CN101687807A - 1-苄基吡唑衍生物、其制备和其治疗用途 - Google Patents
1-苄基吡唑衍生物、其制备和其治疗用途 Download PDFInfo
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- CN101687807A CN101687807A CN200880023268A CN200880023268A CN101687807A CN 101687807 A CN101687807 A CN 101687807A CN 200880023268 A CN200880023268 A CN 200880023268A CN 200880023268 A CN200880023268 A CN 200880023268A CN 101687807 A CN101687807 A CN 101687807A
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- 230000001225 therapeutic effect Effects 0.000 title abstract 2
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Abstract
本发明涉及式(I)的化合物,其中:-Y代表选自以下的基团:-N(R7)CO-,-N(R7)CO-N(R7)-,-OCO-,-N(R7)S(O)n-;-R1代表氢原子或(C1-C4)烷基;-R6代表选自以下的基团:(C1-C6)烷基;苯基;苄基或二苯甲基;杂环基;碳环基团;(C3-C7)环烷基甲基;为碱或与酸的加成盐的形式,以及水合物或溶剂化物的形式。本发明还涉及式(I)化合物的制备方法和它用作CB2受体的拮抗剂的用途,其具有优良的肠屏障通过性,以治疗自身免疫疾病,疼痛,胃肠疾病、心血管疾病和癌症。
Description
本发明涉及1-苄基吡唑衍生物,其制备和其治疗用途。
1-苄基吡唑衍生物在文献中是已知的,特别地欧洲专利EP-B-868420和它的美国等同专利US5925768描述了下式的化合物:
这些化合物具有对人类CB2受体的亲合力。
专利申请FR 2887550描述了下式化合物:
其是CB2大麻素受体的配体。
现在已经发现了为CB2大麻素受体的拮抗剂化合物,其具有优良的肠屏障通过能力。
本发明的目的为对应式(I)的化合物:
其中:
-Y代表选自以下的基团:
i)-N(R7)CO-,
ii)-N(R7)CO-N(R7)-,
iii)-OCO-,
iv)-N(R7)S(O)n-;
-R1代表氢原子或(C1-C4)烷基;
-R2和R4各自彼此独立代表氢或卤素原子,或(C1-C4)烷基、(C1-C4)烷氧基或三氟甲基;
-R3和R5各自彼此独立地代表卤素原子或(C1-C4)烷基、(C1-C4)烷氧基、三氟甲基、三氟甲氧基、氰基或S(O)mAlk基团;
-R6代表选自以下的基团:
.(C1-C6)烷基,其未被取代或用一个或多个独立地选自以下的取代基取代一次或多次:卤素原子或羟基、(C1-C4)烷氧基或三氟甲氧基;
.苯基,其未被取代或用R8取代一次或多次;
.苄基或二苯甲基;
.杂环基,其选自:噻吩基、呋喃基或吡咯基,所述基团未被取代或用卤素原子、(C1-C4)烷基或三氟甲基取代;
.非芳族C3-C12碳环基团,其未被取代或用卤素原子或(C1-C4)烷基、(C1-C4)烷氧基、羟基或氰基取代一次或多次;
.(C3-C7)环烷基甲基,其未被取代或在环烷基上用一个或多个(C1-C4)烷基取代;
.芳氧基甲基,其未被取代或在甲基上用1个或2个烷基取代,其中“芳氧基”代表未被取代的或用R8取代一次或多次的苯氧基;
-R7代表氢原子或(C1-C4)烷基;
-R8代表卤素原子;(C1-C4)烷基;三氟甲基;氰基;(C1-C4)烷氧基;三氟甲氧基;苯基;(C3-C7)环烷基或NHS(O)nAlk基团;
-n代表1或2;
-m代表0、1或2;
-Alk代表(C1-C4)烷基。
式(I)化合物可以以碱或与酸的加成盐形式存在。所述加成盐构成为本发明的一部分。
这些盐有利地使用可药用酸进行制备,但是那些可以用于例如纯化或分离式(I)的化合物的其它酸的盐也构成本发明的一部分。
式(I)化合物还可以以水合物或溶剂化物形式存在,即与一个或多个水分子或与溶剂结合或缔合的形式。所述水合物和溶剂化物也构成为本发明的一部分。
而且,根据本发明的式(I)化合物,如为原样形式或为放射性标记的形式,可以用作为在人类或动物中用于检测和标记CB2大麻素受体的药理学工具。特别地可以提到包含一个或多个标记原子的化合物(I),所述标记原子选自:3H、11C、14C、18F,35S、76Br、123I、125I和131I。
式(I)化合物可以包含一个或多个不对称碳原子。它们因此可以以对映异构物或非对映异构物形式存在。这些对映异构物、非对映异构物和它们的混合物(在此包括它们的外消旋混合物)组成本发明的一部分。
在本发明的范围内,理解以下术语:
-卤素原子:氟、氯、溴或碘,其中氯和氟是优选的;
-(C1-C4)烷基或(C1-C6)烷基:分别为饱和直链或支链的C1-C4或C1-C6脂族基团。作为实例,可以提到甲基、乙基、丙基、异丙基、丁基、异丁基、仲-丁基、叔-丁基,以及对于(C1-C6)烷基,戊基、异戊基、己基、异己基;
-(C1-C4)烷氧基:O-烷基,其中烷基如前所定义;
-C3-C12非芳族碳环基团:单环基团或稠合或桥连的双-或三环基团;“单环基团”理解为环烷基,即环烷基,例如环丙基、环丁基、环戊基、环己基、环庚基,优选环戊基、环己基和环庚基;“稠合或桥连的双-或三环基团”理解为例如双环[2.2.1]庚基、双环[2.2.2]辛基、双环[3.2.1]辛基、金刚烷基。
在根据本发明的式(I)化合物中,区分:
-式(IA)化合物,其中Y代表基团-N(R7)CO-;
-式(IB)化合物,其中Y代表基团-N(R7)CON(R7)-;
-式(IC)化合物,其中Y代表基团-OCO-;
-式(ID)化合物,其中Y代表基团-N(R7)S(O)n-。
在本发明目标式(I)化合物中,可以提到如下定义的优选化合物:
-R1代表氢;
-R2和R3代表在3或4位的氯原子,在4位的三氟甲基,或两个在3和4位的氯原子;
-R4和R5代表在2、3或4位的氯原子、在4位的三氟甲基或在3位的氯原子和在4位的甲基。
在上述4类化合物中,式(IA)和式(ID)的化合物是优选的。
在式(IA)和(ID)化合物中,优选其取代基具有以下定义的化合物:
-R1代表氢原子;
-R2和R3代表在3或4位的氯原子,在4位的三氟甲基,或两个在3和4位的氯原子;
-R4和R5代表在2、3或4位的氯原子、在4位的三氟甲基或在3位的氯原子和在4位的甲基。
-R6代表选自以下的基团:
.(C1-C6)烷基,其未被取代或用一个或多个独立地选自以下的取代基取代一次或多次:卤素原子或羟基、(C1-C4)烷氧基或三氟甲氧基;
.C3-C12非芳族碳环基团,其未被取代或用卤素原子或(C1-C4)烷基、(C1-C4)烷氧基、羟基或氰基取代一次或多次。
特别具体地,以下化合物是优选的:
-N-((1-(3,4-二氯苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲基)-2,2-二甲基丙酰胺;
-和N-((1-(3,4-二氯苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲基)-2-甲基丙烷-2-磺酰胺。
根据本发明,可以根据以下方法进行制备式(I)化合物。这种方法特征在于:
对下式化合物:
其中X代表氧原子、NH或N(R7)和R1、R2、R3、R4、R5如上面对于式(I)化合物所定义,用下面化合物进行处理:
a)或用式R6COOH(III)酸的官能衍生物进行处理,其中R6如上面对于(I)所定义,以获得式(IA)或(IC)化合物,其中Y代表i)或ii)值;
b)或用式R6N=C=O(IV)的异氰酸酯进行处理,其中R6如上面对于(I)所定义,以获得式(IB)化合物,其中Y代表ii)值;
c)或用式R6S(O)nHal的卤化衍生物进行处理,其中Hal代表卤素原子,优选氯,和R6如上面对于(I)所定义,以获得式(ID)化合物,其中Y具有iv)值。
从式(ID)化合物开始,其中Y=-N(R7)SO-,通过氧化(例如在间氯过苯甲酸的作用下)可以制备式(ID)化合物,其中Y=-N(R7)SO2-。
“式R6COOH酸的官能衍生物”理解为酰基氯、酐或例如用苯并三唑-1-基氧基三(二甲基氨基)磷鎓(BOP)六氟磷酸盐或二环己基碳二亚胺(DCC)进行适当活化的游离酸。
通过选自本领域的技术人员已知的方法,式(I)化合物(其中Y代表基团-N(R7)CO-或-N(R7)CON(R7)-)可以由相应的式(I)化合物(其中Y代表基团-NHCO-或-NHCONH-)进行制备。在所述已知方法中,可以提到用甲基卤的烷基化或通过氯甲酸乙酯的作用然后用LiAlH4还原而形成氨基甲酸酯。
根据本发明方法的变体,式(IB)化合物可以用这样的方法获得,该方法特征在于:
c1)式(II)化合物用式HalCOOAr(V)酯处理,其中Hal代表卤素原子和Ar代表芳基如苯基或4-硝基苯基;
c2)由此获得的下式氨基甲酸酯:
用式R6R7NH(VII)处理,其中R6和R7如对于式(IB)化合物所定义。
步骤a)在非质子溶剂(如二氯甲烷、THF或DMF)中在0℃至溶剂的沸点之间的温度下进行。
步骤b)在如二氯甲烷的溶剂中在室温下进行。
步骤c1)在如二氯甲烷的非质子溶剂中在室温下进行。
步骤c2)在如二氯甲烷的非质子溶剂中在室温至溶剂沸点之间的温度下进行。
式(II)化合物根据以下方案进行制备:
方案1
Hal:卤素原子,优选Cl或Br。
当X代表NH基团时,式(II)化合物用式(XI)化合物表示。
当X代表氧原子时,式(II)化合物用式(IX)化合物表示。
在第一步骤(a1)中,式(VIII)酯通过还原剂(如LiAlH4)的作用进行还原。
在下一步骤(a2)中,获得的羟甲基化衍生物(IX)用如PCl5、PBr3、HBr或BBr3的试剂处理以形成式(X)卤代甲基化衍生物。
最后,在步骤(a3)期间通过依次用1,3,5,7-四氮杂三环[3.3.13,7]癸烷(或六亚甲基四胺)然后用强酸(如盐酸)处理式(X)化合物获得式(XI)化合物。
式(VIII)化合物根据描述在专利EP-B868420中的制备方法获得。
式(XI)化合物是新型的。
因此本发明,根据它的另一方面,目的还为式(XII)化合物:
其中:
-W代表羟基或氨基;
-R1代表氢原子或(C1-C4)烷基;
-R2和R4各自彼此独立代表氢或卤素原子,或(C1-C4)烷基、(C1-C4)烷氧基或三氟甲基;
-R3和R5各自彼此独立地代表卤素原子或(C1-C4)烷基、(C1-C4)烷氧基或三氟甲基。
式(XII)化合物可以以碱或与酸的加成盐形式存在。所述加成盐构成为本发明的一部分。
式(XII)化合物还可以以水合物或溶剂化物形式存在,即与一个或多个水分子或与溶剂结合或缔合的形式。所述水合物和溶剂化物也构成为本发明的一部分。这些化合物用作合成根据本发明的式(I)化合物的中间体。
优选地,式(XII)化合物对应于其取代基具有以下定义的化合物:
-R1代表氢原子;
-R2和R3代表在3或4位的氯原子,在4位的三氟甲基、或两个在3和4位的氯原子;
-R4和R5代表在2、3或4位的氯原子、在4位的三氟甲基或在3位的氯原子和在4位的甲基。
-R6代表选自以下的基团:
.(C1-C6)烷基,其未被取代或用一个或多个独立地选自以下的取代基取代一次或多次:卤素原子或羟基、(C1-C4)烷氧基或三氟甲氧基;
.C3-C12非芳族碳环基团,其未被取代或用卤素原子或(C1-C4)烷基、(C1-C4)烷氧基、羟基或氰基取代一次或多次。
以下实施例描述了根据本发明的某些化合物的制备。这些实施例不是限制性的并且仅仅举例说明本发明。例示的化合物的编号参看在下面表中给出的编号,在该表中举例说明了根据本发明的一些化合物的化学结构和物理性质。
在所述实施例中,使用以下缩写:
TA:室温
(déc.):分解
TEA:三乙胺
THF:四氢呋喃
DMF:二甲基甲酰胺
DCM:二氯甲烷
DMSO:二甲亚砜
BOP:苯并三唑-1-基氧基三(二甲基氨基)磷鎓/六氟磷酸盐
K2SO4/KHSO4:pH 2缓冲液(KHSO40.12M和K2SO40.185M)
EtOAc:乙酸乙酯
PyBOP:苯并三唑-1-基氧基三(吡咯烷基)磷鎓六氟磷酸盐
LiHMDS:六甲基二硅氮烷的锂盐
MeOH:甲醇
EtOH:乙醇
Et2O:乙醚
AcOH:乙酸
F:熔点。
对于在200MHz在DMSO-d6中记录的核磁共振谱(NMR),观察到的信号如此进行表示:d:双重峰;bd:宽双重峰;dd:二双重峰;s:单峰;bs:宽单峰;t:三重峰
根据本发明的化合物通过LC/UV/MS(液相色谱/UV检测/质谱)联用进行分析。测量分子峰(MH+)和保留时间(t)(分钟)。
条件(A):
洗脱剂具有以下组成:
-溶剂A:在水中的0.025%三氟乙酸(TFA);
-溶剂B:在乙腈中的0.025%TFA。
梯度:溶剂B的百分比在2分钟内从0变到100%,并在100%B平台期1分钟。
UV检测在210nm-400nm之间进行,质量检测在大气压化学电离模式下进行。
条件(B):
使用对称C18柱,2.1×50mm,3.5μm,在30℃,流量0.4mL/min。
洗脱剂具有以下组成:
-溶剂A:在水中的0.005%三氟乙酸(TFA),pH 3.15;
-溶剂B:在乙腈中的0.005%TFA。
梯度:
时间(min) | %A | %B |
0 | 100 | 0 |
10 | 10 | 90 |
15 | 10 | 90 |
16 | 100 | 0 |
20 | 100 | 0 |
柱温:30℃,流速0.4ml/min。
UV检测在λ=210nM进行和质量检测以正化学电离模式(ESI:电喷雾离子化)进行。
条件(C):
使用对称C18柱,2.1×50mm,3.5μm,在30℃,流量0.4mL/min。
洗脱剂具有以下组成:
-溶剂A:在水中的0.005%三氟乙酸(TFA),pH 3.1;
-溶剂B:在乙腈中的0.005%TFA。
梯度:
时间(min) | %A | %B |
0 | 100 | 0 |
10 | 10 | 90 |
15 | 10 | 90 |
16 | 100 | 0 |
20 | 100 | 0 |
柱温:30℃,流速0.4ml/min.
UV检测在λ=210-220nM进行和质量检测以正化学电离模式(ESI:电喷雾离子化)进行。
条件(D):
使用XTerra MS C18柱,2.1×50mm,3.5μm,在30℃,流量0.4mL/min。
洗脱剂具有以下组成:
-溶剂A:在水中的10mM乙酸铵,pH 7;
-溶剂B:乙腈
梯度:
时间(分钟) | %A | %B |
0 | 100 | 0 |
10 | 10 | 90 |
15 | 10 | 90 |
16 | 100 | 0 |
20 | 100 | 0 |
柱温:30℃,流速0.4ml/min.
UV检测在λ=210nM进行和质量检测以正化学电离模式(ESI:电喷雾离子化)进行。
实施例1:化合物19.
N-((1-(3-氯代-4-甲基苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲基)-1-甲基环己烷甲酰胺
A)(1-(3-氯代-4-甲基苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲醇
将4g1-(3-氯代-4-甲基苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-甲酸甲酯溶解在100ml THF中并且冷却至0℃--5℃,然后每次少量地加入0.6gLiAlH4,同时保持相同的低温。使其返回到TA并且搅拌30分钟。在0℃用NaOH N(100ml)进行水解。过滤,用THF洗涤滤液然后蒸发。将获得的油溶解在乙醚中,用水、NaCl溶液进行洗涤,然后在Na2SO4上进行干燥并且蒸发至干,获得3.5g期望的化合物。
NMR(200MHz)在DMSO-d6中:7.7ppm:d:1H;7.6ppm:d:1H;7.4ppm:dd:1H;7.3ppm:d:1H;7ppm:d:1H;6.8ppm:dd:1H;6.4ppm:s:1H;5.3ppm:s:2H;5.1ppm:t:1H;4.4ppm:d:2H;2.2ppm:s:3H.
B)3-(氯甲基)-1-(3-氯代-4-甲基苄基)-5-(3,4-二氯苯基)-1H-吡唑
将3.45g来自前面步骤的化合物溶解在100ml DCM中。用冰浴冷却并且在低于10℃的温度下每次少量地加入1.96g PCl5。在TA搅拌3小时,然后倒入冰水混合物中并且继续搅拌3小时。使其滗析,然后用NaHCO3溶液然后用水洗涤有机相。在Na2SO4上干燥,然后蒸发至干。获得的油通过色谱分离法在二氧化硅上进行纯化,其中用EtOAc/环己烷(25/75;v/v)混合物洗脱。获得2.35g油形式的期望化合物,其结晶。熔点=88℃。
C)(1-(3-氯代-4-甲基苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲胺盐酸盐
将2.3g来自前面步骤的化合物溶解在200ml CHCl3中并加入0.8g1,3,5,7-四氮杂三环[3.3.13,7]癸烷。在TA下搅拌5天后,加入150ml乙醚,使形成的沉淀除水然后将其溶解在50ml乙醇中。加入2ml浓HCl,然后在50℃加热3小时。将该介质浓缩至一半体积,然后加入50ml乙醚。除水,用乙醚洗涤并且干燥,获得1.78g碱形式的期望化合物。
为了制备盐酸盐,将其溶于50ml乙醇中,加入2ml浓HCl,然后在50℃加热3小时。在真空下浓缩该介质,排水,然后用乙醚洗涤并干燥;获得1.88g期望的盐酸盐。
NMR(200MHz)在DMSO-d6中:8.6ppm:bs:1H;7.7ppm:d:1H;7.6ppm:d:1H;7.4ppm:dd:1H;7.3ppm:d:1H;7.1ppm:d:1H;6.9ppm:dd:1H;6.7ppm:s:1H;6ppm:bs:2H;5.4ppm:s:2H;4ppm:2d:2H;2.3ppm:s:3H.
D)N-((1-(3-氯代-4-甲基苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲基)-1-甲基环己烷甲酰胺
在50ml DMF中使417mg来自前面步骤的化合物、142mg 1-甲基环己烷甲酸和580mg BOP混合,然后加入三乙胺以达到pH10。
在室温下搅拌20小时。
获得的产物通过色谱分离法在二氧化硅上进行纯化,其中用DCM/MeOH混合物(97.5/2.5;v/v)洗脱。获得250mg期望化合物,熔点=63℃。
实施例2:化合物60
N-(叔-丁基)-N’-((1-(3-氯代-4-甲基苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲基)脲
将05g在实施例1的步骤C获得的化合物溶解在30ml DCM中,加入0.137ml 2-异氰氧基-2-甲基丙烷然后加入足够量的三乙胺以达到pH9。在TA搅拌过夜。在加入10ml水后,滗析。依次用NaHCO3、K2SO4/KHSO4水溶液然后水洗涤有机相。在Na2SO4上干燥,然后蒸发至干。将残留物溶于EtOAc/环己烷混合物(50/50;v/v)中。期望的化合物沉淀,为白色固体的形式:m=360mg,熔点=181℃。
实施例3:化合物46
N-((1-(3-氯苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲基)-2,2-二甲基丙酰胺
A)1-(3,4-二氯苯基)-4-甲氧基-3,4-二氧代丁-1-烯-1-醇钠
通过缓慢地将23g钠加入1升甲醇中制备甲醇钠溶液,用冰浴进行冷却并且加入188.97g 1-(3,4-二氯苯基)乙酮然后加入在250ml甲醇中的149.14g草酸乙酯。沉淀形成。加入500ml甲醇,然后搅拌2小时。加入500ml Et2O并且继续搅拌30分钟。过滤已经形成的沉淀,然后干燥,获得297g期望化合物。
B)5-(3,4-二氯苯基)-1H-吡唑-3-甲酸甲酯
将123.43g在前面步骤中获得的化合物放置在800ml AcOH中,滴加25.60ml水合肼并且加热回流过夜。将反应介质倾倒在冰冻水中。使已经形成的沉淀排水,然后用水洗涤。将其溶解在Et2O中,有机相用饱和NaCl溶液洗涤然后在Na2SO4上干燥,蒸发并进行过滤。获得91.85g期望化合物。
C)1-(3-氯苯基)-5-(3,4-二氯苯基)-1H-吡唑-3-甲酸甲酯
将14.50g在前面步骤中获得的化合物放置在250ml甲苯中并且每次一钳地(par pincées)加入2.35g NaH,然后在65℃加热1小时。冷却至TA并且缓慢地加入7.72ml 3-氯苯甲基溴。在回流下加热该反应介质20小时,然后用NH4Cl饱和溶液中和。使有机相滗析,然后用NaCl饱和溶液洗涤。在Na2SO4上干燥然后蒸发。将获得的产物溶解在EtOAc中,然后用NaHCO3饱和溶液、K2SO4/KHSO4溶液然后水进行洗涤。在Na2SO4上干燥并且蒸发,获得64.37g期望化合物。
D)1-(1-(3-氯苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲醇
在氮气氛下将24.26g在前面步骤中获得的化合物溶解在500ml THF中并且冷却至-5℃。在低于0℃的温度下按小份地加入1.47g LiAlH4。使其返回TA然后搅拌1小时。在0℃用1N NaOH水解该反应介质。过滤,然后用THF洗涤该不溶物质。将滤液合并,将其蒸发至干,然后溶解在乙醚中。有机相用NaCl饱和溶液进行洗涤然后在Na2SO4上进行干燥并且蒸发至干。获得的产物通过色谱分离法在二氧化硅上进行纯化,其中用EtOAc/环己烷混合物(50/50;v/v)洗脱。获得6.82g期望化合物,熔点=95℃。
E)1-(3-氯苄基)-3-(氯甲基)-5-(3,4-二氯苯基)-1H-吡唑
将6.7g在前面步骤中获得的化合物溶解在200ml DCM中并且冷却至0℃至-10℃之间。在-10℃每次一钳地加入3.98g PCl5然后在TA搅拌4小时。将反应介质倾倒在冰上并且使其静止过夜。倾析有机相然后再用50ml DCM萃取。合并萃取物,在Na2SO4上干燥并蒸发至干。获得7.41g期望化合物。
F)1-(1-(3-氯苯基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲胺盐酸盐
将7.3g在前面步骤中获得的化合物溶解在500ml氯仿中并加入2.65g1,3,5,7-四氮杂三环[3.3.13,7]癸烷。搅拌5天后,加入500ml乙醚。在2小时后,使已经形成的沉淀除水。将获得的产物溶解在50ml EtOH中,然后加入2ml浓HCl并且在60℃加热3小时。在蒸发至干后,它再被溶解在乙基氯(éther chlorhydrique)中。使形成的沉淀除水然后干燥,得到4.67g期望化合物。熔点=150℃。
G)N-((1-(3-氯苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲基)-2,2-二甲基丙酰胺
将0.6g在前面步骤中获得的化合物和0.18g新戊酸溶解在50ml DMF中,然后加入0.92g PyBOP和0.45ml三乙胺并且在TA搅拌过夜。在蒸发DMF后,然后用EtOAc溶解。用NaHCO3饱和溶液、K2SO4/KHSO4溶液然后水洗涤;在Na2SO4上干燥,然后蒸发至干。获得的产物通过色谱分离法在二氧化硅上进行纯化,用DCM/MeOH混合物(95/5;v/v)洗脱。获得0.31g期望化合物。
NMR:1.12ppm:s:9H;4.25ppm:d:2H;5.34ppm:s:2H;6.33ppm:s:1H;6.85-7.45ppm:m:5H;7.61ppm:d:1H;7.71ppm:d:1H;7.98ppm:t:1H.
实施例4:化合物No.55
新戊酸(1-(3,4-二氯苄基)-5-(4-三氟甲基苯基)-1H-吡唑-3-基)甲基酯
A)1-(4-(三氟甲基苯基)-4-乙氧基-3,4-二氧代丁-1-烯-1-醇锂
在氮气氛下,将24.45g LiHMDS溶解在无水THF中并且冷却至-60℃。另外,将25g 1-(4-三氟甲基苯基)乙酮溶解在50ml Et2O中。在-60℃在LiHMDS溶液中滴加酮溶液,然后使温度上升到-30℃并且快速加入19.85ml草酸二乙酯。在TA下一夜后,将反应介质蒸发至干然后溶解在乙醚中。使形成的沉淀除水,用乙醚洗涤然后干燥。获得33.28g期望化合物。
B)5-(4-三氟甲基苯基)-1H-吡唑-3-甲酸乙酯
将33.2g在前面步骤中获得的化合物溶解在400ml AcOH中并且滴加6.33ml水合肼,然后在搅拌下回流加热5小时。在TA下1夜后,将该介质倾倒在冰冻水中并且在1小时后使形成的沉淀除水。用水洗涤并且干燥,然后溶解在DCM中。在Na2SO4上干燥并且蒸发至干。获得30.37g期望化合物。
C)1-(3,4-二氯苄基)-5-(4-三氟甲基苯基)-1H-吡唑-3-甲酸乙酯
从30.3g在前面步骤中获得的化合物开始,根据描述在实施例3步骤C中的方法制备这种化合物。获得36.24g期望化合物。
D)1-(1-(3,4-二氯苄基)-5-(4-三氟甲基苯基)-1H-吡唑-3-基)甲醇
这种化合物通过以下描述在实施例3,步骤D中的方法进行制备。由33g来自前面步骤的化合物,获得23.10g期望化合物,熔点=96℃
E)新戊酸(1-(3,4-二氯苄基)-5-(4-三氟甲基苯基)-1H-吡唑-3-基)甲基酯
将1g在前面步骤中获得的化合物溶解在50ml DMF中。加入0.37ml新戊酰氯,然后加入0.52ml三乙胺并且在TA搅拌20小时。在真空下蒸发溶剂然后溶解在50ml EtOAc中。用NaHCO3饱和溶液,然后用K2SO4/KHSO4然后用NaCl饱和溶液洗涤。在Na2SO4上干燥,然后蒸发至干。获得的产物通过色谱分离法在二氧化硅上进行纯化,其中用EtOAc/环己烷混合物(25/75;v/v)洗脱。获得0.89g油形式的期望化合物,其结晶。熔点=92℃。
如实施例1的步骤C)进行操作,制备在下表1中描述的中间化合物。当化合物通过LC/UV/MS进行表征时,详细说明操作条件(A),(B),(C)或(D)。
表1
R1 | R2,R3 | R4,R5 | 表征熔点℃或LC/MS | 盐 |
H | 4-Cl | 2,4-二氯 | 176℃ | HCl |
H | 3,4-二氯 | 4-Cl | 237℃ | HCl |
H | 4-Cl | 3,4-二氯 | 214℃ | HCl |
Me | 4-Cl | 2,4-二氯 | 172℃ | HCl |
H | 3-Cl | 3,4-二氯 | 63℃ | HCl |
R1 | R2,R3 | R4,R5 | 表征熔点℃或LC/MS | 盐 |
H | 3,4-二氯 | 4-CF3 | 382℃ | HCl |
H | 3-Cl | 3-Cl | 165℃ | HCl |
H | 4-Cl | 4-Cl | 229℃ | HCl |
H | 3,4-二氯 | 3,4-二氯 | 205℃ | HCl |
H | 3,4-二氯 | 3-Cl,4-OMe | MH+=396t=7.25min(C) | HCl |
H | 3,4-二氯 | 3-Cl,4-OCF3 | MH+=450t=7.25min(C) | HCl |
H | 3,4-二氯 | 3-Cl,4-CF3 | MH+=434t=7.47min(C) | HCl |
H | 3,4-二氯 | 3-CF3,4-Cl | MH+=434t=7.46min(C) | HCl |
H | 4-OMe | 3,4-二氯 | MH+=362t=6.62min(C) | HCl |
实施例5:化合物No.60
N-((1-(3,4-二氯苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲基)-2,2-二甲基丙酰胺
在0.68g PyBOP存在下,将0.50g描述在表I中的1-(1-(3,4-二氯苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲胺,和0.15g新戊酸放置于50mlDMF中并且加入0.28ml TEA。在室温下搅拌过夜后,蒸发溶剂然后溶解在EtOAc中,用NaHCO3饱和溶液,然后用K2SO4/KHSO4洗涤。在Na2SO4上干燥,然后蒸发至干。通过色谱分离法在二氧化硅上进行纯化,其中用EtOAc/环己烷混合物(50/50;v/v)洗脱。获得0.36g期望化合物。熔点=56.5℃。
NMR:1.09ppm:s:9H;4.23ppm:d:2H;5.32ppm:bs:2H;6.31ppm:s:1H;6.96ppm:dd:1H;7.27ppm:d:1H;7.61ppm:d:1H;7.69ppm:d:1H;7.95ppm:t:1H.
实施例6:化合物No.89
N-((1-(3,4-二氯苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲基)-2-甲基丙烷-2-亚磺酰胺
将1.2g描述在表I中的1-(1-(3,4-二氯苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲胺和0.44ml 2-甲基丙烷-2-亚磺酰氯放置于50ml DMF中并且加入1.24ml TEA。搅拌16小时。蒸发溶剂然后通过色谱分离法在二氧化硅上纯化,其中用环己烷然后用环己烷/EtOAc的99/1至70/30的梯度进行洗脱。获得0.85g期望化合物。
NMR:1.12ppm:s:9H;4.15ppm:m:2H;5.37ppm:s:2H;5.71ppm:t:1H;6.52ppm:s:1H;6.99ppm:dd:1H;7.27ppm:d:1H;7.36ppm:dd:1H;7.57ppm:d:1H;7.63ppm:d:1H;7.72ppm:d:1H
实施例7:化合物No.90
N-((1-(3,4-二氯苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲基)-2-甲基丙烷-2-磺酰胺
将0.68g间氯过苯甲酸溶解在55ml DCM中,并冷却至0℃到-5℃之间,然后加入在5ml DCM中的0.55g在前述实施例中获得的化合物。使返回至室温然后搅拌过夜。将该反应介质倾倒在50ml 1N NaOH中,然后滗析。有机相用水洗涤然后干燥并且蒸发至干。通过色谱分离法在二氧化硅上纯化,其中用环己烷然后用环己烷/EtOAc的99/1至50/50梯度(在1小时内)洗脱。获得0.39g期望化合物。熔点=127.4℃。
NMR:1.27ppm:s:9H;4.22ppm:d:2H;5.37ppm:bs:2H;6.50ppm:s:1H;6.97ppm:dd:1H;7.28ppm:d:1H;7.36ppm:dd:1H;7.46ppm:t:1H;7.56ppm:d:1H;7.63ppm:d:1H;7.72ppm:d:1H.
后面的表举例说明了根据本发明的一些化合物的化学结构和物理性质。在这些表中,Me、Et、iPr和tBu分别代表甲基、乙基、异丙基和叔丁基。当该化合物通过LC/UV/MS进行表征时,具体说明操作条件(A),(B),(C)或(D)。
表2
NMR:化合物30:1.0ppm:s:9H;4.1ppm:d:2H;5.2ppm:s:2H;6.2ppm:s:1H;6.9ppm:dd:1H;7.1ppm:d:1H;7.2-7.6ppm:m:5H;7.9ppm:t:1H.
NMR:化合物33:10ppm:s:9H;4.2ppm:d:2H;5.2ppm:s:2H;6.2ppm:s:1H;6.9ppm:d:2H;7.2ppm:m:3H;7.5ppm:d:1H;7.6ppm:d:1H;7.9ppm:t:1H.
NMR:化合物34:1.0-1.6ppm:m:11H;1.8-2.1ppm:d:2H;4.2ppm:d:2H;5.3ppm:s:2H;6.2ppm:s:1H;7.0ppm:d:2H;7.4ppm:m:3H;7.6ppm:d:1H;7.7ppm:d:1H;8.0ppm:t:1H.
表3
化合物s | R2,R3 | R4,R5 | R6 | 表征熔点℃或LC/MS |
81 | 3,4-二氯 | 3-Cl,4-Me | tBu | 熔点=181℃ |
82 | 3,4-二氯 | 3-Cl,4-Me | 环己基 | 熔点=182℃ |
83 | 3,4-二氯 | 3-Cl,4-Me | 2,6-二氟-苯基 | 熔点=128℃(déc.) |
84 | 3,4-二氯 | 3,4-二氯 | tBu | 熔点=150℃ |
表4
表5
化合物s | R2,R3 | R4,R5 | -S(O)n-R6 | 表征熔点℃或LC/MS |
87 | 3,4-二氯 | 3-Cl | -SOCF3 | 熔点=84℃ |
88 | 3,4-二氯 | 3-Cl | -SO2tBu | 熔点=112℃ |
89 | 3,4-二氯 | 3,4-二氯 | -SOtBu | MH+=504t=10.71min(D) |
90 | 3,4-二氯 | 3,4-二氯 | -SO2tBu | 熔点=127℃ |
91 | 3,4-二氯 | 3-Cl,4-OCF3 | -SO2(CH2)3Me | 熔点=101℃ |
92 | 3,4-二氯 | 3-Cl,4-OCF3 | -SOtBu | MH+=554t=11.32min(C) |
93 | 3,4-二氯 | 3-Cl,4-OCF3 | -SO2tBu | MH+=570t=11.69min(C) |
94 | 3,4-二氯 | 3-Cl,4-OMe | -SO2tBu | 熔点=59℃ |
式(I)化合物具有对大麻素CB2受体很好的体外亲合力,无论它是人类的受体或啮齿类动物的受体。亲合力结合试验(essays de liaison paraffinité)用来自啮齿类动物组织和细胞系(在其中已表达CB2受体)的膜来进行(Munro等,Nature 1993,365,61-65),其根据由M.Rinaldi-Carmona在J.Pharmacol.Exp.Therap.1998,287,644-650中描述的实验条件进行。
更特别地,本发明的化合物或其任选的盐是CB2大麻素受体的有效的,选择性配位体,其IC50(引起对照样品的特异结合的50%抑制的浓度)通常为0.1-500nM。它们对CB2受体活性通常是对CB1受体活性的10-1000倍。而且,式(I)化合物的拮抗性质通过在如M.Rinaldi-Carmona等人,J.Pharmacol.Exp.Ther.1996,278,871-878和1998,284,644-650和M.Bouaboula等人,J.BiolChem.,1997,272,22330-22339中描述的腺苷酸环化酶抑制模型中获得的结果得到证明。
使用穿过由Caco-2细胞构成的肠屏障的模型(modèle du passage dela barrière intestinale)研究了根据本发明的化合物。(M.C.Grès,Pharm.Res.,1998,15(5),726-733)。这种模型可以定义产物对于肠上皮细胞的单细胞层加上过滤器的表观渗透率(perméabilitéapparente)的系数Ptot。作为实例,No.60(实施例5)和No.90(实施例7)化合物在这种模型中的Ptot分别为111.97和64.5(10-7cm.sec-1;浓度=20μM;顶点pH=6.5和基础pH=7.4)。这些值是在人类中通过口腔途径给药后的总吸收的预测值。
因此,根据这些方面的另一方面,本发明目的为用于人类或兽类医学的药物,其包含式(I)化合物,或后者与可药用酸的加成盐,或溶剂化物或水合物。根据本发明的化合物可用于人类或动物中(特别地在哺乳动物中,包括并不限制于狗、猫、马、牛、羊)用于治疗或预防涉及大麻素CB2受体的疾病。
这些药物可用于在治疗或预防涉及免疫系统的细胞的病状或免疫紊乱中的治疗用途,例如自身免疫疾病、与器官移植有关的疾病、传染病、变应性疾病、肠胃系统疾病、炎症引起的疾病。更特别地,可以提到以下自身免疫疾病:播散性红斑狼疮、结缔组织疾病或胶原病、综合征、关节强硬性脊椎炎、反应性关节炎、类风湿性多关节炎、未分化椎关节炎、Behcet病、自体免疫性溶血性贫血、多发性硬化、肌萎缩性侧索硬化(Charcot病)、牛皮癣。要治疗的变应性疾病可以是速发过敏性或哮喘类型、过敏性鼻炎、变应性结膜炎或接触性皮炎。而且,化合物和它们可能的可药用盐可以用于治疗多血管(vascularités)、寄生虫感染、病毒感染(Sida)、细菌感染(脑膜炎)、淀粉样蛋白病、影响淋巴造血系统线(maladies affectant les lignées dusystème)的疾病。
根据本发明的式(I)化合物可以用作为在治疗或预防疼痛中的药物:神经疼痛、急性外周疼痛、炎症引起的慢性疼痛。可以提到以下炎症性疾病:关节炎、类风湿性关节炎、骨关节炎、脊椎炎、痛风、Crohn病、溃疡性结肠炎、肠易激综合征(IBS)或炎症性肠病(IBD)、急性胰腺炎。式(I)化合物还可以用于治疗骨疾病和骨质疏松症。
而且,根据本发明的式(I)化合物可以用作为在治疗或预防以下疾病中的药物:胃肠疾病、痢疾、溃疡、呕吐、膀胱和泌尿疾病、肾病、肾缺血、肾炎、内分泌引起的疾病、心血管病、出血性休克、脓毒性休克、慢性肝硬化、哮喘、Raynaud病、青光眼、生殖疾病,和作为用于抗癌(皮肤癌、前列腺癌或脑起源的癌症(cancer d’orgine cérébrale)化疗的药物。根据本发明的式(I)化合物可以用作为在治疗食欲失常和/或进食障碍中的药物,特别地用于治疗恶病质。根据本发明的式(I)化合物可以用作为在预防和/或治疗肥胖症和与心血管病相关的疾病(高血压、血脂异常、动脉粥样硬化)、新陈代谢综合征、胰岛素抵抗(2型糖尿病)和新陈代谢性脂肪肝(stéatohépatopathie métabolique)中的药物。
而且,式(I)化合物可以用作为在治疗局部缺血、头损伤中和在治疗神经变性疾病(包括舞蹈病、亨廷顿舞蹈病、Tourrette综合征)中的神经保护剂(neuroprotecteur)。
根据本发明的式(I)化合物可用作为用于治疗或预防偏头痛、应激反应、心理压力引起的疾病、恐慌发作、癫痫症、运动障碍。
根据本发明的式(I)化合物可以用作在治疗或预防呼吸系统疾病中的药物,如慢性支气管炎、慢性阻塞性肺病(COPD)或肺气肿。
因此,根据本发明的式(I)化合物特别地可用于制备药物和/或可被用于抗癌化疗,所述药物用于治疗和预防免疫性疾病、疼痛、胃肠疾病、心血管或肾病。
根据本发明的另一方面,本发明涉及药物组合物,其包含至少一种根据本发明的式(I)化合物作为活性成分。这些药物组合物包含有效剂量的根据本发明的化合物,或可药用盐,所述化合物的水合物或溶剂化物,以及一种或多种可药用赋形剂。
所述赋形剂根据药物形式和期望给药方法从本领域的技术人员已知的通常赋形剂中进行选择。
除了式(I)化合物或它的可药用盐或水合物或溶剂化物,根据本发明的药物组合物可以包含一种或多种可用于治疗或预防上述病状的其它活性成分。
因此,本发明目的还为包括根据本发明的式(I)化合物的药物组合物,所述化合物与一种或多种选自以下治疗种类中的一种的活性成分相组合:
-大麻素CB1受体的拮抗剂和/或调节剂和/或反向激动剂;
-大麻素CB2受体的另一种拮抗剂和/或调节剂和/或反向激动剂;
-血管紧张素II的AT1受体的拮抗剂;
-转化酶抑制剂;
-钙拮抗剂;
-利尿剂;
-β-受体阻滞剂;
-抗抑郁药、安定药、抗焦虑药;
-抗癌剂或抗增殖剂;
-阿片样物质拮抗剂;
以及:
-改善记忆的药剂;
-用于治疗酒精中毒或戒断综合征;
-用于治疗骨质疏松症的药剂;
-用于治疗自身免疫疾病的药剂;
-用于治疗器官移植排斥的药剂;
-抗炎性非甾醇类或甾醇类;
-抗感染药剂;
-抗寄生虫剂;
-抗病毒剂;
-止痛剂;
-止泻剂;
-止喘药。
根据本发明另一个方面,式(I)化合物或它的溶剂化物或水合物中的一种和其它组合的活性成分可以同时地、分开地或随时间展开地进行给药。
“同时使用”理解为给药包含在同一药物形式中包含的根据本发明的组合物的化合物。
“分开使用”理解为同时给药根据本发明组合物的两种化合物,每种包含在不同的药物形式中。
“随时间展开地使用”表示连续给药本发明的组合物的第一化合物(包含在一种药物形式中),然后根据本发明组合物的第二化合物(包含在不同的药物形式中)。在这种情况下,在给药根据本发明的组合物的第一化合物和给药根据本发明相同组合物的第二化合物之间的时间间隔一般地不超过24小时。
在用于口服、舌下、皮下、肌内、静脉内、体表、局部、气管内、鼻内、经皮或直肠给药的本发明的药物组合物中,上面式(I)的活性成分或它的任选的盐、溶剂化物或水合物可以以单位给药形式(与传统的药物赋形剂混合)向动物和人类给药以预防或治疗上述障碍或疾病。
适当的单位给药形式包括通过口腔途径的形式,如片剂、软或硬胶囊、粉末、颗粒和口服溶液或悬浮液,用于舌下、含服、气管内、眼内或鼻内给药的形式或通过吸入给药、用于体表、经皮、皮下、肌内或静脉内给药形式,用于直肠给药的形式和植入物。对于体表施用,根据本发明的化合物可以以乳膏、凝胶、软膏或洗液进行使用。
作为例子,片剂形式的根据本发明的化合物的单位给药形式可以包含以下组分:
根据本发明的化合物 :50.0mg
甘露醇 :223.75mg
交联羧甲基纤维素钠 :6.0mg
玉米淀粉 :15.0mg
羟丙基甲基纤维素 :2.25mg
硬脂酸镁 :3.0mg
通过口腔途径,每天给药的活性成分的剂量可以达到0.01-100mg/kg,分一个或多个剂量,优选地0.1-50mg/kg。
可能有特定情况,其中更高的或更低的剂量是适当的;上述剂量不超出本发明的范围。根据通常实践,适合于每个患者的剂量由医生根据给药方法和所述患者的重量和反应进行确定。
根据本发明另一方面,其还涉及上述病状的治疗方法,其包括向患者给药有效剂量的根据本发明的化合物或它的可药用盐或它的水合物或它的溶剂化物中的一种。
Claims (13)
1.对应于式(I)的化合物:
其中:
-Y代表选自以下的基团:
i)-N(R7)CO-,
ii)-N(R7)CO-N(R7)-,
iii)-OCO-,
iv)-N(R7)S(O)n-;
-R1代表氢原子或(C1-C4)烷基;
-R2和R4各自彼此独立代表氢或卤素原子,或(C1-C4)烷基、(C1-C4)烷氧基或三氟甲基;
-R3和R5各自彼此独立地代表卤素原子或(C1-C4)烷基、(C1-C4)烷氧基、三氟甲基、三氟甲氧基、氰基或S(O)mAlk基团;
-R6代表选自以下的基团:
.(C1-C6)烷基,其未被取代或用一个或多个独立地选自以下的取代基取代一次或多次:卤素原子或羟基、(C1-C4)烷氧基或三氟甲氧基;
.苯基,其未被取代或用R8取代一次或多次;
.苄基或二苯甲基;
.杂环基,其选自:噻吩基、呋喃基或吡咯基,所述基团未被取代或用卤素原子、(C1-C4)烷基或三氟甲基取代;
.非芳族C3-C12碳环基团,其未被取代或用卤素原子或(C1-C4)烷基、(C1-C4)烷氧基、羟基或氰基取代一次或多次;
.(C3-C7)环烷基甲基,其未被取代或在环烷基上用一个或多个(C1-C4)烷基取代;
.芳氧基甲基,其未被取代或在甲基上用1个或2个烷基取代,其中“芳氧基”代表未被取代的或用R8取代一次或多次的苯氧基;
-R7代表氢原子或(C1-C4)烷基;
-R8代表卤素原子;(C1-C4)烷基;三氟甲基;氰基;(C1-C4)烷氧基;三氟甲氧基;苯基;(C3-C7)环烷基或NHS(O)nAlk基团;
-n代表1或2;
-m代表0、1或2;
-Alk代表(C1-C4)烷基,
为碱或与酸的加成盐的形式,以及水合物或溶剂化物的形式。
2.根据权利要求1的式(IA)化合物,特征在于Y代表基团-N(R7)CO-。
3.根据权利要求1的式(IB)化合物,特征在于Y代表基团-N(R7)CON(R7)-。
4.根据权利要求1的式(IC)化合物,特征在于Y代表基团-OCO-。
5.根据权利要求1的式(ID)化合物,特征在于Y代表-N(R7)S(O)n-。
6.根据权利要求1的化合物,特征在于:
-R1代表氢;
-和/或R2和R3代表在3或4位的氯原子,在4位的三氟甲基,或两个在3和4位的氯原子;
-和/或R4和R5代表在2、3或4位的氯原子、在4位的三氟甲基或在3位的氯原子和在4位的甲基。
7.根据权利要求2或5任一项的化合物,特征在于:
-R1代表氢原子;
-R2和R3代表在3或4位的氯原子,在4位的三氟甲基,或两个在3和4位的氯原子;
-R4和R5代表在2、3或4位的氯原子、在4位的三氟甲基或在3位的氯原子和在4位的甲基,
-R6代表选自以下的基团:
.(C1-C6)烷基,其未被取代或用一个或多个独立地选自以下的取代基取代一次或多次:卤素原子或羟基、(C1-C4)烷氧基或三氟甲氧基;
.C3-C12非芳族碳环基团,其未被取代或用卤素原子或(C1-C4)烷基、(C1-C4)烷氧基、羟基或氰基取代一次或多次。
8.化合物,其选自:
-N-((1-(3,4-二氯苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲基)-2,2-二甲基丙酰胺;
-和N-((1-(3,4-二氯苄基)-5-(3,4-二氯苯基)-1H-吡唑-3-基)甲基)-2-甲基丙烷-2-磺酰胺。
9.制备根据权利要求1-8任一项的式(I)化合物的方法,特征在于对下式化合物:
其中X代表氧原子、NH或N(R7)和R1、R2、R3、R4、R5如上面对于式(I)化合物所定义,用以下化合物进行处理:
a)或用式R6COOH(III)酸的官能衍生物,其中R6如上面对于(I)所定义,以获得式(IA)或(IC)化合物,其中Y代表i)或ii)值;
b)或用式R6N=C=O(IV)的异氰酸酯进行处理,其中R6如上面对于(I)所定义,以获得式(IB)化合物,其中Y代表ii)值;
c)或用式R6S(O)nHal的卤化衍生物进行处理,其中Hal代表卤素原子,优选氯,和R6如上面对于(I)所定义,以获得式(ID)化合物,其中Y具有iv)值。
10式(XII)化合物:
其中:
-W代表羟基或氨基;
-R1代表氢原子或(C1-C4)烷基;
-R2和R4各自彼此独立代表氢或卤素原子,或(C1-C4)烷基、(C1-C4)烷氧基或三氟甲基;
-R3和R5各自彼此独立地代表卤素原子或(C1-C4)烷基、(C1-C4)烷氧基或三氟甲基;
为碱或与酸的加成盐的形式,以及水合物或溶剂化物的形式。
11.药物,特征在于其包含根据权利要求1-8任一项的式(I)化合物,或这种化合物与可药用酸的加成盐,或式(I)化合物的溶剂化物或水合物。
12.药物组合物,特征在于其包含根据权利要求1-8任一项的式(I)化合物,或这种化合物的可药用盐、水合物或溶剂化物,以及至少一种可药用赋形剂。
13.根据权利要求1-8任一项的式(I)化合物用于制备药物的用途,所述药物用于治疗或预防其中涉及大麻素CB2受体的疾病。
14.根据权利要求1-8任一项的式(I)化合物用于制备药物的用途,所述药物用于治疗和预防免疫性疾病、疼痛、胃肠疾病、心血管或者肾病和/或用于抗癌化疗。
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FR0703972A FR2916758B1 (fr) | 2007-06-04 | 2007-06-04 | Derives de 1-benzylpyrazole, leur preparation et leur application en therapeutique |
PCT/FR2008/000739 WO2009004171A2 (fr) | 2007-06-04 | 2008-06-02 | Dérives de 1 -benzylpyrazole, leur preparation et leur application en therapeutique |
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AU2020326627A1 (en) * | 2019-08-02 | 2022-03-17 | Amgen Inc. | KIF18A inhibitors |
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FR2800372B1 (fr) * | 1999-11-03 | 2001-12-07 | Sanofi Synthelabo | Derives tricycliques d'acide 1-benzylpyrazole-3- carboxylique, leur preparation, les medicaments en contenant |
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- 2008-06-02 BR BRPI0812588-0A2A patent/BRPI0812588A2/pt not_active IP Right Cessation
- 2008-06-02 WO PCT/FR2008/000739 patent/WO2009004171A2/fr active Application Filing
- 2008-06-02 KR KR1020097027427A patent/KR20100017964A/ko not_active Application Discontinuation
- 2008-06-02 MX MX2009013139A patent/MX2009013139A/es not_active Application Discontinuation
- 2008-06-02 EP EP08805629A patent/EP2167472A2/fr not_active Withdrawn
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BRPI0812588A2 (pt) | 2015-02-18 |
IL202474A0 (en) | 2010-06-30 |
US20100144818A1 (en) | 2010-06-10 |
MX2009013139A (es) | 2010-02-17 |
RU2009148323A (ru) | 2011-07-20 |
EP2167472A2 (fr) | 2010-03-31 |
FR2916758A1 (fr) | 2008-12-05 |
WO2009004171A2 (fr) | 2009-01-08 |
AU2008270124A1 (en) | 2009-01-08 |
JP2010529093A (ja) | 2010-08-26 |
WO2009004171A3 (fr) | 2009-04-23 |
KR20100017964A (ko) | 2010-02-16 |
CA2689116A1 (fr) | 2009-01-08 |
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