CN1134417A - 2,8-二取代的喹唑啉酮 - Google Patents
2,8-二取代的喹唑啉酮 Download PDFInfo
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- CN1134417A CN1134417A CN96101906A CN96101906A CN1134417A CN 1134417 A CN1134417 A CN 1134417A CN 96101906 A CN96101906 A CN 96101906A CN 96101906 A CN96101906 A CN 96101906A CN 1134417 A CN1134417 A CN 1134417A
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- carbon atoms
- branched alkyl
- expression
- alkyl
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- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 81
- 239000003814 drug Substances 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 5
- 206010061218 Inflammation Diseases 0.000 claims abstract description 4
- 230000004054 inflammatory process Effects 0.000 claims abstract description 4
- 208000001435 Thromboembolism Diseases 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 86
- 125000004432 carbon atom Chemical group C* 0.000 claims description 64
- 238000000034 method Methods 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Substances 0.000 claims description 24
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- -1 2,8-disubstituted quinazolines ketone Chemical class 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 9
- 238000005984 hydrogenation reaction Methods 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000000524 functional group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 3
- 239000004593 Epoxy Substances 0.000 claims description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 150000003053 piperidines Chemical class 0.000 claims description 3
- 125000005936 piperidyl group Chemical group 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 208000005189 Embolism Diseases 0.000 claims description 2
- 230000004913 activation Effects 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
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- 125000005842 heteroatom Chemical group 0.000 claims description 2
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
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- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 238000007142 ring opening reaction Methods 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 230000009424 thromboembolic effect Effects 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
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- 238000006243 chemical reaction Methods 0.000 abstract description 16
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 117
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- 239000000203 mixture Substances 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000003480 eluent Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
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- 238000003756 stirring Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000007738 vacuum evaporation Methods 0.000 description 5
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N 1-Heptene Chemical compound CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 4
- QAXDVKBGZRMSHF-UHFFFAOYSA-N 6-acetyl-5-hydroxy-4-methoxy-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylic acid Chemical compound C1=2C=C(C(O)=O)NC=2C(OC)=C(O)C2=C1CCN2C(C)=O QAXDVKBGZRMSHF-UHFFFAOYSA-N 0.000 description 4
- TYNSUEXNGLNQSS-UHFFFAOYSA-N 6-carbamoyl-5-hydroxy-4-methoxy-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylic acid Chemical compound C1=2C=C(C(O)=O)NC=2C(OC)=C(O)C2=C1CCN2C(N)=O TYNSUEXNGLNQSS-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 108010044467 Isoenzymes Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 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
- 238000002425 crystallisation Methods 0.000 description 3
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- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 3
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明涉及2,8-二取代的喹唑啉酮的制备方法,方法如下:首先将喹唑啉酮基本骨架通过常规反应缩合,然后将所需的取代基引至8位。这些化合物适宜作为药物、尤其是治疗炎症、血栓栓塞疾病和心血管疾病的药物中的活性化合物。
Description
本发明涉及2,8-二取代的喹唑啉酮、其制备方法及其在药物、尤其是治疗炎症、血栓栓塞和心血管疾病和泌尿生殖***疾病的药物方面的用途。
由PCT WO93/12095公开中得知喹唑啉酮具有选择性的cGMP PDE抑制作用。
磷酸二酯酶(PDEs)在调节细胞内cGMP和cAMP水平方面起重要作用。迄今所知的磷酸二酯酶同功酶族PDE I至PDE V[名称根据Beavo和Reifsnyder(参见Beavo,J.A.和Reifsnyder,D.H.:Trends inPharmacol.Sci.11,150-155(1990))]、Ca-调钙蛋白激活的PDEI、cGMP可兴奋的PDE II和cGMP特异性PDE V主要决定着cGMP的代谢。由于这些代谢cGMP的PDE在组织中的分布不同,因此选择性抑制剂应能根据相应同功酶在组织中的分布提高相应组织中的cGMP水平。这可产生特异性的抗聚集、镇痉、血管舒张、抗心律失常和/或抗炎作用。
因此,本发明涉及通式(I)2,8-二取代的喹唑啉酮及其互变异构体和盐:式中A代表可任选地被具有至多8个碳原子的直链或支链烷基取代的环氧乙烷基,所述烷基又可被苯基取代,或者代表下式基团:式中R1表示氢或具有至多6个碳原子的直链或支链烷基,R2表示具有至多8个碳原子的直链或支链烷基,该烷基可任选地被
苯基取代,R3代表具有至多5个碳原子的直链或支链烷基或式-OR6基团,其中
R6表示氢,羟基保护基团或具有至多5个碳原子的直链或支链烷
基,R4表示具有2至10个碳原子的直链或支链烷基,该烷基可任选地被
苯基取代,L表示式-CO-、-CH(OH)、-CH2、-CH(N3)或-CH(OSO2R7)基团,其中R7表示具有至多4个碳原子的直链或支链烷基或苯基,R5表示具有3至8个碳原子的直链或支链烷基,该烷基可任选地被苯
基取代,或表示苄基或2-苯基乙基,D代表氢,或代表式-SO2-NR8R9基团,式中R8和R9相同或不同,表示氢,苯基或具有至多6个碳原子且可任选
地被羟基取代的直链或支链烷基,或者与氮原子一起形成具有至
多2个选自S、N和/或O的另外的杂原子并可任选地被具有至多6
个碳原子的直链或支链烷基取代(包括通过游离的N官能基取代)
的5或6元饱和杂环基团,所述烷基又可被羟基取代,和E代表具有至多8个碳原子的直链或支链烷基。
按照本发明的物质还可以为盐的形式。在本发明范围内优选生理上可接受的盐。
生理上可接受的盐可以是本发明化合物与无机或有机酸形成的盐。优选的盐是与下列酸形成的盐:无机酸,例如盐酸、氢溴酸、磷酸或硫酸,有机羧酸或磺酸,例如乙酸、马来酸、富马酸、苹果酸、柠檬酸、酒石酸、乳酸、苯甲酸或甲磺酸、乙磺酸、苯磺酸、甲苯磺酸或萘二磺酸。
按照本发明的通式(I)化合物可以各种立体化学形式存在,或者呈镜像(对映体)或者不呈镜像(非对映体)。本发明涉及对映体和外消旋体以及非对映体混合物。外消旋体同非对映体一样,可以用已知方法分离成立体异构相同的成分。
通过氮原子键合并可以再含有至多2个氧、硫和/或氮原子作杂原子的5或6元饱和杂环基团一般代表哌啶基、吗啉基或哌嗪基。吗啉基是特别优选的。
在上述定义范围内的羟基保护基团一般代表来自三甲基甲硅烷基、三乙基甲硅烷基、三异丙基甲硅烷基、叔丁基二甲基甲硅烷基、三苯基甲硅烷基或苄基系列的保护基团。优选三甲基甲硅烷基、叔丁基二甲基甲硅烷基或苄基。
优选的化合物是取代基如下定义的通式(I)化合物及其互变异构体和盐:A代表可任选地被具有至多7个碳原子的直链或支链烷基取代的环氧乙烷基,所述烷基又可被苯基取代,或者代表下式基团: 式中R1表示氢或具有至多5个碳原子的直链或支链烷基,R2表示具有至多6个碳原子的直链或支链烷基,该烷基可任选地被
苯基取代,R3代表具有至多4个碳原子的直链或支链烷基或式-OR6基团,其中
R6表示氢,苄基,乙酰基或具有至多4个碳原子的直链或支链烷
基,R4表示具有2至8个碳原子的直链或支链烷基,该烷基可任选地被苯
基取代,L表示式-CO-、-CH(OH)、-CH2、-CH(N3)或-CH(OSO2R7)基团,其中R7表示具有至多3个碳原子的直链或支链烷基或苯基,R5表示具有3至7个碳原子的直链或支链烷基,该烷基可任选地被苯
基取代,或表示苄基或2-苯基乙基,D代表氢,或代表式-SO2-NR8R9基团,式中R8和R9相同或不同,表示氢,苯基或具有至多5个碳原子且可任选
地被羟基取代的直链或支链烷基,或者与氮原子一起形成吗啉基
、哌啶基或哌嗪基环,这些环可任选地被具有至多4个碳原子的
直链或支链烷基取代,包括通过游离的N官能基取代,所述烷基
又可以被羟基取代,和E代表具有至多6个碳原子的直链或支链烷基。
特别优选的化合物是取代基如下定义的通式(I)化合物及其互变异构体和盐:A代表可任选地被具有至多6个碳原子的直链或支链烷基取代的环氧乙烷基,所述烷基又可被苯基取代,或者代表下式基团:式中R1表示氢或具有至多3个碳原子的直链或支链烷基,R2表示具有至多6个碳原子的直链或支链烷基,该烷基可任选地被
苯基取代,R3代表具有至多4个碳原子的直链或支链烷基或式-OR6基团,其中R6表示氢,苄基,乙酰基或具有至多3个碳原子的直链或支链烷
基,R4表示具有2至7个碳原子的直链或支链烷基,该烷基可任选地被苯
基取代,L表示式-CO-、-CH(OH)、-CH2、-CH(N3)或-CH(OSO2R7)基团,其中R7表示具有至多3个碳原子的直链或支链烷基或苯基,R5表示具有3至6个碳原子的直链或支链烷基,该烷基可任选地被苯
基取代,或表示苄基或2-苯基乙基,D代表氢,或代表式-SO2-NR8R9基团,式中R8和R9相同或不同,表示氢,苯基或具有至多3个碳原子的直链或支链烷基,或者与氮原子一起形成吗啉基或哌啶基环,和E代表具有至多4个碳原子的直链或支链烷基。
此外,还发现了用于制备按照本发明的通式(I)化合物的方法,其特征在于:将通式(II)化合物用甲酰胺先环化,得到通式(III)化合物,并在最后一步在惰性溶剂中在碱存在下并在三-邻甲苯基膦/乙酸钯(II)体系中用通式(IV)化合物将它们转化成通式(Ia)化合物,并且,若合适,将双键氢化,或者,在A=取代的环氧乙烷基的情况下,若合适,通过常规方法用氧化剂在惰性溶剂中将双键氧化,得到相应的环氧化合物,并将其通过开环反应转化成相应的羟基化合物,并且,由该羟基化合物出发,若合适,在活化后,进行亲核取代反应,或者将羟基化合物氧化成氧基化合物(oxo compound);所述通式(II)、(III)、(IV)和(Ia)如下:式中D和E的定义同上,T代表C1-C4烷基,和R10代表囟素,优选溴或碘,式中D、E和R10的定义同上,
在反应条件下不变化的惰性有机溶剂均适用于该方法。所述溶剂最好包括醚类,例如***、二氧六环、四氢呋喃或乙二醇一或二甲醚,囟代烃类,例如二氯甲烷,氯仿或四氯化碳、二氯乙烯或三氯乙烯,乙酸乙酯,甲苯,乙腈,二甲基甲酰胺,六甲基磷酸三酰胺和丙酮。当然可以使用所述溶剂的混合物。特别优选二氯甲烷和二甲基甲酰胺。
反应温度一般在相当宽的范围内变动。反应一般在-20℃至200℃、优选0℃至25℃范围内进行。
环化反应一般在+50℃至200℃、优选+160℃至+180℃的温度范围内进行。
通式(Ia)化合物的制备通常在一种上述的溶剂、优选二甲基甲酰胺中并在碱存在下进行。
可用的碱一般是无机或有机碱,最好包括碱金属碳酸盐,例如碳酸钠、碳酸钾或碳酸铯,或碱金属或碱土金属醇化物或氨基化物,例如甲醇钠或钾、乙醇钠或钾、叔丁醇钾或氨基化锂,或有机胺(三烷基(C1-C6)胺),例如三乙胺或三丁胺。特别优选三丁胺。
碱的用量一般为每摩尔式(III)化合物0.05-10mol,优选1-2mol。
按照本发明的方法一般在0℃至180℃、优选+30℃至150℃的温度范围内实施。
按照本发明的操作步骤一般在常压下进行。但也可以在加压或减压下(例如在0.5-5巴范围内)进行。
环氧化一般在一种上述的溶剂、优选无水氯仿中在氧化剂例如间氯过苯甲酸或H2O2存在下进行。优选间氯过苯甲酸。
环氧化一般在-20℃-+50℃、优选0℃-+30℃的温度范围内进行。
氢化一般在一种上述的醇、优选甲醇中进行。
钯化合物一般适宜用作催化剂。优选Pd/C。
催化剂的用量为每摩尔相应的醇0.01-0.4mol,优选0.05-0.2mol。
氢化一般在-20℃-+50℃、优选0℃-+30℃的温度范围内进行。
氢化一般在常压下进行。但也可以在加压或减压下(例如在0.5-5巴范围内)进行。
环氧化物的开环按文献[参见Takano等人,Heterocycles29,(1989),249]中所述的方法,也在一种上述的醇、优选甲醇中在醚合三氟化硼存在下进行。
与烷基磺酰氯的反应由相应的游离羟基化合物出发,在一种上述的溶剂和一种碱、优选二氯甲烷和三乙胺中在-20℃-+20℃温度范围内、优选0℃和常压下进行。
叠氮化物基团的引入一般通过使相应的烷基磺酰氧基取代的化合物在一种上述的溶剂、优选二甲基甲酰胺中在50℃-+120℃的温度范围内、优选100℃和常压下与叠氮化钠反应来进行。
酮用已知方法(Swern氧化)由相应的羟基化合物来制备。
对映体纯的化合物可容易地用常规方法例如通过将通式(I)的外消旋化合物层析分离以手性状态得到。
通式(II)化合物在某些情况下是已知的或是新的,可用下述方法制得:使通式(V)化合物在惰性溶剂中并在碱存在下与式(VI)2-正烷氧基苯甲酰氯反应,所述通式(V)和式(VI)如下:式中R10和T的定义同上,式中D和E的定义同上。
适宜的溶剂是上述的溶剂。优选二氯甲烷。
适宜的碱是环胺,例如哌啶、吡啶、嘧啶或二甲氨基吡啶,或C1-C4烷基胺,例如三乙胺。优选三乙胺和吡啶。
碱的用量在所有情况下一般为每摩尔通式(V)化合物0.5-2mol,优选1-1.2mol。
反应温度一般可在相当宽的范围内变动。反应一般在-20℃-200℃、优选0℃-25℃的范围内进行。
通式(V)化合物(例如J.Heterocyclic.Chem.,26(5),1989,1405-1413)和(VI)(例如EP-0526004A1)是本身已知的。
通式(III)化合物是新的,可按上述制备。
通式(IV)化合物是已知的。
通式(Ia)化合物是新的,可按上述制备。
按照本发明的通式(I)和(Ia)化合物显示出出乎意料的有价值的药理作用谱。
它们能抑制一种或多种代谢cGMP的磷酸二酯酶(PDE I、PDE II和PDE V)。这导致cGMP有区别的上升。cGMP水平增高可产生抗血栓形成、血管舒张、抗心律失常和/或抗炎作用。选择性也可通过同功酶在组织中的分布来测定。
按照本发明的化合物还能增强诸如EDRF(内皮衍生的松驰因子)和ANP(心房钠尿肽)等能增高cGMP水平的物质的作用。
因此可将它们用于下列药物中:治疗炎性疾病例如气喘、炎性皮肤病的药物,治疗高血压、稳定的和不稳定的绞痛、外周和心血管疾病和心律失常的药物,治疗血栓栓塞疾病和局部缺血例如心肌梗塞、脑中风、短暂性缺血发作、心绞痛、外周循环障碍的药物,预防再狭窄例如血栓溶解治疗、经皮经管腔血管成形术(PTA)和分流术、经皮经管腔冠状血管成形术(PTCA)、分流术后再狭窄、败血症性休克和泌尿生殖***疾病例如***肥大、阳萎和无节制的药物。磷酸二酯酶(PDEs)的活性
由猪或牛心肌分离cGMP可兴备的PDE II、cGMP可抑制的PDE III和cAMP特异性PDE IV。Ca-调钙蛋白可兴奋的PDE I由猪主动脉或猪脑中分离。cGMP特异性PDE V由猪肠、猪主动脉和/或人血小板中获得。纯化主要用M.Hoey和Miles D.Houslay的方法(BiochemicalPharmacology,第40卷,193-202(1990))通过在MonoQRPharmacia上的阴离子交换层析来进行。
酶活性在一批在20mMpH7.5的含有5mMMgCl2、0.1mg/ml牛血清白蛋白和800Bq3HcAMP或3Hc GMP的Tris/HCl缓冲液中的100μl试样中测定。相应的核苷酸的最终浓度为10-6mol/l。反应由加入酶开始。酶的加入量应选择为能使底物在30分钟的培养时间中转化大约50%。为测试cGMP可兴奋的PDE II,将3HcAMP用作底物,并将10-6mol/l未标记的cGMP加至该批料中。为测试依赖Ca-调钙蛋白的PDE I,还将1μMCaCl2和0.1μM调钙蛋白加至该反应批料中。反应通过加入100μl含有1mMcAMP和1mMAMP的乙腈终止。将100μl的反应批料经HPLC分离,并用直通型闪烁计数器定量“线上”测定。测定反应速率被降低50%时的物质的浓度。磷酸二酯酶的体外抑制
实施例序号 | PDE IIC50[nM] | PDE IIIC50[nM] | PDE VIC50[nM] |
14 | 5 | 5 | 3 |
15 | 3 | 5 | |
16 | 5 | 5 | |
20 | 10 | 2 | 5 |
29 | 0.5 | 1 |
用麻醉的猪进行所述化合物的抗高血压活性的研究。抗高血压活性在给SHR大鼠静脉用药后测定。
为测定环核苷酸,取出心脏和主动脉组织并立即深度冷冻。将试样在液N2下粉化,用70%乙醇萃取,并用商业性放射免疫测定(Amersham)测定cGMP和cAMP的含量。
用麻醉的家免测定诱导***作用(C.G.Stief等人,WorldJournal Urology1990,第233-236页)。
将所述物质以0.1-10mg/kg的剂量直接给至海绵体或经十二指肠内、经直肠、口服、经皮或静脉内使用。
所述新的活性化合物可用惰性、无毒、适宜药用的载体或溶剂按已知方式转化成常规制剂例如片剂、包衣片剂、丸剂、颗粒剂、气雾剂、糖浆剂、乳剂、混悬剂和溶液剂。治疗活性化合物在各制剂中应以约为总混合物重量的0.5-90%(重量)的浓度存在,即以足以能达到所述剂量范围的量存在。
所述制剂例如如下制备:用溶剂和/或载体扩充活性化合物,若合适,使用乳化剂和/或分散剂,并且,例如在将水用作稀释剂的情况下,若合适,可以用有机溶剂作为助溶剂。
所述制剂按常规方式使用,最好是口服、经肠道外、经皮、经舌或静脉内使用。
业已证明,在静脉内给药的情况下为获得有效结果,用药量一般为约0.01-10mg/kg体重有利,优选为约0.1-10mg/kg体重。
尽管如此,若合适,可能有必要背离所述的量,尤其是当随体重或给药途径、个体对药物的反应、其制剂的性质和用药时间或间隔变化时。因此,在某些情况下用低于上述的最小量足以解决问题,而在另外一些情况下必须超过上述的高限。若用药量较大时,最好是将其分成若干单剂在一天内使用。起始化合物实施例I2-(2-正丙氧基苯甲酰氨基)-3-碘苯甲酸甲酯
将27.9g(0.1mol)2-氨基-3-碘苯甲酸甲酯和15.4ml(0.11mol)三乙胺溶于170ml无水CH2Cl2中。于0℃滴加20g(0.1mol)2-正丙氧基苯甲酰氯的无水CH2Cl2(80mo)溶液。将混合物于20℃搅拌过夜,滤出沉淀,并将产物用100ml 1N HCl、100ml 1N NaOH和100ml饱和NaCl溶液振摇萃取。将有机相用Na2SO4干燥并真空蒸发。将残余物用硅胶层析纯化(洗脱剂:甲苯/乙酸乙酯95∶5)。产量:36g(81.4%)Rf=0.25(甲苯/乙酸乙酯10∶1)
将19.4g(44.17mmol)得自实施例I的化合物在216ml 180℃的甲酰胺中搅拌10小时。冷却后,加入500ml水,并将混合物用CH2Cl2萃取4次,每次300ml。将合并的有机相用MgSO4干燥,真空蒸发溶剂,并将残余物在100ml***和50ml石油醚的混合物中搅拌。将产物吸滤(17.8g)并用250ml无水乙醇重结晶。产量:14.56g(81.2%)熔点:174℃实施例IV2-(2-正丙氧基苯基)-8-溴喹唑啉-4-(3H)-酮
按与实施例III类似的方法由得自实施例II的化合物出发制得标题化合物。收率:60%Rf=0.7(甲苯/乙酸乙酯10∶1)制备实施例2-(2-正丙氧基苯基)-8-(1-庚烯-1-基)喹唑啉-4(3H)-酮
将5g(12.31mmol)得自实施例III的化合物、3.7ml(15.4mmol)三丁胺、6.6ml(46.2mmol)1-庚烯、375mg三邻甲苯基膦(1.23mmol)和138mg乙酸钯(II)(0.6mmol)在50ml 100℃的无水二甲基甲酰胺中搅拌2.5小时。将混合物冷却至室温。加入50ml乙酸乙酯后,用H2O洗涤3次,每次50ml。将有机相用MgSO4干燥后,真空蒸发,并将残余物用甲苯/乙酸乙酯95∶5作洗脱剂进行硅胶层析。将含有产物的流份合并,并将溶剂真空蒸发。将最初的油状残余物通过与35ml石油醚一起搅拌结晶。产量:2.2g(47.5%)熔点:94℃实施例22-(2-正丙氧基苯基)-8-(3-苯基-1-丙烯-1-基)喹唑啉-4(3H)-酮
按与实施例1类似的方法由得自实施例III的化合物和3-苯基-1-丙烯出发制得标题化合物。收率:63.9%熔点:123-126℃(自***中结晶)实施例32-(2-正丙氧基苯基)-8-(4-苯基-1-丁烯-1-基)喹唑啉-4(3H)-酮
按与实施例2类似的方法由得自实施例III的化合物和4-苯基-1-丁烯出发制得标题化合物。收率:49.9%Rf=0.27(甲苯/乙酸乙酯10∶1)实施例4和实施例52-(2-正丙氧基苯基)-8-(5-苯基-2-戊烯-2-基)喹唑啉-4(3H)-酮和2-(2-正丙氧基苯基)-8-(5-苯基-3-戊烯-3-基)喹唑啉-4(3H)-酮
按与实施例1类似的方法由得自实施例III的化合物和5-苯基-2-戊烯出发制得标题化合物。收率:64.6%两种异构体的混合物,不经分离进行氢化(参见实施例8)。实施例62-(2-正丙氧基苯基)-8-(1-庚基)喹唑啉-4(3H)-酮
将20mgPd/C(浓度10%)在2ml无水甲醇中预氢化20分钟。加入200mg(0.53mmol)在2ml无水甲醇和0.8ml乙酸乙酯混合物中的得自实施例1的化合物并于20℃氢化1小时。滤出催化剂,并将溶剂用旋转蒸发器真空去除。将残余物用薄层层析纯化并结晶,在高真空下干燥。产量:180mg(89.6%)熔点:73℃实施例72-(2-正丙氧基苯基)-8-(3-苯基-1-丙基)喹唑啉-4(3H)-酮
按与实施例6类似的方法由得自实施例3的化合物出发制得标题化合物。收率:86.2%熔点:82℃实施例9和实施例102-(2-正丙氧基苯基)-8-(5-苯基-2-戊基)喹唑啉-4(3H)-酮和2-(2-正丙氧基苯基)-8-(5-苯基-3-戊基)喹唑啉-4(3H)-酮
按与实施例6类似的方法由得自实施例4的异构体混合物出发制得标题化合物。用中压硅胶层析以CH2Cl2/乙酸乙酯(20∶5)作洗脱剂进行分离。实施例9的收率:9%实施例10的收率:7.8%实施例9的Rf=0.49(CH2Cl2/乙酸乙酯10∶1)实施例10的Rf=0.51(CH2Cl2/乙酸乙酯10∶1)实施例112-(2-正丙氧基苯基)-8-(1,2-环氧-1-庚基)喹唑啉-4(3H)-酮
将1.5g(3.98mmol)得自实施例1的化合物溶于40ml 0℃的无水氯仿中,加入0.98g(3.98mmol)浓度为70%的间氯过苯甲酸。使混合物升至室温。随后搅拌3小时。用10%的亚硫酸氢钠溶液洗涤3次并用1NNaOH溶液涤涤2次,每次30ml,用MgSO4干燥并真空蒸发。将残余物(1.6g)以甲苯/乙酸乙酯95∶5作洗脱剂进行硅胶层析。产量:1.06g(67.8%)熔点:78℃实施例122-(2-正丙氧基苯基)-8-(3-苯基-1,2-环氧-1-丙基)喹唑啉-4(3H)-酮
按与实施例11类似的方法由得自实施例2的化合物出发制得标题化合物。收率:47%Rf=0.27(甲苯/乙酸乙酯10∶1)实施例132-(2-正丙氧基苯基)-8-(4-苯基-1,2-环氧-1-丁基)喹唑啉-4(3H)-酮
按与实施例11类似的方法由得自实施例3的化合物出发制得标题化合物。收率:61.4%Rf=0.29(甲苯/乙酸乙酯1∶1)实施例142-(2-正丙氧基苯基)-8-(1-甲氧基-2-羟基-1-庚基)喹唑啉-4(3H)-酮
将0.1ml醚合三氟化硼(0.76mmol)于0℃滴加至0.2g(0.51mmol)得自实施例11的化合物的甲醇(6ml)溶液中。于0℃20分钟后,加入75ml乙酸乙酯并将混合物用水振摇萃取3次,每次50ml。将有机相以甲苯/乙酸乙酯5∶1为洗脱剂进行硅胶层析。产量:160mg(73.9%)Rf=0.19(甲苯/乙酸乙酯5∶1)实施例152-(2-正丙氧基苯基)-8-(3-苯基-1-甲氧基-2-羟基-1-丙基)喹唑啉-4(3H)-酮
按与实施例14类似的方法由得自实施例12的化合物出发制得标题化合物。收率:32.5%Rf=0.20(甲苯/乙酸乙酯5∶1)实施例162-(2-正丙氧基苯基)-8-(4-苯基-1-甲氧基-2-羟基-1-丁基)喹唑啉-4(3H)-酮
按与实施例14类似的方法由得自实施例10的化合物出发制得标题化合物。收率:74.4%Rf=0.17(甲苯/乙酸乙酯5∶1)实施例172-(2-正丙氧基苯基)-8-(3-羟基-2-辛基)喹唑啉-4(3H)-酮
将1.9ml 1.6M甲基锂的***溶液(3.06mmol)于-78℃滴加至0.14g(1.53mmol)Cu(I)CN在3ml无水***中的混悬液中。于-78℃1小时后,将混合物温热至-45℃,并滴加在2ml无水***中的200mg(0.51mmol)得自实施例11的化合物。将混合物于0℃搅拌1小时然后于20℃搅拌直至反应结束(用薄层层析监测,约1小时)。加入50ml乙酸乙酯后,将混合物用水洗涤3次,每次30ml。将有机相用Na2SO4干燥并真空旋转蒸发。将残余物以甲苯/乙酸乙酯7∶1作洗脱剂进行硅胶层析。产量:80mg(38.4%)Rf=0.22(甲苯/乙酸乙酯5∶1)实施例182-(2-正丙氧基苯基)-8-(4-苯基-3-羟基-2-丁基)喹唑啉-4(3H)-酮
按与实施例14类似的方法由得自实施例9的化合物出发制得标题化合物。收率:38.5%Rf=0.21(甲苯/乙酸乙酯5∶1)实施例192-(2-正丙氧基苯基)-8-(5-苯基-3-羟基-2-戊基)喹唑啉-4(3H)-酮
按与实施例17类似的方法由得自实施例13的化合物出发制得标题化合物。收率:51.4%非对映体混合物,Rf=0.18和0.24(甲苯/乙酸乙酯5∶1)实施例202-(2-正丙氧基苯基)-8-(4-羟基-3-壬基)喹唑啉-4-(3H)酮
将1.02ml 3MC2H5MgBr的***溶液(3.05mmol)于-20℃滴加至240mg(0.61mmol)得自实施例11的化合物的溶液中,并将混合物于-20℃搅拌45分钟,然后于室温搅拌20分钟。将油状沉淀物通过加入4ml无水四氢呋喃溶解,并再加入1.02ml 3M C2H5MgBr溶液使反应完成。于20℃15分钟后,加入75ml乙酸乙酯,并将混合物用水振摇萃取3次,每次50ml。将有机相用MgSO4干燥后,将溶剂用旋转蒸发器真空去除。将残余物以甲苯/乙酸乙酯10∶1为洗脱剂进行硅胶层析。产量:40mg(15.5%)Rf=0.24(甲苯/乙酸乙酯5∶1)实施例212-(2-正丙氧基苯基)-8-(3-甲磺酰氧基-2-辛基)喹唑啉-4(3H)-酮
将0.17ml(2.17mmol)甲磺酰氯于0℃加至740mg(1.81mmol)在18ml无水CH2Cl2中的得自实施例17的化合物和0.3ml(2.17mmol)三乙胺中。使混合物升至室温,随后搅拌30分钟。依次用1N NaOH和1NHCl各振摇萃取2次,每次30ml。将有机相用MgSO4干燥,并将溶剂用旋转蒸发器真空去除。将固体残余物在30ml乙酸乙酯和30ml石油醚的混合物中搅拌,滤出产物。产量:650mg(73.8%)熔点:195℃实施例222-(2-正丙氧基苯基)-8-(3-叠氮基-2-辛基)喹唑啉-4(3H)-酮
将50mg(0.103mmol)得自实施例18的化合物和13.4ml(0.206mmol)叠氮化钠在2ml无水二甲基甲酰胺中于40℃搅拌过夜。加入5ml乙酸乙酯并将混合物用水振摇萃取3次,每次50ml。将有机相用Na2SO4干燥后,将溶剂用旋转蒸发器真空去除。将残余物用硅胶闪层析(洗脱剂:甲苯/乙酸乙酯5∶1)纯化。产量:31mg(76%)Rf=0.59(甲苯/乙酸乙酯5∶1)实施例232-(2-正丙氧基苯基)-8-(1-甲氧基-2-氧代-1-庚基)喹唑啉-4(3H)-酮
将0.38ml(5.41mmol)在4ml无水CH2Cl2中的无水二甲亚砜于-70℃滴加至在13ml无水CH2Cl2的中0.21ml(2.46mmol)草酰氯中。30分钟后,滴加870mg(2.05mmol)在6ml无水CH2Cl2中的得自实施例14的化合物。再过30分钟后,滴加1.42ml(10.24mmol)N(C2H5)3。使混合物升至室温,10分钟后加入100mlH2O。将水相用CH2Cl2萃取3次,每次50ml。将合并的CH2Cl2相用MgSO4干燥并用旋转蒸发器浓缩。将残余物溶于10ml乙醇中,加入3ml 1N HCl后,将混合物于室温搅拌3小时。真空蒸出乙醇。将残余物溶于30ml乙酸乙酯中,并将混合物用H2O洗涤2次。用MgSO4干燥后,将混合物用旋转蒸发器真空蒸发。将残余物用硅胶层析纯化,以甲苯/乙酸乙酯98∶2作为洗脱剂。产量:510mg(58.9%)Rf=0.26(甲苯/乙酸乙酯5∶1)实施例242-(2-正丙氧基-5-吗啉代磺酰基苯基)-8-(1-庚烯-1-基)喹唑啉-4(3H)-酮
按与实施例1类似的方法由2-(2-正丙氧基-5-吗啉代磺酰基苯基)-8-溴喹唑啉-4-(3H)-酮和1-庚烯出发制得标题化合物。收率:53.2%熔点:112℃(***)实施例252-(2-正丙氧基-5-吗啉代磺酰基苯基)-8-(1,2-环氧-1-庚基)喹唑啉-4(3H)-酮
按与实施例11类似的方法由得自实施例24的化合物出发制得标题化合物。收率:90.7%熔点:96℃实施例262-(2-正丙氧基-5-吗啉代磺酰基苯基)-8-(1-甲氧基-2-羟基-1-庚基)喹唑啉-4-(3H)-酮
按与实施例14类似的方法由得自实施例25的化合物出发制得标题化合物。收率:20.3%Rf=0.42(甲苯/乙酸乙酯2∶1)实施例27和实施例282-(2-正丙氧基-5-吗啉代磺酰基苯基)-8-(5-苯基-2-戊烯-2-基)喹唑啉-4-(3H)-酮和2-(2-正丙氧基-5-吗啉代磺酰基苯基)-8-(5-苯基-3-戊烯-3-基)喹唑啉-4-(3H)-酮(实施例27)(实施例28)
按与实施例1类似的方法由2-(2-正丙氧基-5-吗啉代磺酰基苯基)-8-溴喹唑啉-4-(3H)-酮和5-苯基-2-戊烯出发制得标题化合物。收率:39%两种异构体的混合物,不经分离进行氢化。实施例29和实施例302-(2-正丙氧基-5-吗啉代磺酰基苯基)-8-(5-苯基-2-戊基)喹唑啉-4-(3H)-酮和2-(2-正丙氧基-5-吗啉代磺酰基苯基)-8-(5-苯基-3-戊基)喹唑啉-4-(3H)-酮(实施例29)(实施例30)按与实施例6类似的方法由得自实施例27的异构体混合物出发制得标题化合物。用中压硅胶层析进行分离,以CH2Cl2/乙酸乙酯(2∶1)为洗脱剂。实施例29的收率:36.3%,Rf=0.44(CH2Cl2/乙酸乙酯4∶1)实施例30的收率:18.4%,Rf=0.49(CH2Cl2/乙酸乙酯4∶1)
Claims (10)
1.通式(I)2,8-二取代的喹唑啉酮及其互变异构体和盐:式中A代表可任选地被具有至多8个碳原子的直链或支链烷基取代的环氧乙烷基,所述烷基又可被苯基取代,或者代表下式基团:式中R1表示氢或具有至多6个碳原子的直链或支链烷基,R2表示具有至多8个碳原子的直链或支链烷基,该烷基可任选地被苯基取代,R3代表具有至多5个碳原子的直链或支链烷基或式-OR6基团,其中R6表示氢,羟基保护基团或具有至多5个碳原子的直链或支链烷
基,R4表示具有2至10个碳原子的直链或支链烷基,该烷基可任选地被苯基取代,L表示式-CO-、-CH(OH)、-CH2、-CH(N3)或-CH(OSO2R7)基团,其
中
R7表示具有至多4个碳原子的直链或支链烷基或苯基,R5表示具有3至8个碳原子的直链或支链烷基,该烷基可任选地被苯
基取代,或表示苄基或2-苯基乙基,D代表氢,或代表式-SO2-NR8R9基团,式中R8和R9相同或不同,表示氢,苯基或具有至多6个碳原子且可任选
地被羟基取代的直链或支链烷基,或者与氮原子一起形成具有至
多2个选自S、N和/或O的另外的杂原子并可任选地被具有至多6
个碳原子的直链或支链烷基取代(包括通过游离的N官能基取代)
的5或6元饱和杂环基团,所述烷基又可被羟基取代,和E代表具有至多8个碳原子的直链或支链烷基。
2.按照权利要求1的通式(I)2,8-二取代的喹唑啉酮及其互变异构体和盐,其中A代表可任选地被具有至多7个碳原子的直链或支链烷基取代的环氧
乙烷基,所述烷基又可被苯基取代,或者代表下式基团:式中R1表示氢或具有至多5个碳原子的直链或支链烷基,R2表示具有至多6个碳原子的直链或支链烷基,该烷基可任选地被苯基取代,R3代表具有至多4个碳原子的直链或支链烷基或式-OR6基团,其中R6表示氢,苄基,乙酰基或具有至多4个碳原子的直链或支链烷
基,R4表示具有2至8个碳原子的直链或支链烷基,该烷基可任选地被苯 基取代,L表示式-CO-、-CH(OH)、-CH2、-CH(N3)或-CH(OSO2R7)基团,其中R7表示具有至多3个碳原子的直链或支链烷基或苯基,R5表示具有3至7个碳原子的直链或支链烷基,该烷基可任选地被苯
基取代,或表示苄基或2-苯基乙基,D代表氢,或代表式-SO2-NR8R9基团,式中R8和R9相同或不同,表示氢,苯基或具有至多5个碳原子且可任选
地被羟基取代的直链或支链烷基,或者与氮原子一起形成吗啉基
、哌啶基或哌嗪基环,这些环可任选地被具有至多4个碳原子的
直链或支链烷基取代,包括通过游离的N官能基取代,所述烷基
又可以被羟基取代,和E代表具有至多6个碳原子的直链或支链烷基。
3.按照权利要求1的通式(I)2,8-二取代的喹唑啉酮及其互变异构体和盐,其中A代表可任选地被具有至多6个碳原子的直链或支链烷基取代的环氧乙烷基,所述烷基又可被苯基取代,或者代表下式基团:式中R1表示氢或具有至多3个碳原子的直链或支链烷基,R2表示具有至多6个碳原子的直链或支链烷基,该烷基可任选地被苯基取代,R3代表具有至多4个碳原子的直链或支链烷基或式-OR6基团,其中R6表示氢,苄基,乙酰基或具有至多3个碳原子的直链或支链烷
基,R4表示具有2至7个碳原子的直链或支链烷基,该烷基可任选地被苯
基取代,L表示式-CO-、-CH(OH)、-CH2、-CH(N3)或-CH(OSO2R7)基团,其中R7表示具有至多3个碳原子的直链或支链烷基或苯基,R5表示具有3至6个碳原子的直链或支链烷基,该烷基可任选地被苯基取代,或表示苄基或2-苯基乙基,D代表氢,或代表式-SO2-NR8R9基团,式中R8和R9相同或不同,表示氢,苯基或具有至多3个碳原子的直链或
支链烷基,或者与氮原子一起形成吗啉基或哌啶基环,和E代表具有至多4个碳原子的直链或支链烷基。
4.按照权利要求1至3之任一项的2,8-二取代的喹唑啉酮的治疗用途。
5.按照权利要求1至3之任一项的2,8-二取代的喹唑啉酮的制备方法,其特征在于:将通式(II)化合物用甲酰胺先环化,得到通式(III)化合物,并在最后一步在惰性溶剂中在碱存在下并在三-邻甲苯基膦/乙酸钯(II)体系中用通式(IV)化合物将它们转化成通式(Ia)化合物,并且,若合适,将双键氢化,或者,在A=取代的环氧乙烷基的情况下,若合适,通过常规方法用氧化剂在惰性溶剂中将双键氧化,得到相应的环氧化合物,并将其通过开环反应转化成相应的羟基化合物,并且,由该羟基化合物出发,若合适,在活化后,进行亲核取代反应,或者将羟基化合物氧化成氧基化合物;所述通式(II)、(III)、(IV)和(Ia)如下:式中D和E的定义同上,T代表C1-C4烷基,和R10代表卤素,优选溴或碘,式中D、E和R10的定义同上,
R1-CH=CH-R2 (IV)式中R1和R2的定义同上,式中D、E、R1和R2的定义同上。
6.包含至少一种按照权利要求1至3之任一项的2,8-二取代的喹唑啉酮的药物。
7.将按照权利要求6的药物用于治疗炎症、血栓栓塞疾病和心血管疾病。
8.将按照权利要求6或7的药物用于治疗阳萎。
9.按照权利要求1至3之任一项的2,8-二取代的喹唑啉酮在制备药物方面的用途。
10.按照权利要求9的用途,其特征在于该药物用于治疗炎症、血栓栓塞和心血管疾病。
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DE19501481A DE19501481A1 (de) | 1995-01-19 | 1995-01-19 | 2,8-Disubstituierte Chinazolinone |
DE19501481.2 | 1995-01-19 |
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US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
AU2011302006A1 (en) | 2010-09-15 | 2013-03-07 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase C agonists and methods of use |
WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
JP2017503833A (ja) * | 2014-01-23 | 2017-02-02 | エイチ リー モフィット キャンサー センター アンド リサーチ インスティテュート インコーポレイテッド | イカリイン誘導体 |
JP6687550B2 (ja) | 2014-06-23 | 2020-04-22 | セルジーン コーポレイション | 肝疾患又は肝機能異常を治療するためのアプレミラスト |
WO2024026424A1 (en) * | 2022-07-27 | 2024-02-01 | Black Diamond Therapeutics, Inc. | Quinazolinone derivatives as and related uses |
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US3169129A (en) * | 1963-05-10 | 1965-02-09 | American Cyanamid Co | 2-ortho-hydroxy-phenyl-4-(3h)-quinazolinones |
US4431440A (en) * | 1981-02-20 | 1984-02-14 | American Cyanamid Company | Method to alter or control the development and/or the life cycle of various plant species |
GB9126260D0 (en) * | 1991-12-11 | 1992-02-12 | Pfizer Ltd | Therapeutic agents |
US5294612A (en) * | 1992-03-30 | 1994-03-15 | Sterling Winthrop Inc. | 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-ones and compositions and method of use thereof |
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1995
- 1995-01-19 DE DE19501481A patent/DE19501481A1/de not_active Withdrawn
- 1995-12-26 IN IN2408DE1995 patent/IN184956B/en unknown
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- 1996-01-08 EP EP96100154A patent/EP0722937A1/de not_active Withdrawn
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN100506802C (zh) * | 2004-06-04 | 2009-07-01 | 中国科学院上海药物研究所 | 一类甲酰肽样受体-1调节剂、其制备方法和用途 |
WO2009062402A1 (fr) * | 2007-11-07 | 2009-05-22 | Topharman Shanghai Co., Ltd. | Dérivés de quinazolinone, leurs procédés de préparation et leurs utilisations |
CN110590769A (zh) * | 2019-06-13 | 2019-12-20 | 中山大学 | 一对喹唑啉酮生物碱对映体及其制备方法和应用 |
CN110590769B (zh) * | 2019-06-13 | 2021-09-24 | 中山大学 | 一对喹唑啉酮生物碱对映体及其制备方法和应用 |
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