WO2004101567A1 - Derives de 2-phenyl substitue -6,8-dialkyl-3h-imidazole [1,5a] [1,3,5] triazine-4- one, preparation et utilisation pharmaceutique associees - Google Patents

Derives de 2-phenyl substitue -6,8-dialkyl-3h-imidazole [1,5a] [1,3,5] triazine-4- one, preparation et utilisation pharmaceutique associees Download PDF

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WO2004101567A1
WO2004101567A1 PCT/CN2004/000488 CN2004000488W WO2004101567A1 WO 2004101567 A1 WO2004101567 A1 WO 2004101567A1 CN 2004000488 W CN2004000488 W CN 2004000488W WO 2004101567 A1 WO2004101567 A1 WO 2004101567A1
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substituted
phenyl
straight
branched alkyl
methyl
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PCT/CN2004/000488
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Chinese (zh)
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Yongfeng Wang
Kejun Zhao
Ke Liu
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Tianjin Tasly Group Co., Ltd.
Yantai Development Area North Pharmacuetical R & D Institute
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Publication of WO2004101567A1 publication Critical patent/WO2004101567A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/61—Carboxylic acid nitriles containing cyano groups and nitrogen atoms being part of imino groups bound to the same carbon skeleton

Definitions

  • Trifluorene- 4-one derivative its preparation method and its medicinal use
  • the present invention relates to a 2-substituted phenyl-6, 8-dihydrocarbyl-3H-imidazole [1, 5-a] [1, 3, 5] triazin-4-one derivative and a pharmaceutically acceptable salt thereof, Its preparation method, pharmaceutical composition containing them, and its use in preventing and / or treating therapeutic dysfunction and other diseases related to phospholipase 5 (cGMP PED5) function.
  • Sildenafil (Sildenaf i l (W09428902)) is the first oral lipase 5 inhibitor for the treatment of male erectile dysfunction. It relaxes smooth muscles by suppressing phospholipase 5 in the corpus cavernosum tissue, enhances penile congestion and leads to an erection. Sildenafil is 80% effective in erectile dysfunction in men.
  • Pf izer Ltd. has also developed a large number of other 1, 6-dihydro-pyrrole [4, 3- d] pyrimidine-7-keto-derivatives, and expanded their therapeutic scope to other treatments that can be treated by inhibiting phospholipase 5 Indications.
  • These compounds can be found in EP0951098, W09849116, US6251904 and W00024745, where the latter two patents include compounds in which a substituted phenyl group of C-5 is substituted with a substituted pyridin-2-yl group.
  • Korea DONG A PHARM Co. Ltd. developed monosubstituted derivatives of sulfonamide nitrogen based on the structure of sildenafil (W00027848 and WO0198304).
  • the object of the present invention is to provide compounds having therapeutic effects on dysfunction and other diseases related to phospholipase 5 function and a method for preparing the same. Accordingly, one aspect of the present invention relates to a 2-substituted phenyl-6, 8-dihydrocarbyl-3H-imidazole [1, 5-a] [1, 3, 5] triazine-4-one derivative having the general formula I (Wanzaonaf i 1) or a pharmaceutically acceptable salt thereof:
  • R 1 is H; dC 4 linear or branched alkyl; dC 4 halogenated linear or branched alkyl; C 2 -C 4 alkenyl; C 2 - C 4 alkynyl; pyrazole ⁇ , 1 ⁇ ethyl , Imidazolyl; other than H may be optionally substituted by one or more groups selected from the group consisting of: halogen, cyano, nitro, hydroxy, guanidino, dC 4 alkyl, .dC ⁇ oxy, dC 4 Alkanoyl, C 5 cycloalkyl, substituted phenyl, substituted heterocycle, CONR 5 R 6 , NR 5 R 6 , C0 2 R 7 , NHS0 2 R ⁇ S0 2 NR 9 R 10 ;
  • Substituted phenyl means that the phenyl is substituted by one or more dC 4 alkoxy, halogen, cyano, CF 3 , 0CF 3 , dC 4 straight or branched alkyl groups; substituted heterocycles include one or two Six-membered ring of nitrogen atom and its nitrogen oxide; five-membered ring containing two or three nitrogen, oxygen and sulfur atoms; the substituents on the heterocyclic ring are d- straight or branched alkyl, d- C 4 alkane Oxy, amino and dC 4 linear or branched alkylamino, dC 4 alkoxyamino;
  • R 2 is H; d-Ce linear or branched alkyl group, and may be substituted by C 3 -C 6 cycloalkyl group, dC 4 alkoxy group; c "c 4 alkenyl group; c 2 -c 4 alkynyl group;
  • R 3 is H, dC 6 linear or branched alkyl, and may be substituted by C 3 -C 6 cycloalkyl, dC 4 alkoxy; c 2 -c 4 alkenyl; 0 ′′ 0 4 alkynyl;
  • R 4 is I d- straight or branched alkyl, and may be optionally substituted with 0H, NR 5 R 6 , CN, CON 5 R 6 or CO 2 R 7 ; C 2 -C 4 alkenyl, And optionally substituted with CN, CONR 5 R 6 or C0 2 R 7 ; NR 5 R fi optionally substituted C 2 -C 4 alkoxy; 0H or NR 5 R fi optionally substituted (C 2- C 3 alkoxy) d- linear or branched alkyl; C0NR 5 R 6 ; halogen; D; ⁇ NHS0 2 NR 5 R 6 ; NHS0 2 R 8 ; SO R. Or phenyl optionally substituted by methyl, pyridyl, pyrimidinyl, imidazolyl, 3 ⁇ 4 Oxazolyl, thiazolyl, thienyl or triazolyl;
  • R 5 and R fi are H or C 4 straight or branched alkyl, respectively, or together with the nitrogen atom to which they are attached, form pyrrolinyl, piperidinyl, morpholinyl, 4- N (R U ) -piperyl Azinyl or imidazolyl, said group may be optionally substituted with dC 4 alkyl and hydroxyl;
  • R 7 is H or d-C 6 linear or branched alkyl group, and may be substituted by dC 4 alkoxy group, Ci-C 4 alkylamino group, dialkylamino group; substituted phenyl group, substituted heterocyclic ring; substitution thereof Phenyl and the substituents on the substituted heterocyclic ring are as described above;
  • R 8 is an optionally substituted dC 3 alkyl group
  • R 9 and R ie are H or C, C 12 straight or branched alkyl; dC 4 halogenated straight or branched alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl; or together form a pyrrolinyl (ketone) group, piperidinyl, morphinyl, 4- N (R 12 ) -piperazinyl; or a nitrogen atom connected to them to form a pyrrolinyl ( keto) group, a ⁇ piperazine, morpholino, 4-N (R 12) - piperazinyl; these groups may optionally be 0H, CN, C0 2 R 7 , dC 4 linear or branched alkyl group, Ci-C 3 alkoxy, NR 13 R 14 , CONR 13 R "substituted; substituted phenyl, substituted heterocycle, or dC 6 straight or branched chain
  • R 11 is H; dC 6 straight or branched chain alkyl, and may be optionally substituted with phenyl, hydroxy-substituted C 2 -C 3 alkyl or dC 4 alkoxy; C wide C 3 haloalkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl or C 3 -C 6 cycloalkane;
  • R 12 is H; dC 6 straight or branched alkyl; d- C 3 alkoxy substituted C 6 -C 6 straight or branched alkyl; hydroxy substituted C 2 -C 6 straight or branched alkyl NR 13 R 14 substituted C 2 -C 6 straight or branched alkyl; phenyl substituted C 2 -C 3 straight or branched alkyl; C0NR 13 R 14 substituted d-C 6 straight chain Or branched chain alkyl; C0 2 R 7 substituted C 2 -C 6 straight or branched chain hydrocarbon group, C 2 -C 6 straight or branched chain hydrocarbon group with substituted benzene or substituted heterocyclic ring; C0 2 R 7 , C0NR 13 R 14 , CSNR 13 R "or C (NH) NR 13 R 14 ; d—C 3 halogenated straight or branched alkyl; C ′′ C 6 alkenyl; C ′′ C 6 alkynyl or
  • R 13 and R are H; dC 4 straight or branched alkyl; d-Cs alkoxy substituted C 2 -C 4 straight or branched alkyl; or hydroxy substituted C 2 -C 4 straight Chain or branched alkyl; or with it
  • the nitrogen atoms connected to them together form a pyrrolinyl (keto) group, a piperidinyl group, and a morphinyl group.
  • Another aspect of the present invention relates to a method for preparing a compound of the general formula I described above and to an intermediate used.
  • R l R 2 , R 3 and R 4 are as defined above
  • R. R 2 , R 3 and R 4 have the same definitions as above,
  • R 1 , R 2 , R 3 and R 4 have the same definitions as above,
  • This rearrangement can be performed in organic or non-aqueous non-aqueous or aqueous solvents, and the reaction temperature ranges from room temperature to 160.
  • chlorotrialkylsilane and ditrialkylsilaneamine are used as silanization and dehydration reagents or mixed alone, preferably trimethylchlorosilane and bistrimethylsilylamine are used in an equimolar mixture;
  • R, R 2 and R 3 have the same definitions as above, and react with chlorosulfonic acid to obtain compound IA:
  • the reaction process is generally adding compound IB to excess chlorosulfonic acid for heating.
  • the reaction can also be performed in dichloromethane, chloroform and other inert or polar aprotic solvents, especially when the reactants are soluble in chlorosulfonic acid. When not good, these solvents are more important.
  • the reaction temperature can be raised up to 100. C without obvious by-products, but usually in a water bath,
  • R 1 , R 2 , R 3 and R 4 have the same definitions as above,
  • This acylation reaction can be performed in dichloromethane, chloroform, tertiary amines, and other inert or polar aprotic solvents at reaction temperatures from -78. C to 100 ° C. Equal or excess amines can be used. Excess amine is both reactant and solvent.
  • a compound of formula I is reacted with a pharmaceutically acceptable acid to convert it to its corresponding salt.
  • the intermediate IDs and IEs mentioned above can also be prepared according to literature methods. Even though ethyl cyanoacetate (1) reacts with sodium nitrite in an acidic aqueous solution to give oxime ethyl cyanoacetate (2) (Parker, C. 0; Tetrahedron, 1962, 17, 109-116), ethyl oxime cyanoacetate can Reduced to ethyl cyanocyanate and acylated with acid anhydride (CO) 2 0 without separation (Wilson et al; J.
  • compositions for treating erectile dysfunction in a male animal including a human contains a compound of general formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable diluents, excipients or carriers.
  • the invention also relates to a method for preparing a pharmaceutical composition for treating or preventing erectile dysfunction in male animals including humans, which comprises combining a compound of the general formula I or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable diluent, Formulations or carriers are formulated together.
  • the compounds of the present invention are primarily designed to treat erectile dysfunction or male sexual dysfunction, they can also be used to treat female sexual dysfunction, including those with clitoral disorders Orgasmic dysfunction related to sexual desire.
  • another aspect of the present invention relates to the use of a compound of general formula I for the manufacture of a medicament for the treatment or prevention of erectile dysfunction in male animals, including humans, and diseases related to phospholipase 5 function.
  • the above diseases related to phospholipase 5 function include: male sexual dysfunction (erection), female sexual dysfunction, premature birth, dysmenorrhea, benign prostatic hyperplasia, bladder obstruction, incontinence, regular or irregular angina pectoris, hypertension, pulmonary hypertension, congestion Heart failure, Arteriosclerosis, Stroke, Peripheral circulatory system disease, Decreased vascular openness, Chronic asthma, Allergic asthma, Bronchitis, Allergic rhinitis, Glaucoma, Gastrointestinal disorders, Preconvulsions, Kawasaki Syndrome, Nitrate resistance Severe, multiple sclerosis, diabetic peripheral neurological syndrome, Alzheimer's disease, acute respiratory failure, psoriasis, cutaneous gangrene, cancer cell metastasis, hair loss, anal fissure, and hypoxic vasoconstriction.
  • DC 3 R 1 is a straight-chain or branched-chain alkyl group; which may be optionally substituted with a group selected from the group consisting of one or more substituted: 004 Canton alkyl, d- alkoxy, dC 4 alkyl group, a substituted phenyl Group, substituted heterocyclic ring, C0NR ⁇ , NR 5 R 6 ;
  • Substituted phenyl means that the phenyl is substituted by one or more dC 4 alkoxy, halogen, cyano, CF 3 , 0CF 3 , dC 4 straight or branched alkyl groups; substituted heterocycles include one or two Six-membered ring of nitrogen atom and its nitrogen oxide; five-membered ring containing two or three nitrogen, oxygen and sulfur atoms; the substituents on the heterocyclic ring are dC 4 straight or branched chain alkyl, C 4 c 4 alkyl Oxygen, amino, and c "c 4 linear or branched alkylamino, dC 4 alkoxyamino;
  • R 2 is H; C "C 4 linear or branched i group, and may be substituted by C 3 -C 6 cycloalkyl, dC 4 alkoxy; C 2 -C 4 alkenyl; C 2 -C 4 block base;
  • R 3 is H, dC 4 straight or branched alkyl, and may be substituted by C 3 -C 6 cycloalkyl, dC 3 alkoxy; c "c 4 alkenyl; c 2 -c 4 alkynyl;
  • R 4 is H dd straight or branched alkyl, and may be optionally substituted with 0H, NR 5 R 6 , CN, CONR 5 R 6 or C0 2 R 7 ; NR 5 R 6 optionally substituted (C 2 -C 3 alkoxy) d- C 2 straight or branched chain alkyl; NR 5 R 6 ; NHS0 2 NR 5 R 6 ; NHS0 2 R 8 ; S0 2 NR 9 R 1 () or optionally Methyl-substituted phenyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, thiazolyl, thienyl, or triazolyl;
  • R 5 and R 6 are H or d- C 4 straight or branched alkyl, respectively, or together with the nitrogen atom to which they are attached, form pyrrolinyl, piperidinyl, morpholinyl, 4-N (R 11 ) -Piperazinyl or imidazolyl, said groups may optionally be substituted by methyl and hydroxy;
  • R 7 is H or C, C 4 straight or branched alkyl
  • R 8 is an optionally substituted d-C 3 alkyl group of NR 5 R 6 ;
  • R 9 and R 1D are H or dC 12 straight or branched alkyl; d-Cs halogenated straight or branched alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl; or together form a pyrrolinyl (ketone) group, piperidinyl, morpholinyl, 4-N (R 12 ) -piperazinyl; or a nitrogen atom connected to them to form a pyrrolinyl (ketone ) Group, piperazine, morpholinyl group, 4-N (R 12 ) -piperazinyl group; these groups can be optionally OH, CN, C0 2 R 7 , C-C 4 linear or branched alkyl, d -C 3 alkoxy, NR 13 R 14 , CONR 13 R 14 substitution; substituted phenyl, substituted heterocycle, or Cr-Ce straight or branched pit group substitute
  • R 11 is H; dC 6 straight or branched alkyl, and may be optionally substituted with phenyl, hydroxy-substituted C 2 -C 3 alkyl or dC 4 alkoxy; C 2 -C 6 alkenyl Or C 3 -C 6 cycloalkyl;
  • R 12 is H; dC 6 straight or branched alkyl; dC 3 alkoxy substituted C 2 -C 6 straight or branched alkyl; hydroxy substituted C 2 -C fi straight or branched alkyl ; NR 13 R "substituted C 2 -C 6 straight or branched alkyl; phenyl substituted C" C 3 straight or branched alkyl; C0NR 13 R "substituted d- straight or branched alkyl C0 2 R 7 , C0NR 13 R 14 , CSNR 13 R 14 or C (NH) NR 13 R 14 ; dC 3 halogen Substituted straight or branched chain alkyl; C 2 -C 6 alkenyl; 2-06, or alkynyl group. 3 -0 6 cycloalkyl;
  • R 1 is a C 2 -C 3 straight or branched alkyl group; it may be optionally substituted one or more by a group selected from: a substituted heterocyclic ring, NR 5 R 6 ;
  • Substituted phenyl means that phenyl is substituted by one or more d-alkoxy, halogen, cyano, CF 3 , 0CF 3 , C, C 4 or C 4 linear or branched alkyl groups;
  • R 2 is a C 2 -C 4 straight or branched alkyl group, and may be substituted by C 3 -C 4 cycloalkyl; C 2 -C 4 alkenyl; C "C 4 alkynyl;
  • R 3 is a C 2 -C 4 linear or branched alkyl group, and may be substituted by d- C 3 alkoxy; C "C 4 chain amidino;
  • R 4 is S0 2 NR 9 R 10 ;
  • R 5 and R fi together with the nitrogen atom to which they are attached form a pyrrolinyl, piperidinyl, morpholinyl;
  • R 7 is H or d-C 4 straight or branched alkyl;
  • R 9 and R lfl are H or d-Cu straight or branched alkyl; C 3 -C 6 cycloalkyl; or together form a pyrrolinyl (keto) group, piperidinyl, morpholinyl, 4- N (R 12 ) -piperazinyl; or and The attached nitrogen source forms a pyrrolinyl (ketone) group, a piperidinyl group, a morpholinyl group, a 4-N (R 12 ) -piperazinyl group; these groups can be arbitrarily linear or branched by 0H, d-C 4 Alkyl, dC 3 alkoxy, NR 13 R ", CONR 13 R"substituted; substituted phenyl, substituted heterocyclic, or dC 6 straight or branched pit substituted with substituted phenyl, substituted heterocyclic, these The group may be further substituted with 0H, C0 2 R 7 , NR 13 R "
  • R 12 is H; C wide C 3 straight or branched alkyl; C "C 3 alkoxy substituted C” C 3 straight or branched alkyl; hydroxy substituted C 2 -C 3 straight or branched alkyl; NR 13 R 14 substituted C 2 - 0 6 linear or branched alkyl; phenyl-substituted C 2 -C 3 straight or branched alkyl; wide CONR 13 R 14 substituted C C 6 Linear or branched alkyl; C0 2 R 7 , CONR 13 R 14 ;
  • R 13 and R 14 are H; C "C 4 straight or branched alkyl; dC 3 alkoxy substituted C 2 -C 4 straight or branched alkyl; or hydroxyl substituted C 2 -C 4 Linear or branched alkyl groups; or together with the nitrogen atom to which they are attached, form a pyrrolinyl (keto) group, piperidinyl, morpholinyl group.
  • keto pyrrolinyl
  • the compounds having one or more asymmetric centers in the present invention may have optical or epimers, which can be resolved by classical methods such as kinetic crystallization and chromatography. They can also be prepared by asymmetric synthesis of chiral materials and reagents. All these optical or epimers and their mixtures are within the scope of the present invention.
  • the compounds of the present invention can be used with inorganic or organic acids (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, gluconic acid, lactic acid, maleic acid, fumaric acid, methanesulfonic acid, glycolic acid, succinic acid , P-toluenesulfonic acid, galacturonic acid, glutamic acid, aspartic acid, etc.) and pharmaceutically acceptable salts with inorganic or organic bases, all these salts and their mixtures are in the present Within the scope of invention protection.
  • inorganic or organic acids hydroochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, gluconic acid, lactic acid, maleic acid, fumaric acid, methanesulfonic acid, glycolic acid, succinic acid , P-toluenesulfonic acid, galacturonic acid, glut
  • the active compounds of the general formula I can be prepared as solid oral preparations, such as tablets, pills, capsules, and powders; or liquid oral preparations, such as suspensions, solubilizers, emulsions, and syrups. These preparations may contain various conventional excipients, such as wetting agents, sweeteners, and fragrances. And preservatives. These preparations can also contain conventional functional excipients, such as fillers (starch, sugars), binders (carboxymethyl cellulose, etc.), dispersants (sodium carbonate, calcium, etc.), diluents (glycerin) , Absorption enhancers (quaternary ammonium compounds), lubricants (stearate) and absorbents (kaolin).
  • the active compound of the general formula I can also be formulated into a plaster for external use or a dosage form suitable for intravenous injection.
  • oral administration of the compound of the present invention is the preferred route of administration, as this route is the most convenient and avoids the inconvenience encountered during administration in the penile sponge.
  • the drug can be absorbed parenterally, such as sublingually, buccally, transdermally, or by injection.
  • the compound of formula I or its non-toxic salt is administered in a suitable and acceptable formulation in accordance with general veterinary practice, and the veterinary surgeon will determine the dosage range and route of administration that are most suitable for the particular male animal.
  • Example 1 2- [2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] -6-fluorenyl-8-n-propylimidazole [1, 5-a] Preparation of [1,3,5] triazine-4 (31-one (9)).
  • Ethyl cyanoacetate (33.9 g, 300 ng) was suspended in a solution of sodium nitrite (19.5 g, 283 mmol) in water (240 ml). Under vigorous stirring, keep it at 35-40 ° C for 30 minutes, and add 85% phosphoric acid dropwise around pH 4.5. The reaction solution is at 30. Continue stirring at C for one hour. 25 ml of concentrated hydrochloric acid was added to the reaction solution, and the temperature was raised to 50 ° C. C, then slowly drop to 10. C. The precipitate was collected by filtration and dried under vacuum. The filtrate was extracted with 50 ml of ether, and a part of the product was recovered. A total of 35 g was obtained with a yield of 82%.
  • Ethyl oxime cyanoacetate (2) (14.2 g, 100 legs ol) obtained in Preparation 1 was dissolved in acetic anhydride (28.4 ml, 300 mmol) and acetic acid (100 ml). Zinc powder (4.5 g) was added thereto, and the reaction was stirred at room temperature for 20 hours. After filtering off the powder, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 8. 0 g of white crystals in a yield of 47%.
  • the reaction was started from 2-ethoxy-5- (n-propylamine-1-transacyl) phenylhydrazone (IE) and 2-acetamido-2-ethyl cyano-n-valerate (ID) to obtain the title compound.
  • IE 2-ethoxy-5- (n-propylamine-1-transacyl) phenylhydrazone
  • ID 2-acetamido-2-ethyl cyano-n-valerate
  • the reaction starts from 2-ethoxyphenylhydrazone (IE) and 2- (pyrimidine-2) acetamido-2-ethyl cyano-n-valerate (ID), and 4-ethyl is obtained through the corresponding intermediates IC and IB Oxy-3-(6- (pyrimidine-2) methyl-4-oxo-8-n-propyl-311-imidazole [1,5] -1,3,5-triazin-2-yl) acyl chloride ( IA), and then reacted with 1-ethylpiperazine to give the title compound.

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Abstract

L'invention se rapporte à des composés représentés par la formule (I), à leur préparation et aux compositions pharmaceutiques contenant ces composés. Cette invention a également trait à l'utilisation des composés de la formule (I) dans la préparation de médicaments pouvant inhiber l'enzyme cGMP PDE5 et pouvant notamment traiter ou prévenir les dysfonctionnements sexuels d'animaux dont les humains.
PCT/CN2004/000488 2003-05-16 2004-05-14 Derives de 2-phenyl substitue -6,8-dialkyl-3h-imidazole [1,5a] [1,3,5] triazine-4- one, preparation et utilisation pharmaceutique associees WO2004101567A1 (fr)

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CNA031314996A CN1548438A (zh) 2003-05-16 2003-05-16 2-取代苯基-6,8-二烃基-3H-咪唑[1,5α][1,3,5]三嗪-4-酮衍生物,其制备方法及其药物用途
CN03131499.6 2003-05-16

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Cited By (3)

* Cited by examiner, † Cited by third party
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WO2010066111A1 (fr) 2008-12-10 2010-06-17 上海特化医药科技有限公司 Composés de phénylpyrimidone, compositions pharmaceutiques, leurs procédés de préparation et leurs utilisations
WO2014131855A1 (fr) * 2013-03-01 2014-09-04 Fundación Para La Investigación Médica Aplicada Nouveaux composés comme inhibiteurs double de phosphodiestérases et d'histones déacétylases
CN112961160A (zh) * 2021-03-05 2021-06-15 遂成药业股份有限公司 一种西地那非的改良合成工艺

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CN101456862B (zh) * 2007-12-12 2012-10-24 上海特化医药科技有限公司 含有吡唑并嘧啶酮的苯基胍衍生物、其药物组合物及其制备方法和用途
CN104059074A (zh) * 2014-06-05 2014-09-24 辽宁好护士药业（集团）有限责任公司 一种伐地那非的制备方法
CN106749035A (zh) * 2016-12-09 2017-05-31 辽宁石油化工大学 一种紫外线吸收化合物的制备方法

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WO2001047928A2 (fr) * 1999-12-24 2001-07-05 Bayer Aktiengesellschaft Nouveaux imidazo[1,3,5]triazinones et leur utilisation
WO2003101456A1 (fr) * 2002-06-03 2003-12-11 Bayer Healthcare Ag Utilisation de composes stimulant le gmp cyclique

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WO2010066111A1 (fr) 2008-12-10 2010-06-17 上海特化医药科技有限公司 Composés de phénylpyrimidone, compositions pharmaceutiques, leurs procédés de préparation et leurs utilisations
JP2012511517A (ja) * 2008-12-10 2012-05-24 上海特化医薬科技有限公司 フェニルピリミドン骨格を有する化合物、その薬剤組成物、その製造方法及び用途
US8871777B2 (en) 2008-12-10 2014-10-28 Topharman Shanghai Co., Ltd. Phenylpyrimidone compounds, the pharmaceutical compositions, preparation methods and uses thereof
WO2014131855A1 (fr) * 2013-03-01 2014-09-04 Fundación Para La Investigación Médica Aplicada Nouveaux composés comme inhibiteurs double de phosphodiestérases et d'histones déacétylases
US9573956B2 (en) 2013-03-01 2017-02-21 Fundación Para La Investigación Médica Aplicada Compounds as dual inhibitors of phosphodiesterases and histone deacetylases
CN112961160A (zh) * 2021-03-05 2021-06-15 遂成药业股份有限公司 一种西地那非的改良合成工艺

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