CN1247568C - 可作为香草素受体拮抗剂用于治疗疼痛的脲类化合物 - Google Patents
可作为香草素受体拮抗剂用于治疗疼痛的脲类化合物 Download PDFInfo
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- CN1247568C CN1247568C CNB028177177A CN02817717A CN1247568C CN 1247568 C CN1247568 C CN 1247568C CN B028177177 A CNB028177177 A CN B028177177A CN 02817717 A CN02817717 A CN 02817717A CN 1247568 C CN1247568 C CN 1247568C
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- Prior art keywords
- tetramethyleneimine
- urea
- compound
- pain
- aminomethyl phenyl
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Classifications
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
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- A61P13/10—Drugs for disorders of the urinary system of the bladder
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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Abstract
式(I)化合物,或其可药用盐或溶剂合物,其中R1、R2、P、P′、n、p、q、r和s如说明书中所定义,制备所述化合物的方法,含有所述化合物的药物组合物以及所述化合物和组合物在用于治疗与香草素受体(VR1)相关的疾病如疼痛、偏头痛、神经病、局部缺血、神经变性、中风、多发性硬化、哮喘、炎性疾病中的用途。
Description
本发明涉及新化合物,特别是具有药理活性的脲衍生物,制备它们的方法,包含它们的组合物及其它们在医学,特别是在治疗各种疾病中的用途。
香草素是一类天然及合成的化合物,其特征为有香草基(4-羟基-3-甲氧基苄基)或功能上等价的基团存在。通过这类化合物来调节其功能的香草素受体(VR-1)已被广泛的研究,并且Szallasi和Blumberg对其进行了详尽的评述(The American Society for Pharmacology and Experimental Therapeutics,1999,Vol.51,No.2.)。
在本领域中已知有大量的具有不同的结构的香草素化合物,例如在欧洲专利申请号,EP 0347000和EP 0401903,UK专利申请号GB 2226313和国际专利申请,公开号WO 92/09285中所公开的那些化合物。特别值得注意的香草素化合物或香草素受体调节剂的实例为从胡椒植物辣椒(capsazepine)中分离出来的辣椒素或反8-甲基-N-香草基-6-诺香草胺(Tetrahedron,53,1997,4791)和奥伐尼或-N-(4-羟基-3-甲氧基苄基)油酰胺(J.Med.Chem.,36,1993,2595)。
US 3,424,760和US 3,424,761中都记载了一系列的3-脲基吡咯烷,据说其显示出止疼药、中枢神经系统、精神性药理(pyschopharmacologic)活性。这些专利各自明确公开了1-(1-苯基-3-吡咯烷基)-3-苯基脲和1-(1-苯基-3-吡咯烷基)-3-(4-甲氧基苯基)脲化合物。
国际专利申请,公开号WO02/08221、WO02/16317、WO02/16318和WO02/16319各自公开了香草素受体拮抗剂以及它们在治疗与香草素受体活性相关的疾病方面的用途。
共同待审的国际专利申请号PCT/EP02/04802公开了一系列的脲衍生物以及它们在治疗与香草素受体活性相关的疾病方面的用途。
根据本发明的第一个方面,提供了式(I)化合物或其可药用盐或溶剂合物,
其中:
P和P′独立地选自芳基和杂芳基;
R1和R2独立地选自-H、卤素、烷基、烷氧基、环烷基、芳烷基、芳烷氧基、环烷基烷基、环烷基烷氧基、-CN、-NO2、-OH、-OCF3、-CF3、-NR4R5、-S(O)mR6、-S(O)2NR4R5、-OS(O)2R6、-OS(O)2CF3、-O(CH2)xNR4R5、-C(O)CF3、-C(O)烷基、-C(O)环烷基、-C(O)芳烷基、-C(O)Ar、-C(O)(CH2)xOR6、-C(O)(CH2)xNR4R5、-C(O)烷氧基、-C(O)NR4R5、-(CH2)xC(O)烷氧基、-(CH2)xOC(O)R6、-(CH2)xOR6、-(CH2)xR4R5、-(CH2)xC(O)NR4R5、-(CH2)xN(R4)C(O)R6、-(CH2)xS(O)2NR4R5、-(CH2)xN(R4)S(O)2R6、-ZAr、-(CH2)xS(O)2R6、-(OCH2)xS(O)2R6、-N(R4)S(O)2R6、-N(R4)C(O)R6、-(CH2)xN(R4)S(O)2R6、-(CH2)xN(R4)C(O)R6或-(CH2)xC(O)烷基;R4和R5可以相同或不同,并代表H或烷基,或R4和R5与它们相连的原子一起构成任选地被杂原子如O或-NR7所间断的C3-6氮杂环烷烃、C3-6(2-氧代)氮杂环烷烃环或C5-8聚亚甲基链。
Z为O、S或NR7;
R6为烷基或芳基;
R7为氢、烷基或芳基;
m为1或2;
n为0、1、2或3;
p和q独立地为0、1、2、3或4;
r为1、2或3;
s为0、1或2;并且
x为0、1、2、3、4、5或6;
条件是所述的式(I)化合物不选自:
1-(1-苯基-3-吡咯烷基)-3-苯基脲;
1-(1-苯基-3-吡咯烷基)-3-(4-甲氧基苯基)脲;
N-(4-氟苯基)-N′-[(R)-1-((3-甲基苯基)吡咯烷-2-基甲基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-2-基甲基)]脲;
N-(4-氟苯基)-N′-[((S)-1-(3-甲基苯基)吡咯烷-2-基甲基)]脲;
N-(2-溴苯基)-N′-[((S)-1-(3-甲基苯基)吡咯烷-2-基甲基)]脲;
N-(4-氟苯基)-N′-[((S)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((S)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(4-氟苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(4-氟苯基)-N′-[((R)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(1-萘基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2,3-二氯苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((S)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(4-氟-3-甲基苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3,4-二氟苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3-氟-4-甲基苯基)吡咯烷-3-基)]脲;
N-(3-氯-2-甲基苯基)-N′-[((R-)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2,3-二氯苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2,5-二氯苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2,3-二氯苯基)-N′-[((R)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(2,5-二氯苯基)-N′-[((R)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(3-氯-2-甲基苯基)-N′-[((R)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(3-氯-2-甲基苯基)-N′-[((R)-1-(3,4-二氟苯基)吡咯烷-3-基)]脲;
N-(2,3-二氯苯基)-N′-[((R)-1-(3,4-二氟苯基)吡咯烷-3-基)]脲;
N-(2,5-二氯苯基)-N′-[((R)-1-(3,4-二氟苯基)吡咯烷-3-基)]脲;
N-(3-氯-2-甲基苯基)-N′-[((R)-1-(3-氟-4-甲基苯基)吡咯烷-3基)]脲;和
N-(2,3-二氯苯基)-N′-[((R)-1-(3-氟-4-甲基苯基)吡咯烷-3-基)]脲。
合适地,P和P′独立地选自苯基和杂芳基。
在本发明的优选方面中,其提供式(I)化合物的亚类,式(IA)化合物或其可药用盐或溶剂合物,
其中:
P为苯基、萘基、喹啉基或异喹啉基;
P′为苯基或吡啶基;
R1和R2独立地选自-H、卤素、烷基、烷氧基、环烷基、芳烷基、芳烷氧基、环烷基烷基、环烷基烷氧基、-CN、-NO2、-OH、-OCF3、-CF3、-NR4R5、-S(O)mR6、-S(O)2NR4R5、-OS(O)2R6、-OS(O)2CF3、-(CH2)xNR4R5、-C(O)CF3、-C(O)烷基、-C(O)环烷基、-C(O)芳烷基、-C(O)Ar、-C(O)(CH2)xOR6、-C(O)(CH2)xNR4R5、-C(O)烷氧基、-C(O)NR4R5、-(CH2)xC(O)烷氧基、-(CH2)xOC)R6、-(CH2)xOR6、-(CH2)xR4R5、(CH2)xC(O)NR4R5、-(CH2)xN(R4)C(O)R6、-(CH2)xS(O)2NR4R5、-(CH2)xN(R4)S(O)2R6、-ZAr、-(CH2)xS(O)2R6、-(OCH2)xS(O)2R6、-N(R4)S(O)2R6、-N(R4)C(O)R6、-(CH2)xN(R4)S(O)2R6、-(CH2)xN(R4)C(O)R6或-(CH2)xC(O)烷基;R4和R5可以相同或不同,并代表H或烷基,或R4和R5与它们相连的原子一起构成任选地被杂原子如O或-NR7所间断的C3-6氮杂环烷烃、C3-6(2-氧代)氮杂环烷烃环或C5-8聚亚甲基链。
Z为O、S或NR7;
R6为烷基或芳基;
R7为氢、烷基或芳基;
m为1或2;
n为0、1、2或3;
p和q独立地为0、1、2、3或4;
r为1、2或3;
s为0、1或2;并且
x为0、1、2、3、4、5或6;
条件是所述的式(IA)化合物不选自:
1-(1-苯基-3-吡咯烷基)-3-苯基脲;
1-(1-苯基-3-吡咯烷基)-3-(4-甲氧基苯基)脲;
N-(4-氟苯基)-N′-[(R)-1-((3-甲基苯基)吡咯烷-2-基甲基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-2-基甲基)]脲;
N-(4-氟苯基)-N′-[((S)-1-(3-甲基苯基)吡咯烷-2-基甲基)]脲;
N-(2-溴苯基)-N′-[((S)-1-(3-甲基苯基)吡咯烷-2-基甲基)]脲;
N-(4-氟苯基)-N′-[((S)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((S)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(4-氟苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(4-氟苯基)-N′-[((R)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(1-萘基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2,3-二氯苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((S)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(4-氟-3-甲基苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3,4-二氟苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3-氟-4-甲基苯基)吡咯烷-3-基)]脲;
N-(3-氯-2-甲基苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2,3-二氯苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2,5-二氯苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2,3-二氯苯基)-N′-[((R)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(2,5-二氯苯基)-N′[((R)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(3-氯-2-甲基苯基)-N′-[((R)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(3-氯-2-甲基苯基)-N′-[((R)-1-(3,4-二氟苯基)吡咯烷-3-基)]脲;
N-(2,3-二氯苯基)-N′-[((R)-1-(3,4-二氟苯基)吡咯烷-3-基)]脲;
N-(2,5-二氯苯基)-N′-[((R)-1-(3,4-二氟苯基)吡咯烷-3-基)]脲;
N-(3-氯-2-甲基苯基)-N′-[((R)-1-(3-氟-4-甲基苯基)吡咯烷-3-基)]脲;和
N-(2,3-二氯苯基)-N′-[((R)-1-(3-氟-4-甲基苯基)吡咯烷-3-基)]脲。
合适地,P为苯基、喹啉基或异喹啉基。更合适地,P为苯基、5-喹啉基、7-喹啉基或5-异喹啉基。优选地,P为苯基或5-异喹啉基。
P′合适地为苯基。P′合适地为吡啶基。
R1合适地为卤素、-CF3或烷基。R1优选为氟、氯、溴、-CF3、甲基或叔丁基。
当p为2或3时,基团R1可以相同或不同。
p合适地为1或2。p优选为1。
m合适地为1。
n合适地为0或1。n优选为0。
R2合适地为卤素、烷基、烷氧基、-CN或-CF3。R2优选为氟、氯、溴、甲基、OMe或CF3。
q合适地为1或2。q优选为1。
x合适地为1、2或3。
当q为2或3时,基团R2可以相同或不同。
当q为2时,特别优选的R2实例为3,4-二氟代、3-氟-4-甲基、3-甲基-4-氟代、3-氯-5-三氟甲基、3-氰基-5-三氟甲基和3-氰基-6-三氟甲基。
r和s合适地为定义4-7元环的值。r和s优选地为定义5或6元环的值。r和s更优选地为定义5元环的值。
根据本发明的另一个优选方面,提供了式(I)化合物的亚类,式(IB)化合物或其可药用盐或溶剂合物,
其中:
P为苯基、萘基、喹啉基或异喹啉基;
R1和R2独立地选自-H、卤素、烷基、烷氧基、环烷基、芳烷基、芳烷氧基、环烷基烷基、环烷基烷氧基、-CN、-NO2、-OH、-OCF3、-CF3、-NR4R5、-S(O)mR6、-S(O)2NR4R5、-OS(O)2R6、-OS(O)2CF3、-(CH2)xNR4R5、-C(O)CF3、-C(O)烷基、-C(O)环烷基、-C(O)芳烷基、-C(O)Ar、-C(O)(CH2)xOR6、-C(O)(CH2)xNR4R5、-C(O)烷氧基、-C(O)NR4R5、-(CH2)xC(O)烷氧基、-(CH2)xOC(O)R6、-(CH2)xOR6、-(CH2)xR4R5、(CH2)xC(O)NR4R5、-(CH2)xN(R4)C(O)R6、-(CH2)xS(O)2NR4R5、-(CH2)xN(R4)S(O)2R6、-ZAr、-(CH2)xS(O)2R6、-(OCH2)xS(O)2R6、-N(R4)S(O)2R6、-N(R4)C(O)R6、-(CH2)xN(R4)S(O)2R6、-(CH2)xN(R4)C(O)R6或-(CH2)xC(O)烷基;
R4和R5可以相同或不同,并代表H或烷基,或R4和R5与它们相连的原子一起构成任选地被杂原子如O或-NR7所间断的C3-6氮杂环烷烃、C3-6(2-氧代)氮杂环烷烃环或C5-8聚亚甲基链。
Z为O、S或NR7;
R6为烷基或芳基;
R7为氢、烷基或芳基;
m为1或2;
n为0、1、2或3;
p和q独立地为0、1、2、3或4;
r为1、2或3;
s为0、1或2;并且
x为0、1、2、3、4、5或6;
R1合适地为卤素、羟基、烷基、烷氧基、-CF3、-NO2、-CN、-OCF3、氨基或单烷基氨基或二烷基氨基。R1优选为卤素、-CF3或烷基。R1更优选为溴、氯、氟、-CF3、甲基或叔丁基;
R1合适地为卤素、羟基、烷基、烷氧基、-CF3、-NO2、-CN、-OCF3、氨基或单烷基氨基或二烷基氨基。R2优选为卤素、烷基、烷氧基、-CN或-CF3。R2优选为溴、氯、氟、甲基、-OMe或-CF3;
合适地,p和q独立地为0、1或2;并且
合适地,r和s独立地为1或2。
合适地,x为1、2或3。
根据本发明特别感兴趣的式(IB)化合物为编号1-23、28、19、34-39、44-50和55-76的实施例(下表1中所表示)或其可药用盐或其溶剂合物。
根据本发明的另一方面,还提供式(I)化合物的亚类,式(IC)化合物或其可药用盐或溶剂合物,
其中:
P为苯基、萘基、喹啉基或异喹啉基;
R1和R2独立地选自卤素、羟基、烷基、烷氧基、-CF3、-NO2、-CN、-OCF3、氨基或单烷基氨基或二烷基氨基;
n为0、1、2或3;
p和q独立地为0、1、2、3或4;
r为1、2或3;并且
s为0、1或2;
条件是所述的式(I)化合物不选自:
1-(1-苯基-3-吡咯烷基)-3-苯基脲;
1-(1-苯基-3-吡咯烷基)-3-(4-甲氧基苯基)脲;
N-(4-氟苯基)-N′-[(R)-1-((3-甲基苯基)-吡咯烷-2-基甲基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3-甲基苯基)-吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3-甲基苯基)-吡咯烷-2-基甲基)]脲;
N-(4-氟苯基)-N′-[((S)-1-(3-甲基苯基)-吡咯烷-2-基甲基)]脲;
N-(2-溴苯基)-N′-[((S)-1-(3-甲基苯基)吡咯烷-2-基甲基)]脲;
N-(4-氟苯基)-N′-[((S)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((S)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(4-氟苯基)-N′-[((R)-1-(3-甲基苯基)-吡咯烷-3-基)]脲;
N-(4-氟苯基)-N′-[((R)-1-(3-氟苯基)-吡咯烷-3-基]脲;
N-(2-溴苯基)-N′-[((R)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(1-萘基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2,3-二氯苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((S)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(4-氟-3-甲基苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3,4-二氟苯基)吡咯烷-3-基)]脲;
N-(2-溴苯基)-N′-[((R)-1-(3-氟-4-甲基苯基)吡咯烷-3-基)]脲;
N-(3-氯-2-甲基苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2,3-二氯苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2,5-二氯苯基)-N′-[((R)-1-(3-甲基苯基)吡咯烷-3-基)]脲;
N-(2,3-二氯苯基)-N-[((R)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(2,5-二氯苯基)-N′-[((R)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(3-氯-2-甲基苯基)-N′-[((R)-1-(3-氟苯基)吡咯烷-3-基)]脲;
N-(3-氯-2-甲基苯基)-N′-[((R)-1-(3,4-二氟苯基)吡咯烷-3-基)]脲;
N-(2,3-二氯苯基)-N′-[((R)-1-(3,4-二氟苯基)吡咯烷-3-基)]脲;
N-(2,5-二氯苯基)-N′-[((R)-1-(3,4-二氟苯基)吡咯烷-3-基)]脲;
N-(3-氯-2-甲基苯基)-N′-[((R)-1-(3-氟-4-甲基苯基)吡咯烷-3-基)]脲;和
N-(2,3-二氯苯基)-N′-[((R)-1-(3-氟-4-甲基苯基)吡咯烷-3-基)]脲。
合适地,P为苯基、喹啉基或异喹啉基。
合适地,R1为烷基。R1优选为甲基。
合适地,R2为卤素或烷基。R2合适地为氟或甲基。
合适地,p和q独立地为0、1或2。
合适地,r和s独立地为1或2。
本发明特别感兴趣的式(IC)化合物为编号24-27、30-33、40-43和51-54的实施例(下表1中所举例说明)或其可药用盐或其溶剂合物。
式(I)的某些碳原子为手性碳原子,如标有″*″的碳原子,并因此式(I)化合物可能以立体异构体形式存在。本发明涵盖所有的旋光异构体如含有对映体和其混合物如外消旋物的式(I)化合物的立体异构形式。不同的立体异构形式可通过常规的方法彼此分开或辨别,或者可通过常规的立体专一性合成或不对称合成得到任何指定的异构体。
优选的式(I)化合物为具有R-构型的C*碳。
某些化合物能以不同的互变异构形式存在,并且应当理解为本发明包括所有的这些互变异构形式。
如上文所指出的,式(I)化合物可形成盐,特别是可药用盐。合适的可药用盐为那些在本领域中常用的盐,并且包括那些在J.Pharm.Sci.,1977,66,1-19中所记载的盐,如酸加成盐。
合适的可药用盐包括酸加成盐。
合适的可药用酸加成盐包括与无机酸如氢氯酸、氢溴酸、磷酸或硫酸,或与有机酸如甲磺酸、甲苯磺酸、乙酸、丙酸、乳酸、柠檬酸、富马酸、苹果酸、琥珀酸、水杨酸、马来酸、甘油磷酸或乙酰水杨酸加成的盐。
不可药用的式(I)化合物的盐和/或溶剂合物可用作制备式(I)化合物的可药用盐和/或溶剂合物或式(I)化合物本身的中间体,并且构成了本发明的另一方面。
式(I)化合物可制备成晶形或非晶形形式,并且若为晶状,可任选地为水合或溶剂合的形式。本发明的范围包括化学计量水合物以及含可变量水的化合物。
合适的溶剂合物包括可药用的溶剂合物,如水合物。
溶剂合物包括化学计量溶剂合物和非化学计量溶剂合物。
如文中所用的术语“烷基”其作为基团或基团的一部分,指的是含1-12个碳原子优选1-6个碳原子的直链或支链饱和脂肪族烃基。此烷基基团具体包括甲基(″Me″)、乙基(″Et″)、正丙基(″Prn″)、异丙基(″Pri″)、正丁基(″Bun″)、仲丁基(″Bus″)、叔丁基(″But″)、戊基和己基。适当的时候,此烷基基团可被一个或多个选自卤素(如氟、氯、溴)、-CN、-CF3、-OH、-OCF3、C2-6烯基、C3-6炔基、C1-6烷氧基、芳基和二C1-6烷基氨基的基团所取代。
如文中所用的术语″烷氧基″其作为基团或基团的一部分,指的是烷基醚基,其中术语″烷基″如上定义。此烷氧基基团具体包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基。适当的时候,此烷氧基基团可被一个或多个选自卤素(如氟、氯、溴)、-CN、-CF3、-OH、-OCF3、C1-6烷基、C2-6烯基、C3-6炔基、芳基和二C1-6烷基氨基的基团所取代。
如文中所用的术语″芳基″其作为基团或基团的一部分,指的是碳环芳香基团(″Ar″)。此芳基基团合适地为5-6元单环基团或8-10元稠合的二环基团,特别是苯基(″Ph″)、联苯基和萘基,特别为萘基和苯基。
如文中所用的术语″杂芳基″其作为基团或基团的一部分,指的是稳定的5-7元单环或7-10元二环芳杂环,其由碳原子以及1-4个优选1-2个独立地选自含N、O和S的杂原子所组成,。优选在芳杂环中S和O的原子总数不多于1。合适的杂芳基基团的实例包括但不限于吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并噻吩基(benzothiofuranyl)、苯并苯硫基(benzothiophenyl)、苯并噁唑基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异噁唑基、苯并异噻唑基、苯并咪唑基、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、二氢苯并呋喃基、呋喃基、呋咱基、咪唑基、1H-吲唑基、二氢吲哚基、吲哚基、异苯并呋喃基、异苯并二氢吡喃基、异吲唑基、异吲哚基、异氮茚基、异喹啉基、异噻唑基、异噁唑基、萘啶基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噁唑基、嘧啶基、酞嗪基、蝶啶基、嘌呤基、吡嗪基、吡唑基、吡啶并噁唑基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、吡咯基、喹唑啉基、喹啉基、喹噁啉基、四氢异喹啉基、四氢喹啉基、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、噻唑基、噻吩基、噻吩并噻唑基、噻吩并噁唑基、噻吩并咪唑基、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(xanthenyl)。
除非另外说明,在文中使用术语″卤素″来代表选自氟(″氟代″)、氯(″氯代″)、溴(″溴代″)或碘(″碘代″)。
除非另外说明,在文中使用术语″萘基″来代表萘-1-基和萘-2-基基团。
本发明也提供了制备式(I)化合物或其可药用盐的方法,所述方法包括使式(II)化合物:
其中R1、P和p如式(I)中所定义,与式(III)化合物偶联:
其中P′、R2、n、q、r和s如式(I)中所定义,并且A和B含有能一起反应形成脲部分的适当官能团;
并且随后,当需要时,可进行一个或多个下述反应:
(i)将一种式(I)化合物转化为另一种式(I)化合物;
(ii)除去任何保护基;
(iii)制备所形成的化合物的盐或溶剂合物。
合适的A和B基团的恰当实例包括:
(a)A为-N=C=O且B为NH2;或者A为NH2且B为N=C=O或者
(b)A为NH2且B为NH2连同合适的脲形成剂。
方法(a)中的反应是在惰性溶剂如二氯甲烷或乙腈中进行的。
方法(b)中的脲形成剂可以为羰基二咪唑或光气或三光气,并且是在惰性有机溶剂如乙醚、四氢呋喃或二氯甲烷中于环境温度或高温在有碱如三乙胺或吡啶存在下进行的。
一个可供选择的式(I)不对称脲化合物的合成方法为由二芳基碳酸酯出发,经相应的氨基甲酸酯得到。此方法论被Freer等(Synthetic Communications,26(2),331-349,1996)所记载。应当理解,本领域的普通技术人员可以很容易意识到本方法适于制备式(I)化合物。
本领域普通技术人员应当理解到,在上文提及的某些过程中对某些活性取代基的保护是必须的。可以使用如在Greene T.W.′Protective groups inorganic synthesis′,New York,Wiley(1981)中所记载的那些标准的保护和脱保护技术。例如,可将伯胺保护为苯邻二甲酰亚胺、苄基、苄氧基羰基或三苯甲基衍生物。可将羧酸基团保护为酯。可将醛或酮基团保护为缩醛、缩酮、硫缩醛或硫缩酮。这些基团的脱保护可使用本领域众所周知的常规方法来完成。
式(III)化合物可通过将式(IV)化合物:
其中,P′是如式(I)中所定义的,并且R2′为如上所定义的R2或其保护的形式,L1为离去基团,并且q如上所定义,与式(V)化合物反应制备得到:
其中B′为如上所定义的B或其保护形式并且n、r和s如上所定义。
L1合适地为卤素,如氯。
合适地,式(V)化合物为活化形式,例如离子形式。此活化形式可使用常规的偶联反应方法制备得到,例如通过使化合物(IV)和(V)在碱金属碳酸盐如碳酸钾存在下,于非质子传递溶剂如二甲基甲酰胺中,使用适于所选具体方法的反应条件例如在高温如100℃下反应。
式(IV)和(V)化合物可以在市场上买到,或者通过已知的方法例如在Heterocycles,1984,22(1),117和J.Chem.Soc.,Perkin 1,1988,4,921中所公开的用于制备式(IV)化合物和在J.Med.Chem.,1992,35(10),1764中所公开的用于制备式(V)化合物的那些方法,或者通过与这些公开方法相类似的方法制备得到。
可药用盐可通过与合适的酸或酸的衍生物进行常规反应制备得到。
式(I)化合物和其可药用盐具有香草素受体(VR1)拮抗剂活性并且其被认为可能用于治疗或预防某些疾病或治疗与其相关的疼痛,所述的疼痛如:疼痛、慢性痛、神经性疼痛、术后痛、风湿症后关节炎痛、骨关节炎痛、背痛、内脏痛、癌瘤痛、痛觉、神经痛、牙痛、头痛、偏头痛、神经病、腕管综合征、糖尿病神经病变、HIV-相关的神经病、疱疹后神经痛、纤维肌痛、神经炎、坐骨神经痛、神经损伤、局部缺血局部缺血、神经变性、中风、中风后疼痛、多发性硬化、呼吸系统疾病、哮喘、咳嗽、COPD、支气管狭窄、炎性疾病、食管炎、心脏灼痛、巴雷特氏组织变形、吞咽困难、胃食管返流疾病(GERD)、胃和十二指肠溃疡、机能性消化不良、过敏性肠综合征、炎性肠病、结肠炎、节段性回肠病、骨盆超敏反应、骨盆痛、月经痛、肾绞痛、尿失禁、膀胱炎、灼伤、疥疮、牛皮癣、搔痒症、呕吐(在下文中称为″本发明的疾病″)。
因此,本发明也提供式(I)化合物或其可药用盐或溶剂合物用作为活性治疗物质,特别是用于治疗和/或预防本发明的疾病。
具体的说,本发明提供式(I)化合物或其可药用盐或溶剂合物用于治疗或预防疼痛。
本发明还提供用于治疗或预防包括人在内的哺乳动物中疾病的方法,在所述疾病中香草素(VR1)受体的拮抗作用是有益的,更具体的说为本发明的疾病,所述方法包括给需要的哺乳动物服用治疗有效量的式(I)化合物或其可药用盐或溶剂合物。
本发明提供式(I)化合物或其可药用盐或溶剂合物在用于治疗或预防疾病的药物的制备中的用途,在所述疾病中拮抗香草素(VR1)受体的作用是有益的,特别是本发明疾病。
为了将本发明化合物用于治疗,通常根据标准的制剂操作将其制成药物组合物。因而,本发明也提供一种药用组合物,包括式(I)化合物或其可药用盐或溶剂合物以及可药用载体或赋形剂。
在合适的环境温度并大气压下混合制备得到的本发明的药用组合物,通常适于口服、肠胃外、直肠给药或膀胱内施药给膀胱并且,例如,可以是片剂、胶囊、口服液体制剂、散剂、颗粒、锭剂、可重建的粉末、可注射的或可输注的溶液、混悬剂或栓剂的形式。通常优选可口服的组合物。
用于口服的片剂和胶囊可以为单位剂量的形式,并且可以含有常规的赋形剂,如粘合剂、填充剂、压片润滑剂、崩解剂和可接受的润湿剂。片剂可以根据标准制剂操作中众所周知的方法进行包衣。
口服的液体制剂可以为例如水性的或油性的混悬剂、溶液、乳状液、糖浆或酏剂的形式,或者可以为干物形式,以用于在使用前与水或其它合适的溶媒重构。此液体制剂可含有常规的添加剂如助悬剂、乳化剂、非水溶媒(其可包括食用油)、防腐剂,并且若需要,常规的调味剂或着色剂。
对于肠胃外给药,液体的单元剂量形式可利用本发明化合物或其可药用盐和无菌溶媒制备得到。所述化合物,根据所用的溶媒和浓度,可以被悬浮于或溶于此溶媒中。在调配的溶液中,可将此化合物溶解用于注射,并过滤消毒,随后装入到合适的药水瓶或安瓿中并密封。有利地,佐剂如局部麻醉剂、防腐剂和缓冲剂可溶于溶媒中。为了提高其稳定性,装入到药水瓶后中,真空除去水可将此组合物冰冻。肠胃外的混悬剂可用基本相同的方法制备得到,除了将此化合物悬浮于而不是溶解在溶媒中,并且不能通过过滤实现灭菌以外。此化合物可通过将其暴露于环氧乙烷中进行灭菌,随后将其悬浮于无菌溶媒中。有利地,可将表面活性剂或湿润剂包含在此组合物中,以促使化合物的均匀分配。
依据给药的方法,此组合物可含0.1%-99%重量,优选10-60%重量的活性物质。
用于上述疾病治疗的此化合物剂量通常将会根据疾病的严重性、患者的体重和其它相似的因素而变化。对于全身给药,每千克体重0.01mg-100mg的剂量水平可用于疼痛的治疗。然而,作为一般的指导原则,合适的单位剂量可为0.05-1000mg,更合适的为0.05-20、20-250、或0.1-500.0mg,例如0.2-5和0.1-250mg;并且此单元剂量可以一天多于一次,如一天两或三次被施药,以便使每天的总剂量范围约为0.5-1000mg;并且此治疗可持续数周或数月。
当根据本发明进行施药时,本发明化合物没有显示出不可接受的毒理学效果。
本说明书中所引用所有的出版物,包括但不局限于专利和专利申请,在此引入作为参考,与同每件单独的出版物被具体且独自地引入作为参考一样地陈述完全。
下面的描述和实施例用于举例说明本发明化合物的制备。
缩写词
BINAP-2,2′-双(二苯膦基)-1,1′-联萘
HPLC-高效液相色谱
MgSO4-硫酸镁
TFA-三氟乙酸
DCM-二氯甲烷
描述1
[(R)-1-(5-三氟甲基吡啶-2-基)-吡咯烷-3-基]-氨基甲酸叔丁酯(D1)
向2-氯-5-三氟甲基吡啶(7.3g,0.04mol)和3R-(+)-3-(叔丁氧基羰基氨基)吡咯烷(7.5g,0.04mol)的干燥二甲基甲酰胺(100ml)溶液中加入粉末状碳酸钾(6.6g,0.05mol),并将反应于100℃加热7小时并冷却。将溶剂减压除去,并将残余物在乙酸乙酯和水之间分配。分离有机相,干燥(MgSO4)并过滤。减压除去溶剂得到固体。进行硅胶色谱,用乙酸乙酯和DCM(梯度洗脱,最大量20%)洗脱,得到白色固体的标题化合物。
描述2
(R)-1-(5-三氟甲基吡啶-2-基)-吡咯烷-3-基胺(D2)
将D1(11.5g,0.04mol)的DCM(80ml)溶液冷却(冰浴),并加入三氟乙酸(过量,50ml)。将反应温热至环境温度,搅拌3小时,并在乙酸乙酯和氢氧化钠水溶液之间分配。分离有机相,干燥(MgSO4)并过滤。减压除去溶剂,得到黄色油状粗产物。泡-泡(Bulb to bulb)减压蒸馏得到最初为油状的标题化合物,将其静置后结晶。
描述3
1,3-二甲基-5-硝基异喹啉(D3)
将1,3-二甲基异喹啉[(Chem.Lett.,1983,p.791),2.39g,15.20mM]的浓硫酸溶液(15ml)冷却至<4℃。滴加硝酸钾(1.69g,16.72mM)的浓硫酸溶液,保持温度低于4℃。在完成加入后,将溶液于此温度再搅拌2小时,然后温热至室温1小时。将反应混合物倒到冰水中,并将溶液用氢氧化钠碱化,并用DCM萃取。将提取物用盐水洗,干燥并浓缩,得到黄色固体。经硅胶色谱纯化,得到黄色晶状固体的标题化合物。
描述4
5-氨基-1,3-二甲基异喹啉(D4)
将D3(2.01g,9.94mM)和10%钯炭(1g)的甲醇溶液于大气压下氢化1小时。将催化剂过滤出去,并将滤液减压浓缩,得到灰白色固体的标题化合物。
描述5
3-甲基-5-硝基异喹啉(D5)
将3-甲基异喹啉(5.4g,0.038mol)的浓硫酸(30ml)溶液小心地加入到硝酸钾(4.25g,1.1eq)的浓硫酸(23ml)溶液中,同时保持温度低于4℃(冰浴)。继续搅拌2小时,并且然后将温度升至环境温度。将反应再搅拌3小时,并且然后将其倒到冰-水悬浮液(500ml)中。用碳酸钾固体中和,得到黄色固体,将其过滤并用水洗。将粗产物溶于乙醇(200ml)中,过滤并减压浓缩,得到黄色固体的标题化合物。
描述6
5-氨基-3-甲基异喹啉(D6)
标题化合物是由D5使用描述4中所略述的方法制备得到的。
描述7
N-(2,2-二甲氧基乙基)-(1-苯基)乙胺(D7)
将α-甲基苄基胺(8.37g,0.07mol)和溴代乙醛二甲基缩醛(11.67g,0.07mol)的含碳酸钾(12.39g,0.09mol)的乙腈(150ml)溶液加热回流2天并冷却。将固体过滤出去,并将滤液减压浓缩,剩下油状物。进行硅胶色谱,用乙酸乙酯洗脱得到油状的标题化合物。
描述8
1-甲基异喹啉(D8)
用2小时的时间,向冷却的氯磺酸(16ml,-10℃)中小心地加入D7(5g,0.024mol)。将反应温热至环境温度,并继续搅拌3天。然后将反应倒到冰-水悬浮液(500ml)中,用固体碳酸钾碱化,随后用DCM萃取。分离有机相,经MgSO4干燥,过滤并减压浓缩,剩下油状物。进行硅胶色谱,用乙酸乙酯洗脱得到黄色油状的标题化合物。
描述9
1-甲基-5-硝基异喹啉(D9)
将D8(1g,7mmol)的硫酸(2.5ml)溶液冷却(<4℃),并用10分钟的时间加入浓硝酸(1ml)。将反应搅拌30分钟,并且然后于60℃加热2小时。冷却后将反应混合物倒到冰水混合物(100ml)中,并用固体碳酸钾碱化,随后用DCM萃取。分离有机相,经MgSO4干燥,过滤并减压浓缩,得到白色固体的标题化合物。
描述10
5-氨基-1-甲基异喹啉(D10)
标题化合物是由(D9)使用描述4中所略述的方法制备得到的。
描述11
((R)-1-(3-甲基苯基)吡咯烷-3-基)氨基甲酸叔丁酯(D11)
将BINAP1.25g,2mmol)、醋酸钯(0.3g,1.3mmol)、碳酸铯(6.6g,0.02mol)、3-溴甲苯(4.6g,0.027mol)和(3R)-(+)-3-(叔丁氧基羰基氨基)吡咯烷(2.5g,0.013mol)的1,4-二噁烷(无水的,50ml)的悬浮液在氩气下加热回流18小时。冷却后,减压除去溶剂,并将残余物在DCM和水之间分配。分离有机相,经MgSO4干燥,过滤并减压浓缩,剩下油状物。进行硅胶色谱,用乙酸乙酯和己烷(梯度洗脱,最大量4%)洗脱,得到灰白色固体的标题化合物。
描述12
(R)-1-(3-甲基苯基)吡咯烷-3-基胺(D12)
将D11(2.07g,7.5mmol)的TFA(1.2ml)和DCM(20ml)溶液于环境温度搅拌18小时。将溶剂减压除去,并将残余物在DCM和碳酸氢钠水溶液之间分配。分离有机相,经MgSO4干燥,过滤并减压浓缩,得到油状标题化合物。
描述13
(R)-1-(3-氟苯基吡咯烷-3-基)氨基甲酸叔丁酯(D13)
标题化合物是由(3R)-(+)-3-(叔丁氧基羰基氨基)吡咯烷和1-溴-3-氟代苯使用描述11中所略述的方法制备得到的。
描述14
(R)-1-(3-氟苯基)吡咯烷-3-基胺(D14)
标题化合物是由D13使用描述12中所略述的方法制备得到的。
描述15
(R)-1-(3,4-二氟代苯基)吡咯烷-3-氨基甲酸叔丁酯(D15)
标题化合物是由(3R)-(+)-3-(叔丁氧基羰基氨基)吡咯烷和4-溴-1,2-二氟代苯使用描述11中所略述的方法制备得到的。
描述16
(R)-1-(3,4-二氟代苯基)-吡咯烷-3-基胺(D16)
标题化合物是由D15使用描述12中所略述的方法制备得到的。
描述17
(R)-1-(3-氟-4-甲基苯基)吡咯烷-3-氨基甲酸叔丁酯(D17)
标题化合物是由(3R)-(+)-3-(叔丁氧基羰基氨基)吡咯烷和4-溴-2-氟甲苯使用描述11中所略述的方法制备得到的。
描述18
(R)-1-(3-氟-4-甲基苯基)-吡咯烷-3-基胺(D18)
标题化合物是由D17使用描述12中所略述的方法制备得到的。
描述19
(2,2-二乙氧基乙基)-(2-氟苯亚甲基)胺(D19)
将2-氟代苯甲醛(7.45g)加入到氨基乙醛二乙基缩醛(9.16g)中,并将反应于100℃加热3小时。冷却后,将混合物转移至分液漏斗中,并在乙醚和水之间分配。分离乙醚层,经硫酸镁干燥,过滤并减压浓缩,剩下油状物。于0.6-0.8mm蒸馏,收集沸点为102-106℃的馏分,得到无色油状的标题化合物。
描述20
8-氟代异喹啉(D20)
将五氧化二磷(18g)的浓硫酸(5ml)溶液加热至160℃,用5分钟的时间,将其用D19(11.5g)的浓硫酸(75ml)溶液小心地处理。加热25分钟后,将反应冷却,并倒到冰-水悬浮液(11)中。用固体氢氧化钠碱化至pH为10,随后用乙酸乙酯萃取。将有机相经硫酸镁干燥,过滤并减压浓缩,得到粗产物。进行硅胶色谱,用乙酸乙酯和己烷(梯度,最大为10%)洗脱,得到淡黄色晶状固体的产物。
描述21
8-氟-5-硝基异喹啉(D21)
将D2O(0.278g)的浓硫酸(2ml)溶液冷却至0℃。分批加入硝酸钾(0.21g),同时保持温度在0℃以下。在完成加入后,将溶液于0℃再搅拌1.5小时,并且然后于环境温度搅拌24小时。将反应混合物倒到冰-水悬浮液中,用氢氧化钠碱化,并用乙酸乙酯萃取。将乙酸乙酯溶液经硫酸镁干燥,过滤并减压浓缩,剩下粗产物。经乙酸乙酯洗脱的硅胶色谱法纯化,得到黄色晶状固体的标题化合物。
描述22
5-氨基-8-氟代异喹啉(D22)
将D21(0.283g)的乙醇(2ml)溶液用浓盐酸(2ml)处理。将反应混合物于冰浴中冷却,用10分钟分批加入氯化锡(II)二水合物(1.45g)的乙醇(2ml)溶液。再过20分钟将反应混合物用氢氧化钠碱化,并用DCM萃取。将DCM溶液经硫酸镁干燥,过滤并减压浓缩,剩下粗产物。用乙酸乙酯洗脱的硅胶色谱法纯化,得到乳膏状固体的标题化合物。
描述23
(1-苄基-哌啶4-基)-氨基甲酸叔丁酯(D23)
用2小时的时间,向1-苄基-4-氨基哌啶(30g,0.16mol)的DCM(200ml)溶液中滴加二叔丁基焦碳酸酯(1.1eq.,37.9g)的DCM(100ml)溶液。将反应于环境温度搅拌18小时,并且然后将溶剂减压除去,得到白色固体的标题化合物。
描述24
哌啶-4-基-氨基甲酸叔丁基酯(D24)
将D23(10g,3.4mmol)的甲醇(150ml)溶液于50psi在Parr氢化器中用10%的钯碳催化剂(800mg)氢化18小时。将催化剂过滤出去,并将滤液减压浓缩,得到白色固体的标题化合物。
描述25
1-[(5-三氟甲基吡啶-2-基)哌啶4-基]-氨基甲酸叔丁基酯(D25)
标题化合物是由D24和2-氯-5-三氟甲基吡啶使用描述1中所略述的方法制备得到的。
描述26
1-(5-三氟甲基吡啶-2-基)-哌啶4-基胺(D26)
标题化合物是由D25使用描述2中所略述的方法制备得到的。
描述27
3-(3′-异喹啉-5-基-脲基)-哌啶-1-羧酸叔丁酯(D27)
向1-(叔丁氧基羰基)-3-哌啶羧酸(1g,4.4mmol)的甲苯(10ml)和三乙胺(0.68ml)的悬浮液中加入二苯基磷酰基叠氮化物(1.1eq.,1.33g)。将反应加热回流1小时并冷却。加入5-氨基异喹啉(629mg,4.4mmol),并将反应于环境温度搅拌56小时。减压除去溶剂,并将残余物用己烷/乙酸乙酯(梯度洗脱,最大量50%)洗脱的硅胶色谱纯化,得到泡沫状标题化合物。
描述28
N(异喹啉-5-基)-N-(哌啶-3-基)-脲(D28)
标题化合物是由D27使用描述2中所略述的方法制备得到的。
描述29
[(R)-1-(3-三氟甲基吡啶-2-基)-吡咯烷-3-基]-氨基甲酸叔丁酯(D29)
标题化合物是由2-氯-3-三氟甲基吡啶和3R-(+)-3-(叔丁氧基羰基氨基)吡咯烷使用描述1中所略述的方法制备得到的。
描述30
(R)-1-(3-三氟甲基吡啶-2-基)-吡咯烷-3-基胺(D30)
标题化合物是由D29使用描述2中所略述的方法制备得到的。
描述31
[(R)-1-(4-三氟甲基吡啶-2-基)-吡咯烷-3-基]-氨基甲酸叔丁基酯(D31)
标题化合物是由2-氯-4-三氟甲基吡啶和3R-(+)-3-(叔丁氧基羰基氨基)吡咯烷使用描述1中所略述的方法制备得到的。
描述32
(R)-1-(4-三氟甲基吡啶-2-基)-吡咯烷-3-基胺(D32)
标题化合物是由D31使用描述2中所略述的方法制备得到的。
描述33
[(R)-1-(6-三氟甲基吡啶-2-基)-吡咯烷-3-基]-氨基甲酸叔丁基酯(D33)
标题化合物是由2-氯-6-三氟甲基吡啶和3R-(+)-3-(叔丁氧基羰基氨基)吡咯烷使用描述1中所略述的方法制备得到的。
描述34
(R)-1-(6-三氟甲基吡啶-2-基)-吡咯烷-3-基胺(D34)
标题化合物是由D33使用描述2中所略述的方法制备得到的。
描述35
[(R)-1-(3-氯吡啶-2-基)-吡咯烷-3-基]-氨基甲酸叔丁酯(D35)
标题化合物是由2,3-二氯吡啶和3R-(+)-3-(叔丁氧基羰基氨基)吡咯烷使用描述1中所略述的方法制备得到的。
描述36
(R)-1-(3-氯吡啶-2-基)-吡咯烷-3-基胺(D36)
标题化合物是由D35使用描述2中所略述的方法制备得到的。
描述37
[(R)-1-(5-氯吡啶-2-基)-吡咯烷-3-基]-氨基甲酸叔丁酯(D37)
标题化合物是由2,5-二氯吡啶和3R-(+)-3-(叔丁氧基羰基氨基)吡咯烷使用描述1中所略述的方法制备得到的。
描述38
(R)-1-(5-氯吡啶-2-基)-吡咯烷-3-基胺(D38)
标题化合物是由D37使用描述2中所略述的方法制备得到的。
描述39
[(R)-1-(5-溴吡啶-2-基)-吡咯烷-3-基]-氨基甲酸叔丁基酯(D39)
标题化合物是由2-氯-5-溴吡啶和3R-(+)-3-(叔丁氧基羰基氨基)吡咯烷使用描述1中所略述的方法制备得到的。
描述40
(R)-1-(5-溴吡啶-2-基)-吡咯烷-3-基胺(D40)
标题化合物是由D39使用描述2中所略述的方法制备得到的。
描述41
[(R)-1-(6-甲基吡啶-2-基)-吡咯烷-3-基]-氨基甲酸叔丁酯(D41)
标题化合物是由2-氯-6-甲基吡啶和3R-(+)-3-(叔丁氧基羰基氨基)吡咯烷使用描述1中所略述的方法制备得到的。
描述42
(R)-1-(6-甲基吡啶-2-基)-吡咯烷-3-基胺(D42)
标题化合物是由D41使用描述2中所略述的方法制备得到的。
描述43
1-[(3-三氟甲基吡啶-2-基)哌啶-4-基]-氨基甲酸叔丁基酯(D43)
标题化合物是由D24和2-氯-3三氟甲基吡啶使用描述1中所略述的方法制备得到的。
描述44
1-(3-三氟甲基吡啶-2-基)-哌啶-4-基胺(D44)
标题化合物是由D43使用描述2中所略述的方法制备得到的。
描述45
1-[(6-三氟甲基吡啶-2-基)哌啶-4-基]-氨基甲酸叔丁基酯(D45)
标题化合物是由D24和2-氯-6-三氟甲基吡啶使用描述1中所略述的方法制备得到的。
描述46
1-(6-三氟甲基吡啶-2-基)-哌啶-4-基胺(D46)
标题化合物是由D45使用描述2中所略述的方法制备得到的。
描述47
1-[(4-三氟甲基吡啶-2-基)哌啶-4-基]-氨基甲酸叔丁基酯(D47)
标题化合物是由D24和2-氯-4-三氟甲基吡啶使用描述1中所略述的方法制备得到的。
描述48
1-(4-三氟甲基吡啶-2-基)-哌啶-4-基胺(D48)
标题化合物是由D47使用描述2中所略述的方法制备得到的。
描述49
1-[(3-氯-5-三氟甲基吡啶-2-基)哌啶-4-基]-氨基甲酸叔丁基酯(D49)
标题化合物是由D24和2,3-二氯-5-三氟甲基吡啶描述1中所略述的方法制备得到的。
描述50
1-(3-氯-5-三氟甲基吡啶-2-基)-哌啶-4-基胺(D50)
标题化合物是由D49使用描述2中所略述的方法制备得到的。
下列胺使用上文所记载的那些方法制备得到。
(R)-1-(3-甲基吡啶-2-基)-吡咯烷-3-基胺(D51)。
(R)-1-(4-甲基吡啶-2-基)-吡咯烷-3-基胺(D52)。
(R)-1-(5-甲基吡啶-2-基)-吡咯烷-3-基胺(D53)。
(R)-1-(6-甲氧基吡啶-2-基)-吡咯烷-3-基胺(D54)。
1-(3-氰基-5-三氟甲基吡啶-2-基)-哌啶-4-基胺(D55)。
(3R)-(+)-3-(叔丁氧基羰基氨基)吡咯烷、5-氨基异喹啉、1-氨基异喹啉、5-氨基喹啉和7-氨基喹啉可分别从TCI(日本)、Aldrich化学公司和Specs和BioSpecs B.V.购买得到。二叔丁基焦碳酸酯(Di-tert-butyl tricarbonate)可以根据文献(Org.Synth.,1978,57,p.45)中所略述的方法制备得到。2-甲基-7-氨基喹啉可以根据文献(J Med.Chem.,1977,20(11),p.1528)中所略述的方法制备得到。
实施例1
N-(2-溴苯基)-N′-[((R)-1-(5-三氟甲基-2-吡啶基)吡咯烷-3-基)]脲(E1)
在氩气下于环境温度用0.5小时,将2-溴苯基异氰酸酯(Aldrich化学公司)(27.4ml,0.222mol)的干燥乙醚(65ml)溶液滴加到有效搅拌的D2(51.4g,0.222mol)的干燥乙醚(0.8L)溶液中。搅拌18小时后,过滤出白色沉淀,并用干燥的乙醚(2×150ml)洗。将固体压碎成细粉末,并且然后于环境温度下用乙醚(470ml)再搅拌4小时。过滤出不溶物,用乙醚(100ml)洗,并于50℃/真空/24小时干燥,得到白色固体的标题化合物。
1H NMR(d6-DMSO,400MHz)δ1.94-1.98(1H,m),2.19-2.28(1H,m),3.31-3.41(1H,m),3.56(2H,br,s),3.67-3.71(1H,m),4.34-4.36(1H,m),6.62(1H,d,J 9.0Hz),6.89(1H,t,J 7.8Hz),7.28(1H,t,J 8.5Hz),7.47(1H,d,J 6.7Hz),7.55(1H,dd,J 8.0,1.4Hz),7.76-7.79(2H,m),8.12(1H,dd,J 8.3,1.4Hz),8.41(1H,s)。
MH+429,431。
实施例2
N-(异喹啉-5-基)-N′-[((R)-1-(5-三氟甲基-2-吡啶基)吡咯烷-3-基)]脲(E2)
向二叔丁基焦碳酸酯(0.681g,2.595mmol)的干燥DCM(1ml)溶液中一次性地加入D2(0.5g,2.162mol)的干燥DCM(1ml)溶液。在最初冒泡后,将溶液于室温搅拌0.3小时。加入5-氨基异喹啉(0.312g,2.162mol)的干燥DCM(1ml)溶液。将反应混合物于室温搅拌过夜。将生成的沉淀离心除去,并将固体用乙醚洗,并干燥,得到白色固体的标题化合物。
1H NMR(d6-DMSO,250MHz)δ9.26(1H,s),8.57(1H,s),8.52(1H,d),8.41(1H,s),8.31(1H,d),7.88(1H,d),7.78(1H,dd),7.70(1H,d),7.60(1H,t),6.99(1H,d),6.64(1H,d),4.41(1H,m),3.73(1H,dd),3.59(2H,m),3.42(1H,m),2.28(1H,m)和2.02(1H,m)。
MH+402
实施例3
(±)-N-(异喹啉-5-基)-N′-[(1-(5-三氟甲基-2-吡啶基)哌啶-3基)]脲(E3)
将D28(0.2g,0.74mmol)、2-氯-5-三氟甲基吡啶(3eq.,0.4g)的二甲基甲酰胺(10ml)溶液和细粉末状的碳酸钾(3eq.,0.31g)于90℃加热18小时,并冷却。将溶剂减压除去,并将残余物在乙酸乙酯和水之间分配。分离有机相,干燥(MgSO4)并过滤。减压除去溶剂,得到粗产物。将其用乙酸乙酯洗脱的硅胶色谱法纯化,得到灰白色固体的标题化合物,可将其转化为盐酸盐。
MH+(游离碱)416。
两个对映异构体(E3A和E3B)可用HPLC分开:用Chiralpak AD柱(250×19mm id),用正己烷∶乙醇(80∶20v/v)以1ml/分钟的流速进行洗脱,用215nm的紫外光检测。
表1中所代表的实施例可根据文中所记载的以及与E1-E3相似的那些方法制备得到。
表1
S’Chem=立体化学
药理学数据
(a)体外分析
如上文所引用的,本发明化合物为香草素受体(VR1)拮抗剂,并因而具有有益的药用特性。可以通过使用常规的方法来确定和证实任何具体化合物的香草素受体(VR1)拮抗活性,例如在标准参考文献如D.Le Bars,M.Gozarin和S.W.Cadden,Pharmacological Reviews,2001,53(4),597-652]或文中所提及的其它文献中所公开的那些方法。
用于本发明化合物的筛选方法是基于FLIPR的钙分析方法,其与Smart等(British Journal of Pharmacology,2000,129,227-230)所记载的相类似。稳定表达人VR1的转染星形细胞瘤1321N1细胞以25,000细胞/孔(96-孔板)被接种到FLIPR上并培养过夜。
随后使细胞在室温避光下负载含4μM Fluo-3AM(Molecular Probes)的培养基2小时。然后将板用含1.5mM钙不含丙磺舒的Tyrode洗4次。将细胞与化合物或缓冲液对照于室温预培养30分钟。然后将辣椒素(Sigma)加入到细胞中。对人VR1具有拮抗剂活性的化合物可通过检测加入辣椒素后与没有化合物缓冲对照的相比较的荧光差异来确定。因而,例如在缓冲对照中,加入辣椒素会导致细胞内产生荧光的钙浓度增加。具有拮抗剂活性的化合物会阻滞辣椒素与受体的结合,因而没有信号产生并且细胞内钙浓度也没有增加,并且因此有较弱的荧光。pKb值可使用Cheng-Prusoff方程由IC50值得到。
通过上述方法所检测的所有化合物的pKb>6,优选pKb>7.0的化合物。
(b)豚鼠中的FCA-诱导的痛觉过敏
将100μl的1mg/mlFCA通过足底注射到4组、每组8只雄性Dunkin Hartley豚鼠(批号:6282434,平均体重340g)的左爪中。24小时后,将化合物以0(溶媒)、3、10、30mg/kg的剂量与1%甲基纤维素的溶媒一起进行口服给药,并且剂量体积为2ml/kg,并直接施药于胃中。逐渐将甲基纤维素加入到化合物中,放到研杵和研钵中并一起研磨。
获得FCA施用前(自然状态下读数)、施用FCA后但药物施用前(前剂量读数)和在药物施用后1小时机械痛觉过敏的行为读数。所用的读数为爪的压力(Randall-Sellito),并且终点为爪的收回。爪的压力设备也有一个放在尖端的银制圆盘以2倍放大记分。
在此模型中检测上文的模型(a)中具有体外pKb>7.0的化合物,所述化合物显示出活性。
Claims (4)
1.N-(2-溴苯基)-N′-[((R)-1-(5-三氟甲基-2-吡啶基)吡咯烷-3-基)]脲或其可药用盐或溶剂合物。
2.权利要求1的化合物或其可药用盐或溶剂合物在用于治疗或预防疾病的药物的制备中的用途,在所述的疾病中拮抗香草素受体是有益的。
3.根据权利要求2的用途,其中所述的疾病为疼痛、慢性痛、神经性疼痛、术后痛、风湿症后关节炎痛、骨关节炎痛、背痛、内脏痛、癌瘤痛、痛觉、神经痛、牙痛、头痛、偏头痛、神经病、腕管综合征、糖尿病神经病变、HIV-相关的神经病、疱疹后神经痛、纤维肌痛、神经炎、坐骨神经痛、神经损伤、局部缺血、神经变性、中风、中风后疼痛、多发性硬化、呼吸系统疾病、哮喘、咳嗽、COPD、支气管狭窄、炎性疾病、食管炎、心脏灼痛、巴雷特氏组织变形、吞咽困难、胃食管返流疾病、胃和十二指肠溃疡、机能性消化不良、过敏性肠综合征、炎性肠病、结肠炎、节段性回肠病、骨盆超敏反应、骨盆痛、月经痛、肾绞痛、尿失禁、膀胱炎、灼伤、疥疮、牛皮癣、搔痒症、呕吐。
4.一种药用组合物,其包括权利要求1的化合物或其可药用盐或溶剂合物,以及可药用载体或赋形剂。
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