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CN101429166B - Quinazoline ketone derivant, preparation method and application thereof - Google Patents

Quinazoline ketone derivant, preparation method and application thereofDownload PDF

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CN101429166B
CN101429166BCN2007100479158ACN200710047915ACN101429166BCN 101429166 BCN101429166 BCN 101429166BCN 2007100479158 ACN2007100479158 ACN 2007100479158ACN 200710047915 ACN200710047915 ACN 200710047915ACN 101429166 BCN101429166 BCN 101429166B
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phenyl
quinazoline
ketone
dimethoxy
alkylsulfonyl
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CN101429166A (en
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沈敬山
郑金
赖庆林
王震
张金凤
田广辉
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Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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Topharman Shanghai Co Ltd
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Translated fromChinese

本发明涉及医药技术领域，具体涉及一种喹唑啉酮衍生物及其制备方法和用途。本发明公开了一种具有如结构通式(I)喹唑啉酮化合物，或者其药学上可以接受的盐。这些化合物中多数具有比西地那非更强的PDE5抑制活性，且相对于分布在视网膜的PDE6有更高的选择性。因此本发明提供的化合物可望在临床上表现出更佳的安全性和有效性，临床应用前景广阔。The invention relates to the technical field of medicine, in particular to a quinazolinone derivative and a preparation method and use thereof. The invention discloses a quinazolinone compound with general structural formula (I), or a pharmaceutically acceptable salt thereof. Most of these compounds have stronger PDE5 inhibitory activity than sildenafil, and have higher selectivity relative to PDE6 distributed in the retina. Therefore, the compounds provided by the present invention are expected to show better safety and efficacy in clinical practice, and have broad prospects for clinical application.

Description

Translated fromChinese
喹唑啉酮衍生物及其制备方法和用途Quinazolinone derivatives and their preparation methods and uses

技术领域technical field

本发明涉及医药技术领域，具体涉及一种喹唑啉酮衍生物及其制备方法和用途。The invention relates to the technical field of medicine, in particular to a quinazolinone derivative and a preparation method and use thereof.

背景技术Background technique

磷酸二酯酶(phosphodiesterase，PDE)包括11个酶系(PDE1-PDE11)，它们通过水解cAMP或cGMP，而使细胞内第二信使的活性降低。根据所阻断的特殊的PDE底物的特异性，PDE 5抑制剂能增加细胞内cAMP水平、cGMP水平，或同时增加cAMP和cGMP的水平。这些抑制剂属竞争性抑制剂，因为它们模拟cAMP和cGMP的结构，而cAMP和cGMP是PDE的天然底物。与cAMP和cGMP不同的是，抑制剂不被PDE降解。已知PDE涉及广泛的细胞功能活动。PDE 5是cGMP特异，并且在阴茎海绵体平滑肌细胞高表达的磷酸二酯酶。PDE 5抑制剂通过在性刺激过程中维持阴茎海绵体和供应血管平滑肌细胞内充分的cGMP水平，增加海绵窦的扩张，从而增强勃起功能。Phosphodiesterase (PDE) includes 11 enzyme systems (PDE1-PDE11), which reduce the activity of intracellular second messengers by hydrolyzing cAMP or cGMP. Depending on the specificity of the particular PDE substrate being blocked, PDE 5 inhibitors can increase intracellular cAMP levels, cGMP levels, or both cAMP and cGMP levels. These inhibitors are competitive inhibitors because they mimic the structure of cAMP and cGMP, which are natural substrates of PDEs. Unlike cAMP and cGMP, inhibitors are not degraded by PDEs. PDEs are known to be involved in a wide range of cellular functions. PDE 5 is a phosphodiesterase specific for cGMP and highly expressed in smooth muscle cells of the corpus cavernosum. PDE 5 inhibitors enhance erectile function by increasing the dilation of the cavernous sinus by maintaining adequate cGMP levels in the corpus cavernosum and supplying vascular smooth muscle cells during sexual stimulation.

数十年来，非选择性PDE抑制剂如：咖啡因、茶碱和3-异丁基-1-甲基磺嘌呤(IBMX)已被用于环核苷酸(cNMP)生理作用和PDE活性的研究。虽属同类药物，但上述抑制剂缺乏特异性，它们阻断几乎所有已知的PDE的催化活性，在治疗的同时可能伴发过多的不良反应。For decades, nonselective PDE inhibitors such as caffeine, theophylline, and 3-isobutyl-1-methylsulphonine (IBMX) have been used to investigate the physiological effects and PDE activity of cyclic nucleotides (cNMPs). Research. Although they belong to the same class of drugs, the above-mentioned inhibitors lack specificity, they block the catalytic activity of almost all known PDEs, and may be accompanied by too many adverse reactions during treatment.

PDE 5抑制剂通过抑制PDE 5酶活性、影响PDE 5表达及代谢等调节PDE 5活性从而影响人体生理和病理过程，理论上，PDE 5抑制剂可影响所有与PDE 5有关的生理病理过程。PDE 5 inhibitors regulate PDE 5 activity by inhibiting PDE 5 enzyme activity, affecting PDE 5 expression and metabolism, etc., thereby affecting human physiological and pathological processes. In theory, PDE 5 inhibitors can affect all physiological and pathological processes related to PDE 5.

第一个上市的PDE5抑制剂——西地那非(Sildenafil)，在临床用于男性勃起功能障碍，对女性的性功能障碍和原发性高血压也有效。研发中的PDE5抑制剂还用于糖尿病消化道症状、胰岛素耐受和高血脂。The first PDE5 inhibitor on the market, Sildenafil, is clinically used for male erectile dysfunction, and is also effective for female sexual dysfunction and essential hypertension. PDE5 inhibitors under development are also used for diabetic gastrointestinal symptoms, insulin resistance and hyperlipidemia.

尽管西地那非取得了较显著的临床疗效，但由于其对PDE5以外的其他磷酸二酯酶(PDE)同工酶也有不同程度的抑制作用，临床表现出头痛、潮红、消化不良、鼻塞、视物模糊、光敏、视物色淡等毒副作用。一方面，这些副作用与剂量相关，因此发现作用更强的PDE5抑制剂，才有可能减低剂量、降低毒副作用；另一方面，视觉紊乱症状是西地那非对存在于视网膜的VI型磷酸二酯酶(PDE6)也有抑制作用的结果，所以提高选择性，尤其相对于PDE6的选择性，是寻找新的PDE5抑制剂的又一目标。Although sildenafil has achieved remarkable clinical curative effect, because it also has different degrees of inhibitory effects on other phosphodiesterase (PDE) isozymes other than PDE5, the clinical manifestations are headache, flushing, indigestion, nasal congestion, Toxic and side effects such as blurred vision, photosensitivity, and pale vision. On the one hand, these side effects are related to the dose, so it is possible to reduce the dose and reduce the side effects by finding a stronger PDE5 inhibitor; Esterase (PDE6) also has an inhibitory effect, so improving selectivity, especially relative to PDE6, is another goal for finding new PDE5 inhibitors.

发明内容Contents of the invention

本发明所要解决的技术问题是提供一种新的PDE5抑制剂，为此本发明公开了一种喹唑啉酮衍生物，并公开了其制备方法及其组合物和应用。The technical problem to be solved by the present invention is to provide a new PDE5 inhibitor. To this end, the present invention discloses a quinazolinone derivative, and discloses its preparation method, composition and application.

一种具有下列结构通式(I)喹唑啉酮化合物，或者其药学上可以接受的盐A quinazolinone compound having the following general structural formula (I), or a pharmaceutically acceptable salt thereof

Figure S2007100479158D00021
Figure S2007100479158D00021

其中：in:

R1为H，C1-C6烃基，C3-C6环烷基，C1-C3卤代烷基，卤素，羟基，被C1-C3烷氧基取代的羟基，烷氧基，氨基，酰胺基；R1 is H, C1 -C6 hydrocarbyl, C3 -C6 cycloalkyl, C1 -C3 haloalkyl, halogen, hydroxy, hydroxy substituted by C1 -C3 alkoxy, alkoxy, Amino, amido;

R2，R3和R4为H，C1-C6烃基，C3-C6环烷基，C1-C3卤代烷基，被C1-C3烷氧基取代的C1-C3烷基，或被C3-C6环烷基取代的C1-C3烷基；R2 , R3 and R4 are H, C1 -C6 hydrocarbyl, C3 -C6 cycloalkyl, C1 -C3 haloalkyl, C1 -C substituted by C1 -C3 alkoxy3 alkyl, or C1 -C3 alkyl substituted by C3 -C6 cycloalkyl;

R5为H，OH，卤素，硝基，Ar，Het，NR6R7，五元糖，六元糖，CN，SO2NR6R7，CO(CH2)mNR6R7，NHSO2NR6R7，NHCONR6R7，NHCNNR6R7，NHCOR8，COR8，NHCOOR8，COOR8或C1-C6烷基；R5 is H, OH, halogen, nitro, Ar, Het, NR6 R7 , pentasaccharide, hexasaccharide, CN, SO2 NR6 R7 , CO(CH2 )m NR6 R7 , NHSO2 NR6 R7 , NHCONR6 R7 , NHCNNR6 R7 , NHCOR8 , COR8 , NHCOOR8 , COOR8 or C1 -C6 alkyl;

R6和R7各自独立地为H，C1-C6烷基，COR8，SO2R8；R6和R7能与他们相连的氮原子共同构成吡咯烷、哌啶、吗啉、哌嗪、咪唑或吡唑，其中该含氮杂环可选择性的被R11取代；R6 and R7 are independently H, C1 -C6 alkyl, COR8 , SO2 R8 ; R6 and R7 can form pyrrolidine, piperidine, morpholine, Piperazine, imidazole or pyrazole, wherein the nitrogen-containing heterocycle is optionally substituted by R11 ;

R8为C1-C6烷基(任选被C1-C3烷氧基或被NR12R13基取代)；R8 is C1 -C6 alkyl (optionally substituted by C1 -C3 alkoxy or by NR12 R13 groups);

R9和R10各自独立地为H，C1-C6烷基(任选被C1-C3烷氧基或被NR12R13基取代)；或R9、R10与它们相连的氮原子共同构成Het；R9 and R10 are each independently H, C1 -C6 alkyl (optionally substituted by C1 -C3 alkoxy or NR12 R13 ); or R9 , R10 are connected to them Nitrogen atoms together form Het;

R11为C1-C6烷基；R11 is C1 -C6 alkyl;

R12和R13各自独立地为H，或C1-C6烷基；R12 and R13 are each independently H, or C1 -C6 alkyl;

上述各项中，Of the above items,

m＝0，1，2；m=0,1,2;

Ar代表被一个或二个取代基取代的芳基，取代基选自卤素、NH2、C1-C3烷基、C1-C3烷氧基、CONH2、CN、SO2NH2；Ar represents an aryl group substituted by one or two substituents selected from halogen, NH2 , C1 -C3 alkyl, C1 -C3 alkoxy, CONH2 , CN, SO2 NH2 ;

Het代表含有1-4个杂原子的5和6元杂环，杂原子选自N、S和O；Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms, the heteroatoms being selected from N, S and O;

优选的式I化合物中Among the preferred compounds of formula I

R1为H，C1-C6烃基，C3-C6环烷基，C1-C3卤代烷基，卤素，羟基，被C1-C3烷氧基取代的羟基，烷氧基，氨基，酰胺基；R1 is H, C1 -C6 hydrocarbyl, C3 -C6 cycloalkyl, C1 -C3 haloalkyl, halogen, hydroxy, hydroxy substituted by C1 -C3 alkoxy, alkoxy, Amino, amido;

R2、R3和R4各自独立地为H，C1-C6烷基，C1-C6烯基，C3-C6环烷基，C1-C6卤代烷基或卤素；R2 , R3 and R4 are each independently H, C1 -C6 alkyl, C1 -C6 alkenyl, C3 -C6 cycloalkyl, C1 -C6 haloalkyl or halogen;

R5为SO2NR6R7，CO(CH2)mNR6R7，NHSO2NR6R7，NHCONR6R7，NHCNNR6R7，NR6R7；R5 is SO2 NR6 R7 , CO(CH2 )m NR6 R7 , NHSO2 NR6 R7 , NHCONR6 R7 , NHCNNR6 R7 , NR6 R7 ;

R6和R7各自独立地为H，C1-C6烷基，COR8，SO2R8，被取代基取代的C1-C3烷基，取代基选自OH，胍基，C1-C4烷氧基，C3-C6环烷基，NR9R10，Ar或Het；R6 and R7 are each independently H, C1 -C6 alkyl, COR8 , SO2 R8 , C1 -C3 alkyl substituted by a substituent selected from OH, guanidino, C1 -C4 alkoxy, C3 -C6 cycloalkyl, NR9 R10 , Ar or Het;

R6和R7能与他们相连的氮原子共同构成吡咯烷、哌啶、吗啉、哌嗪、咪唑或吡唑，其中该含氮杂环可选择性的被R11取代；R6 and R7 can form pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole together with their connected nitrogen atoms, wherein the nitrogen-containing heterocycle can be optionally substituted by R11 ;

R8为C1-C6烷基(任选被C1-C3烷氧基或被NR12R13基取代)；R8 is C1 -C6 alkyl (optionally substituted by C1 -C3 alkoxy or by NR12 R13 groups);

R9和R10各自独立地为H，C1-C6烷基(任选被C1-C3烷氧基或被NR12R13基取代)；或R9、R10与它们相连的氮原子共同构成Het；R9 and R10 are each independently H, C1 -C6 alkyl (optionally substituted by C1 -C3 alkoxy or NR12 R13 ); or R9 , R10 are connected to them Nitrogen atoms together form Het;

R11为C1-C6烷基，该烷基可任选被OH、C1-C3烷氧基取代；R11 is C1 -C6 alkyl, which can be optionally substituted by OH, C1 -C3 alkoxy;

R12和R13各自独立地为H，或C1-C6烷基；R12 and R13 are each independently H, or C1 -C6 alkyl;

上述各项中，Of the above items,

m＝0，1，2；m=0,1,2;

Ar代表被一个或二个取代基取代的芳基，取代基选自卤素、NH2、C1-C3烷基、C1-C3烷氧基、CONH2、CN、SO2NH2；Ar represents an aryl group substituted by one or two substituents selected from halogen, NH2 , C1 -C3 alkyl, C1 -C3 alkoxy, CONH2 , CN, SO2 NH2 ;

Het代表含有1-4个杂原子的5和6元杂环，杂原子选自N、S和O，且任选被一个或二个取代基取代，取代基选自卤素、C1-C3烷基、C1-C3烷氧基。Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms, the heteroatoms are selected from N, S and O, and are optionally substituted by one or two substituents, the substituents are selected from halogen, C1 -C3 Alkyl, C1 -C3 alkoxy.

再优选的式I化合物中，Among the preferred compounds of formula I,

R1为H，C1-C6烷基，C1-C6烯基或卤素；R1 is H, C1 -C6 alkyl, C1 -C6 alkenyl or halogen;

R2为C1-C6烷基；R2 is C1 -C6 alkyl;

R3为H或C1-C6烷基；R3 is H or C1 -C6 alkyl;

R4为C1-C6烷基；R4 is C1 -C6 alkyl;

R5为SO2NR6R7；R5 is SO2 NR6 R7 ;

R6和R7各自独立地为H，C1-C3烷基，苄基，吡啶甲基，哌啶-4-基，COR8，被胍基取代的C1-C3烷基，或被NR9R10基取代的C1-C3烷基或者和他们相连的氮原子共同构成吡咯烷、哌啶、吗啉、哌嗪、咪唑或吡唑，其中该含氮杂环可选择性的被R11取代；R6 and R7 are each independently H, C1 -C3 alkyl, benzyl, pyridylmethyl, piperidin-4-yl, COR8 , C1 -C3 alkyl substituted by guanidino, or C1 -C3 alkyl groups substituted by NR9 R10 groups or the nitrogen atoms connected to them together form pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole, wherein the nitrogen-containing heterocycle can optionally is replaced by R11 ;

R8为C1-C4烷基，苯基或吡啶基；R8 is C1 -C4 alkyl, phenyl or pyridyl;

R9和R10各自独立地为H，C1-C3烷基；或R9、R10与它们相连的氮原子共同构成吗啉、硫吗啉、哌嗪、哌啶、吡咯烷杂环；R9 and R10 are each independently H, C1 -C3 alkyl; or R9 , R10 and the nitrogen atom connected to them together form morpholine, thiomorpholine, piperazine, piperidine, pyrrolidine heterocycle ;

R11为C1-C4烷基，该烷基可任选被OH、C1-C3烷氧基取代。R11 is C1 -C4 alkyl, which may be optionally substituted by OH, C1 -C3 alkoxy.

特别优选的式I化合物中，Among particularly preferred compounds of formula I,

R1为H，C1-C6烷基，C1-C6烯基或卤素；R1 is H, C1 -C6 alkyl, C1 -C6 alkenyl or halogen;

R2为H或甲基；R2 is H or methyl;

R3为H或甲基；R3 is H or methyl;

R4为乙基或正丙基；R4 is ethyl or n-propyl;

R5为SO2NR6R7；R5 is SO2 NR6 R7 ;

R6和R7各自独立地为H，被胍基取代的C1-C3烷基，或被NR9R10基取代的C1-C3烷基或者和他们相连的氮原子共同构成吡咯烷、哌啶、哌嗪，其中该含氮杂环可选择性的被R10取代；R6 and R7 are each independently H, C1 -C3 alkyl substituted by guanidino, or C1 -C3 alkyl substituted by NR9 R10 , or together with their connected nitrogen atoms constitute pyrrole Alkane, piperidine, piperazine, wherein the nitrogen-containing heterocycle is optionally substituted by R10 ;

R9和R10各自独立地为H，C1-C3烷基；或R9、R10与它们相连的氮原子共同构成吗啉、哌啶、吡咯烷杂环；R9 and R10 are each independently H, C1 -C3 alkyl; or R9 , R10 and their connected nitrogen atoms together form a morpholine, piperidine, or pyrrolidine heterocycle;

R11为甲基或乙基。R11 is methyl or ethyl.

本发明优选的具体化合物包括：Preferred specific compounds of the invention include:

2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4(3H) -ketone;

2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5-羟基-7-甲氧基-8-溴-喹唑啉-4(3H)-酮；2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-bromo-quinazoline-4(3H )-ketone;

2-{2-丙氧基-5-[N-(2-吗啉-1-乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-(2-morpholine-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quinone Azolin-4(3H)-one;

2-{2-丙氧基-5-[N-(3-吗啉-1-丙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-(3-morpholine-1-propyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quinone Azolin-4(3H)-one;

2-{2-丙氧基-5-[N-(2-二乙胺基乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-(2-diethylaminoethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazole Lin-4(3H)-one;

2-{2-丙氧基-5-[N-(2-二甲胺基乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-(2-dimethylaminoethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazole Lin-4(3H)-one;

2-{2-丙氧基-5-[N-(2-羟乙基)-N-(2-吗啉-1-乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-(2-hydroxyethyl)-N-(2-morpholine-1-ethyl)-aminosulfonyl]-phenyl}-5,7- Dimethoxy-8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-甲基-N-(3-吡咯烷-1-丙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-methyl-N-(3-pyrrolidine-1-propyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-(2-甲氧基乙基)-N-(2-吗啉-1-乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-(2-methoxyethyl)-N-(2-morpholine-1-ethyl)-aminosulfonyl]-phenyl}-5, 7-dimethoxy-8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-(2-乙氧基乙基)-N-(2-吗啉-1-乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-(2-ethoxyethyl)-N-(2-morpholine-1-ethyl)-aminosulfonyl]-phenyl}-5, 7-dimethoxy-8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-乙基-N-(3-哌啶-1-丙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-ethyl-N-(3-piperidine-1-propyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-乙基-N-(2-吗啉-1-乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-ethyl-N-(2-morpholine-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-(2-(2-羟乙氧基)乙基)-N-(2-吗啉-1-乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-(2-(2-hydroxyethoxy)ethyl)-N-(2-morpholine-1-ethyl)-aminosulfonyl]-benzene Base}-5,7-dimethoxy-8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-(2-(2-甲氧基乙氧基)乙基)-N-(2-吗啉-1-乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-(2-(2-methoxyethoxy)ethyl)-N-(2-morpholine-1-ethyl)-aminosulfonyl] -Phenyl}-5,7-dimethoxy-8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-甲基-N-(2-二甲胺基乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-methyl-N-(2-dimethylaminoethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8 - bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-(吡啶-3-甲基)-N-(2-吗啉-1-乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-(pyridine-3-methyl)-N-(2-morpholine-1-ethyl)-aminosulfonyl]-phenyl}-5,7 - Dimethoxy-8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[[1-(4-吡啶甲基)-1-(2-吗啉-1-基)乙基]氨基磺酰基]苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[[1-(4-pyridylmethyl)-1-(2-morpholin-1-yl)ethyl]aminosulfonyl]phenyl}-5,7- Dimethoxy-8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-苄基-N-(2-吗啉-1-乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-benzyl-N-(2-morpholine-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-苄基-N-(3-吗啉-1-丙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-benzyl-N-(3-morpholine-1-propyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-甲基-N-(N-乙基吡咯烷-2-甲基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-methyl-N-(N-ethylpyrrolidine-2-methyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy Base-8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-乙基-N-(N-乙基吡咯烷-2-甲基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-Propoxy-5-[N-ethyl-N-(N-ethylpyrrolidine-2-methyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy Base-8-bromo-quinazolin-4(3H)-one;

2-[2-丙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-[2-Propoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4(3H) -ketone;

2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-8-氯-喹唑啉-4(3H)-酮；2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-chloro-quinazoline-4(3H) -ketone;

2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-8-氟-喹唑啉-4(3H)-酮；2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-fluoro-quinazoline-4(3H) -ketone;

2-[2-乙氧基-5-(4-甲基哌嗪-1-1-磺酰基)-苯基]-5，7-二甲氧基-喹唑啉-4(3H)-酮；2-[2-Ethoxy-5-(4-methylpiperazin-1-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazolin-4(3H)-one ;

8-乙基-2-[2-乙氧基-5-(4-甲基哌嗪-磺酰基)-苯基]-5，7-二甲氧基-8-碘-喹唑啉-4(3H)-酮；8-Ethyl-2-[2-ethoxy-5-(4-methylpiperazine-sulfonyl)-phenyl]-5,7-dimethoxy-8-iodo-quinazoline-4 (3H)-ketone;

2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-喹唑啉-4(3H)-酮；2-[2-Ethoxy-5-(4-methylpiperazin-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazolin-4(3H)-one;

8-甲基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-喹唑啉-4(3H)-酮；8-Methyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4(3H )-ketone;

8-乙基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-喹唑啉-4(3H)-酮；8-Ethyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4(3H )-ketone;

8-丙基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-喹唑啉-4(3H)-酮；8-Propyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4(3H )-ketone;

8-丁基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-喹唑啉-4(3H)-酮；8-Butyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4(3H )-ketone;

8-丁基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-喹唑啉-4(3H)-酮；8-Butyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4(3H )-ketone;

8-乙烯基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-喹唑啉-4(3H)-酮；8-vinyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4(3H )-ketone;

8-烯丙基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-喹唑啉-4(3H)-酮；8-allyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4( 3H)-ketone;

2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5-羟基-7-甲氧基-8-氯-喹唑啉-4(3H)-酮；2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-chloro-quinazoline-4(3H )-ketone;

2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5-羟基-7-甲氧基-8-氟-喹唑啉-4(3H)-酮；2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-fluoro-quinazoline-4(3H )-ketone;

2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5-羟基-7-甲氧基-8-碘-喹唑啉-4(3H)-酮；2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-iodo-quinazoline-4(3H )-ketone;

2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5-羟基-7-甲氧基-喹唑啉-4(3H)-酮；2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazolin-4(3H)-one;

8-甲基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5-羟基-7-甲氧基-喹唑啉-4(3H)-酮；8-methyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazoline-4( 3H)-ketone;

8-乙基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5-羟基-7-甲氧基-喹唑啉-4(3H)-酮；8-Ethyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazoline-4( 3H)-ketone;

8-丙基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5-羟基-7-甲氧基-喹唑啉-4(3H)-酮；8-Propyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazoline-4( 3H)-ketone;

8-丁基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5-羟基-7-甲氧基-喹唑啉-4(3H)-酮；8-Butyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazoline-4( 3H)-ketone;

8-乙烯基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5-羟基-7-甲氧基-喹唑啉-4(3H)-酮；8-vinyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazoline-4( 3H)-ketone;

2-[2-丙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5-羟基-7-甲氧基-8-碘-喹唑啉-4(3H)-酮；2-[2-propoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-iodo-quinazoline-4(3H )-ketone;

2-[2-丙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-8-碘-喹唑啉-4(3H)-酮；2-[2-Propoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-iodo-quinazoline-4(3H) -ketone;

2-{2-丙氧基-5-[N-(2-羟乙基)-N-(2-胍基-1-乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-(2-hydroxyethyl)-N-(2-guanidino-1-ethyl)-aminosulfonyl]-phenyl}-5,7- Dimethoxy-8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-苯基-N-(2-胍基-1-乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-phenyl-N-(2-guanidino-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-(吡啶-3-甲基)-N-(3-胍基-1-丙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-(pyridine-3-methyl)-N-(3-guanidino-1-propyl)-aminosulfonyl]-phenyl}-5,7 - Dimethoxy-8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-苄基-N-(2-胍基-1-乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮；2-{2-propoxy-5-[N-benzyl-N-(2-guanidino-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one;

2-{2-丙氧基-5-[N-(吡啶-4-甲基)-N-(3-胍基-1-丙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮或2-{2-propoxy-5-[N-(pyridine-4-methyl)-N-(3-guanidino-1-propyl)-aminosulfonyl]-phenyl}-5,7 -Dimethoxy-8-bromo-quinazolin-4(3H)-one or

2-{2-丙氧基-5-[N-乙基-N-(2-胍基-1-乙基)-胺基磺酰基]-苯基}-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮。2-{2-propoxy-5-[N-ethyl-N-(2-guanidino-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-Bromo-quinazolin-4(3H)-one.

除通式(I)所表示的化合物以外，本发明还包括这些化合物的药学上可接受的盐、药学上可接受的前药和医药活性代谢物，和这些代谢物在药学上可接受的盐。In addition to the compounds represented by general formula (I), the present invention also includes pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs and pharmaceutically active metabolites of these compounds, and pharmaceutically acceptable salts of these metabolites .

式I的化合物可含有一个或多个手性中心，因此可存在立体异构体，即对映异构体或非对映异构体，及其混合物。本发明包括式I混合物的单个立体异构体及其混合物。Compounds of formula I may contain one or more chiral centers and thus may exist as stereoisomers, ie enantiomers or diastereomers, and mixtures thereof. The present invention includes the individual stereoisomers of the compounds of formula I and mixtures thereof.

式I的化合物可存在互变异构体的形式，而本发明包括了其混合物和单一的互变异构体。The compounds of formula I may exist in the form of tautomers, and the present invention includes mixtures and single tautomers thereof.

本发明包括式I化合物的可药用的盐。优选的盐是甲磺酸盐和盐酸盐。The present invention includes pharmaceutically acceptable salts of compounds of formula I. Preferred salts are methanesulfonate and hydrochloride.

本发明另一方面还公开了一种药物组合物，含有有效量的通式(I)所示化合物和药学上可接受的载体。Another aspect of the present invention also discloses a pharmaceutical composition, which contains an effective amount of the compound represented by the general formula (I) and a pharmaceutically acceptable carrier.

本发明也包括式I化合物的可药用氧化物及其可药用盐和可药用溶剂化物。The present invention also includes pharmaceutically acceptable oxides of compounds of formula I as well as pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof.

此外，本发明还提供了式I化合物或其可药用盐，或它们的可药用溶剂化物，或其可药用的组合物作为人用药物的用途。In addition, the present invention also provides the use of the compounds of formula I or their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates, or their pharmaceutically acceptable compositions as human medicines.

本发明还提供了式I化合物或其可药用盐，或它们的可药用溶剂化物，在制备PDE5抑制剂药物中的用途。The present invention also provides the use of the compound of formula I or its pharmaceutically acceptable salt, or their pharmaceutically acceptable solvate in the preparation of PDE5 inhibitor drugs.

本发明也提供了式I化合物或可其可药用盐，或它们的可药用溶剂化物，或其可药用的组合物，在制备用来治疗或预防男性勃起功能障碍、良性前列腺增生、女性性功能障碍、早产、痛经、膀胱出口梗阻、失禁、不稳定的和变异的Prinzmetal心绞痛、高血压、肺动脉高压、充血性心衰、肾衰竭、动脉粥样硬化、中风、周围血管疾病、雷诺氏症、炎症性疾病、支气管炎、慢性哮喘、过敏性哮喘、过敏性鼻炎、青光眼、以及特征为肠蠕动障碍的疾病(例如应激性肠综合症)的人用药物中的用途。The present invention also provides compounds of formula I or their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates, or their pharmaceutically acceptable compositions, used for the treatment or prevention of male erectile dysfunction, benign prostatic hyperplasia, Female sexual dysfunction, premature labor, dysmenorrhea, bladder outlet obstruction, incontinence, unstable and variant Prinzmetal angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, Raynaud asthma, inflammatory disease, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by disturbances in bowel motility, such as irritable bowel syndrome.

本发明还提供了所述式I化合物的制备方法。(A)：制备式I(I-A，I-B，I-C)化合物及其药用盐的方法：The present invention also provides the preparation method of the compound of formula I. (A): the method for preparing formula I (I-A, I-B, I-C) compound and pharmaceutically acceptable salt thereof:

Figure S2007100479158D00091
Figure S2007100479158D00091

其中R1、R2、R3、R4、R5如权利要求1中的定义。其包括：wherein R1 , R2 , R3 , R4 , and R5 are as defined in claim 1. It includes:

(i)第一类部分式I-A(R1为卤素，R3不为H，R2、R4、R5如权利要求1中的定义)化合物可由式2化合物在碱的存在下，温度通常30-200℃，适当的溶剂中进行反应1-12小时制得。优选的碱包括碱金属烷氧化物(优选叔丁醇钾、乙醇钠)、碱金属或碱土金属氢化物、胺(优选三乙胺)、胺的金属盐、氢氧化物(优选氢氧化钠)、碳酸盐和碳酸氢盐；优选的溶剂包括醇(例如叔丁醇、乙醇、甲醇、异丙醇、乙二醇、乙二醇单甲醚)、芳烃(例如苯、甲苯、氯苯)、吡啶、卤代烃、乙腈、四氢呋喃、二氧六环、二甲亚砜、N，N-二甲基甲酰胺、N-甲基吡咯烷-2-酮等。(i) The first class of partial formula IA (R1 is halogen, R3 is not H, R2 , R4 , R5 are as defined in claim 1) compounds can be prepared from compounds of formula 2 in the presence of a base, the temperature is usually 30-200 ° C, in a suitable solvent for 1-12 hours of reaction in the system. Preferred bases include alkali metal alkoxides (preferably potassium tert-butoxide, sodium ethoxide), alkali metal or alkaline earth metal hydrides, amines (preferably triethylamine), metal salts of amines, hydroxides (preferably sodium hydroxide) , carbonates and bicarbonates; preferred solvents include alcohols (e.g. tert-butanol, ethanol, methanol, isopropanol, ethylene glycol, ethylene glycol monomethyl ether), aromatics (e.g. benzene, toluene, chlorobenzene) , pyridine, halogenated hydrocarbons, acetonitrile, tetrahydrofuran, dioxane, dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidin-2-one, etc.

Figure S2007100479158D00092
Figure S2007100479158D00092

(ii)第二类部分式I-B(R1不为卤素，R3不为H，R2、R4、R5如权利要求1中的定义)化合物可由相应的第一类部分式I-A中的化合物与烃基金属试剂(烃基金属试剂可以是CuI，CH3ZnCl/[(t-Bu)3P]2Pd，C2H5ZnI/[(t-Bu)3P]2Pd，n-C3H7ZnI/[(t-Bu)3P]2Pd，[(t-Bu)3P]2Pd等)在适当的溶剂(溶剂优选N，N-二甲基甲酰胺，二甲亚砜，乙二醇单甲醚，N-甲吡咯烷酮)中加热制得。反应方程式：(ii) the second class of partial formula IB (R1 is not halogen, R3 is not H, R2 , R4 , R5 are as defined in claim 1) compounds can be obtained from the corresponding first class of partial formula IA Compounds and hydrocarbyl metal reagents (hydrocarbyl metal reagents can be CuI, CH3 ZnCl/[(t-Bu)3 P]2 Pd, C2 H5 ZnI/[(t-Bu)3 P]2 Pd, nC3 H7 ZnI/[(t-Bu)3 P]2 Pd, [(t-Bu)3 P]2 Pd, etc.) in a suitable solvent (the solvent is preferably N, N-dimethylformamide, dimethyl sulfoxide, Ethylene glycol monomethyl ether, N-methyl pyrrolidone) in the heating system. Reaction equation:

其中R1、R2、R3、R4、R5如上述定义Wherein R1 , R2 , R3 , R4 , R5 are as defined above

(iii)第三类部分式I-C(R3为H)可由其相应的第一类部分式I-A或I-B中的化合物在适当的溶剂(溶剂优选二氯甲烷，三氯甲烷)中与去烷基化试剂反应得到(去烷基试剂优选三氯化铝，三溴化硼，四氟化硼)。反应方程式：(iii) the third type of partial formula IC (R3 is H) can be dealkylated by the compound in the corresponding first type of partial formula IA or IB in a suitable solvent (preferably dichloromethane, chloroform) Reagent reaction obtains (dealkylation reagent is preferably aluminum trichloride, boron tribromide, boron tetrafluoride). Reaction equation:

Figure S2007100479158D00102
Figure S2007100479158D00102

其中R1、R2、R3、R4、R5如上述定义。Wherein R1 , R2 , R3 , R4 and R5 are as defined above.

(B)：式II化合物通常可由式III化合物与式IX化合物的反应来制备。(B): Compounds of formula II can generally be prepared by reacting compounds of formula III with compounds of formula IX.

操作方法一：先用亚硫酰氯、草酰氯、氯甲酸乙酯等将式IX化合物的羧基转化为酰氯或混合酸酐，再与式III化合物反应得到相应的酰胺II。酰化反应通常在去酸剂存在下，在常用溶剂中进行。优选的去酸剂包括有机碱(优选三乙胺、二异丙基乙基胺、吡啶)和无机碱(优选氢氧化物、碳酸盐)。优选的溶剂包括烷烃类(优选石油醚、正己烷、环己烷)、卤代烃(优选二氯甲烷或氯仿)、醚(优选四氢呋喃、二氧六环、乙醚)、芳香类溶剂(优选甲苯)、以及醇类(优选叔丁醇、异丙醇)。Operation method 1: firstly use thionyl chloride, oxalyl chloride, ethyl chloroformate, etc. to convert the carboxyl group of the compound of formula IX into acid chloride or mixed acid anhydride, and then react with the compound of formula III to obtain the corresponding amide II. The acylation reaction is usually carried out in a common solvent in the presence of an acid scavenger. Preferred acid scavengers include organic bases (preferably triethylamine, diisopropylethylamine, pyridine) and inorganic bases (preferably hydroxides, carbonates). Preferred solvents include alkanes (preferably petroleum ether, n-hexane, cyclohexane), halogenated hydrocarbons (preferably methylene chloride or chloroform), ethers (preferably tetrahydrofuran, dioxane, diethyl ether), aromatic solvents (preferably toluene ), and alcohols (preferably tert-butanol, isopropanol).

操作方法二，采用羧酸和胺直接缩合得到酰胺II。反应通常在活化剂或脱水剂存在下，在无水惰性溶剂中进行。优选的活化剂或脱水剂包括DCC、EDCI、EEDQ、CDI、HOBt等。优选的溶剂包括卤代烃(优选二氯甲烷或氯仿)、醚(优选四氢呋喃、二氧六环、乙醚)、芳烃(优选苯、甲苯)、极性非质子溶剂(二甲亚砜、N，N-二甲基甲酰胺)，或这些溶剂的混合物。The second operation method is to directly condense carboxylic acid and amine to obtain amide II. The reaction is usually carried out in an anhydrous inert solvent in the presence of an activating agent or a dehydrating agent. Preferred activators or dehydrating agents include DCC, EDCI, EEDQ, CDI, HOBt and the like. Preferred solvents include halogenated hydrocarbons (preferably dichloromethane or chloroform), ethers (preferably tetrahydrofuran, dioxane, diethyl ether), aromatic hydrocarbons (preferably benzene, toluene), polar aprotic solvents (dimethylsulfoxide, N, N-dimethylformamide), or a mixture of these solvents.

反应方程式：Reaction equation:

Figure S2007100479158D00111
Figure S2007100479158D00111

其中R1、R2、R3、R4、R5如上述定义。Wherein R1 , R2 , R3 , R4 and R5 are as defined above.

(C)：式III化合物通常可由式IV化合物与NH3缩合反应来制备。反应通常在活化剂或脱水剂存在下，在无水惰性溶剂中进行。优选的活化剂或脱水剂包括DCC、EDCI、EEDQ、CDI、HOBt等。优选的溶剂包括卤代烃(优选二氯甲烷或氯仿)、醚(优选四氢呋喃、二氧六环、乙醚)、芳烃(优选苯、甲苯)、极性非质子溶剂(二甲亚砜、N，N-二甲基甲酰胺)，或这些溶剂的混合物。反应方程式：(C): Compounds of formula III can usually be prepared by condensation reaction of compounds of formula IV with NH3 . The reaction is usually carried out in an anhydrous inert solvent in the presence of an activating agent or a dehydrating agent. Preferred activators or dehydrating agents include DCC, EDCI, EEDQ, CDI, HOBt and the like. Preferred solvents include halogenated hydrocarbons (preferably dichloromethane or chloroform), ethers (preferably tetrahydrofuran, dioxane, diethyl ether), aromatic hydrocarbons (preferably benzene, toluene), polar aprotic solvents (dimethylsulfoxide, N, N-dimethylformamide), or a mixture of these solvents. Reaction equation:

Figure S2007100479158D00112
Figure S2007100479158D00112

其中R1、R2、R3如上述定义。Wherein R1 , R2 , R3 are as defined above.

(D)：式IV化合物通常可由式V化合物在5％-10％NaOH溶液中，与30％H2O2反应制得。反应方程式：(D): The compound of formula IV can usually be prepared by reacting the compound of formula V with 30% H2 O2 in 5%-10% NaOH solution. Reaction equation:

Figure S2007100479158D00121
Figure S2007100479158D00121

其中R1、R2、R3如上述定义。Wherein R1 , R2 , R3 are as defined above.

(E)：式V化合物通常可由式VI化合物与草酰氯在适当溶剂(溶剂优选二氯甲烷，三氯甲烷，1，3-二氯丙烷)中反应制得，温度通常30-100℃。反应方程式：(E): The compound of formula V can usually be prepared by reacting the compound of formula VI with oxalyl chloride in a suitable solvent (preferably dichloromethane, trichloromethane, 1,3-dichloropropane) at a temperature of usually 30-100°C. Reaction equation:

其中R1、R2、R3如上述定义。Wherein R1 , R2 , R3 are as defined above.

(F)：式VI化合物通常可由式VII化合物在HCl/MeOH溶液中回流来制备。(F): Compounds of formula VI can generally be prepared by refluxing compounds of formula VII in HCl/MeOH solution.

Figure S2007100479158D00123
Figure S2007100479158D00123

其中R1、R2、R3如上述定义。Wherein R1 , R2 , R3 are as defined above.

(G)：式VII化合物通常可由式VIII化合物与适当卤代试剂(卤代试剂可为NBS，NCS，F-TEDA-BF4，NaI/t-BuOCl)在适当溶剂(溶剂优选乙睛，二氯甲烷，三氯甲烷，1，3-二氯丙烷)中反应制得，温度通常-20-50℃。(G): The compound of formula VII can usually be prepared from the compound of formula VIII and a suitable halogenating reagent (the halogenating reagent can be NBS, NCS, F-TEDA-BF4 , NaI/t-BuOCl) in a suitable solvent (the solvent is preferably acetonitrile, di Chloromethane, chloroform, 1,3-dichloropropane) reaction in the system, the temperature is usually -20-50 ℃.

其中R2、R3如上述定义。Wherein R2 and R3 are as defined above.

式IX、式VIII化合物可按文献方法制备或商购。Compounds of formula IX and formula VIII can be prepared according to literature methods or purchased commercially.

本发明人设计和合成了一系列新的喹唑啉酮衍生物I，这些化合物中多数具有比西地那非更强的PDE5抑制活性，且相对于分布在视网膜的PDE6有更高的选择性。因此本发明提供的化合物可望在临床上表现出更佳的安全性和有效性，临床应用前景广阔。The inventors designed and synthesized a series of new quinazolinone derivatives I, most of these compounds have stronger PDE5 inhibitory activity than sildenafil, and have higher selectivity relative to PDE6 distributed in the retina . Therefore, the compounds provided by the present invention are expected to show better safety and efficacy in clinical practice, and have broad prospects for clinical application.

具体实施方式Detailed ways

以下结合具体实施例，进一步阐明本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。比例和百分比基于重量，除非特别说明。Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, the conventional conditions or the conditions suggested by the manufacturer are usually followed. Ratios and percentages are by weight unless otherwise indicated.

本发明所使用的部分术语定义如下：Some terms used in the present invention are defined as follows:

“卤素”是指氟、氯、溴和碘。"Halogen" refers to fluorine, chlorine, bromine and iodine.

“烷基”当作一基团或一基团的部分时是指直链或者带有支链的脂肪烃基团。优先选择烷基为C1-C14的烷基；更优先选择为：C1-C10烷基；最优先选择为C1-C6，除非另有指明。直链或和带有支链的C1-C6烷基的实例包括，但不限于：甲基、乙基、正丙基、2-丙基、正丁基、异丁基、特丁基、己基等。"Alkyl" when taken as a group or a part of a group refers to a straight chain or branched aliphatic hydrocarbon group. Preferably, the alkyl group is C1-C14 alkyl; more preferably: C1-C10 alkyl; most preferably, C1-C6, unless otherwise specified. Examples of straight chain or branched C1-C6 alkyl include, but are not limited to: methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, t-butyl, hexyl wait.

“烯基”作为一基团或一基团的一部分时是指至少含有一个碳-碳双键的脂肪烃基团，可为直链也可以带有支链。优先选择具有C2-C14的烯基。C2-C12则更好；最为优先选择的是C2-C6的烯基。该基团可在其主链中含有多个双键且其构象可各自为E或Z。烯基基团的例子包括，但不限于：乙烯基、丙烯基等。"Alkenyl" as a group or a part of a group refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be a straight chain or a branched chain. Preference is given to alkenyl groups having C2-C14. C2-C12 is more preferred; most preferred is C2-C6 alkenyl. This group may contain multiple double bonds in its backbone and its conformation may be E or Z each. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, and the like.

“环烷基”是指饱和或部分饱和的单环、稠环或螺环之碳环。以3-9个碳原子组成的环为优先选择。实例包括，但不限于：环丙基、环丁基、环戊基、环己基等。"Cycloalkyl" means a saturated or partially saturated monocyclic, fused or spiro carbocyclic ring. Rings of 3-9 carbon atoms are preferred. Examples include, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

“芳基”作为一基团或一基团的部分是指：(1)芳香性的单环或稠环；优先选择具有5-12个碳原子的芳香性碳环(环原子均为碳的环状构造)。芳基的实例包括，但不限于：苯基，萘基；(2)可以连接部分饱和的碳环，例如：苯基和C5-7环烷基或C5-7环烯基基团系互相稠合而形成一环状结构。实例包括，但不限于：四氢萘基，茚基或氢茚基等。芳基基团可被一个或多个取代基取代。"Aryl" as a group or part of a group refers to: (1) aromatic single ring or condensed ring; preference is given to aromatic carbocycles with 5-12 carbon atoms (the ring atoms are all carbon ring structure). Examples of aryl groups include, but are not limited to: phenyl, naphthyl; (2) partially saturated carbocyclic rings can be connected, for example: phenyl and C5-7 cycloalkyl or C5-7 cycloalkenyl groups are fused to each other combined to form a ring structure. Examples include, but are not limited to, tetrahydronaphthyl, indenyl or hydroindenyl, and the like. An aryl group may be substituted with one or more substituents.

本发明包括通式(I)所表示的化合物及其可能的各种异构型式。包括：非镜像异构体、镜像异构体、互变异构体和“E”或“Z”构型异构体的几何异构体等。任何具有一定基础的化学工作者均可以分离出上述光学纯或者立体异构纯的化合物。The present invention includes compounds represented by general formula (I) and various possible isomeric forms thereof. Includes: diastereomers, mirror-image isomers, tautomers, geometric isomers of "E" or "Z" configuration isomers, and the like. Any chemist with a certain foundation can isolate the above-mentioned optically pure or stereoisomerically pure compounds.

本发明包括通式(I)所表示的化合物及其可能的消旋体或/和镜像异构物/或/和非镜像异构物的混合物。The present invention includes the compounds represented by general formula (I) and their possible racemates or/and mirror isomers/or/and mixtures of diastereomers.

此外，通式(I)所表示的化合物在应用上也涵盖该化合物的溶剂化及非溶剂化型式。因此，各式均包括具有所指明构造的化合物，包括其水合及无水合型式。In addition, the compound represented by the general formula (I) also covers the solvated and unsolvated forms of the compound in application. Accordingly, each formula includes the compound having the indicated configuration, including hydrated and anhydrous forms thereof.

术语“可药用盐”是指上述化合物能保持原有生物活性并且适合于医药用途的某些盐类。通式(I)所表示的化合物的药学上可接受的盐有两种形成形式：一是与酸形成的盐；另一是与碱或者碱金属形成的盐。与通式(I)所表示的化合物形成可药用盐的酸包括无机酸和有机酸。合适的无机酸包括：盐酸，硫酸和磷酸。合适的有机酸可选自脂肪族、环脂肪族、芳香性、杂环羧酸和磺酸类有机酸；其实例包括但不限于：甲酸、乙酸、丙酸、琥珀酸、甘醇酸、葡萄糖酸、乳酸、苹果酸、酒石酸、甘氨酸、精氨酸、柠檬酸、反丁烯二酸、烷基磺酸、芳基磺酸等。与通式(I)所表示的化合物形成药学上可接受的盐的碱金属包括：锂、钠、钾、镁、钙、铝、锌等；与通式(I)所表示的化合物形成药学上可接受的盐的碱包括：胆碱、二乙醇胺、吗啉等。The term "pharmaceutically acceptable salt" refers to certain salts of the above compounds that can maintain their original biological activity and are suitable for medical use. The pharmaceutically acceptable salt of the compound represented by the general formula (I) has two forms: one is a salt formed with an acid; the other is a salt formed with an alkali or an alkali metal. Acids that form pharmaceutically acceptable salts with compounds represented by general formula (I) include inorganic acids and organic acids. Suitable inorganic acids include: hydrochloric acid, sulfuric acid and phosphoric acid. Suitable organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic organic acids; examples include, but are not limited to: formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, glucose acid, lactic acid, malic acid, tartaric acid, glycine, arginine, citric acid, fumaric acid, alkylsulfonic acid, arylsulfonic acid, etc. The alkali metals that form pharmaceutically acceptable salts with the compounds represented by general formula (I) include: lithium, sodium, potassium, magnesium, calcium, aluminum, zinc, etc.; Bases of acceptable salts include: choline, diethanolamine, morpholine, and the like.

“前药”是一种通式(I)所表示的衍生物，借助于在体内代谢的方式将其于活体内转化(例如：藉由水解，还原或氧化)成通式(I)所表示的化合物。例如，可以将通式(I)所表示的、含有羟基基团的化合物与酸反应制备成相应的酯。相应的酯即为前药，可以再活体内水解母体药物。适合来制备“前药”的酸包括但不限于：乙酸、柠檬酸、乳酸、酒石酸、丙二酸、草酸、水杨酸、琥珀酸、反丁烯二酸、顺丁烯二酸、亚甲基-双-β-羟基萘酸、龙胆酸、羟乙基磺酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸等。"Prodrug" is a derivative represented by general formula (I), which is transformed in vivo by means of in vivo metabolism (for example: by hydrolysis, reduction or oxidation) into a derivative represented by general formula (I). compound of. For example, the compound represented by general formula (I) containing a hydroxyl group can be reacted with an acid to prepare the corresponding ester. The corresponding ester is a prodrug, which can hydrolyze the parent drug in vivo. Acids suitable for preparing "prodrugs" include, but are not limited to: acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, oxalic acid, salicylic acid, succinic acid, fumaric acid, maleic acid, methylene Base-bis-β-hydroxynaphthoic acid, gentisic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

通式(I)所表示的化合物的给药方式可以是胃肠道给药也可以是非胃肠道给药。胃肠道给药：经口或经直肠。非胃肠道给药方式包括：皮下，肌肉，静脉内和皮肤内等途径。通常，通式(I)所表示的活性化合物，在给药时，可以使用药学上可接受的载体或稀释剂。The administration method of the compound represented by the general formula (I) may be gastrointestinal administration or parenteral administration. Gastrointestinal administration: oral or rectal. Parenteral administration methods include: subcutaneous, intramuscular, intravenous and intradermal routes. Usually, the active compound represented by the general formula (I) can be administered with a pharmaceutically acceptable carrier or diluent.

“治疗有效量”或“治疗量”均是指足以产生疗效的量。有效量可分一或多次给药。通常，有效量足以缓和、改善、稳定、减慢或延迟疾病的进一步发展。"Therapeutically effective amount" or "therapeutic amount" both refer to an amount sufficient to produce a therapeutic effect. An effective amount may be administered in one or more divided doses. Usually, the effective amount is enough to alleviate, ameliorate, stabilize, slow down or delay the further development of the disease.

同时，本发明也提供了含有所述式I化合物的可药用的组合物。该组合物由一种或多种式I化合物(或其可药用盐，或它们的可药用溶剂化物)与至少一种可药用辅料组成。药用辅料的选择因施用途径和作用特点而异，通常是填充剂、稀释剂、粘合剂、润湿剂、崩解剂、润滑剂、乳化剂、助悬剂等。Meanwhile, the present invention also provides a pharmaceutically acceptable composition containing the compound of formula I. The composition consists of one or more compounds of formula I (or their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates) and at least one pharmaceutically acceptable auxiliary material. The selection of pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, usually fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers, suspending agents, etc.

本发明的组合物可以口服、注射(静脉、肌肉、皮下和冠状动脉内)、舌下、经颊、经直肠、经尿道、经阴道、经鼻、吸入或局部途径施用。优选的途径是口服。The compositions of the present invention may be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, urethral, vaginal, nasal, inhalation or topical routes. The preferred route is oral.

式I化合物在上述组合物中的所占的比例为总重量的0.1％～99.9％，优选1％～99％。The proportion of the compound of formula I in the above composition is 0.1%-99.9% of the total weight, preferably 1%-99%.

本发明还提供了式I化合物的可药用的组合物的制备方法。通常将式I化合物与可药用辅料相混合，经常规的制备方法制成适于一定途径施用的形式(剂型)。剂型包括片剂、胶囊剂、颗粒剂、丸剂、溶液剂、混悬剂、乳剂、软膏、膜剂、霜剂、气雾剂、注射剂、栓剂等。优选片剂和胶囊剂。The present invention also provides the preparation method of the pharmaceutically acceptable composition of the compound of formula I. Usually, the compound of formula I is mixed with a pharmaceutically acceptable auxiliary material, and prepared into a form (dosage form) suitable for a certain route of administration through conventional preparation methods. Dosage forms include tablets, capsules, granules, pills, solutions, suspensions, emulsions, ointments, films, creams, aerosols, injections, suppositories, and the like. Tablets and capsules are preferred.

片剂和胶囊剂的组方可含有一种或多种式I以及一种或多种常用辅料，例如淀粉、蔗糖、乳糖、葡萄糖、微晶纤维素、甘露糖等填充剂；羧甲基纤维素、明胶、海藻酸盐和聚乙烯吡咯烷酮等粘合剂；甘油等润湿剂；琼脂、乙基纤维素、羧甲基淀粉钠、碳酸钙等崩解剂；硬脂酸镁、滑石粉、聚乙二醇等润滑剂。The composition of tablet and capsule can contain one or more formula I and one or more commonly used excipients, such as fillers such as starch, sucrose, lactose, glucose, microcrystalline cellulose, mannose; Carboxymethyl cellulose Adhesives such as plain, gelatin, alginate and polyvinylpyrrolidone; wetting agents such as glycerin; disintegrants such as agar, ethyl cellulose, sodium carboxymethyl starch, calcium carbonate, etc.; Lubricants such as polyethylene glycol.

本发明化合物的使用剂量一般为每天1～500mg，优选10～100mg，分单次或多次使用。但在必要时，可适当偏离上述剂量。专业人员可根据具体情况和专业知识，确定最佳剂量。这些情况包括疾病的严重程度、患者的个体差异、制剂的特性和给药途径等。The dosage of the compound of the present invention is generally 1-500 mg per day, preferably 10-100 mg, in single or multiple doses. However, when necessary, the above dosage can be appropriately deviated from. Professionals can determine the optimal dosage according to the specific situation and professional knowledge. These circumstances include the severity of the disease, individual differences in patients, properties of the formulation, route of administration, and the like.

下列实施例进一步解释了本发明的化合物及其中间体的合成方法，但并不限制本发明的范围。1H NMR在Mercury-400或Mercury-300核磁共振波谱仪(Varian公司)上完成。常规缩写如下：s，单峰；d，双峰；t，三重峰；q，四重峰；m，多重峰；br，宽峰。The following examples further illustrate the synthesis methods of the compounds of the present invention and their intermediates, but do not limit the scope of the present invention. 1H NMR was performed on a Mercury-400 or Mercury-300 nuclear magnetic resonance spectrometer (Varian). Conventional abbreviations are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.

实施例1  2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮Example 1 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-Kone

步骤1：2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯甲酰氨基]-5，7-二甲氧基-8-溴苯甲酰氨Step 1: 2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-benzamido]-5,7-dimethoxy-8-bromobenzamide

Figure S2007100479158D00161
Figure S2007100479158D00161

将2-乙氧基-5-[(4-甲基-1-哌嗪基)磺酰基]苯甲酸(0.34g，1mmol)溶于20ml二氯甲烷，加羰酰二咪唑(CDI，3mmol)，于室温下搅拌0.5h，再向该混合液中加入2-氨基-4，6-二甲氧基-3-溴苯甲酰氨(0.28g，1mmol)，继续搅拌1-6h，用TLC检测反应终点。反应毕，混合液以氯化铵溶液和饱和食盐水洗，二氯甲烷相用无水硫酸镁干燥，然后减压浓缩至干，残留固体用乙醇重结晶得产物白色粉末0.51g，产率86％。Dissolve 2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoic acid (0.34g, 1mmol) in 20ml of dichloromethane, add carbonyldiimidazole (CDI, 3mmol) , stirred at room temperature for 0.5h, then added 2-amino-4,6-dimethoxy-3-bromobenzamide (0.28g, 1mmol) to the mixture, continued to stir for 1-6h, and analyzed with TLC Detection of reaction endpoints. After the reaction was completed, the mixed solution was washed with ammonium chloride solution and saturated brine, and the dichloromethane phase was dried with anhydrous magnesium sulfate, then concentrated to dryness under reduced pressure, and the residual solid was recrystallized with ethanol to obtain 0.51 g of a white powder with a yield of 86%. .

步骤2：制备2-{2-乙氧基-5-[(4-甲基-1-哌嗪基)磺酰基]苯基}-5，7-二甲氧基-8-溴-喹-4(3H)-酮Step 2: Preparation of 2-{2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-5,7-dimethoxy-8-bromo-quinol- 4(3H)-keto

Figure S2007100479158D00162
Figure S2007100479158D00162

将叔丁醇钾(0.06g，0.55mmol)和步骤1产物(0.3g，0.5mmol)先后加入叔丁醇(15ml)中，于搅拌下加热该混悬液至回流，约30min后变澄清，继续回流10h。停止加热，冷至室温后加入水(20ml)，以4％稀醋酸调至中性，然后冷却至5-10℃。有白色固体析出，过滤，冷水(3×10ml)洗，烘干，用甲醇/乙酸乙酯重结晶得产物0.22g，产率76％。1H-NMR(300MHz，CDCl3)，δ10.56(brs，1H)，9.17(d，J＝2.7Hz，1H)，7.88(dd，J＝8.8，2.7Hz，1H)，7.14(d，J＝8.8Hz，1H)，6.54(s，1H)，4.37(q，J＝7.0Hz，2H)，4.05(s，3H)，4.03(s，3H)，3.21(m，4H)，2.57(m，4H)，2.34(s，3H)，1.63(t，J＝7.0Hz，3H).Potassium tert-butoxide (0.06g, 0.55mmol) and the product of step 1 (0.3g, 0.5mmol) were successively added to tert-butanol (15ml), and the suspension was heated to reflux under stirring, and became clear after about 30min. Continue to reflux for 10h. Stop heating, add water (20ml) after cooling to room temperature, adjust to neutral with 4% dilute acetic acid, then cool to 5-10°C. A white solid precipitated, filtered, washed with cold water (3×10ml), dried, and recrystallized from methanol/ethyl acetate to obtain 0.22g of the product, with a yield of 76%. 1H-NMR (300MHz, CDCl3), δ10.56(brs, 1H), 9.17(d, J=2.7Hz, 1H), 7.88(dd, J=8.8, 2.7Hz, 1H), 7.14(d, J= 8.8Hz, 1H), 6.54(s, 1H), 4.37(q, J=7.0Hz, 2H), 4.05(s, 3H), 4.03(s, 3H), 3.21(m, 4H), 2.57(m, 4H), 2.34(s, 3H), 1.63(t, J=7.0Hz, 3H).

实施例2 8-甲基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-喹唑啉-4(3H)-酮Example 2 8-methyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline- 4(3H)-keto

Figure S2007100479158D00171
Figure S2007100479158D00171

无水氯化锌408mg(3.0mmol)溶于5mL干燥NMP中，冰浴冷却下，滴加2mL2mol/L甲基氯化镁(2.0mmol)THF溶液，转室温搅拌1小时得甲基锌试剂。Dissolve 408 mg (3.0 mmol) of anhydrous zinc chloride in 5 mL of dry NMP, add dropwise 2 mL of 2 mol/L methylmagnesium chloride (2.0 mmol) THF solution under ice cooling, and stir at room temperature for 1 hour to obtain methyl zinc reagent.

2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-8-溴-喹唑啉-4(3H)-酮567mg(10i，1.0mmol)混于5mL干燥NMP中，加入上述制备的甲基锌试剂，氮气保护下加[(t-Bu)3P]2Pd 25mg(0.05mmol)，转40℃加热4小时，降至室温，加10mL二氯甲烷、20mL水分液，水相用3mL二氯甲烷萃取1次，合并有机相，依次用2mL水、饱和食盐水洗1次，无水硫酸钠干燥，硅胶柱层析(CH2Cl2/CH3OH)分离得浅黄色8-甲基-2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5，7-二甲氧基-喹唑啉-4(3H)-酮(10b)固体411mg，产率82％。1H-NMR(300MHz，CDCl3)，δ10.44(brs，1H)，8.93(d，J＝2.4Hz，1H)，7.86(dd，J＝8.8，2.4Hz，1H)，7.14(d，J＝8.8Hz，1H)，6.54(s，1H)，4.35(q，J＝7.0Hz，2H)，4.02(s，3H)，3.98(s，3H)，3.12(m，4H)，2.51(m，4H)，2.44(s，3H)，2.28(s，3H)，1.63(t，J＝7.0Hz，3H)。2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4(3H) - Ketone 567mg (10i, 1.0mmol) was mixed in 5mL of dry NMP, the methyl zinc reagent prepared above was added, and [(t-Bu)3P]2Pd 25mg (0.05mmol) was added under nitrogen protection, and heated at 40°C for 4 hours , down to room temperature, add 10mL dichloromethane, 20mL water solution, extract the water phase once with 3mL dichloromethane, combine the organic phase, wash once with 2mL water and saturated brine, dry over anhydrous sodium sulfate, and use silica gel column layer Analysis (CH2Cl2/CH3OH) isolated light yellow 8-methyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethyl Oxy-quinazolin-4(3H)-one (10b) solid 411 mg, yield 82%. 1H-NMR (300MHz, CDCl3), δ10.44(brs, 1H), 8.93(d, J=2.4Hz, 1H), 7.86(dd, J=8.8, 2.4Hz, 1H), 7.14(d, J= 8.8Hz, 1H), 6.54(s, 1H), 4.35(q, J=7.0Hz, 2H), 4.02(s, 3H), 3.98(s, 3H), 3.12(m, 4H), 2.51(m, 4H), 2.44 (s, 3H), 2.28 (s, 3H), 1.63 (t, J = 7.0 Hz, 3H).

实施例3 2-[2-乙氧基-5-(4-甲基哌嗪-1-磺酰基)-苯基]-5-羟基-7-甲氧基-8-溴-喹唑啉-4(3H)-酮Example 3 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-bromo-quinazoline- 4(3H)-keto

Figure S2007100479158D00172
Figure S2007100479158D00172

取实施例1化合物(0.57g，1.0mmol)溶于20mL干燥二氯甲烷，-10℃冷却搅拌下滴加2mL的三溴化硼(104uL，1.1mmol)二氯甲烷溶液，继续搅拌4小时，加1mL乙醚，继续搅拌30分钟，加20mL二氯甲烷和50mL 5％NaHCO3分液，水相用10mL二氯甲烷萃取1次，合并有机相，依次用5mL 5％NaHCO3、饱和食盐水洗1次，无水硫酸钠干燥，用石油醚/二氯甲烷重结晶得浅黄色固体0.45g，产率82％。Dissolve the compound of Example 1 (0.57g, 1.0mmol) in 20mL of dry dichloromethane, add 2mL of boron tribromide (104uL, 1.1mmol) dichloromethane solution dropwise under cooling and stirring at -10°C, and continue stirring for 4 hours. Add 1mL ether, continue stirring for 30 minutes, add 20mL dichloromethane and 50mL 5% NaHCO3 to separate the liquid, extract the aqueous phase once with 10mL dichloromethane, combine the organic phases, and wash once with 5mL 5% NaHCO3 and saturated saline successively, Dry over anhydrous sodium sulfate and recrystallize from petroleum ether/dichloromethane to obtain 0.45 g of light yellow solid with a yield of 82%.

1H-NMR(300MHz，CDCl3)，δ11.62(s，1H)，10.82(brs，1H)，9.11(d，J＝2.3Hz，1H)，7.90(dd，J＝8.8，2.3Hz，1H)，7.17(d，J＝8.8Hz，1H)，6.57(s，1H)，4.41(q，J＝7.0Hz，2H)，4.00(s，3H)，3.18(m，4H)，2.56(m，4H)，2.31(s，3H)，1.67(t，J＝7.0Hz，3H)。1H-NMR (300MHz, CDCl3), δ11.62(s, 1H), 10.82(brs, 1H), 9.11(d, J=2.3Hz, 1H), 7.90(dd, J=8.8, 2.3Hz, 1H) , 7.17(d, J=8.8Hz, 1H), 6.57(s, 1H), 4.41(q, J=7.0Hz, 2H), 4.00(s, 3H), 3.18(m, 4H), 2.56(m, 4H), 2.31 (s, 3H), 1.67 (t, J = 7.0 Hz, 3H).

实施例4～50Examples 4-50

按照实施例1或2的相同方法，采用不同取代基的起始原料，制备实施例4～50的化合物(如无特别标明，NMR数据所用溶剂无特别说明均为CDCl3。According to the same method of Example 1 or 2, the starting materials of different substituents were used to prepare the compounds of Examples 4-50 (unless otherwise specified, the solvents used in the NMR data were all CDCl3 unless otherwise specified.

Figure S2007100479158D00181
Figure S2007100479158D00181

Figure S2007100479158D00191
Figure S2007100479158D00191

Figure S2007100479158D00201
Figure S2007100479158D00201

Figure S2007100479158D00211
Figure S2007100479158D00211

Figure S2007100479158D00221
Figure S2007100479158D00221

Figure S2007100479158D00231
Figure S2007100479158D00231

Figure S2007100479158D00251
Figure S2007100479158D00251

Figure S2007100479158D00261
Figure S2007100479158D00261

Figure S2007100479158D00271
Figure S2007100479158D00271

Figure S2007100479158D00281
Figure S2007100479158D00281

Figure S2007100479158D00291
Figure S2007100479158D00291

实施例51胶囊剂Embodiment 51 capsules

处方prescription

含吡啶并嘧啶酮衍生物的活性化合物            20.0gActive compound containing pyridopyrimidinone derivatives 20.0g

淀粉                                        80.0gStarch 80.0g

乳糖                                        60.0gLactose 60.0g

微晶纤维素                                  35gMicrocrystalline Cellulose 35g

10％聚乙烯吡咯烷酮乙醇溶液                  适量10% ethanol solution of polyvinylpyrrolidone Appropriate amount

硬脂酸镁                                    0.5gMagnesium stearate 0.5g

共制1000粒A total of 1000 capsules

将含吡啶并嘧啶酮衍生物的活性化合物及各种辅料过80目筛，按处方量称取，以10％聚乙烯吡咯烷酮乙醇溶液为粘合剂，用16目筛制成适宜的颗粒，65℃干燥，14目筛整粒，加入硬脂酸镁混合均匀，测颗粒含量，计算装量，装入胶囊，即得。Pass the active compound containing pyridopyrimidone derivatives and various auxiliary materials through a 80-mesh sieve, weigh according to the prescription amount, use 10% polyvinylpyrrolidone ethanol solution as a binder, and make suitable granules with a 16-mesh sieve, 65 Dry at ℃, sieve with 14 meshes, granulate, add magnesium stearate and mix evenly, measure the content of granules, calculate the filling amount, put into capsules, and obtain.

实施例52片剂(湿制粒法)Embodiment 52 tablet (wet granulation method)

处方prescription

含吡啶并嘧啶酮衍生物的活性化合物             20.0gActive compound containing pyridopyrimidinone derivatives 20.0g

乳糖                   120.0gLactose 120.0g

微晶纤维素             40.0gMicrocrystalline Cellulose 40.0g

8％淀粉浆              适量8% starch slurry Appropriate amount

羧甲基淀粉钠           10.0gSodium carboxymethyl starch 10.0g

硬脂酸镁               1.0gMagnesium stearate 1.0g

共制  1000片A total of 1000 pieces

将含吡啶并嘧啶酮衍生物的活性化合物、微晶纤维素、乳糖、羧甲基淀粉钠过80目筛，混匀，用8％淀粉浆制软材，16目制粒，干燥、整粒后，加入硬脂酸镁混合均匀，测定颗粒含量，计算片重，压片，即得。Pass the active compound containing pyridopyrimidinone derivatives, microcrystalline cellulose, lactose, and sodium carboxymethyl starch through a 80-mesh sieve, mix well, use 8% starch slurry to make soft materials, granulate with 16 mesh, dry, and granulate Finally, add magnesium stearate and mix evenly, measure the content of granules, calculate the weight of the tablet, and compress it to obtain the product.

实施例53片剂(粉末压片法)Embodiment 53 tablet (powder tabletting method)

处方prescription

含吡啶并嘧啶酮衍生物的活性化合物         20.0gActive compound containing pyridopyrimidinone derivatives 20.0g

微晶纤维素                               30.0gMicrocrystalline Cellulose 30.0g

无水乳糖                                 45.0gAnhydrous lactose 45.0g

聚乙烯吡咯烷酮                           3.0gPolyvinylpyrrolidone 3.0g

微粉硅胶                                 0.2gMicropowder silica gel 0.2g

硬脂酸镁                                 0.5gMagnesium stearate 0.5g

共制  1000片A total of 1000 pieces

将含吡啶并嘧啶酮衍生物的活性化合物与微晶纤维素、无水乳糖、聚乙烯吡咯烷酮、微粉硅胶于混合机中混匀，然后加入硬脂酸镁混匀，压片即得。Mix the active compound containing pyridopyrimidinone derivatives with microcrystalline cellulose, anhydrous lactose, polyvinylpyrrolidone, and micropowder silica gel in a mixer, then add magnesium stearate, mix evenly, and compress into tablets.

试验54药效试验Test 54 drug efficacy test

参照文献方法(International Journal of Impotence Research 2002，14，251和TheJournal of Urology 1992，147，1124)，把SD雄性大鼠禁食12小时后，随机分组，每组4只，用戊巴比妥钠(50mg/kg)腹腔注射麻醉，分离，暴露大鼠阴茎海绵体，用穿刺针穿入右侧阴茎海绵体后与电生理仪连接监测海绵体内压(ICP)，游离右侧颈总动脉，留置软管并与电生理仪连接，持续监测动脉血压(Bp)。下腹正中切口，暴露大鼠前列腺后外侧叶，在其表面寻找海绵体神经，用电极钩住神经，刺激参数为3v、2Hz、0.5ms，刺激时间为60s，灌胃给药，剂量为30mg/kg，连续观察用药前后ICP和MBp变化，通过ICP与Bp的比值综合评价药物对神经刺激诱发勃起的作用，把参数(ICP/BP)作为指标判断化合物对于大鼠阴茎海绵体的作用强弱。按上述方法我们测试了西地那非和部分实施例化合物对大鼠阴茎海绵体的作用。采用邓肯氏多重比较法对测试结果进行统计分析，测算空白组和测试化合物各组间差异的统计学意义，统计结果如下：Referring to the literature method (International Journal of Impotence Research 2002, 14, 251 and The Journal of Urology 1992, 147, 1124), SD male rats were fasted for 12 hours, randomly divided into four groups, and treated with pentobarbital sodium (50mg/kg) intraperitoneal injection of anesthesia, separation, exposure of rat corpus cavernosum, after penetrating the right side of the corpus cavernosum with a puncture needle, it is connected with an electrophysiological instrument to monitor the intracavernous pressure (ICP), free right common carotid artery, indwelling The hose is connected to an electrophysiological apparatus to continuously monitor arterial blood pressure (Bp). Make a midline incision in the lower abdomen, expose the posterolateral lobe of the rat prostate, look for the cavernous nerve on its surface, and hook the nerve with electrodes. The stimulation parameters are 3v, 2Hz, 0.5ms, and the stimulation time is 60s. kg, continuously observe the changes of ICP and MBp before and after administration, comprehensively evaluate the effect of the drug on nerve stimulation-induced erection by the ratio of ICP and Bp, and use the parameter (ICP/BP) as an index to judge the strength of the effect of the compound on the rat corpus cavernosum. We tested the effects of sildenafil and some of the compounds of the examples on the corpus cavernosum of rat penis according to the above method. The test results were statistically analyzed by Duncan's multiple comparison method, and the statistical significance of the differences between the blank group and the test compound groups was calculated, and the statistical results were as follows:

    实施例化合物Example compound    ICP/BPICP/BP    空白组blank group    30.04±8.2630.04±8.26    西地那非Sildenafil    55.89±5.59**55.89±5.59**    2020    48.44±2.36**48.44±2.36**    23 twenty three    48.52±9.33*48.52±9.33*    24 twenty four    42.83±7.44*42.83±7.44*

注：与空白组相比，*P＜0.05，**P＜0.01Note: Compared with the blank group,* P<0.05,** P<0.01

由实验数据可知，测试化合物用药后可以显著提高大鼠阴茎海绵体的ICP，增加ICP/BP，增强阴茎勃起功能，因此，可以作为口服药物治疗勃起功能障碍。From the experimental data, it can be known that the test compound can significantly improve the ICP of the rat corpus cavernosum, increase the ICP/BP, and enhance the erectile function of the penis after administration of the test compound. Therefore, it can be used as an oral drug for the treatment of erectile dysfunction.

试验55酶抑制活性试验Test 55 Enzyme Inhibition Activity Test

酶抑制活性测试所用的酶是采用类似于文献报道的方法(Thrombosis Res.1991，62，31和J.Biol.Chem.1997，272，2714)，把不同组织经适当处理，用FPLC分离出试验所需的酶。确切的说，从人的血小板中获得PDE5，从牛的视网膜中分离出PDE6。酶一经分离立即进行酶的抑制活性试验，酶的抑制试验是采用TRKQ7100试剂盒，直接检测cGMP的闪烁接近测定，大致是这样进行的，在不同抑制剂浓度和少量底物存在下，加入10μl的缓冲液(50mM Tris/HCl PH 7.5，8.3mM MgCl2，1.7mMEGTA)，水至最终体积为100μl，用固定量的酶引发反应，30℃保温30分钟，然后用50μl含有硫酸锌的硅酸钇珠终止反应，摇动20分钟后，暗处沉降30分钟，在MicroBeta1450液闪仪上计数，然后根据计数值算出本发明化合物对酶的半数抑制率(IC50)。The enzymes used in the enzyme inhibitory activity test are similar to the methods reported in the literature (Thrombosis Res.1991, 62, 31 and J.Biol.Chem.1997, 272, 2714), different tissues are properly processed, and the test is separated by FPLC. required enzymes. Specifically, PDE5 was obtained from human platelets and PDE6 was isolated from bovine retina. Once the enzyme is separated, the enzyme inhibitory activity test is carried out immediately. The enzyme inhibition test uses the TRKQ7100 kit to directly detect the scintillation proximity assay of cGMP. It is roughly carried out in this way. In the presence of different inhibitor concentrations and a small amount of substrate, add 10 μl of Buffer (50mM Tris/HCl pH 7.5, 8.3mM MgCl2 , 1.7mMEGTA), water to a final volume of 100μl, start the reaction with a fixed amount of enzyme, incubate at 30°C for 30 minutes, and then use 50μl of yttrium silicate containing zinc sulfate The beads terminated the reaction, and after shaking for 20 minutes, settled in the dark for 30 minutes, counted on MicroBeta1450 liquid scintillation instrument, and then calculated the half inhibitory rate (IC50 ) of the compound of the present invention to the enzyme according to the counted value.

PDE5抑制活性实验PDE5 inhibitory activity assay

按照上述方法，测定了西地那非及本发明的部分实施例化合物对人血小板PDE5的抑制活性，测定结果如下表所示：According to the method described above, the inhibitory activity of sildenafil and some embodiment compounds of the present invention to human platelet PDE5 was measured, and the results of the measurement are shown in the table below:

  测试化合物test compoundPDE5 IC50(nM)PDE5 IC50 (nM)测试化合物test compoundPDE5 IC50(nM)PDE5 IC50 (nM)    西地那非Sildenafil    6.46.4    24 twenty four    23.923.9    1 1    15.215.2    2626    25.825.8    33    12.912.9    3232    43.043.0    1414    26.126.1    3636    44.644.6    1717    79.379.3    4242    53.953.9    2020    65.165.1    4444    26.026.0    23 twenty three    12.112.1    4949    16.016.0

由上表化合物对PDE5的抑制活性(IC50)可知，本发明中的大多数化合物具有较强的PDE5抑制活性。From the PDE5 inhibitory activity (IC50 ) of the compounds in the above table, it can be seen that most of the compounds in the present invention have strong PDE5 inhibitory activity.

PDE6抑制活性实验PDE6 inhibitory activity assay

考虑到本发明化合物可能对分布于视网膜的PDE6抑制作用，进而引起视觉障碍作用，我们按上述方法，测定了本发明的部分式I化合物对牛视网膜PDE6的抑制活性，测定结果如下表所示：Considering that the compound of the present invention may inhibit the PDE6 distributed in the retina, and then cause visual impairment, we have measured the inhibitory activity of some formula I compounds of the present invention on bovine retinal PDE6 according to the above method, and the results of the measurement are shown in the following table:

测试化合物test compound  PDE6 IC50(nM)PDE6 IC50 (nM)  PDE5 IC50(nM)PDE5 IC50 (nM)PDE6 IC50/PDE5IC50PDE6 IC50 /PDE5IC50    西地那非Sildenafil    70.070.0    6.46.4    10.910.9    1 1    56505650    15.215.2    371.7371.7    33    83308330    12.912.9    645.7645.7    1414    172172    26.126.1    6.66.6    1717    246246    79.379.3    3.13.1    2020    640640    65.165.1    9.89.8    23 twenty three    262262    12.112.1    21.721.7    24 twenty four    1000010000    23.923.9    418418

    2626    32203220    25.825.8    124.8124.8    3232    21902190    43.043.0    50.950.9    3636    929929    44.644.6    20.820.8    4242    56005600    53.953.9    103.9103.9    4444    203.2203.2    26.026.0    37.637.6    4949    421421    16.016.0    26.326.3

本发明采用IC50 PDE6/IC50 PDE5的比值来判断本专利化合物对于PDE6和PDE5的选择性，结果表明大部分实施例化合物具有比西地那非更强的选择性，因此，相对西地那非本发明化合物引起视觉障碍的可能性更小。The present invention adopts the ratio of IC50 PDE6/IC50 PDE5 to judge the selectivity of the patent compound for PDE6 and PDE5, and the results show that most of the example compounds have stronger selectivity than sildenafil, therefore, relative to sildenafil Compounds not of the present invention were less likely to cause visual disturbances.

试验3急性毒性试验Test 3 Acute Toxicity Test

在该试验中，使用18-22克昆明种雄性小白鼠，随机分组，每组10只。将实施例化合物悬浮于0.5％羧甲基纤维素钠溶液中，按3g/kg的剂量灌胃给药，给药前禁食12小时，观察给药后动物的中毒或者临床死亡信号。试验结果如下表所示：In this test, 18-22 grams of Kunming male mice were used and randomly divided into groups of 10 mice. The compound of the example was suspended in 0.5% sodium carboxymethyl cellulose solution, administered by intragastric administration at a dose of 3 g/kg, and fasted for 12 hours before administration, and the animals were observed for signs of poisoning or clinical death after administration. The test results are shown in the table below:

  测试化合物test compound  动物数(只)Number of animals (only)  死亡动物(只)Dead animals (only)  死亡率(％)Mortality (%)    2020    1010    00    00    23 twenty three    1010    00    00

试验过程中，并未发现给药后小鼠有明显的临床中毒症状，体重变化及死亡现象。试验结果表明本发明中描述的大部分化合物对小白鼠无明显的毒性。During the test, no obvious clinical symptoms of poisoning, body weight change and death were found in the mice after administration. The test results show that most of the compounds described in the present invention have no obvious toxicity to mice.

本发明的范围不受所述具体实施方案的限制，所述实施方案只欲作为阐明本发明各个方面的单个例子，本发明范围内还包括功能等同的方法和组分。实际上，除了本文所述的内容外，本领域技术人员参照上文的描述和附图可以容易地掌握对本发明的多种改进。所述改进也落入所附权利要求书的范围之内。上文提及的每篇参考文献皆全文列入本文作为参考。The scope of the invention is not to be limited by the specific embodiments described, which are intended as single examples illustrating various aspects of the invention, and functionally equivalent methods and components are also intended to be within the scope of the invention. Indeed, various modifications to the present invention, in addition to those described herein, can be readily grasped by those skilled in the art upon reference to the foregoing description and accompanying drawings. Such modifications also fall within the scope of the appended claims. Each of the references mentioned above is incorporated herein by reference in its entirety.

Claims (14)

1. one kind has following general structure (I) quinazolinones, perhaps its pharmacologically acceptable salt
Figure FDA00002866598500011
Wherein:
R1Be H, C1-C6Alkyl, C3-C6Cycloalkyl, C1-C3Haloalkyl, halogen;
R2Be C1-C6Alkyl;
R3Be H or C1-C6Alkyl;
R4Be C1-C6Alkyl;
R5Be SO2NR6R7
R6And R7Be H independently of one another, C1-C6Alkyl is substituted the C that base replaces1-C3Alkyl, substituting group is selected from OH, guanidine radicals, C1-C4Alkoxyl group, C3-C6Cycloalkyl, NR9R10, Ar or Het; R6And R7The nitrogen-atoms that can link to each other with them constitutes tetramethyleneimine, piperidines, morpholine, piperazine, imidazoles or pyrazoles jointly, and wherein this nitrogen heterocyclic ring is optionally by R11Replace;
R9And R10Be H independently of one another, C1-C6Alkyl; Or R9, R10The nitrogen-atoms that links to each other with them constitutes Het jointly;
R11Be C1-C6Alkyl, this alkyl can be chosen wantonly by OH, C1-C3Alkoxyl group replaces;
Above-mentioned every in,
The Ar representative is by one or two aryl that substituting group replaces, and substituting group is selected from halogen, NH2, C1-C3Alkyl, C1-C3Alkoxyl group, CONH2, CN, SO2NH2Described aryl is to have the aromaticity carbocyclic ring of 5-12 carbon atom or phenyl and C5-7 cycloalkyl to condense mutually and form a ring texture or phenyl and C5-7 cycloalkenyl groups system and condense mutually and form a ring texture;
The Het representative contains 1-4 heteroatomic 5 and 6 yuan of heterocycles, and heteroatoms is selected from N, S and O.
2. quinazolinones according to claim 1 or its pharmacologically acceptable salt is characterized in that:
R1Be H, C1-C6Alkyl, C3-C6Cycloalkyl, C1-C3Haloalkyl, halogen;
R2Be C1-C6Alkyl;
R3Be H or C1-C6Alkyl;
R4Be C1-C6Alkyl;
R5Be SO2NR6R7
R6And R7Be H independently of one another, C1-C6Alkyl or be substituted the C that base replaces1-C3Alkyl, substituting group is selected from OH, guanidine radicals, C1-C4Alkoxyl group, C3-C6Cycloalkyl, NR9R10, Ar or Het; R6And R7The nitrogen-atoms that can link to each other with them constitutes tetramethyleneimine, piperidines, morpholine, piperazine, imidazoles or pyrazoles jointly, and wherein this nitrogen heterocyclic ring is optionally by R11Replace;
R9And R10Be H independently of one another, C1-C6Alkyl or R9, R10The nitrogen-atoms that links to each other with them constitutes Het jointly;
R11Be C1-C6Alkyl, this alkyl can be chosen wantonly by OH, C1-C3Alkoxyl group replaces;
Above-mentioned every in,
The Ar representative is by one or two aryl that substituting group replaces, and substituting group is selected from halogen, NH2, C1-C3Alkyl, C1-C3Alkoxyl group, CONH2, CN, SO2NH2Described aryl is to have the aromaticity carbocyclic ring of 5-12 carbon atom or phenyl and C5-7 cycloalkyl to condense mutually and form a ring texture or phenyl and C5-7 cycloalkenyl groups system and condense mutually and form a ring texture;
The Het representative contains 1-4 heteroatomic 5 and 6 yuan of heterocycles, and heteroatoms is selected from N, S and O.
3. quinazolinones according to claim 1 or its pharmacologically acceptable salt is characterized in that:
R1Be H, C1-C6Alkyl, C1-C6Thiazolinyl or halogen;
R2Be C1-C6Alkyl;
R3Be H or C1-C6Alkyl;
R4Be C1-C6Alkyl;
R5Be SO2NR6R7
R6And R7Be H independently of one another, C1-C3Alkyl, the C that is replaced by guanidine radicals1-C3Alkyl, or by NR9R10The C that base replaces1-C3Alkyl or the nitrogen-atoms that links to each other with them constitute tetramethyleneimine, piperidines, morpholine, piperazine, imidazoles or pyrazoles jointly, and wherein this nitrogen heterocyclic ring is optionally by R11Replace;
R9And R10Be H independently of one another, C1-C3Alkyl; Or R9, R10The nitrogen-atoms that links to each other with them constitutes morpholine, parathiazan, piperazine, piperidines, tetramethyleneimine heterocycle jointly;
R11Be C1-C4Alkyl, this alkyl can be chosen wantonly by OH, C1-C3Alkoxyl group replaces.
4. quinazolinones according to claim 1, perhaps its pharmacologically acceptable salt is characterized in that:
R1Be H, C1-C6Alkyl, C1-C6Thiazolinyl or halogen;
R2Be methyl;
R3Be H or methyl;
R4Be ethyl or n-propyl;
R5Be SO2NR6R7
R6And R7Be H independently of one another, the C that is replaced by guanidine radicals1-C3Alkyl, or by NR9R10The C that base replaces1-C3Alkyl or the nitrogen-atoms that links to each other with them constitute tetramethyleneimine, piperidines, piperazine jointly, and wherein this nitrogen heterocyclic ring is optionally by R11Replace;
R9And R10Be H independently of one another, C1-C3Alkyl; Or R9, R10The nitrogen-atoms that links to each other with them constitutes morpholine, piperidines, tetramethyleneimine heterocycle jointly;
R11Be methyl or ethyl.
5. quinazolinones according to claim 1 or its pharmacologically acceptable salt is characterized in that this compound is selected from:
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5-hydroxyl-7-methoxyl group-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-(2-morpholine-1-ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-(3-morpholine-1-propyl group)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-(2-diethylin ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-(2-dimethylamino ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-(2-hydroxyethyl)-N-(2-morpholine-1-ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-methyl-N-(3-tetramethyleneimine-1-propyl group)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-(2-methoxy ethyl)-N-(2-morpholine-1-ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-(2-ethoxyethyl group)-N-(2-morpholine-1-ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-ethyl-N-(3-piperidines-1-propyl group)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-ethyl-N-(2-morpholine-1-ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-(2-(2-hydroxy ethoxy) ethyl)-N-(2-morpholine-1-ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-(2-(2-methoxy ethoxy) ethyl)-N-(2-morpholine-1-ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-methyl-N-(2-dimethylamino ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-(pyridine-3-methyl)-N-(2-morpholine-1-ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[[1-(4-picolyl)-1-(2-morpholine-1-yl) ethyl] amino-sulfonyl] phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-benzyl-N-(2-morpholine-1-ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-benzyl-N-(3-morpholine-1-propyl group)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-methyl-N-(N-ethyl pyrrolidine-2-methyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-ethyl-N-(N-ethyl pyrrolidine-2-methyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-[2-propoxy--5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-8-chloro-quinazoline-4 (3H)-ketone;
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-8-fluoro-quinazoline-4 (3H)-ketone;
2-[2-oxyethyl group-5-(4-methylpiperazine-1-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H)-ketone;
8-ethyl-2-[2-oxyethyl group-5-(4-methylpiperazine-alkylsulfonyl)-phenyl]-5,7-dimethoxy-8-iodo-quinazoline-4 (3H)-ketone;
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H)-ketone;
8-methyl-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H)-ketone;
8-ethyl-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H)-ketone;
8-propyl group-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H)-ketone;
8-butyl-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H)-ketone;
8-butyl-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H)-ketone;
8-vinyl-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H)-ketone;
8-allyl group-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H)-ketone;
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5 hydroxyls-7-methoxyl group-8-chloro-quinazoline-4 (3H)-ketone;
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5 hydroxyls-7-methoxyl group-8-fluoro-quinazoline-4 (3H)-ketone;
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5 hydroxyls-7-methoxyl group-8 iodo-quinazoline-4 (3H)-ketone;
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5-hydroxyl-7-methoxyl group-quinazoline-4 (3H)-ketone;
8-methyl-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5-hydroxyl-7-methoxyl group-quinazoline-4 (3H)-ketone;
8-ethyl-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5-hydroxyl-7-methoxyl group-quinazoline-4 (3H)-ketone;
8-propyl group-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5-hydroxyl-7-methoxyl group-quinazoline-4 (3H)-ketone;
8-butyl-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5-hydroxyl-7-methoxyl group-quinazoline-4 (3H)-ketone;
8-vinyl-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5-hydroxyl-7-methoxyl group-quinazoline-4 (3H)-ketone;
2-[2-propoxy--5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5-hydroxyl-7-methoxyl group-8-iodo-quinazoline-4 (3H)-ketone;
2-[2-propoxy--5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-8-iodo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-(2-hydroxyethyl)-N-(2-guanidine radicals-1-ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-phenyl-N-(2-guanidine radicals-1-ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-(pyridine-3-methyl)-N-(3-guanidine radicals-1-propyl group)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-benzyl-N-(2-guanidine radicals-1-ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;
2-{2-propoxy--5-[N-(pyridine-4-methyl)-N-(3-guanidine radicals-1-propyl group)-amido alkylsulfonyl]-phenyl-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone or
2-{2-propoxy--5-[N-ethyl-N-(2-guanidine radicals-1-ethyl)-amido alkylsulfonyl]-phenyl }-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone.
6. quinazolinones according to claim 1 or its pharmacologically acceptable salt is characterized in that its pharmacologically acceptable salt can be hydrochloride, vitriol, phosphoric acid salt, formate, acetate, propionic salt, succinate, glycol hydrochlorate, gluconate, lactic acid salt, malate, tartrate, glycinate, arginic acid salt, Citrate trianion, fumarate, arylsulphonate, alkylsulfonate.
7. quinazolinones according to claim 6 or its pharmacologically acceptable salt is characterized in that its pharmacologically acceptable salt is mesylate.
8. pharmaceutical composition contains any one described quinazolinones of claim 1-7 and the pharmaceutically acceptable carrier of significant quantity.
9. the purposes of any one described quinazolinones compound or pharmaceutically acceptable salt thereof of claim 1-7 in preparation PDE5 inhibitor medicaments.
10. but any one described quinazolinones of claim 1-7 or its pharmacologically acceptable salt, or its pharmaceutically useful composition, be used for treating or the prevention male erectile dysfunction in preparation, benign prostatic hyperplasia, Female sexual dysfunction, premature labor, dysmenorrhoea, bladder outlet obstruction (BOO), incontinence, unsettled and make a variation Prinzmetal stenocardia, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, apoplexy, peripheral vascular disease, Raynand's disease, diseases associated with inflammation, chronic asthma, allergic asthma, glaucoma, and be characterized as purposes in the human medicine of disease of intestinal peristalsis obstacle.
11. the described preparation method with following general structure (I) quinazolinones of claim 1 is characterized in that:
Work as R1Be halogen, R3Be not H, R2, R4, R5During as the definition in the claim 1 (I-A), by the II ring with obtain,
Figure FDA00002866598500071
Work as R1Be not halogen, R3Be not H, R2, R4, R5During as the definition in the claim 1, can obtain I-B by the compound among I-A and metallic alkide reagent react;
Figure FDA00002866598500081
Work as R3Be H, R1, R2, R4, R5During as the definition in the claim 1, can be by compound and the alkylation removal reagent react among its corresponding first kind segment bounds I-A or the I-B
Figure FDA00002866598500082
Obtain I-C.
12. preparation method according to claim 11 is characterized in that:
II is by following reaction
Figure FDA00002866598500083
Make.
13. preparation method according to claim 12 is characterized in that:
III is by following reaction
Figure FDA00002866598500091
Make.
14. compound shown in the general structure II
R1, R2, R3, R4, R5As the definition in the claim 1.
CN2007100479158A2007-11-072007-11-07Quinazoline ketone derivant, preparation method and application thereofExpired - Fee RelatedCN101429166B (en)

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