Derivatives of 3-n-1,2,3-triazolo-[4,5-d]pyrimidine, pharmaceutical composition and method of production thereof

 

(57) Abstract:

The invention relates to derivatives of 3-N-1,2,3-triazolo-[4,5-d]-pyrimidine of the General formula I, in which a represents O or CH2; X is selected from NR1R2, SR1and C1-C7-alkyl; Y is chosen from SR1, NR1R2and C1-C7-alkyl; R1and R2each independently represents N or C1-C7-alkyl, or R1represents C1-C7-alkyl, optionally substituted in the alkyl chain one atom of O or S or one or more halogen, and R2is hydrogen; R3and R4both represent hydrogen or together form a bond; a is COOH, C(O)NH(CH)pCOOH, C(O)N[(CH2)q-COOH]2WITH(ABOUT)N(COOH)(CH2)rCOOH or 5-tetrazolyl, in which p, q and r each independently is 1, 2 or 3, as well as their pharmaceutically acceptable salts or esters. It also describes the method of obtaining these compounds and containing pharmaceutical composition. The claimed compounds prevent platelet aggregation. 3 S. and 14 C.p. f-crystals.

The scope of the invention

The invention relates to new compounds, method of their derivation, their ispolzovaniem, to prevent platelet aggregation.

Background of the invention and the prior art

A number of interrelated processes leads to platelet aggregation. Whatever the initial stimulus, the final overall result is cross-linking of platelets by binding with fibrinogen binding site of the membrane - glycoprotein (11b/111a GP11b/111a). High antithrombotic efficacy of antibodies or antagonists GP11b/111a can be explained by their effect on the final overall result. However, this efficiency may also explain the problems of bleeding, which was observed when using the agent of this class.

Thrombin can produce platelet aggregation is largely independent from other processes, but significant amounts of thrombin unlikely to attend without prior activation of platelets by other mechanisms. Thrombin inhibitors such as hirudin, are highly effective antithrombotic agents, but again can lead to excessive bleeding, because they act as antiplatelets and anticoagulants (TIMI Investigators 9a (1994), Circulation 90, pp. 1624-1630; The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators (GUSTO) Circulation 90, pp. 1 is satisfied on platelet aggregation (see, for example, Antiplatelet Trialists' Collaboration (1994), Br. Med. J. 308, pp. 81-106; Antiplatelet Trialists' Collaboration (1994), Br. Med. J. 308, pp. 159-168) does not affect the aggregation produced by other sources ADP, such as damaged cells or ADP allocated in conditions of turbulent blood flow. Principal role of the ADF is confirmed by the fact that other means, such as adrenaline and 5-hydroxytryptamine (5-HT, serotonin), produce aggregation only in the presence of ADP.

In the present invention assumed that the antagonist actions of ADP to its receptor in the membrane of the platelet, P2T-purinoceptor, will ensure a more effective antithrombotic agent than aspirin, but less strong effect on bleeding than the antagonists of the fibrinogen receptor.

In U.S. patent 4543255 disclosed carbocyclic analogues of 2-amino-6-substituted-purine-2'- deoxyribofuranosyl and 2-amino-6-substituted-8-agapurin-2'- deoxyribofuranosyl. Compounds described in this patent is shown as having an inhibitory activity against herpes virus.

In patent WO 90/06671 disclosed the use of carbocyclic analogues of various nucleosides for the treatment of diseases caused by Hepatitis C.

The task lying is such an activity in relation to P2T-receptor and significant advantages compared with the known antithrombocyte means, such as improved efficacy, reduced side effects, no toxicity and better selectivity to P2Tthe receptor.

The problem indicated above is solved by obtaining new compounds, which are 5,7-disubstituted 1,2,3-triazolo[4,5-d] -pyrimidine-3-yl derivatives, described below.

Detailed description of the invention

The new compounds of the present invention described General formula (1)

,

where In represents O or CH2;

X represents NR1R2, SR1and C1-C7-alkyl;

Y is SR1, NR1R2and C1-C7-alkyl;

R1and R2each independently represents H or C1-C7-alkyl, optionally substituted in or on the alkyl chain one or more atoms of O, S, N, or halogen;

R3and R4both represent H, or R3and R4together form a bond;

A is COOH, C(O)NH(CH2)pCOOH, C(O)N[(CH2)qCOOH]2C(O)NHCH(COOH) (CH2)rCOOH or 5-tetrazolyl, where p, q and r each independently is 1, 2 or 3.

The term "alkyl" WRC CLASS="ptx2">

Deputy O, S and N can be the substitutes on or in the alkyl chain, which means1-C7-alkyl, in which one methylene chain may be replaced by O, S or NH, and in which the alkyl chain may be substituted by one or more group HE, SH, NH2or halogen.

Halogen includes chlorine and fluoride.

In the scope of the invention also includes pharmaceutically acceptable salts of compounds of formula (1), as well as prodrugs, such as esters and amides of compounds.

Also in the scope of the invention includes compounds of formula (1) in tautomeric, enantiomeric and diastereomeric forms.

Preferred compounds of the invention are the compounds of formula (1), in which

X represents NR1R2;

Y is SR1;

A represents C(O)NHCH(COOH)(CH2)rCOOH;

and in which R1, R2and r is defined above.

Particularly preferred compounds of the invention are the compounds of formula (1), in which

X represents NR1R2where R1is hydrogen and R2defined above;

Y is SR1where R1is1-C5-alkyl, optionally substituted by one or more halog the plants are (E)-N-[1-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] -pyrimidine-3-yl] -1,5,6-trideoxy- -D-libept - 5-informanon]-L-aspartic acid;

[1R-(1 ,2 ,3 ,4 )]-N-[3-[4-[7-(Butylamino) -5-(propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] -2,3 - dihydrocyclopenta]propanol] -L-aspartic acid;

[1R-(1 (E), 2 ,3 ,4 )]-N-[3-[4-[7-(hexylamino)-5-(propylthio)-3H - 1,2,3-triazolo[4,5-d-3-yl] -2,3 - dihydrocyclopenta]-2-propenyl]-L-aspartic acid; and

[1R-(1 (E), 2 ,3 ,4 )]-N-[3-[4-[5-[(3,3,3-Cryptochromes)thio]- 7-[2-(methylthio)ethylamino] -3H-1,2,3-triazolo[4,5-d] pyrimidine - 3-yl/-2,3-dihydrocyclopenta/-2-propanol/-L-aspartic acid, monoammonium salt.

The new compounds of the present invention are useful for therapy, in particular to prevent platelet aggregation. Compounds of the present invention, therefore, are useful as antithrombotic funds and, therefore, are useful for the treatment or prevention of unstable angina, plastic surgery on the coronary vessels and myocardial infarction.

Compounds of the present invention is also useful for the treatment or prevention of primary arterial thrombotic complications of atherosclerosis, such as thrombotic stroke, peripheral vascular disease, myocardial infarction (i.e., without thrombolite).

Further readings when useful connections izobreteny atherosclerotic disease, such as plastic surgery on vessels, endarterectomy, the introduction of the stent, surgery transplant coronary and other vessels.

Further readings when useful compounds of the invention are the treatment or prevention of thrombotic complications of surgical or mechanical damage, such as salvation tissue after injury due to surgery or accident, plastic surgery, including flap of skin, and "reconstructive" surgery, such as breast reconstruction.

Compounds of the invention are also useful for prevention of mechanically-induced platelet activation in vivo, such as cardiopulmonary bypass (prevention of microchromosome), prevention of mechanically-induced platelet activation in vitro, such as the use of the compounds for the preservation of blood products, e.g. platelet concentrates, preventing blockage of the shunt, such as renal dialysis and plasmapheresis, thrombosis, secondary to damage/inflammation of blood vessels, such as vasculitis, Takayasu, glomerulonephritis, and rejection of organ transplant.

Further indications for the use of compounds of the invention is to Congolese, thrombotic purpura, hemolytic urmiiskiy syndrome, thrombotic complications of respiratory distress syndrome in adults, antiphospholipid syndrome, thrombocytopenia caused by heparin, and pre-eclampsia/eclampsia.

Further indications for the use of compounds of the invention are the treatment or prevention of thrombosis, such as trombophlebic, venoocclusive disease, hematological conditions such as thrombocythemia and polycythemia and migraine.

In a particularly preferred embodiment of the present invention compounds used for the treatment of unstable angina, plastic surgery on the coronary vessels and for the treatment of myocardial infarction.

In another particularly preferred variant of the invention the compounds of the present invention are useful as adjunctive therapy in the prevention of coronary arterial thrombosis during treatment of unstable angina, plastic surgery on the coronary vessels and acute myocardial infarction, i.e. penetrability. You can use the tools usually used as additional therapy in the treatment of thrombotic diseases, such as heparin and/or aspne can be obtained in the following ways:

A)

(i) Source material, 4,5-diamino-2,6-dimercaptopropane, alkylate, followed by diazotization with obtaining the compounds of formula (II)

,

in which R1defined as in formula (1).

(ii) the Product of formula (II) stage (i) is reacted with the compound of the formula (III)

,

where P2represents a protective group; and L represents a leaving group;

in an inert solvent and in the presence of a base. Solvents that may be used include DMF, and the base, which can be used include sodium amide. The reaction is carried out at temperatures from -20 to 50oC. Preferably the reaction is carried out at ambient temperature, the solvent is acetonitrile and the base is a sodium hydride. Suitable protective group includes an acyl group such as benzoyl, and a suitable leaving group include halogen, such as bromine.

The reagent of formula (III) used at this stage, get halogenoalkanes respectively protected ribose.

Thus, the group X = NR1R2in which R1and R2defined in the formula (1) above, may be introduced by reaction with the compound of the formula HNR1t 0 to 150oC. Preferably the solvent is 1,4-dioxane and temperature 100oC.

The protective group P2can be removed by treatment with a nucleophile, such as an alkoxide in an alcohol solvent, preferably sodium methoxide in methanol at 60oC.

The product obtained at this stage, is a compound of formula (IV)

,

in which X represents NR1R2; Y represents SR1; and where R1and R2defined in the formula (1) above.

(iii) the Product of formula (IV) stage (ii) is reacted with an appropriate carbonyl compound or orthoevra and inert solvent and in the presence of a acid catalyst is an inorganic or organic acid at a temperature between -15 and 100oC obtaining the compounds of formula (V)

,

in which X represents NR1R2; Y represents SR1; B is O and P1represents a protective group, preferably P1/P1together form a ring.

Preferably P1/P1is ethoxymethylene entered using triethylorthoformate in 1,4 - dioxane at 50oC and in the presence of trichloroacetic acid.

Incoming group to obtain the compounds of formula (VI)

,

in which R1defined in the formula (1); and M represents a leaving group.

Examples of leaving groups that can be used are halogen-free.

The compound of formula (VI) is reacted with a suitably protected 5,6-dihydroxy-2-azabicyclo[2,2,1] heptane-3-one, preferably [3aS-(2a, 4, 7, 7-tetrahydro-2, 2-dimethyl-4,7-methane-1,3-dioxolo[4,5-C]pyridine-6(3aH)-one, in the presence of a base, such as utility, in an inert solvent, such as tetrahydrofuran, at temperatures of 10-100oC obtaining the compounds of formula (VII)

,

in which Y represents SR1; R1defined in the formula (1); M represents a leaving group; and1represents a protective group.

Preferably P1/P1together form a ring, such as isopropylidene, and preferred leaving group is chlorine.

Preferably, the base is sodium hydride, the solvent is DMF and the reaction is carried out at ambient temperature.

(ii) the Nitrogroup and lactam in the product of formula (VII) stage (i) restore and subsequent cyclization with getting triazole.

How nitrogroup reduction that can be alladi-on-coal in a hydrogen atmosphere at a pressure of 1-5 atmospheres in a suitable solvent, for example ethanol. Preferably use iron in an acid solvent such as acetic acid, at temperatures between 20 and 150oC, most preferably at a temperature of 100oC.

The recovery methods that may be mentioned include the use of complex metal hydrides, such as sociallyengaged in an inert solvent, such as tetrahydrofuran, at temperatures from 0 to 100oC. Preferably use natrojarosite in methanol at a temperature of 0-30oC.

Deaminase, thus obtained, cyclist reaction of diazotization using nitrites of metals or alkyl nitrites in a suitable solvent, for example using sodium nitrite in dilute aqueous HCl at a temperature of from -20 to 100oC. Preferably use soliditet in acetonitrile at 80oC.

Group X = NR1R2introduced by reaction with the compound of the formula HNR1R2in an inert solvent at a temperature from 0 to 150oC obtaining the compounds of formula (V) in which X represents NR1R2; Y represents SR1; R1and R2defined in the formula (1); B represents CH2; P1is Samiri temperature 100oC. Preferably P1/P2together form a ring, and most preferably P1/P2is isopropylidene.

C)

(i) the Product of stages a) and B), i.e. the compound of formula (V) obtained in stages a) and B), respectively oxidized and subjected to reaction referirovanija with obtaining the compounds of formula (VIII)

,

which is Oh or CH2; X, Y, and P1defined in the formula (V) in the stages a) and b) respectively; And represents COOR11in which R11is lower (ar)alkyl; and R3and R4together form a bond.

Methods of oxidation that may be mentioned include the reaction Swarna (Swern) and using reagent dess Martin (Dess Martin) in the appropriate solvent at a temperature between -78 and 120oC. Preferably use oxidation Pfitzner - Moffatt (Pfitzner - Mofatt) in DMSO as solvent at ambient temperature, and the protective group P1/P1together form a ring, the most preferred case where P1/P2is isopropylidene. Methods referirovanija that may be mentioned include the reaction of the Peterson) and the reaction Horner - Emmons (Horner - Emmons). Obanno preferred (tert-butoxycarbonylmethylene) triphenylphosphorane.

(ii) R11remove deesterification using acidic or alkaline conditions hydrogenolysis and, in the end, remove the protection with obtaining the compounds of formula (1) in which X represents NR1R2; Y represents SR1; B is Oh or CH2; R1and R2defined in the formula (1); R3and R4together form a bond; and a is COOH.

Group R11that may be mentioned include methyl, ethyl, isopropyl, tert-butyl and benzyl. Group R11can be removed by hydrolysis in acidic or basic conditions. Basic hydrolysis can be carried out using metal hydroxides or Quaternary ammonium hydroxides such as sodium hydroxide in a solvent such as aqueous ethanol, at temperatures between 10 and 100oC. Preferably lithium hydroxide in aqueous tetrahydrofuran at ambient temperature. Acid hydrolysis can be carried out using an inorganic acid, such as HCl, or a strong organic acid, such as triperoxonane acid in a suitable solvent, such as aqueous 1,4-dioxane. Benzyl group can be removed by hydrogenolysis using as catalysts for transition is as acetic acid. Preferably R11represents tert-butyl and the hydrolysis is carried out with the use of triperoxonane acid in dichloromethane.

The protective group in the case of acyl and benzyl may be removed as described for R11above, the silyl protective group may be removed using, for example, fluoride ion. The lower alkyl group may be removed using, for example, tribromide boron. Meriden and ethoxymethylene may be removed using, for example, inorganic or organic acids. All of these methods can be carried out at temperatures between -80 and 150oC. Preferably, R11represents tert-butyl and P1/P1is isopropylidene, and both groups are removed simultaneously using triperoxonane acid in dichloromethane at ambient temperature.

D)

The compound of formula (1) in which X represents SR1, NR1R2or C1-C7-alkyl; Y is SR1, NR1R2WITH1-C7-alkyl; R1and R2defined in the formula (1); B is Oh or CH2; R3and R4represent hydrogen or together form a bond; and a is COOH; enter into reaction with the connection is UP>11)(CH2)rCOOR11where p, q and r is 1, 2 or 3 and R11is lower (ar)alkyl;

using the methods used in peptide synthesis, for example, using the agent combinations. The agents of the combination, which can be used include 1,1'- carbonyldiimidazole and N-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.

At this stage, get the connection formula (1) in which X represents SR1, NR1R2or1-C7-alkyl; Y is SR1, NR1R2or C1-C7-alkyl; B is O or CH2; R3and R4represent hydrogen or together form a bond; and a represents C(O)NH(CH2)pCOOR11C(O)N[(CH2)qCOOR11] 2or C(O)NHCH(COOR11)(CH2)rCOOR11in which p, q and r is 1, 2 or 3 and R11is lower (ar)alkyl;

Group R11that can be used include methyl, ethyl, isopropyl, tert-butyl and benzyl. The reaction mix is carried out in a suitable solvent at a temperature between -15 and 120oC. Preferably use dicyclohexylcarbodiimide or hexaphosphate postreperfusion in N, N-dimethylformamide (DMF) at a temperature between the compounds of formula (1), in which

B represents O or CH2; X represents NR1R2, SR1or1-C7-alkyl; Y is NR1R2, SR1or1-C7-alkyl; R1and R2each independently represents H or C1-C7-alkyl, optionally substituted in or on the alkyl chain by one or more O, S, N, or halogen; R3and R4both represent hydrogen, or R3and R4together form a bond; and a represents C(O)NH(CH2)pCOOH, C(O)N[(CH2)qCOOH]2or C(O)NHCH(COOH)(CH2)rCOOH, where p, q and r is equal to 1,2 or 3.

Group R11that can be used include methyl, ethyl, isopropyl, tert-butyl and benzyl. Group R11can be removed by hydrolysis in acidic or basic conditions. Basic hydrolysis can be carried out using metal hydroxides or Quaternary ammonium hydroxides such as sodium hydroxide in a solvent such as aqueous ethanol, at temperatures between 10 and 100oC. Preferably lithium hydroxide in aqueous tetrahydrofuran at ambient temperature. Acid hydrolysis can be carried out using an inorganic acid, such as HCl, or strong organic insignia group can be removed by hydrogenolysis using as catalysts of transition metals, for example, palladium-on-charcoal, in an atmosphere of hydrogen at a pressure of 1-5 atmospheres in a suitable solvent, such as acetic acid. Preferably R11represents tert-butyl and hydrolysis using triperoxonane acid in dichloromethane.

E)

The product obtained in stage C(ii) restore obtaining the compounds of formula (1), where B,X,Y, R1and R2determined at stage C(ii) above; a is COOH; and R3and R4both represent hydrogen.

The recovery methods that can be used include hydrogenolysis using as catalysts of transition metals, for example palladium-on-charcoal, in an atmosphere of hydrogen in a suitable solvent, such as acetic acid, at a pressure of 1-5 atmospheres. Preferably use diimide obtained from a suitable precursor, such as 2,4,6-triisopropylbenzenesulfonyl, at a temperature between 60 and 100oC in the solvent tetrahydrofuran (THF).

F)

(i) Respectively secured

5-amino-1-(-D-ribofuranosyl)-1,2,3-triazole-4-carboxamide, preferably 5-amino-1-[2,3-O-(1-methylethylidene)--D-RIBO-furanosyl] -1,2,3-triazole-4-carboxamide handle base, with subsequent quenching ISSI alkyl. Then are protected and receive the compound of formula (IX)

,

where Y represents C1-C7-alkyl; P1represents a protective group, and preferably P1/P1together form a ring; P2represents a protective group; and M represents IT.

The protective group P2that can be used include lower alkyl or acyl. Preferably P2represents acetyl, who enter treatment acetylchloride and triethylamine in a suitable solvent, e.g. dichloromethane, at ambient temperature. Most preferably P1/P1is isopropylidene and P2is acetyl.

(ii) a Compound of the formula (IX), where M represents IT, halogenous and lead the group X = NR1R2administered by processing the compound of the formula HNR1R2in an inert solvent at a temperature from 0 to 150oC. and Then removing the protective group P2and get the connection formula Y, in which X represents NR1R2; R1and R2defined in the formula (1); Y represents C1-C7-alkyl; B is O; and P1represents a protective group, and preferably P1/P1together form chaganty, which can be used include halides P(III), or P(V), or S(II), or S(IV), such as trichloride phosphorus at a temperature of from 0 to 150oC. the Reaction can be carried out in the halogenation reagent is used as a solvent or in an inert solvent such as methylene chloride. Preferably thionyl chloride in DMF/chloroform boiling under reflux.

The preferred solvent used for the introduction of group X = NR1R2is 1,4-dioxane at a temperature of 100oC. the protecting group P2can be removed in the same conditions. Alternative it can be removed using acidic or basic hydrolysis.

Preferably used ammonia in methanol at ambient temperature.

(iii) the Product of formula (V) stage (ii) is introduced into the same reaction, which is described in stage C(i) and (ii) obtaining the compounds of formula (1) in which X represents NR1R2; R1and R2defined in the formula (1); B represents O; Y represents1-C7-alkyl; a is COOH; and R3and R4together form a bond.

G)

(i) a Suitable protective group P3enter in the protected 5-amino-1-(-D-ribier carboxamid. The resulting intermediate is treated with a base, preferably sodium hydride, followed by treatment with a reagent of the formula

,

where L represents a leaving group, preferably imidazolyl, obtaining the compounds of formula (X)

,

where P1represents a protective group, preferably when P1/P1together form a ring; and P3represents a protective group, preferably a silyl group. The most preferred case where P1/P1is isopropylidene and P3represents tert-butyldimethylsilyl.

(ii) the Product of formula (X) stage (i) was treated with base, such as utility, in an inert solvent, such as THF, at temperatures between -20 and 50oC, followed by treatment with alkylating reagent R1G, where G represents a leaving group such as halogen, and where R1defined in the formula (1).

Preferably as base using sodium hydride in DMF at ambient temperature, and G is iodine.

Then P3remove from the connection above and replace on a new protective group P2. Preferably P2represents acyl.

P is L. Most preferably3represents tert-butyldimethylsilyl, which is removed by reaction with fluoride, Tetra-n-butylamine in THF, followed by the introduction of the protective group P2reaction with acetylchloride in dichloromethane at ambient temperature.

In the end spend halogenoalkane and get the connection formula (IX), in which M represents a leaving group, e.g. halogen and preferably chlorine; P1represents a protective group, preferably P1/P1together form a ring; and P2represents a protective group, preferably acetyl; and Y represents SR1.

Halogenation reagents that can be used include halides P(III), or P(II), or S(II), or S(IV), such as trichloride phosphorus, at temperatures from 0 to 150oC. the Reaction can be carried out in the halogenation reagent is used as a solvent or in an inert solvent such as methylene chloride. Preferably using thionyl chloride in DMF/chloroform boiling under reflux.

(iii) the Product of stage (ii) was introduced into the reaction with the nucleophilic alkyl, for example, a Grignard reagent, in an inert solvent, such as THF, at temperature in the presence of Pd(II) catalyst. Then the protective group P2removed and received the compound of formula (V) in which X represents C1-C7-alkyl; Y is SR1; R1defined in the formula (1); b is O; and P1represents a protective group, preferably P1/P1together form a ring, which most preferably is isopropylidene.

The protective group P2can be removed by acidic or basic hydrolysis. Preferably P2represents acetyl, which is removed by reaction with ammonia in methanol at ambient temperature.

N)

(i) a Compound of formula (1), in which

X represents NR1R2; Y represents SR1; R1and R2defined in the formula (1); B represents O; R3and R4both represent hydrogen; and A is C(O)NHCH(COOR11)(CH2)rCOOR11in which r is 1, 2 or 3 and R11defined above;

were treated with an oxidant, such as monoperoxyphthalic magnesium in an inert solvent, such as THF, at temperatures between -20 and 100oC, followed by treatment of the compound of the formula HNR1R2in an inert solvent at a temperature from 0 to 150oC obtaining coedine ABOUT;

R3and R4both represent hydrogen; and a is C(O)NHCH (COOR11) (CH2)rCOOR11in which r is 1, 2 or 3 and R11determined at the stage of (D) above.

Preferably as oxidant use m-chloroperoxybenzoic acid in the solvent ethanol at ambient temperature, and the replacement is carried out in 1,4-dioxane at 100oC.

I)

The compound of formula (1) in which X represents SR1; Y represents SR1; B represents O; R3and R4both represent hydrogen; a is COOH;

can be obtained by reaction of compounds of formula (II) in which R1defined in the formula (1), with the compound of formula (XI)

,

in which R12is lower (ar)alkyl and P4represents a protective group such as acetyl.

The reaction can be carried out by heating the compounds together in the presence of acid, such as trichloroacetic acid, under reduced pressure and a temperature between 50 and 175oC. Preferably, R12represents ethyl, P4is acetyl and the reaction is carried out at 140oC in the presence of p-toluenesulfonic acid in a water-jet vacuum pump.

The protective group and the ia of the formula (1), in which X represents SR1; Y represents SR1; R1defined in the formula (1); B represents O; R3and R4both represent hydrogen; a is COOH;

Examples of reagents and conditions, which can be used for hydrolysis are alkoxides of metals in alcohol at a temperature between 0 and 100oC, or, alternatively, can be used triperoxonane acid in dichloromethane. Preferably use R12- ethyl and P4- acetyl and lithium hydroxide in aqueous tetrahydrofuran at ambient temperature.

The compound of formula (XI), which is one of the starting materials in this reaction stage, initially obtained from the ethyl ester of (E)-methyl-5,6-dideoxy-2,3-O-(1-methylethylidene)--D-libept-5-informaziorako acid hydrolysis of aqueous acid such as aqueous acetic acid, and reaction with allermuir reagent, such as acetylchloride, in the presence of a base, such as pyridine, and a suitable solvent, such as methylene chloride, followed by reduction, for example, by hydrogenation using as catalysts of transition metals, such as palladium-on-charcoal, in an atmosphere of hydrogen in a suitable dissolve predstavljaet NR1R2; Y represents SR1; R1and R2defined in the formula (1); B is O or CH2; R3and R4both represent hydrogen; and a represents a 5-tetrazolyl;

was prepared as follows.

The product of stage A(iii) or the product of stage B(ii), for example a compound of the formula (V), which represents Oh or CH2and X and Y defined in formula (Y) above and P1represents a protective group, preferably P1/P1together form a ring, oxidized, followed by reaction referirovanija and subsequent recovery.

Methods of oxidation, which can be used include the reaction Swarna (Swern) and using reagent dess Martin (Dess Martin) in appropriate solvents at temperatures between -78 and 120oC. Preferably use oxidation Pfitzner - Moffatt (Pfitzner - Mofatt) in DMSO as solvent at ambient temperature, using a compound of formula (Y), where P1/P2is isopropylidene. Methods referirovanija that can be used include the reaction of the Peterson) and the reaction Horner - Emmons (Horner - Emmons). Preferably the Wittig reaction with ridom phosphorus(triphenylphosphonium as catalysts of transition metals, such as platinum, in an atmosphere of hydrogen, in a suitable solvent, e.g. acetic acid, at temperatures between 0 and 100oC. it is Preferable to use palladium-on-coal at a pressure of 4 ATM in ethanol at ambient temperature.

The product obtained in this way represents a compound of the formula (XII)

,

in which B represents O or CH2; P1represents a protective group, preferably P1/P1together form a ring, and most preferably P1/P1is isopropylidene; and R1and R2defined in the formula (1).

This compound of formula (XII) is reacted with an azide such as sodium azide, in an inert solvent, for example DMF, at temperatures between 0 and 175oC. Isopropylidene is the preferred protecting group. Preferably use tributylamine in toluene at a temperature of 110oC.

The protective groups are then removed by treatment with inorganic or organic acid in an inert solvent at temperatures between 0 and 100oC. Preferably use triperoxonane acid in dichloromethane at ambient temperature.

So get the product of the formula (1), B represents O or CH2; R3and R4are both hydrogen; and a represents a 5-tetrazolyl.

TO)

The compound of formula (1), in which

X represents SR1, NR1R2or1-C7-alkyl; Y is SR1, NR1R2or1-C7-alkyl; R1and R2defined in the formula (1); b is CH2or O; R3and R4together form a bond; and a represents COOR11in which R11defined in the formula (1) above;

restore with obtaining the compounds of formula (VIII) in which R3and R4represent hydrogen; X, Y, B, A, R11and P1defined above.

The recovery methods that can be used include hydrogenation using as catalysts of transition metals, for example palladium-on-charcoal, in an atmosphere of hydrogen in a suitable solvent, such as acetic acid, at a pressure of 1-5 atmospheres. Preferably use diimide obtained from a suitable precursor, such as 2,4,6-triisopropylbenzenesulfonyl, at a temperature between 60 and 100oC in the solvent tetrahydrofuran.

(ii) the Product of stage (i) is introduced into the same reaction that OPI/SUP> or1-C7-alkyl; Y is SR1, NR1R2or C1-C7-alkyl; R1and R2defined in the formula (1), B represents CH2or O; and a is COOH.

The compounds of formula (1) and their salts and prodrugs, such as esters or amides, can be isolated from the reaction mixtures by conventional methods.

Salts of compounds of formula (1) can be obtained by reaction of the free acid or its salt or the free base or its salt, or a derivative thereof with one or more equivalents of the appropriate base or acid. The reaction can be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, such as water, ethanol, tetrahydrofuran or diethyl ether, which can be removed under vacuum or freeze-drying. The reaction can also be exchange process or may be performed on the ion-exchange resin. The preferred non-toxic physiologically acceptable salts, although they can be useful and other salts, for example, for the isolation or purification of the product.

Pharmaceutically acceptable esters of compounds of formula 1 can be obtained by conventional methods, for example, esterification and pcname methods for example, reaction of the ester of the appropriate acid with ammonia or an appropriate amine.

Detailed description of the invention

The invention is hereinafter described in more detail using examples, which should not be construed as limiting the scope of the invention. The temperatures given in the Examples are in degrees centigrade, unless otherwise specified. Abbreviations: MS = mass spectrometry, E1 - EC (electron impact), APCI - PHI (photoionization), ESI - PI (surface ionization), FAB - the Belarusian library Association (fast atom bombardment).

EXAMPLES

Example

Sodium salt of [1R-(1 (E), 2 , 3, 4)]-3-[4- [7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] -2,3-dihydrocyclopenta]-2-propanolol acid

a) 2-(Propylthio)-4,6(1H,5H)-pyrimidinedione

Propyliodide (136 ml) was added to a suspension of 4,6-dihydroxy-2 - mercaptopyrimidine (200 g) in water (800 ml) containing sodium hydroxide (55,6 g). The reaction mixture was stirred for 2 weeks, then concentrated to half volume, was added 2 N chloride-hydrogen acid and the product was isolated by filtration (167 g).

MS (ES): 186 (M+, 100%).

b) 6-Hydroxy-5-nitro-2-(propylthio)-4(1H)-pyrimidinone

The product of stage (a) (70 g) was slowly added to ice on which were isolated by filtration (65 g).

MS (ES): 231 (M+), 41 (100%).

(C) 4,6-Dichloro-5-nitro-2-(propylthio)pyrimidine

N,N-Diethylaniline (150 ml) was added dropwise to a stirred suspension of the product of stage b) (134 g) in phosphorylchloride (500 ml) and the resulting solution was heated at the boil under reflux for 1 hour. The cooled reaction mixture was poured on ice, then was extracted with diethyl ether (3 x 500 ml). The combined extracts were dried and concentrated. Chromatography (SiO2, isohexane: diethyl ether 19:1 as eluent) gave the target compound indicated in heading (128 g).

MS (ES): 271, 269, 267 (M+), 41 (100%).

d) [3aS- (3a,4,7,7 (a) ]-5-[6-Chloro-5-nitro-2- (propylthio)pyrimidine-4-yl]tetrahydro-2,2-dimethyl-4,7-methane-1, 3-dioxolo[4,5-c]pyridine-6(3aH)-he

Sodium hydride (60%, of 4.00 g) was added in portions to [3aS- (3a,4,7,7 (a)] tetrahydro-2, 2-dimethyl-4,7-methane-1,3-dioxolo[4,5-C] pyridine-6(3aH)-ONU (18.3 g) in THF (500 ml). Under stirring for 1 hour the solution was added dropwise to the product of stage (C) (54,0 g) in THF (500 ml). The reaction mixture was stirred at room temperature for 45 minutes, then concentrated and purified by chromatography (SiO2, dichloromethane:isohexane 3:2 as eluent) to give the compounds specified in the IO) pyrimidine-4-yl] tetrahydro-2,2-dimethyl-4,7-methane-1, 3-dioxolo-[4,5-c] pyridine-6(3aH)-he

Restored iron powder (50 g) was added to a solution of the product of stage (d) (50.0 g) in glacial acetic acid (1.8 l) and the reaction mixture was heated at the boil under reflux for 15 minutes. The cooled reaction mixture was concentrated and the residue was extracted with ether (2 l), then washed with sodium bicarbonate solution (2 x 1 l). The organic phase was dried and concentrated to obtain the compound indicated in heading (42.6 g).

MS (PHI): 387, 385 (M+H+), 385 (100%).

f) [3aR- (3a,4,6,6 (a) ]-6-[5-Amino-6-chloro-2-(propylthio)pyrimidine-4-ylamino] tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-methanol.

Sodium borohydride (of 8.37 g) was added to a cooled with ice to a solution of the product of stage e) (42.6 g) in methanol (1.3 l). After stirring for 1 hour the solution was poured into water (2 l) and was extracted with diethyl ether (2 x 1 l). The combined extracts were dried and concentrated. Cleanup (SiO2dichloromethane : ethyl acetate 1:1 as eluent) gave the connection specified in the header (36,1 g).

MS (PHI): 419, 417 (M+H+), 417 (100%).

g) [3aR-(3a,4,6,6 (a)] -6-[7-Chloro-2-(propylthio)-3H-1,2,3 - triazolo[4,5-d] pyrimidine-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopent - 1,3-dioxol-4-IU Agrawal for 1 hour at 70oC. the Cooled reaction mixture was concentrated and purified (SiO2, dichloromethane:ethyl acetate 4:1 as eluent) to obtain the compound indicated in heading (33.6 g).

MS (ES): 401, 399 (M+H+), 43 (100%).

h) [3aR- (3a,4,6,6 (a) ]-6-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidine-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4 - methanol

The product of stage (g) (x 16.75 g) and butylamine (30 ml) in 1,4-dioxane (500 ml) was heated at the boil under reflux for 1 hour. The reaction mixture was concentrated and the residue was purified (SiO2, dichloromethane:ethyl acetate 4: 1 as eluent) to obtain the compound indicated in heading (17.8 g).

MS (PHI): 437 (M+H+, 100%).

f) [3aR- (3a,4(E),6,6 a) ]-3-[6-[7-(Butylamino)- 5-(propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-yl]-2 - Papanova acid, 1,1-dimethylethylene ether

Stir a solution of the product of stage (h) (0.5 g), pyridine (0,093 ml) and triperoxonane acid (0,048 ml) in DMSO (25 ml) was treated with 1,3-dicyclohexylcarbodiimide (0,72 g) and the mixture was stirred at room temperature for 24 hours. Added tert-butoxycarbonylmethylene (0,69 g) and the reaction was stirred for another new acid (0.51 g). After 30 min the mixture was filtered and the filtrate was washed with saturated sodium bicarbonate solution (100 ml), dried and concentrated. Chromatography (SiO2, hexane:ethyl acetate 5:1 as eluent) gave the connection specified in the header (0.55 g).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 533 (M+H+, 100%).

(j) [1R- (1(E),2,3,4) ] -3-[4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidine-3-yl]-2,3-dihydrocyclopenta]-2-Papanova acid, sodium salt

A solution of the product of stage (i) (0.8 g) in 50% aqueous triperoxonane acid (100 ml) was stirred at room temperature for 5 hours. The reaction mixture was concentrated and the product recrystallized from ethyl acetate (30 ml). The free acid was dissolved in a mixture of methanol : water (2:3, 30 ml) and was passed through an ion-exchange resin Dowex 50 x 100 (sodium form), elwira water. Lyophilization gives the salt of the target compound as a colourless solid (0,43 g).

NMR H (d6-DMSO): 6,59 (1H, DD), of 5.89 (1H, d), 4,94 (1H, m), of 4.45 (1H, t), of 4.12 (1H, t), of 3.45 (2H, m), and 2.83 (3H, m), 2,47 (1H, m), from 2.00 (1H, m), and 1.5 (4H, m), 1,20 (2H, m) of 0.82 (3H, t), of 0.71 (3H, t).

Example 2

[lR- (1(E),2,3,4) ] -N-[3-[4-[7-(Butylamino) - 5-(propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] -2,3 - dihydrocyclopenta]-2-propenyl]-L-aspartic acid, bis(1;1-dimethylaminophenyl]-2-propenyl] -L - aspartic acid, bis(1,1-dimethylethylene)ether

Hydrochloride di-tert-butyl ester of L-aspartic acid and 0.46 g) and triethylamine (0,23 ml) was added to a solution of compound of Example 1 (0.6 g) in DMF (25 ml). Was added 1-hydroxybenzotriazole (0,22 g) and the solution was cooled in an ice bath before the addition of 1,3 - dicyclohexylcarbodiimide (0.34 g). The reaction mixture was stirred for 30 min at 0oC, then at room temperature for 3 days. After removal of the solvent, chromatography (SiO2, chloroform: methanol 40:1 as eluent) gave the connection specified in the header (0,63 g).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 664 (M+H+), 57 (100%).

b) [1R- (1(E),2,3,4) ]-3-[4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3 - triazolo[4,5-d] pyrimidine-3-yl] -2,3,3-dihydrocyclopenta] -2-propenyl]- L-aspartic acid, disodium salt

A solution of the product of stage (a) (0,60 g) in dichloromethane (30 ml) containing triperoxonane acid (30 ml) was stirred at room temperature for 2 hours. The solution was concentrated and the residue was purified (HPLC, column Nova-PakRC18, 0.1% aqueous ammonium acetate:methanol 50:50 to 0:100 over 15 min as eluent) gave the salt found in the header, as a colorless solid (0,19 g).

NMR H (d6-DMSO): 6,74 (1H, DD), ,0 (3H, t), and 0.98 (3H, t).

Example 3

[1S- (1,2,3,4) ]-4-[7-(Butylamino)-5- (propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]-2,3 - dihydroxyacetophenone acid, sodium salt

a) [1S- (1,2,3,4) ] -3-[4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3 - triazolo[4,5-d] pyrimidine-3-yl] -2,3-dihydrocyclopenta-Tyl] -2 - Papanova acid, ethyl ester

Stir a solution of the product of Example 1 (h) (0.6 g), pyridine (0,112 ml) and triperoxonane acid (0,058 ml) in DMSO (25 ml) was treated with 1,3 - dicyclohexylcarbodiimide (0.87 g) and the mixture was stirred at room temperature for 24 hours. Added carbethoxymethylthio (0,90 g) and the reaction was stirred for 18 hours. The reaction mixture was cooled to 0oC, was diluted with ethyl acetate (100 ml) was added oxalic acid (0.51 g). After 30 min the mixture was filtered and the filtrate was washed with saturated sodium bicarbonate solution (100 ml), dried and concentrated. The residue was dissolved in dichloromethane (50 ml)/triperoxonane acid (50 ml) and was stirred over night. The solvent was removed and the residue was purified by chromatography (SiO2, dichloromethane:ethyl acetate 1:1 as eluent) to obtain the compound indicated in heading (0.36 g).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 465 (M+H+, 100%).

b) [the lot, ethyl ester

2,4,6-Triisopropylbenzenesulfonyl (0.50 g) was added to a solution of the product of stage (a) (0.35 g) in dry THF (175 ml) and the resulting solution was heated for 3 hours at 70 C. the Cooled reaction mixture was purified by chromatography (SiO2, dichloromethane : ethyl acetate 1:1 as eluent) to obtain the compound indicated in heading (0.16 g).

MS (ES): 466 (M+), 43 (100%).

(C) [1S- (1,2,3,4) ]-4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidine-3-yl] -2,3-dihydroxyacetophenone acid, sodium salt

The monohydrate of lithium hydroxide (14 mg) was added to a solution of the product of stage (b) (0.16 g) in THF (10 ml)/water (10 ml). The solution was stirred at room temperature for 18 hours, then the solvent was removed in vacuum. Purification (HPLC, column Nova-PakRC18, 0.1% aqueous ammonium acetate : methanol 50: 50 to 0: 100 over 15 min as eluent) gave the acid, which was dissolved in methanol (2 ml) was added 1 N sodium hydroxide solution (0,28 ml). The solution was concentrated and got salt specified in the header (0,13 g).

MS (PI): 439 (M-Na+H+, 100%).

NMR H (D2O): 5,07 (1H, m) and 4.65 (1H, t) 4,08 (1H, t), 3,49 (2H, t), of 3.05 (2H, m), 2,62 (1H, m), a 2.36 (2H, m), 2,17 (1H, m), from 2.00 (1H, m) to 1.70 (2H, m), of 1.65 (2H, m) to 1.61 (2H, m), 1,40 (2H, one-3-yl] -2,3 - dihydrocyclopenta]-2-Papanova acid, sodium salt

a) 2-(pentylthio)-4,6(1H,5H)-pyrimidinedione

To a solution of 4,6-dihydroxy - 2-mercaptopyrimidine (14.4 g) in 2H the solution of sodium hydroxide (100 ml) was added pentolite (15.6 ml) in ethanol (25 ml) and the resulting reaction mixture was stirred at room temperature for 4 days. The ethanol was removed under reduced pressure, was added N,N-dimethylformamide (80 ml) and pentolite (1,56 ml) and the reaction mixture was stirred for 16 hours. The solution was acidified by addition of 2 N solution of HCl and the aqueous layer was decantation. The remaining resin was dissolved in methanol and evaporated to dryness, then spent azeotropic distillation with toluene (×2). The solid is triturated with ether, filtered, dried and got the connection specified in the header in the form of a white solid (11.9 g).

MS (ES): 214 (M+), 144 (100%).

b) 6-Hydroxy-5-nitro-2-(pentylthio)-4(1H)-pyrimidinone

Obtained by the method of Example 1 (b) using the product of stage a).

MS (ES): 259 (M+), 43 (100%).

(C) 4,6-Dichloro-5-nitro-2-pentylthio)pyrimidine

Obtained by the method of Example 1 (C) using the product of stage b).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 295, 297, 299 (M+H+): 41 (100%).

d) [3aS-(3a,4,7,7 (a)-5-[6-Chloro-5-nitro-2- (pentylthio)p is 1 d) using the product of stage (C).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 445, 443 (M+H+), 443 (100%).

e) [3aS- (3a,4,7,7 (a)]-5-[5-Amino-6 - Chloro-2-(pentylthio)pyrimidine-4-yl]tetrahydro-2,2-dimethyl-4,7 - methane-1,3-dioxolo-[4,5-C]pyridine-6(3aH)-he

Obtained by the method of Example 1 (c) using the product of stage d).

MS (ES): 414, 412 (M+), 412 (100%).

f) [3aR- (3a,4,6,6 (a)]-6-[5-Amino-6-chloro-2-(pentylthio)pyrimidine-4-ylamino] tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-methanol.

Obtained by the method of Example 1 (f) using the product of stage e).

MS (EI): 418, 416 (M+), 327 (100%).

q) [3aR- (3a,4,6,6 (a)] -6-[7-Chloro-5-(pentylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-methanol

Obtained by the method of Example 1 d) using the product of stage (f).

MS (PHI): 430, 428 (M+H+), 338 (100%).

h) [3aR- (3a,4,6,6 (a) ]-6-[7-(Butylamino)-5-(pentylthio)-3H - 1,2,3-triazolo[4,5-d] pyrimidine-3-yl] tetrahydro-2,2 - dimethyl-4H-cyclopent-1,3-dioxol-4-methanol

Obtained by the method of Example 1 (h) using the product of stage (g).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 465 (M+H+, 100%).

i) [3aR- (3a,4,6,6 a) ] -3-[6-[7-(Butylamino)-5- (pentylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-yl]-2 - Papanova acid, 1,1-dimethylethyl the +), 505 (100%).

(j) [1R- (1(E),2,3,4) ]-3-[4-[7-(Butylamino)-5-(pentylthio)-3H-1,2, 3-triazolo[4,5-d] pyrimidine-3-yl] -2,3-dihydrocyclopenta] -2-Papanova acid, sodium salt

Obtained by the method of Example 1 (j) using the product of stage (i).

MS (the Belarusian library Association): 487 (M+Na+H+), 465 (100%).

NMR H (d6-DMSO): 9,00 (1H, t), to 6.43 (1H, DD), 5,70 (1H, d), equal to 4.97 (1H, HF), 4,32 (1H, t), a 3.87 (1H, t), 3,50-3,47 (2H, m), 3,12 totaling 3.04 (2H, m), 2,68 (1H, m), 2,38-of 2.34 (1H, m), 1.93 and-1,89 (1H, m) of 1.64 (2H, m) of 1.62 (2H, m), 1,37-of 1.30 (6H, m) of 0.91 (3H, t), of 0.87 (3H, t).

Example 5

The following compound was obtained according to the method of Example 4: [1R- (1(E),2,3,4) ] -3-[4-[7-(Ethylamino)-5- (pentylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidine-3-yl] -2,3 - dihydrocyclopenta] -2-Papanova acid, sodium salt

a) [3aR- (3a,4,6,6 (a) ]-6-[7-(Ethylamino) -5-(pentylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-methanol

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 437 (M+H+, 100%).

b) [3aR- (3a,4(E):6.6 a) ]-3-[6[-7-(Ethylamino)-5- (pentylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-yl]-2 - Papanova acid, 1,1-dimethylethylene ether

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 533 (M+H+), 477 (100%).

(C) [1R- (1(E),2,3,4) ] -3-[4-[7-(Ethylamino)-5- (pentylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] -2,3 - dihydrocyclopenta]-2-Papanova acid, sodium (1H, t), 3,90 (1H, t), 3,81-3,50 (2H, m), 3,16-is 3.08 (2H, m), 2,74-2,70 (1H, m), 2,46-is 2.37 (1H, m), 1,98 -1,89 (1H, m), 1,71-to 1.67 (2H, m) of 1.62 (2H, m), 1,37-1,24 (4H, m) to 1.19 (3H, t) 0,86 (3H, t).

Example 6

[1S- (1,2,3,4) ]-4-[7-(Butylamino)-5-(pentylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidine-3-yl]-2,3-dihydrocyclopenta acid, sodium salt

Obtained by the method of Example 3 (b) using the product of Example 4.

MS (PHI): 467 (M+H+), 295 (100%).

NMR H (d6-DMSO): 8,95 (1H, t), is 4.93-a 4.86 (1H, m), 4,32 (1H, t), 3,88 (1H, t), 3,49 is-3.45 (2H, m), 3,07 was 3.05 (2H, m), 2,74-2,70 (1H, m), 2,28-of 2.08 (1H, m), 2,01-of 1.92 (3H, m), 1,74-of 1.55 (7H, m), of 1.37 and 1.33 (6H, m), of 0.90 (3H, t) 0,86 (3H, t).

Example 7

[1S- (1,2,3,4) ] -4-[7-(Ethylamino)-5- (pentylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]-2,3 - dihydroxyacetophenone acid, sodium salt

Obtained by the method of Example 3 (b) using the product of Example 5.

MS (the Belarusian library Association): 461 (M+Na+H+), 154 (100%).

NMR H (d6-DMSO): 8,96 (1H, t), 4,91 (1H, KB) to 4.33 (1H, t), of 3.75 (1H, t), 3,51 (2H, m), is 3.08-of 3.06 (2H,m), 2,30-of 2.24 (1H, m), 2.06 to of 1.93 (3H, m), 1,75-of 1.55 (5H, m), 1,37-of 1.09 (4H, m) and 1.15 (3H, t), of 0.87 (3H, t).

Example 8

[1S- (1,2,3,5) ]-3-[7-(Butylamino)-5-(propylthio)-3H-1,2,3 - triazolo [4,5-d]pyrimidine-3-yl]-5-[2-(1H-tetrazol-5-yl) ethyl]-1,2-cyclopentanediol

a) [3aR- (3a,4(E),6,6 a) ]-3-[6-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidine-3-yl] -2,2-dimethyl-tetrag the CTE of Example 1 (h) and (triphenylphosphorane)acetonitrile.

MS (ES):457 (M+), 414 (100%).

b) [3aR- (3a,4,6,6 a)] -3-[6- [7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidine-3-yl]-2,2-dimethyl-tetrahydro-4H-cyclopent-1,3 - dioxol-4-yl]-2-propenenitrile

The product of stage a) (0.75 g) in ethanol (300 ml) containing 10% palladium-on-coal (0,37 g), stirred for 48 hours at 4 ATM of hydrogen. The catalyst was removed by filtration and the filtrate was concentrated to obtain the compound indicated in heading (0.34 g).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 460 (M+H+, 100%).

(C) [3aR- (3a,4,6,6 (a) ] -N-Butyl-5-(propylthio)-3-[6- [2-(1H-tetrazol-5-yl)-ethyl] tetrahydro-2, 2-dimethyl-4H-cyclopent-1,3-dioxol-4-yl]-3H-1,2,3-triazolo [4, 5-d]pyrimidine-7-amine

The product of stage (b) (0.40 g) and tributylamine (0,70 g) in toluene was heated at the boil under reflux for 48 hours, then concentrated. Purification by chromatography (SiO2, dichloromethane:methanol 95:5 as eluent) gave the connection specified in the header (0,19 g).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 503 (M+H+, 100%).

d) [1R- (1,2,3,5) ]-3-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidine-3-yl] -5-[2-(1H-tetrazol-5-yl)ethyl] -1,2-cyclopentanediol

Obtained by the method of Example 1 (j) using the product of stage (C).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 463 (M+H+, 100%).

NMR H (d6

Example 9

[lR- (1,2,3,4) ]-N-[3-[4-[7-(Butylamino)- 5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]-2, 3-dihydrocyclopenta]-2-propanol]-L-aspartic acid

a) [1R- (1,2,3,4) ]-3-[4-[7-(Butylamino)-5- (propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl]-2,3 - dihydrocyclopenta]-2-propanol]-L-aspartic acid, bis(1,1-dimethylethylene)ether

N, N-Diisopropylethylamine (0.35 ml) was added to a solution of hydrochloride di-tert-butyl ester of L - aspartic acid (0.28 g), hexaflurophosphate bromotris(pyrrolidino)phosphonium (0,44 g) and the product of Example 3 (0,44 g) in DMF (20 ml). The reaction mixture was stirred for 1 hour at room temperature, then concentrated. Chromatography (SiO2the ethyl acetate as eluent) gave the connection specified in the header (0,49 g).

MS (PHI): 666 (M+H+, 100%).

b) [1R- (1,2,3,4) ]-3-[4-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5]pyrimidine-3-yl]-2,3-dihydrocyclopenta]- -2-propanol]-L-aspartic acid

Obtained by the method of example 2 (b) using the product of stage a).

NMR H (d6-DMSO): 9,03 (1H, CL), 7,79 (1H, d), to 4.92 (1H, m), 4,35 (1H, m), 4,19 (1H, t), of 3.75 (2H, m), 3,49 (2H, t), is 3.08 (2H, m), 2,43 (1H, m), 2,32 (1H, m) to 2.18 (3H, m), 1.91 a (IH, m) of 1.73 (3H, m), 1,58 (2H, m) of 1.34 (2H, eremein-3-yl] 2,3 - dihydrocyclopenta]-2-propenyl]-L-aspartic acid

a) [3aR- (3a,4,6,6 (a) ]-6-[7-(Hexylamino) -5-(propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-methanol

Sodium borohydride (1,16 g) was added to a cooled with ice to a solution of the product of stage 1 (e) (5,90 g) in methanol (200 ml). After stirring for 1 hour the solution was concentrated and the residue was purified by chromatography (SiO2, diethyl ether as eluent). The obtained intermediate was dissolved in acetonitrile (300 ml) and was added soliditet (2.8 ml). The reaction mixture was stirred for 30 minutes at 60oC, concentrated and the residue was dissolved in 1,4-dioxane (300 ml). Added hexylamine (20 ml) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the residue was purified (SiO2, diethyl ether as eluent) and received the connection specified in the header (4,69 g).

MS (PHI): 465 (M+H+, 100%).

b) [1R- (1(E),2,3,4) ] -3-[4-[7-(Hexylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidine-3-yl]-2,3-dihydroxy-cyclopentyl]-2-Papanova acid

Obtained by the method of example 1 (i) and the subsequent method 1 (j) using the product of stage a).

NMR H (D2O): 9,03 (1H, t), of 6.96 (1H, DD), of 5.89 (1H, d), 5,31 (1H, s), 5,10 (1H, s) to 5.00 (1H, m), the 4.29 (1H, (1(E),2,3,4) ]-N-[3-[4-[7-(Hexylamino)-5-(propylthio)-3H-1,2,3 - triazolo[4,5-d] pyrimidine-3-yl] -2,3-dihydrocyclopenta] 2-propenyl]-L-aspartic acid, bis(1,1 - dimethylethylene) ether

Obtained by the method of example 2 (b) using the product of stage b).

MS (PHI): 692 (M+H+, 100%).

d) [1R- (1(E),2,3,4) ]-N-[3-[4-[7-(Hexylamino)-5-(propylthio) -3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] -2,3-dihydrocyclopenta] -2-propenyl]-L-aspartic acid

Obtained by the method of example 2 (b) using the product of stage (C).

NMR H (d6-DMSO): 7,94 (1H, d), 7.23 percent-7,11 (1H, s), of 6.75 (1H, DD), 6,17 (1H, d), 5,19 (1H, s) 5,08 (1H, s) to 5.00 (1H, m), or 4.31 (2H, m), of 3.96 (1H, m), 3,62 (2H, m), of 3.07 (2H, m), of 2.81 (1H, m), 2,49-2,31 (3H, m), a 2.01 (1H, m) to 1.67 (2H, m) to 1.61 (2H, m) is 1.31 (6H, m) to 0.96 (3H, t), of 0.85 (3H, t).

Example 11

The following compounds were obtained according to the method of example 1.

a) [1R- (1(E),2,3,4) ]-3-[4-[7-(3,3-Dimethylbutylamino)-5- (propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] -2,3 - dihydrocyclopenta]-2-Papanova acid

i) [3aR- (3a,4,6,6 a) ]-6-[7-(3,3- Dimethylbutylamino)-5-(propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopent-1,3 - dioxol-4-methanol

MS (PHI): 465 (M+H+, 100%).

ii) [3aR- (3a,4(H),6,6 a) ] -3-[6-[7-(3,3-Dimethylbutylamino)-5- (propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] tetrahydro - 2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-yl] -2-Papanova acid, 1,1-dimethylethylene ether

MS (PHI): 561 (M+H+, 100%).

Tyl]-2-Papanova acid

NMR (d6-DMSO): 8,59 (1H, t), at 6.84 (1H, DD), of 5.84 (1H, d), 5,03-4,96 (1H, m), 3,98 (1H, m), 3,52 (2H, m), of 3.07 (2H, m), of 2.81 (1H, m), 2,43 (IH, m) of 1.97 (1H, m) of 1.75 (2H, m) of 1.55 (2H, m), 0,99 (3H, t), of 0.95 (9H, s).

b) [1R- (1(E),2,3,4)] -3-[4-[7-(2-Methoxyethylamine)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidine-3-yl]-2,3-dihydrocyclopenta]-2-Papanova acid

i) [3aR-(3a,4,6,6 a)] -6-[7-(2-Methoxyethylamine)-5- (propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopent-1,3-dioxol-4-methanol

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 439 (M+H+, 100%).

ii) [3aR- (3a,4(E),6,6 a)]-3-[6-[7-(2-Methoxyethylamine)-5- (propylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidine-3-yl]tetrahydro-2,2 - dimethyl-4H-cyclopent-1,3-dioxol-4-yl] -2-Papanova acid, 1,1-dimethylethylene ether

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 535 (M+H+, 100%).

iii) [1R- (1(E),2,3,4)] -3-[4-[7-(3,3-Dimethylbutylamino)-5-(propylthio) -3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl]-2, 3-dihydrocyclopenta]-2-Papanova acid

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 439 (M+H+, 100%).

Example 12

[1R- (1,2,3,4)] -N-[3-[4-[7-(Hexylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidine-3-yl] -2,3-dihydrocyclopenta] -propanol]-L - aspartic acid

a) [1R- (1,2,3,4) ]-4-[7-(Hexylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidine-3-yl]-2,3-dihydroxyacetophenone acid

Obtained by the method of example 3 (b) (C ispolzovaniya)-3H-1,2,3 - triazolo[4,5-d] pyrimidine-3-yl] -2,3-dihydrocyclopenta]-propanol]- L-aspartic acid, bis(1,1-dimethylethylene)ether

Obtained by the method of example 9 (a) using the product of stage a).

MS (PHI): 694 (M+H+, 100%).

(C) [1R- (1,2,3,4) ] -N-[3-[4-[7-(Hexylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidine-3-yl]-2,3-dihydrocyclopenta]-propanol] -L - aspartic acid

Obtained by the method of example 2 (b) using the product of stage b).

NMR H (d6-DMSO): 8,90 (1H, CL), to 7.61 (1H, d), equal to 4.97 (1H, m), 4,36 (1H, t), is 4.21 (1H, m), of 3.77 (1H, m), 3,47 (2H, m), of 3.07 (2H, t), of 2.51 (2H, m), 2,28 (1H, m), of 2.20 (2H, m) of 1.93 (1H, m), 1.77 in (1H, m) of 1.62 (3H, m) to 1.59 (3H, m) of 1.33 (6H, m), and 1.00 (3H, t) to 0.88 (3H, t).

Example 13

[1R- (1(E),2,3,4) ] -N-[3-[4-[5-[(3,3,3-Cryptosporidia)-7-[2-(methylthio) ethylamino] -3H-1,2,3-triazolo [4,5-d] pyrimidine-3-yl]-2,3-dihydrocyclopenta]-2-propenyl]-L - aspartic acid, monoammonium salt

a) 2-[(3,3,3-Cryptochromes)thio]-4,6(1H,5H)-pyrimidinedione

Obtained by the method of example 1 (a).

MS (PHI, negative ionization): 239 (M-H+), 143 (100%).

b) 2-[(3,3,3-Cryptochromes)thio]-6-hydroxy - 5-nitro-4 (1H)-pyrimidinone.

Obtained by the method of example 1 (b) using the product of stage a).

MS (PHI, negative ionization): 284 (M-H+, 100%).

(C) 4,6-Dichloro-2-[(3,3,3-Cryptochromes)thio]-5 - nitropyrimidin

On).

d) [3aS- (3a,4,7,7 (a) ]-5-[6-Chloro-5-nitro-2-(3,3,3-Cryptochromes)thio] - pyrimidine-4-yl tetrahydro-2,2-dimethyl-4,7-methane-1,3-dioxolo [4, 5-f] pyrimidine-6(3aH)-he

Obtained by the method of example 1 (C) using the product of stage b).

The H NMR (CDCl3): of 4.77 (1H, s), to 4.73 (1H, d), 4,56 (1H, d), to 3.33 (2H, m), 3,05 (1H, s), 2,58 (2H, m), 2,33 (1H, d), of 2.20 (1H, t), of 1.53 (3H, s) of 1.36 (3H, s).

(e) [3aS (3a,4,7,7 (a) ]-5-[5-Amino-6-chloro-2-(3,3,3 - cryptochromes)thio] -pyrimidine-4-yl] tetrahydro-2,2-dimethyl-4, 7-methane-1,3-dioxolo [4,5-e] pyrimidine-6(3aH)-he

Obtained by the method of example 1 (e) using the product of stage d).

MS (PHI): 439 (M+H+, 100%).

f) [3aR- (3a,4,6,6 (a) ] -6-[[5-Amino-6-chloro-2-[(3,3,3 - cryptochromes)-thio] -4-pyrimidinyl] amino] tetrahydro-2,2 - dimethyl-4H-cyclopent-1,3-dioxol-4-methanol

Obtained by the method of example 1 (f) using the product of stage (e).

MS (PHI): 443 (M+H+, 100%).

g) [3aR- (3a,4,6,6 a) ] -6-[5-[(3,3,3-cryptochromes) thio]-7-[(2-(methylthio)ethylamino] -3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl]-tetrahydro-2,2-dimethyl-4H-cyclopent-1,3 - dioxol-4-methanol

Obtained by the method of example 1 (g) using the product of stage (f).

MS (PHI): 509 (M+H+, 100%).

h) [3aR- (3a,4(E),6,6 a) ] -3-[6-[5-[(3,3,3-Cryptochromes)thio]-7-[(2-(methylthio) ethylamino]-3H-1,2,3-triazolo[4,5-d]PI is BR>
Obtained by the method of example 1 (i) using the product of stage (g).

MS (PHI): 605 (M+H+), 549 (100%).

h) [1R- (1(E),2,3,4) ]-3-[4-[5-[(3,3,3- Cryptochromes)thio]-7-[(2-methylthio)ethylamino] -3H-1,2,3 - triazolo[4,5-d]pyrimidine-3-yl]-2,3-dihydrocyclopenta]-2 - Papanova acid

Obtained by the method of example 1 (j) using the product of stage (h).

MS (PHI): 509 (M+H+, 100%).

(j) [1R- (1(E),2,3,4) ]-N-[3-[4-[5-[(3,3,3-Cryptochromes) thio]-7-[(2-(methylthio)ethylamino]-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl]2,3-dihydrocyclopenta] -2-propenyl] -L - aspartic acid, bis(1,1-dimethylethylene)ether

Obtained by the method of example 9 (a) using the product of stage (i).

MS (PHI): 736 (M+H+), 624 (100%).

K) [1R- (1(E),2,3,4) ]-N-[3-[4-[5-[(3,3,3-Cryptochromes)- thio]-7-[(2-methylthio)ethylamino]-3H-1,2,3-triazolo [4,5-d] pyrimidine-3-yl]-2,3-dihydrocyclopenta]-2-propenyl]-L - aspartic acid, monoammonium salt

Obtained by the method of example 2 (b) using the product of stage (j).

NMR H (d6-DMSO): of 7.90 (1H, d), 6,76 of 6.68 (1H, DD), x 6.15 (1H, d), 4,99 (1H, m), 4,30 (2H, m), 3,71 (2H, t), 3,30 (2H, m), is 2.74 (5H, m) of 2.50 (1H, m), 2,42 (2H, m), 2,11 (3H, s) to 1.98 (1H, m).

Example 14

(E)-1-[7-(Butylamino)-5-(propylthio)-3H - 1,2,3-triazolo[4,5-d] -pyrimidine-3-yl]-1,5,6-Trida the 2 ml) was added to a stirred solution of 4,5-diamino-2,6-dimercaptopropane (2.0 g) in 1 N potassium hydroxide solution (26,4 ml). After stirring for 24 hours the solid was collected by filtration and received the connection specified in the header, in the form of a pink solid (2.2 g).

MS (ES): 258 (M+, 100%).

b) 5,7-Bis(propylthio)-1H-1,2,3-triazolo[4,5-d] pyrimidine

A solution of sodium nitrite (0.6 g) in water (7 ml) was added to a stirred suspension of the product of stage a) (2.0 g) in a mixture of acetic acid:water (1:1, 90 ml) at 50oC. the Reaction mixture was stirred for 1 hour at 50oC, the solid was collected by filtration and received the connection specified in the header.

MS (ES): 269 (M+), 43 (100%).

C) 5,7-Bis(propylthio)-3-(2,3,5-tri-O-benzoyl- -D - ribofuranosyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine

Gaseous hydrogen bromide was barbotirovany in ice a solution of 1-O-acetyl-2,3,5-tri-O-benzoyl - D-ribofuranose (2,02 g) in dichloromethane (15 ml) for 15 min. the Reaction was stirred for 1 hour at 0oC, then for 15 min at room temperature. The solution was concentrated, and the residue was subjected to the azeotropic distillation with dichloromethane (3 x 50 ml). Sodium hydride (60%, to 0.19 g) was added to a stirred suspension of the product of stage (b) (1.08 g) in acetonitrile (29 ml). After stirring for 15 min p and within 24 hours. The reaction mixture was distributed between ethyl acetate and water, the organic layer was dried and concentrated. Chromatography (SiO2dichloromethane: diethyl ether 39:1 as eluent) gave a mixture of 5,7-bis(propylthio)-3-(2,3,5-tri-O-benzoyl- -D - ribofuranosyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine [MS (the Belarusian library Association): 714 (M+H+), 105 (100%)] and 5,7-bis(propylthio)-2-(2,3,5-tri-O-benzoyl- -D-ribofuranosyl) -3H-1,2,3-triazolo[4,5-d] pyrimidine [MS (the Belarusian library Association): 714 (M+H+), 105 (100%)] (1,9 g). Further elution gave 5,7-bis(propylthio) -1-(2,3,5-tri-O-benzoyl- -D - ribofuranosyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine as a colorless foam (0,46 g). [MS (THE BELARUSIAN LIBRARY ASSOCIATION): 714 (M+H+), 105 (100%)].

d) N-Butyl-5-(propylthio)-3-( -D-ribofuranosyl)-3H-1,2, 3-triazolo[4,5-d]pyrimidine-7-amine

n-Butylamine (7,37 g) was added to a solution of the mixture of isomers from stage (C) (9.0 g) in 1,4-dioxane (100 ml) and water (30 ml). The solution was heated for 40 hours at 100oC, then concentrated. The residue was dissolved in 0.1 M solution of sodium methoxide in methanol (250 ml) and the reaction mixture was heated at the boil under reflux for 30 minutes After cooling to room temperature was added acetic acid to pH 7 and the solution was concentrated. Chromatography (SiO2, chloroform : isopropanol 85:15 as ale is MS (Elektrorazpredelenie): 399 (M+H+, 100%).

e) N-Butyl-5-(propylthio)-3-(2,3-ethoxymethylene- -D - ribofuranosyl)-3H-1,2,3-triazolo-[4,5-d]pyrimidine-7-amine

A solution of the product of stage (d) (0.40 g) in 1,4-dioxane (5 ml) was treated with trichloroacetic acid (0,44 g) and triethylorthoformate (0,44 g). The resulting solution was heated for 90 min at 50oC. the Cooled solution was diluted with dichloromethane (100 ml), washed with saturated sodium bicarbonate solution (50 ml) and water (50 ml), then dried and concentrated. Chromatography (SiO2, hexane: ethyl acetate 2:1 as eluent) gave the connection specified in the header, in the form of a colorless solid (0.32 g).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 455 (M+H+), 267 (100%).

f) (E)-1-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidine-3-yl]-1,5,6-trideoxy- -D-libept-5 - informanionala acid, ethyl ester

Stir a solution of the product of stage e) (3.25 g), pyridine (0,57 g) and triperoxonane acid (0,41 g) in DMSO (30 ml) was treated with 1,3-dicyclohexylcarbodiimide (4.42 g) and the mixture was stirred at room temperature for 24 hours. Added carbethoxymethylthio (3.98 g) and the reaction was stirred for 18 hours. The reaction mixture was cooled to 0oC, was diluted with ethyl acetate (400 ml) is sodium bicarbonate (200 ml), was dried and concentrated. Chromatography (SiO2, hexane: ethyl acetate 5:1 as eluent) gave the intermediate, which was dissolved in 80% acetic acid (aqueous) (25 ml) and was heated for 2 days at 36oC. the Solution was concentrated and the residue was purified by chromatography (SiO2, hexane: ethyl acetate 2:1 as eluent) to obtain the compound indicated in the title, in the form of a colorless solid (1.84 g).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 467 (M+H+), 267 (100%).

g) (E)-1-[7-(Butylamino)-5-(propylthio)-3H-1,2,3 - triazolo[4,5-d] pyrimidine-3-yl]-1,5,6-trideoxy- -D-libept-5 - infornutanely acid

Obtained by the method of Example 3 (c) using the product of stage (f).

NMR H (d6-DMSO): 9,10 (1H, t), PC 6.82 (1H, DD), x 6.15 (1H, d), of 5.89 (IH, d), was 4.76 (1H, t), 4,60 (1H, t), 4,39 (1H, t), 3,50 (2H, m), is 3.08 (2H, m), 1.69 in (2H, m) to 1.61 (2H, m) of 1.34 (2H, m), and 0.98 (3H, t), of 0.91 (3H, t).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 439 (M+H+), 267 (100%).

Example 15

(E)-N-[1-[7-(Butylamino)-5-(propylthio)-3H-1, 2,3-triazolo[4,5-d]pyrimidine-3-yl] -1,5,6-trideoxy--D - libept-5-informanon]-L-aspartic acid

a) (E)-N-[1-[7-(Butylamino)-5-(propylthio)-3H-1,2,3 - triazolo-[4,5-d]pyrimidine-3-yl] -1,5,6-trideoxy- -D-libept - 5-informanon]-L-aspartic acid, bis(1,1-dimethylethylene) ether

Received ASS="ptx2">

b) (E)-N-[1-[7-(Butylamino)-5-(propylthio)-3H-1,2,3 - triazolo-[4,5-d]pyrimidine-3-yl] -1,5,6-trideoxy--D-libept-5-informanon] -L-aspartic acid

Obtained by the method of Example 2 (b) using the product of stage a).

NMR H (d6-DMSO): 12,57 (2H, CL), which is 9.09 (1H, t), 8,42 (1H, d), 6,70 (1H, DD), 6,13 (2H, m), 5,78 (1H, d), the ceiling of 5.60 (1H, d), 4,71 (1H, m), 4,56 (2H, m), and 4.40 (1H, q), of 3.07 (2H, m), 2.63 in (2H, m), by 1.68 (2H, m) to 1.60 (2H, m) of 1.35 (2H, m), and 0.98 (3H, t), of 0.91 (3H, t).

Example 16

The following compound was obtained according to the method of Examples 14 and 15:

(E)-N-[1-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidine-3-yl] -1,5,6-trideoxy- -D-libept-5 - informanon]-L-aspartic acid, monoammonium salt

a) 5-(Propylthio)-3-( -D-ribofuranosyl)-3H-1,2,3 - triazolo[4,5-d]pyrimidine-7-amine

The solution of the mixture of isomers from Example 14) (12.0 g) in methanol (1 l) was cooled to 0oC and saturated with gaseous ammonia. The solution was stirred at room temperature for 72 hours, then concentrated. Chromatography (SiO2, dichloromethane: methanol 14: 1 as eluent) gave the connection specified in the header as a colourless solid (4.94 g).

MS (Elektrorazpredelenie): 343 (M+H+, 100%).

b) 5-(Propylthio)-3-[2,3-O-(ethoxymethylene)- -D-ribofuranosyl] -3H-1,2,3-triazo is,2,3-triazolo[4,5-d] pyrimidine-3-yl] -1,5,6-trideoxy- -D-libept-5 - infornutanely acid, ethyl ester

MS (Elektrorazpredelenie): 411 (M+H+, 100%).

(d) (E)-1-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo [4,5 - d]pyrimidine-3-yl] -1,5,6-trideoxy- -D-libept-5 - infornutanely acid, ethyl ester

MS (Elektrorazpredelenie): 383 (M+H+, 100%).

(e) (E)-N-[1-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d] - pyrimidine-3-yl] -1,5,6-trideoxy- -D-libept-5 - informanon]-L-aspartic acid, bis(1,1-dimethylethylene) ether

MS (Elektrorazpredelenie): 610 (M+H+, 100%).

f) (E)-N-[1-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] -pyrimidine-3-yl]-1,5,6-trideoxy- -D-libept-5 - informanon]-L-aspartic acid, monoammonium salt

NMR H (d6-DMSO): 8,53 (1H, CL), 8,18 (1H, CL), of 6.66 (1H, DD), 6,62 (1H, d), x 6.15 (1H, d), 5,78 (1H, t), of 4.54 (1H, t), 4,39 (1H, t), 4,25 (1H, m), 3,05 (2H, m), 2,53 was 2.25 (2H, m), by 1.68 (2H, m) to 0.97 (3H, t).

Example 17

(E)-N-[1-[7-(Butylamino)-5- (propylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidine-3-yl] -1,5,6 - trideoxy- -D-libept-5-informanon]-L-aspartic acid, monoammonium salt

a) (E)-1-[7-(Butylamino)-5-(propylthio)-3H-1,2,3 - triazolo[4,5-d]pyrimidine-3-yl]-1,5,6-trideoxy- -D - libept-5-infornutanely acid, ethyl ester

Obtained by the method of Example 3 (b) using the product of stage 14 (f).

MS (Elektrorazpredelenie): 469 (M+H+
Obtained by the method of Example 3 (c) using the product of stage a).

MS (Elektrorazpredelenie, negative ionization): 439 (M-H+, 100%).

(C) (E)-N-[1-[7-(Butylamino)-5- (propylthio)-3H-1,2,3-triazolo-[4,5-d]pyrimidine-3-yl] -1,5, 6-trideoxy- -D-libept-5-informanon]-L-aspartic acid, bis(1,1-dimethylethylene) ether

Obtained by the method of Example 2 (a) using the product of stage b).

MS (Elektrorazpredelenie): 668 (M+H+, 100%).

(d) (E)-N-[1-[7-(Butylamino)-5-(propylthio)-3H-1,2,3 - triazolo-[4,5-d]pyrimidine-3-yl] -1,5,6-trideoxy- -D-libept - 3-informanon]-L-aspartic acid, monoammonium salt

Obtained by the method of Example 2 (a) using the product of stage (C).

NMR H (d6-DMSO): 9,07 (1H, t), of 7.69 (1H, d), 6,04 (1H, d), of 5.50 (2H, sh), was 4.76 (1H, t), 4,18 (2H, m), 3,91 (1H, m), 3,49 (2H, q), is 3.08 (2H, t), 2,46-of 2.23 (2H, m) to 2.18 (2H, t), of 1.93 (1H, m) to 1.70 (3H, m), to 1.60 (2H, m) of 1.34 (2H, m), 0,99 (3H, t), of 0.91 (3H, t).

Example 18

(E)-N-[1,5,6-Trideoxy-1-[7-(hexylamino) - 5-(propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl]- - D-libept-5-informanon]-L-aspartic acid, monoammonium salt

a) 3-(5-O-Benzoyl- -D-ribofuranosyl)-hexyl-5- (propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-7-amine

Obtained by the method of Example 14 (d) with use)- -D - ribofuranosyl]-N-hexyl-5-(propylthio)-3H-1,2,3-triazolo [4, 5-d]pyrimidine-7-amine

The product of stage (a) (4,93 g) in acetone (120 ml) containing 2,2-dimethoxypropane (11,4 ml) was treated with p-toluensulfonate (4.4 g). The resulting solution was stirred for 2 hours at room temperature, was podslushivaet by triethylamine (3,25 ml) and concentrated. Chromatography (SiO2, cyclohexane:ethanol 95:5 as eluent) gave the connection specified in the header (to 5.03 g).

MS (Elektrorazpredelenie): 571 (M+H+, 100%).

C) N-Hexyl-3-[2,3-O-(1-methylethylidene)- -D - ribofuranosyl] -5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidine-7-amine

A solution of the product of stage (b) (5,02 g) in 0.1 M solution of sodium methoxide in methanol (88 ml) was heated at the boil under reflux for 30 minutes was Added acetic acid (1 ml) and the reaction was concentrated. Chromatography (SiO2, dichloromethane: acetonitrile 95:5 as eluent) gave the connection specified in the header (3,63 g).

MS (Elektrorazpredelenie): 467 (M+H+, 100%).

(d) (E)-1,5,6-Trideoxy-1-[7-(hexylamino)-5- (propylthio)-3H-1,2,3-triazolo [4,5-d]-pyrimidine-3-yl]-2,3-O- (1-methylethylidene) -D-libept-5-infornutanely acid, 1,1 - dimethylethylene ether

Obtained by the method of Example 1 (i) using the product of stage (C).

MS (B is-3-yl]- -D - libept-5-infornutanely acid

Obtained by the method of Example 1 (j) using the product of stage d).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 467 (M+H+), 295 (100%).

f) (E)-N-[1,5,6-Trideoxy-1-[7-(hexylamino)-5- (propylthio)-3H-1,2,3-triazolo [4,5-d]-pyrimidine-3-yl]- - D-libept-5-informanon]-L-aspartic acid, bis(1,1 - dimethylethylene) ether

Obtained by the method of Example 9a) using the product of stage (e).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 694 (M+H+), 295 (100%).

g) (E)-N-[1,5,6-Trideoxy-1-[7-(hexylamino)-5- (propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] - -D - libept-5-informanon]-L-aspartic acid, monoammonium salt

Obtained by the method of Example 2 (b) using the product of stage (f).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 582 (M+H+), 295 (100%).

NMR H (d6-DMSO): a total of 8.74 (1H, t), of 8.00 (1H, m), of 6.66 (1H, DD), 6 6,23 (1H, d), x 6.15 (1H, m), was 4.76 (1H, m), 4,55 (1H, t), and 4.40 (1H, t), 4,27 (1H, t), 3,50 (2H, m), of 3.07 (2H, m), of 2.51 (2H, m), by 1.68 (4H, m) of 1.30 (6H, m), and 0.98 (3H, m) of 0.87 (3H, m).

Example 19

(E)-1-[7-(N-Butyl-N-methylamino)-5-(propylthio) -3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl]1,5,6-trideoxy- -D-libept-5-infornutanely acid

a) N-Butyl-N-methyl-5-(propylthio)-3-(-D-ribofuranosyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine-7-amine

Obtained by the method of Example 14 (d) using N-methyl-N-butylamine.

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 413 (M+Hd]pyrimidine - 7-amine

Obtained by the method of Example 18 (b) using the product of stage a).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 453 (M+N+), 281 (100%).

(C) (E)-1-[7-(N-Butyl-N-methylamino)-5-(propylthio)-3H - 1,2,3-triazolo [4,5-d] pyrimidine-3-yl] -1,5,6-trideoxy-2,3 - O-(1-methylethylidene)- -D-libept-5-infornutanely acid, 1,1 - dimethylethylene ether

Obtained by the method of Example 1i) using the product of stage b).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 549 (M+H+, 100%).

(d) (E)-1-[7-(N-Butyl-N-methylamino)-5-(propylthio)-3H-1, 2,3-triazolo[4,5-d] pyrimidine-3-yl]-1,5,6-trideoxy- -D-libept-5-infornutanely acid

Obtained by the method of Example 1j) using the product of stage (C).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 453 (M+H+, 100%).

NMR H (d6-DMSO): 6,51 (1H, DD), 6,12 (1H, d), of 5.83 (1H, d), 4,71 (1H, t), 4,51 (1H, t), or 4.31 (1H, m), 3,76 (2H, m), 3,71 (3H, s), is 3.08 (2H, m), 1.69 in (4H, m) to 1.61 (2H, m) of 1.34 (2H, m) to 0.94 (6H, m).

Example 20

(E)-N-[1-[7-(Butylamino)-5-(propylthio)-3H-1, 2,3-triazolo[4,5-d] pyrimidine-3-yl] -1,5,6-trideoxy- -D - libept-5-informanon]-L-aspartic acid

a) 3-(2,3,5-Tri-O-benzoyl- -D-ribofuranosyl)-5,7 - bis(methylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine and

2-(2,3,5-Tri-O-benzoyl- -D-ribofuranosyl)-5,7-bis (methylthio)-3H-1,2,3-triazole[4,5-d]pyrimidine

Obtained by the method of Example 14c) using 5,7-bis(IU Chromatography (SiO2, dichloromethane:ethyl acetate 99:1 as eluent) gave the connection specified in the header (13.3 g).

MS (Elektrorazpredelenie): 467 (M+H+, 100%).

b) N-Butyl-3-[2,3-O-(1-methylethylidene)- -D-ribofuranosyl]-5- (methylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-7-amine

n-Butylamine (13.5 ml) was added to a solution of the mixture of isomers from step a) are (22.5 g) in a mixture of dioxane (175 ml)/water (25 ml). The solution was stirred at room temperature for 24 hours, then concentrated. The residue was dissolved in 0.1 M solution of sodium methoxide in methanol (500 ml) and was heated at the boil under reflux for 30 minutes After cooling to room temperature the solution was concentrated and the residue was dissolved in DMF (80 ml). Added p-toluensulfonate (5,91 g) and 2,2-dimethoxypropane (50 ml) and the reaction mixture was stirred at room temperature for 24 hours. The solution was concentrated and the residue was distributed between ethyl acetate (500 ml) and saturated sodium bicarbonate solution (500 ml), the organic phase was dried and concentrated. Chromatography (SiO2, hexane:ethyl acetate 7:3 as eluent) gave the connection specified in the header, in the form of a colorless solid (3,67 g).

MS (Elektrorazpredelenie): 411 (M+H+, Liden)- D-libept-5-infornutanely acid, ethyl ester

Obtained by the method of Example 1 (i) using the product of stage b) and arbetarskyddsstyrelsen.

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 479 (M+H+, 100%).

(d) (E)-1-[7-(Butylamino)-5-(methylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl]-1,5,6-trideoxy- -D-libept-5 - infornutanely acid, ethyl ester

The product of stage (C) (1.4 g) was dissolved in 2 M HCl solution in methanol (75 ml) and the reaction mixture was stirred for 15 min at room temperature, then concentrated. The residue was dissolved in ethyl acetate (300 ml), washed with saturated sodium bicarbonate solution (3 x 100 ml), dried and concentrated. Chromatography (SiO2, dichloromethane:methanol 97:3 as eluent) gave the connection specified in the header, in the form of a colorless solid (1.10 g).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 439 (M+H+), 239 (100%).

(e) (E)-1-[7-(Butylamino)-5-(methylthio)-3H-1,2,3-triazolo [4, 5-d]pyrimidine-3-yl]-1,5,6-trideoxy- -D-libept-5 - infornutanely acid

Obtained by the method of Example 3c) using the product of stage d).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 411 (M+H+), 154 (100%).

f) (E)-N-[4-[7-(Butylamino)-5-(methylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidine-3-yl] -1,5,6-trideoxy--D-libept-5 - informanon] -L-aspartic acid, bis(1,1 who (the Belarusian library Association): 638 (M+H+), 239 (100%).

g) (E)-N-[1-[7-(Butylamino)-5-(methylthio)-3H-1,2,3 - triazolo-[4,5-d]pyrimidine-3-yl] -1,5,6-trideoxy--D-libept - 3-informanon]-L-aspartic acid

Obtained by the method of Example 2 (b) using the product of stage (f).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 526 (M+H+), 239 (100%).

Example 21

(E)-1-[5-Butyl-7-(butylamino)-3H-1,2,3-triazolo[1,5-d] pyrimidine-3-yl] -1,5,6-trideoxy--D-libept - 5-infornography acid.

a) 5-Butyl-3,4-dihydro-3-[2,3-O-(1-methylethylidene)- -D-ribofuranosyl] -7H-1,2,3-triazolo[4,5-d]pyrimidine-7-he

Sodium (4.6 g) was dissolved in ethanol (200 ml), then was added 5 - amino-1-[2,3-O-(1-methylethylidene)- -D-ribofuranosyl] -1H - 1,2,3-triazole-4-carboxamide (obtained as described G. Biagi et al., Farmaco, 1992, 47, 525) (6.0 g) and the mixture was heated under reflux. Added methylvalerate (10.5 ml) and boiled under reflux for 17 hours. The mixture was neutralized using Dowex h-200 (N+-form), filtered, the filtrate was concentrated. The residue was dissolved in ethanol, was added acetic acid and the solution was concentrated. Chromatography (SiO2, hexane:ethyl acetate 7:3 as eluent) gave the connection specified in the header, in the form of a colorless oil (is 3.08 g).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 366 (M+H+).

b) 5-the Lamin (0,42 g) and acetylchloride (0.3 g) were added sequentially to a cooled with ice to a solution of product from step a) (1,41 g) in dichloromethane (50 ml). The mixture was stirred for 30 min at 5oC, then washed with a saturated solution of sodium chloride, dried and concentrated. Chromatography (SiO2, dichloromethane : methanol 95:5 as eluent) gave the connection specified in the header (1.2 g).

MS (ES): 408 (M+H+).

C) 5-Butyl-7-chloro-3-[5-O-acetyl-2,3-O-(1-methylethylidene)- -D-ribofuranosyl]-3H-1,2,3-triazolo[4,5-d] pyrimidine

The product of stage (b) (1.19 g) and DMF (299 mg) in chloroform was heated under reflux, was added thionyl chloride (3,47 g) and boiled under reflux for 45 minutes After cooling in an ice bath, the mixture was slowly added to a stirred saturated solution of sodium bicarbonate. The mixture was extracted with dichloromethane (3 x 200 ml), the combined extracts were dried, filtered and concentrated. Chromatography (SiO2, hexane:ethyl acetate 5:1 as eluent) gave the connection specified in the header (1,14 g).

MS (ES): 427, 425 (M+H+).

d) N, 5-Dibutil-3-[2,3-O-(1-methylethylidene)- -D-ribofuranosyl] -3H-1,2,3-triazolo[4,5-d]pyrimidine-7-amine

Obtained by the method of Example 1h) using the product of stage (C).

MS (ES): 420 (M+).

(e) (E)-1-[5-Butyl-7-(butylamino)-3H-1,2,3-triazolo[4, 5-d]pyrimi
Obtained by the method of Example 1 (i) using the product of stage d).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 517 (M+H+, 100%).

f) (E)-1-[5-Butyl-7-(butylamino)-3H-1,2,3-triazolo [4,5-d]pyrimidine-3-yl] -1,5,6-trideoxy- -O-libept-5-infornutanely acid

Obtained by the method of Example 1 (j) using the product of stage (e).

NMR H (d6-DMSO): 8,87 (1H, t), of 6.71 (1H, DD), of 6.20 (1H, m), of 5.89 (1H, d), and 4.75 (1H, m), 4,56 (IH, t), 4,37 (1H, t), of 3.54 (2H, q), by 2.73 (2H, t), of 1.74 (2H, m) of 1.62 (2H, m) of 1.35 (4H, m) of 0.91 (6H, t).

Example 22

(E)-1-[7-Butyl-5-(propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] -1,5,6-trideoxy- -D-libept-5-infornutanely acid

a) 5-Amino-1-[5-O-[(1,1-dimethylethyl)dimethylsilane] -2,3-O-(1-methylethylidene) - -D-ribofuranosyl]-1H-1,2,3-triazole-4-carboxamide

A solution of 5-amino-1-[2,3-O-(1-methylethylidene)- -D-ribofuranosyl]- 1H-1,2,3-triazole-4-carboxamide (obtained as described G. Biagi et al, Farmaco, 1992, 47, 525) (10.0 g), imidazole (2.20 g) and tert-butyldimethylsilyl (to 4.98 g) in DMF (200 ml) was stirred for 16 hours at room temperature. The solution was concentrated and the residue was purified (SiO2, dichloromethane : ethyl acetate 1: 1 as eluent) to give the compounds specified in the header.

MS (ES): 398 (M-CH3+), 73 (100%).

b) 3,6-Dihydro-3-[5-O-[(1,1-dimethylethylamine a) (26,0 g) in DMF (100 ml) was added over 1 hour to a stirred suspension of sodium hydride (60%, 2,52 g) in DMF (200 ml). Added 1,1-thiocarbonyldiimidazole (11.2 g) and the reaction mixture is boiled under reflux for 1 hour, then concentrated. The residue was dissolved in water (1 l), acidified glacial acetic acid and the connection specified in the header, was isolated by filtration (14.1 g).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 456 (M+H+), 69 (100%).

C) 3-[5-O-[(1,1-Dimethylethyl)dimethylsilane]-2,3-O-(1 - methylethylidene) -D-ribofuranosyl]-3,4-dihydro-5-(propylthio) -7H-1,2,3-)triazolo[4,5-d]pyrimidine-7-he

The product of stage (b) (19.3 g) was added to a stirred suspension of sodium hydride (60%, of 1.41 g) in DMF (200 ml). After 15 min was added iodopropane (3.55 g), the mixture was stirred for 1 hour, then concentrated. The residue was distributed between water (1 l) and dichloromethane (1 l). The organic layer was dried, concentrated and received the connection specified in the header (18 g).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 498 (M+H+), 73 (100%).

d) 3-[2,3-O-(1-Methylethylidene)- -D-ribofuranosyl] -3,4 - dihydro-5-(propylthio)-7H-1,2,3-triazolo [4,5-d]pyrimidine-7-he

Fluoride of tributylamine (1 M in TGGF, to 40.6 ml) was added to a stirred solution of the product of stage (C) (20.2 g) in TDF (300 ml) and the reaction mixture was stirred for 12 hours at room temperature. The solution was concentrated and osteodentin, specified in the header (14.1 g).

MS (Elektrorazpredelenie): 382 (M-H+, 100%).

e) 3-[5-O-Acetyl-2,3-O-(1-methylethylidene)--D-ribofuranosyl] - 3,4-dihydro-5-(propylthio)-7H-1,2,3-triazolo[4,5-d]pyrimidine-7-he

Obtained by the method of Example 21 (b) using the product of stage d).

MS (Elektrorazpredelenie): 443 (M+H+, 100%).

f) 3-[5-O-Acetyl-2,3-O-(1-methylethylidene)--D-ribofuranosyl] -7-chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine

Obtained by the method of Example 21 (c) using the product of stage (e).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 444, 446 (M+H+).

g) 3-[5-O-Acetyl-2,3-O-(1-methylethylidene)- -D - ribofuranosyl]- 7-butyl-5-(propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine

Obtained by the method of Example 21 (c) using the product of stage (e).

Bis (triphenylphosphine) palladium (II) chloride (40 mg) and tetrabutyrate (0,81 ml) was added to a solution of the product of stage (f) (500 mg) in 1-methyl-2-pyrrolidinone (5 ml) and the mixture was stirred for 2 hours at 100oC, then at room temperature for 72 hours. The mixture was distributed between water (100 ml) and ethyl acetate (200 ml), the organic layer was washed with a saturated solution of sodium chloride (50 ml), dried and concentrated. Chromatography (SiO2, hexane: ethyl acetate 85:15 in the/P> 7-Butyl-3-[2,3-O-(1-methylethylidene)- -D - ribofuranosyl]-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidine

Obtained by the method of Example 16 (a) using the product of stage (q).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 424 (M+H+).

i) (E)-1-[7-Butyl-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl] -1,5,6-trideoxy- -D-libept-5-infornutanely acid, 1,1-dimethylethylene ether

Obtained by the method of Example 1 (i) using the product of stage (h).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 520 (M+H+).

j) (E)-1-[7-Butyl-5-(propylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidine-3-yl] -1,5,6-trideoxy- -D-libept-5 - infornutanely acid

Obtained by the method of Example 1i) using the product of stage (h).

NMR H (d6-DMSO): 7,00 (1H, d), of 6.52 (1H, s), 6,01 (1H, d), and 5.30 (2H, CL), 4,94 (1H, s), 4,56 (1H, t), 4,76-to 4.81 (2H, d), of 3.12 (4H, W) of 1.80 (2H, HF), to 1.70 (2H, HF), to 1.37 (2H, HF), 0,99 (3H, t) to 0.89 (3H, t).

Example 23

(E)-N-[1-[5,7-Di(butylamino)-3H-1,2,3-triazolo[4,5- (1] pyrimidine-3-yl] -1,5,6-trideoxy- -D - abovereferenced] -L-aspartic acid, monoammonium salt

a) (E)-N-[1-[7-Butylamino-5-(methylsulphonyl)-3H-1,2,3 - triazolo[4,5-d] -pyrimidine-3-yl] -1,5,6-trideoxy- -D-abovereferenced]-L-aspartic acid, 1,1-dimethylethylene ether

3-Chloroperoxybenzoic acid (50%, 0.12 g) in ethanol (1 ml) que 16 hours at room temperature the solution was diluted with dichloromethane (50 ml), then washed with an aqueous solution of sodium metabisulfite (30 ml) and aqueous sodium carbonate solution (2 x 20 ml). The organic layer was dried, concentrated and received the connection specified in the header (90 mg).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 700 (M+H+), 299 (100%).

b) (E)-N-[1-[5,7-Di(butylamino)-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-yl] -1,5,6-trideoxy- -D-abovereferenced] - L-aspartic acid, 1,1-dimethylethylene ether

Obtained by the method of Example 1 (h) using the product of stage a).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 665 (M+H+, 100%).

(C) (E)-N-[1-[5,7-Di(butylamino-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl] -1,5,6-trideoxy- -D-abovereferenced]-L - aspartic acid, monoammonium salt

Obtained by the method of Example 2 (b) using the product of stage b).

MS (Elektrorazpredelenie): 553 (M+H+, 100%).

Example 24

(Z)-1-[7-(Butylamino)-5-(propylthio)-3H-1,2,3 - triazolo[4,5-d]-pyrimidine-3-yl]-1,5,6-trideoxy- -D - libept-5-infornography acid

a) N-Butyl-5-(propylthio)-3-[2,3-O-(1-methylethylidene)- -D - ribofuranosyl]-3H-1,2,3-triazolo[4,5-d]pyrimidine-7 - amine

Obtained by the method of Example 18 (b) using the product of stage 14).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 443 (M+H+), 267 (100%).

b) (Z)-1-[7-(Butylamino)-5-(propylthio)-1 - dimethylethylamine ether

Obtained by the method of Example 1i) using the product of stage a), and the connection specified in the header, was isolated as the product obtained in small quantities.

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 535 (M+H+, 100%).

(C) (Z)-1-[7-(Butylamino-5-(propylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidine-3-yl]-1,5,6-trideoxy- -D-libept-5 - infornutanely acid

Obtained by the method of Example 1 (j) using the product of stage b).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 439 (M+H+), 267 (100%).

Example 25

N-Butyl-5-(propylthio)-3-[5,6-dimethoxy-6-(1H-tetrazol-5 - yl)- -D-removecounter]-3H-1,2,3-triazolo[4,5-d] pyrimidine-7-amine

a) (E)-1-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d] pyrimidine-3-yl] -1,5,6-trideoxy-2,3-O-(1-methylethylidene) - -D-libept-5-infornutanely

Obtained by the method of Example 1 (i) using the product stage 24A) and (triphenylphosphonio)acetonitrile.

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 460 (M+H+, 100%).

b) (E)-1-[7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo [4,5-d]pyrimidine-3-yl] -1,5,6-trideoxy-2,3-O-(1-methylethylidene)- -D-removereference

Obtained by the method of Example 8 (b) using the product of stage a).

MS (PHI): 462 (M+H+, 100%).

C) N-Butyl-5-(propylthio)-3-[5,6-dimethoxy-etelsen (0,30 g) and dibutylamine (32 mg) was added to a solution of the product of stage (b) (0,60 g) in toluene (6 ml) and the resulting solution was boiled under reflux for 72 hours. After cooling to room temperature the solvent was removed and the residue was purified by chromatography (SiO2, ethyl acetate:isohexane:acetic acid 100:100:1 as eluent) to obtain the compound indicated in heading (0.26 g).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 505 (M+H+), 267 (100%).

d) N-Butyl-5-(propertie-3-[5,6-dimethoxy-6-(1H-tetrazol - 5-yl)- -D-removecounter]-3H-1,2,3-triazolo [4,5-d]pyrimidine - 7-amine

Obtained by the method of Example 1 (j) using the product of stage (C).

MS (THE BELARUSIAN LIBRARY ASSOCIATION): 465 (M+H+), 267 (100%).

NMR H (d6-DMSO): remaining 9.08 (1H, t), between 6.08 (1H, d), the 5.65 (1H, d), to 5.35 (1H, m), was 4.76 (1H, t), 4,30 (1H, t), 3,98 (1H, m), 3,50 (2H, m), 3,06 (2H, m), of 2.92 (2H, m), is 2.05 (2H, m), and 1.63 (4H, m) of 1.34 (2H, m) to 0.97 (3H, t) of 0.91 (3H, t).

Example 26

1,5,6-Trideoxy-1-[5,7-bis(propylthio)-3H-1,2,3 - triazolo-[4,5-d]pyrimidine-3-yl]- -D-removefromarray acid, sodium salt

a) (E)-1,2,3-Tri-O-acetyl-5,6-dideoxy- -D-libept-5 - infornutanely acid, ethyl ester

Ethyl ester of (E)-methyl-5,6-dideoxy-2,3-O-(1-methylethylidene)- -D-libept-5-informaziorako acid (obtained as described in A. J. Cooper, R. G. Salomon, Tetrahedron Lett. , 1990, 31, 3813) (88,0 g) was heated at 80oC in a mixture of acetic acid (256 ml) and water (64 ml) for 16 hours at room temperature. Evaporation gave States was diluted with ethyl acetate (500 ml) and washed with diluted HCl. Drying and evaporation gave an oil, which was purified by chromatography (SiO2, isohexane: ethyl acetate 5:1 as eluent) to give the compounds specified in the header, (5.34 g).

MS (the Belarusian library Association+RbI): 431, 429 (M+Rb+), 285 (100%).

b) 1,2,3-tri-O-acetyl-5,6-dideoxy- -D - removefromarray acid, ethyl ester

Obtained by the method of Example 8 (b) using the product of stage a).

MS (the Belarusian library Association+RbI): 433, 431 (M+Rb+), 185 (100%).

C) 2,3-Di-O-acetyl-1,5,6-trideoxy-1-[5,7-bis (propylthio)-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-yl]-D-removefromarray acid, ethyl ester, 2,3-di-O-acetyl-1,5,6-trideoxy-1-[5,7-bis(propylthio)-3H-1, 2,3-triazolo [4,5-d]pyrimidine-2-yl]-D-removefromarray acid, ethyl ester.

The product of stage (b) (1,00 g) and the product of stage 14 (b) (0,78 g) was mixed with p-toluensulfonate (12 mg) and thoroughly mixed with the water-jet vacuum pump. The mixture was immersed in an oil bath heated to 140oC. Heating was continued for 10 min, and then the flask was cooled and the reaction mixture was treated with chloroform. Washing with a saturated solution of sodium bicarbonate, drying, evaporation and chromatography (SiO2, dichloromethane-ethyl acetate 15: 1 as eluent) gave compound, iSolo-[4,5-d]pyrimidine-3-yl]- -D-removefromarray acid, sodium salt

Obtained by the method of Example 3 (c) using the product of stage (C).

MS (the Belarusian library Association+RbI): 433, 431 (M+Rb+).

Pharmaceutical compositions

The new compounds of the present invention may be introduced parenterally, intravenously, by inhalation or ingestion. The preferred route of administration is intravenous infusion.

The dose of administration depends on the method of administration, the severity of the disease, age and weight of the patient, and other factors usually considered a staff physician of the hospital when determining an individual mode and level doses, the most appropriate for a particular patient.

Examples of pharmaceutical compositions that may be used, and suitable fillers, diluents or carriers are:

for intravenous injection or infusion - purified water or saline;

for inhalation compositions, untreated lactose;

for tablets, capsules and pills - microcrystalline cellulose, calcium phosphate, hard-shelled earth, a sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin;

for suppositories - what about for use in aqueous solution, for example, for infusion, it may be necessary to include other fillers. In particular, can be used chelating agents or passivator, antioxidants, agents that regulate the tone, agents regulating pH, and buffer agents. Solutions containing the compound of formula (1), if necessary, can be evaporated, for example, freeze-drying or spray drying to obtain a solid composition that can be recovered before use. The composition may also contain suitable preserving, stabilizing and wetting agents, agents that promote the dissolution of, for example, water-soluble cellulose polymer, such as hypromellose, or water-soluble glycol, such as propylene glycol, sweetening and coloring tools, and odorants. If necessary, the compounds can be formulated in a form with an extended selection.

According to another aspect, the invention relates to the use of compounds of formula (1) or its pharmaceutically acceptable salt for the manufacture of medicaments for treating disorders associated with platelet aggregation.

According to another aspect, the invention relative to the active amount of the compound of formula (1) patient suffering this disease.

Pharmaceutically acceptable salts of compounds of formula (1) include salts of alkali metals, e.g. sodium and potassium salts; salts of alkaline earth metals, e.g. calcium salts and magnesium salts of group III elements, for example, aluminum salts; and ammonium salts. Salts with suitable organic bases, e.g. salts with hydroxylamine; lower bonds alkylamines, e.g. methylamine or ethylamine; with substituted lower alkylamines followed, for example, replacement bonds alkylamines; or monocyclic nitrogen-containing heterocyclic compounds, for example, piperidine or morpholine; and salts with amino acids, such as arginine, lysine, etc. or their N - alkyl derivatives; or amino sugars, for example, N-methyl - D - glucamine or glucosamine. The above salts are only examples of salts that may be used in accordance with the present invention, and the list should not be considered as exhaustive.

Preferred pharmaceutically acceptable salts of compounds of formula (1) are alkali metal salts and ammonium salts, preferred salts are sodium and monoammonium salt.

Biological IV was determined by their ability to act as antagonists of P2T-receptor, as shown in the following text.

Quantitative determination of agonistic/antagonistic activity towards P2T-receptor washed human platelets.

Preparation of

Venous blood (100 ml) was distributed evenly between the 3 test tubes, and each contained a 3.2% trinatriytsitrat (4 ml) as anticoagulant. The tubes were centrifuged for 15 min at 240 G to obtain plasma, platelet-rich (POT), to which was added 300 ng/ml prostacyclin in order to stabilize the platelets during the operation of washing. SWEAT does not contain red cells were obtained by centrifugation for 10 min at 125 G and subsequent centrifugation for 15 min at 640 G. the Supernatant was discarded and the pellet platelets re-suspended in modified, not containing calcium Tyrode solution (tubing) (10 ml) having the composition: NaCl 137 mm NaHCO311.9 mm, NaH2PO40.4 mm, KCl 2.7 mm, MgCl21.1 mm, 5.6 mm dextrose, saturated with gaseous mixture of 9502/5% CO2and kept at 37oC. After adding another 300 ng/ml PG I2the combined suspension was centrifuged again for 15 min at 640 G. Adosados the ordinary to bring the end of platelets to 2 x 105/ml. This final suspension was stored in a 60-ml syringe with 3oC without air. In order to allow restoration of normal function after inhibition of PG I2the platelets used to study aggregation not earlier than 2 hours after the end of resuspendable.

In all studies, 3-ml aliquots of a suspension of platelets were added to tubes containing a solution of CaCl2(60 μl of a 50 mm solution, final concentration 1 mm). Added human fibrinogen (Sigma, F 4883) and 8-sulfopropyl (8-SFT to block any antagonistic activity of the compounds in relation to P1) to obtain the final concentrations of 0.2 mg/ml (60 μl of a solution of protein is able to fold in physiological solution with a concentration of 10 mg/ml) and 300 nm (10 μl of a 15 mm solution in 6% glucose), respectively. Platelets or buffer, respectively, were added in a volume of 150 μl in a separate cell plate with 96 cells. All measurements were made three times with platelets from each donor.

The test report

a) Evaluation of agonistic/antagonistic activity

Aggregatirovannye reaction plate with 96 cells, using the change of absorption, fix registering stroysiti baseline figure. Saline solution or the corresponding solution of the test compounds were added to each well in a volume of 10 μl with a final concentration of 0.001, 0,1, 1, 10 or 100 mm. The tablet was then shaken for 5 min on a rotary shaker at position 10 and recorded the absorption at 660 nm. Aggregation at this point is an indicator of the agonistic activity of the test compounds. Then in each cell was added saline or ADP (30 mm; 10 ál 450 mm solution) and the plate was shaken for 5 min before fixation absorption again at 660 nm.

Agonistic activity was assessed as % inhibition of the control response to ADP. Compounds of the present invention showed antiaggregatory activity when tested by the above method.

The number of the example pIC50< / BR>
1 - 7,60

2 - of 9.30

3 - 5,85

4 - 7,14

5? 7.04 baby mortality

6 - 7,00

7 - 7,15

8 - 6,24

10 - 5,93

14 - 7,39

pIC50is a log10IC50where IC50represents the concentration of antagonist required for 50% inhibition of aggregation.

1. Derivatives of 3H-1,2,3-triazolo-[4,5-d] pyrimidine of the General formula I

< / BR>
in which B represents O Il
, NR1R2and C1-C7-alkyl;

R1and R2each independently represents H or C1-C7-alkyl, or R1is1-C7-alkyl, optionally substituted in the alkyl chain one atom of O or S or one or more halogen, and R2represents hydrogen;

R3and R4represent hydrogen or R3and R4together form a bond;

A is COOH, C(O)NH(CH2)pCOOH, C(O)N[(CH2)q-COOH]2C(O)NHCH(COOH)(CH2)rCOOH or 5-tetrazolyl, in which p, q and r each independently is 1, 2 or 3,

and their pharmaceutically acceptable salts or esters.

2. The compound of formula I under item 1, where X represents NR1R2; Y represents SR1; A represents C(O)NHCH(COOH)(CH2)rCOOH and R1, R2and r is defined in paragraph 1.

3. Connection on p. 2, where X represents NR1R2where R1is hydrogen and R2defined in paragraph (1; Y represents SR1where R1is1-C5-alkyl, optionally substituted with one or more halogen; a represents C(O)NHCH(COOH)(CH2)COOH.

4. Connection on p. 1, which is a

[1R-(1(E),2,3,4)] -3-[4-[7-briewww salt;

[1R-(1(E),2,3,4)] -N-[3-[4-[7-butylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -2,3-dihydrocyclopenta]-2-propenyl]-L-aspartic acid, disodium salt;

[1S-(1,2,3,4)] -4-[7-butylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d]-pyrimidine-3-yl]-2,3-dihydroxyacetophenone acid, sodium salt;

[1R-(1(E),2,3,4)] -3-[4-[7-butylamino)-5-(pentylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -2,3-dihydrocyclopenta] -2-propanolol acid, sodium salt;

[1R-(1(E),2,3,4)] -3-[4-[7-(ethylamino)-5-(pentylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -2,3-dihydrocyclopenta] -2-propanolol acid, sodium salt;

[1S-(1,2,3,4)] -4-[7-butylamino)-5-(pentylthio)-3H-1,2,3-triazolo-[4,5-d]-pyrimidine-3-yl]-2,3-dihydroxyacetophenone acid, sodium salt;

[1S-(1,2,3,4)] -4-[7-(ethylamino)-5-(pentylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -2,3-dihydroxyacetophenone acid, sodium salt;

[1R-(1,2,3,5)] -3-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d]-pyrimidine-3-yl]-5-[2-(1H-tetrazol-5-yl)ethyl-1,2-cyclopentanediol;

[1R-(1,2,3,4)] -N-[3-[4-[7-butylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -2,3-dihydrocyclopenta] propanol]-L-aspartic acid;

[1R-(1(E),2,3,4)] -N-[3-[4-[7-hexylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -2,3-d is ltio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -2,3-dihydrocyclopenta] -2-propanolol acid;

[1R-(1(E),2,3,4)] -3-[4-[7-(2-methoxy)ethylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -2,3-dihydrocyclopenta]-2-propanolol acid;

[1R-(1,2,3,4)] -N-[3-[4-[7-(hexylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -2,3-dihydroxycholecalciferol]-L-aspartic acid;

[1R-(1(E),2,3,4)] -N-[3-[4-[5-(3,3,3-cryptochromes)thio] -7-[2-(methylthio)-ethylamino] -3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl]-2,3-dihydrocyclopenta]-2-propenyl]-L-aspartic acid, monoammonium salt;

(E)-1-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d]-pyrimidine-3-yl]-1,5,6-trideoxy--D-libept-5-inforeuro acid;

(E)-N-[1-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d]-pyrimidine-3-yl] -1,5,6-trideoxy--D-libept-5-informanon] -L-aspartic acid;

(E)-N-[1-[7-amino-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -1,5,6-trideoxy--D-libept-5-informanon]-L-aspartic acid, monoammonium salt;

(E)-N-[1-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d]-pyrimidine-3-yl] -1,5,6-trideoxy--D-abovereferenced]-L-asparginase acid, monoammonium salt;

(E)-N-[1,5,6-trideoxy-1-[7-(hexylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d]-pyrimidine-3-yl]-D-libept-5-informanon]-L-asparginase acid, monoammonium salt;
(E)-N-[1-[7-(butylamino)-5-(methylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl]-1,5,6-trideoxy--D-libept-5-informanon]-L-aspartic acid;

(E)-1-[5-butyl-7-(butylamino)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -1,5,6-trideoxy--D-libept-5-inforeuro acid;

(E)-1-[7-butyl-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -1,5,6-trideoxy--D-libept-5-inforeuro acid;

(E)-N-[1-[5,7-di(butylamino)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -1,5,6-trideoxy--D-abovereferenced]-L-aspartic acid, monoammonium salt;

(Z)-1-[7-butylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl]-1,5,6-trideoxy--D-iboga-5-inforeuro acid;

N-butyl-5-(propylthio)-3-[5,6-dimethoxy-6-(1H-tetrazol-5-yl)-D-removecounter]-3H-1,2,3-triazolo-[4,5-d]-pyrimidine-7-amine or 1,5,6-trideoxy-1-[5,7-bis(propylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl]-D-nebogatikovoj acid, sodium salt.

5. Connection on p. 4, which is (E)-N-[1-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -1,5,6-trideoxy--D-libept-5-informanon]-L-aspartic acid.

6. Connection on p. 4, which is [1R-(1,2,3,4)]-N-[3-[4-[7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine which is [1R-(1(E),2,3,4)] -N-[3-[4-[7-(hexylamino)-5-(propylthio)-3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl]-2,3-dihydrocyclopenta]-2-propenyl]-L-aspartic acid.

8. Connection on p. 4, which is [1R-(1(E),2,3,4)] -N-[3-[4-[5-[(3,3,3-cryptochromes)thio] -7-[2-(methylthio)-ethylamino] -3H-1,2,3-triazolo-[4,5-d] -pyrimidine-3-yl] -2,3-dihydrocyclopenta]-2-propenyl]-L-aspartic acid, monoammonium salt.

9. The compound of formula I under item 1 in the form of salt.

10. Connection on p. 9, which is a salt of an alkali metal or ammonium salt of the compounds of formula I under item 1.

11. Connection on p. 10, which is the sodium salt of the compounds of formula I under item 1.

12. Connection on p. 10, which is monoammonium salt of the compounds of formula I under item 1.

13. The compound of formula I under item 1, which is located in any one of its tautomeric, enantiomeric or diastereoisomeric forms.

14. The compound of formula I under item 1, where B, X, Y, R1, R2, R3and R4defined in paragraph 1 and choose from COOR11C(O)NH(CH2)pCOOR11C(O)N[(CH2)qCOOR11]2or C(O)NHCH(COOR11)(CH2)rCOOR11where p, q and r is 1, 2 or 3 and R11is lower alkyl.

15. The compound of formula I on p. 1 to prevent platelet aggregation.

16. Pharmaceutical composition having inhibit the NTA together with a pharmaceutically acceptable carrier.

17. The method of obtaining the compounds of formula I on p. 1, including (i) the interaction of the compounds of formula I, where X is SR1, NR1R2or1-C7-alkyl; Y is SR1, NR1R2or1-C7-alkyl; R1and R2defined in formula I; B is O or CH2; R3and R4represent hydrogen or together form a bond, and A is COOH, with the connection structure of NH2(CH2)pCOOR11, NH[(CH2)qCOOR11]2or NH2CH(COOR11)(CH2)rCOOR11where p, q and r is 1, 2 or 3 and R11represents lower alkyl, using the methods of peptide synthesis, to obtain the compounds of formula I, where X is SR1, NR1R2or1-C7-alkyl; Y is SR1, NR1R2or1-C7-alkyl; R1and R2defined in formula I; B is O or CH2; R3and R4represent hydrogen or together form a bond, and A represents C(O)NH(CH2)pCOOR11C(O)N[(CH2)qCOOR11]2or C(O)NHCH(COOR11)(CH2)rCOOR11where p, q and r is 1, 2 or 3 and R11represents lower alkyl; (and) deesterification NR1R2, SR1or1-C7-alkyl; Y is SR1, NR1R2or1-C7-alkyl; R1and R2, each independently, represents H or C1-C7-alkyl; R3and R4both represent hydrogen, or R3and R4together form a bond and A represents C(O)NH(CH2)pCOOH, C(O)N[(CH2)qCOOH]2or C(O)NHCH(COOH)(CH2)rCOOH, where p, q and r each independently equal to 1, 2 or 3;

Priority points:

04.07.1996 - PP.1, 2, 4, 5, and 7 - 17;

11.07.1995 - p. 3;

08.11.1995 - p. 6.

 

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< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxide, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

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< / BR>
where R is the specified value,

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< / BR>
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< / BR>
< / BR>
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< / BR>
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