WO2009062402A1 - Dérivés de quinazolinone, leurs procédés de préparation et leurs utilisations - Google Patents

Dérivés de quinazolinone, leurs procédés de préparation et leurs utilisations Download PDF

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Publication number
WO2009062402A1
WO2009062402A1 PCT/CN2008/001859 CN2008001859W WO2009062402A1 WO 2009062402 A1 WO2009062402 A1 WO 2009062402A1 CN 2008001859 W CN2008001859 W CN 2008001859W WO 2009062402 A1 WO2009062402 A1 WO 2009062402A1
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Prior art keywords
phenyl
dimethoxy
bromo
propoxy
ketone
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PCT/CN2008/001859
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English (en)
Chinese (zh)
Inventor
Jingshan Shen
Jin Zheng
Qinglin Lai
Zhen Wang
Jinfeng Zhang
Guanghui Tian
Hongliang Duan
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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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Definitions

  • the invention relates to the technical field of medicine, in particular to a quinazolinone derivative, a preparation method thereof and a use thereof. Background technique
  • Phosphodiesterase includes 11 enzyme systems (PDE1-PDE11) that reduce the activity of intracellular second messengers by hydrolyzing cAMP or cGMP.
  • 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, while cAMP and cGMP are natural substrates for PDE.
  • inhibitors are not degraded by PDE.
  • PDE is known to be involved in a wide range of cellular functional activities.
  • PDE 5 is a phosphodiesterase that is cGMP specific and highly expressed in corpus cavernosum smooth muscle cells. PDE 5 inhibitors enhance erectile function by maintaining adequate cGMP levels in the corpus cavernosum and supplying vascular smooth muscle cells during sexual stimulation, increasing the expansion of the cavernous sinus.
  • non-selective PDE inhibitors such as caffeine, theophylline and 3-isobutyl-1-methylsulfonate (IBMX) have been used for cyclic nucleotide (cNMP) physiological and PDE activities. the study. Although they are of the same class, the above-mentioned inhibitors lack specificity, they block the catalytic activity of almost all known PDEs, and may be accompanied by excessive adverse reactions while being treated.
  • PDE 5 inhibitors affect PDE 5 activity by inhibiting PDE 5 enzyme activity, affecting PDE 5 expression and metabolism, and affecting physiological and pathological processes. In theory, PDE 5 inhibitors can affect all physiological and pathological processes associated with PDE 5.
  • the first PDE5 inhibitor, Sildenafil, is clinically used for male erectile dysfunction and is also effective for female sexual dysfunction and essential hypertension. PDE5 inhibitors in development are also used for diabetic gastrointestinal symptoms, insulin resistance and hyperlipidemia.
  • sildenafil has achieved significant clinical efficacy, it also has different degrees of inhibition on other phosphodiesterase (PDE) isoenzymes other than PDE5, clinically showing headache, flushing, indigestion, nasal congestion, It is toxic and side effects such as blurred vision, light sensitivity and light color. On the one hand, these side effects are dose related, Therefore, it is found that a more potent PDE5 inhibitor can reduce the dose and reduce the side effects.
  • the symptom of visual disorder is that sildenafil also inhibits the type VI phosphodiesterase (PDE6) present in the retina. As a result, increasing selectivity, especially relative to PDE6, is another goal in the search for new PDE5 inhibitors. Summary of the invention
  • the technical problem to be solved by the present invention is to provide a novel PDE5 inhibitor, for which purpose the present invention discloses a quinazolinone derivative, and a process for its preparation, a composition and use thereof are disclosed.
  • R 1 is H, dC 6 hydrocarbyl, C 3 -C 6 cycloalkyl, dC 3 haloalkyl, halo, hydroxy, alkoxy substituted by hydroxy, alkoxy, amino, amido;
  • R 2 is H, dC 6 hydrocarbyl, C 3 -C 6 cycloalkyl, haloalkyl, 3 dC, 3 is dC 3 alkoxy-substituted alkyl, or C 3 -C 6 cycloalkyl Substituted dC 3 alkyl;
  • R 5 is H, OH, halogen, nitro, carboxy, CN, S0 2 NR 6 R 7 , CO(CH 2 ) m NR 6 R 7 , OR 8 , NR 9 R 10 , five-membered sugar, six-membered sugar, COR 11 , NHCOOR 11 , COOR 11 ;
  • R 6 and R 7 are each independently H, dC 6 alkyl, COR 1 1 , S0 2 R n , dC 3 alkyl substituted by a substituent selected from OH, decyl, dC 4 alkoxy, C 3 -C 6 cycloalkyl, NR 12 R 13 , Ar or Het; R 6 and R 7 together with the nitrogen atom to which they are attached constitute pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole, wherein The nitrogen-containing heterocycle is optionally substituted by R 14 ;
  • R 8 is benzyl, acyl, sulfonyl
  • R 9 and R 1Q are each independently H, a five-membered sugar, a six-membered sugar, an acyl group, a sulfonyl group, C(Y)NR 15 R 16 ;
  • R 11 is H, dC 6 alkyl;
  • R 12 and R 13 are each independently H, dC 6 alkyl; or R 12 and R 13 are bonded together with the nitrogen atom to which they are attached Constitute Het;
  • ⁇ 4 is a 6 alkyl group, which may be optionally substituted by OH, dC 3 alkoxy;
  • R 15 and R 16 each independently represent 11, dC 6 alkyl; R 15 and R 16 may form a 4 to 8 membered heterocyclic group together with the nitrogen atom to which they are attached, and the heterocyclic group is morpholinyl, thiomorpholine. Or a piperidinyl group, a pyrrolidinyl group or a piperazinyl group, the above heterocyclic group and optionally selected from OH, dC 6 alkyl, dC 4 alkoxy, C 3 -C 6 cycloalkyl, aryl Substituted with one or more substituents in Het;
  • Y stands for 0, S, NR 14 ;
  • Ar represents an aryl group substituted by one or two substituents selected from the group consisting of halogen, NH 2 , dC 3 alkyl, dC 3 alkoxy, CONH 2 , CN, S0 2 NH 2 ;
  • Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms selected from N, S and 0.
  • R 1 is H, dC 6 hydrocarbyl, C 3 -C 6 cycloalkyl, dC 3 haloalkyl, halo, hydroxy, alkoxy substituted by hydroxy, alkoxy, amino, amido;
  • R 2 , R 3 and R 4 are each independently H, dC 6 alkyl, dC 6 alkenyl, C 3 -C 6 cycloalkyl, dC 6 haloalkyl or halogen;
  • R 5 is H, OH, halogen, nitro, carboxy, CN, S0 2 NR 6 R 7 , CO(CH 2 ) m NR 6 R 7 , OR 8 , NR 9 R 10 , five-membered sugar, six-membered sugar, COR 11 , NHCOOR 11 , COOR 11 ;
  • R 6 and R 7 are each independently H, dC 6 alkyl, COR 1 1 , S0 2 R n , dC 3 alkyl substituted by a substituent selected from OH, decyl, dC 4 alkoxy, C 3 -C 6 cycloalkyl, NR 12 R 13 , Ar or Het; R 6 and R 7 together with the nitrogen atom to which they are attached constitute pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole, wherein The nitrogen-containing heterocycle is optionally substituted by R 14 ;
  • R 8 is benzyl, acyl, sulfonyl
  • R 9 and R 1Q are each independently H, a five-membered sugar, a six-membered sugar, an acyl group, a sulfonyl group, C(Y)NR 15 R 16 ;
  • R 11 is H, dC 6 alkyl;
  • R 12 and R 13 are each independently H, dC 6 alkyl; or R 12 , R 13 together with their attached nitrogen atoms constitute Het;
  • ⁇ 4 is a 6 alkyl group, which may be optionally substituted by OH, dC 3 alkoxy;
  • R 15 and R 16 each independently represent 11, dC 6 alkyl;
  • R 15 and R 16 may form a 4 to 8 membered heterocyclic group together with the nitrogen atom to which they are attached, and the heterocyclic group is morpholinyl, thiomorpholine.
  • a piperidinyl group, a pyrrolidinyl group or a piperazinyl group the above heterocyclic group and optionally selected from OH, dC 6 alkyl, dC 4 alkoxy, C 3 -C 6 cycloalkyl, aryl Substituted with one or more substituents in Het;
  • Y stands for 0, S, NR 14 ;
  • Ar represents an aryl group substituted by one or two substituents selected from the group consisting of halogen, NH 2 , dC 3 alkyl, dC 3 alkoxy, CONH 2 , CN, S0 2 NH 2 ;
  • Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms selected from N, S and 0.
  • R 1 is H, dC 6 alkyl, dC 6 alkenyl or halogen
  • R is a C-Ce thiol group
  • R 3 is 11 or dC 6 alkyl
  • R 4 is a Ci-C 6 yard base
  • R 5 is H, OH, halogen, nitro, carboxy, CN, S0 2 NR 6 R 7 , CO(CH 2 ) m NR 6 R 7 , OR 8 ,
  • R 6 and R 7 are each independently H, dC 6 alkyl, substituted by a substituent, and the substituent is selected from OH, decyl, dC 4 alkoxy, C 3 -C 6 cycloalkyl , NR 12 R 13 , Ar or Het; R 6 and R 7 together with the nitrogen atom to which they are attached constitute pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole, wherein the nitrogen-containing heterocycle is selectively Replaced by R 14 ;
  • R 8 is benzyl, acetyl, isopropionyl, methylsulfonyl, p-toluenesulfonyl;
  • R 9 and R 1Q are each independently H, five-membered sugar, six-membered sugar, acyl group, methylsulfonyl group, p-toluenesulfonyl group, C(Y)NR 15 R 16 ;
  • R 12 and R 13 are each independently H, dC 6 alkyl; or R 12 , R 13 together with their attached nitrogen atoms constitute Het;
  • ⁇ 4 is a 6 alkyl group, which may be optionally substituted by OH, dC 3 alkoxy;
  • R 15 and R 16 each independently represent 11, dC 6 alkyl; R 15 and R 16 may together with the nitrogen atom to which they are attached form a piperidinyl group, a pyrrolidinyl group or a piperazinyl group, the above heterocyclic group and may be optionally
  • the ground is substituted with one or more substituents selected from the group consisting of OH, dC 6 alkyl, dC 4 alkoxy, C 3 -C 6 cycloalkyl, aryl and Het; Among the above,
  • Y stands for 0, S, NR 14 ;
  • Ar represents an aryl group substituted by one or two substituents selected from the group consisting of halogen, NH 2 , dC 3 alkyl, dC 3 alkoxy, CONH 2 , CN, S0 2 NH 2 ;
  • Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms selected from N, S and 0.
  • R 1 is H, dC 6 alkyl, dC 6 alkenyl or halogen
  • R 2 is H or methyl
  • R 3 is H or methyl
  • R 4 is ethyl or n-propyl
  • R 5 is H, OH, halogen, nitro, carboxy, acetyl, CN, S0 2 NR 6 R 7 , CONR 6 R 7 ,
  • R 6 and R 7 are each independently H, dC 3 alkyl, substituted by a substituent, and the substituent is selected from OH, decyl, dC 4 alkoxy, NR 12 R 13 ; R 6 and R 7 together with the nitrogen atom to which they are attached constitute pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole, wherein the nitrogen-containing heterocycle is optionally substituted by R 14 ;
  • R 8 is benzyl, acetyl, isopropionyl, methylsulfonyl, p-toluenesulfonyl;
  • R 9 and R 1Q are each independently H, glucose, mannose, acetyl, isopropionyl, methylsulfonyl, p-toluenesulfonyl, C NR 15 R 16 ;
  • R 12 and R 13 are each independently H, dC 6 alkyl; or R 12 and R 13 together with the nitrogen atom to which they are attached constitute morpholine, piperidine, pyrrolidine heterocycle;
  • R 14 is methyl, ethyl or propyl
  • R 15 and R 16 each independently represent 11, dC 3 alkyl; R 15 and R 16 may together with the nitrogen atom to which they are attached form a piperidinyl, pyrrolidinyl or piperazinyl group;
  • Y stands for 0, S, NR 14 .
  • Preferred specific compounds of the invention include:
  • 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 .
  • the compounds of formula I may contain one or more chiral centers, and thus stereoisomers, i.e., enantiomers or diastereomers, and mixtures thereof may be present.
  • the invention includes individual stereoisomers of the mixture of Formula I and mixtures thereof.
  • the compounds of formula I may exist in the form of tautomers, and the invention includes mixtures thereof and single tautomers.
  • the invention includes pharmaceutically acceptable salts of the compounds of formula I.
  • Preferred salts are the methanesulfonate and the hydrochloride.
  • Another aspect of the invention also discloses a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of the compound of the formula (I) And a pharmaceutically acceptable carrier.
  • the invention also includes pharmaceutically acceptable oxides of the compounds of formula I, and pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. Further, the present invention provides the use of a compound of the formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable composition thereof, as a human medicament.
  • the invention also provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the PDE5 inhibitor.
  • the invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable composition thereof, for use in the treatment or prevention of erectile dysfunction in men, benign prostatic hyperplasia, Female sexual dysfunction, premature labor, dysmenorrhea, bladder outlet obstruction, incontinence, instability and variation of Prinzmetal angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, Renault Use in human medicine for inflammatory disease, inflammatory disease, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by intestinal motility disorders such as stress bowel syndrome.
  • the invention also provides a process for the preparation of the compounds of formula I.
  • RR 2 , R 3 , R 4 , R 5 are as defined in claim 1. It includes:
  • a compound may be a compound of formula 2 in the presence of a base, The temperature is usually from 30 to 200 ° C, and the reaction is carried out in a suitable solvent for 1 to 12 hours.
  • Preferred bases include alkali metal alkoxides (preferably potassium t-butoxide, sodium ethoxide), alkali metal or alkaline earth metal hydrides, amines (preferably triethylamine), metal salts of amines, hydroxides (preferably sodium hydroxide).
  • preferred solvents include alcohols (eg t-butanol, ethanol, methanol, isopropanol, ethylene glycol, ethylene glycol monomethyl ether), aromatic hydrocarbons (eg benzene, toluene, chlorobenzene) , pyridine, halogenated hydrocarbon, B Nitrile, tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidin-2-one, and the like.
  • alcohols eg t-butanol, ethanol, methanol, isopropanol, ethylene glycol, ethylene glycol monomethyl ether
  • aromatic hydrocarbons eg benzene, toluene, chlorobenzene
  • a second type of moiety I-B (R 1 is not halogen, R 3 is not H, R 2 , R 4 , R 5 are as defined in claim 1)
  • the compound may be represented by the corresponding first class I -A compound and a hydrocarbyl metal reagent (hydrocarbon based metal reagent may be Cul, CH 3 ZnCl / [(t-Bu) 3 P] 2 Pd, C 2 H 5 ZnI / [(t-Bu) 3 P] 2 Pd ,
  • Part III of the formula I-C may be in the corresponding solvent of the corresponding first type of the compound of formula I-A or I-B (solvent preferably dichloromethane, chloroform) And reacting with a dealkylating agent (dealkylating agent is preferably aluminum trichloride, boron tribromide, boron tetrafluoride). Reaction equation:
  • the compound of formula II can generally be prepared from the reaction of a compound of formula III with a compound of formula IX.
  • Method 1 First, the carboxyl group of the compound of the formula IX is converted into an acid chloride or a mixed acid anhydride with thionyl chloride, oxalyl chloride, ethyl chloroformate or the like, and then reacted with the compound of the formula III to obtain the corresponding amide II.
  • the acylation reaction is usually carried out in the presence of a deacidifying agent in a usual solvent.
  • Preferred deacidification agents 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 dichloromethane or chloroform), ethers (preferably tetrahydrofuran, dioxane, diethyl ether), aromatic solvents (preferably toluene). ), and alcohols (preferably t-butanol, isopropanol).
  • alkanes preferably petroleum ether, n-hexane, cyclohexane
  • halogenated hydrocarbons preferably dichloromethane or chloroform
  • ethers preferably tetrahydrofuran, dioxane, diethyl ether
  • aromatic solvents preferably toluene
  • alcohols preferably t-butanol, isopropanol.
  • Method 2 direct condensation of a carboxylic acid and an amine to give an amide II.
  • the reaction is usually carried out in the presence of an activator or a dehydrating agent in an anhydrous inert solvent.
  • Preferred activators or dehydrating agents include DCC, EDCK 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 (dimethyl sulfoxide, N, N-dimethylformamide), or a mixture of these solvents.
  • RR 2 , R 3 , R 4 , and R 5 are as defined above.
  • a compound of Formula III can generally be of formula IV NH 3 was prepared in a condensation reaction.
  • the reaction is usually carried out in the presence of an activator or a dehydrating agent in an anhydrous inert solvent.
  • 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 (dimethyl sulfoxide, N, N-dimethylformamide), or a mixture of these solvents.
  • halogenated hydrocarbons preferably dichloromethane or chloroform
  • ethers preferably tetrahydrofuran, dioxane, diethyl ether
  • aromatic hydrocarbons preferably benzene, toluene
  • polar aprotic solvents dimethyl sulfoxide, N, N-dimethylformamide
  • the compound of formula IV can generally be prepared by reacting a compound of formula V in a 5%-10% NaOH solution with 30% 3 ⁇ 40 2 . Reaction equation:
  • the compound of the formula V can be usually obtained by reacting a compound of the formula VI with oxalyl chloride in a suitable solvent (solvent preferably dichloromethane, methyl chloride, 1,3-dichloropropane) at a temperature of usually 30 to 100 °C.
  • solvent preferably dichloromethane, methyl chloride, 1,3-dichloropropane
  • the compound of formula VI can generally be prepared by refluxing a compound of formula VII in a solution of HCl/MeOH.
  • the compound of the formula YD can usually be obtained from a compound of the formula VIII with a suitable halogenating agent (the halogenating agent can be NBS, NCS, F-TEDA-BF 4 , Nal/t-BuOCl) in a suitable solvent (solvent preferably acetonitrile, two Prepared by reaction in methyl chloride, chloroform, 1,3-dichloropropane, usually at -20-50 °C.
  • a suitable halogenating agent can be NBS, NCS, F-TEDA-BF 4 , Nal/t-BuOCl
  • solvent solvent preferably acetonitrile, two Prepared by reaction in methyl chloride, chloroform, 1,3-dichloropropane, usually at -20-50 °C.
  • R2 and R3 are as defined above.
  • the present inventors designed and synthesized a series of new quinazolinone derivatives I, most of which have stronger PDE5 inhibitory activity than sildenafil and have higher selectivity than PDE6 distributed in the retina. . Therefore, the compounds provided by the present invention are expected to exhibit better safety and efficacy in clinical practice, and have a promising clinical application. detailed description
  • Halogen means fluorine, chlorine, bromine and iodine.
  • Alkyl as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group. The alkyl group having a C1-C14 alkyl group is preferred; more preferred is: C1-C10 alkyl; the most preferred is C1-C6 unless otherwise indicated. Examples of straight-chain or branched C1-C6 alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, hexyl Wait.
  • alkenyl as a group or part of a group means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be straight or branched.
  • An alkenyl group having C2-C14 is preferred.
  • C2-C12 is even better; the most preferred is the C2-C6 alkenyl group.
  • the group may contain a plurality of double bonds in its backbone and its conformation may each be £ or ⁇ .
  • alkenyl groups include, but are not limited to, vinyl, propenyl, and the like.
  • Cycloalkyl means a saturated or partially saturated monocyclic, fused or spiro carbon ring. A ring composed of 3-9 carbon atoms is preferred. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • Aryl as a group or a part of a group means: (1) an aromatic monocyclic or fused ring; an aromatic carbocyclic ring having 5 to 12 carbon atoms is preferred (the ring atoms are all carbon) Ring structure).
  • the aryl group include, but are not limited to: phenyl, naphthyl; (2) a partially saturated carbocyclic ring may be attached, for example: a phenyl group and a C5-7 cycloalkyl group or a C5-7 cycloalkenyl group are mutually thick. Together form a ring structure. Examples include, but are not limited to, tetrahydronaphthyl, anthracenyl or hydroquinone. An aryl group can be substituted with one or more substituents.
  • the present invention includes the compounds represented by the formula (I) and various possible isomeric forms thereof. These include: non-mirror isomers, mirror image isomers, tautomers, and geometric isomers of the "E" or "Z” configurational isomers. Any of the above-mentioned chemists can isolate the above optically pure or stereoisomerically pure compounds.
  • the invention includes mixtures of the compounds represented by the general formula (I) and their possible racemates or / and mirror image isomers / or / and non-image mirror isomers.
  • each formula includes compounds having the indicated configurations, including hydrated and anhydrous forms thereof.
  • pharmaceutically acceptable salt refers to certain salts of the above compounds which retain their original biological activity and which are suitable for pharmaceutical use.
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) has two forms of formation: one is a salt formed with an acid; the other is a salt formed with an alkali or an alkali metal.
  • the acid which forms a pharmaceutically acceptable salt with the compound represented by the formula (I) includes inorganic acids and organic acids. Suitable inorganic acids include: hydrochloric acid, sulfuric acid and phosphoric acid.
  • Suitable organic acids may be selected from the group consisting of aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic acid and sulfonic acid organic acids; examples of which 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 and the like.
  • the alkali metal in which the compound represented forms a pharmaceutically acceptable salt includes: lithium, sodium, potassium, magnesium, calcium, aluminum, zinc, etc.; a base which forms a pharmaceutically acceptable salt with the compound represented by the formula (I) Including: choline, diethanolamine, morpholine and the like.
  • a “prodrug” is a derivative represented by the formula (I) which is converted in vivo by means of metabolism in the body (for example: by hydrolysis, reduction or oxidation) to form a formula (I) compound of.
  • a compound having a hydroxyl group represented by the formula (I) can be reacted with an acid to prepare a corresponding ester.
  • the corresponding ester is a prodrug that can hydrolyze the parent drug in vivo.
  • Acids suitable for the preparation of "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- ⁇ -hydroxynaphthoic acid, gentisic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
  • the compound represented by the formula (I) can be administered in a gastrointestinal or parenteral manner.
  • Gastrointestinal administration Oral or rectal.
  • Parenteral administration includes: subcutaneous, intramuscular, intravenous and intradermal routes.
  • the active compound represented by the formula (I) when administered, may be a pharmaceutically acceptable carrier or diluent.
  • “Therapeutically effective amount” or “therapeutic amount” refers to an amount sufficient to produce a therapeutic effect.
  • An effective amount can be administered in one or more divided doses. Generally, an effective amount is sufficient to alleviate, improve, stabilize, slow or delay further progression of the disease.
  • the invention provides a pharmaceutically acceptable composition
  • a pharmaceutically acceptable composition comprising the compound of formula I.
  • the composition consists of one or more compounds of formula I (or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof) and at least one pharmaceutically acceptable adjuvant.
  • the choice of pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and is usually a filler, a diluent, a binder, a wetting agent, a disintegrant, a lubricant, an emulsifier, a suspending agent, and the like.
  • compositions of the invention may be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, transurethral, vaginal, nasal, inhalation or topical routes.
  • injection intravenous, intramuscular, subcutaneous and intracoronary
  • sublingual buccal
  • rectal transurethral
  • vaginal nasal
  • inhalation topical routes.
  • the preferred route is oral.
  • the proportion of the compound of the formula I in the above composition is from 0.1% to 99.9% by weight, preferably
  • the invention also provides a process for the preparation of a pharmaceutically acceptable composition of a compound of formula I.
  • the compound of the formula I is usually mixed with a pharmaceutically acceptable adjuvant and prepared in a form suitable for administration by a conventional preparation method (dosage form).
  • the dosage form includes tablets, capsules, granules, pills, solutions, suspensions, emulsions, ointments, films, creams, aerosols, injections, suppositories, and the like. Preference is given to tablets and capsules.
  • the combination of tablets and capsules may contain one or more of Formula I and one or more conventional excipients, such as Fillers such as powder, sucrose, lactose, glucose, microcrystalline cellulose, mannose; binders such as carboxymethyl cellulose, gelatin, alginate and polyvinylpyrrolidone; wetting agents such as glycerin; agar, ethyl fiber a disintegrant such as sodium carboxymethyl starch or calcium carbonate; a lubricant such as magnesium stearate, talc or polyethylene glycol.
  • Fillers such as powder, sucrose, lactose, glucose, microcrystalline cellulose, mannose
  • binders such as carboxymethyl cellulose, gelatin, alginate and polyvinylpyrrolidone
  • wetting agents such as glycerin
  • agar, ethyl fiber a disintegrant such as sodium carboxymethyl starch or calcium carbonate
  • a lubricant such as magnesium stearate, tal
  • the compound of the present invention is usually administered in a dose of from 1 to 500 mg, preferably from 10 to 100 mg per day, in single or multiple doses. However, if necessary, the above doses may be appropriately deviated. Professionals can determine the optimal dose based on the specific situation and expertise. These conditions include the severity of the disease, individual differences in the patient, the nature of the formulation, and the route of administration.
  • Step 1 2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-benzoylamino]-5,7-dimethoxy-8-bromobenzoylamide
  • Anhydrous zinc chloride 408 mg (3.0 mmol) was dissolved in 5 mL of dry NMP, and 2 mL of 2 mol/L methylmagnesium chloride (2.0 mmol) in THF was added dropwise under ice cooling, and stirred at room temperature for 1 hour to obtain a methyl zinc reagent.
  • Example 1 The compound of Example 1 (0.57 g, 1.0 mmol) was dissolved in 20 mL of dry dichloromethane, and 2 mL of a solution of boron tribromide (104 uL, 1.1 mmol) in dichloromethane was added dropwise with stirring at -10 ° C, stirring was continued. In an hour, force B lmL diethyl ether, continue stirring for 30 minutes, add 20 mL of dichloromethane and 50 mL of 5 % NaHCO3, and extract the aqueous phase with 10 mL of dichloromethane. The organic phase is combined and washed with 5 mL of 5 % NaHC03 and saturated brine.
  • the active compound containing the pyridopyrimidinone derivative and various excipients are sieved through an 80 mesh sieve, and weighed according to the prescription, using a 0% polyvinylpyrrolidone ethanol solution as a binder, and a 16 mesh sieve to prepare suitable granules, 65 Dry at °C, sieve the whole mesh with 14 mesh, add the magnesium stearate and mix evenly, measure the particle content, calculate the loading, and put it into the capsule.
  • the active compound containing the pyridopyrimidinone derivative is mixed with microcrystalline cellulose, anhydrous lactose, polyvinylpyrrolidone, and microsilica gel in a mixer, and then mixed with magnesium stearate to obtain a tablet.
  • the stimulation parameters were 3v, 2Hz, 0.5ms, the stimulation time was 60s, and the dosage was 30mg/ Kg, continuous observation of ICP and BP changes before and after treatment, comprehensive evaluation of the effect of drugs on nerve-induced erection by the ratio of ICP to BP, the parameters (ICP/BPM ⁇ as an indicator to judge the effect of compounds on the rat corpus cavernosum.
  • ICP/BPM ⁇ as an indicator to judge the effect of compounds on the rat corpus cavernosum.
  • test compound can significantly increase the ICP of the rat corpus cavernosum, increase the ICP/BP, and enhance the penile erectile function. Therefore, it can be used as an oral drug for the treatment of erectile dysfunction.
  • the enzyme used in the enzyme inhibition activity test was similar to that reported in the literature (Thrombosis Res.
  • the enzyme initiated the reaction, incubated at 30 ° C for 30 minutes, and then terminated with 50 ⁇ l of zinc sulphate-containing yttrium silicate beads. After shaking for 20 minutes, it was allowed to settle in the dark for 30 minutes, counted on a MicroBetal 450 liquid scintillation meter, and then calculated based on the count value.
  • the half inhibition rate (IC 5Q ) of the compound of the present invention to the enzyme was determined using IC 5Q 450 liquid scintillation meter.
  • the present invention employs IC 5 .
  • PDE6/ IC 50 PDE5 ratio to judge the patented compound for PDE6 and
  • Test 3 Acute toxicity test

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Abstract

L'invention concerne des dérivés de quinazolinone, leurs procédés de préparation et leurs utilisations. Les composés de quinazolinone présentent la structure de formule générale (I) ou ses sels pharmaceutiquement acceptables. La plupart de ces composés présentent de fortes activités d'inhibition de PDE5 et une sélectivité élevée de PDE6 qui est distribué sur la rétine. Il est donc prévu que les présents composés présentent une bonne sécurité et une bonne efficacité et puissent être largement utilisés en clinique.
PCT/CN2008/001859 2007-11-07 2008-11-07 Dérivés de quinazolinone, leurs procédés de préparation et leurs utilisations Ceased WO2009062402A1 (fr)

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