Derivatives of adenosine, the method of production thereof, pharmaceutical composition and method of reception

 

(57) Abstract:

The invention relates to derivatives of adenosine General formula I, where R1is a hydrogen atom, halogen atom, lower alkyl, lower-alkyl, lower S-alkyl or phenyl, and may be in the 2 - or 5-position of the indole; n = 0, 1, and 2, R2- lower alkyl, lower alkenyl, lower quinil,3-C7-cycloalkyl or lower-alkyl, phenyl, possibly substituted by 1-4 substituents selected from a halogen atom, nitro, lower alkyl or O-alkyl groups or a group-NR6R7where R6and R7a hydrogen atom, lower alkyl; pyridyl; thienyl, naphthyl, and in the case when n = 2, R2group-NR8R9where R8and R9at the same time are lower alkyl or form together with the nitrogen atom to which they are attached, a heterocycle selected from the research, piperidine; R3and R4the same or different, is a hydrogen atom or lower alkyl, exhibiting analgesic and antihypertensive activity. The method of obtaining compounds of formula (I) is that the amine of General formula (II) is subjected to interaction with a 7-galacturonase riboside General formula (III), where X is a halogen atom, R11- R5where R5has the criminal code of the e form a dioxolane group, in a solvent such as alcohol or dimethylformamide, in the presence of a base, such as triethylamine, pyridine or sodium carbonate, or, alternatively, in the presence of two equivalents of amine at 20 -140oC, then remove the protective group in the main environment, the ammonium hydroxide solution or the acidic environment with a normal solution of hydrochloric acid at 0 - 70oWith depending on the nature of the protective group. Also describes pharmaceutical compositions based on compounds of formula (I) exhibiting analgesic and/or anti-hypertensive activity. 6 C. and 7 C. p. F.-ly, 2 tab.

The present invention relates to derivatives of adenosine General formula I, below, as new compounds and, if possible, to their addition salts, in particular pharmaceutically acceptable salts.

The proposed compounds have very valuable pharmacological profile because they are, on the one hand, in particular, analgesic properties, on the other hand, antihypertensive properties.

The present invention relates further to a method for producing the above products, the synthesis intermediates and to the use of these products in therapy.

These prescelly radical, the lower O-alkyl radical, a lower S-alkyl radical or phenyl radical, and may be in 2-, 4-, 5-, 6- or 7 - position of the indole;

n = 0 - 4 integer;

R2lower alkyl radical, lower alkanniny radical, lower alkynylaryl radical, C3-C7-cycloalkyl radical or a lower O-alkyl radical, phenyl radical, unsubstituted or substituted from 1 to 4 identical or different substituents selected from a halogen atom, nitro, lower alkyl, lower O-alkyl or lower S-alkyl groups and the group-NR7R8, R7and R8are a hydrogen atom or a lower alkyl radical, heterocyclic radical, selected from pyridine and thiophene, unsubstituted go substituted from 1 to 4 identical or different substituents selected from a halogen atom, nitro, lower alkyl, lower O-alkyl or lower S-alkyl groups, or, alternatively, when n is 2, 3 or 4, the group-NR9R10, R9and R10at the same time are lower alkyl radical, or form together with the nitrogen atom to which they are attached, a heterocycle selected from the research, piperidine and pyrrolidine,

R3and R4identical or different, are ATO is determined as being radical, C3-C7-cycloalkyl radical or lower alkyl chain with an alcohol or ether functional group, or in addition, the group -(CH2)n-NR9R10where n, R9and R10defined above.

Mainly derivatives according to the invention are derivatives of the formula I, in which R1is a hydrogen atom, halogen atom, lower alkyl radical, a lower O-alkyl radical, a lower S-alkyl radical or phenyl radical, and may be in the 2 - or 5-position of indole, n = 0, 1, or 2, R2lower alkyl radical, lower alkanniny radical, lower alkynylaryl radical, C3-C7-cycloalkyl radical or a lower O-alkyl radical, phenyl or nattily radical, unsubstituted or substituted from one to four identical or different substituents selected from a halogen atom, nitro, lower alkyl or lower O-alkyl groups and the group-NR7R8, R7and R8are a hydrogen atom or a lower alkyl radical, heterocyclic radical, selected from pyridine and thiophene, unsubstituted or substituted by halogen atoms, or, alternatively, when n = 2, the group-NR9R10where R9and R103and R4identical or different, are a hydrogen atom or a lower alkyl radical, and R5- group-other11where R11is a lower alkyl radical, C3-C7-cycloalkyl radical or lower alkyl chain with an alcohol or ether group.

In the description and in the form of the invention under the lower alkyl radical is meant a straight or branched hydrocarbon chain having from 1 to 6 carbon atoms. The lower alkyl radical is, for example, methyl radical, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl or isohexyl.

In the description and in the claims under the lower alkenyl radical mean straight or branched hydrocarbon chain having from 1 to 6 carbon atoms and having a double bond such as, for example, attilly radical, and under the lower alkynylaryl radical mean straight or branched hydrocarbon chain having from 1 to 6 carbon atoms and having a triple bond, such as for example, etinilnoy group.

Under C3-C7-cycloalkyl radical is, illogical or cycloheptyl.

Under the halogen imply chlorine atom, bromine, iodine or fluorine.

Under the lower alkyl chain with Apastovo functional group, mean lower chain, in which one of the hydrogen atoms replaced by a hydroxyl group. This line, for example, is a chain of 1-hydroxy-2-methylpropan-2-yl.

Under the lower alkyl chain with ether functional group, imply lower alkyl chain in which one of the hydrogen atoms substituted lower O-alkyl group. This line, for example, is a chain of 2-methoxyethyl.

With regard to therapeutic possibilities of the adenosine, many derivatives of the nucleoside have been described in the literature. The following works may be mentioned as examples: Journal of Medical Chemistry 1973, vol. 16, no. 4, pages 358 - 64; FR 2 154 527; EP 0 267 878; WO 88/03 148; WO 88/03 147; WO 86/00 310; WO 92/05 177; Biochemical Pharmacology, 1974, vol. 23, pages 2283-89; US 4, 167, 565; EP 0 232 813; US 5, 023, 244.

Among the many works were given essentially only two derivatives with indole 6-position of adenosine.

Thus, article published in Journal of Medical Chemistry, and the patent FR 2 154 527 both describe the same product:

N-6 is h, which is also listed in the document FR 2 154 527 (derived B):

< / BR>
It may be noted that article in the Journal of Medical Chemistry describes the derivative of A with inhibiting the aggregation of platelets activity, while French patent mentions the effect on the Central nervous system, the circulation, the heart and without further clarification, determines that the derivative of B has an antilipolytic activity.

You can specify that in the described compounds, on the one hand, indole derivatives never substituted at the nitrogen atom of the indole, and, on the other hand, the sugar from adenosine is not affected.

Currently, the applicant discovered that, surprisingly and unexpectedly, the substitution at the nitrogen atom of indole ring together with the conversion of the primary alcohol sugar amide functional group provides products, especially valuable pharmacological profile, especially in the field of analgesic funds.

In one embodiment, R1is a hydrogen atom; in another embodiment, R1is a methyl radical; in another embodiment, R1is metaxylem radical.

In one embodiment, n = 0; in another embodiment, n = 1; in another embodiment, n = 2.

In one shaft; in another embodiment, R2is the isopropyl radical; in another embodiment, R2is 2,5-dimethylaniline radical; in another embodiment, R2is piperidinyl radical.

In one embodiment, R3is a hydrogen atom.

In one embodiment, R4is a hydrogen atom: in another embodiment, R4is a methyl radical.

In one embodiment, R5is cyclopropylamine radical.

Particularly preferred compounds according to the invention is selected from derivatives of the formula

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
According to the invention the compounds of formula I can be synthesized as follows.

The interaction of the amine of formula II

< / BR>
in which R1, R2, R3and R4and n are defined above,

6 galacturonase riboside formula III

< / BR>
in which X is a halogen atom, preferably chlorine or bromine;

R12is a group COR5where R5defined above, or a group CH2OH;

R13and R14are protective groups for alcohol functional group, such as, for example, acetyl, benzoyl or benzyl, MD, as, for example, an alcohol, or an aprotic solvent such as dimethylformamide, in the presence of a base such as triethylamine, pyridine or sodium carbonate, potassium or calcium, or, alternatively, in the presence of two equivalents of an amine of formula II with 20-140oC,

will yield the compounds of formula IV

< / BR>
in which R1- R14and n are defined above.

If indolamine derivatives of the formula II have a center of asymmetry, the connection should be considered either in racemic form or optically active form. If it is desirable to obtain optically active production, attention will be paid to the separation of stereoisomers at the stage of indolamine, before connecting with a 6-galogenarenov riboside formula III, conventional methods of separation of optical isomers, known to specialists, for example, by recrystallization of salts formed with optically active grape acid. After the separation of optically active tartratami, optically active base, liberated from its grape acid, is contacted with a 6-galogenarenov riboside formula III.

In the case where the radical R12is CH2OH, it can be oxidized, trioxide the arper and A. Hampton, J.Org. Chem. 1970, 35, N 5, 1688, received ribofuranosyl acid is then converted into the acid chloride acid interactions, such as c-thionyl chloride, and then in amide interaction with the amine by methods known in the art. Removing the protective groups from secondary alcohols OR13and OR14can be done in various ways, for example, in a basic environment, such as ammonia, or acidic medium, such as a normal solution of hydrochloric acid or formic acid, at a temperature that ranges from 0 to 70oC depending on the nature of the protective group.

The sequence of these reactions can make possible the transformation of the derivatives of formula IV in derivatives of the formula I.

The compounds of formula II can be obtained either by direct alkylation of derivatives indetermina formula V

< / BR>
in which R1, R3and R4defined above, and which are commercially available, or the synthesis of which is described in the following literature: P. L. Julian, E. W. Meyer and H. C. Printy, Heterocylic Compounds, John Wiley and Sons, Inc. New York, 1952, vol.3, chapter I, p. 51-57, and J. Harley-Mason and A. H. Jackson, J. Chem. Soc. 1954, 1165, derivative of formula VI

R2- (CH2)n- Y

in which R2and n are defined above;

Y is attri or lithium hydride, or alcosta sodium or potassium, in an organic solvent, such as alcohol or dimethylformamide or N-organic, at temperatures between 0 and 60oC,

or by alkylation of 3-farmindale formula VII

< / BR>
in which R1defined above,

with these derivative of formula VI in the presence of metal-containing agent, such as sodium or lithium hydride, or alcosta sodium or potassium, in an organic solvent, such as alcohol or dimethylformamide, to obtain the derivatives of formula VIII

< / BR>
in which R1and R2and n are defined above.

These derivatives are then subjected to the interaction with the corresponding nitroalkanes in the presence of ammonium acetate to obtain nitrobenzylidene formula IX

< / BR>
in which R1- R4and n are defined above.

These derivatives are then restore catalytic hydrogenation in the presence of Raney Nickel or in the presence of sociallyengaged with obtaining the compounds of formula II.

Other methods of synthesis of derivatives of indoleamine mainly described in the literature and can be used. For example, you can mention the method of synthesis, which includes the interaction of oxalicacid correspond with what oduct and the interaction of the amide functional group with sociallyengaged.

3-formylindole formula (VII) used in these syntheses, are commercially available or known to specialists in this field, for example, of the following links: Organic Syntheses Coll, vol. IV, 539, or can be obtained by methods described in the literature, for example, in Organic Syntheses Coll., vol. IV, 542.

6-Halogenfrei formula III obtained from inosine ways described in the following literature:

R. R. Schmid and H. T. Fritz, Chem. Ber. 1970, 103, 1867; H. M. Kissman and M. J. Weiss, T.Org. Chem. 1956, 21, 1053; B. R. Baker, K. Hewson, H. J. Thomas and T. A. Johnson Jr, T.Org. Chem. 1957, 22, 954; J. Zemlicka and F. Sorm, Coll. Czech. Chem. Commun. 1985, 30, (6), 1880.

The compounds of formula I, as described above, and their salts of addition, in particular, pharmaceutically acceptable salt, have a good affinity for adenosine receptors. This affinity leads then to a good analgesic activity and hypertensive properties.

These properties is called the use of derivatives of formula I in therapy, and the invention further relates to the products listed above formula I as medicaments, to their addition salts and, in particular, to pharmaceutically acceptable salts.

Thus, the invention also encompasses a pharmaceutical composition comprising a pharmaceutically effective kolichestvo addition salts, which can be combined or not combined with a pharmaceutically acceptable additive, diluent or carrier.

These compositions may be administered orally, rectal, parenteral, subcutaneous or eye by way of introduction.

These compounds can be solid or liquid and may be in the pharmaceutical forms commonly used in medicine for humans, such as, for example, simple or coated tablets, gelatin capsules, suppositories, preparations for injection. They are obtained in the usual way. An active basis, which contains a pharmaceutically effective amount of at least one of the compounds of formula I, above, or one of its pharmaceutically acceptable salts, may be mixed with additives usually used in these pharmaceutical compositions, such as talc, gum Arabic, lactose, starch, magnesium stearate, polyvidone, derivatives of cellulose, cocoa butter, semisynthetic glycerides, aqueous or non-aqueous solvents, fatty substances of animal or vegetable origin, glycols, various wetting agents, dispersants or emulsifiers, silicone gels, some polymers or copolymers, protective substances, urameshi activity especially successfully used for pain, which contains a pharmaceutically effective amount of at least one of the compounds of formula I, above, or one of its pharmaceutically acceptable salts, which can be combined or not combined with a pharmaceutically acceptable additive, diluent or carrier.

The invention also covers a pharmaceutical composition with antihypertensive activity successfully used to treat hypertension, which contains a pharmaceutically effective amount of at least one of the compounds of formula I, above, or one of its pharmaceutically acceptable salts, which can be combined or not combined with a pharmaceutically acceptable additive, diluent or carrier.

The invention also encompasses a method of obtaining a pharmaceutical composition, which comprises mixing pharmaceutically effective amount of at least one of the compounds of formula I, above, or one of its pharmaceutically acceptable salts to a pharmaceutically acceptable additive, the solvent or carrier. In one implementation of the obtained pharmaceutical composition with analgesic activity with antihypertensive activity is particularly successfully used for hypertension.

In another embodiment, the pharmaceutical composition is made up in the form of gelatin capsules or tablets containing from 5 to 300 mg of active ingredient, or as preparations for injection containing from 0.1 to 100.0 mg of the active ingredient. Can also be used compounds in the form of suppositories, rastrac, creams, gels and aerosol preparations.

The invention also covers a method of therapeutic treatment of mammals, which includes the appointment of this mammal a therapeutically effective amount of at least one of the compounds of formula I, as defined above, or one of its pharmaceutically acceptable salts. In one embodiment of this method of treatment of a compound of formula I either alone or in combination with pharmaceutically acceptable additives used in the form of gelatin capsules or tablets containing from 5 mg to 300 mg of active ingredient for oral administration or in preparations for injection containing from 0.1 to 100.0 mg of the active ingredient, or, alternatively, in the form of suppositories, rastrac, creams, gels and aerosol preparations.

In the treatment of human or animal compounds of formula I or its salts may be administered by themselves AI tablets for oral administration or in the form of an injectable solution for parenteral administration. Can be considered and other forms for use in the treatment, such as suppositories, rubbing, creams, gels and aerosol preparations.

As will become clear from the pharmacological tests, presented in the end of the description, the compounds according to the invention can be used in the treatment of a person under the above testimony, orally in the form of tablets or gelatin capsules containing from 5 to 300 mg of active ingredient, or parenterally in the form of preparations for injection containing from 0.1 to 100.0 mg of the active ingredient, one or more servings per day for an adult with an average weight of from 60 to 70 kg.

When treating animals daily dose, which can be applied, will usually be between 0.1 and 50.0 mg per 1 kg via oral route of administration and between 0.01 and 1.0 mg per 1 kg when administered intravenously.

Further characteristics and advantages of the invention will be understood more clearly from the following description of some examples, which do not imply limitation of the invention, but are given only for the purpose of illustration.

Example 1. - D-Ribofuranoside-1-(6-chloro-N-purine-9-yl)-N - cyclopropyl-1-deoxy-2,3-O-(1-methyl-ethylidene)

Formula III: X - Cl;

< / BR>
R13and R14- isopropylidene

the 50 ml of anhydrous CHCl3stabilized amilina, refluxed for 5 h in the presence of 86 ml SOCl2in 10 ml of anhydrous DMF.

The excess SOCl2and the solvent is distilled off. The residue is treated with 200 ml of anhydrous chloroform and added dropwise in a nitrogen to a mixture of 150 ml of CHCl3and 41 ml of cyclopropylamine, pre-cooled to 5oC. during the addition of the carboxylic acid the temperature of the reaction mixture is kept lower than 10oC.

The mixture is left to react over the next 30 min and then washed 3 times with dilute HCl solution and then with sodium bicarbonate solution. In conclusion, washed with water, then dried and evaporated the solvent, the result of 26.3 g of brown oil.

Purification by chromatography on silica gel (eluent: CH2Cl290%/acetone 10%) give 15.7 g - D-ribofuranoside-1-(6-chloro-N-purine-9-yl)-N-cyclopropyl-1-deoxy - 2,3-O-(1-methylethylidene) as an amorphous solid product.

The compounds of examples 2-4 were obtained by the method of example 1 using the appropriate amine.

Example 2. - D-Ribofuranoside-1-(6-chloro-N-purine-9-yl)- 1-deoxy-N-ethyl-2,3-O-(1-methylethylidene).

Formula III: X - Cl;

R13and RoC.

Example 3. - D-Ribofuranoside-1-(6-chloro-N-purine-9-yl)- 1-deoxy-N-(1-hydroxy-2-methylpropan-2-yl)-2,3-O-(1-methylethylidene).

Formula III: X - Cl;

R13and R14- isopropylidene.

Brown oil purified by chromatography on silica gel (eluent: chloroform 90%/methanol 10%).

Example 4. - D-Ribofuranoside-1-(6-chloro-N-purine-9-yl)- 1-deoxy-N-isopropyl-2,3-O-(1-methylethylidene).

Formula III: X - Cl;

R13and R14- isopropylidene.

Orange oil is purified by chromatography on silica gel (eluent: CHCl390%/acetone 10%).

Example 5. 1-(4-Chlorobenzyl)-3-formylindole.

Formula VIII: R1- H; n = 1; R2- 4-chlorophenyl.

A solution of 58 g of 3-farmindale, 55,9 g K2CO3and 70.9 g of p-chlorobenzylchloride in 200 ml of DMF is refluxed for 2 hours After cooling, the mixture was poured into 2 l of water and pound. The precipitate is filtered off, washed with water and then treated with isopropanol, filtered off, press and washed with pentane to obtain 120 g painted in a cream color solid product.

Purification by recrystallization from ethanol gives 84,4 g of 1-(4-Chlorobenzyl)-3-formylindole, PLA is ptx2">

Example 6. 1-Benzyl-3-formylindole.

Formula VIII: R1- H; n = 1; R2is phenyl.

Recrystallization from ethanol.

The melting point of 111oC (literature: 113-114oC - A. Kalir and S. Szara, J. Med.Chem. (1966), vol. 9, p. 793).

Example 7. 1-(2,6-Dichlorobenzyl)-3-formylindole.

Formula VIII: R1- H; n = 1; R2is 2,6-dichlorophenyl.

Recrystallization from 2-methoxyethanol.

The melting point of 160oC.

Example 8. 1-(Naphthas-1-ylmethyl)-3-formylindole.

Formula VIII: R1- H; n = 1; R2- naphthyl.

The crude solid product is used as such in the next stage.

Example 9. 3-Formyl-1-(pyrid-3-yl)indole.

Formula VIII: R1- H; n = 1; R2pyrid-3-yl.

Purification by chromatography on silica gel (eluent: CHCl395%/methanol 5%).

The melting point 88oC.

Example 10. 1-(4-Methylbenzyl)-3-formylindole.

Formula VIII: R1- H; n = 1; R2- 4-were.

The crude solid product is used as such in the next stage.

The melting point 118oC.

Example 11. 1-(3,4-Dimethylbenzyl)-3-formylindole.

Formula VIII: R1- H; n = 1; R23,4 - dimetilfenil nil)-3-formylindole.

Formula VIII: R1- H; n = 1; R2- 2.5-dimetilfenil.

The crude solid product is used as such in the next stage.

The melting point of 139oC.

Example 13. 1-(2-Methoxyethyl)-3-formylindole.

Formula VIII: R1- H; n = 1; R2- methoxy.

The brown oil is used as such in the next stage.

Example 14. 1-Cyclopentyl-3-formylindole.

Formula VIII: R1- H; n = 0; R2- cyclopentyl.

Brown oil purified by chromatography on silica gel (eluent: chloroform 90%/methanol 10%).

Example 15. 3-Formyl-1-isopropylindole.

Formula VIII: R1- H; n = 0; R2is isopropyl.

The brown oil is used as such in the next stage.

Example 16. 3-Formyl-1-(2-N-morpholinoethyl)indole.

Formula VIII: R1- H; n = 1; R2- N-morpholino.

The solid product is used as such in the next stage.

The melting point of 80oC.

Example 17. 1-(4-Chlorobenzyl)-3-(2-nitrovinyl)indole.

Formula VIII: R1- H; n = 1; R2- 4-chlorophenyl, R3-R4- H.

of 80.9 g of 1-(4-Chlorobenzyl)-3-formylindole obtained in example 5, 18 g of the acetate of shumilkin) is I an orange residue. It is filtered off and washed with water and then with isopropanol and hexane to obtain 81,1 g of orange crystals of 1-(4-Chlorobenzyl)-3-(2-nitrovinyl)indole.

The melting point 178oC.

Nitrobenzylidene examples 18-28 were obtained by the method of example 17.

Example 18. 1-Benzyl-3-(2-nitrovinyl)indole.

Formula IX: R1- H; n = 1; R2is phenyl; R3-R4- H.

The melting point 130oC.

Example 19. 1-(2,6-Dichlorobenzyl)-3-(2-nitrovinyl)indole.

Formula IX: R1- H; n = 1; R2is 2,6-dichlorophenyl, R3= R4- H,

Melting point: 170oC.

Example 20. 1-Naphthylmethyl-3-(2-nitrovinyl)indole.

Formula IX: R1- H; n = 1; R2- naphthyl, R3= R4- H.

The melting point of 196oC.

Example 21. 1-(Pyrid-3-ylmethyl)-3-(2-nitrovinyl)-indole.

Formula IX: R1- H; n = 1; R2pyrid-3-yl; R3= R4- H.

The melting point of 165-170oC.

Example 22. 1-(Methylbenzyl)-3-(2-nitrovinyl)indole.

Formula IX: R1- H; n = 1; R2- 4-were; R3= R4- H.

Orange oil is purified by chromatography on silica gel(eluent:chloroform 95%/Isopropylamine>= 3,4-dimetilfenil; R3=R4- H.

The melting point 135oC.

Example 24. 1-(2,5-Dimethylbenzyl)-3-(2-nitrovinyl)indole.

Formula IX: R1- H; n = 1; R2= 2.5-dimetilfenil; R3= R4- H.

The melting point 145oC.

Example 25. 1-(2-Methoxyethyl)-3-(2-nitrovinyl)indole.

Formula IX: R1- H; n = 2; R2- methoxy, dimetilfenil; R3= R4- H.

The melting point 132oC.

Example 26. 1-Cyclopentyl-3-(2-nitrovinyl)indole.

Formula IX: R1- H; n = 0; R2- cyclopentyl; R3= R4- H.

Orange oil is purified by chromatography on silica gel. Eluent: methylene chloride.

Example 27. 1-Isopropyl-3-(2-nitrovinyl)indole.

Formula IX: R1- H; n = 0; R2is isopropyl, R3= R4- H.

Orange oil is used as such in the next stage.

Example 28. 1-(2-N-Morpholinoethyl)-3-(2-nitrovinyl)-indole.

Formula IX: R1- H; n = 2; R2- N-morpholino; R3= R4- H.

The melting point of 114oC.

Example 29. 1-(4-Chlorobenzyl)-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 1; R2- 4-chlorophenyl; R3= R4
oC. No cooling this solution, injected dropwise a solution of 78.2 g of 1-(4-Chlorobenzyl)-3-(2-nitrovinyl)indole obtained in example 17, in 1000 ml of anhydrous THF.

The mixture is refluxed 1 h 30 min and cooled. A saturated aqueous solution of Na2SO4injected dropwise, and the mixture is filtered on celite 545. After decanting, the organic phase is concentrated to obtain an orange oil.

The connection is cleaned first by distillation (boiling point 180-188oC at 0.1 mm RT. Art. ) and then recrystallized from ethanol to obtain 38,1 g of the hydrochloride of 1-(4-Chlorobenzyl)-3-(2-amino-ethyl)indole.

The melting point of the base 87oC.

The melting point of the hydrochloride 212oC.

Example 30. 1-(4-Chlorobenzyl)-3-(2-amino-ethyl)indole.

Formula III: R1- H; n = 1; R2-4-chlorophenyl; R3= R4- H.

10 g of 3-aminoalkylindole dissolved in 50 cm3DMF. Then add 5.6 g NaH (60%).

The mixture is stirred at room temperature for 30 minutes

Add dropwise a solution of 11.2 g of p-chlorobenzylchloride in 10 ml of DMF. The mixture is heated at 55oC for 2 h and cooled. Insoluble material is filtered off. The filtrate was concentrated in in tryout with the receipt of 20.4 g of brown oil.

Purification by chromatography on silica gel (eluent: CHCl395%/ Isopropylamine 5%) to give 9.7 g of 1-(4-Chlorobenzyl)-3-(2-amino-ethyl)indole.

The melting point of the hydrochloride 214oC.

The following compounds of examples 31-45 have been obtained by one of the methods of examples 29-30.

Example 31. 1-Benzyl-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 1; R2is phenyl; R3= R4- H.

Hydrochloride is purified by recrystallization from isopropanol.

The melting point 176-178oC.

Example 32. 1-(2,6-Dichlorobenzyl)-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 1; R2is 2,6-dichlorophenyl; R3=R4- H.

The melting point 68oC.

Example 33. 1-Naphthylmethyl-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 1; R2- naphthyl; R3= R4- H.

Orange oil is purified by chromatography on silica gel (eluent:chloroform 95%/Isopropylamine 5%).

Example 34. 1-(Pyrid-3-ylmethyl)-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 1; R2pyrid-3-yl; R3= R4-H.

Orange oil is purified by chromatography on silica gel (eluent:chloroform 95%/Isopropylamine 5%).

Example 35. 1-(4-Methyl who CLASS="ptx2">

Orange oil is purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%).

Example 36. 1-(3,4-Dimethylbenzyl)-3-(2-amino-ethyl)-indole.

Formula II: R1- H; n = 1; R23,4 - dimetilfenil; R3= R4- H.

Colorless oil, purified by chromatography on silica gel (eluent: methylene chloride 95%/Isopropylamine 5%).

Example 37. 1-(2,5-Dimethylbenzyl)-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 1; R2- 2.5-dimetilfenil; R3= R4- H.

Orange oil is purified by chromatography on silica gel (eluent: methylene chloride 95%/Isopropylamine 5%).

Example 38. 1-(2-Methoxyethyl)-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 2; R2- methoxy; R3= R4- H.

Orange oil is purified by chromatography on silica gel (eluent: chloroform 90%/Isopropylamine 10%).

Example 39. 1-Cyclopentyl-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 0; R2- cyclopentyl; R3= R4- H.

Yellowish oil, purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%).

Example 40. 1-Isopropyl-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 0; R2who: chloroform 95%/Isopropylamine 5%).

Example 41. 1-(2-N,N-Dimethylaminoethyl)-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 2; R2- N,N-dimethylamino; R3= R4- H.

Orange oil is purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%).

Example 42. 1-(2-N-Morpholinoethyl)-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 2; R2- N-morpholino; R3= R4- H.

Orange oil is purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%).

Example 43. 1-(2-N-Piperidinoethyl)-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 2; R2- N-piperidino; R3= R4- H.

Orange oil is purified by chromatography on silica gel (eluent: methylene chloride 95%/Isopropylamine 5%).

Example 44. 1-(N-Pyrrolidinyl)-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 2; R2- N-pyrrolidino; R3= R4- H.

Orange oil is purified by chromatography on silica gel (eluent: methylene chloride 95%/Isopropylamine 5%).

Example 45. 1-(3.4-Dichlorobenzyl)-3-(2-amino-ethyl)indole.

Formula II: R1- H; n = 1; R23,4 - dichlorophenyl; R3= R4- H.

The melting point of 196oC.

Formula IV: R1- H; n = 1; R2- H-chlorophenyl; R3= R4- H;.

< / BR>
< / BR>
In nitrogen atmosphere suspended in 100 ml of ethanol 49 g of the hydrochloride of 1-(4-Chlorobenzyl)-3-(2-amino-ethyl)indole obtained one way of examples 29 or 30. The suspension is neutralized to 5.1 ml of triethylamine, then added 4.1 g - D-ribofuranoside-1-(6-chloro-9H-purine-9-yl)-N-cyclopropyl-1-deoxy - 2,3-O-(1-methylethylidene) obtained in example 1.

All is refluxed for 7 h and left to stand overnight. The solvent is evaporated and the residue is treated with chloroform, washed with water, dried and concentrated. The obtained solid residue chromatographic on silica gel (eluent: chloroform 90%/methanol 10%) to give 7.2 g of amorphous solid product.

Derivatives of examples 47-59 were obtained as amorphous solid products according to the method of example 1.

Example 47. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-methoxyethyl) indol-3-yl/ethyl/amino/-9H-purine-9-yl/2,3-O-(1-methylethylidene).

Formula IV: R1- H; n = 2; R2- methoxy; R3= R4- H;

< / BR>
< / BR>
Example 48. - D-Ribofuranoside-1-/6-//2-/1-cyclopentyl-indol-3-yl/ethyl/amino/-9H-purine-9-yl/- N-cyclopropyl-1-deoxy-R>
< / BR>
Example 49. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-isopropylindole-3-yl/- ethyl/amino/-9H-purine-9-yl/-2,3-O-(1-methylethylidene).

Formula IV: R1- H; n = 0; R2is isopropyl; R3= R4- H;

< / BR>
< / BR>
Example 50. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-(4-methylbenzyl)indol - 3-yl/ethyl/amino/-9H-purine-9-yl/-2,3-O-(1-methylethylidene).

Formula IV: R1- H; n = 1; R2- 4-were; R3= R4- H;

< / BR>
< / BR>
Example 51. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-(3,4-dimethylbenzyl)- indol-3-yl/-ethyl/amino/-9H-purine-9-yl/2,3-O-(1-methylethylidene).

Formula IV: R1- H; n = 1; R23,4 - dimetilfenil; R3= R4- H;

< / BR>
< / BR>
Example 52. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-(2,5-dimethylbenzyl)- indol-3-yl/-ethyl/amino/-9H-purine-9-yl/-2,3-O-(1-methylethylidene).

Formula IV: R1- H; n = 1; R2- 2.5-dimetilfenil; R3= R4- H:

< / BR>
< / BR>
Example 53. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/(2-N-morpholinoethyl)indol - 3-yl/ethyl/-amino/-9H-purine-9-yl/-2,3-O-(1-methylethylidene).

Formula IV: R1- H; n = 1; R2- morpholino; R3= R4- H;

< / BR>
< / BR>
Example 54. - D-Ribofuranoside-N-loop

Formula IV: R1- H; n = 2; R2- N,N-dimethylamino; R3= R4- H;

< / BR>
< / BR>
Example 55. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-2,3 - O-(1-methylethylidene)-1-/6-//2-/1-(2-N-piperidinoethyl)indol-3 - yl/ethyl/amino/-9H-purine-9-yl/.

Formula IV: R1- H; n = 2; R2- N-piperidino; R3= R4- H;

< / BR>
< / BR>
Example 56. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-2,3 - O-(1-methylethylidene)-1-/6-//2-/1-(2-N-pyrrolidinyl)indol-3 - yl/ethyl/amino/-9H-purine-9-yl/.

Formula IV: R1- H; n = 2; R2- N-pyrrolidino; R3= R4- H;

< / BR>
< / BR>
Example 57. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-(3,4-dichlorobenzyl)indol-3-yl/ethyl/amino/-9H-purine-9-yl/- 2,3-O-(1-methylethylidene),

Formula IV: R1- H; n = 2; R23,4 - dichlorophenyl, R3= R4- H;

< / BR>
< / BR>
Example 58. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-2,3 - O-(1-methylethylidene)-1-/6-//2-/1-(pyrid-3-ylmethyl)indol-3 - yl/ethyl/amino/-9H-purine-9-yl/.

Formula IV: R1- H; n = 2; R2pyrid-3-yl; R3= R4- H;

< / BR>
< / BR>
Example 59. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-2,3 - O-(1-methylethylidene)-1-/6-//2-/1-(the naphthas-1-ylmethyl)indol-3 - yl/ethyl/amino/-9H-purine-9-yl/.

Formula IV: R1- H; n = 1; R2- naphthas-1-renamed, obtained according to example 3.

Example 60. - D-Ribofuranoside-1-/6-//2-/1- (4-Chlorobenzyl)indol-3-yl/ethyl/amino/-9H-purine-9-yl/-1-deoxy - N-(1,1-dimethyl-2-hydroxyethyl)-2,3-O-(1-methylethylidene).

Formula IV: R1- H; n = 2; R2- 4-chlorophenyl; R3= R4- H;

< / BR>
< / BR>
Example 61. - D-Ribofuranoside-1-/6-//2-/1- (4-Chlorobenzyl)indol-3-yl/ethyl/amino/-9H-purine-9-yl/-N-cyclopropyl-1 - deoxy.

Formula IV: R1- H; n = 1; R2- chlorophenyl; R3= R4- H;

< / BR>
7.2 g of Purina obtained in example 46, placed in 135 ml of 1N HCl. The mixture is heated at 60oC for 36 h and cooled. The solution is decanted to separate the aqueous phase from the more or less viscous formed of resin. The aqueous phase is neutralized with sodium bicarbonate solution and extracted with chloroform. The combined organic phases with previously obtained resin. The mixture is washed with water, dried and concentrated to obtain 7 g painted in a cream color solid residue.

Connection purified by chromatography on silica gel (eluent : chloroform 95%/methanol 5%) to obtain 3.7 g - D-Ribofuranoside-1-/6-//2-/1-(4-Chlorobenzyl)indol - 3-yl/ethyl/amino/-9H-purine-9-yl/-N-cyclopropyl-1-deoxy.

The empirical formula C30H30ClNoC for 75 minutes

Compounds of examples 62 - 75 were obtained according to example 61.

Example 62. - D-Ribofuranoside-1-/6-//2-/1- (4-Chlorobenzyl)indol-3-yl/ethyl/amino/-9H-purine-9-yl/-1-deoxy - N-(1,1-dimethyl-2-hydroxyethyl).

Formula I: R1- H; n = 1; R2- 4-chlorophenyl; R3= R4- H;

< / BR>
Purification by chromatography twice in succession on silica gel (eluent: chloroform 90%/methanol 10%).

Empirical formula: C31H34ClN7O5.

The melting point of 189oC.

Example 63. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-(2-methoxyethyl)indol-3-yl/ethyl/amino/-9H-purine-9-yl/.

Formula I: R1- H; n = 2; R2- methoxy; R3= R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 90%/methanol 5%).

The empirical formula C26H31N7O5.

The melting point 132oC.

Example 64. - D-Ribofuranoside-1-/6-//2-/1- /cyclopentylmethyl-3-yl/ethyl/amino/-9H-purine-9-yl/-N - cyclopropyl-deoxy.

Formula I: R1- H; n = 0; R2- cyclopentyl; R3= R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 95%/methanol 5%).

<>Example 65. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-isopropylindole-3-yl/ethyl/amino/-9H-purine-9-yl/.

Formula I: R1- H; n = 0; R2- cyclopentyl; R3= R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 90%/methanol 10%).

The empirical formula C26H31N7O4.

The melting point 135oC.

Example 66. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-(1-methylbenzyl)indol-3-yl/ethyl/amino/-9H-purine-9-yl/.

Formula I: R1- H; n = 1; R2- 4-were; R3= R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 90%/methanol 10%).

The empirical formula C31H33N7O4< / BR>
The melting point 144oC.

Example 67. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-(3,4-dimethylbenzyl)indol-3-yl/ethyl/amino/-9H-purine-9-yl/.

Formula I: R1- H; n = 1; R23,4 - dimetilfenil; R3= R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 95%/methanol 5%).

The empirical formula C32H35N7O4H2O.

The melting point 134oC.

Example 68. - D-Ribaforada I: R1- H; n = 1; R2- 2.5-dimetilfenil; R3= R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 95%/methanol 5%).

The empirical formula C32H35N7O40.5 H2O.

The melting point 130oC.

Example 69. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-(2-N-morpholinoethyl)indol-3-yl/ethyl/amino/-9H-purine-9-yl/.

Formula I: R1- H; n = 2; R2- N-morpholino; R3= R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 95%/methanol 5%).

The empirical formula C29H36N8O50.5 H2O.

The melting point of 109 - 110oC.

Example 70. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-N,N-dimethylaminoethyl)indol-3-yl/ethyl/amino/-9H-purine-9-yl/.

Formula I: R1-H; n = 2; R2- N,N-dimethylamino; R3=R4- H;

< / BR>
Purification by chromatography on silica gel (eluent : chloroform 80%/Isopropylamine 20%).

Empirical formula: C27H34N8O40.5 H2O.

The melting point 112oC.

Example 71. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-N-piperidinoethyl)indol-3-yl/ethyl-aminoate chromatography on silica gel (eluent : chloroform 80%/methanol 20%).

The empirical formula C30H38N8O4.

The melting point of 109oC.

A solution of 11 g of the compound obtained in this way, in 100 ml of ethanol injected dropwise into a solution of 3.7 g of citric acid in 40 ml of ethanol. The mixture is stirred for 1 h at room temperature. The resulting solid product is filtered off, washed with ethanol and dried to obtain 10.6 g of citrate - D-ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-N-piperidinoethyl) indol-3-yl/ethyl/amino/-9H-purine-9-Il/.

The empirical formula C30H38N8O4C6H8O7.

The melting point 138oC.

Example 72. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-N-pyrrolidinyl) indole-3-/ethyl/amino/-9H-purine-9-yl/.

Formula I: R1-H; n = 2; R2-N-pyrrolidino; R3= R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 80%/methanol 20%).

The empirical formula C29H36N8O45H2O

The melting point 126oC.

Example 73. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-(3,4-dichlorobenzyl) indol-3-yl/-/ethyl/amino/-9H-purine-9-yl/.

Formula I: R1-H; n = 1; RRM 80%/methanol 5%).

The empirical formula C30H29Cl2N7O40,8 H2O.

The melting point 141oC.

Example 74. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-(pyridine-3-ylmethyl) indol-3-yl/-/ethyl/amino/-9H-purine-9-yl/.

Formula I: R1-H; n = 1; R2- pyridin-3-yl; R3= R4- H;

< / BR>
Purification by recrystallization from 2-methoxyethanol.

The empirical formula C29H30N8O40,5 CH3OCH2CH2OH.

The melting point of 239oC.

Example 75. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-(the naphthas-1-ylmethyl) indol-3-yl- /ethyl/amino/-9H-purine-9-yl/.

Formula I: R1-H; n = 1; R2- naphthas-1-yl; R3= R4- H;

< / BR>
Purification by chromatography on silica gel (eluent : chloroform 95%/methanol 5%) getting by recrystallization from isopropanol.

Empirical formula: C34H33N7O4.

The melting point of 168oC.

Example 76. N6-/2-/1-(4-Chlorobenzyl)indol-3-yl/ethyl/adenosine.

Formula IV: R1-H; n = 1; R2- 4-chlorophenyl; R3= R4- H; R12- CH2OH; R13= R14- H.

4.5 g of 1-(4-Chlorobenzyl)-3-(2-aminoethyl 2 g of 6-chlorobenzene.

All is refluxed for 6 h, cooled. The resulting residue is filtered and washed with ethanol and then ether.

Recrystallization from ethanol gives 2.5 g of N6-/2-/1-(4-Chlorobenzyl)indol-3-yl/ethyl/adenosine.

The melting point 181oC.

Compounds of examples 77 and 78 were obtained according to example 76.

Example 77. N6-/2-/1-Benzyliden-3-yl/ethyl/adenosine.

Formula IV: R1-H; n = 1; R2is phenyl; R3= R4- H; R12- CH2OH; R13= R14- H.

Purification by recrystallization from ethanol.

The melting point 158oC.

Example 78. N6-/2-/1-(2,6-Dichlorobenzyl)indol-3-yl/ethyl/- adenosine.

Formula IV: R1- H; n = 1; R2is 2,6-dichlorophenyl; R3=R4-H; R12-CH2OH; R13= R14- H.

Purification by recrystallization from ethanol.

The melting point 192oC.

Alcohols of examples 76 to 78 can be oxidized to acids by the interaction with an oxidizing agent such as chromium trioxide in acetone in the presence of sulfuric acid or potassium permanganate in water in the presence of ammonia. They will be sequentially to form the corresponding HLA, as examples 61, 62, 73, or 75 by interacting with the corresponding amines.

Compounds of examples 79 - 100 were obtained according to example 61.

Example 79. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-(pyrid-2-ylmethyl)indol-3-yl/-ethyl/amino/-9H-purine-9-yl/.

Formula I: R1- H: n = 1; R2pyrid-2-yl; R3= R4- H;

< / BR>
Clean three consecutive columns (eluent: chloroform 90%/methanol 10%, chloroform 80%/Isopropylamine 20% methylene chloride to 90%/methanol 10%, respectively).

The empirical formula C29H30N8O4.

The melting point 122oC.

Example 80. - D-Ribofuranoside-1-/6-//2-/1-(4-Chlorobenzyl)-5-Clorinda-3-yl/ethyl/-amino/-9H-purine-9-yl/-N-cyclopropyl-1-deoxy.

Formula I: R1-5-Cl; n = 1; R2- 4-chlorophenyl; R3= R4- H;

< / BR>
Purification by crystallization from isopropanol/ether mixture.

The empirical formula C30H29Cl2N7O4.

The melting point 154oC.

Example 81. - D-Ribofuranoside-1-/6-//2-/1-(2,5-dimethylbenzyl)-5-Clorinda-3-yl/Intel/-amino/-9H-purine-9-yl/-N-cyclopropyl-1-deoxy.

Formula I: R1-5-Cl; n = 1; R2- 2.5-DIMET the>/P>The empirical formula C32H34ClN7O41,1 H2O.

The melting point of 139oC.

Example 82. - D-Ribofuranoside-1-/6-//2-/1-(4-Chlorobenzyl) indol-3-yl/ethyl/amino/-9H-purine-9-yl/-1-deoxy-N-(2-methoxyethyl).

Formula I: R1-H; n = 1; R2- 4-chlorophenyl; R3= R4- H; R5- -NH-CH2-CH2-OCH3.

Purified by treatment with hot ethanol.

The empirical formula C30H32ClN7O5.

The melting point of 193oC.

Example 83. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-arylindole-3-yl/ethyl/amino/-9H-purine-9-yl/.

Formula I: R1-H; n = 1; R2- -HC=CH2; R3= R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 90%/ methanol 10%).

The empirical formula C26H29N7O49 H2O.

The melting point of 117oC.

Example 84: - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1- /6-//2-/1/(prop-2-inyl)indol-3-yl/ethyl/amino/-9H-purine-9-yl/.

Formula I: R1- H; n = 1; R2-CCH; R3= R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 90%/methanol 10%).

Empirical fo: - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-(2,5-dimethylbenzyl)-5-methylindol-3-yl/ethyl/amino/-9H - purine-9-yl/.

Formula I: R1- 5-CH3; n = 1; R2= 2.5-dimetilfenil; R3= R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 90%/methanol 10%).

The empirical formula C33H37N7O40,8 H2O.

The melting point 129oC.

Example 86. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1- /6-//2-/1-(2,5-dimethylbenzyl)-5-methoxy-indol-3-yl/ethyl/amino/-9H - purine-9-yl/.

Formula I: R1- 5 - OCH3; n = 1; R2- 2.5-dimetilfenil; R3=R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 90%/ methanol 10%).

The empirical formula C33H37N7O50,1 H2O.

The melting point 182oC.

Example 87. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1- /6-//2-/1-(2,5-dimethylbenzyl)-2-methylindol-3-yl/ethyl/amino-9H-purine-9-yl/.

Formula I: R1- 2 - CH3; n=1; R2- 2.5-dimetilfenil; R3=R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 90%/ methanol 10%).

Empirical formula: C33H37N7

Formula I: R1- H; n = 1; R2- 4 - OCH3is phenyl; R3=R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 90%/methanol 10%).

The empirical formula C31H33N7O50,8 H2O.

The melting point 134oC.

Example 89. - D-Ribofuranoside-1-/6-//2-/1-cyclopentyl-2 - methylindol-3-yl/ethyl/amino/-9H-purine-9-yl/-N-O cyclopropyl-1-deoxy.

Formula I: R1- 2 - CH3; n=0; R2-cyclopentyl; R3=R4- H;

< / BR>
Purification by chromatography on silica gel (eluent : chloroform 90%/methanol 10%).

The empirical formula C29H35N7O4.

Melting point 140oC.

Example 90. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1-(2-N,N - dimethylaminomethyl)indol-3-yl/ethyl/amino/-9H-purine-9-yl/.

Formula I: R1- H; n=1; R2- 2 - N,N-dimethylaminophenyl; R3=R4- H;

< / BR>
Purification by chromatography on silica gel (eluent : chloroform 90%/ methanol 10%).

Empirical formula: C32H36N8O4.

The melting point of 128-129oC.

Example 91. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1- (3-nitrobenzyl)indol-3-yl/ethyl

Purification by chromatography twice in succession on silica gel(eluent : chloroform 90%/ methanol 10% methylene chloride to 90%/ methanol 10%, respectively).

Empirical formula: C30H30N8O40,3 H2O.

The melting point 129oC.

Example 92. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1-/6-//2-/1- (2,5-dimethylbenzyl)indol-3-yl/propan - 2-yl/amino/-9H-purine-9-yl/.

Formula I: R1- H; n = 1; R2-2.5-dimetilfenil; R3=R4- CH3;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 90%/methanol 10%).

The empirical formula C33H37N7O4.

The melting point 135oC.

Example 93. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1- /6-//2-1-/1-cyclopentylmethyl-3-yl/propan-2-yl/amino/-9H-purine-9-yl/.

Formula I: R1- H; n = 0; R2- cyclopentyl; R3- H; R4- CH3;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 90%/methanol 10%).

The empirical formula C29H35N7O4.

The melting point 130oC.

Example 94. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1- /6-//2-/1-(2,5-dimethylbenzyl)indol-3-yl/propan-2-yl/amino/>/BR>< / BR>
Purification by chromatography on silica gel (eluent: chloroform 95%/methanol 5%).

Empirical formula: C33H37N7O4.

The melting point of 137oC.

Example 95. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1- /6-//2-/1-(2,5-dimethylbenzyl)-2 - phenylindol-3-yl/ethyl/amino-9H-purine-9-yl/.

Formula I: R1- 2 - phenyl; n = 1; R2- 2.5-dimetilfenil; R3=R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 90%/methanol 10%).

The empirical formula C38H39N7O4.

The melting point of 136oC.

Example 96. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-(2,5-dimethylbenzyl)-5-dimethylindole-3-yl/ethyl/amino-9H - purine-9-yl/.

Formula I: R1- 5 - SCH3; n = 1; R2- 2.5 - dimetilfenil; R3=R4- H;

< / BR>
Purification by chromatography on silica gel (eluent: chloroform 90%/ methanol 10%).

Empirical formula: C33H37N7O4S8H2O.

The melting point of 137oC.

Example 97. - D-Ribofuranoside- 1-/6-//2-/1-(5-chlorothieno-2-yl)indol-3-yl/ethyl/amino-9H - purine-9-yl/-N-cyclopropyl-1-deoxy.

Formula I: R1- H; n = 1; R2- canal 10%).

Empirical formula: C28H28ClN7O4S - D-Ribofuranoside-N-cyclopropyl- 1-/6-//2-/1-(cyclopropylmethyl)indol-3-yl/ethyl/amino-9H - purine-9-yl/-1-deoxy.

Formula I: R1- H; n = 1; R2- cyclopropyl; R3=R4- H;

< / BR>
The empirical formula C27H31N7O45H2O.

The melting point 134oC.

Derivatives with respect to examples 99-118 were obtained as amorphous solid products according to the method of example 46, using the appropriate renamed formula III.

Example 99. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-(pyrid-2-ylmethyl)indol-3-yl/ ethyl/amino/-9H-purine-9-yl/-2,3,0-(1-methylethylidene).

Formula IV: R1- H; n=1; R2pyrid-2-yl; R3=R4- H;

< / BR>
< / BR>
Example 100. - D-Ribofuranoside-1-/6-//2-/1-(4-Chlorobenzyl)- 5-Clorinda-3-yl/ethyl/amino/-9H-purine-9-yl/-N-cyclopropyl-1-deoxy - 2,3, O-(1-methylethylidene).

Formula IV: R1- 5 - Cl; n=1, R2- 4-chlorophenyl; R3= R4- H;

< / BR>
< / BR>
Example 101. - D-Ribofuranoside-1-/6-//2-/1-(2,5- dimethylbenzyl)-5-Clorinda-3-yl/ethyl/amino/-9H-purine-9-yl/-N - cyclopropyl-1-deoxy-2,3-O-(1-methylethylidene).

Formula IV: R1- 5 - Cl; n=1; R2- 2.5-dimetilfenil; R

Formula IV: R1- H; n=1; R2- 4-chlorophenyl; R3=R4- H;

< / BR>
< / BR>
Example 103. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1- /6-//2-/1-arylindole-3-yl/ethyl/amino/-9H-purine-9-yl/-2,3-O- (1-methylethylidene).

Formula IV: R1- H; n=1; R2-ethynyl; R3=R4- H;

< / BR>
< / BR>
Example 104. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1- /6-//2-/1-probalility-3-yl/ethyl/amino/-9H-purine-9-yl/-2,3-O- (1-methylethylidene).

Formula IV: R1- H; n=1; R2-ethinyl; R3=R4- H;

< / BR>
< / BR>
Example 105. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6//2-/1-(2,5-dimethylbenzyl)-5-methylindol-3-yl/ethyl/amino-9H - purine-9-yl/-2,3-O-(1-methylethylidene).

Formula IV: R1- 5 - CH3; n=1; R2- 2.5-dimetilfenil; R3=R4- H

< / BR>
< / BR>
Example 106. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1- /6-//2-/1-(2,5-dimethylbenzyl)-5-methoxyindol-3-yl/ethyl/amino/-9H - purine-9-yl/-2,3-O-(1-methylethylidene).

Formula IV: R1- 5 - OCH3; n=1; R2- 2.5 - dimetilfenil; R3=R4- H;

< / BR>
< / BR>
Example 107. - D-Ribofuranoside-N-cyclopropyl-1-deoxy-1- /6-//2-/1-(2,5-dimethylbenzyl)-2-methylindol-3-yl/ethyl/amino-9H-purine - 9-yl/-2,3-O-(1-methylethylidene).

Formula IV: R1- 2 - CHsapropel-1-deoxy-1- /6-//2-/-1-(4-methoxybenzyl)indol-3-yl/-ethyl/amino/-9H-purine-9-yl/- 2,3-O-(1-methylethylidene).

Formula IV: R1- H; n=1; R2- 4 - OCH3is phenyl; R3=R4- H;

< / BR>
< / BR>
Example 109. - D-Ribofuranoside-1-/6-//2-/1-cyclopentyl-2 - methylindol-3-yl/ethyl/amino/-9H-purine-9-yl/-N-cyclopropyl-1-deoxy - 2,3-O-(1-methylethylidene).

Formula IV: R1- 2 - CH3; n=0; R2-cyclopentyl; R3=R4- H;

< / BR>
< / BR>
Example 110. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-(2-N, N-dimethylaminobenzoyl)-indol-3-yl/ethyl/amino/-N - purine-9-yl/-2,3-O-(1-methylethylidene).

Formula IV: R1- H; n = 1; R2- 2-N,N-dimethylaminophenyl; R3=R4- H;

< / BR>
< / BR>
Example 111. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-(3-nitrobenzyl)indol-3-yl/ethyl/amino/-N-purine-9-yl/- 2,3-O-(1-methylethylidene).

Formula IV: R1- H; n = 1; R2- 3-nitrophenyl; R3=R4- H;

< / BR>
< / BR>
Example 112. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-(2,5-dimethylbenzyl)indol-3-yl/propan-2-yl/amino/-N - purine-9-yl/-2,3-O-(1-methylethylidene).

Formula IV: R1- H; n = 1; R2- 2.5-dimetilfenil; R3- H; R4- CH3;

< / BR>
< / BR>
Example 113. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//1-/1-(1-cyclopentylmethyl-3-yl/propan-2-yl/amino/-N-purine - 9-yl/-2,3-O-(1-methylethyl

Example 114. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-(2,5-dimethylbenzyl)-indol-3-yl/propyl/amino/-N-purine - 9-yl/-2,3-O-(1-methylethylidene).

Formula IV: R1- H; n = 1; R2- 2.5-dimetilfenil; R3- CH3; R4- H;

< / BR>
< / BR>
Example 115. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-(2,5-dimethylbenzyl)-2-phenylindol-3-yl/ethyl/amino/-N-purine - 9-yl/-2,3-O-(1-methylethylidene).

Formula IV: R1- 2-phenyl; n = 1; R2- 2.5-dimetilfenil; R3=R4- H;

< / BR>
< / BR>
Example 116. - D-Ribofuranoside-N-cyclopropyl-1-deoxy- 1-/6-//2-/1-(2,5-dimethylbenzyl)-5-dimethylindole-3-yl/propan-2-yl/amino/- N-purine-9-yl/-2,3-O-(1-methylethylidene).

Formula IV: R1- 5-SCH3; n = 1; R2- 2.5-dimetilfenil; R3= R4- H;

< / BR>
< / BR>
Example 117. - D-Ribofuranoside-1-/6-//2-/1-(5-chlortan - 2-yl)indol-3-yl/ethyl/amino/-N-purine-9-yl/-N-cyclopropyl-1-deoxy - 2,3-O-(1-methylethylidene).

Formula IV: R1- H; n = 1; R2- 5-chlortan-2-yl; R3= R4- H;

< / BR>
< / BR>
Example 118. - D-Ribofuranoside-N-cyclopropyl-1-/6-//2-/1- (cyclopropylmethyl)indol-3-yl/ethyl/amino/-N-purine-9-yl/-2,3-O- (1-methylethylidene).

Formula IV: R1- H; n = 1; R2- cyclopropyl; R3= R4
Example 119. 3-(2-amino-ethyl)-5-chloro-(2,5-dimethylbenzyl)indole.

Formula II: R1- 5-Cl; n = 1; R2- 2.5-dimetilfenil; R3= R4- H.

Brown oil purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%).

Example 120. 3-(2-amino-ethyl)-1-arylindole.

Formula II: R1- H; n = 1; R2- ethynyl; R3= R4- H.

Brown oil purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%).

Example 121. 3-(2-amino-ethyl)-1-(pyrid-2-ylmethyl)-indole.

Formula II: R1- 5-Cl; n = 1; R2pyrid-2-yl; R3= R4- H.

Purified by chromatography on silica gel (eluent: CHC1395%/Isopropylamine 5%).

The melting point 237oC.

Example 122. 3-(2-amino-ethyl)-1-5-chloro-(4-Chlorobenzyl)indole.

Formula II: R1- 5-Cl; n = 1; R2- 4-chlorophenyl; R3= R4- H.

Hydrochloride, purified by recrystallization from ethanol.

The melting point of 204oC.

Example 123. 3-(2-amino-ethyl)-1-probalility.

Formula II: R1- H; n = 1; R2- ethinyl; R3=R4- H.

Brown oil purified by chromatography on Seeley the ol.

Formula II: R1- 5-CH3; n = 1; R2- 2.5-dimetilfenil; R3= R4- H.

Hydrochloride, purified by crystallization from ether.

The melting point 198oC.

Example 125. 3-(2-amino-ethyl)-1-(2,5-dimethylbenzyl)-5-methoxyindol.

Formula II: R1- 5-OCH3; n = 1; R2- 2.5-dimetilfenil; R3= R4- H.

Amorphous white solid product purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%).

Example 126. 3-(2-amino-ethyl)-1-(2,5-dimethylbenzyl)-2-methylindole) are studied.

Formula II: R1- 2-CH3; n = 1; R2- 2.5-dimetilfenil; R3= R4- H.

Hydrochloride, purified by chromatography of the ether.

The melting point 250oC.

Example 127. 3-(2-amino-ethyl)-1-(4-methoxybenzyl)indole.

Formula II: R1- H; n = 1; R2- 4-OCH3is phenyl; R3= R4- H.

Brown oil purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%).

Example 128. 3-(2-amino-ethyl)-1-cyclopentyl-2-methylindole) are studied.

Formula II: R1- 2-CH3; n = 0; R2- cyclopentyl; R3= R4- H.

The crude orange oil, used to the B> - 2-phenyl; R3= R4- H.

Hydrochloride, purified by crystallization from isopropanol.

The melting point 266oC.

Example 130. 3-(2-amino-ethyl)-1-(2,5-dimethylbenzyl)-2 - phenylindol.

Formula II: R1- 2-phenyl; n = 1; R2- 2.5-dimetilfenil; R3= R4- H.

Brown oil purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%).

Example 131. 3-(2-amino-ethyl)-1-(2-N,N-dimethylaminomethyl)indole.

Formula II: R1- H; n = 1; R2- 2-N,N-dimethylaminophenyl; R3= R4- H.

Brown oil purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%).

Example 132. 3-(2-amino-ethyl)-1-(3-nitrobenzyl)indole.

Formula II: R1- H; n = 1; R2- 3-NO2is phenyl; R3= R4- H.

Brown oil purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%).

Example 133. 3-(2-Aminopropyl)-1-(2,5-dimethylbenzyl)-indole.

Formula II: R1- H; n = 1; R2- 2.5-dimetilfenil; R3- H; R4- CH3.

The white solid product is purified by crystallization from isopropyl ether.

The melting point 8
- cyclopentyl; R3= R4- CH3.

The crude orange oil, used as such in the subsequent stage.

Example 135. 3-(2-Aminopropan-2-yl)-1-(2,5-dimethylbenzyl)indole.

Formula II: R1- H; n = 1; R2- 2.5-dimetilfenil; R3- CH3; R4- H.

Oil, purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%). The hydrochloride crystallized from isopropanol.

Empirical formula; C20H24N2HCl.

The melting point 178oC.

Example 136. 3-(2-amino-ethyl)-1-/(5-chlortan-2-yl)methyl/indole.

Formula II: R1- H; n = 1; R2- 5-chlortan-2-yl; R3= R4- H.

Brown oil purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%).

Example 137. 3-(Aminoethyl)-1-(cyclopropylmethyl)indole.

Formula II: R1- H; n = 1; R2- cyclopropyl; R3= R4- H.

Brown oil purified by chromatography on silica gel (eluent: chloroform 95%/Isopropylamine 5%).

Example 138. 3-(2-amino-ethyl)-1-(2,5-dimethylbenzyl)-5 - dimethylindole.

Formula II: R1- 5-SCH3; n = 1; R2- 2.5-dimetilfenil; R3=is pelamin 5%).

Nitrobenzylidene examples 139 - 143 were obtained by the method of example 17.

Example 139. 1-(2,5-Dimethylbenzyl)-2-methyl-3-(2-nitrovinyl)indole.

Formula IX: R1- 2-CH3; n = 1; R2- 2.5-dimetilfenil; R3= R4- H.

Orange oil, used as such in the subsequent stage.

The melting point 180oC.

Example 140. 1-(Cyclopentyl)-2-methyl-3-(2-nitrovinyl)indole.

Formula IX: R1- 2-CH3; n = 1; R2- cyclopentyl; R3= R4- H.

Orange oil is purified by chromatography on silica gel (eluent: chloroform).

Example 141. 2-Phenyl-3-(2-nitrovinyl)indole.

Formula IX: R1- 2-phenyl; n = 0; R2- H; R3= R4- H.

Orange oil, used as such in the subsequent stage.

The melting point 180oC.

Connection examples 142 and 143 were obtained by the method of example 17, using instead of nitroethane nitromethane.

Example 142. 1-(2,5-Dimethylbenzyl)-3-(2-methyl-2-nitrovinyl)indole.

Formula IX: R1- H; n = 1; R2- 2.5-dimetilfenil; R3- H; R4- CH3.

The yellow solid product is crystallized from water.

Point plavini; = 0; R2- cyclopentyl; R3- H, R4- CH3.

The yellow solid product is crystallized from isopropanol.

The melting point of 160oC.

The following products are examples of 144 - 146 were obtained by the method of example 5 from the corresponding substituted 3-formylindolo:

Example 144. 1-(2,5-Dimethylbenzyl)-3-formyl-2-methylindole) are studied.

Formula VIII: R1- 2-CH3; n = 1; R2- 2.5-dimetilfenil.

The yellow solid product is crystallized from ether and used in this form in the next stage.

The melting point 155oC.

Example 145. 1-(Cyclopentyl)-3-formyl-2-methylindole) are studied.

Formula VIII: R1- 2-CH3; n = 0; R2- cyclopentyl.

Brown oil purified by chromatography on silica gel (eluent: chloroform 95%/methanol 5%).

Example 146. 3-Formyl-2-phenylindol.

Formula VIII: R1- 2-phenyl; n = 0; R2- H.

A solid cream color used as such in the next stage and obtained by method 6 described in J. Med. Chem. (1964), 7, 735.

The melting point of 253oC.

Example 147. - D-Ribofuranoside-1-(6-chloro-9H - purine-9-yl/-1-deoxy-N-(2-methoxyethyl)-2,3-O-(1-methylethylidene).

The compound of example 148 was obtained in the form of an amorphous solid product according to the method of example 46, using oronamin example 2.

Example 148. - D-Ribofuranoside-1-deoxy-1-/6-//2- /1-(2,5-dimethylbenzyl)indol-3-yl/ethyl/amino/-9H-purine-9-yl/- N-ethyl-2,3-O-(1-methylethylidene).

Formula IV: R1- H; n = 1; R2- 2.5-dimetilfenil; R3= R4- H;

< / BR>
< / BR>
The compound of example 149 was obtained by the method of example 61.

Example 149. - D-Ribofuranoside-1-deoxy-1-/6-//2- /1-(2,5-dimethylbenzyl)indol-3-yl/ethyl/amino/-9H-purine-9-yl/- N-ethyl.

Formula IV: R1- H; n = 1; R2- 2.5-dimetilfenil; R3= R4- H; R5= -NH-CH2-CH3.

The empirical formula C31H35N7O44 H2O.

The melting point 133oC.

Typical pharmaceutical compositions containing the compound according to the invention:

Example 150.

A) Gelatin capsules with a dose of 50 mg of active principle.

Components. -- D-Ribofuranoside, N-cyclopropyl-1-deoxy-1-[6-[[2-[1-(2,5-dimethylbenzyl)-5-methylindol-3-yl] ethyl]amine]-9H-Pirin-9-yl] - 50 mg; magnesium stearate 10 mg; lactose 140 mg; capsule - size N 1.

Example 151.

B) Tablets with a dose of 50 mg active is lindol-3-yl] ethyl]amine]-9H-Pirin-9-yl] - 50 mg; microcrystalline cellulose 400 mg; pre-coated with gelatinous starch is 47.5 mg; magnesium stearate and 2.5 mg.

Example 152.

C) Drugs for injection with a dose of 10 mg of active principle.

Components: -- D-Ribofuranoside, N-cyclopropyl-1-deoxy-1-[6-[[2-[1-(2,5-dimethylbenzyl)5-methylindol - 3-yl]ethyl]amine]-9H-Pirin-9-yl] - 10 mg; Inositol 100 mg; benzyl alcohol 20 mg

Example 153.

G) Candles with 100 mg of the active principle.

Components: -- D-Ribofuranoside, N-cyclopropyl-1-deoxy-1[6-[[2-[1-(2,5-dimethylbenzyl)-5-methylindol - 3-yl] ethyl] amine]-9H-Pirin-9-yl] - 100 mg; wax for candles AML 1900 mg

Example 154.

D) Eye drops dose of 1 mg/ml of active principle.

Components: -- D-ribofuranoside, N-cyclopropyl-1-[6-[1-(2,5-dimethylbenzyl)5-methylindol-3-yl] ethyl]amine]- 9H-Pirin-9-yl] - 1 mg/ml dibasic sodium phosphate is 10.4 mg/ml; monobasic sodium phosphate - 2.4 mg/ml; oxopropanenitrile 5 mg/ml; distilled water - enough for 1 ml; 1N soda - sufficient for a pH of 7.4.

Pharmaceutical compositions containing compounds according to the invention.

Example 155.

A) Gelatin capsules with a dose of 50 mg activl-3-yl] ethyl]amine]-9H-Pirin-9-yl] 50 mg; magnesium stearate 10 mg; lactose 140 mg; gelatin capsules, size N 1.

Example 156.

B) Other gelatin capsules with a dose of 50 mg of active principle.

Components: -- D-ribofuranose, 1-[6-[[2-[1-cyclopentylmethyl-3-yl] ethyl] amine]-9H-Pirin-9-yl]-N-cyclopropyl - 1-deoxy - 50 mg; magnesium stearate 10 mg; lactose 140 mg; gelatin capsule of size N 1.

The pharmacological activity of the products of the examples were evaluated by two different approaches: by binding to adenosine receptors, and/or demonstration of analgesic activity in phenylbenzophenone test.

I Way.

1. Binding to adenosine receptors.

A principle.

Affinity products examples to the Central A1 and A2 adenosinergic receptors determine the comparative method, using the specific ligand binding to A1 receptors (/3H PIA) or A2-receptors (/3H/NECA).

Method.

Method of obtaining A1-receptors.

Preparation of the membrane.

After the animal is slaughtered by decapitation, quickly remove the brain and washed with cold isotonic. Share two hemispheres and weighed, each is tion is carried out, using Ultra-Turrax for 30 s (3 times for 10 s with 10-second intervals, 70% of the maximum speed). Received standard material centrifuged at 1000 g ( 3000 rpm) for 10 min at 4oC.

The supernatant is again centrifuged at 48000 g (20,000 rpm) for 20 minutes at 4oC.

When this phase is complete, the precipitate is treated with 4 volumes of homogenizing buffer, re-suspended using a Vortex, and homogenized using UItra-Turrax. Add adenosine deaminase at a rate of 1 U/ml, i.e. 1 μl/ml of homogenate, using a 1-µl Hamilton syringe.

After processing the homogenate was shaken for 30 min at room temperature and then centrifuged at 80000 g ( 20,000 rpm) for 30 min at 4oC.

The precipitate is again suspended in 10 volumes of homogenizing buffer and passed through an Ultra-Turrax for 20 s (2 times for 10 s with 10-second intervals, 70% of the maximum speed).

The homogenate thus obtained, is used in the comparison tests. It stored at 4oC, if studies are carried out for several days and the long-term at -20oC in 10 ml of parts.

Comparative study.

After thawing of the homogenate at comsat 2/5 incubation buffer and placed in a water bath, thermostated at 4oC, with shaking until the end of the experiment.

50 ml /3H/ PIA at 100 nm, i.e., 2.5 nm in the final reaction medium to achieve dilution 1/40 and 50 l of product for example when considering concentration (10-5M and 10-7M) is introduced into the reaction tubes. The reaction is initiated by adding 1 ml of homogenate and 900 ál of incubation buffer. The method is identical for all beta-blocking radiation.

The tube is shaken and inhibit in a water bath at 20oC for 30 minutes. When incubation is complete, the contents of the test tubes filter paper Whatman GF/B. Each tube twice washed with 2 ml of wash buffer and then filtered and washed with 3 ml of the same buffer.

The filters are then transferred into the accounts of the flask and add 10 ml of liquid scintillator (Ready-Solv Hp/b, Beckman).

After shaking the flask was stored in a refrigerator overnight and then determine the radioactivity in the liquid acquired scintillation counter.

Spend 3 experience for each studied concentration. Nonspecific binding /3H/ PIA assessed by measuring the amount of radioactivity remaining on the filter in the presence of 10-5M phenylisopropyl Method of studying A2-receptors.

Preparation of the membrane.

After the animal is slaughtered by decapitation, quickly remove the brain and washed with cold isotonic. Share two hemispheres and separated from each of the striatum (Bruns et al., 1986), weighed and injected into polyallomer tube containing IG volumes of cold homogenized buffer. The tissue is homogenized using Ultra-Turrax for 30 s (3 times for 10 s with 10-second intervals, 70% of the maximum speed). Received standard material centrifuged at 50000 g ( 20,000 rpm) for 10 min at 4oC.

The precipitate is again suspended in 10 volumes of homogenizing buffer, using a Vortex, and homogenized using Ultra-Turrax (5-10 s, 70% of the maximum speed).

Add adenosine deaminase at a rate of 1 U/ml, i.e. 1 μl/ml of homogenate, using a 1-µl Hamilton syringe. The homogenate thus obtained, shaken for 30 minutes

When incubation is complete, the homogenate was centrifuged at 50000 g ( 20500 rpm) for 10 minutes at 4oC.

The residue is treated with 5 volumes of cold homogenizing buffer and passed through an Ultra-Turrax (2 times for 10 s with 10-second intervals, 70% of the maximum speed), and the homogenate obtained the thawing of the homogenate at room temperature add 15 volumes of incubation buffer. The homogenate was shaken on a Vortex, passed through the hands of the Potter (6 hand-movements back and forth, speed 6), diluted 1/10 incubation buffer and, finally, placed in a water bath thermostated at 4oC, with shaking until the end of the experiment.

50 ml /3H/ NECA at 160 nm, or 3 nm in the final reaction medium that can achieve a dilution of 1/40, and 50 ml of product for example when considering concentration (10-5M and 10-7M) is introduced into the reaction tubes. The reaction is initiated by adding 1 ml of homogenate and 900 ál of incubation buffer. The method is similar for all investigated compounds.

The tube is shaken and inhibit in a water bath at 25oC for 60 minutes When the incubation is complete, the contents of the test tubes filter paper Whatman GF/B. Each tube twice washed with 2 ml of wash buffer and then filtered and washed with 3 ml of the same buffer before entering in the accounts of the flask.

Add 10 ml of liquid scintillator (Ready-Solv HP/b Beckman) in all flasks. They shake and store in the refrigerator overnight. The radioactivity determined in a liquid acquired scintillation counter.

Spend 3 experience for each studied concentration. Especifica the presence of 5 μm of N-ethylcarbodiimide (NECA). The amount of nonspecific binding systematically subtracted from the data for the test.

Processing of data.

The results are expressed for each product as a percentage of replacement (n = 3) of the released ligand at a concentration of 10-5M and 10-7M

2. Phenylbenzophenone study.

Way.

Intraperitoneal injection of phenylbenzophenone causes cruciada and pulling movements in mice. Analgesics prevent or reduce this syndrome, which can be seen as exteriorization or diffuse abdominal pain.

0,02% solution phenylbenzophenone in the water is injected in a volume of 1 ml/100 g

Products examples administered orally one hour before injection of phenylbenzophenone.

Cruciada and pulling movements considered for each mouse during the observation period of 5 minutes

II. Results.

The experimental results show the affinity of the products according to examples for adenosine receptors, and their analgesic properties are presented in table. 1 and 2, respectively.

III. Toxicology.

The tolerance of the products of the examples are evaluated in rats after oral administration. Discovered that all parayi, possess particularly valuable analgesic properties, whose true mechanism of action is a result of interaction with adenosine receptors.

1. Derivatives of adenosine General formula I

< / BR>
where R1is a hydrogen atom, halogen atom, lower alkyl, lower-alkyl, lower S-alkyl or phenyl, and may be in the 2 - or 5-position of the indole;

n = 0, 1, and 2;

R2- lower alkyl, lower alkenyl, lower quinil, C3- C7-cycloalkyl or lower-alkyl, phenyl, possibly substituted by 1 to 4 substituents selected from a halogen atom, nitro, lower alkyl or O-alkyl groups or a group-NR6R7where R6and R7is a hydrogen atom, lower alkyl; pyridyl: pyrrolidin; thienyl, possibly substituted by a halogen atom; a naphthyl; and when n = 2, R2group-NR8R9where R8and R9at the same time are lower alkyl or form together with the nitrogen atom to which they are attached, a heterocycle selected from the research, piperidine;

R3and R4the same or different, is a hydrogen atom or lower alkyl;

R5- OTHER10- lower alkyl, C3- C7-cycloalkyl.

2. The connection I on p. 1, characterized in>- methoxy, cyclopentane, isopropyl, 2,5-dimetilfenil or piperidine.

4. The connection I on p. 1, wherein R3- the hydrogen atom.

5. The connection I on p. 1, wherein R4is a hydrogen atom or methyl.

6. The connection I on p. 1, wherein R5- N-cyclopropylamine.

7. The connection I on p. 1, characterized in that it is chosen from the following compounds of the structure:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
8. The method of obtaining compounds of General formula I according to any one of paragraphs.1 to 7, characterized in that the amine of General formula II

< / BR>
where R1- R4and n have the specified values,

subjected to interaction with a 7-galacturonase riboside General formula III

< / BR>
where X is a halogen atom;

R11- COR5where R5has the specified value, or CH2OH;

R12and R13- protective group such as acetyl, benzoyl, or together form a dioxolane group,

in a solvent such as ethanol or dimethylformamide, in the presence of a base such as triethylamine, pyridine or sodium carbonate, or in addition, in the presence of two equivalents of amine in 20 - 140oWith, and then remove the protective gr is at 0 - 70oWith depending on the nature of the protective group.

9. The pharmaceutical composition exhibiting analgesic and antihypertensive activity, characterized in that it contains an effective amount of at least one of the compounds of formula I according to any one of paragraphs.1 - 7 or one of its pharmaceutically acceptable salts and pharmaceutically acceptable additive, a solvent or carrier.

10. The pharmaceutical composition exhibiting analgesic activity, characterized in that it contains an effective amount of at least one of the compounds of formula I according to any one of paragraphs.1 - 7 or one of its pharmaceutically acceptable salts and pharmaceutically acceptable additive, a solvent or carrier.

11. The pharmaceutical composition exhibiting antihypertensive activity, characterized in that it contains an effective amount of at least one of the compounds of formula I according to any one of paragraphs.1 - 7 or one of the pharmaceutically acceptable salts and pharmaceutically acceptable additive, a solvent or carrier.

12. A method of obtaining a pharmaceutical composition, characterized in that it comprises mixing an effective amount of at least one of the compounds of formula I storytale or media.

13. Composition according to any one of paragraphs.9 to 11, characterized in that it is made in the form of gelatin capsules or tablets containing 5 - 300 mg of the compounds of formula I according to any one of paragraphs.1 - 7 or one of its pharmaceutically acceptable salts, or in the form of injections, containing from 0.1 to 100.0 mg of the compounds of formula I according to any one of paragraphs.1 - 7 or one of its pharmaceutically acceptable salts.

 

Same patents:

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

d-arabinofuranosyl)-n-purine, method for their preparation and use and pharmaceutical composition" target="_blank">

The invention relates to mono-, di - or tri-esters of 2-amino-6-(C1-C5-alkoxy)-9-(-D-arabinofuranosyl)-N-purine General formula (I)

< / BR>
where arabinofuranosyl residue substituted for 2'-, 3'- or 5'-positions, and esters formed by carboxylic acids, in which decarbonising part selected from n-propyl, tert-butyl, n-butyl, methoxymethyl, benzyl, phenoxymethyl, phenyl, methanesulfonyl and succinyl

The invention relates to a process for the preparation of 9-substituted derivatives of guanine General formula I:

< / BR>
where R is C1-C4-alkyl, does not necessarily substituted by one or more groups, or R is:

< / BR>
a benzyl, robotjam, 2-deoxyribosyl or (CH2)n-OR1where n is 1 or 2, and R1is CH2CH2OH or< / BR>
or their salts

The invention relates to a process for the preparation of 9-substituted derivatives of guanine General formula

(l) where R is a C1-C4-alkyl, optionally substituted by one or more hydroxyl groups, or R is

a benzyl, ribosom, 2-deoxyribosyl or (CH2)n-OR SIG1where n is 1 or 2, and R1is CH2CH2HE or CHor their salts

The invention relates to a method for producing derivatives of S-adenosylmethionine (HIMSELF), General formula

< / BR>
where R is benzene, p-toluensulfonyl or linear aliphatic acyl radical containing 2-6 carbon atoms; R1H or benzoyl or linear aliphatic acyl containing 2 to 6 carbon atoms; R and R1same or different when R1has a value other than hydrogen; n is 1-5; And is the equivalent of the acid with PKandless than 2.5

The invention relates to certain substituted purine to arabinoside and acceptable from the physiological standpoint derivatives, in particular esters and their use for the treatment of certain DNA-viral diseases

The invention relates to ophthalmology

The invention relates to medicine and can be used in the treatment of stress lesions of the nervous system in combustionengines, traumatic, neurological and surgical hospitals

The invention relates to medicine, in particular to the experimental therapy, and for the prevention and treatment of atherosclerosis

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

The invention relates to medicine

The invention relates to the field of pharmacy and concerns receiving means having a radioprotective effect
The invention relates to Oncology

FIELD: medicine.

SUBSTANCE: method involves carrying out hernia removal in intralaminar way. Posterior longitudinal ligament defect is covered with Tacho-Comb plate after having done disk cavity curettage. Subcutaneous fat fragment on feeding pedicle is brought to dorsal surface of radix and dural sac.

EFFECT: enhanced effectiveness of treatment; reduced risk of traumatic complications.

1 dwg

FIELD: medicine, obstetrics, gynecology.

SUBSTANCE: at the background of therapy conducted one should introduce derinate immunomodulator into the body of pregnant woman additionally nasally per 1-2 drops of 0.25%-solution into each nasal canal 5-8 times daily for 3-5 d and - parenterally per 5.0 ml of 1.5%-solution once daily for 3-8 d along with preparation that improves microcirculation and along with antioxidant at a certain sequence, moreover, derinate should be introduced 30-40 min after application of microcirculation-improving preparation, and antioxidant - 20-30 min after derinate's introduction. The present innovation favors decreased edemas, decreased body weight, stabilization of Macluer-Aldrich test that in its turn enables to avoid perinatal losses, decrease the risk for the development of fetoplacental insufficiency and intrauterine fetal infection.

EFFECT: higher efficiency of therapy.

1 ex, 2 tbl

FIELD: medicine, otolaryngology.

SUBSTANCE: the present innovation deals with introducing neomycin sulfate antibiotic in granules prepared by the following technique. Tablet of neomycin sulfate 1.0g should be put into a vial with 100 ml distilled water till tablet's decomposition. Then vial's content should be shaken and kept till suspension sedimentation. In a day one should take 1 ml of supernatant liquid to be put into another vial and diluted with distilled water at 1:100 ratio. This procedure should be repeated 4 times more, moreover, during the last procedure one should apply alcohol for dilution. Then one should transfer the drop of alcoholic solution into a vial with granules out of milk sugar to then shaken and kept open for 1 d till granules" drying up. The suggested preparation should be applied per 1 granule under the tongue, moreover, multiplicity and duration of the above-suggested intake should be matched individually by patient's sensitivity and obtaining the clinic effect. The method enables to improve the value of tonic threshold audiometry by about 30-50 dB, decrease perception threshold of vocal range frequencies and widen the range towards high frequencies.

EFFECT: higher efficiency of therapy.

1 dwg

FIELD: medicine, oncology.

SUBSTANCE: invention relates to a method for treatment of chronic lympholeukosis. Method involves intravenous drop and jet administration of antitumor chemopreparations and carrying out the autochemotherapy. At the 1-st and 8-th day of treatment cyclophosphan in the dose 750 mg/m2, vincristine in the dose 1.4 mg/m2 and doxorubicin in the dose 30 mg/m2 incubated with 200 ml of autoblood are administrated to patients. From the 1-st to 14-th day of treatment prednisolone is used every day in the therapeutic dose. The treatment course is repeated in 30-35 days depending on blood indices and patient state. The total treatment of courses is 4-5. Method provides reducing cardiotoxicity of doxorubicin and cumulative toxicity of chemopreparations that allows carrying out administration of antitumor chemopreparations in the full volume to patients of elderly age groups.

EFFECT: improved method for treatment.

1 ex

Up!