Derivatives of acetic acid

 

(57) Abstract:

The proposed derivatives of acetic acid formula

< / BR>
where the values of L, M, Q and T are specified in paragraph 1 of the formula. The compounds may find use in the treatment or prevention of diseases caused by the binding of adhesive proteins to blood platelets, and platelet aggregation and adhesion of cells. The connection is produced by cleavage of the protective groups in the corresponding protected compounds or translation of a cyanic group in amedieval group in the corresponding NITRILES. 21 C.p. f-crystals, 1 table.

The invention relates to new derivatives of acetic acid, the method of production thereof, pharmaceutical preparations containing such compounds and to the use of these compounds in the manufacture of pharmaceutical preparations.

The invention relates in particular to a derivative of acetic acid formula

< / BR>
where L represents a group of formula L1-L5:

< / BR>
< / BR>
moreover, contained in group L and/or between groups L-M associated't amide type carbonyl group can be represented in the form of oxime,

A represents a group of formula A1-A4:

< / BR>
E1and E2alkyl)2C(O)OR1, OC(O)R1, OC(O)OR1or C(O)SR1and at least one of the E1and E2is H or

E1and E2together with the N atoms on which they are linked, represent a (5,5-dimethyl - or 5-oxo)-4,5 - dihydro-1,2,4-oxadiazol-3-yl group,

R1denotes lower alkoxy-lower alkyl, lower alkyl substituted by OH, COOH, lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoyloxy substituted under certain conditions on benzoyloxy or substituted by lower alkyl-CONH lower alkyl, or, under certain conditions, and substituted under certain conditions linked through the lowest alkylene phenyl, or under certain conditions torn O cycloalkyl, one of X and Y represents CH and the other represents CH, C-lower alkyl, C-lower alkoxy or N,

D represents a group (CH2)sor (CH2)tO,

s = 1-4,

m and n = 0-5, and

t = 0 to 3, but m+n = 1-5, and each of m+t and n+t is equal to at least 1,

p and q = 0-5, however, p + q = 2-5,

W1represents CH2, lower alkyl-CH, lower alkyl-OC(O)CH, NH, lower alkyl-N or lower alkoxy-lower alkyl-N,

W2denotes O, NH, acyl-N or lower alkyl-OC(O)-N,

G represents H or characterizing the under certain conditions, substituted lower alkyl, lower alkoxy, OCH2COOH or OCH2COO-lower alkyl 1,4-phenylene,

Q is oxygen, CH2, NH, acyl-N or lower alkyl-OC(O)N, T represents NH2, NH-lower alkyl, NH-lower alkyl (COOH or COO-lower alkyl), substituted lower alkoxy, COOH, COO-lower alkyl, lower alkyl-COO-or lower alkyl-OCOO lower alkyloxy or lower alkenylacyl or group OT', T' represents H, lower alkyl, under certain conditions linked through the lowest alkylene phenyl or pyridyl, or under certain conditions linked through the lowest alkylen and under certain conditions torn O, NH or NCOO-lower alkyl cycloalkyl, provided that

a) T' has a value other than H, lower alkyl and phenyl-lower alkyl, if

L represents a group of the formula

< / BR>
A represents a group of the formula

< / BR>
one of the E1and E2denotes hydrogen and the other denotes hydrogen, tert-butoxycarbonyl or benzyloxycarbonyl,

one of X and Y represents CH and the other represents CH or N and W1represents NH, lower alkyl-N or lower alkoxy-lower alkyl-N,

G has the above value,

M is connected via the N-atom with geography 1,4-piperidinyl, and

Q is oxygen the hat is a group of the formula L11L31or L41:

< / BR>
< / BR>
A represents a group of the formula A1< / BR>
< / BR>
one of the E1and E2denotes hydrogen and the other denotes hydrogen, tert-butoxycarbonyl or benzyloxycarbonyl,

one of X and Y represents CH and the other represents CH, C-lower alkyl, C-lower alkoxy or N,

R0and G0denote H or lower alkyl,

W4indicates C=O or C=NOH,

M represents, under certain conditions, substituted lower alkyl, lower alkoxy, OCH2COOH or OCH2COO-lower alkyl 1,4-phenylene and

Q is oxygen, CH2or NH,

as well as hydrate or solvate, and their physiologically acceptable salts.

In the framework of the present invention the definition of "lower" means a linear or branched group with the number of C-atoms 1-6, preferably 1-4. Thus, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and hexyl are examples of the lower alkyl; methoxy, ethoxy represent lower alkoxy; acetyl and propionyl represent the lowest alkanoyl. Methacryloyl is an example of lower alkanoyl and pentyloxy - example lower alkenylacyl.

Examples of the substituents of the phenyl group, R1can serve as g is UB>3-6-cycloalkyl as tetrahydropyranyl. Examples of the substituents contained in R1bentylbuy group are lower alkanoyloxy group, as acetoxy.

As examples, under certain conditions, related through the lowest alkylen and under certain conditions torn O, NH or NCOO-lower alkyl cycloalkyl groups T' can be called a group with 3-6 C-atoms in the cyclic fragment, as cyclopropylmethyl, cyclohexyl, tetrahydropyranyl, piperidinyl and N-(tert-butoxycarbonyl) piperidinyl.

The term "characterizing group-aminocarbonyl acid" refers to a group G in a natural or synthetic amino acid of the formula H2NCH(G)COOH. Contained in the natural amino acids of G represent methyl (alanine), isopropyl (valine), benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), CH2SH (cysteine). CH2OH (serine), 1-hydroxyethyl (threonine), etc., the Group G represents a further, for example, under certain conditions substituted by OH, SH, lower alkylthio, aryl, NH2, NH-RaN(Ra, Rbor ORathe group of lower alkyl, where Raand Rb- lower alkyl, lower alkoxy-lower alkyl, acyl or lower alkoxycarbonyl. it for example, phenyl or substituted by OH, NH2, NH-RaN(Ra, Rbor ORaphenyl. The above-mentioned acyl is, for example, the lowest alkanoyl, aroyl or heteroaryl, and aroyl is a related through CO, similarly decoded above aryl group as benzoyl or lower alkanoyloxy and heteroaryl - linked through CO, for example, 3-6-membered ring containing O or NH heteroaromatic group, as furoyl.

The compounds of formula I may be subject to solvation, in particular hydration. Hydration can be carried out during the implementation of the method of obtaining or can occur gradually as a consequence of hygroscopic properties initially anhydrous compound of formula I.

Examples of physiologically acceptable salts of the compounds of formula I are salts with physiologically compatible mineral acids as hydrochloric acid, sulfuric acid or phosphoric acid; or salts of organic acids, as methanesulfonate, acetic acid, triperoxonane acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The compounds of formula I with a free carboxyl group can form also salinah metals, ammonium salts and alkylamine, as a salt of sodium, potassium, calcium or Tetramethylammonium. The compounds of formula I can be represented in the form amphoteric ion.

The compounds of formula I containing one or more asymmetric C atoms can be represented in the form of the enantiomers, diastereomers or mixtures thereof, for example, in the form of racemates.

Proposed according to the invention compounds can be subdivided into the following groups:

a) group, where L is a group of L1in which a is a group A1and corresponds to the formula

< / BR>
where E1E2X, Y, W1, G, M, Q and T have the above meaning,

b) groups, where L is a group of L1in which a is a group A3and corresponds to the formula

I-B

where E1, m, n, D, W1, G, M, Q and T have the above meaning,

C) group, where L is a group of L1in which a is a group A2and corresponds to the formula

< / BR>
where E1X, Y, W1, G, M, Q and T have the above significance, in particular Q is oxygen, and T denotes OH or lower alkoxy,

g) group, where L is a group of L1in which a is a group in particular M denotes 1,4-phenylene, Q is oxygen and T denotes lower alkoxy,

d) group, where L is a group of L2in which a is a group A1and corresponds to the formula

< / BR>
where E1E2X, Y, W2, G, M, Q and T have the above significance, in particular M is connected via the N-atom with geography 1,4-piperidinyl, Q is oxygen and T denotes lower alkoxy,

e) group, where L is a group of L3in which a is a group A1and corresponds to the formula

< / BR>
where E1E2X, Y, G, M, Q and T have the above significance, in particular M is connected via the N-atom with geography 1,4-piperidinyl, Q is oxygen and T denotes lower alkoxy,

W) group, where L is a group of L4in which a is a group A1and corresponds to the formula

< / BR>
where E1E2X, Y, G, M, Q and T have the above significance, in particular M denotes 1,4-phenylene, Q is oxygen and T denotes lower alkoxy,

C) group, where L is a group of L5and corresponds to the formula

< / BR>
where E1E2, G, M, Q and T have the above significance, in particular M is connected via the N-atom with geography 1,4-piperidinyl, Q is oxygen and T are about such where L represents a group of the formula

L1< / BR>
A is a group A1, A2or A30:

< / BR>
one of the E1and E2denotes H and the other represents H, lower alkyl, OH, lower alkoxy, lower alkoxy-lower alkyl, carboxy-lower alkyl, PO(O-lower alkyl)2C(O)OR1or OC(O)OR1,

R1denotes lower alkoxy-lower alkyl, lower alkyl substituted by OH, COOH or a lower alkanoyloxy lower alkyl, or, under certain conditions, and substituted under certain conditions linked through the lowest alkylene phenyl, or under certain conditions torn O cycloalkyl, one of X and Y represents CH and the other represents CH or N,

m and n = 0-5, and t = 0 to 3, but m + n = 1-5, and each of m+t and n+t is equal to at least 1,

W1represents CH2, lower alkyl-OCOCH, NH, lower alkyl-N or lower alkoxy-lower alkyl-N,

G represents H or characterizing group - aminocarbonyl acid,

M has the same meaning as in formula 1 of the invention

Q - oxygen

T represents a group OT" and

T represents H, lower alkyl, lower alkoxy-lower alkyl or, under certain conditions, linked through the lowest alkylen and under certain conditions schego of alkyl, if

A represents a group of the formula

< / BR>
E1and E2denote hydrogen, tert.-butoxycarbonyl or benzyloxycarbonyl, X, Y, G, and Q have the above significance,

W1denotes NH, lower alkyl-N or lower alkoxy-lower alkyl-N and M is connected via the N-atom with geography 1,4-piperidinyl, and that

b) T has a value different from H, lower alkyl, phenyl and phenyl-lower alkyl, if

L represents a group of formula L11:

< / BR>
A represents a group of the formula

< / BR>
E1and E2denote hydrogen, tert-butoxycarbonyl or benzyloxycarbonyl, X, Y and Q have the above significance,

R0and G0denote H or lower alkyl and

M represents, under certain conditions, substituted lower alkyl, lower alkoxy, OCH2COOH or OCH2COO-lower alkyl 1,4-phenylene,

and their physiologically acceptable salts.

For the preferred compounds of formula I include those where one of the E1and E2represents H and the other represents H, OH, C (O) OR, or OC(O)OR1and/or where R1represents a lower alkyl as ethyl, butyl or isobutyl, lower alkoxy-lower ALK is cacoxenite, acetoxyethyl or pivaloyloxymethyl, or phenyl and/or

where one of X and Y represents CH and the other represents CH or N, and/or where W1denotes NH or CH2and/or where Q is oxygen or CH2and/or where

G represents H, lower alkyl like methyl or ethyl, or lower alkoxycarbonyl-lower alkyl, as ethoxycarbonylmethyl, and/or where M is a bound through the N-atom with geography 1,4-piperidinyl, 1,4 - phenylene or substituted on OCH2COO-lower alkyl, such as ethoxycarbonylmethoxy, 1,4-phenylene and/or

where T represents a lower alkoxy like methoxy, ethoxy, isopropoxy, isobutoxy, tert-butoxy or hexyloxy, lower alkoxy-lower alkoxy, such as methoxyethoxy, replaced by COO-lower alkyl lower alkenylacyl as 2-isobutoxide-2-pentyloxy, substituted lower alkyl-COO-lower alkoxy, such as pivaloyloxymethyl, substituted lower alkyl-OCOO lower alkoxy, 1-isopropoxycarbonyl-ethoxy, under certain conditions torn O cycloalkane as tetrahydropyranyloxy, which is connected through a lower alkylene pyridyl, as a 3 - or 4-pyridyloxy, or linked via a lower alkylene and under certain conditions torn NCOO-lower Alky vlahuta the following:

ethyl ester of (S)-4-[2-[4-[imino-2-(methoxy-ethoxycarbonyl)- methyl] -benzoylamine]-propionyl]-phenoxyalkanoic acid,

ethyl ester of (Z)-(R,S)-4-[2-[4-[amino-hydroxyimino - methyl]-benzoylamine]-propionyl]-phenoxyalkanoic acid,

tetrahydropyran-4-yl-ester (S)-4-[2-[4-(ethoxycarbonyl-imino - methyl)-benzoylamine]-propionyl]-phenoxyalkanoic acid,

ethyl ester of (Z)-(R,S)-4-[2-[4-[amino-ethoxycarbonylmethyl]- benzoylamine]-propionyl]-phenoxyalkanoic acid,

ethyl ester of (S)-4-[2-[4-(imino-phenoxycarbonylamino-methyl)- benzoylamine]-propionyl]-phenoxyalkanoic acid,

2-methoxy-ethyl ester (S)-4-[2-[4-[imino-(2-methoxy-ethoxy - carbylamine)-methyl]-benzoylamine]-propionyl]-phenoxyalkanoic acid,

ethyl ester of (Z)-(S)-4-[2-[4-(amino-hydroxyimino-methyl)- benzoylamine] -propionyl]-phenoxyalkanoic acid,

isopropyl ether (E/Z)-(S)-1-[2-[4-(amino-ethoxycarbonyl - methyl)-benzoylamine]-propionyl]-piperidine-4-biloxicasino acid,

isopropyl ether (E/Z)-(S)-1-[2-[4-(amino-hydroxyimino-methyl)- benzoylamine]-propionyl]-piperidine-4-biloxicasino acid,

isopropyl ester[1-[4-[4-(ethoxycarbonyl-imino-methyl)- phenyl]-4-oxo-butyryl]-piperidine-4-yloxy]-acetic to the piperidine-4-yloxy]-acetic acid and above all,

ethyl ester of (E/Z)-(S)-1-[2-[4-(amino-hydroxyimino-methyl)- benzoylamine]-propionyl]-piperidine-4-biloxicasino acid,

and from the following groups:

(R/S)-1-isopropoxycarbonyl-ethyl ester (Z)-(S)-[1- [2-[4-(amino-hydroxyimino-methyl)-benzoylamine] -propionyl]- piperidine-4-yloxy]-acetic acid,

pyridine-3-ymetray ether (R)-(E)/(Z)-[1-[4-[4-(amino - hydroxyimino-methyl)-phenyl]-2-methyl-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid,

pyridine-4-ymetray ether (R)-(E)/(Z)-[1-[4-[4-(amino - hydroxyimino-methyl)-phenyl]-2-methyl-4-oxo-butyryl]-piperidine - 4-yloxy]-acetic acid,

tert-butyl ether (E)- or (Z)-(RS)-3-[1-[(R)-4-[4-(amino - hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo-butyryl]-piperidine-4-intoxicatedly] -piperidine-1-carboxylic acid,

ethyl ester (R)-[1-[4-[4-(benzyloxycarbonylamino - imino-methyl)-phenyl]-2-methyl-4-oxo-butyryl]-piperidine-4-yloxy] -acetic acid,

ethyl ester (R)-[1-[4-[4-(imino-pivaloyloxymethyl - methyl)-phenyl]-2-methyl-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid,

tert-butyl ether (E)- or (Z)-(R)-4-[1-[4-[4-(amino-hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4 - intoxicatedly]-piperidine-1-carboxylic acid,
usnei acid and

acetoxymethyl ether (S)-4-[2-(4-ethoxycarbonylmethoxy-phenyl)- 1-methyl-2-oxo-ethyl-carbamoylmethyl]-piperidine-1-carboxylic acid.

Other examples of compounds of formula I are the following:

cyclopropylmethoxy ether (S)-4-[2-[4-(amino-imino-methyl)- benzoylamine] -propionyl]-phenoxyalkanoic acid,

cyclohexyloxy ether (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] - propionyl]-phenoxyalkanoic acid,

ethyl ester of (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine]-3 - hydroxy-propionyl]-phenoxyalkanoic acid,

(S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -3-(4-methoxy-phenyl)- propionyl]-venexiana acid,

ethyl ester of (2S,3R)-4-[2-[4-(amino-imino-methyl)-benzoylamine]-3 - hydroxybutyryl]-phenoxyalkanoic acid,

2-methoxy-ethyl ester (S)-4-[2-[4-(amino-imino-methyl)- benzoylamine] -propionyl]-phenoxyalkanoic acid,

ethyl ester of (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine]-3 - acetoxy-propionyl]-phenoxyalkanoic acid,

ethyl ester of (R,S)-4-[2-[4-(ethoxycarbonyl-imino-methyl)- benzoylamine]-3-methylsulfanyl-propionyl]-phenoxyalkanoic acid,

ethyl ester of (S)-4-[2-[4-(diethoxyphosphoryl-imino-methyl)- benzoylamine]-propionyl]-phenoxyalkanoic acid,

-propionyl]-piperidine - 4-biloxicasino acid,

(E/Z)-(S)-4-[2-[4-(amino-ethoxycarbonylmethyl)-benzoylamine] - 3-(4-isopropoxycarbonyl-piperidine-1-yl)-3-oxo-propyl]- phenyl ester 2-amino-benzoic acid,

(E/Z)-(S)-4-[2-[4-(amino-ethoxycarbonylmethyl)-benzoylamine] - 3-(4-isopropoxycarbonyl-piperidine-1-yl)-3-oxo-propyl]- phenyl ester furan-2-carboxylic acid,

(E/Z)-(S)-4-[2-[4-(amino-ethoxycarbonylmethyl)-benzoylamine] - 3-(4-isopropoxycarbonyl-piperidine-1-yl)-3-oxo-propyl]- phenyl ester 2-acetoxy-benzoic acid,

tetrahydropyran-4-yl-ester (S)-1-[2-(5-amino-imino-methyl-pyridine - 2-ylcarbonyl)-propionyl]-piperidine-4-biloxicasino acid,

isopropyl ether (S)-1-[2-(5-aminomethyl-pyridine-2-ylcarbonyl)- 3-(4-methoxyphenyl)-propionyl]-piperidine-4-biloxicasino acid.

Derivatives of acetic acid according to the invention can be obtained in the following way: a) in the compound of formula II

< / BR>
where L0represents a group of formula L10-L50< / BR>
< / BR>
in which A0is A group containing a protected amino group or amedieval group, a a, W1, W2, G, M, Q and T have the above value, and A01is protected amedieval group /BR>< / BR>
where L100represents a group of formula L101-L501< / BR>
< / BR>
where A100is A group containing a free amedieval group, a a, W1, W2, G, M, Q and T have the above meaning,

or salts of these compounds are free amedieval group transform in amedieval group substituted by a group E1or E2or

the compound of formula IV

< / BR>
where L11represents a group of formula L111-L115< / BR>
< / BR>
< / BR>
in which X, Y, W1, W2, G, M, Q and T have the above value contained in L11cyanic group transform in substituted under certain conditions on the E1or E2amedieval group or

g) amine of the formula

< / BR>
where R2represents H, lower alkyl or lower alkoxy-lower alkyl, a G, M, Q and T have the above meaning, is subjected to the interaction with the acid A-COOH or its functional derivative and

d) optionally contained in the compound of formula I of the reactive functional group and modify

e) if necessary, the compound of formula 1 is transferred in a physiologically compatible salt or salt is connected is rmula II split protected amino group, accordingly ajdinovic groups A0are NH-Boc and NH-Z, C(NH)NH-Boc, C(N-Boc) - N(Boc)2C(N-Boc) - NH-BocH C(NH)NH-z Protected BOC amino group and amidinov groups can be split, for example, using acid as formic acid or triperoxonane acid, optionally in a solvent as dichloromethane, at a temperature of up to 40oC, preferably at room temperature. Contained in the group A0a hydroxyl group can also be protected by tri-lower alkyl-Sieniawa group as tert-butyl-methyl-silanes. Such groups can be split using tetrabutylammonium fluoride in a simple ether like diethyl ether and/or THF, at temperatures up to 40oC, preferably at room temperature.

The reaction transformation b) contained in the compound of formula III or its salts, for example, triptoreline free amedieval group in amedieval group substituted by a group E1or E2may be carried out in a solvent as dichloromethane, optionally in the presence of a base, as NaHCO3or Na2CO3interacting with the compound of the formula R1OC(O)Cl or ClP(O) (O-lower alkyl)2.

For the transformation of the cyanide group in the and a nitrile of the formula IV in pyridine and triethylamine can be subjected to interaction with H2S and obtained H2NC (S) substituted on thiocarbamoyl connection, for example, acetone, metilirovanie use under the conditions at the boiling point corresponding to HN=C(SCH3) substituted on methylthiopyrimidin connection. The interaction of the latter with the compound E-NH2where E represents H, lower alkyl or lower alkoxy-lower alkyl, or additive acid salt of this compound, as the hydrochloride or acetate, in a solvent like THF or methanol, by heating, preferably to the boiling temperature of the reaction mixture, receive appropriate amidin formula I. When the exchange reaction between the nitrile of formula IV and hydroxylamine hydrochloride carried out in a solvent like methanol or DMSO, in the presence of a base, as methanolic sodium or triethylamine, produces the corresponding compound of formula I, where A (L) contains gidrauxilirovaniu amedieval group.

The reaction of transformation of g) it is advisable to use salt, such as hydrochloride, amine of formula V in the presence of a base like pyridine, in a solvent, as a simple ether, at temperatures of up to 40oC, preferably at room temperature.

Contained in the floor is but split by acid, as, for example, formic acid, to the carboxyl group.

As functional modifications reactive groups according to variant d) method used (1) the splitting of the lower alkoxy-carbonyl groups, as COOT1; (2) cleavage, for example, contained in the group G (L) ester groups; (3) the transformation is contained in the group A1(L) or L5unsubstituted amedieval group (E1= E2=H) substituted amedieval group; (4) the transformation is contained in the group A1(L) or L5hydroxyl group (one of the E1and E2represents OH, and the other is H) in R1OC(O) O-group.

These reactions can be carried out by well-known methods. For example, the decomposition (1) can be carried out in a solvent, such as water low alkanol, for example, aqueous methanol or ethanol, using a base as sodium hydroxide; the splitting (2) ether groups as tert-butoxypropan, can be carried out in dichloromethane with triperoxonane acid; reaction of transformation (3) and (4) can be carried out in a solvent as dichloromethane, in the presence of NaHCO3or Na2CO3using the compounds of formula R1OC(O)Cl or DMF in the presence of Tr is eficacia carboxyl groups in the acid of the formula I (T=OH), etherification is contained in the group G (L) hydroxyl group to aminobenzoate, pyrolox-, acetoxy - or acetoxybenzoic, the removal of hydroxyl groups contained in the group A (L) gidroksilirovanii amedieval group and conversion are contained in group L and/or between L and M, connected not by the type of amide bond group O=C= group HON=C= can be implemented, as described in the examples by well-known methods.

Contained in the group A (L) gidrauxilirovannaya medinova group can be transformed in acetone using formic acid when heated, respectively, in the presence of methylmorpholine in dichloromethane using triphosgene when it is cooled (5,5-dimethyl-, 5-oxo)-4,5-dihydro-1,2,4-oxadiazol-3-idgruppo. The transformation is contained in the group A (L) amedieval group substituted with-C(O)-SR1amedieval group can be carried out in dichloromethane in the presence of NaHCO3using appropriate chlorothioformate ClC(O)SR1.

Contained in the group of the formula L N-substituted group A3or A4where E1represents H, can be converted first using acrylic-nitrile in ethanol to the corresponding 2-UP>3or A4in dichloromethane to transform using m-chlorbenzoyl acid to the corresponding N-hydroxy-substituted group A3or A4where E1represents OH.

The compounds of formula II can be obtained by well-known methods. So, those compounds in which L is a N-containing group L10and Q denotes O and which correspond to the formula

< / BR>
where A0, G, M and T have the above value, a R2represents H, lower alkyl, lower alkoxy-lower alkyl, can be obtained from compounds of formula VI

< / BR>
where W represents a protective group Boc, a R2, G and M have the above significance,

through the compounds of formula

< / BR>
The reaction from VI to V-A can be carried out with the help of bromide BrCH2C(O)T in the presence of a base, as K2CO3in a solvent like DMF. The removal of the protective group W in the compound of formula V-A receive connection formula V. the compound or additive salt of the acid, for example, hydrochloride, interaction with the functional derivative of the acid (A)0COOH, for example, acid chloride, in the presence of a base like N-methylmorpholine, in a solvent like THF, transformer the military 1,4-phenylene, known or can be obtained by known methods, for example, from compounds of formula VII

< / BR>
through the compounds of formula VI-A,

< / BR>
where R3, R4and R5represent lower alkyl. The reaction from VII to VI-A can be accomplished using bromide Br-M-OSi(R3,R4,R5in the solvent as THF, at low temperatures, for example at -78oC, in the presence of n-utility in hexane. After removal of Sieniawa group, for example, in a solvent like diethyl ether with tetrabutylammonium fluoride in THF receive the compound of formula VI.

The compounds of formula V-A, where M represents a 1,4-piperidinyl, can be obtained by the interaction of the acid of formula VIII with an amine of the formula IX

< / BR>
Such compounds V-A can be transferred via the compounds of formula V into the corresponding compounds of formula II, where M represents a 1,4-piperidinyl.

The NITRILES of the formula IV can be obtained, for example, the interaction of the compounds of formula V-A (after removal of the protective group W) with the acid chloride

< / BR>
The NITRILES of the formula IV, where M represents a 1,4-piperidinyl, can also be obtained by the interaction of the activated 2-chloro-4,6-dimethoxy-the teachings of NITRILES of the formula IV is the ketone of formula XI is subjected to interaction with the bromide of formula XII

< / BR>
where T2represents lower alkyl, and X, Y, G, M and T1have the above significance. In one embodiment, the acid chloride of formula X via an ester of formula XI, where T2represents tert-butyl, using a bromide of formula XII is transferred to the compound of formula XIII

< / BR>
and tert-butoxycarbonyl group of compounds XIII otscheplaut.

By hydrogenation of the nitrile of the formula IV, where W1(L11) represents NH, N-lower alkyl or lower alkoxy-lower alkyl-N, for example, in the presence of Pd/C catalyst in methanol/water/acetic acid to obtain the compound of formula I, in which group A (L) has the formula A01< / BR>
< / BR>
Substituted in L11on the CYANOGEN source acid L11-COOH can be obtained by reaction of Sandmeyer using the appropriate substituted on the amino acid. The original acid of the formula L115-COOH can be obtained on the basis of 4-zenosociology acid via the compounds of formula

< / BR>
In addition, in some of the following examples are provided to more detailed data regarding the receipt of certain raw materials and premiumecigarette and von Willebrand factor to the fibrinogen receptor of blood platelets (glycoprotein IIb/IIIa), and their linking and binding of other adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various cell types. Thus these compounds have an effect on the interaction of cell-cell and cell - matrix. They prevent primarily education trombozitemii of blood clots and can be used to fight, accordingly, the treatment of diseases such as thrombosis, cerebral hemorrhage, myocardial infarction, inflammation and arteriosclerosis. In addition, these compounds have an effective impact on cancer cells, preventing the spread of metastasis. Thanks to this, they can also be used as anticancer agents. Further, they promote more rapid healing of wounds. Because they also inhibit bone resorption, they can also be used in the treatment of osteoporosis.

The active compounds according to the invention is confirmed by the following experimental data:

After oral administration of a mouse of one of the compounds according to the invention the plasma or diluted plasma (1 part) was mixed with platelet-rich plasma of man (BTP man 3 parts). The volume of plasma mouse trabulse is ekamatra. This amount (IC50) divided by the total volume of the mixture and was multiplied by the dose. Extrapolated in this way the values of the IC50shown in the table correspond to the dose of the test substance, which must be assigned for oral administration for 50% inhibition induced ADP ex vivo platelet aggregation in BTP person.

As mentioned above, drugs, containing one of the compounds of formula I, its MES or its salt, are also subject of the present invention. The subject of the invention is also a method of obtaining such medicines, which differs from one or more of the above mentioned compounds, optionally with the addition of one or more other therapeutic valuable substances, produce drugs in galenical form. Medicines can be prescribed for enteral, e.g. oral, injection in the form of tablets, lacquered tablets, coated tablets, terdoslavich and megkozeliteni capsules, solutions, emulsions or suspensions, or for rectal administration, for example, in the form of suppositories; or in the form of aerosols. However, the introduction can be parenteral, for example, in the form goalachiever capsules the active substance can be mixed with pharmaceutically inert, inorganic or organic excipients. As such for tablets, pills and terdoslavich capsules can be used, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts. As excipients for megkozeliteni capsules are suitable, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; however, in the manufacture megkozeliteni capsules depending on the characteristics of the active substance at all possible to do without the excipients. For the manufacture of solutions and syrups as excipients can be used water, polyols, saccharose, invert sugar and glucose; for injection solutions can be used, for example, water, alcohols, polyols, glycerine and vegetable oils, and suppositories are suitable, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. The pharmaceutical preparations may contain, in addition, and preservatives, substances that promote solubility, stabilizers, moistening agents, emulsifiers, chemicals, improves taste, colorants, flavoring agents, salts for modifying the osmotic pressure, buffers, membranes or antioxidants.

During treatment, a wide range that depends, of course, in each case on the individual characteristics of the patient. For oral administration to an adult patient should basically be prescribed daily dose of about 0.1-20 mg/kg, preferably 0.5 to 4 mg/kg, with, however, the specified upper limit can also be exceeded if it would be appropriate to increase the efficiency.

Example 1

In a solution of 0.5 g of ethyl ester of (S)-4-(2-tert - butoxycarbonylamino-3-phenylpropionyl)-phenoxyalkanoic acid in 2.5 ml dichloromethane add 0.2 ml of attributively in 2 ml dichloromethane and stirred for 15 min at room temperature. Then the reaction solution is treated with 30 ml of HCl in methanol (4H) and concentrate. The residue is dissolved in 5 ml of pyridine and mixed with 275 mg of the hydrochloride of p-amidinopropane for 24 h at room temperature. The suspension is filtered by suction, the mother liquor is concentrated and the residue after evaporation chromatographic on Siciliana silica gel RP 18 using gradient THF/water. The result 222 mg of methyl ester hydrochloride (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -3 - phenyl-propionyl]-phenoxyalkanoic acid, []2D0= +31,1o(C=1, methanol).

oC when removing water add 29 ml of tert-utility (1.4 M in pentane) and stirred for 15 min at -78oC. Then the solution is treated at -78oC 4 g (S)-2-tert-butoxycarbonylamino-N-methoxy-N-methyl-3-phenylpropionamide in 40 ml of THF, stirred for 1 h at -78oC and poured into 300 ml of 1 M phosphoric acid. The aqueous phase is extracted with simple ether, the ether phases are washed with saturated NaCl solution, dried and concentrated. After chromatography of the residue from evaporation on silica gel (hexane/acetic ether 9: 1) obtain 2.95 g of tert-butyl methyl ether (S)-[1-benzyl-2-(4-tert-butyl-dimethyl-silyloxy-phenyl)-2 - oxo-ethyl]-carbamino acid as a colourless oil, []2D0= +40,3o(C=0.8, chloroform).

b) a Solution of 2.24 g of the product from a) in 30 ml of THF is mixed with 0.75 g of cesium fluoride in 2.5 ml of water for 16 h at room temperature and concentrate. After chromatography of the residue on silica gel (hexane/acetic ether 2: 1) receive 2,47 g tert-butyl ether (S)-[1-benzyl-2-(4-hydroxy-phenyl)-2-oxo-ethyl] - carbamino acid, []2D0= +67,0o(C = 0,7, chloroform).

C) Suspension from 2,44 g of the product from b), 2,39 g ethylbromoacetate and of 2.97 g of potassium carbonate in 20 ml Contentresult. After chromatography of the residue on silica gel (hexane/acetic ether 5:1) get 7,44 g of ethyl ester of (S)-4-(2 - tert-butoxycarbonylamino-3-phenyl-propionyl)-phenoxyalkanoic acid, []2D0= +40,6o(C=1, chloroform).

Example 2

A solution of 263 mg of 2-methoxy-ethyl ester 4-tert-butoxycarbonylamino-phenoxyalkanoic acid in 10 ml dichloromethane and 5 ml triperoxonane acid is stirred for 2 h at room temperature and concentrate. The residue is suspended in a simple ether, the crystals are filtered by suction, dissolved in 5 ml of pyridine and stirred with 219 mg of the hydrochloride of amidinopropane for 18 h at room temperature. After concentrating the reaction solution and chromatography of the residue on Siciliana silica gel RP 18 (gradient THF/water) to obtain 35 mg of 2-methoxy-ethyl ester 4-[4-(amino-imino - methyl)-benzoylbenzoate] -phenoxyalkanoic acid, MS (EI - e bombardment): 414 (M+H)+< / BR>
The source material was obtained as follows:

a) a Suspension of 476 mg of tert-butyl methyl ether (R,S)-2-hydroxy-2-(4-hydroxyphenyl)-ethylcarbamate acid, 287 mg (2-methoxy-ethyl)-CHLOROACETATE and 260 mg of potassium carbonate in 13 ml of DMF is stirred during the power of a simple ester, the ether phases are washed with saturated NaCl solution, dried and concentrated. After chromatography of the residue on silica gel (hexane/acetic ester 1:2) to obtain 349 mg of 2-methoxy-ethyl ester (R, S)-4-(2-tert-butoxycarbonylamino - 1-hydroxy-ethyl)-phenoxyalkanoic acid, MS (EI):312 (M-57).

b) By oxidation of 316 mg of the product from a) in 10 ml of dichloromethane with 224 mg pyridinecarboxamide for 3 h at room temperature obtained after concentration of the reaction solution and chromatography on silica gel (hexane/acetic ester 1: 1, 1:2) 284 mg of 2-methoxy-ethyl ester 4-tert-butoxycarbonylamino-phenoxyalkanoic acid, MS (EI): 294 (M-73).

Example 3

A solution of 550 mg cyclopropylmethanol ether (S)-4-(2-tert-butoxy-carbylamine-propionyl)-phenoxyalkanoic acid in 10 ml of dichloromethane is stirred with 0.2 ml of trimethylsilylmethyl for 15 min at 0oC, treated with 0.5 ml of HCl in dioxane (4 M) and concentrate. The residue is subjected analogously to example 1 interaction with 330 mg of the hydrochloride of p - amidinopropane. After chromatography of the crude product on Siciliana silica gel RP 18 (gradient THF/water) receive 313 mg of the hydrochloride and hydroiodide cyclopropylmethanol ether (S)-4- [2-[4-(amino-imino-UB>D0= +56,6o(C=0,5, DMSO).

The source material can be obtained in the following way:

a) In a solution of 43,05 g of p-bromo-tert-butyldimethylsilyloxy in 150 ml of THF at -78oC when the removal of water is added dropwise 94 ml of n-utility (1.6 M in hexane) and stirred for 15 min at - 78oC. and Then for 30 min at -78oC add to 11.61 g (S)-2-tert-butoxycarbonylamino-N-methoxy-N-methyl-propionamide in 150 ml of THF, and then stirred for 0.5 h at -78oC and the reaction mixture is poured into 400 ml of 1 M phosphoric acid. The aqueous phase is extracted with simple ether, the ether phases are washed with saturated NaCl solution, dried and concentrated. After chromatography of the residue from evaporation on silica gel (hexane/acetic ether 9:1) get 17,85 g tert-butyl ether (S)-1-(4-tert-butyl-dimethyl - silyloxy-benzoyl)-ethylcarbamate acid as a colourless oil, Rf=0,43 (hexane/acetic ether 5:1).

b) In a solution of 17,85 g of the product from a) in 180 ml of simple ether added 47 ml of tetrabutylammonium fluoride (1 M in THF) and stirred for 1 h at room temperature. The reaction solution is extracted using 1 M phosphoric acid, washed with saturated NaCl solution, dried and Kona TPL166-168oC []2D0= +24,9o(C=1, chloroform).

the Interaction of 400 mg of the product from b) with cyclopropylmethanol analogously to example 1B) after chromatography on silica gel (hexane/acetic ether 3: 1) obtain 580 mg cyclopropylmethanol ether (S)-4-(2-tert-butoxycarbonylamino - propionyl)-phenoxyalkanoic acid, []2D0= +12,4o(C=0.9, chloroform).

Example 4

Analogously to example 3, 500 mg of cyclohexylurea ether (S)-4-(2-tert - butoxycarbonylamino-propionyl)-phenoxyalkanoic acid is subjected to the first interaction with 0.17 ml of trimethylsilylmethyl, and then with 320 mg of the hydrochloride of p-amidinopropane and after chromatography on Siciliana silica gel RP 18 (gradient THF/water) to obtain 330 mg of the hydrochloride and hydroiodide (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] - phenoxyalkanoic acid (1,06), respectively (1: 0,4), TPL110oC []2D0=+56,7o(C=0,55, DMSO).

The source material can be obtained in the following way:

The interaction of 530 mg of tert-butyl methyl ether (S)-1-(4-hydroxy - benzoyl)-ethylcarbamate acid with 660 mg of cyclohexylpropionate analogously to example 1B) after chromatography-propionyl)-phenoxyalkanoic acid, []2D0= +12,0o(C = 0,5, chloroform).

Example 5

Analogously to example 3 680 mg tetrahydropyran-4-silt ether (S)-4-(2-tert-butoxycarbonylamino-propionyl)- phenoxyalkanoic acid is subjected to the first interaction with 1.7 ml of trimethylsilylacetamide (1 M in dichloromethane), and then with 438 mg of the hydrochloride of p-amidinopropane and after chromatography on Siciliana silica gel RP 18 (gradient THF/water) to obtain 430 mg of the hydrochloride and hydroiodide tetrahydropyran-4-silt ether (S)- 4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid (1: 0,8), respectively (1:0,4), []2D0= +50,3o(C=1, dimethylsulfoxide).

The source material can be obtained in the following way:

a) Interaction of 530 mg of tert-butyl methyl ether (S)-1-(4-hydroxybenzoyl)-ethylcarbamate acid with 670 mg of 4-tetrahydropyranyl-bromoacetate analogously to example 1B) after chromatography on silica gel (hexane/acetic ether 2: 1) receive 736 mg tetrahydropyran-4-silt ether (S)-4-(2-tert-butoxycarbonylamino - propionyl)-phenoxyalkanoic acid, []2D0=+11,1o(C= 0,7, chloroform).

Example 6

A solution of 120 mg of methyl ester hydrochloride (S)-4-[2-[4- (and what of anola and 5 ml of water is stirred for 1 h 15 min at room temperature, acidified with 1H HCl and concentrated. After chromatography of the residue on Siciliana silica gel RP 18 (gradient THF/water) to obtain 60 mg (S)-4-[2-[4-(amino-imino-methyl)- benzoylamine]-3-phenyl-propionyl] -phenoxyalkanoic acid, TPL>200oC, MS (ion bombardment): 446 (M+H)+.

Example 7

The interaction of 800 mg of ethyl ester of 4-[(S)-3-tert-butoxy-2 - tert-butoxycarbonylamino-propionyl]-phenoxyalkanoic acid 450 mg trimethylsilylmethyl and 497 mg of the hydrochloride of p-amidinopropane analogously to example 3 after chromatography on Siciliana silica gel RP 18 (gradient THF/water) to obtain 540 mg of the hydrochloride (1:0.5) and hydroiodide (1:0,4) ethyl ester of 4-(S)-2-[4-(amino-imino - methyl)-benzoylamine]-3-tert-butoxy-propionyl]-phenoxyalkanoic acid, TPL144oC []2D0= +34,2o(C=0,5, DMSO).

The source material can be obtained in the following way:

a) a Suspension of 10 g of salt of N-tert-butoxycarbonyl-O-tert-butyl - L-serine-dicyclohexylamine in 100 ml of THF is mixed with 5.5 ml of N-methylmorpholine, 10.3 g HBTU (hexafluorophosphate O-benzotriazol-1-yl-N,N,N',N'-tetramethylurea) and 2.2 g of the hydrochloride of N,O-dimethylhydroxylamine for 21 h at room temperature and concentrate. After hxi-1-(N-methoxy-N-methyl-carbarnoyl)- ethylcarbamate acid, []2D0= +18,6o(C=0,65, chloroform).

b) a Solution of 3.7 g of the product from a) analogously to example) is subjected to interaction of 7.82 g of p-bromo-tert-butyldimethylsilyloxy and 26 ml of tert-utility (1.4 M in pentane). After chromatography of the residue on silica gel (hexane/acetic ether 5:1) receive 3.58 g of tert-butyl methyl ether (S)-2-tert-butoxy-1-(4-tert-butyl-dimethyl - silyloxy-benzoyl)-ethylcarbamate acid, []2D0= +28,3o(C = 0.6, chloroform).

C) Cleavage silylamines group of 2.5 g of the product from b) with 840 mg of cesium fluoride is carried out according to example 1B). After chromatography on silica gel (hexane/acetic ether 3:1) to obtain 1.08 g of tert-butyl

ether (S)-2-tert-butoxy-1-(4-hydroxy-benzoyl)-ethylcarbamate acid, []2D0=+41,5o(C=1, chloroform).

g) the Interaction of 1 g of the product from b) with 0.5 ml of ethylbromoacetate and of 1.23 g of potassium carbonate analogously to example 1B) after chromatography on silica gel (hexane/acetic ether 3:1) to obtain 1.19 g of ethyl ester of 4-[(S)-3-tert-butoxy-2-tert-butoxycarbonylamino-propionyl] - phenoxyalkanoic acid, []2D0= +27,3o, (C=0.8, chloroform).

Example 8

Analogichny acid is subjected to interaction with, and 0.28 ml of trimethylsilylmethyl and 450 mg of p-amidinopropane and the crude product chromatografic on Siciliana silica gel RP 18 (gradient THF/water). The result 272 mg hydrochloride (1:0.3) and hydroiodide (1: 0,3) ethyl ester of (S)-4-[2-[4-(amino - imino-methyl)-benzoylamine] -3-(4-methoxy-phenyl)-propionyl] - phenoxyalkanoic acid, TPL129oC. []2D0= +20,0o(or = 0.6, DMSO).

The source material can be obtained in the following way:

a) Interaction of 3.5 g of tert-butyl methyl ether (S)-1-(N-methoxy - N-methyl-carbarnoyl)-2-(4-methoxy-phenyl)-ethylcarbamate acid and 8.9 g of p-bromo-tert-butyldimethylsilyloxy and 22.2 ml of tert - utility (1.4 M in pentane) according to For example), and after chromatography of the residue from evaporation on silica gel (hexane/acetic ether 5:1) get 3,66 g tert-butyl ether (S)-1-[4-(tert-butyl - dimethyl-silyloxy)-benzoyl] -2- (4-methoxy-phenyl)-ethylcarbamate acid, []2D0= +23,8o(C=0,5, chloroform).

b) a Solution of 2.5 g of the product from (a) process (the removal of protective group) is similar to that described in example ZB). After chromatography on silica gel (hexane/acetic ether 3:1, 2:1) obtain 1.42 g of tert-butyl methyl ether (S)-1-(4-hydroxy-benzoyl) -2-(4-methoxy-phenyl)-ethylcarbamate acid, TPL133-135oC []2D0= +47,3o(C=0.9, chloroform).

in) Saimei residue on silica gel (hexane/acetic ether 2: 1) get to 1.21 g of ethyl ester of (S)-4-[2-tert - butoxycarbonylamino-3-(4-methoxy-phenyl)-propionyl]-phenoxyalkanoic acid, TPL95-97oC []2D0= +22,6o(C = 0,5, chloroform).

Example 9

A solution of 300 mg of the hydrochloride (1:0.5) and hydroiodide (1:0,4) ethyl ester of (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -3 - tert-butoxy-propionyl]-phenoxyalkanoic acid in 3 ml of dichloromethane is treated with 1 ml triperoxonane acid, stirred for 4 h at room temperature and concentrate. After chromatography of the residue on silica gel (chloroform/ethanol/water 60:30:5) receive 100 mg of triptoreline ethyl ester (S)-4-[2-[4-(amino-imino-methyl) -benzoylamine]-3-hydroxy-propionyl]-phenoxyalkanoic acid, []2D0=+52,0o(C=0.3,and dimethyl sulfoxide).

Example 10

A solution of 260 mg of ethyl ether (S)-4-[2-(4-tert-butoxycarbonylamino-benzoylamine)- propionyl] -phenoxyalkanoic acid in 3 ml of dichloromethane and 1.5 ml triperoxonane acid is stirred for 1 h at room temperature and concentrate. Balance is 260 mg of ethyl ether (S)-4-[2-(4-aminomethyl-benzoylamine)-propionyl] - phenoxyalkanoic acid, []2D0= +43,0o(C = 0.3, and DMSO).

The source material can be obtained in the following way:

a) Interaction of 530 mg of tert-putilovo is matography on silica gel (hexane/acetic ether 5:1) receive 582 mg of ethyl ester of (S)-4-(2-tert-butoxycarbonylamino-propionyl)-phenoxyalkanoic acid, []2D0= -1,8o(C = 0,5, ethanol).

b) By processing (cleavage of the protective group) 620 mg of the product from a) analogously to example 3 to obtain hydrochloride of the ethyl ester of (S)-4-(2-amino-propionyl)-phenoxyalkanoic acid, which as a crude product is subjected to further transformation. A solution of 443 mg 4-tert-butoxycarbonylamino-benzoic acid and 0.43 ml of N-methylmorpholine in 5 ml of THF is treated at 0oC 800 mg HBTU, stirred for 1 h at 0oC and then add 0.3 ml of N-methylmorpholine and the above ethyl ester (S)-4-(2-amino-propionyl)-phenoxyalkanoic acid dissolved in 6 ml of THF. After stirring for 3.5 h at room temperature the solution is concentrated and the residue chromatographic on silica gel (hexane/acetic ester 1:1). As a result, 463 mg of ethyl ether (S)-4-[2-(4-tert-butoxycarbonylamino - benzoylamine)-propionyl] -phenoxyalkanoic acid, []2D0= +50,0o(C = 0,5, chloroform).

Example 11

A solution of 630 mg of the hydrochloride (1:0.3) and hydroiodide (1:0,3) ethyl ester of (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -3-(4-methoxy-phenyl)-propionyl] -phenoxyalkanoic acid (example 8) and 330 mg of sodium hydroxide in 15 ml is the philosophy on Siciliana silica gel RP 18 (gradient THF/water) to obtain 32 mg (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -3-(4 - methoxy-phenyl)-propionyl]-phenoxyalkanoic acid, microanalysis: Rasch. C 65,68, 5,30 H, N 8,84; fact. C 65,77, H 5,12, N 8,73.

A basic example 12

A solution of 1 g of ethyl ester of (S)-4-[2-[4-(tert - butoxycarbonylamino-imino-methyl)-benzoylamine]-3-methyl - butyryl]-phenoxyalkanoic acid in 10 ml dichloromethane and 5 ml triperoxonane acid is stirred for 3 h at room temperature and then concentrated. After chromatography on Siciliana silica gel RP 18 (gradient THF/water) receive 789 mg trifenatate ethyl ester (S)-4-[2-[4-(amino-imino - methyl)-benzoylamine]-phenoxyalkanoic acid, TPL202oC []2D0= +95,5o(C=1, DMSO).

The source material can be obtained in the following way:

a) Analogously to example 3A) 2.6 g (5)-2-tert - butoxycarbonylamino-N-methoxy-N-3-dimethyl-butyramide subjected to interaction with 8.6 g of p-bromo-tert-butyldimethylsilyloxy. After chromatography on 200 g of silica gel (hexane/acetic ether 95:5) to obtain 3.0 g of tert-butyl methyl ether (S)-1-(4-tert-butyl - dimethyl-silyloxy-benzoyl)-2-methyl-propellerbuying acid, []2D0= +83,0o(C=0,5, chloroform).

b) the Removal of protective groups contained in 3.0 g of the product from a), analogously to example 3b) obtain 1.88 g of tert - butyl EPE the forms).

C) By reaction between 1.88 g of the product from b) and ethylbromoacetate analogously to example 1B) and subsequent chromatography on silica gel (hexane/acetic ether 5:1) get 2,02 g of ethyl ester of (S)- 4-(2-tert-butoxycarbonylamino-3-methyl-butyryl)-phenoxyalkanoic acid, []2D0= +86,1o(C=1, chloroform).

g) a suspension of 7 g of 4-amidinopropane acid in 120 ml of dioxane and 88 ml of 1 H of NaOH added at 0oC 13,96 g of di-tert-BUTYLCARBAMATE in 70 ml of dioxane, and then stirred for 1.5 h at room temperature. The precipitate is filtered by suction, the mother liquor is extracted twice with 100 ml of a simple ester, set with 1H HCl to pH 6 and concentrated. After chromatography of the residue on Siciliana silica gel RP 18 (gradient THF/water) gain of 4.2 g of N-tert-butoxycarbonyl-4-amidinopropane acid, TPL>200oC.

d) In a solution of 1.14 g of ethyl ester of (S)-4-(2-tert-butoxycarbonyl-Mino-3-methyl-butyryl)-phenoxyalkanoic acid in 10 ml of anhydrous dichloromethane was added when 0oC 410 μl of trimethylsilylmethyl, stirred for 15 min at 0oC, process yellow solution of 1.5 ml of HCl in dioxane (4H) and then the solvent is evaporated. The residue is dissolved in 10 ml is more for 16 h at room temperature. The resulting suspension is concentrated and the residue chromatographic on silica gel. The result is 1.07 g of ethyl ester of (S)-4-[2-[4-(tert-butoxycarbonylamino-imino-methyl)- benzoylamine] -3-methyl-butyryl]-phenoxyalkanoic acid, MS (ion bombardment): 526 (M+H)+.

Example 13

Analogously to example 12 from 250 mg of ethyl ether (S)-4- [2-[4-(tert-butoxycarbonylamino-imino-methyl)-benzoylamine] -3- [4-(2-methoxy - ethoxy)-phenyl]-propionyl]-phenoxyalkanoic acid and after chromatography on Siciliana silica gel RP 18 (gradient THF/water) to obtain 66 mg of triptoreline ethyl ester (S)-4-[2- [4-(amino-imino-methyl)-benzoylamine]-3-[4-(2-methoxy-ethoxy)- phenyl]-propionyl]-phenoxyalkanoic acid, MS (ion bombardment): 548 (M+H)+.

The source material can be obtained in the following way:

(a) Within 1 h carry out the reaction phase transition between 2.2 g of tert-butyl methyl ether (S)-2-(4-hydroxy-phenyl)-1-(methoxy - methyl-carbarnoyl)-ethylcarbamate acid and 2.5 g of 2-chloroethylnitrosourea ester in 10 ml of toluene and 10 ml of 50% NaOH in the presence of 50 mg of tetrabutylammonium hydrosulfate. Then the aqueous phase is extracted with simple ether, the combined organic phases are washed with saturated rustboro-[4-(2-methoxy-ethoxy)-phenyl]-1-(methoxy-methyl) -carbarnoyl)-ethylcarbamate acid, []2D0= +17,6o(C=1, chloroform).

b) Reaction of transformation of 1 g of the product of the preliminary stage according to example 3A) after chromatography on silica gel (hexane/acetic ether 9:1) receive 326 mg of tert-butyl methyl ether (S)-1-[4-(tert-butyl-dimethyl-silyloxy)-benzoyl]-2- [4-(2-methoxy-ethoxy)-phenyl]-ethylcarbamate acid, MS (ion bombardment): 530 (M+H)+.

C) Reaction of transformation of 310 mg of the product from b) analogously to example 3b) and the alkylation product analogously to example 1B) after chromatography on silica gel (hexane/acetic ether 2:1) obtain 273 mg of ethyl ester of (S)-4-[2-tert-butoxycarbonylamino-3-[4- (2-methoxy-ethoxy)-phenyl] -propionyl] -phenoxyalkanoic acid, MS (ion bombardment): 502 (M+H)+< / BR>
d) By reaction carried out with 250 mg of the product of the preliminary stage according to example d), after chromatography on silica gel (hexane/acetic ester 1: 2) to obtain 267 mg of ethyl ether (S)-4-[2-[4-(tert-butoxycarbonylamino-imino-methyl)-benzoylamine] -3-[4-(2-methoxy - ethoxy)-phenyl] -propionyl] -phenoxyalkanoic acid, MS (ion bombardment): 648 (M+H)+.

A basic example 14

A solution of 400 mg of triptoreline ethyl ester (S)-4-[2- [4-(amino-imino-met mg NaOH, stirred for 1 h at room temperature, acidified with 7 ml 1H HCl and concentrated. After chromatography of the residue on Siciliana silica gel RP 18 (gradient THF/water) receive 287 mg of the hydrochloride (1:0,4) (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine]-3-methyl-butyryl] -phenoxyalkanoic acid, MS (ion bombardment): 398 (M+H)+.

Example 15

To a suspension of 250 mg of triptoreline ethyl ester (S)-4-[2- [4-(amino-imino-methyl)-benzoylamine] -3-hydroxy-propionyl] -phenoxyalkanoic acid in 4 ml dichloromethane and 4 ml of a saturated solution of Na2CO3added 66 mg of 2-methoxy-ethyl-chloroformate and then stirred for 5 min at room temperature. The aqueous phase is extracted with dichloromethane, the dichloromethane phase is washed with water, dried and canceryou. After chromatography of the residue on silica gel (acetic ether) to obtain 55 mg of ethyl ester of (S)-4-[3-hydroxy-2-[4- [imino-(2-methoxyethoxymethyl)-methyl]-benzoylamine] -propionyl]-phenoxyalkanoic acid, MS (ion bombardment): 516 (M+H)+.

Example 16

A solution of 200 mg of tert-butyl methyl ether (S)-4-butoxy-2-[4-tert - butoxycarbonylamino-imino-methyl)-benzoylamine] -propionyl] - phenoxyalkanoic acid in 2 ml dichlormid is OK suspended in methanol, allocate by centrifugation and washed with simple ether. The result is 41 mg trifenatate (S)-4-[2-[4-amino-imino-methyl)- benzoylamine] -3-hydroxy-propionyl] -phenoxyalkanoic acid, MS (ISN): 384 (M-H)-.

The source material can be obtained in the following way:

a) By reaction between 1.35 g of tert-butyl methyl ether (S)-2-tert - butoxy-1-(4-hydroxy-benzoyl)-ethylcarbamate acid and tert - butylbromide analogously to example 1B) obtain 417 mg of tert - butyl methyl ether (S)-4-(2-tert-butoxycarbonylamino-3-tert - butoxy-propionyl] -phenoxyalkanoic acid, MS (ISN): 450 (M-H)-.

b) the Interaction of 400 mg of the product of the pre-stage N - tert-butoxycarbonyl-4-amidinopropane acid according to example 12A) after chromatography on silica gel (hexane/acetic ester 1:1) to obtain 230 mg of tert-butyl methyl ether (S)-4-[3-tert-butoxy-2- [4-(tert-butoxycarbonylamino-imino-methyl)-benzoylamine] -propionyl] - phenoxyalkanoic acid, MS (ISN): 596 (M-H)-.

Example 17

Interaction 100 mg trifenatate ethyl ester (S)-4-[2- [4-(amino-imino-methyl)-benzoylamine] -3-hydroxy-propionyl] -phenoxyalkanoic acid (example 9) with 54 μl of isobutylacetate according to example 15 after chromatog is solumina] -propionyl]-phenoxyalkanoic acid, []2D0= +47.0o(C=0,7, DMSO).

Example 18

The interaction of 170 mg of ethyl ether (S)-4-[2-[4-(tert - butoxycarbonylamino-imino-methyl)-benzoylamine] -3-methoxy-propionyl] - phenoxyalkanoic acid triperoxonane acid analogously to example 12 and after crystallization of the residue using a simple ether obtain 124 mg of triptoreline ethyl ester (S)-4-[2-[4-(amino-imino-methyl)- benzoylamine]-3-methoxy-propionyl]-phenoxyalkanoic acid, MS (ion bombardment): 428 (M+H)+.

The source material can be obtained in the following way:

a) By reaction between 1.18 g (S)-2-tert-butoxycarbonylamino - N,3-dimethoxy-N-methyl-propionamide and p-bromo-tert - butyldimethylsilyloxy analogously to example 3A) after chromatography on silica gel (hexane/acetic ether 8:1) receive 872 mg of tert-butyl methyl ether (S)-1-[4-(tert-butyl - dimethyl-silyloxy)-benzoyl] -2-methoxy-ethylcarbamate acid, MS (ion bombardment): 410 (M+H)+.

b) the Removal silylamines group contained 850 mg of the product of the preliminary stage according to example 3b), and alkylation of the product according to example 1B) receive 546 mg of ethyl ester of (S)-4-(2-tert-butoxycarbonylamino-3-methoxy-propionyl) - and N-tert-butoxycarbonyl-4-amidinopropane acid according to recommendations from the example d) and after chromatography on silica gel (hexane/acetic ester 1:2) to obtain 170 mg of ethyl ether (S)-4-[2- [4-(tert-butoxycarbonylamino-imino-methyl)-benzoylamine] -3-methoxy - propionyl]-phenoxyalkanoic acid, MS (ion bombardment): 528 (M+H)+.

Example 19

Of 510 mg (S)-sec-butyl ether (S)-4-[3-tert - butoxy-2-[4-(tert-butoxycarbonylamino-imino-methyl)- benzoylamine]-propionyl]-phenoxyalkanoic acid get according to example 12 and after chromatography of the crude product on Siciliana silica gel RP 18 (gradient THF/water) 280 mg trifenatate (S)-sec-butyl ether (S)-4-[2-[4-(amino - imino-methyl)-benzoylamine]-3-hydroxy-propionyl] -phenoxyalkanoic acid, TPL85-87oC []2D0= +55,7o(C=0.3, and dimethyl sulfoxide).

The source material can be obtained in the following way:

a) From 790 mg of tert-butyl methyl ether (S)-2-tert-butoxy-1-(4-hydroxy-benzoyl)-ethylcarbamate acid with (S)-sec-butyl ether bromoxynil acid according to example 1B), and after chromatography on silica gel (hexane/acetic ether 9:1) obtain 780 mg of (S)-sec-butyl ether (S)-4-(3-tert-butoxy-2-tert-butoxycarbonylamino-propionyl)- phenoxyalkanoic acid, []2D0= +35,3o(C = 0.45, and chloroform).

b) By reaction between 720 mg of product preliminary stage and 510 mg of N-tert-butoxycarbonyl-4-amidinopropane acid analogously to example d) after chromatography n is oxcarbazepine-imino-methyl)-benzoylamine] -propionyl] - phenoxyalkanoic acid, []2D0= +51,3o(C= 1, chloroform).

Example 20

650 mg of ethyl ester of (2S,3R)-4-[3-tert - butoxy-2-[4-(tert-butoxycarbonylamino-imino-methyl)- benzoylamine]-butyryl]-phenoxyalkanoic acid get according to example 12 and after chromatography on Siciliana silica gel RP 18 (gradient FBL/water) 350 mg trifenatate ethyl ester (2S, 3R)-4-[2-[4-(amino-imino-methyl)-benzoylamine] - 3-hydroxy-butyryl] -phenoxyalkanoic acid, TPL95-97oC []2D0= +98,8o(C = 0,4, DMSO).

The source material can be obtained in the following way:

a) From 15 g of tert-butyl methyl ether (1S,2R)-2 - tert-butoxy-1-carboxy-propellerbuying acid analogously to example 7a) and after chromatography on silica gel (hexane/acetic ether 5:1, 3:1) get 11,19 g tert-butyl ether (1S,2R)-2 - tert-butoxy-1-(methoxy-methyl-carbarnoyl)-propanecarboxylate acid, []2D0= +30,0o(C=0,7, chloroform).

b) By reaction between 17 g of the product preview stage and p-bromo-tert-butyldimethylsilyloxy analogously to example 3A) after chromatography on silica gel (hexane/acetic ether 9:1) get the value of 4.76 g of tert-butyl methyl ether (1S, 2R)-2-tert-butox is UP> (C = 0.3, and chloroform).

C) the Removal silylamines group contained in 4,74 g of the product of the preliminary stage according to example 3b), and alkylation of the product according to example 1B) after chromatography on silica gel (hexane/acetic ether 5:1) get to 3.34 g of ethyl ester of (2S,3R)-4-(3-tert-butoxy-2-tert-butoxycarbonylamino-butyryl)- phenoxyalkanoic acid, []2D0= +71,0o(C=0.3, and chloroform).

d) By reaction between 1,09 g of the product of the pre-stage and N-tert-butoxycarbonyl-4-amidinopropane acid according to example d) and after chromatography on silica gel (hexane/acetic ether 2:1, 1:1) obtain 660 mg of ethyl ester of (2S,3R)-4-[3-tert - butoxy-2-[4-(tert - butoxycarbonylamino-imino-methyl)-benzoylamine] -butyryl] - phenoxyalkanoic acid, []2D0= +126,0o(C=0.3, and chloroform).

Example 21

From 2 g of 2-methoxy-ethyl ester (S)-4-[2-[4- (tert-butoxycarbonyl-Mino-imino-methyl)-benzoylamine] -3-tert - butoxy-propionyl]-processsee acid after processing as in example 12 and chromatography on Siciliana silica gel RP 18 (gradient THF/water) receive 600 mg of triptoreline 2 - methoxy-ethyl ester (S)-4-[2-[4-(amino-imino-methyl)- benzoylamine]-3-Guido).

The source material can be obtained in the following way:

a) Alkylation of 1.64 g of tert-butyl methyl ether (S)-2-tert - butoxy-1-(4-hydroxy-benzoyl)-ethylcarbamate acid with 2-methoxy-ethylbromoacetate according to example 1B) after chromatography on silica gel get 1,58 g 2-methoxy-ethyl ester (S)-4-[3-tert-butoxy-2-tert-butoxycarbonylamino-propionyl] -phenoxyalkanoic acid, MS (ion bombardment): 454 (M+H)+.

b) Interaction of 1.55 g of the product of the pre-stage N-tert-butoxycarbonyl-4-amidinopropane acid according to example d) and after chromatography on silica gel (hexane/acetic ether 2:1, 1:1) to obtain 2.0 g of 2-methoxy-ethyl ester (S)-4-[2-[4-(tert - butoxycarbonylamino-imino-methyl)-benzoylamine] -3-tert-butoxy - propionyl] -phenoxyalkanoic acid, MS (ion bombardment): 600 (M+H)+.

Example 22

Of 4.7 g of 2-methoxy-ethyl ester (S)-4-[2-[4-(tert - butoxycarbonylamino-imino-methyl)-benzoylamine]- propionyl]-phenoxyalkanoic acid according to example 12 and after chromatography on Siciliana silica gel RP 18 (gradient THF/water) receive a rate of 1.67 g of 2-methoxy ethyl ether (S)-4-[2-[4- (amino-imino-methyl)-benzoylamine] -propionyl]-phenoxyalkanoic acid, []f=0,29 (hexane/acetic ester 1:1).

b) By transformation of 3.3 g of the product of the preliminary stage according to example d) after chromatography on silica gel (hexane/acetic ester 1:2) get value of 4.76 g of 2-methoxy-ethyl ester (S)-4-[2-[4-(tert-butoxycarbonylamino-imino-methyl)-benzoylamine] -propionyl]-phenoxyalkanoic acid, MS (ion bombardment): 528 (M+H)+.

Example 23

Interaction 199 mg trifenatate ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid with etelcharge.com according to example 15 after chromatography on silica gel (hexane/acetic ester 1: 2) to obtain 137 mg of ethyl ether (S)-4-[2-[4-(ethoxycarbonyl-imino-methyl)- benzoylamine]-propionyl]-phenoxyalkanoic acid, MS (ion bombardment): 470 (M+H)+.

The source material can be obtained in the following way:

a) Interaction of 530 mg of tert-butyl methyl ether (S)-1-(4-hydroxy-benzoyl)-ethylcarbamate acid with ethylbromoacetate analogously to example 1B) after chromatography on silica gel (hexane/acetic ether 5:1) receive 582 mg of ethyl ester of (S)-4-(2-tert-butoxycarbonylamino - propionyl)-phenoxyalkanoic acid, []2DPL180oC []20D/= +54.2o(or=0.6, DMSO).

Example 24

The removal of protective groups contained in 1 g of ethyl ester of (E,Z)-(S)-4-[3-acetoxy-2-[4-[(di-tert-butoxycarbonylamino)-tert - butoxycarbonylamino-methyl] -benzoylamine]-propionyl] -phenoxyalkanoic acid, analogously to example 12 after crystallization using a simple ether obtain 760 mg of triptoreline ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -3-acetoxy-propionyl] -phenoxyalkanoic acid, MS (ion bombardment): 456 (M+H)+.

The source material can be obtained in the following way:

a) a Solution of 440 mg of ethyl ester of 4-[(S)-3-tert-butoxy-2 - tert-butoxycarbonylamino-propionyl] -phenoxyalkanoic acid in 10 ml of dichloromethane is stirred from 0.28 ml trimethylsilylmethyl for 3 h at room temperature, treated with 1 ml of HCl in dioxane (approximately 4 M) and concentrate. The residue is dissolved in 10 ml of THF, treated 464 mg (E,Z)-4-(tri-tert-butoxycarbonylamino)-benzoic acid, 253 mg of N-methylmorpholine, 379 mg of HBTU and stirred for 16 h at room temperature. The resulting suspension is concentrated and the residue chromatographic on silica gel (hexane/acetic ester 1:1). In the o-methyl] -benzoylamine]-3-hydroxy-propionyl]- phenoxyalkanoic acid, MS (ion bombardment): 714 (M+H)+.

b) Acetylation of 1.42 g of the product of the preliminary stage with 0,156 ml acetylchloride in the presence of 223 mg of triethylamine in 30 ml of simple ether for 1 h at room temperature to obtain a suspension. The precipitate is filtered by suction, the mother liquor is concentrated and the residue chromatographic on silica gel. The result is 1.13 g of ethyl ester of (E,Z)-(S)-4-[3-acetoxy-2-[4-[(di-tert - butoxycarbonylamino)-tert-butoxycarbonylamino-methyl] - benzoylamine] -propionyl] -phenoxyalkanoic acid, MS (ion bombardment): 756 (M+H)+.

Example 25

The interaction of 1 g of methyl ester of 4-[4-(amino-imino-methyl)- benzoylbenzoate] -phenoxyalkanoic acid (example 25 in European application EP 0381033) etelcharge.com analogously to example 15 after crystallization in methanol/THF obtain 810 mg of methyl ester of 4- [4-(ethoxycarbonyl-imino-methyl)-benzoylbenzoate] -phenoxyalkanoic acid, MS (ion bombardment): 442 (M+H)+.

Example 26

400 mg of ethyl ester of (E,Z-(R,S)-4-[2-[4-[(di-tert - butoxycarbonylamino)-tert-butoxycarbonylamino-methyl] - benzoylamine] -3-methylsulfanyl-propionyl] -phenoxyalkanoic acid after removal of samvega ester (R,S)-4-[2-[4-(amino-imino - methyl)-benzoylamine]-3-methylsulfanyl-propionyl]-phenoxyalkanoic acid, MS (ion bombardment): 444 (M+H)+.

The source material can be obtained in the following way:

Suspension of 713 mg of ethyl ester of (E,Z)-(S)-4-[3-acetoxy-2- [4-[(di-tert-butoxycarbonylamino)-tert-butoxycarbonylamino-methyl] - benzoylamine] -propionyl]-phenoxyalkanoic acid (example 246) and 140 mg methanolate sodium in 10 ml of acetonitrile is stirred for 45 min at room temperature, any insoluble components are filtered off by suction, the mother liquor is evaporated and the residue chromatographic on silica gel (hexane/acetic ether 2:1). As a result, 407 mg of ethyl ester of (E,Z)-(R,S)-4- [2-[4-[(di-tert-butoxycarbonylamino)-tert-butoxycarbonylamino-methyl]- benzoylamine] -3-methylsulfanyl-propionyl] -phenoxyalkanoic acid, MS (EI): 744 (M+H)+.

Example 27

From 119 mg trifenatate ethyl ester (R,S)-4-[2-[4-(amino - imino-methyl)-benzoylamine] -3-methylsulfanyl-propionyl]-phenoxyalkanoic acid, similarly to that described in example 15, using 28 mg ethylchloride and after chromatography on silica gel (hexane/acetic ether 2:3) to obtain 78 mg of ethyl ester of (R,S)- 4-[2-[4-(ethoxycarbonyl - Mino-imino-methyl)-benzoylamine] -3-methylsulfanyl-propionyl] -phenoxyalkanoic Chisloth-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid with 2-methoxy-etelcharge.com analogously to example 15, and after chromatography of the residue on silica gel (hexane/acetic ester 1:2) to obtain 280 mg of ethyl ether (S)-4-[2-[4-[imino-2- (methoxy-ethoxycarbonyl)-methyl]-benzoylamine] -propionyl]- phenoxyalkanoic acid, MS (ion bombardment): 500 (M+H)+.

Example 29

The removal of protective groups contained 850 mg tert - butyl ether (S)-4-[2-(4-ethoxycarbonylmethoxy-phenyl)-1 - methyl-2-oxo-ethylcarboxylate] -piperidine-1-carboxylic acid analogously to example 12 after chromatography on Siciliana silica gel RP 18 (gradient THF/water) receive 437 mg trifenatate ethyl ester (S)-4-(2-piperidine-4 - mmoxiccillin-propionyl)-phenoxyalkanoic acid, MS (ion bombardment): 393 (M+H)+.

The source material can be obtained in the following way:

A solution of 702 mg of ethyl ester of (S)-4-(2-tert - butoxycarbonylamino-propionyl)-phenoxyalkanoic acid in 10 ml of dichloromethane is stirred with a 0.27 ml trimethylsilylmethyl for 15 min at 0oC, treated with 1 ml of HCl in dioxane (4 M) and concentrate. The residue is dissolved in 10 ml of dichloromethane. Then for 30 min at 0oC stirred solution of 518 mg of 1-tert - butoxycarbonyl-piperidine-4-yl-exucuse acid, 594 mg TPTU and 0.55 ml of N-methylmorpholine in 10 ml of dichloromethane, after which process it above the rest. After stirring for 2 h at room temperature the reaction solution is concentrated and the residue chromatography is carbonyloxy-phenyl)- 1-methyl-2-oxo-ethylcarboxylate] -piperidine-1-carboxylic acid, MS (ion bombardment): 493 (M+H)+.

Example 30

Interaction 511 mg trifenatate ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid with diethylphosphate analogously to example 15, and after chromatography of the residue on silica gel (dichloromethane/ethanol 9:1) to obtain 340 mg of ethyl ether (S)-4- [2-[4-(diethoxyphosphoryl-imino-methyl)-benzoylamine] - propionyl]-phenoxyalkanoic acid, MS (ion bombardment): 534 (M+H)+.

Example 31

A solution of 1 g of ethyl ester of (S)-4-[2-(4-cyano-benzoylamine)- propionyl] -phenoxyalkanoic acid in 10 ml of pyridine and 1 ml of triethylamine is saturated with hydrogen sulphide and stirred for 16 h at room temperature. Then the reaction mixture was concentrated, the residue is dissolved in acetic ether, washed with sodium hydrogen carbonate solution, a solution of potassium hydrosulfate and a saturated solution of sodium chloride, dried and concentrated. After processing the remainder of simple ether obtain 580 mg of ethyl ether (S)-4-[2-[4-(thiocarbamoyl)-benzoylamine] - propionyl]-ferociously acid. This ether is filtered off by suction, dissolved in 65 ml of acetone and 3.3 ml under the conditions and stirred for 3 hours at a temperature of cieniawa ether (S)-4-[2-[4-(1-methyl-Titrimeter)- benzoylamine]-propionyl] -phenoxyalkanoic acid. 314 mg of the ester dissolved in 10 ml of THF, treated with 110 mg of 2-methoxy - ethylamine and stirred for 64 h at room temperature. After concentration of the solution and chromatography of the residue on Siciliana silica gel RP 18 (gradient THF/water) receive 80 mg of hydroiodide ethyl ester (R,S)-4-[2-[4-[imino-(2-methoxy - ethyl)-amino-methyl]-benzoylamine]-propionyl]-phenoxyalkanoic acid, MS (ion bombardment): 456 (M+H)+.

The source material was obtained in the following way:

The reaction mix 5,62 g of ethyl ester of (S)-4-(2 - butoxycarbonylamino-propionyl)-phenoxyalkanoic acid from 2.82 g of 4-cyanobenzoic acid and in the same way as described in example 12, after chromatography on silica gel (hexane/acetic ether 3:2) get to 3.67 g of ethyl ester of (S)-4-[2-(4-cyano-benzoylamine)-propionyl] - phenoxyalkanoic acid, MS (E1): 381 (M+H)+.

Example 32

The removal of protective groups contained 160 mg of ethyl ester of (R, S)-4-[2-[4-[(tert-butultimately-silanisation)-imino - methyl]-benzoylamine] -propionyl] -phenoxyalkanoic acid, using tetrabutylammonium fluoride as in example 3b) after crystallization of the residue in acetic ether/hexane receive 70 mg of ethyl ester of (Z)-(R,S)-4-[2-[4-[SUP>+
.

The source material can be obtained in the following way:

A solution of 300 mg of ethyl ether (S)-4-[2-[4-(1-methyl - thioformate-yl)-benzoylamine] -propionyl] -phenoxyalkanoic acid (example 31) and 175 mg Of tert-butyl dimethylsilane-hydroxylamine in 10 ml of THF is stirred for 16 h at room temperature, concentrated and the residue chromatographic on silica gel (hexane/acetic ether 3:2). The result is 95 mg of ethyl ester of (R,S)-4-[2-[4-[(tert-butyl-dimethyl-silanisation)-imino - methyl]-benzoylamine]-propionyl]-phenoxyalkanoic acid, MS (EI): 528 (M+H)+.

Example 33

350 mg of the hydrochloride (1:08) and hydroiodide (1:0,4) tetrahydropyran - 4-silt ether (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine]- propionyl]-phenoxyalkanoic acid and 80 mg of ethylchloride receive according to example 15 and after chromatography of the residue on silica gel (hexane/acetic ester 1:2) 204 getregistration-4 - silt ether (S)-4-[2-[4-(ethoxycarbonyl-imino-methyl)- benzoylamine]-propionyl]-phenoxyalkanoic acid, MS (ion bombardment): 526 (M+H)+.

Example 34

From 2.2 g of ethyl ester of (S)-4-[2-(6-tert - butoxycarbonylamino-pyridine-3-ylcarbonyl)-propionyl] - phenoxyalkanoic acid, polang ethyl ester (S)-4-[2-(6-aminomethylpyridine-3-ylcarbonyl)-propionyl]- phenoxyalkanoic acid, MS (ion bombardment): 386 (M+H)+.

The source material can be obtained in the following way:

The reaction mix of 1.97 g (after removal of the protective group) ethyl ester of (S)-4-(2-tert-butoxycarbonylamino-propionyl)- phenoxyalkanoic acid and 1.7 g of 6-tert-butoxycarbonyl-methyl - pyridine-3-carboxylic acid in the presence of 2 g of TPTU and 1.25 g of N-methylmorpholine receive according to example d) and after chromatography on silica gel (hexane/acetic ester 1:2) 2.28 g of ethyl ester of (S)-4-[2-(6-tert-butoxycarbonylamino - pyridine-3-ylcarbonyl)-propionyl] -phenoxyalkanoic acid, MS (ion bombardment): 486 (M+H)+.

Example 35

From 90 mg of ethyl ester of (Z)-(R,S)-4-[2-[4-(amino-hydroxyimino - methyl)-benzoylamine] -propionyl]-phenoxyalkanoic acid and 25 mg of ethylchloride receive according to example 15 and after crystallization of the residue in acetic ether/hexane 57 mg of ethyl ester of (Z)-(R,S)-4-[2- [4-[amino-ethoxycarbonylmethyl] -benzoylamine] -propionyl] - phenoxyalkanoic acid, MS (ion bombardment): 486 (M+H)+.

Example 36

By reaction between 500 mg trifenatate ethyl ester (S)-4-[2- [4-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid and penello ether (S)-4-[2-[4-(imino-phenoxycarbonylamino)-benzoylamine] -propionyl]- phenoxyalkanoic acid, MS (ion bombardment): 518 (M+H)+.

Example 37

By reaction between 511 mg trifenatate ethyl ester (S)-4- [2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid and 4-methoxyphenylacetamide according to example 15 after chromatography on silica gel (hexane/acetic ester 1:2) to obtain 145 mg of ethyl ether (S)-4-[2-[4-[imino-(4-methoxy-phenoxycarbonylamino)- methyl] -benzoylamine]-propionyl]-phenoxyalkanoic acid, MS (ion bombardment): 548 (M+H)+.

Example 38

In a solution of 102 mg of tetrahydro-2H-Piran-4-ol and 101 mg of 4-methoxypropane in 10 ml of dichloromethane added at 0oC 98 mg triphosgene in 5 ml of dichloromethane and then stirred for 2 h at room temperature. This solution is added to a suspension of 511 mg trifenatate ethyl ester (S)-4-[2-[4-(amino-imino-methyl) -benzoylamine] -propionyl] -phenoxyalkanoic acid in 10 ml dichloromethane and 10 ml of a saturated solution of sodium carbonate, stirred for 5 min at room temperature and then the reaction mixture is processed as described in example 15. After chromatography of the residue on silica gel (acetic ether) to obtain 350 mg of ethyl ether (S)-4-[2-[4-[imino-(tetrahydro-Piran-4 - jocstarbunny is SS="ptx2">

Example 39

In the same way as described in example 38, 540 mg of triptoreline tetrahydropyran-4-silt ether (S)-4-[2-[4- (amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid (example 5) also transform. After chromatography of the residue on silica gel (acetic ether) obtain 378 mg tetrahydropyran-4-silt ether (S)-4-[2-[4-[imino-(tetrahydro - Piran-4-eloxierarbeiten)-methyl] -benzoylamine]-propionyl]- phenoxyalkanoic acid. MS (ion bombardment): 582 (M+H)+.

Example 40

By reaction between 920 mg trifenatate 2-methoxy-ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] - phenoxyalkanoic acid and 2-methoxy-etelcharge.com according to example 15 after chromatography on silica gel (hexane/acetic ester 1:3) to obtain 430 mg of 2-methoxy-ethyl ester (S)-4-[2-[4-[imino-(2-methoxy - ethoxy-carbylamine)-methyl]-benzoylamine] -propionyl] -phenoxyalkanoic acid, MS (ion bombardment): 530 (M+H)+.

Example 41

The removal of protective groups contained 160 mg of ethyl ether (S)-4-[2-[4-[(tert-butultimately-silanisation)-imino - methyl]-benzoylamine] -propionyl]-phenoxyalkanoic acid with tetrabutylammonium fluoride similarly Pro-hydroxyimino-methyl)-benzoylamine] -propionyl] - phenoxyalkanoic acid, MS (ion bombardment): 414 (M+H)+, []2D0= +68,8o(C=0,5, DMSO).

The source material can be obtained in the following way:

2 g of 4-cyanobenzoic acid using reactions similar to those described in example 32A), receive N-tert-butyl-dimethylsiloxy - amidinopropane acid. This acid is used directly as a crude product for the implementation of combination reaction with ethyl ester, (S)-4-(2-tert-butoxycarbonylamino-propionyl) -phenoxyalkanoic acid in the presence of TPTU according to example d). After chromatography of the residue on silica gel (hexane/acetic ester 1: 1) receive 561 mg of ethyl ether (S)-4-[2-[4-[(tert-butyl-dimethyl - silanisation)-imino-methyl] -benzoylamine]-propionyl]- phenoxyalkanoic acid, []2D0= +62,0o(C=0,5, chloroform).

Example 42

Interaction 500 mg trifenatate ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl]- phenoxyalkanoic acid with 4-ftorpirimidinam analogously to example 15, and after chromatography of the residue on silica gel (hexane/acetic ester 1:2) to obtain 100 mg of ethyl ether (S)-4- [2-[4-[(4-the fluorine-phenoxycarbonylamino)-imino-methyl] -bertolami is going from 1 g of triptoreline ethyl ester (S)-4-[2-[4-(amino - imino-methyl)-benzoylamine]-propionyl]-phenoxyalkanoic acid, in the same way as described in example 38 using 2-tert-butyl - dimethyl-selanjutnya receive 200 mg of ethyl ether (S)-4-[2-[4-[amino-2-tert-butyl-dimethyl-silyloxy - ethoxycarbonylethyl-methyl] benzoylamine] propionyl] - phenoxyalkanoic acid and then otscheplaut protective group analogously to example 3A) and chromatographic on silica gel (acetic ether/ethanol 95:5). The result is 56 mg of ethyl ether (S)-4-[2-[4-[amino-(2-hydroxyacetanilide)-methyl] - benzoylamine] -propionyl]-phenoxyalkanoic acid, MS (ion bombardment): 486 (M+H)+.

Example 44

On the basis of 527 mg of ethyl ester of (S)-4-(2-tert - butoxycarbonylamino-propionyl)-phenoxyalkanoic acid and 462 mg of triptoreline 4-(amino-methoxyimino-methyl)-benzoic acid, receive analogously to example d) after chromatography on silica gel (hexane/acetic ether 2:3) 500 mg trifenatate ethyl ester (E,Z)-(S)-4-[2-[4-(amino-methoxyimino-methyl)-benzoylamine] -propionyl]-phenoxyalkanoic acid, MS (ion bombardment): 428 (M+H)+.

The source material can be obtained in the following way:

A solution of 1.47 g of tert-butyl methyl ether 4-cyanobenzoic acid analogously to example 31 is subjected to interaction with zerovoltage (hexane/acetic ether 9:1). The result is 1.0 g of tert-butyl ester 4-(amino-methoxyimino-methyl)-benzoic acid. The cleavage of the ether group according to example 12 using triperoxonane acid after crystallization in a simple ether obtain 1.13 g of triptoreline 4-(amino-methoxyimino-methyl)-benzoic acid.

Example 45

In the same way as described in example 3b), using tetrabutylammonium fluoride otscheplaut silylamine group contained 290 mg of ethyl ether (S)-4-[2-[4-[(tert-butyl-dimethyl-silanisation)-imino-methyl]-benzoylamine] -3-hydroxy-propionyl]-phenoxyalkanoic acid. After chromatography on silica gel (acetic ether) to obtain 145 mg of ethyl ester of (Z)-(S)-4-[2-[4-[amino-hydroxyimino-methyl] - benzoylamine]-3-hydroxy-propionyl]-phenoxyalkanoic acid.

The source material can be obtained in the following way:

From a solution of 1.27 g of ethyl ester of 4-[(S)-3-tert-butoxy-2 - tert-butoxycarbonylamino-propionyl]-phenoxyalkanoic acid in 25 ml of dichloromethane receive according to example 24A) of the free amine, which is then analogously to example 41A) is subjected to interaction with N-tert-butyl-dimethylsiloxy-amidinopropane acid. After chromatography of the residue on silica gel (hexane is solumina] -3-hydroxy - propionyl] -phenoxyalkanoic acid, Rfvalue: of 0.68 (chloroform, methanol, acetic acid, 88:10:2).

Example 46

A solution of 0.8 g [[4-(p-amidino-N-methylbenzamide)acetyl-o - phenylene]dioxy]luxusni acid (see Journ. Med. Chem. 1992, 35, 4393-4407) in 2-propanol/concentrated sulfuric acid (20:1) was incubated over night. After removal of solvent the residue is dissolved in 50 ml of water, neutralized by addition of sodium bicarbonate and padlayat 80 ml of dichloromethane. After addition of 0.3 g of the ethyl ether of Harborview acid, and then 20 ml of 0.5 H a solution of sodium hydroxide, the organic phase is separated, washed with water, dried over sodium sulfate and concentrated. After chromatography on silica gel (ethyl ester of acetic acid) and crystallization (diethyl ether) to obtain 0.51 g of diisopropyl ether (E and/or Z)-[[4-((p-amino-ethoxycarbonyl-methyl)-N-methylbenzamide)acetyl-o-phenylene]dioxy]luxusni acid, TPL56-58oC. MS (EI): 512 (M+H)+.

Example 47

From [[1-[N-(p-amidinophenoxy)-L-tyrosyl] -4-piperidinyl]-oxy]- acetic acid (see Journ. Med. Chem. 1992, 35, 4393-4407), similarly to that described in example 46, receive the ethyl ester of (E/Z)- (S)-1-[2-[4-(amino-ethoxycarbonyl-methyl)-benzoylamine] -3-(4-hydroxy-phenyl)-propionyl]-piperidine-4-ionami): 569 (M+H)+.

Example 48

From [[1-[N-(p-amidinophenoxy)-L-tyrosyl] -4-piperidinyl]-oxy]- acetic acid (see Journ. Med. Chem. 1992, 35, 4393-4407), similarly to that described in example 46, receive isopropyl ether (E/Z)-(S)-1-[2-[4-(amino-ethoxycarbonyl-methyl)-benzoylamine] - 3-(4-hydroxy-phenyl)-propionyl] -piperidine-4-biloxicasino acid. TPL88-90oC. MS (ion bombardment): 583 (M+H)+.

Example 49

As a side product in the reaction of transformation described in example 48, was allocated isopropyl ether (E/Z)-(S)-1-[2-[4-(amino - ethoxycarbonyl-methyl)-benzoylamine[]-3-(4-ethoxycarbonylmethoxy-phenyl)- propionyl] -piperidine-4-biloxicasino acid. TPL71-73oC. MS (ion bombardment): 655 (M+H)+.

Example 50

The interaction of [[1-[N-(p-amidinophenoxy)-L-tyrosyl] -4-piperidinyl] - oxy]-acetic acid anhydride of stokesley in the presence of potassium carbonate after the usual processing and chromatographic purification of the crude product is obtained (E/Z)-(S)-4-[2-[4-(amino - ethoxycarbonyl-methyl)-benzoylamine] -3-(4-isopropoxycarbonyl-methoxy - piperidine-1-yl)-3-oxo-propyl]-phenyl ester 2-amino-benzoic acid as a colorless foamy substance. MS (bombing IO is - is XI] -acetic acid chloride furan-2-carboxylic acid in the presence of potassium carbonate after the usual processing and chromatographic purification of the crude product is obtained (E/Z)-(S)-4-[2-[4-(amino-ethoxycarbonyl-methyl)-benzoylamine] -3-(4-isopropoxycarbonyl-piperidine-1-yl)-3-oxo-propyl] - phenyl ester furan-2-carboxylic acid in the form of foamy yellowish substance. MS (ion bombardment): 677 (M+H)+.

Example 52

The interaction of [[1-[N-(p-amidinophenoxy)-L-tyrosyl] -4 - piperidinyl]-oxy] -acetic acid with acetanhydride in the presence of potassium carbonate after the usual processing and chromatographic purification of the crude product is obtained isopropyl ether (E/Z)-(S)-1-[3-[4-acetoxy-phenyl)-2-[4-(amino-ethoxycarbonyl - methyl)-benzoylamine] -propionyl] -piperidine-4-biloxicasino acid as colorless foamy substance. MS (ion bombardment): 625 (M+H)+.

Example 53

The interaction of [[1-[N-(p-amidinophenoxy)-L-tyrosyl] -4-piperidinyl] oxy] acetic acid chloride of acetylsalicylic acid in the presence of triethylamine after the usual processing and chromatographic purification of the crude product is obtained (E/Z)-(S)-4- [2-[4-(amino-ethoxycarbonyl-methyl)-benzo the slots. TPL77-80oC. MS (EI): 745 (M+H)+.

Example 54

Interaction tert-butyl ether [[1-[N-(p-amidinophenoxy)- L-tyrosyl] -4-piperidinyl] oxy] acetic acid (see European patent application EP 505868) with ethyl ether of Harborview acid as described in example 46, and then by treatment with concentrated formic acid after the usual processing and chromatography emit (E/Z)-(S)-1-[2-[4-(amino-ethoxycarbonyl-methyl)-benzoylamine] -3-(4-hydroxy-phenyl)-propionyl]-piperidine-4-biloxicasino acid. TPL134oC. MS (ISN): 539 (M-H)+.

Example 55

By transforming (S)-1-[2-(5-amidinopropane-2-ylcarbonyl)- 3-(4-methoxy-phenyl)-propionyl] -piperidine-4-biloxicasino acid (see European patent application EP 505868), similarly to that described in example 46, receive the ethyl ester of (E/Z)-(S)-1-[2-(5-amino - ethoxycarbonylethyl-methylpyridin-2-ylcarbonyl-amino)-3-(4-methoxy-phenyl)- propionyl] -piperidine-4-biloxicasino acid, []2D0= +22,6o(C = 1,0, EtOH). TPL52-54oC. MS (ion bombardment): 584 (M+H)+.

Example 56

Interaction tert-butyl ether (S)-1-[3-(4-hydroxy - phenyl)-2-[4-(imino-propylamino-methyl)-benzoylamine] - propionyl]-and the crude product on silica gel RP 18 using a gradient of water/methanol receive (S)-1-[3-(4-hydroxy-phenyl)-2-[4-(imino-propylamino - methyl)-benzoylamine] -propionyl] -piperidine-4-biloxicasino acid. TPL160oC. MS (ion bombardment): 511 (M+H)+.

The source material can be obtained in the following way:

a) Reaction of a combination of Z-Tyr-OH with tert-butyl ether 4-piperidinecarboxylic acid (see Journ. Med. Chim. 1992, 35, 4393-4407), and then removing by hydrogenolysis of the Z-protective groups are tert-butyl ester 1-[[L-tyrosyl]-4-piperidinyloxy]acetic acid.

b) Interaction of the product preview stage 4-cyano-benzo-inflorida in the presence of sodium bicarbonate receive tert-butyl ether (S)-1-[3-(4-hydroxy-phenyl)-2-[4-cyano - benzoylamine] -propionyl] -piperidine-4-biloxicasino acid.

By sequential processing of the product preview stage of hydrogen sulfide in pyridine, methyliodide in acetone and n-Propylamine in a mixture of methanol and acetic acid to obtain tert-butyl ether (S)-1-[3-(4-hydroxy-phenyl)-2-[4-(imino-propylamino - methyl)-benzoylamine] -propionyl] -piperidine-4-biloxicasino acid. MS (ion bombardment): 567 (M+H)+.

Example 57

Interaction (S)-4-[[[4-[1-(4-tert-butoxycarbonylamino - piperidine-1-carbonyl)-2-(4-hydroxy-phenyl)-ethylcarboxyl]-phenyl]- aminomethyl]-amino] -butyric acid with kontsentrirovanii-piperidine-1-carbonyl)-2-(4-hydroxy - phenyl)- ethylcarboxyl]-phenyl] -imino-methyl] -amino] -butyric acid. TPL156 to 160oC. MS (ion bombardment): 555 (M+H)+.

The source material can be obtained in the following way:

By sequential processing tert-butyl ether (S)-1- [3-(4-hydroxy-phenyl)-2-[4-cyano-benzoylamine] -propionyl] -piperidine - 4-biloxicasino acid (example 566)) with hydrogen sulfide in pyridine, methyliodide in acetone and 4-aminobutyric acid in a mixture of methanol and acetic ether get (S)-4-[[[4-[1-(4-tert - butoxycarbonyloxyimino-1-carbonyl)-2-(4-hydroxy - phenyl)-ethylcarboxyl]-phenyl]-aminomethyl]-amino]-butyric acid as a colorless foamy substance. MS (ion bombardment): 611 (M+H)+.

Example 58

Interaction tert-butyl ether [[1-[N-(p-amidinophenoxy)- L-alanyl] -4-piperidinyl]oxy]acetic acid (see Journ. Med. Chem. 1992, 35, 4393-4407) with ethyl ether of Harborview acid as described in example 46, and then by treatment with concentrated formic acid after the usual processing and chromatography emit (E/Z)-(S)-[1-[2-[4-(aminoacetanilide-methyl) -benzoylamine] -propionyl] -piperidine-4-yloxy]-acetic acid as colorless foamy substance. MS (ion bombardment): 449 (M+H)+.

Example 59

And, the AK is described in example 46, received the ethyl ester of (E/Z)-(S)-1-[2-[4-(amino-ethoxycarbonyl-methyl)-benzoylamine] -propionyl] -piperidine-4-biloxicasino acid as colorless foamy substance. []2D0= +41,7o(C = 1,0, EtOH)/MS (ion bombardment): 477 (M+H)+.

Example 60

From [[1-[N-(p-amidinophenoxy)-L-alanyl]-4-piperidinyl]oxy]acetic acid (see Journ. Med. Chem. 1992, 35, 4393-4407), similarly to that described in example 46, received isopropyl ether (E/Z)-(S)-1-[2-[4- (amino-ethoxycarbonyl-methyl)-benzoylamine] -propionyl] -piperidine-4-biloxicasino acid as colorless foamy substance. MS (ion bombardment): 491 (M+H)+.

Example 61

From [[1-[N-(p-amidinophenoxy)-L-alanyl] -4-piperidinyl] oxy] acetic acid (see Journ. Med. Chem. 1992, 35, 4393-4407), similarly to that described in example 46, received the ethyl ester of (E/Z)-(S)-1-[2-[4-(amino-n-butoxycarbonylamino-methyl) -benzoylamine] -propionyl] -piperidine-4-biloxicasino acid as colorless foamy substance. []2D0= +37,4o(C = 0,8, EtOH). MS (ion bombardment): 505 (M+H)+.

Example 62

From [[1-[N-(p-amidinophenoxy)-L-alanyl]-4-piperidinyl]oxy] acetic acid (see Journ. Med. Chem. 199 is ebonyemmyo-methyl) -benzoylamine] -propionyl] -piperidine-4-biloxicasino acid as colorless foamy substance. []2D0= +40,0o(C = 0,9, EtOH). MS (ion bombardment): 507 (M+H)+.

Example 63

By the esterification of (S)-1-[2-(5-amino-imino-methyl-pyridine-2 - ylcarbonyl)-propionyl] -piperidine-4-biloxicasino acid (J. Med. Chem. 1992, 35, 4393-4407) tetrahydro-2H-Piran-4-I in the presence of p-toluenesulfonic acid after chromatographic purification of the crude product on silica gel RP 18 using a gradient of water/acetonitrile get p-toluensulfonate salt tetrahydropyran-4-silt ether (S)-1-[2-(5-amino-imino-methyl-pyridine-2-ylcarbonyl)-propionyl] -piperidine-4-biloxicasino acid. []2D0= +28,8o(C=0,5, MtOH). MS (ion bombardment): 462 (M+H)+.

Example 64

From (S)-1-[2-(5-amino-imino-methyl-pyridine-2-ylcarbonyl)- propionyl] -piperidine-4-biloxicasino acid, similarly to that described in example 46, receive isopropyl ether (E/Z)-(S)- 1-[2-(5-amino-ethoxycarbonylethyl-methyl-pyridine-2 - ylcarbonyl)-propionyl] -piperidine-4-biloxicasino acid, []2D0= +42,6o(C = 1,0, EtOH). TPL62-64oC. MS (EI): 492 (M+H)+.

Example 65

From [[1-(p-amidino-N-methylbenzamide)acetyl]-4-piperidinyl]oxy]- acetic acid (see europeancountries-methyl)-benzoyl] -methyl-amino] -acetyl] -piperidine-4-biloxicasino acid, MS (ion bombardment): 477 (M+H)+.

Example 66

From tert-butyl ether (E/Z)-(S)-1-[2-[4-(amino-methoxyimino - methyl)-benzoylamine] -propionyl] -piperidine-4-biloxicasino acid by treatment triperoxonane acid in dichloromethane get (E/Z)-(S)-1-[2-[4-(amino-methoxyimino-methyl)- benzoylamine] -propionyl] -piperidine-4-biloxicasino acid. TPL193-195oC. MS (ion bombardment): 407 (M+H)+.

The source material can be obtained in the following way:

a) Reaction of a combination of Z-Ala-OH with tert-butyl ether 4-piperidinecarboxylic acid (see Journ. Med. Chem. 1992, 35, 4393-4407), and then removing by hydrogenolysis of the Z-protective groups are tert-butyl ester 1-[[L-alanyl]-4-piperidinyloxy] acetic acid.

b) Interaction of the product preview stage 4 - cyano-benzoyl-chloride in the presence of sodium bicarbonate receive tert-butyl ether (S)-1-[2-[4-cyanobenzylidene] - propionyl]-piperidine-4-biloxicasino acid.

By sequential processing of the product preview stage of hydrogen sulfide in pyridine, methyliodide in acetone and the hydrochloride of O-methyl-hydroxylamine in DMF in the presence of triethylamine receive tert-bout is in the form of a viscous, a colorless oil. MS (ion bombardment): 463 (M+H)+.

Example 67

By the esterification of (E/Z)-(S)-1-[2-[4-(amino-methoxyimino - methyl)-benzoylamine] -propionyl] -piperidine-4-biloxicasino acid in the presence of concentrated sulfuric acid to obtain ethyl ester of (E/Z)-(S)-1-[2-[4-(amino-methoxyimino-methyl)-benzoylamine] -propionyl]-piperidine-4-biloxicasino acid as a colourless resin, MS (ion bombardment): 435 (M+H)+.

Example 68

From tert-butyl ether (S)-1-[2-[4-tert - butoxycarbonylamino-benzoylamine)-3-(4-hydroxy-phenyl)-propionyl] - piperidine-4-biloxicasino acid by treatment with formic acid to obtain (S)-1-[2-(4-aminomethyl-benzoylamine)-3-(4-hydroxy - phenyl)-propionyl] -piperidine-4-biloxicasino acid, []2D0= +19,4o(C = 0.5, and H2O). TPL166-168oC. MS (ISN): 454 (M-H)+.

The source material can be obtained by reaction mix tert-butyl ester 1-[[L-tyrosyl]-4-piperidinyloxy]acetic acid (example 56a)) with 4-tert-butoxycarbonylamino-benzoic acid in the presence of 1-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EADG).

Example 69

From tert-butyl ether (S)-1-[2-[4-tert - butoxycarbonyl processing first methyliodide/potassium carbonate, and then formic acid to obtain (S)-1-[2-(4-aminomethyl - benzoylamine)-3-(4-methoxy-phenyl)-propionyl] -piperidine-4 - biloxicasino acid. []2D0= +11,7o(C=0.5, and H2O). TPL130oC. MS (EI): 470 (M+H)+.

Example 70

By the esterification of (S)-1-[2-(4-aminomethyl-benzoylamine)-3-(4 - methoxy-phenyl)-propionyl] -piperidine-4-biloxicasino acid with isopropanol in the presence of sulfuric acid get isopropyl ether (S)-1-[2-(4-aminomethyl-benzoylamine)-3-(4-methoxy-phenyl)-propionyl] - piperidine-4-biloxicasino acid in the form of hemisulfate salt. []2D0= +5,1o(C=0.8, the H2O). TPL138-140oC. MS (EI): 512 (M+H)+.

Example 71

From tert-butyl ether (S)-1-[2-(5-aminomethyl - pyridine-2-ylcarbonyl)-3-(4-methoxy-phenyl)-propionyl] - piperidine-4-biloxicasino acid by treatment with formic acid to obtain (S)-1-[2-(5-aminomethyl-pyridine-2 - ylcarbonyl)-3-(4-methoxyphenyl)-propionyl] -piperidine-4 - biloxicasino acid, []2D0= +20,0o(or = 0.6, H2O). TPL174oC (decomposition). MS (ion bombardment): 471 (M+H)+.

The source material can be obtained by catalytic gidrirovaniya acid (see European application EP 505868) in the presence of palladium on coal in a mixture of methanol/water/acetic ether.

Example 72

From (S)-1-[2-(5-aminomethyl-pyridine-2-ylcarbonyl)-3-(4-methoxy - phenyl)-propionyl]-piperidine-4-biloxicasino acid by esterification with isopropanol as described in example 70, after acidification of the crude product with hydrochloric acid to obtain hydrochloride of isopropyl ether (S)-1-[2-(5-aminomethyl-pyridine-2-ylcarbonyl)- 3-(4-methoxy-phenyl)-propionyl] -piperidine-4-biloxicasino acid. TPL82-84oC (from diethyl ether). MS (ion bombardment): 513 (M+H)+.

Example 73

From tert-butyl ether (S)-4-[1-(4-tert-butoxycarbonylamino - piperidine-ylcarbonyl)-2-(4-hydroxy-phenyl)-ethylcarbamate]- piperidine-1-carboxylic acid by treatment with formic acid to obtain (S)-1-[3-(4-hydroxy-phenyl)-2-piperidine-4-mmoxiccillin - propionyl] -piperidine-4-biloxicasino acid. []2D0= +6,7o(C = 0.7 and H2O). TPL156oC (decomposition). MS (ion bombardment): 464 (M+H)+.

The source material can be obtained in the following way:

(a) By treatment of tert-butyl methyl ether 4-piperidinecarboxylic acid (see the pet-butyl-dicarbonate in dioxane in the presence of sodium liquor can be transformed into 1-tert(-butoxycarbonyl - piperidine-4-biloxicasino acid.

b) the Product of the preliminary stage using tert-butyl ester 1-[[L-tyrosyl] -4-piperidinyloxy]acetic acid (example 56a)) in the presence of 1-ethoxycarbonyl-2-isobutoxy-1,2-dihydroquinoline in dichloromethane can be attached to the reaction mix to tert-butyl ether (S)-4-[1-(4-tert-butoxycarbonylamino - piperidine-1-ylcarbonyl]-2-(4-hydroxy-phenyl)-ethylcarbamate] - piperidine-1-carboxylic acid. MS (ion bombardment): 620 (M+H)+.

Example 74

Interaction (S)-4-[2-[1-tert-butoxycarbonyl-piperidine-4 - mmoxiccillin] -3-(4-ethoxycarbonylmethoxy-1-yl)-3 - oxo-propyl]-phenyl ester 2-acetoxy-benzoic acid with formic acid after the addition of hydrochloric acid to the crude product receive hydrochloric acid salt (S)-4-[2-[1-tert-butoxycarbonyl - piperidine-4-mmoxiccillin] -3-(4-ethoxycarbonylmethoxy-piperidine - 1-yl)-3-oxo-propyl] -phenyl ester 2-acetoxy-benzoic acid. TPL74-76oC (decomposition). MS (ion bombardment): 654 (M+H)+.

The source material can be obtained in the following way:

a) Reaction of a combination of Z-Tyr-OH with ethyl ether 4-piperidinecarboxylic acid (receiving through acidic interesterification of teachingonline), subsequent interaction with the chloride of acetylsalicylic acid in the presence of potassium carbonate and then removing by hydrogenolysis of the Z-protective group to obtain (S)-4-[2-amino-3-(4-ethoxycarbonylmethoxy-piperidine-1-yl)-3-oxo - propyl] -phenyl ester 2-acetoxy-benzoic acid.

b) Reaction of a combination product preliminary stage with 1 - tert-butoxy-carbonyl-piperidine-4-biloxicasino acid (example 736)) in the presence of 1-ethoxycarbonyl-2-isobutoxy-1,2 - dihydroquinoline in dichloromethane receive (S)-4-[2-[1-tert - butoxycarbonyl-piperidine-4-mmoxiccillin]-3-(4 - ethoxycarbonylmethoxy-piperidine-1-yl)-3-oxo-propyl]-phenyl ester 2-acetoxy-benzoic acid. MS (ion bombardment): 754 (M+H)+.

Example 75

By the esterification of (E/Z)-(S)-1-[2-[4-(amino-hydroxyimino-methyl)- benzoylamine] -propionyl]-piperidine-4-biloxicasino acid in the presence of concentrated sulfuric acid to obtain ethyl ester of (E/Z)-(S)-1-[2-[4-(amino-hydroxyimino-methyl)-benzoylamine] -propionyl] -piperidine-4-biloxicasino acid in the form of vatoobraznye crystals. TPL205-207oC. MS (ion bombardment): 421 (M+H)+.

The source material can be obtained in the following way:

a) Ot the s (example 66) with hydroxylamine hydrochloride in methanol in the presence of methanolate sodium after stirring over night and normal processing receive tert-butyl ether (E/Z)-(S)-1-[2- [4-(amino-hydroxyimino-methyl)-benzoylamine]-propionyl] -piperidine-4 - biloxicasino acid. TPL193-194oC. MS (ion bombardment): 449 (M+H)+.

b) treating the product preview stage of formic acid at 50oC after crystallization from acetic ether get (E/Z)-(S)-1-[2-[4-(amino-hydroxyimino-methyl)-benzoylamine] - propionyl]-piperidine-4-biloxicasino acid. TPL176-178oC. MS (ISN): 391 (M+H)+.

Example 76

By the esterification of (E/Z)-(S)-1-[2-[4-amino-hydroxyimino-methyl)- benzoylamine] -propionyl] -piperidine-4-biloxicasino acid (example b)) in 2-propanol in the presence of concentrated sulfuric acid get isopropyl ether (E/Z)-(5)-1-[2-[4-(amino-hydroxyimino - methyl)-benzoylamine]-propionyl] -piperidine-4-biloxicasino acid in the form of vatoobraznye crystals. TPL205-207oC. MS (ion bombardment): 435 (M+H)+.

Example 77

220 mg of tert-butyl methyl ether[1-[4-[4-(tert-butoxycarbonylamino - imino-methyl)-phenyl]-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid and 3.4 ml of formic acid is stirred for 24 h at 20oC . Then the reaction mixture is evaporated in vacuo, the residue is dissolved in water and again evaporated. After crystallization from methanol receive 120 mg[1-[4-[4-(amino-imino-methyl)-phenyl] -4 - odny material can be obtained in the following way:

a) 4-(4-cyano-phenyl)-4-oxomethane acid activate in THF with 2-chloro-4,6-dimethoxy-1,3,5-triazine and N-methylmorpholine and then subjected to interaction with tert-butyl ether piperidine-4-biloxicasino acid, the result is tert-butyl ether [1-[4-(4-cyano-phenyl)-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid.

b) This broadcast transform in pyridine and triethylamine with hydrogen sulfide in tert-butyl ether [1-[4-oxo-4-(4-thiocarbamoyl-phenyl)- butyryl] -piperidine-4-yloxy]-acetic acid, TPL140oC.

in This last first use under the conditions in acetone, and then ammonium acetate and acetic acid in methanol and finally with di-tert-butyl-dicarbonate in DMF/triethylamine transform in tert-butyl ether[1-[4-[4-(tert-butoxycarbonylamino-imino - methyl)-phenyl] -4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid. MS: 518 (100, M+H)+.

Example 78

76 mg of ethyl ether[1-[4-[4-(tert-butoxycarbonylamino-imino - methyl)-phenyl]-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid are stirred in 0.5 ml of methylene chloride and 0.5 ml triperoxonane acid for 2 h at 20oC. Then the reaction mixture is evaporated in vacuo, the residue dissolve the Ute on the suction and dried. The result is 74 mg trifenatate (1:1) ethyl ester[1-[4-[4- (amino-imino-methyl)-phenyl]-4-oxo-butyryl]-piperidine-4-yloxy]- acetic acid, TPL188-190oC.

The source material can be obtained in the following way:

and) [1-[4-[4-(amino-imino-methyl)-phenyl] -4-oxo-butyryl]-piperidine - 4-yloxy]-acetic acid 1H HCl in ethanol was transferred to its ethyl ester.

b) This broadcast transform using di-tert-BUTYLCARBAMATE in DMF/triethylamine in the source material, TPL100oC.

Example 79

A mixture of 160 mg of the hydrochloride of isopropyl ether [1-[[[4-(amino-imino - methyl)-benzoyl]-(2-methoxyethyl)-amino]-acetyl]-piperidine-4 - yloxy]-acetic acid (1:1), 3.2 ml methylene chloride, and 2.6 ml of water and 0.6 ml of a saturated solution of sodium carbonate is treated with 0.036 ml of ethyl ether of Harborview acid and stirred for 2 h at 20oC. Then the reaction mixture is diluted with methylene chloride, washed with water and common salt solution, dried and evaporated in vacuum. After chromatography of the residue on silica gel using methylene chloride/isopropanol obtain 109 mg of isopropyl ether [1-[[[4-(ethoxycarbonyl-imino - methyl)-benzoyl]-(2-methoxy-ethyl)-amino] -acheter> The source material was obtained from [1-[[[4-(amino-imino-methyl)-benzoyl]-( 2-methoxyethyl)-amino] -acetyl] -piperidine-4-yloxy] -acetic acid (see European patent application EP 505868) in 1H HCl in isopropanol at 20oC.

Example 80

In the same way as described in example 79, from modedata isopropyl ester[1-[4-[4-(amino-imino-methyl)-phenyl]-4-oxo-butyryl]- piperidine-4-yloxy] -acetic acid get isopropyl ester[1-[4-[4-(ethoxycarbonyl-imino-methyl)-phenyl] -4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid, TPL86-89oC.

The source material can be obtained in the following way:

a) Tert. -butyl ether [1-[4-oxo-4-(4-thiocarbamoyl-phenyl)-butyryl]- piperidine-4-yloxy] -acetic acid split in methylene chloride and triperoxonane acid, resulting in a gain [1-[4-oxo-4-(4-thiocarbamoyl-phenyl)-butyryl]-piperidine-4-yloxy]- acetic acid, TPL203-207oC.

b) Of this acid with sulfuric acid in isopropanol get isopropyl ester [1-[4-oxo-4-(4-thiocarbamoyl-phenyl)- butyryl] -piperidine-4-yloxy]-acetic acid, TPL123-128oC.

in This broadcast, you first use under the conditions in acetone, and then ammonium acetate and acetic acid, isano in example 79, from modedata isopropyl ester[1-[4-[4-(amino-imino-methyl)-phenyl] -4 - oxo-butyryl]-piperidine-4-yloxy] -acetic acid and isobutyl ether of Harborview acid get isopropyl ester[1-[4-[4-(solutionline-imino-methyl)-phenyl]-4 - oxo-butyryl]-piperidine-4-yloxy]-acetic acid, TPL94oC.

Example 82

1.7 g of tert-butyl methyl ether (RS)-[1-[4-[4-(tert-butoxycarbonylamino - imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid is stirred for 8.5 ml of methylene chloride and 8.5 ml triperoxonane acid for 3 h at 20oC. After evaporation of the solvent in vacuo the residue is dissolved in water and the solution re-evaporated. After drying, the residue is thoroughly stirred in alcohol, filtered by suction and dried. The result is 1.13 g of triptoreline (1:1) (RS)-[1-[4-[4-(amino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl]-piperidine-4-biloxicasino acid, TPL217oC.

The source material can be obtained in the following way:

a) 4-(4-amino-phenyl)-2-methyl-4-oxomethane acid transform via the corresponding diazonium compound (reaction Sandmeyer) 4-(4-cyano-phenyl)-2-methyl-4-oxomethane acid, TPL137oC.

C) Of this product with hydrogen sulfide in pyridine/triethylamine receive tert-butyl ether (RS)-[1-[2-methyl-4-oxo-4-(4-thiocarbamoyl - phenyl)-butyryl]-piperidine-4-yloxy]-acetic acid, TPL152-155oC.

g) This broadcast first use under the conditions in acetone, and then ammonium acetate and acetic acid in methanol and finally with di-tert-butyl-dicarbonate in methylene chloride and water 532 (100, M+H).

Example 83

734 mg trifenatate (RS)-[1-[4-[4-(amino-imino-methyl)-phenyl]-2 - methyl-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid is stirred in 15 ml of 1H HCl in isopropanol for 19 hours at a temperature of about 20oC. After evaporation of the solvent and drying under high vacuum to obtain 650 mg of the hydrochloride of isopropyl ether (RS)-[1-[4-[4-(amino-imino-methyl)-phenyl]-2-methyl-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid (1:1) as a hygroscopic amorphous powder, MS: 376 (100, M+H).

Example 84

In the same way as described in example 79, from the hydrochloride isopropyl ether (RS)-[1-[4-[4-(amino-imino-mate is ccarbonate-imino-methyl)-phenyl - 2-methyl-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid in the form of resinous foam-like substance, MS: 490 (100, M+H).

Example 85

In the same way from the same source material using isobutyl ether of Harborview acid get isopropyl ether (RS)-[1-[4-[4-(solutionline-imino-methyl)-phenyl] -2-methyl-4-oxo - butyryl]-piperidine-4-yloxy] -acetic acid in the form of a foamy substance, MS: 518 (100, M+H).

Example 86

209 mg of ethyl ester of (RS)-2-[4-(tert-butoxycarbonylamino - imino-methyl)-benzoyl] -4-(4-ethoxycarbonylmethoxy-phenyl)-4-oxo - butyric acid and 4.2 ml of formic acid was incubated for 6.5 h at 20oC. Then the reaction mixture is evaporated, the residue is dissolved in water and again evaporated. The dried residue is thoroughly stirred in a simple ether and filtered by suction. The result is 158 mg formate ethyl ester of (RS)-2-[4-(amino-imino-methyl)- benzoyl] -4-(4-ethoxycarbonylmethoxy)-4-oxo-butyric acid (1:1), TPL162oC.

The source material can be obtained in the following way:

a) Of the ethyl ester of 4-cyanobenzoic acid ethyl ester [4-(bromoacetyl)phenoxy] -acetic acid get in acetone in the presence of potassium carbonate ethyl ester of (RS)-2-(4 - cyano-benzoyl)-4-[(4-ethoxycarbonylmethoxy)-phenyl]-4-oxo-butyric to the ethyl ester of (RS)-4-(4-ethoxycarbonylmethoxy-phenyl)- 4-oxo-2-(4-thiocarbamoyl-benzoyl)-butyric acid, MS: 472 (100, M+H).

in This product, you first use under the conditions in acetone, and then ammonium acetate and acetic acid in methanol and finally with di-tert-butyl - dicarbonate in methylene chloride and an aqueous solution of sodium carbonate transform in ethyl ether (RS)-2-[4-(tert - butoxycarbonylamino-imino-methyl)-benzoyl]-4-(4-ethoxycarbonylmethoxy - phenyl)-4-oxo-butyric acid, MS: 555 (100, M+H).

Example 87

In the same way as described in example 79, from formate ethyl ester of (RS)-2-[4-(amino-imino-methyl)-benzoyl] -4-(4 - ethoxycarbonylmethoxy-phenyl)-4-oxo-butyric acid and ethyl ester of Harborview acid get ethyl ester of (RS)-2-[4-(ethoxycarbonyl-imino-methyl)-benzoyl] -4-(4 - ethoxycarbonylmethoxy-phenyl)-4-oxo-butyric acid, MS: 527 (100, M+H).

Example 88

3.8 g of ethyl ester of 4-[3-(4-thiocarbamoyl-benzoyl)-propionyl]- phenoxyalkanoic acid, 76 ml of acetone and 5.9 ml under the conditions stirred for 3 h at 45oC. Then the reaction mixture is evaporated, the residue is dissolved in 117 ml of methanol, treated with 2.2 g of ammonium acetate and 0.54 ml of acetic acid and continue to stir for 3.5 h at 60oC. Then the reaction mixture prior to the crystallization of the concentrate is nitrile. The result is 2 g acetate ethyl ester[4-[4-[4-(amino-imino-methyl)-phenyl] -4-oxo-butyryl] -phenoxy] -acetic acid (1:1), TPL212oC.

The source material can be obtained in the following way:

a) a suspension of 14.4 g of anhydrous magnesium chloride in 151 ml of dry methylene chloride 25.2 ml tert-butyl methyl ether acetoxyl acid at the 5oC is added dropwise to 24.4 ml of pyridine. After 15 min add 25 g of 4-cyanobenzaldehyde, and then stirred for 2 h at 20oC. For further processing dilute acetic ether, washed with ice-cold diluted hydrochloric acid and water, dried and evaporated in vacuum. The residue is dissolved in 600 ml of tert-butyl methyl ether with vigorous stirring, treated with 160 ml of 10% ammonia solution. After 2 h share phase, washed with water, dried and evaporated in vacuum. After filtration on silica gel and crystallization from pentane get to 13.1 g of pure tert-butyl ester 3-(4-cyanophenyl)-3-oxo-propionic acid, TPL82-83oC.

b) This transform ether in acetone in the presence of potassium carbonate using ethyl ester [4-(bromoacetyl)-phenoxy]-acetic acid ethyl ester (RS)-[4-[3-tert-butoxycarbonylamino 4 hours in formic acid at 20oC, evaporated, evaporated with toluene and heated for 1.5 h in toluene to 70oC. the result is the ethyl ester [4-[3-(4-cyano-benzoyl)-propionyl]-phenoxy]-acetic acid, TPL115-116oC.

g) This broadcast transform in pyridine and triethylamine with hydrogen sulfide in the ethyl ester of 4-[3-(4-thiocarbamoyl - benzoyl)-propionyl]-phenoxyalkanoic acid, TPL179-180oC.

Example 89

In the same way as described in example 79, from acetate ethyl ester[4-[4-[4-(amino-imino-methyl)-phenyl] -4 - oxo-butyryl]-phenoxy]-acetic acid getting ethyl ester[4-[4-[4-(ethoxycarbonyl-imino-methyl)-phenyl]-4-oxo-butyryl]- phenoxy]-acetic acid, TPL167-168oC.

Example 90

The interaction of dimethyl ether [[4-(p-cyan-N - methylbenzamide)acetyl-o-phenylene] dioxy] luxusni acid (see Journ. Med. Chem. 1992, 35, 4393-4407) with hydroxylamine hydrochloride in methanol in the presence of methanolate sodium after stirring overnight and processing receive dimethyl ether [[[4-(p-amino-hydroxyimino-methyl)-methylbenzamide]acetyl - o-phenylene] dioxy] luxusni acid as colorless solid. TPL58-60oC. MS (ion bombardment is pional] -piperidine-4-yloxy]-acetylamino] -acetic acid with hydroxylamine hydrochloride in methanol in the presence of methanolate sodium after stirring overnight, processing and chromatographic purification on silica gel (dichloromethane/methanol 6:1) to obtain methyl ester (Z)-(S)-[2- [1-[2-[4-(amino-hydroxyimino-methyl)-benzoylamine]-propionyl]- piperidine-4-yloxy] -acetylamino] -acetic acid. TPL168-172oC. MS (ion bombardment): 464 (M+H)+.

The source material can be obtained in the following way:

(a) By treatment of tert-butyl methyl ether 1-benzyloxycarbonyl - piperidine-4-biloxicasino acid (see Journ. Med. Chem. 1992, 35, 4393-4407) formic acid and then the interaction of the formed product hydrochloride glycine ethyl ester in the presence of hexafluorophosphate O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium (HBTU) and N - methylmorpholine get ethyl ester [[1-benzyloxycarbonyl]- piperidine-4-yloxy-acetylamino]-acetic acid as colorless oil. MS (ion bombardment): 379 (M+H)+.

b) By catalytic hydrogenation of the product of the preliminary stage and the subsequent reaction mix with Z-Ala-OH in the presence of HBTU and N-methylmorpholine receive (S)-benzyl-[2-[4- [[[[etoxycarbonyl]methylamino]-carbonyl] methoxy] piperidinyl] -1-oxopropyl] carbamate in the form of a yellowish oil. MS (ion bombardment): 450 (M+H)+.

Example 92

By the esterification of (Z)-(S)-1-[2-[4-(amino-hydroxyimino-methyl)- benzoylamine] -propionyl] -piperidine-4-biloxicasino acid (example 75) in 1-hexanol in the presence of concentrated sulfuric acid to obtain n-hexyl ester of (Z)-(S)-1-[2-[4-(amino-hydroxyimino-methyl)- benzoylamine]-propionyl] -piperidine-4-biloxicasino acid in the form of vatoobraznye crystals. TPL169-171oC. MS (ion bombardment): 477 (M+H)+.

Example 93

The interaction of (Z)-(S)-1-[2-[4-(amino-hydroxyimino-methyl)- benzoylamine] -propionyl] -piperidine-4-biloxicasino acid (example 75) with isobutyl ether (E/Z)-2-methyl bromide-Penta-2-ene acid (see Journ. Antibiotics, 1992, 45, 1358-1364) in the presence of triethylamine get isobutyl ether (E/Z)-(S)-2-[[1-[2-[4-[(Z)-(amino - hydroxyimino-methyl)-benzoylamine] -propionyl] -piperidine-4-yloxy]- acetoxymethyl]Penta-2-ene acid as colorless crystals. TPL94-96oC. MS (ion bombardment): 561 (M+H)+.

Example 94

The interaction of (Z)-(S)-1-[2-[4-(amino-hydroxyimino-methyl)- benzoylamine] -propionyl] -piperidine-4-biloxicasino acid (example 75) with CHLOROTHALONIL ether pavlinovoi acid in the presence of co] -propionyl] -piperidine-4-biloxicasino acid as colorless crystals. TPL126oC. MS (ion bombardment): 507 (M+H)+.

Example 95

The interaction of (Z)-(S)-1-[2-[4-(amino-hydroxyimino-methyl)- benzoylamine]-propionyl]-piperidine-4-biloxicasino acid (example 75) with 1-Iodate-isopropylcarbonate (see Journ. Antibiotics 1987, 40, 370 - 384) in the presence of dicyclohexylamine in dimethylacetamide get (R/S)-1-isopropoxycarbonyl-ethyl ester (2)-(S)-1-[2-[4- (amino-hydroxyimino-methyl)-benzoylamine] -propionyl]-piperidine - 4-biloxicasino acid as a colourless powder. TPL113oC (decomposition). MS (ion bombardment): 523 (M+H)+.

Example 96

The interaction of (Z)-(S)-1-[2-[4-(amino-hydroxyimino-methyl)- benzoylamine] -propionyl] -piperidine-4-biloxicasino acid (example 75) with methanol as described in example 75, get methyl ester (Z)-(S)-1-[2-[4-(amino-hydroxyimino-methyl)- benzoylamine] -propionyl] -piperidine-4-biloxicasino acid as a colourless powder. TPL177-178oC (decomposition). MS (ion bombardment): 407 (M+H)+.

Example 97

Based on tert-butyl ether (S)-1-[2-(5-cyan-pyridine-2 - ylcarbonyl)-propionyl]-piperidine-4-biloxicasino acid (see Journ. Med. Chem. 1992, 35, 4393-4407), described in example 75 metodiki-4-yloxy] acetic acid as colorless crystals. TPL148-150oC. MS (ion bombardment): 422 (M+H)+.

Example 98

Based on tert-butyl ether (S)-1-[3-(4-hydroxy-phenyl)-2- [4-cyan-benzoylamine] -propionyl] -piperidine-4-yloxy-acetic acid (example b)) as described in example 75 method get ethyl ester (Z)-(S)-[1-[2-[4-(amino-hydroxyimino-methyl)-benzoylamine] -3- (4-hydroxyphenyl)-propionyl] -piperidine-4-yloxy] acetic acid as colorless crystals. TPL107-110oC. MS (ion bombardment): 513 (M+H)+.

Example 99

By the esterification of [[1-[N-(p-amidinophenoxy)-L-arnitel]- piperidine-4-yl] oxy]acetic acid (see Journ. Med. Chem. 1992, 35, 4393-4407) ethanol in the presence of hydrochloric acid and the subsequent interaction of the resulting product with ethyl ether of Harborview acid as described in example 46, receive the ethyl ester of (E/Z)-(S)-[1-[2-[4-(amino - ethoxycarbonyl-methyl)-benzoylamine] -5-ethoxycarbonyl - pentanoyl]-piperidine-4-yloxy] acetic acid as a colorless foamy substance. MS (ion bombardment): 592 (M+H)+.

Example 100

The interaction of ethyl ether (S)-[1-[2-[4-cyan - benzoylamine]-5-benzoylamino-pentanoyl] -piperidine-4-yloxy] acetic acid, with hydrochlor the-benzoylamine] -5-benzoylamino-pentanoyl]- piperidine-4-yloxy] acetic acid as a colourless resin. MS (ion bombardment): 568 (M+H)+.

The source material can be obtained in the following way:

a) Interaction tert-butyl ether [[1-[N5-(tert - butoxycarbonyl)-L-arnitel] -piperidine-4-yl]oxy]acetic acid (see Journ. Med. Chem. 1992, 35, 4393 - 4407) chloride 4-lambertini acid in a two-phase mixture of dichloromethane and saturated sodium hydrogen carbonate solution after processing receive tert-butyl ether (S)-[1-[2-[4-lambertiana] -5-tert - butoxycarbonylamino-pentanoyl] -piperidine-4-yloxy] acetic acid. MS (ion bombardment): 559 (M+H)+.

b) Interaction of the product preview stage with triperoxonane acid in dichloromethane receive (S)-[1-[2-[4- lambertiana]-5-amino-pentanoyl] -piperidine-4-yloxy] acetic acid as a colourless resin. MS (ion bombardment): 403 (M+H)+.

By esterification of the product preview stage of ethanol in the presence of concentrated sulfuric acid and subsequent interaction with the chloride of benzoic acid in a two-phase mixture of dichloromethane and a saturated solution of sodium bicarbonate receive the ethyl ester of (S)-[1-[2-[4-lambertiana] -5-benzoylamino-pentanoyl] - piperidine-4-yloxy]EP 101

The interaction of ethyl ether (S)-[1-[2-[4-cyan-benzoylamine] -5-ethoxycarbonyl-pentanoyl] -piperidine-4-yloxy] acetic acid hydrochloride pyroxyline in the presence methanolate sodium as described in example 75, get ethyl ester (Z)-(S)-[1-[2-[4-(amino-gidroksilaminami)-benzoylamine] -5-ethoxycarbonyl-pentanoyl]-piperidine-4-yloxy] acetic acid as a colorless foamy substance. MS (ion bombardment): 536 (M+H)+.

The source material can be obtained in the following way:

By the esterification of (S)-[1-[2-[4-lambertiana]-5 - aminopentyl-yl]-piperidine-4-yloxy] acetic acid (example 100) ethanol in the presence of concentrated sulfuric acid and subsequent interaction with ethyl ether of Harborview acid in a two-phase mixture of dichloromethane and 1H solution of sodium hydroxide receive the ethyl ester of (S)-[1-[2-[4-cyan - benzoylamine] -5-ethoxycarbonyl-pentanoyl] -piperidine-4 - yloxy] acetic acid. MS (ion bombardment): 503 (M+H)+.

Example 102

The interaction of ethyl ether (S)-[1-[2-[4-cyan-benzoylamine]- 5-(3-butyl-ureido)-pentanoyl]-piperidine-4-yloxy]acetic acid with hydroxylamine hydrochloride in the presence of methylamino] -5-(3-butyl-ureido)-pentanoyl] - piperidine-4-yloxy] acetic acid as a colorless foamy substance. MS (ion bombardment): 563 (M+H)+.

The source material can be obtained in the following way:

By the esterification of (S)-[1-[2-[4-lambertiana]-5 - aminopentyl-yl]-piperidine-4-yloxy]acetic acid (example 100) ethanol in the presence of concentrated sulfuric acid and subsequent interaction with the n-utilitarianism in a two-phase receive ethyl ester (S)-[1-[2-[4-lambertiana] -5-(3 - butyl-ureido)-pentanoyl] -piperidine-4-yloxy] acetic acid. MS (ion bombardment): 530 (M+H)+.

A basic example 103

Based on tert-butyl ester 4-piperidinecarboxylic acid and (S)-2-benzyloxycarbonylamino-butyric acid, by the method described in Journ. Med. Chem. 1992, 35, 4393-4407, get a salt of formic acid (S)-[1-[2-[4-(amino-imino-methyl)-benzoylamine]- butyryl]-piperidine-4-yloxy] acetic acid as colorless crystals. TPL240oC (decomposition). MS (ion bombardment): 391 (M+H)+.

A basic example 104

By the esterification of (S)-[1-[2-[4-(amino-imino-methyl)-benzoylamine]- butyryl] -piperidine-4-yloxy]acetic acid (example 103) in ethanol in the presence of concentrated ser is-4-yloxy] acetic acid as colorless crystals. TPL256-260oC (decomposition). MS (ion bombardment): 419 (M+H)+.

Example 105

The interaction of ethyl ether (S)-[1-[2-[4-(amino-imino-methyl)- benzoylamine] -butyryl] -piperidine-4-yloxy]acetic acid (example 104) with n-butyl ether of Harborview acid in a two-phase mixture of dichloromethane and a saturated solution of sodium bicarbonate receive the ethyl ester of (E/Z)-(S)-[1-[2-[4-(amino-n-butoxycarbonylamino-methyl)- benzoylamine]-butyryl]-piperidine-4-yloxy] acetic acid as a colorless foamy substance. MS (ion bombardment): 519 (M+H)+.

Example 106

By the esterification of (Z)-(S)-[1-[2-[4-(amino-hydroxyimino-methyl)- benzoylamine] -butyryl] -piperidine-4-yloxy] acetic acid in ethanol in the presence of concentrated sulfuric acid to obtain ethyl ester (Z)-(S)-[1-[2-[4-(amino-hydroxyimino-methyl)- benzoylamine] -butyryl]-piperidine-4-yloxy]acetic acid as a colorless foamy substance. MS (ion bombardment): 435 (M+H)+.

The source material can be obtained in the following way:

a) Interaction tert-butyl ether (S)-[1-[2-aminobutanol]-piperidine-4-yloxy] acetic acid (receiving is similar to the method described in Journ. Med. Chem. ]- piperidine-4-yloxy]acetic acid. MS (EI): 429 (M+).

b) Interaction of the product preview stage with hydroxylamine hydrochloride get tert-butyl ester (Z)-(S)-[1- [2-[4-(amino-hydroxyimino-methyl)-benzoylamine] -butyryl] -piperidine-4 - yloxy]acetic acid. MS (ion bombardment): 463 (M+H)+.

C) treating the product preview stage of formic acid to obtain (Z)-(S)-[1-[2-[4-(amino-hydroxyimino - methyl)-benzoylamine]-butyryl] -piperidine-4-yloxy] acetic acid as a colorless foamy substance. MS (ion bombardment): 407 (M+H)+.

A basic example 107

Based on tert-butyl ester 4-piperidinecarboxylic acid and Z-Me-Ala-OH, by the method described in Journ. Med. Chem. 1992, 35, 4393-4407 receive (S)-[1-[2-[[4-(amino-imino-methyl)- benzoyl]-methylamino]-propionyl] -piperidine-4-yloxy]acetic acid as a colourless resin. MS (ion bombardment): 391 (M+H)+.

Example 108

From 1-tert-butoxycarbonyl-piperidine-4-biloxicasino acid (example 73) and tert-butyl ester 1-[[L-alanyl]-4-piperidinyloxy] acetic acid (example 66) as described in example 73 with the method get (S)-[1-[2-(piperidine-4-yloxy-acetamido)-propionyl] -piperidine-4-yloxy] acetic acid bestv�-3-[1-[2-[4-cyan-benzoyl - amino]-propionyl] -piperidine-4-yl] propionic acid hydrochloride, hydroxylamine, as described in example 75, get ethyl ester (Z)-(S)-3-[1-[2-[4-(amino-hydroxyimino - methyl)-benzoyl-amino]-propionyl]-piperidine-4-yl] propionic acid as colorless crystals. TPL194-195oC. []2D0= +75,6o(C=1, acetic acid). MS (ion bombardment): 419 (M+H)+.

The source material can be obtained in the following way:

(a) By the esterification of 3-[piperidine-4-yl]-propionic acid (see Journ. Org. Chem. 1945, 10, 562) ethanol in the presence of concentrated sulfuric acid and subsequent reaction combination with Z-Ala-OH in the presence of 1-ethoxycarbonyl-2-isobutoxy-1,2 - dihydroquinoline (AIDG) in dichloromethane receive the ethyl ester of 3-[1- (2-benzyloxycarbonylamino-propionyl)-piperidine-4-yl] -propionic acid as colorless oil. MS (ion bombardment): 391 (M+H)+.

b) By catalytic hydrogenation of the product of the preliminary stage in ethanol in the presence of 10% Pd/C and the subsequent interaction with 4-siebentischwald get ethyl ester (S)-3-[1-[2-[4-cyan-benzoyl-amino] -propionyl] - piperidine-4-yl] propionic acid as colorless crystals. TPL108-109oC. MS (EI): 385 (M)+.

Example 110

Through the one-4-yl]- amino] -acetic acid in water/acetic acid 9:1 in the presence of 10% Pd/C receive (S)-[[acetyl-1-[2-[4-(amino-imino-methyl)- benzoyl-amino]-propionyl] -piperidine-4-yl] -amino] acetic acid as a colorless powder. TPLover 230oC (decomposition). MS (ion bombardment): 418 (M+H)+.

The source material can be obtained in the following way:

a) Interaction of N-benzyloxycarbonyl-4-piperidone hydrochloride glycine ethyl ester in the presence of sodium borohydride and subsequent acylation of the product with acetic anhydride get ethyl ester acetyl-[1-[benzyloxycarbonyl] -piperidine-4-yl]-aminouksusnoy acid as a colourless oil.

b) By catalytic hydrogenation of the product of the preliminary stage in the presence of 10% Pd/C in ethanol and subsequent reactions combination with Z-Ala-OH in the presence of 1-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EADG) receive the ethyl ester of (S)-[[[acetyl-1-[2-benzyloxycarbonyl-amino] -propionyl] -piperidine-4-yl]-amino] acetic acid as a colorless oil. MS (ion bombardment): 456 (M+Na)+.

b) By catalytic hydrogenation of the product preview stage using 10% Pd/C in ethanol in the presence of acetic acid and subsequent interaction with 4 - siebentischwald in a two-phase mixture of dichloromethane and a saturated solution of sodium bicarbonate receive the ethyl ester of (S)-[[ceasesto. MS (ion bombardment): 428 (M+H)+.

g) the Interaction of the product preview stage with hydroxylamine hydrochloride and subsequent saponification sodium lye obtain (Z)-(S)-[[acetyl-1-[2-[4-(amino-hydroxyimino-methyl)-benzoyl - amino] -propionyl] -piperidine-4-yl] -amino] acetic acid as colorless crystals. TPLover 270oC (decomposition). MS (ion bombardment): 434 (M+H)+.

Example 111

In the same way as described in example 110 using di-tert-butyl-dicarbonate instead of acetic anhydride get ethyl ester (Z)-(R/S)-[[tert-butoxycarbonyl-1-[2-[4-(amino-hydroxyimino - methyl)-benzoyl-amino]-propionyl]-piperidine-4-yl]-amino]acetic acid as a colorless foamy substance. MS (ion bombardment): 520 (M+H)+.

Example 112

By the esterification of (Z)-[l-[2-[4-[amino-hydroxyimino-methyl]- phenylcarbamoyl] -acetyl] -piperidine-4-yloxy] -acetic acid ethanol ethyl ester (Z)-[1-[2-[4-[amino - hydroxyimino-methyl]-phenylcarbamoyl]-acetyl] -piperidine-4 - yloxy]-acetic acid as colorless crystals. TPL180oC (decomposition). MS (ion bombardment): 407 (M+H)+.

Source material mo who have 2-[4-cyan-phenylcarbamoyl]-acetic acid.

b) Reaction of a combination product preliminary stage with tert-butyl ether 4 - piperidinecarboxylic acid (see Journ. Med. Chem. 1992, 35, 4393-4407) in the presence of hexafluorophosphate O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium (HBTU) and N-methylmorpholine receive tert-butyl ether [1-[2-[4-cyan - phenylcarbamoyl]-acetyl]-piperidine-4-yloxy]-acetic acid. MS (EI): 401 (M+).

the Interaction of the product preview stage with hydroxylamine hydrochloride as described in example 75, receive tert-butyl ether (Z)-[1-[2-[4-[amino-hydroxyimino-methyl] -phenylcarbamoyl] -acetyl]-piperidine-4-yloxy] -acetic acid. TPL161-163oC. MS (ion bombardment): 435 (M+H)+.

g) By treatment of the product preview stage of formic acid to obtain (Z)-[1-[2-[4-[amino-hydroxyimino-methyl] -phenylcarbamoyl] -acetyl] -piperidine-4-yloxy] -acetic acid as colorless crystals. TPL133-135oC. MS (ISN): 377 (M-H)+.

Example 113

By catalytic hydrogenation of ethyl ester of (Z)- [1-[2-[4-[amino-hydroxyimino-methyl]-phenylcarbamoyl]-acetyl] -piperidine-4 - yloxy] -acetic acid (example 112) in the presence of 10% Pd/C in ethanol/acetic acid 15:1 get ACET is the notes in the form of colorless crystals. TPL191-192oC. MS (ion bombardment): 391 (M+H)+.

Example 114

Interaction ethyl ester{[1-[2-[4-[amino-imino-methyl]- phenylcarbamoyl] -acetyl] -piperidine-4-yloxy] -acetic acid (example 113) with ethyl ether of Harborview acid in the presence of 0.2 H sodium lye receive the ethyl ester of (E/Z)-[1-[2-[4- [amino-ethoxycarbonylethyl-methyl]-phenylcarbamoyl]-acetyl] -piperidine-4-yloxy]-acetic acid as colorless powder. TPL96-102oC. MS (ion bombardment): 463 (M+H)+.

Example 115

By the esterification of (Z)-(S)-[1-[2-[4-[amino-hydroxyimino-methyl]- benzyloxy] -propionyl] -piperidine-4-yloxy] -acetic acid ethanol ethyl ester (Z)-(S)-[1-[2-[4-[amino-hydroxyimino-methyl] - benzyloxy]-propionyl] -piperidine-4-yloxy] -acetic acid as colorless crystals, []2D0=- 27.3 hwto(C=1, ethanol). TPL137 - 138oC. MS (ion bombardment): 408 (M+H)+.

The source material can be obtained in the following way:

(a) the Interaction of ethyl ester of (L)-(-)-lactic acid with 4-bromomethylbiphenyl in DMF in the presence of silver oxide and subsequent saponification of the product 1H sodium lye receive (S)-2-(4-cyan-the Anna in example 112 b), C) and d) transformation of the product preview stage of get (Z)-(S)-[1-[2-[4-[amino - hydroxyimino-methyl] -benzyloxy] -propionyl] -piperidine-4-yloxy] -acetic acid. MS (ion bombardment): 380 (M+H)+.

Example 116

170 mg of hydroxylamine hydrochloride, and 10.8 ml of DMSO and 0.71 ml of triethylamine is stirred for 10 min at 20oC handle 578 mg ethyl ester [1-[4-(4-cyano-phenyl)-4-oxo - butyryl]-piperidine-4-yloxy]-acetic acid and continue to stir for 20 h at 20oC. Then the reaction mixture is diluted with acetic ether and the solution washed with water and saturated common salt solution, dried and evaporated in vacuum. After chromatography of the residue on silicagel using methylene chloride/ethanol 96:4 obtain 343 mg of ethyl ether (E)/(Z)-[1- [4-[4-(amino-hydroxyimino-methyl)-phenyl]-4-oxo-butyryl]- piperidine-4-yloxy]-acetic acid, TPL166-167oC.

The source material was obtained in the following way:

a) Tert-butyl ether [1-[4-(4-cyano-phenyl)-4-oxo-butyryl]- piperidine-4-yloxy] -acetic acid (example 77A)) in formic acid at 50oC split to [1-[4-(4-cyano-phenyl)-4-oxo-butyryl]- piperidine-4-yloxy]-acetic acid, TPL160-165oC.

Eridan-4-yloxy] - acetic acid, TPL79-83oC.

Example 117

In the same way as described in example 79, from the hydrochloride isopropyl ether (RS)-[1-[4-[4-(amino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid and di-tert-butyl-dicarbonate get isopropyl ether (RS)-[l-[4-[4-(tert-butoxycarbonylamino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid in the form of resinous foam-like substance, MS: 518 (100, M+H).

Example 118

279 mg of ethyl ether (E)/(Z)-[1-[4-[4-(amino-hydroxyimino - methyl)-phenyl] -4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid and 2.8 ml of DMSO, 140 mg of hydroxylamine hydrochloride and 0.28 ml of triethylamine is stirred for 2 days at 20oC. Then the solution was diluted with acetic ether, washed with water and common salt solution, dried and evaporated in vacuum. After chromatography of the residue on silica gel using hexane/acetone 1:2 obtain 207 mg of ethyl ether[1-[4-[4-(E)/(Z)-(amino-hydroxyimino-methyl)- phenyl]-4-(E)/(7)-hydroxyimino-butyryl]-piperidine-4-yloxy]- uksusnoi acid in the form of resinous foam-like substance, MS: 421 (100, M+H).

Example 119

190 mg of ethyl ether (E)/(Z)-[1-[4-[4-(amino-hydroxyimino - methyl)-phenyl]-4-oxo-bout is of 4 hours at 20oC. After the addition of 0.25 ml of the ethanol solution continued to stir for 20 min, then evaporated. From ethanol obtain 170 mg of ethyl ether (E)/(Z)-[1-[4-[4-(acetoxy - imino-amino-methyl)-phenyl] -4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid with TPL134-135oC.

Example 120

180 mg of ethyl ether (E)/(Z)-[1-[4-[4-(amino-hydroxyimino - methyl)-phenyl]-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid, 3,52 ml of acetone and 0.88 ml of formic acid is stirred for 24 h at 60oC. Then the reaction mixture is evaporated until dry and the residue chromatographic using methylene chloride/ethanol 97:3 on silica gel. The result is 152 mg ethyl ester[1-[4-[4-(5,5-dimethyl-4,5-dihydro-1,2,4-oxadiazol-3 - yl)-phenyl]-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid in the form of a foamy substance. MS: 445 (50, M+H).

Example 121 Analogously to example 116 ethyl ester (R)-[1-[4-(4-cyano-phenyl)-2-methyl-4-oxo-butyryl] -piperidine - 4-yloxy] -acetic acid getting ethyl ester (R)-(E)/(Z)- [1-[4-[4-(amino-hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo - butyryl] -piperidine-4-yloxy]-acetic acid, TPL172 - 173oC []2D0= +83,2o(MeOH, C = 0,5%).

Source material moility in formic acid is obtained 4-piperidinecarboxylic acid, TPL>270oC.

b) This acid 5H ethanol HCl was transferred to the hydrochloride of the ethyl ester of 4-piperidinecarboxylic acid, TPL104-106oC.

in) From tert-butyl ether 3-(4-cyano-phenyl)-3-oxo-propionic acid isobutyl ester (R)-2-tripterocalyx - propionic acid in tetrahydrofuran in the presence of bis-(trimethylsilyl)-amide sodium get isobutyl ester 2-(R)-3(R,S)-3-tert-butoxycarbonyl-4-(4-cyano-phenyl)-2-methyl-4-oxo - butyric acid.

g) Of this ester by heating to 45oC in formic acid is obtained isobutyl ether (R)-4-(4-cyano-phenyl)-2-methyl-4-oxo-butyric acid, []2D0=+21o(methanol, C=0.5 per cent).

d) This broadcast omelet in aqueous THF with lithium hydroxide to (R)-4-(4-cyano-phenyl)-2-methyl-4-oxo-butyric acid. TPL125-126oC []2D0= +37,4o(methanol, C = 0.5 per cent).

e) Reaction of a combination of (R)-4-(4-cyano-phenyl)-2-methyl-4-oxo - butyric acid hydrochloride ethyl ester 4 - piperidinecarboxylic acid get ethyl ester (R)-[1-[4- (4-cyano-phenyl)-2-methyl-4-oxo-butyryl]-piperidine-4-yloxy]- acetic acid, TPL97-98oC []2D0= +91,8o(the co-butyryl]-piperidine-4-yloxy]-acetic acid obtain tert-butyl ether (E)/(Z)-[1-[4-[4-(amino - hydroxyimino-methyl)-phenyl]-4-oxo-butyryl]-piperidine-4-yloxy] -acetic acid, TPL188oC.

Example 123

434 mg of tert-butyl methyl ether R)-[1-[4-[4-(tert - butoxycarbonylamino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] - piperidine-4-yloxy]-acetic acid is stirred 4.4 ml of methylene chloride and 4.4 ml triperoxonane acid for 1 h at 20oC. Then the solution is evaporated, the residue is dissolved in water and the solution re-evaporated. After crystallization from acetonitrile get 332 mg trifenatate (1:1) (R)-[1-[4-[4-(amino-imino-methyl)-phenyl] - 2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] acetic acid, TPL212oC []2D0= +69,0o(methanol, C=0.5 per cent).

The source material can be obtained in the following way:

a) Reaction of a combination of (R)-4-(4-cyano-phenyl)-2-methyl-4-oxo - butyric acid tert-butyl ester, piperidine-4-biloxicasino acid get tert-butyl ether (R)-[1-[4-(4-cyano-phenyl)-2 - methyl-4-oxo-, butyryl]-piperidine-4-yloxy] -acetic acid, TPL142oC []2D0= +83,2o(methanol, C= 0.5 per cent).

b) With hydrogen sulfide in pyridine/triethylamine of the above ester receive tert-butyl ether (R)-[1-[2-methyl-4-oxo-4-(4-micrbiol-phenyl)-butyryl] -piperidine-4-yloxy]-acetic acid in vidastat first methyliodide in acetone, then with ammonium acetate and acetic acid in methanol and finally with di-tert-butyl-dicarbonate in methylene chloride and an aqueous solution of sodium carbonate transform in the source material, MS: 532 (100, M+H), []2D0= +64,4o(methanol, C=0.5 per cent).

Example 124

Analogously to example 116 ethyl ester (RS)-[1-[4-(4-cyano - phenyl)-3-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid getting ethyl ester (E)/(Z)-(RS)-[1-[4-[4-(amino - hydroxyimino-methyl)-phenyl]-3-methyl-4-oxo-butyryl] -piperidine-4 - yloxy]-acetic acid in the form of a foamy substance, MS: 420 (100, M+H).

The source material can be obtained in the following way:

a) (RS)-4-(4-amino-phenyl)-3-methyl-4-oxo-butyric acid using the reaction of Sandmeyer transform into (RS)-4-(4-cyano - phenyl)-3-methyl-4-oxo-butyric acid, TPL110-113oC.

b) This latest expose of combination reaction with ethyl ester hydrochloride 4-piperidinecarboxylic acid, which receive the ethyl ester of (RS)-[1-[4-(4-cyano - phenyl)-3-methyl-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid, MS: 387 (100, M+H).

Example 125

Analogously to example 116, from pyridine-3-Eletropaulo ether (R)-[1- [4-(4-cyano-phenyl)-2-methyl-4-oxo-butine-methyl)-phenyl] -3-methyl-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid resin, MS: 483 (100, M+H), []2D0= +69,8o(methanol, C= 0.5 per cent).

The source material can be obtained in the following way:

a) Tert. -butyl ether (R)-[1-[4-(4-cyano-phenyl)-2-methyl-4-oxo - butyryl] -piperidine-4-yloxy]-acetic acid split in formic acid to (R)-[1-[4-(4-cyano-phenyl)-2-methyl-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid, TPL185-186oC []2D0= +to 91.6o(methanol, C=0.5 per cent).

b) This acid etherification in pyridine in the presence of DCC (dicyclo-hexylcaine) and pTsOH (pair-toluensulfonate) using a 3-pyridyl-methanol to pyridine-3-Eletropaulo ether (R)- [1-[4-(4-cyano-phenyl)-2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] - acetic acid, TPL123-124oC []2D0= +77,6o(methanol, C=0.5 per cent).

Example 126

Analogously to example 78 ethyl ester (RS)-[1-[4-[4-(tert - butoxycarbonylamino-imino-methyl)-phenyl]-3-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid ethyl receive ether (RS)-[1-[4-[4-(amino-imino-methyl)-phenyl] -3-methyl-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid in the form of triptoreline (1:1,9), MS: 404 (100, M+H).

The source material can be obtained in the following way:

a) Ethyl EF is omost of hydrogen sulfide is transferred to the ethyl ester of (RS)-N-[3-methyl-4-oxo - 4-(4-thiocarbamoyl-phenyl)-butyryl] -piperidine-4-yloxy] -acetic acid. MS: 386 (0,5 M-H2S).

b) This broadcast first interaction with methyliodide in acetone, then with ammonium acetate/acetic acid in methanol and finally with di-tert-butyl-dicarbonate in methylene chloride/water/sodium carbonate transform in ethyl ether (RS)-[1-[4-[4-(tert - butoxycarbonylamino-imino-methyl)-phenyl] -3-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid, MS: 504 (100. M+H).

Example 127

200 mg trifenatate ethyl ester (RS)-[1-[4-[4-(amino - imino-methyl)-phenyl]-3-methyl-4-oxo-butyryl]-piperidine-4-yloxy] -acetic acid is stirred for 4 h in 20 ml of 25% hydrochloric acid. Then the reaction mixture is evaporated in a vacuum until dry, the residue is dissolved in water and again evaporated until dry. The result is 144 mg hydrate (2: 3)- hydrochloride (8:9) (RS)-[1-[4-[4-(amino-imino-methyl)-phenyl] -3 - methyl-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid. TPL173-175oC.

Example 128

Analogously to example 79 from trifenatate ethyl ester (RS)-[1-[4-[4-(amino-imino-methyl)-phenyl] -3-methyl - 4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid with isobutyl ether of Harborview acid get ethyl ester (RS)-[1-[4-[4-(imino-isobutoxide MS: 504 (100, M+H).

Example 129

Analogously to example 79 from acetate/iodide ethyl ester (R)-[1-[4-[4-(amino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid ethyl ester Harborview acid get ethyl ester (R)-[1-[4- [4-(ethoxycarbonyl-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid in the form of a resin, MS: 476 (36, M+H), []2D0= +72,6o(methanol, C=0.5 per cent).

The source material can be obtained in the following way:

a) Ethyl ester of (R)-[1-[4-(4-cyano-phenyl)-2-methyl-4-oxo-butyryl] - piperidine-4-yloxy] -acetic acid interaction with hydrogen sulfide in pyridine and triethylamine transform in ethyl ether (R)-[1-[2-methyl-4-oxo-4-(4-thiocarbamoyl-phenyl)-butyryl] -piperidine-4-yloxy]-acetic acid, TPL171-172oC []2D0= +88,4o(methanol, C=0.5 per cent).

b) Interaction with methyliodide in acetone and subsequent reaction with ammonium acetate and acetic acid is produced acetate/iodide ethyl ester (R)-[1-[4- [4-(amino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid.

Example 130

In the same way as described in example 129, receive the ethyl ester of (R)-[1-[4: 504 (100, M+H), []2D0= +70,25o(methanol, C=0,4%).

Example 131

Analogously to example 116, from pyridine-4-Eletropaulo ether (R)-[1-[4- (4-cyano-phenyl)-2-methyl-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid get pyridine-4-ymetray ether (R)-(E)/(Z)-[1-[4-[4-(amino - hydroxyimino-methyl)-phenyl]-2-methyl-4-oxo-butyryl]-piperidine-4-yloxy]- acetic acid in the form of a resin, MS: 483 (100, M+H), []2D0= +71,8o(methanol, C=0.5 per cent).

The source material was obtained from (R)-[1-[4-(4-cyano-phenyl)-2-methyl-4 - oxo-butyryl]-piperidine-4-yloxy]-acetic acid and 4-pyridinemethanol in pyridine in the presence of DCC and pTsOH, TPL99-104oC []2D0= +69,8o(methanol, C = 0.5 per cent).

Example 132

Analogously to example 116, from tert-butyl ether (RS)-3-[1-(R) -4-(4-cyano-phenyl)-2-methyl-4-oxo-butyryl] -piperidine-4-intoxicatedly]- piperidine-1-carboxylic acid get tert-butyl ether (E)- or (Z)-(RS)-3-[1-[(R)-4-[4-(amino-hydroxyimino-methyl)-phenyl] -2-methyl-4 - oxo-butyryl]-piperidine-4-intoxicatedly] -piperidine-1 - carboxylic acid, MS: 589 (100, M+H), []2D0= +60o(methanol, C=0.5 per cent).

The source material was obtained from (R)-[1-[4-(4-cyano-phenyl)- 2-methyl-4-oxo-butyryl] -piperidine-4-s in the presence of DCC and pTsOH. MS: 556 (100, M+H), []2D0= +56o(methanol, C = 0.5 per cent).

Example 133

In the same way as described in example 129, receive ethyl ester (R)-[1-[4-[4-(imino-isopropoxycarbonyl-methyl)- phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid. MS: 490 (100, M+H), []2D0= +72o(methanol, with-0.4 percent).

Example 134

Analogously to example 78 ethyl ester (R)-[1-[4-[4-(tert - butoxycarbonylamino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] - piperidine-4-yloxy] -acetic acid get triptorelin ethyl ester (R)-[1-[4-[4-(amino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] - piperidine-4-yloxy] -acetic acid, TPL186oC []2D0= +67,4o(methanol, c=0.5%).

The source material was obtained from the acetate/iodide ethyl ester (R)-[1-[4-[4-(amino-imino-methyl)-phenyl] -3-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid and di-tert-butyl-dicarbonate in methylene chloride/water/Na2CO3; MS: 504 (91, M+H), []2D0= +66o(methanol, C=0.5 per cent).

Example 135

259 mg trifenatate ethyl ester (R)-[1-[4-[4-(amino-imino - methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid, 3,9 ml of DMF, 0,14 ml t is ri room temperature. Then the reaction mixture is evaporated in a vacuum until dry. After chromatography of the residue on silica gel using methylene chloride/isopropanol 19: 1 obtain 223 mg ethyl ester (R)- [1-[4-[4-(benzyloxycarbonylamino-imino-methyl)-phenyl] -2 - methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid, MS: 582 (100, M+H), []2D0= +67,4o(methanol, C=0.5 per cent).

4-nitrophenoxyacetic ester of benzoic acid can be obtained from iodomethyl-4-nitrophenyl-carbonate and silver benzoate in boiling benzene.

Example 136

In the same way as described in example 135, triptoreline ethyl ester (R)-[1-[4-[4-(amino-imino-methyl)-phenyl]-2-methyl - 4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid using 4 - nitrophenoxyacetic ether pavlinovoi acid get ethyl ester (R)-[1-[4-[4-(imino-pivaloyloxymethyl - methyl)-phenyl]-2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid in the form of a foamy substance, MS: 562 (100, M+H), []2D0= +60,8o(methanol, C=0.5 per cent).

4-nitrophenoxyacetic ether pavlinovoi acid can be obtained from iodomethyl-4-nitrophenyl-carbonate and pivalate silver to the-phenyl)-2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid get 2-pyridine-2-jatiluwih ether (R)-(E)/(Z)-[1-[4-[4- (amino-hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo-butyryl]-piperidine-4 - yloxy]-acetic acid, MS: 497 (100, M+H), []2D0= +67o(methanol, C=0.5 per cent).

The source material was obtained from (R)-[1-[4-(4-cyano-phenyl)-2-methyl - 4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid 2-pyridin-2-yl - ethanol in pyridine in the presence of DCC and pTsOH. MS: 464 (100, M+H), []2D0= +72,8o(methanol, C=0.5 per cent).

Example 138

Analogously to example 116 2-pyridine-3-Eletropaulo ether (R)-[1-[4-(4-cyano-phenyl)-2-methyl-4-oxo-butyryl] -piperidine-4 - yloxy]-acetic acid get 2-pyridine-3-jatiluwih ether (R)-(E)/(Z)-[1- [4-[4-(amino-hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid, MS: 497 (100, M+H), []2D0= +65,8o(methanol, C = 0.5 per cent).

The source material was obtained from (R)-[1-[4-(4-cyano-phenyl)-2 - methyl-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid 2-pyridin-3-yl-ethanol in pyridine in the presence of DCC and TpTsOH, MS: 464 (100, M+H), []2D0=+70,8o(methanol, C=0.5 per cent).

Example 139

Analogously to example 78 from tert-butyl ether (E)- or (Z)-(RS)-3-[1-[(R)-4-[4-(amino-hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-intoxicatedly] - piperidine-1-carboxylic acid to obtain (RS)-piperidine-3 - ymetray ether (E)- or (Z)-(R)-[1-[4-[4-(amino-hydrox is 100, M+H), []2D0=+45,75o(methanol, C=0,4%).

Example 140

Analogously to example 116, from tert-butyl ether (R)-4-[[1-[4-(4- cyano-phenyl)-2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetoxymethyl] - piperidine-1-carboxylic acid get tert-butyl ether (E)- or (Z)-(R)-4-[1-[4-[4-(amino-hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-intoxicatedly] - piperidine-1-carboxylic acid; MS: 589 (100, M+H), []2D0= +58,6o(methanol, C=0.5 per cent).

The source material was obtained from (R)-[1-[4-(4-cyano-phenyl)- 2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid tert-butyl ester 4-(hydroxymethyl) piperidine-1-carboxylic acid in pyridine in the presence of DCC and pTsOH. MS: 556 (100, M+H), []2D0= +63,3o(methanol, C=0,3%).

Example 141

Analogously to example 78 from tert-butyl ether (E)- or (Z)-(R)-4-[1-[4-[4-(amino-hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo - butyryl] -piperidine-4-intoxicatedly]-piperidine-1-carboxylic acid get piperidine-4-ymetray ether (E)- or (Z)-(R)-[1 -[4-[4-(amino-hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo - butyryl]-piperidine-4-yloxy]-acetic acid in the form of triptoreline (1:3), MS: 489 (100, M+H), []2D0= +41,5ois-phenyl)-2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] - acetic acid will receive 2-pyridine-4-jatiluwih ether (E)/(Z)-(R)-[1-[4-[4-(amino-hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid, MS: 497 (100, M+H), []2D0= +67o(methanol, C = 0.5 per cent).

The source material was obtained from (R)-[1-[4-(4-cyano-phenyl)-2-methyl-4 - oxo-butyryl]-piperidine-4-yloxy]-acetic acid 2-pyridin-4-yl - ethanol in pyridine in the presence of DCC and pTsOH.

Example 143

Analogously to example 116 (R)-1-phenyl-ethyl ester (R)-[1-[4- (4-cyano-phenyl)-2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid to obtain (R)-1-phenyl-ethyl ester (E)/(Z)-(R)-[1-[4-[4-(amino - hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4 - yloxy] -acetic acid, TPL94oC []2D0= +111,6o(methanol, C=0.5 per cent).

The source material was obtained from (R)-[1-[4-(4-cyano-phenyl)-2-methyl-4 - oxo-butyryl] -piperidine-4-yloxy]-acetic acid and (R)-1-phenyl - ethanol in pyridine in the presence of DCC and pTsOH, []2D0= +96,6o(methanol, C=0.5 per cent).

Example 144

Analogously to example 116 (S)-1-phenyl-ethyl ester (R)-[1-[4- (4-cyano-phenyl)-2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid to obtain (S)-1-phenyl-ethyl ester (E)/(Z)-(R)-[1-[4-[4- (AMR>C []2D0= +32,8o(methanol, C=0.5 per cent).

The source material was obtained from (R)-[1-[4-(4-cyano-phenyl)-2 - methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid and (S)- 1-phenyl-ethanol in pyridine in the presence of DCC and pTsOH, TPL98oC []2D0= +33,8o(methanol, C = 0.5 per cent).

Example 145

Analogously to example 116 (S)-1-pyridin-4-Eletropaulo ether (R)-[1-[4-(4-cyano-phenyl)-2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] - acetic acid to obtain (S)-1-pyridin-4-jatiluwih ether (E)/(Z)-(R)- [1-[4-[4-(amino-hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] - piperidine-4-yloxy]-acetic acid), []2D0= +41o(methanol, C = 0.5 per cent).

The source material was obtained from (R)-[1-[4-(4-cyano-phenyl)-2-methyl-4 - oxo-butyryl]-piperidine-4-yloxy]-acetic acid and (S)-1-(4-pyridyl)-ethanol in pyridine in the presence of DCC and pTsOH, TPL115oC []2D0= +45,8o(methanol, C= 0.5 per cent).

Example 146

Analogously to example 116 (R)-1-pyridin-4-Eletropaulo ether (R)- [1-[4-(4-cyano-phenyl)-2-methyl-4-oxo-butyryl] -piperidine-4 - yloxy] -acetic acid to obtain (R)-1-pyridin-4-jatiluwih ether (E)/(Z)-(R)-[1-[4-[4-(amino-hydroxyimino-methyl)-phenyl] - 2-methyl-4-oxo-butyryl]-piperidine-4-yloxy] -Al obtained from (R)-[1-[4-(4-cyano-phenyl)-2-methyl-4 - oxo-butyryl]-piperidine-4-yloxy]-acetic acid and (R)-1-(4-pyridyl)-ethanol in pyridine in the presence of DCC and pTsOH, TPL115oC []2D0= +to 112.4o(methanol, C=0.5 per cent).

Example 147

Analogously to example 116 methyl ester (R)-[1-[4-(4-cyano - phenyl)-2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid methyl get ether (E)/(Z)-(R)-[l-[4-[4-(amino-hydroxyimino - methyl)-phenyl]-2-methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid, TPL147-149oC []2D0= +86o(methanol, C=0.5 per cent).

The source material was obtained from (R)-[1-[4-(4-cyano-phenyl)-2 - methyl-4-oxo-butyryl] -piperidine-4-yloxy] -acetic acid and methanol in pyridine in the presence of DCC and pTsOH (2:1) adduct using dicyclohexylamine, TPL101oC []2D0= +76,2o(methanol, C=0.5 per cent).

Example 148

Analogously to example 79 from acetate/iodide methyl ester (R)-[1- [4-[4-(amino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid methyl ester Harborview acid get methyl ester (R)-[1-[4- [4-(imino-methoxycarbonylamino-methyl)-phenyl]-2-methyl-4-oxo-butyryl] - piperidine-4-yloxy] -acetic acid, MS: 448 (100, M+H), []2D0= +75,4o(methanol, C=0.5 per cent).

The source material can be obtained sigslot with hydrogen sulfide in pyridine and triethylamine transferred to the methyl ester of (R)- [1- [2-methyl-4-oxo-4-(4-thiocarbamoyl-phenyl)-butyryl] -piperidine-4-yloxy] - acetic acid, TPL172-177oC.

b) Of this ester by the interaction with methyliodide in acetone and subsequent reaction with ammonium acetate and acetic acid in methanol receive acetate/iodide methyl ester (R)-[1-[4-[4- (amino-imino-methyl)-phenyl]-2-methyl-4-oxo-butyryl]-piperidine-4-yloxy]- acetic acid.

Example 149

Analogously to example 79 from acetate/iodide methyl ester (R)-[1- [4-[4-(amino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4 - yloxy]-acetic acid ethyl ester Harborview acid get methyl ester (R)-[1-[4-[4-(ethoxycarbonyl-imino - methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-yloxy]-acetic acid, MS: 462 (100, M+H), []2D0= +66o(methanol, C=0.5 per cent).

Example 150

214 mg of a mixture of pyridine-3-Eletropaulo ether (R)-[1-[4-[4- [tert-butoxycarbonylamino-(isobutoxide-tert-butoxycarbonyl - amino)- methyl] -phenyl] -2-methyl-4-oxo-butyryl]-piperidine-4-yloxy] -acetic acid and pyridine-3-Eletropaulo ether (R)-[1-[4-[4- [(di-tert-butoxycarbonyl-amino)-solutionline-methyl] -phenyl]-2-methyl-4-oxo-butyryl]-piperidine-4-yloxy] -acetic acid is stirred in 1.2 ml of methylene chloride and 1.2 ml triperoxonane kislotolabilen washed with diluted aqueous NaHCO3water and saturated NaCl solution, dried and evaporated in vacuum. The result is 151 mg of pyridine-3-Eletropaulo ether (R)-[1-[4- [4-(imino-solutionline-methyl)-phenyl]-2-methyl-4-oxo - butyryl] -piperidine-4-yloxy] -acetic acid in the form of a foamy substance, MS: 567 (100, M+H), []2D0= +61o(methanol, C=0,2%).

The source material can be obtained in the following way:

a) Ethyl ester of (R)-[1-[4-[4-(imino-solutionline - methyl)-phenyl]-2-methyl-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid transform in acetonitrile in the presence of 4-dimethylamino - pyridine interaction with di-tert-butyl-dicarbonate in a mixture of ethyl ether (R)-[1-[4-[4-[tert-butoxycarbonylamino- (isobutoxide-tert-butoxycarbonyl-amino)-methyl] -phenyl]- 2-methyl-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid ethyl ester (R)-[1-[4-[4-[(di-tert-butoxycarbonyl-amino) -solutionline-methyl] -phenyl] -2-methyl-4-oxo-butyryl]- piperidine-4-yloxy]-acetic acid.

b) From this mixture by saponification with LiOH in aqueous THF receive a mixture of (R)-[1-[4-[4-[tert-butoxycarbonylamino-(isobutoxide - tert-butoxycarbonyl-amino)-methyl] -phenyl] -2-methyl-4-oxo-butyryl]- piperidine-4-ilok is 4 - oxo-butyryl] -piperidine-4-yloxy]-acetic acid.

C) transform the resulting mixture in pyridine interaction with 3-hydroxymethyl-pyridine, DCC and pTsOH in a mixture of pyridine-3 - Eletropaulo ether (R)-[1-[4-[4-[tert-butoxycarbonylamino- (isobutoxide-tert-butoxycarbonyl-amino)-methyl] -phenyl]- 2-methyl-4-oxo-butyryl]- piperidine-4-yloxy] -acetic acid and pyridine-3-Eletropaulo ether (R)-[1-[4-[4-[(di-tert-butoxycarbonyl-amino)- solutionline-methyl] -phenyl] -2-methyl-4-oxo-butyryl]- piperidine-4-yloxy]-acetic acid.

Example 151

Analogously to example 79 from acetate/iodide tert-butyl ether (RS)-3-[[1-[(R)-4-[4-(amino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] - piperidine-4-yloxy] -acetoxymethyl] -piperidine-1-carboxylic acid and methyl ester Harborview acid get tert-butyl ether (RS)-3-[[1-[(R)-4-[4-(imino-methoxy-carbylamine-methyl)-phenyl] -2-methyl-4-oxo-butyryl]-piperidine-4-yloxy] -acetoxymethyl] -piperidine-1-carboxylic acid, MS: 631 (100, M+H), []2D0= +57,2o(methanol, c-0,5%).

The source material can be obtained in the following way:

a) Tert-butyl ether (RS)-3-[1-[(R)-4-(4-cyano-phenyl)-2-methyl - 4-oxo-butyryl] -piperidine-4-yloxy-acetoxymethyl] -piperidine-1 - carboxylic acid transform entries batch-piperidine-4-yloxy] -acetoxymethyl] - piperidine-1-carboxylic acid, MS: 590 (100, M+H), []2D0= +58,8o(methanol, C=0.5 per cent).

b) Of this ester by the interaction with methyliodide in acetone and subsequent reaction with ammonium acetate and acetic acid in methanol receive acetate/iodide tert-butyl ether (RS)-3-[N-[(R)-4- [4-(amino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4 - yloxy]-acetoxymethyl]-piperidine-1-carboxylic acid.

Example 152

Analogously to example 79 from acetate/iodide tert-butyl ether (RS)-3-[[1-[(R)-4-[4-(amino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] - piperidine-4-yloxy]-acetoxymethyl]-piperidine-1-carboxylic acid and ethyl ester of Harborview acid get tert-butyl ether (RS)-3-[[1-[(R)-4-[4-(ethoxycarbonyl-imino-methyl)- phenyl] -2-methyl - 4-oxo-butyryl]-piperidine-4-yloxy] -acetoxymethyl] -piperidine-1 - carboxylic acid, MS: 645 (100, M+H), []2D0= +56,2o(methanol, C = 0.5 per cent).

Example 153

Analogously to example 79 from acetate/iodide ethyl ester[1-[4- [4-(amino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl]-piperidine-4 - yloxy]-acetic acid methyl ester Harborview acid get ethyl ester (R)-[1-[4-[4-(imino-methoxycarbonylamino-methyl)- phenyl]-2-methyl-new ester [4-[4-(4-cyano-phenyl)-4 - oxo-butyryl] -phenoxy] -acetic acid getting ethyl ester (E)/(Z)- [4-[4-[4-(amino-hydroxyimino-methyl)-phenyl] -4-oxo-butyryl]-phenoxy]- acetic acid, TPL174-175oC.

Example 155

Analogously to example 116 ethyl ester (RS)-[4-[4- (4-cyano-phenyl)-2-methyl-4-oxo-butyryl] -phenoxy] -acetic acid getting ethyl ester (E)/(Z)-(RS)-[4-[4-[4-(amino-hydroxyimino - methyl)-phenyl] -2-methyl-4-oxo-butyryl]-phenoxy]-acetic acid, TPL166-167oC.

The source material can be obtained in the following way:

a) Of the ethyl ester [4-(1-oxo-propyl)-phenoxy]-acetic acid and bromine receive acetic acid ethyl ester (RS)-[4-(2-bromo-1-oxo - propyl)-phenoxy]-acetic acid, TPL72-76oC.

b) This transform ether in acetone in the presence of bis- (trimethylsilyl)-amide sodium interaction with tert-butyl ether 3-(4-cyano-phenyl)-3-oxo-propionic acid ethyl ester [4-[3-tert-butoxycarbonyl-3-(4-cyanobenzoyl)-2-methyl-propionyl] -phenoxy]-acetic acid (racemic mixture of diastereomers), MS: 406 (1,7, M-COOC2H5).

in) From the resulting product is obtained in formic acid ethyl ester (RS)-[4-[4-(4-cyano-phenyl)-2-methyl-4-oxo - butyryl] -phenoxy]-acetic acid, TPL117-123oC.

Example 156

365 mg of ethyl ester [4-[4-(4-cyano-phenyl)-4-oxo-butyryl]- phenoxy] -acetic kilocycles concentrated in vacuo, dilute acetic ether and washed with water and saturated salt solution. Acetic ether solution is dried over Na2SO4and evaporated in vacuum. After chromatography of the residue on silica gel using CH2Cl2/ethanol 98: 2 obtain 111 mg ethyl ester [4-[(E)/(Z)-4-[(E)/(Z)-4-(amino-hydroxyimino-methyl)-phenyl] -1 - hydroxyimino-4-oxo-butyl] -phenoxy] -acetic acid, TPL180-181oC.

Example 157

84 mg[4-[4-[4-(tert-butoxycarbonylamino-imino-methyl)- phenyl]-4-oxo-butyryl] -phenoxy]-acetic acid and 1.7 ml of formic acid is stirred for 7 h at 20oC. Then the reaction mixture is evaporated, the residue is dissolved in water and again evaporated. The solid residue is suspended in water, with ammonia set at pH 8, filtered by suction, washed with water and dried. The result is 50 mg[4-[4-[4-(amino-imino-methyl)- phenyl]-4-oxo-butyryl]-phenoxy]-acetic acid, TPL284oC.

The source material can be obtained in the following way:

(a) Acetate ethyl ester[4-[4-[4-(amino-imino-methyl)-phenyl]-4 - oxo-butyryl] -phenoxy] -acetic acid (1: 1) in CH2Cl2and water in the presence of Na2CO3transform interaction with di-tert-butyl-usnei acid, TPL164oC.

b) Of this ester by saponification with NaOH in EtOH get[4-[4-[4-(tert-butoxycarbonylamino-imino-methyl)-phenyl] -4-oxo-butyryl]-phenoxy]-acetic acid, TPL284oC (decomposition).

Example 158

278 mg of hydroxylamine hydrochloride, 4 ml of DMSO and 0.56 ml of triethylamine is stirred for 10 min at 20oC. After the addition of 146 mg of ethyl ester [4-[4-(4-cyano-phenyl)-4 - oxo-butyryl] -phenoxy]-acetic acid is stirred for 3 days at 20oC. Then the reaction mixture is diluted with acetic ether, washed with water and common salt solution, dried and evaporated. After chromatography on silica gel using CH2Cl2/EtOH 9:1 to obtain 42 mg of ethyl ether[4-[4- [4-(amino-hydroxyimino-methyl)-phenyl]-1,4-bis-hydroxyaminobutyryl] -phenoxy]-acetic acid (all oximes: E or Z), TPL210oC (decomposition).

Example 159

Analogously to example 116 ethyl ester (RS)-[4-[2- (2-acetoxyethyl)-4-(4-cyano-phenyl)-4-oxo-butyryl] -phenoxy] - acetic acid getting ethyl ester of (E/Z)-(RS)-[4-[2-(2- acetoxy-ethyl)-4-[4-(amino-hydroxyimino-methyl)-phenyl] -4-oxo - butyryl] -phenoxy] -acetic acid as a colourless resin, MS: 485 (100, M+H).

Source material moussou acid in acetone in the presence of K2CO3get ethyl ester [4-(4-hydroxy-butyryl)- phenoxy]-acetic acid, TPL64-66oC.

b) Of this ether with acetic anhydride in pyridine get ethyl ester [4-(4-acetoxy-butyryl)-phenoxy] -acetic acid, TPL94-96oC.

in This broadcast interaction with bromine in acetic acid transform in ethyl ester [4-(4-acetoxy-2-bromobutyryl)- phenoxy]-acetic acid.

g) This is the last in acetone in the presence of bis-(trimethylsilyl) -amide sodium interaction with tert-butyl ether 3-(4-cyano-phenyl)- 3-oxo-propionic acid transform in tert-butyl ester 5-acetoxy-2-(4-cyano-benzoyl)-3-(4-ethoxycarbonylmethoxy-benzoyl)- pentanol acid (racemic mixture of diastereomers), MS: 478 (0,2, M-CO2Et).

d) By heating in formic acid to 40oC and subsequent chromatography of the above-mentioned ether get ethyl ester (RS)-[4- [2-(2-acetoxy-ethyl)-4-(4-cyano-phenyl)-4-oxo-butyryl] -phenoxy] - acetic acid, TPL102-104oC.

Example 160

425 mg of ethyl ether (RS)-[4-[4-[4-(tert-butoxycarbonylamino - imino-methyl)-phenyl]-2-methyl-4-oxo-butyryl]-phenoxy]-acetic acid are heated for 2.5 h Yong ether/simple ether get 239 mg of ethyl ether (RS)-[4-[4-[4-(amino-imino-methyl)-phenyl]-2-methyl-4-oxo-butyryl]- phenoxy]-acetic acid in the form of acetate (1:1), TPL198oC.

The source material can be obtained in the following way:

a) Ethyl ester of (RS)-[4-[4-(4-cyano-phenyl)-2-methyl-4-oxo-butyryl] - phenoxy]-acetic acid with H2S in pyridine and triethylamine transform in ethyl ether (RS)-[4-[2-methyl-4-oxo-4-(4-thiocarbamoyl - phenyl)-butyryl]-phenoxy]-acetic acid, TPL112-113oC.

b) This broadcast first interaction with methyliodide in acetone, then with ammonium acetate and acetic acid in methanol and finally with di-tert-butyl-dicarbonate in methylene chloride/water/Na2CO3transform in ethyl ether (RS)-[4-[4-[4-[(tert-butoxycarbonylamino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl]-phenoxy]-acetic acid, MS: 497 (100, M+H).

Example 161

Analogously to example 79 ethyl ester (RS)-[4-[4-[4- (amino-imino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -phenoxy] - acetic acid and isobutyl ether of Harborview acid get ethyl ester (RS)-[4-[4-[4-(imino-solutionline - methyl)-phenyl] -2-methyl-4-oxo-butyryl]-phenoxy]-acetic acid in the form of a resin, MS: 497 (100, M+H).

Example 162

Analogously to example 160 of ethyl ether (RS)-[4-[2- (2-acetoxy-ethyl)-4-[4-(tert-butoxycarbonylamino-imino-imino-methyl)-phenyl] - 4-oxo-butyryl] -phenoxy] -acetic acid in the form of acetate (1:1), TPL183oC.

The source material can be obtained in the following way:

a) ethyl ester of (RS)-[4-[2-(2-acetoxy-ethyl)-4-(4-cyano - phenyl)-4-oxo-butyryl] -phenoxy] -acetic acid with H2S in pyridine and triethylamine get ethyl ester (RS)-[4- [2-(2-acetoxy-ethyl)-4-oxo-4-(4-thiocarbamoyl-phenyl)-butyryl] -phenoxy] -acetic acid, MS: 508 (100, M+Na).

b) This broadcast first interaction with methyliodide in acetone, then with ammonium acetate and acetic acid in methanol and finally with di-tert-butyl-dicarbonate in methylene chloride/water/Na2CO3transform in ethyl ether (RS)-[4- [2-(2-acetoxy-ethyl)-4-[4-(tert-butoxycarbonylamino-imino - methyl)-phenyl]-4-oxo-butyryl]-phenoxy]-acetic acid, MS: 569 (100, M+H).

Example 163

A solution of 413 mg of ethyl ester of (Z)-(S)-[4-[2-[4-(amino - hydroxyimino-methyl)-benzoylamine]-propionyl]-phenoxy]-acetic acid and 120 mg of 4-methylmorpholine in 10 ml of dichloromethane is treated at 0oC 98 mg triphosgene in 10 ml dichloromethane and stirred for 2 h at room temperature. Then the reaction mixture is washed with water, dried and concentrated. The residue is suspended in diazol-3 - yl)-benzoylamine]-propionyl]-phenoxy]-acetic acid, MS (ion bombardment): 440 (M+H)+.

Example 164

In a suspension of 650 mg of triptoreline ethyl ester (S)-4-[2- [4-(amino-imino-methyl)-benzoylamine]-propionyl]-phenoxyalkanoic acid in 10 ml dichloromethane and 10 ml of a saturated solution of NaHCO3add a solution of 120 mg of S-ethyl-chlorothioformate in 2 ml of dichloromethane, and then stirred for 47 hours at room temperature. Then the aqueous phase is extracted with dichloromethane, the dichloromethane phase is washed with water, dried and concentrated. After chromatography of the residue on silica gel (hexane/acetic ester 1:2) to obtain 230 mg of ethyl ether (S)-[4-[2-[4-(amino-ethylsulfonylimidazo-methyl)- benzoylamine] -propionyl]-phenoxy]-acetic acid, []2D0= +75,1o(C=0,7, chloroform).

Example 165

A solution of 190 mg of ethyl ether (S)-4-[2-[4-[(amino-(2 - tert-butyl-dimethyl-silyloxy-ethoxycarbonylethyl)-methyl] - benzoylamine]-propionyl]-phenoxy] -acetic acid in 10 ml of tetrahydrofuran is treated at -20oC 0.3 ml of tetrabutylammonium fluoride (1M in tetrahydrofuran) and stirred for 2 h at room temperature. Then the reaction mixture is diluted with acetic ether, extracted with water, dried and kefira (S)-[4-[2- [4-[amino-(2-hydroxy-ethoxycarbonylethyl)-methyl]-benzoylamine]- propionyl]-phenoxy]-acetic acid, MS (ion bombardment): 486 (M+H)+.

The source material can be obtained in the following way:

In a solution of 230 mg of 2-(tert-butyl-dimethyl-silyloxy)-ethanol and 101 mg of 4-methylmorpholine in 8 ml of dichloromethane, is added at 0oC 98 mg triphosgene dissolved in 4 ml dichloromethane and stirred for 2 h at room temperature. Then the reaction solution is added to a suspension of 510 mg of triptoreline ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid in 10 ml dichloromethane and 10 ml of a saturated solution of Na2CO3. After stirring for 10 min at room temperature, the phases are separated, the organic phase is washed with water, dried and concentrated. After chromatography of the residue on silica gel (hexane/acetic ester 1: 2) to receive 200 mg of ethyl ether (S)-[4-[2-[4-[(amino-(2-tert-butyl-dimethyl-silyloxy - ethoxycarbonylethyl)-methyl] - benzoylamine]-propionyl]-phenoxy] -acetic acid, Rf= 0,73 (acetic ether).

Example 166

Analogously to example a) from 511 mg trifenatate ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid and 104 mg of 2-acetoxyethyl after chromatography on silica gel (benzoylamino] -propionyl]-phenoxy]-acetic acid, MS (bombardirovka ions): 528 (M+H)+.

Example 167

Analogously to example a) from 511 mg trifenatate ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid and 118 mg of 2-hydroxy-ethyl ester propionic acid, after chromatography on silica gel (hexane/acetic ester 1:4) to obtain 175 mg of (S)-2-[[4-[2- (4-ethoxycarbonylmethoxy-phenyl)-1-methyl-2-oxo-ethylcarboxyl] -phenyl] -imino-methylcarbamate] -ethyl ester propionic acid, MS (ion bombardment): 542 (M+H)+.

Example 168

Analogously to example a) from 511 mg trifenatate ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid and 132 mg of 2-hydroxy-ethyl ester somaclonal acid, after chromatography on silica gel (hexane/acetic ester 1:2) to obtain 42 mg (S)-1-[[4-[2- (4-ethoxycarbonylmethoxy-phenyl)-1-methyl-2-oxo-ethylcarboxyl] -phenyl] -imino-methylcarbamate]-ethyl ester of 2-methyl-propionic acid. MS (ion bombardment): 556 (M+H)+.

Example 169

Analogously to example a) from 511 mg trifenatate ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid and 130 mg of 2-hydroxy-ethyl ester Carbonyloxy-phenyl)-1-methyl-2-oxo-ethylcarboxyl]- phenyl]-imino-methylcarbamate] -ethyl ester of 2-methyl - acrylic acid, MS (ion bombardment): 554 (M+H)+.

Example 170

Analogously to example a) from 511 mg trifenatate ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine]-propionyl] -phenoxyalkanoic acid and 166 mg of 2-hydroxy-ethyl ester of benzoic acid, after chromatography on silica gel (hexane/acetic ester 1:2) to obtain 130 mg (S)-2-[[4-[2-(4- ethoxycarbonylmethoxy-phenyl)-1-methyl-2-oxo-ethylcarboxyl] -phenyl] -imino-methylcarbamate]-ethyl ester of benzoic acid, MS (ion bombardment): 590 (M+H)+.

Example 171

Analogously to example a) from 511 mg trifenatate ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid and 224 mg of 2-hydroxy-ethyl ether of 2-acetoxybenzoic acid, after chromatography on silica gel (hexane/acetic ester 1: 4) to obtain 210 mg (S)-2-[[4- [2-(4-ethoxycarbonylmethoxy-phenyl)-1-methyl-2-oxo-ethyl-carbarnoyl] -phenyl] -imino-methylcarbamate] -ethyl ester 2-acetoxybenzoic acid, MS (ion bombardment): 648 (M+H)+.

Example 172

Analogously to example a) from 511 mg trifenatate ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid and 103 mg of 2-hydroxyethylamide uxl-amino-ethoxycarbonylethyl)- amino-methyl]-benzoylamine]-propionyl] -phenoxy]-acetic acid, MS (ion bombardment): 527 (M+H)+.

Example 173

Suspension of 263 mg of triptoreline ethyl ester (S)- 4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] - phenoxyalkanoic acid, 217 mg of 4-nitro-phenoxycarbonylamino ester of acetic acid and 165 ml of 4-methylmorpholine in 5 ml dichloromethane and 5 ml of tetrahydrofuran is stirred for 16 h at room temperature. After concentrating the reaction mixture and chromatography of the residue on silica gel (hexane/acetic ester 1:4) to obtain 193 mg of ethyl ether (S)- [4-[2-[4-(acetoxypiperidine-amino-methyl)- benzoylamine] -propionyl] -phenoxy]-acetic acid, []2D0= +65,0o(C = 0.6, chloroform).

Example 174

Analogously to example a) 250 mg trifenatate ethyl ester (S)-4-[2-[4-(amino-imino-methyl)-benzoylamine] -propionyl] -phenoxyalkanoic acid and 104 mg of ethyl ester of (S)-lactic acid, after chromatography on silica gel (hexane/acetic ester 1: 2) to obtain 160 mg of methyl ester of (S)-2-[[4-[(S)-2-(4 - ethoxycarbonylmethoxy-phenyl)-1-methyl-2-oxo-ethylcarboxyl] -phenyl]-imino-methylcarbamate]-propionic acid, MS (ion bombardment): 528 (M+H)+.

Example 175

Analogously to example 31, ishoni acid, after reaction with ammonium acetate, concentration of the reaction solution and precipitation of the product from simple ether obtain 130 mg of the acetate methyl ester 1-[8-(amino-imino-methyl)-5-oxo-2,3,4,5-tetrahydro-1,4 - benzoxazepin-4-ylacetic]-piperidine-4-biloxicasino acid, MS (ion bombardment): 419 (M+H)+.

The source material can be obtained in the following way:

a) a Solution of 1.63 g of 4-zenosociology acid and 1.26 g of N-hydroxy-succinimide in 25 ml of dichloromethane and 25 ml of dimethylformamide is treated at 0oC of 2.06 g dicyclohexylcarbodiimide and stirred for 16 h at 0oC. the Precipitate is filtered off by suction. In the mother liquor is added to 1.4 ml of triethylamine and 1.38 g of tert-butyl ether N-(2-hydroxyethyl)glycine (see European patent application EP 288256) and stirred for 1 h at room temperature. After concentrating the reaction solution and chromatography of the residue on silica gel (hexane/acetic ester 1:2) to obtain 475 mg of tert-butyl methyl ether [(4-cyano-2-hydroxy - benzoyl)-(2-hydroxy-ethyl)-amino]-acetic acid, MS (ion bombardment): 321 (M+H)+.

b) In a solution of 464 mg of tert-butyl methyl ether [(4-cyano-2 - hydroxy-benzoyl)-(2-hydroxyethyl)-amino] -acetic acid and 570 mg of tetrahydrofuran and stirred for 1 h at room temperature. After concentration of the solution and chromatography of the residue on silica gel (hexane/acetic ether 2: 1) receive 300 mg of tert-butyl ester 8-cyano-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl-acetic acid, MS (EI): 246 (M-56).

C) Cleavage of the ether group contained 300 mg of the product of the preliminary stage in 4 ml of dichloromethane and 2 ml triperoxonane acid is carried out at room temperature. Then the solution is concentrated and the residue is filtered off by suction using a simple ester, dissolved in 50 ml of dimethylformamide and treated with 292 mg 4-methylmorpholine, 597 mg hexafluorophosphate O-benzotriazol-1-yl - N, N, N',N'-tetramethylurea and 330 mg of methyl ester hydrochloride 4-piperidinemethanol acid. After stirring for 16 h at room temperature the solution is concentrated and the residue is dissolved in acetic ether, the organic phase is washed with 1M solution of KHSO3and saturated NaCl solution, dried and concentrated. After chromatography of the residue on silica gel (acetic ether) receive 400 mg of methyl ester 1-(8-cyano-5-oxo-2,3,4,5-tetrahydro-1,4 - benzoxazepin-4-ylacetic)-piperidine-4-biloxicasino acid, MS (ion bombardment): 402 (M+H)+.

Example 176

(A) By processing 350 mg red acid hydrogen sulfide, methyliodide and ammonium acetate after chromatography on Siciliana silica gel RP 18 obtain 163 mg of triptoreline ethyl ester (S)-[1-[2-[8-(amino - imino-methyl)-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-4-yl]- propionyl]-piperidine-4-yloxy]-acetic acid, MS (ion bombardment): 447 (M+H)+.

B) a suspension of 135 mg trifenatate ethyl ester (S)- [1-[2-[8-(amino-imino-methyl)-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin - 4-yl] - propionyl] -piperidine-4-yloxy] -acetic acid in 3 ml of dichloromethane and 3 ml of a saturated solution of NaHCO3added 29 mg of ethyl ether of Harborview acid, then stirred for 5 min at room temperature. Then the aqueous phase is extracted with dichloromethane, the dichloromethane phase is washed with water, dried and concentrated. After chromatography of the residue on silica gel (acetic ether) obtain 86 mg of ethyl ether (S)-[1-[2-[8-(amino - ethoxycarbonyl-methyl)-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin - 4-yl] -propionyl] -piperidine-4-yloxy]-acetic acid, MS (ion bombardment): 519 (M+H)+.

The source material can be obtained in the following way:

a) a Solution of 1 g of tert-butyl methyl ether D-lactic acid and 0.95 ml of triethylamine in 10 ml dichlo is UP>oC and re-treated with 0.95 ml of triethylamine and 1.43 g of O-tert-butyl-dimethylsilane-aminoethanol. After stirring for 2 h at room temperature, the reaction mixture was concentrated and the residue chromatographic on silica gel (hexane/acetic ether 2: 1). The result is 990 mg of tert - butyl methyl ether (S)-2-[2-(tert-butyl-dimethyl-silyloxy)- ethylamino] -propionic acid, MS (EI): 246 (M-57).

b) Analogously to example a) 5 g of 4-zenosociology acid transform interaction with 4,36 g of the product of the preliminary stage and the residue after evaporation chromatographic on silica gel (hexane/tert-butyl ether 2: 1). The result is 1.19 g of tert-butyl methyl ether (S)-2-[2-(tert-butyl-dimethyl-silyloxy)- ethyl] -(4-cyano-2-hydroxy-benzoyl)-amino]-propionic acid, MS (EI): 449 (M+H)+.

C) a Solution of 1.19 g of the product of the preliminary stage in 25 ml of a simple ester is treated with 2.7 ml of tetrabutylammonium fluoride (1M in tetrahydrofuran), stirred for 16 h at room temperature, washed with 1M solution of H3PO4and saturated NaCl solution, dried and concentrated. After chromatography of the residue on silica gel (acetic ether) receive 704 mg of tert-butyl methyl ether (S)-2-[(4-cyano-2-hydro is d) Exchange reaction 669 mg of the product of the preliminary stage, carried out analogously to example b), after chromatography on silica gel (hexane/acetic ether 2:1) obtain 345 mg of tert-butyl methyl ether (S)-2-(8-cyano-5-oxo-2,3,4,5 - tetrahydro-1,4-benzoxazepin-4-yl)-propionic acid, MS (EI): 260 (M-56).

d) Analogously to example V) 340 mg of the product of the pre-stage transform interaction with 243 mg of ethyl ester of 4-piperidine-acetic acid. After chromatography of the residue on silica gel (hexane/acetic ester 1: 3) to obtain 365 mg of ethyl ether (S)-[1-[2-(8-cyano-5-oxo-2,3,4.5-tetrahydro-1,4-benzoxazepin-4-yl)- propionyl] -piperidine-4-yloxy] -acetic acid, []2D0= -18,8o(C=0.6, chloroform).

Example 177

By the reaction of 80 mg hydroiodide ethyl ester (R,S)-4-[2- [4-(amino-imino-methyl)-2-methoxy-benzoylamine] -propionyl] -phenoxyalkanoic acid with 22 mg of ethyl ether of Harborview acid according to example b) after chromatography on silica gel (hexane/acetic ester 1:3) to obtain 58 mg of ethyl ester of (R, S)-[4- [2-[4-(amino-ethoxycarbonyl-methyl)-methoxy-benzoylamine] - propionyl]-phenoxy]-acetic acid as colorless oil, MS (ion bombardment): 500 (M+H)+.

The source material can be obtained in the following all of dimethylformamide is treated at 0oC 2,43 g dicyclohexylcarbodiimide and stirred for 16 h at-14-15oC. the Precipitate is filtered off by suction and the mother liquor containing hydroxysuccinimidyl ether 4-zenosociology acid directly used in the carrying out of the subsequent stage.

b) Removal of BOC-group contained in 4.1 g of ethyl ester of (S)-4-(2-tert-butoxycarbonylamino-propionyl)-phenoxyalkanoic acid (example 23a)), carried out with the help of 1.75 ml of trimethylsilylmethyl at 0oC in 40 ml of dichloromethane. After addition of 8 ml 4H HCl in dioxane, the reaction solution is concentrated and the residue is dissolved in 40 ml of tetrahydrofuran and together with 2.6 ml of 4-methylmorpholine add to that obtained at the preliminary stage stock solution containing hydroxysuccinimidyl ether 4-zenosociology acid. After 16 h at room temperature the mixture is concentrated and the residue chromatographic on silica gel (hexane/acetic ether 3:1). The result 2,98 g of ethyl ester of (S)-[4-[2-(4- cyano-2-hydroxy-benzoylamine)-propionyl]-phenoxy]-acetic acid, MS (ion bombardment): 397 (M+H)+.

b) Alkylation 792 mg of the product of the preliminary stage to 0.19 ml under the conditions in the presence of 830 mg of potassium carbonate in 20 ml of deafie residue on silica gel (hexane/acetic ether 3:1) 580 mg of ethyl ester of (R,S)-[4-[2- (4-cyano-2-methoxy-benzoylamine)-propionyl]-phenoxy]-acetic acid, MS (ion bombardment): 411 (M+H)+.

d) Analogously to example 31 290 mg of the product of the preliminary stage is subjected to interaction with hydrogen sulfide, methyliodide and ammonium acetate, after which the reaction solution is concentrated to half volume and the product precipitated additives simple ether. The result is 183 mg hydroiodide ethyl ester (R,S)-[4-[2-[4-(amino-imino-methyl)-2-methoxy-benzoylamine] -propionyl] -phenoxy] -acetic acid, MS (ion bombardment): 428 (M+H)+.

Example 178

The interaction of 1.4 g of ethyl ester of (R,S)-[4-[2-(4-cyano - phenyl)-1-methyl-2-oxo-ethylcarboxyl] -phenoxy] -acetic acid with hydrogen sulfide, methyliodide and ammonium acetate as in example 31 after chromatography of the residue on evaporation at Siciliana silica gel RP 18 (gradient, water/tetrahydrofuran) obtain 410 mg of hydroiodide ethyl ester (R,S)-[4-[2-[4-(amino-imino-methyl)- phenyl] -1-methyl-2-oxo-ethylcarboxyl]-phenoxy]-acetic acid, MS (ion bombardment): 398 (M+H)+.

The source material can be obtained in the following way:

a) a Solution of 10.92 g of 4-bromobenzonitrile in 80 ml of tetrahydrofuran at - 78oC is added dropwise to a 37.5 ml of 1.6 H n-utillity. Produced suspense is Beniamino-N-methoxy-N-methyl-propionamide in 80 ml of tetrahydrofuran and stirred for 1 h at -78oC. the Reaction solution red poured in 1M H3PO4. After extraction with simple ether, washing the organic phases with saturated solution of NaCl, drying and concentrating the solution get a residue, which after chromatography on silica gel get 3,68 g tert-butyl ether (S)-2-(4-cyano-phenyl)-1-methyl-2-oxo-ethylcarbamate acid, []2D0= -5,7o(C=1, chloroform).

b) cleavage of the BOC-group contained in 1.92 g of the product of the preliminary stage, carried out analogously to example b). The resulting amine hydrochloride added at 0oC to 1,89 g of 4-tert-butyl-dimethyl-silyloxy-benzoyl chloride in 20 ml of pyridine and stirred for 16 h at room temperature. After concentration of the solution and chromatography of the residue on silica gel (hexane/acetic ether 2:1) obtain 1.84 g (S)-4-(tert - butyl-dimethyl-silyloxy)-N-[2-(4-cyano-phenyl)-1 - methyl-2-oxo-ethyl]-benzamide, []2D0= +45,9o(C=0,7, chloroform).

C) After removal of the protective group of 1.81 g of the product of the preliminary stage gain of 1.4 g (R,S)-N-[2-(4-cyano-phenyl)- 1-methyl-2-oxo-ethyl]-4-hydroxy-benzamide, MS (ion bombardment): 293 (M-H)+.

g) By a2CO3in dimethylformamide, held for 2 h at room temperature, after removal of the solvent and chromatography on silica gel (hexane/acetic ester 1:1) gain of 1.23 g of ethyl ester of (R,S)-[4-[2-(4-cyano-phenyl)-1-methyl-2-oxo-ethylcarboxyl]-phenoxy] -acetic acid, MS (ion bombardment): 381 (M+H)+.

Example 179

A solution of ethyl ester (R,S)-[4-[2-[4-[amino-(tert-butyl - dimethyl-silyloxy)-methyl]-phenyl]-1-methyl-2-oxo-ethylcarboxyl]- phenoxy]-acetic acid in 1 ml of simple ether is stirred for 1 h at 0oC with 0.1 ml of tetrabutylammonium fluoride (1M in tetrahydrofuran), then concentrated and the residue chromatographic on silica gel (hexane/acetic ester 1:2). The result is 11 mg of ethyl ester of (R,S)-[4-[2-[4-(amino-hydroxyimino-methyl)-phenyl] -1-methyl-2-oxo-ethylcarboxyl]-phenoxy]-acetic acid, MS (ion bombardment): 414 (M+H)+.

The source material can be obtained in the following way:

Analogously to example 31 0.6 g of ethyl ester of (R,S)-[4-[2-(4-cyano-phenyl)-1-methyl-2-oxo-ethylcarboxyl] -phenoxy] -acetic acid is subjected to interaction with hydrogen sulfide and methyliodide. Then 147 mg O-tert-butyl-dimethyl-silyl-hydroxylamine mixed with about what the philosophy of the residue on silica gel (hexane/acetic ether 3:2) to obtain 50 mg of ethyl ester of (R, S)-[4-[2-[4-[amino-(tert-butyl-dimethyl-silyloxy)- methyl] -phenyl] -1-methyl-2-oxo-ethylcarboxyl] -phenoxy]-acetic acid, MS (ion bombardment): 414 (M-113).

Example 180

Out of the 743 mg of the hydrochloride of the ethyl ester of (S)-4-(2-piperidin-4 - mmoxiccillin-propionyl)-phenoxyalkanoic acid in 20 ml ethanol and 20 ml of Acrylonitrile after 5 days at 80oC after chromatography of the residue from evaporation on silica gel (dichloromethane/methanol 5%) to obtain 250 mg of ethyl ether (S)-[4-[2-[1-(2-cyano-ethyl)-piperidine-4 - mmoxiccillin] -propionyl]-phenoxy]-acetic acid, MS (ion bombardment): 446 (M+H)+.

A solution of 250 mg of ethyl ether (S)-[4-[2-[1-(2-cyano-ethyl)- piperidine-4-mmoxiccillin] -propionyl] -phenoxy]-acetic acid in 10 ml of dichloromethane is treated at 0oC 128 mg of meta-chloroperbenzoic acid and stirred for 1 h at 0oC. Then the reaction solution was washed with a saturated solution of NaHCO3and saturated NaCl solution, dried and concentrated. After chromatography of the residue on silica gel get 140 mg of ethyl ether (S)-[4-[2-(1- hydroxy-piperidine-4-mmoxiccillin)-propionyl] -phenoxy]- acetic acid, MS (ion bombardment): 409 (M+H)+.

Example 181

RA - methylmorpholine and 217 mg of 4-nitro-phenoxycarbonylamino ester of acetic acid is stirred for 5 h at room temperature, concentrated and the residue chromatographic on silica gel (hexane/acetic ester 1:2). The result is 205 mg acetoxymethyl ether (S)-4-[2-(4-ethoxycarbonylmethoxy-phenyl)- 1-methyl-2-oxo-ethylcarboxylate] -piperidine-1-carboxylic acid, []2D0= +23,7o(C=0,35, chloroform).

Example 182

The removal of BOC protective groups contained 3.45 g of tert-butyl methyl ether (S)-4-[1-tert-butoxy-methyl-2-(4 - ethoxycarbonylmethoxy-phenyl)-2-oxo-ethylcarboxylate]- piperidine-1-carboxylic acid in 60 ml of dichloromethane and 30 ml triperoxonane acid, after concentration of the solvent and chromatography of the residue on Siciliana silica gel RP 18 (gradient, water/tetrahydrofuran) gain of 1.9 g of triptoreline ethyl ester (S)-[4-[3-hydroxy-2-(2-piperidine-4-mmoxiccillin)- propionyl] -phenoxy] -acetic acid, MS (ion bombardment): 409 (M+H)+.

The source material can be obtained in the following way:

a) Analogously to example b) otscheplaut BOC-group contained 3.5 g of ethyl ester of (S)-4-[3-tert-butoxy-2 - tert-butoxycarbonylamino-propionyl] -phenoxyalkanoic acid (example 7 g)), and the resulting amine for 16 h at room temperature mixed with to 2.57 g 1 is chlormethine. After removal of solvent and chromatography of the residue on silica gel (hexane/acetic ester 1:2) to obtain 3.5 g of tert-butyl methyl ether (S)-4-[1-tert - butoxymethyl-2-(4 - ethoxycarbonylmethoxy-phenyl)-2-oxo - ethylcarboxylate]-piperidine-1-carboxylic acid as a yellow oil, MS (ion bombardment): 565 (M+H)+.

Example 183

Analogously to example 181 480 mg of ethyl ester of (S)-[4-[3-hydroxy - 2-(2-piperidine-4-mmoxiccillin)-propionyl] -phenoxy] - acetic acid is subjected to interaction with 367 mg of 4-nitro - phenoxycarbonylamino-methyl ester of acetic acid and the remainder chromatographic on silica gel (acetic ether). The result is 161 mg of ethyl ether (S)- [4- [2- [(1-acetoxymethyl - piperidine-4-yloxy)-acetylamino]-3-hydroxy - propionyl] -phenoxy] -acetic acid as colorless oil, MS (ion bombardment): 525 (M+H)+.

Example 184

A solution of 800 mg of tert-butyl methyl ether (S)-4-[[2-(4-etoxycarbonyl-methoxy-phenyl)-1-methyl-2-oxo-ethyl] -methyl-carbamoylmethyl]-piperidine-1-carboxylic acid in 10 ml of dichloromethane and 5 ml triperoxonane acid is stirred for 1 h at room temperature and concentrate. After chromatography of the residue on Siciliana silicaglass-acetyl)-amino] -propionyl] -phenoxy]-acetic acid, MS (ion bombardment): 407 (M+H)+.

The source material can be obtained in the following way:

a) the Reaction mix 5 g of (S)-N-tert-butoxycarbonyl-N-methyl-2 - amino-propionic acid with 2,88 g of the hydrochloride of N,O-dimethylhydroxylamine in 100 ml of dichloromethane in the presence of 8,77 g TPTU and 5,96 ml 4-methylmorpholine after stirring for 16 h at room temperature, the concentration of the reaction solution and chromatography of the residue on silica gel (hexane/acetic ether 2: 1) receive 4,43 g tert-butyl ether (S)-[1-(methoxy-methyl-carbarnoyl)-ethyl]-methylcarbamyl acid, []2D0= -62,3o(C=1, chloroform).

b) After exchange reactions 4.1 g of the product of the preliminary stage with p-bromo-tert-butyl-dimethylsilanol analogously to example 3A) and chromatography of the residue on silica gel (hexane/acetic ether 95:5) receive 2,82 g tert-butyl ether (S)-[2-(4-tert - butyl-dimethyl-silyloxy)-phenyl]-1-methyl-2-oxo-ethyl] - methylcarbamyl acid as a colourless oil, []2D0= -127o(C = 0,5, chloroform).

C) After removal of the protective group from 2.2 g of the product of the preliminary stage analogously to example 3b) gain of 1.41 g of tert-butyl methyl ether (S)-[2-(4-hydroxy-phenyl)-

g) By alkylation 615 mg of the product of the preliminary stage analogously to example 3b) and after chromatography of the residue from evaporation on silica gel (hexane/acetic ether 3: 1) receive 674 mg of ethyl ester of (S)-[4-[2-(tert-butoxycarbonyl-methyl-amino) -propionyl] -phenoxy] -acetic acid, []2D0= -135,0o(=to 0.5, chloroform).

d) the Removal of protective TREATMENT group contained in 810 mg of the product of the preliminary stage, carried out analogously to example b) at -78oC. the Resulting amine is mixed with a 498 mg of 1-tert-butoxycarbonylamino-4-yl-exucuse acid in the presence of 570 mg of TPTU and 0.39 ml of 4-methylmorpholine in 30 ml of dichloromethane for 20 h at room temperature. After removal of solvent and chromatography of the residue on silica gel obtain 890 mg of tert-butyl methyl ether (S)-4-[[2-(4- ethoxycarbonylmethoxy-phenyl)-1-methyl-2-oxo-ethyl] -methyl - carbamoylmethyl]-piperidine-1-carboxylic acid as colorless oil, MS (ion bombardment): 507 (M+H)+.

Example 185

A solution of 850 mg of tert-butyl methyl ether (S)-4-[2-[2-(4- ethoxycarbonylmethoxy-phenyl)-1-methyl-2-oxo-ethylcarboxyl] -ethyl] -piperidine-1-carboxylic acid in 5 ml of dichloromethane and 2.5 ml triperoxonane acid paramesh the new ether (S)-[4-[2-(3- piperidine-4-yl-propionamide)-propionyl] -phenoxy]-acetic acid as a colorless oil, MS (ion bombardment): 391 (M+H)+.

The source material can be obtained in the following way:

The removal of protective TREATMENT group contained in 740 mg of ethyl ester of (S)-4-(2-tert-butoxycarbonylamino-propionyl)- phenoxyalkanoic acid is carried out analogously to example b). The resulting amine for 16 h and stirred at room temperature with 500 mg of 1-tert-butoxycarbonylamino-4-yl - propionic acid in the presence of 570 mg of TPTU and 0.46 ml of 4 - methylmorpholine in 10 ml of dichloromethane. After removal of solvent and chromatography of the residue on silica gel (hexane/acetic ether 2:3) obtain 890 mg of tert-butyl methyl ether (S)-4-[2-[2-(4- etoxycarbonyl-methoxy-phenyl)-1-methyl-2-oxo-ethylcarboxyl] - ethyl] -piperidine-1-carboxylic acid as a yellow oil, MS (ion bombardment): 491 (M+H)+.

Example 186

Based on 300 mg of triptoreline ethyl ester (S)-[4- [2-(3-piperidine-4-yl-propionamide)-propionyl] -phenoxy] -acetic acid analogously to example 181 after chromatography on silica gel (hexane/acetic ester 1:2) to obtain 140 mg of ethyl ether (S)-[4-[2-[3-(1-acetoxymethyl-carbonyl-piperidine-4-yl)- propionamido] -propionyl] -phenoxy]-acetic acid, MS (ion bombardment): 507 (M+H)+.

+.

The source material can be obtained in the following way:

a) Reaction of a phase transition between 4.1 g of tert-butyl methyl ether (R)-3-hydroxy-pyrrolidin-1-carboxylic acid and 3.85 ml tert - butyl methyl ether bromoxynil acid in 50 ml toluene and 50 ml of 50% NaOH in the presence of 500 mg of tetrabutylammonium hydrosulfate is carried out for 1 h Then the organic phase is washed with saturated NaCl solution, dried and concentrated, the resulting residue, which after chromatography on silica gel (hexane/acetic ether 3: 1) get to 4.98 g of tert - butyl methyl ether (R)-3-tert-butoxycarbonylmethyl-pyrrolidin-1 - carboxylic acid, MS (ion bombardment): 302 (M+H)+.

b) a Solution of 4.95 g of the product of the preliminary stage in 50 ml of dichloromethane and 25 ml triperoxonane acid is stirred for 3 h at room temperature and concentrate. The residue is dissolved in 40 ml of dioxane and 40 ml of 1H NaOH, Then quenching the reaction mixture was diluted with simple ether, the organic phase is washed 1H NaOH, and the aqueous phase is acidified 3H HCl. After extraction of the aqueous phase using a simple ether, washing, drying and concentration of the ether phase get to 0.72 g of tert-butyl methyl ether (R)-3 - carboxymethoxy-pyrrolidin-1-carboxylic acid. 360 mg of the ester is subjected to interaction with ethyl ether (S)-4-(2-tert - butoxycarbonylamino-propionyl)-phenoxyalkanoic acid, which is derived according to the example b) protective group, in 15 ml of dichloromethane in the presence of 446 mg TPTU and 0.33 ml of 4-methylmorpholine. After concentrating the reaction solution and chromatography of the residue receive 100 mg of tert-butyl methyl ether (R)-3-[(S)-1-(4 - ethoxycarbonylmethoxy-benzoyl)-ethylcarbamate] -pyrrolidin - 1-carboxylic acid, MS (ion bombardment): 479 (M+H)+.

Example 188

A solution of 290 mg of tert-butyl methyl ether (S)-6-[2-(4- ethoxycarbonylmethoxy-phenyl)-1-methyl-2-oxo-ethylcarboxyl] - 1,2,3,4-tetrahydro-isoquinoline-2-carboxylic acid in 4 ml dichloromethane and 2 ml triperoxonane acid is stirred for 1 h at room temperature, concentrated and the residue chromatographic on Siciliana silica gel RP 18 (gradient, water/tetrahydrofuran). The result is 174 mg trifenatate UP>D0= +51,7o(or=0.6, DMSO).

The source material can be obtained in the following way:

a) a solution of 1.46 g of 6-hydroxy-1,2,3,4-tetrahydro-isoquinoline - hydrobromide in 10 ml of dioxane and 2 ml of 1H NaOH at 0oC at the same time add to 1.38 g of di-tert-BUTYLCARBAMATE in 10 ml of dioxane and 10 ml of 1H NaOH. After stirring for 3 h at room temperature the reaction mixture with 1H HCl installed at pH 5, extracted with simple ether, the ether phases are washed with saturated NaCl solution, dried and concentrated. After chromatography of the residue on silica gel obtain 1.07 g of tert-butyl methyl ether 6-hydroxy-1,2,3,4-tetrahydro-isoquinoline-2-carboxylic acid, MS (EI): 192 (M-57).

b) At -15oC solution of 918 mg of the product of the preliminary stage in 10 ml of dichloromethane is treated first with 1.2 ml of triethylamine, and then 0.7 ml of anhydride of triftoratsetata and stirred for 2 h at room temperature. The precipitate is filtered off by suction, the filtrate is concentrated and the residue chromatographic on silica gel (hexane/acetic ether 7:1). The result of 1.02 g of tert-butyl methyl ether 6 - tripterocalyx-1,2,3,4-tetrahydro-isoquinoline-2 - carboxylic acid, MS (EI): 324 (M-57).

in) mg of palladium acetate, 32 mg of 1,3-bis-(diphenylphosphino)-propane and 0.4 ml of triethylamine in 4 ml of DMSO and 2.6 ml of methanol. Then the reaction mixture was diluted with saturated NaCl solution, extracted with simple ether, the ether phases are washed with saturated NaCl solution, dried and concentrated. After chromatography of the residue on silica gel get 443 mg of 6-methyl ester 2-tert-butyl ester of 1,2,3,4-tetrahydro - isoquinoline-2,6-dicarboxylic acid, MS (ion bombardment): 292 (M+H)+.

g) Saponification 387 mg of the product preview stage of 213 mg of NaOH in 9 ml of methanol and 1 ml of water is carried out for 6 h at room temperature. Then the reaction solution was concentrated and diluted with water. The aqueous phase is extracted with a simple ester, with 1H HCl installed at pH 5 and the precipitate is filtered off by suction. After washing the crystals with water and drying obtain 274 mg of 2-tert-butyl ester of 1,2,3,4-tetrahydro - isoquinoline-2,6-dicarboxylic acid. MS (EI): 220 (M-57).

d) After removal of protective OC-group of 313 mg of ethyl ester of (S)-4-(2-tert-butoxycarbonylamino-propionyl) -phenoxyalkanoic acid analogously to example b) receive Amin. This amine within 48 h was stirred at room temperature with 247 mg of the product prior to agile (hexane/acetic ester 1:1) get 444 mg of tert-butyl methyl ether (S)-6-[2-(4-ethoxycarbonylmethoxy-phenyl)-1 - methyl-2-oxo-ethylcarboxyl] -1,2,3,4-tetrahydro-isoquinoline-2 - carboxylic acid, []2D0= +51,3o(C = 0,4, chloroform).

Example 189

A solution of 106 mg of the acetate methyl ester 1-[8-(amino-imino-methyl)- 5 oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-4-ylacetic] -piperidine-4 - biloxicasino acid (example 175) and 18 mg of lithium hydroxide in 5 ml of methanol and 0.5 ml of water is stirred for 16 h at room temperature, with 1H HCl installed at pH 3 and concentrate. After chromatography of the residue on Siciliana silica gel RP 18 (gradient, water/tetrahydrofuran) receive 60 mg of 1-[8-(amino-imino-methyl)- 5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-4-ylacetic] -piperidine-4 - biloxicasino acid as white crystals, MS (ion bombardment): 405 (M+H)+.

Example 190

A solution of 200 mg of tert-butyl methyl ether (R)-3-[(5)-1-(4-tert - butoxycarbonylmethyl-benzoyl)-ethylcarbamate] -pyrrolidin-1 - carboxylic acid in 2 ml of dichloromethane and 1 ml triperoxonane acid is stirred for 4 h at room temperature, concentrated and the residue chromatographic on Siciliana silica gel RP 18 (gradient, water/tetrahydrofuran). The result is 113 mg trifenatate [4-[(S)-2-[(R)-2-pyrrolidin-3-yloxy-acetylamino] -propionyl]-phenoxy] -acetic acid, MS (bombing Etania 360 mg of tert-butyl methyl ether (R)-3-carboxymethoxy-pyrrolidin-1-carboxylic acid (example b)) 569 mg of tert-butyl methyl ether (S)-4-(2-tert - butoxycarbonylamino-propionyl)-phenoxyalkanoic acid, in which analogously to example b) split-off of the protective group, in 15 ml of dichloromethane in the presence of 446 mg TPTU and 0.33 ml of 4 - methylmorpholine after concentration of the reaction solution and chromatography of the residue on silica gel (hexane/acetic ester 1: 3) receive 200 mg of tert-butyl methyl ether (R)-3-[(S)-1-(4-tert - butoxycarbonyloxyimino)-ethylcarbamate] -pyrrolidin - 1-carboxylic acid, MS (ion bombardment): 507 (M+H)+.

Example 191

Analogously to example 185 231 mg of tert-butyl methyl ether (S)-4-[[2-(4-tert-butoxycarbonylamino-phenyl)-1-methyl-2-oxo - ethyl] -methyl-carbamoylmethyl] -piperidine-1-carboxylic acid otscheplaut protective group and chromatographic on Siciliana silica gel RP 18 (gradient, water/tetrahydrofuran). The result is 113 mg trifenatate (S)-4-[2-[methyl-(piperidine-4 - yloxy-acetyl)-amino] -propionyl] -phenoxy] -acetic acid, MS (ion bombardment): 379 (M+H)+.

The source material can be obtained in the following way:

a) By alkylation 723 mg of tert-butyl methyl ether (S)-[2- (4-hydroxy-phenyl)-1-methyl-2-oxo-ethyl] -methylcarbamyl acid analogously to example 3b) and after chromatography of the residue from evaporation on silica gel (hexane/acetic ether 5: 1) sex is, []2D0= -124,5o(C = 0,4, chloroform).

b) Removal of BOC protective groups contained in 394 g of the product of the preliminary stage, carried out analogously to example b) at -78oC. the Resulting amine is stirred with 311 mg of 1-tert - butoxycarbonylamino-4-yl-exucuse acid in the presence of 356 mg TPTU and 222 mg of 4-methyl-research in 45 ml of dichloromethane for 20 h at room temperature. After removal of solvent and chromatography of the residue on silica gel (tert - butyl methyl ether/hexane 4: 1) obtain 179 mg of tert-butyl methyl ether (S)-4-[[2-(4-tert-butoxycarbonylmethylene)-1-methyl-2 - oxo-ethyl] -methyl-carbamoylmethyl] -piperidine-1-carboxylic acid as a pale yellow oil, []2D0= -120,7o(C=0.3, and chloroform).

An example of a

The compound of formula 1 can be used by well-known methods as the active substance for the manufacture of tablets of the following composition; mg per tablet:

Active substance - 200

Microcrystalline cellulose - 155

Corn starch - 25

Talc - 25

The hypromellose - 20 - 425 mg

Example B

The compound of the formula I can be used by well-known methods as BR> Corn starch - 20,0

Milk sugar - 95,0

Talc - 4,5

Magnesium stearate 0.5 to about 220,0

1. Derivatives of acetic acid of formula I

< / BR>
where L is a group of formula L-1- L5:

< / BR>
moreover, contained in group L and/or between groups L and M associated't amide type carbonyl group can be represented in the form of oxime;

A group of the formula A1- A4:

< / BR>
< / BR>
where E1and E2- H, lower alkyl, OH, lower alkoxy, lower alkoxy-lower alkyl, carboxy-lower alkyl, P(O) (O - lower alkyl)2C(O)OR1, OC(O)R1, OC(O)OR1or C(O)SR1and at least one of the E1and E2is H, or E1and E2together with the N atoms on which they are linked, represent a (5,5-dimethyl - or 5-oxo)-4,5-dihydro-1,2,4-oxadiazol-3-yl group;

R1- lower alkoxy-lower alkyl, lower alkyl, lower alkyl, optionally substituted by OH, lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoyloxy, optionally substituted benzoyloxy lower alkyl-CONH-group, or phenyl, optionally substituted alkoxy or halogen, or cycloalkyl optional torn atom ABOUT,

X and Y are the one denoted by the 4;

m and n = 0 to 5;

t = 0 to 3, but m + n = 1 to 5 and each of m + t and n + t is equal to at least 1;

p and q = 0 to 5, however, p + q = 2 to 5;

W1- CH2, lower alkyl-CH, lower alkyl-OC(O)CH, NH, lower alkyl-N or lower alkoxy-lower alkyl-N;

W2- O or NH;

G represents H or characterizing group-aminocarbonyl acid selected from the group comprising lower alkyl, optionally substituted lower alkylthio, -ORa-THE OTHERcor phenyl, optionally substituted-ORb;

Rais hydrogen, lower alkyl or lower alkanoyl;

Rbis hydrogen, lower alkyl, lower alkoxy-lower alkyl, lower alkoxycarbonyl, lower alkanoyl, furoyl or benzoyl, optionally substituted-O-lower alkanoyl or NH2;

Rclowest alkoxycarbonyl, lower alkylaminocarbonyl or benzoyl;

M - linked via the N-atom with geography 1,4-piperidinyl or 1,4-phenylene, optionally substituted lower alkyl, lower alkoxygroup, OCH2COOH-or OCH2COO-lower alkyl;

Q is oxygen, CH2, NH, acyl-N or lower alkyl-OC(O)N;

T - NH2, NH-lower alkyl, NH-lower alkyl(COOH or COO-lower alkyl), lower alkyloxy, optionally substituted lower alkoxygroup, COOH, COO-diphenyl or pyridyl, optional linked through the lowest alkylen, or cycloalkyl, optionally linked through the lowest alkylen and optional torn O, NH or NCOO-lower alkyl, provided that (a) T' has a value other than H, lower alkyl and phenyl-lower alkyl, if L is a group of the formula

< / BR>
where A is a group of the formula

< / BR>
where one of the E1and E2is hydrogen and the other is hydrogen, tert-butoxycarbonyl or benzyloxycarbonyl; one of X and Y is CH and the other is CH or N;

W1- NH, lower alkyl-N or lower alkoxy-lower alkyl-N;

G has the above meaning;

M - 1,4-piperidinyl connected via the N-atom with geography;

Q - oxygen

and that b) T' has a value other than H, lower alkyl, phenyl and phenyl-lower alkyl, if L is a group of the formula L11L31or L41:

< / BR>
where A is a group of the formula A1< / BR>
< / BR>
where one of the E1and E2is hydrogen and the other is hydrogen, tert-butoxycarbonyl or benzyloxycarbonyl; one of X and Y is CH and the other is CH, C - lower alkoxy or N;

R0and G0- H or lower alkyl;

W4- C = O or C = NOH;

M - 1,4-phenylene, optionally substituted lower alkyl, lower alkoxygroup, OCH2COOH or OCH2COO-lower alkyl;< the L - a group of the formula L1and M is 1,4-phenylene; and

d) G is not hydrogen when L is a group of the formula L' and A group of the formula A3or A4,

as well as the hydrate or the solvate and their physiologically acceptable salts.

2. Connection on p. 1, where L is a group of the formula L1< / BR>
where A - group A1, A2or A30:

< / BR>
where one of the E1and E2- H and the other is H, lower alkyl, OH, lower alkoxy, lower alkoxy-lower alkyl, carboxy-lower alkyl, PO(O-lower alkyl)2C(O)OR1or OC(O)OR1where R1- lower alkoxy-lower alkyl, lower alkyl substituted by OH, or a lower alkanoyloxy, or phenyl, optionally substituted alkoxy or halogen, or optionally broken O cycloalkyl;

one of X and Y is CH and the other is CH or N,

m and n = 0 to 5 and t = 0 to 3, but m + n = 1 to 5 and each of m + t and n + t is equal to at least 1;

W1- CH2, lower alkyl-OC(O)CH, NH, lower alkyl-N or lower alkoxy-lower alkyl-N;

G and M have a value under item 1 of the formula;

Q is oxygen;

T - group OT", where T" is H, lower alkyl, lower alkoxy-lower alkyl or, under certain conditions, linked through the lowest alkylen and under certain conditions torn O cycloalkyl, provided that (a) T has a signature is od tert-butoxycarbonyl or benzyloxycarbonyl;

X, Y, G, and Q have the above significance;

W1- NH, lower alkyl-N or lower alkoxy-lower alkyl-N;

M - linked via the N-atom with geography 1,4-piperidinyl, and that

b) T has a value other than H and lower alkyl, if L is a group of the formula L11< / BR>
< / BR>
where A is a group of the formula A1< / BR>
< / BR>
where E1and E2is hydrogen, tert-butoxycarbonyl or benzyloxycarbonyl;

X, Y, G, and Q have the above significance;

R0and G0- H or lower alkyl;

M under certain conditions - substituted by lower alkyl, lower alkoxy, OCH2COOH or OCH2COO-lower alkyl 1,4-phenylene,

and their physiologically acceptable salts.

3. Derivatives of acetic acid on p. 1, where L - group L1in which A is a group A1namely, the group of formula I-A

< / BR>
where E1E2X, Y, W1, G, M, Q and T have the same value under item 1 of the formula.

4. Derivatives of acetic acid under item 1 or 3, where one of the E1and E2- H and the other is H, OH, C(O)OR1or OC(O)OR1.

5. Derivatives of acetic acid on p. 4, where R1- lower alkyl, such as ethyl, butyl or isobutyl, lower alkoxy-lower alkyl, ethyl, acetoxymethyl, acetoxyethyl or pivaloyloxymethyl, or phenyl.

6. Derivatives of acetic acid on PP.1, 3, 4 or 5, where one of X and Y is CH and the other is CH or N, and/or where W1- NH or CH2and/or where Q is oxygen or CH2.

7. Derivatives of acetic acid in one of the paragraphs.1 and 3 to 6, where G is H, lower alkyl, such as methyl or ethyl, or lower alkoxycarbonyl-lower alkyl, such as ethoxycarbonylmethyl.

8. Derivatives of acetic acid in one of the paragraphs.1 and 3 to 7, where M is linked via a N-atom with geography 1,4-piperidinyl, 1,4-phenylene or substituted on OCH2COO-lower alkyl, such as ethoxycarbonylmethoxy, 1,4-phenylene.

9. Derivatives of acetic acid in one of the paragraphs.1 and 3 to 8, where T is lower alkoxy, such as methoxy, ethoxy, isopropoxy, isobutoxy, tert-butoxy or xeloxa, lower alkoxy-lower alkoxy, such as methoxyethoxy, replaced by COO-lower alkyl lower alkenylacyl, such as 2-isobutoxide-2-pentyloxy, substituted lower alkyl-COO-lower alkoxy, such as pivaloyloxymethyl, substituted lower alkyl-OCOO lower alkoxy, such as 1-isopropoxycarbonyloxymethyl, under certain conditions torn O cycloalkyl is hydroxy, or linked via a lower alkylene and under certain conditions torn NCOO-lower alkyl cycloalkyl, such as 1-tert-butoxycarbonyl-3-or 4-piperidinyloxy.

10. Derivatives of acetic acid in one of the paragraphs.1 to 9, selected from the following groups:

ethyl ester of (S)-4-[2-[4-[imino-2-(methoxy-ethoxycarbonyl)-methyl] -benzoylamine]-propionyl]-phenoxyalkanoic acid,

ethyl ester of (Z)-(R, S)-4-[2-[4-[amino-hydroxyimino-methyl]-benzoylamine]-propionyl]-phenoxyalkanoic acid,

tetrahydropyran-4-yl-ester (S)-4-[2-[4-(ethoxycarbonyl-iminomethyl)-benzoylamine]-propionyl]-phenoxyalkanoic acid,

ethyl ester of (Z)-(R, S)-4-[2-[4-[amino-ethoxycarbonylmethyl]-benzoylamine]-propionyl]-phenoxyalkanoic acid,

ethyl ester of (S)-4-[2-[4-(imino-phenoxycarbonylamino-methyl)-benzoylamine]-propionyl]-phenoxyalkanoic acid,

2-methoxy-ethyl ester (S)-4-[2-[4-[imino-(2-methoxy-ethoxycarbonyl)-methyl]-benzoylamine]-propionyl]-phenoxyalkanoic acid,

ethyl ester of (Z)-(S)-4-[2-[4-(amino-hydroxyimino-methyl)-benzoylamine] -propionyl]-phenoxyalkanoic acid,

isopropyl ether (E/Z)-(S)-1-[2-[4-(amino-ethoxycarbonylmethyl)-benzoylamine]-propionyl]-piperidine-4-ilok is piperidin-4-biloxicasino acid,

isopropyl ester[1-[4-[4-(ethoxycarbonyl-imino-methyl)-phenyl]-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid,

isopropyl ether (RS)-[1-[4-[4-(solutionline-aminomethyl)-phenyl]-2-methyl-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid.

11. Connection on p. 10, representing the ethyl ester of (E/Z)-(S)-1-[2-[4-(amino-hydroxyimino-methyl)-benzoylamine] -propionyl] -piperidine-4-biloxicasino acid and its pharmaceutically acceptable salts.

12. Derivatives of acetic acid in one of the paragraphs.1 and 3 to 9, selected from the following groups:

(R/S)-1-isopropoxycarbonyl-ethyl ester (Z)-(S)-[1-[2[4-(amino-hydroxyimino-methyl)-benzoylamine] -propionyl] -piperidine-4-yloxy]-acetic acid,

pyridine-3-ymetray ether (R)-(E)/(Z)-[1-[4-[4-(amino-hydroxyimino-methyl)-phenyl]-2-methyl-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid,

pyridine-4-ymetray ether (R)-(E)/(Z)-[1-[4-[4-(amino-hydroxyimino-methyl)-phenyl]-2-methyl-4-oxo-butyryl]-piperidine-4-yloxy]-acetic acid,

tert-butyl ether (E) - or (Z)-(R/S)-3-[1-[(R)-4-[4-(amino-hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-intoxicatedly]-piperidine-1-carboxylic acid,

ethyl ester (R)-[1-[4-[4-(benzoyloxymethyl the R)-[1-[4-[4-(imino-pivaloyloxymethyl-methyl)-phenyl]-2-methyl-4-oxo-butyryl]piperidine-4-yloxy]-acetic acid,

tert-butyl ether (E)- or (Z)-(R)-4-[1-[4-[4-(amino-hydroxyimino-methyl)-phenyl] -2-methyl-4-oxo-butyryl] -piperidine-4-intoxicatedly]-piperidine-1-carboxylic acid,

ethyl ester of (S)-[4-[2-[4-[(2-acetoxy-ethoxy-carbylamine)-amino-methyl]-benzoylamine]-propionyl]phenoxy]-acetic acid.

13. Derivatives of acetic acid on p. 1, where L - group L1in which A is a group A3namely, the group of the formula

< / BR>
where E1, m, n, D, W1, G, M, Q and T have the values under item 1 of the formula.

14. Derivatives of acetic acid under item 1 or 13, where E1Is H, OH or C(O)OR1, m, and n = 2, and/or D and Q is oxygen, and/or W1- NH, and/or G - lower alkyl, such as methyl, and/or M - 1,4-phenylene, and/or T - lower alkoxy, such as ethoxy.

15. Derivatives of acetic acid on p. 14, where E1- lower alkanoyloxy lowest alkoxycarbonyl, such as acetoxymethyl.

16. Connection on p. 13, 14 or 15, representing acetoxymethyl ether (S)-4-[2-(4-ethoxycarbonylmethoxy-phenyl)-1-methyl-2-oxo-ethylcarboxylate]-piperidine-1-carboxylic acid.

17. Derivatives of acetic acid on p. 1, where L - group L1in which A is a group A2namely, the group of formula I-C

< / BR>
where ASS="ptx2">

18. Derivatives of acetic acid on p. 1, where L - group L1in which A is a group A4namely, the group of formula I-D

< / BR>
where E1, p, q, W1, G, M, Q and T have the values under item 1 of the formula, in particular, M is 1,4-phenylene, Q is oxygen and T - lower alkoxy.

19. Derivatives of acetic acid on p. 1, where L - group L2in which A is a group A1namely, the group of formula I-E

< / BR>
where E1E2X, Y, W2, G, M, Q and T have the values under item 1 of the formula, in particular, M is linked via a N-atom with geography 1,4-piperidinyl, Q is oxygen and T - lower alkoxy.

20. Derivatives of acetic acid on p. 1, where L - group L3in which A is a group A1namely, the group of formula I-F

< / BR>
where E1E2X, Y, G, M, Q and T have the values under item 1 of the formula, in particular, M is linked via a N-atom with geography 1,4-piperidinyl, Q is oxygen and T - lower alkoxy.

21. Derivatives of acetic acid on p. 1, where L - group L4in which A is a group A1namely, the group of formula I-G

where E1E2X, Y, G, M, Q and T have the values under item 1 of the formula, in particular, M is 1,4-phenylene, Q is oxygen and T - lower alkoxy.

22. Derivatives of acetic acid on p. 1, where L - group L5namely, the group is ez N-atom with geography, 1,4-piperidinyl, Q is oxygen and T - lower alkoxy.

23. Derivatives of acetic acid in one of the paragraphs.1 - 22, with the ability to inhibit platelet aggregation, adhesion of cells, and the binding of adhesive proteins to blood platelets.

Priority points

03.12.93 on PP.2 and 10;

25.10.94 on PP.1, 3-9, 11-22.

 

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1 tbl, 1 ex

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20 cl, 2 tbl, 37 ex

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