Derivatives of 8-phenyl-6,9=dihydro[1,24]triazolo[3,4-i]purine-5-one, methods for their preparing, intermediate compounds, pharmaceutical composition and treatment method

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:

wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.

EFFECT: improved preparing method and treatment, valuable properties of compounds.

20 cl, 5 tbl, 149 ex

 

The invention relates to new therapeutically useful derivatives of 8-phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-it, process for their preparation and the pharmaceutical compositions.

EP 0417790 refers to SIMM-triazolo[3,4-i]purines of the General formula

where Y=Z is

where R4represents hydrogen, alkyl, an aromatic heterocyclic group, which is optionally substituted by 1 or 2 substituents, independently selected from C1-C6-alkyl, C1-C6-alkoxy and halogen, or substituted or unsubstituted aryl; and X2represents oxygen, sulfur or NH;

each of R1and R2independently, represents hydrogen, alkyl, cycloalkyl, aralkyl or substituted or unsubstituted aryl;

R3represents alkyl, cycloalkyl, aralkyl or substituted or unsubstituted aryl;

X1represents oxygen or sulfur;

represents a single bond or a double bond and substituted or unsubstituted aryl means aryl, which is optionally substituted by 1 or 2 substituents, independently selected from C1-C6-alkyl, trifloromethyl, hydroxyl, C1-C6-alkoxyl, C1-C6-alkylthio, nitro, halogen, amino, C1-C6-alkylamino, C1-C6-alkanolamine, aroylamino, carboxyl, C1-C6-alkoxycarbonyl, C1-C6alkanoyl and Arola; which have bronchodilator activity, diuretic activity, protecting kidney activity and/or activity against memory loss.

We now discovered that certain derivatives of 8-(disubstituted)phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-it is a potent and selective inhibitors specific to cyclic guanosine-3',5'-monophosphate phosphodiesterase (cGMP-specific PDE), and more specifically, inhibitors of phosphodiesterase 5 (PDE 5), and are useful in the treatment of angina, hypertension, congestive heart failure, stroke, asthma, male erectile dysfunction, female sexual dysfunction, glaucoma and irritable bowel syndrome.

Accordingly, the present invention provides compounds that are derivatives of 8-phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-she of the formula (I):

where

R1, R2and R3each independently represent: hydrogen; alkyl group which is unsubstituted or substituted by hydroxy, alkoxy, alkylthio, amino, mono - or dialkylamino, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl or alkylarene the school group; or a group of the formula

-(CH2)n-R6

where n is an integer from 0 to 4 and R6is cycloalkyl group; phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, hydroxy, alkylenedioxy, alkoxy, amino, mono - or dialkylamino, nitro, cyano or triptoreline groups; or a 3-7-membered ring including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, the said ring may be unsubstituted or substituted by one or more halogen atoms or hydroxy, phenyl, alkoxycarbonyl, amino, mono - or dialkylamino or hydroxycarbonyl groups, or one or more alkyl groups, in turn may be unsubstituted or substituted by one or more halogen atoms or hydroxy, alkoxy, hydroxyalkoxy, phenyl, alkoxycarbonyl, amino, mono - or dialkylamino or hydroxycarbonyl groups;

or R4and R5together with the nitrogen atom to which they are attached, form a 3-7-membered ring comprising from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, the said ring may be unsubstituted or substituted by one or more halogen atoms or hydroxy, oxoalkyl, carbamaepine, hydroxycarbonyl the elegance, alkoxycarbonyl, trifluoracetyl, amino, mono - or dialkylaminoalkyl, or alkilinity group, or one or more alkyl, alkenylamine or alkenylamine groups, which, in turn, can be unsubstituted or substituted by one or more halogen atoms or hydroxy, alkoxy, hydroxyalkoxy, amino, mono - or dialkylaminoalkyl, or

R4and R5independently, represent hydrogen, amidinopropane or alkyl, alkenylphenol or alkenylphenol group which may be unsubstituted or substituted by one or more halogen atoms or hydroxy, alkoxy, alkylthio, amino, mono - or dialkylaminoalkyl, or

R4represents hydrogen or alkyl group, and R5represents a group of the formula

-(CH2)n-R7

where n is an integer from 0 to 4 and R7is cycloalkyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, hydroxy, alkylenedioxy, alkoxy, amino, mono - or dialkylamino, alkylamino, nitro, cyano or triptoreline groups; phenyl group which may be unsubstituted or substituted by one or more halogen atoms or alkyl, hydroxy, alkylenedioxy, alkoxy, amino, mono - or dialkylamino, nitro, cyano or trifter utilname groups; or a 3-7-membered ring including 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, the said ring may be unsubstituted or substituted by one or more halogen atoms or hydroxy, alkoxy, phenyl, alkoxycarbonyl, amino, monoalkylamines, dialkylamines or hydroxycarbonyl groups, or one or more alkyl groups which may be unsubstituted or substituted by one or more halogen atoms or hydroxy, alkoxy, hydroxyalkoxy, phenyl, alkoxycarbonyl, amino, mono - or dialkylamino or hydroxycarbonyl groups;

and their pharmaceutically acceptable salts.

Alkyl groups and the alkyl part, such as part, present in the alkoxy, hydroxyalkoxy, alkylcarboxylic, mono - or dialkylamino, alkylthio, alkylenedioxy, alkylamino and alkoxycarbonyl groups mentioned in relation to groups of R1to R7usually are "lower" alkyl, containing from 1 to 6, especially from 1 to 4 carbon atoms, and the hydrocarbon chain is branched or unbranched. Preferred alkyl groups and, when appropriate, the alkyl part, include methyl, ethyl, propyl, especially n-propyl and butyl, especially n-butyl. Alkeneamine and alkyline groups specified in relation to formula (I)preferably have at to 6 carbon atoms, most preferably, from 2 to 4 carbon atoms.

When alkyl, Alchemilla or Alchemilla group, a ring structure or portion described as substituted by one or more substituents, it is, preferably, means from 1 to 3 substituents, more preferably one or two Deputy.

Cycloalkyl groups specified in respect of the groups R6and R7represent, preferably, With3-10-cycloalkyl group, more preferably, From3-7-cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo and cycloheptyl group. In the compounds of the invention where cycloalkyl group is substituted, preferred substituents include acetamido -, and mono - or dialkylamino, most preferably mono - or diethyl-amino group. Which is the Deputy group may be at any substitutable position cycloalkyl rings. Cycloalkyl ring preferably is substituted in the 1-position.

The halogen atoms mentioned in relation to groups of R4to R7are preferably chlorine atoms or fluorine.

For compounds of the invention where R1, R2or R3represents a group of the formula

-(CH2)nR6,

n can be 0, 1, 2, 3 or 4, preferably 0, 1 or 2.

To connect the third invention, where R6represents a 3-7-membered heterocyclic ring, R6may be unsaturated or saturated and may represent, for example, piperidino, pyrrolidino, azetidinone, aziridinyl, piperazinilnom, morpholinyl, thiomorpholine, pyrrolidino, imidazolidinyl, imidazolidinyl, pyrazolidine, indolinyl, isoindolyl, pyridyloxy, personilnya, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolenine, indazolinone, parinello, hyalinella, izohinolinove, pinolillo, talinolol, naphthyridinone, khinoksalinona, chinazolinei, indolinyl, pteridinyl, hinkleyville, triazolyl, pyrazolidine, triazolyl, tetrazolyl or thienyl group which may be substituted or unsubstituted as described above. In the preferred compounds of the invention where R1, R2or R3represents a group of the formula

-(CH2)nR6,

and where R6represents a 3-7-membered heterocyclic ring,

R6is pyridinol, piperidino, piperazinilnom, morpholinyl, triazolyl or tetrazolyl group.

In the preferred compounds of the invention R1represents hydrogen; C1-C4is an alkyl group or a group of the formula

-(CH2 )nR6,

where n is 0, 1 or 2 and R6represents phenyl, pyridyl or morpholinyl. Most preferably, R1represents hydrogen or a methyl, ethyl, through pyridinol, pyridylmethyl, benzyl or N-morpholinylmethyl group.

In the preferred compounds of the invention R2is1-C5is an alkyl group, especially With1-C4is an alkyl group; substituted C1-C5is an alkyl group; C3-10-cycloalkyl group or a group of the formula

-(CH2)nR6,

where n is 0, 1 or 2 and R6represents unsubstituted or substituted phenyl or pyridyloxy group. Most preferably, R2represents ethyl, through n-boutelou, isobutylene, n-pentelow, methoxyaniline, substituted or unsubstituted benzyl or 3-pyridylmethyl group.

In the preferred compounds of the invention R3is1-C4is an alkyl group; C3-10-cycloalkyl group or a group of the formula

-(CH2)nR6,

where n is 0, 1 or 2 and R6represents unsubstituted or substituted phenyl or pyridyloxy group. Most preferably, R3represents ethyl, sawn or n-boutelou group.

For compounds of the invention where R4and R 5together with the nitrogen atom to which they are attached, form a 3-7-membered ring comprising from 1 to 4 heteroatoms, the ring may be saturated or unsaturated and preferably selected from piperidine, pyrrolidine, azetidine, aziridine, piperazinilnom, [1,4]diazepan-1-ilen, morpholinyl, thiomorpholine, pyrrolidino, pyrazolidine, imidazolidine, imidazolidinyl, pyrazolidine, indolinyl or isoindolyl group with the specified group is unsubstituted or substituted as indicated above. It should be clear that, when the Deputy is Allenova group, it is bound to the heterocyclic ring in any two substitutable positions, which can be adjacent or nesoedinimoe to each other. When the override provisions are not adjacent to each other, Allenova group forms a bridge group. Allenova group preferably has 1 to 5 carbon atoms.

In the preferred compounds of the invention, the ring formed by R4, R5and the nitrogen atom to which they are attached is substituted or unsubstituted piperidine, piperazinilnom, [1,4]diazepan-1-ilen, morpholinyl, pyrazolidine, azetidinone, diaza-bicyclo[2.2.1]hept-2-ilen or hexahydropyrazino[2,1-a]personalni group. Preferably the groups-substituents are 1-C4-alkyl, C2-C4-Alchemilla, carnemolla, amino, di-C1-C4-alkylamino, (2-hydroxyethyl)methylamino, hydroxy, 2,2,2-triptoreline, 2,2,2-triptoreline, formyl group and hydroxyalkyl group, alkoxyalkyl group and hydroxyethoxyethyl group, where the alkyl parts contain 1 to 4 carbon atoms. Most preferably, R4and R5together with the nitrogen atom to which they are attached represent a 4-hydroxypiperidine, 4-carbamoylbiphenyl, 3-carbarnoyl-piperidinol, piperazinilnom, 4-methylpiperidino, 4-ethylpiperidine, 4-formylpiperazine, [1,4]diazepan-1-ilen, 4-methyl-[1,4]diazepan-1-ilen, 4-(2-hydroxyethyl)piperazinilnom, 4-[2-(2-hydroxyethoxy)ethyl]piperazinilnom, morpholinyl, aminopyrazole, diaza-bicyclo[2.2.1]hept-2-ilen, 5-metallizable[2.2.1]hept-2-ilen, 5-(2-hydroxyethyl)diazabicyclo[2.2.1]hept-2-ilen, 3(S)-methylpiperidino, 3(R)-methylpiperazine, (3R,5S) - for 3,5-dimethylpiperidino, (2R,5S)-2,5-dimethylpiperazine, (2S,5R)-2,5-dimethylpiperazine, 3-di-methylaminomethyl, 3-dimethylaminomethylphenol, 4-arylpiperazines, 4-propylpiperazine, hexahydropyrazino [1,2-a]pyrazin-2-ilen, (3R,5S)-3,4,5-trimethylpyrazole, 4-(2-methoxyethyl)piperazinilnom, 4-(2-hydroxyethyl)[1,4]Diaz is pan-1-ilen, 4-(2-hydroxy-1-methyl-ethyl)piperazinilnom, 4-(2-hydroxy-1,1-dimethylethyl)piperazinilnom, 4-(2,2,2-triptorelin)piperazinilnom, 4-(3-hydroxypropyl)piperazinilnom, 4-(isopropyl)piperazinilnom, 4-(2-ethoxyethyl)piperazinilnom, 4-(2,2,2-triptoreline)piperazinilnom, 3-hydroxyazetidine, 3-(2-hydroxyethyl)methyl-aminoantipyrine or 4-(2-hydroxyethyl)piperidino group.

For compounds of the invention where R4and R5independently, represent hydrogen, amidinopropane or alkyl, alkenylphenol or alkenylphenol group which may be unsubstituted or substituted by one or more hydroxy, alkoxy, alkylthio, amino, mono - or dialkylaminoalkyl, R4and R5preferably represent hydrogen or C1-C4is an alkyl group which is unsubstituted or substituted by hydroxy or dimethylaminopropoxy, propionyloxy group or amidinopropane, most preferably, R4and R5independently, represent hydrogen or a methyl, ethyl, through hydroxyethylene, dimethylaminoethanol, propenyloxy, dimethylaminopropyl or amidinopropane.

For compounds of the invention where R4represents hydrogen or alkyl and R5represents a group of the formula

-(CH2)nR7,

n can be 0, 1, 2, 3 or 4, preferably 0, 1, 2, or 3./p>

For compounds of the invention where R7represents a 3-7-membered heterocyclic ring, R7may be unsaturated or saturated and may represent, for example, piperidino, pyrrolidino, azetidinone, aziridinyl, piperazinilnom, morpholinyl, thiomorpholine, pyrrolidino, imidazolidinyl, imidazolidinyl, pyrazolidine, indolinyl, isoindolyl, pyridyloxy, personilnya, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, indolenine, indazolinone, parinello, hyalinella, izohinolinove, pinolillo, talinolol, naphthyridinone, khinoksalinona, chinazolinei, indolinyl, pteridinyl, hinkleyville, triazolyl, pyrazolidine, triazolyl, tetrazolyl or thienyl group which may be substituted or unsubstituted. R7may, alternatively, represent unsubstituted or unsubstituted cycloalkyl or phenyl group as described above.

In the preferred compounds of the invention R4represents hydrogen or C1-C4is an alkyl group, and R5represents a group of the formula

-(CH2)nR7,

n is 0, 1, 2 or 3 and R7is pyridinol, piperidino, piperazinilnom, morpholinyl, triazolyl, tetrazolyl, pyrrol denilou, 1-ethyl-aminocyclopent-1-ilen, 1-diethylaminotoluene-1-ilen, 1-acylaminoalkyl-1-ilen, 1-diethylaminoethyl-1-ilen, 3,4-dimethoxyphenyl, 1-methyl-4-phenylpiperidine-4-ilen, imidazolidinyl, 1 methylpiperidin-4-ilen, tetrahydrofuranyl, 2,2,6,6-tetramethylpiperidine-4-ilen, 4-hydroxybiphenyl-4-ilen, 1-acetamidocinnamate-1-ilen, 1-methyl-3-azetidinol or 4-methylpiperazin-1-ilen group. Most preferred are compounds in which R4represents hydrogen or a methyl or ethyl group, and R5is pyridyloxy, 1-morpholinylmethyl, 1-piperidyl-ethyl, 1-morpholinylcarbonyl, 1-pyrrolidineethanol, 1-ethylenediaminetetramethylene, 1-ethylaminomethyl-methyl, 1-diethylaminocarbonylmethyl, 1-diethyl-aminocyclohexanol, 2-(3,4-acid)ethyl, 1-methyl-4-phenylpiperidine-4-ylmethylene, 1H-[1,2,4]triazole-3-ilen, pyridine-4-ylmethylene, 2-pyridine-2-olatilo, 3-imidazol-1-ylpropyl, 1 methylpiperidin-4-ilen, Tetra-hydrofuran-2-ylmethylene, 2,2,6,6-tetramethylpiperidine-4-ylmethylene, 1-acetamidocinnamate-1-ylmethylene, 1-methyl-azetidin-3-ilen or 4-methylpiperazin-1-ilen group.

Compounds of interest are:

6-ethyl-8-[5-(4-methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-[2-bout the STI-5-(4-methylpiperazin-1-sulfonyl)phenyl]-6-ethyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-[5-(4-methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-[5-(4-methyl[1,4]diazepan-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

6-butyl-8-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxy-N-pyridin-4-albenzaalbenza,

8-[5-((S)-3-methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-[5-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]-triazolo[3,4-i]purine-5-he,

8-[5-(3-dimethylaminomethylene-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-[5-((3R,5S) - for 3,5-dimethylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

N-(3-dimethylamino-2,2-dimethylpropyl)-3-(oxopropyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde,

8-{5-[4-(2-hydroxyethyl)-[1,4]diazepan-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-{5-[4-(2-hydroxy-1,1-dimethylethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

6-butyl-8-{5-[-(2-hydroxy-1,1-dimethylethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-he.

In accordance with the following characteristic of the present invention 8-phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-ones of General formula (I) is produced by interaction of the corresponding derived hydrazinophenyl formula (II):

(where R2, R3, R4and R5have the above values with the corresponding carboxylic acid of General formula

(where R1has the values indicated above) or its reactive derivative. Preferred examples of the reactive derivative of carboxylic acid (III) are gelegenheid, orthoepy or acid anhydride. The interaction can be performed in a solvent, preferably a polar aprotic solvent such as N,N-dimethylformamide, dioxane, acetone or tetrahydrofuran, in the presence of an organic base, preferably an amine, such as triethylamine, and at a temperature of from 15°C to the boiling point of the solvent. The interaction can also be carried out in the absence of solvent, in this case, use an excess of carboxylic acid (III) or a reactive carboxylic acid derivative (III), and the mixture is heated at a temperature of from 40°C to its boiling point. The thus obtained derivative 8-phenyl-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-she then rank what are the usual ways, known in this technical field.

Hydrazinophenyl General formula (II) is produced by interaction of 6-tocophenol General formula (IV)

(where R2, R3, R4and R5have the above values) hydrazinehydrate at a temperature of from 80 to 150°C.

6-Toxaphene General formula (IV) is produced by interaction of 8-phenalkamines General formula (V)

(where R2, R3, R4and R5have the above values) pentasulfide phosphorus or reagent Lawesson (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide). The interaction is preferably carried out in a solvent such as benzene, toluene, dioxane or pyridine, at a temperature of from 40°C to boiling point of solvent.

8-Panelcenter General formula (V) are obtained from the corresponding compounds of formula (VI):

(where R2and R3have the above values) interaction with chlorosulfonic acid (preferably in excess), preferably in a nitrogen atmosphere and at a temperature of from -50°to 100°and using as a solvent of the same chlorosulfonic acid. In this way we obtain sulphonylchloride formula (VII):

where R2and R3 have the above values, the further interaction of which with the corresponding amine (VIII):

where R4and R5have the above values, the gain derived 8-perxantine General formula (VI). The interaction is carried out in an organic solvent, preferably a polar aprotic organic solvent, such as dioxane, methylene chloride or tetrahydrofuran, at temperatures from 10°C to the boiling point of the solvent and in the presence of an organic base, preferably, the base form of the amine, such as triethylamine.

Derivatives of 8-phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-ones of General formula (I) receive, in accordance with the following characteristic of the invention, from the corresponding perxantine formula (IX):

(where R1, R2and R3have the above values) interaction with chlorosulfonic acid (preferably in excess), preferably in a nitrogen atmosphere and at a temperature of from -5°to 10°where the solvent is the same chlorosulfonic acid. In this way we obtain sulphonylchloride formula (X):

where R1, R2and R3have the above values, the further interaction of which correspond with them an amine (VIII)

where R4and R5have the above values, the gain derived 8-phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-it General formula I. Interaction is carried out in an organic solvent, preferably a polar aprotic organic solvent, such as dioxane, methylene chloride or tetrahydrofuran, at temperatures from 10°C to 40°and in the presence of an organic base, preferably an amine such as triethylamine. The thus obtained derivative 8-phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-she then emit the usual way known in the art.

Intermediate compounds of formula (IX) can be obtained by interaction of the corresponding derived hydrazinophenyl formula (XI):

(where R2and R3have the above values) and the corresponding carboxylic acid of General formula (III):

(where R1has the values indicated above) or its reactive derivative. The reactive derivative of carboxylic acid (III) is preferably gelegenheid, orthoepy or acid anhydride. The interaction can be performed in a solvent, preferably a polar aprotic solvent such as N,N-dimethylformamide, dioxane,acetone or tetrahydrofuran, in the presence of an organic base, preferably an amine, such as triethylamine, and at a temperature of from 15°C to 40°C. Interaction can also be carried out in the absence of solvent, in this case, use an excess of carboxylic acid (III) or a reactive carboxylic acid derivative (III) and the mixture is heated at a temperature of from 40°C to its boiling point.

Hydrazinophenyl General formula (XI) are obtained by the interaction of 6-tocophenol General formula (XII)

(where R2and R3have the above values) hydrazinehydrate at a temperature of from 80°to 150°C.

6-Toxaphene General formula (XII) is obtained by interaction of 8-phenalkamines General formula (VI)

(where R2and R3have the above values) pentasulfide phosphorus or reagent Lawesson (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide ohms). The interaction is preferably carried out in a solvent such as benzene, toluene, dioxane or pyridine, at a temperature of from 40°C to boiling point of solvent.

8-Panelcenter General formula (VI) can be obtained by interaction of the corresponding 5,6-diaminofurazan and the corresponding derivatives of salicylic acid by methods known per se, for example, described the publication N. W. Hamilton et al., J. Med. Chem. 1985, 28, 1071-1079 and cited in the references.

Derivatives of 8-phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-she of the formula (I) can be converted by methods known per se, pharmaceutically acceptable salt, preferably an acid additive salt, by treatment with organic or inorganic acids such as fumaric, tartaric, succinic or hydrochloric acid. In addition, derivatives of 8-phenyl-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-she of the formula (I)are the acid group can be converted to a pharmacologically acceptable salt by interaction with the hydroxide of an alkali metal or organic base, such as sodium hydroxide or potassium. Educated thus acid - or alkali-salt additive can be subjected to mutual transformation of suitable pharmaceutically acceptable counterions using a method known in itself.

Specific cyclic GMP phosphodiesterase (PDE 5) was isolated from lysates of human platelets ion exchange chromatography using a column of Mono-Q. Enzymatic activity was determined using 0.25 mm [3H]-cyclic GMP as substrate. Purification of the enzyme and evaluation of PDE 5-inhibitory activity of the proposed compounds were performed essentially as described Gristwood et al., Br.J. Pharmacol.1992, 105, 985-991. The results are given in table 1.

TABLE 1
ExampleIC50(nm)
411
613
171,5
1814
223,7
274
434
861,4
890,51
910,97
930,85
1010,54
1050,34
1081,6
1380,84

From the table it can be seen that the compounds of formula (I) are potent inhibitors specific for cyclic GMP phosphodiesterase (PDE 5). Preferred derivatives of 8-phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-she of the invention have the value of the IC50for inhibition of PDE 5 (defined as above) is less than 30 nm, preferably less than 20 nm, and most preferably less than 15 nm. Derivatives of 8-phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-she of the invention are useful in the treatment of stable, unstable and variant angina, the ISU is renzie, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, conditions of reduced potency of the blood vessels, peripheral vascular disease, vascular disorders (e.g., disease, Raynaud's disease), stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, male erectile dysfunction, female sexual dysfunction and diseases characterized by disorders of the locomotor ability of the intestinal tract, such as irritable bowel syndrome.

Accordingly, derivatives of 8-phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-she of the invention and their pharmaceutically acceptable salts and pharmaceutical compositions comprising such compound and/or salts thereof, can be used in the treatment of disorders of the human body, which includes the introduction of a patient, which requires such treatment, an effective amount of a derivative of 8-phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-she of the invention or its pharmaceutically acceptable salt.

The present invention also provides pharmaceutical compositions which comprise as active ingredient, at least one derivative of 8-phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-she of the formula (I) or its pharmaceutically acceptable salt in combination with a pharmaceutically admission is subject to excipients, such as a carrier or diluent.

The active ingredient may comprise from 0.001% to 99 wt. -%, preferably, from 0.01% to 90 wt. -%, composition, depending on the nature of the finished formulation and whether further dilution before use. The composition is preferably produced in a form suitable for oral, local, nasal, rectal, or subcutaneous injection.

Pharmaceutically acceptable excipients that are mixed with the active compound or salts of such compounds with the formation of the compositions of this invention are well known in themselves, and used these excipients depend, among other things, on the intended route of administration of the compositions.

Compositions of the present invention, preferably, adapted for injection and oral administration. In this case, the compositions for oral administration can be in the form of pills, tablets, sustained-action, sublingual tablets, capsules or liquid preparations such as mixtures, elixirs, syrups or suspensions, all of which contain the compound according to the invention; such preparations can be manufactured by methods well known in the field.

Diluents which can be used to obtain compositions include liquid and solid rabbanites is, compatible with the active ingredient, together, if necessary, coloring agents or korrigentami. Tablets or capsules can in a convenient case to contain between 2 and 500 mg of the active ingredient or the equivalent amount of salt.

Liquid composition adapted for oral use may be in the form of solutions or suspensions. The solutions may be aqueous solutions of soluble salts or other derived active compounds in combination, e.g., with sucrose to form syrup. Suspension may include insoluble active compound of the invention or its pharmaceutically acceptable salt in combination with water, together with suspenders agent or Corrigendum.

Compositions for parenteral injection can be obtained from soluble salts, which may or may not be dried by freezing and which can be dissolved in not containing pyrogens aquatic environment or other suitable for parenteral injection fluid.

Effective doses are usually in the range of 10-600 mg of active ingredient per day. The daily dose can be administered once or several times, preferably from 1 to 4 per day.

The syntheses of the compounds according to the invention and intermediates for use for their production are illustrated by the following examples (including in the minimum level receiving (receiving 1-37)), which in no way limit the scope of the invention.

Spectra1H nuclear magnetic resonance were recorded on a spectrometer Varian Gemini 300. Mass spectra of low-resolution (m/z) were recorded on a mass spectrometer Micromass ZMD using ionization elektrorazpredelenie (ESI). Melting points were recorded using equipment Perkin Elmer DSC-7. Chromatographic separation was performed using Waters 2690 equipped with a column Symmetry C18 (2,1×10 mm, 3.5 Ám). The mobile phase was formic acid (0.4 ml), ammonia (0.1 ml), methanol (500 ml) and acetonitrile (500 ml) and formic acid (0,46 ml), ammonia (0,115 ml) and water (1000 ml) (B): first, from 0% to 95% b for 20 min and then for 4 min 95% Century. While re-balancing between the two injections was 5 min. flow Rate was 0.4 ml/min Volume of injection was 5 Ál. Diode matrix chromatogram collected at 210 nm.

EXAMPLES RETRIEVE

GETTING 1

8-(2-Ethoxyphenyl)-6-ethyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

a) a Solution of 2-ethoxybenzonitrile (12.0 g, 65 mmol) in dimethylformamide (10 ml) is added dropwise to a stirred solution of 5,6-diamino-1-ethyl-1H-pyrimidine-2,4-dione (10.4 g, 61 mmol) and triethylamine (9.8 ml, 65 mmol) in dimethylformamide (250 ml). The resulting mixture is stirred for 20 hours at room temperature, then uprivate reduced pressure. Add an aqueous solution of sodium hydroxide (1 n, 98 ml, 98 mmol), and the mixture is heated at boiling under reflux for 6 hours. The resulting solution is acidified with 1 n hydrochloric acid and the precipitate collected and dried by suction to obtain 8-(2-ethoxyphenyl)-3-ethyl-3,7-dihydropyran-2,6-dione in the form of a beige solid (7.0 g, 72%).

b) To a stirred suspension of the above compound (7.0 g, with 23.3 mmol) in pyridine (115 ml) was added in several portions of pentasulfide phosphorus (5.5 g, 12.4 mmol) and the resulting mixture was stirred at the boil under reflux for 3 hours, then evaporated under reduced pressure. The residue is triturated with dilute hydrochloric acid (2 n, 100 ml) and the precipitate collected by filtration and dried in vacuum to obtain 8-(2-ethoxyphenyl)-3-ethyl-6-mercapto-3,7-dihydropyran-2-it (6,9 g, 95%) as a pale brown solid.

c) Stirring the mixture of the above compound (6.9 g, and 21.8 mmol) and hydrazine monohydrate (100 ml) is heated to 130°C for 3 hours. The resulting mixture is cooled and the precipitate collected by filtration and washed with water and ethanol, then dried in vacuum to obtain 8-(2-ethoxyphenyl)-3-ethyl-6-hydrazino-3,7-dihydropyran-2-she (6.6 g, 97%) as not quite white solid.

d) Stirring the mixture of the above compound (6.6 g, 21,0 mmol) and formic acid is you (110 ml) is heated at the boil under reflux for 2 hours. The resulting solution was concentrated in vacuo and the residue partitioned between dichloromethane and aqueous sodium bicarbonate solution, then the organic phase is separated, washed with water, dried (MgSO4) and evaporated under reduced pressure to obtain specified in the header of the product (5.4 g, 79%) as not quite white solid.

d (DMSO-d6): to 1.38 (3H, t), for 1.49 (3H, t), 4,27 (4H, m), was 7.08 (1H, t), 7,21 (1H, d), 7,47 (1H, t), of 7.97 (1H, d), of 9.21 (1H, s).

GETTING 2

4 Ethoxy-3-(6-ethyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)benzosulphochloride

Specified in the header of the receive connector 1 (5,4 g of 16.6 mmol) is added by portions to undiluted, ice chlorosulfonic acid (16 ml) and the resulting mixture was stirred at 0°C for 30 minutes and at room temperature over night. The reaction mixture is carefully poured into stirred mixture of ice-water and the precipitate collected by filtration and dried under reduced pressure to obtain specified in the title compound (6.4 g, 91%) as a white solid.

d (DMSO-d6): 1,42 (6N, m)to 4.33 (2H, HF), was 4.42 (2H, q), of 7.23 (1H, d), 7,73 (1H, d), 8,39 (1H, s), 9,59 (1H, s).

GETTING 3

6-Ethyl-8-(2-propoxyphenyl)-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-he

Obtained as a white solid (total yield 51%) of 5,6-diamino-1-ethyl-1H-pyrimidine-2,4-dione and 2-propoxybenzaldehyde methodology, description of the TES in receiving 1.

d (DMSO-d6): to 1.15 (t, 3H)and 1.51 (t, 3H), of 2.05 (m, 2H), 4,22 (t, 2H), of 4.44 (q, 2H), 7,05 (d, 1H), 7,12 (t, 1H), 7,42 (t, 1H), 8,40 (d, 1H), of 8.95 (s, 1H), 11,40 (Sirs, 1H).

GETTING 4

3-(6-Ethyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (74%) from the specified in the header of the receive connector 3 using the techniques described in the getting 2.

d (DMSO-d6): of 0.95 (t, 3H), of 1.39 (t, 3H), equal to 1.82 (m, 2H), 4,33 (m, 4H), 7,22 (d, 1H), of 7.75 (d, 1H), 8,28 (s, 1H), of 9.55 (s, 1H), 14.4V (Sirs, 1H).

GETTING 5

8-(2-Butoxyphenyl)-6-ethyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (total yield 70%) of 5,6-diamino-1-ethyl-1H-pyrimidine-2,4-dione and 2-butoxybenzaldehyde technique described in obtaining 1.

d (DMSO-d6): of 1.05 (t, 3H)and 1.51 (m, 5H), of 1.95 (m, 2H), 4,25 (t, 2H), of 4.45 (q, 2H), 7,05 (d, 1H), 7,13 (t, 1H), 7,42 (t, 1H), 8,40 (d, 1H), of 8.95 (s, 1H), 11,55 (Sirs, 1H).

GETTING 6

4 Butoxy-3-(6-ethyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)benzosulphochloride

Obtained as a white solid (42%) from the specified in the header of the receive connector 5 using the techniques described in the getting 2.

d (DMSO-d6): of 0.95 (t, 3H), of 1.40 (m, 5H), of 1.80 (m, 2H), 4,32 (m, 4H), 7,22 (d, 1H), of 7.75 (d, 1H), scored 8.38 (s, 1H), of 9.55 (s, 1H), 13,0 (Sirs, 1H).

GETTING 7

8-(2-Ethoxyphenyl)-6-propyl-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-he

Obtained as a white solid (total yield 28) of 5,6-diamino-1-propyl-1H-pyrimidine-2,4-dione and 2-ethoxybenzonitrile technique described in obtaining 1.

d (DMSO-d6): to 0.96 (3H, t), of 1.41 (3H, t), and 1.83 (2H, m), 4,18 (2H, t), 4,28 (2H, HF), to 7.09 (1H, t), 7,20 (1H, d), 7,46 (1H, t), to 7.93 (1H, d), of 9.21 (1H, s).

GETTING 8

4 Ethoxy-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)benzosulphochloride

Obtained as a white solid (73%) from the specified in the header of the receive connector 7 using the techniques described in the getting 2.

d (DMSO-d6): 0,99 (3H, t), of 1.42 (3H, t), 1,89 (2H, m), 4,22 (2H, t), 4,32 (2H, HF), 7,19 (1H, d), of 7.69 (1H, d), compared to 8.26 (1H, s), was 9.33 (1H, s).

9

8-(2-Propoxyphenyl)-6-propyl-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-he

Obtained as a beige solid (total yield 21%) of 5,6-diamino-1-propyl-1H-pyrimidine-2,4-dione and 2-propoxybenzaldehyde technique described in obtaining 1.

d (DMSO-d6): to 0.96 (3H, t), of 0.99 (3H, t), and 1.83 (4H, m), 4,17 (4H, m), 7,10 (1H, t), 7,22 (1H, d), 7,49 (1H, t), of 7.96 (1H, d), which 9.22 (1H, s).

RECEIVE 10

3-(5-Oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (100%) specified in the header of the receive connector 9 using the techniques described in the getting 2.

d (DMSO-d6): 0,98 (6N, m), a 1.88 (4H, m), 4.26 deaths (4H, m), 7.23 percent (1H, d), 7,71 (1H, d), 8,30 (1H, s), 9,50 (1H, s).

RECEIPT 11

6-Butyl-8-(2-ethoxyphenyl)-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained in the form of not-quite-white solid (total yield 49%) of 5,6-diami is about-1-butyl-1H-pyrimidine-2,4-dione and 2-ethoxybenzonitrile technique described in obtaining 1.

d (CDCl3): of 1.02 (3H, t)to 1.48 (2H, m), and 1.63 (3H, t), of 1.88 (2H, m), 4,39 (4H, m), 7,07 (1H, d), 7,16 (1H, t), 7,42 (1H, d), to 8.41 (1H, d), 8,93 (1H, s), 11,37 (1H, Sirs).

GETTING 12

3-(6-Butyl-3-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-ethoxybenzonitrile

Obtained as a white solid (90%) from the specified in the header of the receive connector 11 using the techniques described in the getting 2.

d (CDCl3): to 0.96 (3H, t), of 1.42 (5H, m), equal to 1.82 (2H, m), 4,28 (2H, t), 4,39 (2H, HF), 7,20 (1H, d), 7,72 (1H, d), 8,29 (1H, s), 9,43 (1H, s).

13

6-Butyl-8-(2-propoxyphenyl)-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-he

Obtained as a beige solid (total yield 41%) of 5,6-diamino-1-butyl-1H-pyrimidine-2,4-dione and 2-propoxybenzaldehyde technique described in obtaining 1.

d (CDCl3): of 1.03 (3H, t), of 1.12 (3H, t)of 1.50 (2H, m), 1,90 (2H, m), is 2.05 (2H, m), 4.26 deaths (2H, t), 4,39 (2H, t), 7,12 (2H, m), the 7.43 (1H, t), of 8.40 (1H, d), of 8.95 (1H, s), 11,36 (1H, m).

GETTING 14

3-(6-Butyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (86%) from the specified in the header of the receive connector 13 using the techniques described in the getting 2.

d (CDCl3): 1,05 (6N, m)of 1.50 (2H, m), of 1.95 (4H, m), and 4.40 (4H, m), 7,35 (1H, d), 8,10 (1H, d), 8,82 (1H, s), 9,05 (1H, s).

RECEIVE 15

8-(2-Butoxyphenyl)-6-butyl-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-he

Obtained in the form of be is avago solids (total yield 22%) of 5,6-diamino-1-butyl-1H-pyrimidine-2,4-dione and 2-butoxybenzaldehyde technique described in obtaining 1.

d (CDCl3): 1,02 (6N, m)of 1.55 (4H, m), of 1.95 (4H, m), 4,35 (4H, m), 7,10 (2H, m), 7,42 (1H, m), 8,40 (1H, d), of 8.95 (1H, s)11,43 (1H, Sirs).

GETTING 16

4 Butoxy-3-(6-butyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)-4-benzosulphochloride

Obtained as a white solid (77%) from the specified in the header of the receive connector 15 using the techniques described in the getting 2.

d (CDCl3): 1,03 (6N, m)of 1.52 (4H, m), of 1.95 (4H, m)to 4.41 (4H, m), 7,25 (1H, d), of 8.09 (1H, d), of 8.95 (1H, s), 9,03 (1H, s)11,94 (1H, Sirs).

GETTING 17

3-Methyl-8-(2-propoxyphenyl)-6-propyl-6,9-dihydro[1,2,4]-triazolo[3,4-i]purine-5-he

A mixture of 8-(2-propoxyphenyl)-3-propyl-6-hydrazino-3,7-dihydropyran-2-she (1.0 g, 2.9 mmol, see 9) and triethylorthoformate (10 ml) is heated at the boil under reflux for 2 hours. The resulting mixture is cooled and the precipitate collected by filtration and washed with water and ethanol, then dried in vacuum to obtain specified in the connection header (0,82 g, 77%) as not quite white solid.

d (DMSO-d6): to 0.92 (3H, t), is 0.96 (3H, t), equal to 1.82 (4H, m), 2,77 (3H, s), 4,24 (4H, m), was 7.08 (1H, t), 7,20 (1H, d), was 7.45 (1H, t), 7,92 (1H, d).

GETTING 18

3-(3-Methyl-5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (88%) of the specified in the header of the receive connector 17 using the methods described in the getting 2.

d (CDCl3): 1,10 (4H, m), a 1.96 (2H, m), is 2.09 (2H, m), 2,96 (3H, s), 4,32 (2H, t), 4,48 (2H, t), 7,28 (1H, d), of 8.09 (1H, d), 9,07 (1H, s), and 11.8 (1H, Sirs).

GETTING 19

6 Hydrazino-8-[5-(4-methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-3-propyl-3,7-dihydropyran-2-he

a) Pentasulfide phosphorus (0.7 g, 3.1 mmol) is added in portions to a stirred suspension of 8-[5-(4-methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-3-propyl-3,7-dihydropyran-2,6-dione (1.5 g, with 23.3 mmol) in pyridine (15 ml) and the resulting mixture was stirred at the boil under reflux for 3 hours, then evaporated under reduced pressure to get crude 8-(2-propoxyphenyl)-3-propyl-6-mercapto-3,7-dihydropyran-2-it (1,38 g), which is used directly in the next stage.

d (DMSO-d6): to 0.89 (3H, t), of 1.03 (3H, t), of 1.75 (2H, m), equal to 1.82 (2H, m), of 2.15 (3H, s), is 2.37 (4H, m), of 2.92 (4H, m), of 3.97 (2H, t), 4,20 (2H, t), 7,42 (1H, d), of 7.82 (1H, d), 8,16 (1H, s), 12,34 (1H, Sirs), 12,67 (1H, Sirs).

b) Stirring the mixture of the above compounds (1,38 g) and hydrazine monohydrate (15 ml) is heated to 130°C for 3 hours. The resulting mixture is cooled and the precipitate collected by filtration and washed with water and ethanol, then dried in vacuo to obtain 6-hydrazino-8-[5-(4-methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-3-propyl-3,7-dihydropyran-2-it (1.08 g, total yield 70%) as not quite white solid.

d (DMSO-d6): to 0.89 (3H, t), was 1.04 (3H, m)to 1.70 (2H, m), 1,89 (2H, m)to 2.13 (3H, s), a 2.36 (4H, m), 2.91 in (4 is, m), of 3.96 (2H, m), 4,28 (2H, m), 7,51 (1H, d), 7,81 (1H, d), 8,51 (1H, s).

20

6 Hydrazino-8-[5-(piperazine-1-sulfonyl)-2-propoxyphenyl]-3-propyl-1,3,6,7-tetrahydropyran-2-he

Obtained as a beige solid (total yield 10%) of 8-[5-(piperazine-1-sulfonyl)-2-propoxyphenyl]-3-propyl-3,7-dihydropyran-2,6-dione by the procedure described in obtaining 19.

d (DMSO-d6): to 0.89 (3H, t), of 1.06 (3H, m), 1,72 (2H, m), at 1.91 (2H, m), 2,71 (4H, m), 2,82 (4H, m), of 3.96 (2H, m), 4,28 (2H, m), 7,51 (1H, d), 7,88 (1H, d), charged 8.52 (1H, s).

GETTING 21

6 Hydrazino-8-[5-(4-methyl[1,4]diazepan-1-sulfonyl)-2-propoxyphenyl]-3-propyl-1,3,6,7-tetrahydropyran-2-he

Obtained in the form of not-quite-white solid (total yield 91%) of 8-[5-(4-methyl[1,4]diazepan-1-sulfonyl)-2-propoxyphenyl]-3-propyl-3,7-dihydropyran-2,6-dione by the procedure described in obtaining 19.

d (DMSO-d6): to 0.89 (3H, t), was 1.04 (3H, m), 1,72 (4H, m), with 1.92 (2H, m), 2,22 (3H, s), 2,4-2,6 (6N, m)to 3.38 (4H, m), 3,98 (2H, t), 4,28 (2H, t), 7,44 (1H, d), 7,86 (1H, d), 8,58 1H, s).

GETTING 22

6 Hydrazino-8-[5-(morpholine-4-sulfonyl)-2-propoxyphenyl]-3-propyl-3,7-tetrahydropyran-2-he

Obtained as a beige solid (total yield 16%) of 8-[5-(morpholine-4-sulfonyl)-2-propoxyphenyl]-3-propyl-3,7-dihydropyran-2,6-dione by the procedure described in obtaining 19.

d (DMSO-d6): to 0.88 (3H, t), of 1.03 (3H, m)of 1.75 (2H, m), with 1.92 (2H, m), of 2.92 (4H, m)to 3.64 (4H, m), of 3.96 (2H, m), 4,25 (2H, m), 7,52 (1H, m), 7,79 (1H, m), 8,51 (1H, s).

23

8-[2-Butoxy-5-(4-methylpiperazin-1 sulfone is)phenyl]-6-hydrazino-3-propyl-3,7-dihydropyran-2-he

Obtained as a beige solid (total yield 71%) of 8-[2-butoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-3-propyl-3,7-dihydropyran-2,6-dione by the procedure described in obtaining 19.

d (DMSO-d6): 0,92 (6N, m)of 1.52 (2H, m), 1,89 (4H, m), 2,12 (3H, s), is 2.37 (4H, m), of 2.92 (4H, m)to 3.99 (2H, t), 4.26 deaths (2H, t), of 7.48 (1H, d), to 7.84 (1H, d), 8,17 (1H, s).

GETTING 24

8-[2-Butoxy-5-(morpholine-4-sulfonyl)phenyl]-6-hydrazino-3-propyl-3,7-dihydropyran-2-he

Obtained as a beige solid (total yield 30%) of 8-[2-butoxy-5-(morpholine-4-sulfonyl)phenyl]-3-propyl-3,7-dihydropyran-2,6-dione by the procedure described in obtaining 19.

d (DMSO-d6): 0,92 (6N, m)of 1.46 (2H, m), by 1.68 (2H, m), equal to 1.82 (2H, m), of 2.86 (4H, m), of 3.60 (4H, m), of 3.94 (2H, t), 4,32 (2H, m)to 7.50 (1H, d), 7,80 (1H, d), 8,49 (1H, s).

RECEIVE 25

8-(2-Propoxyphenyl)-6-pyridin-2-ylmethyl-6,9-dihydro[1,2,4]-triazolo[3,4-i]purine-5-he

Obtained as a beige solid (total yield 19%) of 5,6-diamino-1-pyridin-2-ylmethyl-1H-pyrimidine-2,4-dione and 2-propoxybenzaldehyde technique described in obtaining 1.

GETTING 26

3-(5-Oxo-6-pyridin-2-ylmethyl-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (65%) from the specified in the header of the receive connector 25 using the techniques described in the getting 2.

GETTING 27

6-Butyl-8-(2-propoxyphenyl)-3-propyl-6,9-dihydro[1,2,4]-triazolo[3,4-i]purine-5-he

The floor is EN in the form of a white solid (total yield 28%) of 5,6-diamino-1-butyl-1H-pyrimidine-2,4-dione and 2-propoxybenzaldehyde technique described in getting 1, using triethylorthoformate instead of formic acid in the last stage.

GETTING 28

3-(6-Butyl-5-oxo-3-propyl-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (86%) from the specified in the header of the receive connector 27 using the techniques described in the getting 2.

GETTING 29

6-Isobutyl-8-(2-propoxyphenyl)-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-he

Obtained as a white solid (total yield 21%) of 5,6-diamino-1-isobutyl-1H-pyrimidine-2,4-dione and 2-propoxybenzaldehyde technique described in obtaining 1.

δ (DMSO-d6): 0,93 (N, m)of 1.80 (2H, m), a 2.36 (1H, m), was 4.02 (2H, d), of 4.12 (2H, t), to 7.09 (1H, t), 7,18 (1H, d), 7,44 (1H, t), 7,92 (1H, d), 9,20 (1H, s).

30

3-(6-Isobutyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (62%) from the specified in the header of the receive connector 29 using the techniques described in the getting 2.

δ (DMSO-d6): 1,01 (N, m)to 1.86 (2H, m), a 2.36 (1H, m)4,06 (2H, d), 4,19 (2H, t), 7,18 (1H, d), 7,66 (1H, d), 8,18 (1H, s), 9,27 (1H, s).

GETTING 31

6-Pentyl-8-(2-propoxyphenyl)-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-he

Obtained as a white solid (total yield 19%) of 5,6-diamino-1-pentyl-1H-pyrimidine-2,4-dione and 2-propoxybenzaldehyde method is coy, described in obtaining 1.

δ (DMSO-d6): or 0.83 (3H, t), is 0.96 (3H, t)of 1.33 (4H, m), equal to 1.82 (4H, m), is 4.15 (4H, m), 7,06 (1H, t), 7,19 (1H, d), 7,42 (1H, t), to $ 7.91 (1H, d), 9,19 (1H, s).

GETTING 32

3-(5-Oxo-6-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (55%) from the specified in the header of the receive connector 31 using the techniques described in the getting 2.

δ (DMSO-d6): 0,88 (3H, m), and 0.98 (3H, t)to 1.38 (4H, m), equal to 1.82 (4H, m), 4.26 deaths (4H, m), 7,20 (1H, d), to 7.68 (1H, d), by 8.22 (1H, s), 9,38 (1H, s).

RECEIVE 33

6-(2-Methoxyethyl)-8-(2-propoxyphenyl)-6,9-dihydro[1,2,4]-triazolo[3,4-i]purine-5-he

Obtained as a white solid (total yield 65%) of 5,6-diamino-1-(2-methoxyethyl)-1H-pyrimidine-2,4-dione and 2-propoxybenzaldehyde technique described in obtaining 1.

GETTING 34

3-[6-(2-Methoxyethyl)-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl]-4-propoxybenzaldehyde

Obtained as a white solid (95%) from the specified in the header of the receive connector 33 using the techniques described in the getting 2.

RECEIVE 35

The dihydrochloride of azetidin-3-ylmethylamino

a) a Solution of 1-(1,1-diphenylmethyl)azetidin-3-carbonitrile (7,8 g of 31.4 mmol) in 30 ml of tetrahydrofuran is added slowly to a suspension of sociallyengaged (4.0 g, 105 mmol) in tetrahydrofuran under nitrogen atmosphere and the resulting mixture AC who're asked at boiling under reflux for one hour. Upon cooling the mixture is treated dropwise with water (4 ml), aqueous sodium hydroxide (4 ml, 4 n) and water (12 ml) and filtered. The filtrate is concentrated under reduced pressure to obtain 3-(aminomethyl)-1-(1,1-diphenylmethyl)-azetidine in the form of a white solid (5.2 g, 73%).

b) a Mixture of 3-(aminomethyl)-1-(1,1-diphenylmethyl)azetidine (10,9 g, 43 mmol), formaldehyde (21,8 ml) and formic acid (21,8 ml) stirred at the boil under reflux for one hour and then evaporated under reduced pressure. The resulting residue is mixed with ice, alkalinized aqueous 2 n sodium hydroxide and extracted with dichloromethane. The organic solution is washed with water, saturated salt solution, dried (MgSO4) and evaporated under reduced pressure to obtain [1-(1,1-diphenylmethyl)azetidin-3-ylmethyl]dimethylamine (10.4 g, 86%) as oil.

δ (CDCl3): 2,16 (6N, (C), 2,44 (2H, d), 2,6-2,8 (4H, m)to 3.38 (2H, t), 4,32 (1H, s), 7,1-7,3 (10H, m).

(C) hydrogen Chloride in methanol is added to a mixture of [1-(1,1-diphenylmethyl)azetidin-3-ylmethyl]dimethylamine (9,9 g, 35 mmol) in methanol (150 ml) to achieve pH=4. Added palladium hydroxide (1.5 g, 20%) and the resulting mixture hydronaut at room temperature and 50 psi for 4 days. The mixture is filtered through celite and the filtrate evaporated under reduced pressure to obtain specified in the title compound (5.0 g, 76%) in the de white solid.

δ (DMSO-d6): 2,72 (6N, (C), the 3.2 to 4.1 (8H, m).

GETTING 36

The dihydrochloride of (1S,4S)-2-(2,5-diazabicyclo[2.2.1]hept-2-yl)-ethanol

a) a Mixture of tert-butyl methyl ether (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (0.5 g, 2,52 mmol), 2-(2-bromoethoxy)tetrahydropyran (0,42 ml, 2.77 mmol) and potassium carbonate (1.2 g, 8,82 mmol) 4-methylpentan-2-Ohe stirred at the boil under reflux over night. The resulting mixture was evaporated under reduced pressure and the residue partitioned between water and dichloromethane. The organic layer was washed with a saturated solution of salt, dried (MgSO4) and evaporated under reduced pressure to obtain tert-butyl ester 5-[2-(tetrahydropyran-2-yloxy)ethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (0,80 g, quantitative yield) as oil.

b) a Mixture of tert-butyl ester 5-[2-(tetrahydropyran-2-yloxy)ethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid (0,80 g, 2.4 mmol) and aqueous hydrochloric acid (2 ml, 2 m) in ethanol (10 ml) stirred at the boil under reflux for one hour and then evaporated under reduced pressure to get crude dihydrochloride (1S,4S)-2-(2,5-diazabicyclo[2.2.1]hept-2-yl)ethanol 0.51 g) as a dark oil, which was used in the next stage without additional purification.

GETTING 37

2-Methyl-2-piperazine-1-improper-1-ol

a) a Mixture Ben is silt ether piperazine-1-carboxylic acid (8.8 g, 40 mmol), ethyl ester of 2-bromo-2-methylpropionic acid and potassium carbonate is stirred at 150°C for 24 hours. Upon cooling, the resulting mixture is partitioned between dichloromethane and water. The organic layer was washed with a saturated solution of salt, dried (MgSO4) and evaporated under reduced pressure to obtain benzyl ester 4-(1-etoxycarbonyl-1-methylethyl)piperazine-1-carboxylic acid (10.2 g, 77%) as oil.

b) a Solution of benzyl ester of 4-(1-etoxycarbonyl-1-methylethyl)piperazine-1-carboxylic acid (3.5 g, 10.5 mmol) in 10 ml of dry simple ether is added slowly to a suspension of sociallyengaged (0.3 g, 105 mmol) in tetrahydrofuran at -15°C in nitrogen atmosphere and the resulting mixture was stirred at 0°C for 3 hours. Upon cooling the mixture is treated dropwise with water (0.3 ml), aqueous sodium hydroxide (0.3 ml, 4 n) and water (0.9 ml) and filtered. The filtrate is concentrated under reduced pressure to obtain benzyl ester 4-(2-hydroxy-1,1-dimethylethyl)piperazine-1-carboxylic acid as a white solid (1.2 g, 41%).

c) a Mixture of benzyl ester 4-(2-hydroxy-1,1-dimethylethyl) piperazine-1-carboxylic acid (3.0 g, or 10.3 mmol) in methanol (70 ml) and palladium on coal (0.5 g, 10%) hydronaut at room temperature and at 40 psi overnight. The mixture is filtered through celite and the filtrate evaporated at Pont the leaders introduce pressure to get specified the title compound (1.55 g, 98%) of a white solid.

δ (DMSO-d6): 0,92 (6N, (C), 2,52 (4H, m)of 2.75 (4H, m), 3,23 (2H, s), and 4.8 (2H, Sirs).

EXAMPLES (see table 2).

EXAMPLE 1

8-[2-Ethoxy-5-(4-methylpiperazin-1-sulfonyl) phenyl]-6-ethyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

To the mixture specified in the header of the receive connector 2 (1.1 g, 2.4 mmol) and triethylamine (0.4 ml 2.6 mmol) in dichloromethane (50 ml) added dropwise a solution of 1-methylpiperazine (0.3 ml, 2.6 mmol) in dichloromethane (25 ml) and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane, washed with aqueous sodium bicarbonate solution and water, dried (MgO 4) and evaporated under reduced pressure. The resulting crude residue by crystallization from ethanol gives specified in the title compound (1.1 g, 93%) as a white solid.

TPL 248°C.

d (DMSO-d6): to 1.38 (3H, t)of 1.50 (3H, t), of 2.15 (3H, s), is 2.40 (4H, m), with 2.93 (4H, m), 4,25 (2H, m), and 4.40 (2H, m), 7,45 (1H, d), of 7.90 (1H, d), 8,24 (1H, s), 9.28 are (1H, s), 13,70 (1H, Sirs),

EXAMPLE 2

8-{2-Ethoxy-5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl)-phenyl}-6-ethyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (88%) of the specified in the header of the receive connector 2 and 1-(2-hydroxyethyl)piperazine according to the method of example 1.

TPL 230°C.

d (DMSO-d6): of 1.40 (3H, t)of 1.50 (3H, t), of 2.38 (2H, t), of 2.50 (4H, m), 2,90 (4H, m), 3,40 (2H, m), 4,28 (2H, m), and 4.40 (3H, m), 7,46 (1H, d), of 7.90 (1H, d), compared to 8.26 (1H, s), 9,27 (1H, s), 13,65 (1H, Sirs).

EXAMPLE 3

6-Ethyl-8-[2-propoxy-5-(4-pyridylmethyl)]phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (46%) from the specified in the header of the receive connectors 2 and 4-amino-pyridine according to the method of example 1.

TPL 279°C.

d (DMSO-d6): and 0.98 (3H, t)of 1.39 (3H, t), and 1.83 (2H, m), 4,19 (4H, m)6,94 (2H, Sirs), 7,38 (1H, d), to 7.84 (1H, d), of 8.04 (2H, Sirs), 8,39 (1H, s), which 9.22 (1H, s).

EXAMPLE 4

6-Ethyl-8-[5-(4-methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (61%) from the specified in the header of the receive connector 4 and methylpiperazine by the method of example 1.

TPL 117°C.

d (DMSO-d6): is 1.01 (3H, t), of 1.37 (3H, t)to 1.86 (2H, m), of 2.38 (4H, m), of 2.92 (4H, m), 4.26 deaths (4H, m), of 7.48 (1H, d), 7,80 (1H, d), 8,21 (1H, s), 9.28 are (1H, s)13,72 (1H, Sirs).

EXAMPLE 5

6-Ethyl-8-{2-propoxy-5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]phenyl}-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (86%) from the specified in the header of the receive connector 4 and 1-(2-hydroxyethyl)piperazine according to the method of example 1.

TPL 217°C.

d (DMSO-d6): 1,0 (3H, t), of 1.37 (3H, t), 1,89 (2H, m), a 2.36 (2H, t), of 2.50 (2H, m), and 2.79 (4H, m), 3,40 (2H, m), 4,22 (2H, m), to 4.38 (1H, Sirs), of 7.48 (1H, d), of 7.82 (1H, d), by 8.22 (1H, s), 9.28 are (1H, s), 13,70 (1H, Sirs).

EXAMPLE 6

6-Ethyl-6-(2-butoxy-5-[4-(methylpiperazin-1-sulfonyl)phenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (56%) from the specified in the header of the receive connector 6 and 1-methylpiperazine by the method of example 1.

TPL 206°C.

d (DMSO-d6): to 0.94 (3H, t)to 1.38 (3H, t)to 1.48 (2H, m)of 1.84 (2H, m)of 2.16 (3H, s), of 2.38 (4H, m)to 2.94 (4H, m), or 4.31 (4H, m), 7,80 (1H, d), 7,81 (1H, d), by 8.22 (1H, s), 9,26 (1H, s), 13,71 (1H, Sirs).

EXAMPLE 7

4 Butoxy-3-(6-ethyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)-N,N-his(2-hydroxyethyl)benzosulfimide

Obtained as a white solid (71%) from the specified in the header of the receive connector 6 and diethanolamine according to the method of example 1.

TPL 189°C.

d (DMSO-d6): 0,94 (3H, m)of 1.39 (5H, m)of 1.84 (2H, m), 3,23 (4H, m), of 3.56 (4H, m), the 4.29 (4H, m), the 7.43 (1H, d), 7,89 (1H, d), and 9.5 (1H, C).

EXAMPLE 8

6-Ethyl-8-(2-butoxy-5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]phenyl)-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (54%) from the specified in the header of the receive connector 6 and 1-(2-hydroxyethyl)piperazine according to the method of example 1.

TPL 235°C.

d (DMSO-d6): 0,93 (3H, t), of 1.37 (3H, t)to 1.45 (2H, m)to 1.86 (2H, m), of 2.38 (2H, t), of 2.50 (4H, m), 2.91 in (4H, m), 3,42 (2H, m), 4,30 (5H, m), of 7.48 (1H, d), 7,80 (1H, d), to 8.20 (1H, s), 9,26 (1H, s)13,72 (1H, Sirs).

EXAMPLE 9

4 Butoxy-3-(6-ethyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)-N-(2-morpholine-4-retil)benzosulfimide

Obtained as a white solid (61%) from the specified in the header of the receive connector 6 and N-(2-amino-ethyl)research by the method of example 1.

TPL 158°C.

d (DMSO-d6): 0,93 (3H, m)of 1.41 (5H, m)of 1.84 (2H, m), 2,30 (6N, m), 2,90 (2H, m), of 3.48 (4H, m), 4,30 (4H, m), the 7.43 (1H, d), to 7.59 (1H, m), 7,88 (1H, d), of 8.37 (1H, d), 9,26 (1H, s).

EXAMPLE 10

8-(2-Butoxy-5-{4-[2-(2-hydroxyethoxy)ethyl]piperazine-1-sulfonyl}phenyl)-6-ethyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (70%) from the specified in the header of the receive connector 6 and 1-[2-(2-hydroxyethoxy)ethyl]piperazine according to the method of example 1.

TPL 108°C.

d (DMSO-d6): 0,94 (3H, m)of 1.42 (5H, m)and 1.83 (2H, m), 2,46 (6N, m), 2.91 in (4H, m), 3,36 (6N, m), 4,32 (4H, m), 7,47 (1H, d), 7,78 (1H, d), by 8.22 (1H, d), 9,27 (1H, s).

EXAMPLE 11

8-{2-Ethoxy-5-[4-morpholine-1-sulfonyl]phenyl}-6-propyl-6,9-digit what about[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (37%) from the specified in the header of the receive connector 8 and the research according to the method of example 1.

TPL 265°C.

d (DMSO-d6): of 0.95 (3H, t), of 1.45 (3H, t), of 1.85 (2H, m), 2,90 (4H, m), the 3.65 (4H, m), 4,20 (2H, t), and 4.40 (2H, m), 7,45 (1H, d), 7,80 (1H, d), by 8.22 (1H, s), a 9.25 (1H, s)to 13.7 (1H, Sirs).

EXAMPLE 12

8-[2-Ethoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (68%) from the specified in the header of the receive connector 8 and 1-methylpiperazine by the method of example 1.

TPL 252°C.

d (DMSO-d6): 1,0 (3H, t)to 1.48 (3H, t), of 1.88 (2H, m), are 2.19 (3H, s), is 2.40 (4H, m)to 2.94 (4H, m), is 4.21 (2H, t)to 4.41 (2H, q), of 7.48 (1H, d), of 7.82 (1H, d), by 8.22 (1H, s), 9.28 are (1H, s), 13,68 (1H, Sirs).

EXAMPLE 13

8-{2-Ethoxy-5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-phenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (21%) from the specified in the header of the receive connector 8 and 1-(2-hydroxyethyl)piperazine according to the method of example 1.

TPL 223°C.

d (DMSO-d6): and 0.98 (3H, t)to 1.60 (3H, t), of 1.85 (2H, m), of 2.38 (2H, t), of 2.50 (4H, m), 2.91 in (4H, m)to 3.41 (2H, m), 4,19 (2H, t), 2,39 (3H, m), 7,46 (1H, d), 7,81 (1H, d), by 8.22 (1H, s), 9.28 are (1H, s)13,72 (1H, Sirs).

EXAMPLE 14

8-[2-Ethoxy-5-(piperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (25%) from the specified in the header of the receive connector 10 and piperazine according to the methods of the example 1.

TPL 230°C.

d (DMSO-d6): 0,97 (3H, t), and 1.00 (3H, t), of 1.86 (4H, m), of 2.81 (8H, m), 4,19 (2H, t), 4,37 (2H, t), 7,46 (1H, d), 7,78 (1H, d), 8,19 (1H, s), 9,26 (1H, Sirs).

EXAMPLE 15

8-[5-(Morpholinomethyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Stir the mixture specified in the header of the receive connector 22 (0,22 g, 0.45 mmol) and formic acid (5 ml) is heated at the boil under reflux for 2 hours. The resulting solution was concentrated in vacuo and the residue partitioned between dichloromethane and aqueous sodium bicarbonate solution, then the organic phase is separated, washed with water, dried (MgSO4) and evaporated under reduced pressure to get crude product, which was purified by chromatography on a flash column (SiO2, dichloromethane-methanol, 98:2) to obtain the specified title compound (0.17 g, 76%) as not quite white solid.

TPL 169°C.

d (DMSO-d6): and 0.98 (3H, t), of 1.02 (3H, t), of 1.86 (4H, m), 2,89 (4H, m), 3,61 (4H, m), 4,20 (2H, t), are 4.24 (2H, t), was 7.45 (1H, d), of 7.82 (1H, d), by 8.22 (1H, s), 9.28 are (1H, s), 13,68 (1H, s).

EXAMPLE 16

N-(2-Dimethylaminoethyl)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2, 4]triazolo [3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (36%) from the specified in the header of the receive connector 10 and N,N-dimethyl-Ethylenediamine by the procedure of example 1.

LRMS: m/z 503 (M+1)+.

d (DMSO-d6): and 0.98 (3H, t), of 1.02 (3H, what), to 1.86 (4H, m), 2,89 (4H, m), 3,61 (4H, m), 4,20 (2H, t), are 4.24 (2H, t), was 7.45 (1H, d), of 7.82 (1H, d), by 8.22 (1H, s), 9.28 are (1H, s), 13,68 (1H, s).

EXAMPLE 17

3-(5-Oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxy-N-pyridin-4-albenzaalbenza

Obtained as a white solid (10%) from the specified in the header of the receive connector 10 and 4-aminopyridine according to the method of example 1.

TPL 265°C.

d (DMSO-d6): and 0.98 (3H, t), of 1.02 (3H, t), of 1.86 (4H, m), 2,89 (4H, m), 3,61 (4H, m), 4,20 (2H, t), are 4.24 (2H, t), was 7.45 (1H, d), of 7.82 (1H, d), by 8.22 (1H, s), 9.28 are (1H, s), 13,68 (1H, s).

EXAMPLE 18

8-[5-(4-Metilprednisolone)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (82%) from the specified in the header of the receive connector 19 by the method of example 15.

TPL 272°C.

d (DMSO-d6): and 0.98 (3H, t), and 1.00 (3H, t), and 1.83 (4H, m)to 2.18 (3H, s), of 2.38 (4H, m), of 2.86 (4H, m), 4,19 (2H, t), 4,28 (2H, t), 7,44 (1H, d), 7,80 (1H, d), 8,19 (1H, s), 9,23 (1H, s), of 13.75 (1H, Sirs).

EXAMPLE 19

8-[5-(4-Hydroxypiperidine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (35%) from the specified in the header of the receive connector 10 and 4-hydroxypiperidine by the method of example 1.

LRMS: m/z 516 (M+1)+.

d (DMSO-d6): 0,98 (6N, m)to 1.48 (2H, m), of 1.74 (2H, m)of 1.84 (4H, m), 2,77 (2H, m), and 3.16 (2H, m), of 3.60 (1H, m), is 4.21 (1H, m), and 4.68 (1H, s), 7,45 (1H, d), 7,78 (1H, d), to 8.20 (1H, s), 9,26 (1H, s)13,8 (1H, Sirs).

EXAMPLE 20

N,N-Bis(2-hidroxi who yl)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (28%) from the specified in the header of the receive connector 10 and diethanolamine according to the method of example 1.

LRMS: m/z 520 (M+1)+.

d (DMSO-d6): 0,97 (6N, m)to 1.86 (4H, m), 3,20 (4H, t), of 3.54 (4H, t), 4,20 (4H, m), 4,82 (2H, Sirs), 7,41 (1H, d), 7,83 (1H, d), 8,31 (1H, s), 9,23 (1H, s), 12,0 (1H, Sirs).

EXAMPLE 21

4-[3-(5-Oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde]piperazine-1-carbaldehyde

Obtained as a white solid (28%) from the specified in the header of the receive connector 20 according to the method of example 15.

TPL 232°C.

d (DMSO-d6): of 0.95 (3H, t), and 1.0 (3H, t), of 1.86 (4H, m), with 2.93 (4H, m), of 3.45 (4H, m), 4,20 (2H, t), are 4.24 (2H, t), 7,46 (1H, d), 7,80 (1H, d), 7,94 (1H, s), to 8.20 (1H, s), 9,26 (1H, s), 13,76 (1H, s).

EXAMPLE 22

8-[5-(4-Methyl[1,4]diazepan-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (32%) from the specified in the header of the receive connector 21 according to the method of example 15.

TPL 193°C.

d (DMSO-d6): to 0.96 (3H, t), and 0.98 (3H, t), 1.8 m (6N, m), 2,22 (3H, s)of 2.50 (2H, m), 2,58 (2H, m), 3,32 (4H, m), 4,18 (2H, t), 4.26 deaths (2H, t), 7,40 (1H, d), 7,83 (1H, d), by 8.22 (1H, s), a 9.25 (1H, s).

EXAMPLE 23

8-[5-(4-Ethylpiperazin-1-sophony)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (48%) from the specified in the header of the receive connector 10 and 1-ethylpiperazine by the method of example 1.

LRMS: m/z 529 (M+1)+

d (DMSO-d6): 0,97 (N, m)and 1.83 (4H, m), a 2.36 (2H, m), of 2.45 (2H, m)to 2.94 (4H, m)to 3.35 (2H, m), 4,19 (2H, t), 4,27 (2H, t), 7,47 (1H, d), 7,80 (1H, d), 8,19 (1H, s), 9,26 (1H, s).

EXAMPLE 24

Amide 1-[3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)-4-propoxybenzaldehyde]piperidine-4-carboxylic acid

Obtained as a white solid (12%) from the specified in the header of the receive connector 10 and isonipecotamide by the method of example 1.

TPL 272°C.

d (DMSO-d6): to 0.96 (3H, t), and 0.98 (3H, t), was 1.58 (2H, m), 1,6-1,8 (6N, m)2,07 (1H, m), a 2.36 (2H, m), of 3.57 (2H, m), 4,19 (2H, t), 4,28 (2H, t), for 6.81 (1H, s), 7,20 (1H, s), 7,46 (1H, d), of 7.82 (1H, d), to 8.20 (1H, s), 9,27 (1H, s)13,72 (1H, s).

EXAMPLE 25

Amide 1-[3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)-4-propoxybenzaldehyde]piperidine-3-carboxylic acid

Obtained as a white solid (55%) from the specified in the header of the receive connector 10 and nipecotate by the method of example 1.

LRMS: m/z 543 (M+1)+.

d (DMSO-d6): 0,97 (6N, m)to 1.21 (1H, m), 1,50 (1H, m), 1,82 (6N, m), and 2.26 (2H, m), is 2.40 (1H, m), 3,62 (2H, m), 4,18 (2H, t), 4,27 (2H, t), to 6.95 (1H, s), 7,42 (1H, s), 7,46 (1H, d), 7,80 (1H, d), 8,20 (1H, s), a 9.25 (1H, s), of 13.75 (1H, s).

EXAMPLE 26

3-(5-Oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-N-(2-piperidine-1-retil)-4-propoxyphenol-sulfonamide

Obtained as a white solid (45%) from the specified in the header of the receive connector 10 and 1-(2-amino-ethyl)piperidine according to the method of example 1.

LRMS: m/z 543 (M+1)+.

d (DMSO-d6): 9,26 (1H, s), 8,32 (1H, s), 7,83 (1H, d), a 7.62 (1H, s), the 7.43 (1H, d), is 4.21 (4H, m), of 2.92 (2H, m), 2,41 (6N, m)to 1.86 (4H, m)of 1.46 (4H, m)to 1.38 (2H, m), 0,97 (6N, m).

EXAMPLE 27

8-{5-[4-(2-Hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (41%) from the specified in the header of the receive connector 10 and 1-(2-hydroxyethyl)piperazine according to the method of example 1.

TPL 194°C.

d (DMSO-d6): of 0.95 (3H, t), of 0.99 (3H, t), of 1.84 (4H, m), a 2.36 (2H, m)of 2.50 (4H, m), 2,82 (4H, m), 3,40 (2H, m), 4,18 (2H, t), 4,28 (2H, t), 4,37 (1H, Sirs), 7,46 (1H, d), 7,80 (1H, d), 8,18 (1H, s), 9,26 (1H, s), 13,76 (1H, Sirs).

EXAMPLE 28

N-(2-Morpholine-4-retil)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (40%) from the specified in the header of the receive connector 10 and 4-(2-amino-ethyl)research by the method of example 1.

LRMS: m/z 545 (M+1)+.

d (DMSO-d6): 0,97 (6H, m), of 1.85 (4H, m), 2,28 (6N, m), 2,90 (2H, m), of 3.48 (4H, m)to 4.23 (4H, m), the 7.43 (1H, d), a 7.62 (1H, s), of 7.90 (1H, d), 8,32 (1H, s), 9,26 (1H, s), 13,60 (1H, Sirs).

EXAMPLE 29

N-(3-Morpholine-4-ylpropyl)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (29%) from the specified in the header of the receive connector 10 and 4-(3-aminopropyl)of the research according to the method of example 1.

LRMS: m/z 559 (M+1)+.

d (DMSO-d6): 0,97 (6H, m)to 1.86 (4H, m), is 2.30 (6H, m), of 2.81 (2H, m), 3,51 (4H, is), to 4.23 (4H, m), the 7.43 (1H, d), 7,63 (1H, s), a 7.85 (1H, d), 8,31 (1H, s), a 9.25 (1H, s).

EXAMPLE 30

8-(5-{4-[2-(2-Hydroxyethoxy)ethyl]piperazine-1-sulfonyl}-2-propoxyphenyl)-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (60%) from the specified in the header of the receive connector 10 and 1-[2-(2-hydroxyethoxy)ethyl]piperazine according to the method of example 1.

TPL 116°C.

d (DMSO-d6): 1,03 (6N, m)of 1.84 (4H, m), 2,45 (6N, m)of 2.92 (4H, m), 3,39 (6N, m), is 4.21 (4H, m), 4,58 (1H, s), 7,41 (1H, d).

EXAMPLE 31

8-[2-Butoxy-5-(morpholine-4-sulfonyl)phenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (39%) from the specified in the header of the receive connector 23 by the method of example 15.

TPL 208°C.

d (DMSO-d6): to 0.94 (3H, t), is 0.96 (3H, t)to 1.48 (2H, m)of 1.84 (4H, m), with 2.93 (4H, m)to 3.64 (4H, m), 4,20 (2H, t), or 4.31 (2H, t), of 7.48 (1H, d), of 7.82 (1H, d), to 8.20 (1H, s), 9,26 (1H, s), 13,76 (1H, s).

EXAMPLE 32

8-[5-(2-Butoxy-4-metilprednisolone)phenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (17%) from the specified in the header of the receive connector 24 by the method of example 15.

TPL 208°C.

d (DMSO-d6): of 0.91 (3H, t)to 0.92 (3H, m), USD 1.43 (2H, m), is 1.81 (4H, m), is 2.09 (3H, s), a 2.36 (4H, m), is 2.88 (4H, m), 4,17 (2H, t), 4.26 deaths (2H, t), 7,44 (1H, d), 7,79 (1H, d), 8,17 (1H, s), a 9.25 (1H, s).

EXAMPLE 33

6-Butyl-8-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained in the form of the aircraft the CSO solids (72%) from the specified in the connection header 12 and 1-methylpiperazine by the method of example 1.

TPL 238°C.

d (DMSO-d6): 0,99 (3H, t), of 1.42 (5H, m), equal to 1.82 (2H, m)of 2.16 (3H, s), is 2.40 (4H, m), of 2.92 (4H, m), 4,22 (2H, t), and 4.40 (2H, q), 7,44 (1H, d), 7,80 (1H, d), by 8.22 (1H, s), 9,24 (1H, s), 13,48 (1H, s).

EXAMPLE 34

6-Butyl-8-{2-ethoxy-5-[4-(2-hydroxyethyl) piperazine-1-sulfonyl]phenyl}-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (45%) from the specified in the connection header 12 and 1-(2-hydroxyethyl)piperazine according to the method of example 1.

TPL 241°C.

d (DMSO-d6): to 0.92 (3H, t)to 1.38 (2H, m)of 1.41 (3H, t), of 1.80 (2H, m), of 2.38 (2H, t), 2,48 (4H, m), is 2.88 (4H, m), 3,40 (2H, m), is 4.21 (2H, t), and 4.40 (2H, q), the 7.43 (1H, d), 7,80 (1H, d), 8,24 (1H, s), 9,24 (1H, s), 13,68 (1H, s).

EXAMPLE 35

3-(6-Butyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-N-(2-dimethylaminoethyl)-4-propoxybenzaldehyde

Obtained as a white solid (71%) from the specified in the header of the receive connector 14 and N,N-dimethylethylenediamine by the method of example 1.

TPL 181°C.

d (DMSO-d6): 0,96 (6N, m)to 1.37 (2H, m)of 1.84 (4H, m), 2,08 (6N, C)to 2.29 (2H, m), of 2.86 (2H, m), 4,25 (4H, m), 7,42 (1H, d), EUR 7.57 (1H, Sirs), 7,86 (1H, d), a 8.34 (1H, d), 9,24 (1H, s).

EXAMPLE 36

6-Butyl-8-[2-propoxy-5-(4-pyridylmethyl)]phenyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (39%) from the specified in the header of the receive connector 14 and 4-aminopyridine according to the method of example 1.

TPL 282°C.

d (DMSO-d6): 0,97 (6N, m)of 1.40 (2H, m), equal to 1.82 (4H, m), 4,22 (4H, m), 6,97 (2H, Sirs), 7,38 (1H, d), 789 (1H, d), 8,03 (2H, Sirs), 8,39 (1H, s), 9,23 (1H, s).

EXAMPLE 37

6-Butyl-8-(2-propoxy-5-[4-(methylpiperazin-1-sulfonyl)-phenyl]-6, 9-dihydro [1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (78%) specified in the header of the receive connector 14 and 1-methylpiperazine by the method of example 1.

TPL 220°C.

d (DMSO-d6): 0,83 (6N, m)of 1.36 (2H, m), of 1.80 (4H, m), 2,12 (3H, s), of 2.38 (4H, m), of 2.92 (4H, m)to 4.23 (4H, m), 7,45 (1H, d), 7,79 (1H, d), 8,19 (1H, s), of 9.21 (1H, s), 13,69 (1H; Sirs).

EXAMPLE 38

6-Butyl-8-[5-(4-hydroxypiperidine-1-sulfonyl)-2-propoxyphenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (70%) from the specified in the header of the receive connector 14 and 4-hydroxypiperidine by the method of example 1.

TPL 262°C.

d (DMSO-d6): 0,97 (6N, m)of 1.41 (4H, m), 1,81 (6N, m), 2,78 (2H, m), and 3.16 (2H, m), 3,55 (1H, Sirs), 4,24 (4H, m), of 4.67 (1H, d), was 7.45 (1H, d), 7,80 (1H, d), 8,23 (1H, d), a 9.25 (1H, s).

EXAMPLE 39

3-(6-Butyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i] purine-8-yl)-N,N-bis(2-hydroxyethyl)-4-propoxybenzaldehyde

Obtained as a white solid (50%) specified in the header of the receive connector 14 and diethanolamine according to the method of example 1.

TPL 202°C.

d (DMSO-d6): 0,97 (6N, m)to 1.38 (2H, m), equal to 1.82 (4H, m), 3,19 (4H, m), of 3.54 (4H, m), 4,25 (4H, m), 4,84 (2H, m), 7,42 (1H, d), 7,87 (1H, d), 8,29 (1H, d), a 9.25 (1H, s), 13,69 (1H, s).

EXAMPLE 40

6-Butyl-8-[5-(4-methyl[1,4]diazepan-1-sulfonyl)-2-propoxyphenyl]-6,9-dihydro[1,2,4]triazo what about[3,4-i]purine-5-he

Obtained as a white solid (39%) from the specified in the header of the receive connector 14 and 1-methylhomopiperazine by the method of example 1.

TPL 282°C.

d (CDCl3): of 1.03 (3H, t)to 1.14 (3H, t), of 1.47 (2H, m), 1.8-to 2.2 (6N, m)of 2.38 (3H, s), 2,68 (4H, m), of 3.46 (4H, m), to 4.38 (4H, m), 7,19 (1H, d), 7,86 (1H, d), 8,79 (1H, s), 8,96 (1H, s).

EXAMPLE 41

6-Butyl-8-{2-propoxy-5-[4-(ethylpiperazin-1-sulfonyl)phenyl}-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (61%) from the specified in the header of the receive connector 14 and 1-ethylpiperazine by the method of example 1.

TPL 208°C.

d (CDCl3): 0,98 (6N, m)of 1.16 (3H, t)to 1.48 (2H, m), at 1.91 (2H, m), 2,04 (2H, m), 2,42 (2H, q), of 2.54 (4H, m), of 3.13 (4H, m), 4,37 (4H, m), to 7.09 (1H, d), of 7.82 (1H, d), 8,77 (1H, s), 8,97 (1H, s).

EXAMPLE 42

3-(6-Butyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-N-(2-piperidine-3-retil)-4-propoxybenzaldehyde

Obtained as a white solid (60%) from the specified in the header of the receive connector 14 and 1-(2-amino-ethyl)piperidine according to the method of example 1.

TPL 186°C.

d (DMSO-d6): 0,96 (6N, m)of 1.33 (8H, m)and 1.83 (4H, m), 2,28 (6N, m), 2,87 (2H, m), 4,24 (4H, m), 7,41 (1H, d), 7,51 (1H, m), a 7.85 (1H, d), with 8.33 (1H, d), 9,23 (1H, s).

EXAMPLE 43

6-Butyl-8-(2-propoxy-5-[4-(2-hydroxyethyl) piperazine-1-sulfonyl]phenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (81%) from the specified in the header of the receive connector 14 and 1-(2-hydroxyethyl)piperazine by the method of example 1.

TPL 242°C.

d (DMSO-d6): to 0.96 (3H, t), and 1.0 (3H, t)to 1.38 (2H, m)to 1.86 (4H, m), is 2.37 (2H, t), of 2.50 (4H, m), of 2.92 (4H, m), 3.43 points (2H, m), 4.26 deaths (4H, m), 4,37 (1H, Sirs), 7,47 (1H, d), 7,80 (1H, d), 8,21 (1H, s), 9,25 (1H, s), 13,70 (1H, Sirs).

EXAMPLE 44

3-(6-Butyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-N-(2-morpholine-4-retil)-4-propoxybenzaldehyde

Obtained as a white solid (72%) from the specified in the header of the receive connector 14 and 4-(2-amino-ethyl)research by the method of example 1.

TPL 192°C.

d (DMSO-d6): 0,95 (6N, m)to 1.38 (2H, m)and 1.83 (4H, m), 2,28 (6N, m), 2,90 (2H, m), of 3.46 (4H, m), 4,25 (4H, m), 7,42 (1H, d), to 7.59 (1H, m), 7,87 (1H, d), with 8.33 (1H, d), a 9.25 (1H, s).

EXAMPLE 45

3-(6-Butyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-N-(3-morpholine-4-ylpropyl)-4-propoxybenzaldehyde

Obtained as a white solid (65%) from the specified in the header of the receive connector 14 and 4-(3-aminopropyl)of the research according to the method of example 1.

TPL 174°C.

d (DMSO-d6): 0,96 (6N, m)to 1.38 (2H, m), of 1.52 (2H, m)of 1.84 (4H, m), 2,21 (6N, m), of 2.81 (2H, m), 3,47 (4H, m), 4,25 (4H, m), the 7.43 (1H, d), 7,63 (1H, m), to 7.84 (1H, d), 8,32 (1H, d), a 9.25 (1H, s).

EXAMPLE 46

3-(6-Butyl-6-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i] purine-8-yl)-N-methyl-N-(2-morpholine-4-retil)-4-propoxybenzaldehyde

Obtained as a white solid (65%) from the specified in the header of the receive connector 14 and 4-(3-aminopropyl)of the research according to the method of example 1.

TPL 170°C.

d (DMSO-d6): 0,97 (6N, m)to 1.38 (2H, m), 1,82 (4 is, m), 2,46 (6N, m), was 2.76 (3H, s), of 3.12 (2H, m), 3,51 (4H, m), 4,24 (4H, m), the 7.43 (1H, d), to 7.84 (1H, d), compared to 8.26 (1H, d), a 9.25 (1H, s).

EXAMPLE 47

6-Butyl-8-(5-{4-[2-(2-hydroxyethoxy)ethyl]piperazine-3-sulfonyl}-2-propoxyphenyl)-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-he

Obtained as a white solid (64%) from the specified in the header of the receive connector 14 and 1-[2-(2-hydroxyethoxy)ethyl]piperazine according to the method of example 1.

TPL 143°C.

d (DMSO-d6): 0,83 (6N, m)of 1.27 (2H, m), by 1.68 (4H, m), 2,35 (6N, m)of 2.75 (4H, m), 3,23 (6N, m), 4,11 (4H, m), 7,31 (1H, d), 7,63 (1H, d), of 8.06 (1H, s), 9,10 (1H, s).

EXAMPLE 48

6-Butyl-8-(2-butoxy-5-[4-(methylpiperazin-1-sulfonyl)phenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (62%) from the specified in the header of the receive connector 16 and 1-methylpiperazine by the method of example 1.

TPL 201°C.

d (DMSO-d6): 0,98 (6N, m), and 1.4 (4H, m), 1,8 (4H, m), are 2.19 (3H, s), and 2.4 (4H, m), 2,90 (4H, m), 4,25 (2H, t), 4,30 (2H, t), was 7.45 (1H, d), 7,79 (1H, d), to 8.20 (1H, s), a 9.25 (1H, s), 13,65 (1H, Sirs).

EXAMPLE 49

6-Butyl-8-(2-butoxy-5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl)phenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (66%) from the specified in the header of the receive connector 16 and 1-methylpiperazine by the method of example 1.

TPL 218°C.

d (DMSO-d6): 0,95 (6N, m)of 1.20 (4H, m), of 1.85 (4H, m), 2.40 a (2H, t), of 2.51 (4H, m), of 2.92 (4H, m), 3,40 (2H, m), 4,25 (5H, m), of 7.48 (1H, d), 7,80 (1H, d), 8,24 (1H, s), 9.28 are (1H, s), 13,65 (1H, Sirs).

EXAMPLE 50

<> 8-[5-(4-Methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6-pyridin-2-ylmethyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (82%) from the specified in the header of the receive connector 26 and 1-methylpiperazine by the method of example 1.

TPL 227°C.

d (DMSO-d6): 0,93 (3H, m), of 1.80 (2H, m)to 2.13 (3H, s)to 2.35 (4H, m), 2,87 (4H, m), 4,24 (2H, m), of 5.53 (2H, m), 7,28, (1H, m), 7,44 (2H, m), of 7.75 (2H, m), of 8.09 (1H, d), to 8.45 (1H, d), 9,31 (1H, s).

EXAMPLE 51

8-[5-(N,N-Dimethylaminomethyl)-2-propoxyphenyl]-3-methyl-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (65%) from the specified in the header of the receive connector 18 and dimethylamine according to the method of example 1.

TPL 226°C.

d (DMSO-d6): to 0.96 (3H, t), and 0.98 (3H, t), of 1.84 (4H, m), 2,62 (6N, (C), 2,78 (3H, s)to 4.16 (2H, t), are 4.24 (2H, t), 7,44 (1H, d), 7,81 (1H, d), 8,21 (1H, s)13,59 (1H, s).

EXAMPLE 52

3-Methyl-8-[5-(4-methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (62%) from the specified in the header of the receive connector 18 and 1-methylpiperazine by the method of example 1.

TPL 226°C.

d (DMSO-d6): 0,96 (3H, m), 0,99 (3H, t), equal to 1.82 (4H, m)of 2.16 (3H, s), is 2.37 (4H, m), 2,78 (3H, s)2,84 (4H, m), 4,14 (2H, t), 4,28 (2H, t), 7,44 (1H, d), 7,78 (1H, d), 8,19 (1H, s), 13,60 (1H, s).

EXAMPLE 53

8-{5-[4-(2-Hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-3-methyl-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained in the form of logo solid (61%) from the specified in the header of the receive connector 18 and 1-(2-hydroxyethyl)piperazine according to the method of example 1.

TPL 199°C.

d (DMSO-d6): to 0.92 (3H, t), and 0.98 (3H, t), equal to 1.82 (4H, m), of 2.38 (2H, m), 2,46 (4H, m), 2,77 (3H, s)2,84 (4H, m), 3,39 (2H, m)to 4.16 (2H, t), are 4.24 (2H, t), 4,37 (1H, t), the 7.43 (1H, d), 7,79 (1H, d), 8,18 (1H, s), 13,60 (1H, s).

EXAMPLE 54

6-Butyl-8-[5-(4-methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-3-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i] purine-5-he

Obtained in the form of a cream solid color (77%) from the specified in the header of the receive connector 28 and 1-methylpiperazine by the method of example 1.

TPL 206°C.

d (DMSO-d6): 0,97 (N, m)to 1.37 (2H, m), 1,81 (6N, m), and 2.14 (3H, s), is 2.37 (4H, m), of 2.92 (4H, m), 3,19 (2H, m), 4,17 (2H, m), 4.26 deaths (2H, m), 7,45 (1H, d), 7,79 (1H, d), 8,19 (1H, d), 13,59 (1H, Sirs).

EXAMPLE 55

6-Butyl-8-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-3-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a pale yellow solid (83%) from the specified in the header of the receive connector 28 and 1-(2-hydroxyethyl)piperazine according to the method of example 1.

TPL 193°C.

d (DMSO-d6): 0,97 (N, m)to 1.37 (2H, m), 1,81 (6N, m), and 2.14 (3H, s), is 2.37 (4H, m), of 2.92 (4H, m), 3,19 (2H, m), 4,17 (2H, m), 4.26 deaths (2H, m), 7,45 (1H, d), 7,79 (1H, d), 8,19 (1H, d), 13,59 (1H, Sirs).

EXAMPLE 56

6-Butyl-8-(5-{4-[2-(2-hydroxyethoxy)ethyl]piperazine-1-sulfonyl}-2-propoxyphenyl)-3-propyl-6,9-dihydro[1,2,4]-triazolo[3,4-i]purine-5-he

Obtained as a pale yellow solid (81%) from the specified in the header of the receive connector 28 and 1-[2-(2-hydroxyethoxy)ethyl]piperazine according to the method of the example .

TPL 144°C.

d (DMSO-d6): 0,97 (N, m)to 1.38 (2H, m), 1,81 (6N, m), 2,46 (6N, m), 2.91 in (4H, m), 3,19 (2H, m), 3,37 (6N, m), 4,18 (2H, m), 4,27 (2H, m), 7,45 (1H, d), 7,80 (1H, d), 8,19 (1H, d).

EXAMPLE 57

3-Benzyl-8-[5-(4-methylpiperazin-1-sulfonyl]-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

To the mixture specified in the header of the receive connector 19 (0.5 g, 1.0 mmol) and triethylamine (0.2 ml, 1.3 mmol) in dichloromethane (40 ml) add phenylacetylene (0.17 ml, 1.3 mmol) and the resulting mixture was stirred at room temperature for 24 hours, then evaporated under reduced pressure. To the residue is added toluene (40 ml) and a catalytic amount of p-toluensulfonate acid and the resulting mixture is refluxed for 2 hours using the device, Dean-stark, then evaporated under reduced pressure to get crude product, which was purified by chromatography on a flash column (SiO2, dichloromethane-ethanol-aqueous ammonia, 100:4:0.5) is obtaining specified in the title compound (0.11 g, 18%) as a white solid.

TPL 202°C.

d (DMSO-d6): to 0.92 (3H, t), is 0.96 (3H, t), is 1.81 (4H, m), and 2.14 (3H, s), is 2.37 (4H, m), of 2.92 (4H, m), of 4.12 (2H, t), 4,25 (2H, t)and 4.65 (2H, s), 7,30 (5H, m), 7,45 (1H, d), to 7.77 (1H, d), 8,17 (1H, s).

EXAMPLE 58

6-Isobutyl-8-[5-(4-methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (51%) is C specified in the header of the receive connector 30 and 1-methylpiperazine by the method of example 1.

LRMS: m/z 528 (M+1)+.

δ (DMSO-d6): 0,94 (N, m)and 1.83 (2H, m)to 2.18 (3H, s), is 2.40 (1H, m), of 2.45 (4H, m), with 2.93 (4H, m), was 4.02 (2H, d), are 4.24 (2H, t), 7,44 (1H, d), 7,78 (1H, DD), 8,16 (1:4, d), 9,24 (1H, s)to 13.7 (1H, Sirs).

EXAMPLE 59

6-Isobutyl-8-[5-(4-methyl[1,4]diazepan-1-sulfonyl]-2-propoxyphenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (41%) from the specified in the header of the receive connector 30 and 1-methylhomopiperazine by the method of example 1.

LRMS: m/z 542 (M+1)+.

δ (DMSO-d6): 1,02 (N, m), a 1.88 (5H, m), 2,48 (1H, m), of 2.51 (2H, m), of 2.86 (4H, m), 3,32 (4H, m), of 4.05 (2H, d), 4.26 deaths (2H, t), the 7.43 (1H, d), 7,86 (1H, DD), 8,24 (1H, s), 9,27 (1H, s).

EXAMPLE 60

3-(6-Isobutyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-N-(2-morpholine-4-retil)-4-propoxybenzaldehyde

Obtained as a white solid (49%) specified in the header of the receive connector 30 and 4-(2-amino-ethyl)research by the method of example 1.

LRMS: m/z 558 (M+1)+.

δ (DMSO-d6): 1,00 (N, m), of 1.85 (2H, m), 2,35 (6N, m)to 2.94 (2H, m), 3,40 (4H, m)4,06 (2H, d), 4.26 deaths (2H, t), the 7.43 (1H, d), of 7.70 (1H, Sirs), 7,88 (1H, DD), 8,30 (1H, d), 9,26 (1H, s), 13,65 (1H, Sirs).

EXAMPLE 61

3-(6-Isobutyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-N-(3-morpholine-4-ylpropyl)-4-propoxybenzaldehyde

Obtained as a white solid (29%) from the specified in the header of the receive connector 30 and 4-(3-aminopropyl)of the research according to the method of example 1.

LRMS: m/z 572 (M+1)+.

δ (DMSO-d6): 1,09 (N, m)to 1.59 (2H, m), of 1.85 (2H, m), 2.0 a (6N, m)of 2.81 (2H, m), 3,37 (4H, m)4,06 (2H, d), 4.26 deaths (2H, t), the 7.43 (1H, d), of 7.70 (1H, t), a 7.85 (1H, DD), 8,30 (1H, d), 9,26 (1H, s), and 13.5 (1H, Sirs).

EXAMPLE 62

8-[5-(4-Ethylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6-isobutyl-6,9-dihydro[1,2,4]triazolo[3,4-i] purine-5-he

Obtained as a white solid (52%) from the specified in the header of the receive connector 30 and 1-ethylpiperazine by the method of example 1.

LRMS: m/z 542 (M+1)+.

δ (DMSO-d6): 1,00 (12H, m)to 1.86 (2H, m), of 2.45 (7H, m), of 2.97 (4H, m), of 4.05 (2H, d), 4,27 (2H, t), 7,47 (1H, d), 7,81 (1H, DD), to 8.20 (1H, d), 9,27 (1H, s)to 13.7 (1H, Sirs).

EXAMPLE 63

8-{5-[4-(2-Hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-isobutyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (42%) from the specified in the header of the receive connector 30 and 1-(2-hydroxyethyl)piperazine according to the method of example 1.

LRMS: m/z 558 (M+1)+.

δ (DMSO-d6): 1,00 (N, m)to 1.86 (2H, m), a 2.36 (1H, m)of 2.64 (4H, m), 2,99 (4H, m)to 3.35 (4H, m), of 4.05 (2H, d), 4,27 (2H, t), 4,56 (1H, Sirs), 7,47 (1H, d), 7,81 (1H, DD), 8,19 (1H, d), 9,27 (1H, s)for 13.8 (1H, Sirs).

EXAMPLE 64

8-[5-(4-Hydroxypiperidine-1-sulfonyl)-2-propoxyphenyl]-6-isobutyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (53%) from the specified in the header of the receive connector 30 and 4-hydroxypiperidine by the method of example 1.

LRMS: m/z 529 (M+1)+.

δ (DMSO-d6): 0,95 (N, m)to 1.45 (2H, m)to 1.79 (4H, m), a 2.36 (1H, m), 2,77 (2H, m), 3,17 (2H, m), 3,55 (1H, m), Android 4.04 (2H, d), 4.26 deaths (2H, t), 4,69 (1H, d), was 7.45 (1H, d), 7,80 1H, DD), to 8.20 (1H, d), 9,26 (1H, s), 13,76 (1H, s).

EXAMPLE 65

3-(6-Isobutyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-N-(2-piperidine-1-retil)-4-propoxybenzaldehyde

Obtained as a white solid (60%) from the specified in the header of the receive connector 30 and 1-(2-amino-ethyl)piperidine according to the method of example 1.

LRMS: m/z 556 (M+1)+.

δ (DMSO-d6): 1,00 (N, m)of 1.41 (2H, m)of 1.55 (4H, m)to 1.87 (2H, m), of 2.38 (1H, m), 2,65 (4H, m), 3,03 (4H, m)4,06 (2H, d), 4,27 (2H, t), 7,44 (1H, d), 7,89 (1H, DD), 7,82 (1H, Sirs), 8,31 (1H, d), 9,26 (1H, s).

EXAMPLE 66

N-(2-Dimethylaminoethyl)-3-(6-isobutyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (43%) from the specified in the header of the receive connector 30 and N,N'-dimethylethylenediamine by the method of example 1.

LRMS: m/z 516 (M+1)+.

δ (DMSO-d6): 0,95 (N, m)of 1.84 (2H, m), 2,33 (1H, m), 2,33 (6N, (C), 2,61 (2H, m)to 2.94 (2H, m), a 4.03 (2H, d), to 4.23 (2H, t), 7,41 (1H, d), of 7.82 (1H, Sirs), 7,86 (1H, DD), of 8.28 (1H, d), 9,23 (1H, s).

EXAMPLE 67

6-Isobutyl-8-[5-(morpholinomethyl)-2-propoxyphenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (53%) from the specified in the header of the receive connector 30 and the research according to the method of example 1.

LRMS: m/z 515 (M+1)+.

δ (DMSO-d6): 0,96 (N, m)and 1.83 (2H, m), 2,33 (1H, m), is 2.88 (4H, m), 3,62 (4H, m), was 4.02 (2H, d), are 4.24 (2H, t), was 7.45 (1H, d), 7,78 (1H, d), 8,16 (1H, s), 9,23 (1H, s), 13,77 (1H, s).

EXAMPLE 68

3-(6-Isobutyl-5-oxo-6,9-dihydro-5H-[1,2,]triazolo[3,4-i]purine-8-yl)-N-methyl-N-(2-morpholine-4-retil)-4-propoxybenzaldehyde

Obtained as a white solid (53%) from the specified in the header of the receive connector 30 and 4-[2-(N-methylamino)ethyl]the research according to the method of example 1.

LRMS: m/z 572 (M+1)+.

δ (DMSO-d6): 0,94 (N, m)of 1.84 (2H, m), 2,41 (6N, m)to 2.74 (3H, s), 3,11 (2H, m), 3,52 (4H, m)to 4.01 (2H, d), to 4.23 (2H, t), 7,41 (1H, d), 7,83 (1H, d), by 8.22 (1H, s), 9,23 (1H, s).

EXAMPLE 69

8-[5-(4-Methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6-pentyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (35%) from the specified in the header of the receive connector 32 and 1-methylpiperazine by the method of example 1.

LRMS: m/z 542 (M+1)+.

δ (DMSO-d6): of 0.85 (3H, t), of 0.97 (3H, t)of 1.33 (4H, m)and 1.83 (4H, m), of 2.25 (3H, s), 2,48 (4H, m), 2,96 (4H, m), 4,22 (4H, m), 7,45 (1H, d), 7,78 (1H, d), to 8.20 (1H, s), 9,24 (1H, s)to 13.7 (1H, Sirs).

EXAMPLE 70

8-[5-(4-Methyl[1,4]diazepan-1-sulfonyl)-2-propoxyphenyl]-6-pentyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (40%) from the specified in the header of the receive connector 32 and 1-methyl-homopiperazin by the method of example 1.

LRMS: m/z 556 (M+1)+.

δ (DMSO-d6): to 0.89 (3H, t), of 1.02 (3H, t), of 1.37 (4H, m), of 1.85 (7H, m)of 2.50 (2H, m), 2,98 (4H, m), 3,32 (4H, m)to 4.23 (4H, m), 7,44 (1H, d), 7,86 (1H, DD), of 8.27 (1H, d), 9,26 (1H, s).

EXAMPLE 71

N-(2-Morpholine-4-retil)-3-(5-oxo-6-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (32%) from the specified in the header of the receive connector 32 and 4-(2-am is noetic)of the research according to the method of example 1.

LRMS: m/z 572 (M+1)+.

δ (DMSO-d6): of 0.90 (3H, t), and 0.98 (3H, t), of 1.36 (4H, m)to 1.86 (4H, m), 2,41 (6N, m)to 2.94 (2H, m), 3,53 (4H, m), 4,25 (4H, m), the 7.43 (1H, d), to 7.68 (1H, Sirs), 7,88 (1H, DD), with 8.33 (1H, d), compared to 8.26 (1H, s), 13,65 (1H, Sirs).

EXAMPLE 72

N-(3-Morpholine-4-ylpropyl)-3-(5-oxo-6-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (38%) from the specified in the header of the receive connector 32 and 4-(3-aminopropyl)of the research according to the method of example 1.

LRMS: m/z 586 (M+1)+.

δ (DMSO-d6): of 0.87 (3H, t), of 0.95 (3H, t), of 1.37 (4H, m)to 1.61 (2H, m), of 1.85 (4H, m)2,44 (6N, m), of 2.81 (2H, m)to 3.38 (4H, m), 4,25 (4H, m), 7,44 (1H, d), of 7.69 (1H, Sirs), a 7.85 (1H, DD), 8,32 (1H, d), 9,26 (1H, s)to 13.6 (1H, Sirs).

EXAMPLE 73

8-[5-(4-Ethylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6-pentyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (35%) from the specified in the header of the receive connector 32 and 1-ethylpiperazine by the method of example 1.

LRMS: m/z 556 (M+1)+.

δ (DMSO-d6): of 0.90 (3H, t), and 1.00 (6N, m)to 1.38 (4H, m), of 1.85 (4H, m), 2,49-3,07 (10H, m), 4,22 (2H, t), the 4.29 (2H, t), of 7.48 (1H, d), 7,81 (1H, DD), 8,23 (1H, d), 9,27 (1H, s), of 13.75 (1H, Sirs).

EXAMPLE 74

8-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl)-6-pentyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (33%) from the specified in the header of the receive connector 32 and 1-(2-hydroxyethyl)piperazine according to the method of example 1.

LRMS: m/z 572 (M+1)+.

δ (DMSO-d6): 0,88(3H, t), and 1.00 (3H, t), of 1.36 (4H, m), a 1.88 (4H, m), 2,46 (4H, m), 2,70 (4H, m)to 3.36 (4H, m), 4,28 (4H, m), 4,46 (1H, Sirs), of 7.48 (1H, d), 7,80 (1H, d), by 8.22 (1H, s), 9,27 (1H, s)13,8 (1H, Sirs).

EXAMPLE 75

8-[5-(4-Hydroxypiperidine-1-sulfonyl)-2-propoxyphenyl]-6-pentyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (53%) from the specified in the header of the receive connector 32 and 4-hydroxypiperidine by the method of example 1.

LRMS: m/z 543 (M+1)+.

δ (DMSO-d6): to 0.88 (3H, t), and 1.00 (6N, m), 1,42 (6N, m), 1,82 (6N, m), 2,77 (2H, m), 3,17 (2H, m), of 3.54 (1H, m), 4.26 deaths (4H, m), 4,69 (1H, s), 7,46 (1H, d), 7,80 (1H, DD), 8,23 (1H, d), 9,26 (1H, s), 13,7 (1H, s).

EXAMPLE 76

3-(5-Oxo-6-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-N-(2-piperidine-1-retil)-4-propoxybenzaldehyde

Obtained as a white solid (55%) from the specified in the header of the receive connector 32 and 1-(2-amino-ethyl)piperidine according to the method of example 1.

LRMS: m/z 579 (M+1)+.

δ (DMSO-d6): to 0.88 (3H, t), and 0.98 (3H, t), 1,37 (6N, m)to 1.60 (4H, m), of 1.85 (4H, m), 2,60-of 3.43 (8H, m), 4,25 (4H, m), 7,45 (1H, d), 7,89 (1H, DD), 7,82 (1H, Sirs), with 8.33 (1H, d), 9,26 (1H, s).

EXAMPLE 77

N-(2-Dimethylaminoethyl)-3-(5-oxo-6-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (38%) from the specified in the header of the receive connector 32 and N,N'-dimethylethylenediamine by the method of example 1.

LRMS: m/z 530 (M+1)+.

δ (DMSO-d6): to 0.88 (3H, t), 0,99 (4H, m)of 1.35 (4H, m), of 1.85 (4H, m)2,44 (1H, m)2,44 (6N, (C), 2,4 (2H, m)to 2.99 (2H, m), 4,22 (4H, m), 7,45 (1H, d), 7,89 (1H, DD), to 8.34 (1H, d), 9,26 (1H, s).

EXAMPLE 78

8-[5-(Morpholinomethyl)-2-propoxyphenyl]-6-pentyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (30%) from the specified in the header of the receive connector 32 and the research according to the method of example 1.

LRMS: m/z 529 (M+1)+.

δ (DMSO-d6): of 0.90 (3H, t), of 0.99 (3H, t), of 1.37 (4H, m)of 1.84 (4H, m), 2,89 (4H, m)to 3.64 (4H, m), 4,22 (2H, t), the 4.29 (2H, t), 7,49 (1H, d), 7,81 (1H, d), by 8.22 (1H, s), 9,26 (1H, s), of 13.75 (1H, Sirs).

EXAMPLE 79

8-[2-Ethoxy-5-(piperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (45%) from the specified in the header of the receive connector 4 and piperazine according to the method of example 1.

TPL 196°C.

δ (DMSO-d6): of 0.95 (3H, t), of 1.45 (3H, t), of 1.84 (2H, m), was 2.76 (4H, m), 2,82 (4H, m), 4,19 (2H, t), and 4.40 (2H, t), was 7.45 (1H, d), to 7.77 (1H, d), 8,21 (1H, s), 9,24 (1H, s).

EXAMPLE 80

3-(5-Oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (26%) from the specified in the header of the receive connector 10 and ammonia according to the method of example 1.

TPL 275°C.

δ (DMSO-d6): 0,96 (6N, m), of 1.85 (4H, m), 4,19 (t, 2H), 4.26 DEATHS (2H, t), 7,40 (2H, s), 7,41 (1H, d), 7,87 (1H, d), at 8.36 (1H, s), 9,26 (1H, s)to 13.6 (1H, s).

EXAMPLE 81

3-(5-Oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxy-1-prop-2-inventorcontent

Obtained as a white solid which substances (41%) from the specified in the header of the receive connector 10 and propargylamine by the method of example 1.

TPL 251°C.

δ (DMSO-d6): 0,97 (6N, m), of 1.85 (4H, m), 3,06 (1H, s), 3,71 (2H, s)to 4.23 (4H, m), 7,42 (1H, d), 7,87 (1H, d), with 8.33 (1H, s), 9,26 (1H, s)to 13.6 (1H, s).

EXAMPLE 82

N-(2-Dimethylaminoethyl)-3-(oxopropyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (45%) from the specified in the header of the receive connector 10 and N,N-dimethylethylenediamine by the method of example 1.

TPL 193°C.

δ (DMSO-d6): to 0.96 (3H, t), of 0.99 (3H, t), of 1.86 (4H, m), 2,08 (6N, C)to 2.29 (2H, t), of 2.86 (2H, m), 4,20 (2H, t), 4,27 (2H, t), 7,42 (1H, d), to 7.59 (1H, Sirs), 7,86 (1H, d), 8,32 (1H, s), a 9.25 (1H, s).

EXAMPLE 83

8-{5-[(1S,4S)-(2,5-Diazabicyclo[2.2.1]hept-2-yl)sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (22%) from the specified in the header of the receive connector 10 and tert-butyl(1S,4S)-(-)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate according to the method of example 1, followed by removing protection in a mixture of 1:1 triperoxonane acid and dichloromethane.

TPL 153°C.

δ (DMSO-d6): 0,98 (7H, m), 1,40 (1H, d), of 1.85 (4H, m), and 2.83 (1H, d), is 2.88 (1H, d), 3,11 (1H, d), 3,19 (1H, d), 3,63 (1H, d), 4,22 (4H, m), 4,34 (1H, s)to 4.92 (1H, Sirs), 7,39 (1H, d), a 7.85 (1H, d), 8,29 (1H, s), 9,19 (1H, s).

EXAMPLE 84

8-[5-([1,4]Diazepan-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (59%) from the specified in the header of the receive connector 10 and homepipe the Zina according to the method of example 1.

TPL 208°C.

δ (DMSO-d6): of 0.95 (3H, t), of 1.02 (3H, t), 1,72 (2H, m), of 1.85 (4H, m), 2,80 (2H, t), 2,85 (2H, t), with 3.27 (4H, m), 4,20 (4H, m), 7,38 (1H, d), 7,79 (1H, d), of 8.27 (1H, s), 9,20 (1H, s).

EXAMPLE 85

8-[5-((R)-3-Methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (80%) from the specified in the header of the receive connector 10 and (R)-(-)-2-methylpiperazine by the method of example 1.

TPL 156°C.

δ (DMSO-d6): 0,93 (3H, d), and 0.98 (3H, t), and 1.00 (3H, t), and 1.83 (4H, m)to 2.15 (1H, m), 2,70 (2H, m), 2,90 (1H, m)to 3.41 (4H, m), 4,18 (2H, t), 4.26 deaths (2H, t), was 7.45 (1H, d), 7,78 (1H, d), 8,19 (1H, s), a 9.25 (1H, s).

EXAMPLE 86

8-[5-((S)-3-Methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (85%) from the specified in the header of the receive connector 10 and S-(-)-2-methylpiperazine by the method of example 1.

TPL 163°C.

δ (DMSO-d6): 0,93 (3H, d), and 0.98 (3H, t), and 1.00 (3H, t), and 1.83 (4H, m)to 2.15 (1H, m), 2,70 (2H, m), 2,90 (1H, m)to 3.41 (4H, m), 4,18 (2H, t), 4.26 deaths (2H, t), was 7.45 (1H, d), 7,78 (1H, d), 8,19 (1H, s), a 9.25 (1H, s).

EXAMPLE 87

8-[5-(3-Dimethylimidazolidin-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (82%) from the specified in the header of the receive connector 10 and azetidin-3-ultimatemenu by the method of example 1.

TPL 213°C.

δ (DMSO-d6): of 0.95 (3H, t), is 1.01 (3H, t), of 1.84 (4H, m), of 2.97 (1H, m), 3,36 (6N, s), 3.45 points (2 is, t)of 3.78 (2H, t), 4,19 (2H, t), the 4.29 (2H, t), 7,49 (1H, d), 7,88 (1H, d), of 8.25 (1H, s), 9,27 (1H, s), 13,79 (1H, s).

EXAMPLE 88

N-(3-Dimethylaminopropyl)-3-(oxopropyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (69%) from the specified in the header of the receive connector 10 and N,N-dimethyl-1,3-propandiamine by the method of example 1.

TPL 197°C.

δ (DMSO-d6): to 0.94 (3H, t), of 0.97 (3H, t), for 1.49 (2H, m), equal to 1.82 (4H, m)2,07 (6N, (C), of 2.21 (2H, t), was 2.76 (2H, t), 4,17 (2H, t)to 4.23 (2H, t), 7,40 (1H, d), the 7.65 (1H, Sirs), 7,81 (1H, d), 8,30 (1H, s), which 9.22 (1H, s).

EXAMPLE 89

8-[5-((1S,4S)-5-Methyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]-triazolo[3,4-i]purine-5-he

The mixture specified in the title compound of example 83 (0.51 g, 1.0 mmol), formaldehyde (0.5 ml, 6.2 mmol, 37%) and formic acid (0.3 ml) was stirred at 80°C for 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane, washed with aqueous sodium bicarbonate solution and water, dried (MgSO4) and evaporated under reduced pressure. The resulting crude residue purified by chromatography on a flash column (SiO2, dichloromethane-ethanol-ammonium hydroxide, 140:8:1) to obtain specified in the connection header (0,22 g, 42%) as a white solid.

TPL 194°C.

δ (DMSO-d6): 0,98 (7H, m), 1,60 (1H, d), of 1.85 (4H, m), 2,24 (3H, s)to 2.54 (1H, d), 2,70 (1H, d), 2,99 (1H, d), and 3.3 (s, 1H), 3,39 (1H, d), 4,23 (5H, m), 7,44 (1H, d), 7,89 (1H, d), 8,30 (1H, s), 8,24 (1H, s).

EXAMPLE 90

8-[5-(4-Ethylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (66%) from the specified in the header of the receive connector 10 and the N-ethylpiperazine by the method of example 1.

TPL 192°C.

δ (DMSO-d6): 0,96 (N, m)of 1.84 (4H, m), 2,30 (2H, HF), 2,43 (4H, m), with 2.93 (4H, m), 4,19 (2H, t), 4,27 (2H, t), 7,47 (1H, d), 7,80 (1H, d), to 8.20 (1H, s), a 9.25 (1H, s).

EXAMPLE 91

8-[5-(3-Dimethylaminomethylene-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (51%) from the specified in the header of the receive connector 10 and specified in the header of the receive connector 35 by the method of example 1.

TPL 172°C.

δ (DMSO-d6): 1,01 (6N, m)to 1.87 (4H, m), 2.00 (evens 6N, (C), 2,10 (2H, d), at 2.59 (1H, m), 3,37 (2H, DD), a-3.84 (2H, DD), 4,20 (2H, t), 4,30 (2H, t), 7,51 (1H, d), 7,89 (1H, d), 8,29 (1H, s), 9,26 (1H, s).

EXAMPLE 92

3-(5-Oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxy-N-(2-pyrrolidin-1-retil)benzosulfimide

Obtained as a white solid (56%) from the specified in the header of the receive connector 10 and 1-(2-amino-ethyl)pyrrolidine by the method of example 1.

TPL 198°C.

δ (DMSO-d6): to 0.96 (3H, t), of 0.99 (3H, t), of 1.61 (4H, m)to 1.87 (4H, m), 2,4-2,5 (6N, m), is 2.88 (2H, t), 4,20 (2H, t), 4.26 deaths (2H, t), 7,42 (1H, d), 7,66 (1H, Sirs), 7,86 (1H, d), 8,32 (1H, s), a 9.25 (1H, C).

NOTE THE R 93

8-[5-((3R,5S) - for 3,5-Dimethylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (83%) from the specified in the header of the receive connector 10 and CIS-2,6-dimethylpiperazine by the method of example 1.

TPL 200°C.

δ (DMSO-d6): 0,93 (6N, e), and 1.00 (3H, t), of 1.03 (3H, t), 1,6-1,9 (6N, m), 2,77 (2H, m), 3,50 (2H, m), 4,18 (2H, t), 4.26 deaths (2H, t), was 7.45 (1H, d), 7,78 (1H, d), to 8.20 (1H, s), a 9.25 (1H, s).

EXAMPLE 94

8-[5-((2RS,5SR) - for 3,5-Dimethylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (28%) from the specified in the header of the receive connector 10 and TRANS-2,5-dimethylpiperazine by the method of example 1.

TPL 117°C.

δ (DMSO-d6): 1,02 (N, m)of 1.18 (3H, d), of 1.85 (4H, m), 2,47 (1H, m), 1,8-3,1 (3H, m), of 3.45 (2H, m), 4,18 (2H, t), is 4.2 (2H, t), the 7.43 (1H, d), 7,81 (1H, d), 8,29 (1H, s), a 9.25 (1H, s).

EXAMPLE 95

N-(2-Dimethylaminoethyl)-N-ethyl-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (34%) from the specified in the header of the receive connector 10 and N,N-dimethyl-N'-ethylethylenediamine by the method of example 1.

TPL 105°C.

δ(DMSO-d6): 0,99 (6N, m)of 1.05 (3H, t), of 1.85 (4H, m), 2,16 (6N, C)to 2.41 (2H, t), is 3.21 (4H, m), 4,19 (2H, t), 4.26 deaths (2H, m), to 4.41, (1H, d), 7,87 (1H, d), 8,30 (1H, s), a 9.25 (1H, s).

EXAMPLE 96

3-[5-(4-Arylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]three is gold[3,4-i]purine-5-he

Obtained as a white solid (65%) from the specified in the header of the receive connector 10 and 1-arylpiperazine by the method of example 1.

TPL 187°C.

δ (DMSO-d6): 0,96 (6N, m), of 1.85 (4H, m), 2,43 (4H, m), 2,92 (6N, m), 4,19 (2H, t), 4,27 (2H, t), 5,11 (2H, m), 5,69 (1H, m), 7,47 (1H, d), 7,80 (1H, d), 8,19 (1H, s), 9,27 (1H, s), 13,76 (1H, Sirs).

EXAMPLE 97

3-{5-[(S)-(Hexahydropyrazino[1,2-a]pyrazin-2-yl)sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (65%) from the specified in the header of the receive connector 10 and (S)-octahedral[1,2-a]pyrazine by the method of example 1.

TPL 180°C.

δ (DMSO-d6): 0,99 (6N, m)to 1.21 (1H, m), 1,5-2,2 (11N, m), is 2.37 (1H, t), of 2.8-3.0 (2H, m), 3,60 (1H, d), of 3.75 (1H, d), 4,19 (2H, t), 4,27 (2H, t), 7,42 (1H, d), of 7.82 (1H, d), by 8.22 (1H, s), 9,25 (1H, s), 13,71 (1H, Sirs).

EXAMPLE 98

8-[2-Propoxy-5-(4-propylpiperazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (67%) from the specified in the header of the receive connector 10 and 1-propylpiperazine by the method of example 1.

TPL 192°C.

δ (DMSO-d6): 0,80 (3H, t), and 0.98 (6N, m)of 1.36 (2H, m), equal to 1.82 (4H, m), of 2.21 (2H, t), 2,42 (4H, m), 2.91 in (4H, m), 4,19 (2H, t), 4,27 (2H, t), 7,46 (1H, s), 7,79 (1H, d), 8,19 (1H, s), 9,27 (1H, s).

EXAMPLE 99

8-[2-Propoxy-5-((3R,5S)-3,4,5-trimethylpyrazine-1-sulfonyl)phenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (6%) from the specified in the header of the receive connector 93 according to the method of example 89.

TPL 120°C.

δ (DMSO-d6): 1,00 (N, m), 1.8 to 2.3 (6N, m)of 2.10 (3H, s), 3,48 (2H, d), 4,19 (2H, t), 4,27 (2H, t), 7,46 (1H, d), 7,80 (1H, d), to 8.20 (1H, s), 9,26 (1H, s).

EXAMPLE 100

N-(2-Morpholine-4-retil)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (66%) from the specified in the header of the receive connector 10 and 4-(2-amino-ethyl)research by the method of example 1.

TPL 191°C.

δ (CDCl3)with 1.07 (3H, t), of 1.13 (3H, t), of 1.95 (2H, m), 2,04 (2H, m), 2,31 (4H, m), 2,47 (2H, t), is 3.08 (2H, m), of 3.60 (4H, m), 4,36 (4H, m), of 5.68 (1H, Sirs), 7,18 (1H, d), 7,95 (1H, d), 8,89 (1H, s), 8,97 (1H, s), 11,65 (1H, Sirs).

EXAMPLE 101

N-(3-Dimethylamino-2,2-dimethylpropyl)-3-(oxopropyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (76%) from the specified in the header of the receive connector 10 and N,N,2,2-tetramethyl-1,3-propandiamine by the method of example 1.

TPL 178°C.

δ (DMSO-d6): 0,81 (6N, C)of 0.99 (3H, t), is 1.01 (3H, t), of 1.88 (4H, m), is 2.09 (2H, s), 2,19 (6N, (C), 2,61 (2H, s)to 4.23 (4H, m), 7,42 (1H, d), 7,55 (1H, Sirs), 7,86 (1H, d), a 8.34 (1H, s), 9,24 (1H, s).

EXAMPLE 102

8-{5-((1S,4S)-5-(2-Hydroxyethyl)-2,5-diazabicyclo[2.2.1]-heptane-2-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (67%) from the specified in the header of the receive connector 10 and specified in the header of the receive connector 36 according to the method p is the iMER 1.

TPL 183°C.

δ (DMSO-d6): 0,86 (1H, d), is 0.96 (3H, t), and 1.00 (3H, t), and 1.54 (1H, d), of 1.86 (4H, m), 2.57 m (1H, d), 2,82 (1H, d), of 2.97 (1H, d), to 3.38 (4H,m), 4,24 (5H, m), 7,44 (1H, d), of 7.90 (1H, d), 8,29 (1H, s), 9,27 (1H, s).

EXAMPLE 103

N-(3-Morpholine-4-ylpropyl)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (62%) from the specified in the header of the receive connector 10 and N-(3-aminopropyl)of the research according to the method of example 1.

TPL 195°C.

δ (DMSO-d6): to 0.96 (3H, t), and 0.98 (3H, t), of 1.52 (2H, m)to 1.86 (4H, m), 2,22 (6N, m), 2,80 (2H, m), of 3.48 (4H, m), 4,20 (2H, t), 4.26 deaths (2H, t), the 7.43 (1H, d), the 7.65 (1H, t), to 7.84 (1H, d), 8,32 (1H, s), 9,26 (1H, s), of 13.58 (1H, Sirs).

EXAMPLE 104

8-{5-[4-(2-Methoxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (67%) from the specified in the header of the receive connector 10 and 1-(2-methoxyethyl)piperazine according to the method of example 1.

TPL 177°C.

δ (DMSO-d6): to 0.96 (3H, t), is 1.01 (3H, t), of 1.86 (4H, m), 2,59 (6N, m), 2.91 in (4H, m), 3,17 (3H, s)to 3.35 (2H, t), 4,19 (2H, t), 4,27 (2H, t), 7,47 (1H, d), 7,78 (1H, d), 8,19 (1H, s), 9,27 (1H, s).

EXAMPLE 105

8-{5-[4-(2-Hydroxyethyl)-[1,4]diazepan-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (67%) from the specified in the header of the receive connector 10 and 2-(1,4-diazepan-1-yl)Ethan-1-ol by the method of example 1.

TPL 193°C.

; (DMSO-d6): 0,98 (6N, m), 1,72 (2H, m)to 1.87 (4H, m), 2.63 in (2H, t), of 2.72 (2H, m), 3,35 (10H, m)to 4.23 (4H, m), 7,42 (1H, d), 7,83 (1H, d), of 8.25 (1H, s), 9,26 (1H, s).

EXAMPLE 106

8-{5-[4-(2-Hydroxy-1-methylethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (65%) from the specified in the header of the receive connector 10 and 2-piperazine-1-improper-1-ol by the method of example 1.

TPL 216°C.

δ (DMSO-d6): 0,86 (3H, d), of 0.95 (3H, t), and 0.98 (3H, t), of 1.85 (4H, m), of 2.56 (4H, m), 2,89 (4H, m), 3,20 (1H, m), 3,39 (2H, m), 4,19 (2H, t), 4,27 (2H, t), 7,46 (1H, d), 7,79 (1H, d), 8,18 (1H, s), a 9.25 (1H, s).

EXAMPLE 107

N-(1-Ethylenedicarboxylic)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (71%) from the specified in the header of the receive connector 10 and (1-aminoethylthiomethyl)ethylamine by the procedure of example 1.

TPL 201°C.

δ (DMSO-d6): 0,96 (N, m)of 1.34 (8H, m)to 1.48 (2H, m)of 1.84 (4H, m), 2,35 (2H, m), of 2.72 (2H, s), 4,20 (4H, m), 7,37 (1H, d), of 7.82 (1H, d), at 8.36 (1H, s), 9,24 (1H, s).

EXAMPLE 108

8-{5-[4-(2-Hydroxy-1,1-dimethylethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (85%) from the specified in the header of the receive connector 10 and specified in the header of the receive connector 37 by the method of example 1.

TPL 223°C.

δ (DMSO-d6): 0,88 (6N, C)of 0.93 (3H, t),is 1.01 (3H, t)to 1.86 (4H, m), 2.63 in (4H, m), 2,87 (4H, m), 3,20 (2H, Sirs), to 3.34 (1H, Sirs), 4,20 (2H, t), 4,27 (2H, t), 7,47 (1H, d), 7,76 (1H, d), 8,19 (1H, s), a 9.25 (1H, s).

EXAMPLE 109

8-{2-Propoxy-5-[4-(2,2,2-triptorelin)piperazine-1-sulfonyl]-phenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (36%) from the specified in the header of the receive connector 10 and 1-(2,2,2-triptorelin)piperazine according to the method of example 1.

TPL 202°C.

δ (DMSO-d6): 0,88 (6N, C)of 0.93 (3H, t), is 1.01 (3H, t), of 1.86 (4H, m), 2.63 in (4H, m), 2,87 (4H, m), 3,20 (2H, Sirs), to 3.34 (1H, Sirs), 4,20 (2H, t), 4,27 (2H, t), 7,47 (1H, d), 7,76 (1H, d), 8,19 (1H, s), a 9.25 (1H, s).

EXAMPLE 110

N-(1-Ethylaminoethanol)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (53%) from the specified in the header of the receive connector 10 and (1-aminoethylthiomethyl)ethylamine by the procedure of example 1.

TPL 203°C.

δ (DMSO-d6): of 0.95 (3H, t), and 1.00 (3H, t), 1,2-1,6 (N, m)to 1.86 (4H, m), 2,35 (2H, m), 2,68 (2H, m), 4,19 (2H, t), 4,22 (2H, t), 7,38 (1H, d), of 7.82 (1H, d), at 8.36 (1H, s), 9,19 (1H, s).

EXAMPLE 111

N-(1-Diethylaminocarbonylmethyl)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (35%) from the specified in the header of the receive connector 10 and (1-aminoethylthiomethyl)diethylamine by the method of example 1.

TPL 192°C.

δ (DMSO-d6): 1,0 (N, m), and 1.4 (10H, m)and 1.83 (4H, m), 2,47 (4H, m), 3,06 (2H, s), 4,22 (4H, m), 7,39 (1H, d), a 7.85 (1H, d), 8,31 (1H, s), 9,23 (1H, s).

EXAMPLE 112

N-[2-(3,4-Acid)ethyl]-N-methyl-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (42%) from the specified in the header of the receive connector 10 and 2-(3,4-acid)-N-methylethylamine by the method of example 1.

TPL 92°C.

δ (DMSO-d6): of 0.91 (3H, t), of 0.99 (3H, t), of 1.84 (4H, m), of 2.72 (5H, m), 3,21 (2H, t), of 3.33 (3H, s), 3,70 (3H, s)to 4.15 (2H, t), 4,25 (2H, t), 6,74 (1H, d), PC 6.82 (1H, s), at 6.84 (1H, d), 7,41 (1H, d), 7,80 (1H, d), 8,23 (1H, s), a 9.25 (1H, s), 13,70 (1H, Sirs).

EXAMPLE 113

N-(1-Diethylaminocarbonylmethyl)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (30%) from the specified in the header of the receive connector 10 and (1-aminoethylthiomethyl)diethylamine by the method of example 1.

TPL 171°C.

δ (DMSO-d6): 1,0 (N, m, 1,49 (N, m)of 1.84 (4H, m)of 2.50 (4H, m), 3,05 (2H, s), is 4.21 (4H, m), 7,38 (1H, d), to 7.84 (1H, d), 8,31 (1H, s), which 9.22 (1H, s).

EXAMPLE 114

N-(1-Methyl-4-phenylpiperidine-4-ylmethyl)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde

Obtained as a white solid (54%) from the specified in the header of the receive connector 10 and 4-aminomethyl-1-methyl-4-phenylpiperidine by the method of example 1.

TPL 213°C.

δ (DMSO-d6): of 0.95 (3H, t, 0,99 (3H, t), 1,80 (6N, m)2,04 (4H, m), 2,10 (3H, s), of 2.51 (2H, Sirs), 2,82 (2H, d), 7,0-7,5 (7H, m), 7,73 (1H, d), 8,23 (1H, s), which 9.22 (1H, s).

EXAMPLE 115

8-{5-[4-(3-Hydroxypropyl) piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

To the mixture specified in the header of the receive connector 10 (40 mg, 0.09 mmol) and associated with the polymer research (65 mg, of 2.75 mmol/g based on the analysis of nitrogen) in dichloromethane (3 ml) is added 3-piperazine-1-improper-1-ol (14.1 mg, 0,098 mmol) and the resulting mixture was stirred at room temperature overnight. The reaction mixture is filtered and the filtrate evaporated under reduced pressure. The residue is triturated with diethyl ether and the precipitate collected by filtration and dried in vacuum to obtain specified in the title compound (41 mg, 82%) as a white solid.

ESI/MC m/e 559 ([M+H]+C25H34N8O5S)

retention time (min): 11,7.

EXAMPLES 116-131

N,N-Dimethyl-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]-triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde (116)

N-{1-[3-(5-Oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)-4-propoxyphenyl]sulfanilamide (117)

N-(2-Hydroxyethyl)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde (118)

3-(5-Oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxy-N-(1H-[1,2,4]triazole-3-yl)benzosulfimide (119)

N-(2-Dimethylaminoethyl)-N-methyl-3-(oxopropyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde (120)

3-(5-Oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxy-N-pyridin-4-ylmethylphosphonate (121)

3-(5-Oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxy-N-(2-pyridin-2-retil)benzosulfimide (122)

N-(3-Imidazol-1-ylpropyl)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde (123)

N-Methyl-N-(1-methylpiperidin-4-yl)-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde (124)

8-[5-(4-Isopropylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he (125)

N-Ethyl-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)-4-propoxy-N-(tetrahydrofuran-2-ylmethyl)-benzosulfimide (126)

3-(5-Oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxy-N-(2,2,6,6-tetramethylpiperidine-4-yl)-benzosulfimide (127)

N-(4-Hydroxy-1-methylpiperidin-4-ylmethyl)-N-methyl-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde (128)

N-(4-Hydroxy-1-methylpiperidin-4-ylmethyl)-N-methyl-3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde (129)

8-{2-Propoxy-5-[4-(2,2,2-triptoreline)piperazine-1-sulfonyl]phenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he (130)

N-(1-{[3-(5-Oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl)-4-propoxybenzaldehyde]methyl}-CEC is heptyl)ndimethylacetamide (131)

Specified in the title compounds were synthesized from the specified in the header of the receive connector 10 according to the method of example 115 and using the corresponding reactant respectively. Data ESI/MC, the retention times of HPLC and outputs are summarized in table 3.

TABLE 3
ExampleMolecular formulaESI/MC m/e [M+H]+Retention time (min)Output %
115C25H34N8O5S55911,782
116C20H25N7O4S46016,379
117With19H23N9O4S44516,566
118C20H25N7O5S47613,875
119C20H22N10O4S49915,485
TABLE 3 (continued)
ExampleMolecular formula ESI/MC m/e [M+H]+Retention time (min)Output %
120With23H32N8About4S51711,384
121With23H26N8O4S52313,172
122C25H28N8O4S53713,577
123With24H29N9O4S54011,268
124C25H34N8O4S54311,766
125C25H34N8O4S543to 12.079
126With25H33N7O5S54418,082
127C27H38N8O4S57111,984
128With26H36 8O5S57311,274
129With26H36N8O5S57312,687
130C24H27F3N8O5S597the 17.365
131With28H38N8About5S44716,558

EXAMPLE 132

6-Butyl-8-[5-(3-hydroxyazetidine-1-sulfonyl)-2-propoxyphenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (50%) specified in the header of the receive connector 14 and azetidin-3-ol by the method of example 1.

TPL 238°C.

δ (DMSO-d6): of 0.95 (3H, t), of 1.02 (3H, t)of 1.39 (2H, m)and 1.83 (4H, m), 3,36, and 3,39 (4H, 2D), 3.90 and 3,93 (4H, 2D), are 4.24 (2H, t), or 4.31 (2H, t), 5,74 (1H, d), 7,51 (1H, d), 7,88 (1H, d), 8,29 (1H, s), 9,26 (1H, s)13,8 (1H, s).

EXAMPLE 133

6-Butyl-8-[5-(piperazine-1-sulfonyl)-2-propoxyphenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (60%) from the specified in the header of the receive connector 14 and piperazine according to the method of example 1.

TPL 147°C.

δ (DMSO-d6): of 0.95 (3H, t), of 1.02 (3H, t), 1,72 (2H, m), of 1.85 (4H, m), 2,80 (2H, t), 2,85 (2H, t), with 3.27 (4H, m), 4,20 (4H, m), 7,38 (1H, d), 7,79 (1H, d), 8,27 (1 is, C)to 9.20 (1H, s).

EXAMPLE 134

3-(6-Butyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-N-methyl-N-(1-methylisatin-3-yl)-4-propoxybenzaldehyde

Obtained as a white solid (19%) from the specified in the header of the receive connector 14 and methyl (1-methylisatin-3-yl)amine according to the method of example 1.

TPL 169°C.

δ (CDCl3): of 1.02 (3H, t), of 1.16 (3H, t)to 1.48 (2H, m), 1,89 (2H, m), of 2.08 (2H, m), is 2.30 (3H, s)of 2.75 (3H, s), 3,06 (2H, t), of 3.53 (2H, t), was 4.02 (1H, m), 4,39 (4H, m), 7,19 (1H, d), 7,26 (1H, s), 7,80 (1H, d), a total of 8.74 (1H, s), 8,96 (1H, s).

EXAMPLE 135

6-Butyl-8-[5-(3-dimethylaminomethylene-1-sulfonyl)-2-propoxyphenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (56%) from the specified in the header of the receive connector 14 and is specified in the header of the receive connector 33 by the method of example 1.

TPL 198°C.

δ (DMSO-d6): to 0.96 (3H, t), of 1.03 (3H, t), of 1.37 (2H, m), of 1.80 (2H, m)to 1.87 (2H, m), 1,99 (6N, (C)and 2.1 (2H, d), of 2.51 (1H, m)to 3.36 (2H, m), 3,83 (2H, t), 4,25 (2H, t), or 4.31 (2H, t), to 7.50 (1H, d), 7,88 (1H, d), 8,30 (1H, s), 9,24 (1H, s).

EXAMPLE 136

6-Butyl-8-(5-{3-[(2-Hydroxyethyl)methylamino]azetidin-1-sulfonyl}-2-propoxyphenyl)-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-he

Obtained as a white solid (54%) from the specified in the header of the receive connector 14 and 2-(azetidin-3-ylmethylamino)ethanol according to the method of example 1.

TPL 162°C.

δ (DMSO-d6): 0,46 (4H, m)of 1.33 (2H, m), of 1.80 (4H, m), 1,90 (3H, s)to 2.18 (2H, t), is 3.21 (1H, m), 47 (2H, t in), 3.75 (2H, t), 4,24 (6N, m), 7,47 (1H, d), 7,86 (1H, d), compared to 8.26 (1H, s), 9,23 (1H, s)13,72 (1H, Sirs).

EXAMPLE 137

6-Butyl-8-{5-[4-(2-hydroxy-1-methylethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-he

Obtained as a white solid (65%) from the specified in the header of the receive connector 14 and 2-piperazine-1-improper-1-ol by the method of example 1.

TPL 221°C.

δ (DMSO-d6): 0,86 (3H, d), of 0.95 (3H, t), and 1.00 (3H, t)to 1.38 (2H, m)and 1.83 (4H, m), 2,59 (4H, m), 2,89 (4H, m), 3,21 (1H, m), 3,39 (2H, m), 4,25 (4H, m), 7,46 (1H, d), 7,79 (1H, d), 8,21 (1H, s), a 9.25 (1H, s)to 13.7 (1H, s).

EXAMPLE 138

6-Butyl-8-{5-[4-(2-hydroxy-1,1-dimethylethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-he

Obtained as a white solid (82%) from the specified in the header of the receive connector 14 and is specified in the header of the receive connector 37 by the method of example 1.

TPL 237°C.

δ(DMSO-d6): 0,87 (6N, C)of 0.95 (3H, t), of 1.02 (3H, t)to 1.38 (2H, m), equal to 1.82 (4H, m), 2,62 (4H, m), of 2.86 (4H, m), 3,20 (2H, s), 4,25 (4H, m), 7,46 (1H, d), to 7.77 (1H, d), to 8.20 (1H, s), 9,24 (1H, s).

EXAMPLES 139-142

N,N-Bis(2-hydroxyethyl)-3-(6-isobutyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde (139)

3-(6-Isobutyl-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-N-(4-methylpiperazin-1-yl)-4-propoxybenzaldehyde (140)

8-{5-[4-(2-Hydroxyethyl)piperidine-1-sulfonyl]-2-propoxyphenyl}-6-isobutyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine--he (141)

8-(5-{4-[2-(2-Hydroxyethoxy)ethyl]piperazine-1-sulfonyl}-2-propoxyphenyl)-6-isobutyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he (142)

Specified in the title compounds were synthesized from the specified in the header of the receive connector 30 according to the method of example 115 and using the corresponding reactant respectively. Data ESI/MC, the retention times of HPLC and outputs are summarized in table 4.

TABLE 4
ExampleMolecular formulaESI/MC m/e [M+H]+Retention time(min)Output %
139With23H31About6S53415,162
140With24H33N9O4S54413,178
141With26H35N7O5S55818,775
142With27H38N8About6S60313,777

EXAMPLE 143

N-(2-Hydroxyethyl)-3-[6-(2-methoxyethyl)-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl]-4-propoxy-1-propylbenzenesulfonyl

Obtained as a white solid (43%) from the specified header soy is inane obtain 34 and 2-propylaminoethyl by the method of example 1.

TPL 183°C.

δ (DMSO-d6): of 0.82 (3H, t), of 0.99 (3H, t), of 1.52 (2H, m)to 1.87 (2H, m), of 3.13 (4H, m), 3,30 (3H, s), 3,51 (2H, t), with 3.79 (2H, t), 4,28 (2H, t)to 4.41 (2H, t), the 7.43 (1H, d), 7,89 (1H, d), 8,31 (1H, s), 9,29 (1H, s).

EXAMPLE 144

3-[6-(2-Methoxyethyl)-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl]-N-(2-morpholine-4-retil)-4-propoxybenzaldehyde

Obtained as a white solid (48%) from the specified in the header of the receive connector 34 and 2-morpholine-4-ylethylamine by the method of example 1.

TPL 171°C.

δ (DMSO-d6): and 0.98 (3H, t), of 1.87 (2H, m), and 2.27 (6N, m), 2,89 (2H, m), 3,29 (3H, s), of 3.48 (4H, m), with 3.79 (2H, t), 4,27 (2H, t), 4,42 (2H, t), the 7.43 (1H, d), to 7.61 (1H, t), 7,87 (1H, d), a 8.34 (1H, s), 9.28 are (1H, s).

EXAMPLE 145

8-{5-[4-(3-Hydroxypropyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-(2-methoxyethyl)-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

Obtained as a white solid (32%) from the specified in the header of the receive connector 34 and 3-piperazine-1-improper-1-ol by the method of example 1.

TPL 171°C.

δ (DMSO-d6): 0,99 (3H, t)of 1.50 (2H, m)to 1.87 (2H, m), a 2.36 (2H, m), of 2.45 (4H, m), of 2.92 (4H, m), 3,30 (3H, s), of 3.78 (2H, t), 4,28 (2H, t)to 4.41 (2H, t), of 7.48 (1H, d), 7,78 (1H, d), 8,21 (1H, s), 9.28 are (1H, s).

EXAMPLE 146

3-[6-(2-Methoxyethyl)-5-oxo-6,9-dihydro-5H-[1,2,4]triazolo-[3,4-i]purine-8-yl]-N-(3-morpholine-4-ylpropyl)-4-propoxybenzaldehyde

Obtained as a white solid (47%) from the specified in the header of the receive connector 34 and 3-morpholine-4-iproplatin by the method of example 1.

TPL 49° C.

δ (DMSO-d6): to 0.96 (3H, t), for 1.49 (2H, m)of 1.84 (2H, m), 2,19 (6N, m), 2,78 (2H, m), with 3.27 (3H, s), of 3.45 (4H, m), 3,76 (2H, t), 4,25 (2H, t), 4,39 (2H, t), 7,41 (1H, d), a 7.62 (1H, t), 7,81 (1H, d), 8,31 (1H, s), a 9.25 (1H, s).

EXAMPLES 147-149

N,N-Bis(2-hydroxyethyl)-3-(5-oxo-6-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde (147)

8-{5-[4-(2-Hydroxyethyl)piperidine-1-sulfonyl]-2-propoxyphenyl}-6-pentyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he (148)

8-(5-{4-[2-(2-Hydroxyethoxy)ethyl]piperazine-1-sulfonyl}-2-propoxyphenyl)-6-pentyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he (149)

Specified in the title compounds were synthesized from the specified in the header of the receive connector 32 by the method of example 115 and using the corresponding reactant respectively. Data ESI/MC, the retention times of HPLC and outputs are summarized in table 5.

TABLE 5
ExampleMolecular formulaESI/MC m/e [M+H]+Retention time (min)Output %
147With24H33N7O6S54816,785
148With27H37N7O5S57220,365
149With28H40N8About 6S61715,072

The following examples illustrate pharmaceutical compositions according to the present invention and the method of their preparation.

The EXAMPLE 1 COMPOSITION

50,000 capsules, each contains 100 mg of active ingredient were obtained in accordance with the following ready preparative form:

The active ingredient5 kg
The lactose monohydrate10 kg
Colloidal silicon dioxide0.1 kg
Corn starch1 kg
Magnesium stearate0.2 kg

The method

The above ingredients are screened through a sieve of 60 mesh, loaded in a suitable mixer and the mixture is filled in 50000 gelatin capsules.

EXAMPLE 2 COMPOSITION

50,000 tablets, each containing 50 mg of active ingredient were obtained from the following components:

The active ingredient2.5 kg
Microcrystalline cellulose1,95 kg
Dried spray lactose9,95 kg
Carboximetilkrahmal0.4 kg
The sodium fumarate 0.1 kg
Colloidal silicon dioxide0.1 kg

The method

All the powders are passed through a sieve with openings of 0.6 mm, then mixed in a suitable mixer for 20 minutes and pressed into tablets of 300 mg using 9 mm disk and flat dies with the bevel. The disintegration time of the tablets is approximately 3 minutes.

1. Derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-i]purine-5-she formulas (I)

where R1represents hydrogen; C1-4alkyl group or a group of the formula

-CH2-R6

where R6represents a phenyl group;

R2is1-5alkyl group or a group of the formula

-(CH2)n-R6

where n is an integer 1 or 2 and R6is pyridyloxy group or1-4alkoxy;

R3represents C1-6alkyl group;

or R4and R5together with the nitrogen atom to which they are attached, form a 4-7-membered ring comprising 1 or 2 heteroatoms selected from nitrogen and oxygen, the said ring may be unsubstituted or substituted C1-5alkalinous group or hydroxy, C1-6alkyl group, which, in turn, can be substituted by one or more and what Ohm halogen or hydroxy, With1-4alkoxy, hydroxys1-4alkoxy, CI-C1-4alkylaminocarbonyl; or formyl, C2-4alkenyl, carbamoyl, trifluoracetyl or di-C1-4alkylaminocarbonyl, and one alkyl part of which in turn may be substituted by a hydroxy-group; or

R4and R5each, independently, represent hydrogen or C2-6alkylamino group or1-6alkyl group which may be unsubstituted or substituted by one or more atoms, hydroxy, C1-4alkoxy or di-C1-4alkylaminocarbonyl; or amidinopropane or R4represents hydrogen or C1-4alkyl group, and R5represents a group of the formula

-(CH2)n-R7

where n is an integer from 0 to 4, and R7represents a 3-7-membered ring including 1 to 3 heteroatoms selected from nitrogen and oxygen, the said ring may be unsubstituted or substituted by one or more1-6alkyl groups, hydroxy or phenyl group; C3-7cycloalkyl group, which is substituted mono - or dis1-4alkylaminocarbonyl or1-4alkylaminocarbonyl; or phenyl group, substituted With more than one1-4alkoxy group;

or their pharmaceutically acceptable salt.

2. The compound according to claim 1, where R2predstavljaet 1-C5is an alkyl group or a group of the formula

-(CH2)nR6

where n is 1 or 2 and R6is pyridyloxy group, and R3is1-C5is an alkyl group.

3. The compound according to claim 1 or 2, where R1represents methyl, ethyl, sawn or benzyl group; R2represents ethyl, through n-boutelou, isobutylene, n-pentelow, methoxyethanol or 3-pyridylmethyl group; and R3represents ethyl, sawn or n-boutelou group.

4. The compound according to any one of claims 1 to 3, where the ring formed by R4, R5and the nitrogen atom to which they are attached, is piperidine, piperazinilnom, [1,4]diazepan-1-ilen, morpholinyl, pyrazolidine, azetidinone or diazabicyclo[2.2.1]hept-2-ilen or hexahydropyrazino[2,1-a]personalni group, which is unsubstituted or substituted With1-C4-alkyl, C2-C4-alkenylphenol, carbamoyl, di-C1-C4-alkylamino, (2-hydroxyethyl)methylamino, hydroxy, 2,2,2-cryptomaterial, 2,2,2-triptoreline, formyl, hydroxyalkyl, C1-4alkoxyalkyl and hydroxys1-4alkoxyalkyl groups, where the alkyl parts contain 1 to 4 carbon atoms.

5. The compound according to claim 4, where R4and R5pax is with the nitrogen atom, to which they are attached represent a 4-hydroxypiperidine, 4-carbamoylbiphenyl, 3-carbamoylbiphenyl, piperazinilnom, 4-methylpiperidino, 4-ethylpiperidine, 4-formylpiperazine, [1,4]diazepan-1-ilen, 4-methyl[1,4]diazepan-1-ilen, 4-(2-hydroxyethyl)piperazinilnom, 4-[2-(2-hydroxyethoxy)ethyl]piperazinilnom, morpholinyl, diazabicyclo[2.2.1]hept-2-ilen, 5-metallizable[2.2.1]hept-2-ilen, 5-(2-hydroxyethyl)diazabicyclo[2.2.1 ]hept-2-ilen, 3(S)-methylpiperidino, 3(R)-methylpiperazine, (3R,5S) - for 3,5-dimethylpiperidino, (2R,5S)-2,5-dimethylpiperazine, (2S,5R)-2,5-dimethylpiperazine, 3-dimethylaminoacetyl, 3-dimethylaminomethylphenol, 4-arylpiperazines, 4-propylpiperazine, hexahydropyrazino[1,2-a]pyrazin-2-ilen, (3R,5S)-3,4,5-trimethylpyrazole, 4-(2-methoxyethyl)piperazinilnom, 4-(2-hydroxyethyl)[1,4]diazepan-1-ilen, 4-(2-hydroxy-1-methylethyl)piperazinilnom, 4-(2-hydroxy-1,1-dimethylethyl)piperazinilnom, 4-(2,2,2-triptorelin)piperazinilnom, 4-(3-hydroxypropyl)piperazinilnom, 4-(isopropyl)piperazinilnom, 4-(2-ethoxyethyl)piperazinilnom, 4-(2,2,2-triptoreline)piperazinilnom, 3-hydroxyazetidine, 3-(2-hydroxyethyl)methylaminoacetaldehyde or 4-(2-hydroxyethyl)piperidino group.

6. The compound according to claim 1 or 2, where R4and R5independently presented Aut hydrogen, With1-C4is an alkyl group which is unsubstituted or substituted by hydroxy or dimethylaminopropoxy, propenyloxy group or amidinopropane.

7. The compound according to claim 1 or 2, where R4represents hydrogen or C1-C4is an alkyl group, and R5represents a group of the formula

-(CH2)nR7

n is 0, 1, 2 or 3 and R7is pyridinol, piperidino, piperazinilnom, morpholinyl, triazolyl, pyrrolidinyl, 1-ethyl-aminocyclopent-1-ilen, 1-diethylaminotoluene-1-ilen, 1-acylaminoalkyl-1-ilen, 1-diethylaminoethyl-1-ilen, 3,4-dimethoxyphenyl, 1-methyl-4-phenylpiperidine-4-ilen, imidazolidinyl, 1 methylpiperidin-4-ilen, tetrahydrofuranyl, 2,2,6,6-tetramethylpiperidine-4-ilen, 4-hydroxybiphenyl-4-ilen, 1-acetamidocinnamate-1-ilen, 1-methyl-3-azetidinol or 4-methylpiperazin-1-ilen group.

8. The compound according to any one of claims 1 to 7, characterized in that it has a value IC50for inhibition of PDE 5 is less than 30 nm.

9. The compound according to claim 1, which is

6-ethyl-8-[5-(4-methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-[2-butoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-6-ethyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-[5-(4-methylpiperazin-1-sulfonyl)-2-ProPak iphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-[5-(4-methyl-[1,4]diazepan-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he

6-butyl-8-{5-[4-(2-hydroxyethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

3-(5-oxo-6-propyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxy-N-pyridin-4-albenzaalbenza,

8-[5-((S)-3-methylpiperazin-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-[5-((IS,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]-triazolo[3,4-i]purine-5-he,

8-[5-(3-dimethylaminomethylene-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-[5-((3R,5S) - for 3,5-dimethylpiperazine-1-sulfonyl)-2-propoxyphenyl]-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

N-(3-dimethylamino-2,2-dimethylpropyl)-3-(oxopropyl-6,9-dihydro-5H-[1,2,4]triazolo[3,4-i]purine-8-yl)-4-propoxybenzaldehyde,

8-{5-[4-(2-hydroxyethyl)-[1,4]diazepan-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he,

8-{5-[4-(2-hydroxy-1,1-dimethylethyl)piperazine-1-sulfonyl]-2-propoxyphenyl}-6-propyl-6,9-dihydro[1,2,4]triazolo[3,4-i]purine-5-he, or

6-butyl-8-{5-[4-(2-hydroxy-1,1-dimethyl what Teal)piperazine-1-sulfonyl]-2-propoxyphenyl}-6,9-dihydro[1,2,4]triazolo-[3,4-i]purine-5-one or its pharmaceutically acceptable salt.

10. The compound according to claims 1-9, a suitable method of treatment of a human or animal.

11. A method of obtaining a compound according to any one of claims 1 to 9, including interaction derived hydrazinophenyl formula (II)

where R2, R3, R4and R5have the values listed in any one of claims 1 to 9, with a carboxylic acid of General formula (III)

where R1matter specified in any one of claims 1 to 9, or its reactive derivative, optionally in the presence of a polar aprotic solvent.

12. The method according to claim 11, where this interaction occurs in the presence of organic bases.

13. The compound of formula (II)

where R2, R3, R4and R5have the meanings indicated in claim 1

14. The compound of formula (IV)

where R2, R3, R4and R5have the meanings indicated in claim 1.

15. The compound of formula (V)

where R2, R3, R4and R5have the meanings indicated in claim 1.

16. The compound of formula (VI)

where R2and R3have the meanings indicated in claim 1.

17. SPO is about obtaining the compounds of General formula 1 according to claim 1, characterized in that panelcenter General formula (IX)

where R1, R2and R3have the meanings indicated in claim 1, is subjected to the interaction with chlorosulfonic acid and the resulting sulphonylchloride formula (X)

where R1, R2and R3have the values listed above, then subjected to interaction with the amine of formula (VIII)

where R4and R5have the meanings indicated in claim 1.

18. The method according to 17, characterized in that the chlorosulfonic acid is used in excess or as a solvent, and the second stage of the process is carried out in a polar aprotic solvent and in the presence of organic bases.

19. Pharmaceutical composition having D5-inhibitory activity, comprising as active ingredient at least one compound as described in any one of claims 1 to 9, or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

20. The method of treatment of a human or animal suffering from stable, unstable and variant angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, conditions of reduced potency is ravenskih vessels, peripheral vascular disease, vascular disorders, stroke, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, male erectile dysfunction, female sexual dysfunction, or diseases characterized by disorders of the locomotor ability of the gastrointestinal tract, including the introduction of a specified patient requiring such treatment, an effective amount of a compound according to claim 1.



 

Same patents:

The invention relates to inhibitors tyrosinekinase type bis-indolylmaleimide compounds of the formula I

< / BR>
where Z denotes a group of General formula II

< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds

The invention relates to a method for producing a condensed polycyclic alkaloids of General formula I, including new, including phase cyclization of azometynoylid General formula II, where a is optionally substituted aryl, Z is oxygen, n = 1, Y is optionally substituted aryl, W and X together with the nitrogen atoms and the carbon to which they are attached, form a saturated or unsaturated nitrogen-containing heterocyclic group, possibly substituted and possibly condensed with aryl, carbocyclic or heterocyclic group

The invention relates to novel condensed pyrrolo (2,3-C)carbazole-6-Onam represented by the General formulas (I) and (II)

The invention relates to polypeptide to the compound of General formula I, where R1indicates the lowest alkanoyl, substituted unsaturated 6-membered heterophilically group containing at least one nitrogen atom which may have one or more suitable substituents; lower alkanoyl, substituted 1,2,3,4-tetrahydroisoquinoline, which may have one or more suitable substituents; lower alkanoyl, substituted unsaturated condensed heterocyclic group containing at least one oxygen atom, which may have one or more suitable substituents, or pharmaceutically acceptable salts

-,or- cyclodextrin or its alkyl - or hydroxyalkylated and (6r)- or (6s)-5,10-methylenetetrahydrofolic acid or a salt thereof, a method of stabilizing aqueous solutions and the method of obtaining stable solutions" target="_blank">

The invention relates to new compounds include,-,or-cyclodextrin or its alkyl - or hydroxyalkylated and (6R)-, (6S) - or (6R,S)-5,10 - methylenetetrahydrofolic acid or its salts, stable solutions of compounds include cyclodextrin, a method of stabilizing aqueous solutions and the way to obtain stable solutions, which can be used in the pharmaceutical industry

The invention relates to new chemical compound - vysokomernoa tritium 2-hydroxy-6-mercaptopurine formula (I)

< / BR>
molar radioactivity of 3.1 CI/mmol, radiochemical purity of the compound is more than 98%.

The invention relates to organic chemistry and can find application in biology and medicine

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to novel 2,6,9-triple-substituted purine derivative of General formula I, having the effect of selective inhibitors of kinases of the cell cycle, which can be used, for example, for the treatment of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, diabetes type I, multiple sclerosis, and for the treatment of cancer, cardiovascular diseases such as restenosis, etc

The invention relates to new derivatives of purine of formula I, II, III and IV, pharmaceutical compositions and method of treatment of a pathological state characterized by thrombotic activity

The invention relates to O6substituted derivatives of guanine, method of their production and to their use for the treatment of tumor cells

The invention relates to a new antiviral drug, in particular an ester of the amino purine derivative, and most specifically to air, obtained from the above drug (ganciclovir) and L-valine, and its pharmaceutically acceptable salts

The invention relates to new compounds of formula I Nu-O-Fa, where O is oxygen, Nu is a nucleoside or nucleoside analogue, including such nitrogen base, as adenine, Esenin, cytosine, uracil, thymine; Fa - acyl monounsaturated C18YPD C20-9-fatty acids, which fatty acid etherification hydroxyl group in 5-position of the sugar portion of the nucleoside or nucleoside analog, or a hydroxyl group, an acyclic chain of an analogue of the nucleoside

The invention relates to chemical technology for acyclic guanosine analogues with antiviral activity, in particular, to the drug Acyclovir [9-(2'-hydroxyethoxymethyl )guanine] , used in medicine as an effective means Antiherpes virus effect

The invention relates to analogs of purine nucleosides containing unsaturated carbocyclic ring instead of the sugar residue, their pharmaceutically acceptable derivatives and their use in medical therapy particularly for the treatment of certain viral diseases
Up!