CN106946851A - 一种用于预防和治疗肾结石的药物 - Google Patents
一种用于预防和治疗肾结石的药物 Download PDFInfo
- Publication number
- CN106946851A CN106946851A CN201710151838.4A CN201710151838A CN106946851A CN 106946851 A CN106946851 A CN 106946851A CN 201710151838 A CN201710151838 A CN 201710151838A CN 106946851 A CN106946851 A CN 106946851A
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- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- pyrimidinedione
- prodrugs
- solvates
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 208000000913 Kidney Calculi Diseases 0.000 title claims abstract description 20
- 206010029148 Nephrolithiasis Diseases 0.000 title claims abstract description 20
- 239000003814 drug Substances 0.000 title claims description 9
- -1 pyrimidinedione compound Chemical class 0.000 claims abstract description 57
- 150000003839 salts Chemical class 0.000 claims abstract description 20
- 239000012453 solvate Substances 0.000 claims abstract description 16
- 229940002612 prodrug Drugs 0.000 claims abstract description 15
- 239000000651 prodrug Substances 0.000 claims abstract description 15
- 239000000126 substance Substances 0.000 claims abstract description 14
- 150000001875 compounds Chemical class 0.000 claims description 33
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000006413 ring segment Chemical group 0.000 claims description 12
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 150000008512 pyrimidinediones Chemical class 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 239000011593 sulfur Substances 0.000 claims description 3
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000004955 1,4-cyclohexylene group Chemical group [H]C1([H])C([H])([H])C([H])([*:1])C([H])([H])C([H])([H])C1([H])[*:2] 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical group 0.000 claims description 2
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 2
- 125000000732 arylene group Chemical group 0.000 claims description 2
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 2
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 abstract description 14
- 210000003734 kidney Anatomy 0.000 abstract description 13
- 210000002966 serum Anatomy 0.000 abstract description 12
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- 239000011575 calcium Substances 0.000 abstract description 7
- 229910052791 calcium Inorganic materials 0.000 abstract description 7
- 229940109239 creatinine Drugs 0.000 abstract description 7
- 230000003449 preventive effect Effects 0.000 abstract description 7
- 230000001225 therapeutic effect Effects 0.000 abstract description 7
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 13
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000004575 stone Substances 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
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- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
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- 229910052760 oxygen Inorganic materials 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 0 CC(N1)N(CCCNC(*c2ccccn2)S)C(c2ccccn2)=CC1=* Chemical compound CC(N1)N(CCCNC(*c2ccccn2)S)C(c2ccccn2)=CC1=* 0.000 description 3
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- 150000001298 alcohols Chemical class 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
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- 230000000694 effects Effects 0.000 description 3
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- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
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- VSKOGVQQRUJABB-UHFFFAOYSA-N 6-pyridin-2-yl-1h-pyrimidine-2,4-dione Chemical compound OC1=NC(O)=CC(C=2N=CC=CC=2)=N1 VSKOGVQQRUJABB-UHFFFAOYSA-N 0.000 description 2
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D401/14—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 three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种化学式I的嘧啶二酮类化合物及其药学上可接受的盐、前药和溶剂化物。药理试验表明，本发明所述化学式I的嘧啶二酮类化合物能够显著降低肾脏结石率和肾钙含量、血清尿素氮和血清肌酐，能够明显提高肾脏系数，对于肾结石具有良好的预防和治疗效果。
Description
技术领域
本发明涉及医药技术领域，本发明公开了用于预防和治疗肾结石的药物。
背景技术
肾结石指发生于肾盏，肾盂及肾盂与输尿管连接部的结石。多数位于肾盂肾盏内，肾实质结石少见，平片显示肾区有单个或多个圆形、卵圆形或钝三角形致密影，密度高而均匀，边缘多光滑，但也有不光滑呈桑椹状。泌尿系统任何部位的结石均可原发于肾脏。根据结石成分的不同，肾结石可分草酸钙结石、磷酸钙结石、尿酸(尿酸盐)结石、磷酸铵镁结石、胱氨酸结石及嘌呤结石六类。肾结石是由于机体内胶体和晶体代谢平衡失调所致，与感染、营养代谢紊乱、泌尿系统异物、尿郁积以及地理气候等因素有关，可出现同侧腰痛、肾绞痛、尿内带血等症状，易引发痛风及糖尿病、高血压、急性肾盂肾炎、慢性肾衰竭、尿毒症等多种严重影响健康和生活的疾病，近年临床发病率增高趋势。
目前临床多采取体外冲击碎石术(ESWL)或其他排石技术。这种方法虽可使结石排出，但副作用非常多，而且结石的残留率和复发率非常高。据统计，肾结石的复发危险性5年内达50％，9年内达67％，25年内达75％。因此寻找一种切实有效地治疗方式非常必要。
发明内容
本发明的目的在于提供一种对肾结石具有预防和治疗作用的药物。
根据本发明的一个方面，本发明提供了一种嘧啶二酮类化合物，及其药学上可接受的盐、前药和溶剂化物。
根据本发明的另一个方面，本发明的再一个目的是提供所述嘧啶二酮类化合物，及其药学上可接受的盐、前药和溶剂化物的制备方法。
根据本发明的另一个方面，本发明的再一个目的是提供所述嘧啶二酮类化合物，及其药学上可接受的盐、前药和溶剂化物在制备药物中的应用，所述药物用于预防和治疗肾结石。
根据本发明的另一个方面，本发明的再一个目的是提供一种包含选自所述嘧啶二酮类化合物，及其药学上可接受的盐、前药和溶剂化物中的一种或多种的药物组合物。
根据本发明的嘧啶二酮类化合物由以下化学式I表示：
[化学式I]
式I中，
W1、W2可以相同或不同，各自独立地选自：N或CR1；
A选自：取代或未取代的C1-6亚烷基、取代或未取代的C3-6亚环烷基、取代或未取代的C6-12的亚芳基，其中取代基为C1-6烷基、C3-6环烷基或卤素，并且A中的一个或更多个-CH2-可以任选地被选自-NH-、-O-或-S-的基团所代替，条件是不能有两个选自-NH-、-O-或-S-的基团连接在一起；
R1各自独立地选自：H、卤素、任选被卤素或OH取代的C1-6烷基、CN、OH、氨基、C1-6烷氧基、C2-6炔基、C2-6烯基、C3-6环烷基、C1-6烷基氨基、甲酰基、COOH、COOR2、COR2、CONR2R2a、-NHCOR2、-NHSO2R2、杂环烷基、芳基、杂芳基、C1-6烷基磺酰基、芳基磺酰基或杂芳基磺酰基；R2和R2a各自独立地选自C1-6烷基、C3-6环烷基或杂环烷基，或者，R2和R2a与它们所连接的N原子一起形成3-7元的杂环烷基；
Hy表示杂芳基，该杂芳基任选地被一个或多个取代基取代，这些取代基独立地选自H、卤素、任选被卤素或OH取代的C1-6烷基、CN、OH、氨基、C1-6烷氧基、C2-6炔基、C2-6烯基、C3-6环烷基、C1-6烷基氨基、甲酰基、COOH、COOR3、COR3、CONR3R3a、-NHCOR3、-NHSO3R3；R3和R3a各自独立地选自C1-6烷基、C3-6环烷基或杂环烷基，或者，R3和R3a与它们所连接的N原子一起形成3-7元的杂环烷基；
n表示0、1、2或3。
在一个优选实施方案中，W1、W2各自独立地选自：N。
在一个优选实施方案中，W1选自N，W2选自CR1。
在一个优选实施方案中，A选自：取代或未取代的C1-6亚烷基。
在一个优选实施方案中，A选自：-CH2CH2-、-CH2CH2CH2-、-CH2CH2OCH2-、-CH2CH(CH3)CH2-。
在一个优选实施方案中，A选自：1，4-亚环己基。
在一个优选实施方案中，Hy所表示的杂芳基为包含1至4个选自氧、硫和氮的杂原子作为环原子，其余的环原子为碳的5至10元优选5元或6元的芳基。
本发明优选的化合物是：
在本发明的一个优选实施方案中，本发明提供化学式I的嘧啶二酮类化合物的药学上可接受的盐选自碱加成盐和酸加成盐。优选地，所述碱加成盐选自钠盐、钾盐、钙盐、锂盐、镁盐、锌盐、铵盐、四甲基铵盐、四乙基铵盐、三乙胺盐、三甲基铵盐、乙胺盐、二乙醇胺盐、精氨酸盐或赖氨酸盐；或酸加成盐选自盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、甲磺酸盐或对甲苯磺酸盐。
本发明也包括经同位素标记的本发明的化合物，若非一或多个原子由具有与自然界常见的原子质量或质量数不同的原子质量或质量数的原子替代的情况外，否则该经同位素标记的化合物与本文所述的彼等化合物相同。可并入本发明化合物的同位素的实例包括氢、碳、氮、氧、氟及氯的同位素，诸如2H、3H、13C、14C、15N、18O、17O、18F及36Cl。
在本发明中，对本发明化合物的前药没有具体限制，只要其在生物体内能够代谢成本发明化合物即可，非限制性地包括酯等，例如甲酯、乙酯等。
在本发明中，本发明的溶剂化物是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。
基团定义
除非有相反陈述，否则下列用在说明书和权利要求书中的术语具有下述含义。
术语“烷基”指饱和的脂族烃基团，包括1至20个碳原子的直链和支链基团。优选含有1至10个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2，2-二乙基戊基、正癸基、3，3-二乙基己基、2，2-二乙基己基，及其各种支链异构体等。
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。优选C2-10烯基，更优选C2-6烯基，最优选C2-4烯基。
术语“炔基”指至少由两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，例如乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基等。优选C2-10炔基，更优选C2-6炔基，最优选C2-4炔基。
术语“环烷基”指饱和单环环状烃取代基，其包括3至20个碳原子，优选包括3至12个碳原子，更优选环烷基环包含3至10个碳原子，最优选环烷基环包含3至6个碳原子。单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环庚基、环辛基等，优选环丙基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，更优选苯基和萘基，最优选苯基。
术语“杂芳基”指具有1至4个选自氧、硫和氮的杂原子作为环原子，其余的环原子为碳的5至14元芳基。杂芳基优选为5至10元，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基、四氮唑等。
术语“杂环烷基”指饱和单环或多环环状烃取代基，其包括3至20个环原子，其中一个或多个环原子选自氮、氧或S(O)m(其中m是0至2的整数)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包括3至12个环原子，其中1～4个是杂原子，更优选杂环基环包含3至10个环原子，更优选杂环基环包含5至6个环原子。单环杂环基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基、二氢呋喃基、四氢呋喃基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“卤素”指氟、氯、溴或碘。
药物组合物
所用术语“药物组合物”指的是：含有用药学上可接受的赋形剂配制的至少一种本发明所述的化学式I的嘧啶二酮类化合物及其药学上可接受的盐、前药和溶剂化物的组合物。典型的药物组合物为：散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂、注射剂、喷雾剂、气雾剂、粉雾剂、洗剂、搽剂、软膏剂、硬膏剂、糊剂、贴剂等。
本发明所用术语“赋形剂”指的是：抗黏着剂、抗氧化剂、黏合剂、包衣剂、压片助剂、崩解剂、润滑剂、乳化剂等。典型的赋形剂为：丁羟甲苯、碳酸钙、磷酸钙、硬脂酸钙、交联羧甲基纤维素、交联聚乙烯吡咯烷酮、柠檬酸、交聚维酮、半胱氨酸、乙基纤维素、明胶、羟丙基纤维素、羟丙基甲基纤维素、乳糖、硬脂酸镁、麦芽糖醇、甘露醇、蛋氨酸、甲基纤维素、对羟基苯甲酸甲酯、聚乙二醇、柠檬酸钠、山梨醇、淀粉、硬脂酸、蔗糖、滑石粉、二氧化钛、维生素A、维生素C、维生素E、木糖醇等。
本发明的合成方法
本发明所述化学式I的嘧啶二酮类化合物可通过以下方法制备：
步骤一：
该步骤包括使化学式II的化合物与化学式III的化合物以及钯催化剂、碱在惰性溶剂中反应以制备化学式IV的化合物。
用于该步骤的溶剂可为醇，例如甲醇、乙醇、异丙醇等；芳烃，例如苯、甲苯或二甲苯；卤代烃，例如二氯甲烷、氯仿、四氯化碳；腈类溶剂，如乙腈；醚类溶剂，例如四氢呋喃、1，4-二氧六环；或它们的混合溶剂。溶剂优选为1，4-二氧六环。
用于该步骤的碱可为氢氧化物，例如氢氧化钠、氢氧化钾；碳酸盐，例如碳酸钠、碳酸钾、碳酸铯；碳酸氢盐，例如碳酸氢钠、碳酸氢钾。碱优选为碳酸盐，更优选碳酸钾。
步骤二：
该步骤包括使化学式V的化合物与化学式VI的化合物以及碱、催化剂在惰性溶剂中反应以制备化学式VII的化合物。
用于该步骤的溶剂可为醇，例如甲醇、乙醇、异丙醇等；芳烃，例如苯、甲苯或二甲苯；卤代烃，例如二氯甲烷、氯仿、四氯化碳；腈类溶剂，如乙腈；或它们的混合溶剂。溶剂优选为乙腈。
用于该步骤的碱可为氢氧化物，例如氢氧化钠、氢氧化钾；碳酸盐，例如碳酸钠、碳酸钾；碳酸氢盐，例如碳酸氢钠、碳酸氢钾；醋酸盐，例如醋酸钠或醋酸钾。碱优选为碳酸氢盐，更优选碳酸氢钾。
用于该步骤的催化剂可为亚铜盐，例如碘化亚铜。
步骤三：
该步骤包括使化学式IV化合物与化学式VII化合物以及碱在惰性溶剂中反应以制备化学式I的化合物。
用于该步骤的溶剂可为醇，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、异戊醇、辛醇、环己醇、2-甲氧基乙醇、二甘醇或甘油；芳烃，例如苯、甲苯或二甲苯；卤代烃，例如氯仿、二氯甲烷；或它们的混合溶剂。溶剂优选为芳烃，更优选甲苯。
用于该步骤的碱可为氢氧化物，例如氢氧化钠、氢氧化钾；碳酸盐，例如碳酸钠、碳酸钾、碳酸铯；碳酸氢盐，例如碳酸氢钠、碳酸氢钾。碱优选为碳酸盐，更优选碳酸铯。
上述步骤中，W1、W2、A、R1、Hy、n的定义如上所述，X1、X2可以相同或不同，各自独立地选自卤素，优选氯或溴。
有益效果
本发明所述的嘧啶二酮类化合物能够显著降低肾脏结石率和肾钙含量、血清尿素氮和血清肌酐，能够明显提高肾脏系数，对于肾结石具有良好的预防和治疗效果。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
实施例1：1-(3-(2，4-二氧代-6-(吡啶-2-基)-3，4-二氢嘧啶-1(2H)-基)丙基)-3-(嘧啶-2-基)脲(化合物1)
步骤一、向干燥的Schlenk反应管中加入6-氯嘧啶-2，4(1H，3H)-二酮(0.29g，2.0mmol)、吡啶-2-基硼酸(0.30g，2.2mmol)、四(三苯基膦)钯(29mg，0.025mmol)、K2CO3(0.33g，2.4mmol)，在氮气保护下，加入1，4-二氧六环(10mL)、水(2mL)，45℃反应4h。反应结束后，减压除去溶剂，残余物用乙酸乙酯溶解后用硅胶柱色谱分离，用石油醚/乙酸乙酯20∶1洗脱，得到浅黄色固体6-(吡啶-2-基)嘧啶-2，4(1H，3H)-二酮，其为浅黄色固体0.28g，纯度98％，收率74％。ESI-MS：190.05[M+H]+。
步骤二：将1，3-二溴丙烷(1.00g，5.0mmol)、KHCO3(1.03g，7.5.0mmol)、CuI(0.095g，0.5mmol)和甲苯(50ml)混合在一起，搅拌下加热至80℃，然后将1-(嘧啶-2-基)脲(0.69g，5.0mmol)在甲苯(30ml)中的溶液缓慢滴加进去，1小时滴加完毕，在加热回流下搅拌6小时。反应结束后减压蒸除溶剂，残余物用乙醇重结晶，得到白色晶体1-(3-溴丙基)-3-(嘧啶-2-基)脲1.07g，纯度97％，收率85％。ESI-MS：259.01[M+H]+。
步骤三：将6-(吡啶-2-基)嘧啶-2，4(1H，3H)-二酮(0.19g，1.0mmol)、1-(3-溴丙基)-3-(嘧啶-2-基)脲(0.28g，1.1mmol)、碳酸钾(0.28g，2mmol)在乙腈(30mL)中的混合物在60℃搅拌12h，减压除去溶剂，将残余物通过硅胶柱色谱纯化，用石油醚/乙酸乙酯4∶1洗脱，得到白色固体1-(3-(2，4-二氧代-6-(吡啶-2-基)-3，4-二氢嘧啶-1(2H)--基)丙基)-3-(嘧啶-2-基)脲0.30g，纯度99％，收率81％。
ESI-MS：368.14[M+H]+
元素分析：理论值/实测值，C(55.58/55.42)，H(4.66/4.74)，N(26.69/26.61)，O(13.07/13.23)
1H NMR(400MHz，DMSO-D6)δ11.99(s，1H)，9.92(s，1H)，8.42(m，3H)，7.41-7.48(m，3H)，6.98(q，1H)，6.57(s，1H)，6.04(s，1H)，4.01(t，2H)，3.31(t，2H)，1.74(m，2H)。
按照类似的方法，合成以下化合物：
药理试验实施例：目标化合物对肾结石的预防和治疗作用
1.化合物1-4对大鼠肾结石和肾脏参数的影响
取180-220g的雄性Wistar大鼠60只，随机分为七组，即对照组、模型组、化合物1-5组(统称实验组)。各组大鼠均使用普通饲料和蒸馏水饲养。模型组、实验组五组大鼠使用1％乙二醇(EG)+2％氯化铵(AC)每天灌胃2mL/只。造模开始即给药，每天一次，连续八周。阳性对照组选择中药肾石通颗粒作为阳性对照药，每天灌胃3g/kg。实验组每天灌胃20mg/kg。末次给药1h后，使用戊巴比妥钠麻醉动物，腹主动脉取血，检测血尿素氮、肌酐含量，取肾脏检测肾脏系数，取左肾测肾钙含量，右肾做病理学检查，测成石率。实验结果应用SPSS统计软件。
表1目标化合物对大鼠肾结石的影响
表2目标化合物对大鼠肾脏系数、肾钙含量、血清肌酐和、血清尿素氮的影响
注：与空白对照组比较，*P＜0.05，＊＊P＜0.01；
上述试验结果表明，与对照组相比，模型组大鼠的结石率显著高于对照组，肾脏系数显著低于对照组，肾钙含量、血清尿素氮和血清肌酐显著高于对照组，提示结石模型造模成功。与模型组相比，实验组大鼠的结石率和肾钙含量、血清尿素氮和血清肌酐大幅下降，肾脏系数则是显著提高(P＜0.01)。与阳性对照相比，本发明化合物对于肾结石的预防和治疗效果与现有的肾石通颗粒相当。因此，本发明化合物对于肾结石具有良好的预防和治疗效果。
综上所述，本发明所述的嘧啶二酮类化合物能够显著降低肾脏结石率和肾钙含量、血清尿素氮和血清肌酐，能够明显提高肾脏系数，对于肾结石具有良好的预防和治疗效果。
以上描述了本发明优选实施方式，然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (9)
1.一种化学式I的嘧啶二酮类化合物，及其药学上可接受的盐、前药和溶剂化物：
[化学式I]
式I中，
W1、W2可以相同或不同，各自独立地选自：N或CR1；
A选自：取代或未取代的C1-6亚烷基、取代或未取代的C3-6亚环烷基、取代或未取代的C6-12的亚芳基，其中取代基为C1-6烷基、C3-6环烷基或卤素，并且A中的一个或更多个-CH2-可以任选地被选自-NH-、-O-或-S-的基团所代替，条件是不能有两个选自-NH-、-O-或-S-的基团连接在一起；
R1各自独立地选自：H、卤素、任选被卤素或OH取代的C1-6烷基、CN、OH、氨基、C1-6烷氧基、C2-6炔基、C2-6烯基、C3-6环烷基、C1-6烷基氨基、甲酰基、COOH、COOR2、COR2、CONR2R2a、-NHCOR2、-NHSO2R2、杂环烷基、芳基、杂芳基、C1-6烷基磺酰基、芳基磺酰基或杂芳基磺酰基；R2和R2a各自独立地选自C1-6烷基、C3-6环烷基或杂环烷基，或者，R2和R2a与它们所连接的N原子一起形成3-7元的杂环烷基；
Hy表示杂芳基，该杂芳基任选地被一个或多个取代基取代，这些取代基独立地选自H、卤素、任选被卤素或OH取代的C1-6烷基、CN、OH、氨基、C1-6烷氧基、C2-6炔基、C2-6烯基、C3-6环烷基、C1-6烷基氨基、甲酰基、COOH、COOR3、COR3、CONR3R3a、-NHCOR3、-NHSO3R3；R3和R3a各自独立地选自C1-6烷基、C3-6环烷基或杂环烷基，或者，R3和R3a与它们所连接的N原子一起形成3-7元的杂环烷基；
n表示0、1、2或3。
2.根据权利要求1所述的嘧啶二酮类化合物，及其药学上可接受的盐、前药和溶剂化物，其特征在于，所述W1、W2各自独立地选自：N。
3.根据权利要求1所述的嘧啶二酮类化合物，及其药学上可接受的盐、前药和溶剂化物，其特征在于，所述A选自：-CH2CH2-、-CH2CH2CH2-、-CH2CH2OCH2-、-CH2CH(CH3)CH2-。
4.根据权利要求1所述的嘧啶二酮类化合物，及其药学上可接受的盐、前药和溶剂化物，其特征在于，所述A选自：1，4-亚环己基。
5.根据权利要求1所述的嘧啶二酮类化合物，及其药学上可接受的盐、前药和溶剂化物，其特征在于，Hy所表示的杂芳基为包含1至4个选自氧、硫和氮的杂原子作为环原子，其余的环原子为碳的5至10元优选5元或6元的芳基。
6.根据权利要求1所述的嘧啶二酮类化合物，及其药学上可接受的盐、前药和溶剂化物，其特征在于，所述嘧啶二酮类化合物选自：
7.一种制备根据权利要求1所述的嘧啶二酮类化合物的方法，所述方法包括以下步骤：
步骤一：
该步骤包括使化学式II的化合物与化学式III的化合物以及钯催化剂、碱在惰性溶剂中反应以制备化学式IV的化合物；
步骤二：
该步骤包括使化学式V的化合物与化学式VI的化合物以及碱、催化剂在惰性溶剂中反应以制备化学式VII的化合物；
步骤三：
该步骤包括使化学式IV化合物与化学式VII化合物以及碱在惰性溶剂中反应以制备化学式I的化合物；
上述步骤中，W1、W2、A、R1、Hy、n的定义如权利要求1中所述，X1、X2可以相同或不同，各自独立地选自卤素，优选氯或溴。
8.一种药物组合物，其含有用药学上可接受的赋形剂配制的至少一种根据权利要求1-6任一项所述的化学式I的嘧啶二酮类化合物及其药学上可接受的盐、前药和溶剂化物。
9.根据权利要求1-6任一项所述的化学式I的嘧啶二酮类化合物及其药学上可接受的盐、前药和溶剂化物在制备药物中的应用，所述药物用于预防和治疗肾结石。
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| WO2008084223A2 (en) * | 2007-01-11 | 2008-07-17 | Astrazeneca Ab | Chemical compounds 637: pyridopyrimidinediones as pde4 inhibitors |
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| WO2014205223A1 (en) * | 2013-06-21 | 2014-12-24 | MyoKardia, Inc. | Pyrimidinedione compounds against cardiac conditions |
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| WO2007035629A2 (en) * | 2005-09-16 | 2007-03-29 | Takeda Pharmaceutical Company Limited | Process for the preparation of pyrimidinedione derivatives |
| WO2008084223A2 (en) * | 2007-01-11 | 2008-07-17 | Astrazeneca Ab | Chemical compounds 637: pyridopyrimidinediones as pde4 inhibitors |
| WO2014205223A1 (en) * | 2013-06-21 | 2014-12-24 | MyoKardia, Inc. | Pyrimidinedione compounds against cardiac conditions |
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