Macrolide compounds with antiinflammatory effect

FIELD: chemistry.

SUBSTANCE: invention concerns macrolide compounds of the formula I , where R is hydrogen or methyl; R1 is hydrogen, N,N-di(C1-C3)alkylamino, N,N-di(C1-C3)alkylamino-N-oxide, N-(C1-C3)alkyl-N-benzylamino, N-(C1-C4)acyl-N-(C1-C3)alkylamino, N-[N,N-dimethylamino-(C1-C4)alkylamino]acetyl-N-(C1-C3)alkylamino or a chain of the formula: , where A is hydrogen, phenyl or thiazolyl; X is O or NR6 where R6 is hydrogen; Y is thiazolyl, pyrinidyl or NR6 where R6 is hydrogen; r is a whole number of 1 to 3; m is a whole number of 1 to 6; n is a whole number of 0 to 2; R2 is hydrogen; or R1 and R2 together form a link; R3 is a hydroxygroup or forms a =N-O-R5 group together with R4, where R5 is hydrogen, alkyl or a chain of the formula -(CH2)r-X-(CH2)m-Y-(CH2)n-A where r, m, n are the whole number as defined above; A is hydrogen, thiazolyl, furanyl or thiophenyl; X is NR6 where R6 is hydrogen; Y is a phenylene group or NR6 where R6 is hydrogen; R4 is hydrogen or forms =N-O-R5 group together with R3, with the same R5 as defined above; and its pharmaceutically acceptable salts, on the condition that R1 is not a dimethylamino group when R3 is a hydroxy group, and both R2 and R4 are hydrogen; R1 is not a dimethylamino group when in the =N-O-R5 substitute in 9 position R5 is hydrogen, linear or branched (C1-C5)alkyl; R1 is not a methylamino group when in the =N-O-R5 substitute in 9 position R5 is hydrogen, linear or branched (C1-C5)alkyl. The invention also concerns a method of obtaining the claimed compounds by elimination of L-cladinose residuum in the 3 position in compounds of the general formula II , where R, R1, R2, R3 and R4 are the same as defined above. Besides, the invention also concerns compounds of the general formula II, where R is hydrogen or methyl; R1 is hydrogen, N,N-di(C1-C3)alkylamino, N,N-di(C1-C3)alkylamino-N-oxide, N-(C1- C3)alkyl-N-benzylamino, N-(C1-C4)acyl-N-(C1-C3)alkylamino, N-[N,N-dimethylamino(C1-C4)alkylamino]acetyl-N-(C1-C3)alkylamino or a chain of the formula: where A is hydrogen, phenyl or thiazolyl; X is O or NR6 where R6 is hydrogen or C1-C3alkoxycarbonyl; Y is thiazolyl, pyrinidyl or NR6 where R6 is hydrogen or C1- C3alkoxycarbonyl; r is a whole number of 1 to 3; m is a whole number of 1 to 6; n is a whole number of 0 to 2; R2 is hydrogen; or R1 forms a link together with R2; R3 is a hydroxy group; R4 is hydrogen; and their pharmaceutically acceptable salts; on the condition that (i) R1 is not N,N-dimethylamino or (ii) R1 is not N,N-dimethylamino-N-oxide when R is hydrogen. The invention also concerns pharmaceutical composition based on the compound of the formula I, exhibiting anti-inflammatory effect.

EFFECT: obtaining of compounds with anti-inflammatory effect.

29 cl, 78 ex

 

The present invention relates to macrolide compounds with anti-inflammatory activity and more specifically, relates to macrolide derivatives that do not contain cladinose in position 3, with anti-inflammatory activity, to their pharmaceutically acceptable salts and pharmaceutical compositions containing them as active ingredient.

It is known that many antibiotics, especially the class of macrolides on the basis of erythromycin, containing the loop 14 atoms, have anti-inflammatory properties in addition to their antibacterial activity [Clin. Immunother., (1996), 6, 454-464].

Erythromycin is a natural macrolide (The Merck Index, 13thEdition, No. 3714, R. 654), which finds a very wide clinical use in the treatment of infections caused by gram-positive bacteria, near gram-negative bacteria and mycoplasmas.

Recently, the scientific community became interested in anti-inflammatory and immunomodulatory properties of erythromycin and its derivatives [Journal of Antimicrobial Chemotherapy (1998), 41, Suppl., B, 37-46].

This activity is very well presented as clinical studies and experiments in vivo and in vitro.

For example, it was found that macrolides are effective in the treatment of inflammatory diseases, such as panbronchiolitis [Thorax, (1997), 52, 915-918], bronchial asthma [Chest, (991), 99, 670-673] and cystic fibrosis [The Lancet (1998), 351, 420], as in animal models of inflammation, for example, when caused simhasanam peritonitis in mice [Journal of Antimicrobial Chemotherapy, (1992), 30, 339-348] and is caused by endotoxin accumulation of neutrophils in the lungs of rats [Antimicrobial Agents and Chemotherapy, (1994), 38, 1641-1643], and in vitro studies on cells of the immune system such as neutrophils [The Journal of Immunology, (1997), 159, 3395-4005] and T-lymphocytes [Life Sciences, (1992), 51, PL 231-236], or by modulation of cytokines, such as interleukin 8 (IL-8) [Am. J. Respir. Crit. Care Med., (1997), 156, 266-271] or interleukin 5 (IL-5) [patent application EP 0775489 and EP 0771564, Taisho Pharmaceutical Co., Ltd.].

Introduction macrolide compounds asthma accompanied by a decrease in bronchial secretion and sensitivity (Inflammation, Vol. 20, No. 6, 1996), which is the result of their interaction with neutrophils; and this interaction is believed to prevent many bioactive lipids involved in the pathogenesis of bronchial asthma, exercise them prior to the inflammation of the membrane destabilizing activity.

Special therapeutic efficacy of macrolide compounds for diseases, when anti-inflammatory medications such as corticosteroids are effective [Thorax, (1997), 52, 915-918, already quoted], explains the huge interest in this new effective class protivovospalitel what's assets.

However, the fact that conventional macrolide compounds have strong antibacterial activity, does not allow their wider use in chronic inflammatory processes, not caused by pathogenic microorganisms, as this could lead to the rapid development of resistant lines.

Therefore, it would be desirable to have available new substances with the structure of the macrolide, which have anti-inflammatory activity and which at the same time do not possess antibiotic properties.

For greater clarity, the above formula erythromycin, which shows the numbering adopted in this patent application.

The literature describes a large number of classes eritromicina compounds with antibacterial activity and higher acid stability and therefore, better pharmacokinetic properties.

Patent application WO 96/18633 (Zambon Group) describes compounds 9-[O-(aminoalkyl)oxime]of erythromycin A, which possess antibiotic activity against gram-positive and gram-negative microorganisms.

Derived from erythromycin ketolide modified at position 3' and 6-O-substituted, which is used in the treatment of bacterial infections, described in patent application WO 99/16779 (Abbott Labratories).

Connection 9-examineramerican, esterified at position 3 and 3'modified products, which are useful as antibacterial and antiulcer agents described in patent application JP 2001-181294 (Hokuriku Pharmaceutical Co.).

Among macrolide compounds described in the literature, there are several 3'-destinationin-9-oximino derivatives.

Patent application EP 0254534 (Robinson, William S.), has a very wide class of macrolide compounds, among which are disclosed 9-O-methyloxime erythronolide and 9 oximino-derivatives of erythromycin A, including 9-Of-methyloxime 3'-destinationin-3',4'-dihydroanthracene A.

The above patent publication represent compounds with antiviral activity.

9-Oxime of 3'-destinationin-3',4'-dihydroanthracene and 9-oxime of erythroid As described in U.S. patent 3928387 (Hoffmann-La Roche Inc.) as intermediates which can be used to obtain antibiotic A/X.

The literature describes a number of classes eritromicina compounds with anti-inflammatory activity.

For example, eritromicina compounds modified at positions 3, 9, 11 and 12, as claimed in the above European patent applications owned by Taisho, as effective inhibitors of the synthesis of IL-5.

The use of erythromycin as an anti-inflammatory is the means, which acts by reducing the release of interleukin-1 by inhibition of the mammalian glycoprotein mdr-P, as claimed in patent publication WO 92/16226 (Smith-Kline Beecham Corporation).

Compound 3'-destinationin-9-oxymoronically, possessing anti-inflammatory activity and does not exhibit antibiotic activity, described in patent application WO 00/42055 (Zambon Group).

Effective contribution to the anti-inflammatory activity shown macrolide compounds, can be traced to changes produced on a number of metabolic functions of neutrophils.

In particular, several studies have shown that macrolide compounds interfere with the exocytosis [Journal of Antimicrobial Chemotherapy, 1996, 38, 81] and in the production of oxidizing substances by neutrophils (PMNL) [Journal of Antimicrobial Chemotherapy, 1989, 24, 561].

The role of structural key element in modulating the above-mentioned functional metabolic activity of neutrophils attributed to the presence of L-cladinose in position 3 cycle macrolide compounds [The Journal of Immunology, 1997, 159, 3395-4005, already quoted].

The effect of sugar in accordance with the above article can be caused by either a large value of this sugar in the cellular uptake of macrolide compounds, or their interaction with cellular targets involved in both metabolic is aktivnosti neutrophils.

Named confirms that such neutral sugar L-cladinose, regardless of its inclusion in most macrolide structure, described as having declared anti-inflammatory activity.

Pharmaceutical preparations containing cladinose or L-cladinose as a medical product for the treatment of inflammatory conditions, described in international patent application no WO 97/00684 (Roussel Uclaf).

Unexpectedly, the applicants of this application found that by removing cladinose in position 3 of the derivatives of the macrolide can be obtained compounds with anti-inflammatory activity and essentially no antibiotic properties.

Thus, the purpose of the present invention is to obtain compounds of the formula:

where

R represents a hydrogen atom or methyl group;

R1represents a hydrogen atom, N,N-di(C1-C3)alkylamino, N,N-di(C1-C3)alkylamino-N-oxide group, N-(C1-C3)alkyl-N-benzylamino, N-(C1-C4)acyl-N-(C1-C3)alkylamino, N-[N,N-dimethylamino(C1-C4)alkylamino]acetyl-N-(C1-C3)alkylamino or a chain of formula

where

Represents a hydrogen atom, f is nil or a five - or six-membered heteroaryl cycle, containing one to three heteroatoms selected from nitrogen atom, oxygen and sulfur;

X represents O, S, SO, SO2and NR6and R6represents a hydrogen atom, a linear or branched C1-C3alkyl, C1-C3alkoxycarbonyl group or benzyloxycarbonyl group;

Y represents a C6H4group five - or six-membered heteroaryl cycle containing one to three heteroatoms selected from nitrogen atom, oxygen and sulphur, or represents O, S, SO, SO2or NR6where R6has the values given above;

r takes integer values from 1 to 3;

m takes integer values from 1 to 6;

n takes on integer values from 0 to 2;

or R1forms a bond together with R2;

R2represents a hydrogen atom or forms a bond together with R1;

R3represents a hydroxy-group or form a group =N-O-R5together with R4and R5represents a hydrogen atom, a linear or branched C1-C5alkyl, benzyl, optionally substituted by one or two substituents selected from nitro, hydroxy, carboxy, amino, linear or branched C1-C5of alkyl, C1-C4alkoxycarbonyl groups, aminocarbonyl groups or cyano groups, or is epock formula:

-(CH2r-X-(CH2)m-Y-(CH2)n-A

where

r, m, n, X, Y and a have the meanings defined above;

R4represents a hydrogen atom or forms a group =N-O-R5together with R3and R5has the values defined above;

and their pharmaceutically acceptable salt,

provided, however, that R1is not dimethylaminopropoxy, when R3represents a hydroxy-group, and as R2and R4represent a hydrogen atom.

Both the compounds of formula I, where R represents a hydrogen atom or methyl group, R1is dimethylaminopropyl, R3represents a hydroxy-group, R2and R4represent a hydrogen atom, known as chemical objects. Namely, the compound, where R represents a hydrogen atom, R1is dimethylaminopropyl, R3represents a hydroxy-group, R2and R4represent a hydrogen atom, described in the publication of Max V. Sigal, et al., J. Am. Chem. Soc., 1956, 78, 388-395, as a product of decomposition of erythromycin A. in Addition, both compounds where R represents a hydrogen atom or methyl group, R1is dimethylaminopropyl, R3represents a hydroxy-group, R2and R4represents a hydrogen atom, described in the publication EP-A-0941998 in ka is este source products when receiving macrolides, has antibiotic activity.

However, their anti-inflammatory activity still has not been submitted. Therefore, they are still new as anti-inflammatory drugs.

Oximes of formula I have the Z or E configuration. The compounds of formula I are anti-inflammatory macrolides, does not exhibit antibiotic activity and therefore are useful for the treatment and prevention of inflammatory diseases, also, when R represents a hydrogen atom or methyl group, R1is dimethylaminopropyl, R3represents a hydroxy-group, R2and R4represent a hydrogen atom.

The definition of "linear or branched C1-C5alkyl" means a group selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert.-butyl, n-pentile and isopentyl.

The expression "five - or six-membered heteroaryl cycle containing one to three heteroatoms selected from nitrogen atoms, oxygen and sulfur"means heterocyclic rings such as pyrrole, thiophene, furan, imidazole, pyrazole, thiazole, isothiazol, isoxazol, oxazole, pyridine, pyrazin, pyrimidine, pyridazine, triazole or thiadiazole.

For qualified in the field of specialist it is obvious that the substitution of g is tervailing cycles partially or fully saturated form, and the presence of substituents on the aromatic (phenyl or heteroaryl) cycles, provided the values of a and Y, gives compounds that fall under the scope of the present invention.

Preferred compounds of formula I are compounds where R1, R2, R3, R4, R5and R6have the meanings given in formula I, and R1represents a hydrogen atom, N-(C1-C3)alkyl-N-methylaminopropyl, N-(C1-C3)alkyl-N-methylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-(C1-C4)acyl-N-methylaminopropyl, N-[N,N-dimethylamino(C1-C4)alkylamino]acetyl-N-methylaminopropyl or a chain of formula:

where

Represents a hydrogen atom, phenyl or five - or six-membered heteroaryl cycle containing one to three heteroatoms selected from nitrogen atom, oxygen and sulfur;

X represents O or NR6and R6represents a hydrogen atom or a linear or branched C1-C3alkyl;

Y, when n is 0, is a C6H4group or a five - or six-membered heteroaryl cycle containing one to three heteroatoms selected from nitrogen atom, oxygen and sulfur, or, when n has a value other than 0, represents O, and NR 6and R6represents a hydrogen atom or a linear or branched C1-C3alkyl;

r takes integer values from 1 to 3;

m takes integer values 1 or 2;

n takes on integer values from 0 to 2;

or R1forms a bond together with R2.

In this group of compounds, which are even more preferred are compounds where R1represents a hydrogen atom, N,N-dimethylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-acetyl-N-methylaminopropyl, N-[N,N-dimethylamino(C1-C2)alkylamino]acetyl-N-methylaminopropyl or a chain of formula:

where

Represents a hydrogen atom, phenyl or five - or six-membered heteroaryl cycle selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole;

X represents O or NR6and R6represents a hydrogen atom;

Y, when n is 0, is a C6H4group or a five - or six-membered heteroaryl cycle selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole, or, when n is 1, represents NR6and R6represents a hydrogen atom;

r takes integer values from 1 to 3;

<> m takes integer values 1 or 2;

n takes integer values 0 or 1;

or R1forms a bond together with R2.

Other compounds that belong to this group are even more preferred are compounds where R1represents a hydrogen atom, N,N-dimethylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-acetyl-N-methylaminopropyl, N-[N,N-diethylaminoethylamine]acetyl-N-methylaminopropyl or a chain of formula:

where

Represents a hydrogen atom, phenyl or heteroaryl cycle selected from thiophene, furan, thiazole, pyridine and triazole;

X represents NR6and R6represents a hydrogen atom;

Y, when n is 0, is a C6H4group or heteroaryl cycle selected from thiophene, furan, thiazole, pyridine and triazole, or, when n is 1, represents NR6and R6represents a hydrogen atom;

or R1forms a bond together with R2.

Other preferred compounds are compounds in which R, R1, R2and R6have the meanings already given in formula I, R3represents a hydroxy-group, and R4represents a hydrogen atom, provided, however, that R1is not dimetilan what nography.

Compounds which are preferred within this group are compounds where R1represents a hydrogen atom, N-(C1-C3)alkyl-N-methylaminopropyl, N-(C1-C3)alkyl-N-methylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-(C1-C4)acyl-N-methylaminopropyl, N-[N,N-dimethylamino(C1-C4)alkylamino]acetyl-N-methylaminopropyl or a chain of formula:

where

Represents a hydrogen atom, phenyl or five - or six-membered heteroaryl cycle containing one to three heteroatoms selected from nitrogen atom, oxygen and sulfur;

X represents O or NR6and R6represents a hydrogen atom or a linear or branched C1-C3alkyl;

Y, when n is 0, is a C6H4group or a five - or six-membered heteroaryl cycle containing one to three heteroatoms selected from nitrogen atom, oxygen and sulfur, or, when n has a value other than 0, represents O or NR6and R6represents a hydrogen atom or a linear or branched C1-C3alkyl;

r takes integer values from 1 to 3;

m takes integer values 1 or 2;

n takes on integer values from 0 to 2;

or R1forms with the IDE with R 2.

Compounds that are even more preferred within this group are compounds where R1represents a hydrogen atom, N,N-dimethylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-acetyl-N-methylaminopropyl, N-[N,N-dimethylamino(C1-C2)alkylamino]acetyl-N-methylaminopropyl or a chain of formula:

where

Represents a hydrogen atom, phenyl or five - or six-membered heteroaryl cycle selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole;

X represents O or NR6and R6represents a hydrogen atom;

Y, when n is 0, is a C6H4group or a five - or six-membered heteroaryl cycle selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole, or, when n is 1, represents NR6and R6represents a hydrogen atom;

r takes integer values from 1 to 3;

m takes integer values 1 or 2;

n takes integer values 0 or 1;

or R1forms a bond together with R2.

Compounds of this group are even more preferred are compounds where R1presented yet a hydrogen atom, N,N-dimethylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-acetyl-N-methylaminopropyl, N-[N,N-diethylaminoethylamine]acetyl-N-methylaminopropyl or a chain of formula:

where

Represents a hydrogen atom, phenyl or heteroaryl cycle selected from thiophene, furan, thiazole, pyridine and triazole;

X represents NR6and R6represents a hydrogen atom;

Y, when n is 0, is a C6H4group or heteroaryl cycle selected from thiophene, furan, thiazole, pyridine and triazole, or, when n is 1, represents NR6and R6represents a hydrogen atom;

or R1forms a bond together with R2.

Among the compounds where R, R1and R2have the meanings already given for formula I, and R3form a group =N-O-R5together with R4of the compounds which are preferred are compounds where R5represents a hydrogen atom, a linear or branched (C1-C3)alkyl, benzyl, optionally substituted by one or two substituents selected from nitro, hydroxy, carboxy, amino, linear or branched (C1-C3)alkyl and ceanography, or a chain of formula:

-(CH2r-X-(CH2)m-Y-(CH2)n-A

where

And PR is dstanley a hydrogen atom, phenyl or five - or six-membered heteroaryl cycle containing one to three heteroatoms selected from nitrogen atom, oxygen and sulfur;

X represents O or NR6and R6represents a hydrogen atom or a linear or branched C1-C3alkyl;

Y, when n is 0, is a C6H4group or a five - or six-membered heteroaryl cycle containing one to three heteroatoms selected from nitrogen atom, oxygen and sulfur, or, when n has a value other than 0, represents O or NR6and R6represents a hydrogen atom or a linear or branched C1-C3alkyl;

r takes integer values 1 or 2;

m takes integer values from 1 to 6;

n takes on integer values from 0 to 2.

Compounds which are preferred within this group of compounds of formula I are compounds where R5represents a hydrogen atom, methyl, benzyl, or a chain of formula:

-(CH2r-X-(CH2)m-Y-(CH2)n-A

where

Represents a hydrogen atom, phenyl or five - or six-membered heteroaryl cycle selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole;

X represents O or NR6and R6is the Oh hydrogen atom;

Y, when n is 0, is a C6H4group or a five - or six-membered heteroaryl cycle selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole, or, when n is 1, represents NR6and R6represents a hydrogen atom;

r is 2;

m takes integer values from 1 to 6;

n takes integer values 0 or 1.

Compounds of this group are even more preferred are compounds of formula I, where R5represents a hydrogen atom, methyl, benzyl or a chain of formula:

-(CH2r-X-(CH2)m-Y-(CH2)n-A

where

Represents a hydrogen atom, phenyl or heteroaryl cycle selected from thiophene, furan, thiazole, pyridine and triazole;

X represents NR6and R6represents a hydrogen atom;

Y, when n is 0, is a C6H4group or heteroaryl cycle selected from thiophene, furan, thiazole, pyridine and triazole, or, when n is 1, represents NR6and R6represents a hydrogen atom.

Compounds which are also preferred are compounds where R and R2have the meanings given in formula I; R1represents a hydrogen atom, N-(C1 -C3)alkyl-N-methylaminopropyl, N-(C1-C3)alkyl-N-methylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-(C1-C4)acyl-N-methylaminopropyl, N-[N,N-dimethylamino(C1-C4)alkylamino]acetyl-N-methylaminopropyl or a chain of formula:

where

Represents a hydrogen atom, phenyl or five - or six-membered heteroaryl cycle selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole;

X represents O or NR6and R6represents a hydrogen atom;

Y, when n is 0, is a C6H4group or a five - or six-membered heteroaryl cycle selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole, or, when n is 1, represents NR6and R6represents a hydrogen atom;

r takes integer values from 1 to 3;

m takes integer values 1 or 2;

n takes integer values 0 or 1;

or R1forms a bond together with R2;

at the same time R3form a group =N-O-R5together with R4where R5represents a hydrogen atom, a linear or branched (C1-C3)alkyl, benzyl, optionally substituted by one or two to cover the firs, selected from nitro, hydroxy, carboxy, amino, linear or branched (C1-C3)alkyl and ceanography, or a chain of formula:

-(CH2r-X-(CH2)m-Y-(CH2)n-A

where

Represents a hydrogen atom, phenyl or five - or six-membered heteroaryl cycle containing one to three heteroatoms selected from nitrogen atom, oxygen and sulfur;

X represents O or NR6and R6represents a hydrogen atom or a linear or branched C1-C3alkyl;

Y, when n is 0, is a C6H4group or a five - or six-membered heteroaryl cycle containing one to three heteroatoms selected from nitrogen atom, oxygen and sulfur, or, when n has a value other than 0, represents O or NR6and R6represents a hydrogen atom or a linear or branched C1-C3alkyl;

r takes integer values 1 or 2;

m takes integer values from 1 to 6;

n takes on integer values from 0 to 2.

Compounds which are preferred within this group of compounds of formula I are compounds where R5represents a hydrogen atom, methyl, benzyl or a chain of formula:

-(CH2r-X-(CH2)m-Y-(CH2)n-A

where

And represents the atom in which aroda, phenyl or five - or six-membered heteroaryl cycle selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole;

X represents O or NR6and R6represents a hydrogen atom;

Y, when n is 0, is a C6H4group or a five - or six-membered heteroaryl cycle selected from pyrrole, thiophene, furan, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazole and thiadiazole, or, when n is 1, represents NR6and R6represents a hydrogen atom;

r is 2;

m takes integer values from 1 to 6;

n takes integer values 0 or 1.

Compounds of this group are even more preferred are compounds of formula I, where R5represents a hydrogen atom, methyl, benzyl or a chain of formula:

-(CH2r-X-(CH2)m-Y-(CH2)n-A

where

Represents a hydrogen atom, phenyl or heteroaryl cycle selected from thiophene, furan, thiazole, pyridine and triazole;

X represents NR6and R6represents a hydrogen atom;

Y, when n is 0, is a C6H4group or heteroaryl cycle selected from thiophene, furan, thiazole, pyridine and triazole, or, when n is 1, represents NRsub> 6and R6represents a hydrogen atom.

Compounds of the latter group are even more preferred are compounds of formula I, where R1represents a hydrogen atom, N,N-dimethylaminopropyl, N,N-dimethylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-acetyl-N-methylaminopropyl, N-[N,N-dimethylamino(C1-C2)alkylamino]acetyl-N-methylaminopropyl or a chain of formula:

where

Represents a hydrogen atom, phenyl or heteroaryl cycle selected from thiophene, furan, thiazole, pyridine and triazole;

X represents NR6and R6represents a hydrogen atom;

Y, when n is 0, is a C6H4group or heteroaryl cycle selected from thiophene, furan, thiazole, pyridine and triazole, or, when n is 1, represents NR6and R6represents a hydrogen atom;

or R1forms a bond together with R2.

The aim of the present invention to provide compounds of formula I with Z or E configuration possible oxime in position 9 with a preference for the latter compounds.

Examples of pharmaceutically acceptable salts of the compounds of formula I are salts with organic or mineral acids, such as chloride in dorog, bromide hydrogen, modesty hydrogen, nitric acid, sulfuric acid, phosphoric acid, acetic acid, tartaric acid, citric acid, benzoic acid, succinic acid and glutaric acid.

Specific examples of the compounds of the present invention are the compounds where R, R2and R4have the meanings given for formula I, R1forms a bond together with R2or R1represents a hydrogen atom, N,N-dimethylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-acetyl-N-methylaminopropyl, N-[N,N-diethylaminoethylamine]acetyl-N-methylaminopropyl, N-methyl-N-3-[(2-triazolylmethyl)amino]propylamino, N-2-[2-[(2-triazolylmethyl)amino]ethylamino]ethyl-N-methylaminopropyl or N-2-[2-(benzylamino)ethylamino]ethyl-N-methylaminopropyl, R3represents a hydroxy-group or form a group =N-O-R5together with R4and R5represents a hydrogen atom, methyl, benzyl, 2-[2-[(2-triazolylmethyl)amino]ethylamino]ethyl group, 2-(benzylamino)ethyl group, 2-[2-[(2-furylmethyl)amino]ethylamino]ethyl group, 2-[2-[(3-furylmethyl)amino]ethylamino]ethyl group, 2-[2-[(2-thienylmethyl)amino]ethylamino]ethyl group, or 2-[6-[(2-triazolylmethyl)amino]hexylamino]ethyl group.

The compounds of formula I of the present invention receive in accordance with the synthetic route, which included the AET remove residue L-cladinose in position 3 of the compound of the formula:

where

R, R1, R2, R3and R4have the meanings given for compounds of formula I.

The removal of residual cladinose preferably carried out by reaction of the acid hydrolysis, catalyzed in the presence of a mineral acid, for example sulfuric acid, or hydrogen chloride, and proton organic solvent, such as water, methanol or ethanol.

9-Hydroxycodone, which are intermediate compounds of formula II are new, with the exception of compounds where (i) R1represents N,N-dimethylaminopropyl, and (ii) R represents a hydrogen atom, and R1represents N,N-dimethylamino-N-oxide group.

For example, 9-hydroxycodone, where R represents a hydrogen atom or methyl group and R1represents N,N-dimethylaminopropyl described as antibacterial agents in the publication of R. Faghih et al., J. of Antibiotics, 1990, 43, 1334-36.

The compounds of formula II derived from erythromycin a or 6-O-methylerythromycin And (common name: Clarithromycin) by affecting ketogroup in position 9 and optional on dimethylaminopropyl in position 3'. Preferably, the impact is first sent to ketogroup in position 9; it can be recovered by obtaining hydroxycodone or maybe clicks the nerd reagents, able to give examinatione, which can then be functionalized.

Possible modifications of dimethylaminopropyl in position 3' include oxidation, destruction or demethylation and subsequent functionalization (alkylation and acylation).

For qualified in the field of specialist it is obvious that, in order to exclude the interference of functional groups that may be present in third positions where it can be produced structural modification, will be more or less convenient to appropriately choose the priority for synthetic modifications that should be made.

Thus, for example, possible functionalization of examinatione can take place immediately after their synthesis can be carried out before or after possible modifications, wherever it could be in the position 3', or may be the last stage of the synthesis.

As for another example on deleting cladinose, such removal may be performed after modification ketogroup in position 9, may follow or precede the functionalization of examinatione in this position, you may follow or precede the possible modifications on dimethylaminopropyl or can complete the processsynthesis.

Preferably the hydrolysis reaction is of Achar is carried out after modification ketogroup in position 9 macrolide cycle, to exclude the presence cladinose in the reaction environment and the need for its subsequent separation from the final product, and not from an intermediate connectionsynthesis; however, in the General case there is no interaction that could prevent the removal of cladinose to another intermediate stage or at the end of the synthesis process.

Such procedural alternatives will be determined in each case, technical requirements, aimed at optimizing the synthesis process of the product in question.

The implementation of the above-mentioned structural modifications macrolides described in more detail below.

Oxime erythromycin a with Z and E configuration is known. They are commercially available compounds and can be obtained by conventional methods, for example, in accordance with U.S. patent 3478014 (Pliva or J.C. Gasc et al.) (The Journal of Antibiotics; 44, 313-330, 1991) to obtain compounds of the formula:

where

R has the meanings given for formula I.

Hydroxy in position 9 are compounds that are also known and may be obtained by conventional methods, by treatment with erythromycin And reducing agents such as hydrides (sodium borohydride, lithium borohydride, lamborghini.com sodium or lithium aluminum hydride (Faghih, Joural of Antibiotics, 1990, 1334-1336), or by catalytic hydrogenation to obtain compounds of the formula

where

R has the meanings given for formula I.

The compounds of formula I, where R5matter other than hydrogen atom can be obtained by direct synthesis or by functionalization of the oxime in position 9 by the usual methods.

Usually an optional functionalization of conducting the reaction with the compound of the formula:

where

R5' has all values of R5with the exception of the hydrogen atom, and L represents a leaving group, preferably chlorine atom or bromine or mesyl group.

Another way, which is particularly suitable for producing compounds of formula I, where R5represents a chain of formula:

-(CH2r-X-(CH2)m-Y-(CH2)n-A

where

X, Y, A, r, m and n have the meanings given in formula I;

this involves reacting the compounds of formula II, where R5represents a hydrogen atom and from which cladinose already not necessarily removed, with an intermediate compound of the formula:

where

L, X, Y, m and n have the meanings already given, and Z represents a protective group, such as urethane (carbobenzoxy, carballeira or trichloracetic oxycarbonyl group);

obtaining an intermediate compound of the formula:

where

R, R1, R2X, Y, Z, r and m have the meanings already given, and R7represents a hydrogen atom or L-cladinose; which after removal of the protective group Z, is introduced into reaction with the compound of the formula:

where A, L and n have the meanings given earlier,

obtaining the compounds of formula I.

The compounds of formula I, where Y represents NR6can be obtained by the synthesis method described above, including the use of the aldehyde of the formula:

where a has the above meanings;

instead of the intermediate compounds of formula VII, after removal of the protective group Z from the intermediate compounds of formula VI.

Remove dimethylaminopropyl is carried out by oxidation, pyrolysis or possible restoration in accordance with known methods, for example by the methods described in international patent application WO 00/42055 (Zambon Group) or in U.S. patent 3928387 (Hoffmann-La Roche Inc.), which have already been quoted.

For the person skilled in the art it is obvious that in order to exclude the interference of functional groups that may be present in the substituent R5removing dimethylaminopropyl pre is respectfully conduct in the intermediate compounds of the formula:

where

R and R7have the above significance, and R5" represents a hydrogen atom or a linear or branched C1-C5alkyl.

Oxidation gives N-oxides of the formula:

where

R, R5and R7have the previously given meanings;

which due to pyrolysis, after which not necessarily followed by recovery, give respectively the compounds of the formulas:

and

where

R, R5and R7have the previously given values.

The transformation into the corresponding N-oxides takes place in accordance with known methods by treatment with nagkakamali, for example hydrogen peroxide or meta-chlormadinone acid, in the presence of an organic solvent (U.S. patent 3928387, Hoffmann-La Roche Inc., already quoted) (J. Am. Chem. Soc., 1954, 76, 3121).

Demethylation of dimethylaminopropyl in position 3' may be effected using conventional techniques, for example by treatment with sodium acetate and iodine in the presence of an organic solvent, as described in U.S. patent 3725385 (Abbott Laboratories); subsequent alkylation of the secondary amine thus obtained, carried out in accordance with conventional methods of synthesis.

In addition, the compounds of formula I, g is e R 1=R2=H, can be obtained by reduction of corresponding compounds of formula I, where R1and R2together form a bond.

Another method for the synthesis of 3',4'-dihydroactinidiolide erythromycin And consists in processing, which is described in U.S. patent 3928387 (Hoffmann-La Roche Inc., already quoted), to obtain an intermediate compound of the formula:

and then, depending on the required connection, communication with cladinose can be hydrolyzed, and the oxime in position 9 can be optionally functionalized as described previously, and Vice versa.

Macrolide compounds have a wide therapeutic application as antibacterial agents; in each case, clinical and experimental data show that they can be involved in the modulation of the inflammatory response.

A large body of evidence from studies both in vitro and in vivo, shows that, despite the inhibition of release of cytokines, modulatory effects of macrolide compounds directed to important cellular targets, such as lymphocytes and neutrophils.

These cells, in particular, represent the first line of defense against pathogens, and this function is expressed through phagocytosis, the release of hydrolytic enzymes and the production of toxic is oxygen metabolites.

Although neutrophils are essential for immune protection, it is known that non-physiological release of acidifying substances and hydrolytic enzymes may be involved in many pathological conditions such as atherosclerosis, reperfusion of the ischemic lesion, rheumatoid arthritis, septic shock and chronic pulmonary inflammation, such as ARDS (acute respiratory distress syndrome), COPD and asthma (inflammation and fever; Viera "Stvrtinova, Jan Jakubovsky, Ivan Hulin; Academic Electronic Press, 1995).

Treatment with erythromycin in low doses over a long period of time described as being effective in reducing bronchial hypersensitivity in patients with asthma (H. Miyatake et al., Chest, 1991, 99, 670-673, already quoted).

Additional research shows that a certain treatment of patients suffering from COPD, can significantly reduce the frequency and risk of exacerbation of this disease caused by acute respiratory infections (CHEST 2001, 120, 730-733).

The obtained results explain not antibiotic activity of the macrolide, and inhibits the expression and release of inflammatory cytokines.

This treatment is in accordance with the already cited article preferably should be limited to patients with a high risk of exacerbation of COPD due to the potential risk of emergence of resistant p. togeny lines.

The compounds of formula I of the present invention possess anti-inflammatory activity and does not have antibiotic activity.

The pharmacological activity of the compounds of formula I are estimated in models of skin and lung inflammation in comparison with the known macrolide compounds such as erythromycin and azithromycin, which have both anti-inflammatory and antibiotic activity.

Anti-inflammatory activity assessed as through inhibition of PMA-induced ear edema of mice through a decrease in LPS-induced accumulation of neutrophils in the lungs of rats.

In all experiments, the compounds of the present invention, as installed, are highly active as anti-inflammatory agents and specified activity similar to or higher than the anti-inflammatory activity of the compounds of the comparison.

Antibiotic activity assessed in vitro by the ability to inhibit the development of sensitive to erythromycin bacterial lines.

In addition, the compounds of the present invention do not exhibit antibiotic activity, as demonstrated by tests, and, therefore, can be used for chronic treatment of inflammatory processes without the occurrence of undesirable phenomena sustainability.

Thus it is obvious that the connection is of formula I, possessing anti-inflammatory activity and does not have antibiotic activity, can be used for acute and chronic treatment and prevention of inflammatory diseases, particularly diseases related to impaired cellular functionality of neutrophils, such as rheumatoid arthritis, reperfusion of ischemic damage, septic shock, atherosclerosis, ARDS, COPD and asthma.

therapeutically effective amount will depend on the age and General physiological condition of the patient, the route of administration and used pharmaceutical drug, therapeutic doses generally will be from about 10 to 2000 mg/day and preferably from about 30 to 1500 mg/day.

Compounds of the present invention for use in the treatment and/or prophylaxis of the aforementioned diseases are preferably used in a pharmaceutical form suitable for oral, rectal, sublingual, parenteral, local, transdermal, and inhalation.

Thus, another object of the present invention is the development of pharmaceutical preparations containing a therapeutically effective amount of the compounds of formula I or its salt together with a pharmaceutically acceptable carrier.

Pharmaceutical preparations is s of the present invention can be a liquid, suitable for oral and/or parenteral administration, for example, drops, syrups, solutions, injectable solutions, is now ready for application or obtained by dissolving the lyophilisate, but preferred are solid preparations such as tablets, capsules, granules, powders, pellets, vaginal suppositories, suppositories, creams, lipsticks, gels or ointments; or, on the other hand, solutions, suspensions, emulsion, or other form acceptable to the inhalation and transdermal administration.

Depending on the type of drug such forms will contain a therapeutically effective amount of one or more compound(s) of formula I, solid or liquid fillers or diluents for pharmaceutical applications and optional other excipients normally used in the preparation of pharmaceutical preparations, for example thickeners, agents that cause aggregation, lubricants, dispersing agents, corrigentov and dyes.

The pharmaceutical preparations of the present invention can be obtained in accordance with conventional techniques.

The following examples are given to more clearly illustrate the present invention.

Chemical structure and analytical characteristics of the intermediates and compounds of the formula I are given in the following table./p>

Intermediate compound 25CDCl3: 7,72 (m, 1H, Th); 7,30 (m, 1H, Th); 5,8-6,1 (m, 2H, CH=C allyl); 3,30 (s, 3H, H7"); 2,31 (s, 6H, Me2N); of 0.85 (t, 3H, J=7,3, H15).
The intermediate connection 26CDCl3: 7,72 (m, 1H, Th); 7,30 (m, 1H, Th); 5,8-6,1 (m, 2H, CH=C); to 3.36 (s, 3H, H7"); is 3.21 (s, 6H, Me2N[O]); 0,84 (t, 3H, J=7,1, H15).
The intermediate connection 28CDCl3: of 7.69 (m, 1H, Th); 7,26 (m, 1H, Th); 4,82 (d, 1H, J=4,5, H1"); 4,37 (d, 1H, J=7,2, H1"); to 3.92 (s, 1H, H11); or 3.28 (s, 3H, H7"); 2,28 (s, 6H, Me2N); of 0.82 (t, 3H, J=7,3, H15).
Connection 19CDCl3: to 7.75 (m, 1H, Th); 7,34 (m, 1H, Th); 5,17 with 5.22 (m, 1H, H13); 4,70 (m, 1H, H1'); 4,33 (m, 2H, CH2Th); and 2.83 (s, 6H, Me2N); to 1.47 (s, 3H, H18); 0,76 (t, 3H, J=6,7, H15).
Intermediate compound 29CDCl3: of 7.70 (m, 1H, Th); 7,28 (m, 1H, Th); 4,84 (d, 1H, J=4,5, H1"); 4,50 (d, 1H, J=6,9, H1'); to 3.92 (s, 1H, H11); to 3.34 (s, 3H, H7"); 3,19 (s, 6H, Me2N[O]); or 0.83 (t, 3H, J=7,4, H15).
The connection 20CDCl3: 7,72(m, 1H, Th); 7,30 (m, 1H, Th); 5,19-5,23 (m, 1H, H13); 4,48 (d, 1H, J=7,0, H1'); 4,2 (m, 2H, CH2Th); 3,94 (s, 1H, H11); 3,16 and 3,20 (2c, 6H, Me2N[O]); to 1.42 (s, 3H, H18); or 0.83 (t, 3H, J=7,4, H15).
Connection 21CDCl3: to 7.75 (m, 1H, Th); 7,31 (m, 1H, Th); 5,17-5,31 (m, 1H, H13); the 4.29 (d, 1H, J=7,4, H1'); 4,20 (m, 2H, CH2Th); the 3.89 (S, 1H, H11); to 1.37 (s, 3H, H18); of 0.82 (t, 3H, J=7,4, H15).
The intermediate connection 35CDCl3: 7,34 (m, 2H, Fu), 6,37 (m, 1H, Fu); 5,00-5,09 (m, 1H, H13); of 4.77 (d, 1H, J=4,5, H1"); to 4.23 (d, 1H, J=7,6, H1'); to 3.92 (s, 1H, H11); 3,26 (s, 3H, H7"); to 0.80 (t, 3H, J=7,4, H15).
Intermediate compound 24CDCl3: 7,73 (m, 1H, Th); 7,30 (m, 1H, Th); 5,85 of 6.1 (m, 2H, CH=C allyl); and 3.31 (s, 3H, H7"); of 0.85 (t, 3H, J=7,3, H15).
The intermediate connection 37CDCl3: 7,30, 6,27 and 6,17 (3M, 1H, Fu); 5,03-5,09 (m, 1H, H13); 4,80 (d, 1H, J=4,8, H1"); 4,22 (d, 1H, J=7,4, H1'); 3,81 (s, 1H, H11); 3,26 (s, 3H, H7"); to 0.80 (t, 3H, J=7,5, H15).
Intermediate compound 20CDCl3: 5,0-5,2 (m, 1H, H13); to 4.92 (d, 1H, J=4,5, H1"); or 4.31 (d, 1H, J=7,6, H1'); a 3.83 (s, 3H, CH3-ON=);and 3.31 (s, 3H, H7"); of 0.85 (t, 3H, J=7,3, H15).
Intermediate compound 38CDCl3: 5,19-5,24 (m, 1H, H13), to 4.98 (d, 1H, J=4,6, H1"); 4,50 (d, 1H, J=7,1, H1'); to 3.38 (s, 3H, cladinose CH3O); to 3.35 (s, 3H, H7"); to 2.29 (s, 6H, Me2N); of 0.85 (t, 3H, J=7,2, H15).
The connection 23CDCl3: 7,72 (m, 1H, Th); 7,27 (m, 1H, Th); 5,17-5,23 (m, 1H, H13); was 4.42 (d, 1H, J=7,4, H1'); 4,12 (m, 2H, CH2Th); 3,90 (s, 1H, H11); and 2.26 (s, 6H, Me2N); is 0.84 (t, 3H, J=7,3, H15).
Connection 27D2O: 5,06-5,11 (m, 1H, H13); 3,84 (s, 1H, H11); a 3.06 (s, 3H, CH3CLARITA); 2,64 and 2,74 (2s, 6H, Me2N); to 0.68 (t, 3H, J=7,1, H15).
The connection 28CDCl3: the 4.65 (m, 1H, H1'); 3,95 (s, 1H, H11); 3,20 and 3,16 (2s, 6H, Me2N[O]); 3,14 (s, 3H, CH3CLARITA); 0,81 (t, 3H, J=7,4, H15).
The connection 22CDCl3: to 7.2 to 7.4 (m, 5H, Ph); 5,2-5,3 (m, 1H, H13); 4,29 (d1H, J=7,3, H1'); 3,90 (s, 1H, H11); 3,74 (m, 2H, CH2Ph); and 2.26 (s, 6H, Me2N); 0,86 (t, 3H, 4=7,3, H15).
Connection 13CDCl3: 5,64 (m, 2H, H3' and H4'); 5,17-5,32 (m, 1H, H13); 4,56 (d, 1H, J=7,1, H1'); for 1.49 (S, 3H, H18); from 0.84 (t, 3H, J=7,3, H15).
Connection 6CDCl3: a 4.83-4.92 in (m, 1H, H13); 3,82 (s, 1H, H11); 2,77 and of 2.72 (2s, 3H, conformers MeN); of 2.10 (s, 6H, NMe2); to 0.73 (m, 3H, H15).
Connection 5D2O: 7,66 (m, 1H, Th); 7,47 (m, 1H, Th); 4,91 (m, 1H, H13); a 4.53 (d, 1H, J=8.0 a, H1'); 4,12 (m, 2H, CH2Th); 2,52 (s, 3H, MeN); to 0.72 (t, 3H, J=7,2, H15).
Connection 7CDCl3: 7,72 (m, 1H, Th); 7,31 (m, 1H, Th); is 4.21 (m, 2H, CH2Th); a 3.87 (s, 1H, H11); is 2.37 (s, 3H, MeN); to 0.89 (t, 3H, J=7,2, H15).
Compound 8CDCl3: 7,30-7,40 (m, 5H, Ph); however, 4.40 (d, 1H, J=7,4, H1'); a 3.87 (s, 1H, H11); of 3.80 (m, 2H, CH2Ph); of 2.34 (s, 6H, Me2N); to 0.92 (t, 3H, J=7,1,H15).
Connection 24CDCl3: 7,41 (m, 2H, Fu); 6,44 (m, 1H, Fu); 5,14-5,19 (m, 1H, H13); the 4.29 (d, 1H, J=7,4, H1'); 3,93 (s, 1H, H11); of 1.39 (s, 3H, H18); of 0.82 (t, 3H, J=7,3, H15).
The connection 25CDCl3: of 7.23 (m, 1H, Ti); of 6.96 (m, 2H, Ti); 5,16-to 5.21 (m, 1H, H13); 4,30(d, 1H, J=7,6, H1'); 4,0 (m, 2H, CH2Ti); to 3.92 (S, 1H, H11); of 1.41 (s, 3H, H18); of 0.82 (t, 3H, J=7,4, H15).
The connection 26CDCl3: 7,41, 6,34 and 6,24 (3M, 3H, Fu); 5,17 with 5.22 (m, 1H, H13); to 4.38 (d, 1H, J=7,7, H1'); 3,93 (s, 1H, H11); of 1.41 (s, 3H, H18); or 0.83 (t, 3H, J=7,5, H15).
Connection 4CDCl3: of 7.4 to 7.2 (m, 5H, Ph); 4,55 (m, 1H, H13); of 4.44 (d, 1H, J=7,7, H1'); to 3.89 (s, 1H, H11); of 2.20 (s, 3H, MeN); of 0.93 (t, 3H, J=7,2, H15).
The connection 14CDCl3: 5,18-a 5.25 (m, 1H, H13); 4,34 (d, 1H, J=7,7, H1'); to 3.73 (s, 1H, H11); to 1.47 (s, 3H, H18); 0,86 (t, 3H, J=7,1, H15).
Connection 3CDCl3: 4,51 (d, 1H, J=7,2, H1'); 3,19 and 3,16 (2s, 6H, NMe2[O]); to 0.88 (t, 3H, J=7,2, H15).
Intermediate compound 17CDCl3: 5,10-of 5.15 (m, 1H, H13); however, 4.40 (m, 1H, H1'), of 3.84 (s, 3H, CH3-ON=); 3,69 (s, 1H, H11); is 2.30 (s, 6H, Me2N).
The connection 15CDCl3: 5,20-5,31 (m, 1H, H13); to 4.41 (m, 1H, H1'); 3,85 (s, 3H, CH3-ON=); and 2.27 (s, 6H, NMe2); to 1.42 (s, 3H, H18); 0,86 (t, 3H, H15).
Intermediate compound 18 CDCl3: 5,00-5,20 (m, 1H, H13); of 4.54 (d, 1H, J=7,0, H1'); a 3.83 (s, 3H, CH3-ON=); to 3.36 (s, 3H, H7"); is 3.21 (s, 6H, Me2N[O]); of 1.46 (s, 3H, H18); of 0.85 (t, 3H, J=7,4, H15).
The connection 16CDCl3: 5,28-5,20 (m, 1H, H13); of 4.54 (d, 1H, J=7,0, H1'); 3,85 (s, 1H, H11); 3,15 and 3,20 (2s, 6H, Me2N[O]) of 1.41 (s, 3H, H18); from 0.84 (t, 3H, J=7,5, H15).
Intermediate compound 19CDCl3: 5,7 (m, 2H, H3' and H4'); 5,12-by 5.18 (m, 1H, H13); to 4.92 (d, 1H, J=4.2, and H1"); 4,51 (d, 1H, J=6,5, H1'); 3,85 (s, 3H, CH3-ON=); 3,30 (s, 3H, H7"); of 0.87 (t, 3H, J=7,2, H15).
Connection 17CDCl3: to 5.66 (m, 2H, H3' and H4'); 5,22-of 5.29 (m, 1H, H13); 4,56 (m, 1H, H1'); a 3.87 (s, 3H, CH3-ON=); 3,70 (s, 1H, H11); USD 1.43 (s, 3H, H18); to 0.87 (t, 3H, J=7,3, H15).
The connection 18CDCl3: 5,22-of 5.29 (m, 1H, H13); of 4.35 (d, 1H, J=7,6, H1'); 3,86 (s, 3H, CH3-ON=); 3,69 (s, 1H, H11); of 1.41 (s, 3H, H18); 0,86 (t, 3H, J=7,4, H15).
The intermediate connection 16CDCl3: 5,5 (m, 2H, H3' and H4 '); 5,00-5,04 (m, 1H, H13); 3,81 (s, 3H, H11); of 0.91 (t, 3H, J=7,4, H15).
Connection 1CDCl3: 2,96 and 2.86 (2c, 3H, conformers MeN); 2.21 and 2,17 (2c, 3H, CH3CO)of 0.93 (t, 3H, J=7,4, H15).
Connection 11CDCl3: 5,17-5,24 (m, 1H, H13); however, 4.40 (d, 1H, J=7,4, H1'); 3,72 (c, 1H, H11); and 2.27 (s, 6H, NMe2); of 0.85 (t, 3H, J=7,4; H15).
Connection 12DMSO_d6: 5,14-5,19 (m, 1H, H13); 4,48 (d, 1H, J=7,2, H1'); 3,90 (s, 1H, H11); 3.04 from and 3,00 (2c, 6H, NMe2[O]); of 1.23 (s, 3H, H18); to 0.73 (t, 3H, J=7,1; H15).
Connection 2CDCl3: 4,50 (m, 1H, H13); 4,34 (d, 1H, J=7,4, H1'); to 3.89 (s, 1H, H11); to 2.29 (s, 6H, Me2N); of 0.93 (t, 3H, J=7,4, H15).
Intermediate compound 10CDCl3: 3,33 and 3,31 (2c, 3H, H7"); 3,03 and 2.88 (2c, 3H, MeN); to 0.92 (m, 3H, H15).
Intermediate compound 11DMSO_d6: 4,95 (m, 2H, C[O]CH2N); a 4.83 (m, 1H, H1'); is 2.09 (s, 6H, Me2N); of 0.77 (m, 3H, H15).
The intermediate connection 1 CDCl3: to 4.98 (d, 1H, J=4,1, H1"); 4,91 (m, 1H, H13); of 4.54(d, 1H, J=7,2, H1'); 3,75 (s, 1H, H11); of 3.32 (s, 3H, H7"); is 2.30 (s, 6H, Me2N); to 0.89 (t, 3H, J=7,4, H15).
Intermediate compound 2CDCl3: 5,02(m, 1H, H13);4,78 (d, 1H, J=4,0, H1"); 4,49 (d, 1H, J=7,4, H1'); 3,79 (s, 1H, H11); 3,29 (s, 3H, H7"); is 2.44 (s, 3H, MeN); of 0.91 (t, 3H, J=7,6, H15).
Intermediate compound 3CDCl3: 3,33 and 3,29 (2c, 3H, H7"); 2,93 and 2.88 (2c, 3H, MeN); and 2.14 to 2.18 (2s, 3H, N[CO]CH3); of 0.91 (t, 3H, J=7,1, H15).
Intermediate compound 36CDCl3: 7,17 (m, 1H, Thio), of 6.96 (m, 2H, Thio); of 5.06 (m, 1H, H13); to 4.81 (d, 1H, J=4.2, and H1"); 4,24 (d, 1H, J=7,5, N1'); 3,90 (s, 1H, H11); 3,26 (s, 3H, H7");0,81 (t, J=7,4, H15).
Intermediate compound 7CDCl3: 7,25-7,40 (m, 5H, Ph); 5,02 (d, 1H, J=4,3, H1"); to 4.87(m, 1H, H13); 4,55 (d, 1H, J=7,2, H1'); 3,12 (s, 3H, H7"); of 2.28 (s, 3H, MeN); of 0.90 (t, 3H, J=7,5, H15).
Intermediate compound 8D2O: 4,88 (d, 1H, J=4,3, H1"); 4,78 (m, 1H, H13); 4,55 (d, 1H, J=7,3, H1'); 3,11 (s, 3H, H7"); of 2.16 (s, 3H, MeN); to 0.74 (t, 3H, J=7,3, H15/sub> ).
Intermediate compound 9CDCl3: 7,73 (m, 1H, Th); 7,27 (m, 1H, Th); free 5.01 (d, 1H, J=4.2, and H1"); the 4.90 (m, 1H, H13); 4,55 (d, 1H, J=7,1, H1'); 4,12 (m, 2H, CH2Th); to 3.33 (s, 3H, H7"); of 2.28 (s, 3H, MeN); of 0.90 (t, 3H, J=7,4, H15).
Intermediate compound 12CDCl3: 7,10 (m, 1H, Th); 7,28 (m, 1H, Th); 5,8-6,1 (m, 2H, =CH allyl); 5,02 (d, 1H, J=4,1, H1"); the 4.90 (m, 1H, H13); of 3.77 (s, 1H, H11); 3,30 (s, 3H, H7"); 2,31 (s, 3H, MeN); to 0.89 (t, 3H, J=7,2, H15).
Intermediate compound 13CDCl3: of 7.70 (m, 1H, Th); 7,26 (m, 1H, Th); to 4.98 (d, 1H, J=4.2, and H1"); the 4.90 (m, 1H, H13); a 4.53 (d, 1H, J=7,1, H1'); 4,13 (m, 2H, CH2Th); to 3.73 (s, 1H, H11); of 3.32 (s, 3H, H7"); to 2.29 (s, 3H, MeN); to 0.88 (t, 3H, J=7,1, H15).
Intermediate compound 14CDCl3: 7,20-to 7.32 (m, 5H, Ph); 5,8-6,1 (m, 2H, =CH allyl); 5,00 (d, 1H, J=4,0, H1"); the 4.90 (m, 1H, H13); 3,75 (s, 1H, H11); of 3.32 (s, 3H, H7"); to 2.29 (s, 3H, MeN); of 0.90 (t, 3H, J=7,5, H15).
Intermediate compound 15CDCl3: 7,25-to 7.35 (m, 5H, Ph); 5,00 (d, 1H, J=3,9, H1"); 4,89 (m, 1H, H13); 4,55 (d, 1H, J=7,2, H1'); 3,82 (m, 2H, CH2Ph); of 3.77 (s, 1H, H11); to 3.34 (s, 3H 7"); is 2.30 (s, 3H, MeN); of 0.91 (t, 3H, J=7,5, H15).
The intermediate compound 5CDCl3: to 5.03 (d, 1H, J=3,9, H1"); a 4.83 (m, 1H, H13); 4,69 (d, 1H, J=7,0, H1'); 3,76 (s, 1H, H11);to 3.41 (s, 6H, Me2N[O]); 3,23 (s, 3H, H7"); of 0.91 (t, 3H, J=7,5, H15).
Connection 9CDCl3: 5,69 (m, 2H, H3' and H4'); 4,59 (m, 1H, H13); 4,51 (d, 1H, J=6,9, H1'); 3,85 (s, 3H, H11); to 0.92 (t, 3H, J=7,4, H15).
Connection 10CDCl3: 4,58 (m, 1H, H13); 4,36 (d, 1H, J=7,6, H1'); 3,86 (s, 3H, H11); to 1.35 (s, 3H, H18); to 0.92 (t, 3H, J=7,4, H15).
The intermediate connection 30CDCl3: of 7.1 to 7.4 (m, 10H, 2Ph); and 5.2 (m, 4H, 2CH2Ph); and 4.8 (m, 1H, H1"); 4,4 (m, 1H, H1'); and 3.31 (s, 3H, H7"); to 2.29 (s, 6H, Me2N); of 0.82 (m, 3H, H15).
The intermediate connection 31CDCl3: 7,05-7,38 (m, 5H, Ph); 5,10 (m, 1H, H13); and 4.8 (m, 1H, H1"); and 4.40 (m, 1H, H1'); for 3.28 (s, 3H, H7"); to 2.35 (s, 6H, Me2N); 0,8 (m, 3H, H15).
The intermediate connection 33CDCl3: the 7.65 (m, 1H, Th); from 7.24 (m, 1H, Th; of 5.05 (m, 1H, H13); 4,78 (m, 1H, H1'); of 4.35 (m, 1H, H1'); 3,82 (s, 1H, H11); 3,23 (s, 3H, H7"); of 2.20 (s, 6H, Me2N); to 0.80 (m, 3H, H15).
The intermediate connection 39CDCl3: of 5.05 (m, 1H, H13); to 4.92 (d, 2H, J=4,5, H1"); to 4.41 (d, 2H, J=7,5, H1'); 3,98 (s, 1H, H11); of 3.32 (s, 3H, H7"); 3,03 (s, 3H, CH3CLARITA); to 2.41 (s, 3H, MeN); from 0.84 (t, 3H, J=7,4, H15).
The intermediate connection 40CDCl3: to 5.17 (m, 1H, H13); to 4.41 (d, 2H, J=8,1, H1'); 2,96 (s, 3H, CH3CLARITA); to 2.42 (s, 3H, MeN); or 0.83 (t, 3H, J=7,5, H15).

The connection 30
The intermediate connection 41CDCl3: 4,50 (d, 2H, J=7,4, H1'); 3,93 (s, 1H, H11); 2,96 (s, 3H, CH3CLARITA); only 2.91 (s, 3H, MeN); of 2.15 and 2.12 (2s, 3H, conformers CH3CO); or 0.83 (t, 3H, J=7,4, H15).
The connection 29CDCl3: 5,19 (m, 1H, H13); 4,48 (m, N, H1'); of 3.80 (s, 1H, H11); 3,00 (s, 3H, CH3CLARITA), 2,89 (s, 3H, MeN); to 2.18 and 2.12 (2s, 3H, conformers CH3CON); to 0.92 (m, 3H, H15).
Intermediate compound 4HPLC: Rt 3,01 min
CDCl3: 8,62, 8,56, 7.75, and 7,30 (4m, 4H, Py); 4,74 (s, 2H, CH2Py); the 3.89 (s, 1H, H11); of 2.97 (s, 3H, CH3N); 0.87 (m, 3H, H15).
The intermediate compound 6HPLC: Rt 6,17 min
Key to table: Alloc - Allyloxycarbonyl

Example 1

The production of intermediate compounds 1

A solution of NaBH4(11.3 g, 300 mmol) in N2O (75 ml) is added dropwise (over 20 min) to a solution of erythromycin (100 g, 136,3 mmol) in THF (1.5 l), the temperature of which is maintained at 0°C. the Reaction mixture is stirred 1 hour at 0°and 3 hours at room temperature. After evaporation of THF in vacuo get the crude product, which was dissolved in ethyl acetate (0.5 l) and citric acid (1 l of 5%aqueous solution). The aqueous phase is extracted, washed with ethyl acetate (3×0.5 l) and neutralized To a2CO3. Extraction with ethyl acetate (3×1 l) gives the organic phase, which is dried over sodium sulfate, filtered and evaporated in vacuum, receive intermediate compound 1 (72,1 g, yield 72%, 89,6% d.e.) in the form of a white solid.

[M+1]+736.

Example 2

Obtaining the intermediate 2

A solution of intermediate compound 1 (10.3 g, 14 IMO the ü) in methanol (120 ml) kept in a flow of nitrogen and sequentially added sodium acetate (5.7 g, 70 mmol) and iodine (4,28 g of 16.9 mmol). The reaction mixture was stirred and irradiated for 6 hours UV lamp 400 watts, while maintaining a temperature of 20-30°using an ice bath. The methanol is evaporated in vacuo, the residue taken in ethyl acetate and extracted with 5%metabisulfite sodium. The combined aqueous phase is treated with 10%NaOH solution until an alkaline pH and extracted with ethyl acetate (4×0.5 l). After drying with sodium sulfate the organic phase is filtered and evaporated in vacuum, get 10 grams of white solid crude product, which was dissolved in ethyl acetate (40 ml) at 50° (C) and crystallized receive intermediate compound 2 (5.3 g, yield 53%) as a white solid.

[M+1]+722.

Example 3

The production of intermediate compound 3

A solution of acetic anhydride (31 μl, 0.33 mmol) in dioxane (1 ml) was added to a solution of intermediate compound 2 (200 mg, 0,277 mmol) and K2CO3(76 mg, 0,554 mmol) in dioxane (4 ml) and water (5 ml). After 3 hours, add methanol and the solution evaporated in vacuo. The crude solid is dissolved in ethyl acetate (20 ml) and washed with 5%citric acid (2×10 ml) and 10%solution To2CO3(2×10 ml). The organic phase is dried over sodium sulfate and filtered, the solvent evaporated, to obtain the intermediate compound 3 (130 mg, yield 62%) in view of the white solid.

[M-1]-763.

Example 4

The connection is 1 (1-th path synthesis)

Concentrated HCl (0.5 ml) is added dropwise to a solution of intermediate compound 3 (470 mg, 0,618 mmol) in methanol (50 ml) and the reaction mixture is stirred for 1 hour. After neutralization with concentrated NH3the solution is evaporated, dissolved in CH2Cl2inorganic salts are filtered off and the solvent is distilled off in vacuum. Purification using Biotage chromatography (cartridge with silica 40M, eluent CH2Cl2/Meon, 30/1) gives compound 1 (329 mg, yield 90%) as a white solid.

[M-1]-604.

Example 5

Obtain intermediate compound 4

Concentrated HCl (5 ml) is added to a heterogeneous solution of intermediate 2 (1 g, 1.38 mmol) in N2About (10 ml) and the reaction mixture is stirred intensively for 5 days. To the solution add 1 ml of concentrated NH3(pH>8), then extracted with ethyl acetate (3×10 ml). The combined organic phase is washed with NaCl solution (10 ml, 20%), dried over sodium sulfate, filtered and evaporated in vacuum, receive intermediate compound 4 (0.73 g, yield 90%) as a white solid.

[M+1]+565.

HPLC-MS: column Bond SB-C18, 2.1 a×50 mm, 3.5 mm; column temperature 45°C; mobile phase a is 0.1% formic to the slots in the H 2Oh, In 0.1% formic acid in acetonitrile; gradient 0 min, 5% B, 8 min 95% B; flow rate 1 ml/min; volume of injection of 2 μl; concentration of sample 0.5-1 mg/ml; mass spectrometric detector, equipped with a source of ionization by beam electrons, positive ionization; retention time 3,01 min, which corresponds 3,22 for connection 2; time to the overall experience of 8 min plus 2 min re-equilibration.

Example 6

Getting connection 1 (2nd path synthesis)

Compound 1 is obtained from intermediate 4 (0.73 g, 0.97 mmol) and acetic anhydride (91 ml, 0.97 mmol) in accordance with the methodology described under intermediate compound 3. After 3 hours the reaction mixture was diluted with methanol and evaporated in vacuum. The solid crude product is dissolved in 5%aqueous citric acid solution and extracted with ethyl acetate. The combined organic phases are washed with 20%aqueous NaCl solution, dried over sodium sulfate, filtered and evaporated in vacuum, get connection 1 (0.56 g, yield 95%) as a white solid.

[M-1]-604.

Example 7

Getting connection 2

Compound 2 is obtained from intermediate 1 (322 mg, 0,438 mmol) according to the procedure described to obtain compound 1. After neutralization with concentrated NH3the solution is evaporated. Raw p is oduct dissolved in 1N. HCl, washed with CH2Cl2(3×10 ml) and added to the water phase To2CO3to alkaline pH values. Extraction with ethyl acetate gives the organic phase, which is dried over sodium sulfate and filtered, to obtain compound 2 (225 mg, yield 89%) as a white solid.

[M+1]+578.

Example 8

Obtaining an intermediate compound 5

To a solution of intermediate compound 1 (4.4 g, 6 mmol) in chloroform (250 ml) is added by portions meta-chlormadinone acid (1.35 g, the 6.06 mmol) and the reaction mixture is diluted with 5%sodium bicarbonate solution until basic pH values. The organic phase is separated and the aqueous phase is washed with CH2Cl2(3×50 ml). The combined organic solution washed with 20%NaCl solution, dried over sodium sulfate, filtered and evaporated, get a solid yellow substance. Purification using Biotage chromatography (cartridge with silica 40M, eluent CH2Cl2/Meon/NH3, 20/1/0,1) gives white crystals of intermediate compound 5 (1.3 g, yield 70%).

[M+1]+753.

Example 9

Obtain compound 3

Compound 3 is obtained from the intermediate compound 5 (2,07 g, 0,275 mmol) according to the procedure described to obtain compound 1. Purification using Biotage chromatography (cartridge with silica 40M, eluent CH2Cl2 /Meon/NH3, 16/1/0,1) gives compound 3 (1.44 g, yield 88%) as a white solid.

[M+1]+595.

Example 10

Obtaining an intermediate compound 6

Acetic anhydride (26 ml, 276 mmol) is added dropwise to a solution of intermediate compound 5 (70 g, 95 mmol) in CH2Cl2(0.5 l) and the reaction mixture is stirred for 1 day. Although a small amount of unreacted material is still present, the reaction mass is neutralized by adding 5%aqueous solution of NaHCO3(1 l) and stirred for further 10 minutes the Solution was diluted with CH2Cl2(0.5 l); the organic phase is separated and washed with 10%solution of K2CO3(3×0.5 l), 5%citric acid solution (3×0.5 l) and 20%NaCl solution (0.3 l). The solution is evaporated to obtain a crude white solid product (50 g), which contains 40% of unreacted material is used directly in the next stagesynthesis.

[M-1]-805.

HPLC-MS: column Bond SB-C18, 2.1 a×50 mm, 3.5 mm; column temperature 45°C; mobile phase a is 0.1% formic acid in H2Oh, In 0.1% formic acid in acetonitrile; gradient 0 min, 5% B, 8 min 95% B; flow rate 1 ml/min; volume of injection of 2 μl; concentration of sample 0.5-1 mg/ml; mass spectrometric detector, equipped with a source of ionization by beam electrons, negative ion is the nation's; retention time of 6.17 min, which corresponds 3,22 for connection 2; time to the overall experience of 8 min plus 2 min re-equilibration.

Example 11

The production of intermediate compound 3 (2nd path synthesis)

To a solution of intermediate compound 6 (50 g crude mixture) in methanol (500 ml) and water (160 ml) is added To a2CO3(34 g, 250 mmol) and the mixture was stirred at 60°C for 8 hours. After cooling to 0°With water bath add HCl (120 ml of a 2 n solution) to pH 7. The solution is evaporated in vacuo to remove methanol and extracted with CH2Cl2(4×0.5 l). The organic phase is dried over sodium sulfate, filtered and evaporated, get a crude white solid (36 g). Purification with flash chromatography (silica, eluent CH2Cl2/MeOH, 25/1) to give the intermediate compound 3 (14 g, overall yield of 20% for the last 2 stages).

[M-1]-763.

Example 12

Obtaining an intermediate compound 7

To a solution of intermediate compound 2 (336 mg, 0,465 mmol) in dichloroethane (15 ml) was successively added molecular sieves size 4E (0.2 g), benzaldehyde (to 0.060 l, 0,56 mmol), acetic acid (0.04 ml, 0.7 mmol) and tetramethylethylenediamine (306 g of 1.16 mmol). The reaction mass is stirred for 1 day, filtered through a layer of Celite, rinsing CH2Cl2(20 ml), and diluted with 5%NaHCO 3(10 ml) and 20%NaCl solution (10 ml). The organic layer is separated and the aqueous phase extracted with CH2Cl2(3×20 ml). The combined organic phase is dried over sodium sulfate, filtered and evaporated in vacuum. Purification using Biotage chromatography (cartridge with silica 12M, eluent CH2Cl2/Meon/NH3, 30/1/0,1) gives the intermediate compound 7 (250 mg, yield 67%).

[M+1]+813.

Example 13

Getting connections 4

Compound 4 is obtained from intermediate 2 (200 mg, 0,868 mmol) according to the procedure described to obtain compound 1. Purification using Biotage chromatography (cartridge with silica 12M, eluent CH2Cl2/Meon/NH3, 30/1/0,1) gives compound 4 (92 mg, yield 57%).

[M+1]+654.

Example 14

Obtaining an intermediate compound 8

A solution of intermediate compound 2 (530 mg, 0,734 mmol) in acetonitrile (10 ml) is refluxed for 6 hours. Excess acetonitrile is distilled off in vacuum, get the crude product, N-methyl-N-[2-(cyano)ethyl]derivative, which was dissolved in 1,5M solution of NH3in methanol (10 ml), transferred into a flask of high pressure and after addition of the rhodium catalyst (5% on Al2O3, 100 mg) and 3 cycles of hydrogenation, the reaction mixture is stirred for 4 hours in an atmosphere of hydrogen pressure is 50 psi. Purification using Biotage chromatography (cartridge with silica 12M, eluent CH2Cl2/Meon/NH3, 90/10/1) to give the intermediate compound 8 (310 mg, yield 55% in two stages).

[M+1]+780.

Example 15

Obtaining an intermediate compound (9)

To a solution of intermediate compound 8 (306 mg, 0,397 mmol) in absolute ethanol (5 ml) was successively added molecular sieves size 3E (1 g) and a solution of 2-thiazolecarboxamide (45 mg, 0.4 mmol) in ethanol (1 ml). After 6 hours the reaction mixture was filtered through a layer of silica, washing with ethanol (5 ml), and transferred into a flask of high pressure, which is added acetic acid (0.5 ml) and 10% Pd/C (150 mg). Using a Parr apparatus, the solution is stirred in hydrogen atmosphere overnight at a pressure of 50 psi. Filtration through a layer of Celite, evaporation in vacuo and purification via Biotage chromatography (cartridge with silica 12M, eluent CH2Cl2/Meon/NH3, 20/1/0,1) gives the intermediate compound 9 (140 mg, yield 41%) as a white solid.

[M+1]+877.

Example 16

Getting connection 5

Compound 5 is obtained from the intermediate compound 9 (70 mg, 0.08 mmol) using the procedure described for compound 1. The reaction mixture is diluted with distilled water (20 ml), the solvent is distilled off and the aqueous phase is washed with C 2Cl2(3×10 ml), add concentrated aqueous ammonia to pH>7, the organic phase is dried over sodium sulfate, filtered and evaporated in vacuum, get the connection 5 (50 mg, yield 87%).

[M+1]+719.

Example 17

Obtaining an intermediate compound 10

A mixture of N-cyclohexylcarbodiimide and N-metropolitical (1.8 g, was 1.69 mmol/g) in CH2Cl2(40 ml), centrifuged 5 min, successively added Chloroacetic acid (216 mg, 2.28 mmol) and intermediate compound 2 (1.5 g, 2,078 mmol) and the mixture centrifuged at 300 rpm for 40 hours. The solution is filtered from the resin by washing the resin with methanol, and the filtrate evaporated in vacuum. Purification using chromatography Varian Mega Bond Elut (10 g silica/60 ml cartridge) when the elution of CH2Cl2and methanol (gradient from 0% to 10%) gives an intermediate compound 10 (1.1 g, yield 66%) as a white solid.

[M+1]+799.

Example 18

Obtaining an intermediate compound (11)

A solution of intermediate compound 10 (500 mg, 0,626 mmol), triethylamine (0.35 ml, 2.5 mmol) and diethylaminoethylamine (0,082 ml, 0.75 mmol) in THF (10 ml) is refluxed for 16 hours. The reaction mixture was evaporated and purified using Biotage chromatography (cartridge with silica 40S, eluent CH2Cl2/Meon/NH3, 20/1/0,1), receive the ex is offered by the connection 11 (400 mg, yield 75%) as a white solid.

[M+1]+851.

Example 19

Getting connection 6

Compound 6 is obtained from the intermediate compound (11) (270 mg, 0,323 mmol) using the procedure described for compound 1. Purification using preparative HPLC and elution through a C18 cartridge give compound 6 (100 mg, yield 45%).

[M+1]+693.

Example 20

Obtaining an intermediate compound 12

Intermediate compound 12 is obtained from the intermediate compound 2 (488 mg, 0.67 mmol) and allyl[2-(allyloxycarbonyl-2-thiazolidinone)ethyl]-2-(oxoethyl)carbamate (248 mg, 0.67 mmol) using the procedure described for intermediate 7. Purification using Biotage chromatography (cartridge with silica 40M, eluent CH2Cl2/Meon/NH3, 20/1/0,1) gives the intermediate compound 12 (390 mg, yield 55%) as a brown oil.

[M+1]+1074.

Example 21

Obtaining an intermediate compound 13

To a solution of intermediate compound 12 (380 mg, 0,354 mmol) in CHCl3(5 ml)is situated in the argon atmosphere, consistently add pyrrolidine (0,083 ml, 1 mmol) and tetrakis(triphenylphosphine)palladium (20 mg, 0.02 mmol). The reaction mixture is stirred for 2 hours, neutralized with water (10 ml), the organic phase is separated and the aqueous phase extracted with CH2Cl2(2×10 ml). The combined organic the positive phase is dried over sodium sulfate, filtered and evaporated in vacuum to get crude oil. Purification using Biotage chromatography (cartridge with silica 12M, eluent CH2Cl2/Meon/NH3, 15/1/0,1) gives the intermediate compound 13 (180 mg, yield 56%).

[M+1]+906.

Example 22

Obtain compound 7

Compound 7 is obtained from intermediate 13 (128 mg, 0,141 mmol) using the procedure described for compound 1. The reaction mixture is diluted with distilled water (20 ml) and the methanol evaporated in vacuum, get the water phase, which was washed with CH2Cl2(3×10 ml), add concentrated aqueous ammonia to pH>7 and the mixture is extracted with CH2Cl2(3×10 ml). The combined organic phase is dried over sodium sulfate, filtered and evaporated in vacuum, get the connection 7 (50 mg, yield 47%).

[M+1]+748.

Example 23

Obtaining an intermediate compound 14

Intermediate compound 14 is obtained from intermediate 2 (500 mg, 0,693 mmol) and allyl[2-(allyloxycarbonyl)ethyl]-(2-oxoethyl)carbamate (256 mg, 0.7 mmol) by the procedure described for intermediate 7. Purification using Biotage chromatography (cartridge with silica 40M, eluent CH2Cl2/Meon/NH3, 40/1/0,1) gives the intermediate compound 14 (600 mg, yield 82%) as oil.

[M+1]+1067.

p> Example 24

Obtaining an intermediate compound 15

Intermediate compound 15 is obtained from intermediate 14 (594 mg, 0,557 mmol) using the procedure described for intermediate 13. Purification using Biotage chromatography (cartridge with silica 40S, eluent CH2Cl2/Meon/NH3, 30/1/0,1) gives the intermediate compound 15 (310 mg, yield 62%) as a white solid.

[M+1]+899.

Example 25

Getting connection 8

Compound 8 is obtained from intermediate 15 (250 mg, 0,278 mmol) using the procedure described for compound 1. Purification using Biotage chromatography (cartridge with silica 12M, eluent CH2Cl2/Meon/NH3, 30/1/0,1) gives the intermediate compound 8 (110 mg, yield 54%) as a white solid.

[M+1]+741.

Example 26

Obtaining an intermediate compound 16

To a solution of 3'-destinationin-3',4'-dihydroanthracene And (1.3 g, 1.9 mmol)obtained by the method described in the article in J. Am. Chem. Soc., 1981, 103, (11), 3213-3215)in THF (10 ml) and methanol (20 ml) is added by portions NaBH4(160 mg, 4.2 mmol). The reaction mixture was stirred over night at room temperature, neutralized by adding acetic acid (1 ml) and after stirring for another 30 min add concentrated NH3to an alkaline value is of pH. The solvent is distilled off in vacuo, the crude mixture was dissolved in ethyl acetate (100 ml) and washed with 20%NaCl solution (3×100 ml). The organic phase is dried over sodium sulfate, filtered and evaporated in vacuum. Purification using Biotage chromatography (cartridge with silica 40M, eluent CH2Cl2/Meon, 35/1) gives an intermediate compound 16 (800 mg, yield 65%) as a white solid.

[M+1]+692.

Example 27

Obtaining the compound (9)

Compound 9 is obtained from intermediate 16 (600 mg, 0,868 mmol) using the procedure described for compound 1. Purification using Biotage chromatography (cartridge with silica 40M, eluent CH2Cl2/Meon, 37/1) gives compound 9 (380 mg, yield 82%) as a white solid.

[M+1]+534.

Example 28

The connection 10

To a solution of compound 9 (300 mg, 0,56 mmol) in absolute ethanol add PtO2(10 mg) in the crucible of high pressure. After 3 consecutive cycles of hydrogenation of the reaction mixture was kept in an atmosphere of hydrogen at 45 psi. After 4 hours the mixture is filtered through a layer of Celite and evaporated in vacuum, get the connection 10 (300 mg, yield of 99.9%) as an amorphous white solid.

[M+1]+536.

Example 29

Obtaining the compound (11)

Compound 11 is obtained from the oxime erythromycin a (2,5g, to 3.34 mmol) using the procedure described for compound 1. Purification using Biotage chromatography (cartridge with silica 40M, eluent CH2Cl2/Meon/NH3, 90/5/0,5) gives compound 11 (1.8 g, yield 91%) as a white solid.

[M+1]+592.

Example 30

The connection 12

Compound 12 is obtained from N-oxide erythromycin oxime (3 g, a 3.83 mmol), obtained as described in international patent application WO 00/42055, example 4 (Zambon Group), according to the methods described for compound 1. Purification using Biotage chromatography (cartridge with silica 40M, eluent CH2Cl2/Meon/NH3, 90/10/1) to give compound 12 (1.5 g, yield 65%) as a white solid.

[M+1]+608.

Example 31

The connection 13

Compound 13 is obtained from the reaction of 3'-destinationin-3',4'-dihydroanthracene And (30 g, of 42.6 mmol), obtained as described in international patent application WO 00/42055, example 5 (Zambon Group), according to the methods described for compound 1. Purification with flash chromatography (silica, eluent CH2Cl2/Meon, 90/7) gives compound 13 (19.2 g, yield 82%) as a white solid.

[M+1]+546.

Example 32

The connection 14

Compound 14 is obtained from the reaction of 3'-destinationunreachable And (36,2 g, a 51.3 mmol), obtained as described in international PA is entei application WO 00/42055, example 6 (Zambon Group), according to the methods described for compound 1. Purification with flash chromatography (silica, eluent CH2Cl2/Meon, from 97/3 to 95/5) to give compound 14 (22.1 g, yield 79%) as a white solid.

[M+1]+548.

Example 33

Obtaining an intermediate compound 17

To a solution of erythromycin A (21,9 g, and 29.9 mmol) in methanol (150 ml)under nitrogen atmosphere, add hydrochloride 0-methylhydroxylamine (10 g, 197 mmol), then after 10 minutes add triethylamine (8,33 ml, to 59.8 mmol). After stirring for one day, the reaction mixture is neutralized 10%aqueous ammonia solution (300 ml) and filtered the resulting solid is washed with water and dried in air for 3 days. Purification with flash chromatography (eluent CHCl3/hexane/triethylamine, 50/50/10) gives an intermediate compound 17 (7 g, yield 31%) as a white crystalline solid.

[M+1]+764.

Example 34

The connection 15

Compound 15 is obtained from intermediate 17 (400 mg, 0.52 mmol) according to the methods described for compound 1. Purification using chromatography Variant Mega bond Elut (cartridge with silica, 10 g, eluent from CH2Cl2until CH2Cl2/Meon/NH3, 90/5/0,5) gives compound 15 (249 mg, yield of 78.8%) as a white solid.

[+1] +764.

Example 35

Obtaining an intermediate compound 18

Intermediate compound 18 is obtained from intermediate 17 (0.9 g, 1.18 mmol) according to the methods described for compound 5. The product of 0.91 g, yield 99%) is extracted in pure form without additional purification in the form of a light yellow solid.

[M+1]+779.

Example 36

The connection 16

Compound 16 is obtained from intermediate 18 (720 mg, of 0.92 mmol) according to the methods described for compound 1. Purification using chromatography Variant Mega bond Elut (cartridge with silica, 20 g, eluent from CH2Cl2until CH2Cl2/Meon/NH3, 90/10/1) to give compound 16 (430 mg, yield 84%) as a white solid.

[M+1]+621.

Example 37

Obtaining an intermediate compound 19

Intermediate compound 19 is obtained from intermediate 18 (500 mg, 0.64 mmol) according to the methods described for the reaction of 3'-destinationin-3',4'-dihydroanthracene And obtained as described in international patent application WO 00/42055, example 5 (Zambon Group). Purification using chromatography Variant Mega bond Elut (cartridge with silica, 10 g, eluent from CH2Cl2until CH2Cl2/Meon, 95/5) to give compound 19 (150 mg, yield 32%) as a white solid.

[M+1]+718.

Example 38

Gender is a given compound 17

Compound 17 is obtained from intermediate 19 (720 mg, of 0.92 mmol) according to the methods described for compound 1. Purification using chromatography Variant Mega bond Elut (cartridge with silica, 10 g, eluent from CH2Cl2until CH2Cl2/Meon, 100/1) to give compound 17 (130 mg, yield 68%) as a white solid.

[M+1]+560.

Example 39

Obtaining an intermediate compound 20

Intermediate compound 20 obtained from intermediate 19 (143 mg, 0.20 mmol) according to the methods described for the reaction of 3'-destinationunreachable And obtained as described in international patent application WO 00/42055, example 5 (Zambon Group). After filtration through a layer of Celite and evaporation in vacuum to obtain pure intermediate compound 20 (120 mg, yield of 83.3%) as a white solid.

[M+1]+720.

Example 40

The connection 18

Compound 18 is obtained from intermediate 20 (720 mg, of 0.92 mmol) using the procedure described for compound 1. Purification using Biotage chromatography (cartridge with silica 12M, eluent CH2Cl2/Meon, 100/1,5) gives compound 18 (121 mg, yield 66%) as a white solid.

[M+1]+562.

Example 41

Obtain 2-[2-[(2-triazolylmethyl)amino]ethylamino]ethanol (intermediate compound 21)

To a solution of 2-(2-aminoethylamino is about)ethanol (13,35 g, 128 mmol) in anhydrous ethanol successively added molecular sieves size 3E (22,5 g) and a solution of 2-thiazolecarboxamide (14.5 g, 128 mmol) in ethanol (90 ml). The reaction mixture is stirred for 4 hours, filtered through a layer of Celite, washing with ethanol (100 ml), and placed in a flask high pressure. After adding acetic acid (3 ml) and Pd (10% on C, 2 d) solution is injected into the apparatus Parra and after several cycles of hydrogenation is stirred for 2 days in an atmosphere of hydrogen at 40 psi. The reaction mixture was filtered through a layer of Celite, evaporated in vacuo, and purified flash chromatography (silica, eluent CH2Cl2/Meon/NH3, 80/20/10)will receive 2-[2-[(2-triazolylmethyl)amino]ethylamino]ethanol (15,4 g, yield 60%) as a brown oil.

[M+1]+202.

Example 42

Obtaining allyl[2-(allyloxycarbonyl-2-thiazolidinone]ethyl](2-hydroxyethyl)carbamate

(intermediate compound 22)

When 0°With solution allylbromide (1,22 ml, 11.5 mmol) in CH2Cl2(30 ml) is added dropwise within 30 min to a solution of intermediate 21 (1,16 g, USD 5.76 mmol) and K2CO3(1,14 g, 8.4 mmol) in CH2Cl2(30 ml) and N2About (50 ml). After stirring at room temperature for 16 hours and dilution To2CO3(50 ml of 10%aqueous solution), the organic layer is separated and the aqueous phase extragere the CH 2Cl2(2×40 ml). The combined organic phase was washed with citric acid (50 ml of 5%aqueous solution), dried over sodium sulfate and filtered, the solvent evaporated and the residue purified flash chromatography (silica, eluent CH2Cl2/Meon, 18/1), receive intermediate compound 22 (1.27 g, yield 60%) as a brown oil.

[M+1]+370.

Example 43

Getting ethyl-2-[allyloxycarbonyl-[2-(allyloxycarbonyl-2-thiazolidinone)ethyl]amino]methansulfonate

(intermediate compound 23)

When 0°With solution methylchloride (of 3.64 ml, 47 mmol) in CH2Cl2(10 ml) is added dropwise within 15 min to a solution of intermediate 22 (12,96 g, 35 mmol) and triethylamine (9,74 ml, 70 mmol) in CH2Cl2(130 ml). After 1 hour source material is introduced into the reaction, the reaction mixture was diluted with CH2Cl2(50 ml) and washed with 50 ml of 5%citric acid, 50 ml of 5%aqueous NaHCO3and 20%NaCl solution (50 ml). The organic phase is dried over sodium sulfate and filtered, the solvent evaporated in vacuum, receive intermediate compound 23 (1.6 g, quantitative yield) as a red oil which is used immediately in the next reaction.

[M+1]+448.

Example 44

The production of intermediate compounds 24

A solution of tert.-butoxide potassium (3.6 g, 32.1 IMO the ü) in THF (180 ml) is prepared in a dry flask under nitrogen atmosphere. The reaction of 3'-destinationunreachable And (20.6 g, 29.2 mmol) are added to the reaction mixture and the resulting mixture stirred for 30 min, after which successively added 18-crown-6-ether (7,72 g, 29.2 mmol) and dropwise over 30 min a solution of intermediate 23 (15.7 g, 35 mmol) in THF (70 ml). After 18 hours the mixture was evaporated in vacuo, diluted with 20%NaCl solution (0.5 l) and extracted with ethyl acetate (3×0.5 l). The combined organic phase is dried over sodium sulfate and filtered, the solvent evaporated and the residue purified flash chromatography (silica, eluent CH2Cl2/Meon, 95/5), receive intermediate compound 24 (20 g, yield 65%) as a white solid.

[M+1]+1058.

Example 45

The production of intermediate compounds 25

Intermediate compound 25 is obtained from the oxime erythromycin A (4,2 g, 9,82 mmol) using the procedure described for compound 24. Purification with flash chromatography (silica, eluent CH2Cl2/Meon/NH3, 95/5/0,5) gives the intermediate compound 25 (8.2 g, yield 76%) as a solid.

[M+1]+1101.

Example 46

Obtaining an intermediate compound 26

Intermediate compound 26 is obtained from the intermediate 25 (1.1 g, 1 mmol) according to the methods described to obtain the N-oxide oxime erythromycin A (international pamantasang WO 00/42055, example 4, Zambon Group). The crude reaction mixture is evaporated in vacuo (twice after dilution with distilled water and twice after dilution CH2Cl2obtain the intermediate compound 26 (1 g, yield 90%) as a solid, which is pure enough for the next stagesynthesis.

[M+1]+1117.

Example 47

Obtaining an intermediate compound 27

To a solution of intermediate 24 (14 g, 13,2 mmol) in CH2Cl2(140 ml)under an argon atmosphere, successively added morpholine (2.3 g, 2.7 mmol), triphenylphosphine (262 mg, 1 mmol) and palladium(II) acetate (75 mg, 0.34 mmol). The reaction mixture is stirred for 2 h and neutralized with water (50 ml), the organic phase is separated and the aqueous phase extracted with CH2Cl2(2×50 ml). The combined organic phase is dried over sodium sulfate, filtered and evaporated in vacuum to get crude oil (13,4 g). Purification by chromatography at atmospheric pressure (silicon dioxide 230/70 mesh, eluent CH2Cl2/Meon/NH3, 90/9/0,9) gives the intermediate compound 27 (9.3 g, yield 79%) as a white solid.

Intermediate compound 27 is a known compound, which is described in international patent application WO 00/42055, example 9 (Zambon Group).

Example 48

The intermediate connection 28

Intermediate compound 28 is obtained from the intermediate 25 (1.55 g, of 1.41 mmol) according to the methods described for intermediate 27, substituting morpholine with pyrrolidine (0.5 g, 7 mmol). Purification by chromatography at atmospheric pressure (silicon dioxide 230/70 mesh, eluent CH2Cl2/Meon/NH3, 90/10/1) to give the intermediate compound 28 (1 g, yield 76%) as a solid.

[M+1]+933.

Example 49

Obtaining an intermediate compound 29

The intermediate connection 29 is obtained from intermediate 26 (1 g, of 1.41 mmol) according to the methods described for intermediate 27. Purification using Biotage chromatography (cartridge with silica 40M, eluent CH2Cl2/Meon/NH3, 90/10/1) to give the intermediate compound 29 (0,76 g, yield 90%) as a solid.

[M+1]+949.

Example 50

The connection 19

Compound 19 is obtained from intermediate 28 (600 mg, 0.64 mmol) according to the methods described for compound 1. Considering that the resulting product is soluble in water, the crude solid is dissolved in water (50 ml) and washed with CH2Cl2(3×20 ml). The solvent is evaporated from the aqueous phase in vacuo and dried, to obtain compound 19 (480 mg, yield 95%) as a crystalline solid.

[M+1]+775.

Example 51

Receiving from the organisations 20

The connection 20 is obtained from intermediate 29 (450 mg, 0.47 mmol) by the method described for compound 1. Purification using Biotage chromatography (cartridge with silica 40M, eluent CH2Cl2/Meon/NH3, 90/10/1) gives compound 20 (180 mg, yield 49%) as a white solid.

[M+1]+791.

Example 52

The connection 21

Compound 21 is obtained from intermediate 27 (2.6 g, of 2.92 mmol) according to the methods described for compound 1. Purification by chromatography at atmospheric pressure (silica, eluent CH2Cl2/Meon/NH3, 90/8/0,8) gives compound 21 (1.84 g, yield 86%) as a white crystalline substance.

[M+1]+732.

Example 53

Getting ethyl-2-(benzylbenzimidazole)methansulfonate

Cm. international patent application WO 96/18633, example 1, Zambon Group.

Example 54

Obtaining an intermediate compound 30

The intermediate connection 30 is obtained from the oxime erythromycin A (a total of 8.74 g, 11.7 mmol) and ethyl-2-(benzylpenicillin)methansulfonate (4,24 g, 11.7 mmol) using the procedure described for intermediate 24. Purification with flash chromatography (silica, eluent CH2Cl2/Meon/NH3, 95/5/0,5) gives the intermediate compound 30 (8.5 g, yield 72%).

Example 55

The intermediate connection is the link 31

To a solution of intermediate 30 (8.5 g, at 8.36 mmol) in anhydrous ethanol (180 ml) is added 10% Pd/C (0.85 grams) and after 3 cycles of hydrogenation mixture is stirred in a Parr apparatus in an atmosphere of hydrogen at 20 psi. After one hour the reaction mixture was filtered through a layer of Celite, the solvent evaporated and the residue purified flash chromatography (silica, eluent CH2Cl2/Meon/NH3, 95/5/0,5), obtain the intermediate compound 31 (5 g, yield 67%) as a white solid.

[M+1]+883.

Example 56

The connection 22

Compound 22 is obtained from intermediate 31 (0.5 g, or 0.57 mmol) according to the methods described for compound 1. Purification using Biotage chromatography (cartridge with silica 12M, eluent CH2Cl2/Meon/NH3, 80/4/0,4) gives compound 22 (0.36 g, yield 87%) as a white solid.

[M+1]+725.

Example 57

Obtaining (E)-9-[O-[2-[6-[(2-triptoreline)methylamino]hexylamino]ethyl]oxime] of erythromycin A (intermediate compound 32)

The get connection as described in international patent application WO 96/18633, example 19 (Zambon Group).

Example 58

The intermediate connection 33

To a solution of intermediate 32 (of 7.64 g, to 8.57 mmol) in CH2Cl2(60 ml) was successively added 2-thiazolyl caldigit (1 g, to 8.57 mmol), NaCN(BH3) (0.9 g, 13,71 mmol) and acetic acid (2 ml). The reaction mixture is stirred for 16 hours, filtered through a layer of Celite, rinsing CH2Cl2(20 ml)and dilute aqueous solution of acetic acid (pH 5, 50 ml). The aqueous solution was washed with CH2Cl2(3×30 ml), add NaHCO3to pH 8 and the mixture extracted with CH2Cl2(3×30 ml). Diluted organic phase is dried over sodium sulfate, filtered and evaporated in vacuum. Purification with flash chromatography (silica, eluent CH2Cl2/Meon/NH3, 90/10/1) to give the intermediate compound 33 (2,04 g, yield 24%) as a white solid.

[M+1]+989.

Example 59

Obtaining compounds 23

Compound 23 is obtained from intermediate 33 (100 mg, 0.1 mmol) according to the methods described for compound 1. Purification using Biotage chromatography (cartridge with silica 12S, eluent CH2Cl2/Meon/NH3, 15/1/0,1) gives compound 23 (50 mg, yield 61%) as a white solid.

[M+1]+831.

Example 60

Obtaining (E)-9-[O-[2-[2-(benzyloxycarbonylamino)ethyl]benzyloxycarbonylamino]ethyl] oxime] of 3'-destinationunreachable And

(intermediate compound 34)

The get connection as described in international patent application WO 00/42055, example 7 (Zambon Group).

Example 61

<> The intermediate connection 35

To a solution of intermediate 34 (0.8 g, 1 mmol) in ethanol (16 ml) was successively added molecular sieves (1.8 g) and 3-furaldehyde (98 mg, 1 mmol) and the mixture is stirred for 3 hours. After filtration through a layer of Celite to the solution was added NaBH4(29 mg, 0.75 mmol) and the resulting mixture was stirred for further one hour and evaporated in vacuum. The crude material was dissolved in ethyl acetate and washed with saturated solution of NaCl. The organic phase is dried over sodium sulfate, filtered and evaporated in vacuum. Purification with flash chromatography (silica, eluent CH2Cl2/Meon/NH3, 90/6/0,6) gives the intermediate compound 35 (530 mg, yield 60%) as a solid.

[M+1]+872.

Example 62

Obtaining an intermediate compound 36

The intermediate connection 36 is obtained from intermediate 34 (800 mg, 1 mmol) and thiophenecarbaldehyde (115 mg, 1 mmol) according to the methods described for intermediate 35. Purification with flash chromatography (silica, eluent CH2Cl2/Meon/NH3, 90/6/0,6) gives the intermediate compound 36 (362 mg, yield 40%) as a white solid.

[M+1]+888.

Example 63

Obtaining an intermediate compound 37

The intermediate connection 37 is obtained from intermediate 34 (800 mg, 1 mmol) and 2-fu the aldehyde (98 mg, 1 mmol) according to the methods described for intermediate 35. Purification with flash chromatography (silica, eluent CH2Cl2/Meon/NH3, 90/6/0,6) gives the intermediate compound 37 (475 mg, yield 54%) as a white solid.

[M+1]+872.

Example 64

Obtaining compounds 24

Compound 24 is obtained from intermediate 35 (200 mg, 0.22 mmol) according to the methods described for compound 1. Purification with flash chromatography (silica, eluent CH2Cl2/Meon/NH3, 90/5/0,5) gives compound 24 (120 mg, yield 73%) as a white solid.

[M+1]+715.

Example 65

Obtaining compounds 25

Compound 25 is obtained from intermediate 36 (200 mg, 0.22 mmol) according to the methods described for compound 1. Purification using Biotage chromatography (cartridge with silica 12M, eluent CH2Cl2/Meon/NH3, 90/5/0,5) gives compound 25 (130 mg, yield 81%) as a white solid.

[M+1]+731.

Example 66

The connection 26

Compound 26 is obtained from intermediate 37 (200 mg, 0.23 mmol) according to the methods described for compound 1. Purification using Biotage chromatography (cartridge with silica 12M, eluent CH2Cl2/Meon/NH3, 90/5/0,5) gives compound 26 (125 mg, yield 76%) as white solids

[M+1]+715.

Example 67

Obtaining an intermediate compound 38

The intermediate connection 38 is obtained from clarithromycin (1 g, of 1.33 mmol) according to the methods described for intermediate 16. Purification with flash chromatography (silica, eluent CH2Cl2/Meon/NH3, 90/10/1) to give the intermediate compound 38 (500 mg, yield 50%) as a white solid.

[M+1]+751.

Example 68

The connection 27

Compound 27 is obtained from intermediate 38 (202 mg, 0.27 mmol) according to the methods described for compound 1. Purification using preparative HPLC (mobile phase: water/acetonitrile from 95/5 to 60/40 for 10 min) to give compound 27 (55 mg, yield 36%) as a white solid.

[M+1]+592.

Example 69

The connection 28

The connection 28 is produced from compound 27 (26 mg, 0,034 mmol) according to the methods described to obtain the N-oxide oxime erythromycin A (international patent application WO 00/42055, Zambon Group). The reaction mixture was diluted with water and the solvent evaporated (three times for complete removal of N2About2) and dried, to obtain compound 28 (26 g, yield 95%) as a white solid.

[M+1]+609.

Example 70

The intermediate connection 39

Suspension of clarithromycin (5 g, 6.7 mmol) in methanol (150 ml) is eribaum in a weak current of the N 2under mechanical stirring. Add sodium acetate (0.66 g, 8 mmol) and iodine (2,03 g, 8 mmol) and the resulting mixture was exposed light bulb 400 watt, trying to maintain the temperature at 10-20°using a bath of ice-water. After 6 hours the solvent is distilled off under reduced pressure, the crude product was taken into ethyl acetate and 5%aqueous solution of sodium metabisulfite, the aqueous phase is extracted and alkalinized by adding aqueous ammonia, then extracted with dichloromethane. After drying the organic phase over anhydrous Na2SO4filtered and evaporated the solvent to obtain the crude product (5.1 g), which was purified using Biotage chromatography (cartridge with silica 40M, eluent CH2Cl2/Meon/NH3, 100/3/0,3 and then 100/5/0,5), obtain the intermediate compound 39 (3.2 g, yield 65%).

[M+1]+734,5.

Example 71

The intermediate connection 40

Intermediate compound 39 (2 g, of 2.72 mmol) was dissolved in 1N. HCl solution (50 ml, 50 mmol) and stirred for 2 hours at room temperature. The solution is alkalinized with concentrated NH3and then extracted with ethyl acetate (3×50 ml). The organic phase is dried over anhydrous Na2SO4and filtered, the solvent is distilled receive intermediate compound 40 (1.56 g, yield 90%).

[M+1]+576,3.

the example 72

The intermediate connection 41

A solution of acetic anhydride (has 0.168 ml, 1.78 mmol) in dioxane (3 ml) is added dropwise to a solution of intermediate 40 (0,93 g of 1.62 mmol) in dioxane (30 ml) and N2O (4 ml) and the resulting mixture is stirred for 8 hours. The reaction mass is treated by adding methanol and distillation of the solvent under reduced pressure. The crude product, thus obtained, diluted with 2n. HCl (50 ml) and extracted with ethyl acetate (3×50 ml). The resulting organic solution is dried over anhydrous Na2SO4and filtered, the solvent is distilled receive the intermediate connection 41 of 0.85 g, yield 85%).

[M-1]-616,8.

Example 73

The connection 29

A solution of intermediate 41 (500 mg, 0.79, which mmol) in ethanol (20 ml) is treated with an excess of hydroxylamine hydrochloride (1.5 g, 21.6 mmol) and triethylamine (1.5 ml, 22 mmol) and the reaction mass is maintained at the boil under reflux, controlling the possible decomposition of the product. After 6 hours the solvent is evaporated from the solution and the residue diluted with ethyl acetate and washed with saturated solution of NaCl. The organic solvent is dried over anhydrous Na2SO4and filtered, the solvent is distilled off, get crude solid. Purification using Biotage chromatography (cards who ij 12M column, eluent CH2Cl2/Meon, 100/0 and then 30/1) to give compound 29 (198 mg, yield 40%).

[M+1]+633,4.

Example 74

The intermediate connection 42

The solution pyridinemethanol (0.5 g, 4.7 mmol) in DMF (20 ml) is placed in a properly dried dvuhgolosy round bottom flask, under nitrogen atmosphere, and then add sodium hydride (60%, 0.4 g, 10 mmol). Get a heterogeneous solution, which is stirred for 15 minutes Then added dropwise a solution of 2-(2-bromacil)-1,3-dioxane (0,92 g, 4.7 mmol) in DMF (3 ml) and the resulting mixture is left for the reaction for 16 hours at 60°C. the Reaction medium is diluted with ethyl acetate (100 ml) and washed with 10%aqueous solution of Na2CO3(3×50 ml). The organic phase is dried over anhydrous sodium sulfate Na2SO4and filtered, the solvent evaporated, get the crude reaction product (1 g)which is purified by chromatography (column with silica Varian Mega Bond Elut; eluent from 100% SN2Cl2to 25/1 CH2Cl2/Meon), receive intermediate compound 42 (650 mg, yield 31%) as a colourless liquid.

[M+1]+633,4.

Rt=1,4 min

1H NMR (CDCl3): 8,59, 8,53, 8,01 and 7,25 (4m, 4H, Py); 4,70 (t, 1H,-CH[-O]2); to 4.52 (s, 2H, CH2Py); 4.09 to (m, 2H, O-CH2-C); with 3.79 (m, 2H,-CH2- ); Of 3.60 (m, 2H, CH2dioxane); 2,05, 1.92 and 1,3 (3M, 4H, dioxane)./p>

Example 75

The intermediate connection 43

Excess triperoxonane acid (2 ml) was added to a solution of intermediate 42 (150 mg, 0.67 mmol) in CHCl3(4 ml) and the mixture was left for reaction at room temperature for 48 hours. The reaction medium is diluted with CH2Cl2(50 ml) and washed with 10%aqueous Na2CO3(3×20 ml). The organic phase is dried over anhydrous Na2SO4and filtered, the solvent is evaporated. Purification using Biotage chromatography (column with silica 12M, eluent CH2Cl2/Meon/NH3, 30/1/0,1) gives the intermediate compound 43 (45 mg, yield 40%), which are used directly for the next reaction.

[M+1]+166,4.

Rt=2,5 minutes

HPLC/MS carried out by using a Gilson instrument equipped with a C18 column Bond SBC18 (3.5 µm, 2.1 a×50 mm) and using as detector kit UV diodes (220 nm), mass spectrometer Finnigan Aqa (diffused beam of electrons, positive or negative ionization) and the developer ELSD.

Conditions:

Flow rate: 1 ml/min

The column temperature: 40°

Gradient elution of a/b (eluent A: 0,5% formic acid in water; eluent B: 0,5% formic acid in acetonitrile): t=0 min, a/b=95:5, t=8 min, a/b=5:95.

Example 76

The connection 30

RA is Toru intermediate compounds 4 (100 mg, 0,178 mmol) and 43 (30 mg, 0,178 mmol) in dichloroethane (10 ml) are added sequentially with molecular sieves (4E, 100 mg), acetic acid (16 μl, 0,267 mmol) and hydride tert.-butylamine (120 mg, 0,445 mmol). The mixture is left for reaction for 48 hours at room temperature, then filtered through a layer of Celite, the filtrate is diluted with 10%solution of Na2CO3(20 ml) and extracted with CH2Cl2(3×20 ml). The combined organic extracts dried over anhydrous Na2SO4and filtered, the solvent is distilled off under reduced pressure. Purification using Biotage chromatography (cartridge 12M column, eluent CH2Cl2/Meon/NH3, 30/1/0,1) gives compound 30 (50 mg, yield 39%).

[M-1]-714,5.

Example 77

Pharmacological activity in vivo

A) Acute contact dermatitis

- Animals

Use a group of 5-6 CD1 mice (18-24 g).

Introduction connections

All macrolide compounds dissolved in the system interfacial delivery (Trans-phase Delivery System, TPDS), media obtained from 10% benzyl alcohol, 40% acetone and 50% isopropanol.

On the inner surface of the ear is applied locally 15 microlitres compounds (500 μg)dissolved in TPDS; after 30 min in the same place put 12 microlitres solution tetradecanoylphorbol (TRA), dissolved in acetone, at a concentration of 0.01%.

After 6 hours the animal is killed by inhalation of CO 2.

Outcome evaluation

Use two methods to estimate the ear swelling:

a) Weigh this part of the auricle.

b) Measure the thickness of the ear using an accurate instrument for measuring thickness.

The degree of swelling calculated by subtracting the weight or thickness of the raw ear of the mass or thickness located on the opposite side of the treated ear. To determine the degree of remission of the tumor to the difference (mass or thickness) of the groups treated with a mixture of TRA+macrolides, and then compared with the groups treated only TRA.

The activity of macrolide compounds measured using a modified method Zunic et al. (1998): MDL (Lysyl) GDP, non-toxic derivative of muramyldipeptide, inhibits cytokine production using activated macrophages and protects mice from induced turbolover ether and oxazolone inflammation (J. Invest. Dermatol., 111(1), 77-82).

Data related to erythromycin and azithromycin, refer to treatment a single dose of 500 μg/ear.

The results obtained for a number of compounds of the formula I, which is the typical representatives of the entire class, shown in the following table.

ConnectionSwelling (%inhibition)A method of measuring the swelling
Erythromycin 42and
Azithromycin40and
1531,6and
1672,3and
1741,9and
1854,3and
1377,4and
1471,5and
11to 70.2and
1287,4and
1928,2b
20to 49.9b
2174,1b
365,2and
165,6and
236,2and
630,9and
553,4and
745,0and
932,4and
2944,5and
3039,8and

C) LPS-Induced lung inflammation in rats

- Introduction

Rats give endotracheal path through the oral dose of 0.4 mg/kg LPS (E. coli serotype 026:6). Fuck the social instillation is performed under anesthesia with halothane gas and 20 hours after endotracheal injection of a mixture of LPS/saline animals killed by cordozo urethane.

- Washing

Light washed 4 aliquot 5 ml each, saline with 10 IE/ml heparin. Cell suspension concentrate with a low-speed centrifuge and the pellet of cells was weighed.

- Counting the cells and differentiation

Counting the total number of cells is carried out in hemocytometer.

The differential count is performed on cytogenomic preparations stained with May-Grunwald-Giemsa (Tamaoki J., Tagaya e, Yamawaki I., Sakai N., Nagai, A., Konno K., 1995. Effect of erythromycin on endotoxin-induced microvascular leakage in rat trachea and lungs. Am. J. Respir. Crit. Care Med., 151, 1582-8). Rats give compound orally in doses of 100, 40 and 10 µmol/kg as a single dose orally one hour prior to exposure to LPS.

The value of the ED50represents the dose that causes 50%reduction in the number of neutrophils in the bronchial wash fluid.

Data related to erythromycin, refer to treatment dose of 130 µmol/kg

The results obtained for a number of compounds of the formula I, which is the typical representatives of the entire class, shown in the following table.

ConnectionED50µmol/kg
ErythromycinNot active
1415
17

Example 78

Farmacologicas the th activity in vitro

Antibiotic activity

- Drug testing

All compounds are dissolved in DMSO in a 100-fold concentrated solution at a concentration of 12.8 mg/ml Concentrated solution is diluted in the ratio of 1:100 in incubation medium to a final concentration of 128 μg/ml (final concentration of DMSO 1%). To assess MICK performed serial dilutions 1:2 100-fold concentrated solution in DMSO and diluted to 1:100 in incubation medium.

Experimental method

MIC (minimum inhibitory concentration) or antibiotic activity evaluated at a concentration of 128 µg/ml

Is MICK determined in a liquid medium in accordance with the method described in the publication Manual of Clinical Mircobiology, 7-th edition (1999), American Society for Microbiology".

Use of bacterial line:

Streptococcus pneumoniae ATCC 49619

Staphylococcus aureus ATCC 29213 or ATCC 6538

Enterococcus faecalis ATCC 29212

Streptococcus pyogenes ATCC 19615

- Assessment of data

The results are presented in the form of MIC (μg/ml), estimated as the lowest concentration of the test substance, which completely inhibits growth visible to the naked eye.

The results obtained for a number of compounds of the formula I, which are typical representatives of the class shown in the following tables.

ConnectionStaph.aureus ATCC 29213

MIC (mcg/ml)
Strep.pneum ATCC 49619

MIC (mcg/ml)
Enter. faecalis ATCC 29212

MIC (mcg/ml)
Erythromycin0,250,121
23>128864
27>128>128>128
19>12816>128
20>128>128>128
21>128>128>128
13>128>128>128
3>128>128>128
18>128>128>128
1>128>128>128
11>128>128>128
12>128>128>128
2>128>128>128

ConnectionStaph.aureus

ATCC 6538

128 (µg/ml)
Strep.pyogenes ATCC 19615

128 (µg/ml)
Enter. faecals ATCC 29212

128 (µg/ml)
Erythromycin0.25 microgram/ml (MICK)0.12 µg/ml (MICK)1 µg/ml (MICK)
15Not activeNot activeNot active
26Not activeNot activeNot active
21Not activeNot activeNot active
13Not activeNot activeNot active
3Not activeNot activeNot active
18Not activeNot activeNot active
1Not activeNot activeNot active
11Not activeNot activeNot active
12Not activeNot activeNot active
2Not activeNot activeNot active

The data in the table clearly show that the compounds of formula I of the present invention essentially do not possess antibiotic activity.

1. Macrolide compounds of the formula:

where R represents a hydrogen atom or methyl group;

R1represents a hydrogen atom, N,N-di(C1-C3)alkylamino, N,N-di(C1-C3)alkylamino-N-oxide group, N-(C1-C3)alkyl-N-benzylamino, N-(C1-C4)acyl-N-(C1-C3)alkylamino, N-[N,N-dimethylamino-(C1-C4)alkylamino]acetyl-N-(C1-C3)alkylamino or a chain of formula:

where a represents a hydrogen atom, phenyl or thiazolyl;

X represents O or NR6and R6represents a hydrogen atom;

Y represents thiazolyl or pyridinyl, or represents NR6where R6represents a hydrogen atom;

r takes integer values from 1 to 3;

m takes integer values from 1 to 6;

n takes on integer values from 0 to 2;

R2represents a hydrogen atom; or

R1and R2together form a bond;

R3represents a hydroxy-group or form a group =N-O-R5together with R4where R5represents a hydrogen atom, a linear or branched C1-C5alkyl, or a chain of formula:

-(CH2r-X-(CH2)m-Y-(CH2)n-A,

the de r, m, n have the meanings defined above;

Represents a hydrogen atom, thiazolyl, furanyl or thiophenyl;

X represents NR6and R6represents a hydrogen atom;

Y represents fenelonov group or NR6where R6represents a hydrogen atom;

R4represents a hydrogen atom or forms a group =N-O-R5together with R2and R5has the values defined above;

and its pharmaceutically acceptable salt,

provided that

R1is not dimethylaminopropoxy, when R3represents a hydroxy-group, and as R2and R4represent a hydrogen atom;

R1is not dimethylaminopropoxy when Deputy =N-O-R5in position 9 R5represents a hydrogen atom, a linear or branched (C1-C5)alkyl;

R1is not methylaminopropane when Deputy =N-O-R5in position 9 R5represents a linear or branched (C1-C5)alkyl.

2. The compound according to claim 1, where the group of the oxime, which may be present in position 9 has an E configuration.

3. The compound according to claim 1, where R1represents a hydrogen atom, N-(C1-C3)alkyl-N-methylaminopropyl, N-(C1-the 3)alkyl-N-methylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-(C1-C4)acyl-N-methylaminopropyl, N-[N,N-dimethylamino-(C1-C4)alkylamino]acetyl-N-methylaminopropyl or a chain of formula:

where a represents a hydrogen atom, phenyl or thiazolyl;

X represents O or NR6and R6represents a hydrogen atom;

Y, when n is 0, is thiazolyl or pyridinyl, or, when n has a value other than 0, represents NR6and R6represents a hydrogen atom;

r takes integer values from 1 to 3;

m takes integer values 1 or 2;

n takes on integer values from 0 to 2;

or R1forms a bond together with R2.

4. The compound according to claim 3, where R1represents a hydrogen atom, N,N-dimethylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-acetyl-N-methylaminopropyl, N-[N,N-dimethylamino(C1-C2)alkylamino]acetyl-N-methylaminopropyl or a chain of formula:

where a represents a hydrogen atom, phenyl or thiazolyl;

X represents O or NR6and R6represents a hydrogen atom;

Y, when n is 0, is thiazolyl or pyridinyl, is whether, when n is 1, represents NR6and R6represents a hydrogen atom;

r takes integer values from 1 to 3;

m takes integer values 1 or 2;

n takes integer values 0 or 1;

or R1forms a bond together with R2.

5. The compound according to claim 4, where R1represents a hydrogen atom, N,N-dimethylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-acetyl-N-methylaminopropyl, N-[N,N-diethylaminoethylamine]acetyl-N-methylaminopropyl or a chain of formula:

where a represents a hydrogen atom, phenyl or thiazolyl;

X represents NR6and R6represents a hydrogen atom;

Y, when n is 0, is thiazolyl or pyridinyl,

or, when n is 1, represents NR6and R6represents a hydrogen atom;

or R1forms a bond together with R2.

6. The compound according to claim 1, where R3represents a hydroxy-group, and R4represents a hydrogen atom, provided that R1is not dimethylaminopropoxy.

7. The connection according to claim 6, where R1represents a hydrogen atom, N-(C2-C3)alkyl-N-methylaminopropyl, N-(C1-C3)alkyl-N-methylamino-N-oxide group, N-benzyl-N-methylaminopropyl, -(C 1-C4)acyl-N-methylaminopropyl, N-[N,N-dimethylamino(C1-C4)alkylamino]acetyl-N-methylaminopropyl or a chain of formula:

where a represents a hydrogen atom, phenyl or thiazolyl;

X represents O or NR6and R6represents a hydrogen atom;

Y, when n is 0, is thiazolyl or pyridinyl, or, when n has a value other than 0, represents NR6and R6represents a hydrogen atom;

r takes integer values from 1 to 3;

m takes integer values 1 or 2;

n takes on integer values from 0 to 2;

or R1forms a bond together with R2.

8. The connection according to claim 7, where R1represents a hydrogen atom, N,N-dimethylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-acetyl-N-methylaminopropyl, N-[N,N-dimethylamino(C1-C2)alkylamino]acetyl-N-methylaminopropyl or a chain of formula:

where a represents a hydrogen atom, phenyl or thiazolyl;

X represents O or NR6and R6represents a hydrogen atom;

Y, when n is 0, is thiazolyl or pyridinyl, or, when n is 1, represents NR6and R6is sobo is a hydrogen atom;

r takes integer values from 1 to 3;

m takes integer values 1 or 2;

n takes integer values 0 or 1;

or R1forms a bond together with R2.

9. The connection of claim 8, where R1represents a hydrogen atom, N,N-dimethylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-acetyl-N-methylaminopropyl, N-[N,N-diethylaminoethylamine]acetyl-N-methylaminopropyl or a chain of formula:

where a represents a hydrogen atom, phenyl or thiazolyl;

X represents NR6and R6represents a hydrogen atom;

Y, when n is 0, is thiazolyl or pyridinyl, or, when n is 1, represents NR6and R6represents a hydrogen atom;

or R1forms a bond together with R2.

10. The compound according to claim 1, where R3form a group =N-O-R5together with R4where R5represents a hydrogen atom, a linear or branched (C1-C3)alkyl, or a chain of formula:

-(CH2r-X-(CH2)m-Y-(CH2)n-A,

where a represents a hydrogen atom, thiophenyl, thiazolyl or furanyl;

X represents NR6and R6represents a hydrogen atom or a linear or branched C1-C3alkyl;

Y, when n is 0, is fenelonov group, or when n has a value other than 0, represents NR6and R6represents a hydrogen atom;

r takes integer values 1 or 2;

m takes integer values from 1 to 6;

n takes on integer values from 0 to 2.

11. The connection of claim 10, where R5represents a hydrogen atom, methyl, or a chain of formula:

-(CH2r-X-(CH2)m-Y-(CH2)n-A,

where a represents a hydrogen atom, thiophenyl, thiazolyl or furanyl;

X represents NR6and R6represents a hydrogen atom;

Y, when n is 0, is fenelonov group, or when n is 1, represents NR6and R6represents a hydrogen atom;

r is 2;

m takes integer values from 1 to 6;

n takes integer values 0 or 1.

12. The compound according to claim 1, where R1represents a hydrogen atom, N-(C1-C3)alkyl-N-methylaminopropyl, N-(C1-C3)alkyl-N-methylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-(C1-C4)acyl-N-methylaminopropyl, N-[N,N-dimethylamino-(C1-C4)alkylamino]acetyl-N-methylaminopropyl or a chain of formula:

where a is an atom of odor is Yes, phenyl or thiazolyl;

X represents O or NR6and R6represents a hydrogen atom;

Y, when n is 0, is thiazolyl or pyridinyl, or, when n is 1, represents NR6and R6represents a hydrogen atom;

r takes integer values from 1 to 3;

m takes integer values 1 or 2;

n takes integer values 0 or 1;

or R1forms a bond together with R2;

at the same time R3form a group =N-O-R5together with R4where R5represents a hydrogen atom, a linear or branched (C1-C3)alkyl, or a chain of formula:

-(CH2r-X-(CH2)m-Y-(CH2)n-A,

where a represents a hydrogen atom, thiophenyl, thiazolyl or furanyl;

X represents NR6and R6represents a hydrogen atom;

Y, when n is 0, is fenelonov group, or when n has a value other than 0, represents NR6and R6represents a hydrogen atom;

r takes integer values 1 or 2;

m takes integer values from 1 to 6;

n takes on integer values from 0 to 2.

13. The connection section 12, where R5represents a hydrogen atom, methyl or a chain of formula:

-(CH2r-X-(CHsub> 2)m-Y-(CH2)n-A,

where a represents a hydrogen atom, thiophenyl, thiazolyl or furanyl;

X represents NR6and R6represents a hydrogen atom;

Y, when n is 0, is fenelonov group, or when n is 1, represents NR6and R6represents a hydrogen atom;

r is 2;

m takes integer values from 1 to 6;

n takes integer values 0 or 1.

14. The connection indicated in paragraph 13, where R1represents a hydrogen atom, N-N-dimethylaminopropyl, N-N-dimethylamino-N-oxide group, N-benzyl-N-methylaminopropyl, N-acetyl-N-methylaminopropyl, N-[N,N-dimethylamino-(C1-C2)alkylamino]acetyl-N-methylaminopropyl or a chain of formula:

where a represents a hydrogen atom, phenyl or thiazolyl;

X represents NR6and R6represents a hydrogen atom;

Y, when n is 0, is thiazolyl or pyridinyl, or, when n is 1, represents NR6and R6represents a hydrogen atom;

or R1forms a bond together with R2.

15. A method of obtaining a compound according to claim 1, characterized in that the residue of L-cladinose in position 3 is removed from compounds of General formula II:

where R, R1, R2, R3and R4have the meanings given in claim 1;

by reaction of acid hydrolysis, catalyzed in the presence of mineral acids and proton organic solvent.

16. The method according to clause 15, where in formula II, R3represents a hydroxy-group, and R4represents a hydrogen atom.

17. The compound of the formula:

where R represents a hydrogen atom or a metal group;

R1represents a hydrogen atom, N,N-di(C1-C3)alkylamino, N,N-di(C1-C3)alkylamino-N-oxide group, N-(C1-C3)alkyl-N-benzylamino, N-(C1-C4)acyl-N-(C1-C3)alkylamino, N-[N,N-dimethylamino(C1-C4)alkylamino]acetyl-N-(C1-C3)alkylamino or a chain of formula:

where a represents a hydrogen atom, phenyl or thiazolyl;

X represents O or NR6where R6represents a hydrogen atom or a C1-C3alkoxycarbonyl group;

Y represents thiazolyl, pyridinyl or NR6where R6represents a hydrogen atom or a C1-C3alkoxycarbonyl group;

r accepts zeleznicni from 1 to 3;

m takes integer values from 1 to 6;

n takes on integer values from 0 to 2;

R2represents a hydrogen atom;

or R1forms a bond together with R2;

R3represents a hydroxy-group;

R4represents a hydrogen atom;

and their pharmaceutically acceptable salts;

provided that (i) R1is not N,N-dimethylaminopropoxy or (ii) R1is not N,N-dimethylamino-N-oxide group, when R represents a hydrogen atom.

18. The connection 17, where R represents a hydrogen atom, and R1forms a bond together with R2.

19. The connection 17, where R represents a hydrogen atom, and R1represents N-benzyl-N-methylaminopropyl.

20. The connection 17, where R represents a hydrogen atom, and R1represents N-acetyl-N-methylaminopropyl.

21. The connection 17, where R represents a hydrogen atom, and R1represents N-[N,N-diethylaminoethylamine]acetyl-N-methylaminopropyl.

22. The connection 17, where R represents a hydrogen atom, and R1represents N-methyl-N-3-[(2-triazolylmethyl)amino]propylamino.

23. The connection 17, where R represents a hydrogen atom, and R1represents a N-2-[2-[(2-triazolylmethyl)amino]ethylamino]these is-N-methylaminopropyl.

24. The connection 17, where R represents a hydrogen atom, and R1represents a N-2-[2-(benzylamino)ethylamino]ethyl-N-methylaminopropyl.

25. The Union, representing des(N-methyl)-9-dihydroergotamine And the following formula

26. The Union, representing des(N-methyl)descladinose-9-dihydroergotamine And the following formula

27. Pharmaceutical composition having anti-inflammatory activity, containing a therapeutically effective amount of the compounds of General formula I, characterized in claim 1, or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.

28. The pharmaceutical composition according to item 27 for use in the treatment of inflammatory diseases.

29. The pharmaceutical composition according to item 27 for use in the treatment of respiratory diseases.



 

Same patents:

FIELD: antibiotics.

SUBSTANCE: invention relates to azithromycin as a stable monohydrate comprising from 4.0% to 6.5% of water and to a method for its preparing. Invention provides preparing the stable form of azithromycin monohydrate.

EFFECT: improved preparing method.

3 cl, 2 tbl, 2 ex

FIELD: organic chemistry, antibiotics, pharmacy.

SUBSTANCE: invention describes crystalline forms A, C and D of erythromycin derivative of the formula (VII): . Crystalline forms are prepared by recrystallization of crude fumarate crystal from an alcoholic solvent (form A) and, additionally, from ethyl acetate (form C) or, additionally, from an aqueous ethyl acetate (form D). Also, invention relates to methods for preparing intermediate compounds. Prepared crystalline forms possess the better quality, in particular, high stability that is important in preparing pharmaceutical preparations.

EFFECT: improved preparing methods.

16 cl, 8 dwg, 13 ex

FIELD: organic chemistry, antibiotics, chemical technology.

SUBSTANCE: invention relates to a novel crystalline form E of erythromycin derivative fumarate salt represented by the formula (I)

and to a method for its preparing. Indicated crystalline form E shows strong roentgen diffraction peaks at diffraction angles (2θ) 5.6° and 10.4° that was established by roentgen diffractometry with Cu-Kα-radiation. Also, invention proposes crystalline form D of erythromycin derivative fumarate salt represented by the formula (I) showing average particles size 90 mcm or above and/or the content of residual solvent 1500 ppm or less. Method for preparing indicated crystalline form D involve suspending indicated crystalline form E in mixture ethyl acetate and water in the ratio = (99:1)-(97:3) at temperature from -20°C to 20°C. Invention provides reducing the content of residual solvent and elimination of difficulties in making tablets.

EFFECT: improved preparing methods.

14 cl, 1 tbl, 5 dwg, 6 ex

FIELD: antibiotics, chemical technology.

SUBSTANCE: invention relates to a method for preparing erythromycin oxime in homogenous conditions by oximylation of erythromycin A with hydroxylamine hydrochloride in dry methanol using triethylamine as a base. Method provides enhancing yield and quality of product.

EFFECT: improved method for preparing.

3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: production of macrolide road-spectrum antibiotic tylosine.

SUBSTANCE: claimed method includes tylosine deposition from organic tylosine base concentrate with organic solvent (hexane). Deposition is carried out by addition of organic tylosine base concentrate to hexane at velocity of 3-5 ml/min per 50 ml of concentrate.

EFFECT: method for production of tylosine base in granulated form with homogeneous composition.

2 cl, 6 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing fumarate salt of compound of the formula (II) wherein R1 represents hydrogen atom or lower alkyl group; R2 represents lower alkyl group. Method involves interaction of compound of the formula (I) wherein R1 represents hydrogen atom or lower alkyl group with chloroformate. Then all carbamate groups are removed followed by alkylation of nitrogen atom at 3'-position of desosamine ring to obtain compound of the formula (II) and conversion of this compound to fumarate salt. Interaction of compound of the formula (I) with chloroformate is carried out in the presence of cyclic ether or carboxylic acid ester. Carbamate groups are removed in the presence of sodium hydrocarbonate. Crystallization and re-crystallization of compound of the formula (II) fumarate salt is carried out from alcohol-containing solvent, in particular, from isopropyl alcohol. Method provides increasing yield and enhancing purity of the end product.

EFFECT: improved preparing and purifying method.

28 cl, 11 ex

The invention relates to 3’-Destinationin-9 oxyimino macrolides of formula (I):

in which R represents hydrogen or methyl; R1and R2both represent hydrogen or together form a chemical bond; R3represents hydrogen or linear or branched C1-C5alloy group, or a chain of formula

where a is a hydrogen or phenyl group, or a 5-or 6-membered heterocycle, saturated or unsaturated and contains from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or two substituents selected from C1-C5alkyl groups or phenyl groups, X and Y, identical or different, represent O or NR4where R4is hydrogen, linear or branched C1-C5alkyl group, benzyloxycarbonyl group; r is an integer from 1 to 6; m is an integer from 1 to 8; n is an integer from 0 to 2; and their pharmaceutically acceptable salts; except for compounds of the oxime of 3’-destinationin-3’,4’-dihydroanthracene and 9-O-methyloxime 3’-descimated the

The invention relates to organic chemistry, in particular to methods of producing the compounds of formula (I):

in which m denotes 0, 1 or 2; n is 0, 1, 2 or 3 and a represents a double bond, represents a double or a simple link, With denotes a double bond, D represents a simple bond, E and F represent a double bond; r1denotes N or C1-C8alkyl; r2denotes H, C1-C8alkyl or HE; R3and R4each independently of one another denote H or C1-C8alkyl; R5denotes N or C1-C8alkyl; R6denotes H; R7IT denotes; R8and R9independently of one another denote H or C1-C10alkyl; in free form or in salt form, which consists in the fact that the compound of formula (II):

enter in contact with the biocatalyst, which is able to selectively oxidize the alcohol in position 4", obtaining the compounds of formula (III):

in which R1-R7, m, n, a, b, C, D, E and F have the same meaning as Kazakistan an amine of the formula HN(R8R9in which R8and R9have the same meaning as indicated for formula (I), with subsequent isolation of the target product in free form or in salt form

The invention relates to medicine, in particular to Oncology, and for the treatment of cancer in a mammal

FIELD: chemistry.

SUBSTANCE: invention concerns new tricyclic derivatives of the formula (I) and their pharmaceutically acceptable salts, where: 1 to 3 of A1, A2, A3 and A4 are nitrogen atoms, while the rest are -CH- groups; G1 is a group selected out of -CH2-O-, -CH2-CH2-, - CH=CH-; -N(C1-C4alkyl)-CH2; G2 is a group selected out of -O-CH2-, -CH=CH-, -CH2- CH2-; R4 can be identical or different and are selected out of a group including hydrogen or halogen atoms; p are independently equal to 0, 1 or 2; Y is and optionally substituted residuum selected out of the group of alkyl, cycloalkyl, alkylaryl, alkylcycloalkylalkyl; Z is a tetrazolyl, -COOR5, -CONR5R5, NHSO2R5 or -CONHSO2R5 group, where R5 is hydrogen or optionally substituted alkyl or aryl. The invention also concerns a method of obtaining the claimed compounds.

EFFECT: possible application in treatment and prophylactics of inflammation and allergy diseases.

20 cl, 2 tbl, 46 ex

FIELD: medicine; pharmacology.

SUBSTANCE: wood of Siberian or Daurian larch is debarked, cleaved and dried at 40-50°C to residual moisture 23-27%. Dried wood is chopped, and soluble substances are extracted with 75-85% ethyl alcohol aqueous solution at temperature 45-50°C in ratio raw material:extracting agent 1:(7-10). Further extracting agent is distilled off, and sawdust is supplied to press for additional alcohol return. Then extract aqueous part is cooled to 20-25°C within 20-30 minutes for isolation of resinous impurity accompanying dihydroquercetin (DHQ). Deresined extract aqueous part is added with methyltertbutyl ether (MTBE) in ratio 1: (0.3-0.45), and DHQ is reextracted within 2-3 hours. Extract ether part is isolated separate from aqueous part through sedimentation within 2-2.5 hours and supplied to MTBE evaporation, while target product is crystallised of hot water. Invention enables to produce DHQ with yield 2.2-2.5% of bone-dry wood mass with grade 90-96%.

EFFECT: simplification of process and production of high-quality product.

4 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medical products and concerns composition for treatment of cyclooxygenase-2 dependent disorders or conditions, in the form of tablet of immediate release containing 400 mg 5-methyl-2 (2'-chlorine-6' -fluorineanilin) phenylacetic acid or its pharmaceutically acceptable salt, where tablet includes 5-methyl-2 (2'- chlorine-6'- fluorineanilin) phenylacetic acid or its pharmaceutically acceptable salt within the range between 60 mass% and 70 mass%, and polyvinylpyrrolidone, croscarmellose in sodium form, magnesium stearate and microcrystalline cellulose, in amount which provides release at least about 70% of a preparation in 1000 ml of phosphate buffer (pH 8) with 0.1% twin 80 during 60 min at 37°C. Invention enables to produce tablet of comprehensible size with active substance highly loaded.

EFFECT: production of effective pharmaceutical composition for treatment cyclooxygenase-2 dependent disorders.

8 cl, 7 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of phtalazine with general formula (I) , in which R represents a methyl or difluromethyl group; R1 represents phenyl or oxazolyl or thiophenyl, chemically bonded to a phtalazine ring through a carbon-carbon bond. Both phenyl and the above mentioned heterocycle are substituted with a carboxylic group, and optionally with a second functional group, chosen from methoxy-, nitro-, N-acetylamino-, N-metanesulphonylamino- group. The invention also relates to pharmaceutical salts of such derivatives. The given compounds with general formula (I) are inhibitors of phosphodiesterase.

EFFECT: objective of the invention is also the method of obtaining compounds with general formula (I) and pharmaceutical compositions for treating allergies and antiphlogistic diseases based on the given compounds.

9 cl, 9 tbl, 24 ex

FIELD: medicine.

SUBSTANCE: invention refers to methods and compositions for treatment and/or prevention maintenance of infectious condition in liquid-containing organ or organ with natural external aperture. Composition includes antibacterial agent, and also, probably, other active agents, amphipathic oil which is soluble in water and insoluble in ethanol, microcrystalline wax and pharmaceutically acceptable nonaqueous carrier. The method of treatment is realised by introduction of a pharmaceutical composition in body through natural external aperture.

EFFECT: regarding composition, invention provides stability of the active agent against oxidising decomposition, low interfacial tension of composition, easy solubility in liquids, and short time of excretion; invention provides effective treatment and reduction of by-effects and toxicity.

61 cl, 12 ex

FIELD: medicine.

SUBSTANCE: invention concerns method of pain relief by introduction of pharmaceutical composition containing effective amount of α-adrenergic antagonist and pharmaceutical composition, containing effective amount of the selective α-2A-antagonist.

EFFECT: method provides prolonged relief of chronic pain.

104 cl, 12 dwg, 4 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the compound with the formula (1): where R1 is C1-C12 alkyl group, which can have the substitute, or C2-C12 alkenyl group, which can have the substitute represented with the C6-C14 aryl group, which can be substituted with the halogen atoms; each of R2 and R3 represent the hydrogen atom, alkyl group, hydroxyalkyl group, dihydroxyalkyl group, or R2 and R3 form with the adjacent nitrogen atoms the 5-membered, 6-membered, or 7-membered nitrogen-containing saturated heterocyclic group, which can be substituted with the alkyl group; (the dotted line means the possible double bind), or its salt, as well as to the pharmaceutical composition containing the said compound, and to its application as a pharmaceuticals and to the treatment method.

EFFECT: invented compound demonstrates inhibiting activity against the tumor necrosis factor production (TNF-α) and improved absorbability after oral administration.

16 cl, 1 tbl, 18 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the crystal forms of methanesulfonate (A, B and C forms), methanesulfonate hydrate (F form), solvate with the acetic acid of methanesulfonate (I form), ethanesulfonate (α and β forms), hydrochloride, hydrobromide, n-toluenesulfonate or sulfate 4-(3-chlorine-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, to the methods of their production, to the pharmaceutical compositions based on them and showing the angiogenesis related activity, to the method of prevention or treatment of the disease where inhibiting angiogenesis is effective and to the application of the crystal forms in producing the pharmaceutical agent for prevention or treatment of the disease where inhibiting angiogenesis is effective.

EFFECT: producing the pharmaceutical agent for prevention or treatment of the disease where inhibiting angiogenesis is effective.

45 cl, 21 dwg, 27 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the 2-pyridone derivatives with the common formula where X, Y1, R1, Y2, G1, R5, R4, L, G2 are as specified in the invention formula. The invention also relates to the pharmaceutical agent which inhibits the human neutrophil elastase activity and which contains the compound with the formula (I), in drug manufacturing, and to the method of producing the compound with formula (I).

EFFECT: producing novel compounds which inhibit neutrophil elastase activity.

8 cl, 1 tbl, 96 ex

FIELD: medicine; pharmacology.

SUBSTANCE: pharmaceutical formulation for local application contain ketoprofen, solysobenzone in amount 2-4 mass.%, butylhydroxianisole in amount 0.05 to 0.2 mass.%, if required combined with pharmaceutically acceptable excipient. Composition protects ketoprofen from destruction caused by ultraviolet A, and is applied for treatment of inflammatory pathologies and musculoskeletal diseases.

EFFECT: no phototoxicity and photoallergenicity; increased permeability and rapid analgesic effect.

13 cl, 8 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: troxevazin (Troxerutin) is offered as agent for sports efficiency improvement. Some sportsmen showed maximal oxygen consumption increased after troxevazin application. Invention is distinguished that troxevazin has various action for sports efficiency, and it depends on individual physiological behaviour of sportsman.

EFFECT: improved productivity of cardio-vascular system and increased level of muscular aerobic productivity.

1 tbl, 4 ex

Up!