CN101429166A - Quinazoline ketone derivant, preparation method and application thereof - Google Patents

Quinazoline ketone derivant, preparation method and application thereof Download PDF

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Publication number
CN101429166A
CN101429166A CNA2007100479158A CN200710047915A CN101429166A CN 101429166 A CN101429166 A CN 101429166A CN A2007100479158 A CNA2007100479158 A CN A2007100479158A CN 200710047915 A CN200710047915 A CN 200710047915A CN 101429166 A CN101429166 A CN 101429166A
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phenyl
quinazoline
ketone
alkylsulfonyl
dimethoxy
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CN101429166B (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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Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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Priority to PCT/CN2008/001859 priority patent/WO2009062402A1/en
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Abstract

The invention relates to the technical field of medicine, in particular to a quinazolinone derivative, a preparation method and application thereof. The invention discloses quinazolinone compounds as structural general formula (I) or pharmaceutically acceptable salt thereof. Most of the compounds have stronger PDE5 inhibition activity than that of Sildenafil, and have higher selectivity than that of PDE 6 distributed on a retina. Therefore, the compounds are expected to show better clinical safety and effectiveness, and have wide clinical application prospect.

Description

Quinazol derivative and its production and use
Technical field
The present invention relates to medical technical field, be specifically related to a kind of Quinazol derivative and its production and use.
Background technology
(phosphodiesterase PDE) comprises 11 enzymes systems (PDE1-PDE11) to phosphodiesterase, and they are by hydrolysis cAMP or cGMP, and makes the activity reduction of second messenger in the cell.According to the specificity of the special P DE substrate of being blocked, the PDE5 inhibitor can increase cAMP level, cGMP level in the cell, or increases the level of cAMP and cGMP simultaneously.These inhibitor belong to competitive inhibitor, because they simulate the structure of cAMP and cGMP, and cAMP and cGMP are the natural substrates of PDE.Different with cAMP and cGMP is that inhibitor is not degraded by PDE.Known PDE relates to cell function activity widely.PDE 5 is that cGMP is special, and at the phosphodiesterase of corpus cavernosum penis smooth muscle cell high expression level.PDE 5 inhibitor increase the expansion of cavernous sinus by keep sufficient cGMP level in corpus cavernosum penis and the supply vascular smooth muscle cell in the sexual stimulus process, thereby strengthen erection function.
Recent decades, non-selective PDE inhibitor as: caffeine, theophylline and 3-isobutyl--1-methyl sulphur purine (IBMX) has been used to cyclic nucleotide (cNMP) physiological action and the active research of PDE.Though belong to similar medicine, above-mentioned inhibitor lacks specificity, and they block the catalytic activity of nearly all known PDE, and too much untoward reaction may occur together in treatment.
PDE 5 inhibitor are by suppressing PDE 5 enzymic activitys, influence that PDE 5 expresses and thereby metabolism etc. is regulated PDE 5 activity and influenced Human Physiology and pathologic process, and in theory, PDE 5 inhibitor can influence all physiological and pathological processes relevant with PDE 5.
PDE 5 inhibitor of first listing---Virga (Sildenafil), at the clinical male erectile dysfunction that is used for, also effective to women's sexual dysfunction and essential hypertension.PDE5 inhibitor in the research and development also is used for diabetes symptom of digestive tract, insulin resistant and hyperlipidemia.
Although Virga has been obtained significant clinical efficacy, but since its to other phosphodiesterases (PDE) isozyme beyond the PDE5 also have in various degree restraining effect, clinical manifestation go out headache, flush, maldigestion, nasal obstruction, blurring of vision, photosensitive, look and look for toxic side effect such as light.On the one hand, these side effects are relevant with dosage, so the stronger PDE5 inhibitor of discovery effect, just might lower dosage, reduce toxic side effect; On the other hand, the disorderly symptom of vision is that Virga also has inhibiting result to being present in amphiblestroid VI type phosphodiesterase (PDE6), so improve selectivity, especially with respect to the selectivity of PDE6, is the another target of seeking new PDE5 inhibitor.
Summary of the invention
Technical problem to be solved by this invention provides a kind of new PDE5 inhibitor, the invention discloses a kind of Quinazol derivative for this reason, and discloses its preparation method and composition and application.
A kind of have following general structure (I) quinazolinones, perhaps its acceptable salt pharmaceutically
Figure A200710047915D00121
Wherein:
R 1Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 1-C 3Haloalkyl, halogen, hydroxyl is by C 1-C 3The hydroxyl that alkoxyl group replaces, alkoxyl group, amino, amide group;
R 2, R 3And R 4Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 1-C 3Haloalkyl is by C 1-C 3The C that alkoxyl group replaces 1-C 3Alkyl, or by C 3-C 6The C of cycloalkyl substituted 1-C 3Alkyl;
R 5Be H, OH, halogen, nitro, Ar, Het, NR 6R 7, five yuan of sugar, hexa-atomic sugar, CN, SO 2NR 6R 7, CO (CH 2) mNR 6R 7, NHSO 2NR 6R 7, NHCONR 6R 7, NHCNNR 6R 7, NHCOR 8, COR 8, NHCOOR 8, COOR 8Or C 1-C 6Alkyl;
R 6And R 7Be H independently of one another, C 1-C 6Alkyl, COR 8, SO 2R 8R 6And R 7The 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 R 11 replaces;
R 8Be C 1-C 6Alkyl is (optional by C 1-C 3Alkoxyl group or by NR 12R 13Base replaces);
R 9And R 10Be H independently of one another, C 1-C 6Alkyl is (optional by C 1-C 3Alkoxyl group or by NR 12R 13Base is got
Generation); Or R 9, R 10The nitrogen-atoms that links to each other with them constitutes Het jointly;
R 11 is C 1-C 6Alkyl;
R 12And R 13Be H independently of one another, or C 1-C 6Alkyl;
Above-mentioned every in,
m＝0，1，2；
The Ar representative is by one or two aryl that substituting group replaces, and substituting group is selected from halogen, NH 2, C 1-C 3Alkyl,
C 1-C 3Alkoxyl group, CONH 2, CN, SO 2NH 2
The Het representative contains 1-4 heteroatomic 5 and 6 yuan of heterocycles, and heteroatoms is selected from N, S and O;
In the preferred formula I compound
R 1Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 1-C 3Haloalkyl, halogen, hydroxyl is by C 1-C 3
The hydroxyl that alkoxyl group replaces, alkoxyl group, amino, amide group;
R 2, R 3And R 4Be H independently of one another, C 1-C 6Alkyl, C 1-C 6Thiazolinyl, C 3-C 6Cycloalkyl, C 1-C 6
Haloalkyl or halogen;
R 5Be SO 2NR 6R 7, CO (CH 2) mNR 6R 7, NHSO 2NR 6R 7, NHCONR 6R 7, NHCNNR 6R 7,
NR6R7；
R 6And R 7Be H independently of one another, C 1-C 6Alkyl, COR 8, SO 2R 8, be substituted the C that base replaces 1-C 3
Alkyl, substituting group is selected from OH, guanidine radicals, C 1-C 4Alkoxyl group, C 3-C 6Cycloalkyl, NR 9R 10, Ar or Het;
R 6And R 7The nitrogen-atoms that can link to each other with them constitutes tetramethyleneimine, piperidines, morpholine, piperazine, imidazoles or pyrazoles jointly,
Wherein this nitrogen heterocyclic ring is optionally by R 11Replace;
R 8Be C 1-C 6Alkyl is (optional by C 1-C 3Alkoxyl group or by NR 12R 13Base replaces);
R 9And R 10Be H independently of one another, C 1-C 6Alkyl is (optional by C 1-C 3Alkoxyl group or by NR 12R 13Base replaces); Or R 9, R 10The nitrogen-atoms that links to each other with them constitutes Het jointly;
R 11 is C 1-C 6Alkyl, this alkyl can be chosen wantonly by OH, C 1-C 3Alkoxyl group replaces;
R 12And R 13Be H independently of one another, or C 1-C 6Alkyl;
Above-mentioned every in,
m＝0，1，2；
The Ar representative is by one or two aryl that substituting group replaces, and substituting group is selected from halogen, NH 2, C 1-C 3Alkyl, C 1-C 3Alkoxyl group, CONH 2, CN, SO 2NH 2
The Het representative contains 1-4 heteroatomic 5 and 6 yuan of heterocycles, and heteroatoms is selected from N, S and O, and optional by one or two substituting groups replacements, and substituting group is selected from halogen, C 1-C 3Alkyl, C 1-C 3Alkoxyl group.
In the preferred again formula I compound,
R 1Be H, C 1-C 6Alkyl, C 1-C 6Thiazolinyl or halogen;
R 2Be C 1-C 6Alkyl;
R 3Be H or C 1-C 6Alkyl;
R 4Be C 1-C 6Alkyl;
R 5Be SO 2NR 6R 7
R 6And R 7Be H independently of one another, C 1-C 3Alkyl, benzyl, picolyl, piperidin-4-yl, COR 8, the C that is replaced by guanidine radicals 1-C 3Alkyl, or by NR 9R 10The C that base replaces 1-C 3Alkyl 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 R 11Replace;
R 8Be C 1-C 4Alkyl, phenyl or pyridyl;
R 9And R 10Be H independently of one another, C 1-C 3Alkyl; Or R 9, R 10The nitrogen-atoms that links to each other with them constitutes morpholine, parathiazan, piperazine, piperidines, tetramethyleneimine heterocycle jointly;
R 11Be C 1-C 4Alkyl, this alkyl can be chosen wantonly by OH, C 1-C 3Alkoxyl group replaces.
In the particularly preferred formula I compound,
R 1Be H, C 1-C 6Alkyl, C 1-C 6Thiazolinyl or halogen;
R 2Be H or methyl;
R 3Be H or methyl;
R 4Be ethyl or n-propyl;
R 5Be SO 2NR 6R 7
R 6And R 7Be H independently of one another, the C that is replaced by guanidine radicals 1-C 3Alkyl, or by NR 9R 10The C that base replaces 1-C 3Alkyl 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 R 10Replace;
R 9And R 10Be H independently of one another, C 1-C 3Alkyl; Or R 9, R 10The nitrogen-atoms that links to each other with them constitutes morpholine, piperidines, tetramethyleneimine heterocycle jointly;
R 11Be methyl or ethyl.
The preferred particular compound of the present invention comprises:
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-hydroxyl-7-methoxyl group-8-chloro-quinazoline-4 (3H)-ketone;
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5-hydroxyl-7-methoxyl group-8-fluoro-quinazoline-4 (3H)-ketone;
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5-hydroxyl-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.
Except that the represented compound of general formula (I), the present invention comprises that also the pharmacy acceptable salt of these compounds, pharmaceutically acceptable prodrug and medicinal activity metabolite and these metabolites are at pharmacy acceptable salt.
Therefore the compound of formula I can contain one or more chiral centres, can have steric isomer, i.e. enantiomer or diastereomer, and composition thereof.The present invention includes single steric isomer of formula I mixture and composition thereof.
Can there be the form of tautomer in the compound of formula I, and present invention includes its mixture and single tautomer.
The present invention includes the pharmaceutically useful salt of formula I compound.Preferred salt is mesylate and hydrochloride.
The present invention also discloses a kind of pharmaceutical composition on the other hand, contains compound and pharmaceutically acceptable carrier shown in the general formula (I) of significant quantity.
The present invention also comprises pharmaceutically acceptable oxide compound and the pharmacologically acceptable salt and the acceptable solvent thing of formula I compound.
In addition, the present invention also provides formula I compound or pharmaceutically acceptable salt thereof, or their acceptable solvent thing, or its pharmaceutically useful composition is as the purposes of human medicine.
The present invention also provides formula I compound or pharmaceutically acceptable salt thereof, or their acceptable solvent thing, the purposes in preparation PDE5 inhibitor medicaments.
But the present invention also provides formula I compound or its pharmacologically acceptable salt, or their acceptable solvent thing, 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, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and be characterized as purposes in the human medicine of disease (for example irritable bowel syndrome) of intestinal peristalsis obstacle.
The present invention also provides the preparation method of described formula I compound.(A): preparation formula I (I-A, I-B, I-C) method of compound and pharmaceutical salts thereof:
Figure A200710047915D00191
R wherein 1, R 2, R 3, R 4, R 5As the definition in the claim 1.It comprises:
(i) first kind segment bounds I-A (R 1Be halogen, R 3Be not H, R 2, R 4, R 5As the definition in the claim 1) compound can be by formula 2 compounds in the presence of alkali, and the common 30-200 of temperature ℃, react in the appropriate solvent and made in 1-12 hour.Preferred alkali comprises metal-salt, oxyhydroxide (preferred sodium hydroxide), carbonate and the supercarbonate of alkali metal alkoxide (preferred potassium tert.-butoxide, sodium ethylate), basic metal or alkaline earth metal hydride, amine (preferred triethylamine), amine; Preferred solvent comprises alcohol (for example trimethyl carbinol, ethanol, methyl alcohol, Virahol, ethylene glycol, ethylene glycol monomethyl ether), aromatic hydrocarbons (for example benzene, toluene, chlorobenzene), pyridine, halohydrocarbon, acetonitrile, tetrahydrofuran (THF), dioxane, methyl-sulphoxide, N, dinethylformamide, N-methylpyrrolidin-2-ketone etc.
Figure A200710047915D00192
The (ii) second class segment bounds I-B (R 1Be not halogen, R 3Be not H, R 2, R 4, R 5As the definition in the claim 1) compound can (metallic alkide reagent can be CuI, CH by the compound among the corresponding first kind segment bounds I-A and metallic alkide reagent 3ZnCl/[(t-Bu) 3P] 2Pd, C 2H 5ZnI/[(t-Bu) 3P] 2Pd, n-C 3H 7ZnI/[(t-Bu) 3P] 2Pd, [(t-Bu) 3P] 2Pd etc.) heating makes in appropriate solvent (the preferred N of solvent, dinethylformamide, methyl-sulphoxide, ethylene glycol monomethyl ether, N-first pyrrolidone).Reaction equation:
Figure A200710047915D00201
R wherein 1, R 2, R 3, R 4, R 5As above-mentioned definition
(iii) the 3rd class segment bounds I-C (R 3Be H) can in appropriate solvent (the preferred methylene dichloride of solvent, trichloromethane), obtain (removing the preferred aluminum chloride of alkyl reagent, boron tribromide, tetrafluoride boron) by the compound among its corresponding first kind segment bounds I-A or the I-B with the alkylation removal reagent react.Reaction equation:
Figure A200710047915D00202
R wherein 1, R 2, R 3, R 4, R 5As above-mentioned definition.
(B): formula II compound can be prepared by the reaction of formula III compound and formula IX compound usually.
Working method one: earlier the carboxyl of formula IX compound is converted into acyl chlorides or mixed acid anhydride, reacts with the formula III compound again and obtain corresponding amide II with thionyl chloride, oxalyl chloride, Vinyl chloroformate etc.Acylation reaction in the presence of the disacidify agent, is carried out in common solvent usually.Preferred disacidify agent comprises organic bases (preferred triethylamine, diisopropyl ethyl amine, pyridine) and mineral alkali (preferred oxyhydroxide, carbonate).Preferred solvent comprises alkanes (preferred sherwood oil, normal hexane, hexanaphthene), halohydrocarbon (preferred methylene dichloride or chloroform), ether (preferred tetrahydrofuran (THF), dioxane, ether), aromatic solvents (preferred toluene) and alcohols (preferred tertiary butanols, Virahol).
Working method two adopts carboxylic acid and the direct condensation of amine to obtain acid amides II.Reaction in the presence of activator or dewatering agent, is carried out in anhydrous inert solvent usually.Preferred activator or dewatering agent comprise DCC, EDCI, EEDQ, CDI, HOBt etc.Preferred solvent comprises halohydrocarbon (preferred methylene dichloride or chloroform), ether (preferred tetrahydrofuran (THF), dioxane, ether), aromatic hydrocarbons (preferred benzene, toluene), polar aprotic solvent (methyl-sulphoxide, N, or the mixture of these solvents dinethylformamide).
Reaction equation:
R wherein 1, R 2, R 3, R 4, R 5As above-mentioned definition.
(C): the formula III compound usually can be by formula IV compound and NH 3Condensation reaction prepares.Reaction in the presence of activator or dewatering agent, is carried out in anhydrous inert solvent usually.Preferred activator or dewatering agent comprise DCC, EDCI, EEDQ, CDI, HOBt etc.Preferred solvent comprises halohydrocarbon (preferred methylene dichloride or chloroform), ether (preferred tetrahydrofuran (THF), dioxane, ether), aromatic hydrocarbons (preferred benzene, toluene), polar aprotic solvent (methyl-sulphoxide, N, or the mixture of these solvents dinethylformamide).Reaction equation:
Figure A200710047915D00212
R wherein 1, R 2, R 3As above-mentioned definition.
(D): formula IV compound usually can be by formula V compound in 5%-10%NaOH solution, with 30%H 2O 2Reaction makes.Reaction equation:
Figure A200710047915D00221
R wherein 1, R 2, R 3As above-mentioned definition.
(E): formula V compound can reaction in appropriate solvent (the preferred methylene dichloride of solvent, trichloromethane, 1,3-propylene dichloride) make the common 30-100 of temperature ℃ by formula VI compound and oxalyl chloride usually.Reaction equation:
Figure A200710047915D00222
R wherein 1, R 2, R 3As above-mentioned definition.
(F): formula VI compound can be refluxed in HCl/MeOH solution by formula VII compound usually and prepare.
Figure A200710047915D00223
R wherein 1, R 2, R 3As above-mentioned definition.
(G): formula VII compound usually can (halogenating agent can be NBS, NCS, F-TEDA-BF with suitable halogenating agent by formula VIII compound 4, NaI/t-BuOCl) reaction makes in the appropriate solvent (the preferred second eyeball of solvent, methylene dichloride, trichloromethane, 1,3-propylene dichloride), temperature usually-20-50 ℃.
Wherein R2, R3 such as above-mentioned definition.
Formula IX, formula VIII compound can or be purchased by the literature method preparation.
The inventor designs and has synthesized a series of new Quinazol derivative I, and most in these compounds have the PDE5 inhibition activity stronger than Virga, and with respect to being distributed in amphiblestroid PDE6 higher selectivity is arranged.Therefore compound provided by the invention is expected to show better security and validity clinically, and potential applicability in clinical practice is wide.
Embodiment
Below in conjunction with specific embodiment, further illustrate the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Ratio and per-cent are based on weight, unless stated otherwise.
Part term definition used in the present invention is as follows:
" halogen " is meant fluorine, chlorine, bromine and iodine.
" alkyl " is meant straight chain when being used as the part of a group or a group or has the aliphatic hydrocarbon group of side chain.Preferential selection alkyl is the alkyl of C1-C14; More preferably be chosen as: the C1-C10 alkyl; Override is chosen as C1-C6, unless otherwise.Straight chain or and the example that has a C1-C6 alkyl of side chain include, but are not limited to: methyl, ethyl, n-propyl, 2-propyl group, normal-butyl, isobutyl-, tertiary butyl, hexyl etc.
" thiazolinyl " is meant the aliphatic hydrocarbon group that contains a carbon-to-carbon double bond at least during as a group or a group a part of, can be straight chain and also can have side chain.Preferential thiazolinyl of selecting to have C2-C14.C2-C12 is then better; What the most preferentially select is the thiazolinyl of C2-C6.This group can contain a plurality of pairs of keys and its conformation can respectively do for oneself E or Z in its main chain.The example of alkenyl group includes, but are not limited to: vinyl, propenyl etc.
" cycloalkyl " is meant the carbocyclic ring of monocycle, condensed ring or the volution of saturated or fractional saturation.The ring of forming with 3-9 carbon atom is preferential the selection.Example includes, but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.
" aryl " is meant as the part of a group or a group: the monocycle or the condensed ring of (1) aromaticity; Preferential aromaticity carbocyclic ring (annular atoms is the atoll texture of carbon) of selecting to have 5-12 carbon atom.The example of aryl includes, but are not limited to: phenyl, naphthyl; (2) can the saturated carbocyclic ring in connection portion, for example: phenyl and C5-7 cycloalkyl or C5-7 cycloalkenyl groups system condense mutually and form a ring texture.Example includes, but are not limited to: tetralyl, indenyl or hydrogen indenyl etc.Aromatic yl group can be replaced by one or more substituting groups.
The present invention includes represented compound of general formula (I) and possible various isomery patterns thereof.Comprise: the geometrical isomer of non-mirror image isomer, mirror image isomer, tautomer and " E " or " Z " configurational isomer etc.Any chemist with certain basis all can be isolated the pure compound of above-mentioned optical purity or stereoisomerism.
The present invention includes represented compound of general formula (I) and possible raceme thereof or/and the mirror image isomerism thing/or/and the mixture of non-mirror image isomerism thing.
In addition, the represented compound of general formula (I) is also contained the solvation and the non-solvent pattern of this compound on using.Therefore, the various compound with specified structure that includes comprises its hydration and anhydrous mould assembly formula.
Term " pharmacologically acceptable salt " is meant that above-claimed cpd can keep original biological activity and be suitable for some salt of medicinal use.The pharmacy acceptable salt of the compound that general formula (I) is represented has two kinds of formation forms: the one, with the salt of acid formation; Another is the salt that forms with alkali or basic metal.Comprise mineral acid and organic acid with the acid of the represented compound formation pharmacologically acceptable salt of general formula (I).Suitable mineral acid comprises: hydrochloric acid, sulfuric acid and phosphoric acid.Appropriate organic can be selected from aliphatics, cycloaliphatic, aromaticity, heterocyclic carboxylic acid and sulfonic acid class organic acid; The example includes but not limited to: formic acid, acetate, propionic acid, succsinic acid, glycolic acid, gluconic acid, lactic acid, oxysuccinic acid, tartrate, glycine, arginine, citric acid, FUMARIC ACID TECH GRADE, alkylsulphonic acid, aryl sulfonic acid etc.Comprise with the basic metal of the represented compound formation pharmacy acceptable salt of general formula (I): lithium, sodium, potassium, magnesium, calcium, aluminium, zinc etc.; Comprise with the alkali of the represented compound formation pharmacy acceptable salt of general formula (I): choline, diethanolamine, morpholine etc.
" prodrug " is the represented derivative of a kind of general formula (I), by means of metabolic mode in vivo it become the represented compound of general formula (I) in vivo transforming (for example: by hydrolysis, reduction or oxidation).For example, general formula (I) compound represented, that contain oh group and acid-respons can be prepared into corresponding ester.Corresponding ester is prodrug, can be again hydrolysis parent drug in vivo.The acid that is fit to prepare " prodrug " includes but not limited to: acetate, citric acid, lactic acid, tartrate, propanedioic acid, oxalic acid, Whitfield's ointment, succsinic acid, FUMARIC ACID TECH GRADE, maleic acid, methylene radical-bis-beta-hydroxyethyl base naphthoic acid, gentisinic acid, hydroxyethylsulfonic acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, tosic acid etc.
The administering mode of the compound that general formula (I) is represented can be that gastrointestinal administration also can be a parenteral administration.Gastrointestinal administration: per os or per rectum.The parenteral administration mode comprises: subcutaneous, and muscle, approach such as in intravenously and the skin.Usually, the represented active compound of general formula (I) when administration, can use pharmaceutically acceptable carrier or thinner.
" treatment significant quantity " or " therapeutic dose " all are meant the amount that is enough to produce curative effect.Significant quantity can divide one or multiple dosing.Usually, significant quantity is enough to relax, improve, stablize, slow down or postpone further developing of disease.
Simultaneously, the present invention also provides the pharmaceutically useful composition that contains described formula I compound.Said composition is made up of one or more formulas I compound (or its pharmacologically acceptable salt, or their acceptable solvent thing) and at least a pharmaceutically acceptable auxiliaries.The selection of pharmaceutical excipient is different because of route of administration and effect characteristics, normally weighting agent, thinner, tackiness agent, wetting agent, disintegrating agent, lubricant, emulsifying agent, suspending agent etc.
Composition of the present invention can be oral, injection (in vein, muscle, the subcutaneous and coronary artery), hypogloeeis, use through cheek, per rectum, per urethra, transvaginal, intranasal, suction or local approach.Preferred approach is oral.
The shared ratio of formula I compound in above-mentioned composition is 0.1%～99.9% of gross weight, preferred 1%～99%.
The present invention also provides the pharmaceutically useful preparation of compositions method of formula I compound.Usually formula I compound is mixed mutually with pharmaceutically acceptable auxiliaries, make the form (formulation) that is suitable for certain approach and uses through the preparation method of routine.Formulation comprises tablet, capsule, granule, pill, solution, suspensoid, emulsion, ointment, film, creme, aerosol, injection, suppository etc.Preferred tablet and capsule.
The prescription of tablet and capsule can contain one or more formulas I and one or more auxiliary materials commonly used, for example weighting agents such as starch, sucrose, lactose, glucose, Microcrystalline Cellulose, seminose; Tackiness agents such as carboxymethyl cellulose, gelatin, alginates and polyvinylpyrrolidone; Wetting agents such as glycerine; Disintegrating agents such as agar, ethyl cellulose, sodium starch glycolate, lime carbonate; Lubricants such as Magnesium Stearate, talcum powder, polyoxyethylene glycol.
The using dosage of The compounds of this invention is generally 1～500mg every day, and preferred 10～100mg divides single or multiple to use.But where necessary, can suitably depart from above-mentioned dosage.The professional can be as the case may be and expertise, determines optimal dose.These situations comprise severity, the patient's of disease the characteristic of individual difference, preparation and route of administration etc.
The following example has further been explained the synthetic method of compound of the present invention and intermediate thereof, but does not limit the scope of the invention.1H NMR finishes on Mercury-400 or Mercury-300 nuclear magnetic resonance spectrometer (Varian company).Conventional abbreviation is as follows: s, and unimodal; D, bimodal; T, triplet; Q, quartet; M, multiplet; Br, broad peak.
Embodiment 1 2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone
Step 1:2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-benzamido]-5,7-dimethoxy-8-bromobenzene formyl ammonia
Figure A200710047915D00261
With 2-oxyethyl group-5-[(4-methyl isophthalic acid-piperazinyl) alkylsulfonyl] phenylformic acid (0.34g; 1mmol) be dissolved in the 20ml methylene dichloride; add fmoc-2 imidazole (CDI; 3mmol), under room temperature, stir 0.5h, in this mixed solution, add 2-amino-4 again; 6-dimethoxy-3-bromobenzene formyl ammonia (0.28g; 1mmol), continue to stir 1-6h, with TLC detection reaction terminal point.Reaction is finished, and mixed solution is with ammonium chloride solution and saturated common salt washing, and methylene dichloride is used anhydrous magnesium sulfate drying mutually, is evaporated to driedly then, and residual solids gets product white powder 0.51g, productive rate 86% with ethyl alcohol recrystallization.
Step 2: alkylsulfonyl preparation 2-{2-oxyethyl group-5-[(4-methyl isophthalic acid-piperazinyl)] phenyl }-5,7-dimethoxy-8-bromo-quinoline-4 (3H)-ketone
Figure A200710047915D00262
(0.06g, 0.55mmol) (0.3g 0.5mmol) successively adds in the trimethyl carbinol (15ml), and this suspension of heating extremely refluxes in stirring down, becomes clarification behind about 30min, continues backflow 10h with step 1 product with potassium tert.-butoxide.Stop heating, add entry (20ml) after being chilled to room temperature, transfer to neutrality, be cooled to 5-10 ℃ then with 4% dilute acetic acid.The adularescent solid is separated out, and filters, and (3 * 10ml) wash cold water, and oven dry gets product 0.22g with the methanol/ethyl acetate recrystallization, productive rate 76%.1H-NMR(300MHz，CDCl3)，δ?10.56(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).
Embodiment 2 8-methyl-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H)-ketone
Figure A200710047915D00271
Zinc Chloride Anhydrous 408mg (3.0mmol) is dissolved among the 5mL drying NMP, and the ice bath cooling drips 2mL2mol/L methylmagnesium-chloride (2.0mmol) THF solution down, changes stirring at room and gets the methyl zincon in 1 hour.
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5; 7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone 567mg (10i; 1.0mmol) mix in the dry NMP of 5mL; the methyl zincon that adds above-mentioned preparation; add [(t-Bu) 3P] 2Pd 25mg (0.05mmol) under the nitrogen protection; change 40oC heating 4 hours; reduce to room temperature; add the 10mL methylene dichloride; 20mL moisture liquid; water 3mL dichloromethane extraction 1 time; merge organic phase; use 2mL water successively; saturated common salt washing 1 time, anhydrous sodium sulfate drying, silica gel column chromatography (CH2Cl2/CH3OH) separate light yellow 8-methyl-2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5; 7-dimethoxy-quinazoline-4 (3H)-ketone (10b) solid 411mg, productive rate 82%.1H-NMR(300MHz，CDCl3)，δ?10.44(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)。
Embodiment 3 2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5-hydroxyl-7-methoxyl group-8-bromo-quinazoline-4 (3H)-ketone
Figure A200710047915D00272
Get embodiment 1 compound (0.57g, 1.0mmol) be dissolved in the 20mL dry methylene chloride, drip the boron tribromide (104uL of 2mL under the-10oC cooling and stirring, 1.1mmol) dichloromethane solution, continue to stir 4 hours, add the 1mL ether, continue to stir 30 minutes, add 20mL methylene dichloride and 50mL5%NaHCO3 separatory, water 10mL dichloromethane extraction 1 time merges organic phase, successively with 5mL5%NaHCO3, saturated common salt washing 1 time, anhydrous sodium sulfate drying gets light yellow solid 0.45g with sherwood oil/methylene dichloride recrystallization, productive rate 82%.1H-NMR(300MHz，CDCl3)，δ?11.62(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)。
Embodiment 4～50
According to the same procedure of embodiment 1 or 2, adopt the starting raw material of different substituents, the compound of preparation embodiment 4～50 (does not indicate that as having especially NMR data solvent for use does not have special instruction and is CDCl3.
Figure A200710047915D00281
Figure A200710047915D00291
Figure A200710047915D00301
Figure A200710047915D00311
Figure A200710047915D00331
Figure A200710047915D00351
Figure A200710047915D00361
Figure A200710047915D00371
Figure A200710047915D00391
Embodiment 51 capsules
Figure A200710047915D00392
The active compound and the various auxiliary material that will contain Pyridopyrimidinone derivatives are crossed 80 mesh sieves, take by weighing by recipe quantity, with 10% polyvinylpyrrolidone ethanolic soln is tackiness agent, makes suitable particle with 16 mesh sieves, 65 ℃ of dryings, the whole grain of 14 mesh sieves, add Magnesium Stearate and mix, survey granule content, calculate loading amount, incapsulate, promptly.
Embodiment 52 tablets (wet granulation)
Prescription
Figure A200710047915D00393
Figure A200710047915D00401
Active compound, Microcrystalline Cellulose, lactose, the sodium starch glycolate that will contain Pyridopyrimidinone derivatives are crossed 80 mesh sieves, mixing, and with 8% starch slurry system softwood, 16 orders are granulated, behind dry, the whole grain, add Magnesium Stearate and mix, measure granule content, the calculating sheet is heavy, compressing tablet, promptly.
Embodiment 53 tablets (powder pressing method)
Prescription
Figure A200710047915D00402
To contain the active compound of Pyridopyrimidinone derivatives and Microcrystalline Cellulose, lactose hydrous, polyvinylpyrrolidone, micropowder silica gel mixing in mixing machine, and add the Magnesium Stearate mixing then, compressing tablet promptly.
Test 54 tests of pesticide effectiveness
Reference literature method (International Journal of Impotence Research 2002,14,251 and TheJournal of Urology 1992,147,1124), the fasting of SD male rat after 12 hours, random packet, 4 every group, with vetanarcol (50mg/kg) intraperitoneal injection of anesthesia, separate, expose the rat corpus cavernosum penis, penetrate behind the corpus cavernosum penis of right side with puncture needle and is connected monitoring intracavernous pressure (ICP), the right carotid of dissociating with electrophysiology instrument, keep somewhere flexible pipe and be connected, continue to monitor arteriotony (Bp) with electrophysiology instrument.Median incision of lower abdomen, outer lateral lobe behind the exposure rat prostate, seek cavernosal nerve on its surface, hook nerve with electrode, stimulation parameter is 3v, 2Hz, 0.5ms, stimulation time is 60s, gastric infusion, dosage are 30mg/kg, observe medication front and back ICP and MBp continuously and change, ratio comprehensive evaluation medicine by ICP and Bp brings out the effect of erection to nerve stimulation, and parameter (ICP/BP) is judged the effect power of compound for the rat corpus cavernosum penis as index.We have tested the effect to the rat corpus cavernosum penis of Virga and part embodiment compound as stated above.Adopt Deng Kenshi multiple comparisons method that test result is carried out statistical study, the statistical significance of the blank group of measuring and calculating and each group difference of test compounds, statistics is as follows:
The embodiment compound ICP/BP
Blank group 30.04±8.26
Virga 55.89±5.59 **
20 48.44±2.36 **
23 48.52±9.33 *
24 42.83±7.44 *
Annotate: compare with the blank group, *P＜0.05, *P＜0.01
By experimental data as can be known, can significantly improve the ICP of rat corpus cavernosum penis after the test compounds medication, increase ICP/BP, strengthen penile erectile function, therefore, can be used as the oral drug therapy erective dysfunction.
Test the test of 55 enzyme inhibition activities
The used enzyme of enzyme inhibition activity test is to adopt the method that is similar to bibliographical information (Thrombosis Res.1991,62,31 and J.Biol.Chem.1997,272,2714), and different tissues through suitably handling, is isolated the required enzyme of test with FPLC.Definite says, obtains PDE5 from people's thrombocyte, isolates PDE6 from the retina of ox.Enzyme carries out the inhibition activity test of enzyme immediately once separating, the inhibition test of enzyme is to adopt the TRKQ7100 test kit, the flicker that directly detects cGMP is near measuring, roughly be performed such, in the presence of different inhibitor concentration and a small amount of substrate, the damping fluid (50mM Tris/HCl PH 7.5, the 8.3mM MgCl that add 10 μ l 21.7mMEGTA), water to final volume is 100 μ l, with the enzyme initiation reaction of fixed amount, 30 ℃ are incubated 30 minutes, contain the yttrium silicate pearl termination reaction of zinc sulfate then with 50 μ l, after shaking 20 minutes, dark place sedimentation 30 minutes is counted on the MicroBeta1450 liquid scintillation instrument, calculates the half inhibiting rate (IC of The compounds of this invention to enzyme according to count value then 50).
PDE5 suppresses activity experiment
According to the method described above, measured Virga and part embodiment compound of the present invention inhibition activity to human blood platelets PDE5, measurement result is as shown in the table:
Test compounds PDE5?IC 50(nM) Test compounds PDE5?IC 50(nM)
Virga 6.4 24 23.9
1 15.2 26 25.8
3 12.9 32 43.0
14 26.1 36 44.6
17 79.3 42 53.9
20 65.1 44 26.0
23 12.1 49 16.0
By the inhibition activity (IC of last table compound to PDE5 50) as can be known, the most compounds among the present invention has stronger PDE5 and suppresses active.
PDE6 suppresses activity experiment
Consider that The compounds of this invention may be to being distributed in amphiblestroid PDE6 restraining effect, and then cause the visual disorder effect, we have measured the inhibition activity of segment bounds I compound of the present invention to bovine retina PDE6 as stated above, and measurement result is as shown in the table:
Test compounds PDE6?IC 50(nM) PDE5?IC 50(nM) PDE6?IC 50/PDE5 IC 50
Virga 70.0 6.4 10.9
1 5650 15.2 371.7
3 8330 12.9 645.7
14 172 26.1 6.6
17 246 79.3 3.1
20 640 65.1 9.8
23 262 12.1 21.7
24 10000 23.9 418
26 3220 25.8 124.8
32 2190 43.0 50.9
36 929 44.6 20.8
42 5600 53.9 103.9
44 203.2 26.0 37.6
49 421 16.0 26.3
The present invention adopts IC 50PDE6/IC 50The ratio of PDE5 is judged the selectivity of this patent compound for PDE6 and PDE5, and the result shows that most of embodiment compound has the selectivity stronger than Virga, and therefore, the Virga The compounds of this invention causes that the possibility of visual disorder is littler relatively.
Test 3 acute toxicity tests
In this test, use 18-22 gram Kunming kind male white mouses, random packet, 10 every group.The embodiment compound is suspended in 0.5% carboxymethylcellulose sodium solution, presses the dosage gastric infusion of 3g/kg, fasting is 12 hours before the administration, poisoning or the clinically dead signal of animal after the observation administration.Test-results is as shown in the table:
Test compounds Number of animals (only) Dead animal (only) Mortality ratio (%)
20 10 0 0
23 10 0 0
In the process of the test, do not find administration after mouse tangible clinical toxicity symptom, body weight change and the phenomena of mortality are arranged.Test-results shows that the majority of compounds of describing among the present invention do not have tangible toxicity to small white mouse.
Scope of the present invention is not subjected to the restriction of described specific embodiments, and described embodiment is only desired also to comprise the method and the component of functional equivalent in the scope of the invention as the single example of illustrating all respects of the present invention.In fact, except content as herein described, those skilled in the art can easily grasp multiple improvement of the present invention with reference to above description and accompanying drawing.Described improvement also falls within the scope of appended claims.Every piece of reference mentioned above is listed this paper in as a reference all in full.

Claims (13)

1. one kind has following general structure (I) quinazolinones, perhaps its pharmacologically acceptable salt
Figure A200710047915C00021
Wherein:
R 1Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 1-C 3Haloalkyl, halogen, hydroxyl is by C 1-C 3The hydroxyl that alkoxyl group replaces, alkoxyl group, amino, amide group;
R 2, R 3And R 4Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 1-C 3Haloalkyl is by C 1-C 3The C that alkoxyl group replaces 1-C 3Alkyl, or by C 3-C 6The C of cycloalkyl substituted 1-C 3Alkyl;
R 5Be H, OH, halogen, nitro, Ar, Het, NR 6R 7, five yuan of sugar, hexa-atomic sugar, CN, SO 2NR 6R 7, CO (CH 2) mNR 6R 7, NHSO 2NR 6R 7, NHCONR 6R 7, NHCNNR 6R 7, NHCOR 8, COR 8, NHCOOR 8, COOR 8, C 1-C 6Alkyl or be substituted the C that base replaces 1-C 3Alkyl;
R 6And R 7Be H independently of one another, C 1-C 6Alkyl, COR 8, SO 2R 8, be substituted the C that base replaces 1-C 3Alkyl, substituting group is selected from OH, guanidine radicals, C 1-C 4Alkoxyl group, C 3-C 6Cycloalkyl, NR 9R 10, Ar or Het; R 6And R 7The 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 R 11Replace;
R 8Be C 1-C 6Alkyl is (optional by C 1-C 3Alkoxyl group or by NR 12R 13Base replaces);
R 9And R 10Be H independently of one another, C 1-C 6Alkyl; Or R 9, R 10The nitrogen-atoms that links to each other with them constitutes Het jointly;
R 11Be C 1-C 6Alkyl, this alkyl can be chosen wantonly by OH, C 1-C 3Alkoxyl group replaces;
R 12And R 13Be H independently of one another, or C 1-C 6Alkyl;
Above-mentioned every in,
m＝0，1，2；
The Ar representative is by one or two aryl that substituting group replaces, and substituting group is selected from halogen, NH 2, C 1-C 3Alkyl, C 1-C 3Alkoxyl group, CONH 2, CN, SO 2NH 2
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:
R 1Be H, C 1-C 6Alkyl, C 3-C 6Cycloalkyl, C 1-C 3Haloalkyl, halogen, hydroxyl is by C 1-C 3The hydroxyl that alkoxyl group replaces, alkoxyl group, amino, amide group;
R 2, R 3And R 4Be H independently of one another, C 1-C 6Alkyl, C 1-C 6Thiazolinyl, C 3-C 6Cycloalkyl, C 1-C 6Haloalkyl or halogen;
R 5Be SO 2NR 6R 7, CO (CH 2) mNR 6R 7, NHSO 2NR 6R 7, NHCONR 6R 7, NHCNNR 6R 7Or NR 6R 7
R 6And R 7Be H independently of one another, C 1-C 6Alkyl, COR 8, SO 2R 8Or be substituted the C that base replaces 1-C 3Alkyl, substituting group is selected from OH, guanidine radicals, C 1-C 4Alkoxyl group, C 3-C 6Cycloalkyl, NR 9R 10, Ar or Het; R 6And R 7The 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 R 11Replace;
R 8Be C 1-C 6Alkyl;
R 9And R 10Be H independently of one another, C 1-C 6Alkyl or R 9, R 10The nitrogen-atoms that links to each other with them constitutes Het jointly;
R 11Be C 1-C 6Alkyl, this alkyl can be chosen wantonly by OH, C 1-C 3Alkoxyl group replaces;
R 12And R 13Be H independently of one another, or C 1-C 6Alkyl; Above-mentioned every in,
m＝0，1，2；
The Ar representative is by one or two aryl that substituting group replaces, and substituting group is selected from halogen, NH 2, C 1-C 3Alkyl, C 1-C 3Alkoxyl group, CONH 2, CN, SO 2NH 2
The Het representative contains 1-4 heteroatomic 5 and 6 yuan of heterocycles, and heteroatoms is selected from N, S and O, and optional by one or two substituting groups replacements, and substituting group is selected from halogen, C 1-C 3Alkyl, C 1-C 3Alkoxyl group.
3. quinazolinones according to claim 1 or its pharmacologically acceptable salt is characterized in that:
R 1Be H, C 1-C 6Alkyl, C 1-C 6Thiazolinyl or halogen;
R 2Be C 1-C 6Alkyl;
R 3Be H or C 1-C 6Alkyl;
R 4Be C 1-C 6Alkyl;
R 5Be SO 2NR 6R 7
R 6And R 7Be H independently of one another, C 1-C 3Alkyl, benzyl, picolyl, piperidin-4-yl, COR 8, the C that is replaced by guanidine radicals 1-C 3Alkyl, or by NR 9R 10The C that base replaces 1-C 3Alkyl 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 R 11Replace;
R 8Be C 1-C 4Alkyl, phenyl or pyridyl;
R 9And R 10Be H independently of one another, C 1-C 3Alkyl; Or R 9, R 10 nitrogen-atoms that links to each other with them constitutes morpholine, parathiazan, piperazine, piperidines, tetramethyleneimine heterocycle jointly;
R 11Be C 1-C 4Alkyl, this alkyl can be chosen wantonly by OH, C 1-C 3Alkoxyl group replaces.
4. quinazolinones according to claim 1, perhaps its pharmacologically acceptable salt is characterized in that:
R 1Be H, C 1-C 6Alkyl, C 1-C 6Thiazolinyl or halogen;
R 2Be H or methyl;
R 3Be H or methyl;
R 4Be ethyl or n-propyl;
R 5Be SO 2NR 6R 7
R 6And R 7Be H independently of one another, the C that is replaced by guanidine radicals 1-C 3Alkyl, or by NR 9R 10The C that base replaces 1-C 3Alkyl 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 R 10Replace;
R 9And R 10Be H independently of one another, C 1-C 3Alkyl; Or R 9, R 10The nitrogen-atoms that links to each other with them constitutes morpholine, piperidines, tetramethyleneimine heterocycle jointly;
R 11Be 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-hydroxyl-7-methoxyl group-8-chloro-quinazoline-4 (3H)-ketone;
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5-hydroxyl-7-methoxyl group-8-fluoro-quinazoline-4 (3H)-ketone;
2-[2-oxyethyl group-5-(4-methylpiperazine-1-alkylsulfonyl)-phenyl]-5-hydroxyl-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 especially mesylate of 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. pharmaceutical composition contains any one the described quinazolinones of claim 1-6 and the pharmaceutically acceptable carrier of significant quantity.
8. the purposes of any one described quinazolinones compound or pharmaceutically acceptable salt thereof of claim 1-6 in preparation PDE5 inhibitor medicaments.
9. but any one described quinazolinones of claim 1-6 or its pharmacologically acceptable salt, or their acceptable solvent thing, 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, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and be characterized as purposes in the human medicine of disease of intestinal peristalsis obstacle.
10. the described preparation method with following general structure (I) quinazolinones of claim 1 is characterized in that:
Work as R 1Be halogen, R 3Be not H, R 2, R 4, R 5During as the definition in the claim 1 (I-A), by II ring with obtain,
Figure A200710047915C00091
Work as R 1Be not halogen, R 3Be not H, R 2, R 4, R 5During as the definition in the claim 1, can obtain I-B by compound among the I-A and metallic alkide reagent react;
Figure A200710047915C00092
Work as R 3Be H, R 1, R 2, R 4, R 5During 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 A200710047915C00093
Obtain I-C.
11. preparation method according to claim 10 is characterized in that:
II is by following reaction
Figure A200710047915C00101
Make.
12. preparation method according to claim 11 is characterized in that:
III is by following reaction
Figure A200710047915C00102
Make.
13. compound shown in the general structure II
Figure A200710047915C00103
R 1, R 2, R 3, R 4, R 5As the definition in the claim 1.
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