Analogues 15-desoxypeganine or their salts accession, the retrieval method, intermediate compounds and pharmaceutical composition based analogues 15 - desoxypeganine

 

(57) Abstract:

Disclosed analogs 15-desoxypeganine General formula I

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or their non-toxic salts of accession, where a denotes the group-CO-NH - or a group-NH-CO-; R represents a hydrogen atom or a group CH3*Indicates if R is not a hydrogen atom, asymmetric carbon configuration (R, S) or configuration (R), and the method of their production, intermediate compounds and pharmaceutical composition thereof. The invention can be used to produce a medicinal product intended for use in therapy for the treatment or prevention of immune disorders or malaria. 2 c. and 6 C.p. f-crystals, 1 table.

The invention relates to new compounds whose structure is similar to the 15-desoxypeganine. It relates also to a method for their production and their use in therapy, especially as immunosuppressive agents.

It is known that 15-desoxypeganine (OBS), which corresponds to the formula

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and which are known under the generic international name Gusperimus, has an interesting immunosuppressive activity. Numerous publications have reported this activity, in particular it is described in readet satisfactory chemical stability, therefore, attempts were made to get a more stable connection, for example

(I) replacing - hydroxylysine group 15 - desoxypeganine different or amino groups;

(II) modifying the structure of the Central link, or

(III) modifying the rung containing the guanidine function. Examples of such modifications are described in European patent A-0181592 and A-0105193 and French patent A-2698628.

Modifications made in respect of hydroxylating balance, are generally understood in J. Antibiot. 38: 886 - 898; and J. Antibiot. 41: 1629 - 1643. According to these publications, none of the proposed structures would not achieve the activity, the higher activity of OBS. In addition, changes in spermidine balance, published for example in J. Antibiot 40: 1303 - 1315, in most cases lead to loss of activity, and the presence of spermidine circuit is required to obtain active compounds.

However, now found that compounds having the structure, related to OBS, but not including hydroxylysine chain and spermidine circuit, however, possess immunosuppressive activity, and this activity may be higher activity OBS.

In the present of the and, which is chemically stable and which have activity higher than the activity of the known products of the prior art in the field of immunosuppressive funds.

Compounds according to the invention differ from the known products of the prior art essentially significant change in the Central part of the molecule, which leads to the group of urethane type. In addition, in contrast to all known products of the prior art, related 15-desoxypeganine, the compounds according to the invention do not contain polyominoes chain-type spermidine, but include the group type amerosport.

Compounds according to the invention are characterized in that they are chosen from the group of compounds including:

(1) the compounds of formula (I)

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in which

A represents a group-CO-NH-or a group-NH-CO-;

R denotes a hydrogen atom or methyl group;

*C, when R is not a hydrogen atom is an asymmetric carbon, the configuration of which may be undefined (R, S) or specific (R);

and (II) their salts connection.

According to the invention a method of producing compounds of the formula (I) and their salts accession, with the above method includes removal is H-;

R denotes a hydrogen atom or methyl group;

*C, when R is not a hydrogen atom, a denotes an asymmetric carbon configuration (R, S) or configuration (R);

moreover, at least one of the substituents R1denotes a protective group for aminophenol, while others represent a hydrogen atom;

according to known processing to achieve the removal of the protective groups from aminopentyl, and replace all protective groups R1the hydrogen atom.

The invention relates also to the use of substances of the formula (I), their non-toxic salts of accession and mixtures thereof, to obtain a medicinal product intended for use in therapy for the treatment or prevention of immune disorders or malaria, or for use as a pharmacological agent.

The phrase "salt of accession" understand salt accession acid, obtained by reacting the compounds of formula (I) with inorganic or organic acid. Preferred inorganic acids to obtain salts include hydrochloric, bromatologia, phosphoric acid and sulphuric acid. Preferred organic acids to obtain salts are fumaric, IU (I), compounds according to the invention include carbon, denoted by*C that is, if R is not a hydrogen atom is an asymmetric carbon. If R is not a hydrogen atom, the present invention includes racemic compounds of formula I, where*C has the configuration (R, S), enantiomer, where*C has the configuration (R), according to the rules define the structure described by Cahn, Ingold and Prelog.

If R denotes H, the carbon atom marked as*C is not asymmetric.

In practice of the compounds of formula (I), including asymmetric carbon*C, prefer those in which the above carbon has the configuration (R).

The compounds of formula (I) can be obtained according to known methods, based on the classic reaction mechanisms, in particular with the use of reactions, allowing to obtain the urethane groups of the type.

The method of obtaining compounds of formula (I) according to the invention includes, as described above, removing the protective groups from the compound of formula (II). In practice, the group or groups R1that during the reaction should be replaced by hydrogen atoms, are known protection is on aminophenol.

Groups that are suitable for this purpose, you can use:

a) group oxycarbonyl type, as, for example, alkoxycarbonyl or benzyloxycarbonyl group:

Boc: tert.-butyloxycarbonyl (or 1,1-dimethyl-etoxycarbonyl);

Fmoc: 9-fertilityscore;

Z: benzyloxycarbonyl (or phenylmethanesulfonyl);

Z(p-Cl): 4-chloro-benzyloxycarbonyl;

Z(p-OMe): 4-methoxybenzeneboronic;

(b) the benzyl group type, for example, phenylmethylene group (Bn).

Of these protective groups preferred group according to the invention is a Boc group.

The method of obtaining the compounds of formula (I) or one of its salts accession is that it includes the following stages:

(1) removing the protective groups from the compound of formula (II)

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in which

R denotes a hydrogen atom or methyl group;

A represents a group-CO-NH - or a group-NH-CO-;

*C, if R is not a hydrogen atom, a denotes an asymmetric carbon undefined configuration (R, S) or a specific configuration (R);

moreover, at least one of the substituents R1denotes a protective group AMINOPHENYL oxycarbonyl or Ben is Otke, depending on the nature of the protective group, for example, if the protective group is a group alkoxycarbonyl type, handle a strong acid, such as triperoxonane acid, or, if this protective group is a benzyl group type, carry out the catalytic hydrogenation in the presence of a catalyst based on palladium, to obtain the compounds of formula (I) in free base form or in the form of one of its salts accession; and, if necessary,

(II) receive other salts of accession on the basis of the free base or its salt accession obtained in stage (I). Thus, at stage (II), one of salt accession get other salts joining or using the compounds of formula (I) in free base form or by exchange of the counterion in the presence of an excess of the corresponding received salt of the acid.

To obtain compounds of the formula (II) can be used a method selected from the following variants of its implementation

(a) option a, which includes the following stages:

(1) condensation of the alcohol of formula (III):

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in which R denotes a hydrogen atom or methyl group;

R1denotes a protective group on the third carbon of the configuration (R, S) or (R);

with chloroformiate symmetric or carbonate, for example, 4-nitrophenyl-chloroformate, in the presence of a base, such as triethylamine in an inert solvent and at room temperature (15 - 25oC); then

(II) the interaction obtained in stage (I) compounds with an amine of formula (IV)

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in which R1denotes a protective group aminophenol, for example, a Boc group, in an inert solvent, at a temperature of about 25 - 50oC, to obtain the compounds of formula (II)

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in which A denotes the group-NH-CO-;

R denotes a hydrogen atom or methyl group;

*C indicates if R is not a hydrogen atom, asymmetric carbon configuration (R, S) or (R);

R1denotes a protective group aminophenol, for example, a Boc group,

b) option B, which includes the following stages:

(1) the interaction of the acid of formula (V)

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in which R2denotes a protective group aminophenol, for example benzyloxycarbonyloxy group, with diphenylphosphorylacetate formula VI

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in the presence of a base, such as triethylamine, in a solvent, such as tetrahydrofuran, and at room temperature, to obtain an intermediate compound foam reaction Curtius, and at the same time the thus obtained isocyanate enter into interaction with alcohol of formula (III)

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in which R denotes a hydrogen atom or methyl group;

R1denotes a protective group AMINOPHENYL different from the above-mentioned groups of R2for example a Boc group;

*C indicates if R is not a hydrogen atom, asymmetric carbon configuration (R, S) or (R), in a solvent such as toluene, at a temperature of about 80 - 140oin for 5 to 50 hours, to obtain the compounds of formula (VIII)

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in which R, R1, R2and *C have the above meanings;

(III) removing the protective groups from videolooking the compounds of formula (VIII), according to specific processing with the aim of replacing the protective group R2the hydrogen atom, for example, if R2means benzyloxycarbonyloxy group, carry out the catalytic hydrogenation in the presence of a catalyst based on palladium, to obtain the compounds of formula (IX)

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in which R, R1and*C retain the above values;

(IV) the interaction obtained in stage (III) compounds of the formula (IX) with aminobenzenesulfonate, in a solvent, for example methanol, at SUP>*C have the above meaning;

A represents a group-CO-NH-;

R1denotes a protective group aminophenol, for example, a Boc group, with the exception of two groups of R1that are on guanidino functions and each of them represents a hydrogen atom;

or

(IV') alternatively, the above stage (IV), which consists in the interaction of the compounds of formula (IX) with the compound of the formula (X)

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in which R1denotes a protective group aminophenol, such as a Boc group;

in a solvent, such as tetrahydrofuran, in the presence of a base, particularly triethylamine, at room temperature and for 8 to 100 hours, to obtain the compounds of formula (II)

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in which A denotes the group-CO-NH-;

R denotes a hydrogen atom or methyl group;

R1denotes a protective group aminophenol, such as a Boc group;

*C indicates if R is not a hydrogen atom, asymmetric carbon configuration (R, S) or (R).

The compound of formula (III)

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in which R denotes a methyl group;

*C denotes the carbon atom configuration (R, S) or (R);

R1denotes a protective group aminophenol, such as a Boc group;1 denotes a protective group aminophenol, such as a Boc group;

to obtain the compounds of formula

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then by introducing a protective group of a free aminophenol, for example, by using tert. -BUTYLCARBAMATE (Boc2O) if R1denotes the Boc group, to obtain the target compound of formula (III); or (b) by reacting the halide of the formula:

X - (CH2)4- O - R3,

in which X denotes a halogen such as iodine atom or a bromine atom;

R3denotes a protective group of hydroxyl functions, in particular trityloxy group

with the compound of the formula

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in which R1denotes a protective group aminophenol, for example, a Boc group,

to obtain the compounds of formula (a)

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then, by selective removal of the protective group from the product to obtain the compounds of formula

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and by introducing this connection protective group AMINOPHENYL R1for example the processing of tert.-BUTYLCARBAMATE, if R1denotes the Boc group, to obtain the target compounds of formula (III).

The compounds of formula (III) in which R denotes a methyl group and R1denotes the Boc group, are novel and constitute one of p is polyurethane foam aminophenol, for example, the group Z (benzyloxycarbonyl),

can be derived from compounds of the formula

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sequentially processing:

(a) cyanide, which allows to obtain the connection formula

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(b) a solution of sodium hydroxide, which leads to acid

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(b) with hydrogen in the presence of a hydrogenation catalyst to obtain the amine

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(g) finally, the reagent introducing a protective group aminophenol, such as benzylchloride, to obtain the target compounds of formula (V) in which R2means benzyloxycarbonyl group (Z).

The invention will be better understood when reading the following examples and results of pharmacological tests, obtained by using the compounds according to the invention, compared with the results obtained by applying the known products of the prior art. In the examples used the nomenclature recommended by the Chemical Abstracts; ester-type tert.-butyl...oat" is described in the form of "1,1-dimethylethylene ether .. . OIC acid".

In the experimental part of the description under the title "Preparation" refer to intermediate compounds and the Examples are of products according to the special instructions or instruction (R, S) denotes that we are talking largely about equimolecular mixture of two enantiomers (i.e., about the "racemic" connection). If the same connection is fitted with a sign (R) or (S) immediately after the identification of the position of Deputy, it means that the carbon that contains this Deputy is in the configuration (R) or (S) according to the rules of Cahn, Ingold and Prelog.

The spectral characteristics of the signals in nuclear magnetic resonance (NMR) are given for the proton (1H) or isotope 13 C (13C): specified chemical shift relative to the signal tetramethylsilane, and in parentheses indicate the waveform (c. for singlet; D. for doublet; so for triplet; K. for quadruplet; m for multiplet; sh. C. - broadened signal) and the number of protons is related to the signal. For information, spectra1H-NMR implement at 300 MHz.

Preparation 1

Bis-(1,1-dimethylethylene)ester 3-{/(1,1-dimethylmethoxy)carbonyl/ amino}-21-/(1,1-dimethylmethoxy)carbonyl/-12,15-dioxo-16-oxa-2,4,11, - 14,21,25-hexasaccharides-2-EN-diovol acid

1 g (2,89 10-3mol) of 1,1-Dimethylethylene ether {3-[/(1,1-dimethylmethoxy)carbonyl/amino] propyl} (4-hydroxybutyl)- carbamino acid was dissolved in 20 ml tetrahydrate in the form of a solution in 5 ml THF. The reaction mixture is stirred for 15 hours at room temperature, then add 1.2 g (2,89 10-3mol) of 1,1-dimethylethylene ether 13-amino-3-//(1,1 - dimethylmethoxy)carbonyl/amino/-12-oxo-2,4,11-treasuries-2-ene acid in solution in 6 ml of THF, bring the reaction mixture to a temperature of 40oC and stirred for 5 hours. After concentrating the reaction mixture under reduced pressure, the residue is purified by medium pressure chromatography on silica gel, elwira mixture of methylcyclohexane with ethyl acetate (7/3 by volume), and then pure ethyl acetate. Thus obtain 1 g of the target product in the form of a transparent oil (yield = 44%).

1H-NMR (CDCl3): 1,3-1,9 (m, 50H); 3,05-3,55 (m, 10H); 3,85 (D., 2H), 4,10 (t , 2H), 4,7-5,3 (sh.S., 1H); 5,4-5,6 (sh.S., 1H); 6,0-6,2 (sh.S., 1H); 8,3-8,5 (sh.S., 1H); 11,5 (S., 1H).

Example 1

{ 4-(3-Aminopropyl)amino/butoxycarbonylamino} -N-{6-/(aminoiminomethyl)- amino/hexyl}ndimethylacetamide-Tris(triptorelin)

Prepare a mixture of 1 g (1,27710-3mol) obtained in preparation 1 compound in 10 ml dichloromethane and 10 ml triperoxonane acid and the reaction medium is stirred for 15 hours at room temperature. The solvents are then removed under reduced pressure and the residue purified by cryptorhynchinae acid (2:7, 5:0,5; by volume). The fractions containing pure product are concentrated under reduced pressure, dissolved in water and lyophilizers. So get 0,78 g of the desired product as an amorphous translucent white solid (yield = 84%).

1H-NMR (DMCO-d6): 1,2-1.55V (m, 8H); 1,6-of 1.75 (m, 4H); 1,8-of 1.95 (m, 2H); 2,8-3,1 (m, 10H); 3,55 (D., 2H); 3,95 (t, 2H); of 6.7 to 7.4 (m, 4H); at 7.55 (t, 1H); 7,75-of 8.00 (m, 4H); 8,5-8,65 (m, 3H).

13C-NMR (D2O - dioxane h8): 23,05; 24,55; 26,15; 26,20; 26,30; 28,55; 28,95; 31,05; 37,35; 39,95; 41,88; 45,24; 48,18; 65,71; 158,0; 159,0; 178,5.

Example 1 bis

{ 4-/(3-Aminopropyl)amino/butoxycarbonylamino}-N-{6-/(aminoiminomethyl)- amino/hexyl}acetyl-Tris(hydrochloride)

Prepare a solution of 3.5 g of the compound according to example 1 (4,810-3mol) in 7 ml of anhydrous ethanol at 0oC was added dropwise 10 ml of a 1.3 M solution of hydrogen chloride in ethanol. Stand under stirring within 30 minutes after the addition, then the precipitation is filtered off. After washing the solid anhydrous ethanol, it was dried in vacuum at 35 - 40oC. Thereby obtaining the target product (1,72 g) as a white hygroscopic powder (yield = 72%). So pl. = 107,5oC.

Preparation II

1,1-Dimethylethylene ether {3-[[4-[Tris(510-3mol) of 1,1-dimethylethylene ester [3-(phenylethylamine)-1-(R)- methylpropyl] carbamino acid in 270 ml of butanol, and then add 12 g (27,110-3mol) 1-iodine-4-[Tris(phenyl)methoxy] butane and 3.74 g (27,110-3mol) of potassium carbonate. The reaction mixture is stirred at a temperature of 95-100oC for 48 hours. After cooling, the reaction medium is filtered, and then concentrated under reduced pressure. The residue is then treated with dichloromethane, and the resulting solution washed with water. After concentrating the organic phase under reduced pressure, the product is purified by chromatography on silica gel, elwira with a mixture of hexane with ethyl acetate (80:20 by volume). Thus obtained 6 g of the desired product as oil (yield = 75%).

[]2D4= -0,22o(c = 1,8; CHCl3).

1H-NMR (CDCl3): 1,02 (D., 3H); 1,40 (C., 9H); to 1.59 (m, 6H); of 2.38 (m, 3H); to 2.55 (m, 1H); 3,0 (sh. S., 2H); 3.40 in (D., 1H); 3,6 (D., 2H); 5,70 (S., 1H); 7,21-the 7.43 (m, 20H).

Preparation III

1,1-Dematiaceous ether {3-[[4-hydroxy-butyl]amino]-1-(R)- methylpropyl} -carbamino acid (hydrochloride)

4.94 g (8,3310-3mol) obtained in preparation II compounds are dissolved in 130 ml of 95oaqueous ethanol (i.e. a mixture of ethanol/water is then hydronaut at atmospheric pressure for 40 hours at room temperature. The catalyst is removed by filtration and the filtrate concentrated under reduced pressure. After purification by chromatography on silica gel, elwira with a mixture of chloroform with methanol (9: 1 by volume), gain of 2.09 g of the target product. After washing with diethyl ether to obtain 1.6 g of the pure product as a white crystalline solid (yield = 64,8%). So pl. = 135oC []2D2= to-7.6o(C = 1; CHCl3).

Preparation IV

1,1-Dimethylethylene ether {3-[4(-hydroxy-butyl)(1,1 - dimethylethoxysilane)amino]-1-(R)-methylpropyl}-carbamino acid

Prepare a mixture of 1.54 g (5,1810-3mol) obtained according to preparation III connection, 8 ml of dioxane and a solution of 0.77 g (7,2610-3mol) of sodium carbonate and 5.7 ml of water. This mixture is cooled to 5oC, then add a solution of 1.13 g (5,1810-3mol) di-tert.-butyl-dicarbonate (Boc2O) in 3 ml of dioxane, and the reaction mixture was kept under stirring for 15 hours. After adding 10 ml of water, extracted with ethyl acetate, then the organic phase is concentrated under reduced pressure. After purification by chromatography on silica gel, elwira with a mixture of hexane with ethyl acetate (50:50 by volume), get 1,82 g SS="ptx2">

1H-NMR (CDCl3): 0,87 (D., 3H); 1,44 of 1.46 (2s., 18H); 1,50-1,70 (m, 6H); 3,20 (m, 4H); to 3.67 (t, 3H); to 4.41-4,56 (2 sh.S., 1H).

Preparation V

1,1-Dimethylethylene ether {3-[N-[4-[(4-nitrophenoxy)carbonyloxy] butyl] -N-[1,1-dimethylethoxysilane]amino]-1-(R)-methylpropyl}carbamino acid

Prepare a solution of 2,73 g (7,5710-3mol) obtained in preparation IV compound in 55 ml of toluene and 0.62 ml (7,710-3mol) of pyridine and add 1.6 g (7,710-3mol) of 4-nitrophenyl-chloroformate. The reaction mixture was kept under stirring for 3 hours, then removed by filtering off the formed salt. The filtrate is concentrated under reduced pressure, then purified by chromatography on silica gel, elwira a mixture of dichloromethane with ethyl acetate (90: 10 by volume). Thereby obtaining 3.1 g of the target product (yield = 78%).

1H-NMR (CDCl3): 1,15 (D., 3H); 1.44MB (C., 9H); 1,46 (C., 9H); 1.5 and 1.8 (m , 6H); 3,24 (m, 4H); 3,63 (m, 1H); 4,30 (t, 2H); 7,39 (D., 2H); 8,28 (D., 2H).

Preparation VI

Bis(1,1-dimethylethylamine ether) 3-{ [(1,1-dimethylmethoxy)carbonyl]amino}- [(1,1-dimethylmethoxy)carbonyl]-24-(R)-methyl-12,15-dioxo-16-oxa - 2,4,11,14,21,25-gecause-hexakis-2-EN-dinoboy acid

2.8 g (5,3310-3mol) of the compound according to preparation V restoratives ether 13-amino-3-{[(1,1-dimethylmethoxy)carbonyl] amino} -12-oxo-2,4,11 - treasuries-2-EN-OIC acid in 50 ml of THF. Stand under stirring for 4 hours at room temperature, after which the reaction mixture is concentrated under reduced pressure. The solid residue purified by chromatography on silica gel, elwira with a mixture of hexane with ethyl acetate (30:70, then 10:90 by volume). So get of 3.85 g of the target product as a pale yellow solid (yield = 90,2%). []2D0= +0,4o(c = 2; CHCl3).

1H-NMR (CDCl3): 1,15 (D., 3H); 1,3-1,70 (m, 50H); of 3.25 (m, 6H); 3,39 (K., 2H); 3,63 (m, 1H); 3,83 (D., 2H); to 4.14 (t, 2H); 4,6 (sh. S., 1H); ceiling of 5.60 (sh. S., 1H); 6,13 (sh.S., 1H); 8,31 (S., 1H); 11,50 (S., 1H).

Example 2

{4-[(3-(R)-Amino-butyl)amino]butoxycarbonylamino}-N-[6- (aminoiminomethyl)hexyl]ndimethylacetamide-Tris(triptorelin)

In the flask, cooled to 0oC 3.7 g (4,610-3mol) obtained according to preparation VI compounds and add 37 ml triperoxonane acid. The mixture was kept under stirring for 15 hours at 5 - 10oC, then concentrated under reduced pressure. The crude product is purified by chromatography on grafted silica gel type RP18, elwira a mixture of water/acetonitrile/triperoxonane acid (70:15:15 by volume). Thereby obtaining 3.1 g of the desired product as white solid gyroscope 6): 1,18 (D., 3H); 1.26 in (m, 4H); of 1.41 (m, 4H); to 1.61 (m, 4H); to 1.75 (m, 1H); 1.91 a (m, 1H); 2,85-3,20 (m, 8H); or 3.28 (m, 1H); 3,54 (D. , 2H); 3.96 points (sh. S., 2H); to 7.25 (t, 1H); to 7.64 (S., 1H); 7,86 (t, 1H); 7,98 (C., 3H); 8,62 (S., 2H).

13C-NMR (D2O + dioxane): 17,93; 22,98; 26,06; 26,14; 26,23; 28,49; 28,91; 31,13; 39,89; 41,79; 44,31; 44,52; 46,01; 48,08; 65,60; 157,44; 159,38; 172,64.

Example 2 bis

{4-[(3-(R)-Amino-butyl)amino]butoxycarbonylamino}-N-[6- (aminoiminomethyl)hexyl]ndimethylacetamide-Tris(hydrochloride)

Prepare a solution of 200 mg (0,27 10-3mol) obtained in example 2 compound in 0.5 ml of ethanol and add 0,235 of 10.4 ml n HCl solution in ethanol. Stirred for 15 minutes at room temperature, then add 2 ml of diisopropyl ether. Usageprice the product is separated by decantation, washed it with diisopropyl ether, and then swallow him 3 ml of water and lyophilizers. Thus obtain 117 mg of the desired product as an amorphous solid white (yield = 85%). []2D2,5= +1,45o(c=2; CH3OH).

1H-NMR (DCMO-d6): 1,21 (D., 3H); 1.26 in (m, 4H); to 1.42 (m, 4H); of 1.64 (m, 4H); of 1.88 (m, 1H); 2,04 (m, 1H); 2,89-3,10 (m, 8H); 3,35-3,70 (m, 3H); 3,97 (sh.S., 2H); to 7.32 (t, 1H); 7,80 (t, 1H); 7,92 (t, 1H); 8,24 (C., 3H); 9,16 (S., 2H).

Preparation VII

1.1-Dimethyl {3-[N-[4-hydroxy-butyl]amino]-1- (R,S)-methylpropyl-[(methylsulphonyl)oxy]propyl}carbamino acid in 40 ml of 1,2-dimethoxyethane and added dropwise a solution to 4.14 g (46,5 10-3mol) of 4-aminobutanol in 10 ml of 1,2-dimethoxyethane. The reaction mixture for 18 hours, refluxed, and then concentrated under reduced pressure. The crude product is purified by chromatography on silica gel, elwira a mixture of ethyl acetate with ethanol and 33% ammonia (6:3:0.1). Thereby obtaining 2.5 g of the desired product as oil (yield = 41,5%).

1H-NMR (CDCl3): 1,14 (D., 3H); 1.44MB (C., 9H); 1.5 and 1.8 (m, 6H); of 2.64 (m , 4H); to 3.58 (t, 2H); 3,71 (m, 1H); 4,50 (D., 1H).

Preparation VIII

1,1-Dimethylethylene ether { 3-[N-(4-hydroxy-butyl)-N-(1,1-dimethylmethoxy-carbonyl)amino] -1-(R, S)-methyl-propyl}carbamino acid

Acting similarly to the method of preparation IV, proceeding from the compound obtained according to preparation VII, obtain the target product with a yield of 70%.

1H-NMR (CDCl3): 1,15 (D., 3H); 1,44 of 1.46 (2s., 18H); of 1.5-1.7 (m, 6H); 3,20 (m, 4H); to 3.67 (t, 3H); 4,39-4,56 (2 sh.S., 1H).

Preparation IX

Bis(1,1-dimethylethylamine ether) 3-{[(1,1-dimethylmethoxy)carbonyl]amino}-21-[(1,1-dimethoxyethoxy) carbonyl] -24-(R, S)-methyl-12,15-dioxo-16-oxa-2,4,11,14,21,25-gecause - hexakis-2-EN-dinoboy acid

1,8-g (510-3mol) of the Compound obtained according to the above preparation VII, dissolved in 36 ml of THF, that environment is maintained with stirring for 15 hours, then add a solution of 2.1 g (5,0610-3mol) of 1,1-dimethylethylene ether 13-amino-3-{ [(1,1-dimethylmethoxy)carbonyl] amino}-12 - oxo-2,4,11-triaza-tridec-2-EN-OIC acid in 30 ml of THF and kept under stirring for 18 hours. Formed by the reaction, the solid is removed by filtration, then the solution is concentrated under reduced pressure and the residue purified by chromatography on silica gel, elwira mixture of methylcyclohexane with ethyl acetate (50: 50), then (20:80 by volume). Thus obtain 0.97 g of the desired product as oil (yield = 24,2%).

1H-NMR (CDCl3): 1,15 (D., 3H); 1,20-1,80 (m, 50H); 3,26 (m, 6H); (K., 2H); 3,62 (m, 1H); 3,83 (D., 2H); 4,12 (m, 2H); 4,60 (sh.S., 1H); ceiling of 5.60 (sh. S., 1H); 6,13 (sh.S., 1H); 8.30 to (t, 1H); 11,49 (S., 1H).

Example 3

{ 4-[(3-(R,S)-Amino-butyl)amino]butoxycarbonylamino}- N-[6-amino-aminoethylamino)hexyl]ndimethylacetamide-Tris(triptorelin).

0,95 (1,18 10-3mol) of the Compound obtained according to preparation IX, dissolved in 10 ml dichloromethane, then add 10 ml triperoxonane acid. After stirring for 24 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue purified by chromatography on grafted silica gel type RP18, AluI is up 580 mg of the desired product in the form of a solid white color (yield = 66%).

1H-NMR (DMCO-d6): 1,18 (D., 3H); 1.26 in (m, 4H); of 1.41 (m, 4H); to 1.61 (m, 4H); 1,74 (m, 1H); 1.91 a (m, 1H); 2,85-3,10 (m, 8H); or 3.28 (m, 1H); 3,54 (D. , 2H); 3.96 points (t, 2H); 7.23 percent (t, 1H); 7,58 (t, 1H); 7,93 (C., 3H); 8,56 (m, 2H).

13C-NMR (D2O + dioxane h8): 18,02; 23,09; 26,17; 26,22; 26,30; 28,58; 29,00; 31,24; 40,00; 41,88; 44,40; 44,63; 46,10; 48,19; 65,72; 157,55; 159,55; 172,82.

Preparation X

Complex ethyl ester of N-(6-langecker)glycine

23,73 g (84,7 10-3mol) of a compound ethyl ester of N-(6-Bromhexine)of glycine are dissolved in 200 ml of ethanol and added 6.5 g (0.1 mol) of potassium cyanide in powder form. The reaction mixture is brought to reflux temperature and thus is stirred for 15 hours. After concentrating the mixture under reduced pressure, the residue is treated with dichloromethane and the organic phase is washed with an aqueous solution of sodium chloride. The organic phase is dried and concentrated under reduced pressure. Thus obtain 19 g of the target product (yield = 99%).

1H-NMR (CDCl3): of 1.29 (t , 3H); 1,45-1,55 (m, 2H); of 1.6-1.8 (m, 4H); 1.27mm (t, 2H); of 2.36 (t, 2H); 4,03 (D., 2H); 4,22 (K., 2H); 5,35-6,05 (sh.S., 1H).

Preparation XI

N-(6-Langecker)glycine

Prepare a mixture of 19 g (84 10-3mol) of the compound obtained according to preparation X, 120 ml of 1,2-dimethoxyethane and 120 ml of 1 M p is 00 ml of water and 200 ml of dichloromethane, and acidified to pH=1, cooling in an ice bath. The aqueous phase is extracted several times with dichloromethane, and the combined organic phases are dried and concentrated under reduced pressure. Thus obtain 10.2 g of the desired product in the form of oil, pale yellow (yield = 61%).

1H-NMR (CDCl3): 1,45-1,55 (m, 2H); of 1.6-1.8 (m, 4H); 2,3 (t, 2H); of 2.36 (t, 2H); 4,08 (D., 2H); x 6.15 and 6.25 (W., S., 1H).

Preparation XII

N-(7-Amino-heptanoyl)glycine (sodium salt)

of 8.2 g (41,4 10-3mol) of N-(6-langecker) of glycine are dissolved in 100 ml of ethanol, add 60 ml of a 1M solution of sodium hydroxide and 800 mg of Raney Nickel. The mixture was then stirred in an atmosphere of hydrogen at room temperature and a pressure of 3.5 to 105PA, within 8 hours. Upon completion of the reaction, add 20 ml of 1M hydrochloric acid and concentrated under reduced pressure. Thus obtain 10.2 g of solid pasty white matter, which contains the target salt and sodium chloride and which can be used without other purification in the next stage.

1H-NMR (DMCO-d6): of 1.15 to 1.6 (m, 8H); of 2.08 (t, 2H); of 2.56 (t, 2H); 3,32 (D., 2H); 7,1-7,25 (sh.S., 1H).

Preparation XIII

N-{7-[(Phenylmethanesulfonyl)amino]heptanoyl}glycine

2 g of Compound, recip) of sodium carbonate, then of 2.34 g (19,8 10-3mol) of benzylchloride. After stirring for 15 hours at room temperature, the reaction medium is brought to pH 1 with 1M hydrochloric acid, then extracted with dichloromethane. The organic phase is dried and concentrated under reduced pressure, and the crude product is purified by chromatography on silica gel, elwira a mixture of ethyl acetate/ethanol/hydroxide ammonium (6:3:0.5 to by volume). Thereby obtaining 1.3 g of the desired product in the form of a solid paste-like substance.

1H-NMR (DMCO-d6):of 1.2-1.6 (m, 8H); 2,09 (t, 2H); 2,98 (etc, 2H); 3,64 (D., 2H); 5,01 (S., 2H); to 7.25 (t, 1H); 7.3 to 7.4 (m, 5H); 7,94 (t, 1H).

Preparation XIV

1-(Phenylmethyl)-24-(1,1-dimethylethylene) ether 19-[(1,1-dimethylmethoxy)-carbonyl] -9,13-dioxa-14-oxa-2,10,12,19,23 - pentasa-tetracosanoic acid

0.5 g (1,49 10-3mol) of the Acid obtained according to preparation XIII, dissolved in 25 ml THF, added 0.18 g (1,8 10-3mol) of triethylamine and the mixture cooled to 0oC. and Then added dropwise and 0.46 g (1,67 10-3mol) diphenylphosphinite in the form of a solution in 5 ml THF and left under stirring at room temperature for 45 minutes. The solvent is removed under reduced pressure, the residue is treated with 2 ml of toluene and taxi)carbonyl]amino]propyl}(4-hydroxybutyl) carbamino acid. The reaction mixture is refluxed for 20 hours, then concentrated under reduced pressure. The crude product is purified by chromatography on silica gel, elwira mixture of methylcyclohexane with ethyl acetate in a gradient (8/2 ---> 1/9 by volume). Thus obtain 0.4 g of the desired product in the form of a solid white color (output = 39,6%).

So pl. = 115oC.

1H-NMR (CDCl3): 1,2 - 1,7 (m, 32H); of 2.15 (t, 2H); 3,05 - 3,3 (m, 8H); of 4.05 (t, 2H); 4,5 (t, 2H); 4,7 - 4,9 (sh.S., 1H); 5,08 (S., 2H); 5,7 - 5,9 (sh.S., 1H); 6,4 - 6,6 (sh.S., 1H); 7.3 to 7.4 (m, 6H).

Preparation XV

1,1-Dimethylethylene ether 22-amino-6-[(1,1-dimethylmethoxy)carbonyl] -12,16-dioxo-11-oxa-2,6,13,15 - tetraaza-docosanoic acid

A solution of 0.33 g (0,48 10-3mol) of the compound obtained according to preparation XIV in 15 ml of ethanol is subjected to catalytic hydrogenation in the presence of 30 mg of 5% palladium on coal at atmospheric pressure and at room temperature for 5 hours. After removal of the catalyst by filtration the solvent is removed under reduced pressure and obtain 0.26 g of the desired product in the form of an oil (yield 0,99%).

1H-NMR (CDCl3): 1,2 - a 1.75 (m, 32H); 2,2 (t, 2H); and 2.8 (t, 2H); 2,85 - 3,3 (m, 8H); 4,07 (t, 2H); 4.53-in (t, 2H); 4,7 - 5,4 (detoxi)carbonyl]amino} -21-[(1,1-dimethylmethoxy)carbonyl] -of 11.15-dioxo-16-oxa-2,4,12,14,21,25 - gecause-hexakis-2-EN-diovol acid

Prepare a mixture of 0.26 g (0,477 10-3mol) of the compound obtained according to preparation XV, 0,276 g (0.95 to 10-3mol) of 1,1-dimethylethylene ester {[[(1,1 - dimethylmethoxy)carbonyl]amino](methylthio)methylene}-carbamino acid and 200 μl of triethylamine in 12 ml THF and the reaction medium is maintained with stirring for 4 days at room temperature. After evaporation of the solvent under reduced pressure the crude product is purified by chromatography on silica gel, elwira mixture of methylcyclohexane with ethyl acetate in a gradient (7/3 ---> 2/8 by volume). Thus obtain 0.10 g of the desired product as oil (yield = 26,7%).

1H-NMR (CDCl3): 1,0-1,8 (m, 50H); of 2.16 (t, 2H); 3,05 - 3,3 (m, 6H); 3,4 (etc , 2H); 4,07 (t, 2H); 4,55 (t, 3H); 5,2 - 5,3 (sh.S., 1H); 5,7 - 5,8 (sh.S., 1H); 6,45 - 6,55 (sh.S., 1H); 8.3 (the T., 1H); 11,5 (S., 1H).

Example 4

7-[(Aminoiminomethyl)amino] -N-{ [4-[(3-aminopropyl)amino]butoxy] carbonylmethyl}heptanone-Tris(triptorelin)

Acting similarly to the method of example 3, and proceeding from the compound obtained according to preparation XVI, get the target product yield = 54%.

1H-NMR (DMCO-d6): 1.2 to about 1.35 (m, 4H); 1,4 - 1,7 (m, 8H); 1,8 - of 1.95 (m , 2H); to 2.06 (t, 2H); 2,8 - 3,1 (m, 8H); of 3.96 (t, 2H); 4,32 (t, 2H); 6,85 - 7,4 (sh.S., 3H); 7,55 to 7.7 (m, 2H); 7,8 - 8,0 (m, 4H is LaTeXe)-carbonyl] -22-(R)-methyl-9,13-dioxa-14-oxa - 2,10,12,19,23-pentasa-tetracosanoic acid

Doing the same way as the preparation XIV, on the basis of the acid obtained according to preparation XIII, and of the alcohol obtained according to preparation IV, get the target product in the form of a solid amorphous substance with a yield of 46%. []2D4= -2,2o(c=1,06; CHCl3).

1H-NMR (CDCl3): 1,15 (D., 3H); 1,2 - 1,7 (m, 32H); of 2.15 (t, 2H); 3,05 - to 3.35 (m , 6H); 3,55 to 3.7 (m, 1H); of 4.05 (t, 2H); 4,55 (t, 2H); 4,8 - 4,9 (sh. senior, 1H); 5,09 (c. 2H); 5,01 - 5,2 (sh.S., 1H); 5,7 - 5,9 (sh.S., 1H); 6,45 - 6,6 (sh.S., 1H); 7.3 to 7.4 (m, 5H).

Preparation XVIII

1,1-Dimethylethylene ether 22-amino-6-[(1,1-dimethylmethoxy)carbonyl] -3-(R)-methyl-12,16-dioxo-11 - oxa-2,6,13,15-tetraaza-docosanoic acid

Doing the same way as the preparation of the XV and proceeding from the compound obtained according to preparation XVII, get the target product in the form of an oil with a yield of 99%. []2D0= of-2.1o(c=1; CHCl3).

1H-NMR (CDCl3): 1,15 (D., 3H); 1,2 - 1,7 (m, 32H); 2,19 (t, 2H); 2,77 (t, 2H); 2,85 - 3,3 (m, 6H); 3,55 to 3.7 (m, 1H); 4,07 (t, 2H); to 4.52 (t, 2H); 5,7 - 6,3 (sh.S., 2H); 6,8 - 7,0 (sh.S., 1H).

Preparation XIX

1,1-Dimethylethylene ether 22[(aminoiminomethyl)amino]-6- [(1,1-dimethylmethoxy)carbonyl] -3(R)-methyl-12,16-dioxo-11-oxa - 2,6,13,15-tetrathiocarbonate acid

0.4 g (0,716 10-3mol) of the Compound, p is methansulfonate and the reaction mixture was stirred at room temperature for 3 days. After removal of the solvent under reduced pressure, the crude product is purified by chromatography on silica gel, elwira a mixture of ethyl acetate/ethanol/ammonia (6: 3: 0,1, then 6:3:1; by volume). So get of 0.37 g of the desired product as oil (yield = 86%). []2D2= -1o(c = 0,89; CHCl3).

1H-NMR (CDCl3): 1,15 (D., 3H); 1,2 - 1,7 (m, 32H); 2,2 (t, 2H); 2,9 - 3,3 (m , 6H); 3,5 - of 3.75 (m, 1H); of 4.05 (t, 2H); to 4.52 (t, 2H); 5,4 - 5,7 (sh. S. , 2H); 6,3 - 6,5 (sh.S., 1H); 7,05 - 7,3 (sh.S., 4H); 7,8 - 8,0 (sh.S., 1H).

Example 5

7-[(Aminoiminomethyl)amino] -N-[[4-[(3-(R)-aminobutyl)amino] -butoxy] - carbonylmethyl]heptanone-Tris(triptorelin)

Acting similarly to the method of example 3, and proceeding from the compound obtained according to preparation XIX, obtain the target product as an amorphous solid with a yield of 42%. []2D3= +1,2o(c = 1; CH3OH).

1H-NMR (DMCO-d6): 1,18 (D., 3H); 1.2 to about 1.35 (m, 4H); 1,4-of 1.55 (m, 4H); of 1.55 to 1.7 (m , 4H); from 1.7 to 1.85 (m, 1H); 1.85 to 2.0 a (m, 1H); 2.05 is (t, 2H); 2,85-3,1 (m, 6H); 3,2-of 3.85 (m, 1H); 3.96 points (t, 2H); 4,32 (t, 2H); 6,8-7,5 (M. S. , 3H); of 7.60 (t, 1H); to 7.68 (t, 1H); 7,95 (C., 4H); 8,35 (t, 1H); 8,5-to 8.7 (m, 2H).

13C-NMR (D2O + dioxane h8): 18,0; 23,06; 25,79; 26,12; 26,25; 28,45; 28,50; 31,22; 36,27; 41,86; 44,61; 46,08; 46,55; 48,17; 65,48; 157,52; 159,06; 178,36.

Immunosuppressive Akti is zaina. Male B6D2F1 mice (hybrids of the first generation C57B1/6 DBA/2) immunogenetic by intraperitoneally injection of cyclophosphamide. Three days later (day 0 of the experiment: J0they receive intravenous 4 107the splenocytes of the mouse C57B1/6. Animals then distribute party minimum of 8 individuals and they receive daily treatment in the days of J1- J5and J7- J10intraperitonal. The control group receives one excipient. For the death watch within 60 days (J60). The results, expressed in average survival days at the dose shown in the table, where the figures significantly under test Logrank (probability less than or equal to 5%). For comparison, the table shows the values obtained with the known products (or related structures) prior art: (A) 15-desoxypeganine (Tris/hydrochloride/) and the compound (B), which corresponds to example 16 European patent A-0600762.

Product B

< / BR>
From this comparison it follows that the products according to the invention have higher activity than products of the prior art, or require a lower dosage to achieve the equivalent effect.

The products according to isoo for prophylaxis of rejection of allogenic or xenogenic vascular or non-vascular organs; to prevent reaction of graft-versus-host in the transplantation of blood vessels, in the treatment of autoimmune genetic dependencies or acquired diseases (e.g., disseminated erythematous lupus, multiple sclerosis, rheumatoid arthritis), chronic inflammatory diseases, such as, for example, articular rheumatism, and in case of any abnormalities, in which the immune abnormalities are a cause or factor which saved the deterioration in clinical condition.

The products according to the invention can also be entered as an additive to anti-cancer cytotoxic drugs to limit their secondary effects, and as an additive in the acceptance of products of biological origin, in particular of recombinant cytokines, mono - or polyclonal antibodies, to reduce the appearance of protective antibodies produced by the patient.

The products according to the invention can be used in therapeutic treatment of parasites, in particular in accordance with malaria.

The products according to the invention can be administered orally, by injection (in particular intramuscular or intravenous), topicheskie or by inhalation.

The products according to the invention also find use as pharmacological agents, in particular in the study of autoimmune diseases.

Example A.

Preparation for perfusion.

Preparing a mother liquor from a solution of 200 mg of the compound of example 1 in 5 ml of pure water, which is brought to a pH of 4.0 by the addition of 0.01 N solution of alkali of sodium and add 30 mg of sodium chloride, and then purified water for injection sufficient to volume of 10 ml.

The solution, which is stored at 4oC, injected into the perfusion fluid from the calculation of a dosage of 2 ml/kg/day.

Example B.

Preparation for subcutaneous administration.

Prepare a solution of 12 mg of the compound from example 2, dissolved in 0.5 ml of clean water for injection, and bring the solution to pH 3.0 using a very dilute solution of hydrochloric acid. Added to a solution of clean water to bring to 1 ml of the Solution stored at a temperature of +4oC.

Injectable solution is produced by adding 1 ml of dilution solvent. This diluent is obtained from phosphate buffer pH 7 (Pharmacopoeia), which is diluted to 4% concentration of pure water for injection.

The floor is. The recommended dose of 2 to 4 injections per day depending on the weight of the patient.

Example C.

The lyophilisate for subcutaneous injection.

Get the solution corresponding to 12 mg of compound of example 2 and 120 mg of mannitol dissolved in 2 mg of pure water. The solution is filtered, then lyophilized in a bottle. The lyophilisate stored at 4oC.

Injectable solution is prepared before use by diluting the lyophilized in 4 ml of pure water for injection. The recommended dose is 1-4 injections per day for subcutaneous injection.

Example D.

Tablet containing 50 mg of active principle.

The active principle is 50 mg

Microcrystalline cellulose 400 mg

Pregelatinised starch - 48 mg

Magnesium stearate - 25 of MHI

1. Analogues 15-desoxypeganine General formula I

< / BR>
in which A denotes the group-CO-NH - or a group-NH-CO-;

R denotes a hydrogen atom or a group CH3;

*C indicates if R is not a hydrogen atom, asymmetric carbon configuration (R,S) or configuration (R);

or their salts connection.

2. Connection on p. 1 of the formula I, in which R denotes a methyl group and the asymmetric carbon *C has prisoedinenia under item 1, wherein removing the protective group from compounds of formula II

< / BR>
in which

R denotes a hydrogen atom or methyl group;

A represents a group-CO-NH - or a group-NH-CO-;

*C indicates if R is not a hydrogen atom, asymmetric carbon configuration (R, S) or (R), and at least one of the substituents R1denotes a protective group AMINOPHENYL oxycarbonyl or benzyl type, and the other substituents R1if they are, represent a hydrogen atom, according to the processing corresponding to the nature of the protective group aminophenol with obtaining the compounds of formula (I) in the form of free base or one of its salts accession; and, if necessary, the obtained free base or its salt accession into another additive salt.

4. The method according to p. 3, characterized in that carry out a preliminary stage, namely, that

(a) or (option a):

condense the alcohol of formula III:

< / BR>
in which R denotes a hydrogen atom or methyl group;

R1denotes a protective group AMINOPHENYL

*C indicates if R is not a hydrogen atom, asymmetric carbon configuration (R,S) or (R),oC);

the compound obtained is subjected to interaction with the amine of formula IV

< / BR>
in which R1denotes a protective group aminophenol,

in an inert solvent, at a temperature of about 25 - 50oC, to obtain the compounds of formula II

< / BR>
in which A denotes the group-NH-CO-;

R denotes a hydrogen atom or methyl group;

*C indicates if R is not a hydrogen atom, asymmetric carbon configuration (R,S) or (R);

R1means for protective amine function group;

(b) or (C):

the acid of General formula V

< / BR>
in which R2denotes a protective group aminophenol, is subjected to the interaction with diphenylphosphorylacetate formula VI

< / BR>
in the presence of a base in a solvent at room temperature to obtain the intermediate compounds of formula VII

< / BR>
the resulting compound of formula VII is subjected to rearrangement, known as the reaction Curtius, and at the same time the thus obtained isocyanate enter into interaction with alcohol of the formula III

< / BR>
in which R denotes a hydrogen atom or methyl group;

R1denotes a protective group AMINOPHENYL different from the d configuration (R,S) or (R); in a solvent, at a temperature of about 80 - 140oC, for 5 to 50 hours, to obtain the compounds of formula VIII

< / BR>
in which R, R1, R2and *C have the above meanings;

remove the protective group from the resulting compound of formula VIII according to specific processing, replacement of the protective group R2a hydrogen atom, to obtain the compounds of formula IX

< / BR>
in which R, R1and *C have the above meanings;

and then, the resulting compound of formula IX is subjected to interaction with aminobenzenesulfonate, in a solvent, at room temperature (15 - 25oC) and for 8 - 50 hours, to obtain the compounds of formula II

< / BR>
in which R and *C have the above meaning;

A denotes a group-CO-NH-;

R1denotes a protective group aminophenol, except for two groups of R1that are on guanidino functions and which represent each a hydrogen atom:

or, alternatively, the compound of formula IX is subjected to interaction with the compound of the formula X

< / BR>
in which R1denotes a protective group aminophenol in an inert solvent, in particular in tetrahydrofuran, in the presence of a base, at room temperature (1;

R denotes a hydrogen atom or methyl group;

R1means for protective amine group functions;

*C indicates if R is not a hydrogen atom, asymmetric carbon configuration (R,S) or (R),

and then remove the protective group as described in paragraph 3 to obtain the desired product of formula I.

5. The intermediate compound can be used to produce compounds of formula (1) under item 1, of General formula II

< / BR>
in which A denotes the group-CO-NH - or a group-NH-CO-;

R denotes a hydrogen atom or methyl group;

*C indicates if R is not a hydrogen atom, asymmetric carbon configuration (R,S) or configuration (R),

moreover, at least one of the substituents R1denotes a protective group AMINOPHENYL oxycarbonyl or benzyl type, and the other substituents R1if they are, represent a hydrogen atom.

6. The intermediate compound can be used to produce compounds of formula (1) under item 1, of General formula III

< / BR>
in which R denotes a methyl group;

R1denotes a protective group aminophenol;

*C denotes asymmetric carbon configuration (R,S) or (R).

7. Connection PP.1 and 2, the possession is Noah activity containing the active principle and a pharmaceutically acceptable excipients, characterized in that the active agent contains a compound of formula I or its non-toxic salt of the accession of the formula I on p. 1 in an effective amount.

 

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