Derivatives of thioamide and pharmaceutical composition

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I):

wherein X means group of the formula (X-1) wherein R15 means halogen atom, (lower)-alkyl and perfluoro-(lower)-alkyl; R16 means hydrogen, halogen atom and (lower)-alkyl; or X means group of the formula (X-2) wherein Het means 5- or 6-membered heteroaromatic ring comprising 1 or 2 heteroatoms as nitrogen (N) atom; R15 and R16 have values indicated above for (X-1); R30 means hydrogen atom or (lower)-alkyl; p means a whole number from 0 to 1; or X means group of the formula (X-3) wherein R18 means aryl; R19 means unsubstituted arylalkyl or heteroarylalkyl representing 6-membered heteroaromatic ring comprising nitrogen (N) atom as a heteroatom; R20 means unsubstituted (lower)-alkanoyl; Y means group of the formula (Y-1) wherein R22 and R23 mean independently from one another hydrogen atom, (lower)-alkyl, halogen atom or perfluoro-(lower)-alkyl and at least one of radicals R22 and R23 doesn't mean hydrogen atom; R24 means hydrogen atom; or Y means group of the (Y-3) wherein R25 means group of the formula: R26-(CH2)e- wherein R26 means (lower)-alkoxy-group, (lower)-alkylthio-group, (lower)-alkylsulfonyl; or R26 means group of the formula: -NR28R29 wherein R28 means hydrogen atom; R29 means (lower)-alkanoyl or (lower)-alkylaminocarbonyl; Q means -(CH2)f- wherein e means a whole number from 0 to 4; f means a whole number from 1 to 3; a bond denoted as a dotted line can be hydrogenated optionally; and to its pharmaceutically acceptable salts and esters. Also, invention proposes a pharmaceutical composition designated for treatment or prophylaxis of rheumatic arthritis, cerebrospinal sclerosis, intestine inflammatory disease and asthma and containing compound of the formula (I) or its pharmaceutically acceptable salt or ester in combination with a compatible pharmaceutical carrier. Invention proposes derivatives of thioamide inhibiting interaction between α4-comprising integrins and VCAM-1.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 1 tbl, 86 ex

 

Factor of adhesion 1 cells vascular (VCAM-1), which is representative of the family supergene immunoglobulin (Ig), is expressed on activated, but not expressed on resting endothelium. The integrin VLA-4 (a4b1), which is expressed on the surface of many cell types, including those in blood lymphocytes, eosinophils, basophils and monocytes, but is not expressed on neutrophils, is the main receptor for VCAM-1. Antibodies to VCAM-1 or VLA-4 in vitro to block the adhesion of these mononuclear cells, and melanoma cells to activated endothelium. Several created using animal models of inflammation was found that antibodies to any protein have efficacy in inhibiting the infiltration of leukocytes and prevent tissue damage. It was found that monoclonal antibody (MAB) to the VLA-4 blocking T-cell emigration in adjuvant induced arthritis, prevent the accumulation of eosinophils and bronchostenosis when modeling asthma and reduce paralysis and inhibit the infiltration of monocytes and lymphocytes in experimental autoimmune encephalitis (EAE). It was found that monoclonal entitile to VCAM-1, prolong the time of survival of cardiac allografts. Modern studies have shown that the Mat is VLA-4 can prevent stroke and diabetes in mice-diabetics, not obese, and significantly reduce inflammation in the simulation of colitis using Tamarin made with a cotton swab.

Thus, compounds that inhibit the interaction between containing α4the integrins and VCAM-1 may be used as therapeutic agents for the treatment of chronic inflammatory diseases such as rheumatoid arthritis, multiple sclerosis (PC), asthma, and inflammatory bowel disease (IBD).

One of the objects of the present invention are compounds of the formula:

where X denotes a group of the formula

where

R15denotes halogen, nitro, (ness.)alkylsulfonyl, cyano, (ness.)alkyl, (ness.)alkoxy, (ness.)alkoxycarbonyl, carboxy, (ness.)alkylaminocarbonyl, PERFLUORO(ness.)alkyl, (ness.)alkylthio, hydroxy(ness.)alkyl, alkoxy(ness.)alkyl, (ness.)alkylthio-(ness.)alkyl, (ness.)alkylsulfonyl-(ness.)alkyl, (ness.)alkylsulfonyl-(ness.)alkyl, (ness.)alkylsulfonyl, (ness.)alkanoyl, aroyl, aryl, aryloxy;

R16denotes hydrogen, halogen, nitro, cyano, (ness.)alkyl, HE, PERFLUORO(ness.)alkyl or (ness.)alkylthio;

or X represents a group of formula X-2

where Het denotes a 5 - or 6-membered heterobicycle ring, teramae 1, 2 or 3 heteroatoms selected from N, O and S, or

Het denotes a 9 - or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms selected from O, S and N;

R15and R16have the values specified above for the X-1, and

R30denotes hydrogen or (ness.)alkyl, R denotes an integer from 0 to 1;

or X represents a group of formula X-3

where

R18denotes aryl, heteroaryl, aryl(ness.)alkyl, heteroaryl(ness.)alkyl,

R19denotes a substituted or unsubstituted (ness.)alkyl, aryl, heteroaryl, arylalkyl, heteroallyl and

R20denotes a substituted or unsubstituted (ness.)alkanoyl or aroyl;

and Y denotes a group of formula Y-1

where R22and R23independently of one another denote hydrogen, (ness.)alkyl, (ness.)alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, (ness.)alkylthio, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, (ness.)alkanoyl, halogen or PERFLUORO(ness.)alkyl and at least one of the radicals R22and R23does not denote hydrogen, and

R24denotes hydrogen, (ness.)alkyl, (ness.)alkoxy, aryl, nitro, cyano, (ness.)alkylsulfonyl or halogen, or

Y-2 represents a group of the formula

where Het denotes a 5-or 6-membered hetaeras the aromatic ring, bound through a carbon atom, and the ring contains 1, 2 or 3 heteroatoms selected from the series comprising N, O or S, R30and R31independently of one another denote hydrogen, (ness.)alkyl, cycloalkyl, halogen, cyano, perfluoroalkyl, or aryl and at least one of the radicals R30and R31is adjacent to the attachment point, p denotes an integer of 0 or 1,

or Y represents the group Y-3

where:

R25means (ness.)alkyl, unsubstituted or substituted by fluorine (ness.)alkenyl, or a group of the formula R26-(CH2)e-,

R26denotes aryl, heteroaryl, azido, cyano, hydroxy, (ness.)alkoxy, (ness.)alkoxycarbonyl, (ness.)alkanoyl, (ness.)alkylthio, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkanoyl, nitro, or R26denotes a group of formula-NR26R29,

where R28represents H or (ness.)alkyl,

R29denotes hydrogen, (ness.)alkyl, (ness.)alkoxycarbonyl, (ness.)alkanoyl, aroyl, PERFLUORO(ness.)alkanolamine, (ness.)alkylsulfonyl, (ness.)alkylaminocarbonyl, allumination, or

R28and R29together form a 4-, 5 - or 6-membered saturated carbocyclic ring, optionally including 1 heteroatom selected from O, S and N; and the carbon atoms in the ring can be nezam is disposed of or replaced (ness.)by alkyl or halogen,

Q represents -(CH2)fO-, -(CH2)fS-, - (CH2)fN(R27), -(CH2)for communication;

R27denotes H, (ness.)alkyl, aryl, (ness.)alkanoyl, aroyl or (ness.)alkoxycarbonyl;

e denotes an integer from 0 to 4;

f denotes an integer from 1 to 3; and

communication, indicated by the dashed line, may not necessarily be gidrirovannah;

and their pharmaceutically acceptable salts and esters.

In the context of the present description, the terms have the following meanings:

The term "halogen" denotes bromine, chlorine, fluorine or iodine, and the term "halo" means a halogen as a substituent.

The term "PERFLUORO", for example, PERFLUORO(ness.)the alkyl, PERFLUORO(ness.)alkanoyl and performanceline means the complete replacement of all carbon atoms of fluorine. An example is trifluoromethyl.

The term "(ness.)alkyl, individually or in combination (for example, as part of (ness.)alkanoyl below), denotes an alkyl group with straight chain or branched chain containing up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, etc. (Ness.)alkyl groups can be unsubstituted or can be substituted by one or more groups, independently of each other chosen from the series, including cycloalkyl, who and Jethro, aryloxy, aryl (preferably phenyl or pyridyl), hydroxy ((ness.)alkylperoxy or hydroxy (ness.)alkyl), halogen, cyano, (ness.)alkoxy (alkoxy(ness.)alkyl or (ness.)alkylalkoxy), (ness.)alkanoyl, (ness.)alkylthio ((ness.)alkylthio-(ness.)alkyl), sulfinil ((ness.)alkylsulfonyl), sulfinil(ness.)alkyl ((ness.)alkylsulfonyl-(ness.)alkyl), sulfonyl ((ness.)alkylsulfonyl), sulfonyl(ness.)alkyl ((ness.)alkylsulfonyl-(ness.)alkyl), PERFLUORO (PERFLUORO(ness.)alkyl) and substituted an amino group, such as aminosulfonyl ((ness.)alkylaminocarbonyl) or aminocarbonyl ((ness.)alkylaminocarbonyl). Examples of substituted (ness.)alkyl groups include 2-hydroxyethyl, 3-oxobutyl, tianmei and 2-nitropropyl.

The term "(ness.)alkylthio" means (ness.)the alkyl group attached to a divalent sulfur atom, for example, methylmercapto or isopropylacetate.

The concept of "cycloalkyl" refers to unsubstituted or substituted 3-7-membered carbocyclic ring. Substituents, suitable according to the present invention are hydroxy, halogen, cyano, (ness.)alkoxy, (ness.)alkanoyl, (ness.)alkyl, aroyl, (ness.)alkylthio, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, aryl, heteroaryl and substituted amino group.

The term "(ness.)alkoxy" means (ness.)alkyl group as defined above attached through the atom to which Sloboda. Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy etc.

The term "(ness.)alkenyl" means non-aromatic, partially unsaturated hydrocarbon chain containing at least one double bond, which contains preferably 1-10 and more preferably 1-6 carbon atoms. The group may be unsubstituted or substituted by conventional substituents, preferably fluorine. Examples are vinyl, allyl, dimethylallyl, butenyl, Isobutanol, pentanol.

The term "aryl" means a mono - or bicyclic aromatic group such as phenyl or naphthyl, which is unsubstituted or may be substituted by conventional substituents. Preferred substituents are (ness.)alkyl, (ness.)alkoxy, hydroxy(ness.)alkyl, hydroxy, hydroxyalkoxy, halogen, (ness.)alkylthio, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, cyano, nitro, perfluoroalkyl, alkanoyl, aroyl, aryl, quinil, (ness.)quinil, aminoalkylsilanes (allumination) and (ness.)alkanolamine. Particularly preferred substituents are (ness.)alkyl, hydroxy and PERFLUORO(ness.)alkyl. Examples of aryl groups that may be used according to the invention are phenyl, paratool, parametersetter, parachlorophenyl, metagalaxies, matematicians, 2-methyl-5-nitrophenyl, 2,6-dichlorophenyl, 1-NAF is the sludge etc.

The concept of "arylalkyl" means (ness.)alkyl group as defined above in which one or more hydrogen atoms substituted(s) aryl group as defined above. According to this invention may be used any suitable arylalkyl, such as benzyl and the like, Similarly, the concept of "heteroaromatic" has the same meaning as arolina group, except that instead of the aryl group is a heteroaryl group, as defined below. Any of these groups may be unsubstituted or may be substituted on the ring of a conventional substituents.

The concept of "heteroaryl" refers to unsubstituted or substituted 5 - or 6-membered monocyclic heteroaromatic ring or 9 - or 10-membered bicyclic heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms, which are independently of one another may represent an N, S or O. Examples of heteroaryl rings include pyridine, benzimidazole, indole, imidazole, thiophene, isoquinoline, hinzelin etc. Deputies of heteroaryl include the substituents mentioned above for "aryl". The term "heteroaromatic ring" may be used interchangeably with the concept of "heteroaryl".

The term "(ness.)alkoxycarbonyl" means (ness.)alkoxygroup associated with the carbonyl group. Examples alkoxycarbonyl groups ablauts the etoxycarbonyl etc.

The term "(ness.)alkylcarboxylic" means (ness.)alkylcarboxylic associated with the oxygen atom, such as acetochlor.

The term "(ness.)alkanoyl" means (ness.)alkyl groups associated with the carbonyl group, and includes in the context of the above definitions of groups such as acetyl, propionyl etc. "(Ness.)alcoholnye" group can be unsubstituted or substituted by conventional substituents, such as alkoxy, (ness.)alkyl, hydroxy, aryl and heteroaryl.

The term "(ness.)alkylcarboxylic" means (ness.)alkylcarboxylic groups connected to the nitrogen atom, such as acetylamino.

The concept of "aroyl" denotes a mono - or bicyclic aryl or heteroaryl group associated with the carbonyl group. Examples rolnych groups are benzoyl, 3-tenbensel, 2-naphthyl, etc. Aroline groups can be unsubstituted or substituted by conventional substituents.

The notion of "aryloxy" denotes an aryl group as defined above linked to an oxygen atom. The preferred arroceros is fenoxaprop.

The concept of "electron Deputy" means the Deputy on the aromatic or heteroaromatic ring, which has a positive value of the Sigma Hammett, as defined, for example, in Jerry March, Advanced Organic Chemistry, 2nd ed., McGraw Hill, 1977, pp. 246-253. Tipi is generated electron-withdrawing groups are cyano, nitro, chlorine, alkoxycarbonyl, (ness.)alkylsulfonyl and aminocarbonyl.

In the compound of the formula I Y preferably denotes a group Y-1, as a result, the invention includes a compound of the formula:

where X, R22, R23and R24have the above values.

In the group Y is preferably 1 R22denotes hydrogen, halogen,

(ness.)alkyl, perfluoroalkyl (preferably trifluoromethyl), R23denotes halogen, (ness.)alkyl, perfluoroalkyl (preferably trifluoromethyl), R24denotes hydrogen, (ness.)alkyl, (ness.)alkoxy or halogen; more preferably R22and R23denote (ness.)alkyl, trifluoromethyl or halogen, most preferably R22and R23denote (ness.)alkyl or halogen and R24preferably denotes hydrogen.

Preferred groups Y-1, in which R23means (ness.)alkyl or halogen, are as follows

,,,,,,,,.,,,,. ,

When Y represents the group Y-2, "Het" preferably denotes a 6-membered heterobicycle ring containing 1, 2 or 3 heteroatom represents N; more preferably Y-2 means:

When Y represents the group Y-3, Q preferably represents -(CH2)fO-, -(CH2)fS-, -(CH2)fN(R27or -(CH2)f-, more preferably -(CH2)f-; more preferably Y represents:

where Q has the above values and communication, indicated by the dashed line, may not necessarily be gidrirovannah, preferably Q represents (CH2)f, communication, indicated by the dotted line, gidrirovannah, R25denotes the R26-(CH2)e-; e represents 0 to 4, preferably 2-4, and R26indicates azido, cyano, hydroxy, (ness.)alkoxy, (ness.)alkoxycarbonyl, (ness.)alkanoyl, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, PERFLUORO (ness.)alkanoyl, nitro, (ness.)alkylthio, phenyl or phenyl substituted by alkoxygroup or halogen, preferably of azido, cyano, hydroxy, (ness.)alkoxy, (ness.)alkoxycarbonyl, (ness.)alkanoyl, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, PERFLUORO (ness.)alkanoyl, nitro or (ness.)alkylthio, or R26oboznachennomu formula with other 29; where R29means (ness.)alkanoyl, (ness.)alkoxycarbonyl or (ness.)alkylaminocarbonyl.

More preferably Y-3 denotes 4-5 or 4-6-membered cycloalkyl ring (Q denotes (CH2)ff denotes 1, 2 or 3), R25denotes the R26-(CH2)e-; e represents 0 to 4, preferably 2-4, and R26denotes alkoxy, (ness.)alkylsulfonyl, (ness.)alkylthio, phenyl or phenyl substituted by alkoxygroup or halogen, preferably alkoxy, (ness.)alkylsulfonyl or (ness.)alkylthio, or R26means-other29; where R29means (ness.)alkanoyl, (ness.)alkoxycarbonyl or (ness.)alkylaminocarbonyl, and the relationship indicated by the dotted line, gidrirovannah.

Most preferably Y-3 denotes a group of the formula

In group H-1, the radicals R15and R16preferably denote hydrogen, (ness.)alkyl, nitro, cyano, halogen, (ness.)alkylsulfonyl, (ness.)alkylthio or PERFLUORO(ness.)alkyl, more preferably R15means (ness.)alkyl, nitro, cyano, halogen, (ness.)alkylsulfonyl or PERFLUORO(ness.)alkyl, and R16denotes hydrogen, (ness.)alkyl, nitro, halogen (particularly preferably chlorine or fluorine), PERFLUORO(ness.)alkyl, (ness.)alkylthio or cyano. In particular, R15means (ness.)alkyl, nitro, cyano, halogen, (ISS.)alkylsulfonyl, PERFLUORO(ness.)alkyl (particularly preferably trifluoromethyl), and R16located in the ortho-position and represents hydrogen, (ness.)alkyl, nitro, cyano, halogen, (ness.)alkylthio or PERFLUORO(ness.)alkyl (particularly preferably trifluoromethyl).

Particularly preferably R15and R16independently of one another represent chlorine or fluorine.

Particularly preferred groups X-1 are groups of the formula:

In group H-2 "Het" preferably denotes a 5 - or 6-membered monocyclic heteromyinae ring containing 1, 2 or 3 nitrogen atom or nitrogen atom and sulfur, or nitrogen atom and oxygen. When Het represents a bicyclic heteroaromatic ring, it preferably contains, as heteroatoms 1-3 nitrogen atom. R15preferably represents nitro, (ness.)alkylsulfonyl, cyano, (ness.)alkyl, (ness.)alkoxy, PERFLUORO(ness.)alkyl, (ness.)alkylthio, (ness.)alkanoyl or aryl (particularly preferably unsubstituted phenyl); R16preferably represents hydrogen, halogen, nitro, cyano, (ness.)alkyl, PERFLUORO(ness.)alkyl; and R30if present, preferably denotes hydrogen or (ness.)alkyl.

Particularly preferably the group X-2 "Het" refers to 6-membered monocyclic heteromyinae ring containing 1 or 2 nitrogen atom, predpochtitel what about the pyridine or pyrimidine, or 10-membered bicyclic heteromyinae ring containing 1 nitrogen atom, R15means (ness.)alkyl or PERFLUORO(ness.)alkyl, and R16denotes hydrogen, (ness.)alkyl or PERFLUORO(ness.)alkyl, and R30is missing.

Particularly preferred groups X-2 are groups of the formula:

,,and

In the group X-3 R18preferably denotes phenyl. R19preferably means (ness.)alkyl which may be unsubstituted or substituted by pyridium or phenyl. R20preferably denotes a substituted or preferably unsubstituted (ness.)alkanoyl, and most preferred is acetyl.

In a preferred embodiment, R18denotes phenyl, R19means (ness.)alkyl which may be unsubstituted or substituted by pyridium or phenyl, and R20means (ness.)alkanoyl. In another embodiment, X 3 R18denotes phenyl which may be unsubstituted or substituted with halogen or (ness.)alkoxygroup, R19denotes phenyl (ness.)alkyl which may be unsubstituted or substituted (ness.)alkoxygroup, pyridyl(ness.)the alkyl or (ness.)by alkyl; and R20denotes a substituted or more predpochtitel is but unsubstituted (ness.)alkanoyl, the most preferred is acetyl.

Particularly preferred groups X-3 is a group of the formula:

,,,

,,,,,,,,

Compounds according to the invention can exist in the form of stereoisomers and diastereoisomers, all of which fall under the scope of the present invention.

The following variants of implementation of the specific variants of compounds of formula I.

1.1. One option is the above compound of formula I, where X denotes a group of the formula

and Y, R15and R16have the above values, in particular R15means (ness.)alkyl, nitro, halogen, performer or cyano and R16denotes hydrogen, (ness.)alkyl, nitro, halogen, performer or cyano; especially preferably, R15and R16independently of one another represent chlorine or fluorine, particularly preferably, where X-1 is chosen from the group

1.2. Another embodiment is a compound of formula I, where X denotes a group of formula X-2

and R, Y, R15, R16and R30have the above values, in particular, Het denotes a 5 - or 6-membered monocyclic heteromyinae ring containing 1, 2 or 3 nitrogen atom or nitrogen atom and sulfur, or nitrogen atom and oxygen, or Het denotes a bicyclic heteroaromatic ring containing 1-3 nitrogen atom, most preferably R15denotes nitro, (ness.)alkylsulfonyl, cyano, (ness.)alkyl, (ness.)alkoxy, PERFLUORO(ness.)alkyl, (ness.)alkylthio, (ness.)alkanoyl or aryl (particularly preferably unsubstituted phenyl), in particular R15denotes unsubstituted phenyl, and R16denotes hydrogen, halogen, nitro, cyano, (ness.)alkyl, PERFLUORO(ness.)alkyl; and R30denotes hydrogen or (ness.)alkyl.

In this embodiment, in another particular case, Het denotes a 6-membered monocyclic heteromyinae ring containing 1 or 2 nitrogen atom, or 10-membered Bilichenko heteromyinae ring containing 1 nitrogen atom, R15means (ness.)alkyl or perfluoroalkyl, and R16denotes hydrogen, (ness.)alkyl or perfluoroalkyl, and R30is missing.

Particularly preferably X-2 are selected from the group

,,and

1.3. The following embodiment is a compound of formula I, where X denotes a group of the formula

where Y, R18, R19and R20have the above values, particularly preferably R18denotes phenyl, and particularly preferably R10means (ness.)alkyl which may be unsubstituted or substituted by pyridium or phenyl, and especially preferably R20denotes unsubstituted or substituted (ness.)alkanoyl.

According to a particularly preferred options R18denotes phenyl, R19means (ness.)alkyl which may be unsubstituted or substituted by pyridium or phenyl, and R20means (ness.)alkanoyl or R18denotes phenyl which may be unsubstituted or substituted with halogen or (ness.)alkoxygroup, R19denotes phenyl(ness.)alkyl which may be unsubstituted or substituted (ness.)alkoxygroup, pyridyl(ness.)the alkyl or (ness.)the alkyl, and R20denotes a substituted or unsubstituted (ness.)alkanoyl; and most preferably X-3 is selected from a group

,,,

, ,,,,,

,,

1.4. Another embodiment is a compound of formula I, where Y denotes a group of the formula

and X, R22, R23and R24have the above values, particularly preferably R30denotes hydrogen, (ness.)alkyl, trifluoromethyl or halogen, R23means (ness.)alkyl, trifluoromethyl or halogen, and R24denotes hydrogen, (ness.)alkyl, (ness.)alkoxy or halogen; more preferably R22and R23denote (ness.)alkyl, trifluoromethyl or halogen and R24denotes hydrogen, (ness.)alkyl, (ness.)alkoxy or halogen, particularly preferably Y-1 is chosen from the group

,,,,,,,,.,,,.,and

1.5. The following embodiment is a compound of formula I, where Y denotes a group of formula Y-2

where R, X, Het, R30and R31have the above values, particularly preferably Het denotes a 6-membered heteroaromatic ring, particularly preferably in which the heteroatom represents n Most preferably Y-2 are selected from the group

,and.

1.6. The following embodiment is a compound of formula I, where Y denotes a group of formula Y-3

where Y, R25and Q have the above values, and the relationship indicated by the dashed line, may not necessarily be gidrirovannah, particularly preferably Y is chosen from the group of formulas:

,,,,,,,,,,,,,,, ,,,,,,,,,,,,,,,,,,,,,,,,and

1.7. According to other variants of the implementation of the compounds of formula I, as described previously, X denotes a group of formula X-1 and Y denotes a group of formula Y-1, Y-2 or Y-3; or X represents a group of formula X-2 and Y denotes a group of formula Y-1, Y-2 or Y-3; or X represents a group of formula X-3 and Y denotes a group of formula Y-1, Y-2 or Y-3, where X-1, X-2, X-3, Y-1, Y-2 and Y 3 have the values listed in any of the above embodiments.

According to one of preferred embodiments is a compound of formula I, g is e X denotes a group of formula X-1

where R16located in the ortho-position and represents hydrogen, (ness.)alkyl, nitro, cyano, halogen, (ness.)alkylthio, PERFLUORO(ness.)alkyl, and R15means (ness.)alkyl, nitro, cyano, halogen, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkyl and Y represents a group of formula Y-1

where R22denotes hydrogen, halogen, triptorelin or (ness.)alkyl, and R23denotes halogen, triptorelin or (ness.)alkyl, and R24denotes hydrogen, or Y denotes a group of the formula

where Q has the above values and communication, indicated by the dashed line, may not necessarily be gidrirovannah, R25denotes the R26-(CH2)e-; e denotes 2-4 and R26indicates azido, cyano, hydroxy, (ness.)alkoxy, (ness.)alkoxycarbonyl, (ness.)alkanoyl, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkanoyl, nitro or (ness.)alkylthio, or R25denotes a group of the formula-other29where R29means (ness.)alkanoyl or (ness.)alkylaminocarbonyl; especially preferably, where X denotes a group of formula X-1

where R16located in the ortho-position and represents hydrogen, (ness.)alkyl, nitro, cyano, halogen, (ness.)alkylthio, PERFLUORO(ness.)alkyl, and R15 means (ness.)alkyl, nitro, cyano, halogen, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkyl; and Y denotes a group of formula Y-1

where R22denotes hydrogen, halogen or (ness.)alkyl, and R23denotes halogen or (ness.)alkyl, and R24denotes hydrogen; particularly preferably R16denotes hydrogen or halogen and R15denotes halogen, R22denotes hydrogen, halogen, ethyl, or methyl and R23denotes halogen ethyl or methyl; most preferably R15located in the ortho-position and R15and R16both represent chlorine, and R22denotes methyl, and R23denotes chlorine or ethyl; most preferred is the compound 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-chloro-6-were)taxameter]-L-phenylalanine;

or more preferably, when X denotes a group of formula X-1

where R2located in the ortho-position and represents hydrogen, (ness.)alkyl, nitro, cyano, halogen, (ness.)alkylthio, PERFLUORO(ness.)alkyl, and R15means (ness.)alkyl, nitro, cyano, halogen, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkyl; and Y denotes a group of formula Y-3

which is a 4-6-membered cycloalkyl ring, R25denotes the R26-(CH2/sub> )e-; e denotes 2-4, and R26indicates azido, cyano, hydroxy, (ness.)alkoxy, (ness.)alkoxycarbonyl, (ness.)alkanoyl, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, PERFLUORO (ness.)alkanoyl, nitro or (ness.)alkylthio, and the relationship indicated by the dotted line, gidrirovannah; especially preferably, R16denotes halogen and R15denotes hydrogen or halogen; Y-3 denotes a 5-6-membered ring and R26means (ness.)alkoxy, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl or (ness.)alkylthio; more preferably R15located in the ortho-position and R15and R16both represent chlorine, and R26means (ness.)alkylsulfonyl or (ness.)alkylthio; most preferred is the compound 4-[[(2,6-dichlorophenyl)carbonyl] amino]-N-[[1-[(4-methylsulphonyl)butyl]cyclopentyl]taxometer]-L-phenylalanine;

or more preferably, when X denotes a group of formula X-1

where R16denotes hydrogen or halogen and R15denotes halogen and Y represents a group of formula Y-1

where R22denotes hydrogen, halogen, ethyl, or methyl and R23denotes halogen, ethyl or methyl and R24denotes hydrogen, or Y denotes a group of formula Y-3

where Y-3 refers to 4-clonoe ring and R 25denotes the R26-(CH2)e-; e denotes 2-4, and R26means (ness.)alkoxy, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl or (ness.)alkylthio, and the relationship indicated by the dotted line, gidrirovannah, particularly preferably R15located in the ortho-position and R15and R16both represent chlorine, and Y denotes Y-1, R22denotes methyl and R23denotes chlorine or ethyl, and Y denotes Y-3, Y-3 denotes a 4-to 5-membered ring and R26means (ness.)alkylsulfonyl or (ness.)alkylthio.

According to another variant of implementation of the compounds of formula I, Y is the value specified for formula I, and X denotes X-1

where R15located in the ortho-position and denotes halogen, (ness.)alkyl or perfluoroalkyl, and R16denotes hydrogen, halogen, (ness.)alkyl or perfluoroalkyl; especially preferably, R15represents chlorine and R16denotes hydrogen or chlorine.

In this embodiment, Y preferably denotes Y-1

where R22denotes hydrogen or (ness.)alkyl, R23denotes halogen, (ness.)alkyl or perfluoroalkyl, and R24denotes hydrogen; particularly preferably R15represents chlorine and R16denotes hydrogen or chlorine; most predpochtitel the YMI are such connection, as 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-bromophenyl)taxameter]-L-phenylalanine; 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-ethyl-6-were)taxameter])-L-phenylalanine; 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-forfinal)taxameter])-L-phenylalanine or 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-(trifluoromethyl)phenyl]taxometer] -L-phenylalanine.

In the alternative case of this variant implementation Y denotes a group of formula Y-3

which is a 4-6-membered cycloalkyl ring, R25denotes the R26-(CH2)e-; e denotes 2-4 and R26denotes alkoxy, (ness.)alkylsulfonyl, (ness.)alkylthio; preferably R26denotes methoxy, methylsulphonyl or methylthio, or other29where R29means (ness.)alkoxycarbonyl or (ness.)alkylaminocarbonyl, and the relationship indicated by the dotted line, gidrirovannah; most preferred are compounds selected from a range that includes 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[2-(acetylamino)ethyl]cyclopentyl]taxometer]-L-phenylalanine; [[1-[2-[[(methylamino)carbonyl]amino]ethyl]cyclopentyl]taxometer]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine; 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(2-methoxyethyl)cyclopentyl]taxometer]-L-phenylalanine; 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[(4-methylsulphonyl)butyl]CEC shall Outil]taxometer]-L-phenylalanine; 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[(3-methylthio)propyl]cyclobutyl]taxometer]-L-phenylalanine or 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[(3-methylsulphonyl)propyl]cyclobutyl]taxometer]-L-phenylalanine.

According to the next result of the implementation of the compounds of formula I, Y is the value specified for formula I, and X denotes X-2

where Het represents a pyridine or pyrimidine and R15means (ness.)alkyl or perfluoroalkyl, and R16and R20denote hydrogen, (ness.)alkyl or perfluoroalkyl.

According to this variant Y preferably denotes Y-1

where R22denotes hydrogen or (ness.)alkyl, R23denotes halogen, (ness.)alkyl or perfluoroalkyl, and R24denotes hydrogen.

In the alternative case, in this embodiment, Y represents a group of formula Y-3

which is a 4-6-membered cycloalkyl ring, R25denotes the R26-(CH2)e-; e denotes 2-4 and R26denotes alkoxy, (ness.)alkylsulfonyl, (ness.)alkylthio; preferably methoxy, methylsulphonyl or methylthio, or other29where R29means (ness.)alkoxycarbonyl or (ness.)alkylaminocarbonyl, and the relationship indicated by the dotted line, gidrirovannah; enableprefetcher are compounds selected from a range that includes 4-[(2,6-dimethyl-3-pyridylcarbonyl)amino]-N-[[1-[(4-methylsulphonyl)butyl]cyclopentyl]taxometer]-L-phenylalanine; 4-[[[4-(trifluoromethyl)-5-pyrimidinyl]carbonyl]amino]-N-[[1-[(4-methylsulphonyl)butyl]cyclobutyl]taxometer]-L-phenylalanine or 4-[[(2,4-dimethyl)-6-trifluoromethyl-3-pyridinyl)carbonyl]amino]-N-[[1-[(4-methylsulphonyl)butyl]cyclobutyl]taxometer]-L-phenylalanine.

According to another variant implementation of the compounds of formula I Y has the meanings indicated for formula I, and X represents X-3

where R19denotes pyridinyl(ness.)alkyl or phenyl (ness.)alkyl, R20means (ness.)alkanoyl and R18denotes phenyl.

In particular, in this embodiment, Y represents the Y-1

where R22denotes hydrogen or (ness.)alkyl, R23denotes halogen, (ness.)alkyl or perfluoroalkyl, and R24denotes hydrogen; most preferred is the compound 4-[(2S,4R)-3-acetyl-2-phenyl-4-[(3-pyridinyl) methyl]-5-Oxymetazoline-1-yl]-N-[(2-ethyl-6-were) taxameter]-L-phenylalanine.

In the alternative case, in this embodiment, Y represents a group of formula Y-3

which is a 4-6-membered cycloalkyl ring, R25denotes the R26 2)e-; e denotes 2-4 and R26denotes alkoxy, (ness.)alkylsulfonyl, (ness.)alkylthio; preferably methoxy, methylsulphonyl or methylthio, or R25means other29where R29means (ness.)alkoxycarbonyl or (ness.)alkylaminocarbonyl, and the relationship indicated by the dotted line, gidrirovannah; most preferred are compounds selected from a range that includes 4-[(2S,4R)-3-acetyl-2-phenyl-4-[(3-phenyl)methyl]-5-Oxymetazoline-1-yl]-N-[[(4-methylsulphonyl)butyl]cyclopentyl]taxometer]-L-phenylalanine or 4-[(2R,4R)-3-acetyl-2-phenyl-4-[(3-phenyl)methyl]-5-Oxymetazoline-1-yl]-N-[[(4-methylsulphonyl)butyl]cyclopentyl]taxometer]-L-phenylalanine.

According to the next result of the implementation of the compounds of formula I, X has the meanings indicated for formula I, and Y denotes a group of formula Y-1

where R22denotes hydrogen or (ness.)alkyl, R23denotes halogen, (ness.)alkyl or perfluoroalkyl, and R24denotes hydrogen, preferably R22denotes hydrogen or methyl and R23denotes halogen, ethyl, or trifluoromethyl.

Other preferred compounds of formula I are compounds in which X has the significance indicated for formula I, and Y denotes a group of formula Y-3

which is when the battle 4-6-membered cycloalkyl ring, R25denotes the R26-(CH2)e-; e denotes 2-4 and R26denotes alkoxy, (ness.)alkylsulfonyl, (ness.)alkylthio; preferably methoxy, methylsulphonyl or methylthio, or R25means other29where R29means (ness.)alkoxycarbonyl or (ness.)alkylaminocarbonyl, and the relationship indicated by the dotted line, gidrirovannah.

Compounds of the invention inhibit the binding of VCAM-1 and fibronectin with VLA-4 on the surface in blood lymphocytes, eosinophils, basophils and monocytes ("expressing VLA-4 cells"). It is known that binding of VCAM-1 and fibronectin with VLA-4 in these cells lead to certain painful conditions such as rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and in particular, to the binding of eosinophils to endothelial lining of the lungs, causing pulmonary inflammation that occurs in asthma. Thus, the compounds of the present invention can be used as drugs for the treatment of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and especially asthma.

Since the compounds according to the invention have the ability to inhibit the binding of VCAM-1 and fibronectin with VLA-4 in blood lymphocytes, eosinophils, basophils and monocytes, connections can p imeetsya as medicines for the treatment of diseases, known that they are mediated by this binding. Examples of such diseases are rheumatoid arthritis, multiple sclerosis, asthma and inflammatory bowel disease. Compounds according to the invention is preferably used for the treatment of diseases which are accompanied by pulmonary inflammation, such as asthma. Pulmonary inflammation that occur in asthma, is associated with infiltration of eosinophils into the lungs, while eosinophils are associated with endothelium, which was activated by specific cause asthma conditions or substance.

In addition, the compounds according to the invention also inhibit the binding of VCAM-1 and MAdCAM with the cellular receptor α4-β7, also known as LPAM, which is expressed on the surface of lymphocytes, eosinophils and T-cells. Although the exact role of interaction α4-β7 with different ligands in inflammatory conditions such as asthma, are not fully identified, the compounds according to the invention that inhibit the binding of both α4-β1-and α4-β7 - receptors, are particularly effective in the treatment of asthma during its animal models. In addition, studies with monoclonal antibodies to α4-β7, has allowed to establish that the compounds that inhibit the binding of α4-β7 MAdCAM or VCAM, can be used for treatment in specialnogo bowel disease. They can also be used to treat other diseases in which this binding causes painful disorders or symptoms.

Compounds according to the invention can be administered orally, rectally or parenterally, for example intravenously, intramuscularly, subcutaneously, podvoloshino or transdermal; or sublingual, or in the form of ophthalmic drugs, or in aerosol form for the treatment of pulmonary inflammation. Examples of forms for introduction are capsules, pills, suspensions or solutions for oral administration, suppositories, injectable solutions, eye drops, ointment or spray solutions.

The preferred form of injection is intravenous, intramuscular, oral administration or introduction by inhalation. Dose, in which you must enter the connection according to the invention to ensure their effective amounts depend on the specific nature of the active substance, the age and individual characteristics of the patient and the route of administration. Dose can be determined by any conventional methods, for example, through clinical trials to determine the limit dose. Thus, under the scope of the subject invention is a method of treatment of a host suffering from a disease in which the binding of VCAM-1 or fibronectin to cells expressing VLA-4, which is a factor contributing to the onset of symptoms or disorders associated with the disease, by introducing a number of compounds according to the invention sufficient to inhibit the binding of VCAM-1 or fibronectin to cells expressing VLA-4, in such a degree in order to reduce these symptoms or those violations. Generally preferred are dose comprising about 0.1-100 mg/kg of body weight per day dose, the components of 1-25 mg/kg of body weight per day, are particularly preferred, and the dose components of 1-10 mg/kg body weight per day, are the most preferred.

In addition, the following object of the present invention are pharmaceutical compositions that contain a pharmaceutically effective amount of the compounds according to the invention, including its salts and esters, and pharmaceutically acceptable carrier. Such compositions can be prepared by any conventional methods. In this regard, another object of the present invention is a method for preparing the pharmaceutical compositions, especially pharmaceutical compositions intended for the treatment or prevention of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and asthma, which contains one or more compounds according to the invention or its pharmaceutically acceptable salt or complex is the ether, and optionally one or more other therapeutically valuable substances intended for the introduction of the galenical form in combination with a compatible pharmaceutical carrier. Tablets or granules can contain a number of binders, fillers, carriers or diluents. Liquid compositions can be, for example, in the form of sterile mixing with the water solution. Capsules in addition to current substance may contain a filler or thickener. In addition, there may be additives that improve the taste and substance, commonly used as preservatives, stabilizers, moisture retaining agents and emulsifiers, as well as salts for modifying the osmotic pressure, buffers and other additives.

The above carriers and diluents can be any conventional pharmaceutically acceptable organic or inorganic substances, for example water, gelatine, lactose, starch, magnesium stearate, talc, gum Arabic, polyalkylene glycols, etc.

Standard dosage forms intended for oral administration, such as tablets and capsules, preferably contain from 25 mg to 1000 mg of the compounds according to the invention.

Compounds of the present invention can be obtained by any conventional methods. According to reaction scheme 1 4-nitro-L-phenylalanine derivative of formula 1 in which R1means (ness.)alkyl and which is a known compound or can easily be obtained by a known method and, acelerou using a derivative of benzoic acid of formula 2 in which R2denotes hydrogen, (ness.)alkyl, (ness.)alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, (ness.)alkylthio, (ness.)alkylsulfonyl, (ness.)alkylsulfonyl, (ness.)alkanoyl, halogen or PERFLUORO(ness.)alkyl, R3denotes hydrogen, halogen or (ness.)alkyl, and R4denotes hydrogen, (ness.)alkyl, (ness.)alkoxy, aryl, nitro, cyano, (ness.)alkylsulfonyl or halogen, using conventional methods of amide bond formation. For example, the compound of formula 2 can be converted into the corresponding acid chloride and condensed with the compound of the formula 1 in the presence of a proton acceptor such as a tertiary alkylamine. Alternatively, the compound of formula 1 may be subjected to a combination of a carboxylic acid of formula 2 under standard conditions of peptide combinations, for example with the use of hbtu in the presence of DIPEA in a polar aprotic solvent such as DMF, at a temperature of from 0°to room with obtaining the compounds of formula 3.

The transformation of compounds of formula 3 in the corresponding thioamide formula 4 can be carried out by treatment with a reagent of Lawesson, ie [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide]. The procedure is standard and is described in detail in the literature (see, for example, Scheibey ., Pederson B.S., Lawwesson S.O., Bull. Soc. Chim. Belg. 87, 229, 1978 and Cava MR, Levinson M.I., Tetraherdon, 41, 5061, 1985). The nitro-group of compounds of formula 4 can be recovered to obtain the corresponding amine using any conventional methods can be used for recovery thioamides. In one of the conventional methods as the reductant used powdered zinc in the presence of methanol, ammonium chloride and water at a temperature of from 35 to 60°obtaining the compounds of formula 5. Acylation of this compound with aryl - or heteroarylboronic acid of formula 6 under standard conditions of peptide combinations, for example with the use of hbtu in the presence of DIPEA in a polar aprotic solvent such as DMF, at a temperature of from 0°to room, allows to obtain the compound of formula 7. In some cases, for example, when using non-free carboxylic acids of formula 6, it may be appropriate to obtain the corresponding acid anhydride, and subjecting him to interact with the amine of formula 5, as a rule, in the presence of a small excess of base, such as tertiary amine or 4-(dimethylamino) pyridine. Carboxylic acid of formula 6 can be substituted with halogen, a nitro-group, (ness.)alkylsulfonyl, cyano, (ness.)the alkyl, (ness.)alkoxygroup, (ness.)alkoxycarbonyl, carboxypropyl, (ness.)alkylamino what Ultonia, PERFLUORO(ness.)the alkyl, (ness.)alkylthiol, hydroxy(ness.)the alkyl, alkoxy(ness.)the alkyl, alkylthio(ness.)the alkyl, alkylsulfonyl(ness.)the alkyl, alkylsulfonyl(ness.)the alkyl, (ness.)alkylsulfonyl, (ness.)alkanoyl, Arola, aryl, arroceros. If necessary, can also be included suitably protected reactive functional groups, which must be removed when making final conversion into compounds according to the invention. Selection and application of such groups is well known to specialists in this field. Recommendations on the selection and use of protective groups can be found in such well-known manuals, such as: "T.W. Green and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2-e Izd., Wiley Interscience, New York, 1991". Ester fragment of the compounds of formula 7, as a rule, can be split to obtain the corresponding carboxylic acid by treatment with a hydroxide of an alkali metal, for example lithium hydroxide in aqueous methanol at a temperature from room temperature up to 50°C. depending on the nature of R1preferred can be other methods. The selection conditions of the splitting of the ester bonds in the presence of functional groups such as thioamides, well known to specialists in this field.

Ortho-substituted derivatives of benzoic sour is s, not be available, may be obtained by standard methods. For example, ortho-substituted arisitide or triflate can be carbonyliron in the presence of carbon monoxide and a suitable palladium catalyst. The receipt of such iodides or triflates as intermediates depends on the desired circuits, and they can be obtained direct ladirovannye or diazotizable aniline, followed by treatment with a source of iodide such as potassium iodide. Triflate can be obtained from the corresponding phenols by standard methods such as treatment triftormetilfullerenov anhydride in the presence of a base such as triethylamine or diisopropylethylamine, in an inert solvent. Other methods of producing ortho-substituted benzoic acids include processing 2-methoxyphenylacetone derivative, such as compound of formula 9, the alkyl Grignard reagent followed by hydrolysis oxazolinone ring according to the General procedure described in Meyers, A.I., R. Gabel, Mihelick E.D., J. Org. Chem. 1978, 43, 1372-1379, obtaining the compounds of formula 10. 2 - or 2,6-disubstituted benzonitrile can also serve as suitable precursors of the corresponding benzoic acids. In the case of proprietary (unmanageable) NITRILES, for example, 2-chloro-6-methylbenz the nitrile, conventional hydrolysis in acidic or basic conditions is difficult and the best results are obtained by using the restore using DIBAL to the corresponding benzaldehyde with subsequent oxidation using as oxidant of sodium chlorite/hydrogen peroxide.

The methods generally similar to those described in scheme 1, using a heteroaromatic carboxylic acid instead of the compound of formula 2 allows to obtain the compounds of formula 11.

For the synthesis of analogs of branched chain or cycloalkyl fragment can be used a method similar to that described in scheme 1, using as starting product of the corresponding carboxylic acids with branched chain or cycloalkylcarbonyl acid of formula 12. In this case, R6means (ness.)alkyl, unsubstituted or substituted by fluorine (ness.)alkenyl or substituted (ness.)alkyl group, where the substituents can be selected from a range that includes aryl, heteroaryl, azido, cyano, hydroxy, (ness.)alkoxy, (ness.)alkoxycarbonyl, (ness.)alkylthio, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkanoyl, nitro or protected amino group. Must be selected aminosidine group that is compatible with the reagents necessary for the transformation of carboxamido the thioamides. Acceptable are carbamates, for example, tert-butoxycarbonyl fragment. If necessary, these protective groups can be removed by standard methods at later stages of the synthesis and the resulting free amine using standard methods can be introduced by other functional groups. For example, the amine can be allerban processing corresponding anhydride, isocyanate or acid chloride.

Synthesis imidazolidinone formula 21 is represented by reaction scheme 3.

Aminophenylalanine derivative of structural formula 13, in which R6denotes aryl, heteroaryl branched alkyl chain or a derived compound 12, and R7means (ness.)alkyl, are combined with the N-protected α-amino acid of formula 14 in which R8can be a natural or synthetic side chain of D - or L-α-amino acids, and R9denotes the N-protective group commonly used in the chemistry of peptides, such as, for example, the Fmoc group using standard conditions of peptide combinations, for example, using hbtu in the presence of DIPEA in a polar aprotic solvent such as DMF, at a temperature of from 0°to room, obtaining the compounds of formula 15. Depending on the nature of the protective group R99is a group Fmoc, it can be removed from compounds of formula 15 using conventional processing base, a well-known specialist in the field of peptide chemistry, for example, piperidine in DMF, to obtain an amine of formula 16. Then the compound of formula 16 is subjected to interaction with the aldehyde of formula 17 in which R10means (ness.)alkyl, aryl or aryl(ness.)alkyl, in the presence of the acceptor water, such as molecular sieves of sizein an appropriate solvent, such as dichloromethane or THF, at a temperature of 25-60°obtaining imine of formula 18. Imin formula 18 can then be processed allermuir agent such as acylchlorides formula 19 in which R11may denote an alkyl or aryl group, in the presence of a base, such as DIPEA or DBU, in an appropriate solvent, such as dichloromethane or THF, at a temperature of 25-60°With obtaining ellimination formula 20. Alternatively, this reaction can be used other reactive alleluya groups, such as acid anhydrides or mixed anhydrides. The compound of formula 20 may be turning in the connection according to the invention with the conventional method of hydrolysis, for example, by hydrolysis by treatment with hydroxide WEL knogo metal, such as sodium hydroxide, in an aqueous solution of alcohol with obtaining after acidification carboxylic acid of formula 21.

General notes. The melting temperature was determined with the help of the device Thomas-Hoover, and they are uncorrected. The optical rotation was determined by using a polarimeter, model 241 company Perkin-Elmer.1H-NMR spectra were recorded using a spectrometer type Varian XL-200 and Unityplus 400 MHz using tetramethylsilane (TMS) as internal standard. Mass spectra using electron impact (PI, 70 eV) and the bombardment of accelerated atoms (BUA) were obtained using mass spectrometers type VG Autospec or VG 70E-HF. Used for chromatography on silica gel columns represented silica gel for rapid chromatography type Mallinkrodt SiliCar with a particle size 230-400 mesh mesh; the shoulder on the columns was carried out at a gauge pressure of nitrogen 0-5 psi to improve the flow. Thin-layer chromatogram was obtained on glass plates for thin-layer chromatography, pokrytii silica gel, supplied by E. Megs (I.e. Megs No. 1.05719), and visualized under UV light with a wavelength of 254 nm in the camera for visualization by keeping in an atmosphere of vapor I2or by spraying or phosphomolybdenum acid (PMK) in aqueous solution of ethanol, or 4,4'-tetrameth diaminodiphenylmethane reagent after processing CL 2according to the method described by E. Von Arx, M. Faupel and M. Brugger in J. Chromatography, 1976, 120, 224-228.

Liquid chromatography high-pressure reversed-phase (RP-ghvd) was carried out either using a chromatograph type Waters Delta Prep 4000, equipped with a C-18 column 3×30 cm with sorbent type Waters Delta-Pak, 15 μm, at a flow rate of 40 ml/min using a gradient of acetonitrile:water (each component contained 0,75% TFA), as a rule, with increasing concentration of acetonitrile from 5% to 95% for 35-40 min, or by using a chromatograph type Rainin HPLC, equipped with a C-18 column 41,4×300 mm sorbent type Dynamax™, 8 μm, at a flow rate of 49 ml/min using the same gradient of acetonitrile:water as specified above.

Conditions GHUR usually specify the format type (5-95-35-214); this means a linear gradient from 5% to 95% acetonitrile in water for 35 min, while the eluent is analyzed using a UV detector at a wavelength of 214 nm.

Methylene chloride (dichloromethane), 2-propanol, DMF, THF, toluene, hexane, diethyl ether and methanol had a purity corresponding to reagent purity Fisher, and unless otherwise stated, were used without additional purification, acetonitrile had a purity corresponding to the purity Fisher necessary ghvd, and was used without further purification.

Definitions:

THF means tetrahed furan,

DMF means N,N-dimethylformamide,

HOBT means 1-hydroxybenzotriazole,

BOP means [(benzotriazol-1-yl)oxy]Tris(dimethylamino)fosfodiesterasa,

GATA means of O-(7-asobancaria-1-yl)-1,1,3,3-tetramethylhexadecane,

Gbtu means O-(benzotriazol-1-yl)-N,N,N',N'-tetramethylpropylenediamine,

DIPEA means diisopropylethylamine,

DMAP means of 4-(N,N-dimethylamino)pyridine,

DFFA means diphenylphosphinite,

DFFP means 1,3-bis(diphenylphosphino)propane,

DBU means 1,8-diazabicyclo[5.4.0]undec-7-ene,

NaH mean sodium hydride, brine is a saturated aqueous solution of sodium chloride,

TLC means thin layer chromatography,

GAVE means diisopropylamide lithium

BOP-C1 mean chloride bis(2-oxo-3-oxazolidinyl)phosphine,

N-MP N means-organic,

the reagent Loveson represents a 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide.

Examples

Example 1. Methyl ester of N-{[1-(2-methoxyethyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine

In the solution 4,30 g (11.4 mmole) of the methyl ester {[1-(2-methoxyethyl)cyclopentyl]carbonyl}-4-nitro-L-phenylalanine in 20 ml of toluene was introduced 2,60 g (6,27 mmole) of reagent Loveson. The resulting mixture was heated to 50°and was stirred for 18 hours React the mixture was filtered through a funnel with a filter of sintered glass and under vacuum, the filtrate was concentrated. After treatment, the Express by column chromatography with elution with hexane/ethyl acetate (ratio of 9/1, then 8/1) as a pale yellow oil was obtained of 2.44 g (yield: 54% and 70% in terms of selected source material) methyl ester of N-{[1-(2-methoxyethyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine. Msvr: obnarujeni - 395,1639; rasasi - 395,1640 (M+H).

Example 2. Methyl ester of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-(2-methoxyethyl) cyclopentyl] taxometer} -L-phenylalanine

In the suspension 4,58 g (of 11.6 mmole) of methyl ester of N-{[1-(2-methoxyethyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine, 7.50 g (116 moles) of zinc dust and 9.20 g (174 mmole) of ammonium chloride in 200 ml of methanol slowly over 5 min was introduced 100 ml of N2O. After stirring for 20 min the reaction mixture was diluted with 400 ml ethyl acetate and 150 ml of saturated solution of ammonium chloride and separated the organic layer. The aqueous layer was subjected to back extraction with 3 portions of 100 ml of ethyl acetate and the organic layers were combined, dried over Na2SO4was filtered and vacuum concentrated. The product in the form of oil within 2 hours and dried under high vacuum to obtain 4.5 g of crude methyl ester of 4-amino-N-{[1(2-methoxyethyl)cyclopentyl] taxometer}-L-phenylalanine.

In the solution 3,40 g (~8,77 mmole in terms of 94%is the ü purity) of the crude amine, received on the above, and 1.70 ml (9,65 mmole) of diisopropylethylamine in 15 ml of CH2CL2injected with a solution of 1.9 ml (of 9.21 mmole) of 2,6-dichlorobenzonitrile in 5 ml of CH2Cl2. The resulting mixture was stirred over night. The reaction mixture under vacuum concentrated and transferred into a separating funnel containing 150 ml of ethyl acetate and 40 ml of water. The aqueous layer was separated and subjected to back extraction with 1 portion 50 ml of ethyl acetate. The combined organic layer was washed with saturated solution of Na2CO3and then saturated brine, dried over MgSO4was filtered and vacuum concentrated. After treatment, the Express by column chromatography on silica gel with elution with hexane/ethyl acetate (ratio 3/1) received 4,50 g (yield: 95%) of methyl ester 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-(2-methoxyethyl)cyclopentyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 559,1201; rasasi - 559,1201 (M+Na).

Example 3. 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-(2-methoxyethyl)cyclopentyl] taxometer}-L-phenylalanine

In a solution of 4.00 g (7,44 mmole) of methyl ester of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-(2-methoxyethyl)cyclopentyl]taxometer]-L-phenylalanine in 18 ml Meon injected with a solution of 421 mg (10.5 mmole) of NaOH in 3 ml of water. The mixture was stirred for 2 h, and then acidified with 0.5 the Hcl (to pH ~ 1 to 2). The reaction mixture was poured into a separating funnel containing 150 ml of ethyl acetate and 25 ml of water. The aqueous layer was separated and subjected to back extraction with 2 portions of 50 ml of ethyl acetate. The combined organic layer was washed with saturated brine, dried over MgSO4was filtered and vacuum concentrated. In the purification HPLC (high performance liquid chromatography with reversed phase using acetonitrile in water at a concentration gradient from 15 to 95% over 25 min received 3,05 g (yield: 78%) of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-(2-methoxyethyl)cyclopentyl]taxometer}-L-phenylalanine. Msvr: the detection. weight - 545,1043; rasasi - 545,1045 (M+Na).

Example 4. 1-(2-azidoethyl)cyclopentanecarbonyl acid

In ice, the solution of 56 ml (0,396 mole) of Diisopropylamine in 85 ml of THF over 20 min was administered with 240 ml of 1.6 M (0,393 mole) solution of n-utility in hexane. When 0°the mixture was stirred for 30 min, cooled to a temperature baths -65°and within 20 min was added with 37.4 g (to 0.263 mol) of ethylcyclopentadienyl in 50 ml of THF. After 1 h the solution was added 47 ml (0,545 mole) of 1,2-brometea in 50 ml of THF, the mixture was stirred at -65°C for 3 h and overnight gave it to warm to room temperature. The reaction was suppressed by the addition of 200 ml of a saturated solution of chloride of shumilkin) is, the layers were separated and the aqueous layer was extracted with 100 ml of ethyl acetate. The combined extracts were washed with 250 ml of brine/water in a ratio of 1/1 and dried (Na2SO4). The solution was filtered and concentrated, diluted with 100 ml of toluene and concentrated. Dilution and concentration was repeated twice with the receipt of 52.5 g of ethyl-1-(2-bromacil)cyclopentanecarboxylate.

A solution of 52.5 g (0,211 mole) of the above bromide and 54 g (0,831 mole) of sodium azide in 200 ml of DMF was stirred in nitrogen atmosphere at 50°C for 5 h and filtered. The filtrate was concentrated almost to dryness, diluted with 500 ml ethyl acetate, filtered and concentrated to produce in the form of a brown oil of 40.9 g of crude ethyl-1-(2-azidoethyl)cyclopentanecarboxylate. This material was combined with the product obtained in the previous experiment (63.5 g), and purified by chromatography on 250 g of silica gel, elwira 5% ethyl acetate in hexane, to produce in the form of a light brown oil 50,3 g of the product.

50,3 g (0,238 mole) of the product in the form of oil with the above stage dissolved in 750 ml of THF and 375 ml of methanol and the solution was added 15 g (0,357 mol) of LiOH hydrate in 300 ml of water. The resulting solution was stirred at 40°C overnight and then concentrated. The residue was dissolved in 2 l of water containing 40 ml of 1 N. NaOH, and washed with 1 l of hexane. The aqueous layer was acidified 375 ml 1 N. Hcl and was extracted with 2 porci the mi in 1 l of diethyl ether. The combined extracts were dried (Na2SO4) and concentrated, obtaining the liquid amber of 37.5 g of 1-(2-azidoethyl)cyclopentanecarbonyl acid.

Example 5. Methyl ester of N-{[1-(2-azidoethyl)cyclopentyl]carbonyl}-4-nitro-L-phenylalanine

A solution of 3.0 g (11.5 mmole) of the hydrochloride of the methyl ester 4-nitro-L-phenylalanine, 2.3 g (12.7 mmole) 1-(2-azidoethyl)cyclopentanecarbonyl acid and 5.34 g (12,1 mmole) of BOP in 6 ml of dichloromethane and 4 ml of DMF was treated to 4.2 ml (or 24.2 mmole) of diisopropylethylamine. The mixture was stirred overnight, after which TLC analysis data (hexane/ethyl acetate in a ratio of 1/1) showed greater availability of source material. The mixture was diluted with water and extracted with ethyl acetate. The extracts were washed with water and saturated brine and was dried over sodium sulfate. In the filtration and evaporation was obtained residue, which was purified by chromatography on silica gel, elwira hexane/ethyl acetate in a ratio of 3/1, obtaining 4.26 deaths g of methyl ester of N-{[1-(2-azidoethyl)cyclopentyl]-carbonyl}-4-nitro-L-phenylalanine.

Example 6. Methyl ester of N-{[1-(2-{[(1,1-dimethylmethoxy)carbonyl]-amino}ethyl)cyclopentyl]carbonyl}-4-nitro-L-phenylalanine

A. A solution of 1.92 g (is 4.93 mmole) of methyl ester of N-{[1-(2-azidoethyl) cyclopentyl]carbonyl}-4-neath the o-L-phenylalanine in 20 ml of THF was treated by the addition of a drop of 1 M solution of trimethylphosphine in THF. After completion of the addition the mixture was stirred for 20 min and was added 0.17 ml of water. The reaction mixture was stirred for a further 2 hours, adding a little bit of TPA (triperoxonane acid) and the mixture was dried over sodium sulfate and concentrated.

Vos - benzyloxycarbonyl

B. In a solution of 2.35 g (is 4.93 mmole) of salt triperoxonane acid methyl ester N-{[1-(2-amino-ethyl)cyclopentyl]carbonyl}-4-nitro-L-phenylalanine in 25 ml of dioxane were introduced 0,860 ml (4,93 mmole) of diisopropylethylamine and 1.08 g (is 4.93 mmole) dicret-BUTYLCARBAMATE. The resulting mixture was stirred for 18 hours, the Reaction mixture was filtered through a funnel with a filter of sintered glass and under vacuum, the filtrate was concentrated. After treatment, the Express by column chromatography on silica gel with elution with hexane/ethyl acetate (ratio 3/1) received 2.20 g (yield: 95%) of methyl ester of N-{[1-(2-{[(1,1-dimethylmethoxy)carbonyl]amino}ethyl)cyclopentyl]carbonyl}-4-nitro-L-phenylalanine. Msvr: the detection. weight - 464,2397; rasasi - 464,2397 (M+H).

Example 7. Methyl ester of N-{[1-(2-{[(1,1-dimethylmethoxy)carbonyl]amino}ethyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine

To a solution of 1.00 g (2,16 mmole) of methyl ester of N-{[1-(2-{[(1,1-dimethylmethoxy)carbonyl]amino}ethyl)cyclopentyl]carbonyl}-4-nitro-L-phenyl what Anya's in 10 ml of toluene/dioxane in a ratio of 1/1 was introduced 0,524 g (1,29 mmole) of reagent Loveson. The resulting mixture was heated to 50°and was stirred for 24 h, the Reaction mixture was filtered through a funnel with a filter of sintered glass and under vacuum, the filtrate was concentrated. After treatment, the Express by column chromatography on silica gel with elution with hexane/ethyl acetate (ratio of 6/1, then 4/1) as a pale yellow oil was obtained 460 mg (yield: 44% and 65% in terms of selected source material) methyl ester of N-{[1-(2-{[(1,1-dimethylmethoxy)carbonyl]amino}ethyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine. Msvr: obnarujeni - 478,2014; Rasch. weight - 478,2012 (M-N).

Example 8. Methyl ester of N-{[1-(2-(acetylamino)ethyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine

In a solution of 1.26 g (2,63 mmole) of methyl ester of N-{[1-(2-{[(1,1-dimethylmethoxy)carbonyl]amino]ethyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine in 15 ml of methylene chloride was dropwise introduced 7 ml of TFA and the resulting mixture was stirred for 2 h at room temperature. The reaction mixture was concentrated under vacuum obtaining in the form of a yellow oil, 1.4 g of crude TFA salt of methyl ester of N-{[1-(2-amino-ethyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine.

Into a solution of 1.4 g (~2,63 mmole) obtained in the previous phase of salt in 10 ml of methylene chloride were introduced to 1.37 ml (7,88 mmole) of diisopropylethylamine and 0,250 ml (2,63 mm is La) of acetic anhydride. The resulting mixture was stirred over night. The reaction mixture was concentrated under vacuum and transferred into a separating funnel containing 100 ml of ethyl acetate and 40 ml of water. The aqueous layer was separated and subjected to back extraction with 1 portion 50 ml of ethyl acetate. The combined organic layer was washed with saturated brine, dried over MgSO4was filtered and vacuum concentrated. After treatment, the Express by column chromatography with elution with methylene chloride/acetone (in a ratio of 5/1) received 743 mg (yield: 67%) of methyl ester of N-{[1-(2-(acetylamino)ethyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine. Msvr: obnarujeni - 422,1744; rasasi - 422,1750 (M+H).

Example 9. Methyl ester of 4-amino-N-{[1-(2-(acetylamino)ethyl)cyclopentyl]taxometer}-L-phenylalanine

In the suspension 740 mg (1.75 mmole) of methyl ester of N-{[1-(2-(acetylamino)ethyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine, 1,14 g (of 17.5 mmole) of zinc dust and 1.41 g (to 26.3 mmole) of ammonium chloride in 20 ml of methanol slowly over 5 min was injected 10 ml of N2O. After stirring for 20 min the reaction mixture was diluted with 80 ml of ethyl acetate and 25 ml of saturated solution of ammonium chloride and separated the organic layer. The aqueous layer was subjected to back extraction with 3 portions of 25 ml of ethyl acetate and the organic layers were combined, with the sewed over Na 2SO4was filtered and vacuum concentrated. The product in the form of oil within 2 hours and dried under high vacuum to obtain 750 mg of crude amine compounds. After treatment, the Express by column chromatography on silica gel with elution with methylene chloride/acetone (ratio 2/1) received 650 mg (yield: 95%) of methyl ester of 4-amino-N-{[1-(2-(acetylamino)ethyl)cyclopentyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 392,2016; Rasch. weight - 392,2008 (M+H).

Example 10. 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-(2-(acetyl-amino)ethyl)cyclopentyl] taxometer}-L-phenylalanine

In a solution of 195 mg (0,498 mmole)of methyl ester of 4-amino-N-{[1-(2-(acetylamino)ethyl)cyclopentyl]taxometer}-L-phenylalanine and 0,0950 ml (0,548 mmole) of diisopropylethylamine in 1 ml of CH2Cl2injected with a solution of 110 mg (0,523 mmole) of 2,6-dichlorobenzonitrile in 1 ml of CH2CL2. The resulting mixture was stirred over night. The reaction mixture was concentrated under vacuum and transferred into a separating funnel containing 50 ml of ethyl acetate and 10 ml of water. The aqueous layer was separated and subjected to back extraction with 1 portion in 25 ml of ethyl acetate. The combined organic layer was washed with saturated solution of PA2CO3and then saturated brine, dried over MgSO4was filtered and vacuum concentrated with what rucenim 300 mg of crude methyl ester 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N{[1-(2-(acetylamino)ethyl)cyclopentyl]taxometer}-L-phenylalanine.

Into a solution of 300 mg (~0,498 mmole) mentioned methyl ester in 1 ml Meon was added a solution of 64 mg (14.9 mmole) of NaOH in 1 ml of water. The mixture was stirred for 2 h, and then acidified with 0.5 M Hcl (to pH ~ 1 to 2). The reaction mixture was poured into a separating funnel containing 50 ml of ethyl acetate and 10 ml of water. The aqueous layer was separated and subjected to back extraction with 2 portions of 25 ml of ethyl acetate. The combined organic layer was washed with saturated brine, dried over MgSO4was filtered and vacuum concentrated. In the purification HPLC with reversed phase using acetonitrile/water with the gradient from 15 to 95% over 25 min and freeze-drying the contained product fractions in the form of a white solid substance was obtained 126 mg (yield: 46%) of 4-{[2,6-dichlorophenyl)carbonyl]amino}-N-{[1-(2-(acetylamino)ethyl)cyclopentyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 550,1330; Rasch. weight - 550,1334 (M+H).

Example 11.

{[1-(2-{[(methylamino)carbonyl]amino}ethyl)cyclopentyl]taxometer}-4-{[(2,6-dichlorophenyl)carbonyl]amino}-L-phenylalanine

In accordance with the General method described in examples 8 through 10, of the methyl ester of N-{[1-(2-{[(1,1-dimethylmethoxy)carbonyl]amino}ethyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine and methyl isocyanate received {[1-(2-{[(methylamino)carbonyl]amino}ethyl)cyclopentyl]taxometer}-4-{[(2,6-dichlorophen the l)carbonyl]amino}-L-phenylalanine. Msvr: the detection. weight - 565,1436; rasasi - 565,1443 (M+H).

Example 12. 2-chloro-6-methylbenzaldehyde

In a 500-ml three-neck round bottom flask, equipped with magnetic stirrer, thermometer, dropping funnel and an inlet device for argon, downloaded 75 g (494 mmole) of 2-chloro-6-methylbenzonitrile and 400 ml of toluene (stored overs molecular sieves). The mixture was cooled to -2°With (ice + acetone) and dropwise within 30 min was added 593 ml of 1.0 N. (593 mmole) solution DIBAL-G (diisobutylaluminium) hexano while maintaining the temperature below 0°C. After complete addition the reaction mixture was stirred for 1 h at 0°and then she was allowed to warm to room temperature. Upon completion of the 2-hour exposure at room temperature data TLC analysis indicated the absence of starting material (hexane/diethyl ether in a ratio of 4/1, the results of spraying phosphomolybdenum acid as a means of UV-fluorescence analysis was deceptive). The reaction mixture was poured into 2000 g of ice and 50 ml of concentrated sulfuric acid and stirred over night. Falling precipitated solids were collected by filtration and the filtrate was extracted with 2 portions of 200 ml of diethyl ether. United extrac the s were washed with brine solution and dried over MgSO 4. In the filtration of the drying agent and concentration of the solution was obtained the crude aldehyde, which was combined with the above solid with getting 71,31 g (yield: 93%) of light yellow solid, acceptable for use in the next stage.

Example 13. 2-chloro-6-methylbenzoic acid

In a 1000 ml three-neck round bottom flask, equipped with magnetic stirrer, thermometer, dropping funnel and an inlet device for argon, download, 71,31 g (461 mmol, crude product obtained in the above experiment) of 2-chloro-6-methylbenzaldehyde and 750 ml of acetonitrile. To this suspension at room temperature was added a solution of 15.9 g (115 mmol, 0.25 EQ.) monopotassium phosphate in 240 ml of water and then 50 ml of 30%hydrogen peroxide. Further, when 0°C was added dropwise a solution of 73.5 g (811 mmol, 1,76 EQ.) of sodium chlorite in 700 ml of water while maintaining the temperature below 3°C. After the addition the yellow suspension was stirred at a temperature of from 0°With up to the room within 15 h and after this time period the data TLC analysis of the mixture indicated the absence of the aldehyde. Next dropwise at 0°With a solution of 73 g (701 mmol, 1,52 EQ.) of sodium bisulfite in 200 ml of water was added until disappearance of the yellow color (positive reaction KI-Boo is AGCI). To regulate this exothermic reaction had is cooling. Under vacuum solvent was removed, getting a white solid. By filtering the collected solid material and the filtrate was extracted with 200 ml diethyl ether. This ether solution was dissolved also mentioned the solid and the solution was washed with 2 portions of 200 ml of 10%NaOH solution. Basic aqueous solution was neutralized 10%Hcl to pH ~1. Falling precipitated white solid was collected by filtration and dried in the air, receiving in the form of a white solid 54,88 g (total on two stages, yield: 65%) of 2-chloro-6-methylbenzoic acid.

Example 14. Methyl ester of N-(2-chloro-6-methylphenylsulfonyl)-4-nitro-L-phenylalanine

In a solution of 1.94 g (7,44 mmole) cleaners containing hydrochloride salt of methyl ester 4-nitro-L-phenylalanine, 1.4 g (8.2 mmole) of 2-chloro-6-methylbenzoic acid and 3.11 g (8.2 mmole) of hbtu in 27 ml of DMF at room temperature was introduced 3,24 ml (to 18.6 mmole) of diisopropylethylamine. Clear solution at room temperature was stirred for 48 h and was diluted with 100 ml of ethyl acetate. An ethyl acetate layer was sequentially washed with 2 portions of 50 ml of 0.5 N. hydrochloric acid, 2 portions of 50 ml of saturated sodium bicarbonate solution, 100 ml of brine and dried over anhydrous magnesium sulfate. As a result, is filtrowanie the drying agent and concentration of the solvent in the form of a white solid substance was obtained 2.67 g (yield: 95%) of methyl ester of N-(2-chloro-6-methylbenzoyl)-4-nitro-L-phenylalanine with t PL120-123°C. msvr: the detection. weight - 376,4274; rasasi - 376,4238 (M+H).

Example 15. Methyl ester of N-[(2-chloro-6-were)taxameter]-4-nitro-L-phenylalanine

In a mixture of 3.64 g (9,66 mmole) of methyl ester of N-(2-chloro-6-methylphenylsulfonyl)-4-nitro-L-phenylalanine and 2.46 g (6.0 mmole, 0,62 EQ.) the reagent Loveson at room temperature was injected 15 ml of toluene (stored overs molecular sieves). The suspension was heated to a temperature of from 90 to 100°and was stirred for 24 hours (during this time he formed a clear solution), after which TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was diluted with 50 ml ethyl acetate and washed with 50 ml water, 50 ml saturated sodium bicarbonate solution, 50 ml of brine and dried over anhydrous magnesium sulfate. In the filtration of the drying agent and concentration of the solvent was obtained crude compound, which was purified careful chromatography on silica gel column, elwira hexane/ethyl acetate (ratio of from 4/1 to 2/1), to obtain a yellow solid of 1.52 g (yield: 40%) of methyl ester of N-[(2-chloro-6-were)taxameter]-4-nitro-L-phenylalanine with tPL150-153°With (was ground into powder in diethyl ether and hexane in sootnoshenii/1). Msvr: obnarujeni - 393,0685; rasasi - 393,0677 (M+H).

Example 16. Methyl ester of 4-amino-N-[(2-chloro-6-were)taxameter]-L-phenylalanine

In a mixture of 1.52 g (3,86 mmole) of methyl ester of N-[(2-chloro-6-were)taxameter]-4-nitro-L-phenylalanine, 2.55 g (39.0 mmole, 10 EQ.) zinc dust (particle size ~325 mesh) and to 3.09 g (58,0 mmole, 15 EQ.) ammonium chloride at room temperature was introduced 50 ml of methanol and 25 ml of water. After adding water flowed exothermic reaction and the temperature was raised to level 45 to 50°C. the Suspension was stirred for 2 hours at a bath temperature of 50 to 60°With, then the data of TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was filtered through a layer of brownmillerite and the filter cake was washed with 50 ml of methanol and 40 ml of water. The filtrate was concentrated under vacuum to remove the methanol and the product was extracted with 2 portions of 50 ml of ethyl acetate. The combined extracts were washed with 50 ml brine and dried over anhydrous magnesium sulfate. In the filtration of the drying agent and concentration in the form of an amorphous yellow solid was obtained 1.3 g (yield: 92%) of methyl ester of 4-amino-N-[(2-chloro-6-were)taxameter]-L-phenylalanine, which is directly used in the next stage. Msvr: obnarujal the sa 363,0932; rasasi - 363,0934 (M+H).

Example 17. Methyl ester of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-[(2-chloro-6-were)taxameter]-L-phenylalanine

In the solution 1,296 g (3,57 mmole) of methyl ester of 4-amino-N-[(2-chloro-6-were)taxameter]-L-phenylalanine and 0,785 g of (3.75 mmole) of 2,6-dichlorobenzonitrile in 20 ml of dichloromethane at room temperature was injected with 0.93 ml (5,35 mmole) of diisopropylethylamine. The solution was stirred for 15 h, after this time period the data TLC analysis of the mixture indicated the absence of starting material. Then the solution was diluted with 30 ml of water and the two layers were separated. The aqueous phase was extracted with 20 ml dichloromethane and the combined extracts were washed with 50 ml of brine. After drying over anhydrous magnesium sulfate solution under vacuum concentrated and the residue was purified by chromatography on silica gel column, elwira hexane/ethyl acetate (ratio of from 4/1 to 1/1) to obtain in the form of an amorphous white solids 1,91 g (yield: 83%) of methyl ester of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-[(2-chloro-6-were)taxameter]-L-phenylalanine. Msvr: obnarujeni - 535,0399; rasasi - 535,0416 (M+H).

Example 18. 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-[(2-chloro-6-were)taxameter]-L-phenylalanine

In a suspension of 1.55 g (2,89 mmole) of methyl ester of 4{[(2,6-dichlorophenyl)carbonyl]amino}-N-[(2-chloro-6-were)taxameter]-L-phenylalanine in 8 ml of ethanol at room temperature was injected 5 ml of 1.0 N. aqueous sodium hydroxide. The mixture was heated to a temperature of from 50 to 55°and the resulting clear solution was stirred for 3 to 4 hours; at the end of this period of time the data TLC analysis of the mixture indicated the absence of starting material. The mixture was concentrated to remove ethanol, diluted with 15 ml water and was extracted with 25 ml of diethyl ether to remove neutral impurities. The aqueous layer was acidified using 1 N. Hcl, and fell precipitated white solid was extracted with 2 portions of 30 ml of ethyl acetate. The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. In the filtration of the drying agent and concentration of the solution in the form of an amorphous white solid substance was obtained 1.45 g (yield: 96%) of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-[(2-chloro-6-were)taxameter]-L-phenylalanine. Msvr: obnarujeni - 521,0241; rasasi - 521,0260 (M+H).

Example 19. Sodium salt of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-[(2-chloro-6-were)taxameter]-L-phenylalanine

1.45 g (2,77 mmole) 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-[(2-chloro-6-were)taxameter]-L-phenylalanine at room temperature was dissolved in 10 ml of water containing 4,2 ml (1.5 EQ.) water of 1.0 n sodium hydroxide. The solution was introduced into a column (dimensions: length - 8 inches, diameter - 1.5 inches) on the I chromatography with reversed phase, containing silica gel C-18, and suirable water to remove excess base. The product was suirable methanol in water at a concentration of from 5 to 20%. The combined fractions were concentrated, the residue was dissolved in 50 ml of water and liofilizirovanny obtaining in the form of a white amorphous solid of 1.3 g of sodium salt. Msvr: obnarujeni - 543,0076; rasasi - 543,0079 (M+H).

Example 20. 2-ethyl-6-methylbenzoic acid

h) In 250-ml thick-walled flask was loaded with 7.4 g (30,07 mmole) of 2-ethyl-6-methylidene, 334 mg (1,43 mmole) of Pd(OAc)2and 620 mg (1,43 mmole) DFFP. The flask was closed by a membrane, three times it created a vacuum and then filled with argon. Then using a syringe sequentially added to 96 ml of acetonitrile, 19,0 g (26,25 ml, 189 mmol) of triethylamine and 19.1 ml of water. After that, the rubber membrane was replaced plated Teflon lid connected to a source of carbon monoxide. Then carbon monoxide in the flask was created increased pressure (40 psi) and the excess pressure was discharged. This operation was repeated three times and, finally, under pressure of carbon monoxide 40 psi and the mixture was stirred for 5 minutes Then the flask from a balloon with carbon monoxide was disconnected and was immersed in a pre-heated (to a temperature of from 83 to 85° (C) oil bath. Within 1 h p is a promotional mixture became black, and at this temperature it was stirred for another 14 h then the reaction mixture was cooled to room temperature and the pressure dropped. The resulting mixture was diluted with 200 ml of diethyl ether and 20 ml of 1.0 N. NaOH. The resulting acid was extracted with 2 portions of 100 ml of water. The combined aqueous extracts were neutralized with 1.0 N. Hcl and the acid was extracted with 3 portions of 100 ml of dichloromethane. The combined dichloromethane extracts were washed with brine solution and dried over MgSO4. In the filtration of the drying agent and removal under vacuum of the solvent in the form of a viscous brown oil was obtained 3.58 g (yield: 72,5%) of product, which during the night had hardened. Msvr: obnarujeni - 164,0833; rasasi - 164,0837 (M+).

Example 21. Methyl ester of N-[(2-ethyl-6-were)carbonyl]-4-nitro-L-phenylalanine

Analogously to example 14 as a white solid with a yield of 72% was obtained methyl ester N-[(2-ethyl-6-were)carbonyl]-4-nitro-L-phenylalanine with tPL119-121°C. msvr: obnarujeni - 371,1610; rasasi - 371,1607 (M+H).

Example 22. Methyl ester of N-[(2-ethyl-6-were)taxameter]-4-nitro-L-phenylalanine

Analogously to example 15 in the form of an amorphous white solid with a yield of 47% was obtained methyl ester N-[(2-ethyl-6-were)taxameter]-4-nor the ro-L-phenylalanine. Msvr: obnarujeni - 387,1383; rasasi - 387,1378 (M+H).

Example 23. Methyl ester of 4-amino-N-[(2-ethyl-6-were)taxameter]-L-phenylalanine

Analogously to example 16 in the form of an amorphous white solid with a yield of 94% was obtained methyl ester of 4-amino-N - [(2-ethyl-6-were)taxameter]-L-phenylalanine. Msvr: obnarujeni - 357,1640; rasasi - 357,1638 (M+H).

Example 24. Methyl ester of 4-{[(2,6-dichlorophenyl)carbonyl]amino} -N-[(2-ethyl-6-were)taxameter]-L-phenylalanine

Analogously to example 17 in the form of an amorphous white solid with a yield of 70% was obtained methyl ester 4-{[(2,6-dichlorophenyl)carbonyl]-amino}-N-[(2-ethyl-6-were)taxameter] -L-phenylalanine. Msvr: obnarujeni - 529,1094; rasasi - 529,1119 (M+H).

Example 25. 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-[(2-ethyl-6-were)taxameter]-L-phenylalanine

Analogously to example 18 in the form of an amorphous white solid with a yield of 77% was obtained 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-[(2-ethyl-6-were) taxameter]-L-phenylalanine. Msvr: obnarujeni - 515,0942; rasasi - 515,0963 (M+H).

Example 26. Methyl ester of 4-{[(2R)-(2-FMOC-amino)-3-(3-pyridyl)-1-oxopropyl]amino}-N-[(2-ethyl-6-were)taxameter]-L-phenylalanine (FMOC means fluorenylmethoxycarbonyl)

Analogously to example 1 in the form of an amorphous white solid with a yield of 72% was obtained methyl ester 4-{[(2R)-(FMOC-amino)-3-(3-pyridyl)-1-oxopropyl]amino}-N-[(2-ethyl-6-were)taxameter]-L-phenylalanine. Msvr: obnarujeni - 727,2973; rasasi - 727,2954 (M+H).

Example 27. Methyl ester of 4-{[(2R)-2-amino-3-(3-pyridyl)-1-oxopropyl]amino}-N-[(2-ethyl-6-were)taxameter]-L-phenylalanine

224 mg (0,308 mmole) of the product of example 26 was treated with 3 ml of 25%piperidine in N-MP and the solution was stirred at room temperature for 1 h, after which TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with 25 ml of hexane and separated the two layers. The lower yellow layer was diluted with hexane and separated. Then the bottom, the yellow layer was diluted with water and was extracted with 3 portions of 25 ml of ethyl acetate/THF in a ratio of 2/1. The combined extracts were washed with 50 ml water, 50 ml brine and dried over anhydrous magnesium sulfate. By filtering the drying agent and concentration by removal of solvent received the product which was dried under high vacuum obtaining in the form of an amorphous white solids 126 mg (yield: 81%) of methyl ester of 4-{[(2R)-2-amino-3-(3-pyridyl)-1-oxopropyl]amino}-N-[(2-ethyl-6-were)taxameter]-L-phenylalanine. Msvr: obnarujeni - 505,2270 rasasi - 505,2274 (M+H).

Example 28. Methyl ester of 4-{(2S,4R)-3-acetyl-2-phenyl-[4-(3-pyridinyl)methyl]-5-Oxymetazoline-1-yl}-N-[(2-ethyl-6-were)taxameter]-L-phenylalanine

To a solution of 113 mg (0,224 mmole) of methyl ester of 4-{[(2R)-2-amino-3-(3-pyridyl)-1-oxopropyl]amino}-N-[(etil-6-were)taxameter]-L-phenylalanine in 0.75 ml of dichloromethane and 0.75 ml of CH(OMe)3was introduced to 27.5 mg (0.25 mmole) of benzaldehyde. The resulting light yellow solution was stirred at room temperature for 3 days and the reaction mixture was heated to 90°C (oil bath temperature). Then use the syringe was injected excess amount of acetic anhydride (of 0.21 ml, 2.0 mmole) and the solution was stirred at 110-120°C (oil bath temperature) for 6 hours the Reaction mixture was cooled to room temperature and under vacuum solvent was removed. The crude residue was purified HPLC with reversed phase to produce in the form of an amorphous white solids 95 mg (yield: 67%) of methyl ester of 4-{(2S,4R)-3-acetyl-2-phenyl-4-[(3-pyridinyl)methyl]-5-Oxymetazoline-1-yl}-N-[(2-ethyl-6-were)taxameter]-L-phenylalanine. Msvr: obnarujeni - 635,2672; rasasi - 635,2692 (M+H). The other isomer was obtained in very small quantities (<5% by HPLC), and attempts to allocate not taken.

Example 29. 4-{(2S,4R)-3-acetyl-2-phenyl-4-[(3-pyridinyl)methyl]-5-Oxymetazoline-yl}-N-[(2-ethyl-6-were)taxameter]-L-phenylalanine

Analogously to example 18 was performed hydrolysis and the product was purified HPLC with reversed phase, using a gradient of acetonitrile in water from 5 to 95%, for 30 min, and collect the desired fraction. Under vacuum, remove the acetonitrile and the product was extracted with 2 portions of 25 ml of ethyl acetate/THF in a ratio of 3/1. Combined fractions were washed with brine solution and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solution was concentrated and the residue was dried under high vacuum to obtain 4-{(2S,4R)-3-acetyl-2-phenyl-4-[(3-pyridinyl)methyl]-5-Oxymetazoline-1-yl}-N-[(2-ethyl-6-were)taxameter]-L-phenylalanine in the form of an amorphous white solid (30%yield). Msvr: obnarujeni - 621,2520; rasasi - 621,2535 (M+H).

Example 30. Methyl ester of N-[(2-forfinal)carbonyl]-4-nitro-L-phenylalanine

Analogously to example 14, using as the starting material 2-fermenting acid in the form of a white solid with 99%yield was obtained methyl ester N-[(2-forfinal)carbonyl]-4-nitro-L-phenylalanine with tPL137-139°C. msvr: obnarujeni - 346,0977; rasasi - 346,0980, M+.

Example 31. Methyl ester of N-[(2-forfinal)taxameter]-4-nitro-L-phenylalanine

Analogously to example 15 with use the of in as the starting material methyl ester N-[(2-forfinal)carbonyl]-4-nitro-L-phenylalanine in the form of an amorphous white solid with 99%yield was obtained methyl ester N-[(2-forfinal)taxameter]-4-nitro-L-phenylalanine. Msvr: the detection. weight - 363,0816; rasasi - 363,0815, (M+H).

Example 32. Methyl ester of 4-amino-N-[(2-forfinal)taxameter] -L-phenylalanine

Analogously to example 16, using as the starting material methyl ester N-[(2-forfinal)taxameter]-4-nitro-L-phenylalanine in the form of an amorphous white solid with 87%yield was obtained methyl ester of 4-amino-N-[(2-forfinal)taxameter]-L-phenylalanine. Msvr: obnarujeni - 332,1042; rasasi - 332,1046, (M+H).

Example 33. Methyl ester of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-[(2-forfinal)taxameter]-L-phenylalanine

Analogously to example 17, using as the starting material methyl ester 4-amino-N-[(2-forfinal)taxameter]-L-phenylalanine in the form of an amorphous white solid (74%yield was obtained methyl ester 4-{[(2,6-dichlorophenyl)carbonyl]amino} -N-[(2-forfinal)taxameter]-L-phenylalanine. Msvr: obnarujeni - 505,0561; rasasi - 505,0555, (M+H).

Example 34. 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-[(2-forfinal)taxameter]-L-phenylalanine

Analogously to example 18, using as the starting material methyl ester 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-[(2-forfinal)taxameter]-L-phenylalanine in the form of an amorphous white solid with 89%-the first release was obtained 4-{[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-forfinal)taxameter]-L-phenylalanine. Msvr: obnarujeni - 491,0407; rasasi - 491,0399, (M+H).

Example 35. Methyl ester 4-nitro-N-{[2-(trifluoromethyl)phenyl]carbonyl}-L-phenylalanine

Analogously to example 14, using as the starting material 2-triftorperasin acid in the form of a white solid with tPL152-154°and 69%yield was obtained methyl ester 4-nitro-N-{[2-(trifluoromethyl)phenyl]carbonyl]-L-phenylalanine. Msvr: obnarujeni - 397,1017; rasasi - 397,1011, (M+H).

Example 36. Methyl ester 4-nitro-N-{[2-(trifluoromethyl)phenyl]taxometer}-L-phenylalanine

Analogously to example 15 using as the starting material methyl ester 4-nitro-N-{[2-(trifluoromethyl)phenyl]carbonyl}-L-phenylalanine in the form of an amorphous white solid, 67%yield was obtained methyl ester 4-nitro-N-{[2-(trifluoromethyl)phenyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 412,0752; rasasi - 412,0757, (M+H).

Example 37. Methyl ester of 4-amino-N-{[2-(trifluoromethyl)phenyl]taxometer}-L-phenylalanine

Analogously to example 16, using as the starting material methyl ester 4-nitro-N-{[2-(trifluoromethyl)phenyl]taxometer}-L-phenylalanine in the form of an amorphous white solid with 98%yield was obtained methyl ester of 4-amino-N-{[2-(thrift rmutil)phenyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 382,1072; rasasi - 382,1078, (M+H).

Example 38. Methyl ester of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[2-(trifluoromethyl)phenyl]taxometer}-L-phenylalanine

Analogously to example 17, using as the starting material methyl ester 4-amino-N-{[2-(trifluoromethyl)phenyl]taxometer}-L-phenylalanine in the form of an amorphous white solid with 98%yield was obtained methyl ester 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[2-(trifluoromethyl)phenyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 555,0511; rasasi - 555,0524, (M+H).

Example 39. 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[2-(trifluoromethyl)phenyl]taxometer}-L-phenylalanine

Analogously to example 18, using as the starting material methyl ester 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[2-(trifluoromethyl)phenyl]taxometer}-L-phenylalanine in the form of an amorphous white solid with 99%yield was obtained 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[2-(trifluoromethyl)phenyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 541,0358; rasasi - 541,0367, (M+H).

Example 40. Methyl ester 1-(4-bromobutyl)cyclopentanecarbonyl acid

Into a solution of 21 ml (150 mmol) of Diisopropylamine in 100 ml of THF at -10°With dropwise introduced 58 ml of 2.5 M (145 mmol) of a solution of n-butyl the reality hexano, while maintaining the temperature below 0°C. After complete addition the solution was stirred for 30 min at 0°C. At -70°it was added dropwise a solution of 13.1 g (100 mmol) of methylcyclohexanecarboxylic in 20 ml of THF, while maintaining the temperature of the mass in the range from -60 to -70°C. After the addition, the reaction mixture was stirred for 1 h at a temperature of from -50 to -60°C. Then was added dropwise a solution of 21,59 g (100 mmol) of 1,4-dibromobutane in 20 ml of THF and light brown suspension was stirred for 1 h at a temperature of from -60 to -70°C. Then it was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured into 200 ml of saturated solution of ammonium chloride and the organic compound was extracted with 2 portions of 100 ml of diethyl ether. The combined extracts were washed with 150 ml saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solution was concentrated under vacuum and the resulting residue was distilled at 120-133°C/2.5 mm Hg to produce in the form of a colourless oil 12.8 g (yield: 48%) of methyl ester 1-(4-bromobutyl)cyclopentanecarbonyl acid. Msvr: obnarujeni - 262,0565; rasasi - 262,0568, (M+).

Example 41. Methyl ester 1-[4-(methylthio)butyl]cyclopentanecarbonyl acid

In a solution of 10 g (38 mmol) of methyl ester 1-(4-bromobutyl)cyclopentanecarbonyl acid in 100 ml of DMF were introduced 5,09 g (72,6 mmole) of timelocked sodium. After adding proceeded exothermic reaction and the mixture was turned into a light brown cloudy solution. The mixture was stirred at room temperature for 15 h and was poured into 200 ml of water. The organic compound was extracted with 2 portions of 150 ml of diethyl ether. The combined extracts were washed with 150 ml saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solution was concentrated under vacuum and the residue was purified by chromatography on silica gel column to obtain in the form of a colorless oil 4,43 g (yield: 51%) of methyl ester 1-[4-(methylthio)butyl]cyclopentanecarbonyl acid. Msvr: obnarujeni - 230,1343; rasasi - 230,1341, (M+).

Example 42. Methyl ester 1-[4-(methylsulphonyl)butyl]cyclopentanecarbonyl acid

In the solution 4,43 g (of 19.2 mmole) of methyl ester 1-[4(methylthio)butyl]cyclopentanecarbonyl acid in 20 ml of Asón was injected 10 ml of 30%hydrogen peroxide. The reaction mixture was heated to 70°and was stirred for 15 hours after this time TLC data of the mixture indicated the absence of starting material. The reaction mixture was cooled to room Tempe is atory and under vacuum concentrated. The residue was poured into saturated sodium bicarbonate solution and was extracted with 3 portions of 100 ml of diethyl ether. The combined extracts were washed with 200 ml saturated sodium chloride solution and dried over anhydrous magnesium sulfate. After filtering off the drying agent under vacuum solvent was removed, and the obtained residue was purified by chromatography on silica gel column with getting 4.94 g (yield: 98%) of product as colorless oil. ICSD (C12H22O4S); 263 (M+H).

Example 43. 1-[4-(methylsulphonyl)butyl]cyclopentanecarbonyl acid

In a solution of 4.94 g (18,8 mmole) of methyl ester 1-[4(methylsulphonyl)butyl]cyclopentanecarbonyl acid in a mixture of 38 ml of THF with 38 ml of methanol was administered to 38 ml of 1 n sodium hydroxide. The mixture was stirred at a temperature of from 50 to 55°C for 15 h, after which TLC data analysis of this reaction mixture indicated the absence of starting material, and the mixture was allowed to cool to room temperature. Under vacuum solvent was removed, the residue was diluted with 100 ml of water and to remove neutral impurities were extracted with 2 portions of 50 ml of diethyl ether. Next, the basic aqueous layer was acidified using 1 N. hydrochloric acid and the product was extracted with 2 portions of 75 ml of ethyl acetate. The combined extracts were washed with brine solution and dried over anhydrous Sul is blockhead sodium. After filtering off the drying agent, the solution was concentrated under vacuum and the residue was dried under high vacuum to produce in the form of a low-melting white solid substance or 4.31 g (yield: 92%) specified in the title compounds. ICSD (C11H20O4S); 249 (M+H).

Example 44. 1-[4-(methylthio)butyl]cyclopentanecarbonyl acid

In a solution of 4.94 g (18,8 mmole) of methyl ester 1-[4(methylthio)butyl]cyclopentanecarbonyl acid in a mixture of 38 ml of THF with 38 ml of methanol was administered to 38 ml of 1 n sodium hydroxide. The mixture was stirred at a temperature of from 50 to 55°C for 15 h, after which TLC data analysis of this reaction mixture indicated the absence of starting material. After cooling to room temperature under vacuum solvent was removed, the residue was diluted with 100 ml of water and to remove neutral impurities were extracted with 2 portions of 50 ml of diethyl ether. Next, the basic aqueous layer was acidified using 1 N. hydrochloric acid and the product was extracted with 2 portions of 75 ml of ethyl acetate. The combined extracts were washed with brine solution and dried over anhydrous sodium sulfate. After filtering off the drying agent, the solution was concentrated under vacuum and the residue was dried under high vacuum to produce in the form of a low-melting white solid substance or 4.31 g (yield: 92%) of 1-[4-(methylthio)butyl]cyclopent the carboxylic acid. Msvr: obnarujeni - 216,1181; rasasi - 216,1184, (M+).

Example 45. Methyl ester of N-{[1-((4-methylthio)butyl)cyclopentyl}carbonyl]-4-nitro-L-phenylalanine

In the suspension 47,41 g (181,84 mmole) cleaners containing hydrochloride salt of methyl ester 4-nitro-L-phenylalanine and 38,33 g (177,17 mmole) 1-[4-(methylthio)butyl]cyclopentanecarbonyl acid in 470 ml of DMF at room temperature was introduced and 67.2 g (177,17 mmole) hbtu and 77 ml (443 mmole) of diisopropylethylamine. A clear solution was stirred at room temperature for 15 h and after this time the data TLC analysis of the mixture indicated the absence of starting materials. The reaction mixture was diluted with 600 ml ethyl acetate. An ethyl acetate layer was sequentially washed with 2 portions of 250 ml of 0.5 N. hydrochloric acid, 2 portions of 250 ml of saturated sodium bicarbonate solution, 300 ml of brine and dried over anhydrous magnesium sulfate. In the filtration of the drying agent and concentration of the solvent was obtained the crude product, which was purified by chromatography on silica gel column to obtain in the form of an amorphous white solid 58.5 g (yield: 78%) of methyl ester of N-{[1-((4-methylthio)butyl)cyclopentyl]carbonyl}-4-nitro-L-phenylalanine. Msvr: obnarujeni - 423,1940; rasasi - 423,1953, (M+H).

Example 46. Methyl ester 4-nitro-N-{[1-((4-methylsulphonyl)butyl)is clopotel]carbonyl}-L-phenylalanine

To a solution of 58.5 g (138,4 mmole) of methyl ester of N-{[1-((4-methylthio)butyl)cyclopentyl]carbonyl}-4-nitro-L-phenylalanine in 1.2 l CH2Cl2at -5°With (bath of a mixture of salt with ice) was introduced 71.7 g (415 mmol) m-chloroperbenzoic acid (mjpbk). The suspension was stirred for 30 min at 0°C, allowed it to warm to room temperature and was stirred for another 5 h, after this time the data TLC analysis of the mixture indicated the absence of starting material. The solid was filtered and the filtrate was concentrated under vacuum to obtain white balance. The white residue was dissolved in 600 ml of ethyl acetate and washed with 3 portions of 300 ml of saturated sodium bicarbonate solution. Data TLC analysis indicated the presence of m-chloroperbenzoic acid. Therefore, an ethyl acetate layer was washed with a saturated solution of sodium bisulfite (20 g in 150 ml water), 200 ml of a saturated solution of sodium bicarbonate and 300 ml of brine and dried over anhydrous magnesium sulfate. In the filtration of the drying agent and concentration of the filtrate was obtained the crude product, which was dissolved in ethyl acetate. Added diethyl ether and hexane, with the aim of deposition of oily residue. Under reduced pressure to remove a solvent to obtain a white suspension. is the suspension was further diluted with diethyl ether, the solid material was collected by filtration and washed with hexane. After drying in the form of a white low melting (with tPL40 to 44° (C) solids received 53,9 g (yield: 86%) of methyl ester 4-nitro-N-{[1((4-methylsulphonyl)butyl)cyclopentyl]carbonyl}-L-phenylalanine. Msvr: obnarujeni - 455,1854; rasasi - 455,1852, (M+H).

Example 47. Methyl ester of N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine

In a solution of 15 g (33 mmole) of methyl ester of N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]carbonyl}-4-nitro-L-phenylalanine in 100 ml of toluene (stored overs molecular sieves) and 50 ml of fresh THF at room temperature was introduced 13,35 g (33 mmole, 1.0 EQ.) the reagent Loveson. The solution was heated to a temperature of from 60 to 65°and was stirred for 48 hours after this time the data TLC analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature, poured into 200 ml saturated sodium bicarbonate solution and was extracted with 3 portions of 150 ml of ethyl acetate. In the water layer has been formed substance in the form of oil, which was separated, diluted with water and was extracted with 2 portions of 50 ml of ethyl acetate. United an ethyl acetate extracts were washed with 200 ml saturated races is the thief of sodium bicarbonate, 300 ml of brine and dried over anhydrous magnesium sulfate. In the filtration of the drying agent and concentration of the solvent having a lot in the form of a light brown syrup, which was purified by chromatography on silica gel column, elwira hexane/ethyl acetate (ratio 1/1), to obtain in the form of friable yellow solid 6,87 g (yield: 44%) of methyl ester of N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine. Msvr: obnarujeni - 493,1438; rasasi - 493,1443, (M+Na).

Example 48. Methyl ester of 4-amino-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine

9,07 g (19,3 mmole) poorly soluble methyl ether of N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-4-nitro-L-phenylalanine moderate heat with a hair dryer was dissolved in 150 ml of methanol and 20 ml of THF. In the resulting solution at room temperature was added br12.62 g (193 mmole, 10 EQ.) zinc dust (particle size ~325 mesh) and 15.5 g (289,5 mmole, 15 EQ.) ammonium chloride, and then 75 ml of water. After adding water flowed exothermic reaction and the temperature was raised to level 45 to 50°C. the Suspension was stirred for 1 h, after which TLC analysis of the mixture indicated the absence of starting material. The reaction mixture filters the if and the filter cake was washed with 200 ml of methanol and 100 ml of THF. Methanol and THF under vacuum was removed, and the organic residue was extracted with 2 portions of 200 ml of ethyl acetate. The combined extracts were washed with 250 ml of brine and dried over anhydrous magnesium sulfate. In the filtration of the drying agent and concentration in the form of a white resin like substance was received of 8.37 g (yield: 98%) of methyl ester of 4-amino-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine, which is directly used in the next stage. Msvr: obnarujeni - 441,1884; rasasi - 441,1882 (M+H).

Example 49. Methyl ester of 4-{[(2,6-dichlorophenyl)carbonyl]amino} -N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine

In a solution of 8.37 g (19,0 mmole) of methyl ester of 4-amino-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine and 4.4 g (21 mmol) of 2,6-dichlorobenzonitrile in 90 ml of dichloromethane at room temperature was introduced 5.6 ml (32,3 mmole) of diisopropylethylamine. The solution was stirred for 15 h, after this time the data TLC analysis of the mixture indicated the absence of starting material. Then it was diluted with 100 ml of water and the two layers were separated. The aqueous phase was extracted with 100 ml dichloromethane and the combined extracts were washed with 200 ml of brine. After drying over anhydrous magnesium sulfate solution under vacuum, the oxygen which has demonstrated and the residue was purified by chromatography on silica gel column, elwira hexane/ethyl acetate/CH2CL2(in the ratio of 1/1/1) obtaining in the form of a white solid with tPL200-202°11,54 g (yield: 99%) of methyl ester of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 613,1367; rasasi - 613,1363 (M+H).

Example 50. 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine

In solution trend of 15.87 grams (25,86 mmole) of methyl ester of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine in 75 ml of ethanol at 50°C was added 60 ml of 1,0N. aqueous sodium hydroxide. The mixture was heated to a temperature of from 50 to 55°and the resulting clear light brown solution was stirred for 22 hours after this time the data TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with water, allowed to cool to room temperature and filtered to remove a small amount of solid material. The filtrate was concentrated and the residual aqueous solution was washed with 2 portions of 75 ml of diethyl ether. Basically the aqueous layer was acidified to 3.0 N. Hcl, receiving a turbid suspension, and was extracted with 3 portions of 100 ml of ethyl acetate. The combined extracts were washed with 200 ml of p is the target of brine and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the filtrate was concentrated. The residue was dissolved in dichloromethane and diluted with diethyl ether/hexane in a ratio of 1/1 to obtain solid, which was collected by filtration. This solid was ground into powder in ~100 ml of hot ethyl acetate, obtaining a suspension, which was diluted in ~50 ml of diethyl ether. The solid material was collected by filtration. The above process was repeated to produce in the form of a white solid 10,89 g (yield: 70%) 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl] taxometer}-L-phenylalanine. Msvr: obnarujeni - 599,1193; rasasi - 599,1208 (M+H).

Example 51. Sodium salt of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine

Suspension of 9.89 g (16,49 mmole) of 4-(2,6-dichlorophenylamino)-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine in 100 ml of water at room temperature was treated to 16.4 ml (to 16.4 mmole) and 1.0 n sodium hydroxide. The mixture was heated to a temperature of from 40 to 45°and added a certain amount (~15 ml) of acetonitrile to obtain a clear solution containing a small amount of suspended solids. The solution was filtered and the filtrate liofilizirovanny obtaining in the form of a white TV is Gogo matter of 10.1 g of sodium salt. Msvr: obnarujeni - 621,1023; rasasi - 621,1027 (M+H).

Example 52. Methyl ester of 4-{[(2,4-dimethyl-3-pyridinyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine

Chilled with ice a solution of 45 mg (0.3 mmole) of 2,4-dimethyl-3-pyridineboronic acid in 2 ml of dichloromethane and one drop of DMF at 0°added a 49.5 mg (0,39 mmole) of oxalicacid. At this temperature, the reaction mixture was stirred for 30 min, allowed it to warm to room temperature and was stirred for a further 2 hours the Solution was concentrated and the residue was dried under high vacuum. In the mixture of the above carboxylic acid and 88 mg (0.2 mmole) of methyl ester of 4-amino-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine in 3 ml of dichloromethane at room temperature was added 0,175 ml (1 mmol) diisopropylethylamine. The solution was stirred for 15 hours after this time the data TLC analysis of the mixture indicated the absence of starting material. It was diluted with 20 ml water and 20 ml of dichloromethane and the two layers were separated. The aqueous phase was extracted with 10 ml dichloromethane and the combined extracts washed with 20 ml of brine. After drying over anhydrous magnesium sulfate, the solution was concentrated under vacuum and the residue was purified HPLC with reversed phase to produce in the form of a white Amor the aqueous solids 74 mg (yield: 65%) of pure methyl ester 4-{[(2,4-dimethyl-3-pyridinyl) carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 574,2389; rasasi - 574,2409 (M+H).

Example 53. The TFA salt of 4-[(2,4-dimethyl-3-pyridylcarbonyl)amino)-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine

In a solution of 68 mg (amount of 0.118 mmole) of methyl ester of 4-{[(2,4-dimethyl-3-pyridinyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine in 4 ml of ethanol at room temperature was injected 3 ml of 1.0 N. aqueous sodium hydroxide. The mixture was heated to a temperature of from 45 to 50°and the resulting clear solution was stirred for 3 h, after which TLC analysis of the mixture indicated the absence of starting material. The mixture was concentrated and the crude material was purified HPLC with reversed phase to produce in the form of a white amorphous solid substance of 54.5 mg (yield: 82%) of the TFA salt of 4-[(2,4-dimethyl-3-pyridylcarbonyl)amino]-N-[(2-forfinal)taxameter]-L-phenylalanine. Msvr: obnarujeni - 560,2240; rasasi - 560,2253 (M+H).

Example 54. Ethyl-1-(4-bromobutyl)cyclobutanecarboxylic

Analogously to example 40 using as starting material ethyl ester cyclobutanecarbonyl acid in the form of a colourless oil with a 58%yield was obtained ethyl ester 1-(4-bromobutyl)cyclobutanecarbonyl acid. Msvr: obnarujeni - 263,0563; rasasi - 263,0568 (M+).

P the emer 55. Ethyl ester 1-[4-(methylthio)butyl]cyclobutanecarbonyl acid

Analogously to example 41, using as starting material ethyl ester 1-(4-bromobutyl)cyclobutanecarbonyl acid in the form of a colorless oil in 87%yield was obtained ethyl ester 1-[4-(methylthio)butyl]cyclobutanecarbonyl acid. Msvr: obnarujeni - 230,1339; rasasi - 230,1340 (M+).

Example 56. Ethyl ester 1-[4-(methylsulphonyl)butyl]cyclobutanecarbonyl acid

Analogously to example 46 using as starting material ethyl ester 1-[4-(methylthio)butyl]cyclobutanecarbonyl acid in the form of a colorless oil in 92%yield was obtained ethyl ester 1-[4-(methylsulphonyl)butyl]cyclobutanecarbonyl acid. Msvr: obnarujeni - 262,1231; rasasi - 262,1238 (M+).

Example 57. 1-[4-(methylsulphonyl)butyl]cyclobutanecarbonyl acid

Analogously to example 43 using as starting material ethyl ester 1-[4-(methylsulphonyl)butyl]cyclobutanecarbonyl acid in the form of a low-melting white solid with 92%yield was obtained 1-[4-(methylsulphonyl)butyl]cyclobutanecarbonyl acid. Msvr: obnarujeni - 234,0921; rasasi - 234,0918 (M+).

Example 58. Methyl ester of N-{[1-((4-methylsulphonyl)butyl)shall kilobytes]carbonyl}-4-nitro-L-phenylalanine

Analogously to example 45 using as a starting material, 1-[4-(methylsulphonyl)butyl]cyclobutanecarbonyl acid in the form of a yellow resin with 89%yield was obtained methyl ester N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]carbonyl}-4-nitro-L-phenylalanine. Msvr: obnarujeni - 441,1700; rasasi - 441,1696 (M+H).

Example 59. Methyl ester of N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-4-nitro-L-phenylalanine

Analogously to example 47 using as starting material methyl ester 4-nitro-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]carbonyl}-L-phenylalanine as a white solid, 80%yield was obtained methyl ester N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-4-nitro-L-phenylalanine with tPL150-152°C. msvr: obnarujeni - 457,1464; rasasi - 457,1467 (M+H).

Example 60. Methyl ester of 4-amino-N-{[1-((4-methylsulphonyl)butyl)-cyclobutyl]taxometer}-L-phenylalanine

Analogously to example 48 using as starting material methyl ester N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-4-nitro-L-phenylalanine in the form of hygroscopic solids with 94%yield was obtained methyl ester of 4-amino-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]thixomat the l}-L-phenylalanine. Msvr: the detection. weight - 427,1720; rasasi - 427,1725 (M+H).

Example 61. Methyl ester of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine

Analogously to example 49, using as starting material methyl ester 4-amino-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine in the form of an amorphous white solid with 92%yield was obtained methyl ester 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 599,1207; rasasi - 599,1208 (M+H).

Example 62. 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine

Analogously to example 50 using as starting material methyl ester 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine in the form of an amorphous white solid with 99%yield was obtained 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 585,1038; rasasi - 585,1051 (M+H).

Example 63. Methyl ester of 4-{[(4-(trifluoromethyl)-5-pyrimidinyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-Penilaian is on

Analogously to example 45 using as starting material methyl ester 4-amino-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine in the form of an amorphous white solid with a 32%yield was obtained methyl ester 4-{[(4-(trifluoromethyl)-5-pyrimidinyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 601,1766; rasasi - 601,1766 (M+H).

Example 64. 4-{[(4-(trifluoromethyl)-5-pyrimidinyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine

Analogously to example 50 using as starting material the product of example 63 in the form of an amorphous white solid with 22%yield was obtained 4-{[(4(trifluoromethyl)-5-pyrimidinyl)carbonyl]amino} - N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 587,1619; rasasi - 587,1609 (M+H).

Example 65. Ethyl-1-(3-bromopropyl)cyclobutanecarboxylic

Analogously to example 40 using as starting material ethyl ester cyclobutanecarbonyl acid in the form of a colourless oil with a 33%yield was obtained ethyl ester 1-(3-bromopropyl)cyclobutanecarbonyl acid. Msvr: obnarujeni - 248,0416; rasasi - 248,0412 (M+).

<> Example 66. Ethyl-1-[3-(methylthio)propyl]cyclobutanecarboxylic (Ro 28-1367/000, 29156-271-3) and 1-[3-(methylthio) propyl] cyclobutanecarbonyl acid

Analogously to example 41, using as starting material ethyl ester 1-(3-bromopropyl)cyclobutanecarbonyl acid in the form of a colourless oil with a 58%yield was obtained ethyl ester 1-[3-(methylthio)propyl]cyclobutanecarbonyl acid. Msvr: obnarujeni - 216,1182; rasasi - 216,1184 (M+). Also in the form of a colourless oil with a 16%yield was obtained 1-[3-(methylthio)propyl]cyclobutanecarbonyl acid. Msvr: obnarujeni - 188,0872; rasasi - 188,0871 (M+).

Example 67. Methyl ester of N-{[1-((3-methylthio)propyl)cyclobutyl]carbonyl}-4-nitro-L-phenylalanine

Analogously to example 45 using as source material cleaners containing hydrochloride salt of methyl ester 4-nitro-L-phenylalanine as a yellow viscous oil with 92%yield was obtained methyl ester N-{[1-((3-methylthio)propyl)cyclobutyl]carbonyl}-4-nitro-L-phenylalanine. Msvr: obnarujeni - 395,1638; rasasi - 395,1640 (M+H).

Example 68. Methyl ester of N-{[1-((3-methylthio)propyl)cyclobutyl]taxometer}-4-nitro-L-phenylalanine

Analogously to example 47 using as starting material methyl ester 4-nitro-N-{[1-((3-methylt is about)propyl)cyclobutyl]carbonyl}-4-nitro-L-phenylalanine in the form of a colorless viscous oil with 95%yield was obtained methyl ester N-{[1-((3-methylthio)propyl)cyclobutyl]taxometer}-4-nitro-L-phenylalanine. Msvr: obnarujeni - 411,1408; rasasi - 411,1412 (M+H).

Example 69. Methyl ester of 4-amino-N-{[1-((3-methylthio)propyl)cyclobutyl]taxometer}-L-phenylalanine

Analogously to example 48 using as starting material methyl ester N-{[1-((3-methylthio)propyl)cyclobutyl]taxometer}-4-nitro-L-phenylalanine in the form of a hygroscopic yellow solid with 97%yield was obtained methyl ester of 4-amino-N-{[1-((3-methylthio)propyl)cyclobutyl]taxometer}-L-phenylalanine. Msvr: the detection. weight - 381,1660; rasasi - 381,1671 (M+H).

Example 70. Methyl ester of 4-[(2,6-dichlorophenylamino)amino]-N - {[1-((3-methylthio)propyl)cyclobutyl]taxometer}-L-phenylalanine

Analogously to example 49, using as starting material methyl ester 4-amino-N-{[1-((3-methylthio)propyl)cyclobutyl]taxometer}-L-phenylalanine as a white solid with 83%yield was obtained methyl ester 4-[(2,6-dichlorophenylamino)amino]-N-{[1-((3-methylthio)propyl)cyclobutyl]taxometer}-L-phenylalanine; tPL: 184-186°C. msvr: obnarujeni - 553,1139; rasasi - 553,1153 (M+H).

Example 71. 4-[(2,6-dichlorophenylamino)amino]-N-{[1-((3-methylthio)propyl)cyclobutyl]taxometer}-L-phenylalanine

Analogously to example 50 using as recognize the aqueous material methyl ester 4-[(2,6-dichlorophenylamino)amino]-N-{[1-((3-methylthio)propyl)cyclobutyl]taxometer}-L-phenylalanine as a white solid with a 97%yield was obtained 4-[(2,6-dichlorophenylamino)amino]-N-{[1-((3-methylthio)propyl)cyclobutyl]taxometer}-L-phenylalanine; tPL: 186-188°C. msvr: obnarujeni - 539,0986; rasasi - 539,0996 (M+H).

Example 72. Ethyl ester of 1-[3-(methylsulphonyl)propyl]cyclobutanecarbonyl acid

Analogously to example 46 using as starting material ethyl-1-[3-(methylthio)propyl]cyclobutanecarboxylic in the form of a colorless oil in 87%yield was obtained ethyl-1-[3-(methylsulphonyl)propyl]cyclobutanecarboxylic. Msvr: obnarujeni - 248,1084; rasasi - 248,1082 (M+).

Example 73. 1-[3-(methylsulphonyl)propyl]cyclobutanecarbonyl acid

Analogously to example 43 using as starting material ethyl-1-[3-(methylsulphonyl)propyl]cyclobutanecarboxylic in the form of a white solid with a 76%yield was obtained 1-[3-(methylsulphonyl)propyl]cyclobutanecarbonyl acid; tPL: 113-116°C. msvr: obnarujeni - 220,0770; rasasi - 220,0769 (M+).

Example 74. Methyl ester 4-nitro-N-{[1-((3-methylsulphonyl)propyl)cyclobutyl]carbonyl}-L-phenylalanine

Analogously to example 45 methyl ester N-{[1-((3-methylsulphonyl)propyl)cyclobutyl]carbonyl}-4-nitro-L-phenylalanine was obtained as a white amorphous solid with 76%yield. Msvr: obnarujeni - 427,1526; rasasi - 427,1539 (M+H).

Example 75. Methyl ester of N-{[1-((3-methylsulphonyl)PR who drank)cyclobutyl]taxometer}-4-nitro-L-phenylalanine

Analogously to example 47 using as starting material methyl ester N-{[1-((3-methylsulphonyl)propyl)cyclobutyl]carbonyl}-4-nitro-L-phenylalanine as a yellow sticky solid with 88%yield was obtained methyl ester N-{[1-((3-methylsulphonyl)propyl)cyclobutyl]taxometer}-4-nitro-L-phenylalanine. Msvr: the detection. weight - 443,1309; rasasi - 443,1310 (M+H).

Example 76. Methyl ester of 4-amino-N-{[1-((3-methylsulphonyl)propyl)cyclobutyl]taxometer}-4-nitro-L-phenylalanine

Analogously to example 48 using as starting material methyl ester N-{[1-((3-methylsulphonyl)propyl)cyclobutyl]taxometer}-4-nitro-L-phenylalanine in the form of a hygroscopic yellow solid with 97%yield was obtained methyl ester of 4-amino-N-{[1-((3-methylsulphonyl)propyl)cyclobutyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 413,1556; rasasi - 413,1570 (M+H).

Example 77. Methyl ester of 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((3-methylsulphonyl)propyl)cyclobutyl]taxometer}-L-phenylalanine

Analogously to example 49, using as starting material methyl ester 4-amino-N-{[1-((3-methylsulphonyl)propyl)cyclobutyl]taxometer}-L-phenylalanine as a white amorphous solid substances is and with 82%yield was obtained methyl ester 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((3-methylsulphonyl)propyl)cyclobutyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 585,1056; rasasi - 585,1051 (M+H).

Example 78. 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((3-methylsulphonyl)propyl)cyclobutyl]taxometer}-L-phenylalanine

Analogously to example 50 using as starting material methyl ester 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((3-methylsulphonyl)propyl)cyclobutyl]taxometer}-L-phenylalanine in the form of an amorphous white solid with 87%yield was obtained 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-{[1-((3-methylsulphonyl)propyl)cyclobutyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 571,0894; rasasi - 571,0895 (M+H).

Example 79. 2-chloro-5-(trifluoromethyl)finaldrive

In a solution of 4.8 g (24,4 mmole) of 2-chloro-5-(trifluoromethyl)phenol in 160 ml of CH2Cl2at -70°introduced 6.7 g (54.0 per mmole) DMAP, and then at -70°10,32 g (6,16 ml, 36,6 mmole) of the anhydride of triftoratsetata. After this addition, the suspension was stirred for 30 min at this temperature and then heated to room temperature and stirring for another 3 h, after which TLC of the reaction mixture indicated the absence of starting material. The mixture was diluted with 100 ml of N2Oh, and two layers were separated. The aqueous layer was extracted with 100 ml of CH2Cl2. United dichlorethane extracts prom the Wali solution of brine and was dried over MgSO 4. In the filtration of the drying agent and removal under vacuum of the solvent was obtained white suspension, which was purified by chromatography on silica gel column, elwira hexane/diethyl ether in a ratio of 4/1, to obtain 6.8 g (yield: 75%) of product as colorless oil. Msvr: obnarujeni - 327,9388; rasasi - 327,9392 (M+).

Example 80. 2-chloro-5-(trifluoromethyl)benzoic acid

In a 250-ml thick-walled flask was loaded 6,76 g (to 20.6 mmole) of 2-chloro-5-(trifluoromethyl)fertitlity, 384 mg (1,71 mmole) of Pd(OAc)2and 701 mg (1,71 mmole) DFFP. The flask was closed by a membrane, and in it three times created a vacuum and filled with argon. Then using a syringe sequentially added 114 ml of acetonitrile, a 30.7 ml (225,3 mmole) of triethylamine and 22.2 ml of water. After that, the rubber membrane was replaced plated Teflon lid. Carbon monoxide in the flask was created increased pressure (40 psi) and the gas was released. This operation was repeated three times and, finally, under high pressure, the mixture was stirred for 5 minutes Then the flask from the gas canister was disconnected, was immersed in a pre-heated (to a temperature of from 83 to 85° (C) oil bath and was stirred for 2 hours With the help of carbon monoxide in the flask was again created increased pressure and the mixture was stirred for a further 1 h the donkey that the reaction mixture was cooled to room temperature, the pressure dropped and the mixture was diluted with 250 ml of diethyl ether and 25 ml of 1.0 N. NaOH. The acid was extracted with 2 portions of 100 ml of water. The combined aqueous extracts were neutralized with 1.0 N. Hcl and the acid was again extracted with 3 portions of 100 ml of diethyl ether. The combined ether extracts were washed with brine solution and dried over MgSO4. In the filtration of the drying agent and removal under vacuum of the solvent was obtained a crude light yellow solid. This solid substance was dissolved in 100 ml diethyl ether and was extracted with 2 portions of 50 ml of 1.0 n NaOH solution. Next, the aqueous layer was acidified and extracted with 2 portions of 100 ml of diethyl ether. The combined extracts were washed with 100 ml of brine and was dried over MgSO4. After filtering and concentrating the solution in the form of a white solid substance was obtained 1.6 g (yield: 35%) of 2-chloro-5-(trifluoromethyl)benzoic acid; tPL: 82-83,5°C. msvr: obnarujeni - 223,9852; rasasi - 223,9851 (M+).

Example 81. Methyl ester of 4-{[(2-chloro-5-(trifluoromethyl)phenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine

Analogously to example 52, using as starting material methyl ester 4-amino-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine as a white amorph the CSO solids with 97%yield was obtained methyl ester 4-{[(2-chloro-5-(trifluoromethyl)phenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 633,1477; rasasi - 633,1471 (M+H).

Example 82. 4-{[(2-chloro-5-(trifluoromethyl)phenyl)carbonyl]amino}-N{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine

Analogously to example 50 using as starting material methyl ester 4-{[(2-chloro-5-(trifluoromethyl)phenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine as a white amorphous solid substances with 75%yield was obtained 4-{[(2-chloro-5-(trifluoromethyl)phenyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 619,1315; rasasi - 619,1318 (M+H).

Example 83. Methyl ester of 4-{[(2,4-dimethyl-6-trifluoromethyl-3-pyridinyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine

In the slurry 184 mg (from 0.84 mmole) of 2,4-dimethyl-6-trifluoromethyl-3-pyridineboronic acid in 10 ml dichloromethane and 3 drops DMF at 0°With dropwise within 2 to 3 min was administered to 146 mg (0.1 ml, to 1.14 mmole) of oxalicacid. Once added, the suspension was stirred for 30 min at 0°and then she was allowed to warm to room temperature. A clear solution was stirred for another 2 h at room temperature. Under vacuum solvent was removed and the residue was dried under high vacuo the om within 1 hour The 4-necked flask of the above obtained acid chloride acid in 6 ml of ethyl acetate was added to a mixture of 298 mg (0.7 mmole) of methyl ester of 4-amino-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine with 900 mg (1.4 mmole) of the product Amberlyst A-21 in 10 ml of ethyl acetate (stored over 4s molecular sieves). The mixture was subjected to ultrasonic treatment for 30 min, diluted with 100 ml water and 100 ml of ethyl acetate and the two layers were separated. The aqueous layer was extracted with 50 ml ethyl acetate and the combined extracts were washed with 100 ml of brine and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the solution was concentrated under reduced pressure and the residue was purified HPLC with reversed phase to produce in the form of a white amorphous solids 139 mg (yield: 32%) of methyl ester of 4-{[(2,4-dimethyl-6-trifluoromethyl-3-pyridinyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 628,2122; rasasi - 628,2127 (M+H).

Example 84. 4-{[(2,4-dimethyl-6-trifluoromethyl-3-pyridinyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine

In suspension 125 mg (0.2 mmole) of methyl ester of 4-{[(2,4-dimethyl-6-trifluoromethyl-3-pyridinyl)carbonyl]amino}-N-{[1-((4-methylsulphonyl)butyl)cyclobutyl]taxometer}-L-phenylalanine in 7 ml ethanol at on the th temperature was introduced in 5.0 ml of 1.0 M solution of sodium hydroxide. Within a few minutes had formed a clear solution, which was heated to a temperature of from 45 to 50°and was stirred for 4 h, after which TLC analysis of the mixture indicated the absence of starting material. Next, the mixture was cooled to room temperature and under vacuum, remove the ethanol. The residue was purified HPLC with reversed phase, receiving in the form of an amorphous white solids 67.5 mg (yield: 55%) of 4-{[(2,4-dimethyl-6-trifluoromethyl-3-pyridinyl)carbonyl]-amino}-N-{[1-((4-methylsulphonyl)-butyl)cyclobutyl]taxometer}-L-phenylalanine. Msvr: obnarujeni - 614,1970; rasasi - 614,1970 (M+H).

Example 85. 4-{[(2,6-dichlorophenyl)carbonyl]amino}-N-[(2-bromophenyl)taxameter]-L-phenylalanine

Specified in the title compound was obtained analogously to examples 35 to 39 using as starting material 2-bromobenzoyl acid. Msvr: obnarujeni - 550,9593; rasasi - 550,9598 (M+H).

Example 86. 4-{(2S,4R)-3-acetyl-2-phenyl-4-[(3-phenyl)methyl]-5-Oxymetazoline-1-yl}-N-{[((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine and 4-{(2R,4R)-3-acetyl-2-phenyl-4-[(3-phenyl)methyl]-5-Oxymetazoline-1-yl}-N-{[((4-methylsulphonyl)butyl)cyclopentyl]taxometer}-L-phenylalanine

Specified in the title compounds were obtained analogously to examples 26 to 29. Isomers section is whether chromatography on stage methyl ester. For the 2S,4R-isomer msvr: the detection. weight - 650,2670; rasasi - 650,2665 (M+Na). For 2R,4R-isomer msvr: obnarujeni - 650,2679; rasasi - 650,2665 (M+Na).

Tests:

1. Screening for binding of VLA-4/VCAM-1

Antagonistic activity against VLA-4, which is determined by the ability to compete for binding to immobilized VCAM-1, was evaluated quantitatively using enzyme-linked immunosorbent assay (ELISA) using a double antibody. Associated with VCAM-1, VLA-4 (a4b1integrin) can be found on the education of the next complex: b1 antibody to the integrin/conjugated with horseradish peroxidase (HRP) antimachine IgG/chromogenic substrate (K-Blue). To do this, first covered (senzibilizirani) 96-well plates (firm Nunc Maxisorp) recombinantly human VCAM-1 (0,4 µg in 100 µl SFR (phosphate buffered saline)), sealing each plate and gave the tablet to stand at 4°C for 18 hours Then coated with VCAM the plates were blocked with 250 μl of a mixture of 1% BSA (bovine serum albumin)/0,02% NaN3to reduce nonspecific binding. On the day of analysis, all tablets twice washed with buffer to determine VCAM (200 μl/well of buffer containing 50 mm Tris-HCl, 100 mm NaCl, 1 mm nl2, 0.05% tween-20; pH 7.4). Test compounds were dissolved in 100%DMSO and then asfodeli rate of 1:20 in the buffer to determine VCAM, supplemented with 1 mg/ml BSA (i.e., the final concentration of DMSO was 5%). In order for each of the tested compounds to obtain the concentration range 0.005 nm to 1,563 μm used a dilution of 1:4. To each well coated with VCAM tablets were added to 100 ál of each dilution, and then 10 μl of VLA-4, obtained from a cell line Ramos. These tablets were then shaken on a shaker platform for 1 min, incubated for 2 min at 37°C and then washed four times using 200 μl of buffer to determine VCAM/well. To each well was added 100 μl of mouse antibodies to human integrin β1 (0.6 ág/ml in the buffer to determine VCAM + 1 mg/ml BSA)and incubated for 1 h at 37°C. After this incubation period, all the tablets were washed four times with buffer to determine VCAM (200 µl/well). Then to each well was added the appropriate second antibody, i.e. conjugated with HRP goat antimachine IgG (100 µl/well, dilution 1:800 in the buffer to determine VCAM+1 mg/ml BSA), then incubated for 1 h at room temperature and the process was completed three times washing (200 µl/well) buffer to determine the VCAM. The coloration was initiated by adding 100 μl of K-Blue hole (incubation for 15 min, room temperature) and this process was stopped by adding 100 μl per well BU the EPA type Red Stop. Then all the tablets was investigated in the UV/Vis-spectrophotometer at 650 nm. The results were expressed as % inhibition of total binding (i.e. VLA-4+VCAM-1 in the absence of test compound). The table below presents some of the data obtained using the compounds according to the invention.

2. The Protocol screening at the cellular level by binding definition Ramos (VLA-4)/VCAM-1

Materials:

Soluble recombinant human VCAM-1 (a mixture of 5 - and 7-Ig domains) was purified from the medium for cell culture Chinese hamster ovary (Cho) using immunoaffinity chromatography and maintained in a solution containing 0.1 M Tris-glycine (pH 7.5), 0.1 M NaCl, 5 mm add, 1 mm phenylmethylsulfonyl (MFSF), 0,02% NaN3and 10 μg/ml leupeptin. Calcein-AM was obtained from the company Molecular Probes Inc.

Methods:

Antagonistic activity of compounds against VLA-4 (a4b1integrin), which is determined by the ability to compete with localized on the cell surface of VLA-4 for binding to immobilized VCAM-1, was evaluated quantitatively by analysis of cell adhesion using Ramos-VCAM-1. Cell line Ramos, bearing localized on the cell surface of VLA-4, were labeled with fluorescent dye (calcein-AM) and allowed to contact with VCAM-1 in the presence of test compounds or without him. Reducing intense the particular fluorescence, associated with the attachment of cells (% inhibition) reflects the competitive inhibition of the test compound mediated VLA-4 cell adhesion.

To do this, first coated 96-well plates (firm Nunc Maxisorp) recombinantly human VCAM-1 (100 ng in 100 μl SFR), sealing each plate and gave the tablet to stand at 4°C for 18 hours Then coated with VCAM tablets twice washed 0,05%tween-20 in STR and then blocked for 1 h (room temperature) with 200 μl of blocking buffer (1% BSA/0.02% of thimerosal) with the objective of reducing non-specific binding. After incubation with blocking buffer tablets upset, blotted and the remaining buffer was aspirated. Then each plate was washed with 300 μl SFR, turned and left SFR was sucked out.

Test compounds were dissolved in 100%DMSO and then diluted at the rate of 1:25 in the buffer to determine cell adhesion VCAM (4 mm l2, 4 mm MgCl2in 50 mm Tris-HCl, pH 7.5) (final concentration of DMSO was 4%). For each of the tested compounds were prepared in 8 serial dilutions 1:4 (in General, the concentration range was from 1 nm up to 12,500 nm). Covered VCAM tablets were added to 100 ál of each dilution, and then 100 μl of the cell line Ramos (200,000 cells/well in 1%BSA/SFR). Tablets containing the test compound and cell line is Ramos, allowed to incubated for 45 min at room temperature, then added 165 μl SFR/well. The tablets turned to delete neprecejusies cells, blotted and added 300 μl SFR/well. The tablets again turned, blotted and the remaining buffer was carefully sucked out. To each well was added 100 μl of buffer for lysis (0.1% of DSP in 50 mm Tris-HCl, pH 8.5) and mixed for 2 min on a rotary shaker platform. Then the fluorescence intensity of the tablets was evaluated using a system for measuring fluorescence Cytofluor 2300, Millipore) (wavelength excitation 485 nm, length oxen emission 530 nm).

3. Analysis of MadCAM using cell line PRMI 8866

Activity against binding to MadCAM was evaluated quantitatively using analysis based on the use of cell line PRMI 8866. Cell lines PRMI 8866, bearing the cell surface MadCAM, were labeled with fluorescent dye (calcein-AM) and allowed to contact with MadCAM in the presence of test compounds or without him. The decrease in fluorescence intensity associated with the attachment of cells (% inhibition), reflects the competitive inhibition of the test compound mediated MadCAM cell adhesion.

To do this, first coated 96-well plates (firm Nunc Maxisorp) 25 ng/well MadCAM (100 μl/well buffer for Sens is stabilizing the solution: 10 mm carbonate/bicarbonate buffer, 0.8 g/l of sodium carbonate, 1.55 g/l sodium bicarbonate, pH value of Dovado to 9.6 using 1 N. Hcl), sealed and wrapped in a shell of each plate and kept the tablets in the refrigerator for at least 24 hours Then covered with MadCAM tablets twice washed 0,05%tween-20 in STR and then blocked for 1 h at room temperature with blocking buffer (1% nonfat dry milk in SFR) to reduce nonspecific binding. After incubation with blocking buffer tablets washed SFR, blotted manually and the remaining buffer was aspirated.

Cell lines PRMI 8866 (2×106cells/ml × 10 ml/tablet × number of tablets) was transferred into centrifuge tubes of 50 ml volume, filled SFR, and centrifuged at 200×g for 8 min, after which SFR decanted and debris resuspendable in SFR to obtain a density of 10×106cells/ml. Calcein (diluted with 200 μl of DMSO from the frozen stock solution with a concentration of 5 mg/ml) was added to the cells at a concentration of 5 μl/ml SPR. After incubation at 37°C for 30 min in the dark, cells were washed in SFR and resuspendable based on 2×106cells /ml in a buffer for cells (environment PRMI 8866 (without additives)).

Test compounds were dissolved in 100%DMSO and then diluted at the rate of 1:25 in the buffer for St. the statements (1.5 mm l 2, 0.5 mm MnCl2in 50 mm Tris-HCl, pH is brought to 7.5 with NaOH). Other breeding made using dilution buffer (4% DMSO in buffer for binding - final DMSO concentration of 2% after dilution holes 1:2). For each of the tested compounds were preparing a series of dilutions. In the first series covered MadCAM tablets were added 129 μl of buffer for binding. In the remaining wells were added 100 μl/well of dilution buffer, and then to 5.4 μl of each dilution of each astrologo connection (in triplicate). Added 100 μl of cells (200,000 cells/well). Control wells contained 100 μl of dilution buffer + 100 ál of buffer for cells and 100 ál of dilution buffer + 100 ál of buffer cells. The plates were incubated for 45 min at room temperature, then added SFR based 150 µl/well. The tablets turned to delete neprecejusies cells, blotted and added 200 μl SFR/well. The tablets again turned, blotted and the remaining buffer was carefully sucked out. To each well was added 100 μl SFR. Then the fluorescence intensity of the tablets was evaluated using a system for measuring fluorescence (wavelength excitation 485 nm, the wavelength of emission of 530 nm, the sensitivity is equal to 2). To obtain the values for IC50for each connection is in applied linear regression analysis.

The results are shown in the following table:

ExampleIC50(nm), ELISAIC50, RamosIC50, RPMI
34,066,5 
101,533 
115,642,5 
180,4760 
256,0101 
29 220 
34 4,180 
39 784 
50 30 
53 148 
62 88,7
64 87 
71 926 
78 341 
82   
84  3,58,3

Example 4. Acute airway inflammation in atopic primates.

Inflammation of the respiratory tract in monkeys was determined using a modification of a Protocol described by Turner and co-authors (Turner and others, 1994). For these studies used adult male monkeys cynomolgus (Masasa fascicularis (cynomolgus macaques) Hazelton Labs, Denver, Pennsylvania) with a weight of 3.6 to 5.8 kg All animals gave positive skin reaction and the reaction of the Airways to the antigen Ascaris suum and they found at least 3-fold increased sensitivity to methacholine (MCh) in response to aerosol processing extracts of Ascaris.

On the day of each experiment, animals were subjected to anesthesia with ketamine hydrochloride (12 mg/kg) and xylazine (0.5 mg/kg), intubated with an endotracheal tube with an inflatable cuff (3 mm, Mallinckrodt Medical, St. Louis, Missouri), then placed in a vertical position on a specially designed Plexiglas chair (Plas-Labs, Lansing, Michigan). An endotracheal tube was connected with the heated pneumotachograph type Fleisch. The air flow rate was evaluated using a differential pressure sensor type Validyn (DP 45-24), which was attached to pneumotachograph. Repair pressure was estimated using the second sensor Validyn (DP 45-24), which was placed between acowym shoulder tracheomalacia intratracheal cannula and needle 18 size, introduced in vnutricerepnae space below the left nipple. Check pressure and flow parameters and the calculation of RLwas performed using the system of collecting and processing data Modular Instruments, as described above. The base level of RLevaluated for all animals on the day of each experiment, and the average value was around 0.04 cm H2O/ml/sec

Protocol

Airway inflammation induced aerosol processing of animal extract of A. Ascaris suum within 60 C. the Aerosol was administered using a spray gun (De Vilbiss, model 5000, Healt Inc., Somerset, Pennsylvania), which was connected to the endotracheal tube. For each animal was pre-determined concentration of the extract (from 500 to 50,000 units of protein nitrogen (PNU), which should cause at least a twofold increase the stability of the respiratory tract. After 24 h after control of infection by antigen animals were subjected to anesthesia, as described above, and placed on a stainless steel table. Airway inflammation was assessed by introducing a pediatric bronchoscope into the cavity of the respiratory tract to a depth of about 4 or 5 level bronchi and carefully washed with aliquot 3×2 ml of sterile balanced salt solution Hanks. Received lavagno the fluid is then analyzed in classified and the total number of cells and the number of differentiated cells using standard hematological procedures.

Processing of the medicinal product

Animals were injected with drug or oral media for 2 h prior to infection control antigen. The compound of example 1 caused a significant reduction in the number and percentage of inflammatory cells present in lavagno fluid, compared to control animals treated with media.

Dosage form for oral administration

No.Ingredientsmg tablet
1The active compound according to the invention25100250500
2Anhydrous lactose83351938
3Nutritionnelles681632
4Povidone K561224
5Magnesium stearate1136
      
 Total weight (mg)12015 300600

Method of preparation:

1. In a suitable mixer for 15 minutes mixed components 1, 2 and 3.

2. The mixture obtained in stage 1 in the form of a powder, granularit using a 20%aqueous solution of PVP K30 (polyvinylpyrrolidone).

3. The granules obtained in stage 2, dried at a temperature of 50°C.

4. The granules obtained in stage 3, ground in a specially designated for this device.

5. It crushed the granulate from step 4 add the component 5 and stirred for 3 minutes.

6. The granulate obtained in stage 5, pressed by a pressing device in the tablet.

Composition for use in aerosol form.

ComponentsNumber/ml
The active compound according to the invention3-150 mg*
Sodium chloride8.0 mg
Phosphate buffer (20 mm) pH 7.0**(in sufficient quantity)1,ml
* Depending on the degree of activity of the connection

** The pH value is regulated addition of sodium hydroxide solution (1 BC) or hydrochloric acid (10% wt./about.)

Method of preparation:

1. The active substance is dissolved in the buffer.

2. The obtained R is the target filtered through a filter with a pore size of 0.22 microns.

After spraying the resulting solution of the distribution of particle size is in the range 1-6 MK.

1. Derivatives thioamide formula I

where X denotes a group of the formula

where R15denotes halogen, (ness.)alkyl and PERFLUORO(ness.)alkyl;

R16denotes hydrogen, halogen and (ness.)alkyl;

or X represents a group of formula X-2

where Het denotes a 5 - or 6-membered heterobicycle ring containing 1 or 2 heteroatoms, which are selected N;

R15and R16have the values specified above for the X-1;

R30denotes hydrogen or (ness.)alkyl;

p denotes an integer from 0 to 1;

or X represents a group of formula X-3

where R18denotes aryl;

R19denotes an unsubstituted arylalkyl or heteroaromatic, which represents a 6-membered heteroaromatic ring containing in the quality of heteroatom atom N;

R20denotes unsubstituted (ness.)alkanoyl;

Y denotes a group of formula Y-1

where R22and R23independently of one another denote hydrogen, (n is ZS.)alkyl, halogen or PERFLUORO(ness.)alkyl and at least one of the radicals R22and R23does not denote hydrogen;

R24denotes hydrogen,

or Y represents the group Y-3

where R25denotes a group of formula R26-(CH2)e-,

R26means (ness.)alkoxy, (ness.)alkylthio, (ness.)alkylsulfonyl or R26denotes a group of formula-NR28R29where R28denotes hydrogen, R29means (ness.)alkanoyl or (ness.)alkylaminocarbonyl,

Q represents -(CH2)f-;

e denotes an integer from 0 to 4;

f denotes an integer from 1 to 3;

communication, indicated by the dashed line, may not necessarily be gidrirovannah;

and its pharmaceutically acceptable salts and esters.

2. The compound according to claim 1, where X denotes a group of the formula

and Y, R15and R16have the meanings indicated in claim 1.

3. The compound according to claim 2, in which R15and R16independently of one another represent chlorine or fluorine.

4. The compound according to claim 2, in which X 1 is chosen from the group

5. The connection p is 1, in which X represents a group X-2

where p, Y, R15, R16and R30have the meanings indicated in claim 1.

6. The compound according to claim 5, in which X 2 is chosen from the group

7. The compound according to claim 1, in which X denotes

and Y, R18, R19and R20have the meanings indicated in claim 1.

8. The connection according to claim 7, in which R18denotes phenyl.

9. The connection according to claim 7, in which R19means (ness.)alkyl, which is substituted by pyridium or phenyl.

10. The connection according to claim 7, in which R18denotes phenyl, R19means (ness.)alkyl, which is substituted by pyridium or phenyl, and R20means (ness.) alkanoyl.

11. The connection according to claim 7, in which R18denotes phenyl which may be unsubstituted or substituted with halogen or (ness.)alkoxygroup, and R19denotes phenyl(ness.)alkyl.

12. Connection by claim 11, in which X-3 are selected from the group

13. The compound according to claim 1, in which Y denotes

and X, R22, R23and R24have the meanings indicated in claim 1.

14. The connection indicated in paragraph 13, where Y-1 is chosen from the group

15. The compound according to claim 1, in which Y denotes a group of formula Y-3

and Y, R25and Q have the meanings indicated in claim 1; and the bond indicated by a dashed line, may not necessarily be gidrirovannah.

16. The connection indicated in paragraph 15, in which the connection indicated by the dotted line, gidrirovannah.

17. The connection 15 in which Y-3 are selected from the group

and

18. The compound according to claim 1, selected from the group including

4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-chloro-6-were)taxameter]-L-phenylalanine;

4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[(4-methylsulphonyl)butyl]cyclopentyl]taxometer]-L-phenylalanine;

4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-bromophenyl)taxameter]-L-phenylalanine;

4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-ethyl-6-were)taxameter])-L-phenylalanine;

4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[(2-forfinal)taxameter])-L-phenylalanine;

4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[2-(trifluoromethyl)phenyl]taxometer]-L-phenylalanine;

4-[(2S,4R)-3-acetyl-2-phenyl-4-[(3-pyridinyl)methyl]-5-Oxymetazoline-1-yl]-N-[(2-ethyl-6-were)taxameter]-L-phenylalanine,

4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[2-(acetylamino)ethyl]cyclopentyl]taxometer]-L-phenylalanine;

[[1-[2-[[(methylamino)carbonyl]amino]ethyl]cyclopentyl]taxometer]-4-[[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine;

4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-(2-methoxyethyl)cyclopentyl]taxometer]-L-phenylalanine;

4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[(4-methylsulphonyl)butyl]cyclobutyl]taxometer]-L-phenylalanine;

4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[(3-methylthio)propyl]t is Globotel]taxometer]-L-phenylalanine;

4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[(3-methylsulphonyl)propyl]cyclobutyl]taxometer]-L-phenylalanine;

4-[(2,6-dimethyl-3-pyridylcarbonyl)amino]-N-[[1-[(4-methylsulphonyl)butyl]cyclopentyl]taxometer]-L-phenylalanine;

4-[[[4-(trifluoromethyl)-5-pyrimidinyl]carbonyl]amino]-N-[[1-[(4-methylsulphonyl)butyl]cyclobutyl]taxometer]-L-phenylalanine;

4-[[(2,4-dimethyl)-6-trifluoromethyl-3-pyridinyl)carbonyl]amino]-N-[[1-[(4-methylsulphonyl)butyl]cyclobutyl]taxometer]-L-phenylalanine;

4-[(2S,4R)-3-acetyl-2-phenyl-4-[(3-phenyl)methyl]-5-Oxymetazoline-1-yl]-N-[[(4-methylsulphonyl)butyl]cyclopentyl]taxometer]-L-phenylalanine or

4-[(2R,4R)-3-acetyl-2-phenyl-4-[(3-phenyl)methyl]-5-Oxymetazoline-1-yl]-N-[[(4-methylsulphonyl)butyl]cyclopentyl]taxometer]-L-phenylalanine.

19. The compound according to any one of claims 1 to 18, designed for use as a drug for treatment or prevention of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and asthma.

20. The pharmaceutical composition intended for the treatment or prevention of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and asthma-containing compound according to any one of claims 1 to 18, or its pharmaceutically acceptable salt or ester in combination with a compatible pharmaceutical nose is Telem.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

The invention relates to 1,4 - and 1,3-disubstituted piperidines that have activity, stimulating the secretion of growth hormone by the pituitary gland of a mammal, and can find application in medicine

The invention relates to the use of compounds of formula I to obtain medical drug suitable for the treatment of asthma, seasonal or chronic allergic rhinitis, sinusitis, conjunctivitis, food Allergy, scombroid poisoning, psoriasis, urticaria, pruritus, eczema, rheumatoid arthritis, inflammatory bowel disease, chronic obstructive pulmonary disease, thrombosis and otitis and preferably asthma, seasonal and chronic allergic rhinitis

The invention relates to new imidazole derivative of the formula (I):where R1represents phenyl or pyridinyl, substituted by substituents selected from the group comprising (1) phenyl, (2) furyl, thienyl, (3) halogen, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted phenyl, (8) lower quinil, optionally substituted phenyl, (9) lower alkoxy, optionally substituted cyclo(lower)alkyl or phenyl, (10) lower alkyl, optionally substituted, phenyloxy or (11) amino, optionally substituted protected carboxyla; R2represents lower alkyl; R3represents halogen or lower alkyl; R4represents (1) lower alkenyl, optionally substituted phenyl, (2) phenyl, optionally substituted lower alkyl or lower alkenyl, (3) lower alkyl or (4) thienyl, optionally substituted with halogen; a represents a lower alkylene and L represents a simple bond, a lower albaniles or lower alkylene, optionally substituted phenyl or pyridinyl, or-X-CH2- where X represents O or NR5where R5represents hydrogen or n is

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to indole derivative of General formula I:

where R1represents hydrogen, halogen, methoxy; R2represents hydrogen, halogen, methyl, ethyl, methoxy; R3represents carboxy, tetrazolyl or CONHSO2R4in which R4represents methyl, ethyl, phenyl, 2,5-dimethylisoxazole, trifluoromethyl; T represents-CH2- or-SO2-; and ring a is 3-chlorophenyl, 4-chlorophenyl, 3-triptoreline, 3,4-dichlorophenyl, 3,4-differenl, 3-fluoro-4-chlorophenyl, 3-chloro-4-forfinal, 2,3-dichloride-5-yl; or their pharmaceutically acceptable salts or esters, as well as pharmaceutical compositions containing them

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to new derivatives of azetidine formula

in which R denotes an element of the formula

R1denotes a methyl radical or ethyl, R2denotes a naphthyl radical, hinely, phenyl, possibly substituted by one or more halogen atoms, alkyl radicals, alkoxyl, hydroxyl, etc.,, R3and R4identical or different, represent a phenyl radical, possibly substituted by one or more halogen atoms, alkyl, alkoxyl, formyl, trifluoromethyl, etc.,, R5denotes an alkyl radical or phenyl, substituted by one or more halogen atoms, R6and R7identical or different, denote a hydrogen atom or an alkyl radical, or R6and R7together with the nitrogen atom to which they are connected, form piperidinyl or pieperazinove cycle, substituted alkyl, R’6and R’7identical or different, denote a hydrogen atom or an alkyl radical, or R’6and R’7together with the nitrogen atom to which they are connected, form a pyrolidine or pieperazinove cycle, possibly substituted by one alkyl radical, cycloalkyl, -ALK-O-ALK, hydroxyalkyl, or R6and R7together with the nitrogen atom to which they are connected, form a loop imidazole, piperazinone, thiomorpholine, etc., R8denotes alkyl, R9denotes a hydrogen atom, an alkyl radical or an alkyl, substituted dialkylamino, phenyl, etc.,, R10and R11identical or different, denote a hydrogen atom or alkyl, R12and R13together with the nitrogen atom to which they are connected, form a loop of the research, a R16and R17together with the nitrogen atom to which they are connected, form a loop of piperidine, R’ denotes a hydrogen atom or the radical-CO-ALK, ALK denotes an alkyl or alkylene, and alkyl or alkylene radicals or their parts and CNS radicals or their parts are straight or branched chain, containing from 1 to 6 carbon atoms, and their optical isomers and their salts with mineral or organic acid

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

The invention relates to amide derivative of the formula I

< / BR>
in which R3stands WITH1-C6alkyl or halogen; Q1denotes heteroaryl, which is optionally substituted by 1, 2, 3 or 4 substituents selected from the group comprising hydroxy, halogen, trifluoromethyl, cyano, amino, C1-C6alkyl, C2-C6alkenyl,2-C6quinil,1-C6alkoxy, etc., R2denotes hydroxy, halogen, C1-C6alkyl, C2-C6alkenyl,2-C6quinil,1-C6alkoxy, p = 0, 1, or 2; q = 0, 1, 2, 3 or 4; and Q2denotes aryl, aryl-C1-C6alkoxy, aryloxy, arylamino, N-C1-C6alkylamino, aryl-C1-C6alkylamino, cycloalkyl, heteroaryl, heteroallyl, heteroaryl-C1-C6alkylamino or heterocyclyl and so on, or its pharmaceutically acceptable salt or cleaved in vivo ester

The invention relates to new salts of pyridinium General formula (I) or their pharmaceutically acceptable salts, where R1is-R4- R5or-N(R7)N(R7R9, R4choose from the group of-N(R7R6O-, N(R7R6N(R7), -OR6O-,

-OR SIG6N(R7)-, where R6- alkyl, R5choose from the group of alkyl, aryl, including heteroaryl, -COR7, -SO2R7and-COR10where R7Is H, alkyl or aryl, including heteroaryl, R2Is F, Cl, Br, J, alkyl, aryl, including heteroaryl, formyl, acyl, C(O)NR7R10or C(O)or SIG7, m = 0, 1, or 2, R3selected from the group comprising R7OR7N(R7)(R10) and CH(R7)C(O)R8, R8is R7OR7and NR7R10, R9is hydrogen, alkyl, aryl, including heteroaryl, -C(O)R10, -SO2R10, -C(S)OTHER10, -C(NH)NH(R10), -C(O)OTHER10, R10- H, alkyl, or aryl, including heteroaryl, and in each case, it is not necessarily different from R7X represents an ion halogen provided that 1) when two alkyl groups are the same carbon or nitrogen, they are not necessarily linked together with the formation of a cyclic structure, and (2) nitrogen heteroaryl ring R1

The invention relates to new compounds for combating pests, in particular derivatives carbanilide and fungicide-insecticidal tool based on them
The invention relates to a method (improved) obtain the N-nicotinoyl-aminobutyric acid, used as an intermediate product for the preparation of dosage forms of sodium salt of N-nicotinoyl-aminobutyric acid (picamilon) is a highly effective drug with neuroprotective effect and improves cerebral blood circulation

New benzamidomethyl // 2189973
The invention relates to new derivatives of benzamidomethyl formula (I), where R1- phenyl, naphthalene, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline, pyridine, hinzelin, cinoxacin, and aromatic and heteroaromatic ring can be substituted by the radicals R4; R2is hydrogen, chlorine, bromine, fluorine, alkyl, -NHCO-naphthyl, -NHSO2- C1-4-alkyl, -O-C1-4-alkyl, -CO-NH - C1-4-alkyl, NO2; R3is a hydrocarbon residue with 1 to 6 carbon atoms, which may carry cycloalkyl, indolenine, phenyl ring, or a residue group-SCH3-; R4- alkyl, -O-C1-4-alkyl, chlorine, fluorine, bromine, iodine, CF3, pyridine; X is a bond, - (CH2)m-, - (CH2)m-O-(CH2)0-, - (CH2)m-S-(CH2)o-, - (CH2)m-SO- (CH2)o-, - (CH2)m-SO2- (CH2)0-, -CH=CH-, -CC-, -CO-CH=CH-, -CH= CH-CO-, - (CH2)m-CO-(CH2)0-, - (CH2)m-NR5CO-(CH2)0-, (R5=H, C1-4-alkyl), - (CH2)m- CONR5-(CH2)0-, - (CH2)m-NHSO2-(CH2)0-, - (CH2)m-SO2NH-(CH2)0-, -N

The invention relates to new compounds of the formula (I)

< / BR>
where AG represents a radical selected from formulas (a) and (b) below:

< / BR>
R1represents a halogen atom, -CH3CH2OR SIG7, -OR SIG7, СОR8, R2and R3taken together form a 5 - or 6-membered ring, R4and R5represent H, a halogen atom, a C1-C10-alkyl, R7represents H, R8represents H orX represents the radical-Y-C-, r' and r" is H, C1-C10alkyl, phenyl, Y represents S(O)nor SE, n = 0, 1, or 2, and salts of compounds of formula (I)
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