WO2004101567A1

WO2004101567A1 - 2-SUBSTITUTED PHENYL -6,8-DIALKYL-3H-IMIDAZOLE [1,5a][1,3,5] TRIAZINE -4- ONE DERIVATIVES, THE PREPARATION AND THE PHARMACEUTICAL USE THEREOF

Info

Publication number: WO2004101567A1
Application number: PCT/CN2004/000488
Authority: WO
Inventors: Yongfeng Wang; Kejun Zhao; Ke Liu
Original assignee: Tianjin Tasly Group Co., Ltd.; Yantai Development Area North Pharmacuetical R & D Institute
Priority date: 2003-05-16
Filing date: 2004-05-14
Publication date: 2004-11-25
Also published as: CN1548438A

Abstract

The invention relates to the compounds of formula (I), their preparation and the pharmaceutical compositions containing the compounds. The invention also relates to the use of the compounds of formula (I) in preparing medicines, which can inhibit cGMP PDE5 enzyme and can especially treat or prevent sexual dysfunction of animals including human.

Description

2 -substituted phenyl-6, 8 ~ dihydrocarbyl-3H-imidazole [1, 5a] [1. 3.5]

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.

Background technique

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). Recently, W00216364 described the further development of these 1, 6-dihydro-pyrrole [4, 3-d] pyrimidin-7-one compounds with polyethylene glycol by LG Chem. Inves t. Ltd. to improve its water solubility. derivative. 1,5-dihydropyrrole [3,4- (1) pyrimidin-4-one and 1, 9-dihydropurin-6-one compounds are also therapeutic agents for sexual dysfunction (US6100270) developed by Pfizerizer Ltd. W0 The 3,5-dihydropyrrole [3, 2-d] pyrimidin-4-ones listed in 0160825 can be used for the treatment of impotence. Bayer Co. Ltd. recently disclosed 3H-imidazole [5, 1-f] [ 1,2,4] triazine-4-ones (DE19881732).

Summary of the Invention

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:

among them:

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, ¾ 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 alkyl substituted with substituted phenyl, substituted heterocycle, these groups The group may be further substituted with 0H, C0 ₂ R ⁷ , NR ¹³ R ", CONR ¹³ R ¹⁴ or connected to another substituted phenyl or substituted heterocyclic ring with a carbonyl group; wherein the substituted phenyl group and the substituent on the substituted heterocyclic ring are as above Said;

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 C ₃ -C ₆ cycloalkyl; polyethylene glycol (n-2-20) group, which may be optionally substituted with a dC ₆ alkyl terminal;

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.

The following preparation processes describe the general preparation methods and intermediates used for the compounds of the invention:

Condensation of intermediate ID compounds and IE compounds according to literature methods (Parker, C. 0 .; Tetrahedron, 1962, 17, 109-116, Albertson; J. Amer. Chem. Soc., 1946, 68, 453, Albertson) Response:

Where R _l R ₂ , R ₃ and R ₄ are as defined above

Intermediate IC compounds can be obtained:

Where R. R ² , R ³ and R ^{4 have} the same definitions as above,

The intermediate IC compound is then subjected to a rearrangement reaction to obtain a compound of general formula I:

Wherein 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. C; chlorotrialkylsilane and ditrialkylsilaneamine are used as silanization and dehydration reagents or mixed alone, preferably trimethylchlorosilane and bistrimethylsilylamine are used in an equimolar mixture;

As a special case of the general formula I, the compound of general formula I in which SO lTR ¹¹ is prepared by the following method:

Make the IB compound (R ₄ = H compound of general formula I):

IB

R, R ₂ and R _{3 have} the same definitions as above, and react with chlorosulfonic acid to obtain compound IA:

Where R _l5 R ₂ and R ₃ are as defined above,

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,

The corresponding sulfonyl chloride compound IA is then subjected to an acylation reaction with an appropriate amine to prepare a compound of formula I in which R ⁴ is SO ^ I ^ R ¹¹ :

Wherein 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.

Optionally, 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. Chem, Soc, 1948, 1157), can also be separated and reused (I ^ CO) ₂ 0 or acid chloride I ^ COCl for acylation (Cai l le JC et al; Synthes is, 1995, 635-637); the resulting ethyl amidocyanocyanate (3) is substituted with a hydrocarbon halogenated compound R ² X (X = C1, Br or I) alkylation (Holtwick, J. B; J. Org. Chem. 1979, 44, 3835-3839) to obtain the ID (4). Intermediate IE (5) can be prepared with corresponding substituted benzonitrile and ammonium chloride and trimethylaluminum (Garigipat i, R. S; Tetrahedron Lett, 1990, 31, 1969-1972).

Another aspect of the present invention relates to a pharmaceutical composition for treating erectile dysfunction in a male animal including a human. The composition 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.

Although 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.

Therefore, 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.

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

among them,

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 substituted with substituted phenyl, substituted heterocycle, these groups The group may be further substituted with 0H, C0 ₂ R \ NR ¹³ R ¹⁴ C0NR ¹³ R ¹⁴ or connected to another substituted phenyl or substituted heterocyclic ring with a carbonyl group; wherein the substituted phenyl group and the substituent on the substituted heterocyclic ring are the same as described above. ;

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 ¹³ and R "are H; Ci-C ₄ straight or branched alkyl; dC ₃ alkoxy substituted C ₂ -C ₄ straight or branched alkyl; or hydroxy 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.

In a more preferred embodiment of the invention, it relates to a compound of general formula I or a pharmaceutically acceptable salt thereof:

among them,

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; A six-membered ring of two nitrogen atoms and its nitrogen oxide; a five-membered ring containing two or three nitrogen, oxygen, and sulfur atoms; the substituent on the heterocyclic ring is a d-C ₄ straight or branched alkyl group, d -C ₄ alkoxy, amino and dC ₄ linear or branched alkamino, dC ₄ alkoxyamino.

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;

. 2-C4 block basis;

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 ", C0NR ¹³ R" or connected to another substituted phenyl or substituted heterocyclic ring with a carbonyl group; the substituted phenyl and the substituent on the substituted heterocyclic ring Same as above;

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. The following compounds are particularly preferred in the present invention:

2- [2-ethoxy- 5- (4-ethyltrazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole

[1, 5-a] [1,3,5] triazin-4 (310-one, and its monohydrochloride and dihydrochloride;

2- [2-methoxy- 5- (4-ethylpiperazine-1-sulfonyl) phenyl] 6-methyl-8-n-propylimidazole [1, 5-a]-1, 3 , 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-n-propoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1-5-a] -1, 3, 5-Trilac-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-Allyloxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-n-propoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] -6-ethyl-8-n-propylimidazole [1-5-a] -1, 3,5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl]-6-methyl-8-n-propylimidazole

[1, 5-a] -1, 3, 5-triazine-4 (3-ketone, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -6-ethyl-8-n-propylimidazole [1, 5-a]-1, 3 , 5-triamidine-4 (3H) -one, and its monohydrochloride and dihydrochloride; 2- [2-ethoxy-5- (4-ethoxycarbonylpiperazine-1-sulfonyl) phenyl] 6-methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (4- (2-hydroxyethyl) piperazine-1-sulfonyl) phenyl] 6-methyl-8-n-propylimidazole [1, 5-a ] -1, 3, 5-trifluorene-4 (3-ketone, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy- 5- (pyrrolidinyl-1-sulfonyl) phenyl] 6-methyl-8-n-propylimidazole

[1,5-&]-1,3,5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy-5- [3- (2-oxo-pyrrolidinyl-1) -n-propylamine-N-sulfonyl] phenyl} -6-methyl-8-n-propylimidazole [1 , 51] -1,3,5-triazine-4 (3H) -one, and its monohydrochloride and mer hydrochloride;

2- {2-ethoxy-5- [2- (pyrrolidinyl-1) ethylamine-N-sulfonyl] benzyl} -6-methyl-8-n-propylimidazole [1, 5-a ] -l, 3, 5-triazine-4 (3H) -one, and its mono- and di-salts

2- [2-ethoxy-5- (morpholino-4-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5- Triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (3- (morpholino-4) -n-propylamine-N-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1,5-a ]-1,3,5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (2- (morpholino-4) ethylamine-N-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1,5-a ] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy- 5- (2, 6-dimethylmorpholino-N-sulfonyl) phenyl] 6-methyl-8-n-propylimidazole [1, 5-a] -l, 3, 5-tri "Qin-4 (3H) -one, and its mono- and di-hydrochloride;

2-[2-ethoxy-5- (1-benzylpiperidine-4-aminosulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (2- (piperidin-1-yl) ethylamine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5- a] -1,3,5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (4-benzylpiperazine-1-sulfonyl) phenyl] 6-methyl-8-n-propylimidazole [1, 5-a] -1,3 , 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride; 2- [2-ethoxy-5- (4-phenylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a]-1,3 , 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (piperazine-1-sulfonyl) phenyl] -6-methyl-8-propylimidazole

[1,5-a] -1, 3, 5-trilacryl-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (4-benzo [1,3] dicenylmethylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- [4- (3-phenyl-n-propene-1-yl) piperidine-busulfonyl] phenyl] 6-methyl-8-n-propylimidazole [1 , 5-a] -l, 3, 5-triazine-4 (3H) -one. And its monohydrochloride and double hydrochloride;

2- [2-ethoxy-5- (n-propylamine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole

2- [2-ethoxy-5- (N, N-bis (2-hydroxyethyl) aminosulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-tri "Qin-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (N- (2-hydroxyethyl) -N-fluorenylaminosulfonyl) phenyl] -6-methyl-8-n-propylimidazole [l, 5- a] -1,3,5-triazin-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy-5- [N- (2-hydroxyethyl) -N-ethyl] aminosulfonylphenyl} -6-methyl-8-n-propylimidazole [1, 5- a] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and mer hydrochloride;

2- {2-ethoxy-5- | "(2-hydroxyethyl) -N -n-butyl] aminosulfonylphenyl} -6-methyl-8-n-propylimidazole [1, 5- a]-1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy-5- (p-ethoxycarbonylaniline) -N-sulfonylphenyl} -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy- 5- (o-benzoylaniline) -N-sulfonylphenyl} -6-methyl-8-n-propylimidazole [1, 5-a] -l, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy-5- (N2-acetylhydrazinyl) -N-sulfonyl} phenyl} -6-methyl-8-n-propyl Imidazole [1, 5-a] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy- 5- (2-dimethylaminoethylamine) sulfonyl} phenyl} -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl} -6-ethyl-8-n-propylimidazole [1, 5-a]-1, 3 , 5-triazine-4 (3H) -one, and its mono- and di-hydrochloride;

2- {2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl} -6-morpholinomethyl-8-n-propylimidazole [1, 5-a]- l, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy- 5- (4-ethylpiperazine-1-sulfonyl) phenyl} -6- (pyrimidine-2) methyl-8-n-propylimidazole [1, 5-a ]-1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and mer hydrochloride;

2- {2-ethoxy-5- (4-ethylpipe "qin-1-sulfonyl) phenyl} -6-methyl-8-allylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride The compounds of the present invention may undergo tautomerism, tautomerism and other isomeric differences of all compounds of general formula I The structures and their mixtures are all within the protection scope of the present invention.

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.

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).

In addition, 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.

In general, for humans, 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. For patients with dysphagia or after dysphagia, the drug can be absorbed parenterally, such as sublingually, buccally, transdermally, or by injection.

For veterinary use, 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.

In the in vivo toxicity tests in rats and dogs, neither intravenous injection nor oral administration of the compounds of the invention up to 3 mg / kg showed any obvious signs of adverse acute toxicity. When mice were taken for in vivo toxicity testing, no death occurred when the intravenous injection dose was as high as 10 Omg / kg. detailed description

In the present invention, 2- [2-ethoxy-5- (4-ethylpiperazine-1 monosulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a] The preparation of [1, 3, 5] triazin-4 (3H) -one and its monohydrochloride and dihydrochloride is taken as an example to illustrate the preparation method of the compound of general formula I of the present invention.

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)).

synthetic route:

-15-

(1) ethyl cyanoacetate;

(2) ethyl oxime cyanoacetate;

(3) ethyl acetaminocyanoacetate;

(4) ethyl 2-acetamido-2 -cyano-n-valerate;

(5) 2-ethoxyphenylhydrazone;

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

(7) 2- (2-ethoxyphenyl) -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3 ^)-one;

(8) 4-ethoxy-3- (6-methyl-4-oxo-8-n-propyl-3-imidazole [1, 5-a] -l, 3, 5-triazine-2-yl ) ^ Acyl chloride;

(9) 2- [2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5—a]- 1, 3, 5-triazine-4 (3i¾) -one; Preparation 1. Ethyl oxime cyanoacetate (2):

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%.

Melting point: 129-131. C (Document: 129-131. C)

Literature: Parker, C. 0 .; Tetrahedron, 1962, 17, 109-116. Preparation 2. Acetyl cyanoacetate ethyl acetate (3):

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%.

Melting point: 123- 124 ° C (Document: 129 ° C)

Literature: Wilson, J. Chem. Soc., 1948, 1157-1158. Preparation 3. Ethyl 2-acetamido-2-cyano-n-valerate (4):

Sodium metal (2.3 g, 100 inmol) was dissolved in absolute ethanol (50 ml). To this were added ethyl acetaminocyanoacetate (17.0 g, 100 μl) and n-bromopropane (10.0 ml, HO mmol) obtained in Preparation 2, and the mixture was stirred with heating under reflux for 3 hours. After a little cold, use 150ml water #, collect 13.6g of crystals by filtration, the yield is 64%.

Melting point: 118- 119 ° C (Document: 118 ° C)

Literature: Albertson; J. Amer. Chem. Soc., 1946, 68, 453. Preparation 4. 2-ethoxyphenylhydrazone hydrochloride (5):

Dissolve ammonia chloride (145mg, 2.72mmol) in water-cooled toluene, and slowly add trimethylaluminum-n-hexane solution (2M, 1.36 ml, 2.72 leg ol) to it. The mixture was stirred at room temperature The temperature rose to 80 after two hours. C. To this was added 1-cyano-2-ethoxybenzene (200 mg, 136 legs ol), and the reaction mixture was at 80 ° C. C was stirred for two days. The reaction was slowly poured into a suspension of silica gel (5 g) in chloroform (100 ml). The silica gel was filtered off and washed with methanol-water 1: 1. The filtrate was evaporated to dryness and extracted with dichloromethane and 5 ½ sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate and 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):

Sodium metal (0.23 g, 10 mmol) was dissolved in absolute ethanol (5 ml), and 2-ethoxyphenylhydrazone hydrochloride (5) (1.00 g, 5. 00 mmol) was added thereto, and the mixture was at room temperature Stir for 10 minutes. 5 After adding ethyl 2-acetamido-2-cyano-n-propionate (4) (1.06 g, 5. OO mmol) obtained in Preparation 3, the mixture was stirred under reflux for 20 minutes, and the H value was adjusted to 5.5 with acetic acid. 5 . The mixture was evaporated to dryness and extracted with dichloromethane (20 ml) and filtered. The filtrate was evaporated to dryness to obtain a crude product, which was directly used in the next reaction. Preparation 6. 2- (2-Ethoxyphenyl) -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3H) -one (7 ):

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

Melting point: 141 "142. C.

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; ¾ NMR (CDCI3) 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);

¹³ C NMR (CDCI3) δ (CH ₃ ): 13.9, 14.5, 16.1; (CH ₂ ): 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 spectrum (ES ⁺ ): m / z 300 (M + NH ₄ );

Elemental analysis (C ₁₇ H ₂ .N ₄ 0 ₂ ): Theoretical value: C 65.37; H 6.45; N 17.94; Found: C 65.39; H 6.44; N 17.92. Preparation 7. 4-ethoxy-3- (6-methyl-4-ox-8-n-propyl-3H ~ imidazole [1, 5-a] [1, 3, 5-triazine] 2-yl ) ^ Acyl chloride (8):

The 2- (2-ethoxyphenyl) -6-methyl-8-n-propylimidazole [l, 5-a] -1,3,5-triazine-4 (3H) — Ketone (7) (1.25 g, 3.83 ol) was divided into two batches at 0. C was added to a solution of chlorosulfonic acid (¼1) in ethyl acetate (20 ml) with stirring. The resulting solution is at 0. The reaction was stirred at C for 30 minutes, and then stirred at room temperature for 4 hours. The reaction solution was poured into a mixture of water (50 ml) and dichloromethane (50 ml). The organic layer was separated, washed with cold water (5 ml), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 1.20 g of a yellow foamy product in a yield of 73%. The resulting product was used directly in the next reaction.

Elemental analysis (CnH ^ ClN S): C 49.70%; H 4.66%; C18.63%; N 13.64%; 0 15.58%; S 7.80%. Compound 1. 2- [2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] 6-methyl-8-n-propylimidazole [1, 5-a] [ 1, 3, 5] triazine-4 (3H) -one (9):

Under stirring at 0 ° C, 4-ethoxy-3- (3-methyl-4-oxo-8-n-propyl--imidazole [1, 51] -1, 3, 5 obtained in Preparation 7 -Triazin-2-yl) benzenesulfonyl chloride (8) (1.00 g, 2.43 mM) was dissolved in dichloromethane (20 ml). Slowly add 1-ethylpiperazine (0.78 ml, 6.10 ol). The reaction solution was stirred at 0 ° C for 5 minutes, and then stirred at room temperature for 2 hours. It was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain 1.2 g of a yellow foamy product. Column chromatography Ethyl acetate: methanol 20: 1-10: 1) and then recrystallized from ethyl acetate (5 ml) to obtain 0.73 g of a yellow solid with a yield of 59%.

Melting point: 177-179. C;

IR (cm ^_1 ): 2964, 2935, 2869, 2811, 1741, 1726, 1672, 1604, 1463, 1356, 12 5, 1172, 1147, 950, 740, 617;

^J H MR (CDC1 ₃ ) δ 0.94-1.04 (m, 6H), 1.61 (t, 3H), 1.71-1.80 (ra, 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);

¹³ C NMR (CDCI3) δ (CH ₃ ): 11.8, 13.8, 14.3, 16.1; (CH ₂ ): 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 spectrum (ES +): m / z 506 (M + NH ₄ );

Elemental analysis (C ₂₃ H ₃₂ N ₆ 0 ₄ S): Theoretical value: C 56.54; H 6.60; N 17.20; Found: C 56.51; H 6.59; N 17.21. Compound 1-HCl: 2- [2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a ] 〖1, 3, 5] Triazine-4 (3H) -one monohydrochloride:

The 2- [2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5- a] [1,3,5] Triazin-4 (3H) -one (9) (1.00g, 2.05 let ol) be dissolved in diethyl ether (10ml) and dichloromethane (10ml), and added dropwise thereto with stirring. A 4M solution of hydrochloric acid-dioxane (0.51 ml, 2.04 mmol) diluted with ether (10 ml). After the dropwise addition, stirring was continued at room temperature for 20 minutes, filtered, and dried to obtain 1.02 g of a monohydrochloride salt in a yield of 95%.

Melting point: 219-221. C;

IR cm " ¹ ): 2954, 2937, 2867, 2433, 1745, 1604, 1462, 1357, 1284, 1245, 166, 1153, 731,611; ^J H MR (D ₂ 0): δ 0.85 (t, J = 7.1 Hz, 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, IH), 8.05 (s, IH).

¾ NMR (CDC1 ₃ ): δ 0.98 (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, IH), 7.75 (d, IH), 8.65 (s, IH), 10.01 (b, IH) · Elemental analysis (C ₂₃ H ₃₃ C1N ₆ 0 ₄ S): C 52.61%; H 6.33%; CI 6.75%; N 16.01%; 0 12.19%; S 6.11% . Compound 1-2HC1: 2- [2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a ] [1, 3, 5] triazine-4 (3H) -one dihydrochloride:

Melting point: 213-215. C;

IR (cm ^_1 ): 2960, 2931, 2871, 2723, 2684, 2607, 1766, 1614, 1488, 1458, 1 274, 1159, 1036, 951, 725, 582;

¾ NMR (D ₂ 0): δ 0.93 (t, J = 7.1 Hz, 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, IH ), 8.09 (s, IH), in a similar manner, using the corresponding raw materials, the following compounds can be obtained: Compound 2: 2- 〖2-methoxy-5- (4-ethylpiperazine-1- Sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1,5-a] -1,3,5-triazine-4 (3H) -one:

Starting from 2-methoxyphenylhydrazone (IE) and 2-acetamido-2-cyano-n-valeric acid ethyl ester (ID), 4-methoxy-3 is obtained through the corresponding intermediates IC and IB -(6-fluorenyl-4 -oxo-8-n-propyl-3H-imidazole [1, 5-a]-1, 3, 5-triazin-2-yl) acyl chloride (IA), and then with 1- Ethylpiperazine was reacted to give the title compound.

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Starting from 2-n-propoxyphenylhydrazone (IE) and 2-propionamido-2-ethyl cyano-n-valerate (ID), 4-n-propoxy-3 was prepared via the corresponding intermediate IC and IB -(6-ethyl-4-oxo-8-n-propyl-3H-imidazole [l, 5-a]-1, 3, 5 -trilacryl-2-yl) benzoyl chloride (IA), and 1-ethylpiperazine was reacted to give the title compound.

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MS (ES ⁺ ): m / z 534 (M + NH ₄ ); Compound 6: 2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -6- Methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 monoketone,

4-Ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazole [l, 5-a]-1, 3,5-triazine- 2-yl) acyl chloride was reacted with 1-methylpiperazine to give the title compound.

¹ bandit _{R (D 2 0): 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, IH), 7.78 (dd, lH), 8.66 (d, IH).

^{MS (ES +): m /} z492 (M + NH 4); Compound 7: 2 - [2-ethoxy --5- (4 Yue piperazine-1-yl) phenyl-6-ethylamino〗 Methyl-8-n-propylimidazol [1, 5-a] -l, 3, 5-triazine-4 (3H) -one:

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9 0 OAV -3H-imidazole [l, 5-a] -1,3,5-triazine + yl) acyl chloride and 4-benzylpiperazine to give the title compound.

'HNMR (CDC1 ₃ ) δ: 0.94 (t, 3H), 1.62 (t, 3H), 1.75 (m, 2H), 2.52 (in, 4H), 2.70 (t, 2H), 2.84 (s, 3H), 3.09 (m, 4H), 3.47 (s, 2H), 4.34 (q, 2H), 7.11 (d, IH), 7.21-7.29 (m, 5H), 7.78 (dd, IH), 8.65 (d, IH) ^{, MS (ES +): m} / z 568 (m + NH 4); compound 20: 2- [2-ethoxy-5- (4 - phenylpiperazine --1- sulfonyl) phenyl] -6 -Methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3H) -one:

The reaction starts from 2-ethoxy-5- (4-phenylpiperazin-1-sulfonyl) phenylhydrazone (IE) and 2-acetamido-2-ethyl cyano-n-valerate (ID). The corresponding intermediate IC gave the title compound.

^X HNMR (CDCI3) 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, IH), 8.74 (d, IH), 10.00 (br , IH), '

^{MS (ES +): m /} z 554 (M + NH 4); Compound 21: 2- [2-ethoxy-5- (piperazine-1-sulfonyl) phenyl] -6-methyl-8 -Propylimidazole [1, 5-a]-1, 3, 5-triazine-4 (3H) -one:

4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazole [1, 5-a] -1,3,5-triazine- 2-yl) benzenesulfonyl chloride was reacted with piperazine to give the title compound.

¾ NMR (CDC1 ₂ ) 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, IH), 7.7 6 (dd, IH), 8.67 (d, IH), 9.90 (brs, IH); Compound 22: 2- [2 -Ethoxy-5- (4-benzo [1,3] dimethylocenylpiperazine- 1-sulfonyl) phenyl] -6-methyl-8-propylimidazole [1,51] -1 , 3,5-triazine-4 (3H) -one: 4-ethoxy-3- (6-methyl-4-monochloro-8-n-propyl-3H-imidazole [l, 5-a] -1,3,5-triazine- 2-yl) ^ acyl chloride is reacted with 1-benzo [1,3] diocene-5-ylmethylpiperazine to give the title compound.

¹ band R (CDCls) 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 (ra, 4H), 3.43 (s, 2H), 4.35 (q, 2H), 5.92 (s, 2H), 6.65-6.80 (m, 3H), 7.11 (d, IH), 7.78 ( dd, IH), 8.6 (d, lH),

^{MS (ES +): ra /} z 612 (M + NH 4); Compound 23: 2- [2-ethoxy-5- [4- (3 - phenyl-n-propylene -: 1 - yl) piperidine - 1-sulfonyl] phenyl] -6-methyl-8-n-propylimidazole [1, 5-a] -l, 3, 5-triazine-4 (3H) -one:

4-ethoxy-3-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazole [l, 5-a] -1,3,5-triazine- 2-yl) ^ acyl chloride was reacted with 3-phenyl-n-propane-1-yl) piperidine to give the title compound.

¹ band R (CDC1 ₃ ) δ: 0.97 (t, 3Η), 1.29-1.31 (m, 6Η), 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, IH), 8.66 (d, IH),

^{MS (ES +): m /} z 595 (M + NH 4); Compound 24: 2- [2-ethoxy-5- (n-propyl-1-sulfonyl) phenyl] -6-methyl-8 -N-propylimidazole [1,51] -1,3,5-triazine-4 (3H) -one:

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.

^ NMRC CDC1 ₃ ) 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, IH), 7.92 (dd, IH), 8.78 (d, IH),

^{MS (ES +): m /} z 451 (M + NH 4); Compound 25: 2-ethoxy-2- 〖-5- (N, N - bis (2-hydroxyethyl) amino) benzene [Yl] -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3H) -one:

4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazole [1,5-a] -1,3,5-triazine- Reaction of 2-yl) benzyl chloride with N, N-bis (2-hydroxyethyl) amine yields the title compound.

^! HNMR (CDC1 ₃ ) 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, 2H), 7.12, 1H), 7.89 (dd, 1H), 8.71 (d, 1H),

MS (ES ⁺ ): m / z 497 (M + NH ₄ ); Compound 26: 2- [2-ethoxy-5- (N- (2-hydroxyethyl) -N-methylaminosulfonyl) Phenyl] -6-methyl-8-n-propylimidazole [l, 5-a] -1,3,5-triazine-4 (3H) -one:

4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazole [1,5-a] -1,3,5-triazine- 2-yl) acyl chloride was reacted with N- (2-hydroxyethyl) -N-methylamine to give the title compound.

¹ bandit _{R (CDC1 3) 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 + NH 4); Compound 27: 2- {2-ethoxy--5- [N- (2 - hydroxyethyl) -N- ethyl] amino sulfonyl Phenyl} -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3H) -one:

4-ethoxy-3— (6-methyl-1, 4-chloro-1, 8-n-propyl-3H-imidazole [l, 5-a] -1, 3, 5-triazine- The 2-yl) acyl chloride was reacted with N- (2-hydroxyethyl) -N-ethylamine to give the title compound.

'HNMR (CDCI3) δ · 0.98 (t, 3Η), 1.18 (t, 3H), 1.62 (t, 3H), 1.77 (m, 2Η), 2.78 (t, 2Η), 2.86 (s, 3Η ), 3.31 (m, 4Η) 3.79 (t, 2Η), 4.35 (q, 2H), 7.12 (d, 1H), 7.91 (Id, 1H), 8.76 (d, 1H),

MS (ES ⁺ ): m / z 481 (M + NH ₄ ); '(HI ^) 08-8' (HI 'PP) SO · 8' (H 'P) 6A' (H5 ^) ^ 'LSI ^'(Hl'P) TT 'L (H3' ra) u · 9 —09 · 9 '() 62' (H 's) ^^' Z '(H2) ZL Ί' (EZ

) 96 * 0 * · 9 ( ^ε ΐθαθ) TOH _X

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L No. T Bi

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88t000 / l700 ND / industrial / ^{MS (ES +): m /} z 589 (M + NH 4); Compound 31: 2- {2-ethoxy -5- (N2 - acetyl hydrazino) - N- sulfonyl} phenyl} -6 - Methyl-8-n-propylimidazole [1, 5-a]-1, 3, 5-triazine-4 (3H) -one:

^ I 4-ethoxy-3- (6-methyl-4-chloro-8-n-propyl-3H-imidazole [1,5-a] di 1,3,5-triazine obtained from the above preparation 7) -2-yl) benzenesulfonyl chloride and acetylhydrazine to give the title compound.

^ NMR (CDC1 ₃ ) 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, IH), 7.92 (dd, lH), 8.78 (d, lH),

^{MS (ES +): m /} z 466 (M + NH 4); Compound 32: 2- {2-ethoxy-5- (2 - ethanamine two Yue-ylamino) -N - sulfonyl} phenyl } -6-methyl-8-n-propylimidazole [1, 5-a] -l, 3, 5-triazine-4 (3H) -one:

4-Ethoxy- 3- (6-methyl- 4-chloro-8-n-propyl-3H-imidazole [1,5-a] -1, 3,5-triazine- 2-yl) benzenesulfonyl chloride was reacted with 2-dimethylaminoethylamine to give the title compound.

^ NMR (CDC1 ₃ ) δ: 0.97 (t, 3Η), 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), 7.11 (d, IH), 7.94 (dd, IH), 8.79 (d, IH), MS ( ES ⁺ ): m / z 480 (M + NH ₄ ); Compound 33: 2- {2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl} -6-ethyl -8-n-propylimidazole [1, 5-a] -l, 3, 5-trisamidine-4 (3H) -one:

Starting from 2-ethoxyphenylhydrazone (IE) and 2-propionamido-2-cyano-n-valeric acid ethyl ester (ID), 4-ethoxy-3- (6-ethyl-4-oxo-8-n-propyl-3H-imidazole [1, 5-a] -1, 3, 5-triazine-2-yl) benzenesulfonyl chloride (IA), and then with 1 -Ethylpiperazine reaction to give the title compound.

¹ band R (CDC1 ₃ ) δ: 0.94-1.04 (m, 6Η), 1.56-1.60 (m, 6H), 1.75 (m, 2H) 2.37 (q, 2H), 2.53 (ra, 4H), 2.75-2.88 (m, 4H), 3.06 (ra, 4H), 4.34, 2H), 7.11 (d, 2H), 7.78 (dd) , IH), 8.69 (d, IH), 9.95 (br, IH), MS (ES ⁺ ): m / z 520 (M + NH ₄ ); compound 34: 2- {2-ethoxy-5- ( 4-ethylpiperole-1-sulfonyl) phenyl} -6-morpholinomethyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3H ) -Ketone:

Starting from 2-ethoxyphenylhydrazone (IE) and 2-morpholinoacetamido-2-ethyl cyano-n-valerate (ID), 4-ethoxy groups can be obtained via the corresponding intermediates IC and IB -3- (6 -morpholinomethyl-4 -oxo -8 -n-propyl -3H -imidazole [1, 5-a] -1, 3, 5-triazin-2-yl) benzenesulfonyl chloride ( IA), and then reacted with 1-ethylpiperazine to give the title compound.

'HNMRCCDC ^) δ: 0.94-1.04 (ra, 6Η), 1.61 (t, 3Η), 1.74 (m, 2H) ₀ 2.34-2.55 (m, 10H), 2.75 (t, 2H), 3.07 (m, 4H ), 3.68 (m, 4H) 3.94 (s, 2H), 4.34, 2H), 7.12 (d, IH), 7.78 (dd, IH), 8.70 (d, IH),

^{MS (ES +): m /} z 577 (M + NH 4); Compound 35: 2- {2-ethoxy-5- (4-ethyl-piperazin --1- sulfonyl) phenyl} -6- (Pyrimidine-2) Methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3H) -one:

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.

'HNMR (CDCh) 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 (ra, 4H), 4.01 (s, 2H), 4.35 (q, 2H), 7.11-7.15 (m, lH), 7.77 (dd, IH), 8.68-8.71 (m, 3H),

^{MS (ES +): m /} z 570 (M + NH 4); Compound 36: 2- {2-ethoxy-5- (4-ethyl-piperazine-1-sulfonyl) phenyl} -6- Methyl-8-allylimidazole [1, 5-a] — 1, 3, 5-triazine-4 (3H) -one: The reaction starts from 2-ethoxyphenylhydrazone (IE) and 2-acetamido-2-cyano-n-pent-4-enoic acid ethyl ester (ID), and 4-n-propyl is obtained through corresponding intermediates IC and IB Oxy- 3- (6-monomethyl-4 4-oxy-8-allyl-3H-imidazole [1, 5-a] -1,3,5-tri- ^p- quinone 2-yl) benzenesulfonyl chloride ( IA), and then reacted with 1-ethyl group to obtain the title compound.

'HNMR (CDCh) δ: 1.04 (t, 3Η), 1.59 (t, 3Η), 2.37 (q, 2Η), 2.52 (m, 4Η), 2.81 (s, 3Η), 3.09 (br, 4Η), 3.18 (ra, 2Η), 4.31 (q, 2Η), 5.68 (m, IH), 5.01 (dd, IH), 4.95 (dd, IH), 7.10 (d, IH), 7.80 (dd, IH), 8.70 ( d, IH), 9.86 (br, lH),

^{MS (ES +): m /} z 504 (M + NH 4); Compound 7-2HC1: 2- [2- ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] - 6-methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triazine-4 (3 ^ -one dihydrochloride;

'Η NMR (D ₂ 0) 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, IH), 7.92 (d, IH), 8.02 (s, lH) Compound 8-2HC1: 2- [2-ethoxy-5- (4-ethoxycarbonylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5 -a] -l, 3, 5-triazine-4 (3-ketodihydrochloride;

'Η NMR (CDC 1 ₃ ) 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, IH), 7.86 (d, IH), 8.55 (s, IH), 10.94 (b, IH) Example 1

Penile erection test

In order to confirm the effectiveness of compounds of the general formula I in the treatment of functional impotence, a test of penile erection in a male rabbit model was performed with reference to the method of BISCHOFF (Bischoff E .; Schneider K, International Journal of Impotence Research, 2001, 13, 230 235).

Dissolve 3H-imidazole [1, 5-a] [1, 3, 5] triazin-4-one derivative hydrochloride in water, intravenously Injected in conscious rabbits (0.1 mg-3 mg / kg). The penile erection effect was obtained by comparing the length of the penis in rabbits before, and immediately after injection, 30, 60, 90, and 120 minutes. The results of rabbit penile erection experiments with several typical compounds are listed in Table 1.

3H-imidazole [1, 5-a] [1, 3, 5] triazine-4-one derivative penile erectile effect

* Table data is the average of the results of repeated experiments of three rabbits.

The experimental results show that 3H-imidazole [1, 5-a] [1, 3, 5] triazin-4-one derivative has an excellent effect on functional impotence, and has the characteristics of rapid effect and long action time. In particular, the effect of compound 1-HC1 is extremely significant. Example 3

Reference method for determination of phosphodiesterase 5 inhibitory activity of compounds of formula I (Hidaka H. et al Biochim. Biochira. Biophys. Acta 1976, 429, 485; Kim D- et al Bioorg. Med. Chem. 2001, 9 , 3013), the inhibition rate of compound 1-HC1 on phosphodiesterase 5 was greater than sildenafil (50%) at a concentration of 2. OnM.

Claims

Compound of Formula I or a pharmaceutically acceptable salt thereof

among them,

R ¹ is H; C wide C ₄ straight or branched alkyl; C "C ₄ halogenated straight or branched alkyl; C ₂ -C ₄ alkenyl; C ₂ -C ₄ alkynyl; pyridyl , Pyrimidinyl, imidazolyl; except H may be optionally substituted one or more by a group selected from the group consisting of: halogen, cyano, nitro, hydroxy, guanidino, dC ₄ alkyl, C-C ₄ alkyl Oxy, dC ₄ alkanoyl, C ₃ -C ₅ cycloalkyl, substituted phenyl, substituted heterocyclic, CONR ⁵ R ⁶ , NR ⁵ R ⁶ , C0 ₂ R ⁷ , NHS0 ₂ R ⁸ , S0 ₂ NR ⁹ R ¹⁰ ;

The substituted phenyl refers to phenyl substituted with one or more C ^ alkoxy, halo, cyano, CF _{_3>} 0CF _3, straight-chain or branched alkyl; substituted heterocycle comprising one or two nitrogen atoms comprising Six-membered ring and its nitrogen oxide; five-membered ring containing two or three nitrogen, oxygen, and sulfur atoms; the substituents on the heterocyclic ring are C, C, C ₄ straight or branched chain alkyl, d-C ₄ alkane Oxy, amino and dC ₄ linear or branched alkylamino, dC ₄ alkoxyamino;

R ² is H; dC ₆ linear or branched alkyl group, and may be C ₃ - C ₆ cycloalkyl group, a substituted dC ₄ alkoxy; c ₂ -c ₄ alkenyl group; c ₂ -c ₄ alkynyl;

R ³ is H, C: -C ₆ straight or branched alkyl, and may be substituted by C ₃ -C ₆ cycloalkyl, C ₄ -C ₄ alkoxy; C ₂ -C ₄ -chain cockyl; C _2- C ₄ alkynyl;

R ⁴ is H, Ci-C ₄ linear or branched alkyl, and may be optionally substituted with OH, NR ^S R ⁶ , CN, CONR ⁵ R ⁶ or C0 ₂ R ⁷ ; C ₂ -C ₄ alkenes And may be optionally substituted with CN, CONR ⁵ R ⁶ or C0 ₂ R ⁷ ; NR ¥ optionally substituted C ₂ -C ₄ alkoxy; 0H or NR ⁵ R ^fi optionally substituted (C _2- C ₃ alkoxy) d- C ₂ linear or branched alkyl; CONR ⁵ R ⁶ ; halogen; NR ⁵ R ⁶ ; NHS0 ₂ NR ⁵ R ⁶ ; NHS0 ₂ R ⁸ ; "SOaNR" or phenyl optionally substituted by methyl, pyridyl, pyrimidinyl, imidazolylzolyl, sedazolyl, sehalyl, or triazolyl;

R ⁵ and R ⁶ are H or dC ₄ straight or branched alkyl, respectively, or together with the nitrogen atom to which they are attached, form pyrrolinyl, piperidinyl, morpholinyl, 4-N CI ¹¹ ) -piperazine or imidazolyl, said groups may be optionally substituted d- C ₄ alkyl and hydroxy substituents;

R ⁷ is H or C wide Cs straight or branched chain alkyl, which may be substituted by d-C ₄ alkoxy, C wide C ₄ alkylamino, dialkylamino; substituted phenyl, substituted heterocyclic; Substituents on substituted phenyl and substituted heterocycles are as described above;

R ⁸ is an optionally substituted dC ₃ alkyl group of NR ⁵ R ^fi ;

R ⁹ and R ^ie are H or dC ₁₂ straight or branched alkyl; d- C 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 (keto) group, piperidinyl, morpholinyl, 4-N (R ¹² ) -piperazinyl; these groups can be optionally OH, CN, C0 ₂ R ⁷ , C-C ₄ linear or branched alkyl, dC ₃ alkoxy, NR ¹³ R ¹⁴ , CONR ¹³ R ¹⁴ substituted; substituted phenyl, substituted heterocyclic, or substituted phenyl, substituted hetero Ring-substituted dC ₆ straight or branched alkyl groups, these groups may be further substituted with 0H, C0 ₂ R ⁷ , NR ¹³ R ¹⁴ , CON ¹³ R ¹⁴ or connected to another substituted phenyl or substituted heterocyclic ring with a carbonyl group ; Wherein the substituted phenyl and substituted heterocyclic substituents are as described above;

R ¹¹ is H; dC ₆ linear or branched alkyl, and may be optionally substituted with phenyl, hydroxy-substituted C ₂ -C ₃ alkyl or d-C ₄ alkoxy; C "C ₃ haloalkyl ; C ₂ -C ₆ alkenyl; C ₂ -C ₆ alkynyl or G ₃ -C ₆ cycloalkyl;

R ¹² is H; C wide C ₆ straight or branched alkyl; C wide C ₃ alkoxy substituted C ₂ -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 C ₆ straight or branched chain alkyl; C0 ₂ R ⁷ substituted C ₂ -C _fi 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 , CONR ¹³ R ¹⁴ , CSNR ¹³ R "or C (NH) NR ¹³ R"; C -C ₃ halogenated straight or branched alkyl; C ₂ -C ₆ alkenyl; C ₂ -C ₆ Alkynyl or C ₃ -C ₆ cycloalkyl; polyethylene glycol (n = 2-20) group, which may be optionally substituted with a dC ₆ alkyl terminal;

R ¹³ and R ¹⁴ are H; dC ₄ straight or branched alkyl; C "C ₃ alkoxy substituted C ₂ -C ₄ straight or branched alkyl; or hydroxyl substituted C plant C ₄ straight Chain or branched alkyl; or with it The nitrogen atoms connected to them together form pyrrolinyl (keto), piperidinyl, morpholinyl.

2. The compound according to claim 1, wherein:

R ¹ is a C-C ₃ linear or branched alkyl group; it may be optionally substituted one or more by a group selected from the group consisting of C-C ₄ alkyl, dC ₄ alkoxy, C-C ₄ alkyl Acyl, substituted phenyl, substituted heterocyclic, CONR ⁵ R ⁶ , NR ⁵ R ⁶ ;

Substituted phenyl means that the phenyl group is substituted with one or more dC ₄ alkoxy, halogen, CF ₃ , 0CF ₃ , C and C ₄ linear 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 group, d-alkoxy group , Amino and (^ -0; ₄ straight or branched chain alkylamino, d- alkoxyamino;

R ² is H; C ₂ -C ₄ straight or branched chain alkyl, and may be substituted by C ₃ -C ₆ cycloalkyl, C ₄ -C ₄ alkoxy; C ₂ -C ₄ alkenyl; C "C ₄ alkynyl

R ³ is H, dC ₄ straight or branched: ^ group, and may be substituted by C ₃ -G ₆ ring pit group, 0 ₃ oxycarbon; C "C ₄ alkenyl; C _2- C ₄ alkynyl;

R ⁴ is H, d-C4 straight or branched alkyl, and may be optionally substituted with OH, NR ⁵ R ⁶ , CN, CONR ⁵ R ⁶ or C0 ₂ R ⁷ ; NR ⁵ R ^{6 is} optionally substituted (C ₂ -C ₃ alkoxy) Ci-C ₂ linear or branched alkyl; NR ⁵ R ⁶ ; NHS0 ₂ NR ⁵ R ⁶ ; NHS0 ₂ R ⁸ ; S0 ₂ NR ⁹ R ¹⁰ or optionally Methyl-substituted phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thiahalyl, 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-R ¹¹ ) -piperyl Azinyl or imidazolyl, the group may be optionally substituted with methyl and hydroxyl;

R ⁷ is H or d-C ₄ straight or branched alkyl;

R ⁸ is NR ⁵ R ⁶ optionally substituted C "C ₃ alkyl;

R ⁹ and R ^le are H or d-C ₁₂ straight or branched alkyl; dC ₃ halogenated straight or branched alkyl; C ₂ -C ₆ alkenyl; 0 ₂ -(^ 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 ( keto) group, ^a ^ piperazine, ^{morpholino, 4-N (R 12)} - piperazinyl; these groups may optionally be _{0H, CN, C0 2 R \} dC 4 linear or branched alkyl, dC ₃ alkoxy, NR ¹³ R ¹⁴ , CONR ¹³ R ¹⁴ substituted; substituted phenyl, substituted heterocyclic ring, or substituted with substituted phenyl, substituted heterocyclic ring dC _fi linear or branched fluorenyl groups, these groups may be further substituted with 0H, C0 ₂ R ⁷ , NR ¹³ R ¹⁴ , CONR ¹³ R ¹⁴ or connected to another substituted phenyl or substituted heterocyclic ring with a carbonyl group; Substituents on substituted phenyl and substituted heterocycles are as described above;

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 d- C ₄ alkoxy; C ₂ -C ₆ chain Alkenyl or C ₃ -C ₆ cycloalkyl;

R ¹² is H; C wide C _fi straight or branched alkyl; dC ₃ alkoxy substituted C ₂ -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; CONR ¹³ R ¹⁴ substituted (broad ^ straight chain) Or branched alkyl; C0 ₂ R ⁷ , CONR ¹³ R ¹⁴ , CSNR ¹³ R ¹⁴ or C (NH) NR ¹³ R ¹⁴ ; C "C ₃ halogenated straight or branched alkyl; C ₂ -C ₆ chain Alkenyl; C ₆ C alkynyl or C ₃ -C _fi cycloalkyl;

R ¹³ and R ¹⁴ are H; dC ₄ straight or branched alkyl; dC ₃ alkoxy substituted C ₂ -C ₄ straight or branched alkyl; or hydroxy substituted C ₂ -C ₄ straight Or branched-chain alkyl groups; or together with the nitrogen atom to which they are attached to form a pyrrolinyl (keto) group, piperidinyl, morpholinyl.

3. The compound according to claim 1 or 2, wherein:

R ¹ is a C ₂ -C ₃ straight or branched chain alkyl group; it may be optionally substituted one or more by a group selected from: a substituted heterocyclic ring, NR ⁵ R ^fi ;

Substituted phenyl refers to phenyl substituted with one or more of the CH ^ alkoxy, halo, _{_{cyano, CF 3, 0CF 3, Cx}} -C 4 linear or branched alkyl group; or a substituted heterocycle containing comprising A six-membered ring of two nitrogen atoms and its nitrogen oxide; a five-membered ring containing two or three nitrogen, oxygen, and sulfur atoms; the substituents on the heterocyclic ring are CH ^ straight or branched chain alkyl, d-C ₄ alkoxy, amino and -C ₄ straight or branched chain alkyl, dC ₄ alkoxyamino.

R ² is a C ₂ -C ₄ straight or branched alkyl group, and may be substituted by a C ₃ -C ₄ cycloalkyl group; a C ₂ -C ₄ alkenyl group; a C ₂ -C ₄ alkynyl group;

R ³ is a C ₂ -C ₄ straight or branched alkyl group, and may be substituted by dC ₃ alkoxy; C ₂ -C ₄ alkenyl; C ₂ -C ₄ alkynyl;

R ⁴ is S0 ₂ NR ⁹ R ¹⁰ ;

R ⁵ and R ⁶ together with the nitrogen atom to which they are attached form pyrrolinyl, piperidinyl, morpholinyl; R ⁷ is H or d-C ₄ straight or branched alkyl;

R ⁹ and R are H or dC ₁₂ straight or branched alkyl; C ₃ -C _fi cycloalkyl; or Form pyrrolinyl, piperidinyl, morpholinyl, 4-N (R ¹² ) -piperazinyl; or nitrogen atom connected to them to form pyrrolinyl, ketoridinyl, morpholine Groups, 4-N (R ¹² ) -piperazinyl groups; these groups can be optionally OH, C "C ₄ straight or branched alkyl, d-Ca alkoxy, NR ¹³ R", C0NR ¹³ R "substituted; unsubstituted phenyl, substituted heterocycle, or substituted phenyl, unsubstituted heterocyclic-substituted Cx-C ₆ straight or branched chain alkyl group, these groups may be _{^{0H, C0 2 R 7, NR}} 13 R 14 C0NR ¹³ R "is further substituted or connected to another substituted phenyl or substituted heterocyclic ring with a carbonyl group; wherein the substituted phenyl and substituted heterocyclic ring are the same as described above;

R ¹² is H; dC ₃ straight or branched alkyl; d-Cs alkoxy substituted C ₂ -C ₃ straight or branched alkyl; hydroxy substituted C ₂ -C ₃ 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 "substituted straight or branched alkyl Radical; C0 ₂ R ⁷ , C0NR ¹³ R ¹⁴ ;

R ¹³ and R ¹⁴ are H; dC ₄ straight or branched alkyl; dC ₃ alkoxy substituted C ₂ -C ₄ straight or branched alkyl; or hydroxy substituted C ₂ -C ₄ straight Or branched-chain alkyl groups; or together with the nitrogen atom to which they are attached form a pyrrolinyl (keto) group, piperidinyl, morphinyl.

The compound according to claim 1 or 2, which is selected from:

2- [2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] 6-methyl-8-n-propylimidazole

[1, 5-a] [1, 3, 5] triazin-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-methoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3 , 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-n-propoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1-5-a] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-allyloxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3,5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2 -n-propoxy- 5- (4-ethylpiperazine-1 -sulfonyl) phenyl] -6-ethyl-8-n-propylimidazo [1-5- a]-1 , 3,5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [l, 5-a] -1, 3 , 5-triazine-4 (3 ^)-one, and its mono- and di-hydrochloride;

2- [2-ethoxy-5- (4-methylpiperazine-1-sulfonyl) phenyl] -6-ethyl-8-n-propylimidazole [1, 5-a] -1, 3 , 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride; 2- [2-ethoxy-5- (4-ethoxycarbonylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [l, 5-a] -1, 3,5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (4- (2-hydroxyethyl) piperazine-1-sulfonyl) phenyl] 6-methyl-8-n-propylimidazole [1, 5-a ] -l, 3, 5-triazine-4 (3-ketone, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy- 5- (pyrrolidin-1-sulfonyl) phenyl] 6-methyl-8-n-propylimidazole [1,5-a] -1,3,5- Triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy-5- [3- (2-oxo-pyrrolidinyl-1) -n-propylamine-N-sulfonyl] phenyl} -6-methyl-8-n-propylimidazole [l , 5-a] -1,3,5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy-5- [2- (pyrrolidinyl-1) ethylamine—N-sulfonyl] phenyl} -6-fluorenyl-8-n-propylimidazole [1, 5-a ] -l, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (morpholino-4-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a] -1,3, 5- Triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy- 5- (3- (morpholino-4) -n-propylamine-N-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a ] -l, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy- 5- (2- (morpholino-4) ethylamine-N-sulfonyl) phenyl]-6-methyl-8-n-propylimidazole [1, 5-a ] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (2,6-dimethylmorpholinosulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3,5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (1-benzylpiperidine-4-aminosulfonyl) phenyl] -6-methyl-8-n-propylimidazine [1, 5-a] -1 , 3, 5-tri "Qin-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (2- (piperidin-1-yl) ethylamine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5- a] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy- 5- (4-benzylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a]-1, 3 , 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (4-phenylpiperazine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1, 5-a]-1, 3 , 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (piperazine-1-sulfonyl) phenyl] -6-methyl-8-propylimidazole [1,5-a] -1,3,5-triazine -4 (3H) -one, and its monohydrochloride and dihydrochloride; 2- [2-ethoxy- 5- (4-benzo [1, 3] dicenylmethylpiperazine-1 -sulfonyl) phenyl]-6-methyl-8-propylimidazole [1, 5-a]-1,3,5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- [4- (3-phenyl-n-propen-1-yl) piperidine-l-sulfonyl] phenyl] -6-methyl-8-n-propylimidazole [ 1,5-a] -1,3,5-tri "Qin-4 (3H) -one. And its monohydrochloride and han hydrochloride;

2- [2-ethoxy- 5- (n-propylamine-1-sulfonyl) phenyl] -6-methyl-8-n-propylimidazole

[1,5-a]-1, 3, 5-tri "Qin-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- [2-ethoxy-5- (N, N-bis (2-hydroxyethyl) aminosulfonyl) phenyl] -6-methyl-8-n-propylimidazole [l, 5-a] -1,3,5-triazine-4 (3H) -one, and its mono- and di-salts

2- [2-ethoxy-5- (N- (2-hydroxyethyl) -N-methylaminosulfonyl) phenyl] -6-methyl-8-n-propylimidazole [1,5- &]-1,3,5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy-5- [N- (2-hydroxyethyl) -N-ethyl] amino transverse acylphenyl} -6-methyl-8-n-propylimidazole [1, 5- a] -1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy-5- [N- (2-hydroxyethyl) -N-n-butyl] aminosulfonylphenyl} -6-methyl-8-n-propylimidazole [1, 5 -a] -l, 3,5-triazine-4 (3H) -one, and its mono- and di-hydrochloride;

2- {2-ethoxy-5- (o-benzoylaniline) -N-sulfonylphenyl} -6-methyl-8-n-propylimidazole [1, 5-a] -1, 3, 5-triamidine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy- 5- (N2-acetylhydrazinyl) -N-sulfonyl} phenyl} 6-methyl-8-n-propylimidazole [1, 5-a] -1, 3 , 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2-{2-ethoxy-5- (2-dimethylaminoethylethylamine) -N-sulfonyl} phenyl} -6-methyl-8-n-propylimidazole [1, 5-a] -l, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride; 2- {2-ethoxy- 5- (4-ethylpiperazine-1-sulfonyl) phenyl} 6-ethyl-8-n-propylimidazole [1, 5-a] -1, 3 , 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl} -6-morpholinomethyl-8-n-propylimidazole [1 ', 5-a] -l, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl} -6- (pyrimidine-2) methyl-8-n-propylimidazole [1, 5-a ]-1, 3, 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride;

2- {2-ethoxy-5- (4-ethylpiperazine-1-sulfonyl) phenyl} -6-methyl-8-allylimidazole [1, 5-a]-1, 3 , 5-triazine-4 (3H) -one, and its monohydrochloride and dihydrochloride.

5. A method for preparing a compound of general formula I,

The intermediate ID compound and the IE compound are subjected to a condensation reaction:

ID

Where R _l R ₂ , R ₃ and R ₄ are as defined above

The intermediate IC compound is obtained:

IC

Wherein R ¹ , R ² , R ³ and R ^{4 have} the same definitions as above,

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

Where RR ² , R ³ and R ⁴ are as defined above;

Or,

Compound IB of general formula I with R ₄ = H:

IB

Wherein, R ₂ and R _{3 have} the same definitions as above, and react with chlorosulfonic acid to obtain compound IA:

IA

Where R ₂ and R _{3 have} the same definitions as above,

The corresponding sulfonyl chloride compound IA is then subjected to an acylation reaction with an appropriate amine to obtain a compound of general formula I in which R ⁴ is SO ld ¹¹ :

Wherein R ¹ , R ² , R ³ and R ^{4 have} the same definitions as above;

Optionally, the compound of formula I is reacted with a pharmaceutically acceptable acid to convert it to its corresponding salt.

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

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

8. Use of a compound according to any one of claims 1-4 for the preparation of a medicament for the treatment or prevention of diseases related to the function of cGMP PDE5.

9. The use of claim 8, wherein said diseases 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, Congestive heart failure, Arteriosclerosis, Stroke, Peripheral circulatory disease, Decreased vascular openness, Chronic asthma, Allergic asthma, Bronchitis, Allergic rhinitis, Glaucoma, Gastrointestinal disorders, Precursor convulsions, Kawasaki Syndrome , Nitrate tolerance, multiple sclerosis, diabetic peripheral neurological 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:

9 01 please Z OAV