Biphenyl derivatives

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

 

Description

Background of invention

The technical field to which the invention relates.

The present invention relates to new derivatives of biphenyl, useful for the treatment of lung diseases. This invention relates also to pharmaceutical compositions containing these derivatives of biphenyl, methods and intermediate compounds for obtaining such derivatives of biphenyl and to methods of using these derivatives of biphenyl for the treatment of lung diseases.

The state of the art

Lung diseases such as asthma and chronic obstructive pulmonary disease (COPD; COPD), usually treated with bronchodilators means. One class of commonly used bronchodilators consists of agonists β2-adrenergic receptors (adrenoceptors), such as albuterol, formoterol and salmeterol. These compounds are usually administered by inhalation. Another class bronchodilators consists of antagonists of muscarinic receptors (anticholinergic compounds)such as ipratropium and Tiotropium. These compounds are usually administered by inhalation.

Known also used to treat lung diseases, pharmaceutical compositions containing as an agonist β2-adrenergic receptors, and antagonist of muscarinic receptors. For example, in the tent of the U.S. No. 6433027 disclosed pharmaceutical compositions containing antagonist of muscarinic receptors, such as Tiotropium bromide, and agonist β2-adrenergic receptors, such as fumarate formoterol.

Compounds with activity or agonist β2-adrenergic receptor or an antagonist of muscarinic receptors, known, but not yet disclosed the compounds having activity as agonist β2-adrenergic receptors and an antagonist of muscarinic receptors. Compounds with activity and agonist β2-adrenergic receptors, and antagonist of muscarinic receptors, are highly desirable because such bifunctional compounds would bronchodilatory effect of two independent paths with the pharmacokinetics of a single molecule.

Brief description of the invention

In accordance with the present invention offers a new biphenyl derivatives useful for the treatment of lung diseases. Among other properties, compounds of the present invention have found that activity as agonist β2-adrenergic receptors and an antagonist of muscarinic receptors.

Thus, in one of its aspects the connection structure, the present invention relates to a compound of the formula I:

where:

and p is ecstasy a 0 or an integer from 1 to 3;

each R1independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)quinil, (3-6C)cycloalkyl, cyano, halogen, -OR1a, -C(O)OR1b, -SR1c, -S(O)R1d, -S(O)2R1eand-NR1fR1g;

each of R1a, R1b, R1c, R1d, R1e, R1fand R1gindependently represents hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl;

b represents 0 or an integer from 1 to 3;

each R2independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)quinil, (3-6C)cycloalkyl, cyano, halogen, -OR2a, -C(O)OR2b, -SR2c, -S(O)R2d, -S(O)2R2eand-NR2fR2g;

each of R2a, R2b, R2c, R2d, R2e, R2fand R2gindependently represents hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl;

W is attached at position 3 or 4 in piperidinium ring and represents O or NWa;

Warepresents hydrogen or (1-4C)alkyl;

c represents 0 or an integer from 1 to 4;

each R3independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)quinil, (3-6C)cycloalkyl, cyano, halogen, -OR3a, -C(O)OR3b, -SR3c, -S(O)R3d, -S(O)2R3eand-NR3fR3g; or two groups R3together with the formation of (1-3C)alkylene, (2-3C)Alcanena or oxiran-2,3-deila;

each of R3a, R3b, R3c, R3d , R3e, R3fand R3gindependently represents hydrogen or (1-4C)alkyl;

R4represents a divalent group of the formula:

-(R4A)d(And1)e-(R4b)f-Q-(R4c)g(A2)h-(R4d)i-

where

d, e, f, g, h and i each independently selected from 0 and 1;

R4a, R4b, R4cand R4deach independently selected from (1-10C)alkylene, (2-10C)Alcanena and (2-10C)akinlana, where each Allenova, Alcanena or akinlana group is unsubstituted or substituted by 1-5 substituents independently selected from (1-4C)alkyl, fluorine, hydroxy, phenyl and phenyl-(1-4C)alkyl;

A1and A2each independently selected from (3-7C)cycloalkyl, (6-10)arylene, -O-(6-10C)arylene, (6-10C)Allen-O-, (2-9C)heteroaryl, -O-(2-9C)heteroaryl, (2-9C)heteroaryl-O - and (3-6C)heterocycle, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl, and each Allenova, heteroarenes or heterostropha group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, -S-(1-4C)alkyl, -S(O)-(1-4C)alkyl, -S(O)2-(1-4C)alkyl, -C(O)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifloromethyl, triptoreline;

Q is selected from-O-, -C(O)O-, -OC(O)-, -S-, -S(O)-, -S(O)2-, -N(Qab)-, -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)-, -N(Qg)S(O)2N(Qh)-, -OC(O)N(Qi)-, -N(Qj)C(O)O - and-N(Qk);

Qa, Qb, Qwith, Qd, Qe, Qf, Qg, Qh, Qi, Qjand Qkeach independently selected from hydrogen, (1-6C)alkyl, A3and (1-4C)alkylene-A4where an alkyl group is unsubstituted or substituted by 1-3 substituents, independently selected from fluorine, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R4bor R4Sto which they are attached, form a 4-6-membered azacycloheptane group;

A3and A4each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl and (1-4C)alkoxy;

provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms, which are attached to R4is in the range from 4 to 16;

R5represents hydrogen or (1-4C)alkyl;

R6represents-NR6aCR6b(O) or-CR6sR6dOR6eThe R 7represents hydrogen; or R6and R7together form-NR7aC(O)-CR7b=CR7c-, -CR7d=CR7e-C(O)-NR7f-, -NR7gC(O)-CR7hR7i-CR7jR7kor CR7lR7m-CR7nRO-C(O)-NR7p-;

each of R6a, R6b, R6c, R6dand R6eindependently represents hydrogen or (1-4C)alkyl; and

each of R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R7l, R7m, R7n, R7oand R7pindependently represents hydrogen or (1-4C)alkyl;

or its pharmaceutically acceptable salt, MES or stereoisomer.

In another aspect, related to the connection structure, the present invention relates to the compound of formula II:

where

R4is such as defined in this specification (including any specific or preferred options);

W represents O or NH;

or its pharmaceutically acceptable salt, MES or stereoisomer.

In the following aspect related to the connection structure, the present invention relates to the compound of formula III:

where

R4is such as defined in this specification (including any specific or PR is doctitle options);

W represents O or NH;

or its pharmaceutically acceptable salt, MES or stereoisomer.

In yet another aspect, related to the connection structure, the present invention relates to the compound of formula IV:

where

R4is such as defined in this specification (including any specific or preferred options);

W represents O or NH;

or its pharmaceutically acceptable salt, MES or stereoisomer.

In one aspect, related to the connection structure, the present invention relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt, MES or stereoisomer. These pharmaceutical compositions may, although not necessarily, contain other drugs. Thus, in one embodiment, the present invention relates to a pharmaceutical composition, which further comprises a therapeutically effective amount of a steroid anti-inflammatory drugs, such as a corticosteroid.

Compounds of the present invention possess both agonist activity β2-adrenergic receptors, and antagonist activity m skarynovich receptors. Therefore, the compounds of formula I are useful for the treatment of pulmonary diseases such as asthma and chronic obstructive pulmonary disease.

So, in one of the aspects of the method, the present invention relates to a method of treating a pulmonary disease comprising the administration to a patient in need of such treatment, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt, MES or stereoisomer.

In addition, other aspects of the method, the present invention relates to a method of ensuring the expansion of the bronchial lumen, comprising the administration to a patient in need of the extension of the lumen of the bronchi, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt, MES or stereoisomer.

The present invention relates also to a method of treating chronic obstructive pulmonary disease or asthma, comprising the administration to a patient in need of such treatment, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt, MES or stereoisomer.

Since the compounds of the present invention possess both agonist activity β2-adrenergic receptors and the activity of the antagonist of muscarinic receptors, such connection p is Lesny also as a research tool. Therefore, in the following of the aspects of the method, the present invention relates to a method of applying the compounds of formula I or its pharmaceutically acceptable salt, MES or stereoisomer as a research tool for studying a biological system or sample, or for discovering new chemical compounds which the activity of the agonist β2-adrenergic receptors, and antagonist activity of muscarinic receptors.

The present invention relates also to methods and new intermediate compounds useful for preparing compounds of the formula I or their pharmaceutically acceptable salts, MES or stereoisomer. So, in other related method aspects of the present invention relates to a method for obtaining compounds of formula I, including:

(a) coordination compounds of the formula1or its salt with the compound of the formula2;

(b) coordination compounds of the formula3or its salt with the compound of the formula4;

(C) binding of the compounds of formula5with the compound of the formula6;

(d) for compounds of formula I, where R5represents a hydrogen atom, the coordination compounds of the formula3with the compound of the formula7or its hydrate in risotti reductant;

(e) coordination compounds of the formula1with the compound of the formula8or its hydrate in the presence of a reducing agent;

(f) coordination compounds of the formula9with the compound of the formula10; or

(g) coordination compounds of the formula11or its hydrate with the compound of the formula10in the presence of a reducing agent;

and then remove any of the protective groups with the formation of the compounds of formula I;

moreover, compounds of the formula1-11are as defined in this specification.

In one embodiment, the method additionally includes the stage of formation of pharmaceutically acceptable salts of the compounds of formula I. In other embodiments, the present invention relates to methods described herein, and to the products obtained by any of the methods described above.

The present invention relates also to the compound of formula I or its pharmaceutically acceptable salt, MES or stereoisomer for use in therapy or as a medicine.

In addition, the present invention relates to the use of compounds of formula I or its pharmaceutically acceptable salt, MES or stereoisomer for the manufacture of the drug, in particular for the manufacture of a drug for L. the treatment of lung disease.

Detailed description of the invention

One of the aspects relating to the structure, the present invention relates to novel biphenyl derivative of the formula I or their pharmaceutically acceptable salts, solvate or stereoisomer. These compounds contain one or more chiral centers, and, therefore, the present invention relates to racemic mixtures, pure stereoisomers (enantiomers or diastereomers), enriched by the stereoisomers, the mixtures and the like, unless otherwise indicated. When this description is shown or named specific stereoisomer, specialists in this field will be clear that the structures of the present invention may be present minor amounts of other stereoisomers, unless otherwise stated, provided that the presence of other isomers does not exclude the usefulness of patterns in General.

In particular, the compounds of formula I contain a chiral center at the carbon atom indicated by the symbol * in the following formula:

In one of the embodiments of the present invention, the carbon atom indicated by the symbol *has the (R) configuration. In this embodiment it is preferred that the compounds of formula I have (R) configuration at the carbon atom marked with *, or were enriched CTE is eaitern form, with (Rconfiguration at this carbon atom. In another embodiment of the present invention, the carbon atom indicated by the symbol *has the (S) configuration. In this embodiment it is preferred that the compounds of formula I have (S) configuration at the carbon atom marked with *, or were enriched stereoisomeric form having the (Sconfiguration at this carbon atom. In some cases, to optimize β2-adrenergic agonistic activity of the compounds of the present invention, it is preferable that the carbon atom marked with *, had (Rconfiguration.

The compounds of formula I contain several coreómain groups (e.g. amino groups) and therefore the compounds of formula I can exist in the form of free base or in the form of various salts. All such salt forms are included in the scope of the present invention. In addition, the scope of the present invention included a solvate of the compounds of the formula I or their salts.

In addition, where appropriate, the scope of the present invention is enabled, unless otherwise noted, allCIS-TRANSorE/Zisomers (geometric isomers), tautomeric forms and topoisomerase form compounds of formula I.

Nomenclature names of the compounds of the present invention and their intermediate with the joining was, typically created using commercially available software AutoNom software (MDL, San Leandro, California). Usually the compounds of formula I, where W represents O, called as ester derivatives of biphenyl-2-ylcarbamate acid, and the compounds of formula I, where W is a NWand, was named as a derivative of urea.

Typical options

The following placeholders and values are given as typical examples of various aspects and variations of the present invention. These typical values are given to further define and illustrate these aspects and options, and does not imply exclusion of other options or limit the scope of the present invention. In this regard, the indication that a particular value or a particular Deputy is preferred, in no way implies the exclusion of other values, or Vice of the present invention, if it is not mentioned explicitly.

In certain embodiments of compounds of formula I, a and b independently represent 0, 1 or 2, including 0 or 1. In one embodiment, both a and b equal to 0.

In the presence of each R1may be in position 2, 3, 4, 5 or 6 of the phenyl ring to which it is attached. In one embodiment, each R1independently selected from (1-4C)alkyl, halogen is, -OR1aand-NR1fR1gsuch as methyl, fluorine, chlorine, bromine, hydroxy, methoxy, amino, methylamino, dimethylamino and the like. Special values for R1are fluorine or chlorine.

In the presence of each R2may be in position 3, 4, 5 or 6 in venelinova the ring to which it is attached (when the carbon atom in venelinova ring attached to the nitrogen atom, is in position 1). In one embodiment, each R2independently selected from (1-4C)alkyl, halogen, -OR2aand-NR2fR2gsuch as methyl, fluorine, chlorine, bromine, hydroxy, methoxy, amino, methylamino, dimethylamino and the like. Special values for R2are fluorine or chlorine.

Each R1a, R1b, R1c, R1d, R1e, R1fand R1gand R2a, R2b, R2c, R2d, R2e, R2fand R2gwhen used in R1and R2accordingly, independently represents hydrogen, (1-4C)alkyl or phenyl-(1-4C)alkyl, such as hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl or benzyl. In one embodiment, these groups independently represent hydrogen or (1-3C)alkyl. In another embodiment, these groups independently represent hydrogen, methyl or ethyl.

In one embodiment of the present invention, W represents O. the another embodiment, W is a NW and.

Usually, it has been found that compounds in which W represents O, show a particularly high affinity in relation to muscarinic and β2-adrenergic receptors. Therefore, in a particular embodiment of the present invention preferably W represents O.

Respect to W can be made special mention of the compounds in which W is attached to piperidinium ring in position 4 relative to the nitrogen atom piperidino rings.

When W represents a NWand, Wandrepresents hydrogen or (1-4C)alkyl, such as hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In one embodiment, Wandrepresents hydrogen or (1-3C)alkyl. In another embodiment, Wandrepresents hydrogen, methyl or ethyl, in particular hydrogen or ethyl. In yet another embodiment, Wandrepresents hydrogen, and NWandrepresents NH.

In a particular embodiment, compounds of formula I represents 0, 1 or 2, including 0 or 1. In one embodiment, C is 0.

In one embodiment, each R3is in position 3, 4 or 5 in piperidinium ring (when the nitrogen atom piperidino ring is in position 1). In another embodiment, R3is in position 4 in piperidinium ring. In a particular aspect of these is the option each R 3independently selected from (1-4C)alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In another aspect, each R3independently represents methyl or ethyl.

In another embodiment, R3is in position 1 piperidino ring, i.e. the nitrogen atom piperidino rings forming a salt of the Quaternary amine. In the particular case of this variant, each R3independently selected from (1-4C)alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In another case, each R3independently represents methyl or ethyl.

In yet another embodiment, two groups of R3are connected to each other to form (1-3C)alkalinous or (2-3C)alkenylamine group. For example, two groups of R3in positions 2 and 6 piperidino rings can be connected with the formation of the ethylene bridge of communication (i.e. piperidine ring group and R3form 8-azabicyclo[3.2.1]octane ring) or two groups R3in positions 1 and 4 piperidino rings can be connected with the formation of the ethylene bridge of communication (i.e. piperidine ring group and R3form 1-azabicyclo[2.2.2]octane ring). In the present embodiment can be also represented other groups R3defined in this specification.

In yet another variant DV is the group R 3connected to each other with the formation of oxiran-2,3-deeley group. For example, two groups of R3in positions 2 and 6 piperidino rings can be joined to form a 3-ocatillo[3.3.1.02,4]nonanalog rings. In the present embodiment can be also represented other groups R3defined in this specification.

Each R3a, R3b, R3c, R3d, R3e, R3fand R3gwhen used in R3independently represents hydrogen or (1-4C)alkyl, such as hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In one embodiment, these groups independently represent hydrogen or (1-3C)alkyl. In another embodiment, these groups independently represent hydrogen, methyl or ethyl.

In one embodiment, compounds of the formula I R5represents hydrogen or (1-4C)alkyl, such as hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In another embodiment, each R5independently represents hydrogen, methyl or ethyl. In the private version of R5represents hydrogen.

In one embodiment of the present invention R6represents-NR6aCR6b(O) and R7represents hydrogen, where each of R6Aand R6bindependently represents vodor the d or (1-4C)alkyl, such as hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In one embodiment, these groups independently represent hydrogen or (1-3C)alkyl. In another embodiment, these groups independently represent hydrogen, methyl or ethyl. Private value for R6in this case is-NHCHO.

In another embodiment, R6and R7together form-NR7aC(O)-CR7b=CR7c-, -CR7d=CR7e-C(O)-NR7f-, -NR7gC(O)-CR7hR7i-CR7jR7kor CR7lR7m-CR7nRO-C(O)-NR7p-, where each R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R7l, R7m, R7n, R7oand R7pindependently represents hydrogen or (1-4C)alkyl, such as hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In one embodiment, these groups independently represent hydrogen or (1-3C)alkyl. In another embodiment, these groups independently represent hydrogen, methyl or ethyl. Private values for R6and R7in this variant are the cases when R6and R7together form-NHC(O)-CH=CH-, -CH=CH-C(O)-NH-, -CH2-CH2-C(O)NH - or-NHC(O)-CH2-CH2is, including cases where R6and R7together education is comfort-NHC(O)-CH=CH - or-CH=CH-C(O)-NH -, and in particular, when R6and R7together form-NHC(O)-CH=CH- (i.e., the nitrogen atom is attached at R6and the carbon atom is attached at R7with education together with hydroxyproline ring to which R6and R7attached, 8-hydroxy-2-oxo-1,2-dihydroquinoline-5-ilen group).

In the compounds of the formula I R4represents a divalent group of the formula:

-(R4A)d(And1)e-(R4b)f-Q-(R4c)g(A2)h-(R4d)i-,

where R4aAnd1, R4b, Q, R4c, A2, R4d, d, e, f, g, h and i are as defined herein, the values of each of the components R4aAnd1, R4b, Q, R4c, A2and R4dchosen so that the number of contiguous atoms in the shortest chain between the two nitrogen atoms, which are attached to R4is in the range from 4 to 16 (in particular, as well 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16), including 8, 9, 10, 11, 12, 13 or 14, such as 8, 9, 10, or 11, or 9, or 10. Specialists in this field will be clear that the choice of values for each variable in R4values must be selected so that the formed chemically stable group.

When determining the number of contiguous atoms in the shortest chain between the two nitrogen atoms, which are attached to R4each interconnecting the atom chain is considered sequentially, starting from the first atom in the group R4adjacent to the nitrogen atom piperidino rings, and ending with the last atom in the group R4adjacent to the nitrogen atom aminohydroxylation group. When there are two or more circuits, for determining the number of contiguous atoms using the short circuit. As shown below, for example, when R4represents -(CH2)2-NHC(O)-CH2-hair-dryer-1,4-ilen)-CH2-has 10 contiguous atoms in the shortest chain counted consecutively starting from the first atom in the group R4adjacent to the nitrogen atom piperidino rings, and ending with the last atom in the group R4adjacent to the nitrogen atom aminohydroxylation groups:

In one embodiment, R4the group R4Aselected from (1-10C)alkylene, (2-10C)Alcanena and (2-10C)akinlana where Allenova group is unsubstituted or substituted by 1 or 2 substituents, independently selected from (1-4C)alkyl, hydroxy and phenyl. Typical examples of private values for R4Aare -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9-, -(CH2)10-, -(CH2)CH(CH3)-, -(CH2)C(CH3)2- and -(CH2)2C(phenyl)2-. the other aspect of R 4Arepresents -(CH2) (=CH2)-.

In one embodiment, d is 1.

In one embodiment, And1represents an optionally substituted (3-7C)cycloalkenyl group, including cyclohexylamino group, such as cyclohex-1,4-ilen and cyclohex-1,3-ilen, and cyclopentenone group, such as cyclopent-1,3-safe.

In another embodiment, And1represents an optionally substituted (6-10C)Allenova group, including fenelonov group, such as a dryer-1,4-ilen, Hairdryer-1,3-safe and Hairdryer-1,2-ilen, and Neftyanoy group, such as naphthas-1,4-ilen and naphthas-1,5-safe.

In yet another embodiment, And1represents an optionally substituted (2-9C)heteroarenes group, including piridinovy group, such as pyrid-1,4-ilen, Torrenova group, such as FSD-2,5-ilen and fours-2,4-ilen, thienylene group, such as Tien-2,5-ilen and Tien-2,4-ilen, and pyrrolidino group, such as pyrrol-2,5-ilen and pyrrole-2,4-safe.

In one embodiment, And1represents an optionally substituted (3-6C)heterocycle group, including piperidinyloxy group, such as a piperidine-1,4-ilen, and pyrrolidinium group, such as pyrrolidin-2,5-safe.

In the private version And1represents optionally substituted phenylene, tienlen, cyclopentyl, cyclohexyl or piperidinyl.

In one variant of the E. 0.

In the private version of R4brepresents a (1-5C)alkylene. Typical examples of private values for R4bare-CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-including methylene, ethylene and propylene.

In one embodiment, f is 0.

In the private embodiment, Q is selected from-N(Qa)C(O)-, -C(O)N(Qb)-, -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)-, -OC(O)N(Qi)-, -N(Qj)C(O)O -, or-N(Qk) and represents, for example, a bond, -N(Qa)C(O)- or-C(O)N(Qb)-. Typical examples of private values for Q is a bond, O, NH, -C(O)NH-, -C(O)N(CH3)-, -NHC(O)-, -N(CH3)C(O)-, -S(O)2NH-, -S(O)2N(CH3)-, -NHS(O)2-, -N(CH3)S(O)2- , and-NHC(O)NH-. Another example values for Q, with R4Srepresents-C(O)(piperidine-1,4-ilen).

In one embodiment, Qa, Qb, Qwith, Qd, Qe, Qf, Qg, Qh, Qi, Qjand Qkeach independently selected from hydrogen and (1-6C)alkyl, where the alkyl group is unsubstituted or substituted by 1-3 substituents, independently selected from fluorine, hydroxy and (1-4C)alkoxy. For example, Qa, Qb, Qwith, Qd, Qe, Qf, Qg, Qh, Qi, Qjand Qkeach independently selected from hydrogen and (1-3C)alkyl, including bodoro is, methyl, ethyl, n-propyl and isopropyl. Example values for each of Qa, Qb, Qwith, Qd, Qe, Qf, Qg, Qh, Qi, Qjand Qkis hydrogen.

In another embodiment, Qa, Qb, Qwith, Qd, Qe, Qf, Qg, Qh, Qi, Qjand Qktogether with the nitrogen atom and the group R4bor R4Sto which they are attached, form a 4-6-membered azacycloheptane group. For example, Qaand Qbtogether with the nitrogen atom and the group R4bor R4Sto which they are attached, form a piperidine-4-Elenovo group. For illustration, you can specify that when Q represents-N(Qa)C(O)- and Qatogether with the nitrogen atom and the group R4bto which it is attached, forms a piperidine-4-Elenovo group, R4represents a group of the formula:

Similarly, when Q represents-C(O)N(Qb)and Qbtogether with the nitrogen atom and the group R4Sto which it is attached, forms a piperidine-4-Elenovo group, R4represents a group of the formula:

In the private version of R4Srepresents a (1-5C)alkylene. Typical examples of private values for R4Sare-CH2-, -(CH2)2-, -(CH2)3- -(CH 2)4-, -(CH2)5-including methylene, ethylene and propylene.

In one embodiment, A2represents an optionally substituted (3-7C)cycloalkenyl group, including cyclohexylamino group, such as cyclohex-1,4-ilen and cyclohex-1,3-ilen, and cyclopentenone group, such as cyclopent-1,3-safe.

In another embodiment, A2represents an optionally substituted (6-10C)Allenova group, including fenelonov group, such as a dryer-1,4-ilen, Hairdryer-1,3-safe and Hairdryer-1,2-ilen, and Neftyanoy group, such as naphthas-1,4-ilen and naphthas-1,5-safe.

In yet another embodiment, A2represents an optionally substituted (2-9C)heteroarenes group, including piridinovy group, such as pyrid-1,4-ilen, Torrenova group, such as FSD-2,5-ilen and fours-2,4-ilen, thienylene group, such as Tien-2,5-ilen and Tien-2,4-ilen, and pyrroline, such as pyrrol-2,5-ilen and pyrrole-2,4-safe.

In yet another embodiment, A2represents an optionally substituted (3-6C)heterocycle group, including piperidinyloxy group, such as a piperidine-1,4-ilen, and pyrrolidinium group, such as pyrrolidin-2,5-safe.

In the private version of the A2represents optionally substituted phenylene, tienlen, cyclopentyl, cyclohexyl or piperidinyl.

For illustration, you can specify that A1or A2 or both may represent a phenylene, such as fen-1,4-ilen or Hairdryer-1,3-ilen, where fenelonov group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, -S-(1-4C)alkyl, -S(O)-(1-4C)alkyl, -S(O)2-(1-4C)alkyl, -C(O)O(1-4C)alkyl, carboxy, cyano, hydroxy, nitro, trifloromethyl, triptoreline. Typical examples include Hairdryer-1,3-ilen, Hairdryer-1,4-ilen, 4-chlorphen-1,3-ilen, 6-chlorphen-1,3-ilen, 4-methylphen-1,3-ilen, 2-torpen-1,4-ilen, 2-chlorphen-1,4-ilen, 2-bromphen-1,4-ilen, 2-itfan-1,4-ilen, 2-methylphen-1,4-ilen, 2-methoxide-1,4-ilen, 2-triptorelin-1,4-ilen, 3-nitrogen-1,4-ilen, 3-chlorphen-1,4-ilen, 2,5-deltorphin-1,4-ilen, 2,6-dichlorophen-1,4-ilen, 2,6-dioden-1,4-ilen, 2-chloro-6-methylphen-1,4-ilen, 2-chloro-5-methoxide-1,4-ilen, 2,3,5,6-tetraterpene-1,4-safe.

Alternatively, A1or A2or both could constitute cyclopentyl or cyclohexyl, and Cyclopentanone or cyclohexylurea group is unsubstituted or substituted (1-4C)alkyl. Typical examples include theCIS-cyclopent-1,3-ilen, " TRANS-cyclopent-1,3-ilen, " CIS-cyclohex-1,4-ilenTRANS-cyclohex-1,4-ilen. A1or A2or both can also be an optionally substituted teenren or piperidinyl, for example Tien-2,5-ilen, or piperidine-1,4-safe.

In one embodiment, R4dselected from 1-10C)alkylene, (2-10C)Alcanena and (2-10C)akinlana where alkylene is unsubstituted or substituted by 1 or 2 substituents, independently selected from (1-4C)alkyl, hydroxy and phenyl. Typical examples of private values for R4dare -(CH2)-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7, -(CH2)8-, -(CH2)9-, -(CH2)10- and -(CH2)CH(CH3)-(CH2)-C(CH3)2-(CH2)2-.

In the private version of R4represents a divalent group of the formula -(R4A)d-where R4arepresents (4-10C)alkylene. In one aspect of this option, R4represents a divalent group of the formula -(CH2)j-where j is 8, 9 or 10. Examples of private values for R4in this option are -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)9and -(CH2)10-including -(CH2)8-, -(CH2)9and -(CH2)10-.

In another private embodiment, R4represents a divalent group of the formula:

-(R4A)d(A2)h-(R4d)i-,

where R4arepresents a (1-10C)alkylene, such as -(CH2), -(CH2)2-, -(CH2)3-, A2you submitted the a (6-10C)Allen, such as hair dryer-1,4-ilen or Hairdryer-1,3-ilen, or (2-9C)heteroaryl, such as Tien-2,5-ilen or Tien-2,4-ilen, and R4drepresents a (1-10C)alkylene, such as -(CH2)-, -(CH2)2-, -(CH2)3-. Examples of private values for R4in this option are

-(CH2)-(fen-1,4-ilen)-(CH2)-, -(CH2)-(fen-1,4-ilen)-(CH2)2-,

-(CH2)-(fen-1,4-ilen)-(CH2)3-, -(CH2)2-hair-dryer-1,4-ilen)-(CH2)3,

-(CH2)2-hair-dryer-1,4-ilen)-(CH2)2-, -(CH2)2-hair-dryer-1,4-ilen)-(CH2)5,

-(CH2)3-hair-dryer-1,4-ilen)-(CH2)-, -(CH2)3-hair-dryer-1,4-ilen)-(CH2)2-,

-(CH2)3-hair-dryer-1,4-ilen)-(CH2)3-, -(CH2)4-hair-dryer-1,4-ilen)-(CH2)-,

-(CH2)4-hair-dryer-1,4-ilen)-(CH2)2- and -(CH2)4-hair-dryer-1,4-ilen)-(CH2)3-.

In yet another private embodiment, R4represents a divalent group of the formula:

-(R4A)d-Q-(A2)h-(R4d)i-,

where Q represents-O - or-N(Qk)-, Qkrepresents hydrogen or (1-3C)alkyl, such as methyl or ethyl, R4arepresents a (1-10C)alkylene, such as -(CH2)-, -(CH2)2-, -(CH2)3-, A2is a (6-10C)arisen, such as fen-1,4-ilen or Hairdryer-1,3-ilen, or (2-9C)Goethe is oallen, such as Tien-2,5-ilen or Tien-2,4-ilen, and R4drepresents a (1-10C)alkylene, such as -(CH2)-, -(CH2)2-, -(CH2)3-. Examples of private values for R4in this option are

-(CH2)2-O-(fen-1,4-ilen)-(CH2)-, -(CH2)2-O-(fen-1,4-ilen)-(CH2)2-,

-(CH2)2-O-(fen-1,4-ilen)-(CH2)3-, -(CH2)3-O-(fen-1,4-ilen)-(CH2)-,

-(CH2)3-O-(fen-1,4-ilen)-(CH2)2-, -(CH2)3-O-(fen-1,4-ilen)-(CH2)3-,

-(CH2)2-NH-(fen-1,4-ilen)-(CH2)-,

-(CH2)2-NH-(fen-1,4-ilen)-(CH2)2-,

-(CH2)2-NH-(fen-1,4-ilen)-(CH2)3-, (CH2)3-NH-(fen-1,4-ilen)-(CH2)-,

-(CH2)3-NH-(fen-1,4-ilen)-(CH2)2and

(CH2)3-NH-(fen-1,4-ilen)-(CH2)3-.

In yet another private embodiment, R4represents a divalent group of the formula:

-(R4A)d(And1)e-(R4b)f-Q-(R4c)g(A2)h-(R4d)i-,

where Q represents-N(Qa)C(O)- or-C(O)N(Qb)-. Private value for R4in this case is the formula:

where m is an integer from 2 to 10 and n is an integer from 2 to 10, provided that m+n is an integer from 4 to 1. In this formula for R4d and g are equal to 1 and e, f, h and i is 0, and R4arepresents -(CH2)m, R4crepresents -(CH2)nand Q represents-C(O)NH-. Private values for m are 2 or 3 and n is 4, 5 or 6.

Other private value for R4is the formula:

where o is an integer from 2 to 7, and p is an integer from 1 to 6, provided that o+p is an integer from 3 to 8. In this formula for R4the values of d, h and i are 1 and e, f and g is 0, R4arepresents -(CH2)about-, A2is a dryer-1,4-ilen, R4drepresents -(CH2)pand Q represents-C(O)NH-. Private values for o are 2 or 3 and p is 1 or 2. In this option, the dryer-1,4-Renova group can be optionally substituted as described in this description for A2.

Other private value for R4is the formula:

where q is an integer from 2 to 6, r is an integer from 1 to 5 and s is an integer from 1 to 5, provided that q+r+s is an integer from 4 to 8. In this formula for R4the values of d, g, h and i are 1 and e and f are 0, R4arepresents -(CH2)q-, R4Srepresents -(CH2)r-, A2represents 1,4-phenylene,R 4drepresents -(CH2)sand Q represents-C(O)NH-. Private values for q are 2 or 3, r is 1 or 2 and s is 1 or 2. In this option, the dryer-1,4-Renova group can be optionally substituted as described in this description for A2.

Other private value for R4in this case is the formula:

where t is an integer from 2 to 10 and u is an integer from 2 to 10, provided that t+u is an integer from 4 to 12. In this formula for R4the values of d and g are equal to 1 and e, f, h and i is 0, and R4arepresents -(CH2)t, R4crepresents -(CH2)uand Q represents-NHC(O)-. Private values for t are 2 or 3, and u is 4, 5 or 6.

Other private value for R4is the formula:

where v is an integer from 2 to 7, and w is an integer from 1 to 6, provided that v+w is an integer from 3 to 8. In this formula for R4the values of d, h and i are 1 and e, f and g is 0, R4arepresents -(CH2)v-, A2represents 1,4-phenylene, R4drepresents -(CH2)wand Q represents-NHC(O)-. Private values for v are 2 or 3 and w is 1 or 2. In this option, the dryer-1,4-Renova group can be the ü optionally substituted, as described in this description for A2.

Other private value for R4is the formula:

where x is an integer from 2 to 6, y is an integer from 1 to 5 and z is an integer from 1 to 5, provided that x+y+z is an integer from 4 to 8. In this formula for R4the values of d, g, h and i are 1 and e and f are 0, R4arepresents -(CH2)x-, R4Srepresents -(CH2)y-, A2represents 1,4-phenylene, R4drepresents -(CH2)zand Q represents-NHC(O)-. Private values for x are 2 or 3, y is 1 or 2 and z is 1 or 2. In this option, the dryer-1,4-Renova group can be optionally substituted as described in this description for A2.

To further illustrate R4may be chosen from:

-(CH2)7-;

-(CH2)8-;

-(CH2)9-;

-(CH2)10-;

-(CH2)11-;

-(CH2)2C(O)NH(CH2)5-;

-(CH2)2N(CH3)C(O)(CH2)5-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2-;

-(CH2)2NHC(O)(Hairdryer-1,4-ilen)CH2-;

-(CH2)2NHC(O)NH(CH2)5-;

-(CH2)3NHC(O)NH(CH2)5-;

-(CH2)2C(O)NHCH2(cyclohex-1,3-ilen)CH2-;

-(CH )2NHC(O)(cyclopent-1,3-ilen)-;

-(CH2)2NHC(O)NH(Hairdryer-1,4-ilen)(CH2)2-;

1-[-(CH2)2C(O)](piperidine-4-yl)(CH2)2-;

-(CH2)2NHC(O)(TRANS-cyclohex-1,4-ilen)CH2-;

-(CH2)2NHC(O)(CIS-cyclopent-1,3-ilen)-;

-(CH2)2NH(Hairdryer-1,4-ilen)(CH2)2-;

1-[-(CH2)2NHC(O)](piperidine-4-yl)(CH2)2-;

-CH2(fen-1,4-ilen)NH(Hairdryer-1,4-ilen)CH2-;

-(CH2)2C(O)NHCH2(Hairdryer-1,3-ilen)CH2-;

-(CH2)2C(O)NHCH2(pyrid-2,6-ilen)CH2-;

-(CH2)2C(O)NH(CIS-cyclohex-1,4-ilen)CH2-;

-(CH2)2C(O)NH(TRANS-cyclohex-1,4-ilen)CH2-;

-(CH2)2NHC(O)(CIS-cyclopent-1,3-ilen)CH2-;

-(CH2)2N(CH3)C(O)(Hairdryer-1,3-ilen)CH2-;

-(CH2)2N(CH3)C(O)(TRANS-cyclohex-1,4-ilen)CH2-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)C*H(CH3)-((S)-isomer);

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)C*H(CH3)-((R)-isomer);

2-[(S)-(-CH2-](pyrrolidin-1-yl)C(O)(CH2)4-;

2-[(S)-(-CH2-](pyrrolidin-1-yl)C(O)(Hairdryer-1,4-ilen)CH2-;

-(CH2)2C(O)NH(4-chlorphen-1,3-ilen)CH2-;

-CH2(2-torpen-1,3-ilen)CH2-;

-(CH2)2C(O)NH(4-methylphen-1,3-ilen)CH2

-(CH2)2C(O)NH(6-chlorphen-1,3-ilen)CH2-;

-(CH2)2C(O)NH(2-chlorphen-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2,6-dichlorophen-1,4-ilen)CH2-;

-(CH2)2NHC(O)NHCH2(Hairdryer-1,3-ilen)CH2-;

4-[-CH2-](piperidine-1-yl)C(O)(Hairdryer-1,4-ilen)CH2-;

-(CH2)2C(O)N(CH2CH3)(Hairdryer-1,4-ilen)CH2-;

1-[-(CH2)2NHC(O)](piperidine-4-yl)-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2NHC(O)(Tien-2,5-ilen)CH2-;

-(CH2)2N(CH3)C(O)(3-nitrogen-1,4-ilen)CH2-;

-(CH2)2N(CH3)C(O)(TRANS-cyclohex-1,4-ilen)-;

1-[-CH2(2-torpen-1,3-ilen)CH2]piperidine-4-yl)-;

5-[-(CH2)2NHC(O)](pyrid-2-yl)CH2-;

-(CH2)2(fen-1,4-ilen)(CH2)2-;

-(CH2)3(Tien-2,5-ilen)(CH2)3-;

-(CH2)2(fen-1,4-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

-CH2(fen-1,2-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

1-[-CH2(2-torpen-1,3-ilen)CH2]piperidine-4-yl)(CH2)2-;

1-[-CH2(2-torpen-1,3-ilen)CH2]piperidine-4-yl)CH2-;

-(CH2)2C(O)NH(3-chlorphen-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2-(CF3O -), hair dryer-1,4-ilen)CH2-;

-(CH2)3(Hairdryer-1,3-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2S(O)2NHCH 2)5-;

-CH2(Hairdryer-1,3-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2C(O)NH(2-itfan-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2-chloro-5-methoxide-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2-chloro-6-methylphen-1,4-ilen)CH2-;

-(CH2)2C(O)NH(CH2)5-;

-(CH2)2N(CH3)S(O)2(fen-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2-bromphen-1,4-ilen)CH2-;

-(CH2)3(fen-1,4-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)3(fen-1,2-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

1-[-CH2(2-torpen-1,3-ilen)CH2]piperidine-4-yl)(CH2)3-;

-(CH2)2C(O)NH(2-methoxide-1,4-ilen)CH2-;

-(CH2)5NH(Hairdryer-1,4-ilen)(CH2)2-;

4-[-(CH2)2-](piperidine-1-yl)(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH(CH3)CH2-;

-(CH2)2-(TRANS-cyclohex-1,4-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2C(O)NH(2-torpen-1,4-ilen)CH2-;

-(CH2)2(Hairdryer-1,3-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2C(O)NH(2,5-deltorphin-1,4-ilen)CH2-;

-(CH2)2NHC(O)(Hairdryer-1,4-ilen)(CH2)2-;

1-[-CH2(pyrid-2,6-ilen)CH2]piperidine-4-yl)CH2-;

-(CH2)3NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2H(naphthas-1,4-ilen)(CH 2)2-;

-(CH2)3O(Hairdryer-1,4-ilen)CH2-;

1-[-(CH2)3]piperidine-4-yl)CH2-;

4-[-(CH2)2]piperidine-1-yl)C(O)(Hairdryer-1,4-ilen)CH2-;

-(CH2)3(fen-1,4-ilen)NHC(O)(CH2)2-;

-(CH2)3(Dryer-1,4-ilen)(CH2)2-;

2-[-(CH2)2]benzimidazole-5-yl)CH2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)(CH2)2-;

-(CH2)2-(TRANS-cyclohex-1,4-ilen)NHC(O)(CH2)4-;

-(CH2)2-(TRANS-cyclohex-1,4-ilen)NHC(O)(CH2)5-;

4-[-(CH2)2]piperidine-1-yl)C(O)(CH2)2-;

-(CH2)2NHC(O)NH(Hairdryer-1,4-ilen)CH2-;

-(CH2)2N(CH3)(CH2)2(CIS-cyclohex-1,4-ilen)-;

-(CH2)2C(O)NH(2,3,5,6-tetraterpene-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2,6-dioden-1,4-ilen)CH2-;

4-[-(CH2)2]piperidine-1-yl)C(O)(CH2)3-;

4-[-(CH2)2]piperidine-1-yl)C(O)(CH2)4-;

4-[-(CH2)2]piperidine-1-yl)C(O)(CH2)5-;

-(CH2)2C(O)NHCH2(fen-1,4-ilen)CH2-;

-(CH2)2NHC(O)NHCH2(fen-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2-methylphen-1,4-ilen)CH2-;

1-[-(CH2)3O(Hairdryer-1,4-ilen)(CH2)2]piperidine-4-yl)CH2-;

-(CH2) C(O)NHCH2(Hairdryer-1,3-ilen)(CH2)2-;

-(CH2)2About(hair dryer-1,3-ilen)(CH2)2-;

-(CH2)2N(CH3)C(O)CH2(Dryer-1,4-ilen)CH2-;

-(CH2)2N(CH3)C(O)CH2O(Hairdryer-1,3-ilen)CH2-;

-(CH2)2N(CH3)C(O)(FSD-2,5-ilen)CH2-;

-(CH2)2N(CH3)C(O)(Tien-2,5-ilen)CH2-;

-(CH2)2O(Hairdryer-1,4-ilen)O(CH2)2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)(Hairdryer-1,4-ilen)CH2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)CH2O(Hairdryer-1,2-ilen)CH2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)CH2O(Hairdryer-1,3-ilen)CH2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)CH2O(Hairdryer-1,4-ilen)CH2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)(FSD-2,5-ilen)CH2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)(Tien-2,5-ilen)CH2-;

4-[-(CH2)2]piperidine-1-yl)C(O)CH2O(Hairdryer-1,2-ilen)CH2-;

4-[-(CH2)2}piperidine-1-yl)C(O)CH2O(Hairdryer-1,3-ilen)CH2-;

4-[-(CH2)2]piperidine-1-yl)C(O)CH2(Dryer-1,4-ilen)CH2-;

4-[-(CH2)2]piperidine-1-yl)C(O)(FSD-2,5-ilen)CH2-;

4-[-(CH2)2]piperidine-1-yl)C(O)(Tien-2,5-ilen)CH2-;

-(CH2)2(fen-1,4-ilen)NHC(O)(Hairdryer-1,3-ilen)CH2-;

-(CH2)2 (fen-1,4-ilen)NHC(O)(Hairdryer-1,4-ilen)CH2-;

-(CH2)2(fen-1,4-ilen)NHC(O)CH2About(hair dryer-1,2-ilen)CH2-;

-(CH2)2(fen-1,4-ilen)NHC(O)CH2About(hair dryer-1,3-ilen)CH2-;

-(CH2)2(fen-1,4-ilen)NHC(O)CH2O(Hairdryer-1,4-ilen)CH2-;

-(CH2)2(fen-1,4-ilen)NHC(O)(FSD-2,5-ilen)CH2-;

-(CH2)2(fen-1,4-ilen)NHC(O)(Tien-2,5-ilen)CH2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)(Hairdryer-1,3-ilen)CH2-;

-(CH2)3O(Hairdryer-1,3-ilen)CH2-;

-CH2CH(OH)CH2NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)4NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2NHC(O)CH2-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)(CH2)2NHC(O)CH2-;

-(CH2)2C(O)NHCH2(TRANS-cyclohex-1,4-ilen)CH2-;

-(CH2)2NHC(O)(CH2)5-;

-(CH2)2About(hair dryer-1,3-ilen)O(CH2)2-;

-(CH2)2About(hair dryer-1,2-ilen)O(CH2)2-;

-CH2(fen-1,2-ilen)O(Hairdryer-1,2-ilen)CH2-;

-(CH2)2C(O)NH(CH2)6-;

-(CH2)3(fen-1,4-ilen)(CH2)3-;

-(CH2)3(fen-1,4-ilen)(CH2)2-;

-(CH2)4(fen-1,4-ilen)(CH2)2-;

-(CH2)3(furan-2,5-ilen)(CH2)3-;

-(CH2)2N(CH3)C(O)NH(Hairdryer-1,4-ilen)(CH 2)2-;

4-[-(CH2)2]piperidine-1-yl)C(O)NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)3(Hairdryer-1,3-ilen)(CH2)3-;

-(CH2)3(tetrahydrofuran-2,5-ilen)(CH2)3and

-(CH2)2O(Hairdryer-1,4-ilen)C(O)(CH2)2-.

Typical ogrodowe group

The following ogrodowe formulas and groups of compounds are intended to represent typical examples of various aspects and variations of the present invention and as such does not imply the exclusion of other options or limit the scope of the present invention, unless otherwise indicated.

A private group of compounds of formula I are the compounds disclosed in the provisional application for U.S. patent No. 60/447843, filed February 14, 2003, This group includes the compounds of formula I, where:

and represents 0 or an integer from 1 to 3;

each R1independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)quinil, (3-6C)cycloalkyl, cyano, halogen, -OR1a, -C(O)OR1b, -SR1c, -S(O)R1d, -S(O)2R1eand-NR1fR1g;

each of R1a, R1b, R1c, R1d, R1e, R1fand R1gindependently represents hydrogen or (1-4C)alkyl;

b represents 0 or an integer from 1 to 3;

each R2independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)quinil, (3-6C)cycle is the alkyl, cyano, halogen, -OR2a, -C(O)OR2b, -SR2c, -S(O)R2d, -S(O)2R2eand-NR2fR2g;

each of R2a, R2b, R2c, R2d, R2e, R2fand R2gindependently represents hydrogen or (1-4C)alkyl;

W is attached at position 3 or 4 relative to the nitrogen atom in piperidinium ring and represents O or NWa;

Warepresents hydrogen or (1-4C)alkyl;

c represents 0 or an integer from 1 to 4;

each R3is a Deputy at the carbon atom, independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)quinil, (3-6C)cycloalkyl, cyano, halogen, -OR3a, -C(O)OR3b, -SR3c, -S(O)R3d, -S(O)2R3eand-NR3fR3g;

each of R3a, R3b, R3c, R3d, R3e, R3fand R3gindependently represents hydrogen or (1-4C)alkyl;

R4represents a divalent group of the formula:

-(R4A)d(And1)e-(R4b)f-Q-(R4c)g(A2)h-(R4d)i-,

where

d, e, f, g, h and i each independently selected from 0 and 1;

R4a, R4b, R4cand R4deach independently selected from (1-10C)alkylene, (2-10C)Alcanena and (2-10C)akinlana, where each Allenova, Alcanena or akinlana group is unsubstituted or Sames is 1-5 substituents, independently selected from (1-4C)alkyl, fluorine, hydroxy, phenyl and phenyl-(1-4C)alkyl;

A1and A2each independently selected from (3-7C)cycloalkyl, (6-10)arylene, (2-9C)heteroaryl and (3-6C)heterocycle, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl, and each Allenova, heteroarenes or heterostropha group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl and (1-4C)alkoxy;

Q is selected from-O-, -C(O)O-, -OC(O)-, -S-, -S(O)-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-, -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)-, -N(Qg)S(O)2N(Qh)-, -OC(O)N(Qi)- and-N(Qj)C(O)O-;

Qa, Qb, Qwith, Qd, Qe, Qf, Qg, Qh, Qiand Qjeach independently selected from hydrogen, (1-6C)alkyl, A3and (1-4C)alkylene-A4where an alkyl group is unsubstituted or substituted by 1-3 substituents, independently selected from fluorine, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R4bor R4Sto which they are attached, form a 4-6-membered azacycloheptane group;

A3and A4each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted who passed or substituted by 1-4 substituents, independently selected from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl and (1-4C)alkoxy;

provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms, which are attached to R4is in the range from 8 to 14;

R5represents hydrogen or (1-4C)alkyl;

R6represents-NR6aCR6b(O) and R7represents hydrogen or R6and R7together form-NR7aC(O)-CR7b=CR7c-, -CR7d=CR7e-C(O)-NR7f-, -NR7gC(O)-CR7hR7i-CR7jR7kor CR7lR7m-CR7nRO-C(O)-NR7p-;

each of R6aand R6bindependently represents hydrogen or (1-4C)alkyl; and

each of R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R7l, R7m, R7n, R7oand R7pindependently represents hydrogen or (1-4C)alkyl;

or their pharmaceutically acceptable salt, solvate or stereoisomer.

Another private group of compounds of formula I are the compounds disclosed in the provisional application for U.S. patent No. 60/467035, filed may 1, 2003, This group includes the compounds of formula I, where:

and represents 0 or an integer from 1 to 3;

each R1independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)quinil, (3-6C)cycloalkyl, cyano, halogen, -OR1a, -C(O)OR1b, -SR1c, -S(O)R1d, -S(O)2R1eand-NR1fR1g;

each of R1a, R1b, R1c, R1d, R1e, R1fand R1gindependently represents hydrogen or (1-4C)alkyl;

b represents 0 or an integer from 1 to 3;

each R2independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)quinil, (3-6C)cycloalkyl, cyano, halogen, -OR2a, -C(O)OR2b, -SR2c, -S(O)R2d, -S(O)2R2eand-NR2fR2g;

each of R2a, R2b, R2c, R2d, R2e, R2fand R2gindependently represents hydrogen or (1-4C)alkyl;

W is attached at position 3 or 4 relative to the nitrogen atom in piperidinium ring and represents O or NWa;

Warepresents hydrogen or (1-4C)alkyl;

c represents 0 or an integer from 1 to 4;

each R3is a Deputy at the carbon atom, independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)quinil, (3-6C)cycloalkyl, cyano, halogen, -OR3a, -C(O)OR3b, -SR3c, -S(O)R3d, -S(O)2R3eand-NR3fR3g;

each of R3a, R3b, R3c, R3d, R3e , R3fand R3gindependently represents hydrogen or (1-4C)alkyl;

R4represents a divalent group of the formula:

-(R4A)d(And1)e-(R4b)f-Q-(R4c)g(A2)h-(R4d)i-,

where

d, e, f, g, h and i each independently selected from 0 and 1;

R4a, R4b, R4cand R4deach independently selected from (1-10C)alkylene, (2-10C)Alcanena and (2-10C)akinlana, where each Allenova, Alcanena or akinlana group is unsubstituted or substituted by 1-5 substituents independently selected from (1-4C)alkyl, fluorine, hydroxy, phenyl and phenyl-(1-4C)alkyl;

A1and A2each independently selected from (3-7C)cycloalkyl, (6-10)arylene, (2-9C)heteroaryl and (3-6C)heterocycle, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl, and each Allenova, heteroarenes or heterostropha group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl and (1-4C)alkoxy;

Q is selected from-O-, -C(O)O-, -OC(O)-, -S-, -S(O)-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-, -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)-, -N(Qg)S(O)2N(Qh)-, -OC(O)N(Qi)- and-N(Qj)C(O)O-;

Qa, Qb, Qwith, Qd, Qe, Qsup> f, Qg, Qh, Qiand Qjeach independently selected from hydrogen, (1-6C)alkyl, A3and (1-4C)alkylene-A4where an alkyl group is unsubstituted or substituted by 1-3 substituents, independently selected from fluorine, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R4bor R4Sto which they are attached, form a 4-6-membered azacycloheptane group;

A3and A4each independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl and (1-4C)alkoxy;

provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms, which are attached to R4is in the range from 4 to 14;

R5represents hydrogen or (1-4C)alkyl;

R6represents-NR6aCR6b(O) or-CR6sR6dOR6eand R7represents hydrogen or R6and R7together form-NR7aC(O)-CR7b=CR7c-, -CR7d=CR7e-C(O)-NR7f-, -NR7gC(O)-CR7hR7i-CR7jR7kor CR7lR7m-CRn RO-C(O)-NR7p-;

each of R6a, R6b, R6c, R6dand R6eindependently represents hydrogen or (1-4C)alkyl; and

each of R7a, R7b, R7c, R7d, R7e, R7f, R7g, R7h, R7i, R7j, R7k, R7l, R7m, R7n, R7oand R7pindependently represents hydrogen or (1-4C)alkyl;

or their pharmaceutically acceptable salt, solvate or stereoisomer.

Another private group of compounds of formula I are compounds where a is 0, b is 0, C is 0, W represents O, W is attached in position 4 piperidinyl ring, R5represents hydrogen and R4, R6and R7are as defined herein, or their pharmaceutically acceptable salt, solvate or stereoisomer.

Another private group of compounds of formula I are compounds where a is 0, b is 0, C is 0, W represents NH, W is attached in position 4 piperidinyl ring, R5represents hydrogen and R4, R6and R7are as defined herein, or their pharmaceutically acceptable salt, solvate or stereoisomer.

Another private group of compounds of formula I are compounds where a is 0, b is 0, C is 0, W represents O W attached is ulozhenie 4 piperidinyl ring, R4represents -(CH2)j-where j is 8, 9 or 10, R5represents hydrogen and R6and R7are as defined herein, or their pharmaceutically acceptable salt, solvate or stereoisomer.

Another private group of compounds of formula I are compounds where a is 0, b is 0, C is 0, W represents NH, W is attached in position 4 piperidinyl ring, R4represents -(CH2)j-where j is 8, 9 or 10, R5represents hydrogen and R6and R7are as defined herein, or their pharmaceutically acceptable salt, solvate or stereoisomer.

Another private group of compounds of formula I are compounds where a is 0, b is 0, C is 0, W represents O, W is attached in position 4 piperidinyl ring, R4represents -(CH2)2-C(O)NH-(CH2)5-, R5represents hydrogen and R6and R7are as defined herein, or their pharmaceutically acceptable salt, solvate or stereoisomer.

Another private group of compounds of formula I are compounds where a is 0, b is 0, C is 0, W represents NH, W is attached in position 4 piperidinyl ring, R4represents -(CH2) 2-C(O)NH-(CH2)5-, R5represents hydrogen and R6and R7are as defined herein, or their pharmaceutically acceptable salt, solvate or stereoisomer.

Another private group of compounds of formula I are the compounds of formula II, as defined herein, or their pharmaceutically acceptable salt, solvate or stereoisomer.

Another private group of compounds of formula I are the compounds of formula III, as defined herein, or their pharmaceutically acceptable salt, solvate or stereoisomer.

Another private group of compounds of formula I are the compounds of formula IV, as defined herein, or their pharmaceutically acceptable salt, solvate or stereoisomer.

Another private group of compounds of formula I are as defined in the description of the compounds of formula II, III or IV, where piperidinyl ring is substituted in position 4 by methyl group, or their pharmaceutically acceptable salt, solvate or stereoisomer.

Another private group of compounds of formula I are the compounds of formula V:

where W, R4, R6and R7are as defined in table I, or their pharmaceutically acceptable salt, solvate or stereoisomer.

Table I
Etc.WR4R6R7
1NH-(CH2)9-(racemic)1-NHC(O)CH=CH-2
2O-(CH2)9-(racemic)-NHC(O)CH=CH-
3O-(CH2)9--NHC(O)CH=CH-
4About-(CH2)9--NHC(O)HH
5O-(CH2)9--NHC(O)CH2CH2-
6O-(CH2)2C(O)NH(CH2)5--NHC(O)CH=CH-
7About-(CH2)2N(CH3)C(O)(CH2)5--NHC(O)CH=CH-
8O-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
9O-(CH2)2NHC(O)(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
10O-(CH2)2 NHC(O)NH(CH2)5--NHC(O)CH=CH-
11O-(CH2)3NHC(O)NH(CH2)5--NHC(O)CH=CH-
12O-(CH2)9--CH2OHH
13NH-(CH2)9--CH2OHH
14O-(CH2)2C(O)NHCH2(cyclohex-1,3-ilen)CH2--NHC(O)CH=CH-
15O-(CH2)2NHC(O)(CIS-cyclopent-1,3-ilen)--NHC(O)CH2CH2-
16About-(CH2)2C(O)NH(2-chlorphen-1,4-ilen)CH2--NHC(O)CH=CH-
17O-(CH2)2S(O)2NH(CH2)5--NHC(O)CH=CH-
18About-(CH2)2N(CH3)S(O)2(fen-1,4-ilen)CH2--NHC(O)CH=CH-
19O-(CH2)2NHC(O)NHCH2(Hairdryer-1,3-ilen)CH2--NHC(O)CH=CH-
20O-(CH 2)3(fen-1,4-ilen)NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
21O1-[-CH2(2-torpen-1,3-ilen)CH2]piperidine-4-yl)CH2--NHC(O)CH=CH-
22O-(CH2)3O(Hairdryer-1,4-ilen)CH2)2--NHC(O)CH=CH-
23O-(CH2)2(fen-1,4-ilen)(CH2)2--NHC(O)CH=CH-
24O-(CH2)3(Tien-2,5-ilen)(CH2)3--NHC(O)CH=CH-
25O-(CH2)2C(O)NH(2-chloro-5-methoxide-1,4-ilen)CH2--NHC(O)CH=CH-
26O-(CH2)7--NHC(O)CH=CH-
27O-(CH2)8--NHC(O)CH=CH-
28O-(CH2)2NHC(O)NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
29O1-[-(CH2)2C(O)](piperidine-4-yl(CH2)2--NHC(O)CH=CH-
30O-(CH2 2NHC(O)(TRANS-cyclohex-1,4-ilen)CH2--NHC(O)CH=CH-
31O-(CH2)2NHC(O)(CIS-cyclopent-1,3-ilen)--NHC(O)CH=CH-
32About-(CH2)2NHC(O)NH(CH2)5--NHC(O)HN
33O-(CH2)2NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
34O-(CH2)3NHC(Q)NH(CH2)5--NHC(O)HN
35About1-[-(CH2)2NHC(O)](piperidine-4-yl)(CH2)2--NHC(O)CH=CH-
36O-CH2(fen-1,4-ilen)NH(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
37O-(CH2)2C(O)NHCH2(Hairdryer-1,3-ilen)CH2--NHC(O)CH=CH-
38NH-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
39O-(CH2)2C(O)NHCH2(pyrid-2,6-ilen)CH2--NHC(O)CH=CH-
40 About-(CH2)2C(O)NH(CIS-cyclohex-1,4-ilen)CH2--NHC(O)CH=CH-
41About-(CH2)2C(O)NH(TRANS-cyclohex-1,4-ilen)CH2--NHC(O)CH=CH-
42O-(CH2)2NHC(O)(CIS-cyclopent-1,3-ilen)CH2--NHC(O)CH=CH-
43O-(CH2)2N(CH3)C(O)(Hairdryer-1,3-ilen)CH2--NHC(O)CH=CH-
44O-(CH2)2N(CH3)C(O)(TRANS-cyclohex-1,4-ilen)CH2--NHC(O)CH=CH-
45O-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2-(racemic)-NHC(O)CH=CH-
46O-(CH2)2C(O)NH(Hairdryer-1,4-ilen)C*H(CH3)-((S)-isomer)-NHC(O)CH=CH-
47O-(CH2)2C(O)NH(Hairdryer-1,4-ilen)C*H(CH3)-((R)-isomer)-NHC(O)CH=CH-
48O2-[(S)-(-CH2-](pyrrolidin-1-yl)C(O)(CH2)4--NHC(O)CH-CH-
49O2-[(S)-(-CH 2-](pyrrolidin-1-yl)C(O)(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
50O-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2--NHC(O)HH
51O-(CH2)2C(O)NH(Hairdryer-1,4-ilen)C*H(CH3)-((R)-isomer)-NHC(O)HH
52O-(CH2)2C(O)NH(4-chlorphen-1,3-ilen)CH2--NHC(O)CH=CH-
53NH-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
54NH1-[-(CH2)2C(O)](piperidine-4-yl)(CH2)2--NHC(O)CH=CH-
55NH-(CH2)2C(O)NHCH2(Hairdryer-1,3-ilen)CH2--NHC(O)CH=CH-
56O-CH2(2-torpen-1,3-ilen)CH2--NHC(O)CH=CH-
57O-(CH2)2C(O)NH(4-methylphen-1,3-ilen)CH2--NHC(O)CH=CH-
58About-(CH2)2C(O)NH(6-chlorphen-1,3-ilen)CH2--NHC(O)CH=CH-
59O-(CH2)2C(O)NH(2,6-dichlorophen-1,4-ilen)CH2--NHC(O)CH=CH-
60About4-[-CH2-](piperidine-1-yl)C(O)(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
61O-(CH2)2NHC(O)(Hairdryer-1,4-ilen)CH2--NHC(O)HN
62O-(CH2)2C(O)N(CH2CH3)(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
63O1-[-(CH2)2NHC(O)](piperidine-4-yl)--NHC(O)CH=CH-
64O-(CH2)2C(O)NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
65O-(CH2)2NHC(O)(Tien-2,5-ilen)CH2--NHC(O)CH=CH-
66O-(CH2)2N(CH3)C(O)(3-nitrogen-1,4-ilen)CH2--NHC(O)CH=CH-
67O-(CH2)2C(O)NH(TRANS-cyclohex-1,4-ilen)CH2--NHC(O)HH
68O-(CH2)2N(CH3)C(O)(TRANS-C is logex-1,4-ilen)- -NHC(O)CH=CH-
69About1-[-CH2(2-torpen-1,3-ilen)CH2]piperidine-4-yl)--NHC(O)CH=CH-
70About5-[-(CH2)2NHC(O)](pyrid-2-yl)CH2--NHC(O)CH=CH-
71O1-[-(CH2)3]piperidine-4-yl)CH2--NHC(O)CH=CH-
72O-(CH2)2C(O)NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)HN
73O-CH2(fen-1,2-ilen)NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
74O1-[-CH2(2-torpen-1,3-ilen)CH2]piperidine-4-yl)(CH2)2--NHC(O)CH=CH-
75O-(CH2)3NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
76O-(CH2)2C(O)NH(3-chlorphen-1,4-ilen)CH2--NHC(O)CH=CH-
77About-(CH2)2C(O)NH(2-(CF3O-)Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
78O -(CH2)3(Hairdryer-1,3-ilen)NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
79O-CH2(Hairdryer-1,3-ilen)NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
80O-(CH2)2C(O)NH(2-itfan-1,4-ilen)CH2--NHC(O)CH=CH-
81O-(CH2)2C(O)NH(2-chloro-6-methylphen-1,4-ilen)CH2--NHC(O)CH=CH-
82O-(CH2)2C(O)NH(CH2)5-(racemic)-NHC(O)CH=CH-
83O-(CH2)2C(O)NH(2-bromphen-1,4-ilen)CH2--NHC(O)CH=CH-
84O-(CH2)3(fen-1,2-ilen)NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
85O1-[-CH2(2-torpen-1,3-ilen)CH2]piperidine-4-yl)(CH2)3--NHC(O)CH=CH-
86O-(CH2)2C(O)NH(2-methoxide-1,4-ilen)CH2--NHC(O)CH=CH-
87O-(CH2)5NH(Hairdryer-1,4-ilen)(CH2)2- -NHC(O)CH=CH-
88O4-[-(CH2)2-](piperidine-1-yl)(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
89About-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH(CH3)CH2--NHC(O)CH=CH-
90O-(CH2)2-(TRANS-cyclohex-1,4-ilen)NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
91O-(CH2)2C(O)NH(2-torpen-1,4-ilen)CH2--NHC(O)CH=CH-
92O-(CH2)2(Hairdryer-1,3-ilen)NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
93O-(CH2)2C(O)NH(2,5-deltorphin-1,4-ilen)CH2--NHC(O)CH=CH-
94O-(CH2)2NHC(O)(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
95O1-[-CH2(pyrid-2,6-ilen)CH2]piperidine-4-yl)CH2--NHC(O)CH=CH-
96O-(CH2)2NH(naphthas-1,4-ilen)(CH2)2--NHC(O)CH=CH-
97 O4-[-(CH2)2]piperidine-1-yl)C(O)(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
98O-(CH2)3(fen-1,4-ilen)NHC(O)(CH2)2--NHC(O)CH=CH-
99About-(CH2)3(Dryer-1,4-ilen)CH2--NHC(O)CH=CH-
100About2-[-(CH2)2]benzimidazole-5-yl)CH2--NHC(O)CH=CH-
101O-(CH2)2-(TRANS-cyclohex-1,4-ilen)NHC(O)(CH2)2--NHC(O)CH=CH-
102O-(CH2)2-(TRANS-cyclohex-1,4-ilen)NHC(O)(CH2)4--NHC(O)CH=CH-
103O-(CH2)2-(TRANS-cyclohex-1,4-ilen)NHC(O)(CH2)5--NHC(O)CH=CH-
104About4-[-(CH2)2]piperidine-1-yl)C(O)(CH2)2--NHC(O)CH=CH-
105O-(CH2)2NHC(O)NH(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
106O-(CH2)2N(CH3)(CHsub> 2)2(CIS-cyclohex-1,4-ilen)--NHC(O)CH=CH-
107O-(CH2)2C(O)NH(2,3,5,6-tetraterpene-1,4-ilen)CH2--NHC(O)CH=CH-
108O-(CH2)2C(O)NH(2,6-dioden-1,4-ilen)CH2--NHC(O)CH=CH-
109O4-[-(CH2)2]piperidine-1-yl)C(O)(CH2)3--NHC(O)CH=CH-
110O4-[-(CH2)2]piperidine-1-yl)C(O)(CH2)4--NHC(O)CH=CH-
111O4-[-(CH2)2]piperidine-1-yl)C(O)(CH2)5--NHC(O)CH=CH-
112O-(CH2)2C(O)NHCH2(fen-1,4-ilen)CH2--NHC(O)CH=CH-
113O-(CH2)2C(O)NHCH2(fen-1,4-ilen)CH2--NHC(O)HN
114O-(CH2)2NHC(O)NHCH2(fen-1,4-ilen)CH2--NHC(O)CH=CH-
115O-(CH2)2NHC(O)NHCH2(fen-1,4-ilen)CH2- -NHC(O)HN
116O-(CH2)2C(O)NH(2-methylphen-1,4-ilen)CH2--NHC(O)CH=CH-
117O1-[-(CH2)3O(Hairdryer-1,4-ilen)(CH2)2]piperidine-4-yl)CH2--NHC(O)CH=CH-
118O-(CH2)2C(O)NHCH2(Hairdryer-1,3-ilen)(CH2)2--NHC(O)CH=CH-
119O-(CH2)2O(Hairdryer-1,3-ilen)CH2--NHC(O)CH=CH-
120O-(CH2)2N(CH3)C(O)CH2O(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
121O-(CH2)2N(CH3)C(O)CH2About(hair dryer-1,3-ilen)CH2--NHC(O)CH=CH-
122O-(CH2)2N(CH3)C(O)(FSD-2,5-ilen)CH2--NHC(O)CH=CH-
123O-(CH2)2N(CH3)C(O)(Tien-2,5-ilen)CH2--NHC{O)CH=CH-
124About-(CH2)2O(Hairdryer-1,4-ilen)O(CH2)2--NHC(O)CH=CH-
125 O-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
126O-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)CH2O(Hairdryer-1,2-ilen)CH2--NHC(O)CH=CH-
127About-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)CH2O(Hairdryer-1,3-ilen)CH2--NHC(O)CH=CH-
128O-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)CH2(Dryer-1,4-ilen)CH2--NHC(O)CH=CH-
129O-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)(FSD-2,5-ilen)CH2--NHC(O)CH=CH-
130O-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)(Tien-2,5-ilen)CH2--NHC(O)CH=CH-
131O4-[-(CH2)2]piperidine-1-yl)C(O)CH2O(Hairdryer-1,2-ilen)CH2--NHC(O)CH=CH-
132O4-[-(CH2)2]piperidine-1-yl)C(O)CH2O(Hairdryer-1,3-ilen)CH2--NHC(O)CH=CH-
133O4-[-(CH2)2]piperidine-1-yl)(O)CH 2O(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
134O4-[-(CH2)2]piperidine-1-yl)C(O)(FSD-2,5-ilen)CH2--NHC(O)CH=CH-
135O4-[-(CH2)2]piperidine-1-yl)C(O)(Tien-2,5-ilen)CH2--NHC(O)CH=CH-
136O-(CH2)2(fen-1,4-ilen)NHC(O)(Hairdryer-1,3-ilen)CH2--NHC(O)CH=CH-
137O-(CH2)2(fen-1,4-ilen)NHC(O)(Hairdryer-1,4 - ilen)CH2--NHC(O)CH=CH-
138O-(CH2)2(fen-1,4-ilen)NHC(O)CH2O(Hairdryer-1,2-ilen)CH2--NHC(O)CH=CH-
139O-(CH2)2(fen-1,4-ilen)NHC(O)CH2About(hair dryer-1,3-ilen)CH2--NHC(O)CH=CH-
140O-(CH2)2(fen-1,4-ilen)NHC(O)CH2O(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
141O-(CH2)2(fen-1,4-ilen)NHC(O)(FSD-2,5-ilen)CH2--NHC(O)CH=CH-
142O-(CH2)2(fen-1,4-ilen)NHC(O)(Tien-2,5-ilen)CH2 -NHC(O)CH=CH-
143About-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)(Hairdryer-1,3-ilen)CH2--NHC(O)CH=CH-
144O-(CH2)3O(Hairdryer-1,3-ilen)CH2--NHC(O)CH=CH-
145O-CH2CH(OH)CH2NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
146About-(CH2)4NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
147O-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2NHC(O)CH2--NHC(O)CH=CH-
148About-(CH2)2C(O)NH(Hairdryer-1,4-ilen)(CH2)2NHC(O)CH2--NHC(O)CH=CH-
149O-(CH2)2C(O)NHCH2(TRANS-cyclohex-1,4-ilen)CH2--NHC(O)CH=CH-
150O-(CH2)2NHC(O)(CH2)5--NHC(O)CH=CH-
151O-(CH2)2O(Hairdryer-1,3-ilen)O(CH2)2--NHC(O)CH=CH-
152 O-(CH2)2About(hair dryer-1,2-ilen)O(CH2)2--NHC(O)CH=CH-
153O-CH2(fen-1,2-ilen)O(Hairdryer-1,2-ilen)CH2--NHC(O)CH-CH-
154O-(CH2)2C(O)NH(CH2)6--NHC(O)CH=CH-
155O-(CH2)2NHC(O)(CIS-cyclopent-1,3-ilen)--NHC(O)CH=CH-
156About-(CH2)3(fen-1,4-ilen)(CH2)3--NHC(O)CH=CH-
157About-(CH2)3(fen-1,4-ilen)(CH2)2--NHC(O)CH=CH-
158O-(CH2)4(fen-1,4-ilen)(CH2)2--NHC(O)CH=CH-
159O-(CH2)3(furan-2,5-ilen)(CH2)3--NHC(O)CH=CH-
160O-(CH2)2N(CH3)C(O)NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
161O4-[-(CH2)2]piperidine-1-yl)C(O)NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)H=CH-
162O-(CH2)3(Hairdryer-1,3-ilen)(CH2)3--NHC(O)CH=CH-
163O-(CH2)3(tetrahydrofuran-5-ilen)(CH2)3--NHC(O)CH=CH-
164O-(CH2)2(Dryer-1,4-ilen)C(O)(CH2)2--NHC(O)CH=CH-
1"racemic" in tables I-III indicates that the compound is the racemic chiral carbon atom carrying the hydroxyl group in formula V, VI or VII.

2In this group, the nitrogen atom is attached at R6and the carbon atom is attached at R7.

Another private group of compounds of formula I are the compounds of formula VI:

where W, R1A, R1B, R1C, R2A, R2B, R4, R6and R7are as defined in table II, or pharmaceutically acceptable salt, solvate or stereoisomer.

Table II
Etc.WR1AR1BR1CR2AR2BR4 R6R7
165OHHHBrH-(CH2)9-(racemic)-NHC(O)CH=CH-
166OFHHHN-(CH2)9--NHC(O)CH=CH-
167ONClHFF-(CH2)9--NHC(O)CH=CH-
168OHClClFF-(CH2)9--NHC(O)CH=CH-
169OHHHFF-(CH2)9--NHC(O)CH=CH-

Another private group of compounds of formula I are the compounds of formula VII:

where W, R4, R6and R7are as defined in table III, or pharmaceutically acceptable salt, solvate or stereoisomer.

Table III
Etc.WR4R6R7
170O-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
171O-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2--NHC(O)HH
172O-(CH2)9--NHC(O)CH=CH-
173O-(CH2)9--NHC(O)HH
174O-(CH2)2C(O)NH(CH2)5--NHC(O)CH2CH2-
175O-(CH2)2C(O)NH(CH2)5--NHC(O)HH
176O-(CH2)2NHC(O)(CH2)5--NHC(O)CH=CH-
177O-(CH2)2NHC(O)(CH2)5--NHC(O)HH
178O-(CH2)2NHC(O)(Hairdryer-1,4-ilen)CH2--NHC(O)CH=CH-
179O-(CH2)2NHC(O)(Hairdryer-1,4-ilen)CH2--NH(O)H H
180O-(CH2)3(fen-1,4-ilen)NH(Hairdryer-1,4-ilen)(CH2)2--NHC(O)CH=CH-
181O-(CH2)2NHC(O)(2-chlorphen-1,4-ilen)CH2--NHC(O)CH=CH-
182O-(CH2)2NHC(O)(2-chloro-5-methoxide - 1,4-ilen)CH2--NHC(O)CH=CH-

Definitions

In the description of the compounds, compositions, methods, and methods of the present invention, the following terms have the following meanings, unless otherwise indicated.

The term "alkyl" means a monovalent saturated hydrocarbon group, which may be unbranched or branched. Unless otherwise stated, such alkyl groups contain from 1 to 10 carbon atoms. Typical alkyl groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

The term "alkylene" means a divalent saturated hydrocarbon group, which may be unbranched or branched. Unless otherwise stated, such alkylene groups contain from 1 to 10 carbon atoms. Typical alkylene groups include, for example, methylene, ethane-1,2-diyl ("the stylish"), propane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl and the like.

The term "alkoxy" means a monovalent group of the formula (alkyl)-O-, where alkyl is as defined herein. Typical alkoxygroup include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy and the like.

The term "alkenyl" means a monovalent unsaturated hydrocarbon group, which may be unbranched or branched and which has at least one, usually 1, 2 or 3 carbon-carbon double bond. Unless otherwise stated, such alkeneamine groups typically contain from 2 to 10 carbon atoms. Typical alkeneamine groups include, for example, ethynyl, n-propenyl, Isopropenyl, n-but-2-enyl, n-Gex-3-enyl and the like. The term "albaniles" means a divalent alkenylphenol group.

The term "quinil" means a monovalent unsaturated hydrocarbon group, which may be unbranched or branched and which has at least one, usually 1, 2 or 3 carbon-carbon triple bond. Unless otherwise stated, such alkyline groups typically contain from 2 to 10 carbon atoms. Typical alkyline groups include, for example, ethinyl, n-PROPYNYL, Isopropenyl, n-but-2-inyl, n-Gex-3-inyl and the like. The term "akinyan" about the means of divalent alkylamino group.

The term "aryl" means a monovalent aromatic hydrocarbon group having a single ring (i.e. phenyl) or condensed rings (i.e. naphthalene). Unless otherwise stated, such aryl groups typically contain from 6 to 10 carbon atoms in the ring. Typical aryl groups include, for example, phenyl and naphthalene-1-yl, naphthalene-2-yl and the like. The term "Allen" means a divalent aryl group.

The term "azacyclonol" means a monovalent heterocyclic ring containing one nitrogen atom, i.e. cycloalkyl group in which one carbon atom is replaced by a nitrogen atom. Unless otherwise noted, these azacycloheptane groups typically contain from 2 to 9 carbon atoms. Typical examples azacycloheptane groups are pyrrolidinyl and piperidinyl group. The term "azacycloheptane" means a divalent azacycloheptane group. Typical examples azacycloheptane groups are pyrrolidinyloxy and piperidinyloxy group.

The term "cycloalkyl" means a monovalent saturated carbocyclic hydrocarbon group. Unless otherwise stated, such cycloalkyl groups typically contain from 3 to 10 carbon atoms. Typical cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "cycloalkene the means divalent cycloalkyl group.

The term "halogen" means fluorine, chlorine, bromine and iodine.

The term "heteroaryl" means a monovalent aromatic group having one ring or two condensed rings and containing in the ring at least one heteroatom (typically 1-3 heteroatoms)selected from nitrogen, oxygen or sulfur. Unless otherwise stated, such heteroaryl groups usually contain a total of from 5 to 10 atoms in the rings. Typical heteroaryl groups include, for example, monovalent species of pyrrole, imidazole, thiazole, oxazole, furan, thiophene, triazole, pyrazole, isoxazol, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, indole, benzofuran, benzothiophene, benzimidazole, benzthiazole, quinoline, isoquinoline, heatline, cinoxacin and the like, where the attachment point is at any available carbon atom or nitrogen in the ring. The term "heteroaryl" means a divalent heteroaryl group.

The term "heterocyclyl" or "heterocyclic" means a monovalent saturated or unsaturated (non-aromatic) group having a single ring or multiple condensed rings and containing in the ring at least one heteroatom (typically 1-3 heteroatoms)selected from nitrogen, oxygen or sulfur. Unless otherwise stated, such heterocyclic groups typically contain a total of from 2 to 9 ATO is s carbon in the rings. Typical heterocyclic groups include, for example, monovalent species pyrrolidine, imidazolidine, pyrazolidine, piperidine, 1,4-dioxane, research, thiomorpholine, piperazine, 3-pyrroline and the like, where the attachment point is at any available carbon atom or nitrogen in the ring. The term "heterocycle" means a divalent heterocyclyl or heterocyclic group.

When a defined term is used in this description, it is assumed a specific number of carbon atoms, the number of carbon atoms is shown in parentheses preceding the term. For example, the term(1-4C)alkyl" means an alkyl group containing from 1 to 4 carbon atoms.

The term "pharmaceutically acceptable salt" means a salt that is acceptable for administration to a patient such as a mammal (e.g., salts having acceptable mammalian safety for a given scheme dosing). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and pharmaceutically acceptable inorganic or organic acids. Salts derived from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganic, manganous, potassium, nutrie is s, zinc and the like salts. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, natural amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenziletilendiaminom, diethylamin, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, geranamine, Isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine, procaine, purines, theobromine, triethylamine, trimethylamine Tripropylamine, tromethamine and the like. Salts derived from pharmaceutically acceptable acids include the salts of acetic, ascorbic, benzosulfimide, benzoic, camphorsulfonic, lemon, econsultancy, agisilaou, fumaric, hentaimovi, gluconic, glucuronic, glutamic, hippuric, braiseworth, hydrochloric, italianboy, lactic, lactobionic, maleic, malic, almond, methansulfonate, mucus, naphthalenesulfonates, naphthalene-1,5-disulfonate, naphthalene-2,6-disulfonate, nicotine, nitrogen, orotovoy, pambou, Pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluols honoway, xinafoate and similar acids. Especially preferred are salts of citric, Hydrobromic, hydrochloric, italianboy, maleic, naphthalene-1,5-disulfonate, phosphoric, sulfuric and tartaric acids.

The term "their (his) salt" means a compound formed by replacing the hydrogen of the acid cation such as a metal cation or organic cation, and the like. Preferably the salt is a pharmaceutically acceptable salt, though this is not required for salts of intermediate compounds that are not intended for administration to a patient.

The term "MES" means a complex or aggregate formed by one or more molecules of the solute, i.e. the compounds of formula I or its pharmaceutically acceptable salt and one or more solvent molecules. Such solvate are usually crystalline solids having essentially constant molar ratio of solute and solvent. Typical solvents include, for example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When water is the solvent, the resulting MES is a hydrate.

It is clear that the phrase "or its pharmaceutically acceptable salt, MES or stereoisomer" covers all permutations of salts, solvate and stereoisomers, such is for example, as MES pharmaceutically acceptable salt of the stereoisomer of the compounds of formula I.

The term "therapeutically effective amount" means a quantity sufficient to effect the treatment when administered to a patient in need of such treatment.

The term "treatment" when used in this description means the treatment of a disease or medical condition (such as COPD (COPD)patient such as a mammal (preferably a human)that includes:

(a) preventing the disease or medical condition, i.e. prophylactic treatment of the patient;

(b) reducing the intensity of symptoms or medical condition, i.e., the elimination or induction of regression of the symptoms of the disease or medical condition in a patient;

(C) suppressing the disease or medical condition, i.e., the slowing or stopping the development of the disease or medical condition in a patient; or

(d) relief of the symptoms of the disease or medical condition in a patient.

The term "leaving group" means a functional group or atom which can be replaced with another functional group or another atom during substitution reactions, such as nucleophilic substitution reaction. Typical leaving groups include, for example, chlorine, bromine and iodine, the sulfonic clonaepam the s group, such as mesilate, toilet, brasilit, nosrat and the like, and alloctype, such as acetoxy, triptoreline and the like.

The expression "his (their) protected derivative" means a derivative of a particular connection, in which one or more functional groups of the compounds protected from unwanted reactions protective, or a blocking group. Functional groups that may be protected include, for example, the group of carboxylic acids, amino groups, hydroxyl groups, tirinya group, carbonyl group and the like. Typical protective groups for carboxylic acids include esters (such as n-methoxybenzyloxy ether), amides and hydrazides, amino - carbamates (such as tert-butoxycarbonyl) and amides, hydroxyl groups - ethers, and esters, for tylnej groups - simple thioethers and complex thioethers, for carbonyl groups - acetals and ketals, and the like. These protective groups are well known to specialists in this field and are described, for example, by T.W. Greene and G.M. Wuts,Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999 and references cited therein.

The term "aminosidine group" means a protective group suitable for preventing undesired reactions at the amino group. Typical aminosidine groups include, but are not limited to, tert-butoxy bonil (VOS), trityl (Tr) benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS) and the like.

The term "carboxyamide group" means a protective group suitable for preventing undesired reactions at carboxypropyl. Typical carboxyamide groups include, but are not limited to, esters, such as methyl, ethyl, tert-butyl, benzyl (Bn), p-methoxybenzyloxy (PMB), 9-fluorenylmethyl (Fm), trimethylsilane (TMS), tert-butyldimethylsilyloxy (TBS), diphenylmethylene (benzhydryl, DPM) and the like.

The term "hydroxylamine group" means a protective group suitable for preventing undesired reactions at the hydroxyl group. Typical hydroxylamine groups include, but are not limited to, silyl groups, including three(1-6C)alkylsilane groups, such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS) and the like, esters (acyl groups)including the (1-6C)alcoholnye groups, such as formyl, acetyl and the like, arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), diphenylmethyl (benzhydryl, DPM) and things like that. In addition, the two hydroxyl groups can be protected as alkylidene group, such as prop-2-ridin formed, such as the er, interaction with a ketone, such as acetone.

General methods of synthesis

Derivatives of biphenyl of the present invention can be obtained from readily available starting compounds using the following General methods and techniques, or using other information readily available to specialists in this field. Although this description may be shown and described specific variants of the present invention, the experts in this field will understand that the connection of all options and aspects of the present invention can be obtained by the methods described herein, or using other methods, reagents and reference substances known to specialists in this field. It is also clear that when set to typical or preferred process conditions (i.e. temperature, reaction time, molar ratio of reactants, solvents, pressures, etc), it can also be used for other process conditions, unless otherwise noted. Although the optimum reaction conditions may vary depending on the specific reagents and solvent, such conditions can be easily determined by the person skilled in the art using conventional optimization procedures.

In addition, professionals in this field will understand that may be necessary or desirable cent is as protective group, so as not to expose some functional groups adverse reactions. The selection of a suitable protective group for a particular functional group, as well as suitable conditions for the protection and removal of the protection of such functional groups are well known in this field. If desired, can be used protective group different from the one used in the methods described in this description. For example, many of the protective groups and their introduction and removal are described in T.W. Greene and G.M. Wuts,Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999 and references cited therein.

To illustrate the biphenyl derivatives of the present invention can be obtained by a method including:

(a) interactions of the compounds of formula1:

or its salt with the compound of the formula2:

where X1represents a leaving group, and R1and R2each independently represents a hydrogen atom or hydroxylamino group;

(b) interaction of the compounds of formula3:

or its salt with the compound of the formula4:

where X2represents a leaving group, and R3and R4each independently represents a hydrogen atom or hydroc elsadany group;

(C) binding of the compounds of formula 5:

with the compound of the formula6:

where XQaand XQbeach independently represents a functional group that are associated with the formation of the groups Q, R5Arepresents a hydrogen atom or aminosidine group, and R5band R6each independently represents a hydrogen atom or hydroxylamino group;

(d) for compounds of formula I, where R5represents a hydrogen atom, interaction of the compounds of formula3with the compound of the formula7:

or its hydrate (for example, glyoxal) in the presence of a reducing agent, where R7represents a hydrogen atom or hydroxylamino group;

(e) interaction of the compounds of formula1with the compound of the formula8:

or its hydrate in the presence of a reducing agent, where R8and R9each independently represents a hydrogen atom or hydroxylamino group; R10represents a hydrogen atom or aminosidine group, and R4'represents a residue that, together with the carbon atom to which it is attached, forms a group R4after the reaction;

9:

where X3represents a leaving group, with a compound of the formula10:

where R11and R12each independently represents a hydrogen atom or hydroxylamino group, and R13represents a hydrogen atom or aminosidine group; or

(g) the interaction of the compounds of formula11:

or its hydrate, where R4'represents a residue that, together with the carbon atom to which it is attached, forms a group R4after completion of the reaction, the compound of the formula10in the presence of a reducing agent; and then

the removal of the protective group R1, R2, R3, R4, R5A, R5b, R6, R7, R8, R9, R10, R11, R12or R13obtaining the compounds of formula I and, optionally, the formation of its pharmaceutically acceptable salts.

As a rule, if the methods described above, using salt of one of the original substances, such as acid additive salt, it is usually neutralized before or during the reaction. This neutralization reaction is usually carried out by introducing salt into contact with one molar equivalent of base for each molar equivalent of the acid additive is salt.

In method (a), i.e. in the reaction between the compounds of formulas1and2, the leaving group represented by X1may be, for example, halogen, such as chlorine, bromine or iodine, or a sulfonic ester group, such as mesilate or toilet. Group R1and R2can represent, for example, trimethylsilyl and benzyl, respectively. This reaction is usually carried out in an inert solvent, such as acetonitrile, in the presence of a base. For example, the reaction can be carried out in the presence of a tertiary amine, such as diisopropylethylamine. Typically, this reaction is carried out at a temperature in the range from 0°to 100°until then, until the reaction is substantially completed. The reaction product is then exhale, using traditional methods, such as extraction, recrystallization, chromatography and the like.

Compounds of the formula1usually known or can be obtained from commercially available starting materials and reagents well known methods. For example, the compounds of the formula1can be obtained by removing the protection of the compounds of formula12:

where R14represents aminosidine group such as benzyl group. For illustration, the benzyl group can be removed easily reset is by resolution, using, for example, hydrogen or ammonium formate and a metal of group VIII as a catalyst, such as palladium on carbon. When W represents a NWandthe hydrogenation reaction is usually carried out using the catalyst Perlman (Pearlman) (i.e. Pd(OH)2).

Compounds of the formula12can be obtained by the interaction of the isocyanate of the formula13:

with the compound of the formula14:

Compounds of the formula2can be obtained by various methods, described herein, or by methods well known to specialists in this field. For example, the hydroxyl group of compounds of formula23shown below, can be easily converted into a leaving group using well-known reagents and methods. To illustrate the hydroxyl group can be converted into a halogen group, using gelegenheid inorganic acid, such as thionyl chloride, phosphorous trichloride, the phosphor tribromide, phosphorous oxychloride and the like, or halogen acid, such as Hydrobromic acid.

In method (b), i.e. the interaction of the compounds of the formula3with the compound of the formula4, the leaving group represented by X2that may be the, for example, halogen, such as chlorine, bromine or iodine, or a sulfonic ester group, such as mesilate or toilet. Group R3and R4can represent, for example, tert-butyldimethylsilyl and benzyl, respectively. This reaction is usually carried out in the presence of a base such as sodium bicarbonate, and alkali metal iodide such as sodium iodide. Typically this reaction is carried out in an inert solvent, such as tetrahydrofuran, at a temperature in the range from 25°to 100°until then, until the reaction is substantially completed. The reaction product is then exhale, using traditional methods, such as extraction, recrystallization, chromatography and the like.

Compounds of the formula3can be obtained by removing the protection of the compounds of formula15:

where one or both of R15and R16independently represent a protective group such as tert-butoxycarbonyl, and any remainder is a hydrogen atom. For example, tert-butoxycarbonyl group can be removed by processing a secure connection triperoxonane acid.

Compounds of the formula15can be obtained by the interaction of the compounds of the formula1with the compound of the formula16:

X3-R4-NP15R16

16

where X3represents a leaving group such as halogen, such as chlorine, bromine or iodine, or a sulfonic ester group, such as mesilate or toilet. The reaction is usually carried out by introducing into contact with the compounds of formula1with the compound of the formula16in an inert solvent, such as acetonitrile, DMF or mixtures thereof at a temperature in the range from approximately 0°C to about 100°until then, until the reaction is substantially completed.

Alternatively, the compounds of formula3can be obtained by reductive amination of compounds of formula11. Reductive amination may be performed by the interaction of the compounds of the formula11for example, with benzylamine and hydrogen in the presence of palladium on carbon.

Compounds of the formula11can be obtained by oxidation of the corresponding alcohol of the formula17:

using a suitable oxidant, such as a complex of sulfur trioxide and pyridine, and dimethyl sulfoxide. This oxidation reaction is usually carried out in an inert solvent, such as dichloromethane, in the presence of a tertiary amine, such as diisopropylethylamine, at a temperature in the range of from about -20°With up to about 25°C.

Compounds of the formula17can be is obtained by the interaction of the compounds of the formula 1with the compound of the formula18:

X4-R4HE

18

where X4represents a leaving group such as halogen, such as chlorine, bromine or iodine, or a sulfonic ester group, such as mesilate or toilet.

Compounds of the formula4can be obtained by the interaction of the compounds of the formula19:

with a reducing agent such as borane. If necessary, the restoration can be performed in the presence of a chiral catalyst, giving a compound of the formula4in chiral form. For example, the compounds of the formula19can be restored in the presence of chiral catalyst formed from (R)-(+)-α,α-diphenyl-2-pyrrolidineethanol and trimethylboroxine or (S)-(-)-α,α-diphenyl-2-pyrrolidineethanol and trimethylboroxine. The obtained hydroxyl group can then be protected hydroxylamine group, R3interaction, for example, tert-butyldimethylchlorosilane.

Compounds of the formula19where X2represents a bromine atom, can be obtained by the interaction of the compounds of the formula20:

with bromine in the presence of a Lewis acid such as diethylether of boron TRIFLUORIDE. Connection f is rmula 20well known in this field or can be obtained by well known methods using commercially available starting materials and reagents.

With regard to method (C), i.e. the interaction of the compounds of formula5with the compound of the formula6it is clear that the groups XQaand XQbshould be selected in such a way that after the reaction they gave the desired group Q. for Example, when the desired group Q is an amide group, i.e. N(Qand)C(O)- or-C(O)N(Qb), one of XQaand XQbmay be an amino group (i.e.- NHQandor NHQband the other carboxyl group (i.e.- COOH) or its reactive derivative (such as allalone, such as acylchlorides or Allbreed). Group R5A, R5band R6can represent, for example, benzyl, trimethylsilyl and benzyl, respectively. When Q is an amide group, the reaction can be carried out under normal conditions amide linkage. Similarly, when the desired group Q is a sulfonamide, i.e. N(Qwith)S(O)2- or-S(O)2N(Qd), one of XQaand XQbmay be an amino group, -NHQcor NHQdand the other sulfonylmethane (such as sulphonylchloride or sulfanilamide).

Connection is ormula 5can be obtained by the interaction of the compounds of the formula1with the compound of the formula21:

where X5represents a leaving group comprising halogen, such as chlorine, bromine or iodine, and a sulfonic ester group, such as mesilate or toilet, and XQa'is a XQasuch as carboxyl group or amino group NHQandor a protected derivative, such as (1-6C)alkoxycarbonyl or tert-butoxycarbonylamino. This reaction is usually carried out on the same methodology used to obtain compounds of the formula3with the subsequent removal of the protective group in the XQa'.

Compounds of the formula6can be obtained by the interaction of the compounds of the formula4with the compound of the formula22:

where X6represents a leaving group comprising halogen, such as chlorine, bromine or iodine, and a sulfonic ester group, such as mesilate or toilet, and XQb'is a XQbsuch as carboxyl group or amino group NHQbor a protected derivative, such as (1-6C)alkoxycarbonyl or tert-butoxycarbonylamino. This reaction is usually carried out by a similar method, the COI is lsemaj to obtain compounds of the formula 3with the subsequent removal of the protective group in the XQb'.

With regard to method (d), i.e. the interaction of the compounds of formula3with the compound of the formula7in this reaction, you can use any reducing agent. For example, the reducing agent may be hydrogen in the presence of a catalyst based on a metal of group VIII such as palladium on carbon, or chemical based metal hydride, such as triacetoxyborohydride. The group R7may be, for example, benzyl. This reaction is usually conducted in an inert diluent and proton solvent such as a mixture of dichloromethane and methanol, at a temperature in the range from 0°to 100°until the reaction is substantially completed.

Compounds of the formula7in the form of a hydrate can be obtained in the usual manner, for example by dibromononane compounds of the formula19(where X2in this case, can also be hydrogen) and then hydrolysis of the resulting dibromide with the formation of glyoxal or its hydrate. For example, the compound of the formula19may be subject to interaction with hydrogen bromide and then hydrolysed with water with formation of the corresponding glyoxal hydrate.

With regard to method (e), i.e. the interaction of the compounds of formula1with the compound of the formula8the response is you can use any suitable reducing agent. For example, the reducing agent may be hydrogen in the presence of a catalyst based on a metal of group VIII such as palladium on carbon, or chemical based metal hydride, such as triacetoxyborohydride. Group R8, R9and R10can represent, for example, trimethylsilyl, benzyl and benzyl, respectively. Usually this reduction is carried out in an inert diluent and proton solvent such as dichloroethane and methanol, at a temperature in the range from 0°to 100°until the reaction is substantially completed.

Compounds of the formula8can be obtained by oxidation of compounds of formula23:

using a suitable oxidant, such as a complex of sulfur trioxide and pyridine, and dimethyl sulfoxide. Typically this reaction is carried out in the presence of a tertiary amine, such as diisopropylethylamine, at a temperature in the range of from about -20°With up to about 25°while the oxidation essentially will not end.

Compounds of the formula23can be obtained by the interaction of the compounds of the formula10with the compound of the formula24:

BUT-R4-X7

24

where X7represents a leaving group comprising halogen, such as chlorine, bromine or iodine, and the sulfonic clonaepam the th group, such as mesilate or toilet.

With regard to method (f), i.e. the interaction of the compounds of formula9with the compound of the formula10then the leaving group represented by X3may be, for example, halogen, such as chlorine, bromine or iodine, or a sulfonic ester group, such as mesilate or toilet. Group R11, R12and R13can represent, for example, trimethylsilyl, benzyl and benzyl, respectively. Typically this reaction is carried out in an inert diluent, such as acetonitrile, in the presence of a suitable base. For example, this reaction can be carried out in the presence of a tertiary amine, such as diisopropylethylamine. Typically this reaction is carried out at a temperature in the range from 0°to 100°until the reaction is substantially completed.

Compounds of the formula9can be obtained by carrying out stages similar to the stages of the methods (a)to(e)described above, compounds of the formula1. In addition, the compounds of the formula10can be obtained from compounds of the formula4interaction with the amine of formula R13NH2.

With regard to method (g), i.e. the interaction of the compounds of formula11with the compound of the formula10in this reaction it is possible to use any suitable reducing agent. For example, in what stenopetalum can serve as hydrogen in the presence of a catalyst based on a metal of group VIII, such as palladium on carbon, or chemical based metal hydride, such as triacetoxyborohydride. Group R11, R12and R13can represent, for example, tert-butyldimethylsilyl, benzyl and benzyl, respectively. Usually this reduction is carried out in an inert diluent and proton solvent such as dichloroethane and methanol, at a temperature in the range from 0°to 100°until the reaction is substantially completed.

Compounds of the formula11easily obtained by oxidation of the corresponding alcohol or by hydrolysis of the corresponding acetal. In this reaction to produce aldehyde may be used any suitable oxidizing agent, such as a complex of sulfur trioxide and pyridine, and dimethyl sulfoxide. The acetal can be hydrolyzed to obtain the aldehyde under normal conditions using aqueous acid.

In the private embodiment, some compounds of the formula I get the method including:

(h) removing the protection of the compounds of formula25:

where R17represents a hydrogen atom or aminosidine group, and each of R18, R19and R20independently represents a hydrogen atom or hydroxylamino group, provided that at least one of R18, R19or R20what is a protective group;

(i) removing the protection of the compounds of formula26:

where R21represents a hydrogen atom or aminosidine group, and each of R22and R23independently represents a hydrogen atom or hydroxylamino group, provided that at least one of R21, R22or R23is a protective group; or

(j) removing the protection of the compounds of formula27:

where R24represents a hydrogen atom or aminosidine group, and each of R25and R26independently represents a hydrogen atom or hydroxylamino group, provided that at least one of R24, R25or R26is a protective group;

obtaining the compounds of formula I and, optionally, the formation of pharmaceutically acceptable salts of the compounds of formula I.

As for the method (h), examples of particular values for R17, R18, R19and R20are: for R17is hydrogen or benzyl, R18is hydrogen or tert-butyldimethylsilyl and R19and R20is hydrogen or benzyl or together - propylidene. In this way benzyl protective group is removed by catalytic hydrogenation in the presence of a catalyst based on a metal of group VIII, such to the to palladium on carbon, tert-butyldimethylsilyloxy group is usually removed by treatment with hydrogen fluoride, such as trihydrochloride of triethylamine, and propylidene group is usually removed by treatment with an acid, such as triperoxonane acid.

Compounds of the formula25can be obtained by the methods described herein, such as methods (a)-(g). Alternatively, the compounds of formula25can be obtained by the interaction of the compounds of the formula28:

where R8represents-CH2OPR19, -Cho, -COOH or-C(O)O(1-6)alkoxy, such as carbomethoxy, R9is a-ER18and R10represents a hydrogen atom, or R9and R10together are =O, with a reducing agent. In this reaction may be used any suitable reducing agent, including, for example, reducing agents based on metal hydrides, such as borohydride sodium, sociallyengaged and the like.

Compounds of the formula28where R9and R10together represent a group =O, can be easily obtained by the interaction of the compounds of the formula29:

or its salt with the compound of the formula30:

where X8represents a leaving group, is akuu as bromine.

With regard to method (i), examples of particular values for R21, R22and R23are: for R21is hydrogen or benzyl, R22is hydrogen or tert-butyldimethylsilyl and R23is hydrogen or benzyl. In this way benzyl protective group is removed by catalytic hydrogenation in the presence of a catalyst based on a metal of group VIII such as palladium on carbon, and tert-butyldimethylsilyloxy group is usually removed by treatment with hydrogen fluoride, such as trihydrochloride of triethylamine. Compounds of the formula26can be obtained by the methods described herein, such as methods (a)-(g).

As for the method (j), examples of particular values for R24, R25and R26are: for R24is hydrogen or benzyl, R25is hydrogen or tert-butyldimethylsilyl and R26is hydrogen or benzyl. In this way benzyl protective group is removed by catalytic hydrogenation in the presence of a catalyst based on a metal of group VIII such as palladium on carbon, and tert-butyldimethylsilyloxy group is usually removed by treatment with hydrogen fluoride, such as trihydrochloride of triethylamine. Compounds of the formula27can be obtained by the methods described herein, such as methods (a)-(g).

In addition, soy is inane formula I, where R6and R7together form-NR7gC(O)-CR7hR7i-CR7jR7kor CR7lR7m-CR7nR7o-C(O)-NR7p-can be obtained by reduction of the corresponding compounds of formula I, where R6and R7together form-NR7aC(O)-CR7b=R7cor CR7d=CR7e-C(O)-NR7f-for example, by catalytic hydrogenation, as described below in example 6.

Other details regarding the specific conditions of the reaction and other methods of obtaining typical compounds of the present invention or the intermediate compounds described in the following examples.

Pharmaceutical compositions and preparations

Derivatives of biphenyl of the present invention is usually administered to the patient in a pharmaceutical composition or drug. These pharmaceutical compositions can be administered to the patient in any appropriate manner of administration, including, but not limited to, inhalation, oral, nasal, local (including transdermal and parenteral routes of administration. It is clear that in described in this specification, pharmaceutical compositions can be used in any form compounds of the present invention (i.e. the free base, pharmaceutically acceptable salt, MES etc)suitable for a particular method of administration.

Thus the m one of the aspects of the compositions of the compounds, the present invention relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier or excipient and a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt. If necessary, these pharmaceutical compositions may contain other drugs and/or excipients.

The pharmaceutical compositions of the present invention typically contain a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt. Typically, these pharmaceutical compositions contain from about 0.01 to about 95% by weight of active substance, including from about 0.01 to about 30% by weight, for example from about 0.01 to about 10% by weight, of active substance.

In the pharmaceutical compositions of the present invention may be used any conventional media or excipient. The selection of a particular media or excipient or combinations of carriers or excipients depends on the method of administration used for the treatment of a particular patient, or the type of medical condition or state of illness. In this regard, the preparation of suitable pharmaceutical compositions for the specific method of administration is italnet within the competence of specialists in the field of pharmaceutics. In addition, the components of such compositions are commercially available from e.g. Sigma, P.O. Box 14508, St. Louis, MO 63178. To further illustrate, you can specify that the traditional methods of manufacturing are described inRemington: The Science and Practice of Pharmacy, 20thEdition, Lippincott Williams &White, Baltimore, Maryland (2000); and H.C. Ansel et al.,Pharmaceutical Dosage Forms and Drug Delivery Systems, 7thEdition, Lippincott Williams &White, Baltimore, Maryland (1999).

Typical examples of substances which can serve as pharmaceutically acceptable carriers include, but are not limited to, the following substances: (1) sugars, such as lactose, glucose and sucrose, (2) starches, such as corn starch and potato starch, (3) cellulose, and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate, (4) powdered tragakant, (5) malt (6) gelatin, (7) talc, (8) excipients, such as cocoa butter and waxes for suppositories, (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol, (12) esters, such as etiloleat and tillaart, (13) agar, (14) buferiruemoi substances, such as magnesium hydroxide and aluminum hydroxide (15) alginic acid; (16) pyrogen-free water, (17) ISAT the technical solution, (18) ringer's solution, (19) ethyl alcohol; (20) phosphate buffer solutions, (21) compressed propellant gases, such as chlorofluorocarbons, hydrofluorocarbons, and (22) other non-toxic compatible substances used in pharmaceutical compositions.

The pharmaceutical compositions of the present invention are generally made a complete and careful blending or mixing the compound of the present invention with a pharmaceutically acceptable carrier and one or more optional components. If necessary or desired, obtained uniformly mixed, the mixture can then be molded or download in tablets, capsules, pills, cans, cartridges, dispensers and the like using conventional methods and equipment.

In one embodiment, the pharmaceutical compositions of the present invention are suitable for inhalation. Suitable for inhalation, the pharmaceutical compositions are typically in the form of an aerosol or powder. Such compositions are typically administered using well-known devices for delivery, such as spray the inhaler, the inhaler with a dosage scale (MDI), dry powder inhaler (DPI) or similar device for delivery.

In the private embodiment of the present invention the pharmaceutical composition comprising the active substance, enter the t by inhalation using a spray inhaler. Such spray devices typically generate a high-speed jet of air which causes a pharmaceutical composition containing the active substance to be sprayed in the form of a mist, floating in the respiratory tract of the patient. Therefore, when the manufacture of the drug for use in the spray inhaler active ingredient is usually dissolved in a suitable carrier to form a solution. Alternatively the active ingredient may be finely ground and combined with a suitable carrier with formation of a suspension of finely ground particles suitable for inhalation size, and "finely ground" is generally defined as having about 90% or more of particles with a diameter of less than about 10 microns. Suitable spray devices are commercially available, for example, PARI GmbH (Starnberg, German). Other spray devices include Respimat (Boehringer Ingelheim) and devices are disclosed, for example, in U.S. patent No. 6123068 and in WO 97/12687.

A typical pharmaceutical composition for use in the spray inhaler contains an isotonic aqueous solution containing from about 0.05 mg/ml to about 10 mg/ml of the compounds of formula I or its pharmaceutically acceptable salt, MES or stereoisomer.

In another private embodiment of the present invention the pharmaceutical composition comprising the active substance, introducing the by inhalation through the inhaler dry powder. These inhalers dry powder is usually injected active substance in the form of loose powder, dispergiruyushchei flow inhaled by the patient air. To obtain a free flowing powder active ingredient is usually mixed with a suitable excipient, such as lactose or starch.

A typical pharmaceutical composition for use in dry powder inhaler contains dry lactose having a particle size from about 1 μm to about 100 μm, and finely ground particles of compounds of formula I or its pharmaceutically acceptable salt, MES or stereoisomer.

Such a drug in the form of a dry powder can be manufactured, for example, the Association of lactose with the active substance and then dry mixing of the components. If desired, the composition of the active substance can be manufactured without excipient. The pharmaceutical composition is then typically loaded into a device for issuing a dry powder or in inhalation cartridges or capsules for use with a device for delivery of a dry powder.

Examples of devices for inhaled delivery of dry powder include Diskhaler (GlaxoSmithKline, Research Triangle Park, NC) (see, for example, U.S. patent No. 5035237); Diskus (GlaxoSmithKline) (see, for example, U.S. patent No. 6378519; Turbuhaler (AstraZeneca, Wilmington, DE) (see, for example, U.S. patent No. 4524769); Rotahaler (GlaxoSmithKline) (see, for example, U.S. patent No. 4353365) and Handihaler (Boehringer Ingeheim). Other examples of suitable DPI devices described in U.S. patent No. 5415162, 5239993 and 5715810 and references cited therein.

In yet another private embodiment of the present invention the pharmaceutical composition comprising the active substance is administered by inhalation using a nebulizer with a dosage scale. Such inhalers with dosing scale is usually given metered quantity of the active substance or its pharmaceutically acceptable salt by using a compressed gas propellant. Therefore, the pharmaceutical composition introduced using an inhaler with a dosage scale, usually contain a solution or suspension of the active substance in a liquefied propellant. Can be used any suitable liquefied propellant, including chlorofluorocarbons, such as CCl3F, and hydrofluroalkane (HFA), such as 1,1,1,2-Tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptathlon-n-propane (HFA 227). Due to the fact that chloroflorocarbons affect the ozone layer, typically preferred are preparations containing HFA. Additional optional components containing HFA drugs include co-solvents such as ethanol or pentane, and surfactants, such as sarbatorile, oleic acid, lecithin and glycerin. See, for example, U.S. patent No. 5225183, EP 0717987 A2 and WO 92/22286.

A typical pharmaceutical composition for use in, and is galatoire with a dosage scale contains from about 0.01% to about 5% by weight of compounds of formula I or its pharmaceutically acceptable salt, the MES or stereoisomer, from about 0% to about 20% by weight of ethanol and from about 0% to about 5% by weight surfactant, the rest HFA propellant.

Such compositions are usually prepared by introducing chilled or compressed hydrofluroalkane in a suitable vessel containing the active substance, ethanol (if present) and surfactant (if present). To obtain suspensions of the active substance is finely pulverized and then mixed with the propellant. The drug is then loaded into aerosol containers, which are part of the inhalation device with a dosing scale. Examples inhalation device with a dosing scale, developed specifically for use with the HFA propellants are given in U.S. patent No. 6006745 and No. 6143277. Alternatively, the drug is in suspension can be produced by spray drying shell of surfactants on finely ground particles of the active substance. See, for example, WO 99/53901 and WO 00/61108.

Additional examples of methods of obtaining suitable for inhalation of particles and drugs and devices suitable for dispensing inhalation, see U.S. patent No. 6268533, 5983956, 5874063 and 6221398 and WO 99/55319 and WO 00/30614.

In another embodiment, the pharmaceutical compositions of the present invention suitable for oral administration. Qualifying is for oral administration the pharmaceutical compositions may be in the form of capsules, tablets, pills, cakes, wafers, pills, powders, granules, or in the form of a solution or suspension in aqueous or non-aqueous liquid medium, or in the form of a liquid emulsion of the type oil-in-water or water-in-oil, or as an elixir or syrup and the like, each of these drugs contain the specified number of compounds of the present invention as the active component.

Intended for oral administration in a solid dosage form (i.e. in the form of capsules, tablets, pills and the like) of the pharmaceutical composition of the present invention typically contain a compound of the present invention as an active ingredient and one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate. Optional or alternative, these solid dosage forms may also contain: (1) excipients or enlargers mass, such as starches, lactose, sucrose, glucose, mannitol, and/or silicicola acid, (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or Arabian gum, (3) wetting agents such as glycerin, (4) dezintegriruetsja substances such as agar-agar, calcium carbonate, potato or manioc starch, alginic acid, certain silicates, and/or carbonate soda what I (5) substances retarding dissolution such as paraffin, (6) absorption accelerators, such as Quaternary ammonium compounds, (7) wetting agents such as cetyl alcohol and/or glycerol monostearate, (8) absorbents, such as kaolin and/or bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and/or mixtures thereof, (10) coloring agents; and (11) a buffering agent.

In the pharmaceutical compositions of the present invention may also be present releasing substances, moisturizing agents, substances for coating, podslushivala, substances imparting taste and odor, preservatives and antioxidants. Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, systeemiteoria, sodium bisulfate, metabisulfite sodium, sodium sulfite and the like, (2) soluble in oil; antioxidants, such as ascorbyl palmitate, bottled hydroxyanisol (BHA), bottled hydroxytoluene (EIT), lazetic, propylgallate, alpha-tocopherol and the like, and (3) the originators of chelate complexes, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like. Substances to cover for tablets, capsules, pills and under the service include substances used for intersolubility coatings, such as acatitla cellulose (RAA), polyvinylacetate (PVAP), the phthalate of hydroxypropylmethylcellulose, copolymers of methacrylic acid and a complex of methacrylic acid, acetosella cellulose (CAT), karboksimetiltselljuloza (MIXTURE), acetosella hydroxypropylmethylcellulose (HPMCAS) and the like.

Optionally, the pharmaceutical compositions of the present invention can also be made in the form of drugs with a slow or controlled release of the active component using, for example, hypromellose in different proportions or other polymer matrices, liposomes and/or microspheres.

In addition, the pharmaceutical compositions of the present invention can optionally contain fogging substances and can be made in a manner that provides release of the active ingredient only or mainly in certain parts of the gastrointestinal tract, optionally, in a delayed manner. Examples of compositions for the fill, which can be used include polymeric substances and waxes. The active ingredient, together with one or more of the above of excipients, can also be made, as appropriate, in the form of microcapsules.

Suitable liquid dosage forms for p is moralnego introduction include, for example, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. These liquid dosage forms typically contain the active ingredient and an inert diluent, such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylenglycol, 1,3-butyleneglycol, oils (in particular, cottonseed, groundnut, corn, oil seeds, olive, castor and sesame oils), glycerol, tetrahydrofuranyl alcohol, polyethylene glycols and fatty acid esters of sorbitol and their mixtures. Suspensions, in addition to the active ingredient, may contain suspendresume substances such as, for example, ethoxylated isostearyl alcohols, polyoxyethylenated and complex sorbitane esters, microcrystalline cellulose, Metagalaxy aluminum, bentonite, agar-agar and tragakant and mixtures thereof.

For oral administration the pharmaceutical compositions of the present invention is preferably packaged in a single dosage form. The term "unit dosage form" refers to physically discrete unit suitable for the metered introduction of the patient, i.e. each unit containing a given amount of active substance, intended to create a third which has been created therapeutic effect, alone or in combination with one or more additional units. For example, these unit dosage forms can be capsules, tablets, pills and the like.

Compounds of the present invention can also be entered using transdermal systems known transdermal delivery and excipients. For example, the compound of the present invention may be mixed with amplifiers permeability, such as propylene glycol, polietilenglikolmonostearat, azacycloheptan-2-ones and the like, and is included in the patch, or similar delivery system. Optionally, in the above transdermal compositions can be used for more excipients, including geleobrazuyuschie substances, emulsifiers and buffers.

The pharmaceutical compositions of the present invention may also contain other drugs that are administered together with a compound of formula I, its pharmaceutically acceptable salt, MES or stereoisomer. For example, the pharmaceutical compositions of the present invention can optionally contain one or more drugs selected from other bronchodilators (e.g., PDE inhibitors3, modulators of adenosine 2b and agonists β2-adrenergic receptor), anti-inflammatory drugs (who, for example, steroid anti-inflammatory drugs, such as corticosteroids; non-steroidal anti-inflammatory drugs (NSAID) and PDE inhibitors4other antagonists of muscarinic receptors (i.e. anticholinergics), anti-infective means (e.g., antibiotics against gram-positive and gram-negative bacteria or antiviral agents), antihistamines, protease inhibitors and afferent blockers (e.g., agonists D2and modulators of neurokinin). Other medicines can be used in the form of a pharmaceutically acceptable salt or solvate. In addition, in appropriate cases, other drugs can be used in the form of optically pure stereoisomers.

Typical agonists β2-adrenergic receptors, which can be used in combination with the compounds of the present invention, or in addition thereto, include, but are not limited to, salmeterol, salbutamol, formoterol, salmefamol, fenoterol, terbutaline, albuterol, isoetharine, metaproterenol, bitolterol, pirbuterol, levalbuterol and the like or their pharmaceutically acceptable salts. Other agonists β2-adrenergic receptors, which can be used in combination with the compounds of the present invention include, but are not limited to what are stated by them,

3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)hexyl]oxy}butyl)benzosulfimide and 3-(3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)heptyl]oxy}propyl)benzosulfimide and related compounds disclosed in WO 02/066422 published 29 August 2002;

3-[3-(4-{[6-([(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)phenyl]imidazolidine-2,4-dione and related compounds disclosed in WO 02/070490 published 12 September 2002;

3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl)amino)hexyl]oxy}butyl)benzosulfimide,

3-(4-{[6-({(2S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl)amino)hexyl]oxy}butyl)benzosulfimide,

3-(4-{[6-({(2R/S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl)amino)hexyl]oxy}butyl)benzosulfimide,

N-(tert-butyl)-3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl)amino)hexyl]oxy}butyl)benzosulfimide,

N-(tert-butyl)-3-(4-{[6-({(2S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl)amino)hexyl]oxy}butyl)benzosulfimide,

N-(tert-butyl)-3-(4-{[6-({(2S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl)amino)hexyl]oxy}butyl)benzosulfimide and related compounds disclosed in WO 02/076933, published 3 October 2002;

4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol and odstvennye connection disclosed in WO 03/024439, published on March 27, 2003; and their pharmaceutically acceptable salts. When using the agonist β2-adrenergic receptors present in the pharmaceutical composition in a therapeutically effective amount. Usually agonist β2-adrenergic receptors present in a quantity sufficient to provide from about 0.05 mg to about 500 μg per dose.

Typical steroid anti-inflammatory drugs, which can be used in combination with the compounds of the present invention include, but are not limited to, methylprednisolone, dexamethasone, fluticasonet, S-formerely ether 6,9-debtor-17-[(2-fornicator)oxy]-11-hydroxy-16-methyl-3-oxoandrosta-1,4-diene-17-carbothioic acid, S-(2-oxitetraciclina-3S-yl)new ether 6,9-debtor-11-hydroxy-16-methyl-3-oxo-17-propionylacetate-1,4-diene-17-carbothioic acid, beclomethasone esters (e.g. the 17-propionate ester or the 17,21-dipropionate, budesonide, flunisolide, mometasone esters (e.g. the furoate), triaminobenzene, rofleponide, ciclesonide, butixocort, RPR-106541, and ST-126 and the like or their pharmaceutically acceptable salts. When using steroid anti-inflammatory agent is present in the pharmaceutical composition in a therapeutically effective amount. Usually steroid Ave is tivovospalitiona tool is present in the amount sufficient to provide from about 0.05 mg to about 500 μg per dose.

Other suitable combinations include, for example, other anti-inflammatory drugs such as NSAID (such as cromoglycate sodium, sodium nedocromil, inhibitors of phosphodiesterase (PDE) (for example, theophylline, PDE4 inhibitors or inhibitors of mixed PDE3/PDE4), leukotriene antagonists (e.g., montelukast), inhibitors of leukotriene synthesis, iNOS inhibitors, protease inhibitors, such as inhibitors, tryptase and elastase, antagonists beta-2 integrin and agonists or antagonists of adenosine receptors (e.g., agonists adenosine receptor 2A), antagonists of cytokines (e.g., antagonists of chemokines, such as antibodies to interleukin (antibodies to IL), in particular, IL-4 therapy, IL-13 therapy, or a combination) or inhibitors of cytokine synthesis.

For example, a typical inhibitors of phosphodiesterase-4 (PDE4) or inhibitors of mixed PDE3/PDE4, which can be used in combination with the compounds of the present invention include, but are not limited to,CIS-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid, 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-deformational)cyclohexane-1-he,CIS-[4-cyano-4-(3-cyclopropylmethoxy-4-deformational)cyclohexane-1-ol],CIS-4-cyano-4-(3-cyclopentyloxy-4-methoxy who enyl)cyclohexane-1-carboxylic acid and the like or their pharmaceutically acceptable salts. Other representative PDE4 inhibitors or mixed PDE4/PDE3 include AWD-12-281 (elbion), NCS-613 (INSERM); D-4418 (Chiroscience and Schering-Plough); CI-1018 or PD-168787 (Pfizer), compounds of benzodioxole disclosed in WO99/16766 (Kyowa Hakko), K-34 (Kyowa Hakko), V-11294A (Napp), roflumilast (Byk-Gulden), compounds of phthalazinone disclosed in WO99/47505 (Byk-Gulden), Pumafentrine (Byk-Gulden now Altana), arofylline (Almirall-Prodesfarma), VM554/UM565 (Vernalis), T-440 (Tanabe Seiyaku) and T2585 (Tanabe Seiyaku).

Typical antagonists of muscarinic receptors, which can be used in combination with the compounds of the present invention, or in addition thereto, include, but are not limited to, atropine, atropine sulfate, atropine oxide, nitrate methylatropine, hydrobromide gomatropina, hydrobromide giostsiamina(d,l), the hydrobromide of scopolamine, ipratropium bromide, bromide oxytrope, Tiotropium bromide, methantheline, bromide of propantheline, bromide of anisotropine, bromide, Kleine, capirola (Robinul), iodide isopropamide, bromide mepenzolate, tridihexethyl (Patron), methyl sulfate exactly, hydrochloride cyclopentolate, Tropicamide, hydrochloride of trihexyphenidyl, pirenzepine, telenzepine, AF-DX 116 and metormin and the like or their pharmaceutically acceptable salt, or for those compounds listed as a salt, alternate pharmaceutically acceptable salt.

Typical antihistamines (i.e. antagonists of N1-receptors), which may be used in combination with the compounds of the present invention, include, but are not limited to, ethanolamines, such as the maleate of carbinoxamine, the fumarate of clemastine, hydrochloride diphenylhydramine and dimenhydrinate; ethylendiamine, such as the maleate of pyrilamine, hydrochloride of tripelennamine and citrate of tripelennamine; bonds alkylamines, such as chlorpheniramine, acrivastine; piperazines such as hydroxyzine hydrochloride, pamoate hydroxyzine, hydrochloride cyclizine, lactate of cyclizine, hydrochloride meclizine and cetirizine hydrochloride; piperidine, such as astemizole, hydrochloride levocabastine, loratadine or its decarboxy analogs, terfenadine and hydrochloride of Fexofenadine; hydrochloride azelastina; and the like or their pharmaceutically acceptable salt, or for those compounds listed as a salt, alternate pharmaceutically acceptable salt.

Suitable doses for other drugs, administered in combination with the compound of the present invention are in the range from about 0.05 g/day to about 100 g/day.

These pharmaceutical preparations illustrate typical pharmaceutical compositions of the present invention:

An example of a drug

Dry powder for administration by inhalation receive the following way:

ComponentsNumber
Connect the s of the present invention 0.2 mg
Lactose25 mg

A typical method: Compound of the present invention are finely pulverized and then pereshivayut with lactose. Received the stirred mixture then download in gelatin cartridge for inhalation. The contents of the cartridge is administered to the patient using the inhaler powder.

The example In drug

The composition in the form of a dry powder for use in the device for inhalation of a dry powder is produced as follows:

A typical method: Prepare a pharmaceutical composition having a volume ratio of finely ground connection of the present invention to lactose is 1:200. The composition is Packed into a device for inhalation of a dry powder capable of delivering from about 10 μg to about 100 μg of the compound of the present invention per dose.

The example of the drug

Dry powder for administration by inhalation in the inhaler with a dosage scale is prepared as follows:

A typical method: Prepare a suspension containing 5 wt.% compounds of the present invention and 0.1 wt.% lecithin, dispersive 10 g of compound of the present invention in the form of finely ground particles with an average size of less than 10 μm in a solution formed from 0.2 g of lecithin dissolved in 200 ml of demineralized water. WM is enzio spray dried and the resulting substance is finely ground to particles of a mean diameter of less than 1.5 microns. Particles are loaded into cartridges of compressed 1,1,1,2-Tetrafluoroethane.

Example D drug

Pharmaceutical composition for use in the inhaler with a dosage scale is prepared as follows:

A typical method: Prepare a suspension containing 5% of the compound of the present invention, 0.5% lecithin and 0.5% trehalose, dispersive 5 g of the active component in the form of finely ground particles with an average size of less than 10 μm in a colloidal solution formed from 0.5 g of trehalose and 0.5 g of lecithin dissolved in 100 ml of demineralized water. The suspension is spray dried and the resulting substance is finely ground to particles of a mean diameter of less than 1.5 microns. Particles are loaded into the compressed 1,1,1,2-Tetrafluoroethane.

Example E preparation

Pharmaceutical composition for use in the spray inhaler prepared as follows:

A typical method:

Water aerosol preparative form for use in spray the inhaler is made by dissolving 0.1 mg of the compound of the present invention in 1 ml of 0.9% sodium chloride solution, acidified with citric acid. The mixture is stirred and subjected to ultrasonic treatment, while the active ingredient is dissolved. Bring the solution pH to a value in the range of 3-8 by addition of NaOH.

Example F drugs is and

Hard gelatin capsules for oral administration are made as follows:

ComponentsNumber
The compound of the present invention250 mg
Lactose (spray dried)200 mg
Magnesium stearate10 mg

A typical method: Components are thoroughly mixed and then loaded into hard gelatin capsules (460 mg of composition per capsule).

Example G preparation

Suspension for oral administration are made as follows:

ComponentsNumber
The compound of the present invention1.0 g
Fumaric acid0.5 g
Sodium chloride2.0 g
Methylparaben0.15 g
Propylparaben0.05 g
Granulated sugar25,5 g
Sorbitol (70% solution)is 12.85 g
Veegum k (Vanderbilt Co.)1.0 g
Corrigenta 0.035 ml
Dyes0.5 mg
Di is fillerbunny water to 100 ml

A typical method: Components mixed with formation of a suspension containing 100 mg of the active ingredient per 10 ml of suspension.

Example N preparation

The preparation for injection is made in the following way:

ComponentsNumber
The compound of the present invention0.2 g
Buffer solution (0,4M)containing sodium acetate2.0 ml
HCl (0,5h.) or NaOH (0,5h.)to pH 4
Water (distilled, sterileto 20 ml

A typical method: These components are mixed and the pH adjusted to 4±0,5 using 0,5 N. HCl or 0.5 N. NaOH.

Applicability

Derivatives of biphenyl of the present invention possess both agonist activity β2-adrenergic receptors and the activity of the antagonist of muscarinic receptors, and therefore these compounds are useful for the treatment of physiological conditions mediated β2-adrenergic receptors and muscarinic receptors, i.e. physiological conditions, improve treatment agonist β2-adrenergic receptor or an antagonist of muscarinic receptors. Such physiological status which I include, for example, pulmonary disease, or disease associated with reversible obstruction of the respiratory tract such as chronic obstructive pulmonary disease (e.g. chronic and streamy bronchitis and emphysema), asthma, pulmonary fibrosis, and the like. Other conditions that can be treated include premature labour, depression, congestive heart failure, skin diseases (e.g. inflammatory, allergic, psoriatic and proliferative skin diseases), conditions under which it is desirable reduction of peptic acidity (for example, peptic ulcers and gastric ulcers), and hypertrophy of the muscles.

In accordance with one variant of the present invention relates to a method of treating a pulmonary disease comprising the administration to a patient in need of such treatment, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt, MES or stereoisomer. When used for the treatment of pulmonary diseases compounds of the present invention is usually administered by inhalation multiple doses a day, one dose per day or one dose per week. The usual dose for the treatment of pulmonary diseases is in the range from about 10 μg/day to about 200 μg/day.

With the introduction of inhalation, the compounds of the present invention typically have efficiency is increased bronchial lumen. Therefore, in another of its aspects, related methods, the present invention relates to a method of providing increased bronchial lumen in a patient, comprising the administration to a patient, which requires increasing the lumen of the bronchi, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt, MES or stereoisomer. The usual dose, which increases bronchial lumen is in the range of from about 10 μg/day to about 200 μg/day.

In one embodiment, the present invention relates to a method of treating chronic obstructive pulmonary disease or asthma, comprising the administration to a patient in need of such treatment, a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt, MES or stereoisomer. When used for the treatment of COPD (COPD) or asthma compounds of the present invention is usually administered by inhalation multiple doses per day or one dose per day. Generally, the dose for the treatment of COPD or asthma is in the range from about 10 μg/day to about 200 μg/day.

When used in this description and COPD includes chronic obstructive bronchitis and emphysema (see, for example, Barnes, Chronic Obstructive Pulmonary Disease,N Engl J Med2000: 343-269-78).

When applying for the treatment of pulmonary disease connection Nast is asego invention optionally administered in combination with other drugs. In particular, when combining compounds of the present invention to steroid anti-inflammatory agent (e.g., a corticosteroid) the pharmaceutical composition of the present invention can provide a triple treatment, i.e. to show how the activity of the agonist β2-adrenergic receptor antagonist muscarinic receptors and anti-inflammatory activity, the use of only two active components. Because of the pharmaceutical compositions containing two active components, it is usually easier to produce compositions in comparison with compositions containing the three active components, such two-component compositions provide a significant advantage over compositions containing three active components. Therefore, in the private embodiment, pharmaceutical compositions and methods of the present invention additionally contain a therapeutically effective amount of a steroid anti-inflammatory agents.

Compounds of the present invention exhibit activity as an antagonist of muscarinic receptors and agonist β2-adrenergic receptors. Therefore, particularly interesting compounds are those that, in addition to other properties, demonstrate the value of a constant Kiinhibition of binding with M3muscarinic receptor and meant the e EU 50for agonist activity β2-adrenergic receptor of less than about 100 nm, in particular less than 10 nm. Among these compounds of particular interest are compounds having muscarinic activity, expressed through a constant Kiinhibition of binding M3muscarinic receptor, which has approximately equal agonist activity β2-adrenergic receptor, which is expressed through the half-maximum effective concentration EC50defined in the testin vitrodescribed below, or in other trials. For example, special interest connections are those that are relevant constants Kiinhibition of binding with M3muscarinic receptor EU50for β2-adrenergic receptor in the range from about 30:1 to about 1:30, including from about 20:1 to about 1:20, in particular from about 10:1 to about 1:10.

In one of its aspects, related methods, the present invention also provides a method of treating a pulmonary disease comprising the administration to a patient in need of such treatment, a therapeutically effective amount of a compound which has as activity of the antagonist of muscarinic receptors, and the activity of the agonist β2-adrenergic re is atarov. In the private version of this method the input connection has a constant Kiinhibition of the M3muscarinic receptor, which is less than about 100 nm, and the half-maximum effective concentration EC50for agonism we β2-adrenergic receptor, which is less than about 100 nm. In another embodiment, a method of treating pulmonary disease includes the introduction of a therapeutically effective amount of the compounds for which the ratio of the constants Kiinhibition of the M3muscarinic receptor to the EU50for agonism β2-adrenergic receptor is in the range from about 30:1 to about 1:30.

Since the compounds of the present invention possess both agonist activity β2-adrenergic receptors and the activity of the antagonist of muscarinic receptors, such compounds are also useful as research tools for research or studying biological systems or samples having β2-adrenergic receptors and muscarinic receptors, or for finding new compounds which activity of agonist β2-adrenergic receptors, and antagonist activity of muscarinic receptors. These biological systems and samples can contain β2-ADR is ergicheskie receptors and/or muscarinic receptors. Any suitable biological system or sample, containing β2-adrenergic receptors and/or muscarinic receptors, can be used in these studies that can be conducted orin vitroorin vivo. Typical biological systems or samples for these studies include, but are not limited to, cells, cell extracts, the plasma membrane, tissue samples, mammals (such as mice, rats, Guinea pigs, rabbits, dogs, pigs, etc. and the like.

In this embodiment, a biological system or sample, containing β2-adrenergic receptors or muscarinic receptor, enter in contact with a number of compounds of the present invention, providing the manifestation of agonistic activity β2-adrenergic receptor or antagonist activity of muscarinic receptor. Then determine the results using traditional methods and equipment, such as binding assays using radio-and functional tests. These functional assays include ligand-mediated changes in intracellular cyclic adenosine monophosphate (cyclic amp, camp), ligand-mediated changes in activity of the enzyme adenylylcyclase (which synthesizes camp), ligand-mediated changes include the value of guanosine 5'-O-(-thio)triphosphate([ 35S]GTP S) in the selected membrane through catalyzed by receptor currency GDP [35S]GTP S, ligand-mediated changes in free intracellular calcium ions (measured, for example, the reader FLIPR® from Molecular Devices, Inc). Compounds of the present invention will exert an agonistic effect on β2-adrenergic receptor or to cause its activation and exert antagonistic effects on muscarinic receptors or decrease their activation in any of the functional assays listed above, or assays of a similar nature. The number of compounds used in these studies typically range from about 0.1 nanomoles to about 100 nanomoles.

In addition, the compounds of the present invention can be used as research tools for finding new compounds which activity of agonist β2-adrenergic receptors, and antagonist activity of muscarinic receptors. In this embodiment, data binding β2-adrenergic receptor and muscarinic receptor (for example, certain methodsin vitrosubstitution using radioligand) for the test compound or group of test compounds is compared with data binding β2-adrenergic what eception and muscarinic receptor for compounds of the present invention, to identify the compound, which show binding, approximately equal or superior binding β2-adrenergic receptor and/or muscarinic receptor, if such connection exists. This aspect of the invention includes as separate options, and obtaining data for comparison (using appropriate methods of analysis), and analysis of test data to identify test compounds of interest.

In some cases, compounds of the present invention may have either a weak activity of the antagonist of muscarinic receptors, or a weak agonist activity β2-adrenergic receptors. Specialists in this field will be clear that in these cases, these compounds all have the same usefulness as mainly or agonist β2-adrenergic receptor or an antagonist of muscarinic receptors, respectively.

Properties and applicability of the compounds of the present invention can be demonstrated by different methods of analysisin vitroandin vivowell-known specialists in this field. For example, a typical analysis methods are described in more detail in the following examples.

EXAMPLES

Following receipt and examples are given to illustrate private in the ways of the present invention. These private options, however, do not imply any limitation of the scope of the invention, if it is not mentioned explicitly.

The following abbreviations have the following meanings unless otherwise indicated and any other abbreviations used herein and not defined have their standard values:

AC - adenylylcyclase

Ach - acetylcholine

ATCC - American type culture collection

BSA - bovine serum albumin

of camp (cyclic adenosine - 3'-5' cyclic monophosphate

CHO - Chinese hamster ovary

cM5- cloned M5receptor chimpanzee

DHM - dichloromethane (i.e. methylene chloride)

DIPEA IS N,N-diisopropylethylamine

dPBS - buffered phosphate solution, Dulbecco

DMEM - modified Dulbecco Wednesday Needle

DMSO - dimethyl sulfoxide

EDTA - ethylenediaminetetraacetic acid

Emax - maximum efficiency

EtOAc - ethyl acetate

EtOH - ethanol

FBS - fetal bovine serum

FLIPR - reader tablet reader for fluorimetric analysis

Gly is glycine

HATU - hexaphosphateO-(7-asobancaria-1-yl-N,N,N N'-tetramethylurea)

HBSS - buffer saline, Henk

HEK - cell human embryo kidney

HEPES - 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

hM1- cloned human M1receptor

hM2- clone the integration of human M 2receptor

hM3- cloned human M3receptor

hM4- cloned human M4receptor

hM5- cloned human M5receptor

HPLC - high performance liquid chromatography

IBMX 3 - isobutyl-1-methylxanthines

%Eff - efficiency in %

PBS - buffered phosphate solution

PyBOP - hexaphosphatebenzotriazol-1-electroparadise

rpm - revolutions per minute

TFA - triperoxonane acid

THF (THF - tetrahydrofuran

Tris - Tris(hydroxymethyl)aminomethan

Unless otherwise indicated, the reagents, the starting materials and solvents were purchased from a vending suppliers such as Aldrich, Fluka, Sigma and the like) and used without further purification.

In the examples below, HPLC analysis was performed using the instrument Agilent (Palo Alto, CA) 1100 series with speakers Bond Bonus RP 2,1×50 mm with Agilent (C14 column)having a particle size of 3.5 micrometers. Detection was performed by UV absorption at 214 nm. Data HPLC 10-70 received at a flow rate of 0.5 ml/min 10%-70% In 6 minutes. Mobile phase a consisted of 2%-98%-0,1% ACN-N2O-TFA and mobile phase b consisted of 90%-10%-0,1% ACN-N2O-TFA. Using mobile phases a and b, described above, received data HPLC 5-35 and HPLC data 10-90 5 minute gradient.

Yes the nye liquid chromatography with mass spectrometry (LC-MS) were obtained using the instrument model API-150EX from the company Applied Biosystems (Foster City, CA). Data LC-MS 10-90 received from 10%-90% mobile phase b for 5 min gradient.

Small purification was performed using API-150EX Prep Workststion system from the company Applied Biosystems. Mobile phase was A: water+0.05% of vol./about. TFA; b: acetonitrile+0.05% of vol./about. TFA. For large quantities (usually regenerated sample of about 3-50 mg) used the following conditions: the flow rate of 20 ml/min, 15 min gradient and column Prism RP 20 mm×50 mm particles 5 micrometers (Thermo Hypersil-Keystone, Bellefonte, PA). For large collections (usually more than 100 mg of the crude sample) used the following conditions: a flow rate of 60 ml/min, 30 min gradients and Microsorb column BDS 41,4 mm×250 mm with particles of 10 micrometers (Varian, Polo Alto, CA).

Specific rotation for chiral compounds (designated as [α]20D) was measured using a Jasco Polarimeter (model P-1010) with a halogen light source with a tungsten filament and 589 nm filter at 20°C. the Samples of the tested compounds is usually measured at 1 mg/ml of water.

Getting 1

N-1,1'-Biphenyl-2-yl-N'-4-(1-benzyl)piperidinylidene

Biphenyl-2-isocyanate (50 g, 256 mmol) was dissolved in acetonitrile (400 ml) at ambient temperature. After cooling to 0° (C) was added over 5 min a solution of 4-amino-N-benzylpiperidine (48,8 g, 256 mmol) in acetonitrile (400 ml). Immediately observed sedimentation After 15 min was added acetonitrile (600 ml) and the resulting viscous mixture was stirred for 12 h at 35° C. Then the solid was filtered and washed with cold acetonitrile, and then dried in vacuum to obtain specified in the title compound (100 g, yield 98%). MSm/z: [M+H+] calculated for C25H27N3O 386,22; found 386,3.

Getting 2

N-1,1'-Biphenyl-2-yl-N'-4-piperidinylidene

Product obtain 1 (20 g, 52 mmol) was dissolved in a mixture of anhydrous methanol and anhydrous DMF (3:1, 800 ml). Was added an aqueous solution of hydrochloric acid (0.75 ml of 37% concentrated solution, 7.6 mmol) and the solution was vigorously barbotirovany nitrogen gas for 20 minutes was Added to the catalyst Perlman (Pd(OH)25 g) in a stream of nitrogen, then placing the reaction mixture in an atmosphere of hydrogen (balloon). The reaction mixture was allowed to mix for 4 days and then double-passed through the loose layers of celite to remove the catalyst. Then removed under reduced pressure, the solvent is obtaining specified in the title compound (13 g, yield 85%). MSm/z: [M+H+] calculated for C18H21N3O 296,17; found 296,0.

Alternative,N-1,1'-biphenyl-2-yl-N'-4-piperidinylidene synthesized by heating together biphenyl-2-isocyanate (50 g, 256 mmol) and 4-amino-Nbenzylpiperidine (51,1 g, 269 mmol) at 70°C for 12 h (the reaction was controlled by LC-MS). The reaction is mesh was cooled to 50° With and added ethanol (500 ml) followed by slow addition of 6M hydrochloric acid (95 ml). The reaction mixture was cooled to room temperature. Was added to the reaction mixture of ammonium formate (4,84 g, 768 mmol) and the solution was vigorously barbotirovany nitrogen gas for 20 min, then adding palladium (10 wt.% (on dry matter basis) on activated carbon) (10 g). The reaction mixture was heated at 40°C for 12 h, then filtered through a loose layer of celite was removed under reduced pressure the solvent. To the crude residue was added 1M hydrochloric acid (20 ml) was added 10 n sodium hydroxide, bringing the pH to 12. The aqueous layer was extracted with ethyl acetate (2×80 ml), dried (magnesium sulfate) and removed under reduced pressure, the solvent is obtaining specified in the title compound as a solid (71.7 g, yield 95%). MSm/z: [M+H+] calculated for C18H21N3O 296,17; found 296,0.

Getting 3

N-1,1'-Biphenyl-2-yl-N'-4-[1-(9-hydroxyaryl)]piperidinylidene

9-Bromo-1-nonanol (4,84 g, and 21.7 mmol) was added to a stirred solution of the product obtain 2 (5.8 g, of 19.7 mmol) and diisopropylethylamine (10,29 ml, to 59.1 mmol) in acetonitrile (99 ml) at 50°C. the Reaction mixture was heated at 50°C for 8 hours and Then the reaction mixture was allowed to cool and deletion is whether under reduced pressure the solvent. The residue was dissolved in dichloromethane (100 ml), washed with saturated aqueous sodium bicarbonate (2×50 ml) and dried (magnesium sulfate). Was removed under reduced pressure the solvent. The crude product was purified flash chromatography (system of dichloromethane:methanol:ammonia) to obtain specified in the connection header (7,1 g, 16.2 mmol, yield 82%).

Getting 4

N-1,1'-Biphenyl-2-yl-N'-4-[1-(9-octanoyl)]piperidinylidene

Dimethyl sulfoxide (490 μl, 6,9 mmol) and then diisopropylethylamine (324 μl, of 3.45 mmol) was added to a solution of the product for the preparation of 3 (500 mg, 1.15 mmol) in dichloromethane (11.5 ml) at -10°C in nitrogen atmosphere. The reaction mixture was stirred at -15°C for 15 min and then added to portions of a complex of sulfur trioxide and pyridine (549 mg,of 3.45 mmol). The reaction mixture was stirred at -15°C for 1 h and then added water (10 ml). The organic phase is then separated, washed with water (10 ml) and dried (sodium sulfate). Was removed under reduced pressure, the solvent is obtaining specified in the title compound (475 mg, of 1.09 mmol, yield 95%). LC-MS (10-70) Rt=3,39.

Getting 5

N-1,1'-Biphenyl-2-yl-N'-4-[1-(9-aminanani)]piperidinylidene

Palladium (10 wt.% (on dry matter basis) on activated carbon) (1.5 g) was added to a stirred solution of the product of 4 (1,58 g, 3,63 m is ol) and benzylamine (516 μl, 4,72 mmol) in methanol (36,3 ml). The reaction mixture was placed in an atmosphere of hydrogen. After stirring for 12 h the reaction mixture was filtered through a loose layer of celite and washed with methanol (10 ml). Was removed under reduced pressure, the solvent is obtaining specified in the title compound (1.50 g, of 3.45 mmol, yield 95%). LC-MS (10-70) Rt=2,35; MSm/z: [M+H+] calculated for C27H40N4O1437,06; found 437,5.

Getting 6

8-Benzyloxy-5-(2,2-dihydroxyethyl)-1H-quinoline-2-he

(a) 8-Acetoxy-1H-quinoline-2-he

8-Hydroxyquinoline-N-oxide (160,0 g, 1.0 mol), available from Aldrich company, Milwaukee, WI, and acetic anhydride (800 ml, 8.4 mol) was heated at 100°C for 3 h and then cooled in ice. The product was collected on a Buechner funnel, washed with acetic anhydride (2×100 ml) and dried under reduced pressure to obtain 8-acetoxy-1H-quinoline-2-she (144 g) as a solid.

(b) 5-Acetyl-8-hydroxy-1H-quinoline-2-he

A suspension of aluminium chloride (85,7 g, 640 mmol) in 1,2-dichloroethane (280 ml) was cooled in ice was added the product of stage (a) (56,8 g, 280 mmol). The mixture was heated to room temperature and then was heated at 85°C. After 30 min was added acetylchloride (1.5 ml, 21 mmol) and the mixture was heated for 60 minutes and Then the reaction mixture was cooled and added to 1 N. hydrochloric acid (3 l) at 0°With n the improper mixing. After stirring for 2 h, the solids were collected on a Buechner funnel, washed with water (3×250 ml) and dried under reduced pressure. The crude product is isolated at several download (135 g)were combined and triturated in dichloromethane (4 l) for 6 hours the Product was collected on a Buechner funnel and dried under reduced pressure to obtain 5-acetyl-8-hydroxy-2(1H)-Hinayana (121 g).

(C) 5-Acetyl-8-benzyloxy-1H-quinoline-2-he

The product of stage (b) (37,7 g, 186 mmol) was added N,N-dimethylformamide (200 ml) and potassium carbonate (34,5 g, 250 mmol) and then benzylbromide (31.8 g, 186 mmol). The mixture was stirred at room temperature for 2.25 hours and then was poured into a saturated solution of sodium chloride (3.5 l) at 0°and was stirred for 1 hour. The product was collected and dried on the Buchner funnel for 1 hour, the obtained solid substance was dissolved in dichloromethane (2 l) and the resulting mixture was dried over sodium sulfate. The solution was filtered through a loose layer of Celite, which was then washed with dichloromethane (5×200 ml). The combined filtrate was then concentrated to dryness and the resulting solid triturated in ether (500 ml) for 2 hours the Product was collected on a Buechner funnel, washed with ether (2×250 ml) and dried under reduced pressure to obtain 5-acetyl-8-benzyloxy-1H-quinoline-2-she (44 g) in powder form.

(d) 8-Benzyloxy-5-2,2-dihydroxyethyl)-1H-quinoline-2-he

To a suspension of the product of stage (C) (10.0 g, to 34.1 mmol) in DMSO (60 ml) was added 48% wt./wt. a solution of Hydrobromic acid (11.8 ml of 102.3 mmol). The mixture was heated to 60°C for 16 h and then was allowed to cool to room temperature. Was added water (100 ml) and the resulting suspension was stirred at room temperature for 0.5 h until it has cooled down to 0°C. the Product was collected on a Buechner funnel, then dried under reduced pressure to obtain 8-benzyloxy-5-(2,2-dihydroxyethyl)-1H-quinoline-2-it (12.2 g) as a solid.

Getting 7

1-(1-{9-[2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethylamino]nonyl}piperidine-4-yl)-3-biphenyl-2-rocephine

Products get 5 (183 mg, 0.42 mmol) and receive 6 (149 mg, 0.46 mmol) was stirred in dichloroethane (4,2 ml) at ambient temperature for 2 hours Then added triacetoxyborohydride sodium (267 mg, of 1.26 mmol) and the reaction mixture was stirred for another 12 hours Then the reaction mixture was diluted with dichloromethane (10 ml), washed with saturated aqueous sodium bicarbonate (10 ml), dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude reaction mixture was purified flash chromatography (5-10% methanol in dichloromethane, 0.5% ammonium hydroxide) to obtain the specified title compound (144 mg, 0.20 mmol, yield 48%). LC-MS (10-70) Rt=3,48; the m/z: [M+H+] calculated for C45H55N5O4730,4; found 730,7.

Example 1

1-Biphenyl-2-yl-3-(1-{9-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-yl)urea

To a stirred solution of the product receiving 7 (144 mg, 0.20 mmol) in methanol (2 ml) was added palladium (10 wt.% (on dry matter basis) on activated carbon) (63 mg) and the reaction mixture was placed in an atmosphere of hydrogen. After 12 h stirring, the reaction mixture was filtered through a loose layer of celite, washed with methanol (2 ml) and then was removed under reduced pressure the solvent. The obtained residue was purified preparative HPLC to obtain specified in the title compound (10 mg). LC-MS (10-70) Rt=2,8; MSm/z: [M+H+] calculated for C38H49N5O4640,3; found 640,5.

Getting 8

Piperidine-4-silt ether-biphenyl-2-carbamino acid

Biphenyl-2-isocyanate (97.5 g, 521 mmol) and 4-hydroxy-1-benzylpiperidine (105 g, 549 mmol), both available from Aldrich company, Milwaukee, WI, were heated together at 70°12 h, during which the formation of piperidine-4-silt ether-biphenyl-2-carbamino acid controlled LC-MS. Then the reaction mixture was cooled to 50°and added ethanol (1 l), then slowly added 6M hydrochloric acid. Then the reaction mixture was cooled to a tempera is URS environmental was added ammonium formate (98,5 g, 1.56 mol) and the solution was vigorously barbotirovany nitrogen gas for 20 minutes Then added palladium (10 wt.% (on dry matter basis) on activated carbon) (20 g). The reaction mixture was heated at 40°C for 12 h and then filtered through a loose layer of celite. Then removed under reduced pressure, the solvent and the crude residue was added 1M hydrochloric acid (40 ml). Then added sodium hydroxide (10 BC), bringing the pH to 12. The aqueous layer was extracted with ethyl acetate (2×150 ml) and dried (magnesium sulfate), and then was removed under reduced pressure, the solvent is obtaining specified in the connection header (155 g, 100%). LC-MS (10-70) Rt=2,52; MSm/z: [M+H+] calculated for C18H20N2O2297,15; found 297,3.

9

N,N-(Di-tert-butoxycarbonyl)-9-bromoisatin

A solution of di-tert-butoxycarbonylamino (3,15 g, 14.5 mmol) in N,N-dimethylformamide (0,28 ml) was cooled to 0°C for about 10 minutes was Added sodium hydride, 60% in mineral oil (of 0.58 g, 14.5 mmol) and the reaction mixture was stirred at 0°C for 10 min. the Reaction mixture was removed from the ice bath and allowed to warm to room temperature for about 30 minutes, the Reaction mixture was then again cooled to 0°and the solution was added to 1.9 dibromononane (2,46 ml, 12.1 mmol who) in dimethylformamide (100 ml). The reaction mixture was stirred over night at room temperature. After 24 h MS analysis showed that the reaction had ended. The reaction mixture was concentrated to dryness and diluted with ethyl acetate (100 ml). The organic layer was washed with saturated sodium bicarbonate solution (2×100 ml), saturated salt solution (100 ml), dried (magnesium sulfate) and concentrated under reduced pressure to get crude product, which was purified column chromatography on silica gel using 5% ethyl acetate in hexano, obtaining specified in the connection header. MSm/z: [M+H+] calculated for C19H36N1O4Br 423,18; found 423.

Receive 10

1-(9-Di-tert-butoxycarbonylamino)nonyl]piperidine-4-silt ether-biphenyl-2-carbamino acid

A mixture (1:1) acetonitrile and N,N-dimethylformamide (50 ml) was added to the products obtain 8 (3.0 g, 10.1 mmol) and obtain 9 (5,1 g, 12.2 mmol) and triethylamine (1,42 ml, 10.1 mmol). The reaction mixture was stirred at ambient temperature for 24 h and monitored by the analysis of LC-MS. Then the reaction mixture was concentrated and diluted with ethyl acetate (50 ml). The organic layer was washed with saturated sodium bicarbonate solution (2×50 ml) and saturated salt solution (50 ml). The organic phase is then dried over magnesium sulfate and concentrated with what rucenim 6.5 g of crude oil. The oil was purified by chromatography on silica gel using a mixture (1:1) hexane/ethyl acetate, to obtain specified in the title compound (3 g). MSm/z: [M+H+] calculated for C37H55N3O6638,41; found 639.

Receipt 11

1-(9-Aminanani)piperidine-4-silt ether-biphenyl-2-carbamino acid

Triperoxonane acid (11 ml) was added to a solution of the product 10 (7.2 g, 11.3 mmol) in dichloromethane (56 ml). After 2 h the analysis of LC-MS showed that the reaction had stopped. The reaction mixture was then concentrated to dryness and diluted with ethyl acetate (75 ml). Then added sodium hydroxide (1 BC)until the pH of the mixture has not reached 14. The organic phase was then collected and washed with a saturated solution of sodium bicarbonate (2×50 ml) and saturated salt solution (50 ml). The organic phase is then dried over magnesium sulfate and concentrated to obtain specified in the title compound (5.5 g). MSm/z: [M+H+] calculated for C27H39N3O2438,30; found 439.

Getting 12

1-{9-[2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

The product receiving 11 (196 mg, 0.43 mmol) was dissolved in dichloroethane (4 ml) was added triacetoxyborohydride sodium (101 mg, 0.48 mmol). The reaction mixture was stirred at the tempo is the atur environment for about 10 min and then was added 8-benzyloxy-5-(2,2-dihydroxyethyl)-1H-quinoline-2-he (obtaining 6) (141 mg, 0.43 mmol). Analysis by LC-MS showed that the reaction was over in about 2 hours To the reaction mixture were added methanol (1 ml) and then slowly added borohydride sodium (18 mg, 0.48 mmol). After 1 h the analysis by LC-MS showed that the reaction had ended. Then the reaction mixture was extinguished aqueous solution of ammonium chloride and the resulting mixture was extracted with dichloromethane. The organic phase was washed with saturated sodium bicarbonate solution (2×50 ml) and saturated salt solution (10 ml). Then the organic phase was dried over magnesium sulfate and concentrated to obtain 315 mg of yellow solid. The solid was purified by chromatography on silica gel using 10% methanol in dichloromethane, to obtain specified in the title compound (64 mg). MSm/z: [M+H+] calculated for C43H55N4O5730,40; found 731.

Example 2

DATEFORMAT 1-{9-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

A solution of the product 12 (64 mg, 0.09 mmol) in methanol (450 ml) was purged with nitrogen. Then was added palladium on carbon (10%, 10 mg), the reaction mixture was placed in an atmosphere of hydrogen from the container and then stirred. Analysis by LC-MS showed that the reaction was ended after 9 hours, the Reaction mixture was then filtered and f is ltrate concentrated to obtain a yellow powdery solid. The solid was purified preparative HPLC (5-35 60 min) to obtain the specified title compound (19 mg). MSm/z: [M+H+] calculated for C38H48N4O5641,36; found 641.

13

8-Benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethylsilyloxy)ethyl]-1H-quinoline-2-he

(a) 8-Benzyloxy-5-(2-bromoacetyl)-1H-quinoline-2-he

5-Acetyl-8-benzyloxy-1H-quinoline-2-he (obtaining 6) (20,0 g, 68.2 mmol) was dissolved in dichloromethane (200 ml) and cooled to 0°C. using a syringe was added diethylether of boron TRIFLUORIDE (10.4 ml, 82,0 mmol) and the mixture was heated to room temperature to obtain a thick slurry. The suspension was heated at 45°C (oil bath) was added over 40 minutes a solution of bromine (11.5 g, 72.0 mmol) in dichloromethane (100 ml). The mixture was kept at 45°With a further 15 min and then cooled to room temperature. The mixture was concentrated under reduced pressure and then triturated in 10% aqueous solution of sodium carbonate (200 ml) for 1 h, the Solids were collected on a Buechner funnel, washed with water (4×100 ml) and dried under reduced pressure. The product of the two experiments were combined for purification. The crude product (52 g) was ground in 50% methanol in chloroform (500 ml) for 1 h, the Product was collected on a Buechner funnel and washed with 50% methanol in chloroform (2×50 ml) and methanol (2×50 ml). The solid is left the house taking under reduced pressure to obtain specified in the connection header (to 34.1 g) in powder form.

(b) 8-Benzyloxy-5-((R)-2-bromo-1-hydroxyethyl)-1H-quinoline-2-he

(R)-(+)-α,α-Diphenylprolinol (30.0 g, 117 mmol) trimethylboroxine (11,1 ml, 78 mmol) were combined in toluene (300 ml) and stirred at room temperature for 30 minutes the Mixture was placed in an oil bath at 150°and liquid drove away. Added toluene by aliquot of 20 ml and the distillation was continued 4 hours was added 300 ml of toluene. Then the mixture was cooled to room temperature. An aliquot 500 ál evaporated to dryness and weighed (246 mg), determined that the concentration of the catalyst was 1,8M.

8-Benzyloxy-5-(2-bromoacetyl)-1H-quinoline-2-he (90.0 g, 243 mmol) was placed in a nitrogen atmosphere was added in tetrahydrofuran (900 ml) followed by the addition of the above-described catalyst (1.8m in toluene, 15 ml, 27 mmol). The suspension was cooled to -10±5°in a bath with a mixture of ice/isopropanol. Was added for 4 h borane (1.0m in THF, 294 ml, 294 mmol). The reaction mixture is then stirred for another 45 min at -10°With, then was slowly added to methanol (250 ml). The mixture was concentrated in vacuo and the residue was dissolved in boiling acetonitrile (1.3 l), filtered while hot and then cooled to room temperature. The crystals were filtered off, washed with acetonitrile and dried in vacuum to obtain specified in the connection header (72.5 g, 196 mmol, yield 81%, 95%, 95% purity according to HPLC).

(C) 8-Benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethylsilyloxy)ethyl]-1H-quinoline-2-he

The product of stage (b) (70,2 g, 189 mmol) was added N,N-dimethylformamide (260 ml) and the resulting mixture was cooled in a bath with ice in a nitrogen atmosphere. Within 5 min was added 2,6-lutidine (40,3 g, 376 mmol) and then slowly added tert-butyldimethylchlorosilane (99,8 g, 378 mmol), keeping the temperature below 20°C. the Mixture was allowed to warm to room temperature over 45 min for 10 min was added to the mixture dropwise methanol (45 ml) and the mixture was distributed between a mixture of ethyl acetate/cyclohexane (1:1, 500 ml) and the mixture of water/saturated salt solution (1:1, 500 ml). The organics were washed two more times with a mixture of water/saturated salt solution (1:1, 500 ml each time). The combined organics were evaporated under reduced pressure to obtain light yellow oil. To the oil was added to two separate portions of cyclohexane (400 ml) and continued distillation prior to the formation of thick white mist. To the suspension was added cyclohexane (300 ml) and the resulting white crystals were filtered off, washed with cyclohexane (300 ml) and dried under reduced pressure to obtain specified in the connection header (75,4 g, 151 mmol, yield 80%, 98.6% of it).

Getting 14

1-{9-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethylamino]nonyl}piperidine-4-silt EPE is biphenyl-2-ylcarbamate acid

Product obtain 13 (3,9 g, 8.17 mmol) was added to a solution of the product receiving 11 (5.0 g, to 11.4 mmol) in THF (20 ml) followed by the addition of sodium bicarbonate (2.0 g, 24.5 mmol) and sodium iodide (1.8 g, 12.2 mmol). The reaction mixture was heated at 80°C for 72 h and Then the reaction mixture was cooled, diluted with dichloromethane (20 ml) and the organic phase is washed with saturated sodium bicarbonate solution (2×50 ml) and saturated salt solution (50 ml). Then the organic phase was dried (magnesium sulfate) and concentrated to obtain 6.5 g of the crude product. The crude product was purified by chromatography on silica gel, elwira 3% methanol in dichloromethane, to obtain specified in the title compound (1.4 g, yield 21%).

Receive 15

1-{9-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Hydrofloric of triethylamine (376 μl, 2.3 mmol) was added to a solution of the product receiving 14 (1.3 g, 1.5 mmol) in THF (8 ml) and the reaction mixture was stirred at ambient temperature. After 5 h the reaction was finished according to the analysis of LC-MS. Then the reaction mixture was suppressed by the addition of 1 N. NaOH to pH 14, was diluted with ethyl acetate (20 ml) and then washed with 1 N. NaOH (20 ml) and saturated salt solution (20 ml). The organic phase is then separated, dried over self is that magnesium and concentrated to obtain specified in the title compound (1.1 g).

Example 3

DATEFORMAT 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

A solution of the product receiving 15 (1.1 g, 1.5 mmol) was purged with nitrogen was added palladium on carbon (10%, 110 mg). The reaction mixture was stirred in hydrogen atmosphere at a pressure cylinder. Analysis by LC-MS showed that the reaction was ended after 9 hours, the Reaction mixture was then filtered and the filtrate was concentrated to obtain a yellow solid. The solid was purified preparative HPLC (5-30 for 60 min) to obtain the specified title compound (510 mg). MSm/z: [M+H+] calculated for C38H48N4O5641,36; found 641. HPLC-method 10-70: 3,207. [α]20D=-23,6 (C=1.0 mg/ml, water).

Example 3A

DATEFORMAT 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

An alternative that is listed in the title compound was prepared as follows:

(a) 9-Brokenangel

In a 100-ml round-bottom flask equipped with a magnetic stirrer, addition funnel and temperature controller was added in nitrogen atmosphere 9-brandonanoel (of 8.92 g, 40 mmol) and dichloromethane (30 ml). The resulting mixture was cooled to 5°and was added to dissolve the sodium bicarbonate (0,47 g, 5.6 mmol) and potassium bromide (0,48 g, 4 mmol) in water (10 ml). Added free radical 2,2,6,6-tetramethyl-1-piperidinyloxy (TAMRA) (63 mg, 0.4 mmol) and then was added dropwise 10-13% bleaching solution (27 ml) via addition funnel at a speed that facilitates maintaining the temperature at about 8° (±2° (C) using a cooling bath of ice (about 40 min). After adding the bleach solution and the mixture was stirred 30 min, maintaining the temperature at approximately 0°C. was Added a solution of sodium bisulfite (1.54 g) in water (10 ml) and the resulting mixture was stirred at room temperature for 30 minutes and Then separated the layers of the mixture and turbid aqueous layer was extracted with dichloromethane (1×20 ml). The combined dichloromethane layers were then washed with water (1×30 ml), dried (MgSO4), filtered and concentrated under reduced pressure to obtain specified in the header of the intermediate compound (8,3 g, yield 94%)which was used without further purification in the next stage.

(b) 9-Bromo-1,1-dimethoxysilane

In a 100-ml round bottom flask was introduced 9-brokenangel (7.2 g, 32.5 mmol), methanol (30 ml) and triethylorthoformate (4 ml of 36.5 mmol). Solution was added 4 N. hydrochloric acid in dioxane (0.2 ml, 0.8 mmol) and the resulting mixture was boiled under reflux for 3 hours of Reaction the second mixture was then cooled to room temperature and was added solid sodium bicarbonate (100 mg, 1.2 mmol). The resulting mixture was concentrated under reduced pressure up to a quarter of its original volume and then added ethyl acetate (50 ml). The organic layer was washed with water (2×40 ml), dried (MgSO4), filtered and concentrated under reduced pressure to obtain specified in the header of the intermediate compound (8.44 grams (yield 97%)in the form of a liquid, which was used in the next stage without additional purification.

(C) 1-(9,9-Dimethoxyphenyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

In a 50 ml three-neck round bottom flask was introduced piperidine-4-silt ether-biphenyl-2-ylcarbamate acid (1 g, to 3.38 mmol) and acetonitrile (10 ml) suspension. To the resulting suspension was added 9-bromo-1,1-dimethoxysilane (1.1 g, 1.3 mmol) and triethylamine (0,57 g, 4.1 mmol) and the resulting mixture was heated at 65°C for 6 h (the reaction was monitored by HPLC, as long as the amount of substance was <5%). Then the reaction mixture was cooled to room temperature, and during this time, the mixture formed a thick slurry. Was added water (5 ml) and the mixture was filtered, collecting the solid by a glass filter. The solid is washed pre-mixed solution of acetonitrile (10 ml) and water (5 ml) and then another pre-mixed solution of acetonitrile (10 ml) and water is (2 ml). The obtained solid substance was dried in air to obtain specified in the header of the intermediate compound (1,37 g, 84%, purity>96%according to LC,1H-NMR) as a white solid.

(d) 1-(9-Octanoyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

In a 500-ml round bottom flask with magnetic stirrer was introduced 1-(9,9-dimethoxyphenyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid (7.7 g, 15.9 mmol) and then acetonitrile (70 ml) and aqueous 1M hydrochloric acid (70 ml). The resulting mixture was stirred at room temperature for 1 h and then added dichloromethane (200 ml). The mixture was stirred 15 min and then the layers were separated. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to obtain specified in the header of the intermediate compound (6.8 g)which was used without further purification in the next stage.

(e) 1-(9-{Benzyl-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethyl]amino}nonyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

In a 300-ml round bottom flask was introduced 5-[(R)-2-benzylamino-1-(tert-butyldimethylsilyloxy)ethyl]-8-benzyloxy-1H-quinoline-2-he (5 g, 9.73 mmol), dichloromethane (100 ml) and glacial acetic acid (0.6 ml, 10 mmol). The resulting mixture was cooled to 0°using bath with ice is m, and added with stirring, 1-(9-octanoyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid (4.6 g, 9.73 mmol). The resulting mixture was stirred at 0°C for 30 minutes and then was added in portions over 15 minutes triacetoxyborohydride sodium (6,15 g, 29 mmol). The reaction mixture was stirred at 0°C-10°C for 2 hours and then added to saturated aqueous sodium bicarbonate solution (50 ml) and the mixture was stirred for 15 minutes. Then the layers were separated and the organic layer washed with 5% aqueous sodium chloride solution (50 ml), dried (MgSO4), filtered and concentrated under reduced pressure to obtain specified in the header of the intermediate compound (8.5 g, purity 80% according to HPLC), which was used without further purification in the next stage.

(f) 1-{9-[(R)-2-(tert-Butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

In a 200-ml round bottom flask was introduced intermediate compound from step (e) (8.5 g, 9 mmol), ethanol (100 ml) and glacial acetic acid (0.54 ml, 18 mmol) and the mixture was stirred to dissolve the solids. The reaction mixture was purged with hydrogen for 5 min and then was added 10% palladium on carbon (1.7 g). The resulting mixture was stirred at room temperature, slowly barbotine che is ez reaction mixture hydrogen to becoming > 95%observed by HPLC (about 8-9 hours). The mixture was then filtered through a loose layer of celite was removed under reduced pressure the solvent. The residue was purified by chromatography on silica gel (15 g silica/1 g of raw material), using a 5% Meon in DHM/0,5% NH4HE (10×150 ml), 8% Meon in DHM/0,5% NH4HE (10×150 ml) and 10% Meon in DHM/0,5% NH4HE (10×150 ml). The appropriate fractions were combined and removed under reduced pressure, the solvent while maintaining the temperature <35°With receipt specified in the header of the intermediate compound (4,05 g, purity 97%).

(g) 1-{9-[(R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

In a 200-ml round bottom flask was introduced intermediate compound from step (f) (4,05 g, are 5.36 mmol) and dichloromethane (80 ml) and the resulting mixture was stirred to dissolve the solids. Added trihydrated of triethylamine (2.6 ml, 16 mmol) and continued stirring in nitrogen atmosphere for 18 to 20 hours was Added methanol (20 ml), then was slowly added saturated aqueous sodium bicarbonate solution (50 ml) and the mixture was stirred for 15 minutes and Then layers were separated and the organic layer was washed saturated aqueous sodium chloride (20 ml), dried (MgSO4), filtered and concentrated under reduced pressure p is the receiving specified in the title compound (3.5 g, purity 98% by HPLC) as a yellow solid.

Example 3B

Salt of naphthalene-1,5-disulfonic acid 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

1-{9-[(R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid (1.0 g, 1.56 mmol, free base) was dissolved in methanol (10 ml; low water content). Solution was added naphthalene-1,5-disulfonic acid (0.45 g, 1.56 mmol) in methanol (5 ml; low water content) and the reaction mixture was stirred at 30°C for two hours and then at room temperature overnight (18 h). Obtained a dense suspension was filtered, the residue from the filtration was washed with methanol (5 ml) and then dried to obtain specified in the connection header (1,16 g, yield 80%) as not quite white crystalline solid.

Getting 16

N-{2-Benzyloxy-5-[(R)-2-bromo-1-(tert-butyldimethylsilyloxy)ethyl]phenyl}formamide

(R)-2-Bromo-1-(3-formamido-4-benzyloxyphenyl)ethanol (9,9 g, 28 mmol) was dissolved in dimethylformamide (36 ml). Added imidazole (2.3 g, 34 mmol) and tert-butyldimethylsilyl (4.7 g, 31 mmol). The solution was stirred in nitrogen atmosphere for 72 hours More were added imidazole (0.39 g, 5.7 mmol) and tert-is otherdimensional (0.64 g, 4.3 mmol) and the reaction mixture was stirred for another 20 hours and Then the reaction mixture was diluted with a mixture of isopropylacetate (53 ml) and hexanol (27 ml) and transferred into a separating funnel. The organic layer was washed twice with a mixture of water (27 ml) and saturated aqueous solution of sodium chloride (27 ml) with subsequent final washing with a saturated aqueous solution of sodium chloride (27 ml). The organic layer was dried over sodium sulfate. Was added silica gel (23,6 g) and hexane (27 ml) and the suspension was stirred for 10 minutes, the Solids were removed by filtration and the filtrate was concentrated in vacuum. The residue was led from hexanol (45 ml) with obtaining cent to 8.85 g (19 mmol, 68%) indicated in the title compounds as solids. MSm/z: [M+H+] calculated for C22H30NO3SiBr 464,1; found 464,2.

Starting material, (R)-2-bromo-1-(3-formamido-4-benzyloxyphenyl)ethanol can be obtained, as described in U.S. patent No. 6268533 B1, or in R. Hett et al.,Organic Process Research and Development,1998,2:96-99, or according to the method similar to that described in Hong et al.,Tetrahedron Lett.,1994,35:6631, or similar to that described in U.S. patent No. 5495054.

Getting 17

1-{9-[(R)-2-(4-Benzyloxy-3-formylamino)-2-(tert-butyldimethylsilyloxy)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

The product of 16 (500 mg, 1,008 mmol) and iodide is the atrium (243 mg, of 1.62 mmol) was stirred in tetrahydrofuran (0.5 ml) for 15 min at ambient temperature. Then was added the product receiving 11 (564 mg, 1,29 mmol) and sodium bicarbonate (272 mg, 3,24 mmol) and the reaction mixture was heated at 80°C for 24 h Then the reaction mixture was allowed to cool. Next was added water (2 ml) and the mixture was extracted with dichloromethane (2×2 ml). The combined organic extracts washed with 1M hydrochloric acid (2×1 ml), dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude residue was purified flash chromatography (5-10% methanol/dichloromethane) to obtain the specified title compound (360 mg, 0.44 mmol, yield 41%). HPLC (10-70) Rt=4,96; MSm/z: [M+H+] calculated for C49H68N4O5821,51; found 821,9.

Getting 18

1-{9-[(R)-2-(4-Benzyloxy-3-formylamino)-2-hydroxyethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 17 (360 mg, 0.44 mmol) in tetrahydrofuran (2.2 ml) at ambient temperature was added trihydrated of triethylamine (108 μl, 0.66 mmol). The reaction mixture was stirred 24 h, then was diluted with dichloromethane (5 ml) and washed with 1M hydrochloric acid (2 ml) and saturated aqueous sodium bicarbonate (2 ml). The organic phase sushi is whether (magnesium sulfate) and removed under reduced pressure the solvent. Untreated specified in the title compound was used directly in the next stage without additional purification. HPLC (10-70) Rt=4,6; MSm/z: [M+H+] calculated for C43H54N4O5707,43; found 707,8.

Example 4

DATEFORMAT 1-{9-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Palladium (10 wt.% (on dry matter basis) on activated carbon) (124 mg) was added to a stirred solution of the product receiving 18 (311 mg, 0.44 mmol) in ethanol (4 ml) and the reaction mixture was placed in an atmosphere of hydrogen. After stirring for 12 h the reaction mixture was filtered through a loose layer of celite, washed with methanol (2 ml) and removed under reduced pressure the solvent. The obtained residue was purified preparative HPLC to obtain specified in the title compound (41 mg). HPLC (10-70) Rt=3,0; MSm/z: [M+H+] calculated for C36H48N4O5617,39; found 617,5.

Example 5

DATEFORMAT 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Palladium (10 wt.% (on dry matter basis) on activated carbon) (80 mg) was added to a stirred solution of the product of example 3 (80 mg, 0.11 mmol) in ethanol is (1.1 ml) and the reaction mixture was placed in an atmosphere of hydrogen. The reaction mixture was stirred for 12 h and then filtered through a loose layer of celite, washed with methanol (2 ml) and removed under reduced pressure the solvent. The crude substance was again subjected to the above procedures to ensure full flow of the reaction. The obtained residue was purified preparative HPLC to obtain specified in the title compound (6 mg). HPLC (10-70) Rt=3,23; MSm/z: [M+H+] calculated for C38H50N4O5643,39; found 643,7.

Getting 19

Methyl ester of 3-[4-(biphenyl-2-ylcarbamate)piperidine-1-yl]propionic acid

Methyl-3-bromopropionate (553 μl, 5,07 mmol) was added to a stirred solution of the product obtain 8 (1,00 g, to 3.38 mmol) and DIPEA (of 1.76 ml, 10.1 mmol) in acetonitrile (34 ml) at 50°and the reaction mixture was heated at 50°With during the night. Then removed under reduced pressure, the solvent and the residue was dissolved in dichloromethane (30 ml). The resulting solution was washed with saturated aqueous sodium bicarbonate (10 ml), dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude residue was purified column chromatography (5-10% Meon/DHM) obtaining specified in the title compound (905 mg, 70%).

Receive 20

3-[4-(Biphenyl-2-ylcarbamate)piperidine-1-yl]propionic acid

Paramashiva the initial solution of the product receiving 19 (902 mg, is 2.37 mmol) and lithium hydroxide (171 mg, 7,11 mmol) in a mixture of 50% THF/N2O (24 ml) was heated at 30°C overnight, then acidified with concentrated hydrochloric acid and was liofilizovane obtaining specified in the connection header (output ˜100%, also contains salt LiCl).

Getting 21

tert-Butyl ether {5-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethylamino]pentyl}carbamino acid

Product obtain 13 (600 mg, of 1.23 mmol) and N-tert-butoxycarbonyl-1,5-diaminopentane (622 mg, of 3.07 mmol) was dissolved in dimethyl sulfoxide (1.23 ml) and was heated to 105°C for 6 hours Then the reaction mixture was cooled, diluted with ethyl acetate (10 ml) and washed with saturated aqueous sodium bicarbonate (4 ml). The organic phase was dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude residue was purified column chromatography (5-10% methanol/dichloromethane) to obtain specified in the connection header (output˜100%).

Getting 22

5-[(R)-2-(5-Aminophenylamino)-1-(tert-butyldimethylsilyloxy)ethyl]-8-benzyloxy-1H-quinoline-2-he

A solution of the product receiving 21 (800 mg, 1,31 mmol) in a mixture triperoxonane acid/dichloromethane was stirred at ambient temperature for 1 h Then was removed under reduced pressure, dissolve the spruce, the crude residue was dissolved in dichloromethane (15 ml) and washed with 1 N. sodium hydroxide (8 ml). The organic phase was separated, dried (magnesium sulfate) and removed under reduced pressure, the solvent is obtaining specified in the title compound (509 mg, yield 81% over 2 stages).

23

1-(2-{5-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethylamino]intercalator}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To the product receiving 20 (417 mg, 1.13 mmol) and HATU (430 mg, 1.13 mmol) was added to the product receiving 22 (458 mg, 0.90 mmol) in DMF (1.8 ml) followed by addition of DIPEA (204 μl, of 1.17 mmol). The reaction mixture was stirred at 50°C for 12 h and then was removed under reduced pressure the solvent. The crude residue was dissolved in dichloromethane (4 ml), dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude residue was purified column chromatography (5-10% methanol/dichloromethane and 0.5% NH4HE) to produce specified in the title compound (240 mg, yield 31%).

Getting 24

1-(2-{5-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethylamino]intercalator}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 23 (240 mg, 0.28 mmol) in dichloromethane (2.8 ml) we use the and trihydrated of triethylamine (91 μl, 0,56 mmol). The reaction mixture was stirred for 10 h and then was diluted with dichloromethane (10 ml). The resulting solution was washed with saturated aqueous sodium bicarbonate (5 ml)then the organic phase was dried (magnesium sulfate) and removed under reduced pressure, the solvent is obtaining specified in the title compound (209 mg, yield 100%).

Example 6

DATEFORMAT 1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]intercalator}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 24 (209 mg, 0.28 mmol) in ethanol (2.8 ml) was added palladium (10 wt.% (on dry matter basis) on activated carbon) (81 mg), the reaction mixture was placed in an atmosphere of hydrogen and stirred overnight. Then the reaction mixture was filtered and removed under reduced pressure the solvent. The crude residue was purified preparative HPLC (5-30 for 60 min) to obtain the specified title compound (58 mg). HPLC (10-70) Rt=2,30; MSm/z: [M+H+] calculated for C37H45N5O6656,34; found 656,6; [α]20D=-6,5 (C=1.0 mg/ml, water).

Example 6A

1-(2-{5-[(R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]intercalator}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Alternatively, the decree is Noah in the title compound can be obtained in the following way:

(a) 5-Chloropentyl

In a 2 l three-neck round bottom flask, equipped with magnetic stirrer, addition funnel and temperature controller was added in nitrogen atmosphere 5-chloropentane (53 g, 0,433 mol) and dichloromethane (300 ml). The resulting mixture was cooled to 5°and the solution was added sodium bicarbonate (5 g, 0,059 mol) and potassium bromide (5.1 g, 0,043 mol) in water (225 ml). Added free radical 2,2,6,6-tetramethyl-1-piperidinyloxy (TAMRA) (63 mg, 0.4 mmol) and then was added dropwise 10-13% bleaching solution (275 ml) via addition funnel at a speed that facilitates maintaining the temperature at about 8° (±2° (C) using a cooling bath of ice (about 45 min). After adding the bleach solution and the mixture was stirred 30 min, maintaining the temperature at about 5°C. was Added a solution of sodium bisulfite (4 g) in water (30 ml) and the resulting mixture was stirred at room temperature for 30 minutes and Then separated the layers of the mixture and the aqueous layer was extracted with dichloromethane (1×50 ml). The combined dichloromethane layers were then washed with water (1×50 ml), dried (MgSO4), filtered and concentrated under reduced pressure to obtain specified in the title compound (53 g). The product was distilled at 65°/8 mm RT. Art. with obtaining specified in the connection header (31,16 g) in the form of Oran is avago oil (purity according to GC accounted for 70-80%).

The product was then purified by adding the crude material (4 g) to ethanol (920 ml), ethyl acetate (12 ml) and water (4 ml). Was added sodium bisulfite (4 g), the mixture was boiled under reflux for 4 h, then cooled to room temperature and stirred 14 h at room temperature with the formation of a very thick mist. The solids were filtered off on a sintered filter, washed with a mixed solvent (5 ml) and dried on the filter with the receipt of 8.4 g of the adduct of bisulfite. The obtained substance was added to MTBE (20 ml) and then added 1 n sodium hydroxide (45 ml) with vigorous stirring. The obtained two-phase mixture was vigorously stirred until complete dissolution of all solids (about 15 min) and then layers were separated. The aqueous layer was extracted with MTBE (20 ml) and the combined MTBE layers were dried (MgSO4), filtered and concentrated to obtain of 3.46 g specified in the title compound as a colourless liquid (purity>90% according to GC).

(b) 5-[(R)-2-[Benzyl-(5-chloropentyl)amino]-1-(tert-butyldimethylsilyloxy)ethyl]-8-benzyloxy-1H-quinoline-2-he

In a 1 l three-neck round bottom flask was introduced a product receiving 28 (48,4 g, 94 mmol), dichloromethane (400 ml) and glacial acetic acid (11.3 ml). The resulting mixture was stirred at 0°With (bath with ice) and was added the product from step (a) (12.5 g, 103,6 IMO the b) continuing the stirring for 15 minutes Then added in portions over 15 min triacetoxyborohydride (59,8 g, 282 mmol) and the resulting mixture was stirred at 0°C-10°C for 2 h and Then slowly (gassing) was added saturated aqueous sodium bicarbonate solution (200 ml) and continued stirring for 15 minutes by the Addition of solid sodium carbonate brought the pH of the solution to about 9 and the layers were separated. The organic layer is washed with 5% aqueous solution of sodium chloride (200 ml), dried (MgSO4), filtered and concentrated under reduced pressure to obtain specified in the title compound (53 g).

(C) 5-[(R)-2-[(5-N,N-Diformylpiridine)benzylamino]-1-(tert-butyldimethylsilyloxy)ethyl]-8-benzyloxy-1H-quinoline-2-he

To a stirred solution of the product of stage (b) (26.5 g, 42.8 mmol) in 1-methyl-2-pyrrolidinone (175 ml) was added deformylated sodium (6,1 g, 64,2 mmol) and sodium iodide (2,13 g of 14.3 mmol). The reaction flask was purged with nitrogen and then the mixture was heated at 65°C for 8 hours Then the mixture was cooled to room temperature and added to water (300 ml) and ethyl acetate (100 ml). The resulting mixture was stirred 10 min and then the layers were separated. The aqueous layer was extracted with ethyl acetate (150 ml) and the combined organic layers were washed with water (300 ml), 50% aqueous salt solution (300 ml), water (300 ml), dried (MgSO4), the filter is Wali and concentrated to obtain specified in the title compound (23.3 g).

(d) 5-[(R)-2-[(5-Aminopentyl)benzylamino]-1-(tert-butyldimethylsilyloxy)ethyl]-8-benzyloxy-1H-quinoline-2-he

To a stirred solution of the product from step (C) (10,5 g, 16 mmol) in methanol (75 ml) was added p-toluensulfonate acid (7,42 g, 39 mmol). The resulting mixture was heated at 40°C for 15 h and then concentrated under reduced pressure to about half its volume. Was added methanol (70 ml) and the mixture was heated at 50°C for 2 h and then concentrated under reduced pressure. Was added water (100 ml), methanol (50 ml) and MTBE (100 ml), the mixture was stirred for 15 min and then the layers were separated. To the aqueous layer was added 1N. an aqueous solution of sodium hydroxide (45 ml) and MTBE (100 ml) and the resulting mixture was stirred for 15 minutes and Then layers were separated and the aqueous layer was extracted with MTBE (100 ml). The combined MTBE layers were dried (MgSO4), filtered and concentrated to obtain specified in the title compound as a yellow oil (7.3 km). The resulting material contained about 13% (according to HPLC) of the corresponding des-tert-butyldimethylsilyl connection.

(e) 3-[4-(Biphenyl-2-ylcarbamate)piperidine-1-yl]propionic acid

To a solution of the product obtain 8 (50 g of 67.6 mmol) in dichloromethane (500 ml) was added acrylic acid (15,05 ml, 100 mmol). The resulting mixture was heated at 50°With reverse x is Hladilnika for 18 h and then solvent was removed. Was added methanol (600 ml) and the resulting mixture was heated at 75°C for 2 h and then cooled to room temperature with the formation of a thick suspension. The solid is collected by filtration, washed with methanol (50 ml) and subjected to air drying to obtain specified in the connection header (61 g, purity >96%) as a white powder.

(f) 1-[2-(5-{Benzyl-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethyl]amino}intercalator)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

A mixture of the product of stage (e) (3,68 g, 10 mmol) and N,N-dimethylformamide (50 ml) was heated at 60°to dissolve the solids and then cooled to room temperature. Was added the product of stage (d) (6 g, 10 mmol) and diisopropylethylamine (3.5 ml) and the reaction mixture was cooled to 0°C. was Added in one portion PyBOP (6.25 g, 12 mmol) and the reaction mixture was stirred at a temperature of from 0°C to room temperature for 2 h Then the reaction mixture was poured into cold water (500 ml) under stirring and the pH of the mixture was brought to about 2 using 1M hydrochloric acid. The resulting mixture was stirred 15 min and then filtered to collect the solid, which was washed with water (100 ml) and dried to obtain specified in the title compound (8.7 g, purity according to the on HPLC > 95%) as not quite white solid.

(g) 1-(2-{5-[(R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]intercalator}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

The product of stage (f) can be removed protection using essentially the same methods as described in obtaining 24 and example 6, to obtain specified in the connection header.

Receive 25

2-(N-Benzyloxycarbonyl-N-methylamino)ethanal

(a) 2-(N-Benzyloxycarbonyl-N-methylamino)ethanol

Benzylchloride (19 g, 111,1 mmol) in THF (20 ml) was added dropwise over 15 min to a stirred solution of 2-(methylamino)ethanol (10 g, 133,3 mmol) in THF (100 ml) and aqueous sodium carbonate (100 ml) at 0°C. the Reaction mixture was stirred at 0°C for 12 h and then was extracted with EtOAc (2×200 ml). The organic layer is washed with aqueous sodium carbonate (200 ml), dried (potassium carbonate) and removed under reduced pressure, the solvent is obtaining specified in the title compound (2.25 g, yield 97%).

(b) 2-(N-Benzyloxycarbonyl-N-methylamino)ethanal

DMSO (71 ml, 1 mol) and DIPEA (87,1 ml, 0.5 mol) was added to a stirred solution of the product of stage (a) (of 20.9 g, 0.1 mol) in dichloromethane (200 ml) at -10°C. the Reaction mixture was stirred at -10°C for 15 min, then was added to the complex of sulfur trioxide and PI is Idina (of 79.6 g, 0.5 mol) and the resulting mixture was stirred for 1 h, the Reaction mixture was suppressed by the addition of 1M hydrochloric acid (200 ml). The organic layer was separated and washed with saturated aqueous sodium bicarbonate (100 ml), saturated salt solution (100 ml), dried (potassium carbonate) and removed under reduced pressure, the solvent is obtaining specified in the title compound (20.7 g, output ˜100%).

Getting 26

1-[2-(Methylamino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 25 (20.7 g, 100 mmol) and the product receiving 8 (25 g, 84,7 mmol) in Meon (200 ml) was added triacetoxyborohydride sodium (21.2 g, 100 mmol). The reaction mixture was stirred 12 h at ambient temperature, then extinguished 2M hydrochloric acid was removed under reduced pressure the solvent. The residue was dissolved in ethyl acetate (200 ml), washed with saturated aqueous sodium bicarbonate (100 ml) and saturated salt solution (50 ml), then dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude residue was purified column chromatography (50-90% EtOAc/hexane) to obtain 1-[2-(benzyloxycarbonylamino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid in the form of oil.

The oil was dissolved in methanol (100 ml) and was added palla is s (10 wt.% (on dry matter basis) on activated carbon) (5 g). The reaction mixture was stirred in hydrogen atmosphere (30 psi; 2.1 kg/cm2) and then filtered through Celite, which was washed with methanol, and the solvent evaporated to obtain specified in the connection header (13,2 g, yield 44%).

Getting 27

1-{2-[(6-Bromhexine)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

6-Bromohexadecane (3,23 ml, 21.1 mmol) was added to a stirred solution of the product receiving 26 (6.2 g, 17.6 mmol) and DIPEA (6,13 ml of 35.2 mmol) in dichloromethane (170 ml). The reaction mixture was stirred 1 h, then was diluted with EtOAc (250 ml), washed with saturated aqueous sodium bicarbonate (2×200 ml) and saturated salt solution (200 ml) and then dried (magnesium sulfate). Was removed under reduced pressure, the solvent is obtaining specified in the title compound (6.6 g, yield 73%).

Getting 28

8-Benzyloxy-5-[(R)-2-(N-benzylamino)-1-(tert-butyldimethylsilyloxy)ethyl]-1H-quinoline-2-he

Stir a solution of the product receiving 13 (1,00 g, 2.05 mmol) and benzylamine (493 μl, 4,51 mmol) in DMSO (1.7 ml) was heated at 105°C for 4 h the Reaction mixture was allowed to cool, then diluted it EtOAc (10 ml) and the organic layer was washed with a saturated aqueous solution of ammonium chloride (5 ml) and 1 N. a solution of sodium hydroxide (5 ml), dried (MgSO4) and removed when below the nom pressure of the solvent. The crude residue was purified column chromatography (50% EtOAc/hexane) obtaining specified in the title compound (700 mg, 67%). MSm/z: [M+H+] calculated for C31H38N2O3Si 515,27; found 515,5.

Getting 29

1-{2-[(6-{Benzyl-[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethyl]amino}hexanoyl)methylamino]ethyl} piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 28 (807 mg, 1.57 mmol) and DIPEA (819 μl, 4.7 mmol) in acetonitrile (3,14 ml) was added the product receiving 27 (995 mg, 1.88 mmol). The reaction mixture was heated to 80°C for 24 h was Removed under reduced pressure, the solvent, the residue was dissolved in EtOAc (10 ml) and then washed with saturated aqueous sodium bicarbonate (5 ml), dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude substance was purified column chromatography (4-6% Meon/DHM) obtaining specified in the title compound (452 mg, 30%yield).

30

1-{2-[(6-{Benzyl[(R)-2-(8-benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethyl]amino}hexanoyl)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 29 (452 mg, 0.47 mmol) in dichloromethane (4,7 ml) was added trihydrated treat lamina (116 μl, 0.71 mmol). The reaction mixture was stirred for 10 h and then was diluted with dichloromethane (10 ml) and washed with saturated aqueous sodium bicarbonate (5 ml). Then was dried (MgSO4) the organic phase was removed under reduced pressure, the solvent is obtaining specified in the title compound (yield 100%).

Example 7

DATEFORMAT 1-[2-({6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]hexanoyl}methylamino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receipt 30 (400 mg, 0.47 mmol) in ethanol (4,7 ml) was added palladium (10 wt.% (on dry matter basis) on activated carbon) (160 mg), the reaction mixture was placed in an atmosphere of hydrogen and stirred overnight. Then the reaction mixture was filtered and removed under reduced pressure the solvent. The crude residue was purified preparative HPLC to obtain specified in the title compound (73 mg). HPLC (10-70) Rt=2,33; MSm/z: [M+H+] calculated for C38H47N5O6670,36; found 670. [α]20D=-9,4 (C=1.0 mg/ml, water).

Getting 31

1-[2-(4-Aminomethyl)phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of 4-(N-tert-butoxycarbonylamino)aniline (756 mg, 3.4 mmol), prod the KTA obtain 20 (1.5 g, 4,08 mmol) and HATU (1.55 g, 4,08 mmol) in DMF (6.8 ml) was added DIPEA (770 μl, was 4.42 mmol). The reaction mixture was stirred at 50°during the night and then was removed under reduced pressure the solvent. The obtained residue was dissolved in dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate (10 ml). Then the organic phase was dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude product was purified flash chromatography (5-10% Meon/DHM) to obtain solid, which was dissolved in TFA/DHM (25%, 30 ml) and stirred at room temperature for 2 hours Then removed under reduced pressure, the solvent and the crude residue was dissolved in dichloromethane (30 ml) and washed with 1 N. sodium hydroxide (15 ml). The organic phase was separated, dried (magnesium sulfate) and removed under reduced pressure, the solvent is obtaining specified in the title compound (1.5 g, 94% over two stages).

Getting 32

1-[2-(4-{[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethylamino]methyl}phenylcarbamoyl)ethyl] piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

A solution of the product receiving 31 (489 mg, 1.04 mmol), the product receiving 13 (610 mg, 1.25 mmol), sodium bicarbonate (262 mg, of 3.12 mmol) and sodium iodide (203 mg, 1.35 mmol) in THF (0,52 ml) was heated at 80°C for 12 reaktsionnuyu mixture was diluted with dichloromethane (10 ml) and washed with saturated aqueous sodium bicarbonate (5 ml). The organic phase was dried (MgSO4) and removed under reduced pressure the solvent. The crude residue was purified flash chromatography (10% Meon/DHM) obtaining specified in the title compound as a solid (687 mg, yield 77%).

Receive 33

1-[2-(4-{[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 32 (687 mg, 0.8 mmol) in dichloromethane (8 ml) was added trihydrated of triethylamine (261 μl, 1.6 mmol). The reaction mixture was stirred for 10 h, then was diluted with dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate (10 ml). The organic phase was then dried (magnesium sulfate) and removed under reduced pressure, the solvent is obtaining specified in the header of the compound (500 mg, yield 81%).

Example 8

DATEFORMAT 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 33 (500 mg, of 0.65 mmol) in ethanol (6.5 ml) was added palladium (10 wt.% (on dry matter basis) on activated carbon) (200 mg), the reaction mixture was placed in an atmosphere of hydrogen and stirred for n the Chi. Then the reaction mixture was filtered and removed under reduced pressure the solvent. The crude residue was purified preparative HPLC to obtain specified in the title compound (81 mg, 2 TFA salt). HPLC (10-70) Rt=2,41; MSm/z: [M+H+] calculated for C39H41N5O6676,32; found 676,5.

Getting 34

1-(2-(tert-Butoxycarbonylamino)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product obtain 8 (2.00 g, 6,76 mmol) and DIPEA (3,54 ml, 20.3 mmol) in acetonitrile (67,6 ml) at 50°C was added 2-tert-butoxycarbonylmethylene (1,82 g, 8,11 mmol) and the reaction mixture was heated at 50°With during the night. Was removed under reduced pressure, the solvent, the residue was dissolved in dichloromethane (60 ml) and washed with saturated aqueous sodium bicarbonate (30 ml). The organic phase was dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude residue was purified column chromatography (5% Meon/DHM) obtaining specified in the title compound as a solid (2,32 g, yield 78%).

Receive 35

1-(2-(Aminoethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

The product receiving 34 was dissolved in a mixture of TFA/DHM (25%, 52 ml) and stirred at room temperature for 2 hours Then removed under reduced is th pressure of the solvent, the crude residue was dissolved in dichloromethane (30 ml) and washed with 1 N. sodium hydroxide (15 ml). The organic phase was separated, dried (magnesium sulfate) and removed under reduced pressure, the solvent is obtaining specified in the connection header (1,61 g, yield 90%).

Getting 36

1-[2-(4-(Aminoethylethanolamine)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 35 (339 mg, 1 mmol), 4-(tert-butoxycarbonylamino)benzoic acid (301 mg, 1.2 mmol) and HATU (456 mg, 1.2 mmol) in DMF (2 ml) was added DIPEA (226 μl, 1.3 mmol). The reaction mixture was stirred at room temperature overnight and then was removed under reduced pressure the solvent. The obtained residue was dissolved in dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate (10 ml). Then the organic phase was dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude product was dissolved in a mixture of TFA/DHM (25%, 10 ml) and the resulting mixture was stirred at room temperature for 2 hours was Removed under reduced pressure, the solvent, the crude residue was dissolved in dichloromethane (15 ml) and washed with 1 N. sodium hydroxide (5 ml). The organic phase was separated, dried (magnesium sulfate) and removed under reduced pressure, the solvent is obtaining specified in the compound (472 mg, ˜100% for stage 2).

Getting 37

1-[2-(4-{[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethylamino]methyl}benzoylamine)ethyl] piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

A solution of the product receiving 36 (520 mg, 1.1 mmol), the product receiving 13 (634 mg, 1.3 mmol), sodium bicarbonate (277 mg, 3.3 mmol) and sodium iodide (215 mg, of 1.43 mmol) in THF (0,55 ml) was heated at 80°C for 12 h, the Reaction mixture was diluted with dichloromethane (10 ml) and washed with saturated aqueous sodium bicarbonate (5 ml). The organic phase was then dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude residue was purified flash chromatography (5-10% Meon/DHM) obtaining specified in the title compound as a solid (316 mg, yield 33%).

Getting 38

1-[2-(4-{[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethylamino]methyl}benzoylamine)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 37 (316 mg, 0.36 mmol) in dichloromethane (3.6 ml) was added trihydrated of triethylamine (117 μl, to 0.72 mmol). The reaction mixture was stirred for 10 h, then was diluted with dichloromethane (10 ml) and washed with saturated aqueous sodium bicarbonate (5 ml). The organic phase was dried (MgSO4and del is whether under reduced pressure, the solvent is obtaining specified in the connection header, which is directly used in the next stage (yield 100%).

Example 9

DATEFORMAT 1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoylamine)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 38 (275 mg, 0.36 mmol) in ethanol (3.6 ml) was added palladium (10 wt.% (on dry matter basis) on activated carbon) (275 mg), the reaction mixture was placed in an atmosphere of hydrogen and stirred overnight. Then the reaction mixture was filtered and removed under reduced pressure the solvent. The crude residue was purified preparative HPLC to obtain specified in the title compound (6 mg, 2 TFA salt). HPLC (10-70) Rt=of 2.26; MSm/z: [M+H+] calculated for C39H41N5O6676,32; found 676,5.

Getting 39

1-(2-amino-ethyl) piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

2-tert-Butoxycarbonylmethylene (1.22 g, 5,44 mmol) was added to a solution of the product obtain 8 (1,46 g of 4.95 mmol) and diisopropylethylamine (of 1.03 ml, 5,94 mmol) in acetonitrile (24 ml). The reaction mixture was stirred at 65°C for 12 hours, then MS analysis showed that the reaction had ended. The reaction mixture was concentrated to dryness and then added dichloromethane (10 ml). To the mixture was added TP florexpo acid and the mixture was stirred at room temperature for 4 hours, then MS analysis showed that the reaction had ended. The mixture is then concentrated to half its volume and to the solution was added 1 n sodium hydroxide to bring the pH to 14. The organic layer was washed with saturated salt solution, then dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain 1.6 g of the specified header connection in the form of solids. MSm/z: [M+H+] calculated for C20H25N3O2340,2; found 340.

Receive 40

5-[(R)-2-(5-Aminophenylamino)-1-(tert-butyldimethylsilyloxy)ethyl]-8-benzyloxy-1H-quinoline-2-he

N-tert-butoxycarbonyl-1,5-diaminopentane (1.04 g, 5,12 mmol) was added to a solution of the product receiving 13 (1,00 g, 2.05 mmol) in dimethyl sulfoxide (2 ml). The solution was stirred at 75°C for 12 hours, after which the analysis of LC-MS showed that the reaction had ended. The reaction mixture was then concentrated in vacuum to dryness. To the residue was added dichloromethane (2 ml) and then added triperoxonane acid (1 ml). The solution was stirred at room temperature for about 3 hours, after which MS analysis showed that the reaction had ended. The solution was concentrated to half its volume and added 1 n sodium hydroxide to bring the pH to 14. The organic layer was collected, washed with saturated salt solution, dried over magnesium sulfate and the eat was concentrated with getting 782 mg specified in the connection header in the form of oil. MSm/z: [M+H+] calculated for C29H43N3O3Si 510,8; found 510.

Getting 41

1-[2-(3-{5-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethylamino]pentyl}ureido)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Carbonyldiimidazole (127 mg, 0.78 mmol) was added to a solution of the product receiving 39 (266 mg, 0.78 mmol) in dimethylformamide (4 ml) and the resulting mixture was stirred at room temperature for 3 hours. After 3 hours was added to the reaction mixture, the product receiving 40 (399 mg, 0.78 mmol) and the mixture was stirred 12 hours at room temperature, after which the analysis of LC-MS showed that the reaction had ended. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (5 ml). The organic layer was washed twice with saturated aqueous sodium bicarbonate solution (5 ml) and then with saturated salt solution (5 ml). The organic layer was dried over magnesium sulfate, filtered and then concentrated to obtain 597 mg specified in the connection header in the form of a solid, which was used without further purification. MSm/z: [M+H+] calculated for C50H66N6O6Si 875,5; 875 found.

Getting 42

1-[2-(3-{5-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethylamino]pentyl}ureido)ethyl]piperidin-4-silt ether-biphenyl-2-ylcarbamate acid

Trihydrated of triethylamine (0.16 ml, of 1.02 mmol) was added to a solution of the product receiving 41 (597 mg, of 0.68 mmol) in tetrahydrofuran (3.4 ml) and the resulting mixture was stirred at room temperature for approximately 12 hours, after which MS analysis showed that the reaction had ended. The reaction mixture was diluted with ethyl acetate (5 ml) and the resulting mixture was washed with 1 N. a solution of sodium hydroxide (5 ml), saturated salt solution, dried over magnesium sulfate and concentrated to obtain 417 mg specified in the connection header in the form of solids. MSm/z: [M+H+] calculated for C44H51N6O6760,4; found 760.

Example 10

DATEFORMAT 1-[2-(3-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]pentyl}ureido)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

A solution of the product receiving 42 (417 mg, 0.55 mmol) in ethanol (3 ml) was purged with nitrogen for about 10 minutes. Added palladium (10 wt.% (on dry matter basis) on activated carbon) (200 mg) and the solution was again purged with nitrogen for about 10 minutes. The flask was purged under vacuum, then filled with nitrogen three times and then the flask was connected to the hydrogen-filled balloon. The reaction mixture was stirred in hydrogen atmosphere for 12 hours, after which MS analysis showed that the reaction had ended. Then actionnow the mixture was filtered and the organic filtrate was concentrated and purified HPLC (10-35% for 60 minutes) to give 146 mg specified in the connection header in the form of a powder. MSm/z: [M+H+] calculated for C37H46N6O6671,4; found 670. HPLC (10-70) Rt=2.6 minutes.

Example 11

DATEFORMAT 1-[3-(3-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]pentyl}ureido)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Specified in the title compound was obtained according to the method described above in the receiving 39-42 and example 10, with the substitution of 2-tert-butoxycarbonylmethylene used in obtaining 39, 3-tert-butoxycarbonylamino-1-avramidou. MSm/z: [M+H+] calculated for C38H48N6O6685,4; found 684. HPLC (10-70) Rt=2.6 minutes.

Getting 43

6-(2-Bromo-(R)-1-tert-butyldimethylsilyloxy)ethyl-2,2-dimethyl-1,3-benzodioxan

(a) 6-Bromo-2,2-dimethyl-4H-benzo[1,3]dioxin

To 5-bromo-2-hydroxybenzylidene alcohol (93 g, 0.46 mol, available from the company Sigma-Aldrich) in 2.0 l 2.2-dimethoxypropane was added 700 ml of acetone and then zinc chloride (170 g). After stirring for 18 hours, was added a 1.0m aqueous solution of sodium hydroxide to until the aqueous phase became coreóate. To the resulting suspension was added diethyl ether (1.5 l) and the organic phase decantation in a separating funnel. The organic phase is washed with saturated salt solution, dried over Na2SO4was filtered and the con who was interaval under reduced pressure to obtain specified in the connection header in the form of oil.

(b) 6-Acetyl-2,2-dimethyl-4H-benzo[1,3]dioxin

The product of stage (a) (110 g, 0.46 mol) in 1.0 l of THF at -78°With added 236 ml (0.51 mol) 2,14M n-utility in hexano through an addition funnel. After 30 minutes, was added N-methyl-N-methoxyacetate (71 g, 0.69 mol, available from the company TCI). After 2 hours the reaction mixture was extinguished with water, diluted to 2.0 l of 1.0m aqueous solution of phosphate buffer (pH 7.0) and was extracted once with diethyl ether. Diethylamino phase was washed once with saturated salt solution, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a light orange oil. The oil was dissolved in minimum amount of ethyl acetate, diluted with hexane and as a result received is listed in the title compound as crystalline solid.

(C) 6-Bromacetyl-2,2-dimethyl-4H-benzo[1,3]dioxin

The product of stage (b) (23,4 g, 0,113 mol) in 600 ml THF at -78°With added 135 ml of a 1.0m solution hexamethyldisilazane sodium in THF (Sigma-Aldrich). After 1 hour was added trimethylsilane (15,8 ml, 0,124 mol). After another 30 minutes was added bromine (of 5.82 ml, 0,113 mol). After 10 minutes the reaction was suppressed by diluting the reaction mixture with diethyl ether and poured into a mixture of 500 ml of 5% aqueous solution of Na2SO3pre-mixed with 500 ml of 5% aqueous NaHCO3. Divided phase and organicheskoi the phase was washed with saturated salt solution, dried over Na2SO4, filtered and concentrated under reduced pressure to obtain specified in the connection header in the form of oil, which was hardened during storage in the refrigerator.

(d) (R)-2-Bromo-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol

The product of stage (C) (10 g, and 35.1 mmol) in 100 ml THF was added the solid catalyst receiving 13, stage (C)(1) (0.97 g, 3.5 mmol). The solution was cooled to a temperature of between -20°-10°and added dropwise via addition funnel BH3-THF (35 ml, 35 mmol), diluted with 50 ml THF. After the addition was finished the reaction mixture was allowed to warm to ambient temperature. After 30 minutes the reaction mixture was suppressed by slow addition of 50 ml of methanol and then concentrated to a thick oil. The oil was purified by chromatography on silica gel with elution with a mixture (1:2) ethyl acetate/hexane. Fractions were combined and concentrated to obtain specified in the connection header in the form of not-quite-white solid.

(e) [(R)-2-Bromo-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethoxy-tert-butyldimethylsilyl

The product of stage (d) (10 g, 34.8 mmol) and imidazole (4.7 g, to 69.7 mmol), dissolved in 100 ml of DMF, was added tert-butyldimethylsilyl (5,78 g, to 38.3 mmol). The reaction mixture was stirred 18 hours. Then the reaction mixture was distributed between 200 ml of saturated chlorine is Yes sodium and 200 ml of diethyl ether. The aqueous layer was extracted with 200 ml diethyl ether. Then the organic layers were combined, washed with a saturated solution of sodium chloride (3×100 ml), dried over MgSO4and concentrated. The product was purified by chromatography on silica gel, elwira hexane and then 5% ethyl acetate in hexano. The required fractions were combined and concentrated to obtain specified in the connection header in the form of oil.

Getting 44

1-{9-[2-(tert-Butyldimethylsilyloxy)-2-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

The product receiving 43 (802 mg, 2.00 mmol) and sodium iodide (300 mg, 2.00 mmol) was stirred in tetrahydrofuran (0,77 ml) for 15 min at ambient temperature. Added product receiving 11 (675 mg, 1.54 mmol) and sodium bicarbonate (388 mg, to 4.62 mmol) and the reaction mixture was heated at 80°C for 24 h Then the reaction mixture was cooled and was added water (2 ml). The mixture was extracted with dichloromethane (2×2 ml). The combined organic extracts were dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude residue was purified flash chromatography (5-10% methanol/dichloromethane) to obtain the specified title compound as a solid (798 mg, 1.05 mmol, yield 60%). MSm/z: [M+H+] calculated for C45H67N 3O5Si 758,5; found 758,6.

45

1-{9-[2-(2,2-Dimethyl-4H-benzo[1,3]dioxin-6-yl)-2-hydroxyethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Trihydrated of triethylamine (342 μl, 2.10 mmol) was added to a stirred solution of the product receiving 44 (798 mg, 1.05 mmol) in dichloromethane (10.5 ml) at ambient temperature. The reaction mixture was stirred 24 h, then was diluted with dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate (15 ml). The organic layer was dried (magnesium sulfate) and removed under reduced pressure the solvent. Untreated specified in the title compound was isolated as an oil (659 mg, of 1.02 mmol), which was used in the next stage without additional purification. MSm/z: [M+H+] calculated for C39H53N3O5644,4; found 644,8.

Example 12

DATEFORMAT 1-{9-[(R)-2-hydroxy-2-(4-hydroxy-3-hydroxymethylene)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Triperoxonane acid (2,80 ml) was added to a stirred solution of the product receiving 45 (600 mg, of 0.93 mmol) in a mixture of THF/N2O (14 ml, 1:1) and the reaction mixture was stirred 2 h at ambient temperature. The reaction mixture was concentrated under reduced pressure and was dissolved in 20% MeCN/H2O, then ciali preparative HPLC to obtain specified in the title compound (200 mg, 2TFA salt). HPLC (10-70) Rt=was 2.76; MSm/z: [M+H+] calculated for C36H49N3O5604,4; found 604,8.

Getting 46

1-[1-(9-Benzylamino)piperidine-4-yl]-3-biphenyl-2-rocephine

N-Benzylamine (of 0.903 ml, 8,30 mmol) was added to a solution of the product of 4 (2,40 g, 5,52 mmol) and the resulting mixture was stirred at ambient temperature. After 10 min to the reaction mixture was added triacetoxyborohydride sodium (1.75 g, 8,30 mmol). In the course of the reaction was performed HPLC analysis. After 2 h at ambient temperature the reaction mixture was extinguished with water (5 ml) and then concentrated in vacuo to half its volume. The reaction mixture was diluted with dichloromethane (15 ml) and washed with 1 N. a solution of sodium hydroxide (2×10 ml) and then with saturated salt solution (5 ml). The organic layer was dried over magnesium sulfate and concentrated to obtain specified in the connection header.

Getting 47

Methyl ester of 2-benzyloxy-5-(2-bromoacetyl)benzoic acid

(a) Methyl ester of 2-benzyloxy-5-acetylbenzoic acid

Methyl-5-atsetilsalitsilata (100 g, 0,515 mol) was dissolved in acetonitrile (1 l) in a 2 l flask under conditions of boiling under reflux in a nitrogen atmosphere. Was added in portions over 15 min potassium carbonate (213,5 g 1,545 mol). Added benzylbromide (67,4 ml, 0,566 mol), using the Cape is Inoi funnel, within 15 minutes the Reaction mixture was heated to 85°C for 9 h, then filtered and washed with acetonitrile (100 ml). The solution was concentrated under reduced pressure to a volume of about 300 ml and distributed between water (1 l) and ethyl acetate (1 liter). The organic layer was washed with a saturated solution of sodium chloride (250 ml), dried over magnesium sulfate (75 g), then filtered and washed with ethyl acetate (100 ml). The organic layer was concentrated to obtain methyl ester of 2-benzyloxy-5-acetylbenzoic acid in the form of a solid substance (yield 100%).

(b) Methyl ester of 2-benzyloxy-5-(2-bromoacetyl)benzoic acid

The product of stage (a) (10.0 g, of 35.2 mmol) was dissolved in chloroform (250 ml) in a 500-ml flask in nitrogen atmosphere. Was added via addition funnel over 30 min bromine (1,63 ml, and 31.7 mmol)dissolved in chloroform (50 ml). The reaction mixture was stirred for 2.5 h and then concentrated to obtain a solid substance. The solid was dissolved in toluene (150 ml) at low heat, then add ethyl ether (150 ml) to obtain the specified title compound as crystalline solid (yield 55%).

Getting 48

Methyl ester 5-[2-(Benzyl{9-[4-(3-biphenyl-2-yureina)piperidine-1-yl]nonyl}amino)acetyl]-2-benzyloxybenzyl acid

The product receiving 47 (371 mg, 1.00 mmol) was added to the Astaro product receiving 46 (448 mg, 0.85 mmol) in dimethyl sulfoxide (4,5 ml) followed by addition of potassium carbonate (234 mg, 1.7 mmol). The reaction mixture was stirred at 40°C for 6 h, after which the presence of the product receiving 46 when HPLC analysis was no longer observed. The reaction mixture was cooled to ambient temperature, filtered and then diluted with ethanol (4 ml). Was added to the reaction mixture borohydride sodium (63 mg, 1.7 mmol) and stirred the reaction mixture at ambient temperature for 24 hours, the Reaction mixture was extinguished 0.5m ammonium chloride (5 ml) and was extracted with ethyl acetate (2×10 ml). The combined organic layers were washed with saturated sodium bicarbonate solution (10 ml) and then with saturated salt solution (5 ml). The organic layer was dried over magnesium sulfate and removed under reduced pressure the solvent. The crude residue was purified by chromatography on silica gel (3% methanol in chloroform) to obtain specified in the connection header.

Getting 49

1-[1-(9-{Benzyl-[2-(4-benzyloxy-3-hydroxymethylene)-2-hydroxyethyl]amino}nonyl)piperidine-4-yl]-3-biphenyl-2-rocephine

A solution of the product receiving 48 (163 mg, 0.20 mmol) in tetrahydrofuran (1,00 ml) was cooled to 0°C. To the mixture was added dropwise sociallyengaged (1.0m in THF; and 0.50 ml, 0.50 mmol). After 1 h the reaction mixture was extinguished with water (1 ml) and resbala is and ethyl acetate (2 ml). The organic layer was washed with saturated salt solution, dried over magnesium sulfate, the organic extracts were combined and concentrated to obtain specified in the connection header.

Example 13

The dihydrochloride of 1-biphenyl-2-yl-3-(1-{9-[2-hydroxy-2-(4-hydroxy-3-hydroxymethylene)ethylamino]nonyl}piperidine-4-yl)urea

A solution of the product receiving 49 (130 mg, 0.16 mmol) in isopropanol (0,80 ml) was purged with nitrogen for ten minutes and then was added palladium (10 wt.% (on dry matter basis) on activated carbon) (60 mg). The reaction flask was purged with nitrogen and then the flask was attached a balloon filled with hydrogen, and the reaction mixture was stirred in hydrogen atmosphere. After 72 h the reaction mixture was filtered, concentrated and the residue was purified preparative HPLC. Received detrivorous acid salt specified in the title compound was dissolved in 1 N. hydrochloric acid (5 ml) and was liofilizovane obtaining specified in the connection header in the form of its dihydrochloride salt.

Receive 50

5-[(R)-2-[(3-Aminoethylaminomethyl)amino]-1-(tert-butyldimethylsilyloxy)ethyl]-8-benzyloxy-1H-quinoline-2-he

Stir a solution of the product receiving 13 (1,46 g, 3 mmol) and 1,3-cyclohexanebis(methylamine) (426 mg, 3 mmol) in DMSO (3 ml) was heated at 100°C for 6 hours the Reaction mixtures and allowed to cool, then was diluted with dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate (10 ml). The organic layer was dried (MgSO4) and removed under reduced pressure the solvent. The crude residue was purified flash chromatography (10% Meon/DHM and 0.5% NH4HE) to produce specified in the title compound as a solid (775 mg, yield 50%). MSm/z: [M+H+] calculated for C32H47N3O3Si 550,3; found 550,6.

Getting 51

1-{2-[(3-{[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethylamino]methyl}cyclohexylmethyl) carbarnoyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 50 (552 mg, 1.01 mmol), the product receiving 20 (309 mg, 0.84 mmol) and HATU (384 mg, 1.01 mmol) in DMF (1,68 ml) was added DIPEA (190 μl, of 1.09 mmol). The reaction mixture was stirred at 50°during the night and then was removed under reduced pressure the solvent. The obtained residue was dissolved in dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate (10 ml). The organic phase was dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude residue was purified flash chromatography (5-10% Meon/DHM) obtaining specified in the title compound as a solid (267 mg, yield 36%). LC-MS(10-70) R t=5,04. MSm/z: [M+H+] calculated for C53H69N5O6Si 900,5; found 900,6.

Getting 52

1-{2-[(3-{[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethylamino]methyl}cyclohexylmethyl)carbarnoyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 51 (267 mg, 0.30 mmol) in dichloromethane (3 ml) was added trihydrated of triethylamine (98 μl, 0.6 mmol). The reaction mixture was stirred for 10 h, then was diluted with dichloromethane (10 ml) and washed with saturated aqueous sodium bicarbonate (5 ml). The organic phase was dried (magnesium sulfate) and removed under reduced pressure, the solvent is obtaining specified in the title compound as a solid (236 mg, yield 100%). MSm/z: [M+H+] calculated for C47H55N5O6786,4; found 786,5.

Example 14

1-{2-[(3-{[(R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}cyclohexylmethyl)carbarnoyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 52 (236 mg, 0.30 mmol) in ethanol (3 ml) was added palladium (10 wt.% (on dry matter basis) on activated carbon) (120 mg). The reaction mixture was placed in an atmosphere of hydrogen and stirred overnight. Then the reaction mixture of filtrowanie was removed under reduced pressure the solvent. The crude residue was purified preparative HPLC to obtain specified in the title compound (27 mg, 2 TFA salt). HPLC (10-70) Rt=was 2.76. MSm/z: [M+H+] calculated for C40H49N5O6694,4; found 696,5.

Getting 53

1-{2-[((1R,3S)-3-(Aminocyclopentane)amino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 39 (318 mg, of 0.94 mmol), (1R,3S)-3-tert-butoxycarbonylmethylene acid (258 mg, 1.1 mmol) and HATU (428 mg, 1.1 mmol) in DMF (5 ml) was added DIPEA (245 μl, of 1.09 mmol). The reaction mixture was stirred at room temperature overnight and then was removed under reduced pressure the solvent. The obtained residue was dissolved in dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate (10 ml). The organic layer was dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude residue was purified flash chromatography (5-10% Meon/DHM), then dissolved in a mixture triperoxonane acid/GHM (1 ml/5 ml) and stirred at room temperature for 1 h was Removed under reduced pressure the solvent. The residue was dissolved in dichloromethane (20 ml) and washed with 1M sodium hydroxide (10 ml), dried (magnesium sulfate) and removed under reduced pressure, the solvent is obtaining specified in the title the information of the compound (167 mg, yield 39%).

Getting 54

1-[2-({(1R,3S)-3-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethylamino]cyclopentanecarbonyl}amino) ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

A solution of the product receiving 53 (167 mg, 0.38 mmol) and the product receiving 13 (92 mg, 0,19 mmol) in DMSO (0,38 ml) was heated at 90°C for 5 h the Solution was cooled and was diluted with ethyl acetate (10 ml) and then washed with saturated aqueous sodium bicarbonate (5 ml). The organic phase was dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude residue was purified flash chromatography (5-10% Meon/DHM) obtaining specified in the title compound (343 mg, yield 100%). LC-MS (10-70) Rt=equal to 4.97. MSm/z: [M+H+] calculated for C50H63N5O6Si 858,5; found 858,8.

Receive 55

1-[2-({(1R,3S)-3-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethylamino]cyclopentanecarbonyl}amino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 54 (343 mg, 0.4 mmol) in THF (2 ml) was added trihydrated of triethylamine (130 μl, 0.8 mmol). The reaction mixture was stirred for 10 h and then diluted with EtOAc (10 ml). The reaction mixture was washed with saturated aqueous sodium bicarbonate solution (5 ml), then organic is such a phase was dried (magnesium sulfate) and removed under reduced pressure, the solvent is obtaining specified in the title compound as a solid (298 mg, yield 100%). HPLC (10-70) Rt=2,8. MSm/z: [M+H+] calculated for C44H49N5O6744,4; found 744,4.

Example 15

DATEFORMAT 1-[2-({(1R,3S)-3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)ethylamino]cyclopentanecarbonyl}amino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 55 (236 mg, 0.40 mmol) in ethanol (3 ml) was added palladium (10 wt.% (on dry matter basis) on activated carbon) (120 mg). The reaction mixture was placed in an atmosphere of hydrogen and stirred overnight. The reaction mixture was filtered and removed under reduced pressure the solvent. The crude residue was purified preparative HPLC to obtain specified in the title compound (3 mg, 2 TFA salt). HPLC (5-75) Rt=2,18. MSm/z: [M+H+] calculated for C37H45N5O6656,3; found 656,2.

Getting 56

4-(tert-Butoxycarbonylamino)-2-chlorpheniramine

Stir a solution of 4-aminomethyl-2-chlorpheniramine (940 mg, 6 mmol) and di-tert-BUTYLCARBAMATE (1.44 g, 6.6 mmol) in dichloromethane (30 ml) was stirred at room temperature for 4 h, whereupon analysis by LC-MS showed that the reaction had ended. The reaction mixture was then washed with saturated aqueous sodium bicarbonate (15 ml), the organic layer is sewed over sodium sulfate and removed under reduced pressure the solvent. The obtained orange solid is recrystallized from ethyl acetate to obtain specified in the title intermediate as a white solid (yield˜100%).

Getting 57

N-[4-(tert-Butoxycarbonylamino)-2-chlorophenyl]acrylamide

To a stirred solution of the product receiving 56 (1.54 g, 6.0 mmol) in a mixture of diethyl ether (35 ml) and 1M solution of sodium hydroxide was added dropwise akriloilkhlorida (687 μl, to 8.45 mmol). After 1 h, the organic layer was separated, dried (Na2SO4) and removed under reduced pressure, the solvent is obtaining specified in the title intermediate as a white solid (1.8 g, yield 96%).

Getting 58

1-[2-(4-(tert-Butoxycarbonylamino)-2-chlorpheniramol)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

A solution of the product obtain 8 (1.04 g, 3.5 mmol) and the product receiving 57 (1.19 g, of 3.85 mmol) in a mixture of dichloromethane and methanol (12 ml, 1:1) was heated at 60°C for 12 h the Reaction mixture was allowed to cool and removed under reduced pressure the solvent. The crude substance was purified column chromatography (5-10% Meon/DHM) obtaining specified in the title intermediate as a white solid (2.00 g, yield 94%).

Getting 59

1-[2-(4-Aminomethyl-2-harfe ylcarbonyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

A solution of the product receiving 58 (2.00 g, 3.3 mmol) was stirred in dichloromethane (24 ml) and TFA (8 ml) for 1 h and then was removed under reduced pressure the solvent. The crude reaction mixture was dissolved in dichloromethane (30 ml) and washed with 1M sodium hydroxide solution (2×30 ml). The organic layer was dried (Na2SO4) and removed under reduced pressure, the solvent is obtaining specified in the header of the intermediate compounds in the form of an oily white solid (1,46 g, yield 88%).

Getting 60

1-[2-(4-{[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethylamino]methyl}-2-chlorpheniramol)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Stir a solution of the product receiving 59 (1,41 g, and 2.79 mmol) and the product receiving 13 (680 mg, of 1.39 mmol) in DMSO (1.39 ml) was heated at 90°C for 8 h and then cooled to room temperature. The reaction mixture was diluted with a mixture of ethyl acetate/chloroform (20 ml, 1/1) and the organic layer was washed saturated aqueous sodium bicarbonate (10 ml), dried (Na2SO4) and removed under reduced pressure the solvent. The crude residue was purified column chromatography (5-10% Meon/DHM) obtaining specified in the title intermediate as a white solid (1.12 g,yield 88%). MSm/zM+H+=914,9.

Getting 61

1-[2-(4-{[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethylamino]methyl}-2-chlorpheniramol)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 60 (1.12 g, of 1.23 mmol) in dichloromethane (12 ml) was added Et3N·3HF (401 μl, 0.6 mmol). The reaction mixture was stirred for 10 h and then was diluted with dichloromethane (10 ml). The resulting mixture was washed with saturated aqueous sodium bicarbonate (5 ml), the organic layer was dried (Na2SO4) and removed under reduced pressure, the solvent is obtaining specified in the title intermediate as a white solid (959 mg, yield 100%). MSm/zM+H+=800,5.

Example 16

DATEFORMAT 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product of the receipt 61 (959 mg, 1.2 mmol) in ethanol (12 ml) was added Pd/C (290 mg), the reaction mixture was placed in an atmosphere of hydrogen and stirred overnight. Then the reaction mixture was filtered and removed under reduced pressure the solvent. The crude residue was purified preparative HPLC to obtain specified in the title compound (7 mg, 2 TFA salt). HPLC (10-70) Rt=was 2.76; MSm/zM+H+=710,6.

Getting 62

(5-tert-Butoxycarbonylmethyl)amide 2-chloroethanesulfonate acid

To a stirred solution of 5-(tert-butoxycarbonylamino)pentylamine (1,00 g, 4,94 mmol) and triethylamine (689 μl, 4,94 mmol) in dichloromethane (22 ml) at 0°C was added 2-chloro-1-acanaloniidae (470 μl, 4,50 mmol). The reaction mixture was stirred for 2 h at room temperature and then washed with saturated aqueous sodium bicarbonate (15 ml). The organic layer was dried (Na2SO4) and removed under reduced pressure, the solvent is obtaining specified in the title compound (yield 100%)which was used in the next stage without additional purification.

Getting 63

1-[2-(5-(tert-Butoxycarbonylmethylene)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

A solution of the product obtain 8 (1,33 g, 3.5 mmol) and the product receiving 62 (1,62 g, 4,94 mmol) in a mixture of dichloromethane and methanol (22 ml, 1:1) was heated at 60°C for 5 h the Reaction mixture was allowed to cool to room temperature and was removed at reduced pressure the solvent. The crude residue was dissolved in dichloromethane (20 ml) and washed with saturated aqueous sodium bicarbonate (10 ml). Then the organic layer was dried (Na2SO4) and is dalali under reduced pressure the solvent. The crude residue was purified column chromatography (5-10% Meon/DHM) obtaining specified in the title intermediate as a white solid (1.6 g, yield 55%). MSm/zM+H+=589,6.

Getting 64

1-[2-(5-Aminophenylamino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

A solution of the product receiving 63 (1.6 g, of 2.72 mmol) was stirred in dichloromethane (21 ml) and TFA (7 ml) for 1 h and then was removed under reduced pressure the solvent. The crude reaction mixture was dissolved in dichloromethane (30 ml) and washed with 1M sodium hydroxide solution (2×30 ml). The organic layer was dried (Na2SO4) and removed under reduced pressure, the solvent is obtaining specified in the header of the intermediate compounds in the form of an oily white solid (1.19 g, yield 90%).

Getting 65

1-(2-{5-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethylamino]intercultural}ethyl) piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Stir a solution of the product receiving 64 (917 mg, 1.88 mmol) and the product receiving 13 (460 mg, of 0.94 mmol) in DMSO (0,92 ml) was heated at 90°C for 8 h and then cooled to room temperature. The reaction mixture was diluted with a mixture of ethyl acetate/chloroform (20 ml, 1/1) and the organic layer washed with the saturated aqueous sodium bicarbonate (10 ml), dried (Na2SO4) and removed under reduced pressure the solvent. The crude residue was purified column chromatography (3-6% Meon/DHM) obtaining specified in the title intermediate as a white solid (500 mg, yield 60%). MSm/zM+H+=896,9.

Getting 66

1-(2-{5-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethylamino]intercultural}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To mix the solution is getting 65 (500 mg, of 0.56 mmol) in dichloromethane (5.6 ml) was added trihydrated of triethylamine (183 μl, 1.12 mmol). The reaction mixture was stirred for 10 h and then was diluted with dichloromethane (10 ml). The resulting mixture was washed with saturated aqueous sodium bicarbonate (5 ml). The organic layer was dried (Na2SO4) and removed under reduced pressure, the solvent is obtaining specified in the title intermediate as a yellow solid (437 mg, yield 100%). MSm/zM+H+=782,8.

Example 17

DATEFORMAT 1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]intercultural}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 66 (437 mg, 0,56 mmol) in a mixture of ethanol/methanol (5.6 ml, 1/1) EXT is ulali Pd/C (131 mg), the reaction mixture was placed in an atmosphere of hydrogen and stirred overnight. Then the reaction mixture was filtered and removed under reduced pressure the solvent. The crude residue was purified preparative HPLC to obtain specified in the connection header in the form of a salt detrivorous acid (71 mg). HPLC (10-70) Rt=2,59; MSm/zM+H+=692,6.

Getting 67

1-{2-[(4-Formylbenzenesulfonic)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a stirred solution of the product receiving 26 (350 mg, 1 mmol) and triethylamine (167 μl, 1.2 mmol) in dichloromethane (5 ml) was added 4-formylbenzenesulfonic (225 mg, 1.1 mmol). After 1 h at room temperature the reaction according to MS analysis was completed, and then the reaction mixture was washed with saturated aqueous sodium bicarbonate solution (5 ml). Then was dried (Na2SO4) the organic layer was removed under reduced pressure, the solvent is obtaining specified in the header of the intermediate compound (323 mg, yield 62%). MSm/zM+H+=522,4.

Getting 68

1-{2-[(4-{[(R)-2-(tert-Butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzazolyl)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Solution -[(R)-2-amino-1-(tert-butyldimethylsilyloxy)ethyl]-8-g is droxi-1H-quinoline-2-she (293 mg, to 0.74 mmol) and the product receiving 67 in dichloromethane and methanol (6.2 ml, 1/1) was stirred at room temperature for 1 h and then added triacetoxyborohydride sodium (394 mg, of 1.86 mmol). The reaction mixture was stirred 4 h, after which MS analysis showed that the reaction had ended. Then the reaction mixture was acidified with concentrated hydrochloric acid was removed under reduced pressure, the solvent is obtaining specified in the title compound, which was used in the next stage without additional purification. MSm/zM+H+=840,8.

Example 18

DATEFORMAT 1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzazolyl)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Stir a solution of the product receiving 68 (520 mg, of 0.62 mmol) in 1M hydrochloric acid (5 ml) and acetonitrile (5 ml) was heated at 60°C for 8 h, the Reaction mixture was cooled to room temperature and was removed at reduced pressure the solvent. The crude residue was purified preparative HPLC to obtain specified in the connection header in the form of a salt detrivorous acid (220 mg). HPLC (10-70) Rt=2,77; MSm/zM+H+=726,7.

Getting 69

Hydrochloride (3-aminomethylphenol)methanol

(a) (3-tert-Butoxycarbonyl ethylphenyl)methanol

Brandibelle (2,05 ml, 21.6 mmol) was added to a solution of 3-(tert-butoxycarbonylamino)benzoic acid (1,81 g, 7.20 mmol) in tetrahydrofuran (24 ml) and the resulting mixture was stirred at room temperature for 3 hours. Then the reaction mixture was diluted with ethyl acetate (20 ml) and layers were separated. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate and concentrated to obtain specified in the title compound as a yellow oil (1,71 g).

(b) Hydrochloride (3-aminomethylphenol)methanol

The product of stage (a) (1,71 g, 7.2 mmol) was added a solution of 4M hydrochloric acid in dioxane (9 ml, 36 mmol) and the resulting mixture was stirred at room temperature for 1 h Then the reaction mixture was concentrated, the residue was diluted with diethyl ether (50 ml) and filtered to obtain specified in the title compounds as white solids (1,09 g).

Getting 70

1-{2-[3-(3-Hydroxymethylene)ureido]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

0.2m solution of the product receiving 35 (760 mg, 2,24 mmol) in N,N-dimethylformamide was added dropwise to a solution of 1,1'-carbonyldiimidazole (363 mg, 2,24 mmol) and diisopropylethylamine (0,31 ml, 2,24 mmol) in N,N-dimethylformamide (11 ml) and poluchennymi was stirred at room temperature for 2 hours Added diisopropylethylamine (0,31 ml, 2,24 mmol) and the product is getting 69 (578 mg, 3.4 mmol) and the resulting mixture was stirred at 50°C for 12 h and Then the reaction mixture was concentrated to dryness, the residue was diluted with dichloromethane (20 ml) and the resulting solution was washed with saturated sodium bicarbonate solution (2 times), saturated sodium chloride solution, dried over magnesium sulfate and concentrated to obtain specified in the title compound (1.12 g). LC-MS (2-90) Rt=4,01 min; MSm/zM+H+=503,5.

Getting 71

1-{2-[3-(3-Formylmethyl)ureido]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

A solution of the product receiving 70 (1.12 g, of 2.23 mmol) in dichloromethane (11,1 ml) was cooled to 0°and added diisopropylethylamine (1,17 ml, 6,70 mmol) and dimethylsulfoxide (0,949 ml of 13.4 mmol). After about 10 minutes was added to the complex of pyridine and sulfur trioxide (1.06 g, 6,70 mmol) and the resulting mixture was stirred at 0°C for 2 h Then the reaction mixture was extinguished with water (15 ml) and the organic layer was washed with cold water (3 times), dried over magnesium sulfate and concentrated to obtain specified in the title compound as a yellow brittle substances (609 mg). LC-MS (2-90) Rt=4,13 min; MSm/zM+H=501,3.

Getting 72

1-{2-[3-(3-{[(R)-2-(tert-Butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroindol the h-5-yl)ethylamino]methyl}benzyl)ureido]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

5-[(R)-2-Amino-1-(tert-butyldimethylsilyloxy)ethyl]-8-hydroxy-1H-quinoline-2-he (575 mg, of 1.40 mmol) was added to the product receiving 71 (609 mg, 1.2 mmol) and Diisopropylamine (0.25 ml, of 1.40 mmol) in dichloromethane (6 ml) and the resulting mixture was stirred at room temperature for 45 minutes Then add triacetoxyborohydride sodium (385 mg, of 1.80 mmol) and the resulting mixture was stirred at room temperature for 12 hours Then the reaction mixture was extinguished 10% aqueous hydrochloric acid (5 ml) and layers were separated. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate and concentrated to obtain specified in the connection header (1,11 g). HPLC (10-70) Rt=3,55 min; MSm/zM+H=819,7.

Example 19

DATEFORMAT 1-{2-[3-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzyl)ureido]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Trihydrated of triethylamine (2.4 ml, to 13.6 mmol) was added to a solution of the product receiving 72 (1.1 g, of 1.36 mmol) in dichloromethane (2 ml) and the resulting mixture was stirred at room temperature for 15 hours Then the reaction mixture was concentrated in vacuum to dryness, the residue was dissolved in a mixture (1:1) of water and acetonitrile with 0.1% TFA and the resulting mixture was purified HPLC (5-35 60 min) with what rucenim specified in the connection header in the form of a salt detrivorous acid (296 mg, purity 99%). MSm/zM+H=705,6.

Getting 73

1-[(E)-3-(4-Nitrophenyl)allyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Product obtain 8 (2,96 g, 0.01 mol) and p-nitrocinnamyl (1.77 g, 0.01 mol) was stirred in 50 ml of dichloromethane for 2 hours was Added triacetoxyborohydride sodium (6,33 g, 0.03 mol) and the resulting mixture was stirred for 2 h Then the reaction mixture was extinguished 10 ml of water and the resulting mixture was diluted with dichloromethane (100 ml). The organic layer was washed with saturated sodium bicarbonate solution (2 times), saturated salt solution, dried over Na2SO4, filtered and concentrated to obtain specified in the title compound as a yellow foam (3.8 g, yield 80%).

Getting 74

1-[3-(4-AMINOPHENYL)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

The product is getting 73 (2.5 g, 5.4 mmol) was dissolved in 100 ml of ethanol and the resulting solution was purged with nitrogen for 30 minutes and Then was added palladium on carbon (2.5 g; 50% wt./wt. water; 10% Pd; 1.1 mmol Pd) when degassing with nitrogen. Then the resulting mixture was placed in an atmosphere of hydrogen (50 psi; 2.5 kg/cm2) until, until stopped spending hydrogen (˜30 minutes). Then the mixture was purged with nitrogen, filtered through celite and concentrated. The residue was dissolved in ethyl acetate and the resulting mixture is washed with saturated sodium bicarbonate solution (2 times), saturated salt solution, dried (Na2SO4), filtered and concentrated to obtain specified in the connection header (of 2.08 g, yield 90%). MSm/zM+H=430,5.

Getting 75

1-{3-[4-(4-{2-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-(tert-butyldimethylsilyloxy)ethylamino]ethyl}phenylamino)phenyl]propyl} piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

A 25 ml round bottom flask was introduced product is getting 74 (400 mg, 0.8 mmol), 8-benzyloxy-5-[(R)-2-[2-(4-bromophenyl)ethylamino]-1-(tert-butyldimethylsilyloxy)ethyl]-1H-quinoline-2-he (769 mg, 1.2 mmol), Tris(dibenzylideneacetone)dipalladium(0) (73 mg, 0.08 mmol, 20% Pd) and 2-(dicyclohexylphosphino)biphenyl (84 mg, 0.24 mmol). The resulting mixture was purged with nitrogen, then added dry degassed toluene (8 ml, 0.1 m) and the resulting mixture was heated at 70°C for 30 min and Then was added tert-piperonyl sodium (382 mg, 4.0 mmol) and raised the temperature to 95°C for 4 h, after which the analysis of LC-MS showed complete consumption of the product is getting 74, and a large peak of the product (M+H=956,7). Then the reaction mixture was cooled to room temperature and was diluted with ethyl acetate. The resulting mixture was washed with saturated sodium bicarbonate solution (2 times), saturated salt solution, dried (Na2SO4), filtered and concentrated to obtain specified in the header connect the FL (1.5 g), which was used without further purification.

Getting 76

1-{3-[4-(4-{2-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethylamino]ethyl}phenylamino)phenyl]propyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

The product is getting 75 was dissolved in dichloromethane (10 ml) was added trihydrated of triethylamine (10 EQ.). The reaction mixture was stirred overnight and then was diluted with dichloromethane and the organic layer was washed with saturated sodium bicarbonate solution (2 times), saturated salt solution, dried (Na2SO4), filtered and concentrated to obtain 1.3 g of the crude product. The obtained product was purified by chromatography on silica gel (DHM, with a gradient up to 50% methanol) to obtain the specified title compound (300 mg, purity 75%)which was used without further purification.

Example 20

DATEFORMAT 1-{3-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)phenyl]propyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

The product is getting 76 (300 mg) was dissolved in 10 ml of ethanol and the resulting mixture was purged with nitrogen for 15 minutes. Were added when the degassing palladium on carbon (10% Pd, 50% wt./wt. water, 0.2 EQ. Pd). The resulting mixture was then placed in an atmosphere of hydrogen (1 ATM) for 2 h, PEFC is what the analysis of LC-MS showed the termination of the reaction. Then the solution was purged with nitrogen for 15 min, then filtered through celite and concentrated. The obtained residue was purified preparative HPLC to obtain specified in the connection header in the form of a salt detrivorous acid (59 mg, purity>95%). MSm/zM+H=752,8.

Getting 77

1-[2-Fluoro-3-(4-hydroxyethylpiperazine-1-ylmethyl)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Product obtain 8 (500 mg, was 1.69 mmol), 2,6-bis(methyl bromide)-1-torbenson (476 mg, was 1.69 mmol), piperidine-4-ylmethanol (195 mg, was 1.69 mmol) and potassium carbonate (466 mg, 3,37 mmol) suspended in acetonitrile (5 ml) and stirred at room temperature for 18 hours Then the reaction mixture was concentrated and the residue was dissolved in a mixture of dichloromethane/water. Separated the layers, the organic layer was washed with water (2 times), saturated salt solution, dried (MgSO4) and concentrated. The crude substance was purified column chromatography on silica gel, elwira a mixture of 3% methanol/chloroform, to obtain specified in the title compound as a white foam (282 mg). MSm/zM+H=532,3.

Getting 78

1-[2-Fluoro-3-(4-formylpiperidine-1-ylmethyl)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

The product is getting 77 (282 mg, of 0.53 mmol) was dissolved in dichloromethane and the resulting mixture was added diisopropylethylamine (280 is CL, 1.6 mmol) and dimethylsulfoxide (115 μl, 1.6 mmol). The reaction mixture was cooled to -15°C in an atmosphere of nitrogen, and was added to the complex of pyridine and sulfur trioxide (255 mg, 16 mmol) and the resulting mixture was stirred for 40 minutes Then the reaction mixture was extinguished with water and the layers were separated. The organic layer was washed with an aqueous solution NaH2PO4(1M×3), a saturated solution of salt, dried (MgSO4) and concentrated to obtain specified in the title compound as a foam (253 mg). MSm/zM+H=530,4.

Example 21

DATEFORMAT 1-[2-fluoro-3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}piperidine-1-ylmethyl)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

The product is getting 78 (253 mg, 0.48 mmol) was dissolved in a mixture (1:1) of dichloromethane and methanol (6 ml) and the resulting mixture was added 5-[(R)-2-amino-1-(tert-butyldimethylsilyloxy)ethyl]-8-hydroxy-1H-quinoline-2-oacett (228 mg, of 0.58 mmol) and triacetoxyborohydride sodium (317 mg, 1.5 mmol). The reaction mixture was stirred in nitrogen atmosphere at room temperature for 18 h and then concentrated. The residue was dissolved in a mixture (2:3) of acetonitrile and 6 N. hydrochloric acid and the resulting mixture was heated at 55°C for 4 h Then the reaction mixture was concentrated, the residue was dissolved in a mixture (1:1:0,005) water/acetonitrile/trip orokana acid and was purified column chromatography with reversed phase with obtaining specified in the title compound as a white solid (175 mg). MSm/zM+H=734,5.

Getting 79

2-[4-(3-Bromopropane)phenyl]ethanol

To a solution of 4-hydroxyphenethyl alcohol (4,37 g, was 31.0 mmol) and potassium carbonate (6,55 g, and 47.0 mmol) in acetonitrile (62,0 ml) was added 1,3-dibromopropane (31,0 ml, 316 mmol). The reaction mixture was heated to 70°C for 12 hours and then cooled to room temperature, filtered and concentrated in vacuum. The resulting oil was purified by chromatography on silica gel using a mixture of hexanol and ethyl acetate (4:1), obtaining specified in the connection header (6,21 g) as a white solid.

80

1-{3-[4-(2-Hydroxyethyl)phenoxy]propyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a solution of the product getting 79 (1,11 g, 4.30 mmol) and diisopropylethylamine (0,90 ml, 5,10 mmol) in acetonitrile (21,5 ml) was added the product to obtain 8 (1.27 g, 4.30 mmol) and the resulting mixture was stirred at 60°C for 12 h and Then the reaction mixture was diluted with dichloromethane (20 ml) and washed with saturated sodium bicarbonate solution (25 ml), saturated sodium chloride solution (25 ml), dried over magnesium sulfate and concentrated to obtain specified in the title compound (1.98 g, purity 85%). MSm/zM+H=475,5.

Getting 81

1-{3-[4-(2-Oxoethyl)phenoxy]propyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

R is the target product receiving 80 (723 mg, 1.53 mmol) and dichloromethane (75 ml) was cooled to approximately 5°and added diisopropylethylamine (798 ml, 4,58 mmol) and dimethylsulfoxide (649 ml, to 9.15 mmol). Then added a complex of pyridine and sulfur trioxide (728 mg, 4,58 mmol) and the resulting mixture was stirred at 5°C for 45 minutes Then the reaction mixture was diluted with dichloromethane (20 ml) and washed with saturated sodium bicarbonate solution (25 ml), saturated sodium chloride solution (25 ml), dried over magnesium sulfate and concentrated to obtain specified in the title compound (604 mg). MSm/zM+H=473,4.

Getting 82

1-[3-(4-{2-[(R)-2-(tert-butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenoxy)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

The product is getting 81 (604 mg, 1.28 mmol) was dissolved in methanol (6.4 ml) was added 5-[(R)-2-amino-1-(tert-butyldimethylsilyloxy)ethyl]-8-hydroxy-1H-quinoline-2-he (605 mg, 1.53 mmol) and diisopropylethylamine (with 0.27 ml, 1.53 mmol). Then add triacetoxyborohydride sodium (405 mg, at 1.91 mmol) and the reaction mixture was stirred at room temperature for 3 h Then the reaction mixture was concentrated to dryness, the residue was diluted with ethyl acetate (20 ml) and the resulting solution was washed with saturated sodium bicarbonate solution (25 ml), saturated sodium chloride solution (25 ml), was dried in the magnesium sulfate and concentrated to obtain specified in the header of the compound (704 mg). MSm/zM+H=791,8.

Example 22

DATEFORMAT 1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenoxy)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

Trihydrated of triethylamine (1.5 ml, 8,87 mmol) was added to a solution of the product receiving 82 (702 mg, 0.89 mmol) in dichloromethane (4.5 ml) and the resulting mixture was stirred at room temperature for 24 h Then the mixture was concentrated in vacuum and purified HPLC (2-35 90 min) to obtain the specified title compound (92 mg) as a white powder. MSm/zM+H=677,4.

Getting 83

Methyl-4-idgenerator

To a stirred solution of 4-IOpenRowset acid (5.0 g, 19,1 mmol) in Meon (200 ml) was added 4 N. hydrochloric acid in dioxane (10 ml). The reaction mixture was stirred for 24 h at room temperature and then was removed under reduced pressure, the solvent is obtaining specified in the connection header (of 5.17 g, yield 98%)which was used without further purification.

Getting 84

Methyl[4-(4-hydroxyben-1-inyl)phenyl]acetate

To mix the solution is getting 83 (4.5 g, 16.3 mmol) in diethylamine (100 ml) was added but-3-in-1-ol (1.9 ml, with a 32.6 mmol), Pd(PPh3)2Cl2(500 mg, and 1.63 mmol) and CuI (154 mg, 0,815 mmol) and the resulting mixture was stirred 17 h at room the Oh temperature. Then removed under reduced pressure, the solvent, the residue was dissolved in diethyl ether (200 ml) and the resulting solution was filtered to remove salts. Then removed under reduced pressure, the solvent and the crude product was purified by chromatography on silica gel (60% EtOAc/hexane) to obtain specified in the header of the intermediate compound (3.03 g, yield 91%).

Getting 85

Methyl[4-(4-hydroxybutyl)phenyl]acetate

Stir a solution of the product getting 84 (2.8 g, 12.8 mmol) in methanol (50 ml) was purged with nitrogen and then added 10% palladium on carbon (400 mg, 20% wt./wt.). Then the reaction flask cyclically alternately placed in vacuum and purged with hydrogen, then stirred in hydrogen atmosphere for 14 hours, the Reaction mixture was purged with nitrogen and then filtered and removed under reduced pressure, the solvent is obtaining specified in the connection header (2,75 g, yield 97%)which was used without further purification.

Getting 86

Methyl (4-{4-[4-(biphenyl-2-ylcarbamate)piperidine-1-yl]butyl}phenyl)acetate

(a) Methyl{4-[4-(toluene-4-sulfonyloxy)butyl]phenyl}acetate

To a stirred solution of the product receiving 85 (2.6 g, 12.5 mmol) in THF (100 ml) was added DABCO (2.6 g, 25,0 mmol) and then p-toluensulfonate (2,44 g of 13.75 mmol). The reaction mixture was stirred at room te is the temperature for 23 h, then removed under reduced pressure, the solvent and the residue was dissolved in dichloromethane (200 ml). The organic layer is then washed with water (2×100 ml), 1N. hydrochloric acid (100 ml), saturated aqueous sodium chloride (100 ml), dried (MgSO4), filtered and removed under reduced pressure, the solvent is obtaining specified in the title compound, which was used without further purification.

(b) Methyl(4-{4-[4-(biphenyl-2-ylcarbamate)piperidine-1-yl]butyl}phenyl)acetate

To the crude product from stage (a) was added DMF (50 ml), diisopropylethylamine (3.0 ml, 17.3 mmol) and the product receiving 8 (2.4 g, 8.1 mmol). The reaction mixture was stirred at room temperature for 18 h and then was removed under reduced pressure, the solvent is obtaining specified in the title compound (3.5 g, yield 86,3%). MSm/z501,6 (MH+), Rf4,89 min (10-70% ACN:H2O, HPLC with reversed phase).

Getting 87

1-{4-[4-(2-Hydroxyethyl)phenyl]butyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To mix the solution is getting 86 (2.0 g, 4.0 mmol) in THF (100 ml) was added dropwise DIBAL (24 ml, 24 mmol, 1.0m in THF). After the addition was finished the reaction mixture was stirred for 3 h and then extinguished by slow addition of methanol (up to the cessation of gassing). Then the mixture is PE is amasyali for 30 min and then added ethyl acetate (200 ml) and 1 N. an aqueous solution of sodium hydroxide (200 ml). The organic layer was separated and washed with saturated aqueous sodium chloride (100 ml), dried (MgSO4), filtered and removed under reduced pressure, the solvent is obtaining specified in the title compound (1.3 g, yield 69%)which was used without further purification. MSm/z473,4 (MH+), Rfa 4.53 min (10-70% ACN:H2O, HPLC with reversed phase).

Example 23

1-[2-(4-{2-[(R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To mix the solution is getting 87 (500 mg, 1.06 mmol) in dichloromethane (25 ml) was added dimethyl sulfoxide (of 0.60 ml, 10.6 mmol) and diisopropylethylamine (0,921 ml, 5.3 mmol). Then the reaction mixture was cooled to -10°and added a complex of pyridine and sulfur trioxide (842 mg, 5.3 mmol). The reaction mixture was stirred for 1 h and then was suppressed by addition of water (100 ml). The resulting mixture was stirred 10 min and then the organic layer was separated, washed with saturated aqueous sodium chloride (100 ml), dried (MgSO4) and then filtered.

To the filtrate was added methanol (25 ml), 5-[(R)-2-amino-1-(tert-butyldimethylsilyloxy)ethyl]-8-hydroxy-1H-quinoline-2-oacett (419 mg, 1.06 mmol) and triacetoxyborohydride sodium (468 mg, 2,12 mmol). Obtained from the ect was stirred 16 h, then are condensed and the resulting mixture was added a mixture (1:1) acetonitrile and water 4 N. hydrochloric acid (20 ml). The resulting mixture was heated at 50°C for 17 h and then was removed under reduced pressure the solvent. To the residue was added a mixture (1:1) acetic acid and water (8.0 ml) and the resulting mixture was chromatographically on silica gel with reversed phase (gradient elution, 10-50% ACN/H2(O) obtaining specified in the title compound (67 mg, yield 7% for 3 stages). MSm/z(MH+) 675,5; Rf3,07 (10-70% ACN:H2O, HPLC with reversed phase).

Getting 88

Ethyl-3-[5-(2-ethoxycarbonylphenyl)thiophene-2-yl]acrylate

To a stirred solution of sodium hydride (2.1 g, 53 mmol, 60% in mineral oil) in THF (200 ml) was slowly added triethylphosphite (10 ml, 50 mmol). Observed separation of gaseous hydrogen and the reaction mixture was stirred until the termination of gas (about 30 min). To the obtained reaction mixture was added 2,5-thiophencarboxylic (3 g, 21 mmol) and the reaction mixture was stirred for 1 h was Removed under reduced pressure, the solvent and the residue was dissolved in dichloromethane (200 ml). The organic layer was washed with water (100 ml), aqueous 1 N. hydrochloric acid (100 ml), saturated aqueous sodium chloride (100 ml), dried (MgSO4), filtered and removed the under reduced pressure, the solvent is obtaining specified in the title compound (5.8 g, yield 98%)which was used without further purification.

Getting 89

Ethyl-3-[5-(2-ethoxycarbonylethyl)thiophene-2-yl]propionate

Stir a solution of the product receiving 88 (5.8 g, 21 mmol) in methanol (200 ml) was purged with nitrogen was added 10% palladium on carbon (576 mg, 10% wt./wt.). The reaction flask were successively placed in a vacuum and purged with hydrogen, with 3 of these rings, and then the reaction mixture was stirred in hydrogen atmosphere for 1 h Then the mixture was purged with nitrogen, filtered and removed under reduced pressure, the solvent is obtaining specified in the title compound (5.8 g, yield 99%)which was used without further purification.

Getting 90

3-[5-(3-Hydroxypropyl)thiophene-2-yl]propan-1-ol

To a stirred solution of DIBAL (88 ml, 88 mmol, 1.0m in cyclohexane) in THF (300 ml) at -78°With added dropwise product is getting 89 (5.0 g, 17.6 mmol). After the addition was finished the reaction mixture was heated to room temperature for 30 min and then extinguished by slow addition of water 1 N. hydrochloric acid (200 ml). Added dichloromethane (400 ml) and layers were separated. The aqueous layer was washed with dichloromethane (4×100 ml) and the combined organic layers were washed with saturated aqueous solution of sodium chloride (100 ml), dried (MgSO4), filtered and removed under reduced giving the situation a solvent to obtain specified in the title compound (3.0 g, yield 85%)which was used without further purification.

Getting 91

1-{3-[5-(3-Hydroxypropyl)thiophene-2-yl]propyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

(a) 3-[5-(3-Hydroxypropyl)thiophene-2-yl]propyl ester toluene-4-sulfonic acid

To a stirred solution of the product receiving 90 (423 mg, 2.1 mmol) in THF (20 ml) was added DABCO (420 mg, 4.2 mmol) and then p-toluensulfonate (442 mg, 2.3 mmol). The reaction mixture was stirred at room temperature for 2 h, then was removed under reduced pressure, the solvent and the residue was dissolved in dichloromethane (200 ml). The organic layer was washed with water (2×100 ml), saturated aqueous sodium chloride (100 ml), dried (MgSO4), filtered and removed under reduced pressure, the solvent is obtaining specified in the title compound, which was used without further purification.

(b) 1-{3-[5-(3-Hydroxypropyl)thiophene-2-yl]propyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To the product from step (a) was added acetonitrile (20 ml), diisopropylethylamine (0.5 ml, 2.8 mmol) and the product receiving 8 (626 mg, 2,11 mmol). The reaction mixture was heated to 50°C for 20 h, then cooled to room temperature and was removed at reduced pressure the solvent. The residue was purified by chromatography on silica gel (5% Meon/the HMM with 0.6% of NH 3(aq.)) obtaining specified in the title compound (450 mg, yield 44%). MSm/z(MH+) 479,6; Rf4,15 min (10-70% ACN: H2O, HPLC with reversed phase).

Getting 92

1-[3-(5-{3-[(R)-2-(tert-Butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propyl}thiophene-2-yl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To mix the solution is getting 91 (450 mg, of 0.94 mmol) in dichloromethane (20 ml) was added dimethyl sulfoxide (of 0.21 ml, 3.7 mmol) and diisopropylethylamine (of 0.65 ml, 3.7 mmol). The mixture was cooled to -10°and added a complex of pyridine and sulfur trioxide (444 mg, 2.8 mmol). The reaction mixture was stirred for 3 h and then was suppressed by addition of water (100 ml). The resulting mixture was stirred 10 min, then the organic layer was separated and washed with saturated aqueous sodium chloride (100 ml), dried (MgSO4) and was filtered.

To the filtrate was added methanol (20 ml), 5-[(R)-2-amino-1-(tert-butyldimethylsilyloxy)ethyl]-8-hydroxy-1H-quinoline-2-oacett (368 mg, of 0.93 mmol) and then triacetoxyborohydride sodium (412 mg, of 1.86 mmol). The resulting mixture was stirred 19 h and then are condensed with obtaining specified in the title compound, which was used without further purification. MSm/z(MH+) 795,8; Rfis 4.93 min (10-70% ACN:H2O, HPLC with reversed phase).

P the emer 24

1-[3-(5-{3-[(R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propyl}thiophene-2-yl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To the crude product to obtain 92 was added a mixture (1:1) acetonitrile and water 4 N. hydrochloric acid (25 ml). The resulting mixture was heated at 50°C for 17 h and then was removed under reduced pressure the solvent. To the residue was added a mixture (1:1) acetic acid and water (8.0 ml) and the resulting mixture was chromatographically on silica gel with reversed phase (gradient elution, 10-50% ACN/H2(O) obtaining specified in the title compound (135 mg, yield 16% for stage 3). MSm/z(MH+) 681,5; Rf3,03 (10-70% ACN:H2O, HPLC with reversed phase).

Getting 93

Methyl-4-amino-5-chloro-2-methoxybenzoate

To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (1,008 g, 5.0 mmol) in a mixture of toluene (9 ml) and methanol (1 ml) at 0°With added dropwise (trimethylsilyl)diazomethane (2.0m in hexane, 3.0 ml, 6.0 mmol). Then the reaction mixture was heated to room temperature and was stirred for 16 h Excess (trimethylsilyl)diazomethane was suppressed by the addition of acetic acid until the disappearance of the light yellow color of the reaction mixture. The mixture is then concentrated in vacuum to obtain specified in the connection header as not quite white solid fuel is Dogo substances, which was used without further purification.

Getting 94

Methyl-4-acrylamido-5-chloro-2-methoxybenzoate

To the crude product to obtain 93 was added dichloromethane (10 ml, 0.5m) and triethylamine (2.1 ml, 15 mmol). The resulting mixture was cooled to 0°and added dropwise with stirring, akriloilkhlorida (812 μl, 10 mmol). After 2 h the reaction mixture was suppressed by the addition of methanol (approximately 2 ml) at 0°and the resulting mixture was stirred at room temperature for 15 min and then concentrated in vacuum. To the residue was added dichloromethane (30 ml) and water (30 ml) and the resulting mixture was thoroughly mixed. Separated the layers and the aqueous layer was extracted with dichloromethane (20 ml). The organic layers were combined, dried (Na2SO4), filtered and removed under vacuum, the solvent is obtaining specified in the title compound as a brown foamy solid, which was used without further purification.

Getting 95

Methyl-4-{3-[4-(biphenyl-2-ylcarbamate)piperidine-1-yl]propionamide}-5-chloro-2-methoxybenzoate

To the crude product receiving 94 was added the product to obtain 8 (1,33 g, 4.5 mmol) and a mixture of THF (22.5 ml) and methanol (2.5 ml). The resulting mixture was heated at 50°With stirring for 16 h and then removed in vacuum solvent. The rest of chromatogr who was firvale (silica gel; EtOAc) to obtain specified in the connection header (0,82 g; Rf=0,4; 29% for stage 3) in the form of not-quite-white foamy solid. MSm/z566,4 (M+H calculated 565,20 for C30H32ClN3O6).

Getting 96

1-[2-(2-Chloro-4-hydroxymethyl-5-methoxyphenylacetyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a solution of the product receiving 95 (0,82 mg, 1,45 mmol) in a mixture of THF (4.5 ml) and methanol (0.5 ml) was added borohydride lithium (32 mg, 1,45 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 41 hours Then the reaction mixture was suppressed by the addition of 1 N. hydrochloric acid at 0°s to stop the gassing and the resulting mixture was stirred for 10 minutes was Removed in vacuum, the solvent and the residue was dissolved in acetonitrile (2 ml). The resulting solution was purified preparative HPLC with reversed phase (gradient: 2-50% acetonitrile in water with 0.05% of TFA). The appropriate fractions were collected, combined and liofilizovane obtaining specified in the connection header in the form of a salt triperoxonane acid. This salt was treated with isopropylacetate (10 ml) and 1 N. aqueous sodium hydroxide solution (10 ml) and the organic layer was collected, dried (Na2SO4), filtered and removed under vacuum, the solvent is obtaining specified in sagola the ke of the compound (161 mg, yield 21%) as a white foamy solid. MSm/z538,4 (M+H calculated 537,20 for C29H32ClN3O5).

Getting 97

1-[2-(2-Chloro-4-formyl-5-methoxyphenylacetyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a solution of the product receiving 96 (161 mg, 0.3 mmol) in dichloromethane (3 ml) was added dimethyl sulfoxide (213 μl, 3.0 mmol) and diisopropylethylamine (261 μl, 1.5 mmol). The resulting mixture was cooled to -20°and was slowly added to a complex of pyridine and sulfur trioxide (238 mg, 1.5 mmol). After 30 min the reaction mixture was suppressed by addition of water (approximately 3 ml). Separated the layers, the organic layer was dried (Na2SO4), filtered and removed under vacuum, the solvent is obtaining specified in the title compound as a pale yellow solid. MSm/z536,3 (M+H calculated 535,19 for C29H30ClN3O5).

Getting 98

1-[2-(4-{[(R)-2-(tert-Butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-2-chloro-5-methoxyphenylacetyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

The product is getting 97 in a mixture of dichloromethane (0.5 ml) and methanol (0.5 ml) was added 5-[(R)-2-amino-1-(tert-butyldimethylsilyloxy)ethyl]-8-hydroxy-1H-quinoline-2-oacett (of 124.1 mg, 3.1 mmol) and the resulting mixture was stirred at room te is the temperature for 1.5 hours Added triacetoxyborohydride sodium (190,7 mg, 0.9 mmol) and the resulting mixture was stirred at room temperature for 15 hours, the Reaction mixture was suppressed by addition of water (approximately 0.2 ml) and the mixture was concentrated in vacuum to obtain specified in the title compound, which was used without further purification. MSm/z854,5 (M+H calculated 853,36 for C46H56ClN5O7Si).

Example 25

DATEFORMAT 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxyphenylacetyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

To a suspension of the product receiving 98 in dichloromethane (1.0 ml, 0.3 m) was added trihydrated of triethylamine (245 μl, 1.5 mmol). The resulting mixture was stirred at room temperature for 45 h and then the mixture was concentrated in vacuum. The residue was dissolved in a mixture of DMF (0.5 ml), acetonitrile/water (1:1, with 0.1% TFA, 0.6 ml), TFA (0.3 ml) and acetonitrile (about 1 ml) and the resulting mixture was purified preparative RP-HPLC (gradient: 2-50% acetonitrile in water with 0.05% of TFA). The appropriate fractions were collected and combined and liofilizovane obtaining specified in the title compound (100 mg, yield 34%, purity 98,7% according to HPLC) as not quite white solid. MSm/z740,5 (M+H calculated 739,28 for C40H42ClN5O7).

Using the above methodology and relevant source materials, received the following connections.

1-[2-(4-{[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid/tr>
Etc.ConnectionMS
261-{7-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]heptyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid613,5
271-{8-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]octyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid627,5
281-{2-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenyl)ureido]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid705,3
291-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}piperidine-1-yl)-3-oxopropyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid682,4
301-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}cyclohexanecarbonyl)amino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid682,7
311-[2-({(1R,3S)-3-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]cyclopentanecarbonyl}amino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid 630,2
321-[2-(3-{5-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]pentyl}ureido)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid647,5
331-[2-(4-(2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid662,5
341-[3-(3-{5-[2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]pentyl}ureido)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid661,3
351-{2-[(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}piperidine-1-carbonyl)amino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid697,5
361-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid724,5
371-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid690,3
383-[4-(3-biphenyl-2-yureina)piperidine-1-yl]-N-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydro shall inolin-5-yl)ethylamino]methyl}phenyl)propionamide 675,5
391-{2-[(6-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}pyridine-2-ylmethyl)carbarnoyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid691,5
401-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}cyclohexylcarbamate)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid682,7
411-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}cyclohexylcarbamate)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid682,7
421-[2-({(1R,3S)-3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]cyclopentanecarbonyl}amino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid654,8
431-{2-[(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoyl)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid690,4
441-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}cyclohexanecarbonyl)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid696,5
45No
461-[2-(4-{(S)-1-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid690,7
471-[2-(4-{(R)-1-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid690,7
481-((S)-1-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]pentanoyl}pyrrolidin-2-ylmethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid682,7
491-[(S)-1-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoyl)pyrrolidin-2-ylmethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid716,8
501-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid652,6
511-[2-(4-{(R)-1-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]ethyl}phenylcarbamoyl)e is Il]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid of 666.5
521-[2-(4-chloro-3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid710,5
53N-{2-[4-(3-biphenyl-2-yureina)piperidine-1-yl]ethyl}-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzamide675,5
541-biphenyl-2-yl-3-{1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}piperidine-1-yl)-3-oxopropyl]piperidine-4-yl}urea681,7
553-[4-(3-biphenyl-2-yureina)piperidine-1-yl]-N-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzyl)propionamide689,5
561-(2-fluoro-3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid637,5
571-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-4-methylphenylcarbinol)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid690,4
581-[2-(2-chloro-5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]PI is uridin-4-silt ether-biphenyl-2-ylcarbamate acid 710,6
591-[2-(2,6-dichloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid745,2
601-[1-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoyl)piperidine-4-ylmethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid730,8
611-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}benzoylamine)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid652,5
621-{2-[ethyl-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenyl)carbarnoyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid704,5
631-(3-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]piperidine-1-yl}-3-oxopropyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acidNo
641-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid690,3
651-{2-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-OK, what about the-1,2-dihydroquinoline-5-yl)ethylamino]methyl}thiophene-2-carbonyl)amino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid 682,5
661-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-3-nitrobenzoyl)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid735,7
671-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}cyclohexylcarbamate)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid658,8
681-[2-({4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]cyclohexanecarbonyl}methylamino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid682,7
691-(2-fluoro-3-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]piperidine-1-ylmethyl}benzyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid720,5
701-{2-[(6-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}pyridine-3-carbonyl)amino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid677,5
711-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}piperidine-1-yl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid654,5
721-[2-(4-{2-[(R)-2-(formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]ethyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid of 666.5
731-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid690,3
741-[2-fluoro-3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}piperidine-1-ylmethyl)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid748,5
751-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid676,4
761-[2-(3-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid710,2
771-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-2-triftormetilfullerenov)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid769,2
781-{3-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)phenyl]propyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid752,6
791-[3-(4-{2-[(S)-2-is hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid No
801-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-2-idgenerator)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acidthe 802.1
811-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-6-methylphenylcarbinol)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid724,2
821-(2-{5-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]intercalator}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid656,5
831-[2-(2-bromo-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid756,2
841-{3-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)phenyl]propyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid752,8
851-[2-fluoro-3-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propyl}piperidine-1-ylmethyl)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid762,8
861-[2-(4-{[(R)-2-g is droxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-2-methoxyphenylacetyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid 706,3
871-[5-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)pentyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid704,3
881-{2-[1-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenyl)piperidine-4-yl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid730,8
891-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]-1-methylethyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid704,4
901-{2-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)cyclohexyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid744,4
911-[2-(2-fluoro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid694,3
921-{2-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)phenyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid738,8
931-[2-(2,5-debtor-4-{[(R) - 2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid 712,3
941-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}benzoylamine)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid690,3
951-[6-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}piperidine-1-ylmethyl)pyridine-2-ylmethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid717,5
961-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}naphthalene-1-ylcarbonyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid740,6
971-{2-[1-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoyl)piperidine-4-yl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid744,4
981-[3-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propionamide}phenyl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid704,2
991-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid663,7
1001-[2-(5-{[(R)-2-hydroxy-2-8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-1H-benzoimidazol-2-yl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid 673,7
1011-[2-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propionamide}cyclohexyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid696,4
1021-[2-(4-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]pentanediamine}cyclohexyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid724,4
1031-[2-(4-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]hexanamine}cyclohexyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid738,4
1041-[2-(1-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propionyl}piperidine-4-yl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid682,4
1051-{2-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenyl)ureido]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid691,7
1061-{2-[(2-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]cyclohexyl}ethyl)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid682,7
1071-[2-(2,3,5,6-eruptor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid 748,2
1081-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-2,6-diethenylbenzene)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid928,0
1091-[2-(1-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]butyryl}piperidine-4-yl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid696,4
1101-[2-(1-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]pentanoyl}piperidine-4-yl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid710,4
1111-[2-(1-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]hexanoyl}piperidine-4-yl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid724,4
1121-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid690,5
1131-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}benzylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acidof 666.5
1141-{2-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy--oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzyl)ureido]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid 705,6
1151-{2-[3-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}benzyl)ureido]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid681,7
1161-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-2-methylphenylcarbinol)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid690,4
1171-(3-{4-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}piperidine-1-yl)ethyl]phenoxy}propyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid774,4
1181-[2-(3-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}benzylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid690,4
1191-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid649,5
1201-(2-{[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetyl]methylamino}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid720,4
1211-(2-{[2-(3-{[(R)-2-hydroxy-2(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetyl]methylamino}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid 720,4
1221-{2-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}furan-2-carbonyl)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid680,3
1231-{2-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}thiophene-2-carbonyl)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid696,2
1241-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethoxy}phenoxy)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid679,3
1251-{2-[4-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoylamine)cyclohexyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid758,4
1261-(2-{4-[2-(2-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetylamino]cyclohexyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid788,4
1271-(2-{4-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetylamino]cyclohexyl)ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid788,4
1281-(2-{4-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetylamino]cyclohexyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid788,4
1291-(2-{4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}furan-2-carbonyl)amino]cyclohexyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid748,4
1301-(2-(4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}thiophene-2-carbonyl)amino]cyclohexyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid764,4
1311-(2-{1-[2-(2-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetyl]piperidine-4-yl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid774,4
1321-(2-{1-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetyl]piperidine-4-yl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid774,4
1331-(2-{1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetyl]piperidine-4-yl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid/td> 774,4
1341-{2-[1-(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}furan-2-carbonyl)piperidine-4-yl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid734,4
1351-{2-[1-(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}thiophene-2-carbonyl)piperidine-4-yl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid750,2
1361-{2-[4-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoylamine)phenyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid752,4
1371-(2-[4-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoylamine)phenyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid752,4
1381-(2-{4-[2-(2-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetylamino]phenyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid782,4
1391-(2-{4-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetylamino]phenyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid782,4
1401-(2-{4-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetylamino]phenyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid782,4
1411-(2-{4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}furan-2-carbonyl)amino]phenyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid742,4
1421-(2-{4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}thiophene-2-carbonyl)amino]phenyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acidabout 758,2
1431-{2-[4-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoylamine)cyclohexyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid758,4
1441-[3-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid663,4
1451-[2-hydroxy-3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid692,3
1461-[4-(4(2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)butyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid 690,4
1471-{2-[4-({2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]acetylamino}methyl)phenylcarbamoyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid733,3
1481-{2-[4-(2-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]acetylamino}ethyl)phenylcarbamoyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid747,4
1491-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}cyclohexylmethyl)carbarnoyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid696,6
1501-(2-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]hexanamine}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid656,6
1511-[2-(3-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethoxy}phenoxy)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid679,3
1521-[2-(2-{2-[(S)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethoxy}phenoxy)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid679,3
1531-[2-(2-{[(R)-2-hydroxy-2(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid 711,3
1541-(2-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]exaltabitur}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid670,4
1551-[2-({(1R,3S)-3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]cyclopentanecarbonyl}amino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid654,8
1561-[3-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propyl}phenyl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid675,5
1571-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenyl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid661,3
1581-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenyl)butyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid675,5
1591-[3-(5-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propyl}furan-2-yl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid665,6
1601-{2-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)e is ylamino]ethyl}phenyl)-1-methylurea]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid 719,2
1611-{2-[1-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylcarbamoyl)piperidine-4-yl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid773,3
1621-[3-(3-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propyl}phenyl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid675,5
1631-[3-(5-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propyl}tetrahydrofuran-2-yl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid669,6
1641-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethylcarbamate}phenoxy)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid706,5
1651-{9-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether (5-bromobiphenyl-2-yl)carbamino acidNo
1661-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether (2'-forbiden-2-yl)carbamino acid659,5
1671-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-is)ethylamino]nonyl}piperidine-4-silt ether (3'-chloro-3,5-diferuloyl-2-yl)carbamino acid 711,8
1681-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether (3',5'-dichloro-3,5-diferuloyl-2-yl)carbamino acid745,5
1691-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether (3,5-diferuloyl-2-yl)carbamino acid677,5

Getting 99

1-[2-(4-[1,3]Dioxolane-2-infiniscale)ethyl]-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acid

A mixture of 4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acid (2,73 g, 8,79 mmol) and N-(4-[1,3]dioxolane-2-ylphenyl)acrylamide (2,05 g 8,80 mmol) were heated in 100 ml of a mixture (1:1) methanol/dichloromethane at 50°C in nitrogen atmosphere for 1 h Then the solution was diluted with ethyl acetate and the organic layer was washed with water, saturated salt solution, dried (MgSO4) and concentrated under reduced pressure to obtain specified in the connection header. MSm/zcalculated for C31H35N3O5(M+H)+530,6; found 530,4.

Getting 100

1-[2-(4-formylphenylboronic)ethyl]-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acid

The product is getting 99 re-dissolved in 40 ml of methanol was added 25 ml of aqueous 1N. chloritoid the native acid. The resulting mixture was stirred at room temperature overnight and was removed at reduced pressure of the organic solvent. The residue was dissolved in ethyl acetate and the organic layer was washed with water, saturated salt solution, dried (MgSO4) and removed under reduced pressure the solvent. The product is triturated in dichloromethane to obtain specified in the title compound as a white powder (2,47 g). LC-MS (2-90) Rt=4,27 min; MSm/zcalculated for C29H31N3O4(M+H)+486,6; found 486,5.

Getting 101

1-[2-(4-{[(R)-2-(tert-Butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acid

A mixture of the product receiving 100 (1.70 g, 3,51 mmol) and 5-[(R)-2-amino-1-(tert-butyldimethylsilyloxy)ethyl]-8-hydroxy-1H-quinoline-2-oncethat (1.65 g, 4,19 mmol) in 40 ml of a mixture (1:1) of methanol and dichloromethane was stirred at room temperature overnight. Then added in one portion triacetoxyborohydride sodium (2,23 g, 10.5 mmol) and the reaction mixture was stirred at room temperature for 6 hours Then the reaction mixture was extinguished with water and diluted with ethyl acetate. Separated the layers and the organic layer was washed with saturated sodium bicarbonate solution, saturated salt solution, dried (MgO 4) and removed under reduced pressure, the solvent is obtaining specified in the title compound (2.9 g). MSm/zcalculated for C46H57N5O6Si (M+H)+805,0; found 804,6.

Example 170

1-[2-(4-{[(R)-2-Hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acid

The product is getting 101 (2.9 g, 3.6 mmol) was dissolved in 75 ml of dichloromethane was added trihydrated of triethylamine (0,85 ml, 5.2 mmol). The resulting mixture was stirred at room temperature overnight and then was removed under reduced pressure, the solvent to obtain the crude product as oil. The product is then dissolved in a mixture (1:1) acetic acid/water and purified preparative HPLC to obtain specified in the connection header in the form of not-quite-white solid. LC-MS (2-90) Rt=to 3.67 min; MSm/zcalculated for C40H43N5O6(M+H)+690,8; found 690,3.

Using the above described technique and related source materials, were obtained the following compounds.

Etc.ConnectionMS
1711-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}phenylcarbamoyl)ethyl]-4-meth is piperidin-4-silt ether-biphenyl-2-ylcarbamate acid No
1721-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acidNo
1731-{9-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]nonyl}-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acidNo
1741-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]intercalator}ethyl)-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acidNo
1751-(2-{5-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]intercalator}ethyl)-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acidNo
1761-(2-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]hexanamine}ethyl)-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acidNo
1771-(2-{6-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]hexanamine}ethyl)-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acidNo
1781-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoylamine)ethyl-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acid No
1791-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}benzoylamine)ethyl]-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acidNo
1801-{3-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)phenyl]propyl}-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acid776,5
1811-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acid724,5
1821-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxyphenylacetyl)ethyl]-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acid754,5

Getting 102

(R)-(1-Azabicyclo[3.2.1]Oct-4-yl)new ether-biphenyl-2-ylcarbamate acid

2-Biphenylmethanol (1,00 g, 5,12 mmol) and hydrochloride (R)-(-)-3-hinokitiol (921 mg, 5,63 mmol) were heated together in N,N-dimethylformamide (of 2.06 ml) at 110°C for 12 h the Reaction mixture was cooled, diluted with ethyl acetate (15 ml) and then washed with saturated aqueous sodium bicarbonate (2×10 ml). The organic layer extragear the Wali 1M hydrochloric acid (3× 20 ml) and the combined aqueous extracts were podslushivaet potassium carbonate to pH 8-9. Then the aqueous layer was extracted with ethyl acetate (3×20 ml), the combined organic layers were dried (magnesium sulfate) and removed under reduced pressure, the solvent is obtaining specified in the title compound as a yellow oil (1.64 g, yield 99%).

Getting 103

(R)-4-(Biphenyl-2-ylcarbamate)-1-(9-bromanil)-1-azoniabicyclo[3.2.1]octabrain

To a stirred solution of the product receiving 102 (1,21 g, 3,76 mmol) and triethylamine (1,05 ml, 7,52 mmol) in acetonitrile (18.8 ml) was added to 1.9-dibromononane (994 μl, 4,89 mmol) and the reaction mixture was heated at 50°C for 4 h Then the reaction mixture was cooled and removed under reduced pressure the solvent. The residue was dissolved in dichloromethane (20 ml) and the organic layer was washed saturated aqueous sodium bicarbonate (10 ml), dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude product was purified flash chromatography (10% methanol/dichloromethane, 0.5% ammonium hydroxide) to obtain the specified title compound (1.04 g, 1.97 mmol, yield 52%).

Getting 104

(R)-1-(9-N,N-Di(tert-butoxycarbonyl)aminanani)-4-(biphenyl-2-ylcarbamate)-1-azoniabicyclo[3.2.1]octabrain

To a stirred solution of sodium hydride (60% dispersion in mineral mA the Le) (126 mg, a 3.15 mmol) in N,N-dimethylformamide (10 ml) under nitrogen atmosphere at 0°C was added di-tert-butylimidazolium (513 mg, 2.36 mmol) in N,N-dimethylformamide (5 ml). The reaction mixture was stirred at room temperature for 15 min, then was cooled to 0°and added to it the product is getting 103 (1.04 g, 1.97 mmol) in N,N-dimethylformamide (5 ml). The reaction mixture was allowed to warm to room temperature over 12 h and then was removed under reduced pressure, the solvent is obtaining specified in the title compound, which was used without further purification.

Getting 105

(R)-1-(9-Aminanani)-4-(biphenyl-2-ylcarbamate)-1-azoniabicyclo[3.2.1]octabrain

The product is getting 104 (1.31 g, 1.97 mmol) was dissolved in dichloromethane (15 ml) and slowly added triperoxonane acid (5 ml). The reaction mixture was stirred at room temperature for 1 h and then was removed under reduced pressure the solvent. The residue was dissolved in dichloromethane (20 ml) and washed with 1M aqueous sodium hydroxide (20 ml). The organic layer was extracted with 1M hydrochloric acid (3×20 ml), the combined aqueous extracts were podslushivaet potassium carbonate and was extracted with dichloromethane (3×20 ml). The combined organic layers were dried (magnesium sulfate) and removed under reduced pressure, the solvent with obtaining the criminal code is related to the title compound (210 mg, exit 23% over 2 stages).

Getting 106

(R)-1-{9-[(R)-2-(8-Benzyloxy-2-oxo-1,2-dihydroquinoline-5-yl)-2-hydroxyethylamino]nonyl}-4-(biphenyl-2-ylcarbamate)-1-azoniabicyclo[2.2.2]octabrain

The product is getting 105 (210 mg, 0.45 mmol) and triacetoxyborohydride sodium (286 mg, 1.35 mmol) was stirred in dichloromethane (4.5 ml) at room temperature for 2 h and then was added the product of obtaining 6 (163 mg, 0.50 mmol). The reaction mixture was stirred 12 h, then was diluted with dichloromethane (10 ml) and washed with saturated aqueous sodium bicarbonate (10 ml), dried (magnesium sulfate) and removed under reduced pressure the solvent. The crude reaction product was purified flash chromatography (10-50% methanol/dichloromethane, 0.5% ammonium hydroxide) to obtain the specified title compound (131 mg, yield 38%).

Example 183

DATEFORMAT 4-(biphenyl-2-ylcarbamate)-1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}-1-azoniabicyclo[2.2.2]octapamine

To a stirred solution of the product receiving 105 (131 mg, 0,17 mmol) in methanol (1.8 ml) was added palladium (10 wt.% (on dry matter basis) on activated carbon; 39 mg) and the reaction mixture was placed in an atmosphere of hydrogen. After stirring for 12 h, the reaction mixture was filtered through a loose layer of Celite, washed with methanol (2 ml) and removed when p is low pressure solvent. The obtained residue was purified preparative HPLC to obtain specified in the connection header in the form of a salt detrivorous acid (8 mg). MSm/z667,5.

Using the above described technique and related source materials, were obtained the following compounds.

Etc.ConnectionMS
1848-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}-8-azabicyclo[3.2.1]Oct-3-silt ether-biphenyl-2-ylcarbamate acid667,3
1857-(biphenyl-2-ylcarbamate)-9-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}-9-methyl-3-oxa-9-azoniatricyclo[3.3.1.0*2,4*]nonembroid695,5
1869-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}-3-oxa-9-azatricyclo[3.3.1.0*2,4*]non-7-silt ether-biphenyl-2-ylcarbamate acid681,5

Obtaining And

Cell culture and membrane preparations from cells expressing human β1that β2or β3adrenergic receptors

Cell line of Chinese hamster ovary (Cho)stably expressing cloned human β1that β2or β3 adrenergic receptors, respectively, were cultivated almost to merge in environments Hams F-12 with 10% FBS in the presence of 500 μg/ml of geneticin (Geneticin). The cell monolayer was raised 2 mm EDTA in PBS. Cells were besieged by centrifugation at 1000 rpm and precipitation cells were either stored frozen at -80°With or immediately prepare membranes for use. To obtain membranes expressing β1and β2receptors, cellular precipitation resuspendable in the buffer for lysis (10 mm HEPES/HCl, 10 mm EDTA, pH 7.4 at 4° (C) and homogenized using a tight-fitting glass homogenizer of downs (Dounce) (30 strokes)on ice. For membranes expressing more sensitive to the protease β3receptors, cellular precipitation homogenized in a buffer for lysis (10 mm Tris/HCl, pH 7.4) supplemented with one tablet of Complete Protease Inhibitor Cocktail Tablets with 2 mM EDTA 50 ml buffer (Roche, Catalog No. 1697498, Roche Molecular Biochemicals, Indianapolis, IN). The homogenate was centrifuged at 20000×g and the precipitate was washed once with buffer for lysis by resuspendable and centrifugation as described above. The final precipitate is then resuspendable cooled in ice buffer for analysis on binding (75 mm Tris/HCl pH to 7.4, 12.5 mm MgCl2, 1 mm EDTA). The concentration of proteins in suspension of the membranes was determined by methods described by Lowry et al.,1951,Journal of Biological Chemistry, 193,265; and Bradfor, Analytical Biochemistry,1976,72,248-54. All membranes were stored frozen in aliquot at -80°C or used immediately.

Getting B

Cell culture and membrane preparations from cells expressing human M1M2M3and M4muscarinic receptors

Cell line (Cho)stably expressing the cloned subtypes hM1hM2and hM3human muscarinic receptors, respectively, were cultivated almost to merge in environments HAM''s F-12 with the addition of 10% FBS and 250 μg/ml of geneticin. Cells were cultured in an incubator with 5% CO2at 37°and raised 2 mm EDTA in dPBS. Cells were collected in 5 minute centrifugation at 650×g and precipitation cells were either stored frozen at -80°With or immediately prepare membranes for use. To obtain preparations of cell membranes precipitation resuspendable in the buffer for lysis and homogenized using a tie-breaker fabric transmitter station PT-2100 (Kinematica AG; 20 seconds×2 gap). Crude membranes were centrifuged at 40000×g for 15 minutes at 4°C. the precipitate membranes resuspendable using a buffer to resuspendable, and again homogenized using a tie-breaker fabric transmitter station. The concentration of proteins in suspension of the membranes was determined by the method described by Lowry et al.,1951,Journal of Bochemistry, 193,265. All membranes were stored frozen in aliquot at -80°C or used immediately. Aliquots of the obtained membrane receptors hM5bought directly from the company Perkin Elmer and before the application was stored at -80°C.

Method A test

Test the binding of radioactive ligand for human β1that β2or β3adrenergic receptors

Testing the binding was performed in 96-well tablets when the total volume to 100 µl of the test with 10-15 μg of protein membranes containing human β1that β2or β3adrenergic receptors in the buffer for testing (75 mm Tris/HCl pH 7,4 at 25°C, 12.5 mm MgCl2, 1 mm EDTA, 0.2% BSA). Research associate at saturation to determine the values of Kdradioligand was performed using [3H]-dihydroalprenolol (NET-720, 100 CI/mmol, PerkinElmer Life Sciences Inc., Boston, MA) for β1and β2receptors and [125I]-(-)-incindentally (NEX-189, 220 CI/mmol, PerkinElmer Life Sciences Inc., Boston, MA) at 10 or 11 different concentrations ranging from 0.01 nm to 20 nm. Tests for substitution to determine the values of Kithe tested compounds was performed using [3H]-dihydroalprenolol at 1 nm and [125I]-(-)-incindentally at 0.5 nm to 10 or 11 different concentrations within the range of the x from 10 PM to 10 μm. Nonspecific binding was determined in the presence of 10 μm propranolol. Samples for testing were incubated for 1 h at 37°C and then binding assays were terminated by rapid filtration over plates of glass fiber filter GF/B β1and β2receptors or GF/C β3receptors (Packard BioScience Co., Meriden, CT)pre-soaked in 0.3% polyethylenimine. Plate filter was washed three times filtration buffer (75 mm Tris/HCl pH 7,4 at 4°C, 12.5 mm MgCl2, 1 mm EDTA) to remove unbound radioactivity. The tablets were then dried and added to 50 μl of the liquid for liquid scintillation Microscint-20 (Packard BioScience Co., Meriden, CT) and tablets cheated in a liquid scintillation counter Packard Topcount (Packard BioScience Co., Meriden, CT). Data binding was analyzed by the method of nonlinear regression using the software package GraphPad Prism Software package (GraphPad Software, Inc., San Diego, CA), using a 3-parameter model for a single competition. The minimum of the curve was tied to the value of nonspecific binding in the determination in the presence of 10 μm propranolol. Values of Kifor test compounds were calculated from the observed values of the IC50and values of Kdradioligand using the equation of Cheng-Prusoff (Cheng Y, and Prusoff WH.,Biochemical Pharmacology,1973,22,23, 3099-108).

In this test the lower value of K iindicates that the test compound has a higher affinity of binding to the tested receptor. As was established in this test, taken as an example of the connection of the present invention, which was subjected to the test, usually had a value of Kiless than about 300 nm for β2adrenergic receptor. For example, it has been found that the compounds of examples 3 and 6 are the values of Kiless than 10 nm.

If necessary, the subtype selectivity of the receptor to the test compound can be calculated as the ratio of Ki1)/Ki2or Ki3)/Ki2). Typically, compounds of the present invention showed greater binding at β2adrenergic receptor compared to β1or β3adrenergic receptor, i.e. Ki1or Ki3) is usually higher than the Ki2). As a rule, preferred are compounds having selectivity with respect to β2adrenergic receptor is higher than for β1or β3adrenergic receptors, especially compounds having a selectivity of more than about 5, and in particular, more than about 8. For example, the compounds of examples 3 and 6 were related Ki1)/K i(β2) more than 8.

Methods In tests

Test the binding of radioactive ligand for muscarinic receptors

Tested for binding to the cloned muscarinic receptors was performed in 96-well tablets when the total volume to 100 µl of the test. The membranes of Cho cells stably expressing hM1hM2hM3hM4or hM5the subtype of muscarinic receptors were diluted in buffer for testing to the following concentrations of specific target proteins (µg/well): 10 mcg for hM1, 10-15 mcg for hM2, 10-20 μg for hM3, 10-20 μg for hM4and 10-12 mcg for hM5to obtain the same signal (cpm (pulse / min)). Before adding the tablet to the membrane briefly homogenized using a tie-breaker fabric transmitter station (10 seconds). Research associate at saturation to determine the values of Kdradioligand was performed using L-[N-methyl-N3H]scopolaminepurchase ([3H]-NMS)(TRK666, 84,0 CI/mmol, Amersham Pharmacia Biotech, Buckighamshire, England) at concentrations ranging from 0.001 nm to 20 nm. Tests for substitution to determine the values of Kithe tested compounds was performed with [3H]-NMS at 1 nm and eleven different concentrations. Compound was initially dissolved to a concentration of 400 μm in a buffer for cultivation and setuserinfo diluted 5x buffer diluted to final concentrations ranging from 10 PM to 100 μm. The order and the volume added to the tablets for testing were as follows: 25 μl of radioligand, 25 μl of diluted test compound and 50 μl of the membrane. Tablets for testing were incubated for 60 min at 37°C. binding assays were terminated by rapid filtration over plates of glass fiber filter GF/B (PerkinElmer Inc., Wellesley, MA), pre-treated with a 1% BSA. Plate filter was washed three times proryvnym buffer (10 mm HEPES) to remove unbound radioactivity. The tablets are then dried in the air and to each well was added 50 μl of the liquid for liquid scintillation Microscint-20 (PerkinElmer Inc., Wellesley, MA). Then the tablets were shortchanged in a liquid scintillation counter PerkinElmer Topcount (PerkinElmer Inc., Wellesley, MA). Data binding was analyzed by the method of nonlinear regression using the software package GraphPad Prism Software package (GraphPad Software, Inc., San Diego, CA), using a single model competition. Values of Kifor test compounds were calculated from the observed values of the IC50and values of KDradioligand using the equation of Cheng-Prusoff (Cheng Y; Prusoff WH. (1973)Biochemical Pharmacology,22(23): 3099-108). Values Foritransformed values pKito determine the geometric mean and intervals 95% confidence level. These summary statistics were then converted back to valuesifor the message data.

In this test, a lower value of Kiindicates that the test compound has a higher affinity of binding to the tested receptor. As was established in this test, taken as an example of the connection of the present invention, which was subjected to the test, usually had a value of Kiless than about 300 nm for M3muscarinic receptor. For example, it has been found that the compounds of examples 3 and 6 are the values of Kiless than 10 nm.

The technique tests

A test using a flash-tablets camp in whole cells, Cho cell lines, heterologic expressing human β1that β2or β3adrenergic receptors

Testing camp held in a radioimmunoassay format using flash tablet system for the analysis of activation adenylylcyclase the Flashplate Adenylyl Cyclase Activation Assay System with [125I]-cAMP (NEN SMP004, PerkinElmer Life Sciences Inc., Boston, MA) according to manufacturer's instructions. To determine the agonistic activity towards β receptors (EU50cell line Cho-K1, stably expressing the cloned human β1that β2or β3adrenergic receptors, respectively, were cultivated almost to merge in environments Hams F12 with the addition of 10% FBS and geneticin (250 µg/ml). The cells were rinsed by PBS and was disconnected in dPBS (buffered phosphate solution Dulbecco without CaCl2and MgCl2), containing 2 mm EDTA or a solution of trypsin-EDTA (0.05% trypsin/0.53 mm EDTA). After counting cells in a Coulter counter cell besieged by centrifugation at 1000 rpm and resuspendable in stimulation buffer containing IBMX (PerkinElmer Kit), pre-heated to room temperature, to a concentration of 1.6×106-2,8×106cells/ml In this test used about 60000-80000 cells per well. Compound (10 mm in DMSO) were diluted in PBS containing 0,1% BSA in Beckman Biomek-2000, and was tested at 11 different concentrations ranging from 100 μm to 1 PM. Reactions were incubated for 10 min at 37°C and stopped by adding 100 μl of cold detectiong buffer containing [125I]-cAMP (NEN SMP004, PerkinElmer Life Sciences, Boston, MA). The amount of camp (pmol/well) was calculated based on the pulses observed for samples and standards of camp as described in the guide for consumers. Data were analyzed by the method of nonlinear regression using the software package GraphPad Prism Software package (GraphPad Software, Inc., San Diego, CA)using a sigmoidal equation. To calculate the values EC50used the equation of Cheng-Prusoff (Cheng Y, and Prusoff WH.,Biochemical Pharmacology,1973,22,23, 3099-108).

In this test, a lower value is tion EC 50indicates that the test compound has a higher functional activity of the test receptor. As was established in this test, taken as an example of the connection of the present invention, which was subjected to the test, usually mattered EC50less than about 300 nm for β2adrenergic receptor. For example, it has been found that the compounds of examples 3 and 6 have the meanings EC50less than 10 nm.

If necessary, the subtype selectivity of the receptor to the test compound can be calculated as the ratio EC501)/EC502or EC503)/EC502). Typically, compounds of the present invention showed greater functional activity of the β2adrenergic receptor compared to β1or β3adrenergic receptor, i.e. EC501or EC503) is usually larger than EC502). As a rule, preferred are compounds having selectivity with respect to β2adrenergic receptor is higher than for β1or β3adrenergic receptors, especially compounds having a selectivity of more than about 5, and in particular, more than about 10. For example, the compounds of examples 3 and 6 had the the EC 501)/EC502) more than 10.

Method D test

Functional tests for antagonism on subtypes of muscarinic receptors

A. Blockade mediated by agonist inhibition of the accumulation of camp

In this test the functional activity of the test compounds was determined by measuring the ability of test compounds to block oxotremorine-inhibition mediated by Forskolin accumulation of camp in Cho-K1 cells expressing hM2the receptor. Testing camp held in a radioimmunoassay format using flash tablet system for the analysis of activation adenylylcyclase with125I-cAMP (NEN SMP004, PerkinElmer Life Sciences Inc., Boston, MA) according to manufacturer's instructions. The cells were rinsed once with dPBS and raised a solution of trypsin-EDTA (0.05% trypsin/0.53 mm EDTA)as described above in the section "Cell culture and membrane preparations". Separated cells were washed twice by centrifugation at 650×g for 5 minutes in 50 ml of dPBS. The cells are then resuspendable in 10 ml dPBS and counted by Coulter counter Z1 Dual Particle Counter (Beckman Coulter, Fullerton, CA). Cells are centrifuged at 650×g for five minutes and resuspendable in stimulation buffer to a concentration of test 1,6×106-2,8×106cells/ml

The test joint is initially dissolved to a concentration of 400 μm in a buffer for cultivation (dPBS with the addition of 1 mg/ml BSA (0.1 per cent) and then serially diluted with a buffer for dilution to a final molar concentrations ranging from 100 μm to 0.1 nm. Similarly bred oxotremorine.

To measure inhibition of oxotremorine activity adenylylcyclase (AU) in the wells for testing of agonist was added 25 ml of Forskolin (diluted in dPBS to a final concentration of 25 μm), 25 μl of the diluted oxotremorine and 50 μl of cells. To measure the ability of test compounds to block oxotremorine inhibiting the activity of ACE in the remaining wells to be tested was added 25 μl of Forskolin and oxotremorine (diluted in dPBS to a final concentration of 25 μm and 5 μm, respectively), 25 ml of diluted test compound and 50 μl of cells.

Reactions were incubated for 10 min at 37°C and stopped by adding 100 μl of cooled ice detectiong buffer. Tablets hermetically corked, incubated over night at room temperature and the next morning they carried out the calculations on a liquid scintillation counter PerkinElmer Topcount (PerkinElmer Inc., Wellesley, MA). The amount of camp (pmol/well) was calculated based on the pulses observed for samples and standards of camp as described in the guide for consumers. Data were analyzed by the method of nonlinear regression using the software package GraphPad Prism Software package (GraphPad Software, Inc., San Diego, CA)using a nonlinear regression equation single competition. To calculate the Kiused the equation of Cheng-Prusoff and is EU 50from the curve "concentration oxotremorine-response and concentration oxotremorine for testing as KDand [L], respectively.

In this test a lower value To aiindicates that the test compound has a higher functional activity of the test receptor. As was established in this test, taken as an example of the connection of the present invention, which was subjected to the test, usually had a value of Kiless than about 300 nm for blockade of inhibition by oxotremorine accumulation of camp-mediated foscalina, in Cho-K1 cells expressing hM2the receptor. For example, it was found that the compound of example 3 has a value of Kiless than 10 nm.

C. Blockade of agonist-mediated [35S]GTPγS binding

In the second functional test the functional activity of the tested compounds can be determined by measuring the ability of compounds to block oxotremorine stimulated [35S]GTPγS binding in Cho-K1 cells expressing hM2the receptor.

During use frozen membranes were thawed and then diluted in buffer for testing with the final concentrations of the target tissue 5-10 μg protein per well. Membrane briefly homogenized, using the tie-breaker fabric transmitter station-2100, and then typed in a tablet for testing.

In each experiment was determined by the value of the EU90(effective concentration for maximum response 90%) for stimulation of [35S]GTPγS binding agonist with oxotremorine.

To determine the ability of test compounds to inhibit oxotremorine-stimulated [35S]GTPγS linking to each well of 96-well plates were introduced following: 25 μl of buffer for testing with [35S]GTPγS (0.4 nm), 25 μl oxotremorine (EC90) and GDP (3 μm), 25 μl of diluted test compound and 25 μl of membranes of Cho cells expressing hM2the receptor. Then these plates were incubated at 37°C for 60 minutes. The tablets were filtered over GF/B filters pre-soaked in 1% BSA, using a 96-hole collector cell PerkinElmer. The tablets were rinsed (3×3 seconds) cooled with ice buffer for washing and then dried in air or in vacuum. To each well was added to scintillation fluid Microscint-20 (50 μl), each plate hermetically corked and counted for radioactivity on a Topcounter (PerkinElmer). Data were analyzed by the method of nonlinear regression using the software package GraphPad Prism Software package (GraphPad Software, Inc., San Diego, CA)using a nonlinear regression equation single competition. To calculate the KiISOE is isovale the equation of Cheng-Prusoff and values IC 50from the curve "concentration-response" for the test compounds and concentrations oxotremorine when tested as KDand [L]the concentration of ligand, respectively.

In this test, lower the value To aiindicates that the test compound has a higher functional activity of the test receptor. As was established in this test, taken as an example of the connection of the present invention, which was subjected to the test, usually had a value of Kiless than about 300 nm for blockade-stimulated oxotremorine [35S]GTPγS binding in Cho-K1 cells expressing hM2the receptor. For example, it was found that the compound of example 3 has a value of Kiless than 10 nm.

C. Blockade mediated by agonist release of calcium by the method of analysis using the FLIPR

Subtypes of muscarinic receptors (M1, M3and M5receptors)that are associated with Gq-proteins that activate the path of phospholipase C (PLC) upon binding of agonist to the receptor. In the activated PLC hydrolyzes phosphatidylinositols (PIP2in diacylglycerol (DAG) and phosphatidyl-1,4,5-trisphosphate (IP3), which in turn triggers the release of calcium from intracellular reserves, i.e. endoplasmic and Sark the plasmatic networks. Analysis of the FLIPR (Molecular Devices, Sunnyvale, CA) begins with instructions to increase the content of intracellular calcium using sensitive calcium dye (Fluo-4AM, Molecular Probes, Eugene, OR), which is fluorescent upon binding of free calcium. Fluorescence was measured in real time using FLIPR, which detects the change in fluorescence from the monolayer of cells, cloned receptors M1and M3man and M5chimpanzees. Antagonistic activity can be determined by the ability of antagonists to inhibit mediated agonist increased the content of intracellular calcium.

For FLIPR assays stimulation of calcium Cho cells, stably expressing hM1hM3and cM5receptors were sown in 96-well FLIPR tablets the night before analysis. Seeded cells were washed twice Cellwash (MTX Labsystems, Inc.) with FLIPR buffer (10 mm HEPES, pH of 7.4, 2 mm calcium chloride, 2.5 mm probenecid in the buffer saline, Henk (HBSS) without calcium and magnesium)to remove culture medium, leaving 50 μl/well FLIPR buffer. Cells are then incubated with 50 μl/well of 4 μm FLUO-4AM (there was prepared 2 solution) for 40 minutes at 37°C, in the presence of 5% carbon dioxide. After incubation with the dye, the cells were washed twice FLIPR buffer, leaving a final volume of 50 μl/well.

To determine the antagonistic activity with the achala was determined by dose-dependent stimulation of intracellular release of CA 2+for oxotremorine that later can be measured antagonistic activity upon stimulation oxotremorine at concentrations EU90. Cells are first incubated with buffer for cultivation connection for 20 minutes followed by the addition of agonist, produced using FLIPR. The value of EC90for oxotremorine received in accordance with the method detailed in the measurement using the FLIPR and described below in the section on the transformation of the data, in combination with a formula ECF=((F/100-F)^1/H)*EC50. In tablets to stimulate the received concentration oxotremorine equal to 3×ECF, resulting in the added concentration oxotremorine EC90in each well plates for analysis of inhibition by the antagonist.

For FLIPR used the following parameters: the exposure time of 0.4 seconds, the laser power of 0.5 watt, wavelength excitation 488 nm and emission wavelength of 550 nm. The baseline was determined by measuring changes in fluorescence for 10 seconds before the addition of agonist. After stimulation with agonist FLIPR continuously measured the change in fluorescence every 0.5-1 second for 1.5 minutes to catch the maximum change in fluorescence.

The change in fluorescence was expressed as the maximum fluorescence minus fluorescence at baseline for each hole. Raw d is analyzed by the logarithm of the concentration of the drug by the method of nonlinear regression using the software package GraphPad Prism (GraphPad Software, Inc., San Diego, CA)using integrated model for sigmoidal dependence "dose-response". Values of Kifor antagonist were determined using Prism, using the value of the EU50for oxotremorine asDEU90for oxotremorine as the ligand concentration according to the equation of Cheng-Prusoff (Cheng &Prusoff, 1973).

In this test a lower value To aiindicates that the test compound has a higher functional activity of the test receptor. As was established in this test, taken as an example of the connection of the present invention, which was subjected to the test, usually had a value of Kiless than about 300 nm for blockade-mediated agonist of calcium release in Cho cells stably expressing hM1hM3and cM5the receptors. For example, it was found that the compound of example 3 has a value of Kiless than 10 nm for hM1hM3and cM5receptors.

Method E test

A test using a flash-tablets currents in whole-cell line of lung epithelial cells, endogenously expressing human β2adrenergic receptor

To determine the agonistic activity and efficiency (internal activity) in a cell line expressing endogenous the levels β 2adrenergic receptor, used the line lung epithelial cells (BEAS-2B) (ATCC CRL-9609, American Type Culture Collection, Manassas, VA) (January B, et al.,British Journal of Pharmacology,1998,123,4, 701-11). Cells were grown up to 75-90% confluence in whole serum-free medium (LHC-9 MEDIUM containing epinephrine and retinoic acid, cat # 181-500, Biosource International, Camarillo, CA). The day before the test environment was changed at the LHC-8 (without epinephrine or retinoic acid, cat # 141-500, Biosource International, Camarillo, CA). Testing camp held in a radioimmunoassay format using flash tablet system for the analysis of activation adenylylcyclase with [125I]-cAMP (NEN SMP004, PerkinElmer Life Sciences Inc., Boston, MA) according to manufacturer's instructions. On the day of the test cells were rinsed by PBS, lifted by scraping with 5 mm EDTA in PBS and counted. Cells were besieged by centrifugation at 1000 rpm and resuspendable in the buffer for stimulation, pre-warmed to 37°C, at a final concentration of 600,000 cells/ml In this experiment, the cells were used at a final concentration of 100000-120000 cells/cell. Compound serially diluted in buffer test (75 mm Tris/HCl pH 7,4 at 25°C, 12.5 mm MgCl2, 1 mm EDTA, 0.2% BSA) in a Beckman Biomek-2000. Compound was tested at 11 different concentrations ranging from 10 μm to 10 PM. Reactions were incubated for 10 min at 37°and stopped is by adding 100 μl of cooled ice detectiong buffer. Tablets hermetically corked, incubated over night at 4°and the next morning cheated in a Topcount scintillation counter (Packard BioScience Co., Meriden, CT). The amount of camp per ml of the reaction mixture was calculated according to the pulses observed for samples and standards of camp as described in the guide for consumers. Data were analyzed by the method of nonlinear regression using the software package GraphPad Prism Software package (GraphPad Software, Inc., San Diego, CA), using 4-parametric model for sigmoidal dependence "dose-response".

In this test a lower value EC50indicates that the test compound has a higher functional activity of the test receptor. As was established in this test, taken as an example of the connection of the present invention, which was subjected to the test, usually mattered EC50less than about 300 nm for β2adrenergic receptor. For example, it has been found that the compounds of examples 3 and 6 have the meanings EC50less than 10 nm.

If necessary, the effectiveness of the test compound (%Eff) was calculated from the ratio of the observed Emax (the top point of the empirical curve) and the maximum response obtained for the curve of dependence "dose of isoproterenol-response, and expressed as %Eff about isoprotein the La. Taken as example compounds of the present invention tested in this test, usually showed %Eff more than about 40.

Method F test

The duration of protection of the bronchi in the models caused by acetylcholine or histamine bronchostenosis in Guinea pigs

These testsin vivowere used to estimate bronchospastic effects of the tested compounds exhibiting activity as an antagonist of muscarinic receptors and agonist β2adrenergic receptors. To isolate antagonistic activity against muscarinic receptors on the model caused by acetylcholine of bronchostenosis, animal prior to administration of acetylcholine was introduced propanolol - a compound that blocks the activity β receptors. The duration of protection bronchi model bronchostenosis caused by histamine reflects agonistic activity towards β2adrenergic receptors.

Groups of 6 Guinea pigs males (Duncan-Hartley (HsdPoc:DH) Harlan, Madison, WI) weighing 250-300 g were individually identified cards on the cells. Throughout the study the animals were given access to food and water at will.

Compound was administered by inhalation for 10 minutes in the dosing chambers for exposure of the whole body (R&S Molds, San Carlos, CA). Dozer the possibility cameras were arranged so that the aerosol was done simultaneously in 6 separate chambers of the Central pipeline. Guinea pigs were exposed to the effect of the aerosol of the test compounds or media (WFI). These aerosols created from aqueous solutions using spray set LC Star Nebulizer Set (Model 22F51, PARI Respiratory Equipment, Inc. Midlothian, VA), driven by a mixture of gases (CO2=5%, O2=21% N2=74%) at a pressure of 22 psi (1,55 kg/cm2). The gas flow through a nozzle at the specified operating pressure was approximately 3 l/minute. The generated aerosol is blown into the chamber by the action of the positive pressure. Dilution air at the time of filing sputtered solutions is not used. During the 10 minute spray has been sprayed approximately 1.8 ml. The specified value was measured gravimetrically by comparing the mass of the filled dispenser before and after spraying.

Bronchosan effects of the tested compounds, introduced by inhalation, was evaluated using plethysmography whole body 1.5, 24, 48 and 72 hours after dose.

For forty-five minutes before the start of the lung examination each Guinea pig was anestesiologi intramuscular injection of ketamine (43,75 mg/kg), xylazine (3,50 mg/kg) and acepromazine (1,05 mg/kg). After the plot for surgical intervention was shaved and cleaned with 70% alcohol, made the middle allowing the ventral side of the neck. Then jugular vein was isolated and introduced into it filled with saline polyethylene catheter (PE-50, Becton Dickinson, Sparks, MD) to allow intravenous infusion of acetylcholine (Ach) or histamine in physiological solution. Then was taken away millimetre trachea and Coulibaly her 14G PTFE tube (#NE-0,14, Small Parts, Miami Lakes, FL). If necessary, anesthesia was maintained by additional intramuscular injection above anaesthetic mixture. Depth of anesthesia was controlled and regulated, if the animal responded to the injections in the foot or if respiratory rate exceeded 100 breaths/minute.

At the end of canulate animal was placed in plethysmograph (#PLY3114, Buxco Electronics, Inc., Sharon, CT) was inserted esophageal cannula for measuring the pressure (PE-160, Becton Dickinson, Sparks, MD)to measure pulmonary stimulating pressure (pressure). Teflon tracheal tube was attached to the hole plethysmograph to allow the Guinea pig to breathe room air outside of the camera. Then the chamber was sealed. To maintain the temperature of the body used a heating lamp and a light Guinea pigs were inflated 3 times with 4 ml of air using a 10 ml graduated syringe (#5520 Series, Hans Rudolph, Kansas City, MO)to ensure that the lower respiratory tract will not be spadats and that the animal will not suffer from hyperventilation.

About nedelev, that baseline values were in the range of 0.3-0.9 ml/cm H2O flexibility in the range of 0.1 to 0,199 cm H2O/ml per second when resistance has developed expertise lungs. Computer program Buxco for pulmonary measurements gave the opportunity of collecting and draining values of pulmonary parameters.

Running the specified program, initiated the Protocol of the experiment and data collection. Using pressure sensor Buxco measured volume changes over time occurring in plethysmography with each breath. Summing the signal over the time, determined the size ofthreadinhaled with each breath of air. This signal, together with changes in the lung stimulatingpressurewho collected using the Sensym pressure sensor (#TRD4100), connected through a preamplifier Buxco (MAX 2270) interface data collection (#'s SFT3400 and SFT3813). All other pulmonary parameters were taken from these two input data.

Baseline values were collected for 5 minutes, then Guinea pigs were loaded with Ach or histamine. When evaluating the antagonistic effects against muscarinic receptors in 15 minutes prior to the introduction of Ach was introduced propranolol (5 mg/kg, iv) (Sigma-Aldrich, St. Louis, MO). Ach (Sigma-Aldrich, St. Louis, MO) (0.1 mg/ml) was infused intravenously for 1 minute from sprit-pump (sp210iw, World Precision Instruments, Inc., Sarasota, FL) with the following doses and in the following the set time is the time from the beginning of the experiment: 1.9 µg/minute after 5 minutes, the 3.8 μg/minute after 10 minutes of 7.5 μg/min after 15 minutes of 15.0 µg/minute, 20 minutes, 30 µg/min in 25 minutes and 60 mcg/minute every 30 minutes. Alternatively, bronchosan effects of the tested compounds was evaluated on model load acetylcholine without pre-treatment with beta-blocking connection.

When assessing the agonistic effects of the tested compounds in relation to β2adrenergic receptors were intravenously infused histamine (25 μg/ml) (Sigma-Aldrich, St. Louis, MO) for 1 minute from sprit-pump with the following doses and in the following specific points in time, from the beginning of the experiment: 0.5 μg/minute after 5 minutes of 0.9 µg/minute after 10 minutes, 1.9 µg/min after 15 minutes of 3.8 μg/minute after 20 minutes of 7.5 µg/min in 25 minutes and 15 mcg/minute every 30 minutes. If the resistance or passivity did not return to baseline values after 3 minutes after each entered doses of Ach or histamine, the lungs of Guinea pigs were inflated 3 times with 4 ml of air from a 10 ml graduated syringe. Recorded pulmonary parameters include breathing frequency (breaths/minute), compliance (ml/cm H2O) and pulmonary resistance (cm H2O/ml / sec). After measurements of pulmonary function parameters for 35 minutes, this scheme of the experiment, Guinea pigs were removed from plethysmograph and painlessly cut, call the AB asphyxia carbon dioxide.

Data were assessed in one of two ways:

(a) Pulmonary resistance (RLcm H2O/ml / sec) was calculated from the ratio of the "pressure change" to "change stream. Calculated reaction RLon Ach (60 μg/min, IH) for the media and groups of the tested compounds. To calculate the average value of the response to Ach in the animals treated by the media, in every moment of pre-treatment and used it to calculate the % inhibition of the response to Ach at the appropriate time pre-treatment with each dose of the tested compounds. Selected curves dose inhibition-response for RLin accordance with the four parametric logarithmic equation using GraphPad Prism, version 3.00 for Windows (GraphPad Software, Inc., San Diego, CA)to estimate bronchospastic ID50(dose required to inhibit 50% bronhosujiwatm response to Ach (60 μg/min)). Used the following equation:

where X is the logarithm of dose, Y is the response (% inhibition of the increase in RLcaused Ach). Y starts at Min and asymptotically approaches the Max in a sigmoidal form.

(b) Calculate the number of PD2which is defined as the amount of Ach or histamine needed to cause a doubling of the baseline pulmonary resistance, using sacrilegae resistance, derived fromthreadandpressurein the interval loads of Ach or histamine, according to the following equation (derived from equation used to calculate the values RS20in clinical practice (seeAm. Thoracic Soc, 2000):

where:

With1=concentration of Ach or histamine, previous (2),

With2=concentration of Ach or histamine, leading to at least 2-fold increase in pulmonary resistance (RL),

R0=the base value of RL,

R1=the value of RLafter C1,

R2=the value of RLafter C2.

Statistical analysis of data was performed using two-sided criterion - t-student test. Was considered significant P-value <0,05.

Taken as example compounds of the present invention that were tested in this test, usually given in a dose-dependent bronchospastic effect against bronchostenosis caused by Ach, and bronchostenosis caused His. Typically, this test is usually preferred are compound, with effectiveness (ID50after 1.5 h after dose) is less than about 300 μg/ml for bronchostenosis caused by Ach, and less than about 300 μg/ml for bronchostenosis caused His. For example, it has been found that the compounds of examples 3 and 6 and EUT values IC 50less than about 100 μg/ml for bronchostenosis caused by Ach, and less than about 100 μg/ml for bronchostenosis caused His, 1.5 hours after a dose.

In addition, this test is usually preferred are a compound having a duration (PD T1/2) bronchospastic activity of at least about 24 hours. For example, it has been found that the compounds of examples 3 and 6 have PD T1/2at least about 24 hours after administration of the dose.

Method G test

Model Einthoven (Einthoven) for measuring changes in lung ventilation in Guinea pigs

Bronchodilatory activity of the tested compounds was evaluated on the model shot of Guinea pigs (model Einthoven), which use pressure ventilation as sementelli measures of airway resistance. See, for example, Einthoven (1892)Pfugers Arch. 51:367-445; and Mohammed et al. (2000)Pulm Pharmacol Ther. l3(6):287-92.This model evaluated the activity of the antagonist of muscarinic receptors and agonist β2adrenergic receptors by determining the protective effects against bronchostenosis caused by methacholine (MCh) and bronchostenosis caused by histamine (His).

This test was performed using Guinea pigs Duncan-Hartley (Harlan, Indianapolis, IN) weighing 300-400 g

The test compound or the nose is tel (ie sterile water) metered dose was administered by inhalation (IH) for a period of 10 minutes in the dosing chambers for exposure of the whole body (R+S Molds, San Carlos, CA)using 5 ml of solution for the dosed introduction. Animals were subjected to aerosol, which was created using spray set LC Star Nebulizer Set (Model 22F51, PARI Respiratory Equipment, Inc. Midlothian, VA), driven by Bioblend gas mixture (5% CO2, 21% O2and 74% N2at a pressure of 22 psi (1,55 kg/cm2).

Lung function was assessed at different points in time after the metered inhalations.

For forty-five minutes prior to the assessment of pulmonary function Guinea pigs were anestesiologi intramuscular (IM) injection of a mixture of ketamine (13,7 mg/kg)/xylazine (3.5 mg/kg)/acepromazine (1,05 mg/kg). Allocated jugular vein and carotid artery and Coulibaly them filled with saline polyethylene catheters (microrental and PE-50, respectively, Becton Dickinson, Sparks, MD). The carotid artery was connected to a pressure sensor to enable measurement of blood pressure and jugular vein catheter was used for IV injections of MCh or His. Then was taken away millimetre trachea and Coulibaly her needle 14G (#NE-014, Small Parts, Miami Lakes, FL). At the end of canulate lungs of Guinea pigs was ventolinbuy using a respirator (Model 683, Harvard Apparatus, Inc., MA)that is configured on the amount over the course of 1 ml/100 g body mass, but not to enter the 2.5 ml and a frequency of 100 strokes per minute. Pressure ventilation (VP) was measured at the tracheal cannula using a sensor Biopac attached to the preamplifier Biopac (TSD 137C). Body temperature was maintained at a level of 37°with warmer-cushion. Before beginning data collection was administered intraperitoneally (IP) pentobarbital (25 mg/kg) to suppress spontaneous breathing and sustainable base. Changes in VP were recorded on interface Biopac data acquisition Windows. Baseline values were collected for at least 5 minutes, and then the pigs were injected intravenously decumulative 2-fold increased dose bronchorrhea funds (MCh or His). When used as bronchorrhea funds MCh animals pre-treated with propranolol (5 mg/kg, intravenously) to highlight protivokashlevyh effects of the test compounds. Changes in VP were recorded using software to collect data Acknowledge Data Collection Software (Santa Barbara, CA). At the end of the study animals painlessly cut.

Change VP was measured in cm of water. Change VP (cm H2O)=maximum pressure (after the introduction of bronchorrhea funds)-maximum base pressure. Picked up curve "dose-response" for MCh or His in accordance with the four-parameter logarithmic equation using GraphPad Prism, version 3.00 for Windows (GraphPad Software, San Diego, California). Used to follow the it equation:

where X is the logarithm of dose, Y is the response (reaction). Y starts at Min and asymptotically approaches the Max in a sigmoidal form.

The inhibition percentage of responses to a submaximal dose bronchorrhea funds MCh or His were calculated for each dose of the test compound by the following equation: % inhibition response=100-((peak pressure (after the introduction of bronchorrhea funds, processed animal)-peak base pressure (processed animal)·100%/(peak pressure (after the introduction of bronchorrhea tools, water)peak base pressure (water). Picked inhibition curves using four parametric logarithmic equation of the software GraphPad. If necessary, evaluated also ID50(dose required to provide 50% inhibition of the reaction bronchorrhea funds) and Emax (maximal inhibition).

The amount of bronchospastic at different points in time after inhalation of the test compounds was used to evaluate the pharmacodynamic half-life (PD T1/2). PD T1/2it was determined by the method of selection for non-linear regression using equation single-phase exponential decay (GraphPad Prism, Version 4.00): Y=Span·exp(-K·X)+Plateau; starts at Span+Plateau and valleys to Plateau at constant soon the tee K. PD T1/2=0,69/K. Plateau (Plateau) restricted to 0.

Taken as example compounds of the present invention that were tested in this test, usually given in a dose-dependent bronchospastic effect against bronchostenosis caused by Mch, and bronchostenosis caused His. Typically, this test is usually preferred compound having the ID50less than about 300 μg/ml for bronchostenosis caused by Mch and ID50less than about 300 μg/ml for bronchostenosis caused His, after 1.5 h after dose. In addition, this test is usually preferred are a compound having a duration (PD T1/2) bronchospastic activity of at least about 24 hours.

Methodology N test

Test salivation in Guinea pigs inhalation

Guinea pigs (Charles River, Wilmigton, MA) weighing 200-350 g after arrival acclimatized to life in the colony of Guinea pigs living in the home for at least 3 days. By inhalation (IH) for 10 minutes dosage was administered the test compound or the media in the chamber for the dosed introduction in the form of pie (R+S Molds, San Carlos, CA). Solutions for testing were obtained in sterile water and applied using a spray gun filled with 5.0 ml of solution for injection. Pigs on the whinnying in the chamber for inhalation for 30 minutes. At this time, pigs were restricted area of approximately 110 square inches. This space was sufficient for the animals, so that they can freely turn to change position and to care for themselves. After 20 minutes of acclimatization pigs were subjected to aerosol, which was created using spray set LC Star Nebulizer Set (Model 22F51, PARI Respiratory Equipment, Inc. Midlothian, VA), driven home by air at a pressure of 22 psi (1,55 kg/cm2). After spraying pigs were subjected to examination through 1.5, 6, 12, 24, 48, or 72 hours after treatment.

An hour before the test pigs were anestesiologi intramuscular (IM) injection of a mixture of ketamine (43,75 mg/kg), xylazine (3.5 mg/kg) and acepromazine (1,05 mg/kg) in the amount of from 0.88 ml/kg Animals were placed ventral side on a heated (37° (C) blanket with a slant angle of 20 degrees head in the direction of the slope. In the mouth pigs were inserted 4-layer 2×2 inches (5,8×5.8 cm) gauze pad (Nu-Gauze General-use sponges, Johnson and Johnson, Arlington, TX). Five minutes later introduced the muscarinic agonist pilocarpine (3.0 mg/kg, subcutaneously) and the swab was immediately discarded and replaced it with a new, pre-weighed gauze pad. Saliva was collected for 10 minutes, the swab is then weighed and recorded the difference in mass to determine the number of accumulated saliva (mg). To calculate the average quantity and the creation of saliva in animals received carrier and each dose of the test compound. The average value for the group that received the media believed 100% slyunovydelenie. On the obtained average values (n = 3 or more) to calculate the results. To calculate the confidence intervals (95%) for each dose at each time point using two-factor variance analysis (ANOVA). This model is a modified version of the techniques described in Rechter, "Estimation of anticholinergic drug effects in mice by antagonism against pilocarpine-induced salivation"Ata Pharmacol Toxicol,1996,24:243-254.

Calculate the average mass of saliva in the animals treated by the media, in every moment of pre-treatment and used it to calculate the % inhibition of salivation at the appropriate time pre-processing for each dose. Data dependence "dose inhibition-response coordinated with four parametric logarithmic equation using GraphPad Prism, version 3.00 for Windows (GraphPad Software, San Diego, California)to estimate required against an agent stimulating salivation, ID50(dose required to inhibit 50% caused by pilocarpine salivation). It was used the following equation:

where X is the logarithm of dose, Y is the response (% inhibition of salivation). Y starts at Min and asymptoti the Eski approaching Max in a sigmoidal form.

Relationship ID50against an agent stimulating salivation, bronchospastic ID50used to calculate the indicator explicit selectivity to light the test compounds. Generally preferred are compounds having an explicit indicator of selectivity to light more than about 5. In this test the compound of example 3 has a clear selectivity to light than 5.

Although the present invention described above with reference to specific aspects or options, but the experts in this field will understand that can be made various changes or used replacement equivalents, not beyond being and scope of the invention. In addition, to the extent permitted under applicable patent laws and regulations, all publications, patents and patent applications, which are links that are included in this description in its entirety by reference as if each of them was included in this description by reference individually.

1. The compound of the formula I

where a represents 0 or an integer from 1 to 3;

each R1independently selected from halogen;

b represents 0 or an integer from 1 to 3;

each R2independently selected from a Gal who gene;

W is attached at position 3 or 4 relative to the nitrogen atom in piperidinium ring and represents About;

with represents 0 or an integer from 1 to 4;

each R3independently selected from (1-4C)alkyl; or two groups R3together with the formation of (1-3C)alkylene or oxiran-2,3-deila;

R4represents a divalent group of the formula:

,

where d, e, f, g, h and i each independently selected from 0 and 1;

R4a, R4b, R4cand R4deach independently selected from (1-10C)alkylene, where each Allenova group is unsubstituted or substituted by 1-5 substituents independently selected from (1-4C)alkyl, fluorine and hydroxy;

And1and2each independently selected from (3-7C)cycloalkyl, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)Allen-O-, (2-9C)of heteroaryl and (3-6C)heterocycle, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl, and each Allenova, heteroarenes or heterostropha group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, -S(O)2-(1-4C)alkyl, hydroxy, nitro, triptoreline;

Q is selected from-O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-, -N(Qc )S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and-N(Qk);

Qa, Qb, Qc, Qd, Qe, Qfand Qkeach independently selected from hydrogen, (1-6C)alkyl and3where an alkyl group is unsubstituted or substituted by 1-3 substituents, independently selected from fluorine, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R4bor R4cto which they are attached, form a 4-6-membered azacycloheptane group;

And3independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl and (1-4C)alkoxy; provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms, which are attached to R4is in the range from 4 to 16;

R5represents hydrogen or (1-4C)alkyl;

R6represents-NR6aCR6b(O), and R7represents hydrogen; or

R6and R7together form-NR7aC(O)-CR7b=CR7c-;

each of R6aand R6bthe independent is about represents hydrogen or (1-4C)alkyl; and

each of R7a, R7band R7cindependently represents hydrogen or (1-4C)alkyl;

or its pharmaceutically acceptable salt, MES or stereoisomer.

2. The compound according to claim 1, where the number of contiguous atoms in the shortest chain between the two nitrogen atoms, which are attached to R4is in the range of from 8 to 14.

3. The compound according to claim 2, where the number of contiguous atoms in the shortest chain between the two nitrogen atoms, which are attached to R4is 8, 9, 10 or 11.

4. The compound according to claim 1, where W is attached to piperidinium ring in position 4 relative to the nitrogen atom.

5. The compound according to claim 1, where each of a, b and C are 0, and R5represents hydrogen.

6. The compound according to claim 1, where R6represents-NHCHO, and R7represents hydrogen, or R6and R7together form-NHC(O)-CH=CH-.

7. The compound according to claim 1, where R is a divalent group of the formula -(R4a)d-where R4arepresents (4-10C)alkylene.

8. The connection according to claim 7, where R4represents -(CH2)8-, -(CH2)9- and -(CH2)10-.

9. The compound according to claim 1, where R4represents a divalent group of the formula:

,

where R4arepresents a (1-10C)alkylene; And2represents the FDS is th (6-10C)arisen or (2-9C)heteroaryl, R4drepresents a (1-10C)alkylene.

10. The compound according to claim 1, where R4represents a divalent group of the formula:

,

where Q represents-O - or-N(Qk)-, Qkrepresents hydrogen or (1-3C)alkyl, R4arepresents a (1-10C)alkylene, And2is a (6-10C)arisen or (2-9C)heteroaryl and R4drepresents a (1-10C)alkylene.

11. The compound according to claim 1, where Q represents-N(Qa)C(O)- or-C(O)N(Qb)-.

12. Connection to item 11, where R4chosen from:

where m is an integer from 2 to 10 and n is an integer from 2 to 10, provided that m+n is an integer from 4 to 12;

where o is an integer from 2 to 7 and R is an integer from 1 to 6, provided that o+p is an integer from 3 to 8, and where Hairdryer-1,4-Renova group optionally substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, -S(O)2-(1-4C)alkyl, hydroxy, nitro, triptoreline;

where q is an integer from 2 to 6, r is an integer from 1 to 5 and s is an integer from 1 to 5, provided that q+r+s is an integer from 4 to 8, and where Hairdryer-1,4-Renova group optionally substituted 1-4 will replace the guides and independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, -S(O)2-(1-4C)alkyl, hydroxy, nitro, triptoreline;

where t is an integer from 2 to 10 and u is an integer from 2 to 10, provided that t+u is an integer from 4 to 12;

where v is an integer from 2 to 7, and w is an integer from 1 to 6, provided that v+w is an integer from 3 to 8, and where Hairdryer-1,4-Renova group optionally substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, -S(O)2-(1-4C)alkyl, hydroxy, nitro, triptoreline; and

where x is an integer from 2 to 6, y is an integer from 1 to 5, and z is an integer from 1 to 5, provided that x+y+z is an integer from 4 to 8, and where Hairdryer-1,4-Renova group optionally substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, -S(O)2-(1-4C)alkyl, hydroxy, nitro, triptoreline.

13. The compound according to claim 1, represented by formula II:

where W represents O;

R4represents a divalent group of the formula:

,

where

d, e, f, g, h and i each independently selected from 0 and 1;

R4a, R4b, R4cand R4deach independently selected from (1-10C)alkylene, where each Allenova group is unsubstituted or substituted by 1-5 substituents independently selected from (1-4C)alkyl, fluorine and hydroxy;

And1and2each independently selected from (3-7C)cycloalkyl, (6-10)arylene, -O-(6-10C)arylene, (6-10C)Allen-O-, (2-9C)of heteroaryl and (3-6C)heterocycle, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl, and each Allenova, heteroarenes or heterostropha group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, -S(O)2-(1-4C)alkyl, hydroxy, nitro, triptoreline;

Q is selected from-O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-, -N(Qc)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and-N(Qk);

Qa, Qb, QcQd, Qe, Qfand Qkeach independently selected from hydrogen, (1-6C)alkyl and3where an alkyl group is unsubstituted or substituted by 1-3 substituents, independently selected from fluorine, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R4bor R4cto which they are attached, form a 4-6-membered azacycloheptane group;

And3 independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl and (1-4C)alkoxy;

provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms, which are attached to R4is in the range from 4 to 14;

or its pharmaceutically acceptable salt, MES or stereoisomer.

14. The compound according to claim 1, represented by formula III

where W represents O;

R4represents a divalent group of the formula:

,

where d, e, f, g, h and i each independently selected from 0 and 1;

R4a, R4b, R4cand R4deach independently selected from (1-10C)alkylene, where each Allenova group is unsubstituted or substituted by 1-5 substituents independently selected from (1-4C)alkyl, fluorine and hydroxy;

And1and2each independently selected from (3-7C)cycloalkyl, (6-10)arylene, -O-(6-10C)arylene, (6-10C)Allen-O-, (2-9C)of heteroaryl and (3-6C)heterocycle, where K is jdy cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl, and each Allenova, heteroarenes or heterostropha group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, -S(O)2-(1-4C)alkyl, hydroxy, nitro, triptoreline;

Q is selected from-O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-, -N(Qc)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and-N(Qk);

Qa, Qb, QcQd, Qe, Qfand Qkeach independently selected from hydrogen, (1-6C)alkyl and3where an alkyl group is unsubstituted or substituted by 1-3 substituents, independently selected from fluorine, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R4bor R4cto which they are attached, form a 4-6-membered azacycloheptane group;

And3independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl and (1-4C)alkoxy;

provided that the number of contiguous atoms in the shortest chain between the two atoms is mi of nitrogen, which are attached to R4is in the range from 4 to 14;

or its pharmaceutically acceptable salt, MES or stereoisomer.

15. The connection of item 13 or 14, where the number of contiguous atoms in the shortest chain between the two nitrogen atoms, which are attached to R4is in the range of from 8 to 14.

16. The connection of item 13 or 14, where the number of contiguous atoms in the shortest chain between the two nitrogen atoms, which are attached to R4is 8, 9, 10 or 11.

17. The connection of item 13 or 14, where R4represents a divalent group of the formula -(R4a)d-where R4arepresents (4-10C)alkylene.

18. The connection 17, where R4represents -(CH2)8-, -(CH2)9- and - (CH2)10-.

19. The connection of item 13 or 14, where R4represents a divalent group of the formula:

,

where R4arepresents a (1-10C)alkylene; And2is a (6-10C)arisen or (2-9C)heteroaryl, R4drepresents a (1-10C)alkylene.

20. The connection of item 13 or 14, where R4represents a divalent group of the formula:

,

where Q represents-O - or-N(Qk)-, Qkrepresents hydrogen or (1-3C)alkyl, R4Arepresents a (1-10C)is kilen, And2is a (6-10C)arisen or (2-9C)heteroaryl and R4drepresents a (1-10C)alkylene.

21. The connection of item 13 or 14, where Q represents-N(Qa)C(O)- or - C(O)N(Qb)-.

22. Connection item 21, where R4chosen from:

where m is an integer from 2 to 10 and n is an integer from 2 to 10, provided that m+n is an integer from 4 to 12;

where o is an integer from 2 to 7 and R is an integer from 1 to 6, provided that o+p is an integer from 3 to 8, and where Hairdryer-1,4-Renova group optionally substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, -S(O)2-(1-4C)alkyl, hydroxy, nitro, triptoreline;

where q is an integer from 2 to 6, r is an integer from 1 to 5, and s is an integer from 1 to 5, provided that q+r+s is an integer from 4 to 8, and where Hairdryer-1,4-Renova group optionally substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, -S(O)2-(1-4C)alkyl, hydroxy, nitro, triptoreline;

where t is an integer from 2 to 10, and u is an integer from 2 to 10, provided that t+u is an integer from 4 to 12;

where v is an integer from 2 to 7, and w is an integer from 1 to 6, provided that v+w is an integer from 3 to 8, and where Hairdryer-1,4-Renova group optionally substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, -S(O)2-(1-4C)alkyl, hydroxy, nitro, triptoreline; and

where x is an integer from 2 to 6, y is an integer from 1 to 5, and z is an integer from 1 to 5, provided that x+y+z is an integer from 4 to 8, and where Hairdryer-1,4-Renova group optionally substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl, (1-4C)alkoxy, -S(O)2-(1-4C)alkyl, hydroxy, nitro, triptoreline.

23. The connection of item 13 or 14, where R4chosen from:

-(CH2)7-;

-(CH2)8-;

-(CH2)9-;

-(CH2)10-;

-(CH2)11;

-(CH2)2C(O)NH(CH2)5;

-(CH2)2N(CH3)C(O)(CH2)5-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2-;

-(CH2)2NHC(O)(Hairdryer-1,4-ilen)CH2-;

-(CH2)2NHC(O)NH(CH2)5-;

-(CH2)3NHC(O)NH(CH2)5-;

-(CH2)2C(O)NHCH2(cyclohex-1,3-ilen)CH2-;

-(CH2 )2NHC(O)(cyclopent-1,3-ilen)-;

-(CH2)2NHC(O)NH(Hairdryer-1,4-ilen)(CH2)2-;

1-[-(CH2)2C(O)](piperidine-4-yl)(CH2)2-;

-(CH2)2NHC(O)(TRANS-cyclohex-1,4-ilen)CH2-;

-(CH2)2NHC(O)(CIS-cyclopent-1,3-ilen)-;

-(CH2)2NH(Hairdryer-1,4-ilen)(CH2)2-;

1-[-(CH2)2NHC(O)](piperidine-4-yl)(CH2)2-;

-CH2(fen-1,4-ilen)NH(Hairdryer-1,4-ilen)CH2-;

-(CH2)2C(O)NHCH2(Hairdryer-1,3-ilen)CH2-;

-(CH2)2C(O)NHCH2(pyrid-2,6-ilen)CH2-;

-(CH2)2C(O)NH(CIS-cyclohex-1,4-ilen)CH2-;

-(CH2)2C(O)NH(TRANS-cyclohex-1,4-ilen)CH2-;

-(CH2)2NHC(O)(CIS-cyclopent-1,3-ilen)CH2-;

-(CH2)2N(CH3) () (Hairdryer-1,3-ilen)CH2-;

-(CH2)2N(CH3) (O)(TRANS-cyclohex-1,4-ilen)CH2-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)*N(CH3)-((S)-isomer);

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)*N(CH3)-((R)-isomer);

2-[(S)-(-CH2-](pyrrolidin-1-yl)C(O)(CH2)4-;

2-[(S)-(-CH2-](pyrrolidin-1-yl)C(O)(Hairdryer-1,4-ilen)CH2-;

-(CH2/sub> )2C(O)NH(4-chlorphen-1,3-ilen)CH2-;

-CH2(2-torpen-1,3-ilen)CH2-;

-(CH2)2C(O)NH(4-methylphen-1,3-ilen)CH2-;

-(CH2)2C(O)NH(6-chlorphen-1,3-ilen)CH2-;

-(CH2)2C(O)NH(2-chlorphen-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2,6-dichlorophen-1,4-ilen)CH2-;

-(CH2)2NHC(O)NHCH2(Hairdryer-1,3-ilen)CH2-;

4-[-CH2-](piperidine-1-yl)C(O)(Hairdryer-1,4-ilen)CH2-;

-(CH2)2C(O)N(CH2CH3)(Hairdryer-1,4-ilen)CH2-;

1-[-(CH2)2NHC(O)](piperidine-4-yl)-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)(CH2)2;

-(CH2)2NHC(O)(Tien-2,5-ilen)CH2-;

-(CH2)2N(CH3) (O)(3-nitrogen-1,4-ilen)CH2-;

-(CH2)2N(CH3) (O)(TRANS-cyclohex-1,4-ilen)-;

1-[-CH2(2-torpen-1,3-ilen)CH2]piperidine-4-yl)-;

5-[-(CH2)2NHC(O)](pyrid-2-yl)CH2-;

-(CH2)2(fen-1,4-ilen)(CH2)2-;

-(CH2)3(Tien-2,5-ilen)(CH2)3-;

-(CH2)2(fen-1,4-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

-CH2(fen-1,2-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

1-[-CH2(2-torpen-1,3-ilen)CH2](Pieper is DIN-4-yl)(CH 2)2-;

1-[-CH2(2-torpen-1,3-ilen)CH2]piperidine-4-yl)CH2-;

-(CH2)2C(O)NH(3-chlorphen-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2-(CF3O-)Hairdryer-1,4-ilen)CH2-;

-(CH2)3(Hairdryer-1,3-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2S(O)2NH(CH2)5-;

-CH2(Hairdryer-1,3-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2C(O)NH(2-itfan-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2-chloro-5-methoxide-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2-chloro-6-methylphen-1,4-ilen)CH2-;

-(CH2)2C(O)NH(CH2)5-;

-(CH2)2N(CH3)S(O)2(fen-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2-bromphen-1,4-ilen)CH2-;

-(CH2)3(fen-1,4-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)3(fen-1,2-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

1-[-CH2(2-torpen-1,3-ilen)CH2]piperidine-4-yl)(CH2)3-;

-(CH2)2C(O)NH(2-methoxide-1,4-ilen)CH2-;

-(CH2)5NH(Hairdryer-1,4-ilen)(CH2)2-;

4-[-(CH2)2-](piperidine-1-yl)(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH(CH3)CH2 -;

-(CH2)2-(TRANS-cyclohex-1,4-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2C(O)NH(2-torpen-1,4-ilen)CH2-;

-(CH2)2(Hairdryer-1,3-ilen)NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2C(O)NH(2,5-deltorphin-1,4-ilen)CH2-;

-(CH2)2NHC(O)(Hairdryer-1,4-ilen)(CH2)2-;

1-[-CH2(pyrid-2,6-ilen)CH2]piperidine-4-yl)CH2-;

-(CH2)3NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2NH(naphthas-1,4-ilen)(CH2)2-;

-(CH2)3(Dryer-1,4-ilen)CH2-;

1-[-(CH2)3]piperidine-4-yl)CH2-;

4-[-(CH2)2](piperidine-1-yl)C(O)(Hairdryer-1,4-ilen)CH2-;

-(CH2)3(fen-1,4-ilen)]NHC(O)(CH2)2-;

-(CH2)3(Dryer-1,4-ilen)(CH2)2-;

2-[-(CH2)2]benzimidazole-5-yl)CH2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)(CH2)2-;

-(CH2)2-(TRANS-cyclohex-1,4-ilen)NHC(O)(CH2)4-;

-(CH2)2-(TRANS-cyclohex-1,4-ilen)NHC(O)(CH2)5-;

4-[-(CH2)2]piperidine-1-yl)C(O)(CH2)2;

-(CH2)2NHC(O)NH(Hairdryer-1,4-ilen)CH2-;

-(CH2)2N(sub> 3)(CH2)2(CIS-cyclohex-1,4-ilen)-;

-(CH2)2C(O)NH(2,3,5,6-tetraterpene-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2,6-dioden-1,4-ilen)CH2-;

4-[-(CH2)2]piperidine-1-yl)C(O)(CH2)3-;

4-[-(CH2)2]piperidine-1-yl)C(O)(CH2)4-;

4-[-(CH2)2]piperidine-1-yl)C(O)(CH2)5-;

-(CH2)2C(O)NHCH2(fen-1,4-ilen)CH2-;

-(CH2)2NHC(O)NHCH2(fen-1,4-ilen)CH2-;

-(CH2)2C(O)NH(2-methylphen-1,4-ilen)CH2-;

1-[-(CH2)3(Dryer-1,4-ilen)(CH2)2]piperidine-4-yl)CH2-;

-(CH2)2C(O)NHCH2(Hairdryer-1,3-ilen)(CH2)2-;

-(CH2)2About(hair dryer-1,3-ilen)(CH2)2-;

-(CH2)2N(CH3)C(O)CH2(Dryer-1,4-ilen)CH2-;

-(CH2)2N(CH3)C(O)CH2About(hair dryer-1,3-ilen)CH2-;

-(CH2)2N(CH3) () (FSD-2,5-ilen)CH2-;

-(CH2)2N(CH3) () (Tien-2,5-ilen)CH2-;

-(CH2)2(Dryer-1,4-ilen)O(CH2)2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)(Hairdryer-1,4-ilen)CH2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)CH2O(Hairdryer-1,2-ilen)CH 2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)CH2About(hair dryer-1,3-ilen)CH2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)CH2(Dryer-1,4-ilen)CH2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)(FSD-2,5-ilen)CH2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(O)(Tien-2,5-ilen)CH2-;

4-[-(CH2)2]piperidine-1-yl)C(O)CH2About(hair dryer-1,2-ilen)CH2-;

4-[-(CH2)2]piperidine-1-yl)C(O)CH2About(hair dryer-1,3-ilen)CH2-;

4-[-(CH2)2]piperidine-1-yl)C(O)CH2(Dryer-1,4-ilen)CH2-;

4-[-(CH2)2]piperidine-1-yl)C(O)(FSD-2,5-ilen)CH2-;

4-[-(CH2)2]piperidine-1-yl)C(O)(Tien-2,5-ilen)CH2-;

-(CH2)2(fen-1,4-ilen)NHC(O)(Hairdryer-1,3-ilen)CH2-;

-(CH2)2(fen-1,4-ilen)NHC(O)(Hairdryer-1,4-ilen)CH2-;

-(CH2)2(fen-1,4-ilen)NHC(O)CH2About(hair dryer-1,2-ilen)CH2-;

-(CH2)2(fen-1,4-ilen)NHC(O)CH2About(hair dryer-1,3-ilen)CH2-;

-(CH2)2(fen-1,4-ilen)]NHC(O)CH2(Dryer-1,4-ilen)CH2-;

-(CH2)2(fen-1,4-ilen)NHC(O)(FSD-2,5-ilen)CH2-;

-(CH2)2(fen-1,4-ilen)NHC(O)(Tien-2,5-ilen)CH2-;

-(CH2)2(TRANS-cyclohex-1,4-ilen)NHC(is)(Hairdryer-1,3-ilen)CH 2-;

-(CH2)3About(hair dryer-1,3-ilen)CH2-;

-CH2CH(OH)CH2NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)4NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)CH2NHC(O)CH2-;

-(CH2)2C(O)NH(Hairdryer-1,4-ilen)(CH2)2NHC(O)CH2-;

-(CH2)2C(O)NHCH2(TRANS-cyclohex-1,4-ilen)CH2-;

-(CH2)2NHC(O)(CH2)5-;

-(CH2)2About(hair dryer-1,3-ilen)O(CH2)2-;

-(CH2)2About(hair dryer-1,2-ilen)O(CH2)2-;

-CH2(fen-1,2-ilen) (Hairdryer-1,2-ilen)CH2-;

-(CH2)2C(O)NH(CH2)6-;

-(CH2)3(fen-1,4-ilen)(CH2)3-;

-(CH2)3(fen-1,4-ilen)(CH2)2-;

-(CH2)4(fen-1,4-ilen)(CH2)2-;

-(CH2)3(furan-2,5-ilen)(CH2)3-;

-(CH2)2N(CH3)C(O)NH(Hairdryer-1,4-ilen)(CH2)2-;

4-[-(CH2)2]piperidine-1-yl)C(O)NH(Hairdryer-1,4-ilen)(CH2)2-;

-(CH2)3(Hairdryer-1,3-ilen)(CH2)3-;

-(CH2)3(tetrahydrofuran-2,5-ilen)(CH2)3-and

-(CH2)2(Dryer-1,4-ilen) (O)(CH2)2-.

Any formula I:

where a represents 0 or an integer from 1 to 3;

each R1independently selected from halogen;

b represents 0 or an integer from 1 to 3;

each R2independently selected from halogen;

W is attached at position 3 or 4 relative to the nitrogen atom in piperidinium ring and represents About;

with represents 0 or an integer from 1 to 4;

each R3is a Deputy at the carbon atom, independently selected from (1-4C)alkyl;

R4represents a divalent group of the formula:

,

where d, e, f, g, h and i each independently selected from 0 and 1;

R4a, R4b, R4cand R4deach independently selected from (1-10C)alkylene, where each Allenova group is unsubstituted or substituted by 1-5 substituents independently selected from (1-4C)alkyl, fluorine and hydroxy;

And1and2each independently selected from (3-7C)cycloalkyl, (6-10)arylene, (2-9C)of heteroaryl and (3-6C)heterocycle, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl, and each Allenova, heteroarenes or heterostropha group is unsubstituted or substituted by 1-4 Zam is stitely, independently selected from halogen, (1-4C)alkyl and (1-4C)alkoxy;

Q is selected from-O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-, -N(Qc)S(O)2-, -S(O)2N(Qd)- and-N(Qe)C(O)N(Qf)-;

Qa, Qb, QcQd, Qeand Qfeach independently selected from hydrogen, (1-6C)alkyl and3where an alkyl group is unsubstituted or substituted by 1-3 substituents, independently selected from fluorine, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R4bor R4cto which they are attached, form a 4-6-membered azacycloheptane group;

And3independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl and (1-4C)alkoxy;

provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms, which are attached to R4is in the range from 8 to 14;

R5represents hydrogen or (1-4C)alkyl;

R6represents-NR6aCR6b(O) and R7represents hydrogen; and

R6and R7together form-NR7aC(O)-CR7b=CR7c-;

each of R6aand R6bindependently represents hydrogen or (1-4C)alkyl; and

each of R7a, R7band R7cindependently represents hydrogen or (1-4C)alkyl;

or its pharmaceutically acceptable salt, MES or stereoisomer.

25. The compound according to claim 1, chosen from:

1-{9-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{9-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]intercalator}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-({6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]hexanoyl}methylamino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-hydroxy-2-(8-is hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid;

1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoylamine)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(3-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]pentyl}ureido)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(3-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]pentyl}ureido)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}cyclohexylmethyl)carbarnoyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]intercultural}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzazolyl)methylamino]ethyl} piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[3-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzyl)ureido]ethyl}piperidine-4-silt ether-biphenyl-2-carbamino acid;

1-{3-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)phenyl]propyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-fluoro-3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}piperidine-1-ylmethyl)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenoxy)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}piperidine-1-yl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxyphenylacetyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{7-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]heptyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{8-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]octyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[3-(4-{2[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenyl)ureido]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid,

1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}piperidine-1-yl)-3-oxopropyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}cyclohexanecarbonyl)amino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-({(1R,3S)-3-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]cyclopentanecarbonyl}amino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(3-{5-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]pentyl}ureido)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-(2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(3-{5-[2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]pentyl}ureido)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}piperidine-1-carbonyl)amino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid

1-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

3-[4-(3-biphenyl-2-yureina)piperidine-1-yl]-N-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenyl)propionamide;

1-{2-[(6-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}pyridine-2-ylmethyl)carbarnoyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}cyclohexylcarbamate)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}cyclohexylcarbamate)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-({(1R,3S)-3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]cyclopentanecarbonyl}amino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoyl)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}cyclohexanecarbonyl)methylamino]ethyl}piperidine-4-ilovekeifer biphenyl-2-ylcarbamate acid;

1-[2-(4-{[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{(S)-1-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{(R)-1-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-((S)-1-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]pentanoyl}pyrrolidin-2-ylmethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[(S)-1-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoyl)pyrrolidin-2-ylmethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{(R)-1-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]ethyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-chloro-3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ilkar the amine acid;

N-{2-[4-(3-biphenyl-2-yureina)piperidine-1-yl]ethyl}-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl} benzamide;

1-biphenyl-2-yl-3-{1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}piperidine-1-yl)-3-oxopropyl]piperidine-4-yl}urea;

3-[4-(3-biphenyl-2-yureina)piperidine-1-yl]-N-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl} benzyl)propionamide;

1-(2-fluoro-3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-4-methylphenylcarbinol)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(2-chloro-5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(2,6-dichloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[1-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoyl)piperidine-4-ylmethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}benzoylamine)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid;

1-{2-[ethyl-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenyl)carbarnoyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(3-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]piperidine-1-yl}-3-oxopropyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl} thiophene-2-carbonyl)amino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-3-nitrobenzoyl)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}cyclohexylcarbamate)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-({4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]cyclohexanecarbonyl}methylamino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-fluoro-3-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]piperidine-1-ylmethyl}benzyl)piperidin the-4-silt ether-biphenyl-2-ylcarbamate acid;

1-{2-[(6-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}pyridine-3-carbonyl)amino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(5-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propyl}thiophene-2-yl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{2-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]ethyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)benzyl] piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-fluoro-3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}piperidine-1-ylmethyl)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(3-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-2-triftormetilfullerenov)ethyl]piperidine-4-ilovekeifer biphenyl-2-ylcarbamate acid;

1-{3-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)phenyl]propyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(4-{2-[(8)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-2-idgenerator)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-6-methylphenylcarbinol)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{5-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]intercalator}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(2-bromo-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{3-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)phenyl]propyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-fluoro-3-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propyl}piperidine-1-ylmethyl)benzyl]piperidine-ilobolo ether-biphenyl-2-ylcarbamate acid;

1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-2-methoxyphenylacetyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[5-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)pentyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[1-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenyl)piperidine-4-yl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-(2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]-1-methylethyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)cyclohexyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(2-fluoro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)phenyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(2,5-debtor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]PI is uridin-4-silt ether-biphenyl-2-ylcarbamate acid;

1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}benzoylamine)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[6-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}piperidine-1-ylmethyl)pyridine-2-ylmethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}naphthalene-1-ylcarbonyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[1-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoyl)piperidine-4-yl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propionamide}phenyl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-1H-benzoimidazol-2-yl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propionamide}cyclohexyl)ethyl]piperidine--silt ether-biphenyl-2-ylcarbamate acid;

1-[2-(4-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]pentanediamine}cyclohexyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]hexanamine}cyclohexyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(1-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propionyl}piperidine-4-yl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenyl)ureido]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[(2-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]cyclohexyl}ethyl)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(2,3,5,6-titrator-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-2,6-diethenylbenzene)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(1-{4-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]butyryl}piperidine-4-yl)those who]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid;

1-[2-(1-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]pentanoyl}piperidine-4-yl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(1-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]hexanoyl}piperidine-4-yl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}benzylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[3-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzyl)ureido]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[3-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}benzyl)ureido]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-2-methylphenylcarbinol)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(3-{4-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}piperidine-1-yl)ethyl]phenoxy}propyl)piperidine-4-silt ether-biphenyl--ylcarbamate acid;

1-[2-(3-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}benzylcarbamoyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-l)ethylamino]methyl}phenoxy)acetyl]methylamino}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetyl]methylamino}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}furan-2-carbonyl)methylaminomethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}thiophene-2-carbonyl)methylamino]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethoxy}phenoxy)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[4-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoylamine)cyclohexyl]ethylpiperidine-4-silt ether-biphenyl-2-ylcarbamate acid;

1-(2-{4-[2-(2-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetylamino]cyclohexyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{4-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetylamino]cyclohexyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{4-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetylamino]cyclohexyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}furan-2-carbonyl)amino]cyclohexyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-(4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}thiophene-2-carbonyl)amino]cyclohexyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{1-[2-(2-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetyl]piperidine-4-yl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{1-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetyl]piperidine-4-yl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{1-[2(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetyl]piperidine-4-yl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid;

1-{2-[1-(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}furan-2-carbonyl)piperidine-4-yl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[1-(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}thiophene-2-carbonyl)piperidine-4-yl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[4-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoylamine)phenyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-[4-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoylamine)phenyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{4-[2-(2-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetylamino]phenyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{4-[2-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetylamino]phenyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{4-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)acetylamino]phenyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-the l)ethylamino]methyl}furan-2-carbonyl)amino]phenyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid;

1-(2-{4-[(5-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}thiophene-2-carbonyl)amino]phenyl}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[4-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoylamine)cyclohexyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(3-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-hydroxy-3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[4-(4-(2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)butyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[4-({2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]acetylamino}methyl)phenylcarbamoyl]ethyl} piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[4-(2-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]acetylamino}ethyl)phenylcarbamoyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}cyclohexyl the Il)carbarnoyl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid;

1-(2-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]hexanamine}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(3-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethoxy}phenoxy)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(2-{2-[(S)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethoxy}phenoxy)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(2-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenoxy)benzyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]exaltabitur}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-({(1R,3S)-3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]cyclopentanecarbonyl}amino)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(4-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propyl}phenyl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenyl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[4-(4-{2-[(R)-2-Ki-the Roxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenyl)butyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid;

1-[3-(5-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propyl}furan-2-yl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenyl)-1-methylurea]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{2-[1-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylcarbamoyl)piperidine-4-yl]ethyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(3-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propyl}phenyl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[3-(5-{3-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]propyl}tetrahydrofuran-2-yl)propyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid,

1-[2-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethylcarbamate}phenoxy)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{9-[2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether (5-bromobiphenyl-2-yl)carbamino acids;

1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl} piperidine-4-silt ether (2′-forbiden-2-yl)carbamino key is lots;

1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether (3′-chloro-3,5-diferuloyl-2-yl)carbamino acids;

1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether (3′,5′-dichloro-3,5-diferuloyl-2-yl)carbamino acids;

1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether (3,5-diferuloyl-2-yl)carbamino acids;

1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}phenylcarbamoyl)ethyl]-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{9-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]nonyl}-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]intercalator}ethyl)-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{5-[(R)-2-(3-formylamino-hydroxyphenyl)-2-hydroxyethylamino]intercalator}ethyl)-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acid;

1-(2-{6-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]hexanamine}ethyl)-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acids;

1-(2-{6-[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]hexanamine}ethyl)-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}benzoylamine)ethyl]-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(4-{[(R)-2-(3-formylamino-4-hydroxyphenyl)-2-hydroxyethylamino]methyl}benzoylamine)ethyl]-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acids;

1-{3-[4-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]ethyl}phenylamino)phenyl]propyl}-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}phenylcarbamoyl)ethyl]-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acids;

1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxyphenylacetyl)ethyl]-4-methylpiperidin-4-silt ether-biphenyl-2-ylcarbamate acids;

4-(biphenyl-2-ylcarbamate)-1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}-1-and oneamerica[2.2.2]octane;

8-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}-8-azabicyclo[3.2.1]Oct-3-silt ether-biphenyl-2-ylcarbamate acids;

7-(biphenyl-2-ylcarbamate)-9-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}-9-methyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane, and

9-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}-3-oxa-9-azatricyclo[3.3.1.02,4]non-7-silt ether-biphenyl-2-ylcarbamate acid,

or its pharmaceutically acceptable salt or MES.

26. The compound according to claim 1, which represents the 1-{9-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]nonyl}piperidine-4-silt ether-biphenyl-2-ylcarbamate acid, or its pharmaceutically acceptable salt or MES.

27. The compound according to claim 1, which represents a 1-(2-{5-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]intercalator}ethyl)piperidine-4-silt ether-biphenyl-2-ylcarbamate acid, or its pharmaceutically acceptable salt, or MES.

28. 1-[2-(2-chloro-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxyphenylacetyl)ethyl]piperidine-4-silt ether-biphenyl-2-ylcarbamate acid, or its pharmaceutically acceptable salt, or MES.

29. Pharmaceutical composition having as an asset of the awn antagonist of muscarinic receptors, and the activity of the agonist β2-adrenergic receptors containing a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of claims 1 to, 13, 14, 24, 25, 26, 27 28.

30. The pharmaceutical composition according to clause 29, which further comprises a therapeutically effective amount of a steroid anti-inflammatory agents.

31. The pharmaceutical composition according to clause 29, which further comprises a therapeutically effective amount of a PDE4 inhibitor.

32. A method of treating a pulmonary disease comprising the administration to a patient in need of such treatment, a therapeutically effective amount of a compound according to any one of claims 1 to, 13, 14, 24, 25, 26, 27 28.

33. The way to ensure the patient's expansion of the bronchial lumen, comprising the administration to a patient in need of the extension of the lumen of the bronchi, a therapeutically effective amount of a compound according to any one of claims 1 to, 13, 14, 24, 25, 26, 27 28.

34. A method of treating chronic obstructive pulmonary disease or asthma, comprising the administration to a patient in need of such treatment, a therapeutically effective amount of a compound according to any one of claims 1 to, 13, 14, 24, 25, 26, 27 28.

35. The method of obtaining the compounds of formula I

where a represents 0 or an integer from 1 to 3;

each Rsup> 1independently selected from halogen;

b represents 0 or an integer from 1 to 3;

each R2independently selected from halogen;

W is attached at position 3 or 4 relative to the nitrogen atom in piperidinium ring and represents About;

with represents 0 or an integer from 1 to 4;

each R3independently selected from (1-4C)alkyl; or two groups R3together with the formation of (1-3C)alkylene or oxiran-2,3-deila;

R4represents a divalent group of the formula:

,

where d, e, f, g, h and i each independently selected from 0 and 1;

R4a, R4b, R4cand R4deach independently selected from (1-10C)alkylene, where each Allenova group is unsubstituted or substituted by 1-5 substituents independently selected from (1-4C)alkyl, fluorine and hydroxy;

And1and2each independently selected from (3-7C)cycloalkyl, (6-10)arylene, -O-(6-10C)arylene, (6-10C)Allen-O-, (2-9C)of heteroaryl and (3-6C)heterocycle, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl, and each Allenova, heteroarenes or heterostropha group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl is, (1-4C)alkoxy, -S(O)2-(1-4C)alkyl, hydroxy, nitro, triptoreline;

Q is selected from-O-, -S(O)2, -N(Qa)C(O)-, -C(O)N(Qb)-, -N(Qc)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and-N(Qk);

Qa, Qb, QcQd, Qe, Qfand Qkeach independently selected from hydrogen, (1-6C)alkyl and3where an alkyl group is unsubstituted or substituted by 1-3 substituents, independently selected from fluorine, hydroxy and (1-4C)alkoxy; or together with the nitrogen atom and the group R4bor R4c,to which they are attached, form a 4-6-membered azacycloheptane group;

And3independently selected from (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroaryl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substituents, independently selected from (1-4C)alkyl and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substituents, independently selected from halogen, (1-4C)alkyl and (1-4C)alkoxy; provided that the number of contiguous atoms in the shortest chain between the two nitrogen atoms, which are attached to R4is in the range from 4 to 16;

R5represents hydrogen or (1-4C)alkyl;

R6represents-NR6aCR6b(O), and R7represents the t are hydrogen; or

R6and R7together form-NR7aC(O)-CR7b=CR7c;

each of R6aand R6bindependently represents hydrogen or (1-4C)alkyl; and

each of R7a, R7band R7cindependently represents hydrogen or (1-4C)alkyl;

or its stereoisomer, including:

the interaction of the compounds of formula 11

or its hydrate; where R4'represents a residue that, together with the carbon atom to which it is attached, after the reaction, forms a group R4; with the compound of the formula 10

where R11and R12each independently represents a hydrogen atom or hydroxylamino group, and R13represents a hydrogen atom or aminosidine group; in the presence of a reducing agent; and then

remove any protective group, R11, R12or R13with the formation of compounds of formula I.

36. The method according to 35, which additionally includes the stage of formation of pharmaceutically acceptable salts of the compounds of formula I.

37. The compound according to any one of claims 1 to, 13, 14, 24, 25, 26, 27 or 28 for use as a drug for the treatment of pulmonary diseases.

38. The compound according to any one of claims 1, 13, 14 24, 25, 26, 27 or 28 for the treatment of pulmonary diseases.

39. Drug, with both the activity of the antagonist of muscarinic receptors, and the activity of the agonist β2-adrenergic receptors containing the compound according to any one of claims 1 to, 13, 14, 24, 25, 26, 27 28.

40. The use of compounds according to any one of claims 1 to, 13, 14, 24, 25, 26, 27 or 28 for the manufacture of a medicine for the treatment of lung diseases.

41. The use of compounds according to any one of claims 1 to, 13, 14, 24, 25, 26, 27 or 28 for the treatment of pulmonary diseases.

42. Use p or 41, where pulmonary disease is a chronic obstructive pulmonary disease or asthma.

Priority items:

01.05.2003 according to claims 1 to 23, 25-42;

14.02.2003 at point 24.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel quinuclidine derivatives and their using as pharmaceutical agents. Based on their pharmacological pattern proposed compounds can be useful in treatment of different diseases and disorders associated with cholinergic system of the central nervous system, peripheral nervous system, diseases and disorders associated with contraction of smooth muscle, endocrine diseases or disorders, diseases or disorders associated with neurodegeneration, diseases or disorders associated with inflammation, pain and abstinence syndrome caused by ceasing use of chemical substances.

EFFECT: valuable medicinal properties of compounds.

11 cl, 1 tbl, 46 ex

FIELD: organic chemistry, medicine, chemical technology.

SUBSTANCE: invention describes a method for synthesis of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represented by the formula: . Method involves interaction of 1-hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane with hydrobromic acid or its inorganic salt (for example, sodium bromide or potassium bromide) in water in the ionic exchange reaction. 1-Hexadecyl-R-(-)-3-hydroxy-1-azoniabicyclo[2.2.2]octane bromide represents an immunotropic agent that shows versatile effect on human immune status and elicits antitumor, bacteriostatic and anti-aggregate effects. Invention proposes a method for synthesis of a novel synthetic low-molecular preparation possessing the expressed stimulating effect on the antitumor immunity system that is equal or exceeding by effectiveness effect of the modern domestic and foreign preparation - immunomodulators that represent natural high-molecular biologically active substances prepared by methods of genetic engineering.

EFFECT: improved method of synthesis, valuable medicinal and biological properties of substance.

1 cl, 6 tbl, 21 dwg, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds that represent quaternary ammonium salt of the formula (II): wherein R1 means group chosen from phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl; R2 means group chosen from (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, saturated or unsaturated (C3-C7)-cycloalkyl, saturated or unsaturated (C3-C7)-cycloalkylmethyl, phenyl, benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophen-2-ylmethyl, thiophen-3-ylmethyl, pyridyl and pyridylmethyl; cyclic groups in R1 and R2 are optionally substituted with one, two or three substitutes chosen from halogen atom, linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy group is unsubstituted or substituted with one or more halogen atoms or hydroxy groups; p means 1 or 2, and carbamate group is joined at positions 2, 3 or 4 of azoniabobicyclic ring system; m means a whole number from 1 to 6; n means 0 or 1; A represents -CH2-, -CH=CH-, -C(O)-, -O-, -S- and -NMe-group; B represents hydrogen atom or group chosen from linear or branched (C1-C8)-alkyl, hydroxy, linear or branched (C1-C8)-alkoxy, cyano, nitro, -CH=CR'R'', -C(O)OR', -OC(O)R', (C3-C7)-cycloalkyl, phenyl, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl, benzo[1.3]dioxolyl, 5-10-membered heteroaryl or heterocyclyl group wherein each R' and R'' represents independently hydrogen atom or linear or branched (C1-C8)-alkyl group, and wherein cyclic groups represented as B are substituted optionally with one, two or three substitutes chosen from halogen atom, hydroxy, linear or branched (C1-C8)-alkyl, -OR', -CONR'R'', -CN, and -COOR'; R' and R'' are given above and wherein (C1-C8)-alkyl groups are unsubstituted or substituted with one or more halogen atoms, hydroxy or (C1-C8)-alkoxy groups, and (C1-C8)-alkoxy groups are unsubstituted or substituted with one or more halogen atoms or hydroxy groups; X- represents a pharmaceutically acceptable anion of mono- or polyvalent acid, and involving all individual stereoisomers of compound of the formula (II) and their mixtures. Also, invention relates to a method for inhibition, pharmaceutical composition, combined product and their using in therapeutic treatment as antagonists of M3 muscarinic receptors. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 187 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an improved method for synthesis of 1-(2S,3S)-2-benzhyryl-N-(5-tert.-butyl-2-methoxybenzyl)quinuclidin-3-amine (further named in the claim as "compound of the formula (I)" ) and its pharmaceutically acceptable salts. Invention relates to an improved method of synthesis of citrate monohydrate salt of compound of the formula (Ia):

EFFECT: improved method of synthesis.

10 cl, 2 sch,

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new compounds selected from 3(R)-(2-hedroxy-2,2-dithiene-2yl acetoxy)-1-(3-phenoxypropyl)-1-azoaniabicyclo[2,2,2]octane,X-, and 1-phenerhyl-3(R)-(9[H]-xanthene-9-carbonyloxy)-1-azoaniabicyclo[2,2,2]octane,X-, wherein X- represents pharmaceutically acceptable anion of mono- or polyvalen acid having inhibiting activity in relates to muscarinic M3 receptors. Also disclosed are pharmaceutical compositions containing such compounds and method for treatment of respiratory diseases.

EFFECT: new quinuclidine analogs useful in treatment of respiratory diseases.

20 cl, 1 tbl, 184 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of carbamate of the formula (I): or to their pharmaceutically acceptable salts wherein R1 represents compounds of formulas: , , , ,

, , , or ; R3 means hydrogen, halogen atom or alkyl; R2 means benzyl, phenethyl, furan-2-ylmethyl, furan-3-ylmethyl, thiophene-2-ylmethyl, thiophene-3-ylmethyl or alkyl; p = 1 or 2, and substitution in azabicyclic ring can be at position 2, 3 or 4. Compounds of the formula (I) and their salts possess inhibitory activity with respect to muscarinic M3 receptors and can be used in medicine.

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

25 cl, 1 tbl, 165 ex

FIELD: organic chemistry, medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to an agent eliciting immunomodulating, antitumor, bacteriostatic and anti-aggregation properties and representing 1-hexadecyl-R-(-)-3-oxy-1-azoniabicyclo[2.2.2]octane bromide and a method for its synthesis. Method involves quartenization of R-(-)-azabicyclo[2.2.2]octane-3-ol with hexadecyl bromide at heating in organic solvent medium. Agent shows low toxicity, high effectiveness, it doesn't cause allergic effect and doesn't possess cumulative effect.

EFFECT: valuable medicinal properties of agent.

3 cl, 9 dwg, 6 tbl, 2 ex

FIELD: organic chemistry, pharmacology, pharmacy.

SUBSTANCE: invention relates to derivatives of quinuclidine of the general formula (I): wherein B means phenyl, pyrrolyl and other group; each among R1, R2 and R3 represents hydrogen, halogen atom, phenyl group and others; n means a whole number from 0 to 4; A represents the group chosen from -CH2-, -CH=CR9, -CR9R10 and others wherein R9 and R10 represent hydrogen atom or (C1-C8)-alkyl; m means a whole number from 0 to 8 under condition that if m = 0 then A doesn't mean -CH2-; p means a whole number from 1 to 2; R4 represents phenyl or 5-membered heteroaromatic cycle comprising oxygen or sulfur atom; R5 represents (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl and others; R6 represents hydrogen atom, hydroxy-group and others; X- represents a pharmaceutically acceptable anion of mono- or polyvalent acid. Compounds of the formula (I) possess the inhibitory activity with respect to M3-muscarinic receptors and can be used in medicine.

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

34 cl, 2 tbl, 104 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry.

SUBSTANCE: invention relates to quinuclidine compounds of the formula (I) , its salts or their hydrates wherein R1 represents hydroxyl group; W represents: (1) -CH2-CH2-; 2) -CH=CH-, or 3) -C≡C-; HAr represents 5-10-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom that in addition to the group -X-Ar can be substituted with 1-3 groups taken among: (1) halogen atom; (2) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl group substituted optionally with: (a) hydroxy-group; (b) (C1-C6)-alkoxycarbonyl; (c) (C1-C6)-alkanoyl optionally substituted with (C1-C6)-alkoxy-group; (d) hydroxylated (C3-C8)-cycloalkyl; (e) (C1-C6)-alkoxy-group; (f) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom, or (g) cyano-group; (3) (C1-C6)-alkoxy-group optionally substituted with: (a) hydroxy-group; (b) (C1-C6)-alkoxy-group optionally substituted with (C1-C6)-alkoxy-group; (c) halogen atom; (d) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (e) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (4) (C1-C6)-alkylthio-group optionally substituted with (C1-C6)-alkoxy-group or hydroxy-group; (5) 5-6-membered heterocyclyloxy-group comprising 1-2 oxygen atoms in heterocycle; (6) amino-group represented by the formula: -N(R3)R4 wherein R3 and R4 are similar or different and each represents hydrogen atom or group taken among: (a) (C1-C6)-alkyl group; (b) (C1-C6)-alkoxy-(C1-C6)-alkyl group; (c) carbonyl substituted with (C6-C14)-aryl; (d) (C6-C14)-arylsulfonyl or (e) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom; (7) (C3-C8)-cycloalkyl or cycloalkenyl hydrocarbon group optionally substituted with: (a) oxo-group or (b) hydroxy-group; (8) (C6-C14)-aromatic hydrocarbon ring optionally substituted with: (a) (C1-C4)-alkylene dioxy-group or (b) hydroxy-group; (9) 5-6-membered aromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with: (a) cyano-group or (b) (C1-C6)-alkoxy-group; (10) 4-6-membered nonaromatic heterocycle comprising 1-3 heteroatoms taken among nitrogen atom, sulfur atom and oxygen atom optionally substituted with one or some groups taken among: (a) hydroxy-group; (b) halogen atom; (c) cyano-group; (d) (C1-C6)-alkoxycarbonyl; (e) (C1-C6)-alkyl; (f) (C1-C6)-alkoxy-group that is optionally substituted with halogen atom or (C1-C6)-alkoxy-group; (g) (C1-C6)-alkanoyl; (h) (C1-C6)-alkoxy-(C1-C6)-alkyl; (i) oxo-group; (j) (C1-C4)-alkylenedioxy-group; (k) (C3-C8)-cycloalkylalkoxy-group or (C3-C8)-cycloalkenylalkoxy-group; (11) carbamoyl of the formula: -CO-N(R5)R6 wherein R5 and R6 can be similar or different and represent hydrogen atom, (C6-C14)-aryl wherein indicated aryl is optionally substituted with halogen atom, or (C3-C8)-cycloalkyl; or R5 and R6 form in common 3-6-membered ring; (12) carbonyl optionally substituted with (C1-C6)-alkoxy-group; X represents: (1) a simple bond; (2) (C1-C6)-alkylene chain; (3) (C1-C6)-alkenylene chain; (4) (C1-C6)-alkynylene chain; or (5) formula: -Q- wherein Q represents oxygen atom or sulfur atom; Ar represents: (1) (C6-C14)-aromatic hydrocarbon ring optionally substituted with one or some groups taken among: (a) halogen atom; (b) (C1-C4)-alkoxy-group or (c) (C1-C6)-alkylthio-group; or (2) 5-6-membered aromatic heterocycle comprising 1-2 heteroatoms taken among nitrogen atom and sulfur atom. Compounds of the formula (I) show inhibitory activity with respect to a squalene-synthesizing enzyme. Also, the invention relates to an inhibitor of squalene-synthesizing enzyme and the corresponding medicinal composition based on compound of the invention, a method for prophylaxis and treatment of disease wherein inhibition of squalene-synthesizing enzyme is effective. Also, invention proposes some methods for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable of medicinal and biochemical properties of com[pounds and composition.

25 cl, 10 tbl, 214 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of quinuclidine of the general formula (I):

wherein © represents phenyl ring, (C4-C9)-heteroaromatic group comprising one or some heteroatoms, naphthalenyl, 5,6,7,8-tetrahydronaphthalenyl or biphenyl group; R1, R2 and R3 represent hydrogen halogen atom, phenyl and others; n represents a whole number from 0 to 4; A represents group -CH=CR6-, -CR6=CH-, -CR6R7 and others; R6 and R7 represent hydrogen atom, alkyl and others; m represents a whole number from 0 to 8; p represents a whole number from 1 to 2; and a substitute in azoniabicyclic ring can be at position 2, 3 or 4 including all possible configurations of asymmetric carbon atoms; B represents the group of the formula i) or ii) wherein R10 represents hydrogen atom, hydroxyl group or methyl; each R8 and R9 represents: wherein R11 represents hydrogen, halogen atom, alkyl; Q represents a single bond, -CH2- and others; X represents pharmaceutically acceptable anion of mono- or polyvalent acid. Compounds of the formula (I) possess antagonistic activity with respect to muscarinic M3-receptors and can be used in medicine for treatment of diseases wherein muscarinic M3-receptors are implicated.

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

36 cl, 164 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of phtalazine with general formula (I) , in which R represents a methyl or difluromethyl group; R1 represents phenyl or oxazolyl or thiophenyl, chemically bonded to a phtalazine ring through a carbon-carbon bond. Both phenyl and the above mentioned heterocycle are substituted with a carboxylic group, and optionally with a second functional group, chosen from methoxy-, nitro-, N-acetylamino-, N-metanesulphonylamino- group. The invention also relates to pharmaceutical salts of such derivatives. The given compounds with general formula (I) are inhibitors of phosphodiesterase.

EFFECT: objective of the invention is also the method of obtaining compounds with general formula (I) and pharmaceutical compositions for treating allergies and antiphlogistic diseases based on the given compounds.

9 cl, 9 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to a new method of obtaining derivatives of N-phenyl-2-pyrimidineamine (2-anilinopyrimidine) with general formula (I), which have a wide spectrum of biological effects and can be used mainly, for treating various types of tumours, leucaemia, cerebral ischemia, vascular stenosis and other diseases. In general formula (I) , R1 represents a pyridyl or its oxide bonded to a carbon atom, which can be substituted with a low alkyl or alkoxy, each of R2 and R3 independently represents hydrogen, branched of unbranched low alkyl, phenyl, unsubstituted of substituted with a haloid, R4 represents hydrogen, unbranched or branched low alkyl, R5 represents hydrogen, low alkyl, possibly substituted with halogen atoms. Other representations of radical are given in the formula of invention. The method involves the following stages: A) reaction of urea, mainly in a basic medium with N,N-dialkyamino-1-(3-pyridyl)-2-propene-1-ono with general formula II: with obtaining of the corresponding dihydropyrimidinone with general formula (III) B) oxidation of compound (III) by proton oxidation, with obtaining of the corresponding hydroxypyrimidine with formula IV , C) activation of the hydroxy group in the obtained compound IV , for example, treatment using sulphohalide R'SC2Hal or anhydride R'(SO2)2O, with obtaining of a compound with general formula V , where R' represents aryl of low alkyl, D) reaction of the obtained compound V with the corresponding aromatic amino compound with formula VI , with obtaining of compound with formula (I) and subsequent possible conversion of the obtained compounds to other compounds with general formula (I).

EFFECT: method allows for excluding use of toxic compounds and simplifies the process.

13 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) or their pharmaceutically acceptable salts, where R1 and R2 are H or Me; R3 is H, hydroxy or (1-4C)alkoxi; R4 is H, OH, (1-4C)alkoxi; R5 is OH, (1-4C)alkoxi or R7; provided the R4 is H, then R5 differs from OH or (1-4C)alkoxi; R6 is (2-5C)heteroaryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, bromine or chlorine; (6C)aryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, (1-4)C-alkoxi, bromine, chlorine, phenyl or (1-4C) (di)alkylamino; (3-8C)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C)-alkyl; R7 is amino, (di)(1-4C)alkylamino, (6C)arylcarbonylamino, (2-5C)heteroarylcarbonylamino, (2-5C)heteroaryl-carbonylokxi, R8-(2-4C)alkoxi, R9-methylamino or R9-methoxi; R8 is amino, (1-4C)alkoxi, (di)(1-4C)-alkylamino, (2-6C)-heterocycloalkyl, (2-6C)heterocycloalkylcarbonylamino or (1-4C)-alkoxicarbonylamino; and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl. The invention also relates to the pharmaceutical composition which contains the said derivatives, and to the application of the derivatives in fertility modulating.

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

15 cl, 51 dwg

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of quinoline with general formula Ia or Ib their stereoisomers and pharmaceutical salts, where X represents oxygen or sulphur, Z-CH2, Y-NO2, -C(O)OR5, -NR5SO2R5, -SO2R5 (for Ia) and -NO2 or -C(O)OR5 (for Ib). Description is also given of the method of obtaining Ia and Ib compounds, pharmaceutical compositions based on them, and their use when making medicinal preparations.

EFFECT: compounds can be used for treating lesions, related to inhibition of migration of magrophage, for example, during treatment of septic shock or arthritis.

175 cl, 16 tbl, 22 ex, 16 dwg

FIELD: chemistry.

SUBSTANCE: invention pertains to new 2,4-substituted indole with formula: I, its pharmaceutically accepted salt, where R1 represents phenyl, optionally substituted with one or two substitutes, chosen from a group, consisting of a halogen, C1-12alkyl, halogen C1-12alkyl, or represents thienyl; R2 represents residue of a saturated ring, consisting of six ring atoms, one or two of which are nitrogen atoms, and the others are carbon atoms, optionally substituted with one or two C1-12alkyls; R represents H, C1-12alkyl; R4 represents H; p represents 1 or 2; n represents 0,1 or 2. The compounds have antagonistic activity to the "5-ГТ6" receptor, which allows to use in pharmaceutical mixtures.

EFFECT: use in pharmaceutical mixtures.

10 cl, 7 dwg, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidinium of the general formula (I): possessing antagonistic effect with respect to muscarinic receptors M3 wherein B means phenyl or thienyl group; each radical among R1, R2 and R means independently hydrogen, fluorine, chlorine atom or hydroxyl; n means a whole number from 0 to 1; A means group chosen from groups -CH2 and -O-; m means a whole number from 0 to 6; R means (C1-C8)-alkyl; X- represents a pharmaceutically acceptable anion of mono- or multibasic acid, and involving all separate stereoisomers and their mixtures. Also, invention relates to methods for synthesis of such compounds, pharmaceutical compositions containing such compounds and to their using in therapy as antagonists of muscarinic receptors M3.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

17 cl, 51 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I): wherein R1 means quinolinyl possibly substituted with (C1-C5)-alkoxy-group, isoquinolinyl, quinoxalinyl, pyridinyl, pyrazinyl, benzyl possibly substituted with halogen atom, naphthalinyl, thiophenyl, furanyl, cinnolyl, phenylvinyl, quinolylvinyl or 4-oxo-4H-chromenyl possibly substituted with halogen atom, (C1-C5)-alkyl or (C1-C5)-alkoxy-group; R2, R5, R8 and R11 mean hydrogen atom; R3 and R4 mean halogen atom, (C1-C5)-alkoxy-group; R6 and R7 mean hydrogen atom (H) or (C1-C5)-alkyl or form in common radical -CH2-CH2-; R9 and R10 mean (C1-C5)-alkoxy-group; m and n mean a whole number from 0 to 4 independently; X means -CH2- or sulfur atom (S). Also, invention describes their pharmaceutically acceptable salts, a method for their preparing and pharmaceutical composition based on thereof. Proposed compounds are inhibitors of P-glycoprotein, enhance bioavailability of anti-cancer drug and can be used in medicine.

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

7 cl, 3 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (IA): or the formula (IB): wherein B means hydrogen atom or lower alkyl; A means an unsubstituted or substituted cyclic group chosen from compounds of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) and (k) wherein R1-R4 mean independently of one another hydrogen atom, halogen atom, -CF3, -CHF2, -C(CH3)F2, (C3-C6)-cycloalkyl, lower alkoxy-group, lower alkyl, -OCF3 or phenyl; R5-R10 means independently of one another hydrogen atom, halogen atom, lower alkoxy-group, lower alkyl or -CHF2; R11-R16 mean independently of one another hydrogen atom, halogen atom, alkoxy-group or lower alkyl; R17 means halogen atom or -CHF2; R18-R20 mean independently of one another hydrogen atom, lower alkoxy-group or lower alkyl, and to their pharmaceutically acceptable acid-additive salts. Also, invention relates to a medicinal agent possessing the selective effect of blockers of NMDA receptors of subtype 2B. Invention provides synthesis of novel biologically active compounds and medicinal agents based on thereof.

EFFECT: valuable medicinal properties of compounds and drugs.

6 cl, 180 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

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