New carboxaldehyde cyclic carboxamide derivatives

 

(57) Abstract:

The invention relates to new carboxyterminal cyclic carboxamide derivative of formula 1

< / BR>
where G1- CH2; G2- C(O); m = 2 or 3, n is 0 or 1; R1is 1-3 substituent, independently selected from H, G, C1-C6alkoxy; R2is 1-3 substituent, independently selected from H, C1-C6alkoxy; R3means N or

< / BR>
< / BR>
< / BR>
R4- H; Ar1means

< / BR>
< / BR>
R8means 1-3 substituent, independently selected from H, G; R9means N;

And means

< / BR>
< / BR>
< / BR>
where p = 1, 2, 3, or 4; X is-O-, -CH2-; R10-H, C1-C6alkyl or

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where q = 2 or 3; R5- C1-C4alkyl, (CH2)2HE; R6- C1-C4alkyl, -(CH2)2HE, (CH2)2N(CH3)2; R5', R6' - C1-C4alkyl; R7- C1-C6alkyl, and the stereoisomers and pharmaceutically acceptable salts. The described method of obtaining them. Compounds 1 are agonistically activity against receptors NK1 and NK2, which allows their use in Farmaceutica for new carboxyamide cyclic carboxamide derivatives (shown here as a compound or compounds of formula (1)) and their stereoisomers and pharmaceutically usable salts, and their use as antagonists of receptors tachykinin. Such antagonists are useful in the treatment of tachykinin-mediated diseases and disclosed here of symptoms, including asthma, cough and bronchitis.

SUMMARY OF THE INVENTION

The present invention relates to new carboxyamide cyclic carboxamide derivatives of formula (1):

< / BR>
where G1is CH2or C(O);

G2is CH2or C(O);

m is 2 or 3;

n is 0 or 1;

R1is from 1 to 3 substituents each of which is independently selected from the group consisting of hydrogen, halogen, CF3C1-C6the alkyl and C1-C6alkoxy;

R2is from 1 to 3 substituents each of which is independently selected from the group consisting of hydrogen, halogen, cyano, CF3C1-C6the alkyl and C1-C6alkoxy;

R3represents hydrogen or a radical selected from the group consisting of

< / BR>
< / BR>
< / BR>
where R4selected from the group consisting of hydrogen, C1-C4the alkyl and-CF3;

Ar1represents a radical selected from the group consisting of

< / BR>
< / BR>
where R83C1-C6the alkyl and C1-C6alkoxy;

R9is from 1 to 2 substituents, each of which is independently selected from the group consisting of hydrogen, halogen, CF3C1-C6the alkyl and C1-C6alkoxy;

A represents a radical selected from the group consisting of

< / BR>
< / BR>
< / BR>
where p is 1, 2, 3 or 4;

X represents-O-, -S(O)k- or-CH2-,

in which k is 0, 1 or 2;

R10represents hydrogen, C1-C6alkyl or a radical selected from the group consisting of

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where q is 2 or 3;

R5represents C1-C4alkyl or -(CH2)2OH;

R6represents C1-C4alkyl, -(CH2)2OH or -(CH2)2N (CH3)2;

R5'represents C1-4-alkyl; R6'represents C1-4-alkyl;

R7represents C1-C6alkyl;

provided that when G1is-C(O)-, G2is-CH2-; and when G2is-C(O)-, G1is-CH2-; and stereoisomers and pharmaceutically acceptable salts.

Specialist clear that the connection is by means of formula (1) implies in particular stereoisomers, or a mixture of stereoisomers. Indicates that the connection is supplied by the symbols (+) and (-) - or designations on Kanu-Ing olodo-Prelog (R)- and (S) - stereochemistry of the compounds represented by formula (1) and their intermediates. Specifically noted that the new carboxaldehyde cyclic carboxamide derivatives of the present invention are asymmetric 3-position 3,3-disubstituted pyrrolidine and can exist in the (R)- or (S)-configuration, or may represent a mixture of the two. Also specifically noted that the new substituted cyclic carboxamide derivatives of the present invention can be asymmetric at the place of attachment of carboxyl substituent for the cyclic carboxamide and that asymmetry in the place of attachment of carboxyl Deputy may be in the (R)- or (S)-configuration or to represent their mix.

Specific stereoisomers can be obtained by stereospecific synthesis using enantiomerically pure or enantiomerically enriched starting materials. Specific stereoisomers of source materials or products can be divided and highlight known in the art methods, such as chromatography on chiral stationarystate for this purpose reagents. Useful methods of separation and allocation of specific stereoisomers are known in practice and described in Stereochemistry of Organic Compounds, E. L. Eliel and S. H. Wilen, Wiley (1994), and Enantiomers, Racemates and Resolutions, J. Jacques, A. Collet, and S. H. Wilen, Wiley (1981).

As is already clear to the experts, some compounds of formula (1) may exist as tautomers. Consider that any reference in this application one of the tautomeric compounds of the formula (1) implies each tautomeric form, and mixtures thereof.

In this application the following notation is used:

(a) the term "halogen" refers to fluorine atom, chlorine atom, bromine atom or iodine atom;

b) the term "C1-C6alkyl" refers to branched or linear alkyl, the radical containing from 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.;

C) the term "C1-C4alkyl" refers to branched or linear alkyl, the radical containing from 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.;

g) the term "C1-C4alkoxy" refers to a linear or branched alkoxygroup containing from 1 to 6 atoms of peroxy, hexose and others;

d) the symbol "-C(O) - or S(O)" refers to a carbonyl group of the formula:

< / BR>
(e) designation refers to the connection for which the stereochemistry is not defined;

W) designation refers to communication which is directed forward from the plane of the page;

C) designation refers to communication which is directed backward from the plane of the page;

and) used in the receiving and examples, the terms have the indicated meanings: "ng" means nanogram: "μg" refers to micrograms; "mg" refers to milligrams; "g" refers to grams; "kg" refers to kilograms; "nmol" means nanomole; "mmol" refers mmol; "mol" refers to moles; "μl" refers to Microlitre; "ml" refers to milliliters; "l" refers to liters; "Rf" indicates the factor holding; "oWith" refers to degrees Celsius; "since" refers to boiling point; "mm RT.article" refers to pressure in millimeters of mercury; "so square" refers to melting point; "decomp." refers to decomposition; []20Drefers to specific rotation of the D line of sodium at 20oWith obtained a 1 decimeter cell; "K" refers to concentration in g/ml; "nm" refers to nanomolar; "μm" refers to micromolar; "mm" means millevoi liquid chromatography; "HRMS" refers to mass spectrometry high resolution; "THF" refers to tetrahydrofuran; "brine" refers to a saturated aqueous solution of sodium chloride; "P.F." means loss during drying; "AIBN" means 2,2' - azobisisobutyronitrile; Curie" means microcurie; "V. B." indicates intraperitoneal; "centuries" refers to intravenously; and "decays/min" stands for the number of disintegrations per minute;

K) under the designation

< / BR>
understand that the radical is attached at the 1-position, and the Deputy or deputies, represented as R, can be attached by any of 2, 3, 4, 5, or 6 positions;

l) the symbol

< / BR>
refers to pyridyl or replaced pyridyl, and understand that the radical can be attached at the 2-position, 3-position or 4-position, in addition, understand that when the radical is attached at the 2-position, Deputy or deputies, represented as R, can be attached on any of 3, 4, 5 or 6-position, or when the radical is attached at the 3-position, Deputy or deputies, represented as R, can be attached by any of 2, 4, 5, or 6 positions, and when the radical is attached at the 4-position, Deputy or deputies, represented as R, can be attached on lui the excess of one enantiomer (E1) in a mixture of two enantiomers (E1 plus E2), calculated as

{(E1 - E2): (E1 + E2)} x 100% = ei;

h) the term "their pharmaceutically acceptable salt" means any salt accession acid or basic salts of the merger.

The expression "pharmaceutically acceptable salts join acid" is intended to refer to any non-toxic organic or inorganic salt accession acid basic compounds represented by formula (1). Illustrative inorganic acids which form suitable salts include hydrochloric, Hydrobromic, sulfuric and phosphoric acid and acid metal salts such as monohydratefast sodium and potassium hydrosulfate. Illustrative organic acids which form suitable salts include mono-, di - and tricarboxylic acids. Examples of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, ximalayasha, benzoic, oxybenzone, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, para-toluensulfonate acid, and sulfonic acids, such as benzolsulfonat, methansulfonate, econsultancy and 2-hydroxyethanesulfonic key is in acids such compounds are soluble in water and various hydrophilic organic solvents and compared with the corresponding free bases usually have a higher melting point.

The expression "pharmaceutically acceptable basic salts accession" is intended to refer to any non-toxic organic or inorganic basic salts of joining compounds represented by formula (1). Illustrative bases which form suitable salts include hydroxides of alkaline or alkaline earth metals, such as hydroxides of sodium, potassium, calcium, magnesium or barium; ammonia, and aliphatic, alicyclic, or aromatic organic amines, such as methylamine, dimethylamine, trimethylamine, and picoline. These compounds can form mono - or dienone salt.

As for groups particularly useful structurally related compounds, the end use of the compounds of formula (1) is preferred, certain groups and configurations.

Below is preferred variants of compounds of formula (1):

1) are preferred compounds in which m is 2;

2) are preferred compounds in which n is 0;

3) are preferred compounds in which G1represents-CH2-, and G2represents-C(O)-;

4) are preferred compounds in which m is 2, n is 0, G1represents-CH2-, and G2>6) are preferred compounds in which R3represents hydrogen, and R2is 3,4,5-trimetoksi-group;

7) for compounds in which R3is not hydrogen, are preferred compounds in which R3represents a radical selected from the group

< / BR>
< / BR>
where R4the same as defined above;

8) for compounds in which R3is not hydrogen, preferred compounds in which R3represents the radical

< / BR>
where R4the same as defined above;

9) for compounds in which R3is not hydrogen, preferred compounds in which R2is 2-methoxy, and R3is a 5-position represents the radical

< / BR>
where R4the same as defined above;

10) are preferred compounds in which a represents a radical selected from the group

< / BR>
< / BR>
where R10, R and X are such as defined above;

11) is more preferred compounds in which a represents the radical

< / BR>
where R10and R such as defined above;

12) even more preferred compounds in which a represents the radical

< / BR>
where p is 1, and R10represents hydrogen and/BR>< / BR>
where p is 1, and R10represents hydrogen or ethyl.

It is clear that the requirement of one (or more) of the preferred options 1 through 13 of the formula (1) or, considering the examples here, you can still choose the preferred options of the formula (1).

The following are examples of compounds included in this invention. It is clear that the examples include (R)-isomers and (S)-isomers of the compounds 3-position 3,3-disubstituted pyrrolidine and, where possible, the place of attachment of carboxyl substituent for the cyclic carboxamide, and mixtures thereof. Believe that this list is provided only as an example and in no way limits the scope of this invention.

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3-chlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-differenl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-inboxed)piperidine-1-yl)ethyl)-3-(4-forfinal)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(4-triptoreline)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dimetilfenil)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-acid)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3-methoxyphenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)-pyrrolidin;

1-(4-chlorobenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3-(2-propyloxy)benzoyl-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichloropyridine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido) piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(5-methyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl) ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,5-bis(trifluoromethyl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-benzoyl-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)-pyrrolidin;

1-benzoyl-3-(3-(4-phenyl-4-((4-carbethoxymethylthio the phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)propyl)-3-(3,4-dichlorophenyl)-5-oxopyrrolidin;

1-benzoyl-3-(2-(4-pyrid-4-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl) pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-pyrid-4-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-pyrid-4-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl) ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-4-yl) benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido) piperidine-1-yl) ethyl-3-(3,4-dichlorophenyl) pyrrolidin;

1-benzoyl-3-(2-(4-pyrid-4-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzyl)-3-(2-(4-pyrid-4-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-pyrid-4-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl) carboxamido) piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl) pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-(pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-2-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-(pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-(pyrid-2-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido) piperidine-1-yl)ethyl)-3-(3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-2-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;
1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-differenl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3-forfinal)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(4-forfinal)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(4-triptoreline)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dimetilfenil)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-acid)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3-methoxyphenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

Raiden;

1-(3-(2-propyloxy)benzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido) piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(5-methyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,5-bis(trifluoromethyl)benzoyl)-3-(2-(4-phenyl-4-((44-phenyl-4-((4-carboxymethyllysine-1-yl) carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-benzoyl-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(3-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)propyl)-3-(3,4-dichlorophenyl) pyrrolidin;

1-(3,5-bis(trifluoromethyl)benzyl)-3-(3-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)propyl)-3-(3,4-dichlorophenyl)-5-oxopyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-4-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-pyrid-4-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl) ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-(pyrid-4-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(pyrid-4-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

chlorphenyl)pyrrolidin;

1-benzoyl-3-(2-(4-(pyrid-3-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl) pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl) ethyl) - 3-(3,4-dichlorophenyl) pyrrolidin;

1-benzoyl-3-(2-(4-(pyrid-3-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(pyrid-3-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-2-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-(pyrid-2-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(lH-tetrazol)-1-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)these shall Eridan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-2-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(4-forfinal)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl) ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl) ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-5-yl) benzoyl)-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl) carboxamido) piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-4-yl)-4-((4-carboxy soil)-3-(2-(4-(pyrid-4-yl)-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-4-yl)-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-2-yl)-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((3-carboxypeptidase-1-yl)carboxamido)piperidin is samigo)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl) ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl-3-(2-(4-phenyl-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-phenyl-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-phenyl-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((3-carboxypeptidase-1-yl)carboxamido) piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-pyrid-4-yl)-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl(ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-pyrid-4-yl)-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-3-yl)-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-2-yl)-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(4-forfinal)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl) pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((2-carboxypeptidase-1-yl)carboxamido) piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;
3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-phenyl-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((2-carboxypeptidase-1-yl) carboxamido)piperidine-1-yl) ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-pyrid-4-yl)-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-pyrid-3-yl)-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-2-yl)-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-d is oxamide)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(4-forfinal)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((3-carboxypropyl-1-yl) carboxamido)piperidine-1-yl) ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-phenyl-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((3-carboxypropyl-1-yl)carboxamido) piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-ethoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-3-yl)-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-2-yl)-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((3-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxypropyl-1-yl)carboxamido)-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((4-carboxypropyl-1-yl) carboxamido)piperidine-1-yl) ethyl)-3-(3,4-dichlorophenyl) pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-phenyl-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-phenyl-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((2-carboxypropyl-1-yl) carboxamido) piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-4-yl)-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-3-yl)-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrol the DIN-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-4-yl)-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((3-carboxymethyl-4-yl) carboxamido) piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((3-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl-3-(4-forfinal) pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((3-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((4-carboxymethyl-4-yl)carboxamido) piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((3-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

chlorphenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-phenyl-4-((3-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((3-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-4-yl)-4-((3-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((3-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((3-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-4-yl)-4-((3-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((3-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((3-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-2-yl)-4-((3-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl) is peridin-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((3-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl-3-phenylpyrrolidine

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl-3-(4-forfinal) pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl) pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((2-carboxymethyl-4-yl) carboxamido)piperidine-1-yl) ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-phenyl-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-phenyl-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-benzoyl-3-(2-(4-phenyl-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl) ethyl)-3-phenylpyrrolidine;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-4-yl)-4-((2-carbobenzoxy)-3-(2-(4-(pyrid-4-yl)-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(pyrid-4-yl)-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-3-yl)-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-triazole-1-yl)benzoyl)-3-(2-(4-(pyrid-3-yl)-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-2-yl)-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin;

1-(2-methoxy-5-(1H-tetrazol-3-yl)benzoyl)-3-(2-(4-(pyrid-2-yl)-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine.

In Reaction Scheme a shows the basic synthetic procedure for obtaining such compounds of formula (1). The reagents and starting materials are readily available for professionals. All substances in the Reaction Scheme And is inuu group of the appropriate 3-(-hydroxyalkyl)pyrrolidine formula 2 is transformed into the right of the deleted group L1. Suitable 3-(-hydroxyalkyl)pyrrolidine formula 2 is a substance in which m, n, G1, G2, R1, R2and R3such as is required for the final product of formula (1). Suitable 3-(-hydroxyalkyl)pyrrolidine formula 2 may also have the stereochemistry as desired for the final product of formula (1). Appropriate compounds of formula 2 can be obtained as described herein and in U.S. Patent 5 340 822 and 5 635 510 and in PCT WO 94/26735 and WO 96/06094. Suitable removable group L1is a group that can be removed with a pyridine of the formula 3, having a compound of formula (1) or a protected compound of formula (1). Suitable to be deleted group L1include (but are not limited to) chlorine, bromine, iodine, mesilate, tosylate and the like, with the preferred mesilate. The conversion of hydroxyl groups to delete a group, such as chlorine, bromine, iodine, mesilate and toilet, well known and highly appreciated in practice.

For example, compounds in which L1is bromine, are formed by the interaction of the appropriate 3-(-hydroxyalkyl)pyrrolidine formula 2 with 1.0 to 1.5 molar equivalents chetyrehpostovye carbon and from 1.0 to 1.75 molar equivalents of triphenylphosphine (P. J. Kocienski and other J. Org.Chem. 42, 353-355 (1977)). Reaction about the e, such as dichloromethane or chloroform and then adding a solution of triphenylphosphine in a suitable solvent such as dichloromethane or chloroform. The reaction is usually carried out at temperatures from -10oWith up to room temperature. The reaction typically takes from 5 minutes to 24 hours. The product can be extracted and cleaned known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

Compounds in which L1is bromine, are formed also in the interaction of the appropriate 3-(-hydroxyalkyl)pyrrolidine formula 2 with a small molar excess of triphenylphosphine dibromide (R. F. Borch and others J. Org.Chem. 99, 1612-1619 (1977)). The reaction is carried out in a suitable solvent, such as tetrahydrofuran or diethyl ether. The reaction is carried out in the presence of a suitable base, such as pyridine. The reaction is usually carried out at temperatures from 0 to 50oC. the Reaction generally takes from 5 minutes to 24 hours. The product can be extracted and cleaned known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

Otherwise formed, for example, compounds in which L1is mesilate, by interacting podhodjashee in a suitable solvent, such as dichloromethane, chloroform, toluene, benzene, or pyridine. The reaction is carried out in the presence of a suitable base, such as triethylamine, N, N-diisopropylethylamine, N-methylmorpholine or pyridine. The reaction is usually carried out at temperatures from -20 to 50oC. the Reaction generally takes from 1 hour to 24 hours. The product can be extracted and cleaned known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

The compounds of formula 2A, where L1is iodine, can be obtained from the compounds of formula 2A, where L1is mesilate, chlorine or bromine, the reaction of the exchange, such as the Finkelstein reaction.

For example, the compounds of formula 2A, where L1is mesilate, chlorine or bromine, interact with 1.0 to 10.0 molar equivalents of iodide such as sodium iodide or potassium. The reaction is carried out in a suitable solvent, such as acetone or butanone. The reaction is usually carried out at temperatures from room temperature up to the boiling point of the solvent under reflux. The reaction typically takes from 1 hour to 24 hours. The product can be extracted and cleaned known in practice means, such as extraction, evaporation, Resv>-alkyl)pyrrolidin formula 2 is reacted with a suitable piperidinium compound of formula 3, or its salt. Suitable piperidine compound of formula 3 is a substance in which AG1such as required in the final product of formula (1), and' either is as required in the final product of formula (1) or after removing the protecting network And, as required in the final product of formula (1), or after amidation And gives, as required in the final product of formula (1).

For example, suitable 3-(-L1-alkyl)pyrrolidin formula 2A reacts with a suitable piperidinium compound of formula 3, or its salt, giving the compound of formula (1) or the compound of formula (1) with protection. The reaction is carried out in a suitable essentially anhydrous solvent such as tetrahydrofuran, pyridine, acetonitrile, toluene or dimethylformamide, using from 1.0 to 6.0 molar equivalents of a suitable base, such as triethylamine, pyridine or N, N-diisopropylethylamine. If using salt and the appropriate piperidine of formula 3, then apply additional molar excess of a suitable base. The reaction may be promoted by adding a catalytic amount (from 0.1 to 0.5 molar equivalents) iodide, such corites under reflux. The reaction typically takes from 1 to 72 hours. The product can be extracted and cleaned known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

Differently, conduct the reaction in a suitable mixed solvent such as a mixture of toluene/water mixture of ethyl acetate/water or a mixture of tetrahydrofuran/water, using from 1.0 to 6.0 molar equivalents of a suitable base, such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate. As mentioned above, if using salt and the appropriate piperidine of formula 3, then take the extra molar excess of a suitable base. The reaction may be promoted by adding a catalytic amount (from 0.1 to 0.5 molar equivalents) iodide such as sodium iodide or potassium. The reaction is usually carried out at temperatures from room temperature up to the boiling point of the mixed solvent under reflux. The reaction typically takes from 1 to 150 hours. The product can be extracted and cleaned known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

In optional stage 3 PE is the pressure protection such as the removal of protection with a carboxyl group using a suitable protective group, such as described in T. Greene, Protecting Groups in Organic Synthesis is well known and appreciated in practice.

In addition, well known and appreciated by experts in the ways of the compounds of formula (1) is easily obtained pharmaceutically acceptable salts of the compounds of formula (1).

The reaction Scheme is the main scheme of obtaining alcohols of structure 2 used as starting materials in Reaction Scheme A. the Reagents and starting materials are readily available for professionals. All substances in the Reaction Scheme In pre-identified, unless otherwise indicated.

In stage 1 of the Reaction Scheme In an appropriate nitrile of structure 5 alkylate appropriate protected alcohol of structure 5b, receiving -(protected hydroxy)alkynylaryl patterns 6.

Suitable nitrile of structure 5 is a substance in which R1such as required in the final product of formula (1). Appropriate protected alcohol of structure 5b is a substance in which m is as desired in the final product of formula (1), and remove the group L1such that you can replace the anion derived podila, while the preferred iodine and bromine. Experts are well aware of and appreciate the choice and use of suitable for the protection of hydroxyl groups (Pg1), such as described in T. Greene, Protecting Groups in Organic Synthesis. In stage 1 of the Reaction Scheme In generally prefer to apply a protective group tetrahydropyran-2-yl and tert-butyldimethylsilyl.

For example, an appropriate nitrile of structure 5 interacts with 1.0 to 1.2 molar equivalents of the appropriate protected alcohol of structure 5b. The reaction is carried out in the presence of an approximately equimolar amount of a suitable base such as sodium hydride, sodium bis(trimethylsilyl)amide, tert-butyl potassium or lithium diisopropylamide, with the preferred sodium hydride, sodium bis(trimethylsilyl)amide. The reaction is carried out in a solvent such as dimethylformamide or tetrahydrofuran. The reaction is usually carried out at a temperature of from -78 to 0oC. the Reaction generally takes from 1 to 72 hours. The product can be extracted and cleaned known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

In stage 2 of the Reaction Scheme -(protected hydroxy)alkynylaryl patterns 6 alkylate ethylbromoacetate getting slozhnoefirnoi with about a molar equivalent of ethylbromoacetate. The reaction is carried out in the presence of an approximately molar equivalent of a suitable base, such as sodium bis(trimethylsilyl)amide or lithium diisopropylamide. The reaction is carried out in a suitable solvent, such as tetrahydrofuran. The reaction is usually carried out at a temperature of from -78 to 0oC. the Reaction generally takes from 1 to 72 hours. The product can be extracted and cleaned known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

At stage 3 the Reaction Scheme In ester compound nitrile of structure 7 restore and cyclist, getting 3-(-(protected hydroxy)alkyl)-5-oxopyrrolidin connection structure 8. Cyclization may occur spontaneously after recovery or it can be done in a separate stage after separation of the intermediate amine.

For example, the ester compound nitrile of structure 7 communicates with an excess of a suitable reducing agent such as sodium borohydride in the presence of uranyl chloride cobalt (II) or hydrogen in the presence of a suitable catalyst, such as Raney Nickel or platinum oxide.

When using sodium borohydride in the presence of uranyl chlorine is s at a temperature of from 0 to 50oC. the Reaction generally takes from 1 to 72 hours. Typically, crystallization under these conditions occurs spontaneously. The product can be extracted and cleaned known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

If using Raney Nickel, the reaction is carried out in a suitable solvent containing ammonia, such as ethanol/aqueous ammonium hydroxide or methanol/aqueous ammonium hydroxide. The reaction is usually carried out at temperatures from room temperature up to 70oC. the Reaction with hydrogen is carried out at a pressure of from 1,055 kg/cm2(15 psi) to 8.44 kg/cm2(120 psi) in a device intended for carrying out reactions under pressure. As a rule, these conditions result in spontaneous cyclization. The product can be distinguished by careful removal of the catalyst by filtration and evaporation. To purify the product can be known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

If using platinum oxide, the reaction is carried out in a suitable solvent, such as ethanol, methanol, chloroform, mixtures of ethanol/chloroform or methanol/chloroform. The reaction is usually carried out at a temperature of about the 2 (120 psi) in a device intended for carrying out reactions under pressure, such as a Parr apparatus (Parr). Usually in these conditions receive the intermediate product amine and allocate it by careful removal of the catalyst by filtration and evaporation. Intermediate amine cyclist when heated in a suitable solvent, such as ethanol, methanol, toluene or chlorobenzene. The reaction is usually carried out at a temperature of from 50oC to the boiling point of the solvent under reflux. The reaction usually takes from 8 to 48 hours. The product can be cleaned by extraction, evaporation, trituration, chromatography, and recrystallization.

In optional stage 4 Reaction Scheme 3-(-(protected hydroxy)alkyl)-5-oxopyrrolidin connection structure 8 alkylate suitable alkylating agent, receiving a connection structure 9. Suitable alkylating agent X1-CH2(CH2)n-Ph1is a substance in which X1is methanesulfonyl, chlorine, bromine or iodine, n is as desired in the final product of formula (1), and Ph1represents phenyl or substituted phenyl, with R1and R3such as is required in the final product of formula (1).

On stage 5 of the Reaction Scheme To remove the protection from the compounds of structure 9, receiving the alcohol of structure 2 in which G1represents-C(O)-, and G2represents-CH2-. The reaction of the removal of protection, such as the removal of protecting the hydroxyl groups with the use of suitable protective groups, such as described in T. Greene, Protecting Groups in Organic Synthesis is well known and appreciated in practice.

Not optional stage 6 Reaction Scheme 3-(-(protected hydroxy)alkyl)-5-oxopyrrolidin connection structure 8 restore, getting 3-(-(protected hydroxy)alkyl)pyrolidine connection p is the duty to regulate with an excess of a suitable reducing agent, such as sociallyengaged, aluminiumhydride or dimethylsulfoxide complex of boron. The reaction is carried out in a suitable solvent, such as tetrahydrofuran. The reaction is usually carried out at temperatures fromoC to the boiling point of the solvent under reflux. The reaction typically takes from 1 to 72 hours. The product can be extracted and cleaned well known in practice means, such as a sudden cooling of the complexes of boron or aluminum, extraction, evaporation, rubbing, chromatography and recrystallization.

In optional stage 7 Reaction Scheme 3-(-(protected hydroxy)alkyl)pyrolidine connection structure 11 is treated with the appropriate arailway (aroyl) acid, aronovym ether, halide arailway acid, aronovym anhydride or aronovym mixed anhydride, X2-C(O)-(CH2)n-Ph2receiving the connection patterns 12. Suitable Aronova acid, urology ether, halide arailway acid, urology anhydride or urology mixed anhydride, X2-C(O)-CH2)n-Ph2is the substance in which X2represents a hydroxyl; an activated ester, such as O-hydroxysuccinimide, O-hydroxybenzotriazole; advance the, such as required in the final product of formula (1), and Ph2represents phenyl or substituted phenyl, with R1and R3such as is required in the formula (1).

For example, 3-(-(protected hydroxy)alkyl)pyrolidine connection patterns 11 communicates with 1-1,5 molar equivalents of the appropriate arailway acid, Kolobova ether, halide arailway acid, Kolobova anhydride or Kolobova mixed anhydride. The reaction is carried out in a suitable solvent, such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide or pyridine. The reaction is carried out in the presence of a base, such as triethylamine, N-methylmorpholine, N,N-diisopropylethylamine or pyridine. The reaction is usually carried out at temperatures from -20 to 50oC. the reaction Usually takes from 1 to 6 hours. The product can be extracted and cleaned well known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

In the other, 3-(-(protected hydroxy)alkyl)pyrolidine connection patterns 11 communicates with, for example, about 1-1 .5 molar equivalents of the appropriate arailway acid, Kolobova ether, halide arailway acid, Kolobova anhydride or the furan/water, acetone/water or ethyl acetate/water. The reaction is carried out in the presence of a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide. The reaction can be carried out in the presence of a suitable catalyst, such as sodium iodide or potassium iodide. The reaction is usually carried out at temperatures from -20 to 50oC. the Reaction generally takes from 1 to 24 hours. The product can be extracted and cleaned well known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

On stage 8 of the Reaction Scheme To remove the protection from the connection patterns 12, receiving the alcohol of structure 2 in which G1represents-CH2-, and G2represents-C(O)-. The reaction of the removal of protection, such as the removal of protecting the hydroxyl groups with the use of suitable protective groups, such as described in T. Greene, Protecting Groups in Organic Synthesis is well known and appreciated in practice.

In optional stage 9 Reaction Scheme 3-(-(protected hydroxy)alkyl)pyrolidine connection patterns 11 alkylate suitable alkylhalogenide X3-CH2-(CH2)n-RH3receiving a connection structure, n is as desired in the final product of formula (1), and PH3is phenyl or substituted phenyl, with R2and R3as required in the formula (1).

For example, 3-(-(protected hydroxy) alkyl) pyrolidine connection patterns 11 communicates with 1.0 to 1.2 molar equivalents of a suitable alkylhalogenide. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, dimethyl sulfoxide, acetonitrile, toluene or dimethylformamide. The reaction is usually carried out in prisutstvie base, such as sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine, N,N-diisopropylethylamine or pyridine. Usually the reaction is carried out at a temperature of from 0oC to the boiling point of the solvent under reflux. The reaction typically takes from 1 to 72 hours. The product can be extracted and cleaned well known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

Differently, for example, 3-(-(protected hydroxy)alkyl)pyrolidine connection patterns 11 communicates with 1-1,2 molar equivalents of a suitable alkylhalogenide. The reaction is carried out in a suitable mixed solvent such as tetrahydrofuran, sodium bicarbonate, potassium carbonate or potassium bicarbonate.

The reaction is usually carried out at a temperature of from 0oC to the boiling point of the solvent under reflux. The reaction usually takes from 1 to 72 hours. The product can be extracted and cleaned well known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

On stage 10 of the Reaction Scheme To remove the protection from the connection patterns 13, receiving the alcohol of structure 2 in which G1and G2represent-CH2-. The reaction of the removal of protection, such as the removal of protecting the hydroxyl groups with the use of suitable protective groups, such as described in T. Greene, Protecting Groups in Organic Synthesis is well known and appreciated in practice.

In Reaction Scheme illustrates the synthetic procedure for obtaining alcohols of structure 2 in which m is 2, and intermediates of structure 8, in which m is 2, used in Reaction Scheme C. To obtain alcohols of structure 2 in which m is equal to 2, usually the preferred method of Reaction Scheme C. the Reagents and starting materials of the Reaction Schemes easily available to ordinary specialists, and all substances with the exception of the decree is tructure 5 bis-alkylate ethylbromoacetate, getting bis-ether nitrile of structure 14. Suitable nitrile of structure 5 is a connection defined in stage 1 of the Reaction Scheme C.

For example, an appropriate nitrile of structure 5 interacts with 2.0 to 3.0 molar equivalents of ethylbromoacetate. The reaction is carried out in the presence of about 2.0 to 3.0 molar equivalents of a suitable base, such as sodium bis(trimethylsilyl)-amide or lithium diisopropylamide. The reaction is carried out in a suitable solvent, such as tetrahydrofuran. Usually the reaction is carried out at a temperature of from -78 to 0oC. the Reaction generally takes from 1 to 72 hours. The product can be extracted and cleaned well known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

In stage 2 of the Reaction Scheme With bis-ether nitrile patterns 14 and restore cyclist, receiving 5-oxo-3-acetic acid ester of pyrrolidin patterns 15.

For example, the nitrile bis-ester compound structure 14 communicates with a suitable reducing agent such as sodium borohydride in the presence of uranyl chloride cobalt (II) or hydrogen in the presence of a suitable catalyst, such as Raney Nickel or platinum oxide, according to N. modestum with borane or a complex of borane, such as dimethylsulfoxide complex of borane. The reaction is carried out in a suitable solvent, such as diethyl ether or tetrahydrofuran. The reaction is usually carried out at temperatures from -20oC to the boiling point of the solvent under reflux. The reaction usually takes from 1 to 72 hours. The product can be extracted and cleaned well known in the practice of methods, such as rapid cooling, extraction, evaporation, rubbing, distillation, chromatography and recrystallization.

In optional stage 3 Reaction Scheme 5-oxo-3-acetic acid ester of pyrrolidin patterns 15 hydrolyzing, receiving 5-oxo-3-acetic acid pyrrolidine structure 16.

For example, 5-oxo-3-acetic acid ester of pyrrolidin patterns 15 communicates with a suitable gidrolizuut agent such as sodium hydroxide, potassium hydroxide or lithium hydroxide. The reaction is carried out in a suitable solvent such as water, a mixture of tetrahydrofuran/water, methanol, methanol/water or a mixture of ethanol/water. The reaction is usually carried out at a temperature of from 0oC to the boiling point of the solvent under reflux. The reaction typically takes from 1 to 72 hours. The product can be extracted and cleaned well known for the.

In stage 4 of Reaction Scheme 5-oxo-3-acetic acid pyrrolidin patterns 16 restore, getting 3-(2-hydroxyethyl)-5-oxopyrrolidin structure 17.

For example, 5-oxo-3-acetic acid pyrrolidin patterns 16 communicates with a suitable boranova reagent, such as dimethylsulfoxide complex of borane. The reaction is carried out in a suitable solvent, such as tetrahydrofuran or diethyl ether. The reaction is usually carried out at temperatures fromoC to the boiling point of the solvent under reflux. Upon completion of the reaction it is extinguished, carefully adding a suitable aqueous solution of acid, such as 1M solution of hydrochloric acid. The product can be extracted and cleaned well known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

Different 5-oxo-5-acetic acid pyrrolidin patterns 16 can be restored through the formation of an intermediate mixed anhydride, which is subjected to interaction with a suitable mild reducing agent such as sodium borohydride.

For example, 5-oxo-3-acetic acid pyrrolidin patterns 16 communicates with 1.2 to 1.7 equivalents of a suitable base, such as N-m is laidout to a temperature in the range from -50o(C) 0oWith (preferably from -25o(C) to (-20o(C) before adding 1.2 to 1.7 equivalents of isobutylacetate. The reaction is left to mix for a period of from 30 minutes to 3 hours for the formation of a mixed anhydride. Upon completion of the formation of the mixed anhydride add sodium borohydride. The product can be extracted and cleaned well known in practice means, such as extraction, evaporation, chromatography and recrystallization.

On stage 5 of Reaction Scheme With 3-(2-hydroxyethyl)-5-oxopyrrolidin structure 17 is injected protection with 3-(-(protected-hydroxyethyl)-5-oxopyrrolidin structure 8, which is used in Reaction Scheme C. Experts are well aware of and appreciate the choice and use of suitable protective groups, such as described in T. Greene, Protecting Groups in Organic Synthesis.

In optional stage 6 Reaction Scheme 5-oxo-3-acetic acid ester of pyrrolidin patterns 15 restore, getting 3-(-hydroxyethyl) pyrrolidin structure 18, as shown in optional stage 6 of the Reaction Scheme, using a reducing agent, suitable for recovery of the amide and ester groups.

On stage 7 of the Reaction Scheme With 3-(-hydroxyethyl) pyrrolidin structu, giving alcohol of structure 2. Suitable arilgalogenide, urology anhydride or urology mixed anhydride is a compound described in optional stage 7 of the Reaction Scheme C.

For example, 3-(-hydroxyethyl)pyrrolidin patterns 18 communicates with 1-1,1 molar equivalents of a suitable arilgalogenide, Kolobova anhydride or Kolobova mixed anhydride. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, dichloromethane, acetone, ethyl acetate, toluene or diethyl ether. The reaction is carried out in the presence of a base, such as N-methylmorpholine, sodium carbonate, triethylamine, N,N-diisopropylethylamine, potassium carbonate or sodium bicarbonate. The reaction is usually carried out at temperatures from -78oWith up to room temperature. The reaction typically takes from 1 to 24 hours. The product can be extracted and cleaned well known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

Differently, for example, 3-(-hydroxyethyl)pyrrolidin patterns 18 communicates with 1-1,1 molar equivalents of a suitable arilgalogenide, Kolobova anhydride or Kolobova mixed anhydride under conditions of Schotten-Baumann. The reaction Provo is/water. The reaction is carried out in the presence of a base such as potassium carbonate, potassium bicarbonate, sodium bicarbonate, sodium carbonate, sodium hydroxide or potassium hydroxide. The reaction is usually carried out at temperatures from -20 to 50oC. the Reaction generally takes from 15 minutes to 24 hours. The product can be extracted and cleaned well known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

In optional stage 8 Reaction Scheme 5-oxo-3-acetic acid ester of pyrrolidine patterns 15 alkylate suitable alkylhalogenide, getting 1-arylalkyl-5-oxo-3-acetic acid ester of pyrrolidin structure 19. Suitable alkylhalogenide is a compound described in optional stage 4 Reaction Scheme C.

For example, 5-oxo-3-acetic acid ester of pyrrolidin patterns 15 communicates with 1.0 to 1.2 molar equivalents of a suitable alkylhalogenide. The reaction is carried out in a suitable solvent, such as tetrahydrofuran, dimethyl sulfoxide, acetonitrile or dimethylformamide. The reaction is carried out in the presence of a base such as sodium hydride, sodium bis(trimethylsilyl)amide, tert-butyl potassium. The reaction is usually carried out at temperatures from 0 to 50

On stage 9 of the Reaction Scheme 1 arylalkyl-5-oxo-3-acetic acid ester of pyrrolidin patterns 19 hydrolyzing, getting 1-arylalkyl-5-oxo-3-acetic acid pyrrolidine structure 20.

For example, 1-arylalkyl-5-oxo-3-acetic acid ester of pyrrolidin patterns 19 communicates with a suitable gidrolizuut agent such as sodium hydroxide, potassium hydroxide or lithium hydroxide. The reaction is carried out in a suitable solvent such as water, a mixture of tetrahydrofuran/water, methanol, a mixture of methanol/water or ethanol/water. Usually the reaction is carried out at a temperature of from 0oC to the boiling point of the solvent under reflux. The reaction typically takes from 1 to 72 hours. The product can be extracted and cleaned well known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

On stage 10 of the Reaction Scheme 1 arylalkyl-5-oxo-3-acetic acid pyrrolidine structure 20 restore, as shown in stage 4 of the Reaction Scheme, getting the alcohol of structure 2 in which m is 2, G1represents-C(O)-, and G2represents-CH2

In stage 1 of Reaction scheme D suitable bis-(2-chloroethyl) amine-protected formula 21 alkylate suitable arylacetamides formula 5A, receiving 4-aryl-4-cyanopiperidine protection formula 22. Suitable bis-(2-chloroethyl)amine-protected formula 21 is a connection in which the protective group (Pg2can be C1-C4by alkyl, benzyl, substituted benzyl, para-toluensulfonyl, benzene-sulfonyl or carbamate, such as tert-butoxycarbonyl or etoxycarbonyl. Suitable arylacetamides formula 5A is a compound in which Ar1such as is required in the final product of formula (1). Apkeliausiu of this type are well known and appreciated in practice, some examples of this type of reactions are found among others in the works of T. Caronack and P. C. Reeves, J. Heterocyclic Chem. 23, 73-75 (1986) and C. V. Bercz and R. D. Ice, J. Pharmaceutical Sci., 21, 1316-1317 (1972).

For example, suitable bis-(2-chloroethyl)amine-protected formula 21 communicates with a suitable arylacetamides formula 5A. The reaction is carried out in the presence of a base such as sodium amide, sodium hydride, sodium hexamethyldisilazide, tert-butyl potassium and lithium diisopropylamide. The reaction of CR of 0.01 to 0.5 molar equivalents of a suitable catalyst, such as sodium iodide or potassium iodide. The reaction is usually carried out at temperatures from 0 to 80oC. the Reaction generally takes from 1 to 72 hours. The product can be extracted and cleaned well known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

Differently, for example, suitable bis-(2-chloroethyl) amine-protected formula 21 communicates with a suitable arylacetamides formula 5A in conditions of phase transfer. The reaction can be carried out in water or a solvent consisting of organic and aqueous phases. The reaction is carried out in the presence of a hydroxide such as sodium hydroxide or potassium hydroxide. The reaction is carried out in the presence of a suitable catalyst comprising a salt of Quaternary ammonium and phosphonium, such as tetrabutylammonium bromide, tetrabutylammonium the hydrosulfate, hexadecyltrimethylammonium bromide, designed chloride and the like. The reaction intensively stirred and carried out usually at a temperature of from 0 to 100oC. the Reaction generally takes from 1 to 24 hours. The product can be extracted and cleaned well known in practice means, such as extraction, evaporation, rubbing, chromatography and recrystallization.

2).

Professionals it is clear that the removal of the amine protecting group Pg2you may need before or after stage 2. For example, if Rd2is benzyl, the protective group can be removed, sposobstvovala hydrolysis of the nitrile, and then re-enter after hydrolysis. If protection is removed, then re-introduction of the protective group Rd2(whether benzyl or other protective group) after hydrolysis gives 4-arylpiperazine-4-carboxylic acid of formula 23. Otherwise, the protective group used in stages 1 and 2 of the Reaction Scheme D, can be removed and replaced with another group to facilitate removal of the protecting connection 24 in stage 4 of Reaction Scheme D. the Introduction of protective groups for the amine are well known and appreciated in practice and shown in the work of T. Greene, Protecting Groups in Organic Synthesis, Wiley-Interscience (1981).

At stage 3 of Reaction Scheme D ester 4-arylpiperazine-4-carboxylic acid of formula 23 is subjected to reaction amidino of appropriate carboxy substituted cyclic AI Amin is a connection, which gives the group a', which is the group And, as required in the final product of formula (1) or gives the group a (as required in the final product of formula (1)) after removing the protection or functionalization (functionalization).

Illustrative examples of suitable carboxy-substituted cyclic amines include 4-carbomethoxybiphenyl, 3-carbomethoxybiphenyl, 2-carbomethoxybiphenyl, 4-carbomethoxybiphenyl, 3-carbomethoxybiphenyl, 2-carbomethoxybiphenyl, 4-Carbo-n-propylacetamide, 4-Carbo-tert-butylacetamide, 3-carbomethoxyamino, 2-carbomethoxyamino, 3-carbomethoxyamino, 2-carbomethoxyamino, 4-carbomethoxybiphenyl, 2-carbomethoxybiphenyl, 3-carbomethoxybiphenyl, 4-carbomethoxybiphenyl, 4-Carbo-n-propylacetophenone, 4-turbosuperchargers, 4-Carbo-n-butylacetoacetate, 4-Carbo-tert-butylacetophenone, 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido) piperidine, 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl) carboxamido)piperidine, 4-phenyl-4-((4-Carbo(ethoxycarbonylmethoxy)methylpiperazin-1-yl)carboxamido)piperidine, 4-phenyl-4-((4-Carbo(t-BUTYLCARBAMATE)methylpiperazin-1-yl)carboxamido)piperidine, 4-personalexperience) methylpiperazin-1-yl)carboxamido)piperidine, 4-Carbo-(5-methyl-2-oxo-1,3-dioxol-4-ylethoxy)methylpiperazine, 4-Carbo-(Carbo-(2-(trimethylsilyl)ethoxy)metiloksi)methylpiperazin and the like. Professionals it is clear that further carboxyl functions of the appropriate carboxy substituted cyclic amine can unprotect or functionalitywith (functionalized) after removing the protection to get And as required in the final compound of formula (1). This unlocks or functionalization involves amidation, hydrolysis of esters, the esters and transesterification.

The amidation reaction can proceed through the acid of formula 23 or first acid function of compound 23 can be converted into activated intermediate product, such as an anhydride; a mixed anhydride substituted phosphoric acid such as dialkylphosphinate acid, diphenylphosphoryl acid, haloentomobrya acid; aliphatic carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, somalina acid, pavlikova acid, 2-ethylmalonate acid, trichloroacetic acid, triperoxonane acid and the like; activated ester, such as ether, phenol, ether, para-NITROPHENOL, ether 2,4-dinitrate and the like; activated amide, such as imidazole, dimethylpyrazole, triazole or tetrazole; or an intermediate product formed in the presence of a binding agent, such as dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The activated intermediate products can be obtained and directly used or to receive and allocate before adding the appropriate carboxy substituted cyclic amine. Differently, the activated intermediate products can be obtained, to allocate and clean before adding the appropriate carboxy substituted cyclic amine. Specialists know and understand the use and receipt of activated intermediates.

For example, the acid of formula 23 communicates with a slight molar excess of a suitable carboxy-substituted cyclic amine salt or a suitable carboxy-substituted cyclic amine and 1-hydroxybenzotriazole hydrate in the presence of a slight molar excess of a binding agent, such as dicyclohexylcarbodiimide or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The reaction is carried out in the presence of a suitable base, such as N,N-diisopropylethylamine, N-methylmorpholine or triethylamine, and if ispolzuyetsa a suitable base. The reaction is carried out in a suitable solvent, such as dichloromethane, chloroform or dimethylformamide. The product can be extracted and cleaned well known in practice means, such as extraction, evaporation, chromatography and recrystallization.

Differently, for example, the acid of formula 23 communicates with 1.2 to 1.7 equivalents of a suitable base, such as N-methylmorpholine, in a suitable solvent, such as tetrahydrofuran. As mentioned above, if using salt and a suitable carboxy-substituted cyclic amine, optionally add approximately molar quantity of a suitable base. The reaction mixture is cooled to a temperature of from -50 to 0oWith (preferably from -25oC to -20o(C) before adding 1.2 to 1.7 equivalents of isobutylacetate. The reaction is left to mix for a time from 30 minutes to 3 hours for the formation of the activated intermediate mixed anhydride. Maintaining the temperature between -50 and 0oTo add suitable carboxy-substituted cyclic amine. Upon completion of the addition of amine, the reaction mixture can be heated to room temperature. The reaction typically takes from 2 to 48 hours. The product can be distinguished and the eyes of Lusatia.

In stage 4 of Reaction Scheme D delete a protected 4-aryl-4-carboxamido-piperidine of formula 24, receiving the piperidine of formula 3. Removal of amine protecting groups is well known, evaluated in practice and described in T. Greene, Protecting Groups in Organic Synthesis, Wiley-Interscience (1981).

In addition, the experts it is clear that 4-arylpiperazine-4-carboxylic acid of formula 23 can be obtained from 4-aryl-4-cyanopyridine of the formula 22 further hydrolysis of amide 4-arylpiperazine-4-carboxylic acid obtained by hydrolysis of 4-aryl-4-cyanopiperidine formula 22.

For example, suitable 4-aryl-4-cyanopiperidine formula 22 communicates with the main hydrogen peroxide, giving 4-aryl-4-carboxylates amide-piperidine or 4-aryl-4-carboxylates amide-piperidine N-oxide. The main application of hydrogen peroxide for the hydrolysis of NITRILES to carboxamido well known and appreciated in practice. Reagents for Organic Synthesis, Fieser and Fieser, John Wiley & Sons, Inc. (1967). Suitable bases for this reaction include hydroxides of alkali metals, such as hydroxides of sodium and potassium. The reaction is carried out in a suitable solvent such as water, ethanol, methanol, a mixture of water/ethanol or a mixture of water/methanol. The reaction is carried out at a temperature of from 0o

If you receive a 4-aryl-4-carboxylates amide-piperidine, remove protection, receiving amide 4-arylpiperazine-4-carboxylic acid. If you receive a 4-aryl-4-carboxylates ameripride N-oxide, restore it and remove the protection with amide 4-arylpiperazine-4-carboxylic acid. It is clear that removing protection from amine and recovering the amine oxide can be carried out simultaneously or sequentially. The recovery of oxides of amines well known in the art. After restoring N-oxide remove the amine protecting group Pg2.

The removal of the amine protecting group such as benzyl and substituted benzyl, well known, evaluated in practice and described in T. Greene, Protecting Groups in Organic Synthesis, Wiley-Interscience (1981). The product can be extracted and cleaned well known in practice means, such as filtration, extraction, evaporation, rubbing, chromatography and recrystallization.

Tested in practice, what amide 4-arylpiperazine-4-carboxylic acid can be further hydrolyze in acidic or basic conditions with 4-obecny the synthesis of compounds of formula (1). It should be understood that these examples are merely illustrative and in no way are intended to limit the scope of the present invention.

GETTING 1

salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido) of piperidine and hydrochloric acid.

Combine 4-phenylpiperidine-4-carboxylic acid-paratoluenesulfonyl acid (97.5 g, 0,258 mol), N,N-diisopropylethylamine (55 ml, 0,316 mol) and dimethylformamide (900 ml). Add drop by drop a solution of di-tert-BUTYLCARBAMATE (65.0 g, 0.30 mol) in dimethylformamide. After 20 hours, dilute the reaction mixture with diethyl ether and shaken out three times with water and then brine. Dried the organic layer over MgSO4, filtered, washed gS4, dichloromethane. Evaporated in vacuum, obtaining 1-tert-butoxycarbonyl-4-phenylpiperidine-4-carboxylic acid.

Combine 1-tert-butoxycarbonyl-4-phenylpiperidine-4-carboxylic acid (18.7 g, 97.5 mmol), N,N-diisopropylethylamine (34,0 ml of € 0.195 mol) in dichloromethane (400 ml). Add the hydrate of 1-hydroxybenzotriazole (13,2 g of 97.7 mmol) and utilizedabated (4-carbomethoxybiphenyl) (14.0 g, and 88.8 mmol). Add the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. After 18 hours, dilute the reaction mixture with dichloromethane and DV is t-butoxycarbonyl-4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine.

Combine 1-tert-butoxycarbonyl-4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine (25,0 g, a 56.6 mmol) and dichloromethane (200 ml). Add a solution of hydrochloric acid in dioxane (50 ml, 4M, 200 mmol). After 3 hours, add diethyl ether (400 ml) and filtered, obtaining after drying specified in the header of the connection.

Method of Obtaining synthesize 1:

a) salt of 4-phenyl-4-((3-carbomethoxybiphenyl-1-yl) carboxamido)of piperidine and hydrochloric acid using ethyl nipecotate (3-carbomethoxybiphenyl);

b) salt of 4-phenyl-4-((2-carbomethoxyamino-1-yl) carboxamido)of piperidine and hydrochloric acid using hydrochloride DL-prolongational ester (hydrochloride 2-carbomethoxyamino);

C) salt of 4-phenyl-4-((2-carbomethoxybiphenyl-1-yl)carboxamido )of piperidine and hydrochloric acid using ethylpiperazine (2-carbomethoxybiphenyl);

g) salt of 4-phenyl-4-((2-carbomethoxybiphenyl-4-yl)carboxamido) of piperidine and hydrochloric acid, using (2-carbomethoxybiphenyl).

Example 1

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-acid)pyrrolidin

< / BR>
1. 1. Synthesis of diethyl ether 3-cyano-3-(3,4-acid)pentanedioic to the indicate in a bath of dry ice/acetone. Add drop by drop a solution of sodium bis(trimethylsilyl)amide (226 ml, 1M in tetrahydrofuran, 226 mmol). When the addition is complete, heat the reaction mixture to 10oWith and left to mix for 15 minutes. Cooled in a bath of dry ice/acetone, add drop by drop ethylbromoacetate (37,7 g, 226 mmol). When adding ethylbromoacetate completed, the reaction mixture is heated to room temperature. After 18 hours distribute the reaction mixture between diethyl ether and water. Extracted the organic layer with water and saturated aqueous ammonium chloride. The organic layer is separated, dried over MgSO4, filtered and concentrated in vacuo, receiving the remainder. Chromatografic the residue on silica gel, elwira a mixture of 33% ethylacetate-hexane. Remove the remaining solvent in vacuo at 82oWith that getting mentioned in the title compound: Rf=0,37 (silica gel, 33% ethyl acetate-hexane).

Elemental analysis

Calculated for C18H23NO6: 61,88; N 6,64; N 4,01.

Found: 61,79; N 6,62; N 3,91.

1.2 Synthesis of ethyl ester of (3-(3,4-acid)-5-oxopyrrolidin-3-yl)acetic acid

Combine diethyl ether 3-cyano-3-(3,4-acid)pentanedioic kikoti 20oWith or below using baths with ice, add portions sodium borohydride (2.17 g, 57 mmol). When the addition is complete, leave the reaction mixture to stand at room temperature for 18 hours. Evaporated reaction mixture in vacuum, obtaining the remainder. Divide the residue between dichloromethane and 1M solution of hydrochloric acid. Several times the aqueous layer was extracted with dichloromethane, dried over MgSO4, filtered and concentrated in vacuo, receiving the remainder. Chromatografic the residue on silica gel, elwira a mixture of ethyl acetate/methanol=20/1. Remove the remaining solvent in vacuo at 82oWith that getting mentioned in the title compound: Rf=0,74 (silica gel, ethyl acetate/methanol=5/1); so pl. 116-118oC.

Elemental analysis

Calculated for C16H21NO5: 62,53; N 6,89; N 4,56.

Found: Totals 62.52; H 6,85; N 4,50.

1.3. 3-(3,4-acid)-3-(2-hydroxyethyl)pyrrolidine

Combine sociallyengaged (0,99 g, 26.0 mmol) and anhydrous tetrahydrofuran (20 ml). Slowly add ethyl ester (3-(3,4-acid)-5-oxopyrrolidin-3-yl)acetic acid (2.0 g, 6.5 mmol) in solution in anhydrous tetrahydrofuran (40 ml). When the addition is complete, heat the mixture to boiling reverse the temperature of the reaction mixture did not rise above 20oC. is Cooled to 10oTo add a 15% solution of sodium hydroxide (1.0 ml). Add water (3 ml). After 15 minutes, filter the reaction mixture and concentrate the filtrate under vacuum, obtaining specified in the header connection: Rf=0,68 (silica gel, ethyl acetate/methanol=5/1).

Prepare an analytical sample as follows: combine 3-(3,4-acid)-3-(2-hydroxyethyl)pyrrolidine (0.51 g, 2.02 mmol) and oxalic acid (0.18 g, 2.00 mmol) in tetrahydrofuran (70 ml). After 18 hours, filtered and dried. Triturated with diethyl ether (100 ml), filtered and dried in vacuum at 82oWith that getting mentioned in the title compound in the form of its salt - oxalate: so pl. 140-142oC.

Elemental analysis

Calculated for C14H21NO3C2H2O4: 56,30; N 6,79; N 4,10.

Found: 56,15; N 6,76; N 4,13.

1.4.1 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-acid)-3-(2-hydroxyethyl)pyrrolidine

Combine 3-(3,4-acid)-3-(2-hydroxyethyl) pyrrolidin of 2.27 g, 9,03 mmol) and N-methylmorpholin (2,48 ml, and 22.6 mmol) in anhydrous dichloromethane (100 ml). The reaction mixture cooled down to 5oWith in a bath with ice. Slowly add 3,4,5-trimethoxybenzoate (2.2 g, 9.5 mmol) in solution in dichlone solution of potassium carbonate. Dried the organic layer over Na2SO4, filtered and concentrated in vacuo, receiving the remainder. The remainder chromatographic on silica gel, elwira a mixture of 95% dichloromethane - methanol, receiving the remainder. Combine the residue with dichloromethane (100 ml) and extracted three times 1M solution of hydrochloric acid and a saturated solution of potassium carbonate. Dried the organic layer over Na2SO4, filtered and concentrated in vacuo, receiving the remainder. The remainder chromatographic on silica gel, elwira a mixture of ethyl acetate/ methanol=20/1 and receiving oil: Rf=0,14 (silica gel, ethyl acetate/methanol= 20/1). Dried in vacuum at 110oWith that getting mentioned in the title compound in the form of glass: so pl. 60-62oC.

Elemental analysis

Calculated for C24H31BUT7: 64,70; N 7,01; N 3,14.

Found: 64,40; N 7,21; N 2,85.

1.4.2 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-acid) -3-(2-hydroxyethyl)pyrrolidine

Combine 3-(3,4-acid)-3-(2-hydroxyethyl) pyrrolidine (5.34 g, of 21.2 mmol) and sodium carbonate (1.24 g, 11.7 mmol) in a mixture of ethylacetate/water=4/1 (120 ml). The reaction mixture cooled down to -5oWith in a bath with salt and ice. Slowly add 3,4,5-trimethoxybenzoate (5.14 g of 22.3 mmol) dissolve oderzhivayut the reaction temperature is about 0oC. After 18 hours separated the organic layer. The organic layer is extracted twice 1M aqueous solution of hydrochloric acid, a saturated solution of potassium carbonate, water and saturated sodium chloride solution. Dried the organic layer over Na2SO4, filtered and concentrated in vacuo, receiving the remainder. Combine the aqueous layers and neutralized with a saturated solution of sodium bicarbonate. Extracted neutralized aqueous layers dichloromethane. Dried the organic layer over Na2SO4, filtered and concentrated in vacuo, receiving the remainder. Residues are combined and chromatographic on silica gel, elwira a mixture of dichloromethane/methanol=10/1 and receiving the remainder. Combine the residue with dichloromethane (100 ml) and extracted three times 1M solution of hydrochloric acid and a saturated solution of potassium carbonate. Dried the organic layer over PA2SO4, filtered and concentrated in vacuo, obtaining specified in the header connection: Rf=0,23 (silica gel, ethyl acetate/methanol=10/1).

1.5 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-acid)-3-(2-methanesulfonylaminoethyl)pyrrolidine

Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-acid)-3-(2-hydroxyethyl)pyrrolidine (0,43 g, 0.97 mmol), triethylamine is. Slowly add methanesulfonyl chloride (0,082 ml, 1.06 mmol) at such a speed that the temperature of the reaction mixture did not rise above 2oC. Heat the mixture to room temperature. After 18 hours, quench the reaction by adding ice. The organic layer is separated and extracted three times 1M solution of hydrochloric acid and twice with saturated sodium bicarbonate solution. Dried the organic layer over Na2SO4, filtered and concentrated in vacuo, obtaining specified in the header connection: Rf=0,48 (silica gel, ethyl acetate/methanol=20/1).

1.6 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl) ethyl)-3-(3,4-acid)pyrrolidine

Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-acid) -3-(2-methanesulfonylaminoethyl)pyrrolidin (0,86 g of 1.64 mmol), salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)of piperidine and hydrochloric acid (0,57 g, 1.97 mmol), sodium iodide (0.25 g, of 1.64 mmol) and N,N-diisopropylethylamine (0.84 g, 6.6 mol) in acetonitrile (12 ml). Heated to the boiling temperature under reflux. After 10 hours the reaction mixture is cooled and diluted with ethyl acetate. Shaken out three times with a saturated aqueous solution of ammonium chloride, twice filled trout and evaporated in vacuum, getting listed at the beginning of the connection.

1.7. Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-acid)pyrrolidine

Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl) ethyl)-3-(3,4-acid)pyrrolidine (0.3 g, 0.4 mmol) and lithium hydroxide (60 mg, 2.4 mmol) in a mixture of tetrahydrofuran/water (6 ml/6 ml). After 3 hours the reaction mixture was concentrated in vacuo, removing a large portion of tetrahydrofuran and diluted with water. Bring the pH to approximately 7 using 1M aqueous solution of hydrochloric acid. Extracted three times with dichloromethane, adjust the pH so as to maintain pH 7 in aqueous layer. Dried the organic layer over gSO4, filtered and evaporated in vacuum, obtaining specified in the header of the connection.

Example 2

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
2.1.1 Synthesis of diethyl ether 3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid

Receive by way of Example 1.1, using 3,4-dichlorobenzonitrile (30.0 g, 0,161 mol). Cleaning perform the way recrystallization from di who 68-69oC.

Elemental analysis

Calculated for C16H17Cl2NO4: 53,65; N 4,78; N 3,91.

Found: 53,69; N 4,79; N 3,93.

2.1.2. Synthesis of diethyl ether 3-cyano-3-(3,4-dichlorophenyl)pentadienoic acid

Cool a solution of sodium bis(trimethylsilyl)amide (480 pounds=217,72 kg, 1M in THF) to about -10oWith and mix. Add a solution of 3,4-dichlorobenzonitrile in methyl tert-butyl ether (34,5% by weight, 125 pounds= 56.7 kg of solution) with such speed that the temperature of the reaction mixture did not rise above about 10oC. Merge ethylbromoacetate (94 lb=42,64 kg) and methyl tert-butyl ether (about 125 pounds=56.7 kg) and cooled to approximately -18oWith, and then add the solution obtained above, for 60-90 minutes. Upon completion of the reaction, to determine the chromatographic add water (18 gallons= 68,136 l). Add 12M aqueous hydrochloric acid solution at a pH of about 4. If the pH drops below 3, apply a 20% aqueous sodium hydroxide solution, raising the pH to about 4. Separate the layers and extracted the organic layer with brine. Evaporated in vacuum at a temperature of approximately 40oC receives the remainder. Combine the residue and isopropanol (about 45 pounds=20,4 kg) and evaporated in vacuo to 35oC and then cooled to about -10oWith getting solid. This solid is collected by filtration, washed with cold isopropanol and centrifuged, getting mentioned in the title compound in the form of a wet sludge containing isopropanol.

2.1.1. Synthesis of ethyl ester of (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)acetic acid

Receive by way of Example 1.2 using diethyl ether 3-cyano-3-(3,4-dichlorophenyl)pentadienoic acid (10 g, 28 mmol). Cleaning is performed by way of chromatography on silica gel, elwira successively with a mixture of 3% methanol/dichloromethane and then 6% methanol/dichloromethane, getting listed at the beginning of the connection.

2.2.2 Synthesis of ethyl ester of (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)acetic acid

Combine diethyl ether 3-cyano-3-(3,4-dichlorophenyl) pentadienoic acid (32 g, 89 mmol) and ethanol (150 ml) in a Parr flask (Parr). Add Raney Nickel (100 g) and aqueous concentrated ammonia solution (40 ml). Conduct hydrogenation at 3,515 kg/cm2(50 psi) for 24 hours. Filtered through layers of celite and washed the solid with ethanol. The filtrate is evaporated in vacuum, obtaining the remainder. The remainder chromatographic on silica gel, elwira 6% methanol. 87-90oC.

Elemental analysis

Calculated for C14H15Cl2NO3: 53,18; N 4,78; N 4,43.

Found: 53,34; N 4,71; N 4,51.

2.2.3. Synthesis of ethyl ester of (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)acetic acid

Combine Raney Nickel (24 lb=10,89 kg) and aqueous concentrated ammonia solution (19 pounds=8,62 kg). In a reactor for carrying out the process under pressure is added to a solution of diethyl ether 3-cyano-3-(3,4-dichlorophenyl)pentadienoic acid (15 pounds=6,80 kg) and ethanol (117 pounds=53,07 kg). Conduct hydrogenation at 14,06 kg/cm2(200 psi) and the temperature of the 35oC. After 20 hours the reactor is cooled, opened, rinsed with nitrogen and filtered reaction mixture. Washed the solid with ethanol. The filtrate is evaporated in vacuum, obtaining the remainder. The residue is crystallized by dissolving it in ethyl acetate and rubbing the solution with heptane, get a solid substance. Collect solid, getting listed at the beginning of the connection.

Elemental analysis

Calculated for C14H15Cl2NO3: 53,18; N 4,78; N 4,43.

Found: 53,18; N 4,72; N 4,46.

2.2.4. Synthesis of ethyl ester of (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)acetic acid

Obyedinil, approximately 3% of P.F.) and 3C ethanol (52 kg) in the reactor to work under pressure. Add Raney Nickel in water (17.5 kg, about 11 kg of active catalyst) and aqueous concentrated ammonia solution (8,7 kg). Conduct hydrogenation at 14,06 kg/cm2(200 psi) and the 35oC. Upon completion of reaction, the reactor is cooled, opened and rinsed with nitrogen. Filtered through a bag filter, washed with ethanol and then filtered through a filter with a density of 0.2 micron and washed the solid with ethanol. The filtrate is evaporated in vacuum, obtaining specified in the header of the connection.

2.2.5. Synthesis of ethyl ester of (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)acetic acid

Combine Raney Nickel (washed twice with water and twice with ethanol, 3.6 kg), diethyl ether 3-cyano-3-(3,4-dichlorophenyl)pentadienoic acid (1260 g, 3,51 mol), ethanol (9 l) and aqueous concentrated ammonia solution (1.6 l) autoclave 18.9 l (5 gallon). The hydrogenation is carried out at 3,867 kg/cm3(55 psi). After 20 hours, the reactor is opened, rinsed with nitrogen and filtered reaction mixture. The solid is washed with ethanol (about 1 liter). The filtrate is evaporated in vacuum, obtaining the remainder. Combine the residue and ethyl acetate (10 l) and extracted twice with water (1 l) and then with brine. Su the form of ethyl acetate (about 1.8 l) and heptane (about 7.2 l), getting solid. Gather is a solid substance, receiving specified in the header connection: so pl. 98-99oC.

2.3. Synthesis of 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Cool the solution sociallyengaged (450 ml, 1M in tetrahydrofuran (45 mmol) -10oWith bath ice/acetone. Add drop by drop a solution of sulfuric acid (12 ml, 99,999%, 225,3 mmol) in tetrahydrofuran (35 ml). (Sulfuric acid is carefully added to the tetrahydrofuran and carefully add a solution of sulfuric acid/tetrahydrofuran to a solution of sociallyengaged). When the addition is complete, stir the reaction mixture for 1 hour. Warmed to room temperature and stirred for 2 hours. Add drop by drop a solution of ethyl ester (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)acetic acid (23,2 g, 73.4 mmol) in tetrahydrofuran (70 ml). Heated to 45-50oC for 36 hours. Cooled in a bath with ice. Add drop by drop a solution of tetrahydrofuran/water (1/1, 70 ml). Filter and wash the residue on the filter with tetrahydrofuran and dichloromethane, the filtrate is stored. Combine the residue with the filter with a mixture of tetrahydrofuran/water/15% sodium hydroxide solution (1 l, 70 ml/20 ml) and vigorously stirred for 2 hours. Filtered and the volume of the residue. The residue is dissolved in dichloromethane and dried over MgSO4, filtered and concentrated in vacuo, receiving the remainder. The residue is recrystallized from diethyl ether, obtaining specified in the header connection: Rf=0,27 (silica gel, dichloromethane/methanol/ammonium hydroxide=9:1:0,2); so pl. 91-94oC.

Elemental analysis

Calculated for C12H15Cl2NO: 55,40; N. OF 5.81; N 5,38.

Found: Of 55.64; H 5,88; N 5,20.

2.4. Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (288 mg, 1.1 mmol) and N-methylmorpholine (0.25 ml, of 2.27 mmol) in dichloromethane (10 ml). Cooled to -78oWith in a bath of dry ice/acetone. Add a solution of 3,4,5-trimethoxybenzylamine (250 mg, 1.1 mmol) in dichloromethane (3 ml). Heat the mixture to 0oC. After 1 hour the reaction mixture is extracted with 1M hydrochloric acid and 5% sodium bicarbonate solution. Dried the organic layer over gSO4, filtered and concentrated in vacuo, receiving the remainder. The remainder chromatographic on silica gel, elwira successively with a mixture of 50% ethyl acetate/hexane and 6% methanol/dichloromethane, receiving specified in the header connection: Rf=0,38 (silicagelic)pyrrolidine

Receive by way of Example 1.5 using to obtain specified in the title compound 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine.

2.5.2. Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidine

Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (200 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.17 ml, 0.97 mmol) in dichloromethane (25 ml). Cooled in a bath of dry ice/acetone. Add drop by drop methanesulfonanilide (of 0.066 g, or 0.57 mmol). After 2 hours the reaction mixture is extracted with 1M hydrochloric acid and 5% sodium bicarbonate solution. Dried the organic layer over gSO4, filtered and concentrated in vacuo, obtaining specified in the header connection: Rf=0,42 (silica gel, 6% methanol/dichloromethane), so pl. 64,0-66,0oC.

2.5.3. Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidine

Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (200 mg, 0.44 mmol) and N-methylmorpholin (0.97 mmol) in toluene (10 ml). Add drop by drop methanesulfonanilide (of 0.066 g, or 0.57 mmol). After 12 hours, diluted with toluene (20 ml) and extracted with 1M hydrochloric the vacuum, getting listed at the beginning of the connection.

2.6. Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((3-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Receive by way of Example 1.6 using to obtain specified in the title compound 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidin and salt of 4-phenyl-4-((3-carbomethoxybiphenyl-1-yl)carboxamido)of piperidine and hydrochloric acid.

2.7. Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((3-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidine

Receive by way of Example 1.7 using to obtain specified in the title compound 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((3-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine.

Example 3

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine;

< / BR>
3.1.1 Synthesis of diethyl ether 3-cyano-3-phenylenediacetic acid

Receive by way of Example 1.1, using phenylacetonitrile (5,85 g, 50.0 mmol). Cleaning perform the way chromatography on silica gel, elwira 20% ethyl acetate in GE is .2 Synthesis of diethyl ether 3-cyano-3-phenylenediacetic acid

Combine phenylacetonitrile (5,85 g, 50.0 mmol) and tetrahydrofuran (140 ml). Cool the reaction mixture to about 5oC. Add drop by drop a solution of sodium bis(trimethylsilyl)amide (800 ml, 1M in tetrahydrofuran, 800 mmol). Upon completion of addition the reaction mixture is heated to room temperature and left to mix for 1 hour. The resulting solution is transferred through a tube cooled (-8oC) a solution of ethylbromoacetate (84,5 ml, 762 mmol) in tetrahydrofuran (500 ml) at such a rate that the temperature of the reaction mixture did not rise above about 20oC. Leave mixed at room temperature. After 18 hours, dilute the reaction mixture with diethyl ether (1.5 l) and extracted with saturated aqueous ammonium chloride, then with water and saturated aqueous sodium chloride. Dried the organic layer over MgS4, filtered and concentrated in vacuo, receiving the remainder. The residue is distilled way "bulb-to-bulb distillation", receiving specified in the header connection: so Kip. 140-150oC at 0.2 mm RT.article.

3.1.3 synthesis of the diethyl ester of 3-cyano-3-phenylenediacetic acid

Combine phenylacetonitrile (175,5 g, 1.5 mol) and tetrahydrofuran (1,95 l). Cool the reaction of SMEs in tetrahydrofuran, 3.2 mol). Upon completion of addition the reaction mixture is heated to room temperature and left to mix for 1 hour. The above solution is transferred in about 45 minutes in a refrigerated (approximately -20oC) a solution of ethylbromoacetate (510 g of 3.05 mol) in tetrahydrofuran (1,95 l). Warmed to room temperature and left to mix. After 18 hours, dilute the reaction mixture with diethyl ether (3 l) and water (1.5 l). Extracted twice with a saturated aqueous solution of ammonium chloride (2.25 liters) and then with brine. Dried the organic layer over MgSO4, filtered and concentrated in vacuo, receiving the remainder. The residue is distilled way "bulb-to-bulb distillation", receiving specified in the header connection: so Kip. 180-190oWith 30 mm RT.article.

Elemental analysis

Calculated for C16H19NO4: 66,43; N 6,62; N 4,84.

Found: 66,34; N To 6.57; N 4,82.

3.2.1. Synthesis of ethyl ester of (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid

Receive by way of Example 2.2.2 using to obtain specified in the connection header diethyl ether 3-cyano-3-phenylenediacetic acid: Rf=0,60 (silica gel, 6% methanol/dichloromethane).

3.2.2 Synthesis of ethyl ester of (3-phenyl-5-oxopyrrolidin-3-and the (400 ml) in an autoclave at 7.5 liters (2 gallons). Add Raney Nickel (280 g). Heated to 50oWith and inject hydrogen at 14,6 kg/cm2(200 p. s. i). After 15 min the reactor open and add water a concentrated solution of ammonia (120 ml). Upload the reactor with hydrogen at 14,6 kg/cm2(200 p.s.i). After 7 hours the reactor was opened and incubated for 18 hours. Filtered the reaction mixture through a layer of celite and washed the solid with ethanol. The filtrate is evaporated in vacuum, obtaining the remainder. Combine the residue and the mixture of diethyl ether/hexane 1/5 (500 ml) and cooled to (-20oC). After 18 hours, the mixture is decanted and add a mixture of diethyl ether/hexane 1/5 (500 ml) and cooled to (-20oC) receiving solid.

Collect the resulting solid substance is filtered and triturated with a mixture of diethyl ether/hexane 1/5 (500 ml). Filtered and dissolved in diethyl ether (300 ml) and add hexane (700 ml) to give a solid. Collect the resulting solid substance and dried, obtaining mentioned in the title compound.

Elemental analysis

Calculated for C14H17NO3: 68,00; N 6,93; N 5,66.

Found: 67,63; N. Of 6.99; N 5,81.

3.2.3. Synthesis of ethyl ester of (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid

Of the aqueous ammonia (530 ml) in an autoclave at 7.5 liters (2 gallons).

Add Raney Nickel (410 g). Heated to 24oWith and finish hydrogen at 14,96 kg/cm2(205 p.s.i); 26 hours the reactor was opened and rinsed with nitrogen. The reaction mixture was filtered through a layer of celite and washed obtained solid substance ethanol (1.5 l).

The filtrate is evaporated in vacuum, obtaining mentioned in the title compound.

3.2.4. Synthesis of ethyl ester of (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid.

Combine diethyl ether 3-cyano-3-phenylenediacetic acid (243 g, 0.84 mol) and ethanol (2.5 l), concentrated aqueous ammonia solution (325 ml) and Raney Nickel (250 g, pre-washed three times with water in an autoclave 7.57 l (2 gallons). Download hydrogen to 14,06 kg/cm2(200 psi). Heated to 50oC. After 24 hours, open the reactor and rinsed with nitrogen. Filtered the reaction mixture through a layer of celite and washed the solid with ethanol (1 l). The filtrate is evaporated in vacuum, obtaining specified in the header of the connection.

3.3.1. Synthesis of 3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Receive by way of Example 1.3 using ethyl ether (pyrrolidin-3-yl)acetic acid (8.7 g, 35 mmol) to obtain, after recrystallization from a mixture of dichloromethane/diethyl ether decree>Elemental analysis

Calculated for C12H17NO: 75,36; N 8,96; N 7,32.

Found: 75,78; N 8,96; N 7,45.

3.3.2 Synthesis of 3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine the ethyl ester of (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid (301 g, 1.25 mol) and tetrahydrofuran (3.5 l). Cool to approximatelyoC. Slowly drop by drop add 45 minutes a solution of sociallyengaged in tetrahydrofuran (3.9 l, 1M, 3.9 mol). When the addition is complete, heat to 60oC. After 18 hours, cooled in a bath with ice. Add one drop of a mixture of water/tetrahydrofuran=1/1 (1,95 l) with such a speed that the temperature of the reaction mixture did not rise above 20oC. Dilute the reaction mixture with tetrahydrofuran (2.25 liters) and stirred. After 1.5 hours the reaction mixture is filtered. The solid is suspended in diethyl ether (3 l) and filtered. The filtrates are combined and concentrated in vacuo, receiving the remainder. The residue is combined with dichloromethane (4 l) and extracted three times with water (1 l). Dried the organic layer over MgSO4, filtered and concentrated in vacuo, obtaining a solid substance. This solid is triturated with diethyl ether (0.3 l), collected by filtration, washed with diethyl ether and dried, obtaining AC=9:1:0,1).

3.3.3 Synthesis of 3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine the ethyl ester of (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid (171 g, 0.69 mol) and tetrahydrofuran (2 l). Cooled to about 5oC. Slowly drop by drop add 15 minutes a solution of sociallyengaged in tetrahydrofuran (2,24 l, 1M, 2,24 mol). When the addition is complete, heat to 60oC. After 18 hours, cooled in a bath with ice. Slowly quenched reaction mixture, adding a saturated aqueous solution of sodium tartrate, potassium (208 ml). Upon completion of the quenching type Na2SO4(100 g) and celite (150 g) and stirred. After 3 hours the reaction mixture was diluted with tetrahydrofuran (2 l) and filtered. The solid is suspended in diethyl ether (2 l) and filtered. The filtrates are combined and concentrated in vacuo, obtaining specified in the header connection: so pl. 106-110oC; Rf= 0,12 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia=9:1:0,1).

3.4.1. Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Receive by way of Example 1.4.1, using 3-phenyl-3-(2-hydroxyethyl)pyrrolidine to obtain specified in the header connection: Rf=0,38 (silica gel, 6% methanol/dichloromethane).

3.4.2. Sint is 3-phenyl-3-(2-hydroxyethyl)pyrrolidine to obtain specified in the header connection: Rf=0,05 (silica gel, ethyl acetate).

3.5 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylaminoethyl)pyrrolidine

Combine 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl) pyrrolidine (0.5 g, 1.3 mmol), N,N-diisopropylethylamine (0.5 ml, 2.9 mmol) and bezvodniy dichloromethane (10 ml). Cooled in a bath with ice. Add methanesulfonanilide (201 mg, of 1.36 mmol). After 2 hours, dilute the reaction mixture with dichloromethane and extracted with saturated sodium bicarbonate solution. Dried the organic layer over MgSO4, filtered and concentrated in vacuo, obtaining specified in the header connection: Rf=0,26 (silica gel, ethyl acetate).

3.6. Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine

Receive by way of Example 1.6 using to obtain specified in the title compound 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylaminoethyl)pyrrolidin and salt of 4-phenyl-4-((2-carbomethoxybiphenyl-1-yl)carboxamido) of piperidine and hydrochloric acid.

3.7 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxypeptidase-1-yl) carboxamido) piperidine-1-yl) ethyl)-3-phenylpyrrolidine

Receive by way of Example 1.7 using the DIN-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine.

Example 4

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
4.1 Synthesis of 1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carbomethoxyamino-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Receive by way of Example 1.6 using to obtain specified in the title compound 1-(3,4,5-trimethoxybenzoyl)-3-(3, 4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl) pyrrolidin and salt of 4-phenyl-4-((2-carbomethoxyamino-1-yl)carboxamido)of piperidine and hydrochloric acid.

4.2. Synthesis of 1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Receive by way of Example 1.7 using to obtain specified in the title compound 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carbomethoxyamino-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine.

Getting 2

4-(Pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine

Combine N-benzyl-N-bis(2-chloroethyl)amine hydrochloride (72,0 g, 269 mmol), pyrid-3-ylacetonitrile (31.8 g, 269 mmol) and hexadecyltrimethylammonium (6 g) in water solution hydroclone the mixture to room temperature. Three times, the reaction mixture is extracted with dichloromethane. Combine the organic layers and twice extracted with aqueous 10% solution of hydrochloric acid. Combine the aqueous layers and brought to basic pH with an aqueous solution of sodium hydroxide (50% by weight). The aqueous layer after alkalizing extracted three times with diethyl ether. Dry the combined ether layers over MgSO4and filter, receiving the filtrate. Blow the filtrate gaseous hydrogen chloride, getting solid. Collect the solid by filtration and dried in vacuum at 65oC receives 1-benzyl-4-(pyridyl-3-yl)-4-cyanopiperidine hydrochloride.

Combine 1-benzyl-4-(pyrid-3-yl)-4-cyanopiperidine hydrochloride (10.0 g, 28 mmol), sodium hydroxide (7.6 g, 190 mmol) and water (2 ml) in ethylene glycol (120 ml). Heated to boiling under reflux. After 15 hours, evaporated in vacuum, obtaining the remainder. Combine the residue with methanol (20 ml) and ethanol (20 ml) and stirred for receiving solid. Remove the solid by filtration. Add to the filtrate ethanol (50 ml) and stirred for 1 hour, getting a second solid. Remove the second solid by filtration and the filtrate is acidified aqueous 12M hydrochloric acid.avodat pH of the aqueous layer to 7, using sodium bicarbonate. The aqueous layer was evaporated in vacuum, obtaining the remainder, combine the residue with ethanol and again evaporated in vacuum, obtaining the remainder. Combine the residue with methanol and heated to approximately the 50oWith getting the suspension. The suspension was filtered, added to the filtrate acetone (30 ml) to give a solid. Collect the solid by filtration, washed with acetone and dried, obtaining 1-benzyl-4-(pyrid-3-yl)piperidine-4-carboxylic acid.

Combine 1-benzyl-4-(pyrid-3-yl)piperidine-4-carboxylic acid (5.1 g), 4-carbomethoxybiphenyl (5.8 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.0 g) and 1-hydroxybenzotriazole hydrate (3.6 g) in dimethylformamide (130 ml). After 60 hours, dilute the reaction mixture with ethyl acetate (1 liter). Extracted the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution. Dried the organic layer over MgSO4, filtered and evaporated in vacuum, obtaining the remainder. RUB the residue with diethyl ether, filtered and dried, obtaining 1-benzyl-4-(pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl) carboxamido)piperidine. Rf=0,52 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia=90/10/1).

Combine 1-benzyl-4-(PI is the carbon (1.2 g). Hydronaut in the apparatus for operation under pressure of 4.57 kg/cm2(65 psi). After 17 hours, filtered through celite, removing the catalyst, and the filtrate evaporated in vacuum, obtaining the remainder. The remainder chromatographic on silica gel, elwira successively with a mixture of dichloromethane/methanol=98/2, dichloromethane/methanol= 96/4, dichloromethane/methanol/concentrated aqueous ammonia= 94/6/0,6 and dichloromethane/methanol/concentrated aqueous ammonia=94/8/0,6, receiving specified in the header of the connection.

Example 5

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(pyrid-3-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
5.1.1 Separation of salts of (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid and salts of (R)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid

Combine 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (1.0 g, of 38.5 mmol) and butanone. Add a solution of (R,R)-di-para-insolvency acid (1.6 g, 38,0 mmol) in butanone (80 ml). Heated to the boiling temperature under reflux. After 15 minutes, cooled to room temperature and then further cooled in a bath salt with ice. Filter the resulting solid prophetic)-(-)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (R, R)-di-para-insolvency acid: so pl. 201-204oC (decomposition). []0D2= -18,9(C=0,60, dimethylsulfoxide). The study of x-ray diffraction single crystal confirms (S)-configuration. The analysis method of high performance liquid chromatography (HPLC) analytical sample of the free amine obtained by extraction using a CHIRAL column-CANCER AD 25 cm x 0,46 cm elution with a mixture of pentane/methanol/triethylamine= 80/10/0,1, and flow rate 1.0 ml/min, shows 96% enantiomeric excess (96% of ei), retention time of (S)-isomer 11.2 minutes, retention time of (R )-isomer of 14.5 minutes.

5.1.2 Separation of salts of (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid and salts of (R)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid

Combine (R,R)-di-para-resolving acid (0.8 g, 19 mmol) and water 12M hydrochloric acid (0.16 ml, 19 mmol) in a mixture of water/methanol (10 ml/10 ml). Heated to the boiling temperature under reflux. Add drop by drop a solution of 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (1.0 g, of 38.5 mmol) in methanol (10 ml). After 15 minutes, slowly cooled the reaction mixture to room temperature. Otitis)pyrrolidine and (R,R)-di-para-insolvency acid: so pl. 201-204oC (decomposition). The HPLC analysis described in Example 5.1.1, shows 97% enantiomeric excess (97% of ei).

5.1.3 Synthesis and separation of salts of (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid

Combine the ethyl ester of (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)acetic acid (18.14 kg=40 pounds) and tetrahydrofuran (117,93 kg=260 pounds). Purge the vessel with nitrogen. Add a solution dimethylsulfoxide complex of borane (17,24 kg=38 pounds, 2M solution in tetrahydrofuran). Heated to a temperature of reflux distilled. After 60 hours is distilled until then, until the internal temperature rises to approximately 70oWith, and then slowly quenched the reaction with methanol (294,83 kg=650 lbs). Add water (294,83 kg= 650 lbs). Add methansulfonate acid (7,26 kg=16 pounds). Heated to a temperature of reflux distilled and removed the distillate to remove the majority of the remaining tetrahydrofuran. Combine methanol (approximately 68,14 l=18 gallons) and (R,R)-di-para-resolving acid (14,52 kg=32 lb). Heated to a temperature of reflux distilled and transferred to the vessel containing the above residue. Add the seed crystals and slowly cooled to 10oWith getting solid. Comparatory reflux distilled. After 1 hour, cooled slowly to 10oWith getting solid. Collect this solid after drying receive specified in the header of the connection.

5.1.4 Division with the aim of obtaining (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (4.5 g, 9,9,9 mmol) and a mixture of dichloromethane/pyridine (70 ml, 6/1). Add acetic anhydride (1.04 million ml, 11.0 mmol) and 4-dimethylaminopyridine (50 mg, 0.41 mmol). After 2 hours, concentrate the reaction mixture under vacuum, obtaining the remainder. Dissolve the residue in ethyl acetate and extracted with 1M hydrochloric acid (2 x 200 ml), saturated sodium bicarbonate solution and saturated sodium chloride solution. Dried the organic layer over MgSO4, filtered and concentrated in vacuo, receiving the remainder. The remainder chromatographic on silica gel, elwira with ethyl acetate and receiving 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-acetoxyethyl)pyrrolidin: Rf=0,38 (silica gel, ethyl acetate).

Elemental analysis:

Calculated for C24H27Cl2NO6: 58,07; N. OF 5.48; N 2,82.

Found: 57,67; N 5,46; N 2,84.

Combine 1-(3,4,5-trimethoxybenzoyl will contentresult suspension in vacuum, receiving the remainder. Suspended residue in phosphate buffer (800 ml, 0.1 M, pH 7.5, buffer prepared from 11.5g H2RHO4(85%), diluted to 1 l with deionized water, and bringing the pH to 7.5 grains of solid potassium hydroxide, obtaining a suspension. Process the paste through Lipase (13 g, EC 3.1.1.3, Type VII, from Candida cylindracea). Control the reaction HPLC on a column CHIRALPAK AD 25 x 0,46 cm, elwira a mixture of pentane/ethanol/methanol (80/15/5) at a flow rate of 1.0 ml/min of the Sample for analysis was obtained as follows: the centrifuged solution for 10 minutes at 14000 cm-1remove the supernatant and concentrate in a stream of nitrogen, receiving the residue, dissolving it in dichloromethane (about 1 ml) and injected into the column for analysis. If the enantiomeric excess of satisfactory (>95% ei) for (+)-acetate, the reaction mixture is filtered. Washed the solid with dichloromethane (8 × 500 ml). The filtrate is extracted with dichloromethane (8 × 500 ml). Chromatographic solid on silica gel, elwira a mixture of 6% methanol/dichloromethane. Concentrate the combined washings and extracts in vacuum, obtaining the remainder. Dissolve the residue in dichloromethane, dried over MgSO4, filtered and concentrated in vacuo, receiving the remainder. Chromatographic this residue on silica gel, elwira (silica gel, the ethyl acetate).

Elemental analysis:

Calculated for C24H27Cl2NO60.5 H2O: 57,14; N 5,59; N 2,78.

Found: 57,37; N. Of 5.45; N 2,87.

[]2D0= +36,4(C=0,894, chloroform).

Combine (+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-acetoxyethyl)pyrrolidin (670 mg, 1.35 mmol) and an aqueous solution of lithium hydroxide (4,2 ml, 1M) in methanol (15 ml). After 3.5 hours, concentrated in vacuo, receiving the remainder. Dissolve the residue in dichloromethane and extracted with 1M hydrochloric acid and saturated sodium bicarbonate solution. Dried the organic layer over MgSO4, filtered and concentrated in vacuo, receiving the remainder. The residue is dried under high vacuum for 18 hours, obtaining (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidin: Rf=0,11 (silica gel, ethyl acetate).

5.2.1 Synthesis of (S)-(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine salt (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and (R, R)-di-para-insolvency acid (0.14 g, 0.21 mmol), ethyl acetate (15 ml), acetonitrile (6 ml), water (6 ml) and sodium bicarbonate (0.09 g, of 1.03 mmol). Cooled to 0oWith on bath salt with ice. Add 3,4,5-ü between ethyl acetate and brine. Extracted organic layer 1M solution of hydrochloric acid, then saturated aqueous sodium bicarbonate. Dried the organic layer over gSO4, filtered and evaporated in vacuum, obtaining specified in the header connection: Rf=0,11 (silica gel, ethyl acetate). []2D0= +61,7(C=a 1.01, methanol).

5.2.2 Synthesis of (S)-(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine salt (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and (R, R)-di-para-insolvency acid (6.0 g, 8,84 mmol), acetone (40 ml), water (40 ml), sodium hydroxide (0,335 g, 8,87 mmol) and sodium bicarbonate (to 3.73 g, 8,87 mmol). Cooled to about 0oC. Add about 15 minutes a solution of 3,4,5-trimethoxybenzylamine (2.2 g, 9.7 mmol) in acetone (12 ml). After 3 hours distribute the reaction mixture between ethyl acetate and brine. Extracted organic layer 1M sodium hydroxide solution, saturated sodium bicarbonate solution, 1M hydrochloric acid and then brine. Dried the organic layer over MgSO4, filtered and evaporated in vacuum, obtaining specified in the header connection:

Rf=0,11 (silica gel, ethyl acetate).

5.3. Synthesis of (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-DIH methoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (1,351 mmol) and methanesulfonamide (0,14 ml, is 1.81 mmol) to obtain specified in the header connection: Rf=0,11 (silica gel, ethyl acetate).

5.4.1. Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl) pyrrolidine (2 g), 4-(pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine (5.9 g) and N,N-diisopropylethylamine (1,53 g) in acetonitrile (40 ml). Heated to the boiling temperature under reflux. After 12 hours the reaction mixture is evaporated in vacuum, obtaining the remainder. The remainder chromatographic on silica gel, elwira sequentially with ethyl acetate, a mixture of dichloromethane/methanol= 98/2, dichloromethane/methanol= 96,5/3,5, dichloromethane/methanol=95/5 and then dichloromethane/methanol= 94/6, receiving specified in the header connection: Rf=0,11 (silica gel, dichloromethane/methanol= 9/1).

5.4.2. Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine 3,4,5-trimethoxybenzoic acid (3.5 kg, 16.5 mol), 1,2-dimethoxyethan (14,2 kg) and dimethylformamide (4 g). Cooled in a bath with eh is about being above about 19oC. After 20 hours, concentrated in vacuo at 25oWith, removing approximately 3.7 kg of distillate and receiving a solution of 3,4,5-trimethoxybenzaldehyde.

Combine salt (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and (R, R)-di-para-insolvency acid (9,05 kg, 13.3 mol), potassium carbonate (6.42 per kg) in acetone (27.2 kg)). Cooled to about 5oWith and add water (31,42 l = 8,3 Gal.). Cool about the 3oWith and slowly add a solution of 3,4,5-trimethoxybenzylamine (14,0 kg, 26.9% in 1,2-dimethoxyethane, 16.3 mol) in about 25 minutes. Upon completion of the reaction the reaction mixture is heated to 25oC. Dilute the reaction mixture with toluene (36,35 kg). Separate the layers and extracted the organic layer with water (EUR 7.57 l = 2 Gal.), 3M aqueous solution of hydrochloric acid and then brine. Concentrate the organic layer under vacuum until then, until there is approximately (18,93 l = 5 Gal.). Add toluene (18.2 kg) and again concentrated in vacuo until then, until there is approximately (18,93 l = 5 Gal.). Add toluene (36,15 kg) and cooled to about -3oC. Add N-methylmorpholine (6,85 kg, 67,7 mol) and then methanesulfonanilide (3,40 kg 29.7 mol). Upon completion of the reaction, water is added (18,17 l =4.8 gallon) and heated to approximately 25oC. Share the creative (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidine.

Combine the above solution (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidine, potassium carbonate (4,07 kg 29.5 mol), 4-(pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido) piperidine (to 12.0 mol) and water (12,49 l = 3,3 Gal.). Heated to approximately 70oC. When the reaction is complete, dilute the reaction mixture with methyl ethyl ketone (18,1 kg) and after 15 minutes of mixing separate layers. Extracted the organic layer with water (12,87 l = 3,4 Gal.) and then was concentrated in vacuo, obtaining specified in the header of the connection.

5.5. Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidine (1.1 g) and dichloromethane (50 ml). Purge gaseous hydrogen chloride (about 1.6 g) in about 10 minutes. Evaporated in vacuum, get the remainder, double-add ethanol (50 ml) and evaporated in vacuum, obtaining after drying specified in the header of the connection.

Example 6

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-pyrid-3-yl)-4-((4-CT is Oli (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-3-yl)-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0.3 g, 0.4 mmol) and lithium hydroxide (59 mg, 2.34 mmol) in a mixture of tetrahydrofuran/water (6 ml/6 ml). Cooled in a bath with ice. After 2 hours, evaporated in vacuo to remove tetrahydrofuran, cooled in a bath with ice and acidified with aqueous reaction mixture (pH about 5) using 1M aqueous solution of hydrochloric acid. Bring the pH of the aqueous reaction mixture to about 7 using sodium bicarbonate, and extracted with dichloromethane. Dried the organic layer over MgSO4and filtered. Blow the filtrate gaseous hydrogen chloride and then evaporated in vacuum, obtaining after drying specified in the header connection: Rf=0,11 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia=80/20/1).

Getting 3

Salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)of piperidine and hydrochloric acid

Combine 1-tert-butoxycarbonyl-4-phenylpiperidine-4-carboxylic acid (27,0 g, and 88.5 mmol), N,N-diisopropylethylamine (34 ml, of € 0.195 mol), 4-carbomethoxybiphenyl (5.8 g) and 1-hydroxybenzotriazole hydrate (13,2 g, 98 mmol) in dichloromethane (400 ml). Add a mixture of dichloromethane and extracted twice with water. Dried the organic layer over MgS4, filtered and evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira successively with a mixture of 20% ethyl acetate/hexane, ethyl acetate, a mixture of dichloromethane/methanol=94/6 and then dichloromethane/methanol=90/10, getting 1-tert-butoxycarbonyl-4-phenyl-4-((4-carbomethoxybiphenyl-1-yl) carboxamido)piperidine.

Combine 1-tert-butoxycarbonyl-4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine (37,5 g, 78 mmol) and dichloromethane (300 ml). Add a solution of hydrochloric acid in dioxane (70 ml, 4M, 280 mmol). After 5 hours, add diethyl ether and continue stirring, obtaining a solid substance. Collect the solid, washed with diethyl ether and dried, obtaining specified in the header of the connection.

Example 7

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dimetilfenil)pyrrolidin

< / BR>
7.1.1. Synthesis of diethyl ether 3-cyano-3-(3,4-dimetilfenil)pentadienoic acid

Combine 3,4-dimethylaminoacetonitrile (50.0 mmol) and tetrahydrofuran (140 ml). Cooled to about 5oC. Add drop by drop a solution of sodium bis(trimethylsilyl)amide (800 ml, 1M in tetravalent mixed for 1 hour. Transfer the above solution through a tube into a cooled (-8oC) a solution of ethylbromoacetate (84,5 ml, 762 mmol) in tetrahydrofuran (500 ml) at such a rate that the temperature of the reaction mixture did not rise above 20oC. Leave mixed at room temperature. After 18 hours, diluted with diethyl ether (1.5 l) and extracted with saturated aqueous ammonium chloride, then with water and saturated aqueous sodium chloride. The organic layer is dried over MgSO4, filtered and concentrated in vacuo, obtaining specified in the header of the connection.

7.1.2. Synthesis of diethyl ether 3-cyano-3-(3,4-dimetilfenil)pentadienoic acid

Cool a solution of sodium bis(trimethylsilyl)amide (723 ml, 1M in tetrahydrofuran, 723 mmol) and 0oWith in a bath with ice. Add a solution of 3,4-dimethylaminoacetonitrile (50.0 mmol) in tetrahydrofuran (130 ml) for about 1.5 hours. When the addition is complete, heat the reaction mixture to room temperature and left to mix. After 2 hours, transfer the above solution through a tube into a cooled (-50oC) a solution of ethylbromoacetate (126 g, 757 mmol) in tetrahydrofuran (250 ml). Upon completion of the transfer give the reaction mixture to warm Delaney acid, saturated aqueous sodium bicarbonate and then brine. Dried the organic layer over gSO4, filtered and concentrated in vacuo, receiving the remainder. The residue is recrystallized from diethyl ether, obtaining specified in the title compound in the form of solids.

7.2.1 Synthesis of ethyl ester of (3-(3,4-dimetilfenil)-5-oxopyrrolidin-3-yl)acetic acid

Receive by way of example 2.2.2 using to obtain specified in the connection header diethyl ether 3-cyano-3-(3,4-dimetilfenil)pentadienoic acid.

7.2.2 Synthesis of ethyl ester of (3-(3,4-dimetilfenil)-5-oxopyrrolidin-3-yl)acetic acid

Combine diethyl ether 3-cyano-3-(3,4-dimetilfenil) pentadienoic acid (56 g, 177 mmol) and ethanol (500 ml) in a Parr flask (Parr). Add Raney Nickel (50 g) and aqueous concentrated ammonia solution (85 ml). Conduct hydrogenation at 50oAnd 70,3 kg/cm2(100 psi) for 48 hours. Filtered through layers of celite and washed the solid with ethanol. The filtrate is evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira a mixture of 6% methanol/dichloromethane and receiving specified in the header of the connection.

7.3 Synthesis of 3-(3,4-dimetilfenil)-3-(2-geraldin-3-yl)acetic acid to obtain, after recrystallization from a mixture of dichloromethane/diethyl ether specified in the header connection: Rf= 0,35 (silica gel, dichloromethane/methanol/acetic acid= 85/10/5).

7.4 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimetilfenil)-3-(2-hydroxyethyl)pyrrolidine

Combine 3-(3,4-dimetilfenil)-3-(2-hydroxyethyl)pyrrolidine (20 mmol) and sodium bicarbonate (8,4 g) in a mixture of acetone (50 ml)/water (50 ml). Add a solution of 3,4,5-trimethoxybenzylamine (4.6 g, to 19.9 mmol) in acetone (50 ml). 3 hours three times extracted the reaction mixture with ethyl acetate. Dried the organic layer over MgS4, filtered and concentrated in vacuo, obtaining specified in the header connection: Rf=0,25 (silica gel, 6% methanol/dichloromethane).

7.5. Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimetilfenil)-3-(2-methanesulfonylaminoethyl)pyrrolidine

Receive by way of Example 2.5.2 using 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimetilfenil)-3-(2-hydroxyethyl) pyrrolidine to obtain specified in the header connection: Rf=0,11 (silica gel, ethyl acetate).

7.6 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dimetilfenil)pyrrolidine

Receive by way of Example 1.6 using 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimetilfenil)-3-(2-methanesulfonylaminoethyl)pyrrolidine and 4-phenyl-4-((4-to the tx2">

7.7. Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido) piperidine-1-yl)ethyl)-3-(3,4-dimetilfenil)pyrrolidine

Receive by way of Example 1.7, using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dimetilfenil)pyrrolidin to obtain specified in the connection header.

Getting 4

Salt of 4-phenyl-4-(94-carbomethoxybiphenyl-1-yl)carboxamido) of piperidine and hydrochloric acid

Combine 1-tert-butoxycarbonyl-4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine (26,0 g of 56.7 mmol) and dichloromethane (40 ml). Add gaseous hydrogen iodide (2.8 g). After 3 hours, evaporated in vacuum, obtaining after drying specified in the header of the connection.

In another, combine 1-tert-butoxycarbonyl-4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine (10.0 g, to 21.8 mmol) and ethanol (700 ml). Add an aqueous solution itestosterone acid (57%, to 6.1 ml, 45,75 mmol). After 2 hours, heated to boiling under reflux. After 19 hours, cooled to room temperature and dilute the reaction mixture with diethyl ether (300 ml) to give a solid. Cool on the th specified in the header of the connection.

Elemental analysis:

Calculated for C20H29H3ABOUT32Hl: 39,04; N 5,08; N 6,83.

Found: 39,14; N 5,38; N 6,88.

Example 8

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
8.1.1 Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine) ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidine (2 g) salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)of piperidine and itestosterone acid (3.1 g, 5 mmol) and N,N-diisopropylethylamine (3 ml) in acetonitrile (25 ml). Heated to boiling under reflux. After 28 hours the reaction mixture cooled down and diluted with ethyl acetate (200 ml). Filter the diluted reaction mixture and the filtrate is extracted with twice with saturated aqueous sodium bicarbonate solution and then brine. Dried the organic layer over MgS4, filtered and evaporated in vacuum, obtaining the remainder. Combine the residue and the mixture of diethyl ether/ethyl acetate (300 ml/70 ml). Heated to boiling under reflux and filtered, produces the filtering. Combine solid and a mixture of dichloromethane/saturated aqueous sodium bicarbonate solution (500 ml/500 ml) and stirred. Separate the organic layer over MgS4, filtered and evaporated in vacuum, obtaining specified in the header connection. Rf=0,39 (silica gel, 6% methanol/dichloromethane).

8.1.2. Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidin (43,4 g of 81.5 mmol), salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)of piperidine and hydrochloric acid (32 g, 70 mmol) and potassium carbonate (35 g, 253 mmol) in tetrahydrofuran (225 ml) and water (75 ml). Heated to boiling under reflux. After 108 hours, cool the reaction mixture and separate the organic layer. Twice the aqueous layer was extracted with dichloromethane. Combine the organic layers and dried over MgS4, filtered and evaporated in vacuum, obtaining the remainder. This residue chromatographic on silica gel, elwira sequentially with ethyl acetate, the mixture of 1% methanol/dichloromethane, 2% methanol/dichloromethane, 3% methanol/dichloromethane, 4% methanol/dichloromethane, 5% methanol/dichlor is for C42H53CL2N4ABOUT7: 795,329131.

Found 795,329832.

8.2.1 Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and oxalic acid.

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (1.0 g, of 1.26 mmol) and toluene (10 ml). Add oxalic acid (0.25 g, 2.8 mmol). Add ethyl acetate (5 ml) to give a solid. After 30 minutes, collect the solid by filtration, washed with toluene and dried, obtaining specified in the header of the connection.

8.2.2. Synthesis of salts of (R)-1-(3,4, 5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine) ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and oxalic acid.

Combine (R) -1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (1.0 g, of 1.26 mmol) and toluene (10 ml). Add oxalic acid (0.125 g, 1.4 mmol). Add ethyl acetate (3 ml) to give a solid. After 30 minutes, collect the solid by filtration, washed with toluene and dried((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and oxalic acid.

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (1.0 g, of 1.26 mmol) and butanone (20 ml). Add a solution of oxalic acid (0.125 g, 1.4 mmol) in butanone (5 ml) to give a solid. After 5 minutes, collect the solid by filtration and dried, obtaining specified in the header of the connection.

8.3.1. Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (45.6 g, 57,3 mmol) and dichloromethane (600 ml) and filtered. After 1 hour, evaporated in vacuum, obtaining the remainder. Triturated the residue with diethyl ether, filtered and dried, obtaining specified in the header of the connection.

8.3.2. Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-digislim hydrogen chloride. After 1 hour, evaporated in vacuum, obtaining specified in the header of the connection.

8.4. Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and maleic acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0.88 g, 1.1 mmol) and ethanol (5 ml). Heated to boiling under reflux. Add a solution of maleic acid (0.28 g, 2.4 mmol) in ethanol (5 ml). After 5 minutes the reaction mixture to cool and add diethyl ether, obtaining a solid substance. Collect the solid by filtration and dried, obtaining specified in the header of the connection.

8.5.1. Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine) ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (1.0 g, of 1.26 mmol) and ethyl acetate (5 ml). Heated to boiling under reflux. Add a solution of fumaric acid (0.32 g, was 2.76 mmol) in cm is the remainder. Triturated the residue with diethyl ether, obtaining specified in the header of the connection.

8.5.2. Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido) piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (1.0 g, of 1.26 mmol) and ethanol (20 ml). Heated to boiling under reflux. Added fumaric acid (0,302 g). After 15 minutes the reaction mixture is cooled and evaporated in vacuum, obtaining the remainder. Triturated the residue with diethyl ether, obtaining a solid substance. Collect the solid by filtration and dried, obtaining specified in the header of the connection.

Elemental analysis:

Calculated for C48H58Cl2N4ABOUT131,27 H2O: 58,07; H X 6.15; N 5,64.

Found: 57,95; N 6,13; N 5,46.

8.6.1. Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido) piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and citric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl) - Rev. 50oC. Add a solution of citric acid (0.5 g, 2.6 mmol) in ethanol (5 ml). After 30 minutes the reaction mixture to cool and add diethyl ether, obtaining a solid substance. Evaporated in vacuum, obtaining specified in the header of the connection.

8.6.2. Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and citric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0.5 g, of 0.65 mmol) and ethyl acetate (4 ml). Heated to about 50oC. Add a solution of citric acid (0.25 g, 1.3 mmol) in ethanol (2 ml). After 30 minutes the reaction mixture to cool and add diethyl ether, obtaining a solid substance. Evaporated in vacuum, obtaining specified in the header of the connection.

8.6.3. Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and citric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (1.0 g) and ethanol 30 is in the header of the connection.

8.7 Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and methanesulfonic acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (2.0 g, 2.6 mmol) and ethanol (10 ml). Heated to approximately 45oC. Add a solution methanesulfonic acid (1.0 g, 10.4 mmol) in diethyl ether (2 ml). After 30 minutes, add diethyl ether, obtaining a solid substance. Evaporated in vacuum and add diethyl ether. Four times decanted solvent and add diethyl ether. Collect the solid by filtration and dried, obtaining specified in the header of the connection.

8.8 Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and 2-hydroxyethanesulfonic acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (1.0 g, of 1.26 mmol) and ethanol (10 ml). Add an aqueous solution of 2-hydroxyethanesulfonic acid (14 ml, 0.18 M, 2,52 mmol). Heat is up the residue with diethyl ether, getting solid. Collect the solid by filtration and dried, obtaining specified in the header of the connection.

8.9 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and Hydrobromic acid

Combine ethanol (1 ml) and diethyl ether (10 ml). Cooled in a bath with ice. Add acetylmuramic (0.2 ml). After 5 minutes add the above solution to a solution of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (2 g) in ethyl acetate (20 ml). Add diethyl ether (40 ml) to give a solid. After 1.5 hours, filtered, washed with diethyl ether and dried, obtaining specified in the header of the connection.

8.10 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and tartaric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-((3,4-dichlorophenyl)pyrrolidine (1.0 g, of 1.26 mmol) and (1)-tartaric acid (0.6 g) in acetone (25 ml). Heat up about 50oC. the IDF (40 ml), getting solid. Collect the solid by filtration, washed with diethyl ether and dried, obtaining specified in the header of the connection.

8.11 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and econsultancy acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0.88 g) and ethanol (20 ml). Add econsultancy acid (0.24 g). After 30 minutes, concentrate the reaction mixture under vacuum, obtaining the remainder. Combine the residue with diethyl ether and evaporated, getting listed at the beginning of the connection.

8.12 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido) piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and (1R)-(-)-10-camphorsulfonic acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (1.0 g, of 1.26 mmol) and (1R)-(-)-10-camphorsulfonic acid (0.6 g) in acetone (25 ml). Heated to about 50oC. After 1 hour, cooled to room tempera who have solid by filtration, washed with diethyl ether and dried, obtaining specified in the header of the connection.

Example 9

(R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
9.1 Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

When cooled in a bath with ice combine salt of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine hydrochloric acid (1.0 g, 1.2 mmol) and lithium hydroxide (0.3 g, 12.6 mmol) in a mixture of tetrahydrofuran/water (20 ml/20 ml). After 5 hours the reaction mixture is evaporated in vacuum, removing a large portion of tetrahydrofuran. Bring the pH to 6 using 1M aqueous solution of hydrochloric acid. Extracted neutralized aqueous reaction mixture with dichloromethane. Dried the organic layer over MgS4, filtered and evaporated in vacuum, obtaining specified in the header of the connection.

9.2 Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Combine (R)nil)pyrrolidin (2.25 g, to 2.94 mmol) and a saturated solution of hydrochloric acid in dichloromethane (200 ml). After 2 hours the reaction mixture is evaporated in vacuum, obtaining specified in the header connection. HRMS calculated for C40H49Cl2N4ABOUT7: 767,297831. Found 767,298515.

Getting 5

2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride

Combine 2-hydroxy-5-nitrobenzoic acid (21,5 g, 117 mmol), potassium carbonate (162,3 g 1,174 mol) and methyliodide (136,8 g that 96.4 mmol) in acetone (500 ml). Heated to boiling under reflux. After 18 hours the reaction mixture cooled down to room temperature and add methyliodide (136,8 g that 96.4 mmol). Again heated to boiling under reflux. After 56 hours the reaction mixture cooled down to room temperature and filtered, washed with acetone and the filtrate evaporated in vacuum, obtaining the remainder. The residue is recrystallized from ethanol, obtaining a second residue. Combine the second residue and chloroform (about 100 ml), filtered and the filtrate evaporated in vacuum, obtaining 2-methoxy-5-nitrobenzoate. Rf=0,38 (silica gel, ethyl acetate/hexane=1/1).

Combine methyl 2-methoxy-5-nitrobenzoate (13.3 g, 63 mmol) and methanol. Add 5% palladium-on-carbon (0.66 g). Hydronaut installation dliver the filtrate in a vacuum, receiving the remainder. Combine the residue and dichloromethane and extracted with water. Dried the organic layer over Na2SO4, filtered and evaporated in vacuum, obtaining methyl 2-methoxy-5-aminobenzoate. Rf=0,18 (silica gel, ethyl acetate/hexane=1/1).

Calculated for C9H11NO3: 59,66; N 6,12; N 7,73.

Found: 59,44; N 6,04; N 7,62.

Combine methyl 2-methoxy-5-aminobenzoate (3.94 g, and 21.7 mmol) and triethylorthoformate (12.8 g, to 86.7 mmol) in glacial acetic acid (20 ml). After 20 hours, concentrate the reaction mixture under vacuum, removing the ethanol. Add glacial acetic acid (20 ml) and sodium azide (5,64 g for 86.7 mmol). Heated at 70oC. After 1 hour, add glacial acetic acid (10 ml) and continue heating to 70oC. after Another hour the reaction mixture cooled down to room temperature, diluted with water (500 ml). Collect the solid by filtration, washed with water and dried, obtaining methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate.

Combine methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate (2.86 g, 12.2 mmol) and 1M aqueous sodium hydroxide solution (13,43 ml, 13,43 mmol) in methanol/water (100 ml, 5:1/vol.). Heated to boiling under reflux. After 4 hours, concentrated in HAC is R hydrochloric acid. Evaporated in vacuum, obtaining a solid substance that is suspended is a solid substance with water, filtered and dried, obtaining 2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid.

In another, combine methyl 2-methoxy-5-(lH-tetrazol-1-yl)benzoate (13.3 g, with 56.8 mmol) and methanol (150 ml). Add 1M aqueous sodium hydroxide solution (62.5 ml, 62.5 mmol). Heated to boiling under reflux. After 30 minutes, add methanol (50 ml) and water (50 ml) and continue to heat at boiling under reflux. After 1 hour, concentrated in vacuo, removing the greater part of the solvent. Bring the pH to approximately 1-2 using 1M aqueous solution of hydrochloric acid, obtaining a solid substance. Collect the solid by filtration, washed with water and dried, obtaining 2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid.

Combine 2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid (1.2 g, 5.5 mmol) and dichloromethane (40 ml). Add drop by drop oxalicacid (to 0.72 ml, 8.25 mmol), and then dimethylformamide (3 drops). After 4 hours, evaporated in vacuo and dried, obtaining specified in the header of the connection.

Example 10

(R)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)-1-yl)ethyl)-3-(3,4-dichloro the Il)pyrrolidine

Combine salt (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and (R, R)-di-para-insolvency acid (1,21 g, 5.5 mmol) and sodium bicarbonate (2.6 g, 31 mmol) in a mixture of acetone/water (20 ml/20 ml). Cool the reaction mixture in a bath with ice. Add 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (1.48 g, 6.2 mmol). After 30 minutes, warmed to room temperature. After 6 hours the reaction mixture is filtered and the filtrate is extracted with the ethyl acetate. Extracted the organic layer with saturated aqueous sodium bicarbonate solution and then brine. Dried the organic layer over MgSO4, filtered and evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira sequentially with ethyl acetate, a mixture of 3% methanol/ethyl acetate and then 6% methanol/ethyl acetate, receiving specified in the header connection. Rf=0,38 (silica gel, 6% methanol/dichloromethane).

10.2. (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidine

Receive by way of Example 2.5.2 using (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (0.6 g, 1.3 mmol) and methanesulfonamide (of 0.12 ml, 1.55 mmol) to obtain specified in the header connection: Rf=0,20 (specification of Azin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidine (1.0 g, of 1.62 mmol), salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)of piperidine and hydrochloric acid (0,81 g, 1.3 mmol) and N,N-diisopropylethylamine (1 ml, 5.8 mmol) in acetonitrile (25 ml). Heated to boiling under reflux. After 15 hours, cooled and evaporated in vacuum, obtaining the remainder. Distribute the residue between water and ethyl acetate. Separate the organic layer and extracted with saturated aqueous sodium bicarbonate, and then brine. Dried the organic layer over MgS4, filtered and evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira sequentially with ethyl acetate, a mixture of 3% methanol/ethyl acetate and then 6% methanol/ethyl acetate, receiving specified in the header connection. Rf=0,11 (silica gel, 6% methanol/dichloromethane).

10.4. Synthesis of salts of (R)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Combine (R)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-Denmark gaseous hydrogen chloride. After 1 hour, evaporated in vacuum, obtaining the remainder. Add dichloromethane, evaporated in vacuo and dried, obtaining specified in the header of the connection.

Example 11

Salt (R)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl) ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

< / BR>
11.1. Synthesis of salts of (R)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Combine salt of (R)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid (0.3 g, 0.34 mmol) and lithium hydroxide (50 mg, 2.1 mmol) in a mixture of tetrahydrofuran/water (10 ml/10 ml). After 2 hours, evaporated in vacuum, removing the major part of tetrahydrofuran. Bring the pH to 6 using 1M aqueous solution of hydrochloric acid. Evaporated water, the reaction mixture in vacuum, obtaining the remainder. Combine the residue and ethanol and again evaporated in vacuum, obtaining a remainder, add water, stirred and decanted, receiving the remainder. Combine the residue and 1M hydrochloric acid and evaporated in vacuum, the initial analysis

Calculated for C39H44CL2H8ABOUT52l3,71H2O: 51,17; N 5,88; N 12,24.

Found: 51,35; N 5,80; N 12,02.

Example 12

(S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
12.1 the Separation of salt (R)-(+)-3-(3, 4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and (S,S)-di-para-insolvency acid (0.14 g, 0.21 mmol)

Combine (S,S)-di-para-resolving acid (14,77 g, 35 mmol), water (200 ml) and methanol (200 ml). Heated to boiling under reflux. Add drop by drop a solution of 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (18,36 g, 70 mmol) in methanol (135 ml). After 1.5 hours, add water (135 ml) slowly and the reaction mixture cooled down to room temperature, obtaining a solid substance. Filter the resulting solid and washed with water, getting listed in the header connection: so pl. 201-202oC (decomposition). The HPLC analysis described in Example 5.1.1 shows 99.9% of enantiomeric excess (99.9% of ei). []2D0=+17,9o(C=1,00, dimethylsulfoxide).

12.2. Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Get by way of Primaryusage specified in the header connection: Rf=0,29 (silica gel, 6% methanol/dichloromethane).

12.3. Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidine

Receive by way of Example 2.5.2 using (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine to obtain specified in the header connection: Rf=0,33 (silica gel, ethyl acetate) and Rf=0,44 (silica gel, 6% methanol/dichloromethane).

12.4. Synthesis of (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl) pyrrolidine (5 g, 9.4 mmol), salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl) carboxamido)of piperidine and hydrochloric acid (5.0 g, 8.1 mmol) and N,N-diisopropylethylamine (4.6 g, 35.5 mmol) in acetonitrile (100 ml). Heated to boiling under reflux. After 19 hours the reaction mixture cooled down and evaporated in vacuum, obtaining the first residue. Combine the first residue and dichloromethane and extracted with saturated aqueous sodium bicarbonate and then brine. Dried the organic layer over gS4, filtered and evaporated in vacuum, obtaining a second residue. Chromatograhy/dichloromethane and then 2% methanol/dichloromethane, getting listed at the beginning of the connection.

12.5. Synthesis of salts of (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido) piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Receive by way of Example 8.4, using (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl-3-(3,4-dichlorophenyl) pyrrolidin to obtain specified in the connection header.

Example 13

(S)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

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13.1 Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

Receive by way of Example 9.1 using salt (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid to obtain specified in the connection header.

13.2 Synthesis of salts of (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Receive by way of Example who yl)-3-(3,4-dichlorophenyl)pyrrolidin to obtain specified in the connection header.

Getting 6

Salt of 4-Phenyl-4-(((S)-2-carbomethoxyamino-1-yl)carboxamido) of piperidine and idiscovered acid

Combine 1-tert-butoxycarbonyl-4-phenylpiperidine-4-carboxylic acid (0.64 g, to 3.34 mmol) and N,N-diisopropylethylamine (of 0.58 ml, 6.8 mmol) in dichloromethane (20 ml). Add (S)-2-carbomethoxyamino hydrochloride (hydrochloride of L-prolongational ether, and 0.61 g, to 3.67 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0,70 g, 3.67 mmol) and 1-hydroxybenzotriazole hydrate (0.25 g, 3.67 mmol). After 18 hours, dilute the reaction mixture with dichloromethane and extracted twice with water. Dried the organic layer over MgS4, filtered and evaporated in vacuum, obtaining 1-tert-butoxycarbonyl-4-phenyl-4-(((S)-2-carbomethoxyamino-1-yl) carboxamido) piperidine.

Combine 1-tert-butoxycarbonyl-4-phenyl-4-(((S)-2-carbomethoxyamino-1-yl)carboxamido)piperidine (0.45 g) and dichloromethane (40 ml). Add gaseous hydrogen chloride (about 1 g). After 3 hours, evaporated in vacuum, obtaining after drying specified in the header of the connection.

Example 14

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-(((S)-2-carbomethoxyamino-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin


Receive by way of Example 8.1.1 using salt (S)-1-(3,4, 4-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidin and salt of 4-phenyl-4-(((S)-2-carbomethoxyamino-1-yl)carboxamido)of piperidine and itestosterone acid to obtain after chromatography of the residue on silica gel with elution with a mixture of 10% methanol/ethyl acetate specified in the connection header.

HRMS (FAB+).

Calculated for C40H48Cl2N3ABOUT7: 752,286932.

Found 752,286459.

Example 15

(R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-(((S)-2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
15.1 Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-(((S)-2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-(((S)-2-carbomethoxyamino-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (2.0 g), 1M aqueous sodium hydroxide solution (100 ml, 100 mmol) and methanol (60 ml). After 2 hours, acidifying the reaction mixture to about pH 4 using 1M aqueous solution of hydrochloric acid, and extracted several times with dichloromethane. Combine the organic layers, MS (FAB+).

Calculated for C39H46CL2N3O7: 738,271282.

Found 738,270696.

15.2. Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-(((S)-2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Receive by way of Example 5.5, using (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-(((S)-2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin to obtain specified in the connection header.

Example 16

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine

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16.1.1 the separation of the salt of (+)-3-phenyl-3-(2-hydroxyethyl) pyrrolidine and (R, R)-di-para-insolvency acid and salts of (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and hydrochloric acid

Combine (R, R)-di-para-insolvency acid (1.10 g, 2,62 mmol) in a mixture of water/methanol (13,6 ml/13,6 ml). Add 12M hydrochloric acid (0,217 ml, 2,63 mmol). Add a hot solution of 3-phenyl-3-(2-hydroxyethyl) pyrrolidine (1.0 g, 5.23 mmol) in methanol (13,6 ml). Heated to the boiling temperature under reflux. After 30 minutes, slowly cooled to room temperature, obtaining a solid ve the AZ from methanol/2-butanone and once from ethanol, getting salt of (-)-3-phenyl-3-(2-hydroxyethyl) pyrrolidine and (R,R)-di-para-insolvency acid. After transformation of the sample 3,4,5-trimethoxybenzamide using sodium carbonate and 3,4,5-trimethoxybenzoate in a mixture of acetone/water, HPLC analysis on a column CHIRALPAK AD (10 µm x 4,6 cm x 250 cm) with elution by the mixture of pentanol/ethanol/methanol/triethylamine=80/15/5/0,1 at a flow rate of 1.5 ml/min, shows the enantiomeric excess of 98% (98% of ei), retention time 22,30 minutes for the 3,4,5-trimethoxybenzamide derived from the (-) isomer salts of (R,R)-di-para-insolvency acid.

16.1.2 the separation of the salt of (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R, R)-di-para-insolvency acid and salts of (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid

Add a hot solution of 3-phenyl-3-(2-hydroxyethyl) pyrrolidine (5.0 g, a 20.2 mmol) in ethanol (100 ml) to boiling under reflux a solution of (R, R)-di-para-insolvency acid (16,46 g, a 20.2 mmol) containing a small amount of acetone in ethanol (200 ml). When you are finished adding slowly cooled to room temperature, obtaining a solid substance. Collect the solid by filtration and recrystallized three times from ethanol, getting salt of (-)-3-phenyl-3-(2-hydroxyethyl)pyrrole C12H17NO.C20H18O10: 63,05; N 5,79; N, 2,30.

Found: 62,72; N 5,80; N, 2,33.

After transformation of the sample 3,4,5-trimethoxybenzamide using sodium carbonate and 3,4,5-trimethoxybenzoate in a mixture of acetone/water, HPLC analysis on a column CHIRALPAK AD (10 µm x 4,6 cm x 250 cm) with elution with a mixture of pentane/ethanol/methanol/triethylamine= 80/15/5/0,1 at a flow rate of 1.5 ml/min shows the enantiomeric excess of 99.9% (99.9% of ei), retention time 22,30 minutes for the 3,4,5-trimethoxybenzamide obtained from (-)-isomer salts of (R, R)-di-para-insolvency acid.

After standing above the Queen cells give a solid. This solid is collected by filtration and recrystallized twice from ethanol, getting salt of (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid: t.sq. 175,0-176,0oC.

Elemental analysis:

Calculated for C12H17NO.C20H18O10.0,8 (C3H6ABOUT: WITH 62,98; N 6,11; N 2,13.

Found: 62,86; N 5,94; N, 2,33.

After transformation of the sample 3,4,5-trimethoxybenzamide using sodium carbonate and 3,4,5-trimethoxybenzoate in a mixture of acetone/water analysis HPLC on a column of CHIRALRAK AD (10 µm x 4,6 cm x 250 cm) with elution with a mixture (99.9% of ei), the retention time of 10.26 minutes for the 3,4,5-trimethoxybenzamide obtained from (-)-isomer salts of (R, R)-di-para-insolvency acid.

16.1.3 the separation of the salt of (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R, R)-di-para-insolvency acid and salts of (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid

Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (99,2 g, 659 mmol) and ethanol (2.5 l). Heated to the boiling temperature under reflux. Add boiling under reflux a solution of (R,R)-di-para-insolvency acid (212 g, 507 mmol) in ethanol (5,07 l). When you are finished adding slowly cooled down to room temperature under stirring, obtaining oil. This oil is dissolved in ethanol by boiling under reflux (595 ml) and add boiling under reflux a solution of (R,R)-di-para-insolvency acid (49.2 g) in ethanol (1.1 l). Cool to room temperature under stirring, obtaining a solid substance. Collect the solid by filtration and recrystallized from ethanol (3.2 liters), getting a second solid. Collect the specified second solid by filtration and recrystallized from ethanol (2.6 liters), make the seed crystals of the salt of (-)-3-phenyl-3-one (R,R)-di-para-insolvency acid (121 g).

16.1.4 the separation of the salt of (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R, R)-di-para-insolvency acid and salts of (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid

Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (101 g, 530 mmol) and ethanol (1,92 l). Heated to the boiling temperature under reflux. Add boiling under reflux a solution of (R,R)-di-para-insolvency acid (107 g, 410 mmol) in ethanol (3.9 l). Continue boiling under reflux. After 10 minutes, slowly cooled to room temperature, make the seed crystals. After 18 hours, collect the resulting solid by filtration, washed with ethanol (200 ml), twice paracrystal-soviat from ethanol, getting salt of (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R, R)-di-para-insolvency acid: so LP 179-180oC. (C=1,02, methanol).

16.1.5. The synthesis of the salt of (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and hydrochloric acid

Combine salt of (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid (30,9 g of 50.7 mmol) and sodium bicarbonate (11.6 g, 53.2 mmol) in a mixture of tetrahydrofuran/water=5/1 (200 ml). Cooled in a bath with ice and add di-tert-BUTYLCARBAMATE (charged 8.52 g, 101 mmol). After 18 hours mpariwa the m aqueous solution of ammonium chloride, saturated aqueous sodium bicarbonate and then brine. Dried the organic layer over MgSO4, filtered and evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira a mixture of 50% ethyl acetate/hexane, obtaining 1-tert-butoxycarbonyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidin derived from a salt of (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R, R)-di-para-insolvency acid: Rf=0,25 (silica gel, 50% ethyl acetate/hexane).

Combine 1-tert-butoxycarbonyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (13,0 g and 44.6 mmol) and a solution of hydrochloric acid in dioxane (22,3 ml, 4M, was 89.2 mmol). Heated to 50oC. After 1 hour, cool and add diethyl ether, obtaining a solid substance. Collect the solid by filtration, getting after drying specified in the header connection: so pl. 161-163oC. []2D0= +11,8 (c=0,563, methanol).

Elemental analysis:

Calculated for C12H17NOHCl: 63,29; N. Of 7.97; N 6,15.

Found: 63,21; N 7,86; N 6,05.

16.2.1 the Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine salt of (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid (3,95 g, 6,48 mmol) and acetone (20 ml), water (6 ml) and carbonate Kali is dibenzoylperoxide (1,71 g, 7.4 mmol) in acetone (20 ml). Warmed to room temperature. After 18 hours distribute the reaction mixture between ethyl acetate and saturated aqueous sodium bicarbonate. Separate the organic layer and extracted with brine. Dried the organic layer over Na2SO4, filtered and evaporated in vacuum, obtaining specified in the header connection: Rf= 0,23 (silica gel, ethyl acetate). The analysis method HPLC on a column CHIRALPAK AD (10 µm x 4,6 cm x 250 cm) with elution with a mixture of pentane/ethanol/methanol/triethylamine= 80/15/5/0,1 at a flow rate of 1.5 ml/min, shows the enantiomeric excess of 99.9% (99.9% of ei), retention time 22,30 minutes.

16.2.2 the Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine salt of (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid (56,0 g of 92.1 mmol), sodium carbonate (19.5 g, 184 mmol) in ethyl acetate (2 l) and water (2 l). Cooled to about 0oWith in a bath with ice. After 30 minutes, slowly drop by drop add 3,4,5-trimethoxybenzoate (of 21.2 g of 92.1 mmol). Upon completion of addition the reaction mixture is heated to room temperature. After 1 hour, dilute the reaction mixture with ethyl acetate and extracted with water, 1M aqueous solution of hydrochloric acid as recommended in the header of the connection.

16.3 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylaminoethyl)pyrrolidine

Receive by way of Example 2.5.2 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (derived from salt (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid) (2,21 g, 5.51 mmol) and methanesulfonamide (0.7 ml, 9.0 mmol) to obtain specified in the header connection: Rf=0,47 (silica gel, ethyl acetate).

16.4 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine

Receive by way of Example 8.1.1, using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonylaminoethyl)pyrrolidin (derived from salt (-)-3-phenyl-3-(2-hydroxyethyl) pyrrolidine and (R, R)-di-para-insolvency acid) and salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)of piperidine and idiscovered acid to obtain specified in the connection header.

Example 17

1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-phenylpyrrolidine

< / BR>
17.1 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-taximeters-1-yl)carboxamido)piperidine-1-yl)ethyl-3-phenylpyrrolidine (derived from salt (-)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid) to obtain specified in the connection header.

Getting 7

2-Methoxy-5-(4H-triazole-4-yl)benzoyl chloride

According to method J. Chem.Soc. (S), 1664 (1967) combine methyl 2-methoxy-5-aminobenzoate (2.0 g, 11 mmol), N,N-dimethylformamidine (1.56 g, 11 mmol), paratoluenesulfonyl acid (190 mg) in toluene (25 ml). Equip the reaction vessel inlet for gas, through which the upper space of the vessel is filled with argon, and pass the thread through a dilute aqueous solution of hydrochloric acid. Heated to boiling under reflux. After 20 hours, concentrate the reaction mixture under vacuum, obtaining the remainder. Distribute the residue between dichloromethane and saturated aqueous sodium bicarbonate. Twice the aqueous layer was extracted with dichloromethane. Combine the organic layers, dried over gSO4, filtered and evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira successively with a mixture of 70% ethyl acetate/dichloromethane and then 55% methanol/dichloromethane, receiving the remainder. The residue is recrystallized from a mixture of ethyl acetate/hexane, obtaining methyl 2-methoxy-5-(4H-triazole-4-yl)benzoate: so pl. 191-195,5oC.

Differently, according to the method of J. Med.Chem., 21, 1100 (1978) combine methyl 2-methoxy-5-aminobenzoate (1.8 g, 10 mmol), deformality the th mixture and add saturated aqueous sodium bicarbonate solution. Thrice extracted with dichloromethane. Dry the combined organic layers over MgS4, filtered and evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira successively with a mixture of 40% ethyl acetate/dichloromethane and then 5% methanol/dichloromethane, receiving methyl 2-methoxy-5-(4H-triazole-4-yl)benzoate: so pl. 179-182oC.

Combine 2-methoxy-5-(4H-tetrazol-4-yl)benzoate (56 mmol), methanol (200 ml) and water (50 ml). Add 1M aqueous sodium hydroxide solution (62.5 ml, 62.5 mmol). Heated to boiling under reflux. After 8 hours, concentrated in vacuo, removing the greater part of the solvent. Bring the pH to approximately 1-2 using 1M hydrochloric acid, extracted with saturated dichloromethane. Dried the organic layer over gS4, filtered and evaporated in vacuum, obtaining 2-methoxy-5-(4H-triazole-4-yl)benzoic acid.

Combine 2-methoxy-5-(4H-triazole-4-yl)benzoic acid (5.5 mmol) and dichloromethane (40 ml). Add drop by drop oxalicacid (to 0.72 ml, 8.25 mmol), and then dimethylformamide (3 drops). After 4 hours, evaporated in vacuo and dried, obtaining specified in the header of the connection.

Example 18

(R)-1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxyamino-5-(tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Receive by way of Example 10.1 using to obtain specified in the connection header salt (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and (R, R)-di-para-insolvency acid and 2-methoxy-5-(4H-triazole-4-yl)benzoyl chloride.

18.2. Synthesis of (S)-1-(2-methoxy-5-(4H-tetrazol-4-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidine

Receive by way of Example 2.5.2 using to obtain specified in the connection header (S)-1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-dichlorophenyl)-3-(2-hydroxyethyl)-pyrrolidin and methanesulfonanilide.

18.3 Synthesis of (R)-1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Receive by way of Example 10.3 using to obtain specified in the connection header (S)-1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidin and salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)of piperidine and itestosterone acid.

Example 19

(R)-1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
19.1 Synthesis of (R)-1-(2-methoxy the Nile)pyrrolidine

Receive by way of Example 9.1, using for this the title compound (R)-1-(2-methoxy-5-(4H-triazole-4-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine.

Getting 8

2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl chloride

Combine methyl 2-methoxy-5-formylbenzoate (5.0 g, of 25.9 mmol), hydroxylamine hydrochloride (8,55 g, 133 mmol) and sodium acetate (of 10.25 g, 125 mmol) in a mixture of ethanol/water (200 ml, 1/1). Heated to 50oC. After 1 hour, pour the reaction mixture onto ice, getting solid. Collect the solid by filtration, obtaining methyl 2-methoxy-5-formylbenzoate the oxime: Rf=0,76 (silica gel, dichloromethane/methanol=9/1).

Combine methyl 2-methoxy-5-formylbenzoate the oxime (3.5 g, and 16.7 mmol) in dichloromethane (75 ml) and cooled in a bath with ice. Add one drop of thionyl chloride (2.0 ml, for 27.2 mmol). After 20 minutes, dilute the reaction mixture with dichloromethane and extracted with saturated aqueous sodium bicarbonate, and then brine. Dried the organic layer over MgS4, filtered and evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira a mixture of ethyl acetate/hexane=1/1 and receiving methyl 2-med) and triethylamine hydrochloride (0.14 g, 1,03 mmol) in N-organic (6 ml). Heated to 150oC. After 4 hours, cooled to room temperature and distribute the reaction mixture between water and ethyl acetate. Separate the layers and three times extracted the aqueous layer with ethyl acetate. Bring the pH of the aqueous layer to about 1, using a 1M aqueous solution of hydrochloric acid. The aqueous layer was again extracted three times with ethyl acetate and twice with dichloromethane. The aqueous layer was saturated with sodium chloride and again four times extracted with dichloromethane. Combine the organic layers, dried over MgSO4, filtered and evaporated in vacuum, obtaining methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate.

Combine methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate (1 mmol) and lithium hydroxide (1.1 mmol) in a mixture of tetrahydrofuran/water=1/1 (5 ml). After 24 hours, dilute the reaction mixture with 0.5 M aqueous solution of hydrochloric acid and dichloromethane. Separated the layers and the aqueous layer was extracted three times with dichloromethane. Combine the organic layers, dried over MgSO4, filtered and evaporated vacuum, obtaining 2-methoxy-5-(1H-tetrazol-5-yl)benzoic acid.

Combine 2-methoxy-5-(1H-tetrazol-5-yl)benzoic acid (5 mmol) and dichloromethane (40 ml). Add drop by drop oxalicacid (to 0.72 ml, 8.25 mmol), and then the CLASS="ptx2">

Example 20

(R)-1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-phenyl-4-((carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
20.1. Synthesis of (S)-1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Receive by way of Example 10.1 using to obtain specified in the connection header salt (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine and (R, R)-di-para-insolvency acid and 2-methoxy-5-(1H-tetrazol-5-yl)benzoyl chloride.

20.2. Synthesis of (S)-1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidine

Receive by way of Example 2.5.2 using to obtain specified in the connection header (S)-1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidin and methanesulfonanilide.

20.3. Synthesis of (R)-1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Receive by way of Example 10.3 using to obtain specified in the connection header (S)-1-1-(2-methoxy-5-(1H-triazole-5-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidine (1.0 g, of 1.62 mmol) and salt of 4-phenyl-4-((4-(R)-1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Receive by way of Example 9.1, using for this the title compound (R)-1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine.

Example 21

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
21.1. Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Receive by way of Example 8.1.1, using (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidin and salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)of piperidine and hydrochloric acid to obtain after chromatography on silica gel with elution with a mixture of 3% methanol/dichloromethane specified in the header connection: Rf=0,40 (silica gel, 6% methanol/dichloromethane).

21.2. Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamidates hydrogen chloride for about 10 minutes. Evaporated in vacuo to solids. Collect the solid and dry, receiving specified in the header of the connection.

Elemental analysis

Calculated for C42H51CL2N3ABOUT7HCl1,1 H2ABOUT: 59,94; N 6,53; N 5,02.

Found: 59,92; N 6,40; N 4,86.

Example 22

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
22.1. Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine)-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Combine salt of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid (0.65 g, 0.8 mmol), tetrahydrofuran (15 ml) and water (150 ml). Add lithium hydroxide (0.11 g, 4.8 mmol). After 2 hours, bring the pH to about 6 using 1M aqueous solution of hydrochloric acid, and evaporated in vacuo to remove most of the tetrahydrofuran. Dilute one stripped off the reaction mixture with brine and extracted twice with dichloromethane. The combined organic layers dried over MgSO4, filtered and evaporated in vacuum, obtaining the remainder. Odoe substance. Collect the solid and dry, receiving specified in the header of the connection.

Example 23

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
23.1. Synthesis of diethyl ether 3-cyano-3-(3,4-differenl) pentanedioic acid

Receive by way of Example 3.1.2 using to obtain specified in the connection header 3,4-differentiational.

23.2.1 Synthesis of ethyl ester of (3-(3,4-differenl)-5-oxopyrrolidin-3-yl)acetic acid

Receive by way of Example 2.2.2 using to obtain specified in the connection header diethyl ether 3-cyano-3-(3,4-differenl)pentadienoic acid.

23.2.2 Synthesis of ethyl ester of (3-(3,4-differenl)-5-oxopyrrolidin-3-yl)acetic acid

Combine diethyl ether 3-cyano-3-(3,4-differenl) pentadienoic acid (106 g, 326 mmol), ethanol (3 l), concentrated aqueous ammonia (160 ml) and Raney Nickel (100 g). The hydrogenation is carried out in an autoclave at a temperature of about 50oAnd 14,06 kg/cm2(200 psi). After 22 hours, filtered through celite and washed the solid with ethanol. The filtrate is evaporated in vacuum, obtaining the remainder. The residue is triturated with securiety)pyrrolidine

Receive by way of Example 2,3, using ethyl ether (3-(3,4-differenl)-5-oxopyrrolidin-3-yl)acetic acid to obtain specified in the header connection: Rf=0,26 (silica gel, dichloromethane/methanol/acetic acid=85/10/5).

23.4.1 the separation of the salt of (+)-3-(3,4-differenl)-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid and salts of (-)-3-(3,4-differenl)-3-(2-hydroxyethyl)pyrrolidine and hydrochloric acid

Combine (R, R)-di-para-resolving acid (0,93 g, 0.2 mmol) and water 12M hydrochloric acid (to 0.19 ml, 2.28 mmol) in a mixture of water/methanol (10 ml/10 ml). Heated to boiling under reflux. Add drop by drop a solution of 3-(3,4-differenl)-3-(2-hydroxyethyl)pyrrolidine (1.0 g, 4.4 mmol) in methanol (10 ml). After 15 minutes, slowly cooled to room temperature. Filter the resulting solid and washed with water, getting salt of (-)-3-(3,4-differenl)-3-(2-hydroxyethyl)pyrrolidine and (R, R)-di-para-insolvency acid. []2D0= -25,1 (=1,02, dimethylsulfoxide). Analysis of an analytical sample, obtained by extraction of the free amine, HPLC on a column CHIRALPAK AD (25 cm x 0,46 cm) with elution with a mixture of pentane/methanol/triethylamine=80/10/0,1 at a flow rate of 1.0 ml/min, shows the Omer salt (R, R)-di-para-insolvency acid; retention time of 12.5 minutes for the 3,4,5-trimethoxybenzamide obtained from (+)-isomer salts of (R,R)-di-para-insolvency acid.

23.4.2 the separation of the salt of (+)-3-(3,4-differenl)-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid and salts of (-)-3-(3,4-differenl)-3-(2-hydroxyethyl)pyrrolidine and hydrochloric acid

Combine (R, R)-di-para-insolvency acid (6.6 g, 15.8 mmol) and the mixture of water/methanol (70 ml/70 ml). Heated to boiling under reflux. Add water 12M hydrochloric acid (1.31 ml, 15.7 mmol). Add drop by drop a solution of 3-(3,4-differenl)-3-(2-hydroxyethyl)pyrrolidine (7,15 g of 31.5 mmol) in methanol (70 ml). After 15 minutes, allow the mixture to cool a little and add the seed crystals of the salt of (-)-3-(3,4-differenl)-3-(2-hydroxyethyl)pyrrolidine and (R, R)-di-para-insolvency acid, and then slowly cooled down to room temperature. Filter the resulting solid. Retain the filtrate, which enriched slower eluruumis isomer. Combine the solid with hot ethanol (800 ml), filtered, will reduce the volume of the solution up to about 600 ml and slowly cooled to room temperature, obtaining a solid substance. Collect solids and (R,R)-di-para-insolvency acid. The analytical sample derived 3,4,5-trimethoxybenzamide HPLC on a column CHIRALPAK AD (25 cm x 0,46 cm) with elution with a mixture of pentane/ethanol/methanol/triethylamine=80/15/5/0,1 at a flow rate of 1.0 ml/min, shows the enantiomeric excess of > 99% (>99% of ei).

23.5 Synthesis of (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Receive by way of Example 5.2.2, using to obtain specified in the connection header salt of (-)-3-(3,4-differenl)-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid.

23.6 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-differenl)-3-(2-methanesulfonylaminoethyl)pyrrolidine

Receive by way of Example 2.5.2 using to obtain specified in the title compound 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-differenl)-3-(2-hydroxyethyl)pyrrolidine (derived from salt (-)-3-(3,4-differenl)-3-(2-hydroxyethyl)pyrrolidine and (R,R)-di-para-insolvency acid).

23.7 Synthesis of 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-differenl)pyrrolidine

Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-differenl)-3-(2-methanesulfonylaminoethyl) pyrrolidin (derived from salt (-)-3-(3,4-differenl)-3-(2-hydrotel-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)of piperidine and hydrochloric acid (0.4 g, 0.8 mmol) in a mixture of tetrahydrofuran/water (6 ml/2 ml). Heated to boiling under reflux. After 64 hours, evaporated in vacuum, obtaining the remainder. Combine the residue and dichloromethane and extracted with saturated aqueous sodium bicarbonate. Dried the organic layer over MgSO4, filtered and evaporated in vacuum, obtaining the remainder. This residue chromatographic on silica gel, elwira sequentially with ethyl acetate, the mixture of 1% methanol/dichloromethane, 2% methanol/dichloromethane, 3% methanol/dichloromethane, 4% methanol/dichloromethane and then 5% methanol/dichloromethane, getting listed at the beginning of the connection.

23.8 Synthesis of salts of 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl) carboxamido)piperidine-1-yl)ethyl)-3-(3,4-differenl)pyrrolidine and hydrochloric acid

Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-differenl)pyrrolidin (0,38 g, 0.45 mmol) and dichloromethane. Purge gaseous hydrogen chloride for approximately 5 minutes. Is evaporated in vacuum, obtaining after drying specified in the header of the connection.

Example 24

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)PIP is oxymethylphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-differenl)pyrrolidine

Receive by way of Example 9.1 using to obtain specified in the title compound 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-differenl) pyrrolidin.

Example 25

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carbomethoxybiphenyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
25.1 Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carbomethoxybiphenyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl) pyrrolidine (2 g) salt of 4-phenyl-4-((2-carbomethoxybiphenyl-4-yl)carboxamido)of piperidine and hydrochloric acid (5 mmol) and N,N-diisopropylethylamine (3 ml) in acetonitrile (25 ml). Heated to boiling under reflux. After 10 hours is evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira successively with ethyl acetate and then a mixture of dichloromethane/methanol=95/5, receiving specified in the header connection. Rf= 0,50 (silica gel, dichloromethane/methanol=9/1) and Rf=0,20 (silica gel, ethyl acetate/methanol=9/1).

25.2 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-
Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carbomethoxybiphenyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0.8 g, 1.06 mmol) and fumaric acid (184 mg, 1.6 mmol) in ethanol (10 ml). After 10 minutes, evaporated in vacuum, obtaining the remainder. The residue is triturated with diethyl ether, obtaining a solid substance. Collect the solid, washed with diethyl ether and dried, obtaining specified in the header connection: so pl. 125-128oC.

Example 26

(R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
26.1 Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxymethyl-4-yl) carboxamido) piperidine-1-yl) ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0,77 g of 1.02 mmol) and the hydrate of lithium hydroxide (128 mg, a 3.06 mmol) in a mixture of tetrahydrofuran/methanol/water (2/2/1, 15 ml). After 1 hour, evaporated in vacuum, obtaining the remainder, combine the residue and the water, acidified with 1M aqueous hydrochloric acid and extracted five times with dichloromethane. Combine the organic layers, dried over Na2is irua successively with a mixture of 1% methanol/dichloromethane and then 5% methanol/dichloromethane, receiving specified in the header connection. Rf=0,30 (silica gel, 25% methanol/dichloromethane).

9

Salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido) of piperidine and itestosterone acid

Combine 1-tert-butyl 1-piperidinecarboxylate (10,47 g, and 36.2 mmol), acrylate (8 ml) in ethanol (30 ml). Heated at the boil under reflux. After 5.5 hours the reaction mixture cooled down and evaporated in vacuum, obtaining the remainder. Combine the residue and diethyl ether (200 ml) and extracted with 1M aqueous solution of hydrochloric acid. Bring the pH of the aqueous layer to the core, using sodium bicarbonate, and then extracted with ethyl acetate. Dried the organic layer over MgS4, filtered and evaporated in vacuum, obtaining tert-butyl 4-carboethoxy-1-piperidinecarboxylate.

Combine tert-butyl 4-carboethoxy-1-piperazine-carboxylate (14.3 g, 50 mmol) and dichloromethane (250 ml). Stirred, cooled to about 0oAnd purge gaseous hydrogen chloride. After 43 hours, concentrate the reaction mixture in vacuum, double-add diethyl ether (200 ml) and evaporated in vacuum, obtaining a solid substance. This solid is triturated with diethyl ether and collect orbitomeatal-1-piperazine and hydrochloric acid (6.8 g, to 26.2 mmol), 1-tert-butoxycarbonyl-4-phenylpiperidine-4-carboxylic acid (8.0 g, to 26.2 mmol), N,N-diisopropylethylamine (14 ml) and 1-hydroxybenzotriazole hydrate (3.9 g) in dichloromethane (250 ml). Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.53 g). After 17 hours, dilute the reaction mixture with dichloromethane (300 ml) and extracted with saturated aqueous sodium bicarbonate, water and then 1M aqueous solution of hydrochloric acid. Dried the organic layer over gS4, filtered and evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira sequentially with hexane, a mixture of 20% ethyl acetate/hexane, 30% ethyl acetate/hexane, 50% ethyl acetate/hexane to 60% ethyl acetate/hexane, 50% ethyl acetate/hexane containing 2.0 ml of triethylamine and then with ethyl acetate, obtaining 1-tertbutoxycarbonyl-4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine.

Combine 1-tert-butoxycarbonyl-4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine (7,3 g of 15.3 mmol) and dichloromethane (250 ml). Stirred, cooled to about 0oAnd purge gaseous hydrogen chloride. After 2 hours, warmed to room temperature and rinsed again with gaseous hydrogen chloride. After 3 Calusa solid. Combine this solid, dichloromethane (100 ml) and aqueous sodium bicarbonate solution. Separate the layers, saturate the aqueous layer with sodium chloride and extracted twice with dichloromethane. Combine the organic layers, dried over MgS4, filtered and evaporated in vacuum, obtaining 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine.

Combine 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine (6.0 g) and ethanol (60 ml). Add an aqueous solution itestosterone acid (7.9 g, 57%). After 30 minutes, add diethyl ether (200 ml) to give a solid. Filter, wash the solid with diethyl ether and dried, obtaining specified in the header of the connection.

Example 27

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-differenl)pyrrolidin

< / BR>
27.1 Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-differenl)pyrrolidine

Combine (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidin (and 3.72 g), salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)of piperidine and itestosterone kieres 6 hours, cool the reaction mixture, concentrated in vacuo and diluted with dichloromethane (200 ml). Extracted with saturated aqueous sodium bicarbonate and then with water. Dried the organic layer over MgS4, filtered and evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira sequentially with ethyl acetate, a mixture of 2% methanol/ethyl acetate, 3% methanol/ethyl acetate, 4% methanol/ethyl acetate, 5% methanol/ethyl acetate, getting listed at the beginning of the connection.

27.2 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-kerberosauthentication-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0.7 g, 0.86 mmol) and ethanol (15 ml). Heated to boiling under reflux. Added fumaric acid (206 mg) and continue to heat at boiling under reflux. After 30 minutes, cooled, concentrated in vacuo and triturated with diethyl ether (50 ml). Filtered and dried, obtaining specified in the header of the connection.

27.3 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)Piper-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0.5 g) and ethyl acetate (6 ml). Add a solution of hydrochloric acid in diethyl ether (1.3 ml, 1M), receiving solid. After 30 minutes, filtered and dried, obtaining specified in the header of the connection.

Example 28

(R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxyethylidene-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
28.1 Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxyethylidene-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0,81 g, 1.0 mmol) in tetrahydrofuran (20 ml) and water (20 ml). Cooled in a bath with ice, add lithium hydroxide (0.15 g). After 3 hours, add water (100 ml) and 1M aqueous solution of hydrochloric acid (1.5 ml). Extracted with ethyl acetate (100 ml). Separate the layers, bring the pH of the aqueous layer to about 5 using 1M aqueous solution of hydrochloric acid, and extracted three times with dichloromethane. Combine the organic layers, dried over MgSO4and evaporated in vacuum, obtaining specified in the header of the connection.

28.2 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxyethylpyrrole-1-yl)carboxamido)Piperi-4-((4-carboxyethylpyrrole-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0,57 g) and dichloromethane (20 ml). Add a solution of hydrochloric acid in diethyl ether (1.7 ml, 1M). After 2 hours the reaction mixture is evaporated in vacuum, double-add diethyl ether and evaporated in vacuum, obtaining the remainder. The residue is triturated with diethyl ether, obtaining a solid substance. Collect the solid by filtration and dried, obtaining specified in the header of the connection.

Receive 10

Salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido) of piperidine and idiscovered acid

Combine 1-tert-butyl 1-piperidinecarboxylate (10.7 g, 57.5 mmol), ethyl 4-chlorobutyrate (10.4 ml) and potassium carbonate (8 g) in dimethylformamide (60 ml). Heated at the boil under reflux. After 4.5 hours the reaction mixture cooled down, diluted with aqueous sodium bicarbonate solution and extracted twice with diethyl ether (200 ml). Combine the organic layers and extracted with 1M aqueous solution of hydrochloric acid. Bring the pH of the aqueous layer to the core, using sodium bicarbonate, and then extracted with diethyl ether. Dry the combined organic layer over gS4, filtered and evaporated in vacuum, obtaining the remainder. This residue chromatographic on silica gel, elwira successively with a mixture of 10% ethyl acetate/hexa is UB>f
=0.5 (silica gel, ethyl acetate).

Combine tert-butyl 4-carboethoxy-1-piperidinecarboxylate (7.0 g, with 23.3 mmol) and dichloromethane (100 ml). Stirred, cooled to about 0oAnd purge gaseous hydrogen chloride. After 2 hours, concentrate the reaction mixture in vacuum, double-add diethyl ether (50 ml) and evaporated in vacuum, obtaining a solid substance. This solid is triturated with diethyl ether and collected by filtration, getting salt 4-carboethoxy-1-piperazine and hydrochloric acid.

Combine salt 4-carboethoxy-1-piperazine and hydrochloric acid (5.6 g, 20,5 mmol), 1-tert-butoxycarbonyl-4-phenylpiperidine-4-carboxylic acid (8,13 g of 26.6 mmol), N,N-diisopropylethylamine (7.9 g) and 1-hydroxybenzotriazole hydrate (3.3 g, 24.6 mmol) in dichloromethane (250 ml). Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.72 in g, 24.6 mmol). After 24 hours, dilute the reaction mixture with dichloromethane (100 ml) and extracted with saturated aqueous sodium bicarbonate and then 1M aqueous solution of hydrochloric acid. Dried the organic layer over MgS4, filtered and evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira consistently Huck is ohms and then a mixture of 6% methanol/ethyl acetate, getting 1-tert-butoxycarbonyl-4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine.

Combine 1-tert-butoxycarbonyl-4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine (6.7 g, 12.5 mmol) and ethanol (90 ml). Add an aqueous solution itestosterone acid (6.2 g, 57%). Heated at the boil under reflux. After 15 hours, cooled to room temperature and add diethyl ether (300 ml) to give a solid. Filter, wash the solid with diethyl ether and dried, obtaining salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)of piperidine and itestosterone acid.

Example 29

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
29.1 Synthesis of (R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine) ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Receive by way of Example 28.1, using (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonylaminoethyl)pyrrolidine (4.0 g) and salt of 4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)of piperidine and itestosterone acid. Purification of the methanol/dichloromethane and then 4% methanol/dichloromethane, receiving specified in the header connection: Rf=0,31 (silica gel, 6% methanol/dichloromethane).

29.2. Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine) ethyl)-3-(3,4-dichlorophenyl) pyrrolidine (0.7 g, 0.86 mmol) and ethanol (15 ml). Heated to boiling under reflux. Added fumaric acid (202 mg) and continue to heat at boiling under reflux. After 30 minutes, cooled, concentrated in vacuo and triturated with diethyl ether (50 ml). Filtered and dried, obtaining specified in the header of the connection.

29.3 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0.5 g) and ethyl acetate (8 ml). Add a solution of hydrochloric acid in diethyl ether (1.4 ml, 1M), receiving solid. After 30 minutes, filter enyl-4-((4-carboxypropylbetaine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
30.1 Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypropylbetaine-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Receive by way of Example 28.1, using (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl) carboxamido)piperidine) ethyl)-3-(3, 4-dichlorophenyl)pyrrolidin to obtain specified in the connection header.

30.2 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypropylbetaine-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid

Receive by way of Example 28.2, using (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypropylbetaine-1-yl) carboxamido) piperidine) ethyl)-3-(3, 4-dichlorophenyl) pyrrolidine (0,63 g) to obtain specified in the connection header.

Receipt 11

Salt of 4-phenyl-4-((4-Carbo(ethoxycarbonylmethoxy)methylpiperazin-1-yl)carboxamido)of piperidine and hydrochloric acid

Combine 4-carbomethoxybiphenyl (100 g, 580 mmol) and dichloromethane (750 ml). Cooled in an ice bath with methanol. Add a solution of di-tert-butyl dicarbonate (131 g, 600 mmol) in dichloromethane (250 ml). After 18 hours, evaporated in vacuum, obtaining the remainder. Divide the remainder into three parts, and XP is e substance. Evaporated fractions containing the product, and recrystallized from a mixture of ethyl acetate/hexane, obtaining 1-tert-butoxycarbonyl-4-carbomethoxybiphenyl in the form of a solid substance, so pl. 67-69oC.

IR spectrum (KBR) pmax 2980, 1748, 1679, 1461, 1423, 1366, 1296, 1251, 1214, 1188, 1170, 1131, 1035 cm-1;1NMR (D13) memorial plaques 4,19 (q, 2H, J=7,1 Hz), 3,49 (t, 4H, J=4,7 Hz), 3,23 (s, 2H), 2,53 (t, 4H, J=4.9 Hz), of 1.46 (s, N), of 1.28 (t, 3H, J=7,1 Hz);13WITH NMR (D13) memorial plaques 170,06, 154,64, 79,68, 60,68, 59,39, 52,65, 28,39, 14,20;

MS (CI/NH3) m/z 273 (M+1)+.

Combine 1-tert-butoxycarbonyl-4-carbomethoxybiphenyl (20,8 g, a 76.5 mmol) and lithium hydroxide (of 6.71 g, 160 mmol) in tetrahydrofuran (100 ml) and water (100 ml). After 60 minutes, concentrated in vacuo, obtaining a solid substance. Combine this solid and water, extracted with diethyl ether. Combine the water layer and 1M aqueous solution of potassium hydrosulfate (160 ml). Thrice extracted with chloroform. The aqueous layer was evaporated, obtaining a solid substance. Pound is a solid several times with warm ethyl acetate and isopropanol and filtered. Every time after grinding the reaction mixture is evaporated, obtaining a solid substance. Combine the obtained upon evaporation of solids dissolved in chloroform and weilpetersson in the form of solids, so pl. 195-197oC. IR spectrum (KBr) nmax 3007, 2934, 1691, 1631, 1479, 1453, 1427, 1415, 1393, 1366, 1301, 1283, 1232, 1209, 1177, 1139, 1084 cm-1;1NMR (CDCl3) memorial plaques 3,71 (broad s, 4H), of 3.56 (broad s, 2H), 3,12 (broad s, 4H), of 1.46 (s, N);

13With NMR (CDCl3) memorial plaques 169,10, 154,13, 80,70, 58,49, 52,38, 28,25; MS (CI/NH3) m/z 245 (M+1)+.

Combine chloromethylphosphonate (19 ml) and dichloromethane (300 ml) and cooled in a bath with ice. Add one drop of approximately 1 hour, a solution of ethanol (11.7 ml) and triethylamine (30,7 ml) in dichloromethane (100 ml). After 3.5 hours, filter and concentrate the filtrate, receiving the remainder. The residue is partitioned between diethyl ether and water. Separate the organic layer and dried over MgS4, filtered and evaporated in a vacuum, getting ethylchlorothioformate.

Combine 1-tert-butoxycarbonyl-4-carboxymethyllysine (10 g, of 40.9 mmol), sodium iodide (6,15 g), cesium carbonate (13.3 g), ethylchlorothioformate (9.6 g) in dimethylformamide (250 ml). Heated to 65oC. After 3 hours, cooled to room temperature and continue stirring. After 18 hours, concentrated in vacuo, receiving the remainder. The remainder chromatographic on silica gel, elwira successively with a mixture of 5% ethyl acetate/hexane, 10% ethyl acetate/hexane to 15% ethyl acetate/hexane and then 20% et>Combine 1-tert-butoxycarbonyl-4-Carbo(ethoxycarbonylmethoxy)methylpiperazin (9.5 g) and dichloromethane (500 ml). Cooled in a bath of ice and rinsed with gaseous hydrogen chloride. After 1 hour, concentrated in vacuo, receiving the remainder. Combine the residue and diethyl ether and evaporated, obtaining a residue, which is dried in vacuum at 56oFrom getting listed at the beginning of the connection.

Getting 12

(R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-carboxypeptidase-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

Combine amide(+)-1-(2-(3-(3,4-dichlorophenyl)-1-(3,4,5-trimethoxybenzoyl)pyrrolidin-3-yl)ethyl)-4-phenylpiperidine-4-carboxylic acid obtained by the method of U.S. Patent 5635510 dated June 3, 1997 (200 g, 300 mmol), dioxane (400 ml), concentrated aqueous hydrochloric acid solution (400 ml) and water (400 ml). Heated to boiling under reflux. After 26 hours, cooled to room temperature and concentrate the reaction mixture in vacuum at 60oWith up to a volume of approximately 700 ml of water is Added (400 ml) and extracted with a mixture of ethyl acetate/hexane= 9/1. Separated the layers and the aqueous layer was extracted twice with a mixture of ethyl acetate/hexane=1/1. Using sodium hydroxide bring the pH of the aqueous layer to about 7, getting pedestr> Combine (S)-3-(2-(4-phenyl-4-carboxypeptidase-1-yl) ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (50 g, 112 mmol) and sodium bicarbonate (30 g) in tetrahydrofuran (1300 ml) and water (300 ml). Add the parts about 45 minutes, a solution of 3,4,5-trimethoxybenzylamine (26 g, 112 mmol) in tetrahydrofuran (130 ml). After 2 hours, diluted with water (1000 ml). Bring the pH to about 4 using concentrated aqueous hydrochloric acid solution, and get a solid substance. Collect the solid by filtration and washed with water. RUB it solid with methanol (1300 ml) and water (1300 ml). Filtered, washed with water and dried in vacuum, obtaining specified in the header of the connection.

In another way, get listed in the title compound in a manner analogous to the one described in Example 5.4.1, using (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methansulfonate)pyrrolidine and 4-phenylpiperidine-4-carboxylic acid.

Example 31

(R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(ethoxycarbonylmethoxy)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
31.1 Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(ethoxycarbonylmethoxy)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (10 g, 15,52 mmol) and salt of 4-phenyl-4-((Carbo(ethoxycarbonylmethoxy)methylpiperazin-1-yl)carboxamido)of piperidine and hydrochloric acid (6 g, an 18.8 mmol) and N,N-diisopropylethylamine (13 ml) in dichloromethane (400 ml). Add 1-hydroxybenzotriazole hydrate (2.1 g, a 15.5 mmol) in dichloromethane and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3 g, of 15.5 mmol). After 18 hours the reaction mixture is extracted with water. Dried the organic layer over gS4, filtered and concentrated in vacuo, receiving the remainder. Chromatografic the residue on silica gel, elwira successively with a mixture of 0.3% methanol/dichloromethane, to 0.6% methanol/dichloromethane, 1.0% methanol/dichloromethane, 1.5% methanol/dichloromethane and then 2.5% methanol/dichloromethane, receiving the remainder. The residue is re-chromatographic on silica gel, elwira successively with a mixture of 1.0% methanol/dichloromethane, 2.0% methanol/dichloromethane and then 3.0% methanol/dichloromethane, getting listed at the beginning of the connection.

31.2 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(ethoxycarbonylmethoxy)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(ethoxycarbonylmethoxy)matile is 17 mmol) in 2-butanone (40 ml). Heated to boiling under reflux. After 20 minutes, cooled to room temperature. Concentrated in vacuo, receiving the remainder. RUB the residue with diethyl ether, obtaining a solid substance. Collect the solid by filtration, washed with diethyl ether and dried, obtaining specified in the header of the connection.

13

Salt of 4-phenyl-4-((4-Carbo(t-BUTYLCARBAMATE)methylpiperazin-1-yl)carboxamido)of piperidine and hydrochloric acid

Combine 1-tert-butoxycarbonyl-4-carboxymethyllysine (1.22 g, 5 mmol) and cesium carbonate (1.63 g, 5 mmol) in anhydrous dimethylformamide (20 ml). After 1.5 hours, add chlorocyphidae (828 mg, 5.5 mmol) and sodium iodide (750 mg, 5 mmol). Heated to 60oC. After 3 hours, allow the reaction mixture to cool to room temperature. After 18 hours, evaporated in vacuum, obtaining the remainder. The residue is distributed between ethyl acetate and water. Separate the layers and twice extracted the aqueous layer with ethyl acetate. Combine the organic layers and extracted several times with water and then brine. Dried over MgSO4and concentrated in vacuo, receiving the remainder. Chromatografic the residue on silica gel, elwira a mixture of 75% ethyl acetate/hexane, obtaining 1-t is 1173, 1107, 1019, 1009, 986 cm-1;1H NMR (D13) memorial plaques 5,79 (s, 2H), 3,48 (t, 4H, J=4,7 Hz), 3,23 (s, 2H), 2,53 (t, 4H, J=5.0 Hz), of 1.46 (s, N), to 1.21 (s, N);13WITH NMR (D13) memorial plaques 177,07, 168,84, 154,61, 79,75, 79,45, 77,20, 58,92, 52,49, 38,76, 28,41, 26,84; MS (CI/CH4m/z 359 (M+1)+.

Elemental analysis:

Calculated for C17H30N2ABOUT6: 56,96; N 8,44; N OF 7.82.

Found: 56,93; N 8,43; N To 7.77.

Combine 1-tert-butoxycarbonyl-4-Carbo(t-BUTYLCARBAMATE)methylpiperazin (960 mg, 2.7 mmol) in anhydrous dioxane. Cooled in a bath with ice. Add a solution of hydrochloric acid in dioxane (6 ml, 4M). After 3 hours, remove the cooling bath and allow the reaction mixture to warm to room temperature. Evaporated in vacuum, obtaining a solid substance: so pl. 156-159oC; IR (KBR) pmax 2981, 2937, 2923, 2719, 1763, 1459, 1417, 1396, 1209, 1156, 1123, 1006 cm-1; 1H NMR (DMSO-D6) memorial plaques at 9.53 (broad s, 2H), 5,77 (s, 2H), 3,99 (broad s, 2H), 3,26 (broad s, 4H), 3,19 (broad s, 4H) and 1.15 (s, N);13WITH NMR (DMSO-D6) memorial plaques 176,10, 166,31, 79,78, 55,14, 51,21, 48,26, 26,48; (CI/NH3) m/z 259 (M+1)+.

Elemental analysis:

Calculated for C12H22N2ABOUT42HCl: 43,51; N 7,30; N 8,46.

Found: 43,90; N. Of 7.55; N 7,94.

Example 32

(R)-1-(3,4,5-trimethoxybenzoyl chlorphenyl)pyrrolidin

< / BR>
32.1 Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-((4-Carbo-(tert-BUTYLCARBAMATE)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-carboxypeptidase-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (11,7 g, 18,24 mmol) and salt of 4-phenyl-4-((Carbo(tert-BUTYLCARBAMATE)methylpiperazin-1-yl)carboxamido)-piperidine and hydrochloric acid (6 g, of 18.1 mmol) and N,N-diisopropylethylamine (9,5), HATU (O-7-asobancaria-1-yl)-N,N, N', N'-tetramethyluronium hexaflurophosphate) (7 g, 18.4 mmol) and anhydrous dimethylformamide (100 ml). After 48 hours distribute the reaction mixture between ethyl acetate (500 ml) and 0.1 M aqueous solution of hydrochloric acid. Separated the layers and the aqueous layer was extracted with ethyl acetate. Combine the organic layers and extracted with water and then brine. Dried the organic layer over MgS4, filtered and evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira successively with a mixture of 1% methanol/dichloromethane, 2% methanol/dichloromethane and then 3% methanol/dichloromethane, getting listed at the beginning of the connection.

32.2 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-((4-Carbo(t-BUTYLCARBAMATE)or (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(t-BUTYLCARBAMATE)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (830 mg) in butanone (5 ml) is heated to approximately the boiling temperature under reflux. Combined with a solution of fumaric acid (221 mg, 1,90 mmol) in 2-butanone (30 ml), heated nearly to boiling under reflux. After 30 minutes, cooled to room temperature and evaporated in vacuum, obtaining the remainder. RUB the residue with diethyl ether and stirred. After approximately 1 hour, allowing the particulate matter to settle, carefully decanted solvent and add diethyl ether. Several times decanted and add diethyl ether. Filtered and dried, obtaining specified in the header connection: so pl. 135-140oC.

Getting 14

Salt of 4-phenyl-4-((4-Carbo(N,N-diethylcarbamoyl)methylpiperazin-1-yl)carboxamido)of piperidine and hydrochloric acid

Combine 1-tert-butoxycarbonyl-4-carboxymethyllysine (1.0 g, 4.1 mmol) and cesium carbonate (1,33 g) in dimethylformamide (20 ml). After 2.5 hours, add 2-chloro-N,N-diethylacetamide (0,67 g) and sodium iodide (0.6 g). Heated to 65oC. After 3 hours, allow the reaction mixture to cool to room temperature. After 18 hours distribute the balance between diethyl ether and saturated aqueous sodium bicarbonate. The aqueous layer was extracted with diethyl ether. Combine the organic layers and extracted several times with water, and static on silica gel, elwira successively with a mixture of 1% methanol/dichloromethane, 2% methanol/dichloromethane and then 3% methanol/dichloromethane, getting 1-tert-butoxycarbonyl-4-Carbo(N,N-diethylcarbamoyl)methylpiperazin.

Combine 1-tert-butoxycarbonyl-4-Carbo(N, N-diethylcarbamoyl)methylpiperazin (0.3 g) and dichloromethane (10 ml). Cooled in a bath with ice. Purge gaseous hydrogen chloride. After 2 hours, evaporated in vacuo, add dichloromethane and dried in vacuum, obtaining specified in the header of the connection.

Example 33

(R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo (N, N-diethylcarbamoyl)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
3.3.1 Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo (N,N-diethylcarbamoyl)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine.

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl)ethyl-3-(3,4-dichlorophenyl) pyrrolidine (1,9 g, 1.5 mmol) and salt of 4-phenyl-4-((Carbo(N, N-diethylcarbamoyl)methylpiperazin-1-yl)carboxamido) of piperidine and hydrochloric acid (0,49 g, 1,49 mmol), N,N-diisopropylethylamine (0,58 g), 1-hydroxybenzotriazole hydrate (0.28 g, 218 unite hours, the reaction mixture with saturated aqueous sodium bicarbonate (200 ml) and extracted three times with ethyl acetate. Combine the organic layers and evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira successively with a mixture of 1% methanol/dichloromethane, 2% methanol/dichloromethane, 3% methanol/dichloromethane, 4% methanol/dichloromethane and then 5% methanol/dichloromethane, getting listed at the beginning of the connection.

33.2 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(N,N-diethylcarbamoyl)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine and fumaric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(N, N-diethylcarbamoyl)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine (0,47 g) and fumaric acid (0.125 g) in 2-butanone (10 ml). Heated to approximately 45oC. After 15 minutes, concentrate the reaction mixture under vacuum, obtaining the remainder. RUB the residue with diethyl ether, getting a solid connection. Collect the solid compound by filtration, washed with diethyl ether and dried in vacuum, obtaining specified in the header connection:

Elemental analysis:

Calculated for C50H60Cl2N5O13: 57,34; H X 6.15; N IS 6.19.

Found: 57,71; N 6,36; N 6,09.

Poluchenii acid

Combine 1-tert-butoxycarbonyl-4-carboxymethyllysine (2,44 g) and cesium carbonate (3.3 g) in dimethylformamide (60 ml). After 1 hour, add Bromeliaceae (2 g) and sodium iodide (1.5 g). Heated to 65oC. After 3 hours, allow the reaction mixture to cool to room temperature. After 18 hours, filter and dilute the filtrate with diethyl ether for sediment. Filter, removing the precipitate and washed with diethyl ether, the filtrate evaporated in vacuum, obtaining the remainder. Chromatografic the residue on silica gel, elwira successively with a mixture of 5% ethyl acetate/hexane, 10% ethyl acetate/hexane to 15% ethyl acetate/hexane, 20% ethyl acetate/hexane and then with 25% ethyl acetate/hexane, obtaining 1-tert-butoxycarbonyl-4-Carbo(methylcarbonate)methylpiperazin.

Combine 1-tert-butoxycarbonyl-4-Carbo(methylcarbonate) methylpiperazin (2.5 g) and dichloromethane (50 ml). Cooled in a bath with ice. Purge gaseous hydrogen chloride. After 2 hours, evaporated in vacuum, several times, add diethyl ether and evaporated. Add diethyl ether, filtered and dried in vacuum, obtaining specified in the header of the connection.

Example 34

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo (metalcarbon.1. Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(methylcarbonate)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

Receive by way of Example 31.1, using (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-carboxypeptidase-1-yl)-ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (3.5 g) and salt of 4-phenyl-4-((4-Carbo(methylcarbonate)methylpiperazin-1-yl)carboxamido)of piperidine and hydrochloric acid (1.4 g) to obtain after chromatography on silica gel with elution successively with a mixture of 1% methanol/dichloromethane, 2% methanol/dichloromethane, 3% methanol/dichloromethane specified in the connection header.

34.2. Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(methylcarbonate)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid

Receive by way of Example 33.2, using (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(methylcarbonate)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0.97 g) and fumaric acid (0.27 g) to obtain specified in the connection header.

Getting 16

Salt of 4-phenyl-4-((4-Carbo(profilereminder.exe)methylpiperazin-1-yl)carboxamide after chromatography on silica gel with elution with a mixture of 75% ethyl acetate/hexane 1-tert-butoxycarbonyl-4-Carbo(profilereminder.exe)methylpiperazine: IR (pure) pmax 2973, 1763, 1696, 1457, 1422, 1366, 1291, 1276, 1262, 1247, 1173, 1127, 1101, 1008, 988 cm-1;1H NMR (D13) memorial plaques 5,79 (s, 2H), 3,48 (t, 4H, J=4.9 Hz), 3,29 (s, 2H), 2,54 (t, 4H, J=5.0 Hz), 2.35 t, 4H, J=7,3 Hz), 1,71-to 1.61 (m, 2H), 1,49 (s, N), is 0.96 (t, 3H, J=7,3 Hz).

Combine 1-tert-butoxycarbonyl-4-Carbo(profilereminder.exe)methylpiperazin (1,15 g, 3,30 mmol) and anhydrous dioxane (20 ml). Cooled in a bath with ice. Add a solution of hydrochloric acid in dioxane (7 ml, 4M). After 18 hours, concentrated in vacuo, obtaining specified in the header connection: so pl. 137-140oC.

Example 35

(R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(profilereminder.exe)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
35.1. Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(profilereminder.exe)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

Receive by way of Example 32.1, using (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-carboxypeptidase-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (1.3 g) and salt of 4-phenyl-4-((4-Carbo(profilereminder.exe)methylpiperazin-1-yl)carboxamido)of piperidine and hydrochloric acid (635 mg) to obtain after chromatography on silica gel with elution posledovateley.

35.2. Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(profilereminder.exe)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid

Receive by way of Example 3.2 using (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(profilereminder.exe)methylpiperazin-1-yl)carboxamido)piperidine) ethyl)-3-(3,4-dichlorophenyl)pyrrolidin and fumaric acid to obtain specified in the title compound: IR (pure) pmax 1761, 1632, 1583, 1459, 1418, 1237, 1128, 1102, 1005, 845 cm-1; MS (CI/NH3) m/z 906 (M+1)+.

Getting 17

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo (carboxymethoxy)methylpiperazin-1-yl)carboxamido)piperidine-1 - yl)ethyl)-3-{ 3,4-dichlorophenyl)pyrrolidin

Combine 2-(trimethylsilyl)ethanol (7.3 ml) and triethylamine (25 ml) in dichloromethane (80 ml). Cooled in a bath with ice. Add drop by drop chlorocatechol (6,9 g). Upon completion of addition the reaction mixture is heated to room temperature. After 5 hours, add chlorocatechol (2.8 g). After 2 hours, filter the reaction mixture and extracted with saturated aqueous sodium bicarbonate and then with water. Dried the organic layer over MgS4, filtered and evaporated in vacuum, polucha">

Combine 1-tert-butoxycarbonyl-4-carboxymethyllysine (1,25 g, 5.1 mmol) and cesium carbonate (1.66 g, 5.1 mmol) in anhydrous dimethylformamide (15 ml). Add a solution of 2-(trimethylsilyl)ethylchloride (1.1 g, 5.6 mmol) in dimethylformamide (5 ml) and sodium iodide (0,77 g). Heated to 70oC. After 1.5 hours, cooled to room temperature. After 18 hours, dilute the reaction mixture with water and extracted three times with diethyl ether. Combine the organic layers, dried over MgS4and concentrated in vacuo, receiving the remainder. Chromatografic the residue on silica gel, elwira successively with a mixture of 0.5% methanol/dichloromethane, 1% methanol/dichloromethane and then 2% methanol/dichloromethane, getting 1-tert-butoxycarbonyl-4-Carbo(Carbo(2-(trimethylsilyl)ethoxy)-methoxy)methylpiperazin.

Combine 1-tert-butoxycarbonyl-4-Carbo(Carbo(2-(trimethylsilyl)ethoxy)methoxy)methylpiperazin (2.1 g) and dichloromethane (20 ml). Cooled in a bath with ice. Purge gaseous hydrogen chloride. After 2.5 hours, evaporated in vacuum, obtaining the remainder. Combine the residue and dichloromethane and evaporated in vacuum, obtaining the remainder. RUB the residue with diethyl ether, filtered and dried, obtaining salt 4-Carbo (Carbo(2-(trimethylsilyl)ethoxy)methoxy)methylpiperazine and hydrochloric acid (0,92 g, 2.45 mmol), (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-carboxypeptidase-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (5,1 g, 7.9 mmol) and N,N-diisopropylethylamine (5 ml) in dichloromethane (100 ml). After stirring for 10 minutes, add 1-hydroxybenzotriazole hydrate (1.1 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1,53 g). After 18 hours chromatografic the reaction mixture on silica gel, elwira successively with a mixture of 0.5% methanol/dichloromethane, 1% methanol/dichloromethane and then with 1.5% methanol/dichloromethane, obtaining (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((Carbo(Carbo(2-(trimethylsilyl)ethoxy)methoxy)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin: f= 0,38 (silica gel, 6% methanol/dichloromethane).

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((Carbo(Carbo(2-(trimethylsilyl)ethoxy)methoxy)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (of 3.78 g, 4,15 mmol) and tetrahydrofuran (50 ml). Add a solution of tetrabutylammonium in tetrahydrofuran (6.6 ml, 1M, 6.6 mmol). After 1 hour, add a solution of tetrabutylammonium in tetrahydrofuran (3.0 ml, 1M). After 4.5 hours the reaction mixture is evaporated in vacuum, obtaining the remainder. Divide the remainder between dij is the best specified in the header of the connection.

Example 36

(R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((Carbo(N, N-di-(2-hydroxyethyl)carboxamidates)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
36.1. Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(N,N-di-(2-hydroxyethyl)carboxamidates)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(carboxymethoxy)methylpiperazin-1-yl)carboxamido) piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (2.1 g, 2.54 mmol), diethanolamine (0.27 g, 2.54 mmol), 1-hydroxybenzotriazole hydrate (0.3 g, 2.8 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.54 g, 2.8 mmol) and N,N-diisopropylethylamine (0.75 ml) in dichloromethane (30 ml). After 18 hours chromatografic the reaction mixture on silica gel, elwira successively with a mixture of 2% methanol/dichloromethane, 3% methanol/dichloromethane, 4% methanol/dichloromethane, 5% methanol/dichloromethane, 6% methanol/dichloromethane, 6% methanol/dichloromethane containing 2 ml/l of concentrated ammonium hydroxide, 6% methanol/dichloromethane containing 4 ml/l of concentrated ammonium hydroxide, 6% methanol/dichloromethane containing 6 ml/l of concentrated hydroxide, shumilkin) the l/dichloromethane, 4% methanol/dichloromethane, 6% methanol/dichloromethane and then 6% methanol/dichloromethane containing 6 ml/l of concentrated ammonium hydroxide, receiving the remainder. Re chromatografic the residue on silica gel, elwira a mixture of dichloromethane/methanol/concentrated ammonium hydroxide=95/5/0,5, receiving specified in the header of the connection.

36.2 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(N, N-di-(2-hydroxyethyl)carboxamidates)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(di-(2-hydroxyethyl)carboxamidates) methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (0.75 g) and fumaric acid (0,190 g) in 2-butanone (40 ml). Heated to boiling under reflux. After 20 minutes the reaction mixture cooled down and concentrated in vacuo, receiving the remainder. RUB the residue with diethyl ether, filtered and dried, obtaining specified in the header of the connection.

Example 37

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(N-methyl-N-(2-dimethylaminoethyl)carboxamidates)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)peroxometallic)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(carboxymethoxy)methylpiperazin-1-yl)carboxamido) piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (2.2 g, 2.7 mmol), N,N,N'-trimethylethylenediamine (0.3 g, 2.9 mmol) and N,N-diisopropylethylamine (0.8 ml) in dichloromethane (30 ml). After 10 minutes, add 1-hydroxybenzotriazole hydrate (0.39 g, 2.9 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.56 g, 2.9 mmol). After 18 hours chromatografic the reaction mixture on silica gel, elwira successively with a mixture of 2% methanol/dichloromethane, 3% methanol/dichloromethane, 4% methanol/dichloromethane, 5% methanol/ dichloromethane, 6% methanol/dichloromethane containing 5 ml/l of concentrated ammonium hydroxide, receiving the remainder. Combine the residue and dichloromethane (200 ml), extracted with brine, dry the organic layer over MgS4, filtered and evaporated in vacuum, obtaining specified in the header connection: Rf=0.5 (silica gel, dichloromethane/methanol/concentrated ammonium hydroxide = 90/10/0).

37.2 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(N-methyl-N-(2-dimethylaminoethyl)carboxamidates)methylpiperazin-1-yl)carboxamido)piperidine-1-yl) ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid

Get JV is semicomatose)methylpiperazin-1-yl) carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin to obtain specified in the connection header.

Getting 18

Salt 4-Carbo-(5-methyl-2-oxo-1,3-dioxol-4-ylethoxy)methylpiperazine and hydrochloric acid

Combine 4-dimethyl-1,3-dioxol-2-he (3.42 g, 30 mmol), N-bromosuccinimide (5.34 g, 30 mmol) and AIBN (2,2'-azobisisobutyronitrile) (500 mg, 3 mmol) in anhydrous carbon tetrachloride (100 ml). Heated at the boil under reflux. After 2 hours, cooled and filtered. Concentrate the filtrate, receiving 4-methyl bromide-5-methyl-1,3-dioxol-2-he (6.5 g, crude) in the form of oil that can be used in the next stage without additional purification.

Combine 1-tert-butoxycarbonyl-4-carboxymethyllysine (980 mg, 4,01 mmol), the crude 4-methyl bromide-5-methyl-1,3-dioxol-2-he (1,21 g, about 70% purity, 4.4 mmol) and cesium carbonate (1.30 grams, 3,99 mmol) in dimethylformamide (16 ml). Heated to approximately 60oC. After 4 hours the reaction mixture is cooled, diluted with water and extracted three times with ethyl acetate. Combine the organic layers, extracted with water and concentrated in vacuo, receiving the remainder. The remainder chromatographic on silica gel, elwira with ethyl acetate and receiving 1-tert-butoxycarbonyl-4-Carbo-(5-methyl-2-oxo-1,3-dioxol-4-ylethoxy)methylpiperazin: IR (KBr) nmax 2976, 1825, 1750, 1693, 1423, 1247, 1231, 1169, 1130, 1012 cm-1;1H NMR (CDCl3) m/z 357 (M+1)+.

Elemental analysis:

Calculated for C16H24N2ABOUT7: 53,93; N 6,79; N 7,86.

Found: 54,11; N. Of 6.71; N 7,52.

Combine 1-tert-butoxycarbonyl-4-Carbo-(5-methyl-2-oxo-1,3-dioxol-4-ylethoxy)methylpiperazin (832 mg, 2.3 mmol) and anhydrous dioxane (20 ml). Cooled in a bath with ice. Add a solution of hydrochloric acid in dioxane (6 ml), 4M Hcl). After 1 hour, warmed to room temperature. After 18 hours, evaporated in vacuum at about 50oFrom getting listed at the beginning of the connection, so pl. 79-82oC.

Elemental analysis:

Calculated for C11H16N2ABOUT52hcl: 40,14; N 5,51; N 8,51.

Found: 39,89; N 5,88; N 7,35.

Example 38

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(5-methyl-2-oxo-1,3-dioxol-4-ylethoxy)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

< / BR>
38.1 Synthesis of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(5-methyl-2-oxo-1,3-dioxol-4-ylethoxy)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidin

Combine (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-carboxypeptidase-1-yl)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine (1.28 g, 2.00 mmol), HATU (O-7-azabenzo the si)methylpiperazine and hydrochloric acid (658 mg, 2 mmol) and N,N-diisopropylethylamine (2.0 ml) in anhydrous dimethylformamide (10 ml). After 72 hours, evaporated in vacuum at 60oWith, removing the greater part of the solvent. Distribute the evaporated reaction mixture between ethyl acetate and saturated aqueous sodium bicarbonate. Separated the layers and the aqueous layer was extracted with another portion of ethyl acetate. Combine the organic layers and extracted with water and then brine. Concentrated in vacuo, receiving the remainder. The remainder chromatographic on silica gel, elwira successively with a mixture of 3.75% methanol/dichloromethane, 5% methanol/dichloromethane and then with 7.5% methanol/dichloromethane, getting listed at the beginning of the connection.

38.2 the Synthesis of salts of (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(5-methyl-2-oxo-1,C-dioxol-4-ylethoxy) methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid

Receive by way of Example, 36.2, using (R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(5-methyl-2-oxo-1,3-dioxol-4-ylethoxy)methylpiperazin-1-yl)carboxamido)piperidine-1-yl) ethyl)-3-(3,4-dichlorophenyl)pyrrolidine (955 mg, 1,085 mmol) and fumaric acid (252 mg, 2,17 mmol) to obtain specified in the connection header. IR (KBR) pmax 3438, 2939, 1821, 1711, 1633, 1601, 158), to 2.18 (s, 3H), 1,71 (broad, 1H, H2O), 1,45 (s, N); MS (CI, CH4) m/z 883, 881, 879 (M+1)+.

Elemental analysis:

Calculated for C45H52Cl2N4ABOUT101,754H4ABOUT40,6(C2H5)2HE2ABOUT:

WITH 57,04; N 5,90; N 4,89.

Found: 57,09; N. Of 5.81; N To 4.52.

Tachykinin are a class of neuropeptides that are involved in the normal C-terminal sequence Phe-Xaa-Gly-Leu-Met-NH2. Tachykinin widely distributed in the peripheral and Central nervous systems, where they bind at least three types of receptors. Receptors NK1NK2and PC3determined by the ability of the preferred binding of substance P, narocin A (NKA) and neurokin B (NKB), respectively.

The use of antagonists tachykinin shown in the treatment of a variety of tachykinin-mediated diseases and conditions including cystitis; bronchostenosis; allergic reactions; pain; peripheral neuropathy; neuralgia after shingles; adverse immunological reactions; respiratory diseases such as asthma, bronchitis, cough, rhinitis, allergies and the like; ophthalmic diseases such as conjunctivitis and spring conju the e disease, such as rheumatoid arthritis, osteoarthritis and the like; gastrointestinal symptoms, such as Crohn's disease, vomiting and ulcerative colitis; condition caused by dilation of blood vessels, such as angina and migraine; conditions and diseases of the Central nervous system such as anxiety, depression, psychosis, schizophrenia, dementia.

It is clear that tachykinin-mediated diseases and conditions are those diseases and conditions which include tachykinin, in whole or in part, in their clinical manifestations (forms). In addition, the inclusion of tachykinins not necessarily the cause of a specific tachykinin-mediated diseases and conditions. Antagonists tachykinin useful in regulating or providing therapeutic relief of such tachykinin-mediated diseases and conditions.

The present invention provides new and useful antagonists tachykinin formula (1) and their stereoisomers and pharmaceutically acceptable salts. In particular, the present invention provides compounds of formula (1), which are antagonists of receptors NK1and NK2.

Another variant of the present invention provides a method which then includes the introduction of the indicated patient a therapeutically effective amount of the compounds of formula (1). Various diseases and conditions that are subject to treatment by this method is well known and understood by professionals. It is also recognised that specialist may affect related diseases and conditions in the treatment of a patient suffering currently from these diseases or conditions, or for prophylactic treatment of the patient a therapeutically effective amount of compounds of formula (1).

Used herein, the term "patient" refers to warm-blooded animal such as a mammal that is suffering from a specific tachykinin-mediated disease or condition. It is clear that the area covered by this term includes Guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep and people. The patient needs treatment tachykinin-mediated diseases and conditions, if he suffers from one or more of these diseases or conditions.

Identification of those patients who need treatment tachykinin-mediated disease or condition, succeeds within the capabilities and competencies of the specialist. The practitioner can easily perform identification using clinical tests, physical examinations "therapeutically effective amount" of the compounds of formula (1) denotes a quantity, which is effective in regulating tachykinin-mediated diseases and conditions. The term "regulation" is intended to refer to all processes in which you can slow down, interrupt, delay or halt the development of these diseases or conditions, but do not necessarily indicate the complete elimination of the illness and symptoms, and is intended to include prophylactic treatment of tachykinin-mediated diseases or conditions.

therapeutically effective amount can be easily determined, attracting diagnostician as a specialist, using well-known techniques and watching the results obtained in similar circumstances. When determining therapeutically effective amount, the dose diagnostician considers a number of factors, including (but not limited to) type of mammal; its size, age and General health; the specific disease; the extent of injury or the severity of the disease; the response of the individual patient; the particular accept the connection; the route of administration; the characteristic of the biological suitability of the drug received; the selected regimen of the medication; the use of concomitant drug is the number of compounds of formula (1) ranges from about 0.1 to 100 mg/kg/day. The expert is able to determine the preferred number.

Effective treatment of a patient suffering from the above tachykinin-mediated diseases and conditions, the compound of formula (1) can be entered in any form or by any means, which makes this compound is biologically acceptable and effective amount, including oral intake, inhalation, parenteral and local techniques. For example, the compounds of formula (1) can be administered orally in the form of inhalation of aerosol or dry powder, subcutaneous, intramuscular, intravenous, intranasal way, rectal, transdermal, locally and similar ways. For the treatment of respiratory diseases and conditions, such as asthma, bronchitis and cough preferably oral administration or inhalation. Expert in preparation of medicines can easily choose the appropriate form and method of reception depending on the specific characteristics of the selected connection and subject to treatment of a disease or condition, disease stage and other relevant circumstances (Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990).

Compounds of the present invention can be entered by themselves or in the form of formats edalat by the solubility and chemical properties of the selected connection, route of administration and standard pharmaceutical practice. Compounds of the present invention, when their self-efficacy, can be prepared and introduced in the form of their pharmaceutically acceptable salts such as salts of joining acids or salts attaching grounds, for the purposes of stability, convenience of crystallization, increased solubility and the like.

In another embodiment, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of the compounds of formula (1) in the mixture (or other Association) with one (or more) pharmaceutical carrier or excipient.

Pharmaceutical compositions get well known in the pharmaceutical practice way. The carrier or excipient may be semi-solid or liquid material which can serve as a carrier or medium for the active ingredient. Suitable carriers or excipients are well known in practice. The pharmaceutical composition can be used for oral administration, inhalation, parenteral or local use, and you can enter the patient in the form of tablets, capsules, aerosols, inhalation drugs, suppositories, RAS is, with an inert solvent or suitable for food carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic treatment of compounds of formula (1) can be incorporated with excipients and used in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 4% of the compound of formula (1) is the active ingredient, but the amount can vary depending on the specific form, and in the conventional case, it can be from 4 to about 70 wt.% the standard dose. The amount present in the composition of the active ingredient is such that it receives the right to receive a standard dosage form.

Tablets, pills, capsules, lozenges, etc. can also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, tragakant or gelatin; excipients such as starch or lactose; a disintegrator such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; agents for imparting sliding (glidants - glidant), such as colloidal silicon dioxide; and can also disalicylate or orange flavoring. When the standard dosage form is a capsule, in addition to materials of the above types it can contain a liquid carrier such as polyethylene glycol or fatty oil. Other standard dosage forms can contain various other materials which modify the physical form of the dosage unit, for example, shell. Thus, tablets or pills may be coated with sugar, shellac or other agents to intersolubility shells. Syrups in addition to the compounds of this invention may contain sucrose as a sweetening agent and certain preservatives, dyes and color agents, flavorings. Used in preparing these various compositions of the materials should be pharmaceutically pure and non-toxic in the quantities used.

For parenteral therapeutic injection of the compounds of the present invention can be included in the solution or suspension. These preparations should contain at least 0.1% of the compounds of this invention, but their number can be changed from 0.1 to about 50 wt.%. The number present in such compositions the active ingredient is what gives you the right dosage. The specialist is the train to include one or more of the following adjuvants: sterile diluents, such as water for injection, saline solution, certain oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents for the regulation of toxicity such as sodium chloride or dextrose. Preparations for parenteral administration can be enclosed in ampoules, available syringes and vials on multiple doses, made of glass or plastic.

Compounds of the present invention can also enter through inhalation of an aerosol or dry powder. Filing can be done using a liquefied or compressed gas, or by using a suitable pump which sprays the compounds of the present invention or their drugs. Preparations for administration by inhalation the compounds of formula (1) may be submitted in the form of a single-phase, two-phase or three-phase system. For the introduction of the compounds of formula (1) in aerosol form acceptable variety of systems. Drugs - dry powders receive masiania granulated or powdered compounds of formula (1) with a suitable material of the carrier, such as lactose and the like. The feeder through inhalation includes the necessary container, activators, valves, subcontainers, and the like. The specialist can determine the preferred aerosol and dry powder preparations for administration by inhalation.

Compounds of the present invention can also be applied locally, with a suitable carrier may include a base in the form of a solution, ointment or gel. The basis of, for example, may include one or more of the following ingredients: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents, such as water and alcohol, emulsifiers and stabilizers. Preparations for local application can have the concentration of the compounds of formula (1) or its pharmaceutically suitable salt from about 0.1 to 10% (mass/volume).

Receptor antagonists tachykinin of the present invention can be evaluated using the procedures described below.

An example of a

Antagonism alleged antagonists bind iodized tachykinin with NK1and NK2receptors

The specialist can determine the affinity of the receptor NK1and receptor NK2in vitro as follows. The affinity of the receptor NK12appreciate the cells HSKR-1 (which are fibroblasts T expressing human analny receptor NK2). Tissues or cells are homogenized with a transmitter station in 15 volumes of 50 mm buffer Tris-Hcl (pH 7.4, 4oC) and centrifuged. The pellets re-suspended in buffer Tris-Hcl and centrifuged; the pellets washed twice by repeated suspendirovanie. The final pellets again suspended at a concentration of 40 mg/ml for tissue and 20 mg/ml for cells in incubation buffer and leave before use at room temperature, for at least 15 minutes. Binding receptors initiate by adding 250 μl of membrane preparation (two parallel experiment) to 0.1 nm following radio: 125I-Bolton Hunter Lys-3 labeled substance P and125yudhister-1-neurokinin A; in final volume of 500 μl of buffer containing 50 mm Tris-Hcl (pH 7.4 at room temperature), 0.1% of bovine serum albumin, 2 mm manganese chloride, 40 μg/ml bacitracin (bacitracin), 4 μg/ml leupeptin (lupeptin) and hemostatis (chymostatin), 10 μm of Tirana (thiorphan and various doses of the alleged antagonists tachykinin. Incubation was performed at room temperature for 90 minutes (the study of receptor NK1) or 2 hours (study recees filters, GF/B, pre-soaked in 0.1% polyethylenimine (the study of receptor NK1) or 0.5% bovine serum albumin (study receptor NK2). Using a gamma counter conduct quantitative determination of filter binding radioactivity. Nonspecific binding is defined as binding in the presence of 1 μm substance P or neirokinina A. Specific binding is calculated by subtracting the nonspecific binding from the total binding. Competition iodized SP (substance P) or the binding of NKA (neirokinina a) of the investigated compounds or standards expressed as a percentage of the maximum binding. The values of the IC50(concentration required to inhibit 50% of binding receptors) are obtained for each of the investigated compounds by nonlinear regression using the iterative fitting curve (GraphPAD Inplot, San Diego, CA).

The example IN

Antagonism alleged antagonists of tachykinin-induced turnover of phosphatidylinositol (PI) in vitro

The specialist may also determine the strength of the antagonism of the receptor NK1and receptor NK2in vitro as follows. Tachykinin-mediated accumulation of phosphatidylinositol (PI, Ino or NK2, respectively. Tissue incubated in buffered Krebs-Henseleit at 37oC filling gas: 95% oxygen - 5% carbon dioxide. Then the tissue is incubated in fresh buffer containing 100 microcurie m & e in[23H(N)]Inositol at 37oWith over 60 minutes at a peaceful evolution of gas. After two times washing at room temperature in 5 ml of buffer containing 10 mm lithium chloride, tissue incubated for 30 minutes at room temperature with the replacement of the buffer after 15 minutes. Buffer remove and add buffer Krebs-Henseleit (containing 40 μg/ml bacitracin (bacitracin), 4 μg/ml leupeptin (leupeptin) and hemostatis (chymostatin), 0.1% of bovine serum albumin, 10 μm of Tirana (thiorphan) and 10 μm of lithium chloride), including the compounds. To start the reaction after 15 minutes add SP to the UC11 cells or NKA cells SKLKB82#3 at various concentrations. After incubation for 60 minutes at room temperature the reaction is stopped by adding to each tube 930 μl of a mixture of chloroform:methanol (1:2 by volume), and then 310 μl of chloroform and 310 μl of double-distilled water. The samples are mixed, centrifuged, delete 0.9 ml of aqueous (upper) phase and add up to 2 ml double-distilled water. The mixture is stirred and load in inoome is vital distilled water, 2) a mixture of 5 ml of 5 mm disodium tetraborate/60 mm sodium formate, and 3) a mixture of 5 ml of 1M ammonium formate/0.1 M formic acid. The third wash is collected and 1 ml counted in 7 ml scintillation fluid. Remove an aliquot 50 ál of the organic (lower) phase, is dried in a scintillation vial and counted in 7 ml scintillation fluid.

Calculate the ratio of DPM in the aliquot of the aqueous phase (total Inositol phosphates) to DPM in 50 µl of the organic phase (total number included [3H]-Inositol) for each sample. Data expressed as percentage of agonist-induced accumulation of [3H]-Inositol phosphates beyond basic levels. Compare the ratio in the presence of the compounds and/or standards related to the ratios for the control samples (i.e., without stimulating agonist).

Build graphs of dose-response and using computer programs determine the ability of these compounds to inhibit tachykinin-induced turnover of phosphatidylinositol. Data expressed as a percentage of total incentive accumulation of Inositol phosphate in excess of the basic levels and normalized relative to the maximum response induced by tachykinins. Espadero antagonist, and is designated as RA2that is the negative logarithm of the molar concentration of the agonist, which reduces the effect of the dose of the agonist to half of the value expected at the dose of agonist. If the slope of the lines obtained by analyzing (Schild analysis), not significantly different from (1), the connection acts as a competitive antagonist.

Example WITH

Evaluation of antagonism NK1in vivo

The specialist may also determine in vivo that the compounds of the present invention are antagonists of the receptor NK1assessing the ability of compounds to inhibit induced by substance P transudate plasma protein in the Guinea-pig trachea. Induced by substance P leakage of protein through the postcapillary venules examined by measuring the accumulation of the dye Evans Blue dye in the trachea of the Guinea pig. Animals spend anesthetic pentobarbital, then inject dye Evans Blue dye (20 mg/kg, intravenously, prepared in 0.9% sodium chloride solution). One minute after injection of dye injected antagonist (intravenous), and then the substance P (1,0 nmol/kg, intravenously), and after 5 minutes, the excess dye is removed from circulation by transcardial perfusion with 50 ml of 0.9% sodium chloride solution. bookmark dye produce spectrophotometer (620 nm) after extraction of tissues in formamide for 24 hours at 50oC. Value is subtracted from base (only the dye without agonist). ED50(the dose of a compound that inhibits 50% induced by substance P transudate plasma protein) calculated by linear regression analysis.

Example D

Evaluation of antagonism NK2in vivo

The specialist may determine in vivo that the compounds of the present invention are antagonists of the receptor NK2assessing the ability of compounds to inhibit bronchostenosis caused selective receptor antagonist NK2[-Ala8]NKA 4-10 in Guinea pigs. Animals spend anesthesia with urethane and then kanalirovanie through the jugular vein, carotid artery and the trachea. The cannula of the carotid artery connected to a pressure transducer (Statham pressure transducer) to measure blood pressure, and located in the cervical Vienna catheter used for the introduction of the investigated compounds. The tracheal cannula is inserted into the T-connection unit. One shoulder T-connection attached to the respiratory pump, while the other shoulder is attached to another pressure sensor. Respiratory pump regulate so that he did 64 stroke per minute and the amount of supplied air was such that the pressure of the injection composition is anoe pressure. Prospective antagonists tachykinin or filler injected and the tube washed with water. Then build curves reactions to dose selective receptor antagonist NK2[-Ala8]NKA 4-10 at doses of 1-30 nmol/kg, intravenously. From the dose-dependent increase in pulmonary pressure injection, which occurs in response to agonist, conclude bronchostenosis. Antagonism of the compounds under study is determined from the shift to the right on the chart the dose of agonist-response, and suppression of the maximum pressure injection, produced in response to [-Ala8]NKA 4-10.

Example E

Evaluation of antagonism NK1and NK2in vivo

The specialist may determine in vivo that the compounds of the present invention are antagonists of the receptor NK2assessing the ability of these compounds to inhibit capsaicin-induced (capsaicin-induced) respiratory effects, which are known to release SP and NKA from sensory nerves in the Airways. Antagonism of capsaicin-induced respiratory effects in conscious Guinea pigs is as follows. The in vivo experiments carried out using male Guinea pigs Dunkin Hartley (250-350 g). Simultaneously monitor change device which consists of four small plexiglass boxes, each of which is connected with a box of comparison across the differential pressure sensor Validyne DP 45-16. 4 Boxes equipped with pipe, air feed (also used to deliver aerosol), and outputs the duct. Supply line and output have the same length and the narrow opening from the total of the feed chamber and the common chamber for outgoing air. This system is used to provide conditions when the fluctuation of the supplied air and the atmospheric pressure remains in phase and are removed from the useful signal by means of differential pressure sensors. Analog pressure signals converted into digital form by Converter (Data Translation DT2821 A to D board). Data are collected at a rate of 100 samples/second/animal. Each cycle of pressure change analyze, using the following parameters: the slope of the rise and fall that is defined between the minimum and maximum pressure, the ratio of the slope of the ascent to the slope of the decline and magnitude of changes between the initial pressure and the maximum pressure of the cycle. Using these values (and watching the animals), characterized by cycles of pressure as normal breathing, increased breathing (can be seen on the rising edge), critical respiratory events (SREs; usually cough, management, which are distinguishable from noise and traffic/noise when using the computer RSAT 286, the control operating system, System V UNIX. Dyspnea is defined as a significant long-term increase in pressure in plethysmography, which is associated with the observed in animals shift to shortness of breath.

During a typical experiment, which examined the sensitivity of the Airways to various causes bronchostenosis agents within 19 minutes serves aerosols (0.33 ml/min) using an ultrasonic nebulizer DeVil-biss Ultraneb 99, and during this time watching the animals. Before spraying watching 1 minute of quiet respiration to obtain the baseline. In preliminary experiments to evaluate different concentrations casparini and choose a concentration of 0.001%, which maximized the number of animals showing shortness of breath, but minimized the severity of the reaction. Prospective antagonists tachykinin injected 20 minutes before the start of the supply of spray or orally 1 hour prior to the filing of the aerosol.

Binding receptors tachykinin (value IC50for a typical compounds of the present invention is shown in the table. 1. The values in the table. 1 is defined by way of example And the present image is for the purposes of the compounds show high affinity for both receptors NK1and NK2.

The following are the data on physico-chemical properties of the compounds of the present application (table. 2).

The melting point of the compound of example 26: 182-185oC.

The following NMR data for compounds of the following examples:

Example 4: Range1H NMR (300 MHz, DMSO-D6): 12,5 cm.with (proton of carboxylic acid), and 11.2-10.0 number of Shir.with (proton piperidine), to 7.67-a number of 7.23 m (8H; aromatic protons), 6.83 and 6,79 (2N; trimethoxyphenyl), 4,36-1,39 number m (25N; aliphatic Metin and methylene), 3,81 (6N; aromatic methoxy), 3,71 and of 3.69 (3H; aromatic methoxy).

Example 6: Range1H NMR (300 MHz, DMSO-D6): the 11.6-11,25 several Shir. with (proton piperidine), 8,64-8,44 the number m (2H; H - and H - pyridine), 7,82-7.22 number m (5H; H - and N - pyridine and dichlorophenyl), 6,85 and 6,79 (2N; trimethoxyphenyl), 4,05-2.00 number m (28N; aliphatic methylene), 3,82 (6N; aromatic methoxy), 3,71 and 3,68 (3H; aromatic methoxy).

Example 8: Range1H NMR (300 MHz, Dl3), two distinct conformer (approximately 1: 1, attributed to pyrrolidinium the amide rotamers); 7,44-7,15 the number m (7H; aromatic rotons), 7,11 and 6,98 DD (J=8,5 2 Hz; H-6 dichlorophenyl), of 6.71 and 6,70 (2N; trimethoxyphenyl), 4,12 kV (2H, J=7 Hz, methylene group of ethyl ether), a 4.03-1,70 is t (3H, J= 7 Hz, methyl group, ethyl ether).

Example 9: Range 1H NMR (300 MHz, Dl3): 7,43 and 7,38 Shire.d (J=8.5 Hz; H-5 dichlorophenyl), 7,31 and 7,15 Shire. with (N-2 dichlorophenyl), 7,25-6,92 the number m (6N; the protons of the phenyl and N-6 dichlorophenyl), of 6.71 and 6,69 Shire. (2H; trimethoxyphenyl), 4,15-1,80 number m (28N; aliphatic methylene), 3,88-3,84 line with (N; aromatic methoxy).

Example 10: Range1H NMR (300 MHz, Dl3): the 12.1-11.6 number of Shir.with (proton piperidine), 9,9-9.6 number of Shir.with (proton tetrazole), 8,05-7,10 number m (11N; aromatic protons), 4,30-2.10 number m (28N; aliphatic methylene), 4,20 and 4,18 kV (2H, J=7 Hz, methylene group of ethyl ether), 3,97 and 3,93 (3H; aromatic methoxy), 1,26 and 1,24 t (3H, J=7 Hz, methyl group, ethyl ether).

Example 14: Range1H NMR (300 MHz, Dl3), two distinct conformer (approx. 1: 1, attributed to pyrrolidinium rotamers); 7,43 and 7,38 d (J= 8.5 Hz; H-5 dichlorophenyl), 7,38-7.19 number m (6N; aromatic protons), 7,12 and 6,99 DD (J= 8,5, 2 Hz; H-6 dichlorophenyl), of 6.71 (2H; trimethoxyphenyl), 4,51-to 4.41 m (Proline N-), was 4.02-3,36 number m (N; aromatic methoxy, carbomethoxy and aliphatic methylene), 3.04 from-1,42 number m (20N; aliphatic methylene).

Example 15: Range1H NMR (300 MHz, CDCl3): 7,50-6.95 number m (8H; aromatic protons), 6,74-6,70 a number of Shire. with (2N;x2">

Example 21: Range of1H NMR (300 MHz, DCl3), multiple distinguishable conformers (referred to pyrrolidinium rotamers and piperidinium the conformers); 12,37 Shire.with (proton of trialkylamine), 7,50? 7.04 baby mortality the number m (8H; aromatic protons), 6,84 and 6.71 (approx. in relation to 60:40, 2H; trimethoxyphenyl), 4,45-0.85 number m (N; aliphatic Metin and methylene), 4,06 square (2H, J=7 Hz, methylene group of ethyl ether), 3,90 (6N; aromatic methoxy), of 3.84 (3H; aromatic methoxy), 1,19 t (3H, J= 7 Hz, methyl group, ethyl ether).

Example 23: Range19F NMR (300 MHz, CDCl3), two distinct conformer (approx. 70: 30, referred to pyrrolidinium rotamers or piperidinium the conformers); -135,6 and -135,9 m (approx. in relation to 30:70), -138,7 and -139,0 m (approx. in relation to 30:70).

Example 31: Range1H NMR (300 MHz, DMSO-D6): 7,60-7,08 a number m (8H; phenyl and dichlorophenyl), 6,76 and 6,74 Shire. with (2N; trimethoxyphenyl), 6,56 (approx. 3.5 N; protons fumarata, approx. of 1.75 mol.equiv.) 5,62 with (2N; methylendioxy), 4,12 square (2H, J=7 Hz, methylene group of ethyl ether), 3,85-1,60 a number m (N; aliphatic methylene), of 3.77 and 3.76 (6N; aromatic methoxy), the 3.65 (3H; aromatic methoxy), 3,17 (2N; dedicated methylene), 1,18 t (3H, J=7 Hz, methyl group, ethyl ether).

Example enil), 6,59 (approx. 3,7 N; protons fumarata, approx. of 1.85 mol.equiv.) the 5.65 (2H; methylendioxy), 3,90-1.70 number m (N; aliphatic methylene), 3,80, and of 3.78 (6N; aromatic methoxy), 3,68, with (3H; aromatic methoxy), and 3.16 (2H; dedicated methylene), 2.30 (2H, J=7 Hz, methylene group bateryjnego balance), 1,51 TCEs (2H, J=7, 7.5 Hz; methylene group bateryjnego balance), 0,85 kW (3H, J=7.5 Hz; methyl group bateryjnego balance).

With regard to Toxicological data for compounds of Example 8.3.1, LD50=800 mg/i.R., determined in accordance with the PROTOCOL TESTS ON ACUTE TOXICITY after intraperitoneal injection in mice.

METHODS: Male mice (groups of 4 animals) were administered increasing doses of the test compound by intraperitoneal injection. Used 3 standard dose: 10, 30 and 100 mg/kg of the General behavior of the animals was observed for 0.5 h immediately after the injection and noted changes in behavior. If the observed discrepancy observationsa and Autonomous effects had been recorded, for example, stimulation or suppression of spontaneous behavior, ataxia, loss of installation reflex; tremor; convulsions, and respiratory rate. The total observation period was 7 days, the deaths were registered.

For example,

The approximate value LD50= 30 mg/kg:

Dose - deaths

10 - 0/4

30 - 2/4

100 - 4/4

Example 36:

Pharmaceutical compositions based on compounds of this invention was prepared as follows:

Tablets: Connection example 37 was added to a thoroughly stirred mixture of starch, talc and magnesium oxide. The resulting mixture tabletirujut with reception of tablets of the following composition:

The connection 37 50 mg

Starch 40 mg

Talc 10 mg

Magnesium oxide 10 mg

Capsules: Connection example 37 was added to a thoroughly stirred mixture of starch, talc and carboxymethylcellulose. The mixture is filled capsules to obtain capsules of the following composition:

The connection 37 to 100 mg

Starch - 120 mg

Talc - 40 mg

Carboxymethylcellulose - 40 MGK

1. New carboxaldehyde cyclic carboxamide derivatives

< / BR>
where G1is CH2;

G2represents C(O);

m = 2 or 3;

n = 0 or 1;

R1is 1-3 substituent, each of which is independently selected from grupido of which is independently selected from the group consisting of hydrogen and C1-C6alkoxy;

R3represents hydrogen or a radical selected from the group consisting of

< / BR>
< / BR>
< / BR>
where R4means hydrogen,

AG1represents a radical selected from the group consisting of

< / BR>
< / BR>
where R8is 1-3 substituent, each of which is independently selected from the group consisting of hydrogen, halogen;

R9means hydrogen;

A represents a radical selected from the group consisting of

< / BR>
< / BR>
< / BR>
where p = 1, 2, 3 or 4;

X represents-O-, or-CH2-,

R10represents hydrogen, C1-C6alkyl or a radical selected from the group consisting of

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where q = 2 or 3;

R5is1-C4alkyl or -(CH2)2IT;

R6is1-C4alkyl, -(CH2)2HE or -(CH2)2N(CH3)2;

R'5is1-C4alkyl;

R'6is1-C4alkyl;

R7is1-C6alkyl;

and stereoisomers and pharmaceutically acceptable salts.

2. Connection on p. 1, where n = 0.

2represents-C(O)-.

5. Connection on p. 4, where a represents the radical

< / BR>
where p = 1;

R10selected from the group consisting of hydrogen and C1-C6the alkyl.

6. Connection on p. 5, where R10represents hydrogen.

7. Connection on p. 5, where R10represents ethyl.

8. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-(((R) or (S)-2-carboxypropyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

9. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-(((R)or (S)-2-carbomethoxyamino-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

10. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-pyrid-3-yl)-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

11. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-pyrid-3-yl)-4-((4-carboxymethyllysine-1-yl) carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

12. Link is)carboxamido)piperidine-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

13. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

14. Connection on p. 1, where the compound is (R )or (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

15. Connection on p. 1, where the compound is (R)- or (S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

16. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

17. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypeptidase-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

18. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carbene under item 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine and hydrochloric acid or mixtures thereof.

20. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and maleic acid or their mixture.

21. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine and fumaric acid or mixtures thereof.

22. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine and citric acid or mixtures thereof.

23. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine and methanesulfonic acid or mixtures thereof.

24. Connection on p. 1, where the compound is the Teal)-3-(3,4-dichlorophenyl) pyrrolidine and 2-hydroxyethanesulfonic acid or mixtures thereof.

25. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine and Hydrobromic acid, or their mixture.

26. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine and tartaric acid, or mixtures thereof.

27. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine and econsultancy acid or mixtures thereof.

28. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine and (1R)-(-)-10-camphorsulfonic acid or mixtures thereof.

29. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-differenl) pyrrolidines or mixtures thereof.

30. Connection on p. 1, where is oxamide)piperidine-1-yl)ethyl)-3-(3,4-differenl) pyrrolidine and hydrochloric acid or mixtures thereof.

31. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxymethyllysine-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-differenl)pyrrolidines or mixtures thereof.

32. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carbomethoxybiphenyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine or mixtures thereof.

33. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carbomethoxybiphenyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid or mixtures thereof.

34. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((2-carboxymethyl-4-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

35. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

36. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxen the s on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and hydrochloric acid or mixtures thereof.

38. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxyethylpyrrole-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

39. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxyethylpyrrole-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine and hydrochloric acid or mixtures thereof.

40. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

41. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carbomethoxybiphenyl-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine and fumaric acid or mixtures thereof.

42. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-CA their mix.

43. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypropylbetaine-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine or mixtures thereof.

44. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-carboxypropylbetaine-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl) pyrrolidine and hydrochloric acid or mixtures thereof.

45. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(ethoxycarbonylmethoxy)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

46. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(ethoxycarbonylmethoxy)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid or mixtures thereof.

47. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(t-BUTYLCARBAMATE)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

48. Connection on p. 1, where sedimentary-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid or mixtures thereof.

49. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(N, N-diethylcarbamoyl)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

50. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(N, N-diethylcarbamoyl)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid or mixtures thereof.

51. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(methylcarbonate)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

52. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(methylcarbonate)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid or mixtures thereof.

53. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(profilereminder.exe)methylpiperazin-1-yl)carboxamido)piperidine)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

55. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(N,N-di-(2-hydroxyethyl)carboxamidates)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

56. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(N, N-di-(2-hydroxyethyl)carboxamidates)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid or mixtures thereof.

57. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(N-methyl-N-(2-dimethylaminoethyl)carboxamidates)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine or mixtures thereof.

58. Connection on p. 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(N-methyl-N-(2-dimethylaminoethyl)carboxamidates)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid or mixtures thereof.

59. Connection on p. 1, where the compound is (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(5-methyl-2-oxo-1,3-dioxol-4-ylethoxy)methylpentene under item 1, where the compound is a salt of (R)- or (S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-phenyl-4-((4-Carbo(5-methyl-2-oxo-1,3-dioxol-4-ylethoxy)methylpiperazin-1-yl)carboxamido)piperidine-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine and fumaric acid or mixtures thereof.

61. The pharmaceutical composition exhibiting antagonistic activity against receptors NK1 and NK2, including a connection on p. 1 as an active ingredient, and a pharmaceutically acceptable carrier.

62. The method of suppressing the activity of receptors NK1 and NK2 in the treatment of diseases selected from asthma, cough and bronchitis, characterized in that it includes an introduction to the needy in this patient an effective amount of the compounds under item 1.

63. The method according to p. 62, wherein the disease is asthma.

64. The method according to p. 62, wherein the disease is coughing and/or bronchitis.

65. Connection on p. 1 as an active ingredient of the medicinal product, indicated for conditions requiring suppression of the activity of receptors NK1 and NK2.

66. Connection on p. 65, where the specified condition is asthma.

67. Connection on p. 65, where the specified condition is coughing.

68. The
< / BR>
where G1is CH2;

G2represents C(O);

m = 2 or 3;

n = 0 or 1;

R1is 1-3 substituent, each of which is independently selected from the group consisting of hydrogen, halogen and C1-C6alkoxy;

R2is 1-3 substituent, each of which is independently selected from the group consisting of hydrogen, and C1-C6alkoxy;

R3represents hydrogen or a radical selected from the group consisting of

< / BR>
< / BR>
< / BR>
where R4means hydrogen,

AG1represents a radical selected from the group consisting of

< / BR>
< / BR>
where R8is 1-3 substituent, each of which is independently selected from the group consisting of hydrogen, halogen;

R9means hydrogen;

A represents a radical selected from the group consisting of

< / BR>
< / BR>
< / BR>
where p = 1, 2, 3 or 4;

X represents-O-, or-CH2-,

R10represents hydrogen, C1-C6alkyl or a radical selected from the group consisting of

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where q = 2 or 3;

R5is1-C4alkyl or -(CH2)2IT;

R6is dstanley1-C4alkyl;

R'6is1-C4alkyl;

R7is1-C6alkyl;

and stereoisomers and pharmaceutically acceptable salts, characterized in that it includes the interaction of the compounds of formula

< / BR>
where m, n, G1, G2, R1, R2and R3such as described above;

L1is the deleted group selected from the group consisting of chlorine, bromine, iodine, nelfinavir and tosilata,

with the compound of the formula

< / BR>
where AG1such as described above;

A' is A, as required for the final product of formula (1) and the optional formation of a pharmaceutically suitable salt.

Priority points:

17.11.1997 - under item 1 of part R10hydrogen or C1-C6alkyl and PP.34-59;

19.12.1996 - p. 1 except R10hydrogen or C1-C6alkyl and PP.2-33, 60-69.

 

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The invention relates to new isoxazol derivative of formula 1, where D represents hydrogen; one of a and b is a group (1) -E-N= C(NR25R26)NR27R28; E represents a direct link or alkilinity group; R25and R26each represents, independently, hydrogen; C1-4-alkyl; -(CH2)n-CO2R32, n is an integer of 1-3, and R32represents hydrogen, C1-4-alkyl; -(CH2)m-CO2R35m is 2 or 3 and R35represents hydrogen, C1-4-alkyl; -(CH2)mHE, m defined above, or -(CH2)n-C(O)R36n is defined above and R3represents hydrogen, C1-4-alkyl; and t

The invention relates to new derivatives of oxazolidinones General formula I, where R' denotes H, CN, Hal, or OA; R2, R3each independently of one another denotes H, CN, Hal, or2and R3together form methylenedioxy; And denotes alkyl with 1-6 C-atoms; Hal denotes F, Cl, Br, J; as well as their enantiomers and physiologically acceptable salts

The invention relates to new derivatives of kalaidjieva, fungicides, method of combating fungal diseases of crops and intermediate compounds for obtaining

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts

The invention relates to 1,4-disubstituted the piperazines of General formula I, the method of production thereof, containing compositions and their use for the clinical treatment of painful conditions, increased pain sensitivity and/or inflammatory conditions in which the pathophysiological role of C-fibers, causing neurogenic pain or inflammation

The invention relates to new derivatives of spirobiindane General formula (I), where R1represents a phenyl group which may be optionally substituted by 1-3 substituents selected from halogen atoms, lower alkyl groups, halogenized alkyl groups, lower alkoxygroup, lower alkoxycarbonyl groups, hydroxyl groups, lower aliphatic acylamino, cyano groups, or a 5 - or 6-membered heterocyclic group containing 1-3 oxygen atom, sulfur and/or nitrogen, which may be optionally condensed with a phenyl group; R2represents a phenyl group which is substituted by 1-3 fluorine atoms or chlorine; a represents a carbonyl group; represents a simple bond; D represents an oxygen atom or sulfur; E represents C1-4Allenova group;represents a group of formula (II), where G represents C5-8alonovoa ring, which is substituted by hydroxyl group; Ar represents a phenyl ring; n represents the integer 1 or 2, or a pharmacologically acceptable salt

The invention relates to new imidazole derivative of General formula (1), where n1is an integer from 1 to 3, a represents hydrogen, linear or branched C1-C10-alkyl, which may be optionally substituted C3-C7-cycloalkyl or lower alkoxy, or a radical selected from the group shown in the formula of the invention, Y represents a radical selected from the group described in the claims, or to his new pharmaceutically acceptable salts

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< / BR>
where R10- H or C(O)N(R1)YZ, R1- N, Y - (CH2)p, (CH2)qCH(R3) or CH(R3)(CH2)q, R3- aryl, aralkyl or heteroaryl, q = 1-3, p = 2 or 3, Z - CO2H, CO2-alkyl or 5-tetrazol, X-S(O) M-(CH2)nor piperidine-1-yl, m = 2, n = 2, R5Mr. And selected from piperidine-2-yl, piperidine-3-yl, piperidine-4-yl or N-substituted piperidine

The invention relates to new imidazole derivative of General formula (1), where n1is an integer from 1 to 3, a represents hydrogen, linear or branched C1-C10-alkyl, which may be optionally substituted C3-C7-cycloalkyl or lower alkoxy, or a radical selected from the group shown in the formula of the invention, Y represents a radical selected from the group described in the claims, or to his new pharmaceutically acceptable salts

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