New acylated pseudodipeptides, a method of receiving and containing pharmaceutical compositions

 

The invention relates to N-acylated to pseudodipeptides corresponding to General formula Iin which R1and R2denote each acyl group of the carboxylic acid having from 2 to 24 carbon atoms, which may be saturated or unsaturated, linear or branched, unsubstituted or having one or more substituents selected from hydroxyl, alkyl, alkoxy groups, acyloxy, amino, acylamino, atillio and C1-C24alkylthio; handles m, p and q can take values from 1 to 10; descriptor n can take values from 0 to 10; X and Y each represent hydrogen or an acid group selected from the following groups: carboxy-C1-C5-alkyl, -CH-[(CH2)mCOOH][(CH2)nCOOH], where m = 0-5 and n = 0-5, phosphono-C1-C5-alkyl, dihydroxystearic-C1-C5-alkyl, dimethoxyphosphoryl, phosphono, hydroxysulfonic, hydroxysulfonic-C1-C5-alkyl, hydroxysulfonic C1-C5-alkyl in neutral or charged form, provided that at least one of the substituents X and Y designates defined above acid group in neutral or charged form, a and b independently dig their preparation and pharmaceutical compositions have immunomodulatory properties, containing as active ingredient at least one compound of General formula I. 3 C. and 16 h.p. f-crystals, 23 tab., 48 Il.

Description text in facsimile form (see graphic material)and

Claims

1. N-acylated pseudodipeptides corresponding to General formula I

in which R1and R2denote each acyl group of the carboxylic acid having from 2 to 24 carbon atoms, which may be saturated or unsaturated, linear or branched, unsubstituted or having one or more substituents selected from hydroxyl, alkyl, alkoxy groups, acyloxy, amino, acylamino, atillio and C1-C24-alkylthio;

descriptors m, p and q can take values from 1 to 10;

descriptor n can take values from 0 to 10;

X and Y each represent hydrogen or an acid group selected from the following groups: carboxy-C1-C5-alkyl, CH-[(CH2)mCOOH] [(CH2)nCOOH], where m=0-5 and n=0-5, phosphono-C1-C5-alkyl, dihydroxystearic-C1-C5-alkyl, dimethoxyphosphoryl, phosphono, hidroxil the Federal or charged form, provided that at least one of the substituents X and Y designates defined above acid group in neutral or charged form;

A and b independently of one another represent an oxygen atom, sulfur or aminogroup-NH-,

and their therapeutically acceptable salts.

2. Compounds of General formula I under item 1, in which X and/or Y are acid groups converted into the salt form by using inorganic or organic predominantly therapeutically compatible base.

3. Compounds of General formula I’ under item 1 or 2

in which R1and R2each designate an acyl group of the carboxylic acid having from 2 to 24 carbon atoms, which may be saturated or unsaturated, linear or branched, unsubstituted or having one or more substituents selected from the group comprising hydroxyl, alkyl, alkoxy, acyloxy, amino, acylamino, atillio and C1-C24-alkylthio;

descriptors m, p and q can take different values from 1 to 10;

descriptor n can take values from 0 to 10;

X and Y each represent hydrogen or phosphonic group.

4. Connection PP.1-3, in particular 1 - and/or 10-dihydrophosphate 3-(3-products with inorganic or organic bases.

5. Connection PP.1-3, particularly 1,10-bis(dihydrophosphate) 3-(3-dodecadodecahedron)-9-(3-hydroxyacetylamino)-4-oxo-5-Azadegan-1,10-diol and its salt adducts with inorganic or organic bases.

6. Connection PP.1-3, particularly 1,10-bis(dihydrophosphate) 3(3-hydroxyacetylamino)-9-(3-dodecadodecahedron)-4-oxo-5-Azadegan-1,10-diol and its salt adducts with inorganic or organic bases.

7. Connection PP.1-3, in particular 1-dihydrogenphosphate 3-(3-dodecadodecahedron)-9-(3-hydroxyacetylamino)-4-oxo-5-Azadegan-1,10-diol and its salt adducts with inorganic or organic bases.

8. Connection PP.1-3, in particular 1-dihydrogenphosphate 3-(3-hydroxyacetylamino)-9-(3-dodecadodecahedron)-4-oxo-5-Azadegan-1,10-diol and its salt adducts with inorganic or organic bases.

9. Compounds of General formula I on p. 1, containing the elements of the configuration R or S or racemic.

10. The method of producing pseudodipeptides General formula I on p. 1

in which R1and R2denote each acyl group of the carboxylic acid having from 2 Oh or having one or more substituents, selected from hydroxyl, alkyl, alkoxy groups, acyloxy, amino, acylamino, atillio and C1-C24-alkylthio, and at least one of the substituents R1or R2denotes alltoall;

descriptors m, p and q can take different values from 1 to 10;

descriptor n can take values from 0 to 10;

X and Y each represent hydrogen or an acid group selected from the following groups: carboxy-C1-C5-alkyl, CH-[(CH2)mCOOH] [(CH2)nCOOH], where m=0-5 and n=0-5, phosphono-C1-C5-alkyl, dihydroxystearic-C1-C5-alkyl, dimethoxyphosphoryl, hydroxysulfonic, hydroxysulfonic-C1-C5-alkyl, hydroxysulfonic-C1-C5-alkyl, phosphono, neutral or charged form, provided that at least one of the substituents X and Y designates defined above acid group in neutral or charged form;

A and b have the above meaning,

characterized in that protect the amino function in position (q+1) anddiaminoanisole H2N(CH2)pCHNH2(CH2)q-1COOH protecting group, can be easily removed, respectively, by acid hydrolysis and hydrogenolysis, existing alcohol; free amino function in position (q+1), which is then acelerou with functional carboxylic acid derivative of formula R2OH, in which R2is above a certain value, then released via hydrogenolysis terminal amine function, receiving as a result, the diamine of General formula II

in which R2denotes the acyl group of the carboxylic acid having from 2 to 24 carbon atoms, which is saturated or unsaturated, linear or branched, unsubstituted or substituted by one or more of the above defined substituents;

p and q each represents an integer from 1 to 10,

which condense in the presence of the agent is a peptide condensation in an inert solvent derived-hydroxy-,-amino - or-diaminoanisole General formula III

in which R1denotes the acyl group of the carboxylic acid having from 2 to 24 carbon atoms, which is saturated or unsaturated, linear or branched, unsubstituted or substituted by one or more of the above defined substituents;

X denotes defined above acid group, which may be in ester form,

resulting in pseudodipeptides General formula IV

in which the substituents R1and R2and the handles m, n, p, and q are as defined above values,

in which if you want you can make a substitution, alkylation or acylation of the free terminal alcohol groups using replacement alkylating or allerease reagent in the presence of, if necessary, blending agent, and subjected to catalytic hydrogenation or any other way of removing protection, resulting in a derivative of General formula I

in which the substituents a, b, X, Y, R1R2and descriptors n, m, p and q have the previously given values.

11. The method according to p. 10 get postprivatization General formula I’ under item 1 or 2

in which R1and R2each designate an acyl group of the carboxylic acid having from 2 to 24 carbon atoms, which may be saturated or unsaturated, linear or branched, unsubstituted or has one or more b>-C24-alkylthio;

descriptors m, p and q can take values from 1 to 10;

descriptor n can take values from 0 to 10;

X and Y each represent hydrogen or a phosphonic group in neutral or charged form,

characterized in that protect the amino function in position (q+1) anddiaminoanisole formula H2N(CH2)pCHNH2(CH2)q-1COOH protecting group, can be easily removed, respectively, by acid hydrolysis and hydrogenolysis remaining free carboxyl function is subjected to the action of a reducing agent to obtain the corresponding alcohol; free amino function in position (q+1), which is then acelerou with functional carboxylic acid derivative of formula R2OH, in which R2is above a certain value, then released via hydrogenolysis terminal amine function, receiving the result amerosport General formula II

in which R2denotes the acyl group of the carboxylic acid having from 2 to 24 carbon atoms, which is saturated or unsaturated, linear or branched, unsubstituted or substituted by one or neskolku in the presence of the agent is a peptide condensation in an inert solvent derived-hydroxy-amino acids of General formula III’

in which R1denotes the acyl group of the carboxylic acid having from 2 to 24 carbon atoms, which is saturated or unsaturated, linear or branched, unsubstituted or substituted by one or more substituents;

m is an integer from 1 to 10;

n is a whole number from 0 to 10;

X denotes dealkylase or dialogsettings a radical of the formula

resulting in pseudodipeptides General formula IV

in which the substituents R1, R2and the handles m, n, p, and q are as defined above values;

R is labile to hydrogenolysis radical,

where (pseudodipeptides) optionally fosforilirovanii alcohol function fosforiliruyusciye agent in the presence of, if necessary, agent combination and subjected to two-stage catalytic hydrogenation in order to release the alcohol function, which may be present in the acyl group R2and to release the phosphate function, and then be released by hydrogenolysis second possible f">

in which Y represents either hydrogen or phosphonic group.

12. The method according to p. 10, in which the additional step of salt formation with inorganic or organic bases.

13. The method according to p. 10, in which stage the salt formation is carried out using a therapeutically compatible inorganic or organic bases.

14. The method according to p. 10, in which the carboxylic acid R1OH is a 3-dodecadodecahedron acid.

15. The method according to p. 10, in which the carboxylic acid R2OH is a 3-hydroxydecanoate acid.

16. Pharmaceutical composition having immunomodulatory properties, containing as active principle a compound according to any one of paragraphs.1-9.

17. The pharmaceutical composition according to p. 16 in which the compound of formula I is one in which X and/or Y denote toponomy radical, and a and b are atoms of oxygen.

18. The pharmaceutical composition according to p. 17, in which the active principle is a salt with a therapeutically compatible inorganic or organic base.

19. The pharmaceutical composition according to one of paragraphs.16-18, in which the active principle is an enantiomerically pure FD is

 

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