CN1548438A

CN1548438A - 2-substituted phenyl-6, 8-dialkyl-3H-imidazole [1,5 alpha ] [1,3,5] triazine-4-one derivative, preparation method and pharmaceutical application thereof

Info

Publication number: CN1548438A
Application number: CNA031314996A
Authority: CN
Inventors: 王永峰; 赵柯君; 刘柯
Original assignee: BEIFANG INST OF PHARMACOLOGY Y; Tianjin Tasly Group Co Ltd
Current assignee: BEIFANG INST OF PHARMACOLOGY Y; Tianjin Tasly Group Co Ltd
Priority date: 2003-05-16
Filing date: 2003-05-16
Publication date: 2004-11-24
Also published as: WO2004101567A1

Abstract

The present invention relates to compounds of general formula , a process for their preparation and pharmaceutical compositions containing them. The invention also relates to the use of the compounds of the general formula I for the preparation of a medicament for the inhibition of the cGMP PDE5 enzyme, in particular for the treatment or prevention of sexual dysfunction in animals, including humans.

Description

2-substituted phenyl-6, 8-dialkyl-3H-imidazole [1, 5a ] [1, 3, 5] triazine-4-one derivative, preparation method and pharmaceutical application thereof

Technical Field

The invention relates to 2-substituted phenyl-6, 8-dialkyl-3H-imidazole [1, 5-a ] [1, 3, 5] triazine-4-one derivatives and pharmaceutically acceptable salts thereof, a preparation method thereof, a pharmaceutical composition containing the same, and application thereof in preventing and/or treating sexual dysfunction and other diseases related to phospholipase 5 (cGMPED 5) function.

Background

Sildenafil (WO9428902)) is the first oral phospholipase 5 inhibitor to treat male erectile dysfunction. It enhances penile engorgement and erection by inhibiting phospholipase 5 in the cavernous tissue of the penis to relax smooth muscle. Sildenafil is 80% effective in male erectile dysfunction.

Pfizer ltd. a number of other 1, 6-dihydro-pyrrolo [4, 3-d ] pyrimidin-7-one derivatives were also developed and expanded their therapeutic range to other indications treatable by inhibition of phospholipase 5. These compounds are described in EP0951098, WO9849116, US6251904 and WO0024745, the latter two patents including compounds in which a substituted phenyl group of C-5 is replaced by a substituted pyridin-2-yl group. Korean DONG a PHARM co.ltd. developed derivatives mono-substituted on sulfonamide nitrogen based on sildenafil structure (WO0027848 and WO 0198304). Derivatives of these 1, 6-dihydro-pyrrolo [4, 3-d ] pyrimidin-7-ones with polyethylene glycol, which were further developed to improve their water solubility, were recently described in WO 0216364. 1, 5-dihydropyrrolo [3, 4-d ] pyrimidin-4-one and 1, 9-dihydropurin-6-one compounds are also therapeutic agents for sexual dysfunction developed by Pfizer Ltd (US 6100270). The 3, 5-dihydropyrrolo [3, 2-d ] pyrimidin-4-ones listed in WO 0160825 are useful for the treatment of impotence. Bayer co.ltd. more recently 3H-imidazo [5, 1-f ] [1, 2, 4] triazin-4-one compounds have been disclosed (DE 19881732).

Disclosure of Invention

The invention aims to provide a compound with the function of treating sexual dysfunction and other diseases related to the function of phospholipase 5 and a preparation method thereof.

Accordingly, one aspect of the present invention relates to 2-substituted phenyl-6, 8-dihydrocarbyl-3H-imidazo [1, 5-a ] [1, 3, 5] triazin-4-one derivatives (wanzaneafil) having the general formula I:

wherein:

R¹is H; c₁-C₄A linear or branched alkyl group; c₁-C₄A halogenated linear or branched alkyl group; c₂-C₄An alkenyl group; c₂-C₄An alkynyl group; pyridyl, pyrimidinyl, imidazolyl; optionally mono-or polysubstituted in addition to H by a group selected from: halogen, cyano, nitro, hydroxy, carboxy, guanidino, C₁-C₄Alkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkanoyl radical, C₃-C₅Cycloalkyl, substituted phenyl, substituted heterocycle, CONR⁵R⁶、NR⁵R⁶、CO₂R⁷、NHSO₂R⁸、SO₂NR⁹R¹⁰；

Substituted phenyl means phenyl substituted by one or more C₁-C₄Alkoxy, halogen, cyano, CF₃、OCF₃、C₁-C₄Linear or branched alkyl substitution; substituted heterocycles include six-membered rings containing one or two nitrogen atoms and their nitroxides; a five-membered ring containing two or three nitrogen, oxygen, sulfur atoms; the substituents on the heterocyclic ring being C₁-C₄Straight or branched alkyl, C₁-C₄Alkoxy, amino and C₁-C₄Straight-chain or branched alkylamino, C₁-C₄An alkoxyamino group;

R²is H; c₁-C₆Straight or branched chain alkyl, and may be substituted by C₃-C₆Cycloalkyl radical, C₁-C₄Alkoxy substitution; c₂-C₄An alkenyl group; c₂-C₄An alkynyl group;

R³is H, C₁-C₆Straight or branched chain alkyl, and may be substituted by C₃-C₆Cycloalkyl radical, C₁-C₄Alkoxy substitution; c₂-C₄An alkenyl group; c₂-C₄An alkynyl group;

R⁴is H, C₁-C₄Straight or branched chain alkyl, and optionally substituted by OH, NR⁵R⁶，CN，CONR⁵R⁶Or CO₂R⁷Substitution; c₂-C₄Alkenyl, and optionally substituted by CN, CONR⁵R⁶Or CO₂R⁷Substitution; NR (nitrogen to noise ratio)⁵R⁶Optionally substituted C₂-C₄An alkoxy group; OH or NR⁵R⁶Optionally substituted (C)₂-C₃Alkoxy) C₁-C₂A linear or branched alkyl group; CONR⁵R⁶(ii) a Halogen; NR (nitrogen to noise ratio)⁵R⁶；NHSO₂NR⁵R⁶；NHSO₂R⁸；SO₂NR⁹R¹⁰Or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl optionally substituted by methyl;

R⁵and R⁶Are each H or C₁-C₄Straight or branched chain alkyl, or together with the nitrogen atom to which they are attached form pyrrolinyl, piperidinyl, morpholinyl, 4-N (R)¹¹) -piperazinyl or imidazolyl, which groups may optionally be substituted by C₁-C₄Alkyl and hydroxy substitution;

R⁷is H or C₁-C₆Straight or branched alkyl, which may be C₁-C₄Alkoxy radical, C₁-C₄Alkylamino and dialkylamino substitution; substituted phenyl, substituted heterocycle; wherein the substituents on the substituted phenyl and the substituted heterocycle are as described above;

R⁸is NR⁵R⁶Optionally substituted C₁-C₃An alkyl group;

R⁹and R¹⁰Are each H or C₁-C₁₂A linear or branched alkyl group; c₁-C₄A halogenated linear or branched alkyl group; c₂-C₆An alkenyl group; c₂-C₆Alkynyl or C₃-C₆A cycloalkyl group; or together form pyrrolinyl (keto), piperidyl, morpholinyl, 4-N (R)¹²) -a piperazinyl group; or together with the nitrogen atom to which they are attached to form pyrrolinyl (keto) yl, piperidinyl, morpholinyl, 4-N (R)¹²) -a piperazinyl group; these groups may optionally be substituted by OH, CN, CO₂R⁷、C₁-C₄Straight or branched alkyl, C₁-C₃Alkoxy radicals, NR¹³R¹⁴、CONR¹³R¹⁴Substitution; substituted phenyl, substituted heterocycle, or C substituted by substituted phenyl, substituted heterocycle₁-C₆Straight or branched chain alkyl groups, which groups may be substituted by OH, CO₂R⁷、NR¹³R¹⁴、CONR¹³R¹⁴Further substituted or connected with another substituted phenyl or substituted heterocycle by carbonyl; wherein the substituents on the substituted phenyl and the substituted heterocycle are as described above;

R¹¹is H; c₁-C₆C being straight-chain or branched alkyl and optionally substituted by phenyl, hydroxy₂-C₃Alkyl or C₁-C₄Alkoxy substitution; c₁-C₃A haloalkyl group; c₂-C₆An alkenyl group; c₂-C₆Alkynyl or C₃-C₆A cycloalkyl group;

R¹²is H; c₁-C₆A linear or branched alkyl group; c₁-C₃Alkoxy-substituted C₂-C₆A linear or branched alkyl group; hydroxy-substituted C₂-C₆A linear or branched alkyl group; NR (nitrogen to noise ratio)¹³R¹⁴Substituted C₂-C₆A linear or branched alkyl group; phenyl-substituted C₂-C₃A linear or branched alkyl group; CONR¹³R¹⁴Substituted C₁-C₆A linear or branched alkyl group; CO 2₂R⁷Substituted C₂-C₆Straight or branched chain hydrocarbon radical, C with substituted benzene or substituted heterocycle₂-C₆A straight or branched chain hydrocarbon group; CO 2₂R⁷，CONR¹³R¹⁴，CSNR¹³R¹⁴Or C (NH) NR¹³R¹⁴；C₁-C₃A halogenated linear or branched alkyl group; c₂-C₆An alkenyl group; c₂-C₆Alkynyl or C₃-C₆A cycloalkyl group; polyethylene glycol (n-2-20) group, which may be optionally substituted with C₁-C₆Alkyl terminal substitution;

R¹³and R¹⁴Are respectively H; c₁-C₄A linear or branched alkyl group; c₁-C₃Alkoxy-substituted C₂-C₄A linear or branched alkyl group; or hydroxy-substituted C₂-C₄A linear or branched alkyl group; or together with the nitrogen atom to which they are attached form pyrrolinyl, piperidinyl, morpholinyl.

In another aspect the invention relates to a process for the preparation of the compounds of formula I above and to intermediates used therein.

The following preparations describe the general preparation of the compounds of the invention and the intermediates used:

the condensation of the intermediate ID and IE compounds was carried out according to literature procedures (Parker, C.O.; Tetrahedron, 1962, 17, 109-116, Albertson; J.Amer.chem.Soc., 1946, 68, 453, Albertson):

wherein R is₁，R₂，R₃And R₄The definition of (A) is the same as that of (B),

intermediate IC compounds can be obtained:

wherein R is¹，R²，R³And R⁴The definition of (A) is the same as that of (B),

the intermediate IC compound is then subjected to a rearrangement reaction to give a compound of general formula I:

this rearrangement reaction can be carried out in an organic or inorganic basic nonaqueous or aqueous solvent at a temperature of from room temperature to 160 ℃; chlorotrialkylsilane and ditrialkylsilane amine are used as silanization and dehydration reagent, or are used independently, and trimethylchlorosilane and ditrimethylsilyl amine are preferably used in equimolar mixture;

in which R is a special case of the formula I⁴Is SO₂NR¹⁰R¹¹The compounds of formula I can be prepared by the following process:

reacting IB compound (R)₄Compounds of general formula I ═ H):

wherein R is₁、R₂And R₃As defined above, with chlorosulfonic acid to give compound IA:

wherein R is₁，R₂And R₃Is as defined inIn the above-mentioned manner,

the reaction is generally carried out by adding compound IB to an excess of chlorosulfonic acid and heating, and may also be carried out in methylene chloride, chloroform and other inert or polar aprotic solvents, which are particularly important when the reactants are not well soluble in chlorosulfonic acid. The reaction temperature can be raised to up to 100 c without significant by-products, but is usually carried out in an ice-water bath,

then subjecting the corresponding sulfonyl chloride compound IA to acylation reaction with an appropriate amine to prepare the compound wherein R⁴Is SO₂NR¹⁰R¹¹A compound of the general formula I:

this acylation reaction can be carried out in dichloromethane, chloroform, tertiary amines and other inert or polar aprotic solvents at temperatures from-78 ℃ to 100 ℃. An equal or excess amount of amine may be used. The excess amine is both a reactant and a solvent.

Optionally, the compound of formula I is converted to its corresponding salt by reacting it with a pharmaceutically acceptable acid.

The intermediates ID and IE referred to above can likewise be prepared according to literature procedures. Even if ethyl cyanoacetate (1) is reacted with sodium nitrite in an acidic aqueous solution to give oxime ethyl cyanoacetate (2) (Parker, C.O; Tetrahedron, 1962, 17, 109-¹CO)₂Acylation of O (Wilson et al; J. chem, Soc, 1948, 1157), and isolation and reuse (R)¹CO)₂O or acyl chloride R¹Acylation of COCl (Caille J.C.et al; Synthesis, 1995, 635-); the resulting amido cyanoacetic acid ethyl ester (3) is halogenated with a hydrocarbon compound R²X(X＝Cl，Br orI) Alkylation (Holtwick, J.B; chem.1979, 44, 3835-3839) to obtain ID (4). Intermediate IE (5) can be prepared from the corresponding substituted benzonitrile with ammonium chloride and trimethylaluminum (Garigippiti, R.S.; Tetrahedron Lett, 1990, 31, 1969-.

Another aspect of the invention relates to a pharmaceutical composition for the treatment of erectile dysfunction in male animals including humans. The composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable diluents, excipients or carriers.

The invention also relates to a process for the preparation of a pharmaceutical composition for the treatment or prophylaxis of erectile dysfunction in male animals including humans, which comprises formulating a compound of formula I or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable diluent, excipient or carrier.

While the compounds of the present invention are primarily designed to treat erectile dysfunction or male sexual dysfunction, they may also be used to treat female sexual dysfunction, including orgasmic dysfunction associated with clitoral disorders.

Therefore, another aspect of the present invention relates to the use of a compound of formula I for the preparation of a medicament for the treatment or prevention of erectile dysfunction and diseases related to phospholipase 5 function in male animals including humans.

The diseases related to the function of the phospholipase 5 comprise: male sexual dysfunction (erectile) disorder, female sexual dysfunction, premature labor, dysmenorrhea, benign prostatic hyperplasia, bladder obstruction, incontinence, regular or irregular angina, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, stroke, peripheral circulatory system diseases, reduced vascular patency, chronic asthma, allergic asthma, bronchitis, allergic rhinitis, glaucoma, gastrointestinal motility disorders, pre-eclampsia, kawasaki syndrome, nitrate tolerance, multiple sclerosis, diabetic peripheral nerve syndrome, alzheimer's disease, acute respiratory failure, psoriasis, skin gangrene, cancer cell metastasis, hair loss, anal fissure, and hypoxic vasoconstriction.

In a preferred embodiment the invention relates to compounds of general formula I and pharmaceutically acceptable salts thereof:

wherein,

R¹is C₁-C₃A linear or branched alkyl group; which may be optionally mono-or polysubstituted with a group selected from: c₁-C₄Alkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkanoyl, substituted phenyl, substituted heterocycle, CONR⁵R⁶、NR⁵R⁶；

R²is H; c₂-C₄Straight or branched chain alkyl, and may be substituted by C₃-C₆Cycloalkyl radical, C₁-C₄Alkoxy substitution; c₂-C₄An alkenyl group; c₂-C₄An alkynyl group;

R³is H, C₁-C₄Straight or branched chain alkyl, and may be substituted by C₃-C₆Cycloalkyl radical, C₁-C₃Alkoxy substitution; c₂-C₄An alkenyl group; c₂-C₄An alkynyl group;

R⁴is H, C₁-C₄Straight or branched chain alkyl, and optionally substituted by OH, NR⁵R⁶，CN，CONR⁵R⁶Or CO₂R⁷Substitution; NR (nitrogen to noise ratio)⁵R⁶Optionally substituted (C)₂-C₃Alkoxy) C₁-C₂A linear or branched alkyl group; NR (nitrogen to noise ratio)⁵R⁶；NHSO₂NR⁵R⁶；NHSO₂R⁸；SO₂NR⁹R¹⁰Or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl optionally substituted by methyl;

R⁵and R⁶Are each H or C₁-C₄Straight or branched chain alkyl, or together with the nitrogen atom to which they are attached form pyrrolinyl, piperidinyl, morpholinyl, 4-N (R)¹¹) -piperazinyl or imidazolyl, which groups may be optionally substituted by methyl and hydroxy;

R⁷is H or C₁-C₄A linear or branched alkyl group;

R⁸is NR⁵R⁶Optionally substituted C₁-C₃An alkyl group;

R⁹and R¹⁰Are each H or C₁-C₁₂A linear or branched alkyl group; c₁-C₃A halogenated linear or branched alkyl group; c₂-C₆An alkenyl group; c₂-C₆Alkynyl or C₃-C₆A cycloalkyl group; or together form pyrrolinyl (keto), piperidyl, morpholinyl, 4-N (R)¹²) -a piperazinyl group; or together with the nitrogen atom to which they are attached to form pyrrolinyl (keto) yl, piperidinyl, morpholinyl, 4-N (R)¹²) -a piperazinyl group; these groups may optionally be substituted by OH, CN, CO₂R⁷、C₁-C₄Straight or branched alkyl, C₁-C₃Alkoxy radicals, NR¹³R¹⁴、CONR¹³R¹⁴Substitution; substituted phenyl, substituted heterocycle, or C substituted by substituted phenyl, substituted heterocycle₁-C₆Straight or branched chainAlkyl, these radicals being optionally substituted by OH, CO₂R⁷、NR¹³R¹⁴、CONR¹³R¹⁴Further substituted or connected with another substituted phenyl or substituted heterocycle by carbonyl; wherein the substituents on the substituted phenyl and the substituted heterocycle are as described above;

R¹¹is H; c₁-C₆C being straight-chain or branched alkyl and optionally substituted by phenyl, hydroxy₂-C₃Alkyl or C₁-C₄Alkoxy substitution; c₂-C₆Alkenyl or C₃-C₆A cycloalkyl group;

R¹²is H; c₁-C₆A linear or branched alkyl group; c₁-C₃Alkoxy-substituted C₂-C₆A linear or branched alkyl group; hydroxy-substituted C₂-C₆A linear or branched alkyl group; NR (nitrogen to noise ratio)¹³R¹⁴Substituted C₂-C₆A linear or branched alkyl group; phenyl-substituted C₂-C₃A linear or branched alkyl group; CONR¹³R¹⁴Substituted C₁-C₆A linear or branched alkyl group; CO 2₂R⁷，CONR¹³R¹⁴，CSNR¹³R¹⁴Or C (NH) NR¹³R¹⁴；C₁-C₃A halogenated linear or branched alkyl group; c₂-C₆An alkenyl group; c₂-C₆Alkynyl or C₃-C₆A cycloalkyl group;

In a more preferred embodiment the invention relates to a compound having the general formula I:

wherein,

R¹is C₂-C₃A linear or branched alkyl group; which may be optionally mono-or polysubstituted with a group selected from: substituted heterocycles, NR⁵R⁶；

Substituted phenyl means phenyl substituted by one or more C₁-C₄Alkoxy, halogen, cyano, CF₃、OCF₃、C₁-C₄Linear or branched alkyl substitution; substituted heterocycles include six-membered rings containing one or two nitrogen atoms and their nitroxides; a five-membered ring containing two or three nitrogen, oxygen, sulfur atoms; the substituents on the heterocyclic ring being C₁-C₄Straight or branched alkyl, C₁-C₄Alkoxy, amino and C₁-C₄Straight-chain or branched alkylamino, C₁-C₄An alkoxyamino group.

R²Is C₂-C₄Straight or branched chain alkyl, and may be substituted by C₃-C₄Cycloalkyl substitution; c₂-C₄An alkenyl group; c₂-C₄An alkynyl group;

R³is C₂-C₄Straight or branched chain alkyl, and may be substituted by C₁-C₃Alkoxy substitution; c₂-C₄An alkenyl group; c₂-C₄An alkynyl group;

R⁴is SO₂NR⁹R¹⁰；

R⁵And R⁶Together with the nitrogen atom to which they are attached form pyrrolinyl, piperidinyl, morpholinyl;

R⁷is H or C₁-C₄A linear or branched alkyl group;

R⁹and R¹⁰Are each H or C₁-C₁₂Straight chainOr a branched alkyl group; c₃-C₆A cycloalkyl group; or together form pyrrolinyl (keto), piperidyl, morpholinyl, 4-N (R)¹²) -a piperazinyl group; or together with the nitrogen atom to which they are attached to form pyrrolinyl (keto) yl, piperidinyl, morpholinyl, 4-N (R)¹²) -a piperazinyl group; these groups may be optionally substituted by OH, C₁-C₄Straight or branched alkyl, C₁-C₃Alkoxy radicals, NR¹³R¹⁴、CONR¹³R¹⁴Substitution; substituted phenyl, substituted heterocycle, or C substituted by substituted phenyl, substituted heterocycle₁-C₆Straight or branched chain alkyl groups, which groups may be substituted by OH, CO₂R⁷、NR¹³R¹⁴、CONR¹³R¹⁴Further substituted or connected with another substituted phenyl or substituted heterocycle by carbonyl; wherein the substituents on the substituted phenyl and the substituted heterocycle are as described above;

R¹²is H; c₁-C₃A linear or branched alkyl group; c₁-C₃Alkoxy-substituted C₂-C₃A linear or branched alkyl group; hydroxy-substituted C₂-C₃A linear or branched alkyl group; NR (nitrogen to noise ratio)¹³R¹⁴Substituted C₂-C₆A linear or branched alkyl group; phenyl-substituted C₂-C₃A linear or branched alkyl group; CONR¹³R¹⁴Substituted C₁-C₆A linear or branched alkyl group; CO 2₂R⁷，CONR¹³R¹⁴，

The following compounds are particularly preferred according to the invention:

2- [ 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] [1, 3, 5] triazin-4 (3H) -one, and mono-and bis-hydrochloride salts thereof;

2- [ 2-methoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-n-propoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1-5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-allyloxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-n-propoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-ethyl-8-n-propylimidazo [1-5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl ] -6-ethyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (4-ethoxycarbonylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (4- (2-hydroxyethyl) piperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (pyrrolidinyl-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- { 2-ethoxy-5- [3- (2-oxo-pyrrolidinyl-1) N-propylamine-N-sulfonyl ] phenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and its mono and di-hydrochloride salts;

2- { 2-ethoxy-5- [2- (pyrrolidinyl-1) ethylamine-N-sulfonyl ] phenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and its mono-and di-hydrochloride salts;

2- [ 2-ethoxy-5- (morpholino-4-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (3- (morpholino-4) N-propylamine-N-sulfonyl) phenyl ] -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and mono and bis hydrochloride salts thereof;

2- [ 2-ethoxy-5- (2- (morpholino-4) ethylamine-N-sulfonyl) phenyl ] -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (2, 6-dimethylmorpholino-N-sulfonyl) phenyl ] -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and di-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (1-benzylpiperidine-4-sulfamoyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (2- (piperidin-1-yl) ethylamine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (4-benzylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (4-phenylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (piperazine-1-sulfonyl) phenyl ] -6-methyl-8-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (4-benzo [1, 3] dioxolanylmethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- [4- (3-phenyl-n-propen-1-yl) piperidine-1-sulphonyl ] phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one. And mono-and di-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (n-propylamine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (N, N-bis (2-hydroxyethyl) aminosulfonyl) phenyl ] -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- [ 2-ethoxy-5- (N- (2-hydroxyethyl) -N-methylaminosulfonyl) phenyl ] -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- { 2-ethoxy-5- [ N- (2-hydroxyethyl) -N-ethyl ] aminosulfonylphenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and di-hydrochloride salts thereof;

2- { 2-ethoxy-5- [ N- (2-hydroxyethyl) -N-butyl ] aminosulfonylphenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and di-hydrochloride salts thereof;

2- { 2-ethoxy-5- (p-ethoxycarbonylaniline) -N-sulfonylphenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and its mono-and bis-hydrochloride salts;

2- { 2-ethoxy-5- (o-benzoylaniline) -N-sulfonylphenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and its mono-and bis-hydrochloride salts;

2- { 2-ethoxy-5- (N2-acetylhydrazino) -N-sulfonyl } phenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and di-hydrochloride salts thereof;

2- { 2-ethoxy-5- (2-dimethylaminoethylamine) -N-sulfonyl } phenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and di-hydrochloride salts thereof;

2- { 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl } -6-ethyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- { 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl } -6-morpholinomethyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- { 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl } -6- (pyrimidin-2) methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof;

2- { 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl } -6-methyl-8-allylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof

Tautomerism of the compounds of the present invention is possible and all tautomeric and other isomeric forms of the compounds of formula I and mixtures thereof are within the scope of the present invention.

Compounds of the invention in which one or more asymmetric centers are present 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 using chiral starting materials and reagents. All such optical or epimers and mixtures thereof are within the scope of the invention.

The compounds of the present invention can form pharmaceutically acceptable salts with inorganic or organic acids (hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, citric, tartaric, gluconic, lactic, maleic, fumaric, methanesulfonic, glycolic, succinic, p-toluenesulfonic, galacturonic, glutamic, aspartic, and the like) and with inorganic or organic bases, and all such salts and mixtures thereof are within the scope of the present invention.

The active compounds of formula I can be formulated into solid oral preparations such as tablets, pills, capsules and powders; it can also be made into liquid oral preparations, such as suspension, solution, emulsion and syrup. These preparations may contain conventional various excipients, such as wetting agents, sweeteners, aromatics, preservatives and the like. These preparations may also contain conventional functional excipients such as fillers (starches, saccharides), binders (carboxymethylcellulose, etc.), dispersants (sodium carbonate, calcium, etc.), diluents (glycerin), absorption promoters (quaternary ammonium compounds), lubricants (stearate salts) and absorbents (kaolin).

In addition, the active compounds of the general formula I can also be prepared into a paste for external use or a preparation suitable for intravenous injection.

In general, oral administration of the compounds of the present invention is the preferred route of administration for humans, as this route is most convenient and avoids the inconvenience encountered with administration in the corpora cavernosa. For patients with swallowing disorders or impaired drug absorption following oral administration, parenteral administration may be employed, for example, sublingually, buccally, transdermally or by injection.

For veterinary use, the compound of formula I or a non-toxic salt thereof is administered in a suitable acceptable formulation according to common veterinary practice and the veterinary practitioner will determine the dosage range and route of administration which will be most suitable for the particular male animal.

In vivo toxicity tests in rats and dogs, up to 3mg/kg of the compound of the invention injected intravenously and orally, did not show any significant signs of adverse acute toxicity. When mice are taken for in vivo toxicity test, no death occurs when the intravenous injection dosage is up to 100 mg/kg.

Detailed Description

The preparation of 2- [ 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] [1, 3, 5] triazin-4 (3H) -one and its monohydrochloride and dihydrochloride are used as examples to illustrate the preparation of the compounds of general formula I according to the invention.

Example 1: preparation of 2- [ 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] [1, 3, 5] triazin-4 (3H) -one (9).

The synthetic route is as follows:

(1) ethyl cyanoacetate;

(2) oxime ethyl cyanoacetate;

(3) acetylamino cyanoacetic acid ethyl ester;

(4) 2-acetamido-2-cyanon-pentanoic acid ethyl ester;

(5) 2-ethoxybenzamidine;

(6) 5-acetamido-6-amino-4, 5-dihydro-2- (2-ethoxyphenyl) -5-n-propylpyrimidin-4-one;

(7)2- (2-ethoxyphenyl) -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one;

(8) 4-ethoxy-3- (6-methyl-4-oxo-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride;

(9)2- [ 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one;

preparation 1. oxime cyanoacetic acid ethyl ester (2):

ethyl cyanoacetate (33.9g, 300mmol) was suspended in a solution of sodium nitrite (19.5g, 283mmol) in water (240 ml). Under vigorous stirring, the temperature is kept between 35 and 40 ℃ for 30 minutes, and 85 percent phosphoric acid is dripped into the mixture at the pH value of about 4.5. The reaction solution was further stirred at 30 ℃ for one hour. 25ml of concentrated hydrochloric acid was added to the reaction solution and the temperature was raised to 50 ℃ and then slowly decreased to-10 ℃. The precipitate was collected by filtration and dried in vacuo. The filtrate was extracted with 50ml of ether, and a part of the product was recovered, 35g in total, in 82% yield.

Melting point: 129-131 ℃ (document: 129-131 ℃)

The literature: parker, c.o.; tetrahedron, 1962, 17, 109-.

Preparation 2-Ethylacetaminocyanoacetate (3):

ethyl oxime cyanoacetate (2) (14.2g, 100mmol) prepared in preparation 1 was dissolved in acetic anhydride (28.4ml, 300mmol) and acetic acid (100 ml). Zinc powder (4.5g) was added thereto, and the reaction was stirred at room temperature for 20 hours. After filtering out zinc powder, the solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to give 8.0g of white crystals, yield 47%.

Melting point: 123-124 deg.C (literature: 129 deg.C)

The literature: wilson, j. chem. soc., 1948, 1157-1158.

Preparation of ethyl 3.2-acetamido-2-cyanon-pentanoate (4):

metallic sodium (2.3g, 100mmol) was dissolved in anhydrous ethanol (50 ml). Ethylacetaminocyanoacetate (17.0g, 100mmol) obtained in preparation 2 and n-bromopropane (10.0ml, 110mmol) were added thereto, and the mixture was stirred under heating and refluxing for 3 hours. After a little cooling, the mixture was diluted with 150ml of water, and 13.6g of crystals were collected by filtration in a yield of 64%.

Melting point: 118 + 119 ℃ (118 ℃ in the literature)

The literature: albertson; j.amer.chem.soc., 1946, 68, 453.

Preparation of 4.2-ethoxybenzamidine hydrochloride (5):

ammonia chloride (145mg, 2.72mmol) was dissolved in ice-cold toluene, to which was slowly added a trimethylaluminum n-hexane solution (2M, 1.36ml, 2.72 mmol). The mixture was stirred at room temperature for two hours, then warmed to 80 ℃ and 1-cyano-2-ethoxybenzene (200mg, 136mmol) was added thereto, and the reaction mixture was stirred at 80 ℃ for two days. The reaction was slowly poured into a suspension of silica gel (5g) in chloroform (100 ml). The silica gel was filtered off and washed with methanol-water 1: 1. The filtrate was evaporated to dryness, extracted with dichloromethane and 5% sodium hydroxide solution, the organic layer was dried over anhydrous sodium sulfate, evaporated to dryness to obtain a white solid product.

Preparation of 5.5-acetamido-6-amino-4, 5-dihydro-2- (2-ethoxyphenyl) -5-n-propylpyrimidin-4-one (compound 6):

metallic sodium (0.23g, 10mmol) was dissolved in absolute ethanol (5ml), 2-ethoxybenzamidine hydrochloride (5) (1.00g, 5.00mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. After addition of ethyl 2-acetamido-2-cyano-n-propionate (4) obtained in preparation 3 (1.06g, 5.00mmol), the mixture was stirred under reflux for 20 min and adjusted to pH 5.5 with acetic acid. The mixture was evaporated to dryness and extracted with dichloromethane (20ml) and filtered. The filtrate is evaporated to dryness to obtain a crude product which can be directly put into the next reaction.

Preparation 6.2- (2-ethoxyphenyl) -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one (7):

5-acetamido-6-amino-4, 5-dihydro-2- (2-ethoxyphenyl) -5-n-propylpyrimidin-4-one (6) obtained in preparation 5 was mixed with triethylamine (20ml) and chlorotrimethylsilane (1.26ml, 10mmol), and stirred at room temperature for 30 minutes. After hexamethyldisilane (2.09ml, 10mmol) was added thereto, the reaction mixture was heated under stirring at reflux for 10 minutes. The solvent was evaporated under reduced pressure, and anhydrous methanol (50ml) was added to the residue and stirred for 45 minutes. The methanol clear solution was evaporated to dryness under reduced pressure to give 1.25g of a white solid product in 80% yield.

Melting point: 141 ℃ and 142 ℃.

IR(cm^-1)：3311，2981，2958，2931，2865，1738，1604，1585，1568，1510，1473，1452，1353，1297，1238，1164，1125，1111，1032，752，729，677；

¹H NMR(CDCl₃)δ：0.98(t，3H)，1.57(t，3H)，1.68-1.83(m，2H)，2.76(t，2H)，2.84(s，3H)，4.25(q，2H)，6.98(d，1H)，7.12(t，1H)，7.44(m，1H)，8.35(dd，1H)，10.30(brs，1H)；

¹³C NMR(CDCl₃)δ(CH₃)：13.9，14.5，16.1；(CH₂)：22.4，28.2，65.1；(CH)：112.6，121.6，130.3，132.4；(C)：118.4，132.0，132.4，138.6，143.5，144.9，146.2，156.5；

Mass Spectrometry (ES)⁺)：m/z 300(M+NH₄)；

Elemental analysis (C)₁₇H₂₀N₄O₂): theoretical value: c65.37; h6.45; n17.94; measured value: c65.39; h6.44; and (6) N17.92.

Preparation of 7.4-ethoxy-3- (6-methyl-4-oxo-8-n-propyl-3H-imidazo [1, 5-a ] [1, 3, 5-triazine ] 2-yl) benzenesulfonyl chloride (8):

2- (2-Ethoxyphenyl) -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one (7) (1.25g, 3.83mmol) obtained in preparation 6 was added in two portions to a solution of chlorosulfonic acid (4ml) in ethyl acetate (20ml) with stirring at 0 ℃. The resulting solution was stirred at 0 ℃ for 30 minutes and then at room temperature for 4 hours. The reaction solution was poured into a mixture of ice water (50ml) and methylene chloride (50 ml). The organic layer was separated, washed with cold water (5ml), dried over anhydrous sodium sulfate and evaporated to dryness to give 1.20g of a yellow foamy product in 73% yield. The product obtained can be used directly in the next reaction.

Elemental analysis (C)₁₇H₁₉ClN₄O₄S)：C 49.70％；H 4.66％；Cl 8.63％；N 13.64％；O 15.58％；S 7.80％。

The compound 1.2- [ 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] [1, 3, 5] triazin-4 (3H) -one (9):

4-ethoxy-3- (3-methyl-4-oxo-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride (8) (1.00g, 2.43mmol) obtained in preparation 7 was dissolved in dichloromethane (20ml) with stirring at 0 ℃. 1-ethylpiperazine (0.78ml, 6.10mmol) was added slowly. The reaction mixture was stirred at 0 ℃ for 5 minutes and then stirred at room temperature for 2 hours. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 1.2g of a yellow foamy product. Column chromatography (ethyl acetate: methanol 20: 1-10: 1) followed by recrystallization from ethyl acetate (5ml) gave 0.73g of a yellow solid in 59% yield.

Melting point: 177-179 ℃ C;

IR(cm^-1)：2964，2935，2869，2811，1741，1726，1672，1604，1463，1356，1265，1172，1147，950，740，617；

¹H NMR(CDCl₃)δ：0.94-1.04(m，6H)，1.61(t，3H)，1.71-1.80(m，2H)，2.37(q，2H)，2.52(m，4H)，2.75(dd，2H)，2.83(s，3H)，3.07(brs，4H)，4.33(q，2H)，7.10(d，1H)，7.79(dd，1H)，8.68(d，1H)，9.96(brs，1H)；

¹³C NMR(CDCl₃)δ(CH₃)：11.8，13.8，14.3，16.1；(CH₂)：22.2，28.2，45.9*，51.6，51.7，66.0；(CH)：113.1，130.3，131.7；(C)：119.6，128.3，132.0，133.1，139.2，141.8，144.7，159.4；

mass Spectrometry (ES)⁺)：m/z 506(M+NH₄)；

Elemental analysis (C)₂₃H₃₂N₆O₄S): theoretical value: c56.54; h6.60; n17.20; measured value: c56.51; h6.59; and (6) N17.21.

Compound 1-HCl: 2- [ 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] [1, 3, 5] triazin-4 (3H) -one monohydrochloride:

2- [ 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] [1, 3, 5] triazin-4 (3H) -one (9) (1.00g, 2.05mmol) obtained in preparation 8 was dissolved in diethyl ether (10ml) and methylene chloride (10ml), and a 4M hydrochloric acid-dioxane (0.51ml, 2.04mmol) solution diluted with diethyl ether (10ml) was added dropwise thereto with stirring. After the completion of the dropwise addition, stirring was continued at room temperature for 20 minutes, followed by filtration and drying to obtain 1.02g of monohydrochloride in a yield of 95%.

Melting point: 219-221 ℃;

IR(cm^-1)：2954，2937，2867，2433，1745，1604，1462，1357，1284，1245，1166，1153，731，611；

¹H NMR(D₂O)：δ0.85(t，J＝7.1Hz，3H)，1.29(t，J＝7.0Hz，3H)，1.47-1.58(m，5H)，2.49(m，2H)，2.58(s，3H)，3.23(q，2H)，3.42(brs，8H)，4.22(m，2H)，7.20(d，1H)，7.79(d，1H)，8.05(s，1H).

¹H NMR(CDCl₃)：δ0.98(t，3H)，1.44(t，3H)，1.65(t，3H)，1.79(q，2H)，2.76(t，2H)，2.86(s，3H)，3.06(q，2H)，3.18(b，2H)，3.46(b，2H)，3.86(b，2H)，4.35(dd，2H)，7.14(d，1H)，7.75(d，1H)，8.65(s，1H)，10.01(b，1H).

elemental analysis (C)₂₃H₃₃ClN₆O₄S)：C 52.61％；H 6.33％；Cl 6.75％；N 16.01％；O 12.19％；S 6.11％。

Compound 1-2 HCl: 2- [ 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] [1, 3, 5] triazin-4 (3H) -one dihydrochloride:

melting point: 213-215 ℃;

IR(cm^-1)：2960，2931，2871，2723，2684，2607，1766，1614，1488，1458，1274，1159，1036，951，725，582；

¹H NMR(D₂O)：δ0.93(t，J＝7.1Hz，3H)，1.29(t，J＝7.0Hz，3H)，1.46(t，J＝6.4Hz，3H)，1.69-1.77(m，2H)，2.84(m，4H)，3.03(s，3H)，3.20(m，4H)，3.64-3.69(d，2H)，3.90-3.95(d，2H)，4.31(m，2H)，7.38(d，1H)，7.98(d，1H)，8.09(s，1H)。

in a similar manner, using the corresponding starting materials, the following compounds are obtained:

compound 2: 2- [ 2-methoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

starting from 2-methoxybenzamidine (IE) and ethyl 2-acetamido-2-cyano-n-pentanoate (ID), the corresponding intermediate IC, IB was used to prepare 4-methoxy-3- (6-methyl-4-oxo-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride (IA), which was then reacted with 1-ethylpiperazine to give the title compound.

¹HNMR(CDCl₃)δ：0.96-1.04(m，6H)，1.76(m，2H)，2.38(q，2H)，2.52(m，4H)，2.74(t，2H)，2.84(s，3H)，3.06(br，4H)，4.04(s，3H)，7.11(d，1H)，7.78(dd，1H)，8.67(d，1H)。

MS(ES⁺)：m/z 492(M+NH₄)；

Compound 3: 2- [ 2-n-propoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1-5-a ] -1, 3, 5-triazin-4 (3H) -one:

starting from 2-n-propoxybenzamidine (IE) and ethyl 2-acetamido-2-cyano-n-pentanoate (ID), 4-n-propoxy-3- (6-methyl-4-oxo-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride (IA) is prepared via the corresponding intermediates IC, IB and reacted with 1-ethylpiperazine to give the title compound.

¹HNMR(CDCl₃)δ：0.95-1.03(m，6H)，1.19(，3H)，1.73(m，2H)，2.01(m，2H)，2.38(q，2H)，2.5 1(m，4H)，2.73(dd，2H)，2.82(s，3H)，3.08(br，4H)，4.21(t，2H)，7.10(d，1H)，7.80(dd，1H)，8.68(d，1H)。

MS(ES⁺)：m/z 520(M+NH₄)；

Compound 4: 2- [ 2-allyloxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

starting from 2-Dipropoxybenzamidine (IE) and ethyl 2-acetamido-2-cyano-n-pentanoate (ID), 4-allyloxy-3- (6-methyl-4-oxo-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride (IA) is prepared via the corresponding intermediates IC, IB and reacted with 1-ethylpiperazine to give the title compound.

¹HNMR(CDCl₃)δ：0.96-1.04(m，6H)，1.74(m，2H)，2.37(q，2H)，2.52(m，4H)，2.75(t，2H)，2.83(s，3H)，3.07(br，4H)，4.65(m，2H)，5.25(m，2H)，5.90(m，1H)，7.12(d，1H)，7.79(dd，1H)，8.69(d，1H)，9.97(br，1H)。

MS(ES⁺)：m/z 518(M+NH₄)；

Compound 5: 2- [ 2-n-propoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl ] -6-ethyl-8-n-propylimidazo [1-5-a ] -1, 3, 5-triazin-4 (3H) -one:

starting from 2-n-propoxybenzamidine (IE) and ethyl 2-propionamido-2-cyano-n-pentanoate (ID), 4-n-propoxy-3- (6-ethyl-4-oxo-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride (IA) is prepared via the corresponding intermediates IC, IB and reacted with 1-ethylpiperazine to give the title compound.

¹HNMR(CDCl₃)δ：0.94-1.05(m，9H)，1.54(t，3H)，1.76-1.82(m，4H)，2.40(q，2H)，2.52(m，4H)，2.75-2.86(m，4H)，3.07(br，4H)，4.28(t，2H)，7.11(d，1H)，7.78(dd，1H)，8.67(d，1H)。

MS(ES⁺)：m/z 534(M+NH₄)；

Compound 6: 2- [ 2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one,

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride from preparation 7 above by reaction with 1-methylpiperazine.

¹HNMR(D₂O)：δ0.96(t，3H)，1.62(t，2H)，1.75(m，2H)，2.31(s，3H)，2.53(m，4H)，2.75(t，2H)，2.84(s，3H)，3.07(m，2H)，4.34(q，2H)，7.12(d，1H)，7.78(dd，1H)，8.66(d，1H)。

MS(ES⁺)：m/z492(M+NH₄)；

Compound 7: 2- [ 2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl ] -6-ethyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

starting from 2-ethoxybenzamidine (IE) and ethyl 2-propionamido-2-cyano-n-pentanoate (ID), the intermediate IC, IB was used to prepare 4-ethoxy-3- (6-ethyl-4-oxo-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride (IA), which was then reacted with 1-methylpiperazine to give the title compound.

¹HNMR(CDCl₃)δ：0.96(t，3H)，1.56-1.60(m，6H)，1.75(m，2H)，2.28(s，3H)，2.53(m，4H)，2.75-2.88(m，4H)，3.06(m，4H)，4.34(q，2H)，7.11(d，1H).7.78(dd，1H)，8.69(d，1H)，

MS(ES⁺)：m/z 506(M+NH₄)；

Compound 8: 2- [ 2-ethoxy-5- (4-ethoxycarbonylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with 1-ethoxycarbonylpiperazine.

¹HNMR(CDCl₃)δ：1.00(t，3H)，1.18(t，3H)，1.65(t，3H)，1.91(m，2H)，2.99(m，5H)，3.20(s，4H)，3.56(m，4H)，4.05(dd，2H)，4.16(m，2H)，7.19(d，1H)，7.16(d，1H)，8.55(s，1H)，10.94(b，1H)，

MS(ES⁺)：m/z 550(M+NH₄)；

Compound 9: 2- [ 2-ethoxy-5- (4- (2-hydroxyethyl) piperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one;

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with 1- (2-hydroxyethyl) oxazine.

¹H NMR(CDCl₃)δ：0.96(t，3H)，1.61(t，3H)，1.72(m，2H)，2.52-2.56(m，6H)，2.75(t，2H)，2.82(s，3H)，3.07(brs，4H)，3.67(m，2H)，4.33(q，2H)，7.11(d，1H)，7.79(1d，1H)，8.68(d，1H)，

MS(ES⁺)：m/z522(M+NH₄)；

Compound 10: 2- [ 2-ethoxy-5- (pyrrolidinyl-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with pyrrolidine.

¹HNMR(CDCl₃)δ：0.97(t，3H)，1.62(t，3H)，1.79(m，6H)，2.80(t，2H)，2.92(s，3H)，3.27(m，4H)，4.35(q，2H)，7.13(d，1H)，7.90(dd，1H)，8.72(d，1H)，

MS(ES⁺)：m/z 463(M+NH₄)；

Compound 11: 2- { 2-ethoxy-5- [3- (2-oxo-pyrrolidinyl-1) N-propylamine-N-sulfonyl ] phenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above and 3- (2-oxo-pyrrolidinyl-1) n-propylamine.

¹HNMR(CDCl₃)δ：0.95(t，3H)，1.56(t，2m)，1.72(m，4H)，2.00(m，2H)，2.31(t，2H)，2.74(t，2H)，2.83(s，3H)，2.86(m，2H)，3.09(m，2H)，3.32(m，2H)，4.30(q，2H)，7.08(d，1H)，7.92(dd，1H)，8.67(d，1H)，

MS(ES⁺)：m/z 534(M+NH₄)；

Compound 12: 2- { 2-ethoxy-5- [2- (pyrrolidinyl-1) ethylamine-N-sulfonyl ] phenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with 2- (pyrrolidinyl-1) ethylamine.

¹HNMR(CDCl₃)δ：0.97(t，3H)，1.57(t，3H)，1.78(m，4H)，1.8-2.2(m，6H)，2.78(t，2H)，2.90(s，3H)，3.39(m，2H)，3.89(m，2H)，4.31(q，2H)，7.15(d，1H)，7.51(br，1H)，8.02(d，1H)，8.67(s，1H)，

MS(ES⁺)：m/z 506(M+NH₄)；

Compound 13: 2- [ 2-ethoxy-5- (morpholino-4-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 2-ethoxy-5- (morpholino-4-sulfonyl) benzamidine (IE) and ethyl 2-acetamido-2-cyanon-pentanoate (ID) via the corresponding intermediate IC.

¹HNMR(CDCl₃)δ：0.98(t，3H)，1.64(t，3H)，1.78(m，2H)，2.78(t，2H)，2.92(s，3H)，3.03(m，4H)，3.75(m，4H)，4.37(q，2H)，7.18(d，1H)，8.20(d，1H)，8.68(s，1H)，10.12(br，1H)，

MS(ES⁺)：m/z 479(M+NH₄)；

Compound 14: 2- [ 2-ethoxy-5- (3- (morpholino-4) N-propylamine-N-sulfonyl) phenyl ] -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above and 3- (morpholino-4) n-propylamine.

¹HNMR(CDCl₃)δ：0.97(t，3H)，1.61(t，3H)，1.74(m，4H)，2.54(m，4H)，2.75(t，2H)，2.78(s，3H)，3.1 1(t，2H)，3.75(m，4H)，4.34(q，2H)，7.13(d，1H)，7.92(d，1H)，8.76(s，1H)，

MS(ES⁺)：m/z 536(M+NH₄)；

Compound 15: 2- [ 2-ethoxy-5- (2- (morpholino-4) ethylamine-N-sulfonyl) phenyl ] -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with 2- (morpholino-4) ethylamine.

¹HNMR(CDCl₃)δ：0.98(t，3H)，1.61(t，3H)，1.74(m，2H)，2.32(m，4H)，2.44(t，2H)，2.76(t，2H)，2.84(s，3H)，3.03(t，2H)，3.61(m，4H)，4.34(q，2H)，7.12(d，1H)，7.92(d，1H)，8.79(s，1H)，

MS(ES⁺)：m/z 522(M+NH₄)；

Compound 16: 2- [ 2-ethoxy-5- (2, 6-dimethylmorpholino-N-sulfonyl) phenyl ] -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared starting from 2-ethoxy-5- (2, 6-dimethylmorpholino-4-sulfonyl) benzamidine (IE) and ethyl 2-acetamido-2-cyanon-pentanoate (ID).

¹HNMR(CDCl₃)δ：0.98(t，3H)，1.18(s，3H)，2.21(s，3H)，1.63(t，3H)，1.73(m，2H)，2.77(t，2H)，2.87(s，3H)，3.04(dd，1H)，3.25(m，1H)，3.71(m，4H)，4.35(q，2H)，7.16(d，1H)，7.80(dd，1H)，8.66(d，1H)，9.98(br，1H)，

MS(ES⁺)：m/z 507(M+NH₄)；

Compound 17: 2- [ 2-ethoxy-5- (1-benzylpiperidine-4-sulfamoyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with 1-benzyl-4-aminopiperidine.

¹HNMR(CDCl₃)δ：0.95(t，3H)，1.51-2.04(m，13H)，2.73(t，2H)，2.80-2.96(m，4H)，3.46(s，2H)，4.31(q，2H)，7.07(d，1H)，7.21-7.27(m，5H)，7.92(dd，1H)，8.73(d，1H)，

MS(ES⁺)：m/z 582(M+NH₄)；

Compound 18: 2- [ 2-ethoxy-5- (2- (piperidin-1-yl) ethylamine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with 2- (piperidin-1-yl) ethylamine.

¹HNMR(CDCl₃)δ：0.97(t，3H)，1.35(m，2F)，1.56-1.78(m，9H)，2.59(m，4H)，2.71-2.76(m，4H)，2.82(s，3H)，3.15(t，2H)，4.32(q，2H)，7.13(d，1H)，7.95(d，1H)，8.74(s，1H)，

MS(ES⁺)：m/z 520(M+NH₄)；

Compound 19: 2- [ 2-ethoxy-5- (4-benzylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with 4-benzylpiperazine.

¹HNMR(CDCl₃)δ：0.94(t，3H)，1.62(t，3H)，1.75(m，2H)，2.52(m，4H)，2.70(t，2H)，2.84(s，3H)，3.09(m，4H)，3.47(s，2H)，4.34(q，2H)，7.11(d，1H)，7.2 1-7.29(m，5H)，7.78(dd，1H)，8.65(d，1H)，

MS(ES⁺)：m/z 568(M+NH₄)；

Compound 20: 2- [ 2-ethoxy-5- (4-phenylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

starting from 2-ethoxy-5- (4-phenylpiperazine-1-sulfonyl) benzamidine (IE) and ethyl 2-acetamido-2-cyanon-pentanoate (ID), the title compound was obtained via the corresponding intermediate IC.

¹HNMR(CDCl₃)δ：0.99(t，3H)，1.63(t，3H)，1.77(m，2H)，2.78(t，2H)，2.86(s，3H)，3.22(m，8H)，4.36(q，2H)，6.84-6.91(m，3H)，7.13-7.21(m，3H)，7.21-7.09(m，5H)，7.84(dd，1H)，8.74(d，1H)，10.00(br，1H)，

MS(ES⁺)：m/z 554(M+NH₄)；

Compound 21: 2- [ 2-ethoxy-5- (piperazine-1-sulfonyl) phenyl ] -6-methyl-8-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with piperazine.

¹H NMR(CDCl₂)δ：0.94(t，3H)，1.61(t，3H)，1.75(m，2H)，2.65(m，4H)，2.75(dd，2H)，2.83(s，3H)，3.10(brs，4H)，4.33(q，2H)，7.11(d，1H)，7.76(dd，1H)，8.67(d，1H)，9.90(brs，1H)；

Compound 22: 2- [ 2-ethoxy-5- (4-benzo [1, 3] dioxolanylmethylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with 1-benzo [1, 3] dioxan-5-ylmethyl piperazine.

¹HNMR(CDCl₃)δ：0.95(t，3H)，1.62(t，3H)，1.73(m，2H)，2.49(m，4H)，2.71(t，2H)，2.84(s，3H)，3.11(m，4H)，3.43(s，2H)，4.35(q，2H)，5.92(s，2H)，6.65-6.80(m，3H)，7.11(d，1H)，7.78(dd，1H)，8.6(d，1H)，

MS(ES⁺)：m/z 612(M+NH₄)；

Compound 23: 2- [ 2-ethoxy-5- [4- (3-phenyl-n-propen-1-yl) piperidine-1-sulfonyl ] phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with 3-phenyl-n-propan-1-yl) piperidine.

¹HNMR(CDCl₃) δ：0.97(t，3H)，1.29-1.31(m，6H)，1.58-1.80(m，8H)，2.50-2.67(m，6H)，2.76(t，2H)，2.85(s，3H)，4.33(q，2H)，7.08-7.29(m，6H)，7.80(dd，1H)，8.66(d，1H)，

MS(ES⁺)：m/z 595(M+NH₄)；

Compound 24: 2- [ 2-ethoxy-5- (n-propylamine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

starting from 2-ethoxy-5- (n-propylamine-1-sulfonyl) phenylamidine (IE) and ethyl 2-acetamido-2-cyanon-pentanoate (ID), the reaction gave the title compound.

¹HNMR(CDCl₃)δ：0.94-0.99(m，6H)，1.51(q，2H)，1.61(t，3H)，1.75(m，2H)，2.75(t，2H)，2.85(s，3H)，2.96(q，2H)，4.34(q，2H)，7.11(d，1H)，7.92(dd，1H)，8.78(d，1H)，

MS(ES⁺)：m/z 451(M+NH₄)；

Compound 25: 2- [ 2-ethoxy-5- (N, N-bis (2-hydroxyethyl) sulfamoyl) phenyl ] -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-N-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with N, N-bis (2-hydroxyethyl) amine.

¹HNMR(CDCl₃)δ：0.97(t，3H)，1.62(t，3H)，1.79(m，2H)，2.78(t，2H)，2.85(s，3H)，3.33(t，4H)，3.33(t，4H)，3.87(t，4H)，4.35(q，2H)，7.12(d，1H)，7.89(dd，1H)，8.71(d，1H)，

MS(ES⁺)：m/z 497(M+NH₄)；

Compound 26: 2- [ 2-ethoxy-5- (N- (2-hydroxyethyl) -N-methylaminosulfonyl) phenyl ] -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-N-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with N- (2-hydroxyethyl) -N-methylamine.

¹HNMR(CDCl₃)δ：0.97(t，3H)，1.62(t，3H)，1.76(m，2H)，2.77(t，2H)，2.86(s，6H)，3.21(t，2H)，3.78(t，2H)，4.35(q，2H)，7.15(d，1H)，7.86(dd，1H)，8.71(d，1H)，

MS(ES⁺)：m/z 467(M+NH₄)；

Compound 27: 2- { 2-ethoxy-5- [ N- (2-hydroxyethyl) -N-ethyl ] aminosulfonylphenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-N-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with N- (2-hydroxyethyl) -N-ethylamine.

¹HNMR(CDCl₃)δ：0.98(t，3H)，1.18(t，3H)，1.62(t，3H)，1.77(m，2H)，2.78(t，2H)，2.86(s，3H)，3.31(m，4H)3.79(t，2H)，4.35(q，2H)，7.12(d，1H)，7.91(1d，1H)，8.76(d，1H)，

MS(ES⁺)：m/z 481(M+NH₄)；

Compound 28: 2- { 2-ethoxy-5- [ N- (2-hydroxyethyl) -N-butyl ] aminosulfonylphenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-N-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with N- (2-hydroxyethyl) -N-butylamine.

¹HNMR(CDCl₃)δ：0.92-1.00(m，6H)，1.69-1.41(1，4H)，1.64(t，3H)1.75(m，2H)，2.76(t，2H)，2.84(s，3H)，3.11(m，2H)3.26(m，2H)，3.77(t，2H)，4.34(q，2H)，7.11(d，1H)，7.89(dd，1H)，8.74(d，1H)，

MS(ES⁺)：m/z 509(M+NH₄)；

Compound 29: 2- { 2-ethoxy-5- (p-ethoxycarbonylaniline) -N-sulfonylphenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with p-ethoxycarbonylaniline.

¹HNMR(CDCl₃)δ：0.96(t，3H)，1.30(t，3H)，1.54(t，3H)，1.72(m，2H)，2.72(t，2H)，2.85(s，3H)，4.29(m，4H)，6.62(d，2H)，7.09(d，1H)，7.82(d，2H)，7.95(dd，1H)，8.76(d，1H)，

MS(ES⁺)：m/z 557(M+NH₄)；

Compound 30: 2- { 2-ethoxy-5- (o-benzoylaniline) -N-sulfonylphenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with o-benzoylaniline.

¹HNMR(CDCl₃)δ：0.96(t，3H)，1.54(t，3H)，1.72(m，2H)，2.72(t，2H)，2.85(s，3H)，4.29(m，2H)，6.60-6.72(m，2H)7.11(d，1H)，7.25-7.45(m，5H)，7.79(d，2H)，8.05(dd，1H)，8.80(d，1H)，

MS(ES⁺)：m/z 589(M+NH₄)；

Compound 31: 2- { 2-ethoxy-5- (N2-acetylhydrazino) -N-sulfonyl } phenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was obtained by reacting 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above with acethydrazide.

¹HNMR(CDCl₃)δ：0.97(t，3H)，1.61(t，3H)，1.76(m，2H)，2.02(s，3H)，2.76(t，2H)，2.87(s，3H)，4.34(q，2H)，7.11(d，1H)，7.92(dd，1H)，8.78(d，1H)，

MS(ES⁺)：m/z 466(M+NH₄)；

Compound 32: 2- { 2-ethoxy-5- (2-dimethylaminoethylamine) -N-sulfonyl } phenyl } -6-methyl-8-N-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

the title compound was prepared from 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride obtained in preparation 7 above by reaction with 2-dimethylaminoethylamine.

¹HNMR(CDCl₃)δ：0.97(t，3H)，1.61(t，3H)，1.75(m，2H)，2.11(s，3H)，2.25(s，3H)，2.54(m，2H)，2.79(t，2H)2.93(s，3H)，3.02(m，2H)，4.34(q，2H)，7.1 1(d，1H)，7.94(dd，1H)，8.79(d，1H)，

MS(ES⁺)：m/z 480(M+NH₄)；

Compound 33: 2- { 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl } -6-ethyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

starting from 2-ethoxybenzamidine (IE) and ethyl 2-propionamido-2-cyano-n-pentanoate (ID), the corresponding intermediate IC, IB is reacted to give 4-ethoxy-3- (6-ethyl-4-oxo-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride (IA), which is then reacted with 1-ethylpiperazine to give the title compound.

¹HNMR(CDCl₃)δ：0.94-1.04(m，6H)，1.56-1.60(m，6H)，1.75(m，2H)2.37(q，2H)，2.53(m，4H)，2.75-2.88(m，4H)，3.06(m，4H)，4.34(q，2H)，7.11(d，2H)，7.78(dd，1H)，8.69(d，1H)，9.95(br，1H)，

MS(ES⁺)：m/z 520(M+NH₄)；

Compound 34: 2- { 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl } -6-morpholinomethyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

starting from 2-ethoxybenzamidine (IE) and ethyl 2-morpholinoacetamido-2-cyano-n-pentanoate (ID), 4-ethoxy-3- (6-morpholinomethyl-4-oxo-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride (IA) is prepared via the corresponding intermediates IC, IB and reacted with 1-ethylpiperazine to give the title compound.

¹HNMR(CDCl₃)δ：0.94-1.04(m，6H)，1.61(t，3H)，1.74(m，2H)。2.34-2.55(m，10H)，2.75(t，2H)，3.07(m，4H)，3.68(m，4H)3.94(s，2H)，4.34(q，2H)，7.12(d，1H)，7.78(dd，1H)，8.70(d，1H)，

MS(ES⁺)：m/z 577(M+NH₄)；

Compound 35: 2- { 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl } -6- (pyrimidin-2) methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

starting from 2-ethoxybenzamidine (IE) and ethyl 2- (pyrimidine-2) acetamido-2-cyano-n-pentanoate (ID), 4-ethoxy-3- (6- (pyrimidine-2) methyl-4-oxo-8-n-propyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride (IA) was prepared via the corresponding intermediates IC, IB and reacted with 1-ethylpiperazine to give the title compound.

¹HNMR(CDCl₃)δ：0.94-1.04(m，6H)，1.60(t，6H)，1.75(m，2H)2.37(q，2H)，2.53(m，4H)，2.75(t，2H)，3.06(m，4H)，4.01(s，2H)，4.35(q，2H)，7.11-7.15(m，1H)，7.77(dd，1H)，8.68-8.71(m，3H)，

MS(ES⁺)：m/z 570(M+NH₄)；

Compound 36: 2- { 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl } -6-methyl-8-allylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one:

starting from 2-ethoxybenzamidine (IE) and ethyl 2-acetamido-2-cyano-n-pent-4-enoate (ID), 4-n-propoxy-3- (6-methyl-4-oxo-8-allyl-3H-imidazo [1, 5-a ] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride (IA) is prepared via the corresponding intermediates IC, IB and reacted with 1-ethylpiperazine to give the title compound.

¹HNMR(CDCl₃)δ：1.04(t，3H)，1.59(t，3H)，2.37(q，2H)，2.52(m，4H)，2.81(s，3H)，3.09(br，4H)，3.18(m，2H)，4.31(q，2H)，5.68(m，1H)，5.01(dd，1H)，4.95(dd，1H)，7.10(d，1H)，7.80(dd，1H)，8.70(d，1H)，9.86(br，1H)，

MS(ES⁺)：m/z 504(M+NH₄)；

Compound 7-2 HCl: 2- [ 2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one dihydrochloride;

¹H NMR(D₂O)δ：0.85(t，3H)，1.38(t，3H)，1.63(dd，2H)，2.78(m，4H)，2.83(s，3H)，2.96(s，3H)，3.19(t，2H)，3.52(d，2H)，3.84(d，2H)，4.22(m，2H)，7.34(d，1H)，7.92(d，1H)，8.02(s，1H)。

compound 8-2 HCl: 2- [ 2-ethoxy-5- (4-ethoxycarbonylpiperazine-1-sulfonyl) phenyl ] -6-methyl-8-n-propylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one dihydrochloride;

¹H NMR(CDCl₃)δ1.00(t，3H)，1.18(t，3H)，1.65(t，3H)，1.91(m，2H)，2.99(m，5H)，3.20(s，4H)，3.56(m，4H)，4.05(dd，2H)，4.16(m，2H)，7.19(d，1H)，7.86(d，1H)，8.55(s，1H)，10.94(b，1H)。

example 2

Penile erection test

To confirm the utility of the compounds of formula I for the treatment of functional Impotence, male rabbit model penile erection experiments were performed in accordance with the method of BISCHOFF (Bischoff E.; Schneider K, International Journal of Impace Research, 2001, 13, 230-.

The hydrochloride of the 3H-imidazole [1, 5-a ] [1, 3, 5] triazine-4-one derivative is dissolved in water and is injected into a conscious rabbit (0.1mg-3mg/kg) by an intravenous injection. Penile erection was achieved by comparing the lengths of the rabbits' penis before and immediately after drug injection, at 30, 60, 90 and 120 minutes. The results of several exemplary compound rabbit penile erection experiments are shown in Table 1.

TABLE 1.3H-imidazo [1, 5-a ]][1，3，5]Penile erection efficacy of triazin-4-one derivatives

Compound (I)	Rabbit penis length (mm)
	Rabbit penis length (mm)					At once	30 (minutes)	60 (minutes)	90 (minutes)	120 (minutes)
	Compound 1-HCl	6.3	10	6.7	2.3	At once	30 (minutes)	60 (minutes)	90 (minutes)	120 (minutes)	0.0
Compound 1-2HCl	Compound 1-HCl	6.3	10	6.7	2.3	2.3	2.3	3.0	2.0	2.0	0.0
Compound 1-2HCl	Compound 6-2HCl	6.0	2.7	1.3	0.3	2.3	2.3	3.0	2.0	2.0	0.0
Compound 8-2HCl	Compound 6-2HCl	6.0	2.7	1.3	0.3	1.3	3.0	2.0	1.3	0.0	0.0

Data are the average of three rabbit replicates.

Experimental results prove that the 3H-imidazole [1, 5-a ] [1, 3, 5] triazine-4-one derivative has excellent effect of treating functional impotence, and has the characteristics of quick response and long action time. Especially, the effect of the compound 1-HCl is extremely remarkable.

Example 3

Reference methods for determining phosphodiesterase 5 inhibiting activity of compounds of formula I (Hidaka H. et al Biochim. Biophys. acta 1976, 429, 485; KimD-K et al bioorg. Med. chem.2001, 9, 3013) completed that the inhibition of phosphodiesterase 5 by compound 1-HCl was greater than that of sildenafil (50%) at a concentration of 2.0 nM.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof

Wherein,

R¹is H; c₁-C₄A linear or branched alkyl group; c₁-C₄A halogenated linear or branched alkyl group; c₂-C₄An alkenyl group; c₂-C₄An alkynyl group; pyridyl, pyrimidinyl, imidazolyl; optionally in addition to HIs mono-or polysubstituted with a group selected from: halogen, cyano, nitro, hydroxy, carboxy, guanidino, C₁-C₄Alkyl radical, C₁-C₄Alkoxy radical, C₁-C₄Alkanoyl radical, C₃-C₅Cycloalkyl, substituted phenyl, substituted heterocycle, CONR⁵R⁶、NR⁵R⁶、CO²R⁷、NHSO₂R⁸、SO₂NR⁹R¹⁰；

R⁸is NR⁵R⁶Optionally substituted C₁-C₃An alkyl group;

R⁹and R¹⁰Are each H or C₁-C₁₂A linear or branched alkyl group; c₁-C₄A halogenated linear or branched alkyl group; c₂-C₆An alkenyl group; c₂-C₆Alkynyl or C₃-C₆A cycloalkyl group; or together form pyrrolinyl (keto), piperidyl, morpholinyl, 4-N (R)¹²) -a piperazinyl group; these groups may optionally be substituted by OH, CN' CO₂R⁷、C₁-C₄Straight or branched alkyl, C₁-C₃Alkoxy radicals, NR¹³R¹⁴、CONR¹³R¹⁴Substitution; substituted phenyl, substituted heterocycle, or C substituted by substituted phenyl, substituted heterocycle₁-C₆Straight or branched chain alkyl groups, which groups may be substituted by OH, CO₂R⁷、NR¹³R¹⁴、CONR¹³R¹⁴Further substituted or substituted withThe carbonyl is connected with another substituted phenyl or substituted heterocycle; wherein the substituents on the substituted phenyl and the substituted heterocycle are as described above;

R¹¹is H; c₁-C₆C being straight-chain or branched alkyl and optionally substituted by phenyl, hydroxy₂-C₃Alkyl or C₁-C₄Alkoxy substitution; c₁-C₃A haloalkyl group; c₂-C₃An alkenyl group; c₂-C₆Alkynyl or C₃-C₆A cycloalkyl group;

2. The compound of claim 1, wherein,

R⁴is H, C₁-C₄Straight or branched chain alkyl, and optionally substituted by OH, NR⁵R⁶，CN，CONR⁵R⁶Or CO₂R⁷Substitution; NR (nitrogen to noise ratio)⁵R⁶Optionally substituted (C)₂-C₃Alkoxy) C₁-C₂A linear or branched alkyl group; NR (nitrogen to noise ratio)⁵R⁶；NHSO₂NR⁵R⁶；NHSO₂R⁸；SO₂NR⁹R¹⁰Or may optionally be provided withPhenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl or triazolyl substituted with methyl;

R⁷is H or C₁-C₄A linear or branched alkyl group;

R⁸is NR⁵R⁶Optionally substituted C₁-C₃An alkyl group;

R⁹and R¹⁰Are each H or C₁-C₁₂A linear or branched alkyl group; c₁-C₃A halogenated linear or branched alkyl group; c₂-C₆An alkenyl group; c₂-C₆Alkynyl or C₃-C₆A cycloalkyl group; or together form pyrrolinyl (keto), piperidyl, morpholinyl, 4-N (R)¹²) -a piperazinyl group; or together with the nitrogen atom to which they are attached to form pyrrolinyl (keto) yl, piperidinyl, morpholinyl, 4-N (R)¹²) -a piperazinyl group; these groups may optionally be substituted by OH, CN, CO₂R⁷、C₁-C₄Straight or branched alkyl, C₁-C₃Alkoxy radicals, NR¹³R¹⁴、CONR¹³R¹⁴Substitution; substituted phenyl, substituted heterocycle, or C substituted by substituted phenyl, substituted heterocycle₁-C₆Straight or branched chain alkyl groups, which groups may be substituted by OH, CO₂R⁷、NR¹³R¹⁴、CONR¹³R¹⁴Further substituted or connected with another substituted phenyl or substituted heterocycle by carbonyl; wherein the substituents on the substituted phenyl and the substituted heterocycle are as described above;

3. The compound of claim 1 or 2, wherein,

R⁴is SO₂NR⁹R¹⁰；

R⁷is H or C₁-C₄A linear or branched alkyl group;

R⁹and R¹⁰Are each H or C₁-C₁₂A linear or branched alkyl group; c₃-C₆A cycloalkyl group; or together form pyrrolinyl (keto), piperidyl, morpholinyl, 4-N (R)¹²) -a piperazinyl group; or together with the nitrogen atom to which they are attached to form pyrrolinyl (keto) yl, piperidinyl, morpholinyl, 4-N (R)¹²) -a piperazinyl group; these groups may be optionally substituted by OH, C₁-C₄Straight or branched alkyl, C₁-C₃Alkoxy radicals, NR¹³R¹⁴、CONR¹³R¹⁴Substitution; substituted phenyl, substituted heterocycle, or C substituted by substituted phenyl, substituted heterocycle₁-C₆Straight or branched chain alkyl groups, which groups may be substituted by OH, CO₂R⁷、NR¹³R¹⁴、CONR¹³R¹⁴Further substituted or connected with another substituted phenyl or substituted heterocycle by carbonyl; wherein the substituents on the substituted phenyl and the substituted heterocycle are as described above;

R¹²is H; c₁-C₃A linear or branched alkyl group; c₁-C₃Alkoxy-substituted C₂-C₃A linear or branched alkyl group; hydroxy-substituted C₂-C₃A linear or branched alkyl group; NR (nitrogen to noise ratio)¹³R¹⁴Substituted C₂-C₆A linear or branched alkyl group; phenyl-substituted C₂-C₃A linear or branched alkyl group; CONR¹³R¹⁴Substituted C₁-C₆A linear or branched alkyl group; CO 2₂R⁷，CONR¹³R¹⁴；

4. The compound of claim 1 or 2, selected from:

2- { 2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl } -6-methyl-8-allylimidazo [1, 5-a ] -1, 3, 5-triazin-4 (3H) -one, and the mono-and bis-hydrochloride salts thereof.

5. A process for the preparation of a compound of the general formula I,

subjecting the intermediate ID compound and IE compound to a condensation reaction:

to give the intermediate IC compound:

wherein R is¹，R²，R³And R⁴The definition of (1) is as above;

or,

make R₄Compound IB of formula I ═ H:

wherein R is₁，R₂And R₃The definition of (A) is the same as that of (B),

the corresponding sulfonyl chloride compound IA is then acylated with the appropriate amine to give R therein⁴Is SO₂NR¹¹R¹¹A compound of the general formula I:

wherein R is¹，R²，R³And R⁴The definition of (1) is as above;

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 and a veterinarily acceptable excipient.

8. Use of a compound according to any one of claims 1 to 4 for the preparation of a medicament for the treatment or prophylaxis of diseases which are associated with cGMPPDE5 function.

9. The use of claim 8, wherein the disease comprises: male sexual dysfunction (erectile) disorder, female sexual dysfunction, premature labor, dysmenorrhea, benign prostatic hyperplasia, bladder obstruction, incontinence, regular or irregular angina, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, stroke, peripheral circulatory system diseases, reduced vascular patency, chronic asthma, allergic asthma, bronchitis, allergic rhinitis, glaucoma, gastrointestinal motility disorders, pre-eclampsia, kawasaki syndrome, nitrate tolerance, multiple sclerosis, diabetic peripheral nerve syndrome, alzheimer's disease, acute respiratory failure, psoriasis, skin gangrene, cancer cell metastasis, hair loss, anal fissure, and hypoxic vasoconstriction.

10. Intermediates IA-IE involved in the preparation of compounds of general formula I: