比林(dichloralphenazone)、依来曲普坦(eletriptan)、夫罗曲普坦(frovatriptan)、麦角乙脲(lisuride)、那拉曲坦(naratriptan)、培高利特(pergolide)、普拉克索(pramipexole)、利扎曲普坦(rizatriptan)、罗匹尼罗(ropinirole)、舒马普坦(sumatriptan)、佐米曲坦(zolmitriptan)、佐米格(zomitriptan)及它们的等价物和一种或更多种药学活性异构体和一种或更多种代谢物;
(ix)中风治疗剂,包括但不限于例如阿昔单抗(abciximab)、阿替普酶(activase)、NXY-059、胞磷胆碱(citicoline)、克罗奈汀(crobenetine)、去氨普酶(desmoteplase)、瑞匹诺坦(repinotan)、曲索罗地(traxoprodil)及它们的等价物和一种或更多种药学活性异构体和一种或更多种代谢物;
(x)尿失禁治疗剂,包括但不限于例如达非那新(darafenacin)、黄酮哌酯(falvoxate)、奥昔布宁(oxybutynin)、丙哌维林(propiverine)、罗巴佐坦(robalzotan)、索利那新(solifenacin)、托特罗定(tolterodine)及它们的等价物和一种或更多种药学活性异构体和一种或更多种代谢物;
(xi)神经病性疼痛治疗剂,包括但不限于例如加巴喷丁(gabapentin)、lidoderm、普瑞巴林(pregablin)及它们的等价物和一种或更多种药学活性异构体和一种或更多种代谢物;
(xii)伤害感受性疼痛治疗剂,包括但不限于例如塞来考昔(celecoxib)、艾托考昔(etoricoxib)、芦米考昔(lumiracoxib)、罗非考昔(rofecoxib)、伐地考昔(valdecoxib)、双氯芬酸(diclofenac)、洛索洛芬(loxoprofen)、萘普生(naproxen)、对乙酰氨基酚(paracetamol)及它们的等价物和一种或更多种药学活性异构体和一种或更多种代谢物;
(xiii)失眠治疗剂,包括但不限于例如阿戈美拉汀(agomelatine)、阿洛巴比妥(allobarbital)、阿洛米酮(alonimid)、异戊巴比妥(amobarbital)、苯佐他明(benzoctamine)、仲丁巴比妥(butabarbital)、卡普脲(capuride)、氯醛(chloral)、氯哌喹酮(cloperidone)、氯乙双酯(clorethate)、环庚吡奎醇(dexclamol)、乙氯维诺(ethchlorvynol)、依托咪酯(etomidate)、格鲁米特(glutethimide)、哈拉西泮(halazepam)、羟嗪(hydroxyzine)、甲氯喹酮(mecloqualone)、褪黑激素(melatonin)、甲苯比妥(mephobarbital)、甲喹酮(methaqualone)、咪达氟(midaflur)、尼索氨酯(nisobamate)、戊巴比妥(pentobarbital)、苯巴比妥(Phenobarbital)、丙泊酚(propofol)、雷美替胺(ramelteon)、咯来米特(roletamide)、三氯福司(triclofos)、司可巴比妥(secobarbital)、扎来普隆(zaleplon)、唑吡坦(zolpidem)及它们的等价物和一种或更多种药学活性异构体和一种或更多种代谢物;
(xiv)情绪稳定剂,包括但不限于例如卡马西平(carbamazepine)、双丙戊酸钠(divalproex)、加巴喷丁(gabapentin)、拉莫三嗪(lamotrigine)、锂(lithium)、奥氮平(olanzapine)、喹硫平(quetiapine)、丙戊酸盐(valproate)、丙戊酸(valproicacid)、维拉帕米(verapamil)及它们的等价物和一种或更多种药学活性异构体和一种或更多种代谢物;
(xv)胰岛素或胰岛素类似物;
(xvi)促胰岛素分泌剂,包括磺酰脲类(例如格列本脲(glibenclamide)、格列吡嗪(glipizide))、餐时血糖调节剂(prandialglucoseregulator)(例如氯茴苯酸类(meglitinde),如瑞格列奈(repaglinide)和那格列奈(nateglinide));
(xvii)二肽基肽酶IV抑制剂(例如沙格列汀(saxagliptin)、西他列汀(sitagliptin)、阿格列汀(alogliptin)或维格列汀(vildagliptin);
(xviii)胰岛素敏化剂(insulinsensitisingagent),包括PPARγ激动剂(例如吡格列酮(pioglitazone)和罗格列酮(rosiglitazone))和具有PPARα和γ组合活性的药剂;
(xix)调节肝脏葡萄糖平衡的药剂(例如双胍类,如二甲双胍(metformin)、果糖1,6二磷酸酶抑制剂、糖原磷酸化酶抑制剂、糖原合酶激酶抑制剂);
(xx)设计成降低从肠道吸收葡萄糖的药剂(例如α葡糖苷酶抑制剂,如阿卡波糖(acarbose));
(xxi)防止由肾脏再吸收葡萄糖的药剂(例如SGLT-2抑制剂,如达格列净(dapagliflozin)或卡纳格列净(canagliflozin));
(xxii)设计成治疗延长的高血糖并发症的药剂(例如醛糖还原酶抑制剂);
(xxiii)抗肥胖症化合物,例如奥利司他(orlistat)(EP129748)或西布曲明(sibutramine)(GB2,184,122和US4,929,629);
(xxiv)抗血脂异常剂,如HMG-CoA还原酶抑制剂(例如他汀类(statins),如罗苏伐他汀(rosuvastatin));PPARα激动剂(贝特类(fibrates),如非诺贝特(fenofibrate)、氯贝丁酯(clofibrate)和吉非贝齐(gemfibrozil));胆汁酸多价螯合剂(考来烯胺(cholestyramine));胆固醇吸收抑制剂(植物甾烷醇(plantstanol)、合成抑制剂);胆汁酸吸收抑制剂(IBATi)和烟酸及类似物(烟酸(niacin)及缓释制剂);
(xxv)抗高血压药,如β阻滞剂(如阿替洛尔(atenolol)、心得尔(inderal));ACE抑制剂(如赖诺普利(lisinopril));钙拮抗剂(如硝苯地平(nifedipine));血管紧张素受体拮抗剂(如坎地沙坦(candesartan))、α拮抗剂和利尿剂(如呋塞米(furosemide)、苄噻嗪(benzthiazide));
(xxvi)止血调节剂,如抗血栓药、纤维蛋白溶解的活化剂、凝血酶拮抗剂;Xa因子抑制剂;VIIa因子抑制剂;抗血小板药剂(如阿司匹林(aspirin)、氯吡格雷(clopidogrel));抗凝血剂(肝素(heparin)和低分子量类似物,水蛭素(hirudin))和华法林(warfarin);
(xxvii)拮抗糖原作用的药剂;
(xxviii)消炎药,如非甾体消炎药(如阿司匹林)和甾体消炎药(例如,可的松(cortisone));
(xxix)抗高血压化合物,如血管紧张素转换酶(ACE)抑制剂、血管紧张素II受体拮抗剂、肾上腺素能阻断剂、α肾上腺素能阻断剂、β肾上腺素能阻断剂、混合的α/β肾上腺素能阻断剂、肾上腺素能兴奋剂、钙通道阻断剂、AT-1受体阻断剂、促尿食盐排泄药(saluretic)、利尿剂或血管舒张剂(vasodilator);
(xxx)PDK抑制剂;
(xxxi)植物甾醇化合物;
(xxxii)11βHSD-1抑制剂;
(xxxiii)UCP-1、2或3活化剂;
(xxxiv)CB1受体调节剂,如逆激动剂或拮抗剂,如利莫那班(rimonabant)或taranabant;
(xxxv)NPY受体调节剂;如NPY激动剂或NPY2激动剂或NPY5拮抗剂;
(xxxvi)MC4r调节剂,如MC4r激动剂;
(xxxvii)MC3r调节剂,如MC3r激动剂;
(xxxviii)阿立新(orexin)受体调节剂,如拮抗剂;
(xxxix)核受体(如LXR、FXR、RXR、GR、ERRα、β、PPARα、β、γ、δ和RORα)的调节剂;
(xl)DGAT1抑制剂;
(xli)DGAT2抑制剂;
(xlii)DGAT2反义寡核苷酸;
(xliii)脂肪酸合酶抑制剂
(xliv)CETP(胆甾醇基酯转移蛋白)抑制剂;
(xlv)胆固醇吸收拮抗剂;
(xlvi)MTP(微粒体转移蛋白)抑制剂;
(xlvii)普罗布考(probucol);
(xlviii)GLP-1激动剂;
(xlix)葡萄糖激酶调节剂
l)脑肠肽(ghrelin)抗体;
li)脑肠肽(ghrelin)拮抗剂;
lii)GPR119激动剂,和
liii)另一种黑色素聚集激素(MCH)调节剂,如MCH-1拮抗剂;
或其药学上可接受的盐、溶剂化物、此类盐或前药的溶剂化物,任选与药学上可接受的稀释剂或载体一起施用到需要此类治疗性治疗的温血动物,如人。
当与式I化合物或其药学上可接受的盐或其混合物联合使用时,上述其它药物活性化合物可例如按Physicians’DeskReference(PDR)中所示的量使用或由本领域普通技术人员确定的其它量使用。
对于本文提及的用途、方法、药物和组合物,式I化合物或其药学上可接受的盐或其混合物的使用量和给药剂量可随着所采用的式I化合物或其药学上可接受的盐或其混合物和/或所需的施用模式和/或治疗而变化。然而,通常,当以约0.1mg至约20mg/kg动物体重的日剂量施用根据式I的化合物或其药学上可接受的盐或其混合物时,获得令人满意的结果。此类剂量可按每天1至4次的分剂量施用或按持续释放形式施用。对于人类,总日剂量可为例如约5mg至约1,400mg,更特别为约10mg至约100mg的范围。适合于口服施用的单位剂型通常包括与至少一种固体和/或液体药用载体、润滑剂和/或稀释剂混合的例如约2mg至约1,400mg至少一种根据式I的化合物或其药学上可接受的盐或其混合物。
然而,对于任意特定的受试者,具体剂量水平和给药频率可发生变化并且通常取决于多种因素,所述因素包括但不限于例如所施用形式的一种或更多种具体式I化合物或其药学上可接受的盐或其混合物的生物利用度;一种或更多种具体式I化合物或其药学上可接受的盐或其混合物的代谢稳定性和作用时间长度;受试者的物种、年龄、体重、一般健康、性别和饮食;施用模式和施用时间;排泄速度;药物联合;和特定病症的严重性。
可通过适合于待治疗的病症和待递送的式I或其药学上可接受的盐或其混合物的量的任意方式施用根据式I的化合物或其药学上可接受的盐或其混合物。
可通过任意途径按常规药物组合物形式施用一种或更多种根据式I的化合物或其药学上可接受的盐或其混合物,所述途径包括但不限于例如口服、肌内、皮下、局部、鼻内、硬脊膜外、腹腔内、胸内、静脉内、鞘内、脑室内和注射到关节中。
在一个实施方案中,施用途径为口服施用、静脉内施用或肌内施用。
式I化合物、或药学上可接受的盐、或其混合物可单独使用或以用于肠道施用或胃肠外施用的适当药物制剂形式使用。
可接受的固体药物组合物包含但不限于例如粉末、片剂、可分散颗粒剂、胶囊剂、扁囊剂和栓剂。
在固体药物组合物中,药学上可接受的载体包括但不限于例如至少一种固体、至少一种液体和其混合物。固体载体也可以是稀释剂、调味剂、增溶剂、润滑剂、助悬剂、粘合剂、包囊材料和/或片剂崩解剂。合适的载体包括但不限于例如碳酸镁、硬脂酸镁、滑石、乳糖、糖、果胶、糊精、淀粉、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂和其混合物。
可通过例如以下方式制备粉剂:将细碎的固体与至少一种细碎的式I化合物或其药学上可接受的盐或其混合物混合。
可通过例如以下方式制备片剂:将至少一种根据式I的化合物或其药学上可接受的盐或其混合物与具有必要粘合性质的药学上可接受的载体以适当的比例混合,并压制成所需的形状和大小。
可通过例如以下方式制备栓剂:将至少一种式I化合物或其药学上可接受的盐或其混合物与至少一种在直肠温度下为液态但在低于直肠温度的温度下为固态的合适的非刺激性赋形剂混合,其中,首先将非刺激性赋形剂熔化并将式I化合物分散在其中。然后将熔融的均匀混合物倾入合宜大小的模具中并使其冷却和固化。示例性的非刺激性赋形剂包括但不限于例如可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇的混合物和聚乙二醇的脂肪酸酯。
可接受的液体药物组合物包括但不限于例如溶液、混悬剂和乳剂。
适合于胃肠外施用的示例性液体药物组合物包括但不限于,例如至少一种根据式I的化合物或药学上可接受的盐或其混合物的无菌水溶液或水-丙二醇溶液,以及至少一种根据式I的化合物或药学上可接受的盐或其混合物的聚乙二醇水溶液。
可通过以下方式制备用于口服施用的水溶液:将至少一种根据式I的化合物或其药学上可接受的盐或其混合物溶解在水中并按需求加入合适的着色剂、调味剂、稳定剂和/或增稠剂。
可通过以下方式制备用于口服施用的水性混悬液:将至少一种细碎的式I化合物或其药学上可接受的盐或其混合物与粘性物质一起分散于水中,所述粘性物质为例如天然合成胶、树脂、甲基纤维素和羧甲基纤维素钠。
在一个实施方案中,所述药物组合物含有约0.05%至约99%w(重量百分比)的至少一种根据式I的化合物或药学上可接受的盐或其混合物。所有重量百分比基于组合物总重量。
在另一个实施方案中,所述药物组合物含有约0.10%至约50%w(重量百分比)的至少一种根据式I的化合物或药学上可接受的盐或其混合物。所有重量百分比基于组合物总重量。
本文还提供用于制备药物组合物的方法,其包括将所述成分混合或配混(compounding)在一起并使混合的成分形成片剂或栓剂;将所述成分封装在胶囊中;或将所述成分溶解,以形成可注射溶液。
测定方法:
MCH结合测定:
可用放射性配体-结合测定来测量黑色素聚集激素(MCH)的结合,所述测定采用[125I]MCH和表达人黑色素聚集激素受体1(MCHR1)的膜。与MCHR1结合的配体可通过它们与[125I]MCH结合竞争的能力来识别。
可从PerkinElmer购买[125I]MCH(NEK373050UC25μCi)。可从表达人MCH受体1的CHOK1细胞(例如可从EuroScreen获得的那些细胞)来制备膜(2.20mg/mL)。可从Sigma购买Trizma、BSA、NaCl和MgCl26H2O。可从Bachem购买人MCH(0.5mg,目录编号H-1482)。
可在含有3mMMgCl2和0.05%BSA的50mMTris(pH7.4)中运行饱和结合测定。为了实施测定,向浅的96-孔板的孔中加入100μL的2倍连续稀释的放射性配体[125I]MCH。在这之后加入100μL测定缓冲液,该测定缓冲液含有最终蛋白浓度为20μg/mL的膜。将混合物在室温下孵育1小时,然后使用细胞收获器(Skatron),通过经0.1%PEI处理的WallacA-过滤器过滤。将收集的膜用300μL/孔的洗涤缓冲液(50mMTris,pH7.4,含有5mMMgCl2和50mMNaCl)洗涤3次,然后风干过夜或在60℃下干燥。通过闪烁计数法测量125I。
在配体竞争结合测定中可采用在固定浓度或一系列浓度的试验化合物的存在下实施的[125I]MCH结合测定。对于剂量-反应测定,可在测定板中对化合物进行3-倍连续稀释,以产生一定范围的浓度。对于单点测定,可将[125I]MCH和膜预混合,且然后转移到测定板中,其中最终膜蛋白和放射性配体的浓度分别为20μg/mL和0.04nM。
对于分析来自饱和结合的数据,将cpm转化为dpm,使用销售商提供的放射性比度来计算放射性配体浓度(nM)。
可使用方程(1)来分析饱和结合数据:
其中B为结合的配体的浓度,Bmax为结合的配体的最大浓度,和Kd为配体的解离常数。
可使用方程(2)来计算抑制百分比(%Inh):
可通过常规方法,使用非线性二乘法分析来计算IC50值。
MCHR1受体激活测定:
黑色素浓度激素受体1(MCHR1)为G-蛋白偶联受体,其与含Gαi/o亚基的异源三聚G蛋白相互作用。MCH与MCHR1的结合导致与激活的受体相关的Gαi/o蛋白上GDP交换成GTP。该激活可通过测量GTP类似物(GTPγ35S)的量来定量,所述GTPγ35S与膜相关受体结合。GTPγ35S并不被G-蛋白的内在GTP酶活性所水解,而是形成稳定的复合物。因此,MCH1受体的激活可通过测量GTPγ35S的量来定量,所述GTPγ35S与由表达此类受体的细胞制备的膜结合。膜可通过过滤来分离,或可结合在SPA珠子(Amersham)上。然后可通过确定35S的存在量来定量结合的GTPγ35S。因此可通过在此类竞争配体的存在下,与膜结合的GTPγ35S的量的减少来评估竞争配体对MCH结合的抑制。
评价小分子与肝细胞中的蛋白的共价结合:
该测定是基于对所公布方法的改进(Day,S.H.;Mao,A.;White,R.;Schulz-Utermoehl,T.;Miller,R.;Beconi,M.G.(2005)Asemi-automatedmethodformeasuringthepotentialforproteincovalentbindingindrugdiscovery.J.Pharmacol.Toxicol.Methods52,278-285.)。简言之,在24孔板中在放射性标记的药物候选物的存在下将低温保藏的人肝细胞孵育预定时间期间以允许母体化合物的足够周转。孵育期后,将样品取出并且通过冷丙酮淬灭,以促进蛋白质沉淀。使用Brandel收集器在玻璃纤维滤纸上收集所沉淀的蛋白质样品并且用80%甲醇洗涤以除去非共价结合的母体药物和代谢物。在滤纸上收集的蛋白质溶解后,确定放射性含量和蛋白质的量以给出每mg蛋白质所结合的等价药物分子pmol的估值。除评价共价结合程度之外,对母体药物的周转进行定量以给出导致共价结合(fCVB)的代谢物分数的估值。
IC
50
值
在上文提及的测定中测试时的实施例的化合物具有低于约500nM的IC50值。实施例化合物的IC50值在下文表1中列出。
表1
本发明某些化合物是有优势的,因为它们表现出在其MCH活性与其hERG活性之间的选择性。本发明某些化合物特别有优势,因为它们出乎意料地在体内比根据其体外活性所期望的更有效和/或因为它们具有有优势的代谢特征。代谢特征的一个方面是反应性代谢物的形成,其中本发明化合物通常不太倾向于形成此类反应性代谢物。对反应性代谢物形成的体外评价可根据上述方法通过测量3H-或14C标记的化合物与人肝细胞的结合程度来作出。然后可计算fCVB值。例如,对于本发明的实施例5,fCVB值实测为0.0069,可将其与WO2010/125390中所述的实施例4(其fCVB值根据在相同的测定条件下进行的实验经计算为0.02)相比较。
为了更全面地评价反应性代谢物的存在,也必须考虑每日人剂量预测。所计算的组合值被称为共价结合载量。(参考文献:Thompson,R.等人Chem.Res.Tox.2012公布于网页:dx.doi.org/10.1021/tx300091x)。本发明某些化合物不同于之前描述于WO2010/125390中的化合物,因为可根据使用所预测的人的日剂量和与人肝细胞的共价结合程度(fCVB)两者的组合评价来计算共价结合载量的较低值。
实施例
在以下实施例中进一步定义本发明。应理解,仅以举例说明的方式给出实施例。从以上讨论和实施例,本领域技术人员可确定本发明的必要特征而不背离本发明的精神和范围,可进行各种改变和修改以使本发明适应各种用途和条件。因此,本发明不受下文陈述的示例性实施例的限制,而是由所附权利要求书所定义。
通常,可根据本领域技术人员的常识和/或使用实施例和/或随后的中间体章节中陈述的方法来制备式I化合物。溶剂、温度、压力和其它反应条件可由本领域普通技术人员容易地选择。原料为商业上可获得的和/或由本领域技术人员容易地制备。在化合物的制备中可采用组合技术,例如,当中间体具有适合于这些技术的基团时。
本文采用以下缩写:ACN:乙腈;APCI:大气压化学电离;aq.:水溶液(aqueous);BOC:1,1-二甲基乙氧基羰基;Cs2CO3:碳酸铯;DCM:二氯甲烷;DIAD:偶氮二羧酸二异丙酯;DIBAL-H:二异丁基氢化铝;DIPEA:N,N-二异丙基乙基胺;DMSO:二甲亚砜;EDCI:1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐;Et2O:乙醚;EtOAc:乙酸乙酯;EtOH:乙醇;h:小时;HPLC:高效液相色谱法;HCl:盐酸(当给出摩尔浓度时)或氯化氢气体(当使用除水之外的溶剂时);H2O:水;K2CO3:碳酸钾;LC:液相色谱法;MeOH:甲醇;MgSO4:硫酸镁;min:分钟;MS:质谱;NaCl:氯化钠;NH4Cl:盐酸氨;NaHCO3:碳酸氢钠;Na2SO4:硫酸钠;NH3:氨;NMR:核磁共振;psi:每平方英寸磅数;RT:室温;sat.:饱和的;TBTU:2-(1H-苯并[d][1,2,3]三唑-1-基)-1,1,3,3-四甲基异脲四氟硼酸盐;TEA:三乙胺;TFA:三氟乙酸;和THF:四氢呋喃。
分析型LC/MSHPLC方法:WatersAcquityUPLC柱AcquityUPLCBEHC18,1.7um,2.1x100mm。在60℃,梯度5-95%乙腈在pH10的碳酸铵(40mMNH3+6.5mMH2CO3)中,5.8分钟。流速0.8mL/min。
制备型HPLC方法:常规使用制备型HPLC来分离示例性化合物。仪器:FractionLynxI流动相:梯度5-95%ACN在pH10的0.2%NH3中,柱:Xbridge制备型C18,5μmOBD19*150mm。
通过由CambridgeSoftCorporation,Cambridge,MA02140,USA提供的软件来产生化学IUPAC名称。
式IV的胺是商业上可获得的。
实施例1
(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮
将2-氧杂-7-氮杂螺[4.4]壬烷HCl盐(0.057g,0.35mmol)溶解于二氯甲烷(2ml)中。向所得溶液加入三乙胺(0.052ml,0.38mmol),然后加入4-(1-(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(0.11g,0.29mmol)和三乙酰氧基硼氢化钠(0.123g,0.58mmol)。将混合物在环境温度下搅拌过夜。然后将反应混合物用二氯甲烷(10ml)稀释且与NaHCO3(饱和2ml)振摇。使用相分离器分离两相。蒸发有机相。通过制备型反相HPLC(pH10)纯化产物,以得到0.066g(46%)为固体状的所需产物。1H NMR(400MHz,CDCl3)δ1.92(ddd,4H),2.42(d,1H),2.62(dd,3H),3.58(d,3H),3.71(d,1H),3.84(ddd,2H),3.92(s,3H),4.35(d,1H),4.67(dd,1H),4.77(d,1H),5.04–5.19(m,2H),6.75(d,2H),7.05(d,2H),7.29(d,2H),8.12(d,2H).MS(APCI+)m/z491.3[M+H]+,LC纯度:97%
本领域技术人员应明白该标题化合物是手性的。单独对映异构体:
(+)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮和(-)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮使用包含庚烷/THF/三乙胺60/40/0.1的流动相通过在IA柱(由ChiralTechnologiesEurope供应)上的手性色谱法而获得。
实施例2
(+/-)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮
(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮(来自手性LC分离的异构体1)通过柱色谱法(ISOLUTESI,10/70ml)进一步纯化、用NH3在MeOH(2M)/DCM(2:98)中的溶液洗脱,在蒸发溶剂混合物后获得3mg(2%)。
旋光度未知。1H NMR(400MHz,CDCl3):δ1.77–1.99(m,4H),2.39(d,1H),2.53–2.69(m,3H),3.5–3.6(m,3H),3.69(d,1H),3.75–3.87(m,2H),3.89(s,3H),4.33(dd,1H),4.6–4.68(m,1H),4.71–4.78(m,1H),5.02–5.16(m,2H),6.72(d,2H),6.99–7.05(m,2H),7.25(d,2H),8.07–8.13(m,2H).MS(APCI+)m/z491.3[M+H]+,LC纯度:99%
实施例3
(+/-)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮
(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮(来自手性LC分离的异构体2)通过柱色谱法(ISOLUTESI,10/70ml)进一步纯化,用NH3的MeOH(2M)/DCM(2:98)溶液洗脱,以在蒸发溶剂混合物后获得3mg(2%)。
旋光度未知。1H NMR(400MHz,CDCl3):δ1.77–1.98(m,4H),2.39(d,1H),2.52–2.7(m,3H),3.49–3.6(m,3H),3.68(d,1H),3.75–3.87(m,2H),3.88(d,3H),4.33(dd,1H),4.6–4.68(m,1H),4.7–4.79(m,1H),5.01–5.15(m,2H),6.72(d,2H),6.98–7.05(m,2H),7.26(d,2H),8.06–8.12(m,2H).MS(APCI+)m/z491.3[M+H]+,LC纯度:99%。
实施例4
(3-(4-(5-氧杂-2-氮杂螺[3.4]辛-2-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮
将5-氧杂-2-氮杂螺[3.4]辛烷HCl盐(0.052g,0.35mmol)溶解于二氯甲烷(2ml)中。加入三乙胺(0.052ml,0.38mmol),然后加入4-(1-(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(0.11g,0.29mmol)及最后加入三乙酰氧基硼氢化钠(0.123g,0.58mmol)。将反应在环境温度下搅拌过夜。然后将反应混合物用二氯甲烷(10ml)稀释,且随后与NaHCO3(饱和2ml)振摇。使用相分离器分离两相。蒸发有机相。通过制备型反相HPLC在pH10)纯化产物,以得到23mg(17%)为固体状的所需产物。1H NMR(500MHz,CDCl3):δ1.90(p,2H),2.13(t,2H),3.16(d,2H),3.37(d,2H),3.62(s,2H),3.80(t,2H),3.91(s,3H),4.33(dd,1H),4.62–4.7(m,1H),4.73–4.78(m,1H),5.03–5.16(m,2H),6.74(d,2H),7.04(d,2H),7.25(d,2H),8.11(d,2H).MS(APCI+)m/z477.3[M+H]+,LC纯度:97%
实施例5
(3-(4-(6-氧杂-2-氮杂螺[3.4]辛-2-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮
将6-氧杂-2-氮杂螺[3.4]辛烷HCl盐(0.052g,0.35mmol)溶解于二氯甲烷(2ml)中。加入三乙胺(0.052ml,0.38mmol),接着加入4-(1-(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(0.11g,0.29mmol),及然后加入三乙酰氧基硼氢化钠(0.123g,0.58mmol)。将反应在环境温度下搅拌过夜。然后用二氯甲烷(10ml)稀释反应混合物,之后将其与NaHCO3(饱和2ml)振摇。通过使用相分离器分离两相。蒸发二氯甲烷获得粗材料,其通过制备型反相HPLC在pH10下纯化,以得到59mg(43%)为固体状的所需产物。1H NMR(400MHz,CDCl3):δ2.12(t,2H),3.24(s,4H),3.58(s,2H),3.79(t,2H),3.85(s,2H),3.92(s,3H),4.34(dd,1H),4.66(dd,1H),4.76(d,1H),5.04–5.18(m,2H),6.75(d,2H),7.05(d,2H),7.25(d,2H),8.12(d,2H).MS(APCI+)m/z477.3[M+H]+,LC纯度:96%。
实施例6
(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮
向4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(70mg,0.20mmol)在二氯甲烷(2mL)中的溶液加入三乙胺(0.100mL,0.72mmol)和2-氧杂-7-氮杂螺[4.4]壬烷盐酸盐(77mg,0.47mmol)。将所得的混合物在环境温度搅拌30分钟,之后加入三乙酰氧基硼氢化钠(114mg,0.54mmol)。在环境温度持续搅拌过夜,之后将NaHCO3(饱和水溶液,5ml)加至反应混合物。使用相分离器分离各相。将水相用二氯甲烷萃取两次且借助于相分离器干燥。将合并的有机相真空浓缩,以获得称重为112mg的无色残余物。通过制备型反相HPLC在pH10纯化粗材料,以得到75mg(81%)为固体状的所需产物。1H NMR(600MHz,CDCl3):δ1.75(t,2H),1.79–1.89(m,2H),2.32(d,1H),2.45–2.49(m,2H),2.59(dd,1H),3.43(d,1H),3.48–3.56(m,3H),3.63–3.75(m,2H),4.10(dd,1H),4.56(dd,1H),4.61–4.67(m,1H),5.10(dd,1H),5.16(ddd,1H),6.86(d,2H),7.26(d,2H),7.63–7.73(m,3H),8.06-8.11(m,2H).MS(APCI+)m/z461.2[M+H]+,LC纯度:97%
本领域技术人员应明白该标题化合物是手性的。单独对映异构体:
(+)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮和(-)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮可通过手性色谱法获得。
实施例7
(3-(4-(6-氧杂-2-氮杂螺[3.4]辛-2-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮
向4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(70mg,0.20mmol)在二氯甲烷(2mL)中的溶液加入6-氧杂-2-氮杂螺[3.4]辛烷盐酸盐(56mg,0.37mmol)和三乙胺(0.100mL,0.72mmol)。在环境温度搅拌30分钟后,加入三乙酰氧基硼氢化钠(95mg,0.45mmol)。在环境温度持续搅拌过夜,之后加入NaHCO3(饱和水溶液,5ml)。借助于相分离器分离各相。将水相用二氯甲烷萃取两次且使用相分离器干燥。将合并的有机相真空浓缩,以获得无色残余物,称重为92mg。
通过制备型反相HPLC在pH10纯化粗材料,以得到63mg(71%)为固体状的所需产物。1H NMR(600MHz,DMSO)δ2.00(t,2H),3.11(q,4H),3.49(s,2H),3.64(t,2H),3.69(s,2H),4.07–4.11(m,1H),4.55(ddd,1H),4.63(ddd,1H),5.07–5.17(m,2H),6.82–6.86(m,2H),7.23(d,2H),7.63–7.72(m,3H),8.06–8.1(m,2H).MS(APCI+)m/z447.2[M+H]+,LC纯度:98%
实施例8
(3-(4-(5-氧杂-2-氮杂螺[3.4]辛-2-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮
向4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(70mg,0.20mmol)在二氯甲烷(2mL)中的溶液加入5-氧杂-2-氮杂螺[3.4]辛烷盐酸盐(80mg,0.53mmol)和三乙胺(0.100mL,0.72mmol)。在环境温度搅拌30分钟后,加入三乙酰氧基硼氢化钠(70mg,0.33mmol)。在环境温度持续搅拌过夜,之后加入NaHCO3(饱和水溶液,5ml)。借助于相分离器分离各相。将水相用二氯甲烷萃取两次且借助于相分离器干燥。将合并的有机相真空浓缩,以获得88mg无色残余物。
通过制备型反相HPLC在pH10纯化粗材料,以得到68mg(76%)为固体状的所需产物。1H NMR(600MHz,DMSO)δ1.80(p,2H),2.00(t,2H),2.98(d,2H),3.22(dd,2H),3.51(s,2H),3.65(q,2H),4.09(ddd,1H),4.53–4.57(m,1H),4.63(ddd,1H),5.10(ddd,1H),5.15(ddd,1H),6.84(t,2H),7.23(d,2H),7.68(dtd,3H),8.08(dd,2H).MS(APCI+)m/z447.2[M+H]+,LC纯度:99%
实施例9
(3-(4-(6-氧杂-2-氮杂螺[3.4]辛-2-基甲基)-3-甲基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮
将6-氧杂-2-氮杂螺[3.4]辛烷HCl盐(0.064g,0.43mmol)溶解于二氯甲烷(2ml)中。加入三乙胺(0.064ml,0.47mmol),然后加入2-甲基-4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(0.13g,0.36mmol)和三乙酰氧基硼氢化钠(0.152g,0.72mmol)。将混合物在环境温度下搅拌过夜。将反应混合物用二氯甲烷(10ml)稀释且然后与NaHCO3振摇。通过使用相分离器分离两相。蒸发二氯甲烷而获得粗材料,其通过制备型反相HPLC在pH10下纯化,以得到66mg(40%)为固体状的所需产物。1H NMR(600MHz,DMSO)δ2.01(t,2H),2.27(s,3H),3.13(q,4H),3.47(s,2H),3.64(t,2H),3.70(d,2H),4.08(dd,1H),4.51–4.56(m,1H),4.63(dd,1H),5.06–5.15(m,2H),6.65(dd,1H),6.71(d,1H),7.18(d,1H),7.62–7.73(m,3H),8.06–8.11(m,2H).MS(APCI+)m/z461.2[M+H]+,LC纯度:98%
实施例10
(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)-3-甲基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮
将2-氧杂-7-氮杂螺[4.4]壬烷HCl盐(0.07g,0.43mmol)溶解于二氯甲烷(2ml)中。加入三乙胺(0.064ml,0.47mmol),然后加入2-甲基-4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(0.13g,0.36mmol)和三乙酰氧基硼氢化钠(0.152g,0.72mmol)。将所得的混合物在环境温度搅拌过夜。将反应混合物用二氯甲烷(10ml)稀释,且然后与NaHCO3(饱和3ml)振摇。通过使用相分离器分离两相。蒸发有机相获得粗材料,其通过制备型反相HPLC在pH10纯化,以得到85mg(50%)为固体状的所需产物。
1H NMR(600MHz,DMSO)δ1.76(t,2H),1.78–1.89(m,2H),2.32(d,4H),2.47(d,2H),2.57–2.61(m,1H),3.41(d,1H),3.45–3.54(m,3H),3.65–3.74(m,2H),4.09(dd,1H),4.54(dd,1H),4.61–4.66(m,1H),5.12(dtd,2H),6.66(dd,1H),6.72(d,1H),7.18(d,1H),7.63–7.73(m,3H),8.08(dd,2H).MS(APCI+)m/z475.2[M+H]+,LC纯度:98%。本领域技术人员应明白该标题化合物是手性的。单独对映异构体:(+)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)-3-甲基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮和(-)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)-3-甲基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮可通过手性色谱法获得。
实施例11
(3-(4-(5-氧杂-2-氮杂螺[3.4]辛-2-基甲基)-3-甲基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮
将5-氧杂-2-氮杂螺[3.4]辛烷HCl盐(0.064g,0.43mmol)溶解于二氯甲烷(2ml)中。加入三乙胺(0.064ml,0.47mmol),然后加入2-甲基-4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(0.13g,0.36mmol),且最后加入三乙酰氧基硼氢化钠(0.152g,0.72mmol)。所得的混合物在环境温度搅拌过夜。将反应混合物用二氯甲烷(10ml)稀释且与NaHCO3(饱和3ml)振摇。通过使用相分离器分离两相。蒸发有机相获得固体残余物,将其再溶解于二氯甲烷(约20ml)中,用水(20ml)洗涤,通过相分离器过滤且蒸发。残余物通过柱色谱法(ISOLUTESI,20g/70ml)纯化,用NH3的MeOH(2M)/二氯甲烷(1:99,2:98)溶液洗脱。蒸发溶剂混合物后,获得112mg(68%)所需产物,为固体状。1H NMR(400MHz,CDCl3)δ1.91(p,2H),2.14(t,2H),2.33(s,3H),3.15(d,2H),3.39(d,2H),3.59(s,2H),3.82(t,2H),4.35(dd,1H),4.67(dd,1H),4.74–4.8(m,1H),5.11(ddt,2H),6.57(dd,1H),6.62(d,1H),7.22(d,1H),7.53–7.65(m,3H),8.16–8.23(m,2H).MS(APCI+)m/z461.3[M+H]+,LC纯度:99%
实施例12
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮
将2-氧杂-5-氮杂螺[3.4]辛烷(0.03g,0.26mmol)溶解于二氯甲烷(2ml)中。加入三乙胺(0.04ml,0.29mmol),然后加入4-(1-(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(0.1g,0.26mmol),且最后加入三乙酰氧基硼氢化钠(0.112g,0.53mmol)。将混合物在环境温度下搅拌过夜。然后将反应混合物用二氯甲烷(10ml)稀释,且随后与NaHCO3(饱和3ml)振摇。通过使用相分离器分离两相。蒸发有机相获得残余物,其通过制备型反相HPLC在pH10纯化,以得到0.075g(60%)为固体状的所需产物。1H NMR(600MHz,DMSO)δ1.62(dt,2H),2.1–2.15(m,2H),2.49(t,2H),3.88(s,3H),3.91(s,2H),4.09(ddd,1H),4.43(d,2H),4.54(ddd,1H),4.63(ddd,1H),4.80(d,2H),5.09(ddd,1H),5.16(ddd,1H),6.86(d,2H),7.17–7.21(m,2H),7.30(d,2H),8–8.04(m,2H).MS(APCI+)m/z477.2[M+H]+,LC纯度:95%
实施例13
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮
将2-氧杂-5-氮杂螺[3.4]辛烷TFA盐(0.16g,67%,0.47mmol)溶解于二氯甲烷(3ml)中。加入三乙胺(0.119ml,0.86mmol),然后加入4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(0.15g,0.43mmol),且最后加入三乙酰氧基硼氢化钠(0.182g,0.86mmol)。将混合物在环境温度下搅拌过夜。然后将反应混合物用二氯甲烷(10ml)稀释且与NaHCO3(饱和3ml)振摇。通过使用相分离器分离两相。蒸发有机相获得无色残余物,其通过制备型反相HPLC在pH10纯化,以得到0.140g(73%)为固体状的所需产物。1H NMR(600MHz,DMSO)δ1.62(dt,2H),2.09–2.15(m,2H),2.47–2.5(m,2H),3.90(d,2H),4.08–4.14(m,1H),4.43(d,2H),4.54–4.59(m,1H),4.64(ddd,1H),4.80(d,2H),5.09–5.13(m,1H),5.16(ddd,1H),6.87(d,2H),7.30(d,2H),7.64–7.74(m,3H),8.07–8.13(m,2H).MS(APCI+)m/z447.2[M+H]+,LC纯度:94%。
实施例14
(3-(4-(7-氧杂-1-氮杂螺[4.4]壬-1-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮
将7-氧杂-1-氮杂螺[4.4]壬烷TFA盐(0.07g,0.29mmol)溶解于二氯甲烷(2ml)中。加入三乙胺(0.044ml,0.32mmol),然后加入4-(1-(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(0.11g,0.29mmol),最后加入三乙酰氧基硼氢化钠(0.123g,0.58mmol)。将混合物在环境温度下搅拌。然后将反应混合物用二氯甲烷(10ml)稀释且与NaHCO3(饱和3ml)振摇。通过使用相分离器分离两相。蒸发有机相获得残余物,其通过制备型反相HPLC(pH10)纯化,以得到0.072g(51%)为固体状的所需产物。1H NMR(600MHz,DMSO)δ1.62–1.74(m,3H),1.79–1.9(m,2H),2.10(dd,1H),2.42(dd,1H),2.53–2.55(m,1H),3.41(d,1H),3.48(d,1H),3.63(d,1H),3.69(q,1H),3.80(d,1H),3.88(s,3H),3.91(td,1H),4.09(dd,1H),4.54(dd,1H),4.62(ddd,1H),5.08(ddd,1H),5.15(ddd,1H),6.84(d,2H),7.17–7.21(m,2H),7.25(d,2H),8–8.05(m,2H).MS(APCI+)m/z491.2[M+H]+,LC纯度:96%
本领域技术人员应明白该标题化合物是手性的。单独对映异构体(+)-(3-(4-(7-氧杂-1-氮杂螺[4.4]壬-1-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮和(-)-(3-(4-(7-氧杂-1-氮杂螺[4.4]壬-1-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮可通过手性色谱法获得。
实施例15
(3-(4-(7-氧杂-1-氮杂螺[4.4]壬-1-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮
将7-氧杂-1-氮杂螺[4.4]壬烷TFA盐(0.07g,0.29mmol)溶解于二氯甲烷(2ml)中。加入三乙胺(0.044ml,0.32mmol),然后加入4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(0.101g,0.29mmol),且最后加入三乙酰氧基硼氢化钠(0.123g,0.58mmol)。然后将反应混合物用二氯甲烷(10ml)稀释且与NaHCO3(饱和3ml)振摇。通过使用相分离器分离两相。蒸发有机相获得残余物,其通过制备型反相HPLC在pH10下纯化,以得到0.081g(61%)为固体状的所需产物。1H NMR(600MHz,DMSO)δ1.62–1.74(m,3H),1.79–1.9(m,2H),2.10(dt,1H),2.37–2.45(m,1H),2.54(dd,1H),3.41(d,1H),3.48(d,1H),3.63(d,1H),3.69(q,1H),3.80(d,1H),3.91(td,1H),4.10(dd,1H),4.56(dd,1H),4.63(ddd,1H),5.07–5.18(m,2H),6.84(d,2H),7.25(d,2H),7.64–7.73(m,3H),8.08(dd,2H).MS(APCI+)m/z461.2[M+H]+,LC纯度:97%
本领域技术人员应明白该标题化合物是手性的。单独对映异构体(+)-(3-(4-(7-氧杂-1-氮杂螺[4.4]壬-1-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮和(-)-(3-(4-(7-氧杂-1-氮杂螺[4.4]壬-1-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮可通过手性色谱法获得。
实施例16
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)-3-甲氧基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮
将2-氧杂-5-氮杂螺[3.4]辛烷TFA盐(0.111g,约70%,0.34mmol)和2-甲氧基-4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(0.13g,0.34mmol)在二氯甲烷(2ml)中混合。然后加入三乙胺(0.1ml,0.72mmol),接着加入三乙酰氧基硼氢化钠(0.145g,0.69mmol)。将混合物在环境温度下搅拌过夜。LC-MS显示一些剩余原料。加入另外量的三乙酰氧基硼氢化钠(0.11g)且将搅拌持续6小时。然后将反应混合物用二氯甲烷(10ml)稀释且与NaHCO3(饱和3ml)振摇。通过使用相分离器分离两相。蒸发有机相获得无色残余物,其通过制备型反相HPLC在pH10纯化,以得到0.113g(69%)为固体状的所需产物。1H NMR(600MHz,DMSO)δ1.58–1.66(m,2H),2.07–2.12(m,2H),2.55–2.58(m,2H),3.81(s,3H),3.88(s,2H),4.08–4.12(m,1H),4.44(d,2H),4.54–4.58(m,1H),4.64(ddd,1H),4.79(d,2H),5.10(ddd,1H),5.19(ddd,1H),6.42(dd,1H),6.54(d,1H),7.20(d,1H),7.64–7.72(m,3H),8.05–8.11(m,2H).MS(APCI+)m/z477.2[M+H]+,LC纯度:93%
实施例17
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)-2-甲氧基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮
将2-氧杂-5-氮杂螺[3.4]辛烷TFA盐(0.111g,约70%,0.34mmol)和3-甲氧基-4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(0.13g,0.34mmol)在二氯甲烷(2ml)中混合。然后加入三乙胺(0.1ml,0.72mmol),接着加入三乙酰氧基硼氢化钠(0.145g,0.69mmol)。将混合物在环境温度下搅拌过夜。LC-MS显示一些剩余原料。加入另外量的三乙酰氧基硼氢化钠(0.1g)且将搅拌持续6小时。然后将反应混合物用二氯甲烷(10ml)稀释且与NaHCO3(饱和3ml)振摇。通过使用相分离器分离两相。蒸发有机相获得残余物,其通过制备型反相HPLC在pH10纯化,以得到0.107g为固体状的所需产物。通过自动快速色谱法在10g柱上纯化所获得的产物。将MeOH/EtOAc中的3%NH3(2M)用作流动相。通过UV检测器在274nm检测产物。在蒸发溶剂混合物后获得0.09g(55%)为固体状的所需产物。
1H NMR(400MHz,CDCl3)δ1.71(dt,2H),2.18–2.24(m,2H),2.60(t,2H),3.89(s,3H),3.97(s,2H),4.39–4.47(m,1H),4.57(d,2H),4.63(dd,1H),4.83(t,1H),4.90(d,2H),5.03–5.15(m,2H),6.63(d,1H),6.87(d,1H),6.95(s,1H),7.5–7.62(m,3H),8.17(d,2H).MS(APCI+)m/z477.3[M+H]+,LC纯度:97%。
实施例18
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)-2-甲氧基苯氧基)氮杂环丁烷-1-基)(5-(4-(二氟甲基)苯基)-1,3,4-噁二唑-2-基)甲酮
将2-氧杂-5-氮杂螺[3.4]辛烷TFA盐(0.11g,约70%,0.34mmol)和4-(1-(5-(4-(二氟甲基)苯基)-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)-3-甲氧基苯甲醛(0.146g,0.34mmol)在二氯甲烷(2ml)中混合。加入三乙胺(0.1ml,0.72mmol),然后加入三乙酰氧基硼氢化钠(0.144g,0.68mmol)。将混合物在环境温度搅拌过夜(16h)。LC-MS显示一些剩余原料且加入另外量的三乙酰氧基硼氢化钠(0.113g)。持续搅拌6h。然后将反应混合物用二氯甲烷(10ml)稀释且与NaHCO3(饱和3ml)振摇。通过使用相分离器分离两相。蒸发有机相获得残余物,其通过制备型反相HPLC在pH10下纯化,以得到0.112g(62%)为固体状的所需产物。
1H NMR(500MHz,CDCl3):δ1H NMR(600MHz,DMSO)δ1.63(dt,2H),2.13(dd,2H),2.51–2.53(m,2H),3.78(d,3H),3.90(d,2H),4.12(dd,1H),4.43(d,2H),4.60(ddd,2H),4.80(d,2H),5.04–5.12(m,2H),6.78(d,1H),6.87(dd,1H),7.00(d,1H),7.18(t,1H),7.84(d,2H),8.23(d,2H).
MS(APCI+)m/z527.2[M+H]+,LC纯度:93%。
实施例19
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)-3-甲氧基苯氧基)氮杂环丁烷-1-基)(5-(4-(二氟甲基)苯基)-1,3,4-噁二唑-2-基)甲酮
将2-氧杂-5-氮杂螺[3.4]辛烷TFA盐(0.11g,约70%,0.34mmol)和4-(1-(5-(4-(二氟甲基)苯基)-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)-2-甲氧基苯甲醛(0.146g,0.34mmol)在二氯甲烷(2ml)中混合。加入三乙胺(0.1ml,0.72mmol),然后加入三乙酰氧基硼氢化钠(0.145g,0.68mmol)。将混合物在环境温度下搅拌过夜。LC-MS显示原料完全耗尽。然后将反应混合物用二氯甲烷(10ml)稀释且与NaHCO3(饱和3ml)振摇。通过使用相分离器分离两相。蒸发有机相获得残余物,其通过制备型反相HPLC在pH10纯化,以得到0.119g(67%)为固体状的所需产物。1H NMR(500MHz,CDCl3):δ1H NMR(600MHz,DMSO)δ1.56–1.68(m,2H),2.06–2.14(m,2H),2.55–2.58(m,2H),3.81(s,3H),3.88(s,2H),4.11(dd,1H),4.44(d,2H),4.54–4.59(m,1H),4.63–4.68(m,1H),4.79(d,2H),5.09–5.13(m,1H),5.17–5.22(m,1H),6.42(dd,1H),6.54(d,1H),7.18(t,1H),7.21(d,1H),7.85(d,2H),8.23(d,2H).MS(APCI+)m/z527.2[M+H]+,LC纯度:97%。
实施例20
(3-(4-(6-氧杂-2-氮杂螺[3.4]辛-2-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮
在氮气气氛和室温下,将中间体IIIE(16.1g,55.7mmol)溶解于MeOH(150mL)中。在5分钟内向该溶液分小部分加入5-(4-甲氧基苯基)-1,3,4-噁二唑-2-羧酸乙酯–对于制备,参见例如Journal für Praktische Chemie,327,109-16(1985)-(14.5g,58.5mmol)。由于产物在5至10分钟搅拌下沉淀,溶液变得浑浊。将悬浮液在RT搅拌两天且通过过滤收集产物。用MeOH(5x50ml)洗涤滤饼,且然后将产物在40℃在真空中干燥过夜。获得25.7g(97%)为固体状的所需产物。1H NMR(400MHz,DMSO-d6):δ1.88(t,2H),2.99(b,4H),3.37(s,2H),3.54(m,4H),3.76(s,3H),3.92(d,1H),4.44(m,2H),4.99(m,2H),6.72(d,2H),7.09(m,4H),7.90(d,2H).MS(APCI+)m/z477.1[M+H]+.LC纯度:99%。
使用常规方法该化合物形成结晶盐酸盐和结晶甲磺酸盐。
实施例21
(3-(4-(1-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮
将1-氧杂-7-氮杂螺[4.4]壬烷盐酸盐(65mg,0.40mmol)和TEA(0.082mL,0.59mmol)与DCM(4mL)混合。向混合物加入溶解于DCM(1mL)中的4-(1-(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(0.150g,0.40mmol)。搅拌10min后,加入三乙酰氧基硼氢化钠(0.168g,0.79mmol)且将反应混合物在RT搅拌过夜。加入NaHCO3水溶液(8%,10mL)且将混合物用DCM(15mL)萃取两次。将有机层经相分离器干燥且在减压下浓缩。通过在硅胶(25g)上的色谱法用EtOAc与在MeOH中的氨(2M)的混合物20:1洗脱而纯化粗品。在减压下浓缩掺并的级分,获得为白色固体状的所需化合物(95mg,49%)。1H NMR(400MHz,CDCl3):δ1.73(m,5H),1.86(m,1H),2.57(m,3H),2.69(m,1H),3.56(m,2H),3.77(m,2H),3.88(s,3H),4.32(dd,1H),4.63(m,1H),4.73(dd,1H),5.07(m,2H),6.71(d,2H),7.01(d,2H),7.27(d,2H),8.09(d,2H).MS(APCI+)m/z491.5[M+H]+.LC纯度:94%。
实施例22
(3-(4-(1-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮
使用实施例21中所述的类似方案但是采用1-氧杂-7-氮杂螺[4.4]壬烷盐酸盐(70mg,0.43mmol)和4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛(150mg,0.43mmol)作为原料,获得103mg(52%)22。1H NMR(400MHz,DMSO-d6):δ1.81(m,6H),2.50(m,4H),3.50(m,2H),3.65(m,2H),4.10(dd,1H),4.56(dd,1H),4.63(dd,1H),5.10(dd,1H),5.16(m,1H),6.86(d,2H),7.27(d,2H),7.68(m,3H),8.08(d,2H).LC纯度:95%。
中间体醛
如WO2010/125390中所述,制备4-(1-(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛。
中间体I
4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛
IA.(3-羟基氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮
向5-苯基-1,3,4-噁二唑-2-羧酸乙酯(0.40g,1.83mmol)在无水甲醇(5mL)中的澄清溶液加入氰化钠(18mg,0.37mmol)。在环境温度加入3-羟基氮杂环丁烷盐酸盐(0.45g,2.84mmol)和三乙胺(0.40mL,2.84mmol)在甲醇(5mL)中的溶液。搅拌20min后加入水(20mL)和二氯甲烷(30mL)。分离各层且将水相用二氯甲烷(30mL)萃取两次。蒸发合并的有机层。然后将粗产物用甲苯(5mL)处理,过滤,用甲苯(5mL)洗涤且真空干燥。获得0.40g(90%)为固体状的53A。1H NMR(400MHz,DMSO-d6):δ3.84(dd,1H),4.31(m,2H),4.56(m,1H),4.79(dd,1H),5.87(d,1H),7.64(m,3H),8.05(d,2H),MS(APCI+)m/z246[M+H]+。
IB.甲烷磺酸1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基酯
将IA(2.00g,8.16mmol)在二氯甲烷(200mL)中的悬浮液在冰浴中冷却。加入三乙胺(1.58mL,11.42mmol),然后加入甲烷磺酰氯(0.85mL,11.01mmol)。添加后,移除冷却浴。将混合物搅拌过夜,且然后转移至分液漏斗。将混合物用水,然后用NaHCO3水溶液洗涤。将有机溶液干燥(相分离器)且蒸发。获得2.58g(98%)为固体状的甲烷磺酸1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基酯。1H NMR(500MHz,CDCl3):δ3.13(s,3H),4.43(dd,1H),4.64(dd,1H),4.87(dd,1H),5.12(dd,1H),5.40(m,1H),7.54(t,2H),7.59(t,1H),8.15(d,2H),MS(APCI+)m/z324[M+H]+.
IC.4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛
将4-羟基苯甲醛(1.10g,9.17mmol)、碳酸铯(3.49g,10.70mmol)和甲烷磺酸1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基酯(IB)(2.70g,7.64mmol)与DMF(80mL)混合。将混合物在110℃搅拌18h,且然后冷却至RT。滤去固体且蒸发滤液。将残余物用甲醇处理且通过过滤收集所形成的固体。在真空下干燥,获得1.8g(62%)为米色固体状的标题化合物。1H NMR(500MHz,DMSO-d6):δ3.85(s,3H),4.13(dd,1H),4.57(dd,1H),4.65(dd,1H),5.12(dd,1H),5.29(m,1H),7.10(d,2H),7.16(d,2H),7.90(d,2H),8.00(d,2H),9.90(s,1H),MS(APCI+)m/z380[M+H]+.
中间体II
2-甲基-4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛
在氮气下向4-羟基-2-甲基苯甲醛(0.11g,0.79mmol)和甲烷磺酸1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基酯(0.20g,0.62mmol,上述中间体IB)在DMF(10mL)中的溶液加入Cs2CO3(0.24g,0.74mmol)。将混合物在90℃搅拌20h,冷却至RT,且然后用DCM稀释。滤去固体且蒸发滤液。通过制备型HPLC(Kromasil,C8)用乙腈和乙酸与水的混合物(0.2%)的梯度洗脱而纯化产物两次。将纯级分合并,且浓缩。将水性残余物用DCM萃取且蒸发有机溶液。获得162mg(72%)为固体状的标题化合物。1H NMR(500MHz,CDCl3):δ2.66(s,3H),4.34(d,1H),4.69(dd,1H),4.76(d,1H),5.17(m,2H),6.64(d,1H),6.72(dd,1H),7.53(t,2H),7.59(t,1H),7.78(d,1H),8.15(d,1H),10.14(s,1H),MS(APCI+)m/z364[M+H]+.
通过与紧接的上文的方法类似的方法制备下列化合物:
2-甲氧基-4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛;
3-甲氧基-4-(1-(5-苯基-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)苯甲醛;和4-(1-(5-(4-(二氟甲基)苯基)-1,3,4-噁二唑-2-羰基)氮杂环丁烷-3-基氧基)-3-甲氧基苯甲醛。
中间体III
IIIA.2-苄基-6-氧杂-2-氮杂螺[3.4]辛-1-酮
将反应在装备有温度计和含有NaOH水溶液(5M,500mL)的洗涤器的2-L圆底烧瓶中进行。在氮气气氛下,将DCM(1100mL)和吡啶(2.27mL,26.7mmol)加至四氢呋喃-3-羧酸(155g,1.34mol)。使用外部水浴将混合物加热至25℃。在搅拌下于15min中加入氯化亚砜(102mL,1.40mol)。在添加期间将反应温度维持在25-27℃之间。当已加入约1/3氯化亚砜时观察到气体逸出。添加后,将混合物在25℃搅拌1小时,且然后在30℃再搅拌1小时,此后观察到更多的气体逸出。接着将反应混合物在环境温度搅拌2h,且然后使用干冰浴冷却约1小时,直到混合物的温度变为-72℃。缓慢加入三乙胺(555mL,4.00mol)以使温度未超过-55℃。同时在单独瓶中,在氮气和RT下,将1,3,5-三苄基-1,3,5-三嗪烷(trianinane)(162g,0.45mol)溶解于DCM(250mL)中且在5min内向所得溶液缓慢加入(二乙基氧鎓)三氟硼酸盐(168mL,1.34mol)。在RT搅拌20分钟后,将后者混合物缓慢加至前者混合物。在持续约20min的添加期间反应温度决不允许超过-45℃。然后使用外部冰浴将温度缓慢达到0℃。当温度达到-10℃时,反应温度快速增加至约12℃,其通过进一步冷却混合物得以补偿。在混合物达到0℃后,将温度保持在0℃达20min。加入水(500ml),并将混合物搅拌过夜。将有机层用KHSO4水溶液(2M,500ml)洗涤,且然后用水(500ml)洗涤。通过蒸发除去溶剂,且然后将残余油使用旋转蒸发仪进一步浓缩过夜。获得264g(91%)所需中间体IIIA,95%测定通过NMR确定。1H NMR(400MHz,CDCl3):δ2.11(m,1H),2.42(m,1H),3.13(d,1H),3.18(d,1H),3.87(m,2H),3.98(m,2H),4.39(m,2H),7.31(m,5H).
IIIB.2-苄基-6-氧杂-2-氮杂螺[3.4]辛烷
将已在50℃干燥过夜的3-L反应器装入无水THF(900mL)。将溶剂冷却至-10℃且以小部分加入三氯化铝(108g,0.813mol),其添加速率使温度从不超过10℃。添加持续约90min,之后将外部油浴的温度调节至-5℃。30min后,在40min内加入氢化铝锂(1.0M于THF中,800mL,0.80mol)。在添加期间温度决不超过10℃。在1小时内将所得无色溶液缓慢升温至19℃。将混合物保持在19℃达另一小时,且然后在25min的时间内将其冷却至1℃。加入溶解于THF(200mL)中的中间体IIIA(149g,0.67mol),其添加速率使温度决不超过10℃。添加在90min内结束,且然后将表面用THF(50mL)漂洗。将外部油浴调节至5℃且在已搅拌反应混合物1小时后,在105min内逐滴加入EtOAc(80mL,0.82mol)。在外部冷却下将反应混合物放置过夜,其已调节至-10℃。允许混合物升温至0℃,进一步逐滴加入EtOAc(15mL,0.15mol)。将混合物在5℃搅拌1小时,且然后冷却至0℃。在1小时内加入乙醇胺(300mL),且然后将油浴温度逐渐调节至20℃。将混合物搅拌1天,且然后过滤。将滤饼用THF(2x1L)漂洗。使用旋转蒸发仪将合并的溶液浓缩至干。借助于DCM(1500mL)和水(500mL)将残余油转移至分液漏斗。一天后相分离。将有机溶液通过过滤,且然后使用旋转蒸发仪浓缩成油。获得117g(87%)所需中间体IIIB,90%测定通过NMR确定。1H NMR(400MHz,CDCl3):δ2.09(t,2H),3.23(m4H),3.61(s,2H),3.76(t,2H),3.83(s,2H),7.27(m,5H),MS(APCI+)m/z204.0[M+H]+.
IIIC.6-氧杂-2-氮杂螺[3.4]辛-2-羧酸叔丁酯
在氮气下将3-L反应器装入钯/炭(52.4g,10%)以及少量的EtOH。将中间体IIIB(50g,0.25mol)溶解于EtOH(100mL)中且将所得溶液加至反应器,用EtOH(100mL)漂洗,且然后加入另外的EtOH(1.8L)。在5min内加入溶解于水(100mL)中的甲酸铵(62g,0.98mol),用另外的水(400mL)漂洗。在30min内将温度调节至50℃后,将混合物搅拌4h。在40min内将温度调节至20℃,且然后在数分钟内加入三乙胺。在20min内分六次加入二碳酸二叔丁酯(56.8g,0.26mol)。搅拌2h后,且在已加入另外三份二碳酸二叔丁酯(总共11.5g,53mmol)后,将混合物通过(Seitz,K200)过滤。将固体材料用EtOH(2x500mL)漂洗且在旋转蒸发仪上将合并的溶液浓缩至干。向残余物加入甲基叔丁基醚(200mL)和水(100mL)且将所得两相混合物在环境温度放置过夜。借助于甲基叔丁基醚(300mL)和水(150mL)将混合物转移至分液漏斗。通过添加约12mLNaOH水溶液(4M)将水相中和至pH7。将各相分离后,将有机溶液通过(Seitzfilter,K200)过滤,且然后使用旋转蒸发仪浓缩至干。将残余物再溶解于甲基叔丁基醚中,且将所得溶液再次浓缩至干。获得52.8g(90%)为油状的所需中间体IIIC,82%测定通过NMR确定。
1H NMR(400MHz,CDCl3):δ1.43(s,9H),2.10(t,2H),3.81(m,4H),3.87(s,4H).
IIID.3-(4-(6-氧杂-2-氮杂螺[3.4]辛-2-基甲基)苯氧基)氮杂环丁烷-1-羧酸叔丁酯
在30min内将中间体IIIC(260g,0.98mol)缓慢加至TFA(500ml)。在添加期间借助于外部冷却将温度保持在18至20℃之间。将表面用TFA(100ml)漂洗,且然后将温度升至25℃。搅拌2h后,将混合物转移至20-L蒸发瓶,用甲醇漂洗。浓缩混合物,且然后在35℃与甲醇(3x1L)共蒸发。将残余物溶解于EtOAc(2.5L)中且将所得溶液转移至10-L反应器。加入DIPEA(455g,3.5mol),然后分批加入3-(4-甲酰基苯氧基)氮杂环丁烷-1-羧酸叔丁酯(275g,0.99mol)。将溶液冷却至17℃后,加入三乙酰氧基硼氢化钠(255g,1.2mol),且然后将混合物在27℃搅拌20h。加入另一部分的三乙酰氧基硼氢化钠(54g,0.25mol)。将混合物搅拌另一24h,用水(1.35L)稀释,且然后在35℃蒸发。将大部分有机溶剂和一些水蒸发后,加入乙酸水溶液(5%,3.66L),然后加入甲苯(750ml)和庚烷(750ml)的混合物。彻底混合后,除去有机相,且将水溶液用甲苯(150mL)和庚烷(150mL)的混合物洗涤。加入MTBE(1000ml)且通过添加NaOH水溶液(50%,403g)将水相的pH调节至9.5。分离有机相且向水相加入另一部分的NaOH(50%,120g),以得到9.74的pH。将混合物用MTBE(1000ml)萃取且将合并的有机溶液经碳酸钾干燥,通过硅藻土过滤,且然后浓缩至1.5L。加入庚烷且混合物加热至45℃,冷却至35℃,然后在3h内冷却至5℃,且最后冷却至5℃过夜。将混合物过滤且将滤饼用庚烷(400mL)洗涤。在25℃真空干燥过夜后,获得271g(72%)为固体状的中间体IIID。1H NMR(400MHz,甲醇-d4):δ1.50(s,9H),2.14(t,2H),3.31(m,4H),3.62(s,2H),3.79(t,2H),3.84(s,2H),3.94(m,2H),4.378m,2H),5.00(m,1),6.82(d2H),7.28(d,2H),MS(APCI+)m/z375.2[M+H]+.
IIIE.2-(4-(氮杂环丁烷-3-基氧基)苄基)-6-氧杂-2-氮杂螺[3.4]辛烷
将中间体IIID(23.2g,56mmol)——其与上述类似的方法制备但掺杂有约10%乙醇——溶解于DCM(70mL)中。浓缩溶液以便除去大部分乙醇。然后向残余物在RT加入DCM(70mL),然后逐滴加入TFA(12.6mL,169mmol)。将混合物搅拌1小时,且然后加入第二部分的TFA(12.6mL,169mmol)。在搅拌三个另外的小时(包括添加另外两部分TFA(2x12.6mL,169mmol)后-用冰浴冷却混合物,且然后缓慢加入氢氧化钠水溶液(25%,200mL)。将混合物剧烈搅拌10min,且然后分离两层。将水层用DCM(50mL)萃取三次。将合并的有机溶液用水(50ml)洗涤,且然后使用旋转蒸发仪浓缩至油。获得16g(定量)所需中间体IIIE,95%测定通过NMR确定。1H NMR(400MHz,CDCl3):δ2.01(t,2H),3.13(m,4H),3.46(s,2H),3.71(m,6H),3.84(m,2H),4.90(m,1H),6.63(m,2H),7.10(m,2H),MS(APCI+)m/z275.1[M+H]+.
Claims (15)
9.根据权利要求1所述的化合物,其选自下列化合物或其药学上可接受的盐中的一种或更多种:
(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮;
(+)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮;
(-)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(5-氧杂-2-氮杂螺[3.4]辛-2-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(6-氧杂-2-氮杂螺[3.4]辛-2-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(+)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(-)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(6-氧杂-2-氮杂螺[3.4]辛-2-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(5-氧杂-2-氮杂螺[3.4]辛-2-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(6-氧杂-2-氮杂螺[3.4]辛-2-基甲基)-3-甲基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)-3-甲基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(+)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)-3-甲基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(-)-(3-(4-(2-氧杂-7-氮杂螺[4.4]壬-7-基甲基)-3-甲基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(5-氧杂-2-氮杂螺[3.4]辛-2-基甲基)-3-甲基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(7-氧杂-1-氮杂螺[4.4]壬-1-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮;
(+)-(3-(4-(7-氧杂-1-氮杂螺[4.4]壬-1-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮;
(-)-(3-(4-(7-氧杂-1-氮杂螺[4.4]壬-1-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(7-氧杂-1-氮杂螺[4.4]壬-1-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(+)-(3-(4-(7-氧杂-1-氮杂螺[4.4]壬-1-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(-)-(3-(4-(7-氧杂-1-氮杂螺[4.4]壬-1-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)-3-甲氧基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)-2-甲氧基苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)-2-甲氧基苯氧基)氮杂环丁烷-1-基)(5-(4-(二氟甲基)苯基)-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(2-氧杂-5-氮杂螺[3.4]辛-5-基甲基)-3-甲氧基苯氧基)氮杂环丁烷-1-基)(5-(4-(二氟甲基)苯基)-1,3,4-噁二唑-2-基)甲酮;
(3-(4-(1-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-(4-甲氧基苯基)-1,3,4-噁二唑-2-基)甲酮;和
(3-(4-(1-氧杂-7-氮杂螺[4.4]壬-7-基甲基)苯氧基)氮杂环丁烷-1-基)(5-苯基-1,3,4-噁二唑-2-基)甲酮。
10.一种药物组合物,其包含至少一种根据权利要求1-9任一项所述的化合物和药学上可接受的载体和/或稀释剂。
11.一种用于治疗或预防其中调节MCH1受体是有益的疾病或病症的方法,其包括对需要此类治疗或预防的温血动物施用治疗有效量的根据权利要求1-9任一项所述的化合物。
12.根据权利要求1-9任一项所述的化合物在治疗或预防其中调节MCH1受体是有益的的疾病或病症中的用途。
13.根据权利要求12所述的化合物,其中所述疾病或病症是肥胖症。
15.式V的中间体化合物
其中R2、R3、A1、A2、X和Y如权利要求1中所定义。
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TWI802591B (zh) | 2017-09-14 | 2023-05-21 | 日商第一三共股份有限公司 | 具有環狀構造的化合物 |
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