Phosphonic acid compounds as serine proteinase inhibitors

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to phosphonic acid compounds used as inhibitors of serine proteinase of the general formula (I): wherein R1 is chosen from group comprising piperidinyl, pyrrolidinyl and 1,3,8-triazaspiro[4,5]dec-8-yl (wherein heterocyclic ring as added to nitrogen atom in ring) and -N(R7R80 wherein this heterocyclic ring is substituted optionally with one or two substitutes chosen independently from group comprising the following compounds: (a) C1-C8)-alkyl substituted optionally at terminal carbon atom with a substitute chosen from group comprising aryl, heteroaryl; c) phenyl and naphthalenyl; i) benzothiazolyl; R7 is chosen from group comprising hydrogen atom and (C1-C8)-alkyl; R8 is chosen from group comprising: (aa) (C1-C8)-alkyl; (ab) cycloalkyl; (ac) cycloalkenyl, and (ad) heterocyclyl (wherein R8 is added to carbon atom in ring) wherein (ab) cycloalkyl; (ac) cycloalkenyl, and (ad) heterocyclyl (wherein heterocyclyl (ad) comprises at least one cyclic nitrogen atom) substitutes and cycloalkyl moiety (aa) of a substitute is substituted optionally with substitutes chosen independently from group comprising: (ba) (C1-C8)-alkyl substituted at terminal carbon atom with a substitute chosen from group comprising amino-group (with two substitutes chosen independently from group comprising hydrogen atom and (C1-C8)-alkyl); (bb) (C1-C8)-alkoxy-group substituted at terminal carbon atom with a substitute chosen from group comprising carboxyl; (bc) carbonyl substituted with a substitute chosen from group comprising (C1-C8)-alkyl, aryl, aryl-(C2-C8)-alkenyl; (bd) aryl; (be) heteroaryl; (bf) amino-group substituted with two substitutes chosen independently from group comprising hydrogen atom and (C1-C8)-alkyl; (bh) halogen atom; (bi) hydroxy-group; (bk) heterocyclyl wherein (bd) is aryl substitute, and heteroaryl moiety (bc) comprise a substitute (halogen atom)1-3; R4 is chosen from group comprising aryl and heteroaryl wherein heteroaryl comprises halogen atom as a substitute; R2 and R3 are bound with benzene ring and represent hydrogen atom, and R2 and R3 form in common optionally at least one ring condensed with benzene ring forming polycyclic system wherein this polycyclic system is chosen from group comprising (C9-C14)-benzocondensed cycloalkenyl, (C9-C14)-benzocondensed phenyl; R5 is chosen from group comprising hydrogen atom and (C1-C8)-alkyl; R6 is chosen from group comprising (C1-C8)-alkyl and hydroxy-group; Y is absent, and X represents a single substitute that is added by a double bond and represents oxygen atom (O), and Z is chosen from group comprising a bond, hydrogen atom, and its salts. Also, invention relates to a method for synthesis of these compounds, to their composition inhibiting serine proteinase and to a method for its preparing. Proposed invention describes a method for treatment of inflammatory or serine proteinase-mediated disorder.

EFFECT: valuable biochemical and medicinal properties of compounds.

64 cl, 5 tbl, 38 ex

 

Cross references to related applications

This application claims the priority of provisional application serial number 60/330343, filed October 19, 2001, which is incorporated herein by reference.

The scope of the invention

The present invention relates to certain new compounds, methods of producing these compounds, to compositions based on them, the intermediate compounds and derivatives and to the treatment of inflammatory and mediated by the serine proteinase diseases. More specifically, the compounds of phosphonic acids of the present invention are inhibitors of serine proteases that can be used for the treatment of inflammatory and mediated by the serine proteinase diseases.

Prerequisites to the creation of inventions

Serine proteases are a broad class of endopeptidases that are involved in physiological processes such as blood coagulation, activation of complement, phagocytosis and the turnover of damaged cell tissue. For example, cathepsin G (cat G) is a chymotrypsin-like serine-protease found in azurophilic granules of polymorphonuclear leukocytes. Along with other serine proteases such as neutrophil elastase and proteinase 3, cat G performs the function of the breakdown of proteins during vos is Alitalia reactions. I think that cat G cleaves human elastin during chronic inflammation of the lungs, and this process can be partly the cause of asthma, emphysema, chronic obstructive pulmonary disease (COPD)and other lung inflammatory conditions. Similarly human chymase (NS) is a chymotrypsin-like serine of the protease synthesized in mastocyte. NS has many functions, including the cleavage of extracellular matrix proteins, cleavage of angiotensin I to angiotensin II and activation of matrix proteases and cytokines. Inadequate regulation by their natural inhibitors may lead to degradation of these enzymes healthy components of the extracellular matrix and, therefore, contribute to inflammatory disorders such as asthma, emphysema, bronchitis, psoriasis, allergic rhinitis, viral rhinitis, ischemia, arthritis and trauma during re-perfusion. Thus, apparently, a small molecule inhibitors of cat G and NA are therapeutically useful agents.

In U.S. patent 5508273 issued by Beers et al. and inBioorganic & Med. Chem. Lett.,1995, 5 (16), 1801-1806, describes the connection of phosphonic acids used for the treatment of diseases of bone loss. In particular, as inhibitors osteoclastic acid phosphatase have been described p is osvitnye 1-naphthylethylene acid of the formula:

Accordingly, the present invention is to develop compounds phosphonic acids, which are inhibitors of serine proteases (in particular, inhibitors of cathepsin G and chymase), which can be used for the treatment of inflammatory and mediated by the serine proteinase diseases. Another objective of the present invention is to develop methods for obtaining compounds of phosphonic or phosphinic acids, compositions based on them, intermediates and derivatives. Another objective of the present invention is the development of methods of treatment of inflammatory and mediated by the serine proteinase diseases.

Brief description of the invention

This invention relates to the compound of formula (I):

where

R1selected from the group comprising a heterocyclic ring (where the place of attachment of the heterocyclic ring R1is the nitrogen atom of the cycle) and-N(R7R8)where the heterocyclic ring optionally substituted by from one to two substituents, independently selected from the group including:

a)1-8alkyl, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising aryl, heteroaryl, (halogen)1-3and hydroxy,

(b) (C1-8alkoxy, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising carboxyl, (halogen)1-3and hydroxy,

C) aryl,

d) heteroaryl,

e) cyano,

f) halogen,

(g) hydroxy,

h) nitro and

i) heterocyclyl, optionally substituted from one to two substituents, independently selected from the group comprising oxo and aryl, and optionally condensed with a connecting carbon atom with the formation of spiroheterocyclic fragment

and where the aryl portion (a) and (i) substituent, heteroaryl part a) Deputy and C) aryl and (d) heteroaryl substituents optionally substituted from one to four substituents, independently selected from the group comprising From1-4alkyl, C2-4alkenyl,1-4alkoxy, cycloalkyl, heterocyclyl, aryl, aryl(C1-4)alkyl, aryloxy, heteroaryl, heteroaryl(C1-4)alkyl, halogen, hydroxy, nitro, (halogen)1-3(C1-4)alkyl and (halogen)1-3(C1-4)alkoxy,

R7selected from the group comprising hydrogen, C1-8alkyl and C2-8alkenyl,

R8selected from the group including:

AA)1-8alkyl, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising cycloalkyl, heterocyclyl, aryl, heteroaryl, amino (with two substituents which, independently selected from the group comprising hydrogen and C1-8alkyl), (halogen)1-3and hydroxy,

ab) cycloalkyl,

AU) cycloalkenyl and

ad) heterocyclyl (where the place of attachment of R8is the carbon atom of the cycle), where ab) cycloalkenyl, AU) cycloalkenyl and ad) heterocyclyl (where ad) heterocyclyl contains at least one cyclic nitrogen atom) deputies and cycloalkyl, heterocyclyl, aryl and heteroaryl part AA) Deputy optionally substituted from one to four substituents, independently selected from the group including:

ba)1-8alkyl, optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl), (halogen)1-3and hydroxy,

bb)1-8alkoxy, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising carboxyl, (halogen)1-3and hydroxy,

bc) carbonyl, substituted Deputy selected from the group comprising From1-8alkyl, aryl, aryl(C1-8)alkyl, aryl(C2-8)alkenyl, heteroaryl, heteroaryl(C1-8)alkyl and heteroaryl(C2-8)alkenyl,

bd) aryl,

be) heteroaryl,

bf) amino substituted by two substituents, independently selected from GRU the dust, comprising hydrogen and1-8alkyl,

bg) cyano,

bh) halogen,

bi) hydroxy,

bj) nitro,

bk) heterocyclyl, optionally substituted by one or two oxo-substituents, and

bl) sulfonyl, substituted Deputy selected from the group comprising From1-8alkyl, aryl, aryl(C1-8)alkyl, aryl(C2-8)alkenyl, heteroaryl, heteroaryl(C1-8)alkyl and heteroaryl(C2-8)alkenyl,

where bd) aryl, be) heteroaryl and bk) heterocyclyl substituents and the aryl and heteroaryl portion bc) Deputy optionally substituted from one to four substituents, independently selected from the group comprising From1-4alkyl (optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl), (halogen)1-3and hydroxy)1-4alkoxy (optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising (halogen)1-3), amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), halogen, hydroxy and nitro,

and provided that the optional Deputy attached to the nitrogen atom of the ring heterocyclyl ad), not selected from a group including bf) amino (zameshannym substituents, independently selected from the group comprising hydrogen and C1-8alkyl), bh) halogen, bi) hydroxy and bj) nitro,

R4selected from the group comprising From1-4alkyl (optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising aryl and heteroaryl), aryl and heteroaryl, where aryl and heteroaryl and aryl and heteroaryl portion of the substituted alkyl optionally substituted from one to four substituents, independently selected from the group comprising From1-4alkyl, amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), cyano, halogen, hydroxy and (halogen)1-3(C1-8)alkyl,

R2and R3linked with the benzene ring and independently selected from the group including

sa) hydrogen

cb)1-4alkyl, optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), (halogen)1-3and hydroxy,

SS)1-4alkoxy, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising (halogen)1-3and hydroxy,

cd)2-4alkenyl,

ce) amino substituted by two substituents, independently selected from the group including the setup portion of the hydrogen and C 1-4alkyl,

cf) halogen and

cg) hydroxy,

optional R2and R3together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group comprising From9-C14benzoannelirovannykh cycloalkyl,9-C14benzoannelirovannykh cycloalkenyl,9-14benzoannelirovannykh aryl, benzoannelirovannykh heterocyclyl and benzoannelirovannykh heteroaryl, and where the polycyclic system may be optionally substituted by from one to four substituents, independently selected from the group including

da)1-4alkyl, optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), (halogen)1-3and hydroxy,

db)1-4alkoxy, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising (halogen)1-3and hydroxy,

dc) amino substituted by two substituents, independently selected from the group comprising hydrogen and C1-4alkyl,

dd) halogen,

de) hydroxy and

df) nitro,

R5selected from the group comprising hydrogen and C1-8alkyl (obazatelno substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), (halogen)1-3and hydroxy) and aryl (optionally substituted by one to four substituents, independently selected from the group comprising From1-8alkyl and halogen),

R6selected from the group comprising From1-8alkyl, aryl(C1-8)alkyl, C1-8alkoxy, aryl(C1-8)alkoxy, C2-8alkenyl,2-8alkenylacyl, aryl(C2-8)alkenyl, aryl(C2-8)alkenylamine, aryl, aryloxy and hydroxy,

X and Y are independently selected from the group comprising hydrogen, C1-8alkyl (optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising cycloalkyl, heterocyclyl, aryl, heteroaryl, amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl), (halogen)1-3and hydroxy, C1-8alkoxy (optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising aryl, (halogen)1-3and hydroxy)2-8alkenylacyl, cycloalkyl, heterocyclyl, aryl, aryloxy, heteroaryl and hydroxy, optionally X and Y condensed with the connecting carbon, forming spiratically or heterocyclic fragment, and, optionally, no where X represents the only Deputy, which is attached via a double bond, and is selected from the group comprising O, S, imino, (C1-4)alkylamino, hydroxyamino, and

Z is selected from the group comprising a bond, hydrogen, and C1-8alkyl when Z is a bond (where Z forms a double bond with the carbon atom binding for X), then Y is absent and X is the only Vice that is attached via a direct connection, and selected from the group comprising hydrogen, C1-8alkoxy, C2-8alkenylacyl, aryloxy, aryl(C1-4)alkoxy and hydroxy,

and their isomers, racemates, enantiomers, diastereomers and salts.

Ways of implementation of the present invention include a method for obtaining compounds of formula (I), which consists in binding in suitable conditions, the first compound of the formula (A):

with a second compound selected from the group comprising the compounds of formula (I) and formula (C):

obtaining a third compound selected from the group comprising the compounds of formula (D) and formula (E):

where

R7selected from the group comprising hydrogen, C1-8alkyl and C2-8alkenyl,

R8selected from the group including:

AA)1-8alkyl, optionally substituted at the terminal carbon atom by a Deputy, is elected from the group including cycloalkyl, heterocyclyl, aryl, heteroaryl, amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl), (halogen)1-3and hydroxy,

ab) cycloalkyl,

AU) cycloalkenyl,

ad) heterocyclyl (where the place of attachment of R8is the carbon atom of the cycle),

where ab) cycloalkenyl, AU) cycloalkenyl and ad) heterocyclyl (where ad) heterocyclyl contains at least one cyclic nitrogen atom) deputies and cycloalkyl, heterocyclyl, aryl and heteroaryl part AA) Deputy optionally substituted from one to four substituents, independently selected from the group including:

ba)1-8alkyl, optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl), (halogen)1-3and hydroxy,

bb)1-8alkoxy, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising carboxyl, (halogen)1-3and hydroxy,

bc) carbonyl, substituted Deputy selected from the group comprising From1-8alkyl, aryl, aryl(C1-8)alkyl, aryl(C2-8)alkenyl, heteroaryl, heteroaryl(C1-8)alkyl and heteroaryl(C2-8)alkenyl,

bd) and the sludge

be) heteroaryl,

bf) amino substituted by two substituents, independently selected from the group comprising hydrogen and C1-8alkyl,

bg) cyano,

bh) halogen,

bi) hydroxy,

bj) nitro,

bk) heterocyclyl, optionally substituted from one to two oxo-substituents, and

bl) sulfonyl, substituted Deputy selected from the group comprising From1-8alkyl, aryl, aryl(C1-8)alkyl, aryl(C2-8)alkenyl, heteroaryl, heteroaryl(C1-8)alkyl and heteroaryl(C2-8)alkenyl,

where bd) aryl, be) heteroaryl and bk) heterocyclyl substituents and the aryl and heteroaryl portion Deputy bc) optionally substituted from one to four substituents, independently selected from the group comprising From1-4alkyl (optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl), (halogen)1-3and hydroxy)1-4alkoxy (optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising (halogen)1-3, amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), halogen, hydroxy and nitro,

and provided that the optional Deputy, to recognize the military to the nitrogen atom of the ring heterocyclyl ad), not selected from the group including bf) amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl), bh) halogen, bi) hydroxyI bj) nitro,

R4selected from the group comprising From1-4alkyl (optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising aryl and heteroaryl), aryl and heteroaryl, where aryl and heteroaryl and aryl and heteroaryl portion of the substituted alkyl optionally substituted from one to four substituents, independently selected from the group comprising From1-4alkyl, amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), cyano, halogen, hydroxy and (halogen)1-3(C1-8)alkyl,

R2and R3linked with the benzene ring and independently selected from the group including

sa) hydrogen

cb)1-4alkyl, optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), (halogen)1-3and hydroxy,

SS)1-4alkoxy, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising (halogen)1-3and hydroxy,

cd)2-4alkenyl,

ce) amino substituted by two substituents, independently selected from the group comprising hydrogen and C1-4alkyl,

cf) halogen and

cg) hydroxy,

optional R2and R3together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group comprising From9-C14benzoannelirovannykh cycloalkyl,9-C14benzoannelirovannykh cycloalkenyl,9-14benzoannelirovannykh aryl, benzoannelirovannykh heterocyclyl and benzoannelirovannykh heteroaryl, and where the polycyclic system may be optionally substituted by from one to four substituents, independently selected from the group including

da)1-4alkyl, optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), (halogen)1-3and hydroxy,

db)1-4alkoxy, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising (halogen)1-3and hydroxy,

dc) amino substituted by two substituents, independently selected from the group comprising hydrogen and C1-4alkyl,

dd) halogen,

de) hydroxy and

df) nitro,

R5 selected from the group comprising hydrogen and C1-8alkyl (optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), (halogen)1-3and hydroxy) and aryl (optionally substituted by one to four substituents, independently selected from the group comprising From1-8alkyl and halogen),

R6selected from the group comprising From1-8alkyl, aryl(C1-8)alkyl, C1-8alkoxy, aryl(C1-8)alkoxy, C2-8alkenyl,2-8alkenylacyl, aryl(C2-8)alkenyl, aryl(C2-8)alkenylamine, aryl, aryloxy and hydroxy,

X is selected from the group comprising O, S, imino, (C1-4)alkylamino, hydroxyamino, and

Z is selected from the group comprising a bond, hydrogen, and C1-8alkyl when Z is a bond (where Z forms a double bond with the carbon atom binding for X), then X is selected from the group comprising hydrogen, C1-8alkoxy, C2-8alkenylacyl, aryloxy, aryl(C1-4)alkoxy and hydroxy,

and their isomers, racemates, enantiomers, diastereomers and salts.

Ways of implementation of the present invention include a compound of formula (C):

where

R2and R3linked with the benzene ring and the independent is selected from the group including

sa) hydrogen

cb)1-4alkyl, optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), (halogen)1-3and hydroxy),

SS)1-4alkoxy, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising (halogen)1-3and hydroxy,

cd)2-4alkenyl,

ce) amino substituted by two substituents, independently selected from the group comprising hydrogen and C1-4alkyl,

cf) halogen and

cg) hydroxy,

optional, R2and R3together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group comprising From9-14benzoannelirovannykh cycloalkyl,9-14benzoannelirovannykh cycloalkenyl,9-14benzoannelirovannykh aryl, benzoannelirovannykh heterocyclyl and benzoannelirovannykh heteroaryl, and where the polycyclic system may be optionally substituted by from one to four substituents, independently selected from the group including

da)1-4alkyl, optionally substituted at the terminal atom of carbon is and Deputy selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), (halogen)1-3and hydroxy,

db)1-4alkoxy, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising (halogen)1-3and hydroxy,

dc) amino substituted by two substituents, independently selected from the group comprising hydrogen and C1-4alkyl,

dd) halogen,

de) hydroxy and

df) nitro,

R4selected from the group comprising From1-4alkyl (optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising aryl and heteroaryl), aryl and heteroaryl, where aryl and heteroaryl and aryl and heteroaryl portion of the substituted alkyl optionally substituted from one to four substituents, independently selected from the group comprising From1-4alkyl, amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), cyano, halogen, hydroxy and (halogen)1-3(C1-8)alkyl,

R5selected from the group comprising hydrogen and C1-8alkyl (optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising water the genus and 1-4alkyl), (halogen)1-3and hydroxy) and aryl (optionally substituted by one to four substituents, independently selected from the group comprising From1-8alkyl and halogen),

and

R6selected from the group comprising From1-8alkyl, aryl(C1-8)alkyl, C1-8alkoxy, aryl(C1-8)alkoxy, C2-8alkenyl,2-8alkenylacyl, aryl(C2-8)alkenyl, aryl(C2-8)alkenylamine, aryl, aryloxy and hydroxy.

Ways of implementation of the present invention include a method of obtaining benzoylacetone formula (C), which consists in

(a) the interaction between the anhydride of formula (F):

with the compound of the formula (G):

in suitable conditions in the presence of alkali metal (M) to obtain the compounds of formula (H):

b) and the interaction of the compounds of formula (H) under conditions suitable to obtain benzoylacetone formula (C):

where

R2and R3linked with the benzene ring and independently selected from the group including

sa) hydrogen

cb)1-4alkyl, optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising hydrogen and the 1-4alkyl), (halogen)1-3and hydroxy,

SS)1-4alkoxy, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising (halogen)1-3and hydroxy,

cd)2-4alkenyl,

ce) amino substituted by two substituents, independently selected from the group comprising hydrogen and C1-4alkyl,

cf) halogen and

cg) hydroxy,

optional R2and R3together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group comprising From9-C14benzoannelirovannykh cycloalkyl,9-C14benzoannelirovannykh cycloalkenyl,9-14benzoannelirovannykh aryl, benzoannelirovannykh heterocyclyl and benzoannelirovannykh heteroaryl, and where the polycyclic system may be optionally substituted by from one to four substituents, independently selected from the group including

da)1-4alkyl, optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), (halogen)1-3and hydroxy,

db)1-4alkoxy, optionally substituted at the end of the second carbon atom Deputy selected from the group including halogen)1-3and hydroxy,

dc) amino substituted by two substituents, independently selected from the group comprising hydrogen and C1-4alkyl,

dd) halogen,

de) hydroxy and

df) nitro,

R4selected from the group comprising From1-4alkyl (optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising aryl and heteroaryl), aryl and heteroaryl, where aryl and heteroaryl and aryl and heteroaryl portion of the substituted alkyl optionally substituted from one to four substituents, independently selected from the group comprising From1-4alkyl, amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), cyano, halogen, hydroxy and (halogen)1-3(C1-8)alkyl,

R5selected from the group comprising hydrogen and C1-8alkyl (optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), (halogen)1-3and hydroxy) and aryl (optionally substituted by one to four substituents, independently selected from the group comprising From1-8alkyl and halogen),

and

R6selected from the group comprising From1-8alkyl, aryl(C 1-8)alkyl, C1-8alkoxy, aryl(C1-8)alkoxy, C2-8alkenyl,2-8alkenylacyl, aryl(C2-8)alkenyl, aryl(C2-8)alkenylamine, aryl, aryloxy and hydroxy.

Brief description of drawings

Figure 1 shows the percentage change in specific pulmonary resistance (SRL) relative to the baseline for the connection of 2 compared to the control, on the model of asthma in sheep, spontaneously induced antigenascaris suumwithin 8 hours.

Figure 2 shows the change in the cumulative dose of carbachol necessary to improve SRL400% (RS 400) relative to the baseline (BSL), measured 24 hours after dosing connection 2 for a model of asthma in sheep, spontaneously induced antigenascaris suumcompared to 24 hours after dosing stimulation carbachol (post-antigen).

Detailed description of the invention

The embodiments of the present invention include such compounds, where R1selected from the group comprising a heterocyclic ring (where the place of attachment of the heterocyclic ring R1is the nitrogen atom of the cycle) and-N(R7R8), where the heterocyclic ring optionally substituted by a Deputy selected from the group comprising a) aryl(C1-4)alkyl, (C) aryl, d) heteroaryl and i) heterocyclyl (optionally substituted from one to two mixing what italiani, independently selected from the group comprising oxo and aryl, and optionally condensed with the connecting carbon atom with the formation of spiroheterocyclic fragment), and where the aryl portion (a) and (i) Deputy and C) aryl Deputy optionally substituted from one to two substituents, independently selected from the group comprising From1-4alkyl, C1-4alkoxy, aryl, heteroaryl, halogen, hydroxy, (halogen)1-3(C1-4)alkyl and (halogen)1-3(C1-4)alkoxy, and all other variables are defined above.

Preferably R1selected from the group comprising a heterocyclic ring (where the place of attachment of the heterocyclic ring R1is the nitrogen atom of the cycle) and-N(R7R8), where the heterocyclic ring optionally substituted by a Deputy selected from the group comprising a) aryl(C1-4)alkyl, (C) aryl, d) heteroaryl and i) heterocyclyl (optionally substituted by one to two substituents, independently selected from the group comprising oxo and aryl, and optionally condensed with the connecting carbon atom with the formation of spiroheterocyclic fragment), and where the aryl portion (a) and (i) Deputy and C) aryl Deputy optionally substituted from one to two substituents, independently selected from the group comprising From1-4alcox and aryl, and all other variables are defined above.

More preferably R1selected from the group comprising pyrrolidinyl, piperidinyl and-N(R7R8), where the place of connection of pyrrolidinyl and piperidinyl is the nitrogen atom of the cycle and where pyrrolidinyl and piperidinyl optionally substituted Deputy selected from the group comprising a) phenylethyl, (C) phenyl (optionally substituted by methoxy), (d) benzothiazolyl and i) imidazolidinyl (optionally substituted by two substituents, independently selected from the group comprising oxo and phenyl, and optionally condensed with the connecting carbon atom with the formation of spiroheterocyclic fragment), and all other variables are defined above.

Most preferably R1selected from the group comprising pyrrolidinyl, piperidinyl and-N(R7R8), where the place of connection of pyrrolidinyl and piperidinyl is the nitrogen atom of the cycle in one position and where pyrrolidinyl and piperidinyl optionally substituted Deputy selected from the group comprising a) phenylethyl, (C) phenyl (optionally substituted by methoxy), (d) benzothiazolyl and i) imidazolidinyl (optionally substituted by two substituents, independently selected from the group comprising oxo and phenyl, and optionally condensed with the linking carbon atom OBR is reattaching the spiroheterocyclic fragment), and all other variables are defined above.

Preferred embodiments of the present invention include compounds in which R7selected from the group comprising hydrogen, C1-4alkyl and C2-4alkenyl.

More preferably R7selected from the group comprising hydrogen and C1-4alkyl.

Most preferably R7selected from the group comprising hydrogen and methyl.

Preferred modes of implementation of the present invention include compounds in which R8selected from the group including:

AA)1-8alkyl, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising cycloalkyl, heterocyclyl, (halogen)1-3and hydroxy,

ab) cycloalkyl,

AU) cycloalkenyl and

ad) heterocyclyl (where the place of attachment of R8is the carbon atom of the cycle),

where ab) cycloalkenyl, AU) cycloalkenyl and ad) heterocyclyl deputies (where ad) heterocyclyl contains at least one cyclic nitrogen atom) and cycloalkyl part AA) Deputy optionally substituted from one to four substituents, independently selected from the group including:

ba)1-8alkyl, optionally substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (with two C what Mascitelli, independently selected from the group comprising hydrogen and C1-8alkyl), (halogen)1-3and hydroxy,

bb)1-8alkoxy,

bc) carbonyl, substituted Deputy selected from the group comprising From1-8alkyl, aryl, aryl(C1-8)alkyl, aryl(C2-8)alkenyl, heteroaryl, heteroaryl(C1-8)alkyl and heteroaryl(C2-8)alkenyl,

bd) aryl,

be) heteroaryl,

bf) amino substituted by two substituents, independently selected from the group comprising hydrogen and C1-8alkyl,

bh) halogen,

bi) hydroxy,

bk) heterocyclyl and

bl) sulfonyl, substituted Deputy selected from the group comprising From1-8alkyl, aryl, aryl(C1-8)alkyl, aryl(C2-8)alkenyl, heteroaryl, heteroaryl(C1-8)alkyl and heteroaryl(C2-8)alkenyl,

where bd) aryl, be) heteroaryl and bk) heterocyclyl substituents and the aryl and heteroaryl portion bc) Deputy optionally substituted from one to four substituents, independently selected from the group comprising From1-4alkyl (optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising (halogen)1-3)1-4alkoxy, amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), halogen and hydroxy,

and provided that the optional replacement of the Titel, attached to the nitrogen atom of the ring heterocyclyl ad), not selected from a group including bf) amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl), bh) halogen, bi) hydroxy and bj) nitro.

Preferably R8selected from the group including AA) cycloalkyl(C1-4)alkyl, ab) cycloalkyl, AU) cycloalkenyl and ad) heterocyclyl (where the place of connection ad) heterocyclyl R8is the carbon atom of the cycle and ad) heterocyclyl contains a single cyclic nitrogen atom), where ab) cycloalkenyl, AU) cycloalkenyl and ad) heterocyclyl deputies and cycloalkyl part AA) Deputy optionally substituted from one to two substituents, independently selected from the group comprising ba)1-4alkyl, bc) carbonyl (replaced by Deputy selected from the group comprising From1-4alkyl, aryl, aryl(C1-4)alkyl and aryl(C2-4)alkenyl) and bd) aryl (where bd) the aryl substituent and the aryl part bc) Deputy optionally substituted from one to two substituents, independently selected from the group comprising From1-4alkyl, C1-4alkoxy, di(C1-4alkyl)amino, halogen, hydroxy and (halogen)1-3(C1-4)alkyl.

More preferably R8selected from the group including AA) adamant-1-ylmethyl, ab) cyclopentyl, ab) cyclohexyl, AU) cyclohexen is l, ad) pyrrolidinyl and ad) piperidinyl (where the place of connection of pyrrolidinyl and piperidinyl R8is the carbon atom of the cycle), where ab) cyclohexyl, AU) cyclohexenyl, ad) pyrrolidinyl and ad) piperidinyl optionally substituted from one to two substituents, independently selected from the group comprising ba)1-4alkyl, bc) carbonyl (replaced by Deputy selected from the group comprising From1-4alkyl, aryl, aryl(C1-4)alkyl and aryl(C2-4)alkenyl) and bd) aryl, where bd) the aryl substituent and the aryl part bc) Deputy optionally substituted from one to two substituents, independently selected from the group comprising From1-4alkyl, C1-4alkoxy, di(C1-4alkyl)amino, halogen, hydroxy and (halogen)1-3(C1-4)alkyl.

Most preferably R8selected from the group including AA) adamant-1-ylmethyl, ab) cyclopentyl, ab) cyclohexyl, AU) cyclohexenyl, ad) pyrrolidinyl and ad) piperidinyl (where the place of connection of pyrrolidinyl and piperidinyl R8is the carbon atom of the cycle), where ab) cyclohexyl, AU) cyclohexenyl, ad) pyrrolidinyl and ad) piperidinyl optionally substituted from one to two substituents, independently selected from the group comprising ba) methyl, ba), tert-butyl, bc) methylcarbamyl, bc) isopropylcarbonate, bc) phenylcarbinol, bc) naphthaleneboronic, bc) ventilkappen, bc) finite ylcarbonyl and bd) phenyl, and where bd) phenyl substituent and the phenyl and naphthalenamine part bc) Deputy optionally substituted from one to two substituents, independently selected from the group comprising methyl, methoxy, N,N-dimethylamino, fluorine, bromine, hydroxy and trifluoromethyl.

The embodiments of the present invention include compounds in which R2and R3linked to the benzene ring shown in formula (I) adjacent carbon atoms. Preferred embodiments of the present invention include such compounds, where R2and R3independently selected from the group comprising CA) hydrogen, cb)1-4alkyl, SS)1-4alkoxy, cd)2-4alkenyl, CE) amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), cf) halogen and cg) hydroxy,

optional R2and R3together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group comprising naphthalene and anthracene, and where the polycyclic system may be optionally substituted by from one to four substituents, independently selected from the group including da)1-4alkyl, db)1-4alkoxy, dc) amino (substituted with two substituents, independently selected, is suspended from the group comprising hydrogen and1-4alkyl), dd) halogen and de) hydroxy.

More preferably R2and R3linked with the benzene ring adjacent carbon atoms and are independently selected from the group comprising CA) hydrogen, cb)1-4alkyl, cd)2-4alkenyl, cf) halogen and cg) hydroxy,

optional R2and R3together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system is a naphthalene and polycyclic where the system may be optionally substituted by from one to four substituents, independently selected from the group including da)1-4alkyl, db)1-4alkoxy, dc) amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), dd) halogen and de) hydroxy.

Most preferably polycyclic this system represents an unsubstituted naphthalene.

The embodiments of the present invention include such compounds, where R4selected from the group comprising aryl and heteroaryl, optionally substituted from one to two substituents, independently selected from the group comprising From1-4alkyl, amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4/sub> alkyl), cyano, halogen, hydroxy and (halogen)1-3(C1-8)alkyl.

Preferably R4selected from the group comprising aryl and heteroaryl (where heteroaryl optionally substituted from one to two substituents, independently selected from the group comprising From1-4alkyl, amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), cyano, halogen, hydroxy and (halogen)1-3(C1-8)alkyl.

More preferably R4selected from the group comprising phenyl, naphthalenyl and benzothiazyl (where benzothiazyl optionally substituted from one to two halogen substituents).

Most preferably R4selected from the group comprising phenyl, naphthalenyl and benzothiazyl (where benzothiazyl optionally substituted chloride Deputy).

The embodiments of the present invention include such compounds, where R5selected from the group comprising hydrogen and C1-4alkyl, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising amino, (substituted with two substituents, independently selected from the group comprising hydrogen and C1-4alkyl), (halogen)1-3and hydroxy.

Preferably R5selected from the group comprising hydrogen and C1-4alkyl.

More preferably R5selected the C group, comprising hydrogen and methyl.

Most preferably R5represents hydrogen.

Preferred embodiments of the present invention include such compounds, where R6selected from the group comprising From1-4alkyl, aryl(C1-4)alkyl, C1-4alkoxy, aryl(C1-4)alkoxy, C2-4alkenyl,2-4alkenylacyl, aryl(C2-4)alkenyl, aryl(C2-4)alkenylamine, aryl, aryloxy and hydroxy.

More preferably R6selected from the group comprising methyl, methoxy, phenyloxy and hydroxy.

Most preferably R6selected from the group comprising methyl and hydroxy.

Preferred embodiments of the present invention include compounds where Y is absent and X is a single Deputy, which is attached through a double bond and selected from the group comprising O, S, imino, (C1-4)alkylamino, hydroxyamino.

More preferably Y is absent and X is a single Deputy, which is attached through a double bond and selected from the group comprising O, imino, hydroxyimino.

Most preferably Y is absent, and X represents O, which is attached through a double bond.

Preferred embodiments of the present invention include such compounds is of, where Z is selected from the group comprising hydrogen and C1-4alkyl.

More preferably Z represents hydrogen.

The embodiments of the present invention include compounds where formula (Ia)listed in table 1.

Table 1< / br>
< / br>
where

R7and R8dependently selected from the group including:
Connection.R7R8
1CH34-phenylcyclohexyl
2CH31-(2-naphthalenesulfonyl)-4-piperidinyl
3CH31-[(6-methoxy-2-naphthalenyl)carbonyl]-3-pyrrolidinyl
4CH31-[(6-bromo-2-naphthalenyl)carbonyl]-4-piperidinyl
5CH31-[3-(4-forfinal)-1-oxo-2-propenyl]-3-pyrrolidinyl
6CH31-[1-oxo-3-phenyl-2-propenyl]-4-piperidinyl
9CH31-[3-(4-were)-1-oxo-2-propenyl]-4-piperidinyl
10CH31-[1-oxo-3-[4-(trifter ethyl)phenyl]-2-propenyl]-4-piperidinyl
13CH31-[3-[4-(dimethylamino)phenyl]-1-oxo-2-propenyl]-4-piperidinyl
15CH31-benzoyl-4-piperidinyl
17CH3Cyclohexyl
18CH31-[1-oxo-3-[4-(trifluoromethyl)phenyl]propyl]-4-piperidinyl
20CH31-(2-methyl-1-oxopropyl)-4-piperidinyl
21CH3Cyclopentyl
22CH34-(1,1-dimethylethyl)cyclohexyl
24CH31-[(6-hydroxy-2-naphthalenyl)carbonyl]-4-piperidinyl
26CH31-acetyl-4-piperidinyl
27CH34-methylcyclohexyl
28CH3adamant-1-ylmethyl
29CH34-phenyl-3-cyclohexen-1-yl
And
30N1-(2-naphthalenesulfonyl)-4-piperidinyl

and their racemates, the enantiomers, the diastereomers and Sol is.

The embodiments of the present invention include compounds where formula (Ib), are shown in table 2.

Table 2< / br>
< / br>
where

R1selected from the group including:
Connection.R1
74-phenyl-1-piperidinyl
84-oxo-1-phenyl-1,3,8-diazaspiro[4.5]Dec-8-yl
124-(4-methoxyphenyl)-1-piperidinyl
144-(3-methoxyphenyl)-1-piperidinyl
164-(2-benzothiazolyl)-1-piperidinyl
193-phenyl-1-pyrrolidinyl
and
253-(2-phenylethyl)-1-pyrrolidinyl

and their racemates, enantiomers, diastereomers and salts.

The embodiments of the present invention include compounds where formula (Ic), are shown in table 3.

Table 3< / br>
< / br>
where

R2, R3, R4, R5and R6dependently selected from the group including:
Connection.R2/sub> R3R4R5R6
11together form a phenylPhenylNHE
23together form a phenyl1-naphthalenylCH3HE
31NN1-naphthalenylNHE
32together form a phenyl1-naphthalenylNCH3
And
33together form a phenyl5-chlorobenzo[b]Tien-3-ylNHE

and their racemates, enantiomers, diastereomers and salts.

Compounds of the present invention can also be in the form of pharmaceutically acceptable salts. For medical use, salts of the compounds of this invention are non-toxic "pharmaceutically acceptable salts". FDA approved forms of pharmaceutically acceptable salts (Ref. International J. Pharm.1986, 33, 201-217;J. Pharm. Sci.,1977, Jan, 66(1), p1), including pharmaceutically acceptable acidic/anionic or basic/cationic salts.

Pharmaceutically acceptable acidic/anionic salts include, but are not limited to, acetate, bansilalpet, benzoate, bicarbonate, bitartrate, chloride, edetate calcium, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, Eilat, fumarate, gluceptate, gluconate, glutamate, picolylamine, hexylresorcinol, geranamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isetionate, lactate, lactobionate, malate, maleate, mandelate, mesilate, bromide, methylnitrate, methyl sulfate, mukat, napsylate, nitrate, pamoate, Pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, peracetate, succinate, sulfate, tannat, tartrate, teoclate, tosylate and triethiodide. Organic or inorganic acids include, but are not limited to, yodiewonderdog, perchloric, sulfuric, phosphoric, propionic, glycolic, methansulfonate, hydroxyethanesulfonic, oxalic acid, 2-naphthalenesulfonate, p-toluolsulphonyl, cyclohexanesulfamic, some saccharine or triperoxonane acid.

Pharmaceutically acceptable basic/cationic salts include, but are not limited to, aluminum salts, 2-amino-2-hydroxymethylpropane-1,3-diol (also known as Tris(hydroxymethyl)aminomethan, trometer, or "TRIS"), ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calcium hydroxide, chlorine is Rogaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, Ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH3, NH4OH, N-ethyl-D-glucamine, piperidine, potassium of potassium tert-butylate, potassium hydroxide (aqueous), procaine, quinine, SEH, sodium, sodium carbonate, 2-ethylhexanoate sodium, sodium hydroxide, triethanolamine (tea), or zinc.

Compounds of the present invention may form a salt with a pharmaceutically acceptable cation selected from the group comprising aluminum, 2-amino-2-hydroxymethylpropane-1,3-diol (also known as Tris(hydroxymethyl)aminomethan, trometer, or "TRIS"), ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, Ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH3, NH4OH, N-methyl-D-glucamine, piperidine, potassium, tert-butyl potassium, potassium hydroxide (aqueous), procaine, quinine, SEH, sodium, sodium carbonate, 2-ethylhexanoate, sodium, sodium hydroxide, triethanolamine (tea), or zinc.

The preferred cations for the present compounds selected from the group comprising benzathine, t-butylamine, calcium gluconate, calcium hydroxide, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, Ethylenediamine, LiOMe, L-lysine, NH3, NH4OH, N-methyl-D-glitch the min, piperidine, tert-butyl potassium, potassium hydroxide (aqueous), procaine, quinine, sodium carbonate, 2-telekanal sodium, sodium hydroxide, triethanolamine and trometer.

More preferably the cations for the present compounds selected from the group comprising tert-butylamine, NH4OH and trometer.

The most preferred cation for these compounds is trometer.

The present invention encompasses prodrugs based on the compounds of the invention. In General, such prodrugs will be functional derivatives of these compounds, which are easily converted toin vivoin active connection. Thus, in the treatment methods of the present invention, the term "introduction" will include the treatment of various violations described specifically described compound or prodrug, which, obviously, is included in the scope of the invention, although not specifically described, including, but not limited to, diphenylphosphonate or diphenylphosphinite esters of some of these compounds. Standard methods of selecting and obtaining the appropriate proletarienne derivatives described, for example, in the "Design of Prodrugs", ed. H.Bundgaar, Elsevier, 1985. It is understood that the prodrugs based on phosphonic acid (described De Lombaert, S., et al, Non-Peptidic Inhibitors of Neutral Endopeptidase 24, 11; Design and Pharmacology of Orally Active Phosphonate Prodrugs,Bioorganic and Medicinal Chemistry etters, 1995, 5(2), 151-154; De Lombaert, S., et al, N-Phosphonomethyl Dipeptides and Their Phosphonate Prodrugs, a New Generation of Neutral Endopeptidase (NEP, EC 3.424,11) inhibitors,J.Med. Chem.,1994, 37, 498-511) and prodrugs based on the phosphinic acids are included in the scope of the present invention.

Compounds in accordance with this invention may have at least one chiral center and therefore can exist as enantiomers. In addition, the compounds of the present invention can also contain two or more chiral centers and therefore may exist as diastereomers. When the methods of obtaining these compounds lead to mixtures of stereoisomers, these isomers can be divided by conventional methods such as preparative chromatography. Accordingly, the compounds can be obtained in the form of a racemic mixture or by enantiospecific synthesis or separation of individual enantiomers. Compounds, for example, can be isolated from the racemic mixture in the form of components of the racemate by standard methods, such as the formation of diastereomeric pairs in the formation of salts with optically active base, followed by fractional crystallization and regeneration of the compounds of the present invention. The racemic mixture can also be divided by obtaining the diastereomeric esters or amides with subsequent chromatography is graficheskim separation and removal of the chiral auxiliary substances. Alternative compounds can be separated using chiral HPLC column. Note that all such isomers and mixtures thereof are within the scope of the present invention.

Compounds according to the invention, where Z forms a double bond with carbon, which is attached to X, Y is absent and X is a hydroxy, can be represented in the form of at least one keto-enol tautomeric forms and, therefore, can exist as an equilibrium mixture of geometric isomers.

It should be noted that all such isomers and mixtures thereof are included in the scope of the present invention.

When any of the methods of obtaining the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the participating molecules. This can be done using conventional protective groups such as protective groups described inProtective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Green & P.G.M. Wuts,Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protective group can be removed at an appropriate later stage by means known in the art methods.

In addition, some of the crystalline forms of the compounds may exist as polymorphs, and assumes that they are included in the present invention. In addition to this, some soy is inania may form a solvate with water (hydrates) or common organic solvents, and it is implied that such a solvate is also included to the scope of this invention.

As used here, unless otherwise specified, "alkyl", whether he used separately, or as part of a replacement group refers to a linear or branched carbon chains containing from 1 to 8 carbon atoms or any number within this interval. The term "alkoxy" refers to-O-alkyl replacement group, in which alkyl is defined above. Similarly, the terms "alkenyl" and "quinil" refers to linear or branched carbon chains containing from 2 to 8 carbon atoms or any number within this interval, where Alchemilla chain contains at least one double bond in the chain, and Alchemilla chain contains at least one triple bond in the chain. Alkyl and CNS chain may be substituted at the terminal carbon atom or, if it acts as a linking group within the carbon chain.

The term "cycloalkyl" refers to a saturated, monocyclic or polycyclic hydrocarbon cycles containing from 3 to 20 carbon atoms (preferably from 3 to 12 carbon atoms). In addition, cycloalkyl ring may be optionally condensed with one or more cycloalkyl rings. Examples of such cycles include, but are not limited to cyclopropyl, cyclobutyl is m, cyclopentyl, cyclohexyl, cycloheptyl or adamantium.

The term "cycloalkenyl" refers to partially unsaturated non-aromatic monocyclic or polycyclic hydrocarbon cycles containing from 3 to 20 carbon atoms (preferably from 3 to 12 carbon atoms). Usually 3-5-membered cycle contains one double bond, and 6-9-membered cycle contains several double bonds. In addition, cycloalkenyl ring may be optionally condensed with one or more cycloalkyl rings or cycloalkenyl rings. Examples of such cycles include, but are not limited to cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.

The term "heterocyclyl" refers to a nonaromatic 5-8 membered cycle in which from 1 to 4 members represent a nitrogen atom, or a nonaromatic 5-8-membered cycle in which zero, one or two members are nitrogen atom, and one of the members is oxygen or sulfur, where, optionally, the cycle contains zero, one or two unsaturated linkages. Alternative heterocyclic ring may be condensed with benzene ring (benzoannelirovannykh heterocyclyl), 5-6-membered heteroaryl cycle (containing one of O, S or N and, optionally, one additional nitrogen atom), a 5-7 membered cycloalkyl or cycloalkyl the ilen ring, 5-7-membered heterocyclyl ring (defined as before, but with no extra condensed cycle) or condensed with a carbon atom, a binder for cycloalkenes, cycloalkenyl or heterocyclyl ring with the formation of Spiro-fragment. For these compounds, cyclic carbon atoms constituting heterocyclyl ring is fully saturated. Other compounds of the invention may contain a partially unsaturated heterocyclyl ring. In addition, heterocyclyl can be a bridge with the formation of the bicyclic rings. The preferred fully saturated heterocyclyl rings may contain from one to two double bonds. Such compounds are not considered fully aromatic, and are not called heteroaryl compounds. Examples heterocyclyl groups include, but are not limited to pyrrolidino (including 2H-pyrrole, 2-pyrrolyl or 3-pyrrolyl), pyrrolidinium, 2-imidazolinium, imidazolidinyl, 2-pyrazolinone, pyrazolidine, piperidinium, morpholinium, thiomorpholine and piperazinil. In the present invention, where R1selected from heterocyclyl, the term "heterocyclyl" refers to a nonaromatic 5-8 membered cycle in which from 1 to 4 members represent a nitrogen atom, in which place to recognize the value heterocyclyl rings R 1isthe nitrogen atom of the cycle and in the cycle which optionally contains zero, one (5 - and 6-membered cycles) or two (for 6-, 7 - and 8-membered cycles) bonds.

The term "aryl" refers to an unsaturated aromatic monocyclic ring containing 6 carbon atoms, or polycyclic aromatic ring containing from 10 to 20 carbon atoms. In addition, aryl cycle can be optionally condensed with one or more benzene rings (benzoannelirovannykh aryl), cycloalkyl rings (for example, benzoannelirovannykh cycloalkyl) or cycloalkenyl rings (for example, benzoannelirovannykh cycloalkenyl), where for the purpose of these definitions, cycloalkyl rings or cycloalkenyl rings can be condensed with additional benzene ring (with the formation of polycyclic systems, such as fluoran). Examples of such aryl cycles include, but are not limited to phenyl, naftalina, fluorenyl, indenolol or AstraZeneca.

The term "heteroaryl" refers to 5 - or 8-membered aromatic cycle, where a cycle consists of carbon atoms and contains at least one heteroatom. Suitable heteroatoms include nitrogen, oxygen, or sulfur. In the case of 5-membered cycles heteroaryl cycle contains one atom of nitrogen, oxygen or sulfur and, in addition, m which may contain up to two additional nitrogen atoms. In the case of a 6-membered cycles heteroaryl cycle can contain from one to three nitrogen atoms. When 6-membered cycle contains three nitrogen atom, for the most part, two atoms of nitrogen are adjacent. Optional, heteroaryl cycle condensed with benzene ring (benzoannelirovannykh heteroaryl), 5 - or 6-membered heteroaryl cycle (containing O, S or N and, optionally, one additional nitrogen atom), 5-7-membered alicyclic ring or a 5-7 membered heterocycle (such as defined above, but in the absence of additional condensed cycle). Examples of heteroaryl groups include, but are not limited to fullam, teinila, pirrallo, oxazolium, thiazolium, imidazolium, pyrazolyl, isoxazolyl, isothiazolines, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinium; fused heteroaryl groups include indolyl, isoindolyl, indolinyl, benzofuran, benzothiazyl, indazoles, benzimidazoles, benzothiazoles, benzoxazoles, benzisoxazole, benzothiadiazoles, benzotriazolyl, hemolysins, chinoline, ethenolysis or hintline.

The term "arylalkyl" means alkyl group, substituted aryl group (e.g. benzyl, phenethyl). Similarly, the term "Allakaket" means alkoxy group, Thames is nnow aryl group (for example, benzyloxy).

As used here, the term "carboxyl" refers to a linking group-C(O)O - or (when appropriate) to the Deputy-COOH; the term "imino" refers to the Deputy HN=.

Whenever the term "alkyl" or "aryl" or the prefix roots are found in the name of a substituent (for example, arylalkyl, alkylamino), it should be understood that it includes all the limitations given above for "alkyl" or "aryl". The indicated number of carbon atoms (for example, C1-C6) will independently relate to the number of carbon atoms in the alkyl fragment or the alkyl portion of a larger substituent in which alkyl appears as its prefix root. However, for clarity in terms of "9-C14benzoannelirovannykh cycloalkyl", "C9-C14benzoannelirovannykh cycloalkenyl", "C9-14benzoannelirovannykh aryl" C9-C14refers to the number of carbon atoms in a benzene ring (6)and the number of carbon atoms in the cycle, condensed with the benzene ring, but does not include carbon atoms, which may represent the side groups for data polycyclic systems. The number of substituents associated with the fragment, "optionally containing from one to five substituents"is limited to the number of free valences in the data the m fragment, available for substitution.

Usually, according to the rules of standard nomenclature used in this description, first describe the end portion of the designated side chain, then the functional group adjacent to the place of connection. For example, the Deputy "panels1-C6alkylamides1-C6alkyl" refers to a group of the formula:

It is implied that the definition of any substituent or variable in a specific position of the molecule is independent of its definition elsewhere in another place of this molecule. It is clear that the specialist in the art can choose the substituents and the nature of the substitution in the compounds of this invention in such a way that they are chemically stable and can be readily synthesized by methods known in the art, and by using these methods.

As an example in the description of a composition comprising a pharmaceutically acceptable carrier and any of the above compounds. In addition, as an example in the description of a composition obtained by mixing any of the above compounds with a pharmaceutically acceptable carrier. An additional illustration of the invention is a method of obtaining a composition comprising mixing any of the above vissoedineniya with a pharmaceutically acceptable carrier. The present invention relates also to compositions containing one or more compounds according to this invention together with a pharmaceutically acceptable carrier.

Compounds of the present invention are useful inhibitors of serine proteases (in particular, inhibitors of cathepsin G and chymase), suitable for the treatment of inflammatory and mediated by the serine proteinase violations. Some of these disorders include inflammatory and mediated by the serine proteinase violations, including, but not limited to, pulmonary inflammatory conditions, chronic obstructive pulmonary disease, asthma, emphysema, bronchitis, psoriasis, allergic rhinitis, viral rhinitis, ischemia, arthritis, glomerulonephritis, post-operative scarring and trauma during re-perfusion. These compounds could be useful for the treatment of diseases caused by angiotensin II, including, but not limited to, hypertension, myocardial infarction with cardiomegaly, arteriosclerosis, diabetic and medicationsbuy retinopathy, vascular restenosis, and so forth. In addition, these compounds can be used for immune modulation. The suitability of a compound for the treatment of inflammatory and mediated by the serine proteinase violations can be defined with the accordance with the methodology described here.

One of the ways of implementation of the present invention is a method of treating inflammatory and mediated by the serine proteinase disorders in need thereof of a subject, which includes the introduction of this subject a therapeutically effective amount of any of the above compounds or compositions. In addition, the invention encompasses the use of compounds of formula (I) for drugs for treatment of inflammatory and mediated by the serine proteinase disorders in need of this subject. Used herein, the term "treatment" refers to the way of improvement, stop, slow or relief of the inflammatory and mediated by the serine proteinase disorders in need of this subject. It is implied that all such methods of treatment are within the scope of the present invention.

In accordance with the methods of the present invention, the individual components described herein, can also be entered separately at different times during the course of therapy or concurrently in divided or single combination. Therefore, it is necessary to note that the present invention includes all such regimes of simultaneous or alternating treatment and the term "introduction" should be interpreted accordingly.

Used herein, the term "subject"refers to an animal (preferably a mammal most preferably human), which was the object of treatment, observation or experiment.

Used here, the term "therapeutically effective amount" refers to an amount of active compound or pharmaceutical agent that causes medical response in a tissue system, animal or person, search for the researcher, veterinarian, medical doctor or other Clinician, which includes alleviation of the symptoms of a subject to treatment of diseases or disorders.

It is implied that used here, the term "composition" includes a product containing certain ingredients in certain amounts, as well as any product obtained directly or indirectly from the combination of certain ingredients in certain amounts.

To obtain the compositions of this invention one or more compounds of the formula (I) or their salts are thoroughly mixed with a pharmaceutical carrier in accordance with standard pharmaceutical techniques of mixing, and the media can take many forms depending on the type of medication required for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers well known in this field. Descriptions of some of these pharmaceutically acceptable carriers which you can find in The Handbook of Pharmaceutical Excipientspublished by the American pharmaceutical Association and the pharmaceutical society of great Britain.

Methods of making compositions have been described in numerous publications, such asPharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al;Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and inPharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

To obtain the compositions of the present invention in the form of liquid dosage forms for oral, local, inhalation/insufflation and parenteral administration can be used with any conventional pharmaceutical environment or excipients. So, for liquid dosage forms, such as suspensions (i.e. colloids, emulsions and dispersions and solutions, suitable carriers and additives include, but are not limited to, pharmaceutically acceptable moisturizing agents, dispersing agents, flocculosa agents, thickeners, pH regulators (i.e. buffers), osmotic agents, coloring agents, flavoring agents, fragrances, preservatives (that is, to control microbial growth, and so forth) and you can use the carrier liquid. For each liquid dosage forms need not be all of the above components.

For solid oral preparations, for example, the x as powders, granules, capsules, pills, capsules, gelatin capsules, pills and tablets (each of which includes formulations with immediate release, timed release and prolonged release), suitable carriers and additives include, but are not limited to, diluents, granulating agents, lubricants, binders, agents, giving the property is slipping, loosening agents and so forth. Due to the simplicity of the introduction of tablets and capsules are the most preferred form of the standard oral dose, in which case, will certainly use a solid pharmaceutical carriers. If desired, the tablets may be coated with sugar, gelatin, film or intersolubility floor using standard methods.

Preferably these compositions are presented in the form of standard dosage forms, such as tablets, pills, capsules, powders, granules, pellets, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, devices for autoinjection or suppositories for administration orally, by vnutrimyshernm, sublingual, intraocular, transdermal, parenteral, rectally, vaginal, inhalation or insufflation way. Alternative compositions can be is represented in the form suitable for introduction once a week or once a month; for example, to obtain a depot preparation for intramuscular injection can be used insoluble salt of the active compound, such as decanoate salt.

For solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, for example a standard tabletiruemye ingredients such as diluents, binders, bonding agents, disintegrating agents, lubricants, substances that prevent bonding, and agents, giving the property slip. Suitable diluents include, but are not limited to, starch (i.e. corn, wheat or potato starch, which can be hydrolysed), lactose (granulated spray-dried or anhydrous), sucrose diluent based on sucrose (sugar confectionery, sucrose with the addition of from about 7 to about 10 weight percent, sucrose, about 3 weight percent of modified dextrin, sucrose with the addition of invert sugar, about 4 weight percent invert sugar, from about 0.1 to about 0.2 weight percent corn starch and magnesium stearate), dextrose, Inositol, mannitol, sorbitol, microcrystalline cellulose (i.e. microcrystalline cellulose AVICEL™manufactured by FMC Corp.), dicalcium phosphate, di is igrat calcium sulfate, the trihydrate of the calcium lactate and so on. Suitable binding agents and adhesives include, but are not limited to, Arabian gum, guar gum, tragacanth gum, sucrose, gelatin, starch and cellulose derivatives (methylcellulose, carboxymethylcellulose sodium, ethylcellulose, hypromellose, hydroxypropylcellulose and so on), water soluble or dispersible binders (i.e. alginic acid and its salts, magnesium aluminosilicate, hydroxyethyl cellulose [i.e TYLOSE™manufactured by Hoechst Celanese], polyethylene glycol, polysaccharide acids, bentonites, polyvinylpyrrolidon, polymethacrylate and pre gelatinizing starch and so on). Suitable disintegrating agents include, but are not limited to, starch (corn, potato and so on), starch sodium glycolate, pre gelatinisation starches, clay (aluminum silicate of magnesium), cellulose (such as cross-linked carboxymethylcellulose sodium and microcrystalline cellulose), alginates, pre gelatinisation starches (e.g. corn starch), vegetable gum (i.e. Arabian, guar, gum carob, karaya, pectin and tragacanth gum), cross-linked polyvinylpyrrolidone, and so forth. Suitable lubricants including the Ute, but not limited to, stearates (magnesium, calcium and sodium), stearic acid, talc, waxes, stearic fat (stearowet), boric acid, sodium chloride, DL-leucine, carbowax 4000, carbowax 6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, lauryl sulfate, magnesium and so on. Suitable agents to impart slip properties include, but are not limited to, talc, corn starch, silicon oxide (silica CAB-OSIL™produced by Cabot, silica SYLOID™manufactured by W.R. Grace/Davison, and silica Aerosil™manufactured by Degussa), and so on. In chewing solid dosage forms can be added sweeteners and substance, giving a taste, to improve appatichnosti oral dosage forms. In addition, in the solid dosage forms can be added or applied dyes and coatings for easy identification of the medicinal product or for aesthetic purposes. These carriers are mixed with the pharmaceutically active substance to obtain accurate appropriate dose of pharmaceutically active substances with therapeutic profile release.

Typically, these carriers are mixed with the pharmaceutically active substance to obtain a solid composition for pre-preparation containing a homogeneous mixture of pharmaceutically active substances of the present invention, or agopermalink acceptable salt. Usually pre-preparation receive one of three General ways: (a) wet granulation, (b) dry granulation, and (C) dry blending. Calling song data before drugs homogeneous, mean that the active ingredient is uniformly dispersed throughout the volume of the composition so that the composition can easily be divided into dosage forms equal efficiency, such as tablets, pills and capsules. Then this solid composition pre-preparation is divided into single unified dose type described above containing from about 0.01 mg to about 500 mg of the active ingredient of the present invention. Tablets or pills containing compositions can also be manufactured in a multilayer tablets or pills in order to obtain products with long or double release. For example, the tablet or pill with a dual release may contain internal dose component and the component of the external dose, the latter forms an envelope around the first. These two components can be separated intersolubility layer, which prevents destruction in the stomach and allowing the inner component to pass in intact into the duodenum or to obtain a delay in the release. For such intersolubility layers or coatings can be used many substances, the ri such substances include a number of polymeric substances, such as shellac, acetate cellulose, acetate cellulose phthalate, polyvinyl acetate phthalate, phthalate of polyhydroxyethylmethacrylate, acetate succinate of hydroxypropylmethylcellulose, copolymers of methacrylate and acrylate, and so forth. Tablets with prolonged-release can also be manufactured by using the coating film or a wet granulation using a slightly soluble or insoluble substances in the solution (which in the case of wet granulation act as binding agents) or low-melting solids in the form of a melt (wet granulation may contain the active ingredient). Such substances include natural or synthetic polymer waxes, hydrogenated oils, fatty acids and alcohols (for example, beeswax, Carnauba wax, cetyl alcohol, cetylstearyl alcohol, etc.), esters of fatty acids, metallic Soaps and other appropriate substances that can be used for granulation, coating, seizing or limitation of any other way of solubility of the active ingredient to obtain a product with a prolonged or sustained release.

Liquid form, which may include new compounds of the present invention, for administration orally or by injection include, but are not limited to DNAME solutions suitably flavored syrups, suspensions in water or oil, and flavored emulsions with edible oils such as oil of cotton seeds, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable suspendresume agents for aqueous suspensions include, but are not limited to, synthetic and natural resins, such as the Arabian gum, agar-agar, alginate (i.e. propylaniline, sodium alginate, etc.), guar gum, karaya, the fruit of the carob tree, pectin, tragacanth and xanthan gum, cellulose derivatives such as carboxymethylcellulose sodium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the hypromellose and combinations thereof, synthetic and PropertyName polymers, such as polyvinylpyrrolidone, carbomer (i.e. carboxypolymethylene) and polyethylene glycol, clays, such as bentonite, hectorite, attapulgite or thick, and other pharmaceutically acceptable suspendresume agents such as lecithin, gelatin or the like. Suitable surfactants include, but are not limited to docusinate sodium, lauryl sulfate, Polysorbate, octoxynol-9, nonoxynol-10, Polysorbate 20, Polis is rbinom 40, the Polysorbate 60, Polysorbate 80, poloxamer 188, poloxamer 235 and their combinations. Suitable deflocculate or dispersing agent include lecithins pharmaceutical quality. Suitable flockhouse agent includes, but is not limited to simple neutral electrolytes (e.g. sodium chloride, potassium chloride, and so forth), vysokopatogennyj insoluble polymers and polyelectrolyte substances, water-soluble divalent or trivalent ions (i.e. calcium salts, alum or sulfates, citrates and phosphates (which can be used in drugs at the same time as pH buffers and flocculosa agents)). Suitable preservatives include, but are not limited to parabens (i.e. methyl, ethyl, n-propyl and n-butyl), sorbic acid, thimerosal, Quaternary ammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate, phenylethanol and so on. There are many liquid media that can be used for liquid pharmaceutical dosage forms, however, the carrier liquid used in a particular dosage must be compatible with suspenders agent (agents). For example, nonpolar liquid media, such as fatty acid esters and liquid media based oils are best to use with such suspendresume Agen the AMI, as surfactants with low HLB (hydrophilic-lipophilic balance), hectorite stearalkonium, water-insoluble resins, water-insoluble film-forming polymers, and so forth. In contrast, polar liquids such as water, alcohols, polyols and glycols, it is best to use with such suspendresume agents like surfactants with high HLB, silicate clays, gums, water-soluble cellulose derivatives, water-soluble polymers, and so forth. For parenteral administration is desirable sterile suspensions and solutions. Liquid forms suitable for parenteral administration include sterile solutions, emulsions and suspensions. If it is desirable intravenous use isotonic preparations, which usually contain suitable preservatives.

In addition, the compounds of the present invention can be introduced in the form vnutripuzarnoe dosage forms with the help of local use of the appropriate vnutriskalnyh media or via percutaneous transdermal patches, the composition of which is well known to specialists in this field of technology. For administration in the form of a percutaneous delivery system introduction therapeutic doses, of course, be continuous and not interrupted on the continuation of dosage.

Connections on the present and the finding can also be entered in the form, suitable for vnutripuzarnoe or inhalation therapy. For such therapy, the compounds of the present invention typically come in the form of a solution or suspension from a container with pumped-in spray, in pumped or compressed, or in the form of an aerosol spray from a pressurized container or dispenser (such as a nebulizer with a measured dose, or other standard or non-standard methods or devices for inhalation delivery), with the use of a suitable propellant, such as DICHLORODIFLUOROMETHANE, Trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas). In the case of a pressurized aerosol single dose can be determined by setting the valve for delivering metered quantities. In a pressurized container or nebulizer may contain a solution or suspension of the active compound. It is possible to make capsules or ampoules (such as capsules or capsules made from gelatin) for use in an inhaler or insufflator containing a powder mix of the compound of the invention and a suitable powder base such as lactose or starch.

Compounds of the present invention can also be entered in form of systems, liposomal delivery, such as small monolayer vesicles, bol is a major monolayer bubbles and so on. Liposomes can be obtained from a large number of phospholipids, such as cholesterol, stearylamine, phosphatidylcholine and so on.

Compounds of the present invention can also be delivered using monoclonal antibodies as individual carriers with associated molecule compounds. Compounds of the present invention can also be combined with soluble polymers as carriers of drugs that can be a target. Such polymers can include, but are not limited to polyvinylpyrrolidone, a copolymer of Piran, polyhydroxyethylmethacrylate, polyhydroxyethylmethacrylate or polyethylenepolyamine, substituted Palmitoyl balance. In addition, the compounds of the present invention can be linked to a class of biodegradable polymers suitable for achieving controlled release of drugs, for example, homopolymers and copolymers (which means polymers containing two or more chemically distinct repeating units), or lactide (which includes d-, l - and mesolectal lactic acid), glycolide (including glycolic acid), ε-caprolactone, p-dioxanone (1,4-dioxane-2-one), trimethylantimony (1,3-Iksan-2-one), alkyl derivatives of trimethylhexanoate, δ-valerolactone, β-butyrolactone, &x003B3; -butyrolactone, ε-decalactone, hydroxybutyrate, hydroxyvalerate, 1,4-dioxan-2-ONU (including its dimer 1,5,8,12-tetrachloroethylene-7,14-dione), 1,5-oxepin-2-ONU, 6,6-dimethyl-1,4-dioxane-2-ONU, polyarteritis, polyacetale, policyidreference, polycyanoacrylates and cross-linked or the amphiphilic copolymers of hydrogels or their mixtures.

A therapeutically effective amount of the compound or composition can be from about 0.001 mg/kg/dose to about 300 mg/kg/dose. Preferably a therapeutically effective amount may be from about 0.001 mg/kg/dose to about 100 mg/kg/dose. More preferably, therapeutically effective amount may be from about 0.001 mg/kg/dose to about 50 mg/kg/dose. Most preferably therapeutically effective amount may be from about 0.001 mg/kg/dose to about 30 mg/kg/dose. Therefore, a therapeutically effective amount of the active ingredient contained in this standard dosage form (e.g. tablet, capsule, powder, injection, suppository, teaspoonful and so on)will be in the range from about 1 mg/day to about 21000 mg/day for the subject, for example, the average weight of 70 kg For oral administration of the composition is preferably provided in the form of tablets containing the 0.01 to 0.5, 0,1, 0,5, 1,0, 2,5, 5,0, 10,0, 15,0, 25,0, 50,0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the subject to treatment of a subject.

Specialists in this field will easily determine the optimal dose for the introduction, and they will vary depending on the specific compound, the route of administration, the strength of the preparation and progress of the disease condition. In addition, factors related to the specific subject of treating a subject, including age of the subject, weight, diet and time of administration, will need to adjust the dose until an appropriate therapeutic level. Mainly compounds of the present invention can be introduced in the form of a single daily dose, or the total daily dose can be administered in divided doses of two, three or four times daily.

Representative names by IUPAC for the compounds of the present invention were given when using the nomenclature of the computer program ACD/LABS SOFTWARE™ Index Name Pro Version 4.5, provided by Advanced Chemistry Development, Inc., Toronto, Ontario, Canada.

In the present description, in particular in the schemes and the examples used the following abbreviations:

Boc = tert-butoxycarbonyl

Buli = utility

Cpd(Conn) = connection

DCC = dicyclohexylcarbodiimide

h = hour/hours

HOBT = hydroxybenzotriazole

KN = hydride potassium

MeI = iodide m is Teal

NT = not tested

K.T./K.T. = room temperature

TFU = triperoxonane acid

TMSBr = trimethylborazine

General methods of synthesis

Representative compounds of the present invention can be synthesized in accordance with the General methods of synthesis described below and illustrated more specifically in the following outline. The diagram is illustrative, and should not be considered that the invention is limited given the chemical reactions and conditions. For various starting compounds used in the schemes, is within the skills of specialists in this field of technology.

Scheme And

Scheme And is an illustration of a General method of preparing compounds of the invention by addition of phosphonate - or phosphinate anion derived from a compound ofA2phosphonate or phosphinate and ORGANOMETALLIC base such as n-utility, the anhydride compoundA1in a solvent such as THF, to obtain the connectionA3califofnia or califorina, where Z is hydrogen, Y is absent and X represents one of an oxygen Deputy, linked by a double bond with a carbon atom in β-position to R4.

Other compounds of the present invention can be obtained from the connectionA3using the standard p is obrazovanii ketones, where the carbon atom in β-position can be recovered from the ketone in the compound of formula (I), where X and Y are present in both, or where Z is a bond. Examples of transformation of ketones include, but are not limited to, the use of 1) ORGANOMETALLIC reagents for producing alkoxy-groups, 2) hydroxylamino to get imino-groups, and 3) reagent Lawson to replace ketone group, thio group (with appropriate protective groups, added to shows COOH group).

ConnectionA2where R6the same as previously defined, can be obtained by known methods such as methods described Katritsky et al.,Org. Prep. Proced. Int.,1990, 22(2), 209-213;J. Amer. Chem. Soc.,2002, 124, 9386-9387; and inChem. Ber.,1963, 96, 3184-3194. In one of the ways to implement the General method for the synthesis of substituent R5connectionA4represents hydrogen, and the substituent R6represents ethoxy.

ConnectionA2where R4is heteroaryl, can be obtained from commercially available or known halogenallylacetic heteroaryl parent compounds (such as 3-methyl bromide-5-Cl-benzothiophen used to obtain compound 33) by methods known to experts in this field of technology.

ConnectionA3can be combined with the fragment of R1formula (I) with the help article is Hartig reactions combination. For example, if R1represents a secondary amine in the heterocyclic ring, the nitrogen atom of the cycle can be combined with the connectionA3(by analogy with the reaction shown in scheme A; for example, the nitrogen atom of the cycle in the connectionA4could be combined with the connectionA8). To minimize undesirable side reactions you can use the appropriate blocking group. A similar reaction combination with the connectionA3you can implement when R1represents-N(R7R8for combinations of substituted amine with a carboxylic acid compoundA3. In one of the ways of implementing the present invention in order to further illustrate the present invention provides a reaction mix connectionA3with R1when R1is-N(R7R8and R8represents a heterocycle.

The diagram And the interaction appropriately protected aminosilanes heterocyclic compoundsA4(where protected amino substituted by hydrogen atom for R7and unsubstituted ad) heterocycle for R8) with Q replaced by R8aconnectionA5(where Q is a suitable leaving group (such as halogen atom, but not limited to them) and R8athe Deputy, identified earlier in the R8ba)-bl) list) will dissolve in the Le, such as DMF, containing a base (such as creatinin, but not limited to them), leading to R8bsubstituted connectionA6.

In one of the ways to implement the General method for the synthesis of heterocyclic fragment connectionA4optionally substituted on the nitrogen atom by interaction with the acid chloride of the acid compoundsA5where Q part represented chlorine and R8athe fragment is bc) carbonyl, substituted R8bDeputy selected from C1-8of alkyl, aryl, aryl(C1-8)alkyl, aryl(C2-8)alkenyl, heteroaryl, heteroaryl(C1-8)alkyl or heteroaryl(C2-8)alkenyl. In an alternate method of performing this reaction can be carried out by the interaction with the acid chloride of the acid compoundsA5where Q is chlorine and R8athe fragment is bc) sulfonyl, substituted R8bDeputy, where R8bis defined above.

The process of joiningA6base, such as potassium hydride, followed by treatment with alkylating reagent R7X, such as logmean, in a solvent such as THF, leads to the connectionA7. Amine compoundA8can be obtained from the connectionA7when removing the protective group Boc as a result of processing acid, such as TFU, in a solvent such as CH2Cl2 . ConnectionA8in the form of the free base is obtained by treatment with base, such as aqueous Na2CO3.

ConnectionA9can be obtained by the standard method combination connectionA3connectionA8when using standard reagents such as DCC and HOBT in a solvent such as CH3CN. In the dealkylation of the compoundA9this reagent, as trimethylamine, in a solvent such as pyridine, followed by treatment with diluted HCl get connectionA10(which is one of the ways to implement the General method for the synthesis of R5ethyl group, and R6ethoxyline groups were replaced by hydrogen). Sol connectionA10such as the target connectionA11can be obtained by treating compoundA10monobasic or dibasic amine such as Tris(hydroxymethyl)aminomethan in the solvent system, such as I-D and water.

Scheme And

Scheme

Diagram is an illustration of an alternative General method for the synthesis of compounds of the invention by adding connection toA2(in one of the ways to implement alternative General method substituent R5connectionA2represents ethyl, and the substituent R6the submitted is ethoxy) and R M (where R M is an ORGANOMETALLIC reagent, such as LiHMDS (hexamethyldisilazide lithium), tetramethylpiperidine lithium or NaHMDS (hexamethyldisilazane)) to the anhydride compoundA1.

Then the reaction mixture was quenched with pH from about 4 to a pH of about 6, receiving enol connectionB1where the compounds of formula (I) Z is a bond, Y is absent and X is the only oxygen Deputy, connected by a double bond with a carbon atom in β-position to R4. Other compounds of the present invention can be obtained from the connectionB1using standard manipulations with ketones, where the double bond of the enol can be restored to the ketone where to compounds of formula (I) is absent, and X is the only oxygen Deputy, connected by a double bond with a carbon atom in β-position. You can then use the linking reagent (such as chloroformiate, but not limited to (such as isobutylparaben, but not limited to, cyanuric chloride, methanesulfonate, diethylphosphate or mixtures thereof) to close the loop with the formation of intermediate compoundsB2substituted lactone in the presence of a base such as Et3N, but not limited to them.

Interaction connectionB3dihydroxytoluene heterocycle (or other ketones, or other protected ketones) with Q replaced by R8aconnect the drug A5in a solvent (such as CH2Cl2, THF or mixtures thereof, but not limited to)containing a base (such as sodium bicarbonate, potassium carbonate, but not limited to), leads to R8bsubstituted connectionB4.

ConnectionB4processed R7NH2in a solvent (such as CH2Cl2, THF or mixtures thereof, but not limited to), then subjected to recovery or aminating hydrogenation using a hydride reducing agent such as NaBH(OAc)3but not limited to them) or generowania using Pd, Pt or Ni catalyst. The free base compoundsA8acquired by quenching the reaction mixture with a base, such as aqueous Na2CO3.

ConnectionA9(in tautomeric equilibrium with the connectionB6) received at the opening of the 5-membered lactone ring cycle intermediateB2connectionA8(or connectionB5, salt compoundA8in the presence of DIEA (diisopropylethylamine) in a solvent (such as acetone or MEK (methyl ethyl ketone), but not limited to).

In the dealkylation equilibrium mixture of compoundA9connectionB6using a reagent (such as TMSBr (trimethylamine), but is not limited to them) in a solvent (such as CH3CN or pyridine, but not limited the camping them) followed by recrystallization received connection A10(in which ethyl group, R5replaced by hydrogen, and ethoxy group R6replaced by hydroxyl). Sol connectionA10such as the connectionA11(and its tautomers), were received while processing the connectionA10a diamine, such as Tris(hydroxymethyl)aminomethan in the solvent system, such as a mixture of EtOH and water.

Circuit

Scheme

The scheme is an illustration of an alternative method of obtaining the intermediateB2in which the enol compoundB1transferred to the connectionA3ketone free acid, bringing the pH to about pH 1, followed by a standard reaction mix to obtain the target lactone intermediateB2.

Scheme

Scheme D

Scheme D illustrates an alternative method of obtaining protonated compoundsB5in which the connectionA8protonium acid (such as HCl, HBr or p-toluensulfonate, but not limited to, receiving the target connectionB5that can be entered instead of connecting toA8in the reaction with the compoundB2.

Scheme D

Specific examples of synthesis

Specific compounds, which are representative in this invented and, received according to the following examples and sequences of reactions; examples and diagrams that shows the sequence of reactions, which are provided as illustrations to facilitate understanding of the invention and should not be construed as in any way limiting the invention which is set forth in the following claims. Provides intermediate compounds can also be used in the following examples, additional compounds of the present invention. These reactions can be further optimized to improve outputs. Specialist in the art will know how you could improve these outputs using standard changes the reaction time, temperature, solvents and/or reagents.

All chemical reagents were obtained from commercial suppliers and used without further purification. The NMR spectra of1H and13With were recorded on a spectrometer Bruker AC 300B (300 MHz for proton) or a Bruker AM-400 (400 MHz for proton) with Me4Si as internal standard (s=singlet, d=doublet, t=triplet, br=broadened). APCI-MS and ES-MS were recorded on a mass spectrometer VG Platform II.

Example 1

[2-[3-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid (compound 2)

To a solution of 2.5m n-BuLi in hexane (40 ml, 0.1 mol) in 70 ml THF at -78°C was added dropwise a solution of 1-naphthylmethylphosphonate (connection1A, 28 g, 0.1 mol) in 60 ml of THF for 30 minutes After stirring for another 30 min to the mixture for 20 min servings anhydride was added 2,3-naphthaleneboronic acid (compound1B, 20 g, 0.1 mol) through the funnel for the addition of solids. Upon completion of addition, the suspension was given gradually to reach 0°C and kept at this temperature for 1.5 hours was Added an excess of NH4Cl (feast upon., aq.) and the mixture was filtered through a layer of celite 545. The filtrate was extracted with 200 ml EtOAc and the layers were separated. The organic phase was concentrated (without drying) under reduced pressure at K.T. and the residue was washed 4X in boiling ether. The residue was treated with 200 ml of EtOAc and brought to pH 3 using 2 N. HCl (aq.) with vigorous stirring. The layers were separated and once washed the organic phase H2Oh, dried (Na2SO4) and concentrated, gaining 24 g of compound1Sin the form of a white powder: Mass (ES) of MN+=477; HPLC: 3,68 minutes

To a solution of compound1D(4 g, 20 mmol)containing 3.1 ml of triethylamine (22 mmol) in 45 ml of DMF, was added connection to1E(3.8 g, 20 mmol). After stirring overnight the mixture was filtered and concentrated under reduced pressure. The residue was dissolved the CH 2Cl2and then washed N2Oh, Na2CO3(10%aq.), H2Oh, KHSO4(1 n aq.) and H2O. the Organic phase was dried (Na2SO4) and concentrated, obtaining 6.0 g connection1Ffoam: Mass (ES) of MN+=355.

The potassium hydride (2.3 g 35%dispersion in oil, 20 mmol) was washed with hexane, then was treated with 30 ml of THF and cooled to 0°C. To this suspension was added dropwise a solution of compound1F(5.9 g, a 16.8 mmol) in 15 ml THF. The mixture was stirred at 0°C for 0.5 h, then was stirred for another 0.5 h at K.T. Mixture was cooled to 0°and there was added dropwise logmean (15.7 g, 100 mmol). The mixture was stirred at 0°C for 0.5 h, then was heated to K.T. and stirred another 1.5 hours was Slowly added to an excess of 10%Na2CO3(aq.) when 0°and removing volatile components under reduced pressure. The aqueous layer was extracted three times EtOAc and the combined extracts were dried (Na2SO4) and concentrated, obtaining of 6.1 g of compound1Gfoam: HPLC Rt=3,76 min, 100%; Mass (ES) of MN+=369.

A solution of compound1G(6,1 g, 16.5 mmol) was dissolved in 15 ml of a 1:1 TFU:CH2Cl2and was stirred for 1 h at K.T. Volatiles were removed under reduced pressure, and the residue was dissolved in CH2Cl2and was treated with excess 10%aqueous Na2CO3(aq.). the LOI was separated and the aqueous phase was extracted three times CH 2Cl2. The organic extracts were combined, dried (Na2SO4) and concentrated, obtaining 4.3 g of compound1Hin the form of a viscous oil: HPLC Rt=1.5 min, 100%; Mass (ES) of MN+=269.

A solution of compound1S(4.9 g, or 10.3 mmol), compound1H(3,3 g, 12.3 mmol) and HOBT (2.1 g, to 15.4 mmol) in 100 ml of CH3CN was treated with a solution of DCC (2.5 g, 12.3 mmol) in 7 ml of CH3CN. After stirring for 12 h was added 5 ml of DIPEA and stirred the reaction mixture for 48 hours the Mixture was filtered and concentrated. The residue was purified column flash chromatography (silica gel:CH2Cl2:Meon an increase from 98:1 to 95:5), receiving of 6.9 g of compound1I. HPLC Rt=4,3 min, Mass (ES) of MN+=727.

To a solution of compound1Iin 15 ml of pyridine was added 5 ml of trimethylsilane. This mixture was stirred for 15 min, then concentrated under reduced pressure. The residue was treated with excess 3 N. HCl (aq.), then was stirred for 3 hours the White precipitate was collected and washed with water, then rubbed in CH3CN, receiving of 5.1 g of compound1J. HPLC Rt=3.6V min, Mass (ES) of MN+=671. To a solution of compound1Jin 50 ml of CH3CN was added a solution of Tris(hydroxymethyl)aminomethane (0.9 g, 7.7 mmol) in 7 ml of N2O. the Solution was filtered and the filtrate liofilizirovanny after partial concentration for removal of the h the STI CH 3CN. The obtained white solid was recrystallized from i-D, getting 5.5 g connection2as not quite white solid. HPLC Rt=3.6V min, 100%; Mass (ES) of MN+=671. Anal. calc. for C40H35N2O6P·1.0 C4H11NO3·1,0 I-D·1,5 H2O: C, 64,23; H, is 6.54; N, 4,79; H2O, is 3.08. Found: C, 63,93; H, 6,40; N, 4,85; H2O, 2,74.

In example 1 TLC was performed using plates Whatman silica gel 250 μm. Preparative TLC was performed on plates with silica gel GF firms Analtech 100 μm. Column flash chromatography was performed on a column of flash silica gel (40-63 μm), and column chromatography was performed using a conventional silica gel. HPLC separation was performed on three cassettes Waters PrepPak® (25 x 100 mm, Bondapak® C18, 15-20 μm, 125 E)connected in series; the determination was carried out at 254 nm using a UV detector (Waters 486. Analytical HPLC was performed on a column of Supercosil ABZ+PLUS (5 cm x 2.1 mm) with definition at 254 nm using a Hewlett Packard 1100 UV detector. Microanalysis was performed at Robertson Microlit Laboratories, Inc.

According to the method of example 1 and with appropriate substitution of the original substances, compounds and reagents were obtained the following compounds 1 and 3-33 according to this invention:

(9)
Connection.NameMass m/e< / br>
(MH+)
(1)[2-[3-[[methyl-(4-phenylcyclohexyl)amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid592
(3)[2-[3-[[[1-[(6-methoxy-2-naphthalenyl)carbonyl]-3-pyrrolidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid687
(4)[2-[3-[[[1-[(6-bromo-2-naphthalenyl)carbonyl]-4-piperidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid771

(M+Na)
(5)[2-[3-[[[1-[(2E)-3-(4-forfinal)-1-oxo-2-propenyl]-3-pyrrolidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid651
(6)[2-[3-[[methyl[1-[(2E)-1-oxo-3-phenyl-2-propenyl]-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid647
(7)[1-(1-naphthalenyl)-2-oxo-2-[3-[(4-phenyl-1-piperidinyl]carbonyl]-2-naphthalenyl]ethyl]phosphonic acid564
(8)[1-(1-naphthalenyl)-2-oxo-2-[3-[(4-oxo-1-phenyl-1,3,8-diazaspiro[4.5]Dec-8-yl)carbonyl]-2-naphthalenyl]ethyl]phosphonic acid634
[2-[3-[[methyl[1-[(2E)-3-(4-were)-1-oxo-2-propenyl]-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid661
(10)[2-[3-[[methyl[1-[(2E)-1-oxo-3-[4-(trifluoromethyl)phenyl]-2-propenyl]-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid715
(11)[2-[3-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-2-oxo-1-phenylethyl]phosphonic acid621
(12)[2-[3-[[4-(4-methoxyphenyl)-1-piperidinyl]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid594
(13)[2-[3-[[[1-[(2E)-3-[4-(dimethylamino)phenyl]-1-oxo-2-propenyl]-4-piperidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid690
(14)[2-[3-[[4-(3-methoxyphenyl)-1-piperidinyl]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid594
(15)[2-[3-[[(1-benzoyl-4-piperidinyl)methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid621
(16)[2-[3-[[4-(2-benzothiazolyl)-1-piperidinyl]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphono the traveler acid 621
(17)[2-[3-[(cyclohexylethylamine)carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid516
(18)[2-[3-[[methyl[1-[1-oxo-3-[4-(trifluoromethyl)phenyl]propyl]-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid717
(19)[1-(1-naphthalenyl)-2-oxo-2-[3-[(3-phenyl-1-pyrrolidinyl)carbonyl]-2-naphthalenyl]ethyl]phosphonic acid550
(20)[2-[3-[[methyl[1-(2-methyl-1-oxopropyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid587
(21)[2-[3-[(cyclopentylmethyl)carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid502
(22)[2-[3-[[[4-(1,1-dimethylethyl)cyclohexyl]methylamino)carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid572
(23)Methyl ester [2-[3-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid685
(24)[2-[3-[[[1-[(6-hydroxy-2-naphthalenyl)carbonyl]-4-piperidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]f spanova acid 687
(25)[1-(1-naphthalenyl)-2-oxo-2-[3-[[3-(2-phenylethyl)-1-pyrrolidinyl]carbonyl]-2-naphthalenyl]ethyl]phosphonic acid578
(26)[2-[3-[[(1-acetyl-4-piperidinyl)methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid559
(27)[2-[3-[[methyl-(4-methylcyclohexyl)amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid530
(28)[2-[1-[[methyl(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid582
(29)[2-[3-[[methyl-(4-phenyl-3-cyclohexen-1-yl)amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid590
(30)[1-(1-naphthalenyl)-2-[3-[[[1-(2-naphthalenesulfonyl)-4-piperidinyl)amino]carbonyl]-2-naphthalenyl]-2-oxoethyl]phosphonic acid657
(31)[2-[3-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]phenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid621
(32)Methyl-[2-[3-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphinic acid 669
(33)[1-(5-chlorobenzo[b]Tien-3-yl)-2-[3-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-2-oxoethyl]phosphonic acid712

Example 2

An alternative method of synthesis of compounds 2

In a flask were mixed THF (tetrahydrofuran) (1081,0 ml) and the connection2B1-afterdelivery (223,0 g, 0,7612 mol) and cooled to about -20°using a cooling bath of dry ice-methanol. To the cooled mixture was added a solution of 1M LiHMDS (1597,0 ml, 1,597 mol) in THF, maintaining the temperature at about -20°receiving a thin slurry, which was stirred for another 30 minutes. Portions anhydride was added 2,3-naphthaleneboronic acid, the connection2A(158,80 g, 0,7612 mol) over 1 h, maintaining the temperature of the mixture at about -20°C. an addition funnel and the wall of the flask was washed THF (100,0 ml), was sacked cooling bath and the temperature of the mixture to about 5°for 1.5 hours once the reaction was completed (determined by HPLC), the final pH of the mixture was brought to approximately pH 5 by slowly adding 6N HCl (422 ml, 2.34 mol), maintaining the temperature of the mixture at about 5°C. the Mixture was stirred for another 30 min at about 5°To give crude product as a fine white solid. The crude product was filtered on a porcelain filter. P is after this wet solid was washed with water (1000,0 ml), left to filter overnight, and then dried at 70°receiving deliciious salt compounds2C(365,1 g, mass. output: 100,6%). Connection2Cused in the next stage without additional purification.

Into the flask was placed methanol (2500,0 ml) and water (360,0 ml) and stirred. To the solution under stirring was added connection to2C(365,1 g, 0,7612 mol) and washed flask with methanol (100,0 ml)to give a suspension. This suspension was stirred at K.T. for 30 min, and then for 2 min was added 12 N. HCl a (80.0 ml, 0,960 mol), as what the suspension turned into a cloudy solution. This solution was stirred at K.T. until then, until crystallization started, then was cooled to approximately 5°C for 1 h, give crude product as a white granular solid. The product was filtered and washed with water (500,0 ml), then dried in vacuum overnight at a temperature of about 50°receiving the connection2D(280 g, dry wt. output: 77,3%).

In a flask were mixed connection2D(199,8 g) and THF (2 l), then stirred and cooled to a temperature of from about 0°up to about 5°C. To the flask was added NMM (4 methylmorpholin) (51,5 ml), maintaining the temperature of the mixture at a temperature of from about 0°up to about 5°C. the mixture is Then stirred for another 15 min or until the solution. Portions were added IBCF (isobutylparaben) (56 ml), TF is Riva the temperature of the mixture at a temperature of from about 0° With up to about 15°C. Upon completion of addition, the temperature of the mixture was raised to a temperature of from about 20°With up to about 25°With, then was stirred for 1 h after the reaction of salt NMM was filtered off, washed with THF (150 ml) and left to dry. Then, the filtrate was mixed with n-heptane (2.5 l) for approximately 10 min, and then stirred at a temperature of from about 20°With up to about 25°C for about 30-45 minutes for approximately 10 min was added n-heptane (1.5 l). After that, the mixture was cooled to a temperature of from about 0°up to about 5°and left to form a suspension for 1.5 hours, the resulting suspension was filtered and washed with n-heptane (250 ml), left to air dry for approximately 30 min, and then dried in vacuum overnight at a temperature of from about 45°With up to about 50°receiving the connection2E(165 g, mass. output: 88,4%).

In a flask were mixed DCM (methylene chloride) (600 ml) and 2-aftercare connection2F(189,0 g) and stirred until dissolution. Then, through the addition funnel was added the hydrochloride hydrate of 4-piperidone, the connection2G(150 g) and NaHCO3NaHCO3(sodium bicarbonate) (260.0 g). For rinsing the funnel used DCM (300 ml)and the resulting mixture was stirred for 18 hours At the completion of the reaction (determined by HPLC) in a flask was added water (2.6 l) and vigorously stirred CME is ü for dissolution of NaHCO 3. Through the period of time from about 5 to about 10 minutes gave the layers to separate for approximately 30 minutes. The aqueous layer was separated. Again added a saturated aqueous solution of NaHCO3(300 ml) and stirred the mixture for from about 5 to about 10 minutes. The layers were allowed to separate for approximately 30 minutes and the separated aqueous layer. Was added water (300 ml) and gently stirred the mixture for from about 5 to about 10 minutes. The layers were allowed to separate for approximately 30 minutes, and separated the organic layer (˜960 ml)containing compound2N(the concentration is2Nin DCM: 235,98 mg/ml, the calculated mass of compound2Nin DCM: 226,54 g, the calculated masses. output: 93,46%).

In a flask were mixed connection2N(˜50 g, ˜265 mg/ml in DCM) and acetic acid (4.9 ml) and cooled the mixture to a temperature of from about 0°up to about 5°C. Portions was added 2.0m MeNH2(methylamine) (296 ml) in THF, maintaining the mixture at a temperature of from about 0°up to about 19°C. the Mixture was left to warm to room temperature and was stirred for approximately 30 minutes. After that, portions were added NaBH(OAc)3(triacetoxyborohydride sodium) (51,4 g), maintaining the solution at a temperature of from about 19°C to about 27°C. the Mixture was left to ripen for about 40 minutes at a temperature of from room temperature up to about 27°C. Upon completion reacts and (determined by HPLC) was added water (500 ml), maintaining the solution at a temperature below about 30°C. Then, to the mixture was added sodium hydroxide (115 ml, 5% weight/volume in water) to raise pH from about pH 10 to about pH 11. The mixture was vigorously stirred for from about 3 to about 10 minutes, the Layers were separated and the separated aqueous layer. Was added water (143 ml) and stirred the mixture for from about 3 to about 10 minutes, the Layers were again separated and the separated organic layer containing the compound2I(the concentration is2Iin DCM: 0,229 mg/ml, the calculated mass of compound2Iin DCM: 45,18 g, the calculated masses. output: 85,3%).

Connection2I(150 ml 0,069 mol) were placed in a solution of CH2Cl2:THF (150 ml, 1:8) and concentrated in vacuum, maintaining the mixture at a temperature below about 40°using a cooling bath. To a thick oil portions was added 2-butanone (320 ml) to transfer the oil to another flask. The mixture was stirred and added EtN(I-Pr)2(diisopropylethylamine) (11,0 ml 0,063 mol) and the connection2E(27,3 g 0,057 mol). The mixture was heated to a temperature of about 65°C for from about 6 to about 7 hours At the end of the reaction (determined by HPLC), the mixture was cooled to ambient temperature and was led in the course of from about 72 to about 96 h (to start the crystallization of the product can take up to 48 hours, at the time of emergence of the cloud point of the SOS is to place about 28 hours). The product was filtered and washed with acetone (2 x 10 ml) (each wash), and then dried in vacuum overnight at a temperature of about 75°receiving the connection2J(of 31.4 g, output: 75,1%) as a white powder.

Into the flask were placed compound2J(10.0 g) and acetonitrile (40 ml)to give a suspension. This suspension was stirred for from about 5 to about 10 min, then through an addition funnel were added trimethylamine (10 ml) for from about 10 to about 15 minutes at K.T. Upon completion of the reaction (determined by HPLC), the mixture was transferred into an addition funnel and then added to water (250 ml). The resulting suspension is vigorously stirred during the addition and maintained at temperatures ranging from about 20°With up to about 25°C. the Suspension is stirred for from about 1 to about 1.5 h, then filtered and washed with water (2 x 15 ml). Then the obtained wet the filter residue was dried in vacuum overnight at a temperature of about 40°To give crude product compound2K(10.2 g) as a white solid.

Into the flask were placed compound2K(110,0 g to 0.127 mol) and methanol (550 ml)to give a suspension. This suspension was stirred at K.T. within from about 55 to about 60 minutes (the mixture for recrystallization formed a cloudy solution within 5 minutes after adding the Meon and gradually turned into a white suspension about h is cut to 30 minutes). To the suspension was added a solution of acetone:water (1100 ml, 4:1) and stirred suspension when K.T. within from about 180 to about 190 minutes, getting a white solid. This solid was filtered and washed with water (3 x 350 ml), getting wet the filter residue, which was then dried in vacuum overnight at a temperature of from about 30 to about 35°receiving recrystallized connection2K(82.3 g, yield: 96.1 per cent) in the form of a fine white solid.

In a flask were mixed recrystallized connection2K(30.0 g, 0,0431 mol) and Tris(hydroxymethyl)aminomethan (13,07 g, 0,107 mol, pure white crystalline substance) was added ethanol (300 ml) and water (30 ml). The solution was mixed, obtaining a clear solution after about 15 minutes Over a period of time from about 2 to about 3 h formed small suspension, and after a period of time from about 3 to about 5 h formed a thick white suspension (if after 3 h is not formed small suspension, you may need to make a seed to accelerate crystallization). This suspension was stirred at K.T. within 4 hours the Thick suspension was diluted by adding ethanol (180 ml), then filtered and washed with ethanol (120 ml), left to air dry for approximately 30 min, and then dried in vacuum for about 24 hours to about 67 hours at a temperature of about 40°receiving the connection 2E(38,6 g, output: 91,8%) in the form of bis-trimethanol salt (ratio of Tris(hydroxymethyl)aminomethan:connection2E:1,99:1).

In example 2, analytical HPLC was performed using a column Phenomenex Luna (15 cm x 4.6 mm; 5 MK; the determination was carried out at 220 nm), Phenomenex Luna 5 micron C18(2) (4.6 mm x 250; the determination was carried out at 225 nm) and Synergi 4 MK MAX-RP 80A (15 cm x 4.6 mm; determination was carried out at 225 nm). Microanalysis was performed Quantitative Technologies, Inc.

Example 3

As a concrete example, receiving oral composition, 100 mg of compound 2 of example 1 was mixed with enough powdered lactose, receiving a total amount of 580 to 590 mg to fill the O-shaped hard gelatin capsules.

Examples of biological experiments

The applicability of the compounds of the present invention as inhibitors of serine proteases and, in particular, as an inhibitor of cathepsin G and chymase, suitable for the treatment of inflammatory or mediated by the serine proteinase violations can be determined in accordance with the methods described here.

Example 1

The reaction of the enzyme-catalyzed hydrolysis - cathepsin G

The rate of enzyme-catalyzed hydrolysis was determined spectrophotometrically using the neutrophil to the of tasina G man (Athens Research and Technology) or chymase human skin (Cortex Biochem), chromogenic substrate (Suc-Ala-Ala-Pro-Phe-pNa) (Bachem) in aqueous buffer (100 mm Hepes, 500 mm NaCl, pH 7.4 for catG; 450 mm Tris, 1800 mm NaCl, pH 8.0 for chymase) and a microplate reader (Molecular Devices). IC50the experiments were conducted by fixing the concentration of enzyme and substrate (70 nm enzyme, 5 mm substrate for catG; 10 nm enzyme, 0.7 mm substrate for chymase) and varying concentrations of inhibitor. The changes in absorption were observed using the software Softmax (Molecular Devices) adding the enzyme in the presence or in the absence of inhibitor at 37°C for 30 minutes. The percentage of inhibition was calculated from the comparison of the initial slopes of the reaction samples without inhibitor and tilt the initial reaction of the samples with inhibitor. The value of the IC50was determined using chetyrehmetrovoy logistic model description. The term "NT" denotes a compound that is not tested.

Table 4 shows the results of inhibition of cathepsin G and chymase for compounds of the present invention:

10
Table 4
Connection.IC50(µm)

catG
NIC50(µm)

chymase
n
10,083±0,01470,0053±0,00198
2700,0067±0,001870
30,068±0,01920,072±0,0083
40,090±0,02050,0039±0,00014
50,072±0,02150,2±0,46
60,067±0,01440,0035±0,00152
70,210±0,050120,008±0,0221
80,130±0,010110,0074±0,00228
90,053±0,01550,011±0,0032
100,053±0,0165Q 014±0,0065
114,9±2,82to 0.0321
120,179±0,038100,0073±0,001710
130,064±0,00830,0041
140,230± 0,03060,010±0,0019
150,075± 0,0305/td> 0,017±0,0053
160,190±0,02070,0085±0,00237
170,098±0,02640,0072±0,00156
180,028±0,00630,00101
190,238±0,03080,022±0,0629
200,090±0,02350,004±0,0022
210,070±0,02050,0096±0,00345
220,140±0,040180,009±0,02312
230,67010,4161
240,078±0,01570,0035±0,00136
250,156±0,02870,0097±0,00357
260,096±0,01830,015±0,0013
270,070±0,01040,0051±0,00224
280,400±0,09011being 0.036±0,011
290,150±0,0301,30,0082±0,002810
300,590±0,04020,0158±0,00082
31>100,0114,95±0,672
320,86±0,0320,311
330,121+0,00720,001±0,0002

Example 2

Antiasthmatic effects on a model of asthma in sheep

The effectiveness of compound 2 for the treatment of asthma has been evaluated at an approved model induced by antigenascaris suumasthmatic reactions in in consciousness sheep (Abraham, W.M., Pharmacology of allergen-induced early and late responses and antigen airway hyperresponsiveness in allergic sheep,Pulmonary Pharmacology,1989, 2, 33-40).

The Protocol of the experiment

Basic curves dose-response to aerosol carbachol received for 1-3 days prior to antigenic stimulation. Received basic values specific lung resistance (SRL), and then the sheep were given a certain amount (mg) of test compounds in the form introduced by inhalation aerosol at some time before antigenic stimulation. Received measurement SRLafter drug, and then spent the incentive is aciu sheep antigen Ascaris suum. Measurement of SRLconducted immediately after stimulation every hour, starting from 1-6 hours after stimulation and every half hour in 61/2-8 h after stimulation. Measurement of SRLconducted 24 h after stimulation, then after 24 h post-stimulation carbachol to determine the increased reactivity of the Airways.

Compound 2 was administered in aerosol form at 0.1 mg/kg/dose twice daily (BID) for three consecutive days, then the dose on day 4 for 0.5 hour before antigenic stimulation. Stimulation by antigenAscaris suumcarried out at the zero time point.

Figure 1 shows that the early response of the respiratory tract (0-2 h after antigenic stimulation) decreased significantly and late reaction of the respiratory tract (6-8 h after antigenic stimulation) was completely blocked (n=4 sheep per group).

Figure 2 shows that the detained increased airway reactivity, measured 24 h after antigenic stimulation, as measured using a stimulation carbachol, was also completely blocked.

In addition to blocking the increased resistance of the respiratory tract, as shown in table 5, compound 2 also inhibits the increase in the number of inflammatory cells in the samples broncho-alveolar washing liquid (BAL)obtained from these sheep.

Table 5
ProcessingAccount BAL cells (x1000/ml)
BasisNeutrophilsLymphocytesEosinophilsMacrophages
Basis22,04±12,894,82±1,746,29±3,98172,2±20,8
After 8 h after antigenRUB 24.55±14,0813,39±5,4461,58±29,87209,3±44,7
After 24 h after antigen111,7±38,936,30±15,68168,4±95,1to 245.6±20,4
Compound 2 (1.0 mg/kg x 4 days) (last dose=30 min prior to antigenic stimulation)
Basis12,66±2,073,15±0,790,0069,06±1,97
After 8 h after antigen3,17±0,654,16±1,100,37±0,3277,85±2,36
After 24 h after antigen3,86±0,953,72±0,770,04±0,0375,16±2,71

Although in the foregoing description the principles of the present invention, with examples provided for purposes of illustration, it is clear that prakticheskoe implementation of the invention includes all the usual changes adaptation and/or modifications that are included in the scope of the following claims and its equivalents.

1. The compound of formula (I)

where R1selected from the group comprising piperidinyl, pyrrolidinyl and 1,3,8 diazaspiro[4,5]Dec-8-yl (where the place of attachment of the heterocyclic ring is nitrogen atom of the cycle) and-N(R7R8)where the heterocyclic ring optionally substituted by from one to two substituents, independently selected from the group including

a)1-8alkyl, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising aryl, heteroaryl,

(C) phenyl and naphthalenyl,

i) benzothiazolyl,

R7selected from the group comprising hydrogen and C1-8alkyl R8selected from the group including:

aa)1-8alkyl,

ab) cycloalkyl,

ac) cycloalkenyl and

ad) heterocyclyl (where the place of attachment of R8is the carbon atom of the cycle),

where ab) cycloalkenyl, AU) cycloalkenyl and ad) heterocyclyl (where ad heterocyclyl contains at least one cyclic nitrogen atom) deputies and cycloalkyl part AA) Deputy optionally substituted substituents, independently selected from the group including:

ba)1-8 alkyl substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl),

bb) C1-8alkoxy, substituted at the terminal carbon atom by a Deputy selected from the group comprising carboxyl,

bc) carbonyl, substituted Deputy selected from the group comprising From1-8alkyl, aryl, aryl(C2-8)alkenyl,

bd)aryl,

be) heteroaryl,

bf) amino substituted by two substituents, independently selected from the group comprising hydrogen and C1-8alkyl,

bh) halogen,

bi)hydroxy,

bk) heterocyclyl,

where bd) aryl Deputy and heteroaryl part bc include Deputy (halogen)1-3

R4selected from the group comprising aryl and heteroaryl where heteroaryl includes Deputy halogen;

R2and R3linked with the benzene ring and represent hydrogen optional R2and R3together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group comprising From9-C14benzoannelirovannykh cycloalkenyl,9-C14benzaken Tserovani phenyl;

R5selected from the group comprising hydrogen and C1-8alkyl;

R6selected from the group comprising From1-8alkyl and hydroxy, Y is absent and X is the only Vice that is attached via a double bond, and is Oh, and Z is selected from the group comprising a bond, hydrogen, and its salts.

2. The compound according to claim 1 where Z is selected from the group comprising hydrogen.

3. The compound according to claim 1 of formula (Ia)

where R7selected from the group comprising hydrogen and C1-8alkyl,

R8selected from the group including

aa)1-8alkyl,

ab) cycloalkyl,

ac) cycloalkenyl,

ad) heterocyclyl (where the place of attachment of R8is the carbon atom of the cycle),

where ab) cycloalkenyl, AU) cycloalkenyl and ad) heterocyclyl (where ad heterocyclyl contains at least one cyclic nitrogen atom) deputies and cycloalkyl part AA) Deputy optionally substituted substituents, independently selected from the group including:

ba)1-8alkyl substituted at the terminal carbon atom by a Deputy, selected from the group consisting of amino (with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl),

bb)1-8alkoxy, Zam is placed at the end carbon atom Deputy selected from the group comprising carboxyl,

bc) carbonyl, substituted Deputy selected from the group comprising From1-8alkyl, aryl, aryl(C2-8)alkenyl,

bd)aryl,

be) heteroaryl,

bf) amino substituted by two substituents, independently selected from the group comprising hydrogen and C1-8alkyl,

bh) halogen,

bi)hydroxy,

bk) heterocyclyl,

where bd) aryl, and heteroaryl portion Deputy bc include (halogen)1-3

and its salts.

4. The compound according to claim 3, where R7selected from the group comprising hydrogen and C1-4alkyl.

5. The compound according to claim 3, where R7selected from the group comprising hydrogen and methyl.

6. The compound according to claim 3, where R8selected from the group including:

aa)1-8alkyl,

ab) cycloalkyl,

ac) cycloalkenyl and

ad) heterocyclyl (where the place of attachment of R8is the carbon atom of the cycle),

where ab) cycloalkenyl, AU) cycloalkenyl and ad) heterocyclyl deputies (where ad) heterocyclyl contains at least one cyclic nitrogen atom) and cycloalkyl part AA) Deputy optionally substituted substituents, independently selected from the group including:

ba)1-8alkyl substituted at the terminal carbon atom by a Deputy selected from the gr is PPI, consisting of amino (with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl),

bb)1-8alkoxy, substituted at the terminal carbon atom by a Deputy selected from the group comprising carboxyl,

bc) carbonyl, substituted Deputy selected from the group comprising From1-8alkyl, aryl, aryl(C2-8)alkenyl,

bd) aryl,

be) heteroaryl,

bf) amino substituted by two substituents, independently selected from the group comprising hydrogen and C1-8alkyl,

bh) halogen,

bi) hydroxy,

bk) heterocyclyl and

where bd) aryl Deputy and heteroaryl portion bc) includes a Deputy (halogen)1-3,

and provided that the optional Deputy attached to the nitrogen atom of the ring heterocyclyl ad) is not selected from the group including bf) amino (substituted with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl), bh) halogen and bi) hydroxy.

7. The compound according to claim 3, where R8selected from the group comprising ab) cycloalkyl, AU) cycloalkenyl and ad) heterocyclyl (where the place of attachment of R8is the carbon atom of the cycle), where ab) cycloalkenyl, AU) cycloalkenyl and ad) heterocyclyl deputies and cycloalkyl part AA) optionally substituted by substituents independently selected from the group including ba)1-4alkyl, bc) carbonyl (replaced by Deputy selected from the group comprising C1-4alkyl, aryl, and aryl(C2-4)alkenyl) and bd) aryl (where bd) the aryl substituent and the aryl part bc) Deputy substituted with halogen.

8. The compound according to claim 3, where R8selected from the group comprising ab) cyclopentyl, ab) cyclohexyl, AU) cyclohexenyl, ad) pyrrolidinyl and ad) piperidinyl (where the place of connection of pyrrolidinyl and piperidinyl R8is the carbon atom of the cycle), where ab) cyclohexyl, AU) cyclohexenyl, ad) pyrrolidinyl and ad) piperidinyl optionally substituted substituents, independently selected from the group comprising ba)1-4alkyl, bc) carbonyl (replaced by Deputy selected from the group comprising From1-4alkyl, aryl and aryl(C2-4)alkenyl) and bd) aryl, where bd) the aryl substituent and the aryl part bc) Deputy substituted with halogen.

9. The compound according to claim 3, where R8selected from the group comprising ab) cyclopentyl, ab) cyclohexyl, AU) cyclohexenyl, ad) pyrrolidinyl and ad) piperidinyl (where the place of connection of pyrrolidinyl and piperidinyl R8is the carbon atom of the cycle), where ab) cyclohexyl, AU) cyclohexenyl, ad) pyrrolidinyl and ad) piperidinyl optionally substituted substituents, independently selected from the group comprising ba) methyl, ba), tert-butyl, bc) methylcarbamyl, bc) isopropylcarbonate is l, bc) phenylcarbinol, bc) naphthaleneboronic, bc) ventilkappen, bc) peniteniary and bd) phenyl, and where bd) phenyl substituent and the phenyl and naphthalenamine part bc) Deputy optionally substituted from one to two substituents, independently selected from the group comprising fluorine, bromine.

10. The compound according to claim 3, where the compound of formula (Ia) selected from the group including

[2-[3-[[methyl-(4-phenylcyclohexyl)amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[[1-[(6-methoxy-2-naphthalenyl)carbonyl]-3-pyrrolidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[[1-[(6-bromo-2-naphthalenyl)carbonyl]-4-piperidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[[1-[(2E)-3-(4-forfinal)-1-oxo-2-propenyl]-3-pyrrolidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[methyl[1-[(2E)-1-oxo-3-phenyl-2-propenyl]-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[methyl[1-[(2E)-3-(4-were)-1-oxo-2-propenyl]-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic to the slot

[2-[3-[[methyl[1-[(2E)-1-oxo-3-[4-(trifluoromethyl)phenyl]-2-propenyl]-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[[1-[(2E)-3-[4-(dimethylamino)phenyl]-1-oxo-2-propenyl]-4-piperidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[(1-benzoyl-4-piperidinyl)methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[(cyclohexylethylamine)carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[methyl[1-[1-oxo-3-[4-(trifluoromethyl)phenyl]propyl]-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[methyl[1-(2-methyl-1-oxopropyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[(cyclopentylmethyl)carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[[4-(1,1-dimethylethyl)cyclohexyl]methylamino)carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl] phosphonic acid

[2-[3-[[[1-[(6-hydroxy-2-naphthalenyl)carbonyl]-4-piperidinyl]methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl] phosphonic acid

[2-[3-[[(1-acetyl-4-piperidinyl)methylamino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl] phosphonic acid

[2-[3-[[METI is-(4-methylcyclohexyl)amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[1-[[methyl(tricyclo[3.3.1.13,7]Oct-1-ylmethyl)amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[methyl-(4-phenyl-3-cyclohexen-1-yl)amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

and

[1-(1-naphthalenyl)-2-[3-[[[1-(2-naphthalenesulfonyl)-4-piperidinyl)amino]carbonyl]-2-naphthalenyl]-2-oxoethyl]phosphonic acid.

11. The compound of claim 10 where the compound of formula (Ia) is associated with a pharmaceutically acceptable cation with the formation of salts.

12. Connection claim 11, where the cation is selected from the group comprising aluminum, ammonia, benzathine, t-butylamine, calcium, calcium gluconate, calcium hydroxide, chloroprocaine, choline, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, Ethylenediamine, lithium, LiOMe, L-lysine, magnesium, meglumine, NH3, NH4OH, N-methyl-D-glucamine, piperidine, potassium, tert-butyl potassium, potassium hydroxide (aqueous), procaine, quinine, SEH, sodium, sodium carbonate, 2-ethylhexanoate, sodium, sodium hydroxide, triethanolamine, trometer and zinc.

13. The connection section 12, where the cation is selected from the benzathine, t-butylamine, calcium gluconate, calcium hydroxide, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, Ethylenediamine, LiOMe, L-lysine, NH3, NH4OH, N-methyl-D-glucamine, piperidine, of potassium tert-butylate, potassium hydroxide (in the underwater), of procaine, quinine, sodium carbonate, 2-ethylhexanoate sodium, sodium hydroxide, triethanolamine and tromethane.

14. The connection indicated in paragraph 13, where the cation is selected from tert-butylamine, NH4OH and tromethane.

15. The connection 14, where the cation is trometer.

16. The compound of claim 10 where the compound is a [2-[3-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid.

17. Connection P16, where the connection is associated with a pharmaceutically acceptable cation with the formation of salts.

18. The connection 17, where the cation is selected from tert-butylamine, NH4OH and tromethane.

19. Connection P16, where the joint is associated with trometamol with the formation of dibasic salt.

20. The compound according to claim 1 of formula (Ib)

where R1selected from the group comprising piperidinyl, pyrrolidinyl and 1,3,8 tratosphere[4,5]Dec-8-yl(where the place of attachment of the heterocyclic ring is nitrogen atom of the cycle, and-N(R7R8)where the heterocyclic ring optionally substituted by from one to two substituents, independently selected from the group including:

a)1-8alkyl, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising aryl, heteroaryl,

(C) the dryer is l and naphthalenyl

and

i) benzothiazolyl

and its salts.

21. Connection claim 20, where R1selected from the group comprising piperidinyl, pyrrolidinyl and 1,3,8 tratosphere[4,5]Dec-8-yl(where the place of attachment of the heterocyclic ring is nitrogen atom of the cycle where the heterocyclic ring optionally substituted by from one to two substituents, independently selected from the group including

(C) phenyl or naphthalenyl and i) benzothiazolyl, and where the aryl part i) Deputy and (C) phenyl or naphthalenyl optionally substituted substituents, independently selected from the group of halogen.

22. Connection item 21, where R1selected from the group comprising piperidinyl, pyrrolidinyl and 1,3,8 tratosphere[4,5]Dec-8-yl (where the place of attachment of the heterocyclic ring is nitrogen atom of the cycle where the heterocyclic ring optionally substituted by from one to two substituents, independently selected from the group including:

(C) phenyl or naphthalenyl and i) benzothiazolyl.

23. Connection claim 20, where R1selected from the group comprising pyrrolidinyl and piperidinyl (where the place of connection of pyrrolidinyl and piperidinyl R1is the nitrogen atom of the cycle), optionally substituted Deputy selected from the group comprising C) phenyl and (i) benzothiazolyl.

24. Connection claim 20, where the connection forms of the crystals (Ib) selected from the group including

[1-(1-naphthalenyl)-2-oxo-2-[3-[(4-phenyl-1-piperidinyl]carbonyl]-2-naphthalenyl]ethyl]phosphonic acid

[1-(1-naphthalenyl)-2-oxo-2-[3-[(4-oxo-1-phenyl-1,3,8-diazaspiro[4.5]Dec-8-yl)carbonyl]-2-naphthalenyl]ethyl]phosphonic acid

[2-[3-[[4-(4-methoxyphenyl)-1-piperidinyl]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[4-(3-methoxyphenyl)]-1-piperidinyl]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[3-[[4-(2-benzothiazolyl)-1-piperidinyl]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[1-(1-naphthalenyl)-2-oxo-2-[3-[(3-phenyl-1-pyrrolidinyl)carbonyl]-2-naphthalenyl]ethyl]phosphonic acid

and

[1-(1-naphthalenyl)-2-oxo-2-[3-[[3-(2-phenylethyl)-1-pyrrolidinyl]carbonyl]-2-naphthalenyl]ethyl]phosphonic acid.

25. The compound according to claim 1 of formula (Ic)

where R2and R3linked with the benzene ring and independently selected from the group including

sa)hydrogen

optional R2and R3together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group comprising From9-C14benzoannelirovannykh cycloalkenyl,9 14benzoannelirovannykh phenyl,

R4selected from the group comprising aryl and heteroaryl, where aryl and heteroaryl includes Deputy halogen;

R5selected from the group comprising hydrogen and C1-8alkyl

and

R6selected from the group comprising From1-8alkyl and hydroxy,

and its salts.

26. Connection A.25, where R2and R3independently selected from the group comprising CA) hydrogen, optionally R2and R3together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group comprising naphthalene and anthracene.

27. Connection p, where R2and R3independently selected from the group comprising CA) hydrogen, optionally R2and R3together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system is naphthalene.

28. Connection A.25, where R4selected from the group comprising aryl and heteroaryl where heteroaryl includes Deputy halogen.

29. Connection A.25, where R4selected from the group comprising phenyl, naphthalenyl and benzothiazyl (where benzothiazyl optionally substituted from one of the two halogen substituents).

30. Connection A.25, where R4selected from the group comprising phenyl, naphthalenyl and benzothiazyl (where benzothiazyl optionally substituted chloride Deputy).

31. Connection A.25, where R5selected from the group comprising hydrogen and C1-4alkyl.

32. Connection A.25, where R5selected from the group comprising hydrogen and methyl.

33. Connection A.25, where R5represents hydrogen.

34. Connection A.25, where R6selected from the group comprising From1-4alkyl and hydroxy.

35. Connection A.25, where R6selected from the group comprising methyl and hydroxy.

36. Connection A.25, where the compound of formula (Ic) selected from the group including

[2-[3-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-2-oxo-1-phenylethyl]phosphonic acid

methyl ester [2-[3-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

[2-[2-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]phenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphonic acid

methyl-[2-[3-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphinic acid

and

[1-(5-chlorobenzo[b]Tien-3-yl)-2-[3-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]-2-Naftali is Il]-2-oxoethyl]phosphonic acid.

37. Connection p, where the compound is a methyl-[2-[3-[[methyl[1-(2-naphthalenesulfonyl)-4-piperidinyl]amino]carbonyl]-2-naphthalenyl]-1-(1-naphthalenyl)-2-oxoethyl]phosphinic acid.

38. The method of obtaining the compounds of formula (I), which consists in the interaction in suitable conditions, the first compound of the formula (A)

with a second compound selected from the group comprising the compounds of formula (I) and formula (C)

obtaining a third compound selected from the group comprising the compounds of formula (D) and formula (E)

where R7selected from the group comprising hydrogen and C1-8alkyl R8selected from the group including

aa)1-8alkyl,

ab) cycloalkyl,

ac) cycloalkenyl and

ad) heterocyclyl (where the place of attachment of R8is the carbon atom of the cycle),

where ab) cycloalkenyl, AU) cycloalkenyl and ad) heterocyclyl (where ad) heterocyclyl contains at least one cyclic nitrogen atom) deputies and cycloalkyl part AA) Deputy optionally substituted substituents, independently selected from the group including

ba)1-8alkyl substituted at the terminal carbon atom by a Deputy, using the data from the group consisting of amino (with two substituents, independently selected from the group comprising hydrogen and C1-8alkyl),

bb) C1-8alkoxy, optionally substituted at the terminal carbon atom by a Deputy selected from the group comprising carboxyl,

bc) carbonyl, substituted Deputy selected from the group comprising From1-8alkyl, aryl, aryl(C2-8)alkenyl,

bd)aryl,

be) heteroaryl,

bf) amino substituted by two substituents, independently selected from the group comprising hydrogen and C1-8alkyl,

bh) halogen,

bi)hydroxy,

bk) heterocyclyl,

where bd) aryl Deputy and heteroaryl part bc include Deputy (halogen)1-3

R4selected from the group comprising aryl and heteroaryl where heteroaryl includes Deputy halogen;

R2and R3linked with the benzene ring and represent hydrogen

optional R2and R3together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group comprising From9-C14benzoannelirovannykh cycloalkenyl,9-C14benzoannelirovannykh phenyl;

R5selected from groups who, comprising hydrogen and1-8alkyl;

R6selected from the group comprising From1-8alkyl and hydroxy,

Y is absent and X is the only Vice that is attached via a double bond, and a represents Oh, and

Z is selected from the group comprising a bond, hydrogen, and its salts.

39. The method according to § 38, where the first compound of the formula (A) is selected from compounds of formula (A')

where R8bselected from the group comprising From1-8alkyl.

40. The method according to § 38, where the second compound of the formula (I) selected from the compounds of formula (a')

41. The method according to § 38, where the interaction is carried out in the presence of a solvent selected from the group comprising acetone and mediatisation.

42. The method according to § 38, where the interaction is carried out at a temperature of about 65°C.

43. The method according to § 42, where the interaction is carried out at a temperature of about 65°C for from about 6 to about 7 o'clock

44. The method according to § 38, where the third connection clear.

45. The method according to item 44, where cleaning is carried out by crystallization.

46. The method according to § 38, where the third compound selected from the group comprising the compounds of formula (D) and formula (E), where R5selected from the group comprising From1-8alkyl, and

R6selected from the group comprising From18 alkyl

subjected to hydrolysis in suitable conditions to convert R5in N and R6in IT.

47. The method according to § 38, where the compound of formula (D) or formula (E) is associated with the cation with the formation of salts.

48. The method according to p, where the cation is selected from the group including benzathine, t-butylamine, calcium gluconate, calcium hydroxide, choline bicarbonate, choline chloride, cyclohexylamine, diethanolamine, Ethylenediamine, LiOMe, L-lysine, NH3, NH4OH, N-methyl-D-glucamine, piperidine, tert-butyl potassium, potassium hydroxide (aqueous), procaine, quinine, sodium carbonate, 2-ethylhexanoate, sodium, sodium hydroxide, triethanolamine and trometer.

49. The method according to p, where the cation is provided in a quantity sufficient to obtain a primary dibasic salt.

50. The compound of formula (C)

R2and R3linked with the benzene ring and independently selected from the group including

sa)hydrogen

optional R2and R3together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group comprising From9-C14benzoannelirovannykh cycloalkenyl,9-C14benzoannelirovannykh phenyl;

R4selected from g is PPI aryl and heteroaryl, where heteroaryl includes Deputy halogen,

R5selected from the group comprising hydrogen and C1-8alkyl,

and

R6selected from the group comprising From1-8alkyl and hydroxy.

51. Connection item 50, where R2and R3linked with the benzene ring adjacent carbon atoms and are independently selected from the group comprising CA) hydrogen, optionally, R2and R3form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group comprising naphthalene and anthracene.

52. Connection item 50, where R2and R3linked with the benzene ring adjacent carbon atoms and are independently selected from the group comprising CA) hydrogen, optionally, R2and R3together form a ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system is naphthalene.

53. Connection item 50, where

R2and R3linked with the benzene ring adjacent carbon atoms and together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group including the nd naphthalene and anthracene,

R4represents aryl,

R5selected from the group comprising hydrogen and C1-8alkyl, and

R6represents a C1-8alkyl or hydroxy.

54. Connection item 50, where

R2and R3linked with the benzene ring adjacent carbon atoms and together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group comprising naphthalene and anthracene,

R4is an aryl selected from the group comprising phenyl, naphthalenyl and sensational,

R5selected from the group comprising hydrogen and C1-4alkyl, and

R6selected from the group comprising methyl and hydroxy.

55. The method of producing benzoylacetone formula (C), including (a) the interaction between the anhydride of formula (F)

with the compound of the formula (G)

in suitable conditions in the presence of alkali metal (M) to obtain the compounds of formula (H)

b) and the interaction of the compounds of formula (H) under conditions suitable to obtain benzoylacetone formula (C)

where R2and Rsub> 3linked with the benzene ring and independently selected from the group including

sa) hydrogen

optional R2and R3together form at least one ring condensed with the benzene ring, forming, thus, a polycyclic system, where the polycyclic system selected from the group comprising From9-C14benzoannelirovannykh cycloalkenyl,9-C14benzoannelirovannykh phenyl,

R4selected from the group comprising aryl and heteroaryl where heteroaryl includes Deputy halogen

R5selected from the group comprising hydrogen and C1-8alkyl, and

R6selected from the group comprising From1-8alkyl and hydroxy.

56. Composition, inhibiting serine protease containing compound according to claim 1 and a pharmaceutically acceptable carrier.

57. A method of obtaining a composition, comprising mixing the compound according to claim 1 and a pharmaceutically acceptable carrier.

58. A method of treating inflammatory or mediated by the serine proteinase disorders ordaudio in this subject, comprising the introduction of this subject a therapeutically effective amount of a compound according to claim 1.

59. The method according to § 58, where the inflammatory or mediated by the serine proteinase breach selected from the group comprising lung FOTS the extreme condition, chronic obstructive pulmonary disease, asthma, emphysema, bronchitis, psoriasis, allergic rhinitis, viral rhinitis, ischemia, arthritis, glomerulonephritis, post-operative scarring, trauma during re-perfusion, hypertension, myocardial infarction with cardiac hypertrophy, arteriosclerosis, retinopathy, and vascular restenosis.

60. The method according to § 58, where a therapeutically effective amount of a compound according to claim 1 is from about 0.001 to about 300 mg/kg/day.

61. The method according to § 58, including an introduction to the subject a therapeutically effective amount of the composition according p.

62. The method according to p, where a therapeutically effective amount of a compound according to claim 1 is from about 0.001 to about 300 mg/kg/day.

63. A method of treating asthma in need thereof of a subject, comprising the introduction of this subject a therapeutically effective amount of a compound according to claim 1.

64. The method according to p, where a therapeutically effective amount of a compound according to claim 1 is from about 0.001 to about 300 mg/kg/day.



 

Same patents:

FIELD: chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2,4-dichloro-2-dichlorophosphorylbutanoic acid chloroanhydride of the formula: . Method involves interaction of phosphorus pentachloride with γ-butyrolactone in inert organic solvent medium followed by formation of intermediate adduct of phosphorus pentachloride and γ-butyrolactone that then is treated with sulfur-containing compound up to preparing the end product. As a sulfur-containing compound the method involves using sulfuryl chloride, and treatment is carried out at temperature above 25°C. Method provides simplifying process and enhanced yield of the end product.

EFFECT: improved preparing method.

1 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for preparing 7,7-dichlorobicyclo[4,1,0]heptyl-2-phosphonic acid dichloroanhydride of the formula (1):

. Method for preparing 7,7-dichlorobicyclo[4,1,0]heptyl-2-phosphonic acid dichloroanhydride of the formula (1) involves interaction of dichlorobicyclo[4,1,0]heptane with phosphorus trichloride taken in the mole ratio = 1:2 in the presence of oxygen. Synthesized compound represents a valuable semi-finished product used in synthesis of organophosphorus substances.

EFFECT: improved preparing method, expanding assortment of organophosphorus compounds.

2 ex

FIELD: organic synthesis.

SUBSTANCE: invention relates to synthesis of organophosphorous compounds bearing P-C bond, in particular to preparation of novel 2-dichloromethylenecyclohexylphosphonic acid dichloride (formula I: comprising reaction of 2-alcoxy-7,7-dichlorobicyclo[4.1.0]heptane with phosphorus trichloride in presence of aluminum trichloride used at molar ratio 1:1:1 or 1:2:1, followed by treatment of resulting complex with water in dichloromethane.

EFFECT: increased choice of organophosphorous compounds for use as intermediates in organophosphorous synthesis.

4 ex

The invention relates to organic chemistry, specifically to the method of disposal of toxic phosphorus-containing organic compounds, in particular sarin and soman

The invention relates to an improved process for the preparation of organophosphorus compounds

The invention relates to the field of chemistry of organophosphorus compounds and can be used to produce fire-resistant hydraulic and lubricating fluids used in power, metallurgical, coal, machine building and other industries, for example in control systems and lubrication of steam turbines, hydraulic coal mining machines, hydraulic machines, injection molding etc

FIELD: chemistry of organophosphorus compounds.

SUBSTANCE: invention relates to the improved method for synthesis phosphorus-chlorine-containing methacrylates that can be used in synthesis of polymeric, among them, uncolored, optically transparent and composition materials with reduced inflammability. Invention describes a method for synthesis of phosphorus-chlorine-containing methacrylates of the general formula:

wherein R means lower alkyl, chloroalkyl, alkoxyl, phenoxyl or group of the formula:

R1 means lower alkoxyl, phenoxyl or group of the formula:

Method involves interaction of phosphoric pentavalent acid chloroanhydrides with methacrylic acid glycidyl ester at heating in the presence of hexamethylenephosphorotriamide or dimethylformamide as a catalyst wherein catalyst is taken in the amount 0.3-0.6% of reagents mass, and process is carried out at rise of temperature from 40°C to 80°C in the presence of compound chosen from the group: alkyl- or alkoxy-substituted phenols taken in the amount 0.03-0.3% of reagents mass. Method provides decreasing water absorption of (co)polymerization products of synthesized phosphorus-chlorine-containing methacrylates and reducing retention time of surface stickiness of fiber glass synthesized on their basis and at retention the level of other properties, among them transparence and colorless.

EFFECT: improved method of synthesis, improved and valuable properties of compounds.

2 tbl, 10 ex

FIELD: organic chemistry, chemical technology, medicine.

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

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

16 cl, 10 tbl, 87 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing N-phosphonomethylglycine. Method involves interaction of derivative of hexahydrotriazine of the formula (II):

wherein X represents CN, COOZ, CH2OY and others; Z and Y represent hydrogen atom and others with triacylphosphite of the formula: P(OCOR3)3 (III) wherein R3 means (C1-C18)-alkyl or aryl that can be substituted. The prepared product is hydrolyzed and (if X represents CH2OY) oxidized. The proposed method is a simple in realization, economy and provides high degree of the end product purity.

EFFECT: improved preparing method.

19 cl, 11 ex

FIELD: chemistry of organophosphorus compounds.

SUBSTANCE: invention relates to compounds with the bond C-P, namely to phosphorus-boron-containing methacrylate that can be used as inhibitor of combustion of polyvinyl alcohol-base film materials. Invention describes phosphorus-boron-containing methacrylate of the following formula: wherein n = 4-8. Polyvinyl alcohol films modified with indicated phosphorus-boron-containing methacrylate shows the enhanced refractoriness, rupture strength up to 206 kgf/cm2, water absorption up to 240% and relative elongation up to 12%.

EFFECT: valuable properties of substance.

1 tbl, 2 ex

FIELD: organic chemistry, in particular improved method for production of phosphorinated and chlorinated methacrylates.

SUBSTANCE: invention relates to method for production of compounds having general formula , wherein R is lower alkyl and R1 is lower alkoxyl, phenoxyl, or group of formula . Claimed method includes reaction of pentavalent phosphorous acid chloroanhydride with glycydil methacrylate at 20-50°C in presence of titanium tetrachloride as catalyst in amount of 0.02-0.05 % calculated as reagent mass.

EFFECT: one-step method for production of phosphorous and chlorine containing methacrylates with improved water resistance.

2 tbl, 7 ex

The invention relates to new biologically active phosphonate derivative of acyclovir

The invention relates to the chemistry of organophosphorus compounds, and in particular to a new method of obtaining N-substituted phosphorylated of imidates having the structure zenatello group

The invention relates to derivatives of phosphinic and phosphonic acids of the formula (I)

where R1means unsubstituted or substituted phenyl, -O-(C1-C6)-alkyl, R2means hydrogen, RR3mean hydrogen, alkyl, unsubstituted or substituted phenyl, COOH group or - (CH2)2-CH(COOH)-NH-SO2-C6H4-C6H4-Cl(n), t stands for an integer of 1-4, And is a covalent bond, X is a group-CH=CH -, - group,- (CH2)about- where is 0,1,2 or 3, Y1and Y2mean-OH, -(C1-C4)-alkyl, -O-(C1-C4)-alkyl, and/or their stereoisomeric forms and/or physiologically acceptable salts

The invention relates to new derivatives of benzazepine-N-acetic acid, substituted phosphonic acid, which are pharmaceutically active compounds

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a novel method for synthesis of N-phosphonomethylglycine. Method involves interaction of hexahydrotriazine compound with triacyl phosphite in organic solvent, saponification of formed phosphonic compound after preliminary extraction into aqueous phase, separation of organic phase and precipitation of N-phosphonomethylglycine by pH value control in the range from 0.5 to 2.0. Invention prevents decomposition of an organic solvent in saponification.

EFFECT: improved method of synthesis.

8 cl, 3 tbl, 4 ex

FIELD: chemical industry; methods of production of the water solution of disodium or dipotassium salt of zinc oxyethyledene phosphonate.

SUBSTANCE: the invention is pertaining to the method of production of the water solutions of disodium or dipotassium salt of zinc oxyethyledene phosohonate with concentration of 15-23 % used as the mineral salts sediments inhibitors and as the microfertilizers and having the properties to inhibit corrosion. The method provides for interaction of the water solution of the sodium zincate or the potassium zincate with the 20-60 % water solution of the oxyethyledenephosphonic acid at the temperature of 60-80°С. As a rule, the sodium zincate or the potassium zincate are produced by interaction of 5-20 % water solution of the sodium hydroxide or the potassium hydroxide with zinc oxide at the temperature of 50-75°С at the molar relation of 2:1.

EFFECT: the invention ensures, that as the rule the sodium zincate or the potassium zincate are produced by interaction of the low-concentration water solutions of the sodium hydroxide or the potassium hydroxide with zinc oxide at the temperature of 50-75°С at the molar relation of 2:1.

2 cl, 1 tbl, 11 ex

FIELD: industrial and waste water treatment.

SUBSTANCE: composition contains 10-25% sodium alkylaminophosphonates having general formula: , in which n=9-19, 1-5% sodium chloride, and 70-89% water. Composition is prepared by heat treatment of industrial-grade aliphatic amines with phosphorous acid and formaldehyde. In particular, treatment of aliphatic amines of formula CH3-(CH2)-NH2 (n=9-19) is carried out in presence of hydrochloric acid as catalyst at 95-105°C for 1.5-3.0 h followed by cooling and neutralization with sodium alkali to pH 10.

EFFECT: enhanced treatment efficiency.

2 cl, 1 tbl

FIELD: chemical technology.

SUBSTANCE: invention relates to technology for synthesis of crystalline nitrilotrimethylphosphonic acid sodium salts. For synthesis of nitrilotrimethylphosphonic acid disodium salt monohydrate the method involves preliminary synthesis of nitrilotrimethylphosphonic acid by interaction of phosphorus trichloride, formaldehyde and ammonia or its derivative followed by neutralization with sodium hydroxide in the content in the reaction mass 46-54 wt.-% of nitrilotrimethylphosphonic acid and 6.0-16.0 wt.-% of hydrogen chloride up to pH value 2.5-4.5, and isolation of the end compound by crystallization. The mass part of the main substance in synthesized product is 88-95%, the content of chloride ions is 1.2-2.0%, yield is 50-60% as measured for PCl3. Synthesized compound is recommended for using as chelate compounds as a component of detergents, anti-rheological additive in drilling solutions, plasticizing agents for building concretes, in wine-making industry, as inhibitors of salt depositions in heat and power engineering and others fields.

EFFECT: improved method of synthesis.

2 tbl, 12 ex

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