Derivatives of beta-amino acid nitriles

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

 

The present invention relates to new derivatives of NITRILES β-amino acids, their preparation and use as pharmaceuticals. In particular, the invention relates to new derivatives of NITRILES β-amino acids of General formula (I)

where

R1means hydrogen, aryl, -CO-Raor-SO2-Rbwhere

Rameans (ness.)alkyl, (ness.)alkoxy, cycloalkyl,

cycloalkyl(ness.)alkyl, cycloalkyl(ness.)alkoxy, cycloalkane, aryl, aryloxy, aryl(ness.)alkyl, aryl(ness.)alkoxy, aryloxy(ness.)alkyl, aryl-S-(ness.)alkyl, aryl(ness.)alkenyl, heteroaryl, heteroaryl(ness.)alkyl or heteroaryl(ness.)alkoxy,

Rbmeans aryl, aryl(ness.)alkyl or heteroaryl,

R2means hydrogen or (ness.)alkyl,

R3means hydrogen or (ness.)alkyl,

R4means hydrogen or (ness.)alkyl,

R5means hydrogen, (ness.)alkyl, cycloalkyl or aryl,

n denotes 1 or 2,

and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

Cysteine protease treated as a lysosomal mediators terminal protein degradation. However, some newly discovered members of this class of enzymes are regulated proteases with limited expression in tissues that assistance mewet specific role in cellular physiology and, therefore, allows for a specific focus of these types of activity that do not overlap with the normal degradation of lysosomal proteins. The creation of specific inhibitors of cysteine proteases heralds getting new products for the correction of immunity, osteoporosis, neurodegeneration, chronic inflammation, cancer and malaria (Drug News Perspect 1999, 12(2), 73-82; Chapman and others, Annu. Rev. Phys. 1997, 59, 63-88).

Cysteine protease can be grouped into two subfamilies: the family enzyme associated with the conversion of interleukin-1β (ICE), and Papanova superfamily of cysteine proteases. Currently, there are at least 12 human proteases papadopulo of the superfamily, which received sequence (cathepsin B, L, H, S, O, K, S, W, F, V(L2), Z(X) and biomaterials). Cathepsin It was first opened in the form of cDNA, characteristic of rabbit osteoclasts and designated as OS-2 (Tezuka and others, J. Biol. Chem. 1994, 269, 1106-1109). Recent observations indicate that cathepsin It is the most powerful of these is still Lactasoy mammals. Catepsin To, as well as cathepsins S and L are also powerful collagenases and gelatinases. Macrophages under special circumstances, apparently, able to mobilize to the surfaces of the cell active protease inside endosomal and/or lysosomal comp is rtmental. In this case, the surface of the partition cell surface/substrate becomes compartment, from which are excluded endogenous inhibitors, and can be considered as a physiological extension complementary mechanism. This physiological type is a natural characteristic of osteoclasts, macrophages and bone may also be used by other macrophages or cells in the context of inflammation. The excess of cathepsin K in osteoclasts leads to the assumption that cathepsin To play an important role in bone resorption, Studies have shown that cathepsin It is the predominant cysteine protease in osteoclasts and is specifically expressed in human osteoclasts. Reported correlation between the inhibition of the activity of cysteine protease and bone resorption (Lerner and others, J.Bone Min. Res. 1992, 7, 433; Everts and others, J.Cell. Physiol. 1992, 750, 221). Cathepsin It was determined in synovial fibroblasts of patients with radioactivity, as well as in mouse the hypertrophic chondrocytes (Hummel and others, J.Rheumatol. 1998, 25(10), 1887-1894). Both results indicate a direct role of cathepsin K in erosion of the cartilage. In the publication .Libby (Libby and others, J.Clin. Invest. 1998, 102 (3), 576-583) reported that normal arteries contain little or do not contain quite catepsin To or S, whereas macrophages in atheroma contain excessive amounts of immunoreactive cathepsins K and S. the First is the first part alactolyticus activity in tissue extracts, associated with human atheroma compared to naturescience arteries could be suppressed by using A, selective inhibitor of cysteine proteases.

Tumor progression and metastases are characterized by invasion of the tumor into surrounding tissues, as well as the collapse of tumor cells from primary tumors and metastatic infiltration of cells into organs. These processes are associated with degradation of extracellular matrix proteins and, therefore, require proteolytic activity. Cathepsin identified in primary breast tumors, and formed from the tumors of breast cancer bone metastases (Littlewood-Evans and others, Cancer Res. 1997, 57, 5386-5390).

Different classes of compounds, such as aldehydes, α-Methocarbamol derivatives, kaleidocycle, diazomethylene (acyloxy)methylketone, ketomalonate salt, epoxyacrylate derivatives, vinylsulfonic, aminoketone and hydrazides, identified as inhibitors of cysteine proteases (Schirmeister, etc., Chem. Rev. 1997, 97, 133-171; Veber and others, Proc. Natl. Acad. Sci. USA 1997, 94, 14249-14254). The disadvantages of these compounds include the loss of selectivity, poor solubility, quick removal of plasma and cytotoxicity. There is therefore a need in the creation of new inhibitors that are applicable in the treatment of diseases caused by PA the ideological levels of proteases, particularly cysteine proteases, including cathepsins, especially cathepsin K.

Derivatives of NITRILES R-amino acids according to the present invention have inhibitory activity against cysteine proteases, more particularly in respect of cysteine proteases papadopulo of the superfamily, even more specifically in relation to the cysteine protease family of cathepsins, most specifically in relation to cathepsin K. it has been Unexpectedly found that this inhibitory effect on cathepsin It is selective with respect to other cathepsins. Despite the fact that compounds of General formula (I) very effectively inhibit cathepsin To the inhibition of other proteases, such as cathepsin S, cathepsin L and cathepsin In much weaker. Therefore, the new compounds of General formula (I) are useful for specific inhibition of cathepsin K. Accordingly, they can be used for treating diseases associated with cysteine-proteases, such as osteoporosis, osteoarthritis, rheumatoid arthritis, metastatic tumors, glomerulonephritis, atherosclerosis, myocardial infarction, angina, unstable angina, stroke, perforation of blood platelets, transient ischemic attacks, transient blindness, a disease associated with blocked peripheral arteries, restenosis after angioplasty and insertion of a stent formed the E. aneurysm of the abdominal aorta, inflammation, autoimmune disease, malaria, cytopathy tissue of the ocular fundus and respiratory diseases. Accordingly, the present invention relates to a method for prevention and/or therapeutic treatment of diseases associated with cysteine-proteases, such as osteoporosis, osteoarthritis, rheumatoid arthritis, metastatic tumors, glomerulonephritis, atherosclerosis, myocardial infarction, angina, unstable angina, stroke, perforation of blood platelets, transient ischemic attacks, transient blindness, a disease associated with blocked peripheral arteries, restenosis after angioplasty and insertion of the stent, the formation of aneurysms of the abdominal aorta, inflammation, autoimmune disease, malaria, cytopathy tissue of the ocular fundus and respiratory diseases, the method which includes introducing the compound of the formula (I) a person or an animal. The present invention relates also to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier and/or excipient. In addition, the present invention relates to the use of such compounds in the preparation of medicines for the treatment of disorders that are associated with the cysteine proteases. The present invention relates also to methods of preparing compounds is ormula (I).

If not indicated otherwise, the following definitions are adopted for illustration and designation of the meaning and boundaries of the various terms used in the context of the description.

In this description, the term “lower” is used to represent the group consisting of 1 to 7, preferably from 1-4 carbon atoms.

The term “alkyl” refers to monovalent saturated hydrocarbon radical is branched or linear chain of 1-20 carbon atoms, preferably from 1 to 16 carbon atoms. Alkyl groups can be substituted, e.g. by halogen atoms.

The term “(ness.)alkyl” refers to monovalent alkyl, the radical is branched or linear chain of 1 to 7 carbon atoms, preferably 1-4 carbon atoms. Further, this term is illustrated as examples of such radicals as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl and the like.

The term “cycloalkyl” refers to a monovalent carbocyclic the radical of 3-10 carbon atoms, preferably 3-6 carbon atoms.

The term “halogen” refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine are preferred, more preferred are chlorine and bromine.

The term “alkoxy” refers to the group R'-O-, where R' is alkyl. The term “(ness.)alkoxy” refers to the group R'-O-, where R' means(ness.)alkyl.

The term “alkenyl” means by itself or in combination with other groups, the remainder of the hydrocarbon with a linear or branched chain containing the double bond and up to 20, preferably up to 16 carbon atoms. The term “(ness.)alkenyl” refers to the residue of a hydrocarbon with a linear or branched chain containing the double bond and up to 7, preferably up to 4 carbon atoms.

The term “aryl” refers to phenyl or naftilos group, which optionally may be mono - or mnogozahodnoy-alkyl, halogen, hydroxy, nitro, alkoxy, alkylcarboxylic, aryl, aryloxy or Allakaket. Preferred substituents are (ness.)alkyl, fluorine, chlorine, bromine, hydroxy, (ness.)alkoxy, (ness.)alkylcarboxylic, phenyl, phenoxy, aryl(ness.)alkyl and aryl(ness.)alkoxy. More preferred substituents are hydroxy, methyl, chlorine, bromine and methoxy. The term “aryl”also refers to substituted phenyl group, which represents benzo[1,3]dioxol-5-ilen group.

The term “heteroaryl” refers to an aromatic 5 - or 6-membered cycle which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen or sulphur, such as furyl, pyridyl, 1,2-, 1,3 - and 1,4-diazines, thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, and furyl and thienyl are preferred. The term “heteroaryl”, which IMO this means bicyclic aromatic group comprising two 5 - or 6-membered cycle in which one or both of the loop can contain 1, 2 or 3 atoms selected from nitrogen, oxygen or sulfur, such as, for example, benzo[1,2,5]oxadiazol or benzofuranyl. Heteroaryl group may be of such a character substitution, which is described earlier in connection with the term “aryl”.

The term “pharmaceutically acceptable salt” includes salts of compounds of formula (I) with inorganic or organic acids, such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, n-toluensulfonate and the like, acids which are non-toxic to living organisms.

The term “pharmaceutically acceptable esters” means esters of compounds of formula (I)in which hydroxyl groups are converted into the corresponding esters with inorganic or organic acids, such as hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, n-colorswitch the slot, etc, with acids, which are non-toxic to living organisms.

In detail, the present invention refers to compounds of formula (I)

where

R1means hydrogen, aryl, -CO-Raor-SO2-Rbwhere

Rameans (ness.)alkyl, (ness.)alkoxy, cycloalkyl, cycloalkyl(ness.) alkyl, cycloalkyl(ness.)alkoxy, cycloalkane, aryl, aryloxy, aryl(ness.)alkyl, aryl(ness.)alkoxy, aryloxy(ness.)alkyl, aryl-S-(ness.)alkyl, aryl(ness.)alkenyl, heteroaryl, heteroaryl(ness.)alkyl or heteroaryl(ness.)alkoxy,

Rbmeans aryl, aryl(ness.) alkyl or heteroaryl,

R2means hydrogen or (ness.)alkyl,

R3means hydrogen or (ness.)alkyl,

R4means hydrogen or (ness.)alkyl,

R5means hydrogen, (ness.)alkyl, cycloalkyl or aryl,

n denotes 1 or 2,

and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

The compounds of formula (I) contain at least 2 asymmetric carbon atoms and can exist in the form of optically pure enantiomers or in the form of racemates. The invention encompasses all these forms. Preferred compounds of formula (I) are the compounds of formula (Ia)

where

R1, R2, R3, R4, R5and n have the given the data above values, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters. The compounds of formula (Ia) include CIS-and TRANS-isomers. Other preferred compounds of formula (I) are CIS-isomers of formula (Ib)

where

R1, R2, R3, R4, R5and n have the above meanings, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters. Additional preferred compounds of formula (I) are the compounds of formula (IC)

where

R1, R2, R3, R4, R5and n have the above meanings, and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters. The compounds of formula (IC) include CIS-and TRANS-isomers.

The compounds of formula (I)in which n is 2 are preferred. The compounds of formula (I)in which R2, R3and/or R4means a hydrogen atom, are preferred. Another preferred embodiment of the invention relates to compounds of formula (I)in which R5means aryl, especially those compounds in which R5means phenyl or naphthyl, optionally substituted (ness.)by alkyl, halogen, hydroxy, (ness.)alkoxy or (ness.)alkylcarboxylic and, or in which R5means benzo[1,3]dioxol. In addition, compounds of General formula (I)in which R5means phenyl or naphthyl, optionally substituted by hydroxy, methoxy, stands, acetoxy, chlorine or bromine, or where R5means benzo[1,3]dioxin, are also preferred when the substitution of phenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-were, 2,4-acid, 3,4-acid, 3-chlorophenyl, 3-Bromphenol, 4-bromperidol or benzo[1,3]dioxol-5-yl, which is especially preferred. Other preferred compounds of formula (I) are those in which R5means hydrogen. Additional preferred compounds of formula (I) are those in which R5means cycloalkyl, more preferably cyclopropyl.

The compounds of formula (I)in which R1means-CO-Raand Rahas the above meaning, are preferred. The compounds of formula (I)in which R1means-CO-Raand Rameans cycloalkyl, cycloalkyl(ness.)alkyl, cycloalkane, aryl, aryloxy, aryl(ness.)alkyl, aryl(ness.)alkoxy, aryloxy(ness.)alkyl, aryl-S-(ness.)alkyl, aryl(ness.)alkenyl or heteroaryl(ness.)alkoxy, especially preferred. Additional preferred embodiments of the invention are compounds f is rmula (I), in which R1means-CO-Raand Rameans phenyl, optionally substituted phenyl, cyano and/or fluorine, or Rameans benzyloxy, optionally substituted stands, chlorine, fluorine, methoxy, nitro and/or by trifluoromethyl, or Rameans phenylidole, thiophenemethylamine, cyclopentyloxy, thiophenemethylamine, naphthyloxy, difeniltiomochevinoi or phenoxy. Especially preferred are the compounds of formula (I), where R1means-CO-Raand Rameans benzyloxy, phenylfenesin, thiophene-2-ylmethylene or thiophene-3-ylmethylene. Another preferred embodiment relates to compounds of formula (I), where R1means-SO2-Rband Rbhas the above specified values. Preferably Rbmeans phenyl, optionally substituted by chlorine, cyano and/or methylcobalamine, or Rbmeans benzyl or benzo[1,2,5]oxadiazol. Most preferably, Rbmeans 4-chlorophenyl. Additional preferred embodiment of the invention relates to compounds of formula (I), where R1means phenyl, optionally substituted by ataxia. Other preferred compounds of formula (I) are those in which R1means-CO-Raand Rameans benzyl, optionally substituted by chlorine, or phenyl, optional what about the substituted (ness.)the alkyl, (ness.)alkoxy or cyano, preferably those in which Rameans 4-ethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-cyanophenyl, 4-tert.-butylphenyl or 4-Chlorobenzyl. Additional preferred compounds of the present invention are those in which R1means-CO-Raand Rameans heteroaryl, preferably those in which Ramean 5-methoxybenzophenone-2-yl.

Preferred compounds of formula (I) are those selected from the group consisting of

benzyl ester (1R,2R)-(2-{(S)-[cyano(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide of CIS-1-(3-phenylacetylamino)-cyclohexanecarbonyl acid,

benzyl ether of (R)-{2-[(S)-(cianfanelli)-(R)-carbarnoyl]cyclohexyl}-carbamino acid,

benzyl ester SYN-{2-[(S)-(cianfanelli)carbarnoyl]cyclohexyl}-carbamino acid,

benzyl ester of CIS-(2-{(R)- and (S)-[cyano-(2,4-acid)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

[cyano-(3-hydroxyphenyl)methyl]amide, TRANS-2-(4-chlorobenzenesulfonamide)-cyclohexanecarbonyl acid,

benzyl ester, TRANS-{2-[(benzo[1,3]dioxol-5-altianalis)carbarnoyl]-cyclohexyl}carbamino acid,

benzyl ester of CIS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}cyclohexyl)-to raminosoa acid,

benzyl ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

(R)- and (S)-cyanophenylacetic CIS-2-(3-phenylacetylamino)cyclohexanecarbonyl acid,

benzyl ether (2-{[cyano-(3,4-acid)methyl]carbarnoyl}cyclohexyl)-carbamino acid (1 CIS-racemate),

benzyl ether of CIS-{2-[(R)- and (S)-(cyano-m-trimethyl)carbarnoyl]cyclohexyl}-carbamino acid,

thiophene-3-Eletropaulo ether (2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ester of CIS-(2-{(R)- and (S)-[cyano-(4-methoxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ester of CIS-(2-{(R)- and (5)-[cyano-(3-methoxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

thiophene-2-Eletropaulo ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ester of CIS-(2-{(R)- and (S)-[(3-chlorophenyl)cyanomethyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ether of CIS-{2-[(cianfanelli)carbarnoyl]cyclohexyl}carbamino acid,

benzyl ester, TRANS-(2-{[(3-bromophenyl)cyanomethyl]carbarnoyl}cyclohexyl)-carbamino acid,

benzyl ester of CIS-(2-{(R)- and (S)-[(4-bromophenyl)cyanomethyl]carbarnoyl}-cyclohexyl)carbamino acid,

cyclopentenone ester of CIS-(2-{[(R)- and (S)-cyano-(3,4-dimetho Setenil)methyl]-carbarnoyl}cyclohexyl)carbamino acid,

2-thiophene-2-Eletropaulo ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]-carbarnoyl} cyclohexyl)carbamino acid,

2-methylbenzylamino ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

[cyano-(3-hydroxyphenyl)methyl]amide, TRANS-2-phenylmercurydimethyldithiocarbamate acid,

2-chlorobenzylamino ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ester of CIS-(2-{(R)- and (S)-[(4-chlorophenyl)cyanomethyl]carbarnoyl}-cyclohexyl)carbamino acid,

4-fermentelos ether (2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}cyclohexyl)carbamino acid,

naphthalene-2-silt ether of CIS-[2-[(R)- and (S)-(sanofisynthelabo]-cyclohexyl}carbamino acid,

benzyl ether of CIS-{2-[(R)- and (S)-(cyanonaphthalene-2-ylmethyl)carbarnoyl]-cyclohexyl) carbamino acid,

3-thiophene-2-ylpropionic ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]-Kar bamol} cyclohexyl)carbamino acid,

[cyano-(3-hydroxyphenyl)methyl]amide, TRANS-2-(4-cyanobenzenesulfonyl)-cyclohexanecarbonyl acid,

benzyl ester, TRANS-(2-{[(3-bromophenyl)cyanomethyl]carbarnoyl}cyclohexyl)-carbamino acid,

4-(R)- and (S)-[(2-benzyloxycarbonylglycine)amino]cyanomethyl)-phenyl ester acetic acid,

CIS-N-(2-{[(R)- and (S)-cyano-(3,4-acid)methyl]carbarnoyl}cyclohexyl)-benzamide,

benzyl ester, TRANS-(2-[[(3-bromo-4-methoxyphenyl)cyanomethyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ether of CIS - {2-[(R)- and (S)-(cyanonaphthalene-1-ylmethyl)carbarnoyl]-cyclohexyl} carbamino acid,

2-methoxybenzamido ester, TRANS-(2-([cyano-(3-hydroxyphenyl)methyl]carbarnoyl)-cyclohexyl)carbamino acid,

benzyl ester (1R,2R)-(2-{(R)-[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ester, TRANS-(2-[[(3-bromo-4-methoxyphenyl)cyanomethyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ether of TRANS-[2-(cyanomethylene)cyclohexyl]carbamino acid,

3-chlorobenzylamino ester, TRANS-(2-([cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

3-methylbenzylamino ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl)-cyclohexyl)carbamino acid,

(2-{[(R)- and (S)-cyano-(3,4-acid)methyl]carbarnoyl}cyclohexyl)amide-biphenyl-4-carboxylic acid,

phenyl ether of CIS-{2-[(R)- and (S)-(sanofisynthelabo]cyclohexyl)-carbamino acid,

[cyano-(3-hydroxyphenyl)methyl]amide, TRANS-2-(4-acetamidobenzenesulfonyl)cyclohexanecarbonyl acid,

CIS-N-{2-[(R)- and (S)-(sanofisynthelabo]cyclohexyl}Ben is amide,

3-methoxybenzamido ether TRANS-2-([cyano-(3-hydroxyphenyl)methyl]carbarnoyl)-cyclohexyl)carbamino acid,

4-methylbenzylamino ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl)-cyclohexyl)carbamino acid,

benzyl ether of CIS-{2-[(benzo[1,3]dioxol-5-altianalis)carbarnoyl]-cyclohexyl}carbamino acid,

TRANS-4-cyano-N-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}cyclohexyl)-benzamide,

4-methoxybenzylthio ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide CIS-2-(3-cyclopentylpropionyl)cyclohexanecarbonyl acid,

benzyl ether (2-{[cyano-(3,4-acid)methyl]carbarnoyl}cyclohexyl)-carbamino acid (1 CIS-racemate),

4-nitrobenzyl ether CIS-{2-[(R)- and (S)-(sanofisynthelabo]-cyclohexyl}carbamino acid,

4-nitrobenzyl ester of CIS-(2-{[(R)- and (S)-cyano-(3,4-acid)methyl]-carbarnoyl}cyclohexyl)carbamino acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide CIS-2-(3-phenylpropionylamino)-cyclohexanecarbonyl acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide CIS-2-(cyclopropanecarbonyl-amino)cyclohexanecarboxylic acid,

cyclopentolate ether CIS-{2-[(R)- and (S)-(sanofisynthelabo]cyclohexyl}-carbamino acid,

3-n-Tripropylamine ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ether of CIS-[2-((R)- and (S)-1-cyano-3-methylbutanoyl)cyclohexyl] -carbamino acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide CIS-2-(2-phenoxyethylamine)-cyclohexanecarbonyl acid,

[cyano-(3-hydroxyphenyl)methyl]amide, TRANS-2-(2-phenoxyethylamine)-cyclohexanecarbonyl acid,

benzyl ester of CIS-(2-{(R)- and (S)-[cyano-(2,4-dimetilfenil)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide CIS-2-[2-(4-chlorphenoxy)-acetylamino]cyclohexanecarbonyl acid,

(R)- and (S)-cyanophenylacetic CIS-2-(2-vinylsulfonylacetamido acid,

3-(4-chlorophenyl)propyl ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]-carbarnoyl} cyclohexyl)carbamino acid,

[(R)- and (5)-cyano-(3,4-acid)methyl]amide CIS-2-(2-vinylsulfonylacetamido)cyclohexanecarbonyl acid,

[cyano-(3-hydroxyphenyl)methyl]amide, TRANS-2-(benzo[1,2,5]oxadiazol-4-sulfonylamino)cyclohexanecarbonyl acid,

TRANS-N-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}cyclohexyl)-4-fluoro-benzamide,

(R)- and (S)-cyanophenylacetic CIS-2-[2-(4-chlorophenoxyacetate]-cyclohexanecarboxylic acid,

(cianfanelli)amide CIS-2-(-phenylpropionylamino)cyclohexanecarbonyl acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide CIS-2-phenylacetylcarbinol acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide CIS-2-phenylmethanesulfonyl-aminocyclohexanecarboxylic acid,

[cyano-(3-hydroxyphenyl)methyl]amide, TRANS-2-(2-vinylsulfonylacetamido)-cyclohexanecarbonyl acid,

benzyl ether of CIS-[2-((R)- and (S)-1-Langenselbold)cyclohexyl]-carbamino acid,

(R)- and (S)-cyanophenylacetic CIS-2-(2-peroxyacetylnitrate acid,

(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}cyclohexyl)amide, TRANS-isoxazol-5-carboxylic acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide CIS-2-(3-cyclohexylcarbodiimide)cyclohexanecarbonyl acid,

4-triftormetilfosfinov ether (2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide CIS-2-(cyclobutanecarbonyl)cyclohexanecarbonyl acid,

(R)- and (S)-cyanophenylacetic CIS-2-[2-(4-chlorophenethylamine]-cyclohexanecarboxylic acid,

(R)- and (S)-cyanophenylacetic CIS-2-(cyclopentanecarbonyl-cyclohexanecarbonyl acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide CIS-2-[2-(4-chlorophenyl)-acetylamino]cyclohexanecarbonyl acid,

benzyl ester (1S,2R)-{2-(R)- and (S)-[(cianfanelli)to rebamol]cyclohexyl}-carbamino acid,

benzyl ester (1S,2R)-(2-(R')- and (S)-{[cyano-(3-methoxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}cyclohexyl)amide, TRANS-cinoxacin-2-carboxylic acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide CIS-2-(2-benzyloxycarbonylamino)-cyclohexanecarbonyl acid,

[cyano-(3-hydroxyphenyl)methyl]amide, TRANS-2-(2-thiophene-2-ylacetamide)-cyclohexanecarbonyl acid,

benzyl ether of CIS-[2-{(R)- and (S)-1-cyanopropionic)cyclohexyl]-carbamino acid,

(R)- and (S)-cyanophenylacetic CIS-2-phenylacetylcarbinol acid,

(R)- and (S)-cyanophenylacetic CIS-2-(2-benzyloxycarbonylamino acid,

(R)- and (S)-cyanophenylacetic CIS-2-(cyclopropanecarbonitrile acid,

(R)- and (S)-cyanophenylacetic CIS-2-(3-cyclopentanoperhydrophenanthrene acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide CIS-2-(cyclopentanecarbonyl-amino)cyclohexanecarboxylic acid,

(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}cyclohexyl)amide, TRANS-thiophene-2-carboxylic acid,

(R)- and (S)-cyanophenylacetic CIS-2-(3-phenylpropionylamino acid,

(R)- and (S)-cyanophenylacetic CIS-2-phenylmercurydimethyldithiocarbamate acid,

benzo is gross ester, TRANS-(2-{[cyano-(3-methoxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

[cyano-(3-hydroxyphenyl)methyl]amide CIS-2-(4-ethoxybenzylidene)-cyclohexanecarbonyl acid,

(cianfanelli)amide 2-(4-ethoxybenzylidene)cyclohexanecarbonyl acid,

[(3-bromophenyl)cyanomethyl]amide CIS-2-(4-ethoxybenzylidene)cyclohexanecarbonyl acid,

(benzo[1,3]dioxol-5-altianalis)amide CIS-2-(4-ethoxybenzylidene)-cyclohexanecarbonyl acid,

[cyano-(4-methoxyphenyl)methyl]amide CIS-2-(4-ethoxybenzylidene)-cyclohexanecarbonyl acid,

(benzo[1,3]dioxol-5-altianalis)amide CIS-2-veniaminocimeges.narod.ru acid (cianfanelli)amide 2-veniaminocimeges.narod.ru acid,

benzyl ester of CIS-(2-{(R)- and (S)-[cyano-(3,4-acid)methyl]carbarnoyl}-cyclopentyl)carbamino acid,

benzyl ester, TRANS-(2-{[(3-chlorophenylacetyl]carbarnoyl}cyclopentyl-carbamino acid,

benzyl ester, TRANS-(2-([cyano-(3-methoxyphenylacetyl]carbarnoyl}cyclopentyl-carbamino acid,

benzyl ester, TRANS-(2-[(sanofisynthelabo]cyclopentyl}-carbamino acid and

benzyl ester, TRANS-{2-[(cyano-m-trimethylsilanol]cyclopentyl}-carbamino acid,

and their pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

Especially preferred compounds of General formula (I) are: benzyl ester (1R,2R)(2-{(S)-[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide of CIS-1-(3-phenylacetylamino)-cyclohexanecarbonyl acid,

benzyl ether of (R)-{2-[(S)-(cianfanelli)-(R)-carbarnoyl]cyclohexyl}-carbamino acid,

benzyl ether SYN-{2-[(5)-(cianfanelli)carbarnoyl]cyclohexyl}-carbamino acid,

benzyl ether of CIS-(2-{(R)- and (S)-[cyano-(2,4-acid)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

[cyano-(3-hydroxyphenyl)methyl]amide, TRANS-2-(4-chlorobenzenesulfonamide)-cyclohexanecarbonyl acid,

benzyl ether of TRANS-(2-[(benzo[1,3]dioxol-5-altianalis)carbarnoyl]-cyclohexyl)carbamino acid,

benzyl ether of CIS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}cyclohexyl)-carbamino acid,

benzyl ether of TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}cyclohexyl)-carbamino acid,

(R)- and (S)-cyanophenylacetic CIS-2-(3-phenylacetylamino)cyclohexane-carboxylic acid,

benzyl ether (2-{[cyano-(3,4-acid)methyl]carbarnoyl}cyclohexyl)-carbamino acid (1 CIS-racemate),

benzyl ether of CIS-{2-[(R)- and (S)-(cyano-m-trimethyl)carbarnoyl]cyclohexyl}-carbamino acid,

thiophene-3-ymetray ether (2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ether of CIS-(2-{(R)- and (S)-[cyano-(4-methoxyphenyl)methyl]carbarnoyl}-cyclohe the forces)carbamino acid,

benzyl ether of CIS-(2-{(R)- and (S)-[cyano-(3-methoxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

thiophene-2-ymetray ether of TRANS-(2-([cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ether of CIS-(2-{(R)- and (S)-[(3-chlorophenyl)cyanomethyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ether of CIS-{2-[(cianfanelli)carbarnoyl]cyclohexyl}carbamino acid,

benzyl ether of TRANS-(2-{[(3-bromophenyl)cyanomethyl]carbarnoyl}cyclohexyl)-carbamino acid,

benzyl ether of CIS-(2-[(R)- and (S)-[(4-bromophenyl)cyanomethyl]carbarnoyl}-cyclohexyl)carbamino acid and

benzyl ether of CIS-(2-{(R)- and (S)-[cyano-(3,4-acid)methyl]carbarnoyl}-cyclopentyl)carbamino acids and their pharmaceutically acceptable esters

Other preferred compounds of formula (I) are those selected from the group consisting of:

benzyl ester of CIS-(2-[(cyanocobalamin)carbarnoyl]cyclohexyl}-carbamino acid,

2-chlorobenzylamino ether of CIS-[2-(cyanomethylene)cyclohexyl]carbamino acid,

2-bromobenzylamine ether of CIS-[2-(cyanomethylene)cyclohexyl]carbamino acid,

3-nitrobenzyl ether of CIS-[2-(cyanomethylene)cyclohexyl]carbamino acid,

4-chlorobenzylamino ether of CIS-[4-(cyanomethylene)qi is logical]carbamino acid,

3,4-dihlorbenzilovy ether of CIS-[4-(cyanomethylene)cyclohexyl]-carbamino acid,

3-chlorobenzylamino ether of CIS-[4-(cyanomethylene)cyclohexyl]carbamino acid,

2-chlorobenzylamino ether of TRANS-[4-(cyanomethylene)cyclohexyl]carbamino acid,

2-bromobenzylamine ether of TRANS-[4-(cyanomethylene)cyclohexyl]carbamino acid,

3-nitrobenzyl ether of TRANS-[4-(cyanomethylene)cyclohexyl]-carbamino acid,

phenyl ester, TRANS-[4-(cyanomethylene)cyclohexyl]carbamino acid,

3,4-dihlorbenzilovy ether of TRANS-[4-(IEnumerable)cyclohexyl]-carbamino acid,

[2-(cyanomethylene)cyclohexyl]amide CIS-5-methoxybenzophenone-2-carboxylic acid,

[2-(cyanomethylene)cyclohexyl]amide, TRANS-5-methoxybenzophenone-2-carboxylic acid,

TRANS-N-[2-(cyanomethylene)cyclohexyl]-2-chloro-4-fermentated,

TRANS-N-[2-(cyanomethylene)cyclohexyl]-2-methoxy-3-methylbenzamide,

TRANS-N-[2-(cyanomethylene)cyclohexyl]-2,6-dichloro-4-methoxybenzamide,

CIS-N-[2-(cyanomethylene)cyclohexyl]-3-fluoro-4-methylbenzamide,

CIS-N-[2-(cyanomethylene)cyclohexyl]-3-chloro-4-methylbenzamide,

TRANS-N-[2-(cyanomethylene)cyclohexyl]-3-bromo-4-methylbenzamide,

TRANS-N-[2-(cyanomethylene)cyclohexyl]-4-cyano who ethylbenzamide,

CIS-[2-(cyanomethylene)cyclohexyl] - for 3,5-di(trifluoromethyl)benzamide,

CIS-N-[2-(cyanomethylene)cyclohexyl]-4-tert.-butylbenzamide,

CIS-N-[2-(cyanomethylene)cyclohexyl]-3-chloro-6-methoxybenzamide,

TRANS-N-[2-(cyanomethylene)cyclohexyl]-3-chloro-6-methoxybenzamide,

CIS-N-[2-(cyanomethylene)cyclohexyl]-3-chlorobenzamide,

CIS-N-[2-(cyanomethylene)cyclohexyl]-3-acetylaminobenzoic,

TRANS-N-[2-(cyanomethylene)cyclohexyl]-3-acetylaminobenzoic,

CIS-N-[2-(cyanomethylene)cyclohexyl]-4-acetylaminobenzoic,

TRANS-N-[2-(cyanomethylene)cyclohexyl]-4-acetylaminobenzoic,

CIS-[2-(cyanomethylene)cyclohexyl]-4-acetylbenzoate,

TRANS-[2-(cyanomethylene)cyclohexyl]-4-acetylbenzoate,

CIS-N-[2-(cyanomethylene)cyclohexyl]-2-chloro-5-(methylthio)benzamide,

CIS-N-[2-(cyanomethylene)cyclohexyl]-2,3-dichlorobenzamide,

TRANS-N-[2-(cyanomethylene)cyclohexyl]-2,3-dichlorobenzamide,

CIS-N-[2-(cyanomethylene)cyclohexyl]-2,4-dichlorobenzamide,

CIS-N-[2-(cyanomethylene)cyclohexyl]-2,5-dichlorobenzamide,

CIS-N-[2-(cyanomethylene)cyclohexyl]-2,6-dichlorobenzamide,

CIS-N-[2-(cyanomethylene)cyclohexyl]-3,4-dichlorobenzamide,

TRANS-N-[2-(cyanomethylene)cyclohexyl]-3,4-dichlorobenzamide,

CIS-N-[2-(who animationname)cyclohexyl]-3,4-dichlorobenzamide,

TRANS-N-[2-(cyanomethylene)cyclohexyl] - for 3,5-dichlorobenzamide,

CIS-2-{[(4-chlorophenyl)acetyl]amino}-N-[cyano(cyclopropyl)methyl]cyclohexanecarboxylate,

CIS-N-[cyano(cyclopropyl)methyl]-2-{[3-(3-methoxyphenyl)propanol]amino}-cyclohexanecarboxylic,

CIS-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethylbenzamide,

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethoxybenzene,

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-methoxybenzamide,

TRANS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-methoxybenzamide,

TRANS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethylbenzamide,

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-3,4-differentated,

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-cyanobenzene,

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-tert.-butylbenzamide and

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino)carbonyl)cyclohexyl]-3,4,5-trimethoxybenzamide,

and their pharmaceutically acceptable esters.

Other particularly preferred compounds of General formula (I) are:

[2-(cyanomethylene)cyclohexyl]amide CIS-5-methoxybenzophenone-2-carboxylic acid,

[2-(cyanomethylene)cyclohexyl]amide, TRANS-methoxybenzo the RAS-2-carboxylic acid,

CIS-2-{[(4-chlorophenyl)acetyl]amino}-N-[cyano(cyclopropyl)methyl]cyclohexanecarboxylic,

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethylbenzamide,

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethoxybenzene,

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-methoxybenzamide,

TRANS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-methoxybenzamide,

TRANS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethylbenzamide,

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-cyanobenzene and

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-tert.-butylbenzamide

and their pharmaceutically acceptable esters.

The invention relates also to the use of compounds of formula (I)with the above values, for treatment or prevention of diseases associated with cysteine-proteases, such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina, unstable angina, stroke, perforation of blood platelets, transient ischemic attacks, transient blindness, a disease associated with blocked peripheral arteries, restenosis after angioplasty and insertion of the stent, education aneurysmectomy aorta, inflammation, autoimmune disease, malaria, cytopathy tissue of the ocular fundus and respiratory diseases. In a preferred variant embodiment of the invention relates to the use of the above compounds in the treatment or prevention of osteoporosis, unstable angina or perforation of platelets.

In addition, the invention relates to the use of the above compounds as pharmaceutically active substances, especially against diseases that are associated with the cysteine proteases, such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina, unstable angina, stroke, perforation of blood platelets, transient ischemic attacks, transient blindness, a disease associated with blocked peripheral arteries, restenosis after angioplasty and insertion of the stent, the formation of aneurysms of the abdominal aorta, inflammation, autoimmune disease, malaria, cytopathy tissue of the ocular fundus and respiratory diseases. In a preferred variant embodiment of the invention relates to the use of the above compounds as therapeutically active substances, especially against the background of osteoporosis, unstable angina or perforation of platelets.

The invention relates also to pharmaceutical is m songs containing the above compound and a pharmaceutically acceptable carrier and/or excipient, in particular, for use against the background of these diseases that are associated with the cysteine proteases, such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina, unstable angina, stroke, perforation of blood platelets, transient ischemic attacks, transient blindness, a disease associated with blocked peripheral arteries, restenosis after angioplasty and insertion of the stent, the formation of aneurysms of the abdominal aorta, inflammation, autoimmune disease, malaria, cytopathy tissue of the ocular fundus and respiratory diseases. In a preferred variant embodiment of the invention relates to pharmaceutical compositions containing the above compound and a pharmaceutically acceptable carrier and/or excipient for use in the background of osteoporosis, unstable angina or perforation of platelets.

Another variant of the embodiment according to the present invention relates to the use of the above compounds when getting medicines for the treatment or prevention of diseases associated with cysteine-proteases, such as osteoporosis, osteoarthritis, rheumatoi the hydrated arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina, unstable angina, stroke, perforation of blood platelets, transient ischemic attacks, transient blindness, a disease associated with blocked peripheral arteries, restenosis after angioplasty and insertion of the stent, the formation of aneurysms of the abdominal aorta, inflammation, autoimmune disease, malaria, cytopathy tissue of the ocular fundus and respiratory diseases. In a preferred variant embodiment of the invention relates to the use of the above compounds when getting medicines for the treatment or prevention of osteoporosis, unstable angina or perforation of platelets. These drugs contain the connection, as described above.

An additional variant embodiment of the invention relates to a method of prophylactic and/or therapeutic treatment of disorders in which cathepsin It plays a significant pathological role, such as osteoporosis, osteoarthritis, rheumatoid arthritis, tumor metastasis, glomerulonephritis, atherosclerosis, myocardial infarction, angina, unstable angina, stroke, perforation of blood platelets, transient ischemic attacks, transient blindness, a disease associated with blocked peripheral arteries, restenosis after any the plastics and the introduction of the stent, the formation of aneurysms of the abdominal aorta, inflammation, autoimmune disease, malaria, cytopathy tissue of the ocular fundus and respiratory diseases. The preferred embodiment of the invention relates to a method of prophylactic and/or therapeutic treatment of osteoporosis, unstable angina or perforation of platelets, the method which includes the introduction of the above-described compounds to the human or animal.

Further, the invention relates to a method of obtaining compounds of General formula (I), the method which includes

(a) interactions of the compounds of formula (II)

with the compound of the formula (III)

where R1, R2, R3, R4, R5and n have the meanings given above, or (b) the interaction of the compounds of formula (IV)

with the compound of the formula (V) or (VI)

where R2, R3, R4, R5, Ra, Rband n have the meanings given above.

As described above, the invention relates also to a method that includes obtaining pharmaceutically acceptable salts and/or pharmaceutically acceptable esters. The formation of esters and/or salts can be carried out at various stages of the method, for example, connected with the eating of the formula (I) or the relevant background materials.

The reaction of the compound of formula (II) with the compound of the formula (III) may be carried out by methods known to the expert in this area. For convenience, the reaction can be carried out by dissolving the compound (II), compound (III), TPTU [tetrafluoroborate O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N’,N’-tetramethylurea] and base Hunya (N-ethyldiethanolamine) in acetonitrile and stirring the mixture at room temperature for 6 to 16 hours, the Reaction mixture can be concentrated, and the product obtained by methods known to the expert in this field, for example by extraction and column chromatography. The alternate connection of the formula (II) can be dissolved in dichloromethane and interact 6-16 h at room temperature with a compound of formula (III) in the presence of N-methylmorpholine, NOT (1-hydroxybenzotriazole) and EDCI (N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide]. The product can be isolated by methods known in nature, for example, by extraction and HPLC.

The reaction of the compound of formula (IV) with the compound of the formula (V) or (VI) for facilities spend, getting solution of the compound (IV) in dichloromethane and adding a solution of the compound (V) or (VI) in the same solvent. To this mixture is added triethylamine and after shaking for 6-16 h at room temperature was added formic acid. The product can be isolated and purified known essentially what means, for example by evaporation of the solvent and HPLC.

In order to obtain pharmaceutically acceptable salts and/or pharmaceutically acceptable esters of compounds of formula (I), it is possible to prepare the corresponding esters and/or salts, based on the compounds of formula (I). It is also possible to form esters and/or salts at an earlier stage, for example, to form the corresponding salts and/or esters from the corresponding starting materials. Methods of obtaining pharmaceutically acceptable salts and/or pharmaceutically acceptable esters, described earlier, is known in this field.

The compounds of formula (II) are obtained by methods known to the expert in this area. For convenience, the corresponding amino acid is associated with the desired substituent R' is similar to the methods described in the examples. The resulting compound (II) are known essentially ways, for example by extraction and evaporation of the solvent.

The compounds of formula (III) can be easy obtained by addition of a solution of the appropriate aldehyde in dichloromethane to a solution of ammonium chloride and sodium cyanide in water and methanol at 0°C. the Mixture is stirred and allowed to warm to room temperature. After addition of ammonia solution and complete reaction of the resulting compound of formula (III) is isolated and purified by methods known the tion specialist in this field, for example by extraction. The corresponding hydrochloride may be obtained in known inherently ways.

Chiral compounds of the formula (III) can be conveniently obtained by adding ammonium bicarbonate to a mixed anhydride [obtained from a suitable protected t-BOC (tert.-butyloxycarbonyl) amino and di-tert.-BUTYLCARBAMATE] 15°C. the Reaction mixture was stirred at room temperature for 1-5 hours After completion of the reaction the formed amide t-BOC-amino acid is isolated and purified by methods known to the expert in this field, for example by extraction. Amide BOC-amino acid and triethylamine dissolved in THF and triperoxonane anhydride at 0°C. the Mixture is stirred for 2 h at -10°C. After extraction and purification of the resulting intermediate product, for example, by evaporation of the solvent and flash chromatography of the protective t-BOC group can be split by the action of hydrogen chloride in acetic acid, giving the desired compound of formula (III).

The compounds of formula (IV) can be conveniently obtained by the interaction of the corresponding t-BOC-amino acid with the compound of the formula (III), similarly to the above-described method. After isolation and purification of the resulting intermediate product, for example, by evaporation of the solvent and flash chromatography of the protective t-BOC group can be the ü split by trifluoroacetic acid, giving the desired compound of formula (IV) in the form of triptoreline.

Compounds of formulas (V) and (VI), or commercially available, or can be obtained by methods known in this field.

The following diagram (the same way W in the experimental section) illustrates another possibility of obtaining compounds of the present invention using the solid-phase synthesis.

Rinkmeans resin Rinca
Rmeans any combination of hydrogen atom, alkyl, halogen, acetyl, aminoacetyl, alkoxy, nitro, thio, thioalkyl, sulfonyl, sulfoxyl;
TFKmeans triperoxonane acid;
FMOCmeans 9-fluorenylmethoxycarbonyl;
NMMmeans N-methylmorpholin

1 EQ associated with the resin Rinca glycine (see Rink, Tetrahedron Lett. 1987, 28, 3787) in DMF was added 1 EQ of the product extract 1 (derived cyclohexanecarbonyl acid), EDCI, NOWT and NMM (N-methylmorpholine). The reaction mixture was shaken overnight at room temperature. The solvent was removed and the resin was washed with dichloromethane, methanol and again with dichloromethane. Then the resin is suspended in DMF and was added 20% piperidine. Polypropolene reaction for 30 min at room temperature the solvent was removed by filtration. The resin was washed with dichloromethane, methanol and again with dichloromethane. The resin is again suspended in DMF and was added 3 EQ of the corresponding succinimidylester (product extract 2). The reaction mixture was shaken overnight at room temperature. Then the resin was separated by filtration and washed with dichloromethane, methanol and again with dichloromethane. Then the resin suspended in a 10% solution triperoxonane acid in dichloromethane. After soaking for 30 min at room temperature the resin was separated by filtration and washed with dichloromethane. The filtrate was concentrated to dryness, obtaining the amide. Amide was subjected to dehydration using the Burgess reagent (internal salt methoxycarbonylamino-triethylammonium, see Burgess E.M, Atkins G.M. J. Am. Chem. Soc. 1968, 90, 4744). Amide was diluted in dichloromethane or in the case of TRANS-derived 1,4-dioxane. Was added 1 EQ of Burgess reagent and the reaction mixture was stirred for 2 h at room temperature, then added a second equiv of Burgess reagent, and the reaction mixture was stirred for additional 2 hours the Crude reaction mixture was evaporated to dryness, then the residue was dissolved in ethyl acetate. The desired compound was isolated and purified by methods known to the expert in this field, for example by extraction and preparative HPLC.

The following diagram(corresponding to method 3 in the experimental part) shows another possibility of obtaining compounds of the present invention using the solid-phase synthesis.

The means rink resin Rinca

R means any combination of hydrogen atom, alkyl, halogen, acetyl, aminoacetyl, alkoxy, nitro, thio, thioalkyl, sulfonyl, sulfoxyl;

TFK appoints triperoxonane acid;

FMOC means 9-fluorenylmethoxycarbonyl;

NMM means N-methylmorpholin

1 EQ associated with the resin Rinca glycine (see Rink, Tetrahedron Lett. 1987, 28, 3787) in DMF was added 1 EQ of the product extract 1 (derived cyclohexanecarbonyl acid), EDCI, NOWT and NMM. The reaction mixture was shaken overnight at room temperature. The solvent was removed and the resin was washed with dichloromethane, methanol and again with dichloromethane. Then the resin is suspended in DMF and was added 20% piperidine. After continuing the reaction for 30 min at room temperature the solvent was removed by filtration. The resin was washed with dichloromethane, methanol and again with dichloromethane. The resin is again suspended in DMF and was added 3 EQ of the corresponding carboxylic acid (product extract 2) along with EDCI, NOWT and NMM. The reaction mixture was shaken overnight at room temperature. Then the resin was separated by filtration and washed with dichloromethane, methanol and again with dichloromethane. Then the resin suspended in a 10% solution triperoxonane acid in dichloromethane. After soaking for 30 min at room temperature the resin was separated by filtration and washed with dichloromethane. The filtrate was concentrated to dryness, obtaining the amide. Amide was subjected to dehydration using the Burgess reagent (internal salt methoxycarbonylamino-triethylammonium, see Burgess E.M. Atkins G.M. J. Am. Chem. Soc. 1968, 90, 4744). Amide was diluted in dichloromethane or in the case of TRANS-derived 1,4-dioxane. Was added 1 EQ of Burgess reagent, the reaction mixture was stirred for 2 h at room temperature, then added a second equiv of Burgess reagent, and the reaction mixture was stirred for additional 2 hours the Crude reaction mixture was evaporated to dryness and then the residue was dissolved in ethyl acetate. The desired compound was isolated and purified by methods known to the expert in this field, for example by extraction and preparative HPLC.

All products extraction used to obtain compounds by solid-phase synthesis, or are commercially available or can be obtained by methods known in this field, or in the ways described in the context.

The following diagram (corresponding to methods And E in the experimental part) shows another possibility of obtaining compounds of the present invention.

Cbz or Zmeans benzyloxycarbonyl (carbobenzoxy),
DIPEA means diisopropylethylamine.

And) was Added NOT to the acid solution in DMF. The mixture was stirred at room temperature for 1 h and was added 2-aminocyclohexanecarboxylic acid, hydrochloride (1-cyano-1-cyclopropylethyl)amide, EDCI and NMM (N-methylmorpholine). The mixture was stirred at room temperature overnight and concentrated. The desired compound was isolated and purified by methods known to the expert in this field, for example, by extraction and preparative TLC.

E) was Added DIPEA (diisopropylethylamine) to a solution of acetic acid salt (1-cyano-1-cyclopropylethyl)amide 2-aminocyclohexanecarboxylic acid in dichloromethane. The mixture was stirred at room temperature for 45 minutes was Added the acid chloride of the acid and the reaction mixture was stirred under nitrogen at room temperature over night. The desired compound was isolated and purified by methods known to the expert in this field, for example, by extraction and preparative TLC (path E).

Selected CIS - and TRANS-isomers of the compounds were obtained on the basis of the respective CIS - and TRANS-isomers of cyclohexane derivative.

The present invention applies to all compounds of formula (I)are obtained by one of the methods described above.

The invention relates also to compounds of the formula (IV)

where R2, R3, R4, R5and n have the meanings given above.

Inhibitory activity of compounds against cathepsin K, S, L and investigated at room temperature in 96-well opaque white polystryrene tablets (firm Costar). Inhibitory activity of cathepsin K was investigated as follows: 5 μl of inhibitor dissolved in 5 mm sodium phosphate, 15 mm NaCl, pH of 7.4, containing 1% DMSO (final concentration 10-0,0001 μm)was preincubated for 10 min with 35 ál of human recombinant cathepsin K (final concentration 1 nm), dissolved in analytical buffer [100 mm sodium acetate, pH 5.5, containing 5 mm EDTA (ethylenediaminetetraacetic acid) and 20 mm cysteine]. After addition of 10 µl fluorogenic substrate Z-Leu-Arg-MCA(monochloracetic)diluted in analytical buffer (final concentration 5 μm), measured by the increased fluorescence (excitation at 390 nm and emission at 460 nm) in a period of 7.5 min every 45 seconds. Initial speed [RFU(relative unit fluorescence)/min] deduced by direct selection of the 11 points of the reading.

Inhibitory activity of cathepsin b was analyzed under the same conditions as the inhibitory activity of cathepsin K, using cathepsin from human liver (Calbiochem) at a final concentration of 1 nm.

Inhibitory activity of cathepsin L analysis is Aravali under the same conditions, as the inhibitory activity of cathepsin K, using cathepsin L from human liver (Calbiochem) at a final concentration of 3 nm.

Inhibitory activity of cathepsin S were analyzed similarly inhibitory activity of cathepsin K with the exception that the buffer was 100 mm potassium phosphate, 5 mm EDTA, 5 mm DTT (dithiotreitol) (newly added), 0.01 Triton X-100, pH 6.5 and fluorogenic substrate served as Z-Val-Val-Arg-MCA (company Bachem) (final concentration 20 μm). Human recombinant cathepsin S (Wiederanders, and others, Eur. J.Biochem. 1997, 250, 745-750) was used at a final concentration of 0.5 nm.

The results are shown as the values of the IC50that means the concentration of inhibitor at which the enzyme activity is inhibited by 50%. The values of the IC50determined by curve linear regression of logit-log graph.

0,029
ExampleCatepsin TO the IC50(µm/l)Cathepsin S IC50(µm/l)Cathepsin L IC50(µm/l)Cathepsin In the IC50(µm/l
8,10,005>10the 4.74,6
8,20,0160,641,20,095
8,150,0161,260,580,44
8,122,611,380,64
8,70,027>104,691,38

It will be recognized that compounds of General formula (I) according to this invention can be subjected to transformations of functional groups with the formation of derivatives, which in vivo is able again to turn in the parent connection.

As mentioned above, the medicinal product containing the compound of formula (I)are the object of the present invention as a method of obtaining drugs such method, which involves combining one or more compounds of the formula (I) and, optionally, one or more other therapeutically important compounds in herbal form of introduction.

The pharmaceutical compositions can be administered orally, for example in the form of tablets, coated tablets, pills, hard or soft gelatin capsules, solutions, emulsions or suspensions. The introduction can be done rectally, for example, using suppositories; local or percutaneously, for example, using ointments, creams, gels or solutions; or parenterally, for example intravenously, intramuscularly, subcutaneously, vnutriobolochechnoe or transdermal, using, for example, solutions for injection. In addition, the introduction may be the hyoid and is in the form of ophthalmic drugs or in aerosol form, for example, in the form of spray.

To obtain tablets, coated tablets, coated tablets or hard gelatin capsules of the compounds of the present invention can be mixed with farmatsevticheskii inert inorganic or organic fillers. Examples of appropriate excipients for tablets, coated tablets or hard gelatin capsules include lactose, corn starch or its derivatives, talc or stearic acid or its salts.

Appropriate fillers for use in soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid or liquid polyols etc; however, depending on the nature of the active ingredients can be the case when for soft gelatin capsules do not need any filler.

Upon receipt of solutions and syrups fillers that can be used include, for example, water, polyols, saccharose, invert sugar and glucose.

For injectable fillers that can be used include, for example, water, alcohols, polyols, glycerine and vegetable oils.

For suppositories and local or percutaneous introduction of fillers that can be used include, for example, natural or hardened oils, waxes, fats and semi-solid or liquid polyols.

Pharmaceutical companies who stand may also contain preservatives, dissolving agents, stabilizers, moisturizers, emulsifiers, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, buffers, agents for coating or antioxidants. As mentioned above, they can also contain other therapeutically useful agents.

A necessary precondition is that all excipients used in obtaining drugs are non-toxic.

The preferred form of administration is intravenous, intramuscular or oral administration. The dosages in which the compounds of formula (I) is administered in effective amounts depend on the nature of the specific active ingredient, the age and needs of the patient and the route of administration. In General, discusses dose of about 1-1000 mg, preferably 5-500 mg per day.

The following examples will illustrate preferred embodiments of the invention, but they are not intended to limit the scope of the invention.

The corresponding starting materials or are commercially available or can be obtained by known methods (for example, DE 26 24 290; WO 98/0354; Chem. Pharm. Bull., 38(2), 350-354 (1990) "Chiral synthon obtained using pork liver esterase: the introduction of chiral centers in cyclohexenones skeleton"; J.Chem. Soc. Perkin Trans., 1, 1411-1415 (1994) "Asymmetric synthesis of (-)-(1R,2S)-the IP-pentatsin and related CIS - and TRANS-2-aminocyclopentane - and cyclohexane-1-carboxylic acid") or can be obtained by means similar to those described above.

Example 1

Receiving (R,S-α-amino-3-bromophenylacetonitrile

Dissolved ammonium chloride (2.14 g, 40 mmol) and sodium cyanide (1,96 g, 40 mmol) in 20 ml of water and 20 ml of methanol and cooled to 0°C. a Solution of 3-bromobenzaldehyde (4,68 ml, 40 mmol) in 15 ml dichloromethane and 15 ml of methanol was added dropwise within 30 minutes the Mixture was allowed to warm to room temperature and was stirred for 0.5 hours was Added a solution of ammonia (25% in water) (6 ml, 80 mmol). The mixture was stirred for 16 h at room temperature. The organic solvent was evaporated and water was added (5-10 ml). The aqueous layer was extracted with dichloromethane (2×50 ml), the latter washed with water (20 ml) and brine (20 ml), dried over sodium sulfate and evaporated. The oily residue was dissolved in 75 ml of ether. With vigorous stirring, added dropwise was added a 4 M solution of hydrogen chloride in dioxane. Precipitated solid substance was separated by filtration and dried. For recrystallization of the solid was dissolved in perhaps a small amount of methanol (not heat!). At this time, with stirring, was added ether until then, until the end of the precipitation. The precipitate was separated by filtration and dried in vacuum.

Yield 40%. MS: 229 (M+NH4)+.

Example 2

Obtaining chiral aminona the silts

tert.-Butyl ether (S)-(carbamoylmethyl)carbamino acid

Added 0,628 g (7.95 mmole, 1 EQ) of ammonium bicarbonate to a mixed anhydride (obtained from 7.95 mmole (S)-BOC-phenylglycine, of 10.4 mmole of di-tert.-BUTYLCARBAMATE in 40 ml of dioxane and 2,39 mmole of pyridine) at 15 C. the Mixture was stirred for 8 h at this temperature and then concentrated. The residue was dissolved in 20 ml of ethyl acetate, washed with saturated sodium bicarbonate solution, 2 N. hydrochloric acid, brine, dried over sodium sulfate and evaporated.

Yield 92%. MS: 251 (M+N)+. [α]

25
D
=-120,4 (1,00, ethanol)

tert.-Butyl ether (R)-(carbamoylmethyl)carbamino acid was obtained similarly tert.-butyl ether (S)-(carbamoylmethyl)carbamino acid.

Getting tert.-butyl ether (S)-(cianfanelli)carbamino acid

Was dissolved tert.-butyl ether (S)-(carbamoylmethyl)carbamino acid (1.8 g, 7,19 mmole) and triethylamine (2.2 ml, 15.8 mmole) in THF (40 ml) at -10°C. was Added triperoxonane anhydride (1.1 ml, to $ 7.91 mmole) for 30 min. the Mixture was stirred at -10°C for 2 h and evaporated. Added dichloromethane and water. The organic phase was separated, dried over sodium sulfate and evaporated. Not the shelled product was purified using chromatography (silica gel, the ethyl acetate/hexane, 4:1, Rf=0,5).

Yield 81%. MS: 231 (M-N)-. [α]

25
D
=+4,1 (1,00, ethanol).

tert.-Butyl ether (R)-(cianfanelli)carbamino acid was obtained similarly tert.-butyl ether (S)-(cianfanelli)carbamino acid.

Obtaining hydrochloride (S)-aminophenylacetylene

Was dissolved tert.-butyl ether (S)-(cianfanelli)carbamino acid (0.5 g, of 2.15 mmole) in 5 ml of 10% solution of hydrogen chloride in anhydrous acetic acid. The mixture was stirred at room temperature for 2 h and evaporated. The product was washed with diethyl ether and dried in vacuum.

Yield 98%. MS: 192 (M+Na)+. [α]=+38,6 (1,00, water).

Hydrochloride (R)-aminophenylacetylene received similarly hydrochloride (S)-aminophenylacetylene.

Example 3

Getting benzyl ester of CIS-(2-{(R}- and (S)-[cyano-(2,4-acid)-methyl]carbarnoyl}cyclohexyl)carbamino acid

A solution of 0.7 mmole CIS-benzyloxycarbonylglycine acid (purged extract 1), 5.2 mmole N-methylmorpholine, 0.15 mmole NOT and of 1.78 mmole EDCI in 12 ml of dichloromethane was added to 0.97 mmole hydrochloride amino-(2,4-acid)acetonitrile (product extract 2). After shaking overnight, the reaction to the offer was extracted with 10 ml of 1 N. hydrochloric acid, dichloromethane was evaporated. The compound was purified HPLC:

column:HP-CombiHT XDB-C18, EXT. dia. 21,2 mm×50 mm, series No. DN 1020
Method:flow: 40 ml/min
0 min80% water, 20% acetonitrile
0,2 min80% water, 20% acetonitrile
3,5 min5% water, 95% acetonitrile
4,7 min5% water, 95% acetonitrile
4,8 min80% water, 20% acetonitrile
4,9 min80% water, 20% acetonitrile
instrument:Prep HPLC System Dynamax model SD-1, UV-1

Yield 59%. MS: 452 (M+N)+.

Example 4

Getting benzyl ester (1S,2R)-{2-(R)- and (S)-[(cianfanelli)carbarnoyl]cyclohexyl}carbamino acid

A solution of 0.18 mmole (1S,2R)-2-benzyloxycarbonylglycine acid (product extract 1), 0.72 mmole of N-ethyldiethanolamine and 0.18 mmole TPTU [tetrafluoroborate O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethylurea] in 10 ml of acetonitrile was added to the 0.18 mmole hydrochloride aminophenylacetylene (product extract 2). After stirring overnight the solvent was evaporated. The residue was dissolved in ethyl acetate, was extracted with a solution of bi is carbonate sodium (3x) and brine. The solution was dried over sodium sulfate and evaporated. The compound was purified flash chromatography (silica gel, ethyl acetate/hexane, 7:3).

Yield 83%. MS: 390 (M-N)-.

Example 5

Obtain TRANS-2-(4-chlorobenzenesulfonamide)cyclohexanecarbonyl acid

Dissolved TRANS-2-aminocyclohexanecarboxylic acid (0,150 g, 1.05 mmole) in 1.5 ml of water was added sodium hydroxide (0.09 g, 2.25 mmole) in 1.5 ml of water at 0°C. was Added 4-chlorobenzenesulfonamide (0,243 g, 1.15 mmole) in 1.5 ml of toluene. The reaction mixture was stirred at room temperature for 16 hours the Toluene layer was separated, the aqueous layer was twice washed with toluene. Toluene layers were discarded. Ethyl acetate was added to the water layer (15 ml) and 2 M hydrochloric acid to pH<7. Divided in two phases, the aqueous layer was extracted with ethyl acetate (3×15 ml). The combined organic phases are washed with saline (20 ml), dried over magnesium sulfate and ethyl acetate was removed under reduced pressure, obtaining white solid, which was dissolved in toluene (2×10 ml) and evaporated. The product was dried in vacuum.

Exit 70, MS: 316 (M-N)-.

Getting [cyano-(3-hydroxyphenyl)methylamide TRANS-2-(4-chlorobenzenesulfonamide)cyclohexanecarbonyl acid

Dissolved TRANS-2-(4-chlorobenzenesulfonamide)cyclohexanecarbonyl acid (0,095 g, 0.3 mmole) in acetonitrile. Probabl is whether titrator Borat O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethylurea (TPTU, 90,2 mg, 0.3 mmole), N-ethyldiethanolamine (DIPEA, 0,208 ml of 1.21 mmole). Added amino-(3-hydroxyphenyl)acetonitrile in acetonitrile (1.5 ml). The mixture was stirred at room temperature for 16 hours the Solution was filtered and concentrated. The residue was dissolved in dichloromethane (15 ml) and was extracted with a solution of ammonium chloride (2×10 ml). The aqueous layers were extracted with dichloromethane (2×15 ml). The combined dichloromethane layers were dried over magnesium sulfate and evaporated. The solid was purified preparative HPLC.

column:YMC; CombiPrep ODS_AQ; 50×20 mm (int. dia.); S-a 5 um, 120A
method:flow: 40 ml/min
0 min90% water, 10% acetonitrile
0.1 l90% water, 10% acetonitrile
3,5 min5% water, 95% acetonitrile
5,5 min5% water, 95% acetonitrile
5,7 min80% water, 20% acetonitrile
5,8 min80% water, 20% acetonitrile
instrument:Prep HPLC System Dynamax model SD-1, UV-1

Exit 26%, MS: 470 (M+Na)+.

Example 6

Getting 4-nitrophenylthio ester thiophene-2-Eletropaulo ester of carbonic acid

To a solution of thiophene-2-ylmethanol (0,412 g, 3 mmole) in dichloromethane (6 ml) was added pyridine (0,291 ml, 3.6 mmole) and 4-nitrophenylphosphate (0,728 g, 3.6 mmole) at 0°C. After shaking overnight, the reaction mixture was extracted with a solution of ammonium chloride (5 ml) and dichloromethane was evaporated, obtaining a white solid, which was used without further purification.

Obtain TRANS-2-(thiophene-2-ylmethoxycarbonyl)cyclohexanecarbonyl acid

To a solution of TRANS-2-amino-1-cyclohexanecarboxylic acid (100 mg, 0.7 mmole) in 1 ml of water was added 2 M aqueous sodium carbonate solution at pH 9-10 (2 ml). A solution of 4-nitrophenylthio ester thiophene-2-Eletropaulo ester of carbonic acid (195 mg, 0.7 mmole) in THF (1 ml) was added at 0°C, 10 min to the reaction mixture were added 1 ml of 2 M aqueous solution of sodium carbonate. The mixture was allowed to warm to room temperature and vigorously stirred during the night. The reaction mixture was diluted to 0.5 N. hydrochloric acid to pH 4-3 and the aqueous layer was extracted three times with dichloromethane (10 ml). The organic phases were combined, dried (magnesium sulfate) and concentrated under reduced pressure. The obtained product was used in the next step without further purification.

Yield 68%, MS: 282 (M-N)-.

Getting thiophene-2-Eletropaulo ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}cyclohexyl)carbamino acid

Dissolved TRANS-2-(thiophene-2-ylmethoxycarbonyl)qi is agexanorhoole acid (0,094 g, of 0.33 mmole) in DMF (1 ml). Were added tetrafluoroborate O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethylurea (TPTU, 0,099 mg of 0.33 mmole) and N-ethyldiethanolamine (DIPEA, 0,228 ml of 1.32 mmole). Added amino-(3-hydroxyphenyl)acetonitrile in DMF (1.5 ml), the mixture was stirred over night at room temperature. The reaction mixture was filtered and the product was obtained using HPLC.

Column:YMC; CombiPrep ODS_AQ; 50×20 mm (int. dia.); S-a 5 um, 120A
method:flow: 40 ml/min
0 min90% water, 10% acetonitrile
0.1 l90% water, 10% acetonitrile
3,5 min5% water, 95% acetonitrile
5,5 min5% water, 95% acetonitrile
5,7 min80% water, 20% acetonitrile
5,8 min80% water, 20% acetonitrile
instrument:Prep HPLC System Dynamax model SD-1, UV-1

Yield 24%, MS: 436 (M+Na)+.

Example 7

Getting [cyano-(3,4-acid)methyl]amide 2-aminocyclohexanecarboxylic acid in the form of triptoreline

To a solution of 15.7 mmole of 2-tert.-butoxycarbonyloxyimino acid, 17.2 mmole hydrochloride (R,S)-amino-(3,4-acid)acetonitrile, of 1.57 mmole NOWT and 8.8 mmole EDCI in 150 ml of dichloromethane was added 109,7 mmole N-methylmorpholine. After stirring over night at room temperature the mixture was extracted with 150 ml of 10% solution of potassium bisulfate and 150 ml saturated sodium bicarbonate solution, dried over magnesium sulfate, evaporated and purified flash chromatography (porous glass filter height 4 cm, 2 cm silica gel 0,04-0,063, eluent 400 ml dichloromethane). Cleavage of the BOC-group was conducted with 17 ml of TFA in 50 ml of dichloromethane for 4 h at room temperature. Evaporation gave a brown oil which was used without further purification.

Getting [(R)- and (S)-cyano-(3,4-acid]methylamide CIS-2-(3-phenylacetylamino)yclohexanol acid

To a solution of 0.17 mmole [cyano-(3,4-acid)methyl]amide CIS-2-aminocyclohexanecarboxylic acid in the form of triptoreline (product extraction 1) in 3 ml dichloromethane was added a solution of 0,187 mmole of acid chloride of TRANS-cinnamic acid (product extract 2) in 1 ml dichloromethane. To this mixture was added to 0.36 mmole of triethylamine. After shaking overnight at room temperature was added formic acid, dichloromethane was evaporated and the compound was purified HPLC:

column:HP-CombiHT XDB-C18, 21,2 mm (EXT. dia.)×50 mm, series No. DN 1020
method:flow: 40 ml/min
0 is INF 80% water, 20% acetonitrile
0,2 min80% water, 20% acetonitrile
3,5 min5% water, 95% acetonitrile
4,7 min5% water, 95% acetonitrile
4,8 min80% water, 20% acetonitrile
4,9 min80% water, 20% acetonitrile
instrument:Prep HPLC System Dynamax model SD-1, UV-1

Exit 19%, MS: 448 (M+H)+.

Example 8

Obtain other compounds of General formula (I)

Received some additional compounds of General formula (I). In the following table 1 provides an overview of the compounds, products, extraction and methods used for their preparation.

Used the following methods.

Method: condensation of protected amino acids with aminonitriles

A solution of 1 equiv of CIS-2-benzyloxycarbonylglycine acid, 7 EQ N-methylmorpholine, 0.2 EQ NEWT and 2.4 equiv EDCI in 7 ml of dichloromethane was added to 1.1-1.3 EQ hydrochloride aminonitriles. After shaking overnight, the reaction mixture was extracted with 1 N. hydrochloric acid and dichloromethane and evaporated. The compound was purified HPLC:

column:HP-CombiHT XDB-C18. 21,2 mm (EXT. dia.)×50 mm, the series is DN 1020
method:flow: 40 ml/min
0 min80% water, 20% acetonitrile
0,2 min80% water, 20% acetonitrile
3,5 min5% water, 95% acetonitrile
4,7 min5% water, 95% acetonitrile
4,8 min80% water, 20% acetonitrile
4,9 min80% water, 20% acetonitrile
instrument:Prep HPLC System Dynamax model SD-1, UV-1

Method a-2

Protected amino acid, aminonitriles, TPTU [tetrafluoroborate O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-tetramethylurea] and base Hunya (N-ethyldiethanolamine) was dissolved in acetonitrile. The mixture was stirred at room temperature for 6 to 16 hours the Solution was concentrated, the residue was dissolved in ethyl acetate and was extracted with water. The aqueous layers were extracted with ethyl acetate. The combined organic layers were washed with sodium bicarbonate solution, brine, dried over sodium sulfate and evaporated. The crude product was separated from impurities column chromatography.

The output of 60-90%.

Method B: the crude mixture of triptoreline amide amino acids (product extraction 1) + (a) carbonylchloride (product izvlechenia 2) or (b) sulphonylchloride (product extract 2) + triethylamine

It is aStore 1 equiv of triptoreline amide 2-aminocyclohexanecarboxylic acid (product extraction 1) in dichloromethane was added a solution of 1.1 EQ of carbonylchloride (product extract 2) or sulphonylchloride (product extract 2), or isothiocyanate (product extract 2) in dichloromethane. To this mixture was added 2.1 equivalents of triethylamine. After shaking overnight at room temperature was added formic acid, dichloromethane was evaporated and the compound was purified HPLC:

column:HP-CombiHT XDB-C18. 21,2 mm (EXT. dia.)×50 mm, series No. DN 1020
method:flow: 40 ml/min
0 min80% water, 20% acetonitrile
0,2 min80% water, 20% acetonitrile
3,5 min5% water, 95% acetonitrile
4,7 min5% water, 95% acetonitrile
4,8 min80% water, 20% acetonitrile
4,9 min80% water, 20% acetonitrile
instrument:Prep HPLC System Dynamax model SD-1, UV-1

Method In

Dissolved TRANS-cyclohexanecarbonyl acid (product extraction 1.1 EQ) in anhydrous acetonitrile (0.2 M). To the resulting solution was added a solution of TPTU (1 EQ), DIPEA (4 EQ) in anhydrous acetonitrile (0.2 M) at room temperature. Added amino-(3-hydroxyphenyl)acetonitrile (product extraction 2.1 EQ)dissolved in acetonitrile (0.2 M), the mixture was stirred over night. The reaction mixture was filtered and concentrated. The residue was dissolved in 1 ml of acetonitrile and purified HPLC:

column:YMC; CombiPrep ODS_AQ; 50×20 mm (int. dia.); S-a 5 um, 120A
method:flow: 40 ml/min
0 min90% water, 10% acetonitrile
0.1 l90% water, 10% acetonitrile
3,5 min5% water, 95% acetonitrile
5,5 min5% water, 95% acetonitrile
5,7 min80% water, 20% acetonitrile
5,8 min80% water, 20% acetonitrile
instrument:Prep HPLC System Dynamax model SD-1, UV-1

Method D

The reaction can be conveniently carried out by dissolving TRANS-aminocarbonylmethyl acid (product extraction 1) in DMF, adding TPTU (1 equiv), base Hunya (4 EQ), 2-amino-2-(3-hydroxyphenyl)acetonitrile (product extract 2, 1 EQ) in DMF and stirring the mixture at room temperature for 16 hours, the Reaction mixture can be filtered, the product can be obtained using HPLC.

column:YMC; CombiPrep ODS_AQ; 50×20 mm (int. dia.); S-a 5 um, 120A
method:flow: 40 ml/min
0 min90% water, 10% acetonitrile
0.1 l90% water, 10% acetonitrile
3,5 min5% water, 95% acetonitrile
5,5 min5% water, 95% acetonitrile
5,7 min80% water, 20% acetonitrile
5,8 min80% water, 20% acetonitrile
instrument:Prep HPLC System Dynamax model SD-1, UV-1

It is convenient to obtain TRANS-aminocarboxylic acid (product extraction 1) the addition of the mixed carbonate in THF (obtained from the corresponding alcohol, 4-nitrophenylphosphate and pyridine in dichloromethane) to the corresponding amino acid, dissolved in 10% aqueous solution of sodium bicarbonate. The reaction mixture was vigorously stirred at room temperature for 16 hours after completion of the reaction of the resulting compound were isolated by methods known to the expert in this field, for example, by extraction.

Method D

A solution of 2-veniaminocimeges.narod.ru acid (product extract 1, 1 EQ), 3 EQ of N-ethyldiethanolamine and 1 EQ TPTU in acetonitrile was added 1 EQ hydrochloride aminophenylacetylene (product extract 2). After stirring overnight the solvent was evaporated. The residue was dissolved in ethyl acetate, etc is mawali with sodium bicarbonate solution (3x) and brine. The solution was dried over sodium sulfate and evaporated. The compound was purified flash chromatography (silica gel).

Method E

Was added DIPEA (diisopropylethylamine) (3 EQ) to a solution of acetic acid salt (1-cyano-1-cyclopropylethyl)amide 2-aminocyclohexanecarboxylic acid (1 EQ) in dichloromethane (anhydrous, 5 ml) and the mixture was stirred at room temperature for 45 minutes was Added the acid chloride of acid (1 EQ), the reaction mixture was stirred at room temperature under nitrogen overnight. The reaction mixture was diluted with dichloromethane, washed with 1 N. hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified preparative TLC (silica gel; hexane-ethyl acetate, 1:1)to give product as white solid. The output of 60-85%.

Way W

1 EQ associated with the resin Rinca glycine in DMF was added 3 EQ of the product of the extraction of 1, 3 equiv EDCI, 1 EQ NEWT and 9 EQ NMM. The reaction mixture was shaken at room temperature overnight. The solvent was removed, the resin washed three times with dichloromethane, three times with methanol and again three times with dichloromethane. Then the resin is suspended in DMF and was added 20% piperidine. After continuing the reaction for 30 min at room temperature the solvent was removed by filtration. The resin is washed three times dichlor the tan, three times with methanol and again three times with dichloromethane. Then the resin is suspended in DMF and was added 3 EQ of succinimidylester (product extract 2). The reaction mixture was shaken overnight at room temperature. Then the resin was separated by filtration and washed three times with dichloromethane, three times with methanol and again three times with dichloromethane. Then the resin suspended in a 10% solution triperoxonane acid in dichloromethane. After 30 minutes of reaction at room temperature the resin was separated by filtration and repeatedly washed with dichloromethane. The filtrate was concentrated to dryness, obtaining the amide. Amide was subjected to dehydration using the Burgess reagent. Amide was dissolved in dichloromethane or in the case of the TRANS-isomer, 1,4-dioxane. Was added 1 EQ of Burgess reagent and the reaction mixture was stirred for 2 h at room temperature, then added a second equiv of Burgess reagent, and the reaction mixture was stirred for additional 2 hours the Crude reaction mixture was evaporated to dryness and then the residue was dissolved in ethyl acetate. The organic layer was washed with 10% sodium bicarbonate solution, water and brine. Then the organic layer was dried, filtered and evaporated to dryness. If necessary, purification was performed that using HPLC.

The initial conditions of the fluid supply pump for HPLC-Shimadzu
And%80[H2O (TFA 0,1)]
B%20 (CH3CN)
Feed rate (ml/min):2,500
Stop time (min):10,0
High pressure (lb/in2):4000
Low pressure (lb/in2):0
Set temperature (°C):40
Temperature limit (°C):45

Gradient timing diagram of the fluid supply pump for HPLC-Shimadzu

Gradient timing chart contains the following 5 items.
TimeAnd%B%The feed speedThe characteristic curve
1,0080202,506
3,0065352,506
5,0045552,506
7,0075252,506
10,0080202,50 6

Method 3

1 EQ associated with the resin Rinca glycine in DMF was added 3 EQ of the product of the extraction of 1, 3 equiv EDCI, 1 EQ NEWT and 9 EQ NMM. The reaction mixture was shaken overnight at room temperature. The solvent was removed and the resin washed three times with dichloromethane, three times with methanol and again three times with dichloromethane. Then the resin is suspended in DMF and was added 20% piperidine. After a 30-minute exposure reactional mixture at room temperature the solvent was removed by filtration. The resin is washed three times with dichloromethane, three times with methanol and again three times with dichloromethane. Again suspended resin in DMF was added 3 equivalents of carboxylic acid (product extract 2) along with 3 equiv EDCI, 1 EQ NEWT and 9 EQ NMM. The reaction mixture was shaken overnight at room temperature. Then the resin was separated by filtration and washed three times with dichloromethane, three times with methanol and again three times with dichloromethane. Then the resin suspended in a 10% solution triperoxonane acid in dichloromethane. After 30-min exposure at room temperature the resin was separated by filtration and repeatedly washed with dichloromethane. The filtrate was concentrated to dryness, obtaining the amide. Amide was subjected to dehydration using the Burgess reagent. Amide was dissolved in dichloromethane or in the case of the TRANS isomer of 1,4-dioxane. Added 1 equiv of reagent Burg is sa and the reaction mixture was stirred for 2 h at room temperature, then added a second equiv of Burgess reagent and the reaction mixture was stirred for additional 2 hours the Crude reaction mixture was evaporated to dryness, the residue was dissolved in ethyl acetate. The organic layer is washed with 10% aqueous sodium bicarbonate solution, water, saline solution. Then the organic layer was dried, filtered and evaporated to dryness. If necessary, purification was performed that using HPLC.

Method And

Added NOWT (2 equiv) to a solution of acid (the product of extract 2, 1 EQ) in DMF (anhydrous, 5 ml) and the mixture was stirred at room temperature for 1 h was Added acetic acid salt (1-cyano-1-cyclopropylethyl)amide 2-aminocyclohexanecarboxylic acid (1 EQ), EDCI (2 EQ) and NMM (6 EQ) and the mixture was stirred at room temperature under nitrogen overnight, evaporated. The residue was dissolved in dichloromethane, washed with dilute aqueous hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The residue was purified preparative TLC (silica gel; hexane-ethyl acetate, 2:1)to give product as white solid. The output of 65-85%.

Example 9

Obtain hydrochloride of 2-amino-2-cyclopropanecarbonitrile

Dissolved sodium cyanide (3.5 g, 71.4 mmole) and ammonium chloride (3,82 g, 71.7 mmole) in water (20 ml) and methanol (20 ml) and Rast is the PR was cooled to 0° C. To the resulting cooled mixture was added dropwise over 20 min a solution of cyclopropanecarboxaldehyde (5.0 g, 71.3 mmole) in methanol (15 ml) and dichloromethane (15 ml). The mixture was stirred at 0°C for 30 min, were added ammonium hydroxide (28% ammonia in water, 8,64 ml of 142.8 mmole). The reaction mixture was allowed to warm to room temperature overnight and concentrated. The residue was distributed between water and dichloromethane. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated, obtaining a clear oil. This clear oil was dissolved in ether (50 ml) and was slowly added 4 n solution of hydrogen chloride in dioxane. A white precipitate was separated by filtration, washed with ether and dried in vacuum for 2 h, receiving the product as a white powder. Output 7,89 g, 83,9%.

Getting benzyl ether {2-[(1-cyano-1-cyclopropylmethyl)carbarnoyl]cyclohexyl}carbamino acid

A solution of 2-benzyloxycarbonylglycine acid (1,46 g of 5.26 mmole), hydrochloride 2-amino-2-cyclopropanecarbonitrile (0,70 g, at 5.27 mmole), 1-hydroxybenzotriazole (0,89 g of 5.82 mmole) and N-methylmorpholine (1.07 g, of 10.58 mmole) in DMF was cooled to 0°and treated With the hydrochloride of 1-ethyl-3-(3-dimethylamino)propylbromide (2,02 g, 10,54 mmole). The reaction mixture was allowed to warm to room temperature during the night and Ko is centered. The residue was dissolved in dichloromethane and washed with dilute aqueous hydrochloric acid and saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated, obtaining a brown oil. This brown oil was purified by flash chromatography with a mixture of hexane-ethyl acetate, 6:1 to 3:1, receiving the product as a white foam. The output of 1.55 g, 82.9 per cent.

Obtaining acetic acid salt (1-cyano-1-cyclopropylethyl)amide 2-aminocyclohexanecarboxylic acid

To a solution of benzyl ester 2-[(1-cyano-1-cyclopropylmethyl)carbarnoyl]-cyclohexylcarbamate acid (0.15 g, of 0.42 ml) in 50 ml of ethyl acetate with 1% acetic acid (volume/volume) was carefully added under nitrogen, Pd/C (10%) (0.05 g). The mixture was fully degirolami before filling the reaction flask with hydrogen from a balloon. The reaction mixture was stirred for 45 minutes, TLC showed no starting material. The reaction mixture was filtered through a layer of celite. The filtrate was concentrated, receiving a yellow oil. Yield 0.17 g, 100%. Selected CIS - and TRANS-isomer of the product was obtained based on the respective CIS - and TRANS-isomer of a derivative of cyclohexane.

Example 10

Obtain CIS-2-[9H-fluoren-9-ylmethoxycarbonyl(RMOS)amino]cyclohexanecarbonyl acid

Dissolved CIS-β-aminocyclohexanecarboxylic acid (1 g, 7 mmol) in 18 ml of 10% vodno the solution of sodium carbonate. Was added dioxane (10.5 ml) and the solution was cooled in a bath of ice. Added by portions with FMOC-chloride and continued stirring the reaction mixture for 4 h in a bath of ice. The reaction mixture was allowed to warm to room temperature over night. The reaction was stopped by adding water to homogeneity. The aqueous layer was washed twice with ether and then acidified. The acidified layer was extracted with 3×100 ml of dichloromethane. The combined organic layers were dried over sodium sulfate and the reaction mixture are condensed in a vacuum. The solid was purified using flash chromatography with a mixture of hexane-ethyl acetate-acetic acid, 1:1:0,16. Got a pure substance with a yield of 50%, MS: 366,2 (M+H)+.

Obtain TRANS-2-[N-fluoren-9-ylmethoxycarbonyl(FMOC)amino]cyclohexanecarbonyl acid

Dissolved TRANS-β-aminocyclohexanecarboxylic acid (1 g, 7 mmol) in 18 ml of 10% aqueous solution of sodium carbonate. Was added dioxane (10.5 ml) and the solution was cooled in a bath of ice. Added by portions with FMOC-chloride, continued stirring the reaction mixture for 4 h in a bath of ice. The reaction mixture was allowed to warm to room temperature over night. The reaction was stopped by adding water to homogeneity. The aqueous layer was washed twice with ether and then acidified. Upon acidification the desired substance is precipitated. OS the dock was separated by filtration and washed, the white substance was used without purification.

An example of a

Tablets containing the following ingredients can be cooked the conventional way.
IngredientsPills
The compound of the formula Iof 10.0-100.0 mg
Lactose125,0 mg
Corn starch75,0 mg
Talc4.0 mg
Magnesium stearate1.0 mg
Example B

Capsules containing the following ingredients can be cooked the conventional way.
IngredientsOn capsule
The compound of the formula I25.0 mg
Lactose150,0 mg
Corn starch20.0 mg
Talc5.0 mg
The example In

The injection solution may have the following structure
The compound of the formula I3.0 mg
Gelatin150,0 mg
Phenol4,7 mg
Water for injection solutionsto 1.0 ml

1. Derivatives of NITRILES β-amino acids fo the formula (I)

where R1means-CO-Ra, -SO2-Rbor aryl, optionally substituted lower alkoxyl, where Rameans cycloalkyl, cycloalkyl(ness.)alkyl, cycloalkane, aryl, aryloxy, aryl(ness.)alkyl, aryl(ness.)alkoxy, aryloxy(ness.)alkyl, aryl-S-(ness.)alkyl, aryl(ness.)alkenyl, and aryl group optionally substituted by halogen, lower alkyl, hydroxyl, nitro, cyano, lower alkoxyl, phenyl, CF3CN-(ness.)the alkyl, nissalke-C(O)NH, nissalke-(CO) and nissalke-S; heteroaryl, heteroaryl(ness.)alkyl or heteroaryl(ness.)alkoxy, and heteroaryl represents a 5 - or 6-membered ring or bicyclic aromatic group, consisting of two 5 - or 6-membered ring containing 1-3 heteroatom selected from oxygen, nitrogen or sulfur, and heteroaryl group may be optionally substituted lower alkoxyl;

Rbmeans aryl, aryl(ness.)alkyl or heteroaryl, and the aryl group may be optionally substituted with halogen, CN, nissalke-C(O)NH;

R2means hydrogen;

R3means hydrogen;

R4means hydrogen or lower alkyl;

R5means hydrogen, (ness.)alkyl, cycloalkyl, benzodioxol or aryl, optionally substituted lower alkyl, ha is ogena, lowest alkoxyl, hydroxyl, (ness.)alkyl-C(O)O;

n denotes 1 or 2,

and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters.

2. Compounds according to claim 1, where n means 2.

3. Compounds according to any one of items 1 and 2, where R2means hydrogen.

4. Compounds according to any one of items 1 to 3, where R3means hydrogen.

5. Compounds according to any one of items 1 to 4, where R4means hydrogen.

6. Compounds according to any one of items 1 to 5, where R5means aryl.

7. Compounds according to any one of items 1 to 6, where R5means phenyl or naphthyl, optionally substituted (ness.)by alkyl, halogen, hydroxy, (ness.)alkoxy or (ness.)alkylcarboxylic, or R5means benzo[1,3]dioxol.

8. Compounds according to any one of items 1 to 7, where R5means phenyl or naphthyl, optionally substituted by hydroxy, methoxy, stands, acetoxy, chlorine or bromine, or R5means benzo[1,3]dioxol.

9. Compounds according to any one of items 1 to 8, where R5means phenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-were, 2,4-acid, 3,4-acid, 3-chlorophenyl, 3-bromophenyl, 4-bromophenyl or benzo[1,3]dioxol-5-yl.

10. Compounds according to any one of items 1 to 5, where R5means hydrogen.

11. Compounds according to any one of items 1 to 5, where R5means cycloalkyl.

12. Compounds according to any one of items 1 to 5, where R5means qi is sapropel.

13. Compounds according to any one of items 1 to 12, where R1means-CORaand Ramatter according to claim 1.

14. Compounds according to any one of items 1 to 13, where R1means-CORaand Rameans cycloalkyl, cycloalkyl(ness.)alkyl, cycloalkane, aryl, aryloxy, aryl(ness.)alkyl, aryl(ness.)alkoxy, aryloxy(ness.)alkyl, aryl-S-(ness.)alkyl, aryl(ness.)alkenyl or heteroaryl(ness.)alkoxy.

15. Compounds according to any one of items 1 to 14, where R1means-CORaand Rameans phenyl, optionally substituted phenyl, cyano and/or fluorine, or Rameans benzyloxy, optionally substituted stands, chlorine, fluorine, methoxy, nitro and/or by trifluoromethyl, or Rameans phenylidole, thiophenemethylamine, cyclopentyloxy, thiophenemethylamine, naphthyloxy, difeniltiomochevinoi or phenoxy.

16. Compounds according to any one of items 1 to 15, where R1means-CORaand Rameans benzyloxy, phenylfenesin, thiophene-2-ylmethylene or thiophene-3-ylmethylene.

17. Compounds according to any one of items 1 to 13, where R1means-CORaand Rameans benzyl, optionally substituted by chlorine, or phenyl, optionally substituted (ness.)the alkyl, (ness.)alkoxy or cyano.

18. Connection 17, where R1means Raand Rameans 4-ethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-cyanophenyl, 4-tert.-butif the Nile or 4-Chlorobenzyl.

19. Compounds according to any one of items 1 to 13, where R1means-COR3and R3means heteroaryl.

20. Compounds according to claim 19, where R1means-CORaand Ramean 5-methoxybenzophenone-2-yl.

21. Compounds according to any one of items 1 to 12, where R1means-SO2Rband Rbmatter according to claim 1.

22. Compounds according to item 21, where R1means-SO2Rband Rbmeans phenyl, optionally substituted by chlorine, cyano and/or methylcobalamine or Rbmeans benzyl or benzo[1,2,5]oxadiazol.

23. Compounds according to any one of PP and 22, where R1means-SO2Rband Rbmeans 4-chlorophenyl.

24. Compounds according to any one of items 1 to 12, where R1means phenyl, optionally substituted, ethoxy.

25. Derivatives of NITRILES β-amino acids of formula (Ia)

where R1means-CO-Ra, -SO2-Rbor aryl, optionally substituted lower alkoxyl, where Rameans cycloalkyl, cycloalkyl(ness.)alkyl, cycloalkane, aryl, aryloxy, aryl(ness.)alkyl, aryl(ness.)alkoxy, aryloxy(ness.)alkyl, aryl-S-(ness.)alkyl, aryl(ness.)alkenyl, and aryl group optionally substituted by halogen, lower alkyl, hydroxyl, nitro, cyano, lower alkoxyl, phenyl, CF3CN-(ness.)the alkyl, nissalke-C(O)NH, NISS.the lcil-(CO) and nissalke-S; heteroaryl, heteroaryl(ness.)alkyl or heteroaryl(ness.)alkoxy, and heteroaryl represents a 5 - or 6-membered ring or bicyclic aromatic group, consisting of two 5 - or 6-membered ring containing 1-3 heteroatom selected from oxygen, nitrogen or sulfur, and heteroaryl group may be optionally substituted lower alkoxyl;

Rbmeans aryl, aryl(ness.)alkyl or heteroaryl, and the aryl group may be optionally substituted with halogen, CN, nissalke-C(O)NH;

R2means hydrogen;

R3means hydrogen;

R4means hydrogen or lower alkyl;

R5means hydrogen, (ness.)alkyl, cycloalkyl, benzodioxol or aryl, optionally substituted lower alkyl, halogen, lower alkoxyl, hydroxyl, (ness.)alkyl-C(O)O;

n denotes 1 or 2,

and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters,

26. Derivatives of NITRILES β-amino acids of formula (Ib)

where R1means-CO-Ra, -SO2-Rbor aryl, optionally substituted lower alkoxyl, where Rameans cycloalkyl, cycloalkyl(ness.)alkyl, cycloalkane, aryl, aryloxy, aryl(ness.)alkyl, aryl(ness.)alkoxy, aryloxy(ness.)alkyl, aryl-S-(n is ZS.)alkyl, aryl(ness.)alkenyl, and aryl group optionally substituted by halogen, lower alkyl, hydroxyl, nitro, cyano, lower alkoxyl, phenyl, CF3CN-(ness.)the alkyl, nissalke-C(O)NH, nissalke-(CO) and nissalke-S; heteroaryl, heteroaryl(ness.)alkyl or heteroaryl(ness.)alkoxy, and heteroaryl represents a 5 - or 6-membered ring or bicyclic aromatic group, consisting of two 5 - or 6-membered ring containing 1-3 heteroatom selected from oxygen, nitrogen or sulfur, and heteroaryl group may be optionally substituted lower alkoxyl;

Rbmeans aryl, aryl(ness.)alkyl or heteroaryl, and the aryl group may be optionally substituted with halogen, CN, nissalke-C(O)NH;

R2means hydrogen;

R3means hydrogen;

R4means hydrogen or lower alkyl;

R5means hydrogen, (ness.)alkyl, cycloalkyl, benzodioxol or aryl, optionally substituted lower alkyl, halogen, lower alkoxyl, hydroxyl, (ness.)alkyl-C(O)O;

n denotes 1 or 2,

and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters,

27. Compounds characterized by the formula (IC)

where R1means-CO-Ra, -SO2 -Rbor aryl, optionally substituted lower alkoxyl, where Rameans cycloalkyl, cycloalkyl(ness.)alkyl, cycloalkane, aryl, aryloxy, aryl(ness.)alkyl, aryl(NISS,)alkoxy, aryloxy(ness.)alkyl, aryl-S-(ness.)alkyl, aryl(ness.)alkenyl, and aryl group optionally substituted by halogen, lower alkyl, hydroxyl, nitro, cyano, lower alkoxyl, phenyl, CF3CN-(ness.)the alkyl, nissalke-C(O)NH, nissalke-(CO) and nissalke-S; heteroaryl, heteroaryl(ness.)alkyl or heteroaryl(ness.)alkoxy, and heteroaryl represents a 5 - or 6-membered ring or bicyclic aromatic group, consisting of two 5 - or 6-membered ring containing 1-3 heteroatom selected from oxygen, nitrogen or sulfur, and heteroaryl group may be optionally substituted lower alkoxyl;

Rbmeans aryl, aryl(ness.)alkyl or heteroaryl, and the aryl group may be optionally substituted with halogen, CN, nissalke-C(O)NH;

R2means hydrogen;

R3means hydrogen;

R4means hydrogen or lower alkyl;

R5means hydrogen, (ness.)alkyl, cycloalkyl, benzodioxol or aryl, optionally substituted lower alkyl, halogen, lower alkoxyl, hydroxyl, (ness.)alkyl-C(O)O;

n denotes 1 or 2,

and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters,

28. The compound according to any one of items 1-27, selected from the group consisting of benzyl ester of (1R,2R)-(2-{(S)-[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

[(R)- and (S)-cyano-(3,4-acid)methyl]amide CIS-2-(3-phenylacetylamino)-cyclohexanecarbonyl acid,

benzyl ether of (R)-{2-[(S)-(cianfanelli)-(R)-carbarnoyl]cyclohexyl}-carbamino acid,

benzyl ester SYN-{2-[(S)-(cianfanelli)carbarnoyl]cyclohexyl}-carbamino acid,

benzyl ester of CIS-(2-{(R)- and (S)-[cyano-(2,4-acid)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

[cyano-(3-hydroxyphenyl)methyl]amide, TRANS-2-(4-chlorobenzenesulfonamide)-cyclohexanecarbonyl acid,

benzyl ester, TRANS-{2-[(benzo[1,3]dioxol-5-altianalis)carbarnoyl]-cyclohexyl} carbamino acid,

benzyl ester of CIS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}cyclohexyl)-carbamino acid,

benzyl ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

((R)- and (S)-cyanovinylene)amide CIS-2-(3-phenylacetylcarbinol acid,

benzyl ether (2-{[cyano-(3,4-acid)methyl]carbarnoyl}cyclohexyl)-carbamino acid (1 CIS-racemate),

benzyl ether of CIS-{2-[(R)- and (S)-cyano-m-trimethyl)carbarnoyl]cyclohexyl}-carbamino acid,

thiophene-3-Eletropaulo ether (2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ester of CIS-(2-{(R)- and (S)-[cyano-(4-methoxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ester of CIS-(2-{(R)- and (S)-[cyano-(3-methoxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

thiophene-2-Eletropaulo ester, TRANS-(2-{[cyano-(3-hydroxyphenyl)methyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ester of CIS-(2-{(R)- and (S)-[(3-chlorophenyl)cyanomethyl]carbarnoyl}-cyclohexyl)carbamino acid,

benzyl ether of CIS-{2-[(cianfanelli)carbarnoyl]cyclohexyl} carbamino acid,

benzyl ester, TRANS-(2-{[(3-bromophenyl)cyanomethyl]carbarnoyl}cyclohexyl)-carbamino acid,

benzyl ester of CIS-(2-{(R)- and (S)-[(4-bromophenyl)cyanomethyl]carbarnoyl}-cyclohexyl)carbamino acid and

benzyl ester of CIS-(2-{(R)- and (S)-[cyano-(3,4-acid)methyl]carbarnoyl}-cyclopentyl)carbamino acid, and their pharmaceutically acceptable esters.

29. The compound according to any one of items 1-27, selected from the group consisting of [2-(cyanomethylene)cyclohexyl]amide CIS-5-methoxybenzophenone-2-carboxylic acid,

[2-(cyanomethylene)cyclohexyl]amide, TRANS-5-methoxybenzophenone-2-carboxylic sour is s,

CIS-2-{[(4-chlorophenyl)acetyl] amino}-N-[cyano(cyclopropyl)methyl]cyclohexanecarboxylate,

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethylbenzamide,

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethoxybenzene,

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-methoxybenzamide,

TRANS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-methoxybenzamide,

TRANS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-ethylbenzamide,

CIS-N - [2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-cyanobenzene and

CIS-N-[2-({[cyano(cyclopropyl)methyl]amino}carbonyl)cyclohexyl]-4-tert.-butylbenzamide,

and their pharmaceutically acceptable esters.

30. Method of preparing compounds according to any one of items 1 to 29, the method that includes (a) the interaction of the compounds of formula (II)

with the compound of the formula (III)

where R1, R2, R3, R4, R5and n have the meanings according to any one of items 1 to 24.

31. Method of preparing compounds according to any one of items 1 to 29, the method that includes (b) the interaction of the compounds of formula (IV)

with the compound of the formula (V) or (VI)

where R2, R3, R4, R5, Ra, Rband n have the meanings according to any one of items 1 to 24.

32. The compounds of formula IV

where R2means hydrogen;

R3means hydrogen;

R4means hydrogen or lower alkyl;

R5means hydrogen, (ness.)alkyl, cycloalkyl, benzodioxol or aryl, optionally substituted lower alkyl, halogen, lower alkoxyl, hydroxyl, (ness.)alkyl-C(O)O;

n denotes 1 or 2.

33. Compounds according to any one of items 1 to 29, with inhibitory activity against cysteine protease family of cathepsins.

34. Pharmaceutical composition having inhibitory activity against cysteine protease family of cathepsins, including the compound according to any one of items 1 to 29 and a pharmaceutically acceptable carrier and/or excipient.



 

Same patents:

The invention relates to compounds of the following formula 1, which inhibit the enzyme glycinamide ribonucleotide the formyl transferase (GARFT)

The invention relates to the field of chemical technology, specifically to a method for producing a thiophene-2,5-dicarboxylic acid, which is used as starting product for the production of high-performance optical brighteners for polymeric materials and can be used to obtain a polyester (modified) and polyamide fibres and plastics

The invention relates to new derivatives of 4-oxobutanoic acid of formula 1, where groups a and b independently from each other selected from mono - or bicyclic aryl group selected from phenyl and naphthyl, cycloalkyl group having 5 to 8 carbon atoms, a saturated heterocyclic group selected from tetrahydrofuryl groups; group a and b may have 1 to 3 substituents selected from C1-C6alkyl group, a C1-C6alkoxygroup, halogen; or two Deputy together represent methylenedioxy

The invention relates to new derivatives of Anthranilic acid of General formula (1) or their pharmacologically acceptable salts, where R1, R2, R3and R4- same or different and mean a hydrogen atom, halogen atom, optionally halogenated lower alkoxygroup, nitro, cyano, pyrazolidine group, a group of the formula (II), where R9and R10are the same or different and mean a hydrogen atom, a lower alkyl group and p is an integer from 0 to 6, a group of the formula (III), where R13represents a hydrogen atom, a lower alkyl group, q is an integer from 0 to 2; and R2may be 1,2,4-triazoline group; R5and R6are the same or different and represent a hydrogen atom, halogen atom, cyano, lower alkoxygroup, or R5and R6together with the carbon atoms to which they are attached, form oxolane ring, 1,3-dioxolane or 1,4-dioxane ring; W represents a group - N = or-CH=; R7and R8are the same or different and represent a hydrogen atom, a lower alkyl group, or R1and R7together with the carbon atoms and nitrogen, respectively, to which they are attached, form the second alkyl group or a group of the formula-X-(CH2)m-Z, where X represents-CO-, -CH2- or-S(O)2-; Z represents hydrogen, halogen, phenyl group which may be substituted by lower alkyl, lower alkoxygroup, carboxypropyl or lower alkoxycarbonyl group, pyridyloxy group, a group of the formula NR11R12where R11and R12together with the nitrogen atom to which they are attached, form piperidino or pyrolidine ring which may be substituted by a lower alkyl group, actigraphy, carboxypropyl, lower alkoxycarbonyl group, cycloalkyl group containing 3-8 carbon atoms which may be substituted by actigraphy, cyano, lower alkylcarboxylic, carboxypropyl or lower alkoxycarbonyl group, piperidino group, m is an integer from 0 to 6, Y is an oxygen atom; n is an integer from 0 to 6

The invention relates to 3-dibenzoylethylene-7-nitro-2-honokalani form (1) with analgesic activity

The invention relates to tsianinajoelson derivative of the formula (II), useful as a preventive or therapeutic agent for treatment of diseases caused by hypervisortm glutamate receptors

The invention relates to a derivative of khinoksalinona used in medicines and the way they are received

The invention relates to the derivatives of cinoxacin used in therapy

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

in which U represents O or a lone pair of electrons; V represents O, S, - CH2-, - CH=CH - or - C-; W represents CO, COO, CONR1CSO , CSNR1, SO2or SO2NR1; m and n independently of one another each represents a number from 0 to 7, and the sum of m+n is from 0 to 7, provided that m represents 0, if V denotes O or S; AND1represents H, lower alkyl, hydroxy(ness.)alkyl or (ness.)alkenyl; AND2means (ness.)alkyl, cycloalkyl, cycloalkyl(lower)alkyl or (ness.)alkenyl, optionally substituted by a group R2;3and4each denotes a hydrogen atom or (ness.)alkyl; AND5denotes H, (ness.)alkyl, (ness.)alkenyl or aryl(ness.)alkyl; AND6means (ness.)alkyl, cycloalkyl, aryl, aryl(lower)alkyl, heteroaryl, heteroaryl(ness.)alkyl, (ness.)alkoxycarbonyl(ness.)alkyl; R2denotes hydroxy, hydroxy(ness.)alkyl, (ness.)alkoxy, (ness.)alkoxycarbonyl, N(R4,R5) or thio(ness.)alkoxy; R1, R3, R4and R5each independent is asepticheski acceptable esters

The invention relates to inhibitors of potassium channel, in particular a derivative of tetrahydronaphthalene formula (I) or their pharmaceutically acceptable salts, stereoisomers, crystalline or amorphous forms

< / BR>
where t is 1; a and b each represent H; R1represents aryl, optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, nitro, trifloromethyl, triptoreline; aromatic 5-membered monocyclic system which consists of carbon atoms and contains sulfur as one heteroatom; a saturated 5-membered monocyclic system which consists of carbon atoms and contains nitrogen as one heteroatom, which is optionally substituted by aralkyl, and aryl optionally substituted with halogen; provided that when R1represents optionally substituted aryl, R1is not dialkoxybenzene; Y2represents (CH2)qwhere q is 0; X2is SO2; R3represents H, lower alkyl, in which one hydrogen atom substituted aromatic 6-membered monocyclic system which consists of atom N; R2represents aryl, optionally substituted by one or more groups selected from lower alkyl, lower alkoxy, nitro, trifloromethyl, triptoreline; aromatic 5-membered monocyclic system which consists of carbon atoms and contains sulfur as one heteroatom; a saturated 5-membered monocyclic system which consists of carbon atoms and contains nitrogen as one heteroatom, which is optionally substituted by aralkyl, and aryl optionally substituted with halogen; Y1represents (CH2)pwhere p is 1; NS=SN or ethinyl; X1is C=O or (CH2)nwhere n is 0, 1 or 2; R4represents H, lower alkyl, in which one hydrogen atom substituted aromatic 6-membered monocyclic system which consists of carbon atoms and contains nitrogen as heteroatom

FIELD: medicine, cardiology.

SUBSTANCE: it is suggested to apply cortisol antagonists in addition to clonidine while manufacturing preparation to treat heart failure. Moreover, one should introduce cortisol antagonist or a product that includes cortisol antagonist along with the second medicinal preparation being a combined preparation to be applied either simultaneously, separately or successively. The present innovation provides decreased symptoms of heart failure at decreasing cardiac muscle's fibrosis and heart sizes due to preferable impact upon glucocorticoid receptors in patient's heart and/or kidneys.

EFFECT: higher efficiency of application.

12 cl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves administering Noliprelum in postoperative period for reducing left ventricle hypertrophy.

EFFECT: enhanced effectiveness of treatment in early postoperative period.

Up!