New acyclic nucleoside phosphonate derivatives, their salts and method for preparing these compounds

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to acyclic nucleoside phosphonate derivatives of the formula (1): wherein means a simple or double bond; R1 means hydrogen atom; R2 and R3 mean hydrogen atom or (C1-C7)-alkyl; R7 and R8 mean hydrogen atom or (C1-C4)-alkyl; R4 and R5 mean hydrogen atom or (C1-C4)-alkyl possibly substituted with one or more halogen atoms, or -(CH2)m-OC(=O)-R6 wherein m means a whole number from 1 to 5; R6 means (C1-C7)-alkyl or 3-6-membered heterocycle comprising 1 or 2 heteroatoms taken among the group consisting of nitrogen (N) and oxygen (O) atoms; Y means -O-, -CH(Z)-, =C(Z)-, -N(Z)- wherein Z means hydrogen atom, hydroxy-group or halogen atom, or (C1-C7)-alkyl; Q (see the claim invention); its pharmaceutically acceptable salts or stereoisomers. Also, invention proposes methods for preparing compounds of the formula (1) and their using in treatment of hepatitis B or preparing a medicinal agent designated for this aim.

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

16 cl, 10 tbl, 87 ex

 

The present invention relates to acyclic nukleotidfosfatazu derivative represented by the following formula (1):

in which

represents a single bond or a double bond,

R1, R2, R3, R7and R8independently of one another represent hydrogen, halogen, hydroxy, amino, C1-C7-alkyl, C2-C6alkenyl,1-C5-alkylamino,1-C5-aminoalkyl or1-C5-alkoxy,

R4and R5independently of one another represent hydrogen, or represent With1-C4-alkyl, possibly substituted by one or more halogen, C1-C4-alkoxy, phenoxy,7-C10-funeralcare and C2-C5-acyloxy, or represent With1-C7-acyl, C6-C12-aryl or possibly substituted carbarnoyl, or represent -(CH2)m-OC(=O)-R6where m denotes an integer from 1 to 12 and R6represents a C1-C12-alkyl, C2-C7alkenyl, C1-C5-alkoxy, C1-C7-alkylamino, di(C1-C7-alkyl)amino, C3-C6-cycloalkyl, or a 3-6-membered heterocycle containing 1 or 2 heteroatoms selected from the group consisting of azo is a and oxygen

Y represents-O-, -S-, -CH(Z)-, =C(Z)-, -N(Z)-, =N-, -SiH(Z)-, or =Si(Z)-where Z represents hydrogen, hydroxy or halogen, or represents C1-C7-alkyl, C1-C5-alkoxy, allyl, hydroxy-C1-C7-alkyl, C1-C7-aminoalkyl or phenyl,

Q represents a group having the following formula:

where

X1X2X3and X4independently of one another represent hydrogen, amino, hydroxy or halogen, or represent With1-C7-alkyl, C1-C5-alkoxy, allyl, hydroxy-C1-C7-alkyl, phenyl or phenoxy, each of which may substituted by nitro or1-C5-alkoxy, or represent With6-C10-aaltio, which may substituted by nitro, amino, C1-C6-alkyl or C1-C4-alkoxy, or represent With6-C12-arylamino,1-C7-alkylamino, di(C1-C7-alkyl)amino, C3-C6-cyclooctylamino or structurewhere n denotes an integer of 1 or 2 and Y1represents O, CH2or N-R (R represents a C1-C7-alkyl or C6-C12-aryl), suitable as an antiviral agent (in particular, against hepatitis b virus), the pharmacist who Cesky acceptable salts, the stereoisomers and the method of production of these compounds.

Purine or pyrimidine derivatives exhibit anti-cancer and antiviral activity, and more than 10 types of compounds, including AZT, 3TC and ACV are already commercial products. In particular, since, as acyclic nukleotidfosfatazu derivatives showed potent antiviral activity, cidofovir became a commercial product as an antiviral agent, and many compounds, including RMAA, RMR, are currently undergoing clinical trials. However, the previously developed connections have been flawed from the point of view of toxicity or pharmaceutical activity, and therefore there is still a need to develop connections, not shown toxicity, and also has excellent activity. Previous studies on purine or pyrimidine derivative or acyclic nucleotidebinding derivatives, disclosed in the following publications: patents: U.S. 5817647; USA 5977061; USA 5886179; USA 5837871; USA 6069249; international publication WO99/09031; international publication WO96/09307; international publication WO95/22330; USA 5935946; USA 5877166; USA 5792756; International Journal of Antimicrobial Agents 12 (1999), 81-95; Nature 323 (1986), 464; Heterocycles 31 (1990), 1571; J.Med.Chem. 42 (1999), 2064; Pharmacology & Therapeutics 85 (2000), 251; Antiviral Chemistry & Chemtherapy 5 (1994), 57-63; Bioorganic & Medicinal Chemistry Letters 10 (2000), 2687-2690; Biochemical Pharmacology 60 (2000), 1907-1913; Antiviral Chemistry &Chemotherapy 8 (1997), 557-564; Antimicrobial Agent and Chemotherapy 42 (1999), 2885-2892.

The present invention is the development of compounds with excellent biological activity (pharmaceutical effect), as well as having lower toxicity than existing commercial acyclic nucleosidase or undergoing clinical trials. As a result, the researchers found that the above compound of formula (1), characterized by a unique chemical structure, has a strong pharmaceutical activity, and the obtained data allowed to complete the present invention.

Therefore, the present invention is the creation of the compounds of formula (1), its pharmaceutically acceptable salts or isomers, suitable as an antiviral agent.

Another objective of the present invention is to develop a method for obtaining compounds of formula (1).

In addition, the present invention is the creation of intermediate compounds that are mainly used for obtaining the compounds of formula (1).

The best way of carrying out the invention

The compound of formula (1) according to the present invention, as presented below, is an acyclic is nukleotidfosfatazu derivative, having a natural base, such as, for example, adenine, guanine, uracil, cytosine, thymine or derivatives thereof:

in which

represents a single bond or a double bond,

R1, R2, R3, R7and R8independently of one another represent hydrogen, halogen, hydroxy, amino, C1-C7-alkyl, C2-C6alkenyl,1-C5-alkylamino, C1-C5-aminoalkyl or1-C5-alkoxy,

R4and R5independently of one another represent hydrogen, or represent With1-C4-alkyl, possibly substituted by one or more halogen, C1-C4-alkoxy, phenoxy,7-C10-funeralcare and C2-C5-acyloxy, or represent With1-C7-acyl, C6-C12-aryl or possibly substituted carbarnoyl, or represent -(CH2)m-OC(=O)-R6where m denotes an integer from 1 to 12 and R6represents a C1-C12-alkyl, C2-C7alkenyl,1-C5-alkoxy, C1-C7-alkylamino, di(C1-C7-alkyl)amino, C3-C6-cycloalkyl, or a 3-6-membered heterocycle containing 1 or 2 heteroatoms selected from the group consisting of nitrogen and oxygen,

Y pre which represents an-O-, -S-, -CH(Z)-, =C(Z)-, -N(Z)-, =N-, -SiH(Z)-, or =Si(Z)-where Z represents hydrogen, hydroxy or halogen, or represents C1-C7-alkyl, C1-C5-alkoxy, allyl, hydroxy-C1-C7-alkyl, C1-C7-aminoalkyl or phenyl,

Q represents a group having the following formula:

where

X1X2X3and X4independently of one another represent hydrogen, amino, hydroxy or halogen, or represent With1-C7-alkyl, C1-C5-alkoxy, allyl, hydroxy-C1-C7-alkyl, phenyl or phenoxy, each of which may substituted by nitro or1-C5-alkoxy, or represent With6-C10-aaltio, which may substituted by nitro, amino, C1-C6-alkyl or C1-C4-alkoxy, or represent With6-C12-arylamino,1-C7-alkylamino, di(C1-C7-alkyl)amino, C3-C6-cyclooctylamino or structurewhere n denotes an integer of 1 or 2, and Y1represents O, CH2or N-R (R represents a C1-C7-alkyl or C6-C12-aryl).

Since the compound of the formula (1) according to the present invention can have one or more asymmetric atoms angle of the ode in the structure depending on the type of substituents, it can be in the form of individual enantiomers, diastereomers or mixtures thereof, including the racemate. In addition, when the structure has a double bond, the compound can be in the form of E-or Z-isomer. Thus, the present invention also includes all of these isomers and mixtures thereof.

The compound of formula (1) according to the present invention can form pharmaceutically acceptable salt.

Such salt includes a non-toxic additive salt of the acid containing pharmaceutically acceptable anion, for example, salts formed with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Hydrobromic acid, uudistoodetena acid, etc., salt, formed with organic carboxylic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, triperoxonane acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, etc. or a salt formed with sulfonic acids, such as methanesulfonate benzosulfimide, p-toluensulfonate, naphthalenesulfonate etc., particularly preferably sulfuric acid, methanesulfonate or halomonadaceae acid, etc.

Along with connected the eating of formula (1), manifesting powerful pharmaceutical activity, preferred compounds are such compounds where

represents a single bond,

R1, R2, R3, R7and R8independently of one another represent hydrogen, fluorine, hydroxy, C1-C7-alkyl, C2-C6alkenyl,1-C5-alkylamino,1-C5-aminoalkyl or1-C5-alkoxy,

R4and R5independently of one another represent hydrogen, or represent With1-C4-alkyl, possibly substituted by one or more substituents selected from the group consisting of fluorine,1-C4-alkoxy, phenoxy, or represent carbarnoyl, substituted C1-C5-alkyl, or represent -(CH2)m-OC(=O)-R6where m denotes an integer from 1 to 12 and R6represents a C1-C12-alkyl, C2-C7alkenyl,1-C5-alkoxy, C1-C7-alkylamino, di(C1-C7-alkyl)amino, C3-C6-cycloalkyl, or a 3-6-membered heterocycle containing 1 or 2 heteroatoms selected from the group consisting of nitrogen and oxygen,

Y represents-O-, -S-or-N(Z), where Z represents hydrogen, hydroxy, C1-C7-alkyl or hydroxy-C1 -C7-alkyl,

Q represents a group having the following formula:

where

X1represents hydrogen, amino, hydroxy or halogen, or represents C1-C7-alkyl, C1-C5-alkoxy, hydroxy-C1-C7-alkyl or phenoxy, each of which may substituted by nitro or1-C5-alkoxy, or represents C6-C10-aaltio, which may substituted by nitro, amino, C1-C6-alkyl or C1-C4-alkoxy, or represents C6-C12-arylamino,1-C7-alkylamino, di(C1-C7-alkyl)amino, C3-C6-cyclooctylamino or structurewhere n denotes an integer of 1 or 2 and Y1represents O, CH2or N-R (R represents a C1-C7-alkyl), and

X2X3and X4independently of one another represent hydrogen, amino, hydroxy, halogen, C1-C7-alkyl, C1-C5-alkoxy or C1-C7-alkylamino.

The most preferred compounds are such compounds in whichrepresents a single bond, R1, R3, R7and R8independently of one another represent hydrogen, R2predstavljaet a hydrogen or methyl, R4and R5independently from each other represent a tert-BUTYLCARBAMATE, isopropoxycarbonyloxymethyl or 2,2,2-triptorelin, Y represents-O-, Q is awhere X1represents hydrogen, hydroxy, ethoxy, 4-methoxyphenyl or 4 nitrophenylthio, and X2represents amino.

Typical examples of the compounds of formula (1) according to the present invention are described in the following tables 1-7.

Table 1A
Connection # StructureConnection # Structure
12
34
56
78

Table 1b
9 10
1112
1314
1516

Table 1c
1718
1920
2122
2324

Table 1d
2526
27 28
2930
3132

Table 1E
3334
3536
3738
3940

Table 1f
4142
4344

Table 2A
Connection # X1X2R4R5
45OHNH2CH2CF3CH2CF3
46ClNH2CH2CF3CH2CF3
47NH2NH2CH2CF3CH2CF3
48NH2HCH2CF3CH2CF3
49HNH2CH2CF3CH2CF3
50NH2CH2CF3CH2CF3
51NHC2H5NH2CH2CF3CH2CF3
52N(CH3)2NH2CH2CF3CH2CF3
53 NH2CH2CF3CH2CF3
54OCH3NH2CH2CF3CH2CF3
55CH3NH2CH2CF3CH2CF3
56C2H5NH2CH2CF3CH2CF3
57NH2CH2CF3CH2CF3
58NH2CH2CF3CH2CF3
59NH2CH2CF3CH2CF3

Table 2b
60NH2CH2CF3CH2CF3
61NH2CH2CF3 CH2CF3
62NH2CH2CF3CH2CF3
63NH2CH2CF3CH2CF3
64NH2CH2CF3CH2CF3
65NH2HH
66NH2HH
67NH2HH
68NH2
69HNH2

Table 2C
70H NH2
71HNH2
72HNH2
73HNH2
74HNH2
75HNH2
76HNH2
77HNH2
78HNH2
79 NH2

Table 2d
80HNH2
81HNH2
82HNH2
83OHNH2
84OHNH2
85NH2
86OHNH2
87NH2
88NH2
89NH2H

td align="center"> H
Table 2E
90NH2H
91NH2H
92NH2
93NH2
94NH2HH
95NH2HH
96NH2HH

Table 3A
Connection # X1X2R4R5
97OHNH2HH
98HNH2HH
99NH2HH
100NH2HH
101NH2HH
102NH2NH2HH
103NH2HHH
104OHH HH
105OHNH2
106HNH2
107NH2H

Table 3b
108NH2
109OHNH2
110HNH2
111NH2H
112NH2
113NH2
114NH2CH2CF3CH2CF3
115NH2CH2CF3CH2CF3
116NH2
117NH2
118NH2

Table 4
Connection # ZX1 X2R4R5
119HOHNH2HH
120HHNH2HH
121HNH2HHH
122CH3OHNH2HH
123CH3HNH2HH
124CH3NH2HHH
125C2H5NH2HHH
126CH3NH2H
127CH3NH2H
128C2H5HNH2
129C2H5HNH2

Table 5
Connection # ZX1X2R4R5
130NHENH2NN
131NNNH2NN
132NNH2NNn
133NHENH2
134NNH2N
135CH3HENH2NN
136CH 3NNH2NN
137CH3NH2NNN

Table 6
Connection # ZX1X2R4R5
138NHENH2NN
139NNNH2NN
140NNH2NNN
141NNH2NN
142CH3HENH2NN
143CH3NH2NNN
144CH3NNH2NN
145 3NH2N

td align="center"> HE
Table 7
Connection # X1X2R4R5
146HENH2NN
147NNH2NN
148NH2NNN
149HENH2
150NNH2
151NH2N
152NH2N
153NH2

Along with the compounds described in the above tables 1-7, in detail, the following preferred compounds:

({1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate acid (compound 1);

3-[({1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 2);

({1-[(2-amino-6-chloro-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate acid (compound 3);

3-[({1-[(2-amino-6-chloro-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 4);

({1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate acid (compound 5);

3-[({1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 6);

({1-[(2-amino-6-fluoro-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate acid (compound 7);

3-[({1-[(2-amino-6-fluoro-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 8);

({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate acid (compound 9);

3-[({1-(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ 5-Fofanov-1-yl, pivalate (compound 10);

({1-[(2-amino-6-cyclopropylamino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate acid (compound 11);

3-[({1-[(2-amino-6-cyclopropylamino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 12);

[(1-{[2-amino-6-(dimethylamino)-N-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate acid (compound 15);

3-{[(1-{[2-amino-6-(dimethylamino)-N-purine-9-yl]methyl}cyclopropyl)oxy]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 16);

[(1-{[2-amino-6-(isopropylamino)-9H-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate acid (compound 17);

3-{[(1-{[2-amino-6-(isopropylamino)-N-purine-9-yl]methyl}cyclopropyl)oxy]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 18);

({1-[(2,6-diamino-9H-purine-9-yl)-methyl]cyclopropyl}oxy)methylphosphonate acid (compound 19);

3-[({1-[(2,6-diamino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 20);

({1-[(2-amino-6-methoxy-9H-purine-9-yl)-methyl]cyclopropyl}oxy)methylphosphonate acid (compound 21);

3-[({1-[(2-amino-6-methoxy-N-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 2);

({1-[(2-amino-6-ethoxy-9H-purine-9-yl)-methyl]cyclopropyl}oxy)methylphosphonate acid (compound 23);

3-[({1-[(2-amino-6-ethoxy-N-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 24);

({1-[(2-amino-6-methyl-N-purine-9-yl)-methyl]cyclopropyl}oxy)methylphosphonate acid (compound 25);

3-[({1-[(2-amino-6-methyl-N-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 26);

[(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}cyclopropyl)oxy]methylphosphonate acid (compound 31);

8,8-dimethyl-3-{[(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}cyclopropyl)oxy]methyl}was 3.7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 32);

[(1-{[2-amino-6-(4-morpholinyl)-N-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate acid (compound 37);

3-{[(1-{[2-amino-6-(4-morpholinyl)-N-purine-9-yl]methyl}cyclopropyl)oxy]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 38);

bis(2,2,2-triptorelin)({1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 45);

bis(2,2,2-triptorelin)({1-[(2-amino-6-chloro-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 46);

bis(2,2,2-triptorelin)({1-[(2,6-diamino-N-purine-9-yl)methyl]cyclopropyl}is XI)methylphosphonate (compound 47);

bis(2,2,2-triptorelin)({1-[(6-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 48);

bis(2,2,2-triptorelin)({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 49);

bis(2,2,2-triptorelin)({1-[(2-amino-6-dimethylamino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 52);

bis(2,2,2-triptorelin)({1-[(2-amino-6-isopropylamino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 53);

bis(2,2,2-triptorelin)({1-[(2-amino-6-methoxy-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 54);

bis(2,2,2-triptorelin)[(1-{[2-amino-6-(4-morpholinyl)-N-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate (compound 58);

bis(2,2,2-triptorelin)[(1-{[2-amino-6-(phenylsulfanyl)-N-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate (compound 61);

bis(2,2,2-triptorelin){[1-({2-amino-6-[(4-were)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (compound 62);

bis(2,2,2-triptorelin){[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (compound 63);

bis(2,2,2-triptorelin){[1-({2-amino-6-[(4-nitrophenyl)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (compound 64);

[(1-{[2-amino-6-(phenylsulfanyl)-N-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate acid (compound 65);

{[1-({2-amino-6-[(4-were)sulfanyl]-N-purine-9-yl}IU the Il)cyclopropyl]oxy}methylphosphonate acid (compound 66);

3-({[1-({2-amino-6-[(4-were)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 68);

bis{[(tert-butoxycarbonyl)oxy]methyl}({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 69);

bis{[(isopropoxycarbonyl)oxy]methyl}({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 70);

bis{[(etoxycarbonyl)oxy]methyl}({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 71);

bis{[(isobutoxide)oxy]methyl}({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 72);

3-[({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-9-methyl-3,7-dioxo-2,4,6-trioxa-3λ5-popadic-1-yl 3-methylbutanoate (compound 74);

3-[({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8-methyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl 2-methylpropanoate (compound 78);

3-({[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 79);

3-[({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]was 3.7-dioxo-7-(1-pyrrolidinyl)-2,4,6-trioxo-3λ5-phospahate-1-yl 1-pyrrolidinecarboxylic (compound 80);

3-[({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methyl]was 3.7-dioxo--(1-piperidinyl)-2,4,6-trioxo-3λ 5-phospahate-1-yl 1-piperidinecarboxylate (compound 81);

3-[({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-7-(4-morpholinyl)was 3.7-dioxo-2,4,6-trioxa-3λ5-phospahate-1-yl 4-morpholinylcarbonyl (compound 82);

bis{[(tert-butoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate (compound 83);

bis{[(isopropoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate (compound 84);

bis{[(isopropoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (compound 85);

3-[({1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-7-cyclopentyl-3,7-dioxo-2,4,6-trioxa-3λ5-phospahate-1-Il cyclopentanecarboxylate (compound 86);

3-({[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 87);

bis{[(isopropoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (compound 88);

bis{[(isopropoxycarbonyl)oxy]methyl}({1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 89);

3-[({1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl)oxy)methyl]-9-methyl-3,7-dioxo-2,4,6-trioxa-3λ5-octadec-1-yl 3-methylbutanoate (compound 90);

3-[({1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-7-cyclopentyl-3,7-dioxo-2,4,6-trioxa-3λ5-phospahate-1-Il cyclopentanecarboxylate (compound 91);

bis{[(tert-butoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (compound 92);

bis{[(tert-butoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (compound 93);

{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate acid (compound 95);

{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate acid (compound 96);

({1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate acid (compound 97);

({1-[(2-amino-9H-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate acid (compound 98);

{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate acid (compound 99);

{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-N-purine-9-yl}-methyl)-2-methylcyclopropyl]oxy}methylphosphonate acid (compound 100);

{[1-({2-amino-[6-(4-were)sulfanyl]-N-purine-9-yl}-methyl)-2-methylcyclopropyl]oxy}methylphosphonate acid (compound 101);

({1-[(2,6-diamino-N-purine-9-yl)methyl]-2-methylcyclopropyl the yl}oxy)methylphosphonate acid (compound 102);

({1-[(6-amino-N-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate acid (compound 103);

3-[({1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl]-8,8-dimethyl-Z,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 105);

3-[({1-[(2-amino-9H-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 106);

3-[({1-[(6-amino-N-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 107);

3-({[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-N-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 108);

bis{[(isopropoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purine-9-yl]methyl}-2-methylcyclopropyl)oxy]methylphosphonate (compound 109);

bis{[(isopropoxycarbonyl)oxy]methyl}({1-[(2-amino-N-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate (compound 110);

bis{[(isopropoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-N-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (compound 112);

bis{[(tert-butoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (compound 113);

bis(2,2,2-triporati what){[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (compound 114);

bis(2,2,2-triptorelin){[1-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (compound 115);

bis{[(tert-butoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-N-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (compound 116);

bis{[(isopropoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-N-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (compound 117);

3-({[1-({2-amino-6-[(4-nitrophenyl)sulfanyl]-N-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 118);

({1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]cyclopropyl}amino)methylphosphonous acid (compound 119);

({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}amino)methylphosphonous acid (compound 120);

({1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}amino)methylphosphonous acid (compound 121);

[{1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]cyclopropyl}(methyl)amino]methylphosphonous acid (compound 122);

[{1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}(ethyl)amino]methylphosphonous acid (compound 125);

3-{[{(1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}(methyl)amino]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 126);

bis{[(isopropoxycarbonyl)oxy]methyl}[{1-[(6-amino-N-purine-9-yl)meth is l]cyclopropyl}(methyl)amino}methylphosphonate (compound 127);

3-{[{1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}(ethyl)amino]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 129);

[(E)-2-{1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]cyclopropyl}vinylphosphonic acid (compound 130);

(E)-2-{1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}vinylphosphonic acid (compound 131);

(E)-2-{1-[(6-amino-N-purine-9-yl)methyl]cyclopropyl}vinylphosphonic acid (compound 132);

3-({(E)-2-{1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]cyclopropyl}vinyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 133);

3-((E}-2-[1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}vinyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 134);

(E}-2-{1-[(6-amino-N-purine-9-yl)methyl]cyclopropyl}-1-propenylboronic acid (compound 137);

2-{1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]cyclopropyl}ethylphosphonate acid (compound 138);

2-{1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}ethylphosphonate acid (compound 139);

2-{1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}ethylphosphonate acid (compound 140);

2-[1-({2-amino-6-[(4-were)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]ethylphosphonate acid (compound 141);

2-{1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]cyclopropyl}propylphosphonic acid (compound 142);

2-{1-[(6-amino-N-purine-9-yl)methyl]C is chlorophil}propylphosphonic acid (compound 143);

2-{1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}propylphosphonic acid (compound 144);

3-(-2-{1-[(6-amino-N-purine-9-yl)methyl]cyclopropyl}propyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pialat(compound 145);

({1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methylphosphonate acid (compound 146);

({1-[(2-amino-9H-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methylphosphonate acid (compound 147);

({1-[(6-amino-9H-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methylphosphonate acid (compound 148);

3-[({1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 149);

3-[({1-[(2-amino-N-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 150);

3-[({1-[(6-amino-9H-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 151);

bis{[(isopropoxycarbonyl)oxy]methyl)({1-[(6-amino-9H-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methylphosphonate (compound 152); and

bis{[(isopropoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purine-9-yl]methyl}-2,2-dimethylcyclopropane)oxy]methylphosphonate (compound 153).

The compound of formula (1) according to this the mu invention can be obtained by way disclosed below, and thus, the present invention is to provide such a method of obtaining. However, the conditions under which the process is carried out, such as, for example, types of reagents, solvents, bases, amounts of reagents used and so on, are not limited to those conditions which are disclosed below. The connection according to the present invention can also be simply obtained by the combinability of different synthetic methods described in the present description or known in this field, and this combination can easily make a qualified specialist in this field.

The compound of formula (1) according to the present invention can be obtained through the

(a) interaction of the compounds represented by the following formula (2):

in which R1, R2, R3, R4, R5, R7, R8and Y are as previously described, and L represents a removable group, preferably methanesulfonate, p-toluensulfonate or halogen, with a compound represented by the following formula (3):

in which Q is a group defined previously, to obtain the compounds of formula (1),

(b) interaction of the compounds represented by the following formula (a):

in which R1, R2, R3, R7, R8, Y and L are as previously described, and R9and R10independently from each other represent a possibly substituted alkyl, with a compound of the formula (3) to obtain the compounds represented by the following formula (10):

in which R1, R2, R3, R7, R8, Y, Q, R9and R10are as previously described, and the obtained compound of the formula (10) hydrolyzing in the presence of a Lewis acid to obtain compounds represented by the following formula (1A):

in which R1, R2, R3, R7, R8, Y and Q are as previously described, and, if necessary,

(C) in the compound of formula (1A) to introduce the group R4'and R5'to obtain compounds represented by the following formula (1b):

in which R1, R2, R3, R7, R8, Y and Q are as previously described, and R4'and R5'are R4and R5with the exception of hydrogen, respectively, or the next, thus obtained compound is subjected to the usual transformations (see U.S. patent 6037335, 5935946 and 5792756).

In the above-described embodiments (a)-(C) of the method of obtaining the soybean is inane formulas (1) the reaction can be performed in a solvent and in the presence of a base. The solvent may be used one or more solvents selected from the group consisting of dimethylformamide, dichloromethane, tetrahydrofuran, chloroform, 1-methyl-2-pyrrolidinone and dimethylacetamide, and as a base may be used one or more bases selected from the group consisting of sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, tert-butoxide potassium bis(trimethylsilyl)amide, sodium amide, cesium carbonate and bis(trimethylsilyl)amide potassium. The Lewis acid, which can be used in variant (b) of the method includes trimethylsilylethynyl. In addition, option (C) of the method for introduction of the group R4'and R5'in the compound of formula (1A) the specified connection is subjected to interaction with alkylhalogenide in the presence of a base with the formation of a simple ester or treated with thionyl chloride, oxalylamino or with phosphorus pentachloride to obtain dichlorophosphate derivative, which is then subjected to interaction with a suitable alcohol or amine with the aim of obtaining the desired connection.

Phosphonate compound of the formula (2)used as starting material in the above way, is in itself a new connection. Therefore, another objective of the present invention is to create is of the compounds of formula (2).

The compound of the formula (2), where Y means O, R1means hydrogen and each of R2, R3, R7and R8means hydrogen or alkyl, i.e. a compound of the following formula (8) can be obtained by (i) interaction of ethylglycol, alcohol group which is protected, represented by the following formula (4):

in which P1is a blocking alcohol group, preferably a benzyl (Bn), tetrahydropyranyl (TNR), tert-butyldiphenylsilyl (TBDPS) or tert-butyldimethylsilyl (TBDMS), with ethylmagnesium [C2H5MgBr] or the corresponding alkalinisation or alkalinisation in the presence of tetraisopropoxide titanium [Ti(OiPr)4], and (ii) subsequent interaction obtained cyclopropanol, represented by the following formula (5):

in which P1is the group described previously, and each of R2', R3', R7'and R8'groups represents hydrogen or alkyl, in the presence of a base with a compound represented by the following formula (6) with the formation of simple broadcast:

in which L, R4and R5are such as previously described, to obtain the phosphate compounds of the formula (7):

in which P 1, R2', R3', R7', R8', R4and R5are such as previously described, and (iii) with subsequent removal of the blocking alcohol group of the obtained compound of the formula (7) and the introduction of the deleted group (L) to obtain the compounds represented by the following formula (8):

in which L, R2', R3', R7', R8', R4and R5are as described previously.

The method of obtaining the simplest compounds of the formula (8) (i.e. all R2', R3', R7'and R8'are hydrogens) are briefly described in the following reaction scheme 1:

The reaction scheme 1

Concerning the specific reaction conditions of the above method, you can refer to the following preparations and examples.

In addition, the compound of the formula (2), where Y represents-CH2-and each of R1, R2, R3, R7and R8means hydrogen, i.e. the compound of the following formula (11):

in which L, R4and R5are such as previously described, can be obtained by the method described in the following reaction scheme 2:

The reaction scheme 2

The reaction scheme 2 are briefly described below. (i) According to a known method (see JOC, 1975, Vol. 40, 2969-2970) dialkylamino the antibody is subjected to interaction with dehalogenation obtaining malonic acid, where cyclopropyl group introduced in position 2 of this acid. (ii) Malonic acid restores obtaining diol, one hydroxyl group which protects a suitable protecting group (P1is the same as described above). Then the other hydroxyl group is oxidized to aldehyde groups. (iii) the Obtained aldehyde compound is subjected to interaction with tetraalkylammonium to give the desired phosphonate compounds. (iv) thus Obtained phosphonate compound restores obtaining compounds having no unsaturated bond, blocking the alcohol group (P1) remove and delete the group (L) is injected with obtaining the compounds of formula (11).

In addition, the compound of the formula (2), where Y represents-N(CH3)- and each of R1, R2, R3, R7and R8means hydrogen, i.e. the compound of the following formula (12):

in which L, R4and R5are such as previously described, can be obtained by the method described in the following reaction scheme 3:

The reaction scheme 3

The reaction scheme 3 are briefly described below. (i) Diethyl 1,1-cyclopropanedicarboxylic selectively hydrolyzing with getting monocarboxylic acid. (ii) the Amino group is introduced into monocarboxylic acid according to the known reaction of kurzius (see: S.Linke, G.T.Tisue and W.Lowowski, SOC. 1967, 89, 6308). (iii) protect the Amino group of a suitable protecting group [P2may be a carbamate or different benzyl protective group, or alkyl group (methyl, ethyl, etc.)]. (iv) Located opposite the ester group is reduced to hydroxyl groups, which then protects (R1is the same as described earlier). (v) Blocked the protective groups of the compound is subjected to interaction with methyliodide in the presence of sodium hydride with the aim of introducing a methyl group into the amino group. (vi) Blocking the amino group is removed and the compound obtained is subjected to interaction with dialkylammonium to give the desired phosphonate compounds. (vii) Blocking spirograph (R1) are removed from the thus obtained phosphonate compounds and then enter a group to delete (L) to obtain the compounds of formula (12).

Concerning the specific reaction conditions of the above methods, you can refer to the following preparations and examples.

Upon completion of the reaction, the resulting product can then be separated and cleaned by conventional means, such as, for example, chromatography, recrystallization, etc.

The compound of formula (1) according to the present invention can be effectively used as an antiviral agent. So the task is altoadige of the invention is a composition for the treatment of viral diseases which includes a compound of formula (1) as the active ingredient, its pharmaceutically acceptable salt, hydrate, MES or isomer together with a pharmaceutically acceptable carrier.

When using the active compounds according to the present invention for clinical purposes it is preferable to introduce it in number, ranging usually from 0.1 to 10,000 mg, preferably from 0.5 to 100 mg per kg of body weight per day. The total daily dose may be entered in one step or in several steps. However, some imposed by the patient dose can vary depending on the specific connection, body weight, sex or sanitary conditions of the patient, diet, time and route of administration, rate of excretion, the ratio of the agent in the mixture, the severity of the disease that is being treated, etc.

The connection according to the present invention can be introduced in the form of injections or oral medication.

Injectable preparations, for example, sterile aqueous or oily suspension for injection, can be obtained in a known manner using a suitable dispersing agent, wetting agent or suspendisse agent. Solvents that can be used to prepare drugs for injection include water, liquid ringer's solution and isotonic NaCl solution, and the moreover, as solvent or suspendida environment can be used sterilized non-volatile oil. Any nelinumeroisia non-volatile oil, including mono-, diglycerides may be used for this purpose. Fatty acid such as oleic acid, may also be used to prepare drugs for injection.

As a solid preparation for oral administration may be referred to capsules, tablets, pills, powders and granules, etc., preferably capsules and tablets. It is also desirable that pills and tablets were prepared in the form of a coated intersolubility shell of the drug. Solid preparations can be prepared by mixing the active compounds of the formula (1) according to the present invention, at least one carrier selected from the group consisting of inactive diluents such as sucrose, lactose, starch, etc., lubricating agents such as magnesium stearate, dezintegriruetsja agent and a binding agent.

When the connection according to the present invention is clinically used to achieve the desired antiviral effect, an active compound of formula (1) can be entered with one or more substances selected from the known anticancer or antiviral agents. As anticancer or antiviral Agay is tov, which can be introduced together with the connection according to the present invention, may be mentioned 5-fluorouracil, cisplatin, doxorubicin, Taxol, gemcitabine, lamivudine, etc.

However, preparations containing the compound according to the present invention is not limited to the above drugs, but can contain any of the substances used for the treatment or prevention of cancer or viral diseases.

The present invention will be described in more detail in the following examples and experiments. However, it should be understood that these examples and experiments are intended to illustrate the present invention, but they in no way limit the scope of the present invention.

Example obtain 1

Synthesis of 1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropanol

According to the description in the link (see: Syn. Lett. 07, 1053-1054 (1999) is listed in the title compound was prepared as follows. 12 g (35 mmol) of Ethyl 2-{[tert-butyl(diphenyl)silyl]oxy}acetate was dissolved in 200 ml of tetrahydrofuran (THF) and the solution was added 2.2 ml of cytotecmisoprostol. To the mixture was slowly added 29,2 ml ethylacetamide (3.0 M in THF) and the reaction solution was stirred for 12 hours at room temperature. To stop the reaction was added to 20 ml of a saturated solution of ammonium chloride. Approximately 150 ml tetrahydrofur the Ana (THF), used as solvent were removed by distillation under reduced pressure and the reaction mixture was extracted with twice 200 ml of ethyl acetate. An ethyl acetate extract was distilled under reduced pressure to obtain 11.4 g (yield 100%) specified the title compound as a white solid.

1H NMR (CDCl3) (0,44 (kV, 2H), 0,78 (kV, 2H), 1,09 (s, N), to 3.67 (s, 2H), 7,41 (m, 6N), of 7.70 (m, 4H)

ESI: 344 (M+NH4)+C20H26O2Si

Example of getting 2

Synthesis aminobutiramida {[1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]oxy}methylphosphonate

The compound (6.5 g)synthesized according to the example of obtaining 1, was dissolved in 10 ml of dimethylformamide (DMF), to the solution was added 32 ml of tert-butoxide lithium (1.0 M in THF)and the resulting mixture was stirred for 10 minutes. To the mixture was added 7.0 g diisopropylfluorophosphate and then the temperature was raised to 40°and the mixture was stirred for 4 hours. Dimethylformamide (DMF) was removed by distillation under reduced pressure, to the residue was added 40 ml of a saturated solution of ammonium chloride and then extracted with ethyl acetate. An ethyl acetate extract was distilled under reduced pressure and the residue was purified column chromatography on silica gel (eluent: a mixture of ethyl acetate/n-hexane=1/1, vol/about.) to obtain 6.8 g (yield 70%) specified in the connection header.

sup> 1H NMR (CDCl3) (0,53 (m, 2H), 0.88 to (m, 2H), 1,07 (s, N), of 1.29 (t, N), of 3.78 (s, 2H), 3,98 (d, 6N), and 4.75 (m, 2H), 7,40 (m, 6N), to 7.67 (m, 4H).

Example of getting 3

Synthesis aminobutiramida{1-[(hydroxymethyl)cyclopropyl]-oxy}methylphosphonate

Connection (8,3 g)synthesized according to example getting 2, was dissolved in 100 ml of methanol, to the solution was added 3.1 g ammonium fluoride and the resulting mixture was heated under reflux for 2 hours. Upon completion of the reaction, the methanol was removed by distillation under reduced pressure and the residue was purified column chromatography on silica gel (eluent: a mixture of dichloromethane/methanol=20/1, vol./about.) to obtain 3.6 g (yield 82%) specified in the connection header.

1H NMR (CDCl3) (0,60 (t, 2H), 0,87 (t, 2H), 1.28 (in d, N), 2,5 (ush. s, 1H), the 3.65 (s, 2H), 3,83 (d, 2H), 4,82 (m, 2H)

ESI: 267 (M+1)+C11H23O4P

Example 4

Synthesis of {1-[(diisopropoxyphosphoryl)methoxy]-cyclopropyl}methylmethanesulfonate

The compound (1.5 g)synthesized according to example getting 3, was dissolved in 50 ml of dichloromethane, to the solution was added to 0.85 ml of triethylamine and 0.84 g of methanesulfonamide and the resulting mixture was stirred for 30 minutes at room temperature. To stop the reaction was added a saturated solution of ammonium chloride. The product was extracted with dichloromethane and the dichloromethane extract was concentrated n the means of distillation under reduced pressure. The residue was purified column chromatography on silica gel (eluent: a mixture of ethyl acetate/hexane=1/1, vol/about.) to obtain 1.63 g (yield 81%) specified in the connection header.

1H NMR (CDCl3) (0,77 (m, 2H), 1,09 (m, 2H), 1,32 (m, N), 3,10 (s, 3H), 3,82 (m, 2H), 4,33 (s, 2H), 4,71 (m, 2H)

Example of getting 5

Synthesis aminobutiramida({1-[(6-amino-N-purine-9-yl)methyl]-cyclopropyl}oxy)methylphosphonate

The compound (430 mg)synthesized according to example 4, was dissolved in 18 ml of dimethylformamide, to the solution was added 57.6 mg (60% pure) of sodium hydride and 162 mg of adenine and the resulting mixture was heated under reflux over 4 hours. To stop the reaction was added a saturated solution of ammonium chloride. The product was extracted with ethyl acetate and an ethyl acetate extract was distilled under reduced pressure. The residue was purified column chromatography on silica gel (eluent: a mixture of dichloromethane/methanol=20/1, vol./about.) to obtain 201 mg (yield 44%) specified in the connection header.

1H NMR (CDCl3) (0,86 (t, 2H), 1,01 (t, 2H), 1,24 (d, 6N), of 1.34 (d, 6N), 3,86 (d, 2H), 4,34 (s, 2H), 4,71 (m, 2H), 5,97 (ush. s, 2H), 8,32 (s, 1H), 8,58 (s, 1H)

ESI: 384 (M+1)+C16H25N5O4P

An example of obtaining 6

Synthesis aminobutiramida({1-[(2-amino-6-chloro-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate

The compound (1.64 g)synthesized according to example 4, was dissolved in 70 ml of dimethylformamide, to the solution was added 219 mg (60% pure) of sodium hydride and 773 mg of 2-amino-6-chloro-N-purine and the resulting reaction mixture was stirred for 4 hours while heating up to a temperature of 80°C. To stop the reaction was added a saturated solution of ammonium chloride. The product was extracted with ethyl acetate and an ethyl acetate extract was distilled under reduced pressure. The residue was purified column chromatography on silica gel (eluent: a mixture of dichloromethane/methanol=20/1, vol./about.) obtaining 765 mg (yield 40%) specified in the connection header.

1H NMR (CDCl3) (0,80 (t, 2H), 1,02 (t, 2H), 1.27mm (d, 6N), of 1.28 (d, 6N), 3,82 (d, 2H), is 4.21 (s, 2H), and 4.68 (m, 2H), 5,13 (ush. s, 2H), 8,15 (s, 1H)

ESI: 418 (M+1)+C16H25ClN5O4P

Example of getting 7

Synthesis aminobutiramida[(1{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}cyclopropyl)oxy]methylphosphonate

Compound (118 mg)synthesized according to example 4, and thymine were subjected to interaction according to the same method described in the example of a 6, which led to headline the connection number of 26 mg (yield 21%).

1H NMR (CDCl3) (0,82 (t, 2H), 0,95 (t, 2H), 1,31 (m, N), with 1.92 (s, 3H), 3,74 (d, 2H), with 3.89 (s, 2H), 4,71 (m, 2H), 7.62mm (who, 1H), 9.15, with (s, 1H)

ESI: 375 (M+1)+C16H27N2O6P

Example obtain 8

Synthesis of 1-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-methylcyclopropane

According to the description in the message (see: Syn. Lett. 07, 1053-1054, 1999) is listed in the title compound was prepared as follows: 50 g (146 mmol) of ethyl 2-{[tert-butyl(diphenyl)silyl]oxy}acetate was dissolved in 700 ml of tetrahydrofuran (THF) and added 30,0 ml cytotecmisoprostol. To the mixture was slowly added to 290 ml of propylaniline (2.0 M in THF) at -10°and the reaction solution was stirred for 12 hours at room temperature. To stop the reaction was added to 200 ml of a saturated solution of ammonium chloride. Tetrahydrofuran (THF)used as solvent were removed by distillation under reduced pressure and the reaction mixture was extracted with twice 200 ml of n-hexane. n-Hexane extract was distilled under reduced pressure and was purified column chromatography on silica gel to obtain 42 g specified in the connection header.

1H NMR (CDCl3) (0,06 (t, 1H), 0,88 (DD, 2H), of 0.97 (d, 3H), of 1.09 (s, N), 1,1 (m, 1H), 2,78 (s, 1H), 3,70 (d, 1H), 3,86 (d, 1H), 7,41 (m, 6N), of 7.70 (m, 4H)

ESI: 363 (M+Na)+C21H28O2Si

Example of getting 9

Synthesis aminobutiramida {[1-({[tert-butyl(diphenyl)silyl]oxy}-methyl)-2-methylcyclopropyl]oxy}metalf Sonata

Connection (4,2 g)synthesized according to example get 8 used hereinafter for the reaction carried out in the same manner as described in example getting 2 that resulted in the receipt of 3.3 grams specified in the connection header.

1H NMR (CDCl3) (0,04 (t, 1H), 0,96 (DD, 1H), 0,97 (d, 3H), of 1.05 (m, 1H), 1.06 a (s, N), of 1.23 (t, N), and 3.72 (d, 1H), 3,95 (d, 2H), 3,98 (d, 1H), 4.75 in (m, 2H), 7,40 (m, 6N), to 7.68 (m, 4H)

Example 10

Synthesis aminobutiramida{1-[(hydroxymethyl)-2-methylcyclopropyl]oxy}methylphosphonate

Connection (3.3 grams), synthesized according to example receiving 9, used further for the reaction carried out in the same way, which is described in the example of a 3, which led to headline the connection in the amount of 1.7 g

1H NMR (CDCl3) (0,03 (t, 1H), 0,95 (DD, 1H), 0,96 (m, 1H), 1,11 (d, 3H), of 1.35 (d, N), 2,17 (ush. s, 1H), 3,80 (d, 2H), 3.96 points (d, 1H), 4,80 (m, 2H)

ESI: 303 (M+Na)+C12H22O5P

Example of getting 11

Synthesis aminobutiramida({1-[(6-amino-N-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate

The compound (1.5 g)synthesized according to example 10, was dissolved in 50 ml of dichloromethane, was added to 0.85 ml of triethylamine and 0.84 g of methanesulfonamide and the resulting mixture was stirred for 30 minutes is at room temperature. To stop the reaction was added a saturated solution of ammonium chloride. The product was extracted with dichloromethane and the dichloromethane extract was concentrated by distillation under reduced pressure. The residue was used in next reaction without any purification.

1H NMR (CDCl3) (0,42 (m, 1H), 1,12 (d, 3H), 1,25 (m, 1H), 1,32 (m, N), of 1.33 (m, 1H), 3,10 (s, 3H), 3,76 (m, 2H), or 4.31 (d, 1H), 4,71 (d, 1H), amounts to 4.76 (m, 2H)

Thus obtained the methanesulfonate (430 mg) was dissolved in 18 ml of dimethylformamide was added and 57.6 mg (60% pure) of sodium hydride and 162 mg of adenine. The reaction mixture was heated under reflux over 4 hours. To stop the reaction was added a saturated solution of ammonium chloride. The product was extracted with ethyl acetate and an ethyl acetate extract was concentrated by distillation under reduced pressure. The residue was purified column chromatography on silica gel (eluent: a mixture of dichloromethane/methanol=20/1, vol./about.) to obtain 201 mg (yield 44%) specified in the connection header.

1H NMR (CDCl3) (0,53 (t, 1H), 1,13 (d, 3H)and 1.15 (m, 1H), 1,30 (m, N), of 1.41 (m, 1H), 1,85 (ush. s, 2H), 3,81 (m, 2H), 4,43 (m, 2H), 4,70 (m, 2H), 5,65 (ush. s, 2H), compared to 8.26 (s, 1H), 8.34 per (s, 1H)

ESI: 398 (M+1)+C17H28N5O4P

Example 12

Synthesis aminobutiramida({1-[(2-amino-6-chloro-N-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate

The compound synthesized according to example 10, was used further for the reaction carried out in the same manner as described in example receiving 11, except that 6-chloroguanine (2-amino-6-chloro-N-purine) was used in place of adenine with obtaining specified in the connection header.

1H NMR (CDCl3) (0,47 (t, J=6,4 Hz, 1H), 1,12 (m, 4H), 1,24 (DD, J=2,8 Hz, 6.4 Hz, 6N), of 1.28 (t, J=6.0 Hz, 6N), to 1.38 (m, 1H), 3,80 (m, 2H), 4,28 (m, 2H), and 4.68 (m, 2H), 5,13 (ush. s, 2H), 8,15 (s, 1H)

ESI: 432 (M+1)+C17H27ClN5O4P

Example of getting 13

Synthesis aminobutiramida[(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}-2-methylcyclopropyl)oxy]methylphosphonate

The compound synthesized according to example 10, was used further for the reaction carried out in the same manner as described in example receiving 11, except that thymine was used instead of adenine, obtaining specified in the connection header.

1H NMR (CDCl3) (0,48 (t, 1H), 1,10 (m, 4H), 1,24 (DD, 6N), of 1.28 (t, J=6N), to 1.38 (m, 1H), 1,92 (s, 3H), 3,80 (m, 2H), 4,28 (m, 2H), and 4.68 (m, 2H), 7.62mm (s, 1H), 9.15, with (s, 1H)

ESI: 389 (M+1)+C17H29N2O6P

Example of getting 14

Synthesis of 1-(etoxycarbonyl)cyclopropanecarbonyl acid

Diethyl 1,1-cyclopropanedicarboxylic (20g) hydrolyzed in 1N NaOH (107 ml) and ethanol (220 ml) for 16 hours and the ethanol was removed by distillation under reduced pressure. Residual starting material was removed using ethyl acetate, and the aqueous layer was acidified using 1N HCl. The reaction mixture was extracted with ethyl acetate and distilled under reduced pressure. The residue was purified on a column of silica gel and got mentioned in the title compound with a yield of 94%.

1H NMR (CDCl3) (of 1.06 (t, 3H), of 1.53 (m, 2H), 1,62 (m, 2H), is 4.21 (q, 2H)

ESI: 159 (M+1)+C7H10O4

Example get 15

Synthesis of ethyl 1-{[(benzyloxy)carbonyl]amino}of cyclopropanecarboxylate

Carboxylic acid (16 g)synthesized according to example receiving 14, was dissolved in dichloromethane, was added dropwise to 10.8 ml oxalicacid and 2 drops of dimethylformamide. The reaction mixture was stirred at room temperature for 3 hours and distilled under reduced pressure to obtain etoxycarbonyl 1,1-cyclopropanecarbonitrile. The specified connection, the crude was dissolved in 30 ml of dimethylformamide and the resulting solution was cooled water with ice. Then added 36 g NaN3and the interaction was carried out at room temperature for 3 hours. The reaction solution was extracted with 100 ml of water and 200 ml of diethyl ether and the ether extract was concentrated to obtain crude compound which was purified on a column of silica gel to obtain azide compounds

1H NMR (CDCl3) (of 1.28 (t, 3H), and 1.54 (m, 4H), 4,19 (kV, 2N)

To the thus obtained azide compound (13 g) was added dropwise 11 ml of benzyl alcohol and the reaction mixture was heated to a temperature of 100°in which the reactants are vigorously engaged with each other with the formation of gas. The reaction mixture was heated at 100°C for a further 1 hour, cooled to room temperature and distilled under reduced pressure to remove benzyl alcohol. The residue was purified on a column of silica gel with obtaining specified in the connection header.

1H NMR (CDCl3) (1,19 (m, 5H), and 1.54 (m, 2H), 4,11 (m, 2H), 5,15 (ush. s, 2H), 7,32 (m, 5H)

Example 16

Synthesis of benzyl 1-{[tert-butyl(divinycell)oxy]methylcyclopropyl}(methyl)carbamate

Carboxylate (13,2 g)synthesized according to example getting 15, was dissolved in diethyl ether, the solution slowly dropwise added 1.3 g LiBH4.The reaction mixture was stirred at room temperature for 16 hours and was added dropwise 50 ml of methanol and 5 ml of 1N HCl. The reaction mixture was stirred for 2 hours, the precipitate was removed with filter operating under vacuum, and the solvent of the filtrate was removed by distillation under reduced pressure. The residue was purified on a column of silica gel with obtaining b is nil 1-(hydroxymethyl)cyclopropylamine.

The specified connection (9.3 g) was dissolved in dichloromethane and properly added to 4.2 g of imidazole and 13.5 ml of tert-butyldiphenylsilyl. The reaction mixture was stirred at room temperature for 4 hours and the solvent was removed by distillation under reduced pressure. The residue was purified on a column of silica gel to obtain benzyl 1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropanecarboxamide.

1H NMR (CDCl3) (0,71-1,19 (m, 4H), 1.04 million (s, N), 3,68 (ush. s, 2H), 5,04 (s, 2H), 7,25 was 7.45 (m, 11N), a 7.62 (d, 4H)

The resulting carbamate (5.5 g) was dissolved in THF was added dropwise 3.5 ml of methyliodide (MeJ) and then added 1 g NaH. The reaction mixture was stirred at room temperature for 4 hours and then was extracted with 100 ml diethyl ether and 100 ml of water. Extract diethyl ether was concentrated by distillation under reduced pressure and the residue was purified on a column of silica gel with obtaining specified in the connection header.

1H NMR (CDCl3) (0,78-0,84 (m, 4H), of 1.03 (s, N), 3,03 (s, 3H), 3,55-of 3.80 (m, 2H), 5,10 (s, 2H), 7,24 was 7.45 (m, 11N), to 7.61 (m, 4H)

Example of getting 17

Synthesis aminobutiramida [1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl)(methyl)amino]methyl phosphonate

Carbamate (1.0 g)synthesized according to example 16, was dissolved in ethanol, dobavlyali mg 10%Pd/C and the reaction mixture was subjected to hydrogenation in a hydrogen atmosphere. Upon completion of the reaction the solvent was removed by distillation under reduced pressure. The residue was purified on a column of silica gel to obtain 1-({[tert-butyl(diphenyl)silyl]oxy}methyl)-N-methylcyclopropane.

1H NMR (CDCl3) (0,36 (m, 2H), 0,65 (m, 2H), of 1.05 (s, N), a 2.36 (s, 3H), of 3.57 (s, 2H), 7,37 was 7.45 (m, 11N), 7,66 (d, 4H)

Thus obtained methylcyclopropane (1.0 g) was dissolved in dichloromethane, to the solution was added dropwise to 1.03 ml diisopropylethylamine and 1.3 ml (diisopropoxyphosphoryl)methyltrichlorosilane. The reaction was carried out with stirring at room temperature for 4 hours and then the reaction mixture was extracted with 100 ml diethyl ether and 100 ml of water. The solvent of the ether extract was removed by distillation under reduced pressure and the residue was purified on a column of silica gel with obtaining specified in the connection header.

1H NMR (CDCl3) (0,42 (m, 2H), 0.69 (m, 2H), 1.04 million (s, N), 1,25 (d, 6N), of 1.30 (d, 6N), 2,62 (s, 3H), of 3.25 (d, 2H), to 3.64 (s, 2H), and 4.68 (m, 2H), 7,39 (m, 6N), the 7.65 (d, 4H)

Example of getting 18

Synthesis aminobutiramida(1-{[(6-amino-N-purine-9-yl)methyl]cyclopropyl}(methyl)amino)methylphosphonate

Compound (0.32 g)synthesized according to example receiving 17, was dissolved in methanol and was added dropwise to 1.5 g of ammonium fluoride. The reaction was carried out under stirring PR is 60° C for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified on a column of silica gel to obtain metilaminopropionitrila 1,1-cyclopropanation alcohol.

1H NMR (CDCl3) (0,56 (m, 2H), 0,73 (m, 2H), 1,31 (m, N), of 2.56 (s, 3H), 3,11 (d, 2H), 3,55 (s, 2H), 4,70 (m, 2H)

Synthesized thus the connection is then used for the reaction carried out in the same manner as described in examples 4 and 5, which led to headline the connection.

1H NMR (CDCl3) (0,78 (m, 2H), 0,86 (m, 2H), 1,25 (m, N), to 2.35 (s, 3H), 4,10 (s, 2H), and 4.68 (m, 2H), 5,13 (m, 2H), 8,32 (s, 1H), 8,58 (s, 1H)

ESI: 397 (M+1)+C17H29N6O3P

Example of getting 19

Synthesis aminobutiramida(1-{[(2-amino-6-chloro-N-purine-9-yl)methyl]cyclopropyl}(methyl)amino)methylphosphonate

Compound (0.32 g)synthesized according to example receiving 17, was dissolved in methanol and was added dropwise to 1.5 g of ammonium fluoride. The reaction was carried out under stirring at 60°C for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified on a column of silica gel to obtain metilaminopropionitrila 1,1-cyclopropanation alcohol.

1H NMR (CDCl3) (0,56 (m, 2H), 0,73 (m, 2H), 1,31 (m, N), of 2.56 (s, 3H), 311 (d, 2H), 3,55 (s, 2H), 4,70 (m, 2H)

Synthesized thus the connection is then used for the reaction carried out in the same manner as described in examples 4 and 6, which led to headline the connection.

1H NMR (400 MHz, CD3OD): (0,79 (m, 2H), 0,89 (m, 2H), 1.26 in (m, N), of 2.38 (s, 3H), was 2.76 (d, 2H, J=7 Hz), 4,11 (s, 2H)and 4.65 (m, 2H), 5,13 (m, 2H), 8,02 (s, 1H)

ESI: 431 (M+1)+C17H28ClN6O3P

Example of getting 20

Synthesis aminobutiramida[(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}cyclopropyl)(methyl)amino]methylphosphonate

Compound (0.32 g)synthesized according to example receiving 17, was dissolved in methanol and was added dropwise to 1.5 g of ammonium fluoride. The reaction was carried out under stirring at 60°C for 24 hours and then the solvent was removed by distillation under reduced pressure. The residue was purified on a column of silica gel to obtain metilaminopropionitrila 1,1-cyclopropanation alcohol.

1H NMR (CDCl3) (0,56 (m, 2H), 0,73 (m, 2H), 1,31 (m, N), of 2.56 (s, 3H), 3,11 (d, 2H), 3,55 (s, 2H), 4,70 (m, 2H)

Synthesized thus the connection is then used for the reaction carried out in the same manner as described in examples 4 and 7, which led to headline the connection.

1H NMR (CDCl3)(0,79 (m, 2N), of 0.90 (m, 2H), 1,31 (m, N), with 1.92 (s, 3H), of 2.38 (s, 3H), of 3.75 (d, 2H), 4,10 (s, 2H)and 4.65 (m, 2H), 7.62mm (s, 1H), 9.15, with (s, 1H)

Example of getting 21

Synthesis of 1,1-cyclopropanedicarboxylic acid

In 187 ml of 50%NaOH was dissolved 15 g of diethylmalonate at room temperature. Then add benzyltriethylammonium (21,3 g) and the resulting mixture was stirred for 10 minutes. To the reaction solution was added 1,2-dibromoethane (12.3 g)and the resulting mixture was stirred for 18 hours or more at room temperature. The reaction mixture was neutralized by adding dropwise concentrated sulfuric acid and then was extracted with ethyl acetate. The extract was distilled under reduced pressure to obtain 6.2 g specified in the title compound as a white solid.

1H NMR (CDCl3) (a 1.88 (s, 4H)

Example of getting 22

Synthesis of [1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]methanol

Sociallyengaged (LAH) and 15.3 g) was dissolved in 39 g of tetrahydrofuran and slowly added dropwise at 0°With added 11.7 g of the carboxylic acid obtained according to example getting 21. The reaction solution was boiled under reflux for 17 hours. The reaction was stopped by adding 10%HCl solution at room temperature and the mixture was extracted with et is lacerata. The extract was distilled under reduced pressure and the residue was purified on a column of silica gel with receipt of 8.2 g of diol compounds.

1H NMR (CDCl3) (0,56 (s, 4H), 2,22 (s, 2H), 3,63 (s, 4H)

Thus obtained compound (400 mg) was dissolved in 12 ml of THF, was added 184 mg of NaH and of 1.16 g of tert-butyldiphenylsilyl (TBDPSCl) and the resulting mixture was boiled under reflux for 6 hours. The reaction was stopped by adding 10 ml of water and the mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and the residue was purified on a column of silica gel to obtain 1.1 g specified in the connection header.

1H NMR (CDCl3) (0,33 (t, 2H), 0,48 (t, 2H), 1,23 (s, N)and 3.59 (d, 4H), 7,42 (m, 6N), to 7.68 (m, 4H)

An example of retrieving 23

Synthesis of diethyl(E)-2-[1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]vinylphosphonate

Compound (2 g)synthesized according to example receiving 22, was dissolved in 50 ml dichloromethane was added at room temperature of 1.03 g of N-oxide N-methylmorpholine and 103 mg of tetrapropylammonium (TRAR). The reaction mixture was stirred for 1 hour at room temperature and the reaction was stopped by adding 20 ml of water. The reaction solution was extracted with dichloromethane and the extract was concentrated under reduced pressure to obtain 2.0 g of aldeh the underwater connection.

1H NMR (CDCl3) (1,03 (s, N), was 1.04 (t, 2H), 1,05 (t, 2H), 3,94 (s, 2H), 7,37 (m, 6N), to 7.64 (m, 4H), 9,10 (s, 1H)

Tetraethylethylenediamine (1.7 g) was dissolved in 60 ml of tetrahydrofuran (THF). Then at -78°With added 264 mg of NaH and the mixture was stirred for 20 minutes and then was added to 1.9 g of the aldehyde compound obtained above. The reaction solution was stirred at room temperature for 1 hour and the reaction was stopped by adding 20 ml of water. The reaction solution was extracted with ethyl acetate and the extract was concentrated under reduced pressure. The residue was purified on a column of silica gel with getting 2,32 g specified in the connection header.

1H NMR (CDCl3) (0,76 (t, 2H), 0,81 (t, 2H), 1.04 million (s, N), 1,31 (t, 6N), 3,71 (s, 2H), of 4.05 (m, 4H), 5,70 (m, 1H), 6.42 per (m, 1H), 7,43 (m, 6N), to 7.64 (d, 4H)

ESI: 501 (M+1)+C28H41O4PSi

Example of getting 24

Synthesis of diethyl 2-[1-(hydroxymethyl)cyclopropyl]vinylphosphonate

The compound synthesized according to example receiving 23, used for the reaction carried out in the same way, which is described in the example of a 3, which led to headline the connection.

1H NMR (CDCl3) (0,76 (t, 2H), 0,81 (t, 2H), 1.04 million (s, N), 1,31 (t, 6N), 3,71 (s, 2H), of 4.05 (m, 4H), 5,70 (m, 1H), 6.42 per (m, 1H), 7,43 (m, 6N), to 7.64 (d, 4H)

ESI: 501 (M+1)+C28H41O4PSi/p>

Example get 25

Synthesis of diethyl 2-{1-[(6-amino-N-purine-9-yl)methyl]cyclopropyl}vinylphosphonate

The compound synthesized according to example obtain 24, used for the reaction carried out in the same manner as described in examples 4 and 5, which led to headline the connection.

1H NMR (CDCl3) (1,07 (t, 2H), 1,19 (t, 2H), 1,22 (t, 6N), 3,93 (s, 4H), to 4.33 (s, 2H), of 5.55 (s, 2H), 5,63 (m, 1H), of 6.49 (m, 1H), 7,88 (s, 1H), of 8.37 (s, 1H)

ESI: 352 (M+1)+C15H22N5O3P

Example of getting 26

Synthesis of diethyl 2-{1-[(2-amino-6-chloro-N-purine-9-yl)methyl]cyclopropyl}vinylphosphonate

The compound synthesized according to example obtain 24, used for the reaction carried out in the same manner as described in examples 4 and 6, which led to headline the connection.

1H NMR (CDCl3) (1,06 (t, 2H)and 1.15 (t, 2H), 1,23 (t, 6N), 3,93 (s, 4H), 4,18 (s, 2H), 5,12 (s, 2H), 5,59 (m, 1H), return of 6.58 (m, 1H), 7,81 (s, 1H)

ESI: 386 (M+1)+C15H21ClN5O3P

Example of getting 27

Synthesis of diethyl 2-(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}cyclopropyl)vinylphosphonate

The compound synthesized according to example obtain 24, used for the reaction, assests the emnd in the same way, as described in examples 4 and 7, which led to headline the connection.

1H NMR (CDCl3) (0,93 (t, 2H), 1,01 (t, 2H), 1,24 (t, 6N), with 1.92 (s, 3H), 3,91 (s, 2H), 3.96 points (m, 4H), 5,49 (m, 1H), by 5.87 (m, 1H), 7.62mm (s, 1H), 9.15, with (s, 1H)

ESI: 343 (M+1)+C15H23N2O5P

Example of getting 28

Synthesis of 1-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2,2-dimethylcyclopropane

According to the description in the message (see: Syn. Lett. 07, 1053-1054, 1999) is listed in the title compound was prepared as follows. Was dissolved 10 g (29 mmol) of ethyl 2-{[tert-butyl(diphenyl)silyl]oxy}acetate in 100 ml of tetrahydrofuran (THF) and added to 6.0 ml of cytotecmisoprostol. To the mixture was slowly added 37 ml of isobutylamine (2.0 M in THF) at -10°and the reaction solution was stirred for 12 hours at room temperature. To stop the reaction was added to 50 ml of a saturated solution of ammonium chloride. Tetrahydrofuran (THF)used as solvent were removed by distillation under reduced pressure and the reaction mixture was extracted with twice 500 ml of n-hexane. n-Hexane extract was distilled under reduced pressure and was purified on a column of silica gel with obtaining specified in the connection header.

1H NMR (CDCl3) (0.25 in (d, 1H), 0,51 (d, 2H), 0,99 (s, 3H), of 1.07 (s, N), 1,22 (s, 3H), 3,71 (d, 1H), 3,91 (d, 1H), 7,41 (m, 6 is), of 7.70 (m, 4H)

ESI: 355 (M+1)+C22H30O2Si

An example of obtaining 29

Synthesis aminobutiramida{[1-({[tert-butyl(diphenyl)silyl]oxy}-methyl)-2,2-dimethylcyclopropane]oxy}methylphosphonate

The compound synthesized according to example receiving 28, used for the reaction carried out in the same manner as described in example getting 2 that led to headline the connection.

1H NMR (CDCl3) (0,29 (d, 1H), 0,60 (d, 1H), 1.06 a (s, 3H), of 1.09 (s, N), of 1.27 (s, 3H), of 1.30 (m, N in), 3.75 (m, 2H), 3,92 (m, 2H), 4.72 in (m, 2H), 7,41 (m, 6N), to 7.67 (m, 4H)

ESI: 519 (M+1)+C28H43O5PSi

Example 30

Synthesis aminobutiramida{1-[(hydroxymethyl)-2,2-dimethylcyclopropane]oxy}methylphosphonate

The compound synthesized according to example receiving 29, used for the reaction carried out in the same way, which is described in the example of a 3, which led to headline the connection.

1H NMR (CDCl3) (0,39 (d, 1H), 0,59 (d, 1H), 1,13 (s, 3H), 1,21 (s, 3H), of 1.33 (d, N), 3,76 (m, 2H), 3,86 (m, 2H), amounts to 4.76 (m, 2H)

ESI: 295 (M+1)+C13H27O4P

An example of retrieving 31

Synthesis aminobutiramida({1-[(6-amino-N-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methylphosphonate

The compound synthesized is according to example 30, used for the reaction carried out in the same manner as described in example receiving 11, which led to headline the connection.

1H NMR (500 MHz, CDCl3): (0,62 (d, J=5,9 Hz, 1H), 0,81 (d, J=5,9 Hz, 1H), 1,10 (s, 3H), of 1.23 (m, 15 NM), and 3.72 (DD, J=15,1, and 11.0 Hz, 1H), 3,85 (DD, J=15,1, and 5.5 Hz, 1H), 4,28 (d, J=15.1 Hz, 1H), 4,58 (d, J=15.1 Hz, 1H), and 4.68 (m, 2H), 5,79 (ush. s, 2H), 8,19 (s, 1H), 8,32 (s, 1H)

ESI: 412 (M+1)+C18H30N5O4P

Example of getting 32

Synthesis aminobutiramida({1-[(2-amino-6-iodine-N-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methylphosphonate

The compound synthesized according to example 30 was used for the reaction carried out in the same manner as described in example 12, except that 6-Johann was used instead of 6-chloroguanine that led to headline the connection.

1H NMR (500 MHz, CDCl3): (0,58 (d, J=6,4 Hz, 1H), 0,80 (d, J=6,4 Hz, 1H), 1,10 (s, 3H), 1,24 (m, 8H), and 3.72 (DD, J=13,0, and 11.0 Hz, 1H), 3,88 (DD, J=13,0, and 9.3 Hz, 1H), 4,08 (d, J=15.1 Hz, 1H), 4,47 (d, J=15.1 Hz, 1H), 4,67 (m, 2H), of 5.05 (ush. s, 1H), 8,10 (s, 1H)

ESI: 538 (M+1)+C18H29IN5O4P

An example of obtaining 33

Synthesis aminobutiramida[(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}-2,2-dimethylcyclopropane)oxy]methylphosphonate

The compound synthesized in accordance with the ERU 30, used for the reaction carried out in the same manner as described in example receiving 13, which led to headline the connection.

1H NMR (CDCl3) (0,58 (d, 1H), 0,80 (d, 1H), 1,10 (s, 3H), 1,24 (DD, 6N), of 1.28 (t, 6N), was 1.58 (s, 3H), of 1.92 (s, 3H), and 3.72 (DD, 1H), 3,88 (DD, 1H), 4,08 (d, 1H), 4,47 (d, 1H), 4,67 (m, 2H), 7.62mm (s, 1H), 9.15, with (s, 1H)

ESI: 403 (M+1)+C18H31N2O6P

An example of retrieving 34

Synthesis of 1-[1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]-1-methyl alcohol

In 150 ml of dichloromethane was dissolved 6 g of the compound synthesized according to example getting 22. Then added at room temperature, 3.0 g of N-oxide and 103 mg of tetrapropylammonium (TRAR). The reaction mixture was stirred for approximately 1 hour at room temperature and the reaction was suppressed by adding 20 ml of water. The reaction mixture was extracted with dichloromethane and the extract was concentrated under reduced pressure to obtain 6.0 g of the aldehyde compound, which was used for subsequent reactions without further purification.

In 350 ml of THF was dissolved 5,23 g of aldehyde. The solution was cooled to -78°and to the solution was slowly added 10.3 ml of methylacrylamide (3.0 M solution) and then was stirred for 1 hour at room temperature. The reaction was suppressed by adding 0.5 ml water and 0.5 ml of m is of canola and concentrated under reduced pressure. The residue was purified column chromatography on silica gel (eluent: a mixture of ethyl acetate/n-hexane=1/8, vol./about.) to obtain 3.57 g specified in the connection header.

1H NMR (CDCl3) (0,22 (m, 1H), 0,39 (m, 2H), and 0.61 (m, 1H), 1.06 a (s, N), of 1.24 (d, 3H), 3,3 (d, 1H), 3,47 (s, 2H), 3,9 (d, 1H), 7,43 (m, 6N), to 7.64 (m, 6N)

Example of getting 35

Synthesis of diethyl(E)-2-1-[1-({[tert-butyl(diphenyl)silyl]oxy}methyl)cyclopropyl]-1-propylphosphonate

In 10 ml of dichloromethane was dissolved 4 g of the compound synthesized according to example obtain 34, was added at room temperature, 2.1 g of N-oxide n-research and 209 mg of tetrapropylammonium (TRAR). The reaction mixture was stirred for approximately 1 hour at room temperature and the reaction was suppressed by adding 20 ml of water. The reaction mixture was extracted with dichloromethane and the extract was concentrated under reduced pressure to obtain 4.0 g of the compound that was used in subsequent reactions without further purification.

Tetraethylethylenediamine (2.7 g) was dissolved in 30 ml of tetrahydrofuran (THF) at -78°and added 4 ml of n-utillity. The resulting mixture was stirred for 20 minutes and then added 1.0 g of ketone compounds, prepared as described above. The reaction mixture was stirred at room temperature for 1 hour and the reaction was stopped by PU is eat add 20 ml of water. The reaction mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residue was purified on a column of silica gel with getting 654 mg specified in the connection header.

1H NMR (CDCl3) (0,58 (m, 1H), 0.69 (m, 2H), 1,02 (s, N), 1,20 (t, 6N), is 2.09 (d, 3H)and 3.59 (s, 2H), of 4.05 (m, 4H), 5,61 (d, 1H), 7,38 (m, 6N), 7,63 (d, 4H)

Example 1

Synthesis of ({1-[(6-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid (compound 1)

The compound (159 mg)synthesized according to example getting 5, was dissolved in 15 ml of dichloromethane, was added 1.27 g of trimethylsilylpropyne and the resulting mixture was heated under reflux for 18 hours. Upon completion of the reaction, the reaction mixture was extracted with water and the aqueous extract was distilled under reduced pressure. The residue was purified by high-performance liquid chromatography (HPLC) with receipt of 0.89 g (yield 90%) indicated in the title compound as a white powder.

1H NMR (MeOH-d4) (1,02 (d, 4H), of 3.95 (d, 2H), 4,55 (s, 2H), 8,40 (s, 1H), 8,55 (s, 1H)

ESI: 300 (M+1)+C10H14N5O4P

Example 2

Synthesis of 3-[({1-[(6-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl pivalate (compound 2)

Specified in the title compound was obtained according to the method described in the message (see: J. Med. Chem., 37 (12), 1857 (1994)) and the U.S. patent 5663159(1998).

Connection of 1.00 g)obtained according to example 1, was dissolved in 150 ml of dry dimethylformamide and added 2,08 g (to 7.32 mmol) N,N'-DICYCLOHEXYL-4-morpholinylcarbonyl and 2.75 g (to 18.3 mmol) climaterealists. After approximately 1 hour the reaction mixture became homogeneous, it was stirred for 5 days at room temperature. The reaction solution was filtered, the filtrate was concentrated under reduced pressure and the residue was fractionally by 50 ml of water and 50 ml of toluene to separate the organic layer. The aqueous layer was extracted with twice 50 ml of toluene. The combined organic layers were concentrated under reduced pressure. The residue was purified column chromatography (eluent: methanol/dichloromethane=1/20, vol./about.) with the receipt of 0.59 g (yield 32%) indicated in the title compound as a white solid.

1H NMR (500 MHz, CDCl3) (0,91 (m, 2H), 1,12 (m, 2H), 1,20 (m, N), 1,90 (ush. s, 2H), 3,90 (d, 2H), 4,32 (s, 2H), 5,65 (m, 4H), to 8.14 (s, 1H), 8,31 (s, 1H)

ESI: 528 (M+1)+C22H34N5O8P

Example 3

Synthesis of ({1-[(2-amino-6-chloro-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid (compound 3)

Compound (73 g)synthesized according to example getting 6, used further for the reaction carried out in the same manner as described in example 1 to obtain 46 mg (yield 80%)specified in the connection header.

Example 4

Synthesis of ({1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid (compound 5)

Compound (41 mg)obtained according to example 3, was dissolved in 5 ml of 2N hydrochloric acid and heated under reflux for 6 hours. Water was removed by distillation under reduced pressure to obtain 37 mg (yield 95%) indicated in the title compound as a white solid.

1H NMR (MeOH-d4) (0,98 (m, 2H), 1.06 a (m, 2H), 3,92 (d, 2H), of 4.45 (s, 2H), 9,20 (s, 1H)

ESI: 316 (M+1)+C10H14N5O5P

Example 5

Synthesis of ({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid (compound 9)

The compound (150 mg)obtained according to example getting 6, was dissolved in 15 ml of tetrahydrofuran, was added 15 mg of 5%palladium-on-coal, and the connection was restored in an atmosphere of hydrogen at a pressure of 1 ATM., within 18 hours. Upon completion of the reaction, palladium-on-coal was removed by filtration on a filter, operating under vacuum, and the filtrate was distilled under reduced pressure. The residue was purified column chromatography on silica gel (eluent:a mixture of dichloromethane/methanol=20/1, vol./about.) to obtain 130 mg of diisopropyl connection (ESI: 384 (M+1)+C16H26N5O4P). This compound was treated with trimethylsilylpropyne according to the SNO same way, described in example 1 to obtain 91 mg (yield 90%) specified in the connection header.

1H NMR (MeOH-d4) (0,94 (m, 2H), of 1.03 (m, 2H), 3,93 (d, 2H), and 4.40 (s, 2H), 8,66 (s, 1H), total of 8.74 (s, 1H)

ESI: 300 (M+1)+C10H14N5O4P

Example 6

Synthesis of 3-[({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl pivalate (compound 10)

The compound synthesized according to example 5, was used further for the reaction carried out in the same way as described in example 2, obtaining specified in the connection header.

1H NMR (CDCl3-d4) (0,90 (m, 2H), of 1.05 (m, 2H), 1,20 (m, N), of 3.96 (d, 2H), 4,22 (s, 2H), 5,65 (m, 4H), 8,03 (s, 1H), 8,69 (s, 1H)

ESI: 528 (M+1)+C22H34N5O8P

Example 7

Synthesis of ({1-[(2-amino-6-cyclopropylamino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid (compound 11)

The compound synthesized according to example getting 6, (200 mg) was dissolved in 20 ml of ethanol, was added 53 ml of triethylamine and 82 mg of cyclopropylamine, and the resulting mixture was heated under reflux for 18 hours. To stop the reaction was added water and the product was extracted with ethyl acetate. An ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified column chromatography on silicagel the (eluent: a mixture of dichloromethane/methanol=20/1, about./about.) to obtain 178 mg (yield 85%) diisopropyl connection.

1H NMR (CDCl3) (0,59 (t, 2H), or 0.83 (m, 4H), and 1.00 (t, 2H), 1,24 (d, 6N), of 1.29 (d, 6N), 3,0 (ush. s, 1H), 3,80 (d, 2H), 4,15 (s, 2H), 4,70 (m, 2H), 4,71 (ush. s, 2H), 5,71 (s, 1H), 7,68 (s, 1H)

Thus obtained compound was treated with trimethylsilylpropyne according to the same method described in example 1, which resulted in headline connection in the amount of 128 mg (yield 90%).

1H NMR (MeOH-d4) (0,86 (m, 2H), were 0.94 (m, 2H), 1,02 (m, 2H), 1,07 (m, 2H), 2,90 (ush. s, 1H), 3,93 (d, 2H), 4,39 (s, 2H), 8,43 (ush. s, 1H)

ESI: 355 (M+1)+C13H19N6O4P

Example 8

Synthesis of ({1-[(2-amino-6-ethylamino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid (compound 13)

Compound (115 mg)synthesized according to example getting 6, was dissolved in 20 ml of ethanol, was added 31 ml of triethylamine and 0.07 ml of ethylamine and the mixture was heated under reflux for 18 hours. To stop the reaction was added water and the product was extracted with ethyl acetate. An ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified column chromatography on silica gel (eluent:a mixture of dichloromethane/methanol=20/1, vol./about.) to obtain 104 mg (yield 89%) diisopropyl connection.

1H NMR (CDCl3) (0,82 (m, 2H), and 1.00 (m, 2H), 1,24 (d, 6N), of 1.27 (t, 3H), of 1.29 (d, 6N), 3,60 ush. s, 2H), 3,81 (d, 2H), 4,15 (s, 2H)and 4.65 (m, 4H), 5,50 (ush. s, 1H), 7,78 (s, 1H)

Synthesized thus the connection used hereinafter for the reaction carried out in the same way as described in example 1, which resulted in a headline connection in the amount of 75 mg (yield 90%).

1H NMR (MeOH-d4) (0,89 (m, 2H), 1.04 million (m, 2H), 1,31 (t, 3H), 3,59 (ush. s, 2H), 3,92 (d, 2H), 4,35 (s, 2H), 9,95 (ush. s, 1H)

ESI: 343 (M+1)+C13H19N6O4P

Example 9

Synthesis of [(1-{[2-amino-6-(dimethylamino)-N-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonic acid (compound 15)

Compound (115 mg)synthesized according to example getting 6, was dissolved in 20 ml of ethanol was added and 38.6 ml of triethylamine and of 1.74 ml of N,N-dimethylamine and the mixture was heated under reflux for 18 hours. To stop the reaction was added water and the product was extracted with ethyl acetate. An ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified column chromatography on silica gel (eluent:a mixture of dichloromethane/methanol=20/1, vol./about.) to obtain 119 mg (yield 81%) diisopropyl connection.

1H NMR (CDCl3) (0,75 (t, 2H), 0,93 (t, 2H), 1,16 (d, 6N), 1,22 (d, 6N), 3,3 (ush. C, 6N), 3,74 (d, 2H), 4.09 to (s, 2H), 4,60 (m, 2H), 4,69 (ush. s, 2H), 7,68 (s, 1H)

Synthesized thus the connection used hereinafter for the reaction carried out by t is m the same way, described in example 1, which resulted in a headline connection in the amount of 86 mg (yield 90%).

1H NMR (MeOH-d4) (0,89 (m, 2H), of 1.05 (m, 2H), 3,30 (ush. C, 6N), 3,90 (d, 2H), 4,37 (s, 2H), 7,92 (ush. s, 1H)

ESI: 343 (M+1)+C12H19N6O4P

Example 10

Synthesis of [(1-{[2-amino-6-(isopropylamino)-N-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonic acid (compound 17)

The compound (133 mg)synthesized according to example getting 6, was dissolved in 20 ml of ethanol, was added 0,049 ml of triethylamine and 0,082 ml Isopropylamine and the resulting mixture was heated under reflux for 18 hours. To stop the reaction was added water and the product was extracted with ethyl acetate. An ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified column chromatography on silica gel (eluent:a mixture of dichloromethane/methanol=20/1, vol./about.) to obtain 95 mg (yield 68%) diisopropyl connection.

1H NMR (CDCl3) (0,83 (m, 2H), and 0.98 (m, 2H), 1.28 (in m, N), with 3.79 (d, 2H), 4,15 (s, 2H), 4,60 (ush. s, 1H), and 4.68 (s, 2H), 4,70 (m, 2H), 5.40 to (ush. s, 1H), to 7.77 (s, 1H)

Synthesized thus the connection used hereinafter for the reaction carried out in the same way as described in example 1, which resulted in a headline connection in the amount of 72 mg (yield 91%).

1H NMR (MeOH-d4) (0,89 (m, 2H), of 1.05 (m, 2H), 1,34 (d, 6N) 3,30 (ush. s, 1H), 3,90 (d, 2H), 4,36 (s, 2H), 8,01 (ush. s, 1H)

ESI: 357 (M+1)+C12H19N6O4P

Example 11

Synthesis of ({1-[(2,6-diamino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid (compound 19)

The compound (246 mg)synthesized according to example 4, and 2,6-diaminopurine were subjected to interaction in the same way, which is described in the example of a 5, which led to the diisopropyl compound in the amount of 78.5 mg (yield 29%).

1H NMR (CDCl3) of 0.85 (t, 2H), and 1.00 (t, 2H), 1,25 (d, 6N), of 1.29 (d, 6N)and 1.83 (ush. s, 2H), 3,82 (d, 2H), 4,15 (s, 2H), and 4.68 (m, 2H), 5,39 (d, 2H), a 7.85 (s, 1H)

ESI: 399 (M+1)+C16H27N6O4P

Synthesized thus the connection used hereinafter for the reaction carried out in the same way as described in example 1, which resulted in a headline connection in the amount of 72 mg (yield 91%).

1H NMR (DMSO-d6+CF3COOH) (0,70 (m, 2H), 0,82 (m, 2H), to 3.58 (d, 2H), is 4.21 (s, 2H), 8,16 (ush. s, 1H).

ESI: 315 (M+1)+With10H15N6About4P

Example 12

Synthesis of ({1-[(2-amino-6-ethoxy-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid (compound 23)

The derivative of 6-chloroguanine (100 mg)synthesized according to example getting 6, was dissolved in 10 ml of ethanol, was added 32 ml of triethylamine and 53 mg of sodium methoxide and the mixture boil is whether under reflux for 4 hours. The reaction was stopped by adding 10 ml of water. The reaction solution was extracted with dichloromethane and distilled under reduced pressure. The residue was purified on a column of silica gel to obtain compounds in which the 6 position of guanine was replaced by ethoxypropane.

1H NMR (CDCl3) (0,83 (t, 2H), and 1.00 (t, 2H), 1,24 of 1.28 (m, N), a 1.45 (t, 3H), 3,82 (d, 2H), is 4.21 (s, 2H), 4.53-in (m, 2H), 4,67 (m, 1H), USD 5.76 (s, 2H), of 7.90 (s, 1H)

Synthesized thus the connection used for the reaction carried out in the same way as described in example 1, which resulted in a headline connection.

1H NMR (MeOH-d4) (0,99 (t, 2H), 1.06 a (t, 2H), 1,48 (t, 3H), 3,91 (d, 2H), 4,51 (s, 2H)and 4.65 (m, 2H), 9,18 (s, 1H)

ESI: 344 (M+1)+C12H18N5O5P

Example 13

Synthesis of ({1-[(2-amino-6-methyl-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonic acid (compound 25)

A flask with a volume of 10 ml was dried under vacuum and gradually contributed 53 mg (0,238 mmol) of zinc bromide in the atmosphere of nitrogen. Was added dropwise 2 ml of dry tetrahydrofuran, the temperature was lowered to -78°S, was added to 0.08 ml (20,238 mmol) methylacrylamide and the resulting mixture was stirred for 1 hour. Then the reaction mixture was heated to room temperature, was slowly added to approximately 10 mol% of paradimethylaminobenzaldehyde. To this reaction solution was added dropwise the 50 mg (0,119 mmol) of the compound, obtained by procedure 6 in 1 ml of tetrahydrofuran. The resulting mixture was heated for 1 hour. The solvent was removed by distillation under reduced pressure, the residue was separated by water and ethyl acetate and the organic layer was concentrated by distillation under reduced pressure. The residue was purified column chromatography on silica gel (eluent: a mixture of methylene chloride/methanol=90/10, about./about.) to obtain 20 mg (yield 42%) diisopropyl connection.

1H NMR (MeOH-d4) (0,95 (m, 2H), and 0.98 (m, 2H), 1,17 (d, 6N), of 1.23 (d, 6N), at 2.59 (s, 3H), was 4.02 (s, 1H), 4,10 (s, 1H), 4,32 (s, 2H), 4,59 (m, 2H), 8,12 (s, 1H)

ESI: 398 (M+1)+C17H28N5O4P

Synthesized thus the connection used for the reaction carried out in the same way as described in example 1, which resulted in a headline connection in the amount of 8.0 mg (yield 50%).

1H NMR (D2O) (0.87 (m, 2H), 1,02 (m, 2H), 3,79 (s, 1H), 3,81 (s, 1H), 4.53-in (s, 2H), of 8.25 (s, 1H)

ESI: 314 (M+1)+C11H16N5O4P

Example 14

Synthesis of [(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}cyclopropyl)oxy]methylphosphonic acid (compound 31)

The compound (19 mg)synthesized according to example receiving 7, used further for the reaction carried out in the same way as described in example 1, which resulted in indicated in the title the connection information in the amount of 14 mg (yield 95%).

ESI: 291 (M+1)+C10H11N2O6P

1H NMR (MeOH-d4) (0,82 (t, 2H), 0,97 (t, 2H), 1,87 (s, 3H), 3,83 (d, 2H), of 3.97 (s, 2H), 7,55 (s, 1H)

Example 15

Synthesis of [(1-{[2-amino-6-(4-morpholinyl)-N-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonic acid (compound 37)

The compound (134 mg)synthesized according to example getting 6, was dissolved in 20 ml of ethanol, was added 0,049 ml of triethylamine and of 0.085 ml of the research and the resulting mixture was heated under reflux for 18 hours. To stop the reaction was added water and the product was extracted with ethyl acetate. An ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified column chromatography on silica gel (eluent: a mixture of dichloromethane/methanol=20/1, vol./about.) to obtain 66 mg (yield 44%) diisopropyl connection.

1H NMR (CDCl3) (0,83 (m, 2H), 0,99 (m, 2H), 1,24 (d, 6N), of 1.30 (d, 6N), with 3.79 (m, 6N), 4,18 (s, 2H), 4,21 (ush. s, 4H), of 4.67 (m, 2H), 4,80 (ush. s, 2H), 7,78 (s, 1H)

ESI: 469 (M+1)+C20H33N6O5P

Synthesized thus the connection was handled by trimethylsilylpropyne in the same way as described in example 1, which resulted in headline connection in the amount of 49 mg (yield 91%).

1H NMR (MeOH-d4) (0,89 (m, 2H), 1,07 (m, 2H), 3,81 (m, 4H), to 3.92 (d, 2H), 4,40 (ush. C, 6N), 7,87 (s, 1H)

ESI: 384 (M+1)+C14H21N 6O5P

Example 16

Synthesis of [(1-{[2-amino-6-(1-piperidinyl)-N-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonic acid (compound 39)

The compound (154 mg)synthesized according to example getting 6, was dissolved in 20 ml of ethanol, was added 0,049 ml of triethylamine and 0.11 ml of piperidine and the obtained mixture was heated under reflux for 18 hours. To stop the reaction was added water and the product was extracted with ethyl acetate. An ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified column chromatography on silica gel (eluent: a mixture of dichloromethane/methanol=20/1, vol./about.) to obtain 123 mg (yield 72%) diisopropyl connection.

1H NMR (CDCl3) (0,80 (m, 2H), 0,99 (m, 2H), 1,22 (d, 6N), of 1.26 (d, 6N), and 1.63 (m, 4H), to 1.67 (m, 2H), 3,78 (d, 2H), 4,14 (C, 6N), 4,54 (ush. s, 2H)and 4.65 (m, 2H), 7,72 (s, 1H)

ESI: 467 (M+1)+C21H35N6O4P

Synthesized thus the connection is then used for the reaction carried out in the same way as described in example 1, which resulted in a headline connection in the amount of 87 mg (yield 91%).

1H NMR (MeOH-d4) (0,89 (m, 2H), 1.06 a (m, 2H), 1,73 (m, 4H), to 1.79 (m, 2H), 3,90 (d, 2H), 4,37 (s, 2H), 4,43 (ush. s, 4H), 7,89 (s, 1H)

ESI: 383 (M+1)+C15H23N6O4P

Example 17

Synthesis of [(1-{[2-amino-6-(4-methyl-1-piperazinil)-N-purin-yl]methyl}cyclopropyl)oxy]methylphosphonic acid (compound 41)

The compound (128 mg)synthesized according to example getting 6, was dissolved in 20 ml of ethanol, was added 0.10 ml of 4-methyl-1-piperazine and the mixture was heated under reflux for 18 hours. To stop the reaction was added water and the product was extracted with ethyl acetate. An ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified column chromatography on silica gel (eluent: a mixture of dichloromethane/methanol=20/1, vol./about.) to obtain 123 mg (yield 83%) diisopropyl connection.

1H NMR (CDCl3) (0,80 (m, 2H), and 0.98 (m, 2H), 1,21 (d, 6N), 1.27mm (d, 6N), is 2.30 (s, 3H), 2,48 (m, 4H), of 3.78 (d, 2H), 4,13 (s, 2H), 4,22 (ush. s, 4H), of 4.57 (s, 2H), 4,66 (m, 2H), 7,73 (s, 1H)

ESI: 482 (M+1)+C21H36N7O4P

Synthesized thus the connection is then used for the reaction carried out in the same way as described in example 1, which resulted in a headline connection in the amount of 87 mg (yield 85%).

1H NMR (MeOH-d4) (0,89 (m, 2H), 1,07 (m, 2H), 3.00 and (s, 3H), and 3.72 (m, 4H), 3,91 (d, 2H), of 4.45 (s, 2H), 4,89 (m, 2H), 5,70 (ush. s, 2H), to $ 7.91 (s, 1H)

ESI: 398 (M+1)+C15H24N7O4P

Example 18

Synthesis of [(1-{[2-amino-6-(1-pyrrolidinyl)-N-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonic acid (compound 43)

The compound (122 mg)synthesized according to example getting 6, was dissolved the 20 ml of ethanol, added 0,07 ml pyrrolidine and the resulting mixture was heated under reflux for 18 hours. To stop the reaction was added water and the product was extracted with ethyl acetate. An ethyl acetate extract was concentrated by distillation under reduced pressure and the residue was purified column chromatography on silica gel (eluent: a mixture of dichloromethane/methanol=20/1, vol./about.) to obtain 110 mg (yield 83%) diisopropyl connection.

1H NMR (CDCl3) (0,78 (m, 2H), 0,96 (m, 2H), 1,20 (d, 6N), of 1.26 (d, 6N), 2,00 (ush. s, 4H), 3,60 (ush., 3H), of 3.78 (d, 2H), 4.09 to (ush., 2H), 4,12 (s, 2H), 4,63 (m, 2H), 7,69 (s, 1H)

ESI: 453 (M+1)+C20H33N6O4P

Synthesized thus the connection is then used for the reaction carried out in the same way as described in example 1, which resulted in a headline connection in the amount of 76 mg (yield 85%).

1H NMR (MeOH-d4) (0,94 (m, 2H), of 1.03 (m, 2H), 2,15 (m, 4H), 3,76 (m, 2H), 3,91 (d, 2H), 4,18 (m, 2H), and 4.40 (s, 2H), 5,70 (ush. s, 2H), 8,42 (s, 1H)

ESI: 369 (M+1)+C14H21N6O4P

Example 19

Synthesis of 3-[({1-[(2-amino-N-purine-9-yl)-methyl]cyclopropyl}oxy)methyl]-9-methyl-3,7-dioxo-2,4,6-trioxa-3λ5-popadic-1-yl 3-methylbutanoate (compound 74)

The compound (100 mg)synthesized according to example 5, was dissolved in dimethylformamide (2 ml) and then were subjected to interaction with chloromethyl 3-methyl is uthiradam in the presence of triethylamine (3 equivalents) at room temperature for 24 hours. The obtained product was purified on a column of silica gel and got mentioned in the title compound with a yield of 41%.

1H NMR (CDCl3) (0,89 (t, 2H), were 0.94 (d, N), was 1.04 (t, 2H), 2,10 (m, 2H), 2,22 (d, 4H), of 3.97 (d, 2H), 4,23 (s, 2H), total of 5.21 (s, 2H), 5,65 (m, 4H), of 8.00 (s, 1H), 8,69 (s, 1H)

ESI: 527 (M+1)+C23H35N4O8P

Example 20

Synthesis of 3-[({1-[(2-amino-N-purine-9-yl)-methyl]cyclopropyl}oxy)methyl]was 3.7-dioxo-2,4,6-trioxa-3λ5-popadic-1-yl of butyrate (compound 75)

The compound synthesized according to example 5 were subjected to interaction with chloromethylstyrene in the same way as described in example 19, at room temperature for 24 hours. The obtained product was purified on a column of silica gel and got mentioned in the title compound with a yield of 24%.

1H NMR (CDCl3) (0,88 (t, 2H), 0,92 (d, 6N), to 1.60 (m, 4H), 2,32 (t, 4H), of 3.96 (d, 2H), 4,22 (s, 2H), 5,00 (s, 2H), 5,62 (m, 4H), of 8.00 (s, 1H), 8,68 (s, 1H)

ESI: 499 (M+1)+C21H31N4O8P

Example 21

Synthesis of 3-[({1-[(2-amino-N-purine-9-yl)-methyl]cyclopropyl}oxy)methyl]-8-methyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl 2-methylpropanoate (compound 78)

The compound synthesized according to example 5 were subjected to interaction with chloromethylstyrene in the same way as described in example 19, at room temperature for 24 hours. The obtained product was purified n is a column of silica gel and got mentioned in the title compound with a yield of 21%.

1H NMR (CDCl3) (0,84 (t, 2H), 0,97 (t, 2H), 1,11 (d, N), 2,52 (m, 2H), 3,91 (d, 2H), 4.16 the (s, 2H), total of 5.21 (s, 2H), 5,58 (m, 4H), of 7.96 (s, 1H), 8,61 (s, 1H)

ESI: 499 (M+1)+C21H31N4O8P

Example 22

Synthesis of 3-[({1-[(2-amino-N-purine-9-yl) methyl]cyclopropyl}oxy)methyl]was 3.7-dioxo-7-(1-pyrrolidinyl)-2,4,6-trioxo-3λ5-phospahate-1-yl 1-pyrrolidinecarboxylic (compound 80)

The compound synthesized according to example 5 were subjected to interaction with chloromethyl 1-pyrrolidinecarboxylic in the same way as described in example 19, at room temperature for 24 hours. The obtained product was purified on a column of silica gel and got mentioned in the title compound with a yield of 35%.

1H NMR (CDCl3) (0,82 (t, 2H), 0.87 (m, 8H), and 0.98 (t, 2H), 1.57 in (d, 4H), and 2.26 (t, 4H), 3,91 (d, 2H), 4.16 the (s, 2H), 5,12 (s, 2H), 5,57 (m, 4H), 7,98 (s, 1H), to 8.62 (s, 1H)

ESI: 553 (M+1)+C23H33N6O8P

Example 23

Synthesis of 3-[({1-[(2-amino-N-purine-9-yl)-methyl]cyclopropyl}oxy)methyl]was 3.7-dioxo-7-(1-piperidinyl)-2,4,6-trioxo-3λ5-phospahate-1-yl 1-piperidinecarboxylate (compound 81)

The compound synthesized according to example 5 were subjected to interaction with chloromethyl 1-piperidinecarboxylate in the same way as described in example 19, at room temperature for 24 hours. The obtained product was purified on a column of silica gel and recip is whether specified in the title compound with yield of 39%.

1H NMR (CDCl3) (0,86 (t, 2H), 1,02 (t, 2H), 1,47-1,58 (ush. m, N), 3,40 (ush. m, 8H), 3,99 (d, 2H), 4,22 (s, 2H), 5,00 (s, 2H), 5,69 (m, 4H), of 8.00 (s, 1H), 8,67 (s, 1H)

ESI: 581 (M+1)+C25H37N6O8P

Example 24

Synthesis of 3-[({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-7-(4-morpholinyl)was 3.7-dioxo-2,4,6-trioxa-3λ5-phospahate-1-yl 4-morpholinylcarbonyl (compound 82)

The compound synthesized according to example 5 were subjected to interaction with chloromethyl 4-morpholinylcarbonyl in the same way as described in example 19, at room temperature for 24 hours. The obtained product was purified on a column of silica gel and got mentioned in the title compound with a yield of 40%.

1H NMR (CDCl3) (0,89 (t, 2H), of 1.03 (t, 2H), 3,47 (ush. m, 8H), 3,65 (ush. m, 8H), 4.00 points (d, 2H), 4,24 (s, 2H), 5,04 (s, 2H), 5,70 (m, 4H), 8,07 (s, 1H), 8,69 (s, 1H)

ESI: 586 (M+1)+C23H33N6O10P

Example 25

Synthesis of {[1-({2-amino-6-[(4-were)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonic acid (compound 66)

The derivative of 6-chloroguanine (a 4.86 g)synthesized according to example getting 6, was dissolved in 85 ml of methanol and was added 1.4 g of triethylamine and 2.9 g of 4-methylthioribose. The reaction mixture is boiled under reflux for 24 hours. The reaction was stopped by adding 20 ml of water and the methanol was removed by means of the PTO distillation under reduced pressure. The reaction mixture was extracted with dichloromethane and purified on a column of silica gel to obtain compounds in which the 6 position of guanine was substituted 4-methylphenylthio.

1H NMR (CDCl3) (0,84 (t, 2H), 1,02 (t, 2H), of 1.25 to 1.31 (m, N), is 2.40 (s, 3H), 4,20 (d, 2H), 4,69 (m, 2H), 4,74 (s, 2H), 7,22 (d, 2H), 7,50 (d, 2H), 8,00 (s, 1H)

Synthesized thus the connection used hereinafter for the reaction carried out in the same way as described in example 1, and then recrystallized from methanol-diethyl ether (1/20, vol./about.) obtaining specified in the connection header.

1H NMR (MeOH-d4) (0,98 (t, 2H), 1.06 a (t, 2H), 2,42 (s, 3H), 3,92 (d, 2H), 4,48 (s, 2H), 7,35 (d, 2H), 7,55 (d, 2H), 9,05 (s, 1H)

ESI: 421 (M+1)+C18H21N4O4PS

Example 26

Synthesis of 3-({[1-({2-amino-6-[(4-were)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl pivalate (compound 68)

Methylphosphonous acid, synthesized according to example 25 was used further for the reaction carried out in the same way as described in example 2, which led to headline the connection.

1H NMR (CDCl3) (0,82 (t, 2H), and 0.98 (t, 2H), 1,18 (s, N), a 2.36 (s, 3H), 3,93 (d, 2H), 4,15 (s, 2H), is 4.93 (s, 2H), ceiling of 5.60 (m, 4H), 7,18 (d, 2H), of 7.48 (d, 2H), 7,88 (s, 1H)

ESI: 649 (M+1)+C30H41N4O8PS

Example 27

Synthesis of {[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonic acid (compound 96)

The derivative of 6-chloroguanine (a 4.86 g)synthesized according to example getting 6, was dissolved in 85 ml of methanol and was added 1.4 g of triethylamine and 2.9 g of 4-methoxythiazole. The reaction mixture is boiled under reflux for 24 hours. The reaction was stopped by adding 20 ml of water and the methanol was removed by distillation under reduced pressure. The reaction mixture was extracted with dichloromethane and purified on a column of silica gel to obtain compounds in which the 6 position of guanine was substituted 4-methoxybenzylthio.

Synthesized thus the connection used hereinafter for the reaction carried out in the same way as described in example 1, and then recrystallized from methanol-diethyl ether (1/20, vol./about.) obtaining specified in the connection header.

1H NMR (MeOH-d4) (0,77 (m, 2H), of 1.05 (m, 2H), a 3.87 (s, 3H), 3,92 (d, 2H), of 4.45 (s, 2H), 7,10 (d, 2H), to 7.59 (d, 2H), of 8.09 (s, 1H)

ESI: 438 (M+1)+C17H20N5O5PS

Example 28

Synthesis of {[1-({2-amino-6-[(4-nitrophenyl)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonic acid (compound 95)

The compound synthesized according to example getting 6, used further for the reaction carried out in the same manner as described in example 27, except that 4-nitrothiazol was used instead of 4-Metacritic the ash, obtaining specified in the connection header.

1H NMR (MeOH-d4) (0,86 (m, 2H), 0,95 (m, 2H), 3,82 (d, 2H), 4,35 (s, 2H), 7,81 (d, 2H), by 8.22 (d, 2H), 8,72 (s, 1H)

ESI: 453 (M+1)+C16H17N6O6PS

Example 29

Synthesis of ({1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonic acid (compound 97)

The derivative of 6-chloroguanine, synthesized according to example 12, was used subsequently for the reaction carried out in the same manner as described in examples 3 and 4, which led to headline the connection.

1H NMR (MeOH-d4) (0,73 (t, 1H)and 1.15 (m, 1H), 1,21 (d, 3H), 1,38 (t, 1H), 1,48 (m, 1H), 3,85 (t, 1H), 3.96 points (t, 1H), 4,42 (d, 1H), 4,69 (d, 1H), 9,12 (s, 1H)

Example 30

Synthesis of {[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-N-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonic acid (compound 99)

The derivative of 6-chloroguanine, synthesized according to example 12, was used further for the reaction carried out in the same manner as described in example 27, which led to headline the connection.

1H NMR (MeOH-d4) (0,67 (t, 2H), 1,13 (m, 2H), 1,20 (d, 3H), of 1.45 (m, 1H), 3,85 (m, 1H), 3,86 (s, 3H), of 3.94 (m, 1H), 4,42 (d, 1H), and 4.68 (d, 1H), to 7.09 (d, 2H), to 7.59 (d, 2H), 9,00 (s, 1H)

ESI: 452 (M+1)+C18H22N5O5PS

Example 31

Synthesis of {[1-({2-amino-[6-(4-were)sulfanyl]-N-purine-9-yl}methyl)-2-metallic propyl]oxy}methylphosphonic acid (compound 101)

The derivative of 6-chloroguanine, synthesized according to example 12, was used further for the reaction carried out in the same manner as described in example 25, with the receipt specified in the connection header.

1H NMR (MeOH-d4) (0,68 (t, 1H)and 1.15 (m, 1H), 1,20 (d, 3H), of 1.45 (m, 1H), 2,42 (s, 3H), of 3.84 (m, 1H), 3.96 points (m, 1H), 4,43 (d, 1H), and 4.68 (d, 1H), was 7.36 (d, 2H), 7,55 (d, 2H), 9,05 (s, 1H)

ESI: 436 (M+1)+C18H22N5O4PS

Example 32

Synthesis of {[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-N-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonic acid (compound 100)

The derivative of 6-chloroguanine, synthesized according to example 12, was used further for the reaction carried out in the same manner as described in example 28, which led to headline the connection.

1H NMR (MeOH-d4) (0,49 (t, 1H), 0,93 (m, 1H), and 1.00 (d, 3H), 1,25 (m, 1H), to 3.64 (m, 1H), 3,76 (m, 1H), 4,28 (d, 1H), 4.53-in (d, 1H), 7,72 (d, 2H), 8,14 (d, 2H), 9,10 (s, 1H)

ESI: 467 (M+1)+C17H19N6O6PS

Example 33

Synthesis of ({1-[(6-amino-N-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonic acid (compound 103)

A derivative of adenine, synthesized according to example receiving 11, used for the reaction carried out in the same way as described in example 1, which resulted in a headline connection.

1H NMR (MeOH-d4) (0,64 (t, 1H), 1,09 (who, 1H), 1,20 (d, 3H), USD 1.43 (m, 1H), 3,83 (m, 1H), 3,95 (m, 1H), 4,49 (d, 1H), 4.75 in (d, 1H), 5,49 (s, 2H), 8,39 (s, 1H), 8,55 (s, 1H)

ESI: 314 (M+1)+C11H16N5O4P

Example 34

Synthesis of bis{[(tert-butoxycarbonyl)oxy]methyl}({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 69)

The compound (187 mg)synthesized according to example 5, was mixed with 6 ml of N-methyl-2-pyrrolidone was added 300 mg of triethylamine and 150 mg of chloromethyl tert-BUTYLCARBAMATE. The reaction solution was stirred at room temperature for 4 hours. The reaction was stopped by adding 10 ml of water, and the reaction mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and was purified on a column of silica gel with obtaining specified in the connection header.

1H NMR (CDCl3) (0,86 (m, 2H), 1.06 a (m, 2H), 1,47 (s, N), 4,01 (d, 4H), 4,22 (s, 2H), 5,00 (ush. s, 2H), 5,61 (m, 4H), to 7.99 (s, 1H), 8,69 (s, 1H)

ESI: 344 (M+1)+C22H34N5O10P

Example 35

Synthesis of bis{[(isopropoxycarbonyl)oxy]methyl}({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 70)

The compound (100 mg)synthesized according to example 5, was mixed with 5 ml N-methyl-2-pyrrolidone was added 110 mg of triethylamine and 150 mg chlorotriisopropylsilane. The reaction solution was stirred at 50°C for 4 hours. The reaction was stopped by the ay add 10 ml of water, and the reaction mixture was extracted with ethyl acetate. The extract was distilled under reduced pressure and was purified on a column of silica gel with obtaining specified in the connection header.

1H NMR (CDCl3) (0,88 (s, 2H), 1.06 a (s, 2H), 1,29 (d, 2H), 1,31 (d, 2H), 4,01 (d, 4H), is 4.21 (s, 2H), 4.92 in (m, 2H), 5,01 (ush. s, 2H), 5,64 (m, 4H), to 7.99 (s, 1H), 8,69 (s, 1H)

ESI: 532 (M+1)+C20H30N5O10P

Example 36

Synthesis of ({1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methylphosphonic acid (compound 146)

The compound synthesized according to example getting 32, subsequently used for the reaction carried out in the same manner as described in examples 1 and 4, which led to headline the connection.

1H NMR (MeOH-d4) (0,78 (d, 1H), 0,82 (d, 1H), 1,21 (s, 3H), of 1.27 (s, 3H), 3,90 (d, 1H), 3,91 (d, 1H), 4,58 (s, 2H), 9,12 (s, 1H)

ESI: 344 (M+1)+C12H18N5O5P

Example 37

Synthesis of ({1-[(2-amino-N-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methylphosphonic acid (compound 147)

The compound synthesized according to example getting 32, used for the reaction carried out in the same manner as described in example 5, which led to the compound, which the 6 position of guanine was recovered hydrogen.

1H NMR (CDCl3) (0,60 (d, 1H), 0,82 (d, 1H), 1,21 (s, 3H), 1,22 (s, 3H), 1,22 (m, 15 NM), to 3.73 (m, N), a 3.87 (m, 1H), 4,13 (d, 1H), 4,49 (d, 1H), 4,67 (m, 2H), 4,98 (ush. s, 2H), of 8.09 (s, 1H), 9,67 (s, 1H)

Synthesized thus the connection used hereinafter for the reaction carried out in the same manner as described in example 1, which resulted in a headline connection.

1H NMR (MeOH-d4) (0,74 (d, 1H), 0,81 (d, 1H), 1,21 (s, 3H), 1.26 in (s, 3H), 3,91 (d, 2H), 4,49 (d, 1H), 4,57 (d, 1H), 8,63 (s, 1H), total of 8.74 (s, 1H)

ESI: 328 (M+1)+C12H18N5O4P

Example 38

Synthesis of ({1-[(6-amino-N-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methylphosphonic acid (compound 148)

The compound synthesized according to example getting 31, further used for the reaction carried out in the same manner as described in example 1, obtaining specified in the connection header.

1H NMR (Meon-d4) (0,77 (d, 1H), 0,79 (d, 1H), 1,25 (s, 3H), 1.28 (in s, 3H), 3,90 (d, 2H), br4.61 (d, 1H), 4,70 (d, 1H), scored 8.38 (s, 1H), 8,51 (s, 1H)

ESI: 328 (M+1)+C12H18N5O4P

Example 39

Synthesis of (E)-2-{1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]cyclopropyl}oxy)vinylphosphonic acid (compound 130)

The compound synthesized according to example receiving 26, further used for the reaction carried out in the same manner as described in example 1, to obtain the derivative of phosphonic acid.

1H NMR (Meon-d4) (1,07 (t, 2H), 1,33 (t, 1H), to 4.41 (s, 2H), USD 5.76 (DD, 1H), 6,45 (DD, 1H), 9,18 (s,1H)

Synthesized thus the connection is then used for the reaction carried out in the same manner as described in example 4, to obtain specified in the connection header.

1H NMR (Meon-d4) (1,08 (t, 2H), 1,34 (t, 1H), to 4.38 (s, 2H), 5,78 (DD, 1H), 6,46 (DD, 1H), 9,11 (s, 1H)

ESI: 312 (M+1)+C11H14N5O4P

Example 40

Synthesis of 2-{1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}ethylphosphonic acid (compound 139)

The compound synthesized according to example receiving 26, further used for the reaction carried out in the same manner as described in example 5, to obtain specified in the connection header.

1H NMR (Meon-d4) (0,58 (t, 2H), 0,85 (t, 2H), 1,42 (m, 2H), 1,95 (m, 2H), 4,11 (s, 2H), 5,78 (DD, 1H), 8,55 (s, 1H), up 8.75 (s, 1H)

ESI: 298 (M+1)+C11H16N5O3P

Example 41

Synthesis of (E)-2-{1-[(6-amino-N-purine-9-yl)methyl]cyclopropyl}vinylphosphonic acid (compound 132)

The compound synthesized according to example get 25, then used for the reaction carried out in the same manner as described in example 1, obtaining specified in the connection header.

1H NMR (Meon-d4) (0,94 (t, 2H), 1,20 (t, 2H), 4,36 (s, 2H), 5,63 (DD, 1H), 6,37 (DD, 1H), 8.30 to (s, 1H), 8,31 (s, 1H)

ESI: 296 (M+1)+C11H14N5O3P

Example 42

Synthesis of 2-{1-[(6-amino-N-purine-9-yl)methyl]C is chlorophil}ethylphosphonic acid (compound 140)

The compound synthesized according to example get 25, then used for the reaction carried out in the same manner as described in example 5, to obtain specified in the connection header.

1H NMR (Meon-d4) (0,58 (t, 2H), 0,87 (t, 2H), 1,37 (m, 2H), of 1.97 (m, 2H), 4,24 (s, 2H), 8,31 (s, 1H), 8,42 (s, 1H)

ESI: 298 (M+1)+C11H16N5O3P

Example 43

Synthesis of 2-{1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]cyclopropyl}ethylphosphonic acid (compound 138)

The compound synthesized according to example receiving 26, further used for the reaction carried out in the same manner as described in example 12, to obtain compounds in which the 6 position of guanine substituted ethoxypropane.

1H NMR (Meon-d4) (1,00 (t, 2H), 1,10 (t, 2H), 1,16-to 1.21 (m, N), 3,90 (m, 4H), to 4.01 (m, 2H), 4,13 (s, 2H), 4.92 in (s, 2H), to 5.58 (DD, 1H), of 6.49 (DD, 1H), 7.62mm (s, 1H)

Synthesized thus the compound (80 mg) was dissolved in methanol and the reaction was carried out in hydrogen atmosphere in the presence of 20 mg of 10%Pd/C to obtain compounds in which the double bond was restored.

1H NMR (CDCl3) (0,49 (t, 2H), 0,66 (t, 2H), 1,21 (t, 6N), of 1.42 (m, 2H), 2,01 (m, 2H), 3,99 (m, 6N), 4,96 (s, 2H), to 7.59 (s, 1H)

Synthesized thus the connection is then used for the reaction carried out in the same manner as described in example 1, obtaining specified in the header with the organisations.

1H NMR (Meon-d4) (0,60 (t, 2H), 0,87 (t, 2H), 1,47 (m, 2H), of 1.97 (m, 2H), 4.16 the (s, 2H), 9,12 (s, 1H)

ESI: 314 (M+1)+C11H16N5O4P

Example 44

Synthesis of 2-{1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}propylphosphonic acid (compound 144)

The compound synthesized according to example receiving 35, further used for the reaction carried out in the same manner as described in examples obtain 24, 26 and example 5, which led to headline the connection.

1H NMR (Meon-d4) (0,62 of 0.77 (m, 4H), was 1.04 (d, 3H), of 1.52 (m, 2H), 1,90 (m, 1H), 4,24 (m, 2H), 8,58 (s, 1H), total of 8.74 (s, 1H)

ESI: 312 (M+1)+C12H18N5O3P

Example 45

Synthesis of (E)-2-{1-[(6-amino-N-purine-9-yl)methyl]cyclopropyl}-1-propylphosphonic acid (compound 137)

The compound synthesized according to example receiving 35, further used for the reaction carried out in the same manner as described in examples obtain 24, 25 and example 1, which resulted in a headline connection.

1H NMR (Meon-d4) (0,86 (t, 2H), 1,10 (t, 2H), 2,19 (d, 3H), of 4.38 (s, 2H), 5,23 (d, 1H), 8.34 per (s, 1H), of 8.37 (s, 1H)

ESI: 310 (M+1)+C12H16N5O3P

Example 46

Synthesis of 2-{1-[(6-amino-N-purine-9-yl)methyl]cyclopropyl}propylphosphonic acid (compound 143)

The compound synthesized according to example receiving 35, further used to implement the tion, carried out in the same manner as described in examples obtain 24, 25 and example 5, which led to headline the connection.

1H NMR (Meon-d4) (0,65 (t, 2H), 0,78 (t, 2H), 0,95 (m, 1H), and 1.00 (d, 3H), 1,53 (s, 1H), 1,90 (m, 1H), 4,3 (kV, 2H), to 8.41 (s, 1H), 8,45 (s, 1H)

ESI: 312 (M+1)+C12H18N5O3P

Example 47

Synthesis of bis(2,2,2-triptorelin) ({1-[(6-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 48)

To methylphosphonic acid (150 mg)synthesized according to example 1, was added dropwise dichloromethane was then added dropwise to 0.73 ml of N,N-diethyltoluenediamine and the resulting mixture was stirred at room temperature for 2 hours. In the reaction vessel was made oxalicacid (0.15 ml) and 2 drops of dimethylformamide. The mixture was stirred for another 2 hours and the solvent was removed by distillation under reduced pressure. To the residue was added 10 ml of pyridine and 2 ml of triptoreline and the reaction was carried out under stirring for 16 hours. The solvent was removed by distillation under reduced pressure and the residue was purified on a column of silica gel with obtaining specified in the connection header.

1H NMR (CD3OD) (1,02 (m, 4H), 4,30 (d, 2H), 4.53-in (m, 6N), to 8.40 (s, 1H), 8,46 (s, 1H)

ESI: 464 [M+H]+: C14H16F6N5O4P

Example 48

Synthesis of bis(2,2,2-triptorelin) ({1-[(2-amino-N-purine-9-yl)meth is l]cyclopropyl}oxy)methylphosphonate (compound 49)

The compound synthesized according to example 5, then used for the reaction carried out in the same manner as described in example 47, obtaining specified in the connection header.

1H NMR (CDCl3) (0,88 (m, 2H), 1.04 million (m, 2H), 4,07 (d, 2H), 4,22 (s, 2H), 4,33 (m, 4H), 5,06 (ush. s, 2H), 7,92 (s, 1H), 8,68 (s, 1H)

ESI: 464 [M+H]+C14H16F6N5O4P

Example 49

Synthesis of bis(2,2,2-triptorelin) [1-({2-amino-[6-(4-were)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (compound 62)

The compound synthesized according to example 25, further used for the reaction carried out in the same manner as described in example 47, obtaining specified in the connection header.

1H NMR (CDCl3) (0,88 (m, 2H), of 1.03 (m, 2H), 2,39 (s, 3H), 4,06 (d, 2H), 4,19 (s, 2H), 4,33 (m, 4H), 4,76 (ush. s, 2H), 7,22 (d, 2H), 7,50 (d, 2H), 7,82 (s, 1H)

ESI: 586 [M+H]+C21H22F6N5O4PS

Example 50

Synthesis of bis(2,2,2-triptorelin) [(1-{[2-amino-6-hydroxy-N-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate (compound 45)

The compound synthesized according to example 4, then used for the reaction carried out in the same manner as described in example 47, obtaining specified in the connection header.

1H NMR (CDCl3) (0,91 (m, 2H), of 1.05 (m, 2H), 4,08 (d, 2H), 4,17 (s, 2H), 4,35 (m, 4H), 4,70 (s, 2H), 7,69 (s, 1H)

MW=478 [M+H]+479 C14H16F6N5O5P

Example 51

Synthesis of bis(2,2,2-triptorelin)(1-{[2-amino-6-cyclopropylamino-N-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate (compound 50)

The compound synthesized according to example 7, then used for the reaction carried out in the same manner as described in example 47, obtaining specified in the connection header.

1H NMR (CDCl3) (0,60 (ush. s, 2H), 0,84 (ush. s, 4H), 1,01 (m, 2H), 2,98 (ush. s, 1H), 4,05 (d, 2H), 4,14 (m, 4H), 4,70 (ush. s, 2H), 5,67 (ush. s, 1H), 7,60 (s, 1H)

ESI: 519, [M+H]+C17H21F6N6O4P

Example 52

Synthesis of ({1-[(2-amino-N-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonic acid (compound 98)

The derivative of 6-chloroguanine, synthesized according to example 12, further used for the reaction carried out in the same manner as described in example 5, to obtain specified in the connection header.

1H NMR (MeOH-d4) (0,68 (t, 1H), 1,13 (m, 1H), 1,21 (d, 3H), of 1.42 (t, 1H), 3,84 (t, 1H), 3,97 (t, 1H), and 4.40 (d, 1H), 4,66 (d, 1H), 8,63 (s, 1H), 8,73 (s, 1H)

ESI: 314 (M+1)+C11H16N5O4P

The connection according to the present invention has potent pharmacological activity against cell lines hepatitis b, HepG2.2.15, and to transgenic mice, widely used for development of therapeuti the definition of the agent against hepatitis b virus in intravenous and oral administration. Experimental conditions and results obtained are described below.

Experiment 1

Identification and analysis of the inhibitory action against the hepatitis b virus (HBV)

(1) cell Culture and treatment drugs

HepG2.2.15 cells (M.A.Shells et al., P.N.A.S. 84, 1005 (1987)), the cell line of hepatocarcinoma producing hepatitis b virus, were maintained in DMEM (GIBCO BRL, #430-2200)containing 10% FBS (fetal bovine serum, GIBCO BRL, #16000-044), 1% AB (antibiotic-antimycotic agent, GIBCO BRL, #16000-028) and 400 μg/ml of geneticin (Sigma #G-9516), in T-75 flask in terms incubator with 5% CO2and 37°when diluted in the ratio of 1:3 with an interval of 3 days. The cells were distributed in 96-well tablet 4×104/well, and then, when they reached 80-90% of the density of cells, the old medium was replaced with 200 μl of DMEM medium containing 2% FBS, 1% ABAM and 400 μg/ml of geneticin. The solution of a medicinal product was sequentially diluted each time five-fold, from 100 M to 0.16 M in order to minimize experimental error, each treatment with appropriate drugs were repeated 2-3 times. The medium was changed every two days. On the 10th day after treatment drug selected 100 µl of the environment and determined the degree of inhibition of drug virus replication by quantitative PCR method (polymerase is a chain reaction).

(2) Determination of cytotoxicity

After 100 μl of medium was selected on the 10th day after the treatment drug, to each well was added a solution of 7.5 mg/ml MTT (Thiazolyl Blue Tetrazolium Bromide, Amresco, #0793-5G) in an amount of 30 μl/well and each cell was cultured for 2 hours at 37°C incubator in an atmosphere of 5% CO2. The solution was discarded and each well was added a solution of isopropanol containing 10% Triton X-100 and 0.4 µl of concentrated HCl, in the amount of 120 µl/well. Thus, the stained cells were transferred to isopropanolic solution by shaking for 2 hours. Then the absorbance was measured at 540 nm using Elisa Reader.

(3) evaluation of the inhibitory actions in relation to the replication of hepatitis b virus, carried out using PCR

The degree of inhibition by drugs of the replication of hepatitis b virus was determined using solution culture cells collected on day 10 after treatment this drug. Solution culture cells treated with each drug was diluted ten times with distilled water and subjected to the pretreatment in order to destroy cells by heating them for 15 minutes at 95°C. For amplification of the gene fragment using PCR, consisting of 320 base pairs, base in 2001 the position that is to nservative all podstupah hepatitis b virus, and the base 2319 position that is between the core gene of the antigen and polymerase gene, was used as the 5'-end and 3'end primers, respectively. Then estimated the amount of DNA of the genome of hepatitis b virus and, based on this determined the inhibitory effect exerted drugs on viral replication of hepatitis C.

First, the solution cell culture hepatitis b virus, which was not treated with the drug, serially diluted and amplified by PCR. Amplified DNA was subjected to electrophoresis in 2%agarose gel and stained with ethidiumbromid (EtBr)to analyze by using the IS-1000 (Innotech Scientific Corporation) Digital Imaging System. Then spend analysis solution cell culture treated with drug using thinning in the area where continued linearity. DNA obtained from cell cultures treated with the medicinal product, amplified by the same PCR method were subjected to electrophoresis in 2%agarose gel, stained with ethidiumbromid and analyzed by using the IS-1000. The degree of inhibition drugs virus replication was assessed quantitatively by calculating the relationship of the tested cell cultures to the control cell culture. Table 8 summarizes the data inhibit the nogo activity (pharmacological activity and toxicity) of typical compounds according to the present invention.

Table 8
Connection # EU50(μm) in HBVCC50(μm) in HepG2.2.15
Comparative compound PMEA5,0>500
1>1,0>1000
2>0,1>1000
3>0,5>1000
5>0,1>1000
9>0,3>1000
10>0,08>1000
11>20>1000
13>1,0>1000
15>0,8>1000
17>0,5>1000
19>0,3>1000
23>0,1>1000
25>5,0>1000
31>50>1000
37>5,0>1000
41>1,0>1000
45>0,5>1000
46>1,0>1000
62>0,5>1000
66>0,1>1000
69>1,0>1000
95>0,5>1000
97>0,05>1000
98>1,0>1000
99>5,0>1000
100>0,05>1000
101>0,1>1000

As can be seen from the data presented in table 8, the connection according to the present invention exhibits 4-10 times more active than the comparative compound, RMEA, which is in phase III clinical trials.

Experiment 2

Pharmacological test carried out on transgenic mice (T/G mouse)

The following test compounds according to the invention was administered subcutaneous and oral.

The test compounds were injected 4-5 weeks HBV transgenic mice, which were obtained from mice of the FVB strain by the method described in the message (see Jone D.Morrey, Kevin W.Bailey, Brent E.Korba, Robert W.Sidwell, "Utilization of transgenic mice replicating high levels of hepatitis B virus for antiviral evaluation of lamivudine" Antiviral research, 1999, 42, 97-108), subcutaneously within 9 days at 10 mg/kg/day orally for 9 days at 10, 2 and 0.4 mg/khder, once per day, respectively (use the same number of males and females). The blood was collected from the tail of a mouse and received 5 μl of serum. To this serum was added 15 ml of Genereleaser sol, which was then subjected to pre-treatment at different temperatures. DNA HBV (hepatitis b virus) were prepared from the treated solution. DNA amplified by PCR method (polymerase chain reaction) in the presence of 4 μl of 10 (buffer (Perkin Elmer), and 0.8 μl of 10 mm dNTP, 500 ng of the same HBV primers that were used in experiment 1, 2,125 mm MgCl2, DMSO and Taq polymerase. To assess pharmacological actions of the compounds according to the present invention determined the amount of virus DNA (HBV by electrophoresis. The results are shown in the following table 9. In the following table 9 shows that mice who had observed pharmacological effect, represent mice whose blood does not contain HBV DNA.

td align="center"> 4/4
Table 9
Connection # Quantity (mg/kg/day)Results*Route of administration
23104/4Subcutaneous
66104/4Subcutaneous
9710Subcutaneous
95103/4Subcutaneous
98104/4Subcutaneous
RMEA dipivoxil21/3Oral
RMEA dipivoxil0,41/6Oral
1024/4Oral
100,45/6Oral
*The results indicate the number of mice that have watched farmakologicheski effect/number of mice in the experiment.

As can be seen from the above table, the connection according to the present invention has a powerful therapeutic effect against hepatitis b In the test animals after oral or subcutaneous administration. In particular, because the connection according to the present invention showed better results than the comparative compound, RMEA, which is in phase III clinical trials, I believe that the connection according to the present invention can be effectively used for the treatment of hepatitis C.

1. Acyclic nukleotidfosfatazu derivative represented by the following formula (1)

in which

represents a single bond or a double bond, R1represents hydrogen,

R2, R3independently from each other represent hydrogen or C1-C7-alkyl,

R7and R8independently from each other represent hydrogen or C1-C4-alkyl,

R4and R5independently of one another represent hydrogen or represent a1-C4-alkyl, possibly substituted by one or more halogen, or represent -(CH2)m-OC(=O)-R6where m denotes an integer from 1 to 5 and R6represents a C1-C7-alkyl or a 3-6-membered heterocycle containing 1 or 2 heteroatoms selected from the group consisting of nitrogen and oxygen,

Y represents-O-, -CH(Z)-,=C(Z)-,-N(Z), where Z represents hydrogen, hydroxy or halogen, or represents C1-C7-alkyl,

Q represents a group having the following formula:

where

X1represents hydrogen, amino, hydroxy or halogen, or represents C1-C7-alkyl, C1-C5-alkoxy, or represents C6-C10-aaltio, which may substituted NITR is, amino, C1-C6-alkyl or C1-C4-alkoxy, or represents C1-C7-alkylamino, di(C1-C7-alkyl) amino, C3-C6-cyclooctylamino, or structurewhere n denotes an integer of 1 or 2 and Y1represents O, CH2or N-R (R represents a C1-C7-alkyl),

X2represents hydrogen, amino,

X3represents hydrogen or C1-C7-alkyl,

X4represents amino,

its pharmaceutically acceptable salt or stereoisomer.

2. The compound according to claim 1 where the pharmaceutically acceptable salt is a salt of sulfuric acid, methanesulfonate or kaleidotrope acid.

3. The compound according to claim 1, where

represents a single bond,

R1, R2, R3, R7and R8represent hydrogen,

R4and R5independently of one another represent hydrogen, or represent With1-C4-alkyl, possibly substituted by one or more fluorine atoms, or represent -(CH2)m-OC(=O)-R6where m denotes an integer from 1 to 5 and R6represents a C1-C7-alkyl, C1-C5-alkoxy or a 3-6-membered hetero is ikl, containing 1 or 2 heteroatoms selected from the group consisting of nitrogen and oxygen,

Y represents-O - or-N(Z), where Z represents hydrogen, hydroxy, C1-C7-alkyl,

Q represents a group having the following formula:

where

X1represents hydrogen, amino, hydroxy or halogen, or represents C1-C7-alkyl, C1-C5-alkoxy, or represents C6-C10-aaltio, which may substituted by nitro, amino, C1-C6-alkyl or C1-C4-alkoxy, or represents C1-C7-alkylamino, di (C1-C7-alkyl) amino, C3-C6-cyclooctylamino or structurewhere n denotes an integer of 1 or 2 and Y1represents O, CH2or N-R (R represents a C1-C7alkyl), and

X2represents hydrogen, amino, X3represents hydrogen or C1-C7-alkyl, X4represents amino.

4. The compound according to claim 1, which is selected from a group representing the following connections:

({1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate acid (compound 1);

3-[({1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ 5-Fofanov-1-yl, pivalate (compound 2);

({1-[(2-amino-6-chloro-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate acid (compound 3);

3-[({1-[(2-amino-6-chloro-9H-purine-9-yl) methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 4);

({1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate acid (compound 5);

3-[({1-[(2-amino-6-hydroxy-9H-purine-9-yl) methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 6);

({1-[(2-amino-9H-purine-9-yl) methyl]cyclopropyl}oxy)methylphosphonate acid (compound 9);

3-[({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 10);

({1-[(2-amino-6-cyclopropylamino-9H-purine-9-yl) methyl]cyclopropyl}oxy)methylphosphonate acid (compound 11);

[(1-{[2-aminc-6-(dimethylamino)-9H-purine-9-yl]methyl}cyclopropyl) oxy]methylphosphonate acid (compound 15);

3-{[(1-{[2-amino-6-(dimethylamino)-9H-purine-9-yl]methyl}cyclopropyl)oxy]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 16);

[(1-{[2-amino-6-(isopropylamino)-9H-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate acid (compound 17);

3-{[(1-{[2-am is but-6-(isopropylamino)-9H-purine-9-yl]methyl}cyclopropyl)oxy]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ 5-Fofanov-1-yl, pivalate (compound 18);

({1-[(2,6-diamino-9H-purine-9-yl)-methyl]cyclopropyl}oxy)methylphosphonate acid (compound 19);

3-[({1-[(2,6-diamino-9H-purine-9-yl)methyl]cyclopropyl}oxy) methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 20);

({1-[(2-amino-6-methoxy-9H-purine-9-yl)-methyl]cyclopropyl}oxy)methylphosphonate acid (compound 21);

3-[({1-[(2-amino-6-methoxy-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 22);

({1-[(2-amino-6-ethoxy-9H-purine-9-yl)-methyl]cyclopropyl}oxy)methylphosphonate acid (compound 23);

3-[({1-[(2-amino-6-ethoxy-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 24);

[(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl}cyclopropyl)oxy]methylphosphonate acid (compound 31);

8,8-dimethyl-3-{[(1-{[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]methyl-cyclopropyl)oxy]methyl}was 3.7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 32);

[(1-{[2-amino-6-(4-morpholinyl)-9H-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate acid (compound 37);

3-{[(1-{[2-amino-6-(4-morpholinyl)-9H-purine-9-yl]methyl}cyclopropyl)oxy]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trick the a-3λ 5-Fofanov-1-yl, pivalate (compound 38);

bis(2,2,2-triptorelin)({1-[(2-amino-6-hydroxy-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 45);

bis(2,2,2-triptorelin)({1-[(2-amino-6-chloro-9H-purine-9-yl) methyl] cyclopropyl} oxy) methylphosphonate (compound 46);

bis(2,2,2-triptorelin)({1-[(2,6-diamino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 47);

bis(2,2,2-triptorelin)({1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy) methylphosphonate (compound 48);

bis(2,2,2-triptorelin)({1-[(2-amino-9H-purine-9-yl)methyl] cyclopropyl}oxy) methylphosphonate (compound 49);

bis(2,2,2-triptorelin)({1-[(2-amino-6-dimethylamino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 52);

bis(2,2,2-triptorelin)({1-[(2-amino-6-isopropylamino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 53);

bis(2,2,2-triptorelin)({1-[(2-amino-6-methoxy-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 54);

bis(2,2,2-triptorelin)[(1-{[2-amino-6-(4-morpholinyl)-9H-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate (compound 58);

bis(2,2,2-triptorelin)[(1-{[2-amino-6-(phenylsulfanyl)-N-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate (compound 61);

bis(2,2,2-triptorelin){[1-({2-amino-6-[(4-were)sulfanyl]-9H-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (connected to the e 62);

bis(2,2,2-triptorelin){[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (compound 63);

bis(2,2,2-triptorelin){[1-({2-amino-6-[(4-nitrophenyl)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (compound 64);

[(1-{[2-amino-6-(phenylsulfanyl)-9H-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate acid (compound 65);

{[1-({2-amino-6-[(4-were)sulfanyl]-9H-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate acid (compound 66);

3-({[1-({2-amino-6-[(4-were)sulfanyl]-N-purine-9-yl}methyl)cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 68);

bis{[(tert-butoxycarbonyl)oxy]methyl}({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 69);

bis{[(isopropoxycarbonyl)oxy]methyl}({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 70);

bis{[(etoxycarbonyl)oxy]methyl}({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 71);

bis{[(isobutoxide)oxy]methyl}({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 72);

3-[({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-9-methyl-3,7-dioxo-2,4,6-trioxa-3λ5-popadic-1-yl 3-methylbutanoate (compound 74);

3-[({1[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8-methyl-3,7-dioxo-2,4,6-trioxa-3λ 5-Fofanov-1-yl 2-methylpropanoate (compound 78);

3-({[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 79);

3-[({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]was 3.7-dioxo-7-(1-pyrrolidinyl)-2,4,6-trioxo-3λ5-phospahate-1-yl 1-pyrrolidinecarboxylic (compound 80);

3-[({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]was 3.7-dioxo-7-(1-piperidinyl)-2,4,6-trioxo-3λ5-phospahate-1-yl 1-piperidinecarboxylate (compound 81);

3-[({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-7-(4-morpholinyl)was 3.7-dioxo-2,4,6-trioxa-3λ5-phospahate-1-yl 4-morpholinylcarbonyl (compound 82);

bis{[(tert-butoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate (compound 83);

bis{[(isopropoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purine-9-yl]methyl}cyclopropyl)oxy]methylphosphonate (compound 84);

bis{[(isopropoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (compound 85);

3-[({1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-7-cyclopentyl-3,7-dioxo-2,4,6-trioxa-3λ5-phospahate-1-Il cyclopentanecarboxylate (compound 8);

3-({[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purine-9-yl}methyl)cyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 87);

bis{[(isopropoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (compound 88);

bis{[(isopropoxycarbonyl)oxy]methyl}({1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate (compound 89);

3-[({1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-9-methyl-3,7-dioxo-2,4,6-trioxa-3λ5-popadic-1-yl 3-methylbutanoate (compound 90);

3-[({1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-7-cyclopentyl-3,7-dioxo-2,4,6-trioxa-3λ5-phospahate-1-Il cyclopentanecarboxylate (compound 91);

bis{[(tert-butoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)-cyclopropyl]oxy}methylphosphonate (compound 92);

bis{[(tert-butoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate (compound 93);

{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate acid (compound 95);

{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)cyclopropyl]oxy}methylphosphonate acid (compound 96);

({1-[(2-and the Ino-6-hydroxy-9H-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate acid (compound 97);

({1-[(2-amino-9H-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate acid (compound 98);

{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate acid (compound 99);

{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate acid (compound 100);

{[1-({2-amino-[6-(4-were)sulfanyl]-9H-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate acid (compound 101);

({1-[(2,6-diamino-9H-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate acid (compound 102);

({1-[(6-amino-9H-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate acid (compound 103);

3-[({1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 105);

3-[({1-[(2-amino-9H-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 106);

3-[({1-[(6-amino-N-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 107);

3-({[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5Foz is anon-1-yl, pivalate (compound 108);

bis{[(isopropoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purine-9-yl]methyl}-2-methylcyclopropyl)SCSI]methylphosphonate (compound 109);

bis{[(isopropoxycarbonyl)oxy]methyl}({1-[(2-amino-N-purine-9-yl)methyl]-2-methylcyclopropyl}oxy)methylphosphonate (compound 110);

bis{[(isopropoxycarbonyl)oxy]methyl}-{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-N-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (compound 112);

bis{[(tert-butoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (compound 113);

bis(2,2,2-triptorelin){[1-({2-amino-6-[(4-methoxyphenyl)sulfanyl]-9H-purine-9-yl}methyl)-2 - methylcyclopropyl]oxy}methylphosphonate (compound 114);

bis(2,2,2-triptorelin){[1-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (compound 115);

bis{[(tert-butoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (compound 116);

bis{[(isopropoxycarbonyl)oxy]methyl}{[1-({2-amino-[6-(4-nitrophenyl)sulfanyl]-9H-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methylphosphonate (compound 117);

3-({[1-({2-amino-6-[(4-nitrophenyl)sulfanyl]-9H-purine-9-yl}methyl)-2-methylcyclopropyl]oxy}methyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5 -Fofanov-1-yl, pivalate (compound 118);

({1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]cyclopropyl}amino)methylphosphonous acid (compound 119);

({1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}amino)methylphosphonous acid (compound 120);

({1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}amino)methylphosphonous acid (compound 121);

[{1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]cyclopropyl}(methyl)amino]methylphosphonous acid (compound 122);

[{1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}(ethyl)amino]methylphosphonous acid (compound 125);

3-{({(1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl} (methyl) amino]methyl}-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 126);

bis{[(isopropoxycarbonyl)oxy]methyl}[{1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}(methyl)amino]methylphosphonate (compound 127);

3-{[{1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl} (ethyl) amino] methyl}-8,8-dimethyl-3,7-dioxo-2,4, 6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 129);

2-{1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl] cyclopropyl}ethylphosphonate acid (compound 138);

2-{1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}ethylphosphonate acid (compound 139);

2-{1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}ethylphosphonate acid (compound 140);

2-[1-({2-amino-6-[(4-were)Sul is panel]-9H-purine-9-yl}methyl)cyclopropyl]ethylphosphonate acid (compound 141);

2-{1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]cyclopropyl}propylphosphonic acid (compound 142);

2-{1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}propylphosphonic acid (compound 143);

2-{1-[(2-amino-9H-purine-9-yl)methyl]cyclopropyl}propylphosphonic acid (compound 144);

3-(-2-{1-[(6-amino-9H-purine-9-yl)methyl]cyclopropyl}propyl)-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 145);

({1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methylphosphonate acid (compound 146);

({1-[(2-amino-9H-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methylphosphonate acid (compound 147);

({1-[(6-amino-9H-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methylphosphonate acid (compound 148);

3-[({1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 149);

3-[({1-[(2-amino-9H-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 150);

3-[({1-[(6-amino-9H-purine-9-yl)methyl]-2,2-dimethylcyclopropane}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pivalate (compound 151);

bis{[(isopropoxycarbonyl)oxy]methyl}({1-[(6-amino-9H-purine-9-yl)methyl]-2,dimethylcyclopropene}oxy)methylphosphonate (compound 152); and

bis{[(isopropoxycarbonyl)oxy]methyl}[(1-{[2-amino-6-hydroxy-9H-purine-9-yl]methyl}-2,2-dimethylcyclopropane)oxy]methylphosphonate (compound 153).

5. The compound according to claim 1, whererepresents a single bond, R1, R3, R7and R8independently of one another represent hydrogen, R2represents hydrogen or methyl, R4and R5independently from each other represent a tert-BUTYLCARBAMATE, isopropoxycarbonyloxymethyl or 2,2,2-triptorelin, Y represents-O-, Q is a

where X1represents hydrogen, hydroxy, ethoxy, 4-methoxyphenyl or 4 nitrophenylthio, X2represents amino.

6. The method of obtaining the compounds of formula (1)as defined in claim 1, characterized in that the compound represented by the following formula (2)

in which R1, R2, R3, R4, R5, R7, R8and Y are as defined in claim 1, L represents a removable group, including methanesulfonate, p-toluensulfonate group or halogen interacts with the compound represented by the following formula (3):

QH (3)

in which Q is a group defined in claim 1, with the teachings of the compounds of formula (1).

7. The method of obtaining the compounds of formula (1)as defined in claim 1, characterized in that the compound represented by the following formula (9)

in which R1, R2, R3, R7, R8, Y and L are as described in claim 6, and R9and R10independently from each other represent

possibly substituted alkyl, interacts with the compound of the formula (3)

QH (3)

in which Q is a group defined in claim 1,

to obtain compounds represented by the following formula (10)

in which R1, R2, R3, R7, R8, Y, Q, R9and R10are as previously described, and the obtained compound of the formula (10) hydrolyzing in the presence of a Lewis acid to obtain compounds represented by the following formula (1A):

in which R1, R2, R3, R7, R8, Y and Q are as described above, or

group R4'and R5'introducing the compound of the formula (1A) to obtain the compounds represented by the following formula (1b):

in which R1, R2, R3, R7, R8, Y and Q are as described above and R 4'and R5'are R4and R5with the exception of hydrogen, respectively.

8. Phosphonate compound represented by the following formula (2):

in which

R1, R2, R3, R4, R5, R7, R8and Y are as defined in claim 1, and

L represents a group to delete, including methanesulfonate, p-toluensulfonate group or halogen.

9. The use of acyclic nukleotidfosfatazu derivative of formula (1), its pharmaceutically acceptable salt or stereoisomer for the treatment of hepatitis C.

10. The compound according to claim 1, which represents a ({1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]cyclopropyl}oxy)-methylphosphonous acid.

11. The compound according to claim 1, which represents a({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate acid.

12. The compound according to claim 1, which represents a 3-[({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methyl]-8,8-dimethyl-3,7-dioxo-2, 4, 6-trioxa-3λ5-Fofanov-1-yl, pialat.

13. The use of acyclic nukleotidfosfatazu derivative of formula (1), its pharmaceutically acceptable salt or stereoisomer in getting medicines for the treatment of hepatitis B.

14. Use item 13, where the acyclic nucleotidebinding proizvoditeli (1) is ({1-[(2-amino-6-hydroxy-9H-purine-9-yl)methyl]cyclopropyl}oxy)-methylphosphonous acid.

15. Use item 13, where the acyclic nucleotidebinding derivative of formula (1) is ({1-[(2-amino-N-purine-9-yl)methyl]cyclopropyl}oxy)methylphosphonate acid.

16. Use item 13, where the acyclic nucleotidebinding derivative of formula (1) is 3-[({1-[(2-amino-9H-purine-9-yl) methyl] cyclopropyl}oxy) methyl]-8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3λ5-Fofanov-1-yl, pialat.



 

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FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to technology of organic compounds, namely, to 5'-aminocarbonylphosphonates d4T that are inhibitors of the human immunodeficiency virus reproduction. Invention describes 5'-aminocarbonylphosphonates d4T of the general formula: wherein R' means hydrogen atom (H), alkyl, aryl; R'' means hydrogen atom (H), alkyl, aryl; R', R'' mean cyclic alkyl; R means alkyl. These compounds are inhibitors of the human immunodeficiency virus reproduction. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable medicinal properties of compounds.

2 dwg, 1 tbl, 5 ex

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The invention relates to methods for treating diseases caused by hepatitis B virus (also known as HBV and Epstein-Barr (also known as EBV, which include the introduction of an effective amount of one or more of the active compounds disclosed here, or farmatsevticheskii acceptable derivatives or prodrugs of one of these compounds

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The invention relates to new chemical compounds - salts 3'-aminopropionic (1'R, 5'R)-3'-Aza-1'-(6-aminopurin-9)-3'-diethoxyacetophenone - 6'-diphosphate General formula

< / BR>
where

< / BR>
or

< / BR>
Cat+is a cation of an alkali metal,

as a specific fluorescent inhibitors of myosin adenosine-5'-triphosphatase (ATPase)

FIELD: organic chemistry, biochemistry, medicine.

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< / BR>
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19 cl, 11 ex

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