Derivatives of nitrogen-containing heterocyclic compounds, methods for their preparing, pharmaceutical composition based on thereof and methods for treatment of inflammatory diseases and respiratory ways diseases


FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nitrogen-containing heterocyclic compounds of the general formula (I'):

wherein R represents the group:

m = 0-3; R1 represents halogen atom, cyano-group and others; X represents oxygen or sulfur atom, or the group -CH2 and others; Z1 and Z2 represents the group -CH2 and others; Q represents oxygen or sulfur atom, or the group -CH2 or -NH; R2 represents substituted phenyl; n = 0-2; R3 represents (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl group and others; R4, R5, R6 and R7 represent hydrogen atom or (C1-C6)-alkyl and others; R8 represents hydrogen atom, (C1-C6)-alkyl. Compounds of the formula (I') possess of activity modulating activity of chemokine MIP-1α receptors and can be used in medicine in treatment of inflammatory diseases and respiratory ways diseases.

EFFECT: improved preparing method, improved methods for treatment, valuable medicinal properties of compounds and composition.

20 cl, 283 ex

 

The present invention relates to new compounds, methods for their preparation, containing their pharmaceutical compositions and their use in therapy.

In the US 5789402 describes some indole derivatives, which, allegedly, are useful for treating diseases that are caused by or resulting from violations of serotonin-dependent nervous systems, in particular systems associated with serotonin receptor 1Aand systems associated with capture of a serotonin.

Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules represent a growing superfamily of proteins by mass of 8-14 kDa, characterized conservative chetyrehzvennoy motive. The superfamily of chemokines can be divided into two main groups, demonstrating the characteristic structural motifs: a family of Cys-X-Cys (C-X-C) and Cys-Cys (C-C). They differ by the insertion of one amino acid between the NH-terminal pair of cysteine residues and the similarity of the sequence.

Chemokines of the C-X-C include several strong chemoattractants and activators of neutrophils, such as interleukin-8 (IL-8) and neutrophil-activating peptide-2 (NA-2).

Chemokines C-C include strong chemoattractant monocytes and lymphocytes, but not neutrophils, such as chemotactic proteins human monocytes 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated upon activation, expressed and secreted normal T-lymphocytes), eotaxin and inflammatory proteins macrophages 1α and 1β (MIP-1α and MIP-1β).

Studies have demonstrated that the actions of chemokines is mediated by subfamilies of receptors associated with G-protein, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors are good targets for drug development, because the agents that modulate these receptors, can be useful in the treatment of disorders and diseases, such as disorders and diseases mentioned earlier.

In accordance with the present invention, thus, the proposed compound of General formula

where R represents a or group

or group

m is 0, 1, 2 or 3;

each R1independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-C6cycloalkyl,1-C6alkoxy, C1-C6alkoxycarbonyl, C1-C6halogenous is l, C1-C6halogenoalkane, -NR9R10With3-C6cyclooctylamino, C1-C6alkylthio,1-C6alkylsulphonyl,1-C6alkylcarboxylic, sulfonamide (SO2NH2)1-C6alkylsulfonyl, -C(O)NR11R12, -NR13C(O)-(NH)pR14, phenyl or C1-C6alkyl, possibly substituted by carboxyla or C1-C6alkoxycarbonyl;

p is 0 or 1;

X represents an oxygen atom or sulfur, or CH2CH(CH3), Co2CH2O, CH2NH, NH or carbonyl group, and Y represents a nitrogen atom or a group CH or C(OH), provided that when X represents an oxygen atom or sulfur or a group CH2O, CH2NH or NH, then Y is a group CH;

Z1represents a bond or a group (CH2)qwhere q is 1 or 2;

Z2represents a bond or a group CH2provided that Z1and Z2both simultaneously represent a bond;

Q represents oxygen atom or sulfur or a group CH2or NH;

R2represents a group

,,,

,or ;

n is 0, 1 or 2;

each R3independently represents a C1-C6alkyl, C1-C6alkoxycarbonyl, -CH2OH or a carboxyl group;

R4, R5, R6and R7each independently represents a hydrogen atom or a C1-C6alkyl group, or R4, R5, R6and R7together represent a C1-C4alkylenes chain linking the two carbon atoms to which they are attached, with the formation of a 4-7-membered saturated carbocycle,

or R5, R6and R7each represents a hydrogen atom, and R4and R8together with the carbon atoms to which they are attached, form a 5-6-membered saturated carbocycle;

R8represents a hydrogen atom, a C1-C6alkyl group or is linked to R4as defined above;

R9and R10each independently represents a hydrogen atom or a C1-C6alkyl group, or R9and R10together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle;

R11and R12each independently represents a hydrogen atom or a C1-C6alkyl group, possibly substituted C1-C6alkoxycarbonyl;

R13represents a hydrogen atom is Li 1-C6alkyl group;

R14represents a hydrogen atom or a C1-C6alkyl group, possibly substituted by carboxyla,1-C6alkoxy or1-C6alkoxycarbonyl;

R15is carboxyl,1-C6alkylsulphonyl,1-C6alkoxycarbonyl,1-C6alkoxycarbonyl1-C6alkyl or the group-NR17R18, -NHSO2CH3, -NHC(O)CH3, -C(O)NR17R18, -NHC(O)NR17R18, -OC(O)NR17R18, -OCH2C(O)NR17R18, -NHC(O)OR17or17,;

t is 0, 1, 2 or 3;

each R16independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-C6cycloalkyl,3-C6alkoxy, C1-C6alkoxycarbonyl,1-C6halogenoalkane, C1-C6halogenoalkane, -NR19R20With3-C6cyclooctylamino,1-C6alkylthio,1-C6alkylsulphonyl,1-C6alkylcarboxylic, sulfonamide (SO2NH2)1-C6alkylsulfonyl, -C(O)NR21R22, -NR23C(O)(NH)vR24, phenyl or1-C6alkyl, possibly substituted by carboxyla or1-C6alkoxycarbonyl;

R17and R18each independently represents(1) hydrogen atom, (2) a 5-6-membered saturated or unsaturated ring, which may include at least one heteroatom selected from nitrogen, oxygen and sulfur, and the ring possibly substituted by at least one Deputy, selected from halogen, methyl and trifloromethyl, or (3) C1-C6alkyl group, possibly substituted by at least one Deputy, selected from halogen, trifloromethyl, carboxyl,1-C6alkoxycarbonyl and 5-6-membered saturated or unsaturated ring which may contain at least one heteroatom selected from nitrogen, oxygen and sulfur, and the ring possibly substituted by at least one Deputy, selected from halogen, methyl and trifloromethyl, or

R17and R18together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle;

R17'represents a hydrogen atom or a C1-C6alkyl group, possibly substituted by carboxyla or1-C6alkoxycarbonyl;

R17"defined as R17above, except that R17"does not represent a hydrogen atom;

R19and R20each independently represents a hydrogen atom or a C1-C6alkyl group, or R19and R20together with the nitrogen atom to which they are connected is ineni, form a 4-7-membered saturated a heterocycle;

R21and R22each independently represents a hydrogen atom or a C1-C6alkyl group, possibly substituted C1-C6alkoxycarbonyl;

v is 0 or 1;

R23represents a hydrogen atom or a C1-C6alkyl group; and

R24represents a hydrogen atom or a C1-C6alkyl group, possibly substituted by carboxyla,1-C6alkoxy or1-C6alkoxycarbonyl;

provided that when X represents an oxygen atom or a group CH2, Y is CH, Z1and Z2each represents a group CH2and Q represents an oxygen atom, then R2different from unsubstituted indolines group;

or its pharmaceutically acceptable salt or MES.

In the context of the present description, the alkyl substitution group or an alkyl group in the replacement group may be linear or branched.

In one aspect of the present invention proposed a compound of General formula

where R

represents a group

m is 0, 1, 2 or 3;

each R1independently represents halogen, cyano, nitro, carboxyl, hydroxyl, -C6cycloalkyl,1-C6alkoxy, C1-C6alkoxycarbonyl,1-C6halogenoalkane,1-C6halogenoalkane, -NR9R10With3-C6cyclooctylamino,1-C6alkylthio,1-C6alkylsulphonyl, C1-C6alkylcarboxylic, sulfonamide,1With6alkylsulfonyl, -C(O)NR11R12, -NR13C(O)-(NH)pR14, phenyl or1-C6alkyl, possibly substituted by carboxyla or C1-C6alkoxycarbonyl;

p is 0 or 1;

X represents an oxygen atom or sulfur, or CH2CH(CH3), OCH2CH2O, CH2NH, NH or carbonyl group, and Y represents a nitrogen atom or a group CH or C(OH), provided that when X represents an oxygen atom or sulfur or a group CH2O, CH2NH or NH, then Y is a group CH;

Z1represents a bond or a group (CH2)qwhere q represents 1 or 2;

Z2represents a bond or a group CH2provided that Z1and Z2both simultaneously represent a bond;

Q represents oxygen atom or sulfur or a group CH2or NH;

R2represents a group

n is 0, 1 or 2;

each R3the independent is IMO is a 1-C6alkyl, C1-C6alkoxycarbonyl, -CH2HE or carboxyl group;

R4, R5, R6and R7each independently represents a hydrogen atom or a C1-C6alkyl group, or R4, R5, R6and R7together represent a1-C4alkylenes chain linking the two carbon atoms to which they are attached, with the formation of a 4-7-membered saturated carbocycle,

or R5, R6and R7each represents a hydrogen atom, and R4and R8together with the carbon atoms to which they are attached, form a 5-6-membered saturated carbocycle;

R8represents a hydrogen atom, a C1-C6alkyl group or is linked to R4as defined above;

R9and R10each independently represents a hydrogen atom or a C1-C6alkyl group, or R9and R10together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle;

R11and R12each independently represents a hydrogen atom or a C1-C6alkyl group, possibly substituted C1-C6alkoxycarbonyl;

R13represents a hydrogen atom or a C1-C6alkyl group;

R14represents the atom in Dorada or 1-C6alkyl group, possibly substituted by carboxyla,1-C6alkoxy or1-C6alkoxycarbonyl;

R15is carboxyl,1-C6alkylsulphonyl,1-C6alkoxycarbonyl,1-C6alkoxycarbonyl1-C6alkyl or the group-NR17R18, -NHSO2CH3, -NHC(O)CH3, -C(O)NR17R18, -NHC(O)NR17R18, -OC(O)NR17R18, -OCH2C(O)NR17R18, -NHC(O)OR17'or17";

t is 0, 1, 2 or 3;

each R16independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-C6cycloalkyl,1-C6alkoxy, C1-C6alkoxycarbonyl,1-C6halogenoalkane,1-C6halogenoalkane, -NR19R20With3-C6cyclooctylamino,1-C6alkylthio,1-C6alkylsulphonyl,1-C6alkylcarboxylic, sulfonamide (SO2NH2)1-C6alkylsulfonyl, -C(O)NR21R22, -NR23C(O)(NH)vR24, phenyl or1-C6alkyl, possibly substituted by carboxyla or1-C6alkoxycarbonyl;

R17and R18each independently represents (1) hydrogen atom, (2) a 5-6-membered saturated or unsaturated ring, which may with erati at least one heteroatom, selected from nitrogen, oxygen and sulfur, and the ring possibly substituted by at least one Deputy, selected from halogen, methyl and trifloromethyl, or (3) (C1-C6alkyl group, possibly substituted by at least one Deputy, selected from halogen, trifloromethyl, carboxyl,1-C6alkoxycarbonyl and 5-6-membered saturated or unsaturated ring which may contain at least one heteroatom selected from nitrogen, oxygen and sulfur, and the ring possibly substituted by at least one Deputy, selected from halogen, methyl and trifloromethyl, or

R17and R18together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle;

R17'represents a hydrogen atom or a C1-C6alkyl group, possibly substituted by carboxyla or1-C6alkoxycarbonyl;

R17"defined as R17above, except that R17"does not represent a hydrogen atom;

R19and R20each independently represents a hydrogen atom or a C1-C6alkyl group, or R19and R20together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle;

R21and R22each independently represents Alamogordo or C 1-With6alkyl group, possibly substituted C1-C6alkoxycarbonyl;

v is 0 or 1;

R23represents a hydrogen atom or a C1-C6alkyl group; and

R24represents a hydrogen atom or a C1-C6alkyl group, possibly substituted by carboxyla,1-C6alkoxy or1-C6alkoxy carbonyl;

or its pharmaceutically acceptable salt or MES.

In another aspect of the present invention proposed a compound of General formula

where R represents a group

m is 0, 1, 2 or 3;

each R1independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-C6cycloalkyl,1-C6alkoxy, C1-C6alkoxycarbonyl,1-C6halogenoalkane,1-C6halogenoalkane, -NR9R10With3-C6cyclooctylamino,1-C6-alkylthio, C1-C6alkylsulphonyl, C1-C6alkylcarboxylic, sulfonamide, C1-C6alkylsulfonyl, -C(O)NR11R12, -NR13C(O)-(NH)pR14, phenyl or1-C6alkyl, possibly substituted by carboxyla or1-C6alkoxycarbonyl;

p is 0 or 1;

X made the focus of an atom of oxygen or sulfur or CH 2CH(CH3), OCH2CH2O, CH2NH, NH or carbonyl group, and Y represents a nitrogen atom or a group CH or C(OH), provided that when X represents an oxygen atom or sulfur or a group CH2O, CH2NH or NH, then Y is a group CH;

Z1represents a bond or a group (CH2)qwhere q is 1 or 2;

Z2represents a bond or a group CH2provided that Z1and Z2both simultaneously represent a bond;

Q represents oxygen atom or sulfur or a group CH2or NH;

R2represents a group

,,

,or;

n is 0, 1 or 2;

each R3independently represents a C1-C6alkyl, C1-C6alkoxycarbonyl, -CH2OH or a carboxyl group;

R4, R5, R6and R7each independently represents a hydrogen atom or a C1-C6alkyl group, or R4, R5, R6and R7together represent a1-C4alkylenes chain linking the two carbon atoms to which they are attached, with the formation of a 4-7-membered saturated Carbo is the ikl,

or R5, R6and R7each represents a hydrogen atom, and R4and R8together with the carbon atoms to which they are attached, form a 5-6-membered saturated carbocycle;

R8represents a hydrogen atom, a C1-C6alkyl group or is linked to R4as defined above;

R9and R10each independently represents a hydrogen atom or a C1-C6alkyl group, or R9and R10together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle;

R11and R12each independently represents a hydrogen atom or a C1-C6alkyl group, possibly substituted C1-C6alkoxycarbonyl;

R13represents a hydrogen atom or a C1-C6alkyl group; and

R14represents a hydrogen atom or a C1-C6alkyl group, possibly substituted by carboxyla,1-C6alkoxy or1-C6alkoxycarbonyl;

provided that when X represents an oxygen atom or a group CH, Y is CH, Z1and Z2each represents a group CH2and Q represents an oxygen atom, then R2does not represent unsubstituted indolenine group;

or its pharmaceutically who ramlila salt or MES.

In another aspect of the present invention proposed a compound of General formula

where

R represents a group

m is 0, 1, 2 or 3;

each R1independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-C6cycloalkyl,1-C6alkoxy, C1-C6alkoxycarbonyl,1-C6halogenoalkane,1-C6halogenoalkane, -NR9R10With3-C6cyclooctylamino,1-C6alkylthio,1-C6alkylsulphonyl,1-C6alkylcarboxylic, sulfonamide,1-C6alkylsulfonyl, -C(O)NR11R12, -NR13C(O)-(NH)pR14, phenyl or C1-C6alkyl, possibly substituted by carboxyla or C1-C6alkoxycarbonyl;

p is 0 or 1;

Q represents oxygen atom or sulfur or a group CH2or NH;

R2represents a group

,,,

,or;

R4, R5, R6and R7each independently represents a hydrogen atom or a C1-C6alkyl group, or R , R5, R6and R7together represent a C1-C6alkylenes chain linking the two carbon atoms to which they are attached, with the formation of a 4-7-membered saturated carbocycle,

or R5, R6and R7each represents a hydrogen atom, and R4and R8together with the carbon atoms to which they are attached, form a 5-6-membered saturated carbocycle;

R8represents a hydrogen atom, a C1-C6alkyl group or is linked to R4as defined above;

R9and R10each independently represents a hydrogen atom or a C1-C6alkyl group, or R9and R10together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle;

R11and R12each independently represents a hydrogen atom or a C1-C6alkyl group, possibly substituted C1-C6alkoxycarbonyl;

R13represents a hydrogen atom or a C1-C6alkyl group;

R14represents a hydrogen atom or a C1-C6alkyl group, possibly substituted by carboxyla, C1-C6alkoxy or C1-C6alkoxycarbonyl;

R15is carboxyl, C1-C6alkylsulphonyl, C1-C6alkoxide is of IMT, With1-C6alkoxycarbonyl1-C6alkyl or the group-NR17R18, -NHSO2CH3, NHC(O)CH3, -C(O)NR17R18, -NHC(O)NR17R18, -OC(O)NR17R18, -OCH2C(O)NR17R18, -NHC(O)OR17'or17";

t is 0, 1, 2 or 3;

each R16independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C1-C6cycloalkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, C1-C6halogenoalkane, C1-C6halogenoalkane, -NR19R20C3-C6Cipollino, C1-C6alkylthio, C1-C6alkylsulphonyl, C1-C6alkylcarboxylic, sulfonamide (SO2NH2), C1-C6alkylsulfonyl, -C(O)NR21R22, -NR23C(O)(NH)vR24, phenyl or C1-C6alkyl, possibly substituted by carboxyla or C1-C6alkoxycarbonyl;

R17and R18each independently represents (1) hydrogen atom, (2) a 5-6-membered saturated or unsaturated ring which may contain at least one heteroatom selected from nitrogen, oxygen or sulfur, and the ring possibly substituted by at least one Deputy, selected from halogen, methyl and trifloromethyl, or (3) C1-C6alkyl group, possibly substituted by the second at least one Deputy, selected from halogen, trifloromethyl, carboxyl, C1-C6alkoxycarbonyl and 5-6-membered saturated or unsaturated ring which may contain at least one heteroatom selected from nitrogen, oxygen and sulfur, and the ring possibly substituted by at least one Deputy, selected from halogen, methyl and trifloromethyl, or

R17and R18together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle;

R17'represents a hydrogen atom or a C1-C6alkyl group, possibly substituted by carboxyla or C1-C6alkoxycarbonyl;

R17"defined as R17above, except that R17"does not represent a hydrogen atom;

R19and R20each independently represents a hydrogen atom or a C1-C6alkyl group, or R19and R20together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle;

R21and R22each independently represents a hydrogen atom or a C1-C6alkyl group, possibly substituted C1-C6alkoxycarbonyl;

v is 0 or 1;

R23represents a hydrogen atom or a C1-C6alkyl group; and

R24represents the atom in Dorada or C 1-C6alkyl group, possibly substituted by carboxyla, C1-C6alkoxy or C1-C6alkoxycarbonyl;

or its pharmaceutically acceptable salt or MES.

The integer m is preferably 0, 1 or 2.

Each R1independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C1-C6preferably C1-C4alkoxy (for example methoxy, ethoxy, n-propoxy or n-butoxy), C1-C6preferably C1-C4alkoxycarbonyl (such as methoxycarbonyl or etoxycarbonyl), C1-C6preferably C1-C6halogenoalkane (for example trifluoromethyl), C1-C6preferably C1-C6halogenoalkane (for example, triptoreline), -NR9R10C3-C6cyclooctylamino (for example, cyclopropylamino, cyclobutylamine, cyclopentylamine or cyclohexylamino), C1-C6preferably C1-C4alkylthio (for example methylthio or ethylthio), C1-C6preferably C1-C6alkylaryl (such as methylcarbamoyl, ethylcarbazole, n-propylboronic, isopropylcarbonate, n-butylcarbamoyl, n-internabonal or n-hexylcaine), C -C6preferably C1-C4alkylcarboxylic (for example, methylcobalamin or ethylcarbodiimide), sulfonamide, C1-C6preferably C1-C4alkylsulfonyl (for example methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, n-peterculter or n-hexylsilane), -C(O)NR11R12, -NR13C(O)-(NH)pR14, phenyl or C1-C6preferably C1-C6alkyl (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), possibly substituted by carboxyla or C1-C6preferably C1-C4alkoxycarbonyl (such as methoxycarbonyl or etoxycarbonyl).

Most preferably, each R1independently represents halogen (in particular chlorine or fluorine), cyano, nitro, C1-C6alkoxy (especially methoxy), C1-C6alkylsulphonyl (especially methylcarbamyl) or C1-C6alkylcarboxylic (especially methylcobalamine).

Preferably X represents an oxygen atom or CH2The co2CH2Oh, NH or carbonyl group.

Preferably Y is a nitrogen atom or a group CH.

Preferred combinations of X-Y include O-CH, och2CH, NH-CH, CH2/sub> O-CH, CH2-N, C(O)-N and CH2-CH.

The preferred combination of Y, Z1and Z2include:

YZ1Z2
SNCH2link
CHlinkCH2
SNCH2CH2
CH(CH2)2link
NCH2CH2

Q preferably represents an oxygen atom.

Each R3independently represents a C1-C6preferably C1-C6alkyl (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C1-C6preferably C1-C4alkoxycarbonyl (such as methoxycarbonyl or etoxycarbonyl), -CH2HE or carboxyl group. Preferably, R3represented a methyl, methoxycarbonyl, etoxycarbonyl, -CH2OH or a carboxyl group.

R4, R5, R6and R7each independently represents a hydrogen atom or a C1-C6preferably C1-C4alkyl (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R4, R5, R6and R7together represent a C1-C4alkylenes chain linking the two carbon atoms to which they are attached, with the formation of a 4-7-membered saturated carbocycle (such as cyclohexyl or preferably of cyclopentyl), or R5, R6and R7each represents a hydrogen atom, and R4and R8together with the carbon atoms to which they are attached, form a 5-6-membered saturated carbocycle (preferably cyclopentyl).

R8represents a hydrogen atom, a C1-C6preferably C1-C4alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or associated with R4as specified above.

R9and R10each independently represents a hydrogen atom or a C1-C6preferably C1-C4alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R9and R10together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle (preferably pyrrolidinyl or piperidinyl).

R11and R12each independently represents a hydrogen atom or a C1-C6prepost is positive With 1-C4alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), possibly substituted C1-C6preferably C1-C4alkoxycarbonyl replacement group.

R13represents a hydrogen atom, a C1-C6preferably C1-C6alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).

R14represents a hydrogen atom or a C1-C6preferably C1-C6alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), possibly substituted by carboxyla, C1-C6preferably C1-C4alkoxy or C1-C6preferably C1-C4alkoxycarbonyl.

R15is carboxyl, C1-C6preferably C1-C6alkylaryl (such as methylcarbamoyl, ethylcarbazole, n-propylboronic, isopropylcarbonate, n-butylcarbamoyl, n-internabonal or n hexylcaine), C1-C6preferably C1-C4alkoxycarbonyl (such as methoxycarbonyl or etoxycarbonyl)1-C6alkoxycarbonyl1-C6alkyl, preferably C1-C6alkoxycarbonyl the l C 1-C6alkyl (e.g. methoxycarbonylmethyl or methoxycarbonylethyl), or the group-NR17R18, -NHSO2CH3, -NHC(O)CH3, -C(O)NR17R18, -NHC(O)NR17R18, -OC(O)NR17R18, -OCH2C(O)NR17R18, -NHC(O)OR17'or17".

Preferably, R15represented With1-C4alkoxy (especially methoxy), C1-C4alkylsulphonyl (especially methylcarbamyl or ethylcarboxyl), C1-C6alkoxycarbonyl1-C4alkyl (in particular methoxycarbonylmethyl or methoxycarbonylethyl), -NHC(O)CH3, -C(O)NR17R18, -NHSO2CH3or-NHC(O)NR17R18.

Each R16independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C1-C6preferably C1-C4alkoxy (for example methoxy, ethoxy, n-propoxy or n-butoxy), C1-C6preferably C1-C6alkoxycarbonyl (such as methoxycarbonyl or etoxycarbonyl), C1-C6preferably C1-C6halogenoalkane (for example trifloromethyl), C1-C6preferably C1-C6halogenoalkane (for example, triptoreline), -NR19R2 C3-C6Cipollino (for example, cyclopropylamino, cyclobutylamine, cyclopentylamine or cyclohexylamino), C1-C6preferably C1-C6alkylthio (for example methylthio or ethylthio), C1-C6preferably C1-C6alkylaryl (such as methylcarbamoyl, ethylcarbazole, n-propylboronic, isopropylcarbonate, n-butylcarbamoyl, n-internabonal or n-hexylcaine), C1-C6preferably C1-C4alkylcarboxylic (for example, methylcobalamin or ethylcarbodiimide), sulfonamide, C1-C6preferably C1-C4alkylsulfonyl (for example methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, n-peterculter or n-hexylsilane), -C(O)NR21R22, -NR23C(O)-(NH)vR24, phenyl or C1-C6preferably C1-C4alkyl (for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), possibly substituted by carboxyla or C1-C6preferably C1-C6alkoxycarbonyl (such as methoxycarbonyl or etoxycarbonyl).

Preferably, each R16independently represents halogen (in particular chlorine or fluorine), hydroxyl, cyano, C1-C4alkoxy (especially the ti methoxy), C1-C4alkoxycarbonyl (especially methoxycarbonyl), C1-C6halogenoalkane (especially trifluoromethyl), C1-4alkylsulphonyl (especially methylcarbamyl), phenyl or Sglcy (for example methyl or tert-butyl).

R17and R18each independently represents (1) hydrogen atom, (2) a 5-6-membered saturated or unsaturated ring which may contain at least one heteroatom (e.g. one, two or three heteroatoms independently)selected from nitrogen, oxygen or sulfur (such as cyclopentyl, cyclohexyl, pirolli, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl or furanyl), and ring possibly substituted by at least one substituent (e.g. one, two or three substituents independently)selected from halogen (e.g. fluorine, chlorine, bromine or iodine), methyl and trifloromethyl, or (3) C1-C6preferably C1-C6alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), possibly substituted by at least one substituent (e.g. one, two or three substituents independently)selected from halogen (e.g. fluorine, chlorine, bromine or iodine), trifloromethyl, carboxyl, C1-C6preferably C1-C6alkoxycarbonyl, the person who values methoxycarbonyl, and 5-6-membered saturated or unsaturated ring which may contain at least one heteroatom (e.g. one, two or three heteroatoms independently)selected from nitrogen, oxygen and sulfur (such as cyclopentyl, cyclohexyl, pirolli, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl or furanyl), and ring possibly substituted by at least one substituent (e.g. one, two or three substituents independently)selected from halogen (e.g. fluorine, chlorine, bromine or iodine), methyl and trifloromethyl, or

R17and R18together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle (preferably pyrrolidinyl or piperidinyl).

R17'represents a hydrogen atom or a C1-C6preferably C1-C4alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), possibly substituted by carboxyla or, more preferably, C1-C6preferably C1-C4alkoxycarbonyl, especially methoxycarbonyl,

R19and R20each independently represents a hydrogen atom or a C1-C6preferably C1-C4alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-BU the sludge, n-pentyl or n-hexyl), or R19and R20together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle (preferably pyrrolidinyl or piperidinyl).

R21and R22each independently represents a hydrogen atom or a C1-C6preferably C1-C4alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), possibly substituted C1-C6preferably C1-C4alkoxycarbonyl replacement group.

R23represents a hydrogen atom or a C1-C6preferably C1-C6alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).

R24represents a hydrogen atom or a C1-C6preferably C1-C6alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Tert-butyl, n-pentyl or n-hexyl), possibly substituted by carboxyla, C1-C6preferably C1-C4alkoxy or C1-C6preferably C1-C4alkoxycarbonyl.

Preferred compounds according to this invention include:

The hydrochloride of N-(2-{3-[3R,S-(4-chlorphenoxy)pyrrolidinyl-1-yl]-2R,S-hydroxypropoxy}phenyl)and is etamide,

The hydrochloride of N-(5-chloro-2-{3-[3R,S-(4-chlorphenoxy)pyrrolidin-1-yl]-2R,S-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

The dihydrochloride of 1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanol,

The hydrochloride of N-(2-{3-[3-(3,4-dichlorophenoxy)-1-pyrrolidinyl)-2-hydroxypropoxy}phenyl)acetamide", she

Methyl ester 2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxypropoxy}benzoic acid,

Methyl ester 2-(2-{3-[4-(3,4-divergence)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid,

N-[2-({(1R,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopent}oxy)phenyl]acetamide", she

N-[2-({(1S,2S,R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopent}oxy)phenyl]acetamide", she

N-[2-({(2,3-TRANS)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclohexyl}oxy)phenyl]acetamide", she

N-(5-Chloro-2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(3-Acetyl-2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide,

1-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)propan-2-ol,

1-(7-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroc is propoxy}indol-1-yl)Etalon,

N-(4-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)acetamide", she

N-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide,

N-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Chloro-2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(3-Acetyl-2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide,

1-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)propan-2-ol,

1-(7-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-indol-1-yl)Etalon,

N-(4-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)acetamide", she

N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide,

N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Chloro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(3-Acetyl-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(5-fluoro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

1-[3-(4-Pertenece)pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)propan-2-ol,

1-(7-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}indol-1-yl)Etalon,

N-(4-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)acetamide", she

N-(4-fluoro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Chloro-2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(3-Acetyl-2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide,

1-[3-(3,4-Divergence)pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)propan-2-ol,

1-(7-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}indol-1-yl)Etalon,

N-(4-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)acetamide", she

N-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide,

N-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(3,divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Chloro-2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(3-Acetyl-2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide,

1-(7-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}indol-1-yl)Etalon,

N-(4-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)acetamide", she

N-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide,

N-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Chloro-2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(3-Acetyl-2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide,

1-(7-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}indol-1-yl)Etalon,

N-(4-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)acetamide", she

N-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-4-forfinal)and Itemid,

N-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-{5-Chloro-2-[3-(8-chloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]phenyl}acetamide", she

N-{3-Acetyl-2-[3-(8-chloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-5-were}ndimethylacetamide,

N-{2-[3-(8-Chloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-4-were)ndimethylacetamide,

N-{2-[3-(8-Chloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-5-forfinal)ndimethylacetamide,

1-(8-Chloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-3-(1H-indol-7-yloxy)propan-2-ol,

1-{7-[3-(8-Chloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]indol-1-yl}Etalon,

N-{4-[3-(8-Chloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]biphenyl-3-yl)acetamide", she

N-{2-[3-(8-Chloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-4-forfinal)ndimethylacetamide,

N-{2-[3-(8-Chloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-5-were)ndimethylacetamide,

N-{2-[3-(8-Chloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]phenyl}acetamide", she

N-{5-Chloro-2-[3-(8-fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]phenyl}acetamide", she

N-{3-Acetyl-2-[3-(8-fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-5-were}ndimethylacetamide,

N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-g is doxyprex]-4-were)ndimethylacetamide,

N-{5-fluoro-2-[3-(8-fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]phenyl}acetamide", she

1-(8-Fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-3-(1H-indol-7-yloxy)propan-2-ol,

1-{7-[3-(8-Fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]indol-1-yl}Etalon,

N-{4-[3-(8-Fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]biphenyl-3-yl)acetamide", she

N-{4-fluoro-2-[3-(8-fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]phenyl}acetamide", she

N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-5-were}ndimethylacetamide,

N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]phenyl}acetamide", she

N-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

Methyl ester 3-(2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-3-(2,6-dimethoxyphenoxy)propan-2-ol,

1-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he,

1-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)Etalon,

Methyl ester 3-(2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-(2,6-Dimethoxyphenoxy)-3-[3-4-pertenece)pyrrolidin-1-yl]propane-2-ol,

1-[3-(4-Pertenece)pyrrolidin-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

Methyl ether (2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

Methyl ether (2-{3-[3-(4-chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

Methyl ester 2-(2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid,

2-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)Etalon,

1-(2-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he,

1-(2-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)Etalon,

N-[2-(3-{[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}-2-hydroxypropoxy)-4-were]ndimethylacetamide,

Methyl ester 3-(2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-[3-(3,4-Divergence)pyrrolidin-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

Methyl ether (2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)Etalon,

1-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropan and}phenyl)propane-1-he,

1-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)Etalon,

N-(2-{3-[4-(3,4-Dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

Methyl ester 3-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-3-(2,6-dimethoxyphenoxy)propan-2-ol,

1-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

Methyl ether (2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

Methyl ester 2-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid,

2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)Etalon,

1-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he,

1-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)Etalon,

N-(2-{3-[3-(4-Cianfrocca)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

Methyl ester 3-(2-{3-[3-(4-cianfrocca)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

Methyl ether (2-{3-[3-(4-cianfrocca)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

2-{3-[3-(4-Cianfrocca)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

4-{1-[2-Hydroxy-3-(propionyloxy)propyl]pyrrolidin-3-yloxy}benzonitrile,

N-(2-{2-Hydroxy-3-[3-(4-methoxyphenoxy)pyrrolidin-1-yl]-propoxy}phenyl)acetamide", she

N-(4-Chloro-2-{3-[4-(3,4-dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

Methyl ester 3-(2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

Methyl ether (2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

Methyl ester 2-(2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid,

2-{3-[3-(4-Dichlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)Etalon,

1-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he,

1-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)Etalon,

N-(2-{3-[4-(3,4-Divergence)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

Methyl ester 3-(2-{3-[4-(3,4-divergence)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

2-{3-[4-(3,4-Divergence)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[4-(3,4-Divergence)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he,

Methyl ether (2-{3-[4-(3,4-divergence)piperidine-1-yl]-2-hydroxypropoxy}benzo is ylamino)acetic acid,

N-(2-{3-[3-(3,4-Diferenciate)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(4-Pertenece)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

Methyl ester 3-(2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-(2,6-Dimethoxyphenoxy)-3-[4-(4-pertenece)piperidine-1-yl]-propan-2-ol,

1-[4-(4-Pertenece)piperidine-1-yl]-3-(2-methoxyphenoxy)-propan-2-ol,

1-(2-{3-[4-(4-Pertenece)piperidine-1-yl]-2-hydroxypropoxy}phenyl)Etalon,

2-{3-[4-(4-Pertenece)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[4-(4-Pertenece)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he,

Methyl ether (2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

N-(2-{3-[3-(4-Forfinancial)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

Methyl ester 3-(2-{3-[3-(4-forfinancial)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-[3-(4-Forfinancial)piperidine-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

1-(2-{3-[3-(4-Forfinancial)piperidine-1-yl]-2-hydroxypropoxy}phenyl)Etalon,

Methyl ester 2-(2-{3-[3-(4-forfinancial)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid,

2-{3-[3-(4-Forfinancial)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[3-(4-Forfinancial)piperidine-1-yl]-2-guide is oxopropoxy}-6-methoxyphenyl)Etalon,

N-(2-{3-[4-(4-Acetylaminophenol)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(4-{1-[3-(2-Acetylphenol)-2-hydroxypropyl]-piperidine-4-yloxy}phenyl)acetamide", she

N-(4-cyano-2-{3-[4-(3,4-dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

Methyl ester 3-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-[4-(4-Chlorophenoxy)piperidine-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

1-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)Etalon,

Methyl ester 2-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid,

2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)Etalon,

1-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he,

Methyl ether (2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

N-(2-{3-[3-(4-Chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

Methyl ester 3-(2-{3-[3-(4-chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-(2-{3-[3-(4-Chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)Etalon,

2-{3-[3-(4-Chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[3-(4-Chlorphenoxy who yl)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he,

N-[2-({(1R,2R)-2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-1-hydroxycyclopent}methoxy)phenyl]acetamide", she

The hydrochloride of methyl (2S,4R)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-[(4-Chlorobenzyl)oxy]-2-pyrrolidinecarboxylic,

N-(2-{3-[4-(3,4-Dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[4-(4-Chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(4-Chloro-2-{3-[4-(4-chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(4-Chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-cyanophenyl)ndimethylacetamide,

N-(2-{3-[4-(4-Chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(5-Chloro-2-{3-[4-(4-foronline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Chloro-2-{3-[4-(3,4-diptiranjan)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Cyano-2-{3-[4-(4-foronline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Cyano-2-{3-[4-(3,4-diptiranjan)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(4-Foronline)-1-piperidinyl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[4-(3,4-Diptiranjan)-1-piperidinyl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[3(S)-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-(R)-hydroxypropoxy}phenyl)acetamide", she

The hydrochloride of N-(2-{3-[3S-(4-chlorphenoxy)pyrrolidin-1-yl]-2S-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[3(R)-(4-Chlorphenoxy)pyrrole the Jn-1-yl]-2-(S)-hydroxypropoxy}phenyl)acetamide", she

N-[5-Chloro-2-({(2S)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide", she

N-[5-Chloro-2-({(2R)-3-[(3R)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide", she

N-[5-Chloro-2-({(2S)-3-[(3R)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide", she

N-[5-Chloro-2-({(2R)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide", she

N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4,5-differenl)ndimethylacetamide,

N-{5-Chloro-2-[2-hydroxy-3-(3-phenoxypyridine-1-yl)propoxy]phenyl}acetamide", she

N-(5-Chloro-2-{2-hydroxy-3-[3-(4-nitrophenoxy)pyrrolidin-1-yl]propoxy}phenyl)acetamide", she

N-(5-Acetyl-2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

Methyl ester of 4-acetylamino-3-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoic acid,

N-(3-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}naphthalene-2-yl)acetamide", she

N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-cyanophenyl)ndimethylacetamide,

Methyl ester of 4-acetylamino-3-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoic acid,

N-(3-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}naphthalene-2-yl)acetamide", she

N-(5-Cyano-2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-triptoreline the Il)ndimethylacetamide,

Triptorelin N-(5-chloro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

Triptorelin N-(5-acetyl-2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)methanesulfonamide,

N-(5-Chloro-2-[3-[3,4-dichlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy]phenyl)urea,

2,2,2-Triptorelin 1-(3-{2-[(aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(4-chlorphenoxy)pyrrolidine,

2,2,2-Triptorelin 1-(3-{2-[(aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(3,4-dichlorophenoxy)pyrrolidine,

2,2,2-Triptorelin 1-(3-{2-[(aminocarbonyl)amino]-4-chlorophenoxy}-2-hydroxypropyl)-3-(4-chlorphenoxy)pyrrolidine,

The hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N'-utilmately,

The hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N'-metalmachine,

(2S,4S)-1-{3-[2-(Acetylamino)phenoxy]-2-hydroxypropyl}-4-(4-chlorophenoxy)-2-pyrrolidinecarbonyl acid; compound with triperoxonane acid,

Ethyl-(2S,4S)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(3,4-dichlorophenoxy)-2-pyrrolidinecarboxylic; salt triperoxonane acid,

N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide; salt triperoxonane acid,

N-[2-({(2R)-3-[(2S,4S)-4-(4-Chlorphenoxy)2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide; salt triperoxonane acid,

The hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxy-2-methylpropoxy}phenyl)acetamide", she

N-(2-{(1S*,2S*,3S*)-3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)acetamide", she

N-(2-{(1R*,2R*,3R*)-3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)acetamide", she

N-(2-{(2R*,3R*)-3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxyethoxy}phenyl)acetamide", she

N-(2-{(1R*,2R*,3R*)-3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxycyclopent}phenyl)acetamide", she

N-(2-{(2R*,3R*)-3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxyethoxy}phenyl)acetamide", she

N-(2-{(2R*,3R*)-3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxyethoxy}phenyl)acetamide", she

N-(2-{(2R*,3S*)-3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxyethoxy}phenyl)acetamide", she

N-(2-{(1S*,2R*,3S*)-3-[4-(3-Chlorophenoxy)piperidine-1-yl]-2-hydroxycyclopent}phenyl)acetamide", she

N-[5-Chloro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclopent}oxy)phenyl]acetamide", she

N-[4-fluoro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclopent}oxy)phenyl]acetamide", she

The dihydrochloride of N-(2-{3-[4-(3,4-dichlorobenzyl)-1-piperazinil]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(3,4-Dichlorobenzyl)-1-piperazinil]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide,

N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Chloro-2-{3-[4-(3,4-dichlorobenzyl)-1-Pieper is sinil]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Chloro-2-{3-[4-(3,4-dichlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide,

N-(2-{3-[(S*R*)-4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[(S*R*)-4-(4-Chlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Chloro-2-{3-[(S*R*)-4-(3,4-Dichlorobenzyl)-2,5-dimethylpiperazine]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Chloro-2-{3-[(S*R*)-4-(4-Chlorobenzyl)-2,5-dimethylpiperazine]-2-hydroxypropoxy}phenyl)acetamide", she

1-(5-Chloro-2-{3-[4-(4-chlorobenzoyl)-1-piperazinil]-2-hydroxypropoxy}phenyl)-1-Etalon,

N-(5-Cyano-2-{3-[(S*R*)-4-(3,4-dichlorobenzyl)-2,5-dimethylpiperazine]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[(S*R*)-4-(4-Chlorobenzyl)-2,5-dimethylpiperazine]-2-hydroxypropoxy}-5-cyanophenyl)ndimethylacetamide,

N-(5-Chloro-2-{3-[4-(4-Chlorobenzyl)-1-piperazinil]-2-hydroxypropoxy}phenyl)acetamide", she

N-(4-Chloro-2-{3-[4-(4-Chlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(4-Chlorobenzoyl)-1-piperazinil]-2-hydroxypropoxy}-5-cyanophenyl)ndimethylacetamide,

N-(2-{3-[4-(4-Chlorobenzoyl)-1-piperazinil]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-[5-Chloro-2-({(1R,2S,3R)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxyzin opentel}oxy)phenyl]acetamide", she

N-{2-[(2S)-(3-{(3S)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-forfinal}ndimethylacetamide,

The hydrochloride of N-[2-({(2S)-3-[(3S)-3-(4-chlorbenzyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide", she

N-(5-Chloro-2-{3-[3-(4-chlorbenzyl)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide; salt triperoxonane acid,

Triptorelin N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-were)-1-pyrrolidinecarboxamido,

Triptorelin N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-hydroxyphenyl)ndimethylacetamide,

N-[2-({(2S)-3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl}oxy)-4-forfinal]ndimethylacetamide; salt triperoxonane acid,

The hydrochloride of N-(2-(3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4,6-differenl)ndimethylacetamide,

N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl]-2-hydroxypropyl}oxy)-4-forfinal]ndimethylacetamide; salt triperoxonane acid,

The hydrochloride of N-[2-({(2S)-3-[(3R)-3-(4-chlorbenzyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide", she

N-{2-[(2R)-(3-{(3S)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-forfinal}ndimethylacetamide,

N-[2-({(2S)-3-[(2R,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide; salt triperoxonane acid,

N-{2-[(2S)-(3-{(3R)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-forfinal}ndimethylacetamide,

Triptorelin N'-(2-{3-[3-(4-chlorophenoxy)-1-pyrrole inyl]-2-hydroxypropoxy}-4-were)-N,N-dimethylation,

N-(2-{3-[3-(4-Chloroanilino)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

The hydrochloride of N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-1-methylpropyl)oxy]phenyl}acetamide", she

The hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-methoxyphenyl)acetamide", she

N-(2-[3-(4-Chlorobenzoyloxy)pyrrolidin-1-yl]-2-hydroxypropoxy)phenyl)ndimethylacetamide; salt triperoxonane acid,

N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxy-2-methylpropoxy}phenyl)acetamide", she

N-(2-{(1S,2R,3S)*-3-[(3S)-3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxycyclopent}-5-chlorophenyl)ndimethylacetamide (diastereoisomer mix),

N-[2-({(2R,3S)*-3-[(3S)-3-(4-Chlorphenoxy)pyrrolidinyl]-2-hydroxybutyl}oxy)-4-were]ndimethylacetamide (diastereoisomer mix),

The hydrochloride of N-{2-[(3-{4-[(3,4-dichlorophenyl)oxy]-1-piperidinyl}-2-hydroxy-2-methylpropyl)oxy]-4-forfinal}ndimethylacetamide,

N-(2-{(1S,2R,3S)*-3-[(3S)-3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}-4-forfinal)ndimethylacetamide (diastereoisomer mix),

N-(5-Chloro-2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Chloro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(4-Cyano-2-{3-[4-(3,4-dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(4-Hydroxy-2-{(1S,2R,3S)*-3-[(3S)-3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)ndimethylacetamide (diastase the isomeric mixture),

N-(4-Hydroxy-2-{(1S,2R,3S)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)acetamide", she

N-(4-Hydroxy-2-{(1R,2S,3R)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)acetamide", she

N-[2-({(1S,2R,3S)-3-[(3S)-3-(4-Chlorphenoxy)pyrrolidinyl]-2-hydroxycyclopent}oxy)phenyl]acetamide", she

N-[2-({(1R,2S,3R)-3-[(3S)-3-(4-Chlorphenoxy)pyrrolidinyl]-2-hydroxy-cyclopentyl}oxy)phenyl]acetamide", she

N-[5-Chloro-2-({(1S,2R,3S)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxycyclopent}oxy)phenyl]-acetamide", she

N-{5-Chloro-2-[((1S,2R,3S)*-3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxycyclopent)oxy]phenyl}ndimethylacetamide (racemic mixture), and

N-[2-({(2S)-3-[(3S)-3-(4-Chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)-4-hydroxyphenyl]ndimethylacetamide.

In addition, the present invention provides a method of obtaining compounds of formula (I)as defined above, in which

(a) compound of General formula

where R is as defined in formula (I), is subjected to the interaction with the compound of General formula

where Q, R2, R4, R5, R6, R7and R8such as defined in formula (I); or

(b) a compound of General formula

where R, R4, R5, R6, R7and R8such as defined in formula (I), is subjected to inter eastview with the compound of General formula

where L1represents a hydrogen atom or an activating group (e.g. Li, when Q represents CH2), and Q and R2such as defined in formula (I);

and maybe after that carry out the conversion of the compounds of formula (I) into another compound of formula (I); and, if desired, receive a pharmaceutically acceptable salt or MES the compounds of formula (I).

In one aspect, the invention provides a method of obtaining compounds of formula (I')as defined previously, in which

(a) compound of General formula

where R is as defined in formula (I'), is subjected to the interaction with the compound of General formula

where Q, R2, R4, R5, R6, R7and R8such as defined in formula (I); or

(b) a compound of General formula

where R, R4, R5, R6, R7and R8such as defined in the formula (I'), is subjected to the interaction with the compound of General formula

where L1represents a hydrogen atom or an activating group (e.g. Li, when Q represents CH2), and Q and R2such as defined in the formula (I');

and maybe after that osushestvleniya the compounds of formula (I') into another compound of formula (I'); and if you want, get a pharmaceutically acceptable salt or MES the compounds of formula (I').

In another aspect, the invention provides a method of obtaining compounds of formula (I)as defined previously, in which

(a) compound of General formula

where R is as defined in formula (I), is subjected to the interaction with the compound of General formula

where Q, R2, R4, R5, R6, R7and R8such as defined in formula (I); or

(b) a compound of General formula

where R, R4, R5, R6, R7and R8such as defined in formula (I), is subjected to the interaction with the compound of General formula

where L1represents a hydrogen atom or an activating group (e.g. Li, when Q represents CH2), and Q and R2such as defined in formula (I");

and maybe after that carry out the conversion of the compounds of formula (I) into another compound of formula (I); and, if desired, receive a pharmaceutically acceptable salt or MES the compounds of formula (I").

In another aspect, the invention provides a method of obtaining compounds of formula (I')as defined previously, in which

(and compounds of General formula

where R is as defined in formula (I"'), is subjected to the interaction with the compound of General formula

where Q, R2, R4, R5, R6, R7and R8such as defined in formula (I"'); or

(b) a compound of General formula

where R, R4, R5, R6, R7and R8such as defined in the formula (I"'), is subjected to the interaction with the compound of General formula

where L1represents a hydrogen atom or an activating group (e.g. Li, when Q represents CH2), and Q and R2such as defined in formula (I"');

and maybe after that turn the compound of formula (I"') into another compound of formula (I"'); and, if desired, receive a pharmaceutically acceptable salt or MES the compounds of formula (I"').

The method according to this invention can be conveniently carried out in a solvent, for example an organic solvent such as alcohol (e.g. methanol or ethanol), a hydrocarbon (for example toluene or acetonitrile, at a temperature of for example 15°With or higher, such as a temperature in the range from 20 to 120°C.

Compounds of formula (II), (II'), (II), (II'), (III), (III'), (III), (III'), (IV), (IV'), (IV), (IV'), (V), (V'), (V) and (V') or are commercially available, x is well known from the literature or can be easily obtained using known methods.

The compounds of formula (I), (I'), (I") or (I"') can be converted into other compounds of formula (I), (I'), (I") or (I"') using standard methods. For example, the compound of formula (I), where R15represents-NHC(O)CH3can be converted into another compound of formula (I), where R15represents-NH2by hydrolysis in the presence of hydrochloric acid.

Specialist in the art will understand that the methods of the present invention in the initial reagents or intermediate compounds may need the protection of certain functional groups such as hydroxyl or amino groups, protective groups. Thus obtaining compounds of formula (I), (I'), (I") or (I"') can include at an appropriate stage to delete one or more than one protective group.

The introduction and removal of protecting functional groups described in "Protective Groups in Organic Chemistry", edited by J. W.F.McOmie, Plenum Press (1973) and ' Protective Groups in Organic Synthesis", 2ndedition, T.W.Greene and P.G.M.Wuts, Wiley-lnterscience (1991).

The compounds of formula (I), (I'), (I") or (I') above can be converted in their pharmaceutically acceptable salt or MES, preferably salt accession acids, such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or paratoluenesulfonyl.

The compounds of formula(I), (I'), (I") or (I"') can exist in stereoisomeric forms. It is clear that the invention encompasses all geometric and optical isomers of compounds of formula (I), (I'), (I") or (I"') and mixtures thereof, including racemates. The use of tautomers and their mixtures are also aspect of the present invention. Enantiomerically pure forms are especially desirable.

The compounds of formula (I), (I'), (I") or (I"') have activity as pharmaceuticals, in particular as modulators of the activity of chemokine receptors (in particular, the receptor of the chemokine MIP-1α), and can be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically mediated diseases including rejection of transplanted organs or tissues and acquired immunodeficiency syndrome (AIDS).

Examples of these conditions are:

(1) (the respiratory tract) respiratory disease, including chronic obstructive pulmonary disease (COPD), such as irreversible COPD); asthma, such as bronchial, allergic, hereditary, acquired asthma and asthma caused by dust, particularly chronic or inveterate asthma (for example late asthma and hypersensitivity of the respiratory tract); bronchitis; the Stryi, allergic, atrophic rhinitis and chronic rhinitis including rhinitis chronic with the formation of caseous masses, hypertrophic rhinitis, purulent rhinitis, dry rhinitis and rhinitis drug; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis, and zolotushnyh rhinitis; seasonal rhinitis including nervous rhinitis (hay fever) and vasomotor rhinitis; sarcoidosis, exogenous allergic alveolitis and related diseases, pneumosclerosis and idiopathic interstitial pneumonia;

(2) (bone and joints) rheumatoid arthritis, seronegative of spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and the disease Reiter), Behcet's disease, Sjogren syndrome and systemic sclerosis;

(3) (skin) psoriasis, diffuse neurodermatitis, contact dermatitis and other edematous dermatitis, seborrheic eczema, red flat zoster, disease, bullous disease, congenital bullous bullosa, urticaria, angiodema, vasculitis, erythema, cutaneous eosinophilia, uveitis, alopecia areata and vernal conjunctivitis;

(4) (gastrointestinal tract) disease of the abdomen, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, food allergies, which have the action removed from the intestine, for example, mi is the root, rhinitis and eczema;

(5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilic fasciitis, Hyper-IgE syndrome, lepromatosis leprosy, reticular erythroderma and idiopathic thrombocytopenic purpura;

(6) (graft rejection) acute and chronic, for example, after transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic homologous disease;

(7) a malignant tumor, especially namelocation lung cancer (NSCLC) and squamous sarcoma;

(8) diseases in which angiogenesis is associated with elevated levels of the chemokine receptor CXCR2 (e.g. NSCLC); and

(9) cystic fibrosis, stroke, reperfusion damage in the heart, brain, limbs and sepsis.

Thus, the present invention provides a compound of formula (I), (I'), (I") or (I') or its pharmaceutically acceptable salt or MES, as defined previously, for use in therapy.

In another aspect the present invention provides the use of compounds of formula (I), (I'), (I") or (I') or its pharmaceutically acceptable salt or MES, as defined previously, in the manufacture of medicaments for use in therapy.

Unless otherwise stated, in the context of the present description, the term "therapy" also includes "prevention". The terms "therapeutic" and "therapeutically" should be interpreted accordingly.

This invention also provides a method of treating inflammatory disease in a patient suffering from the specified disease or having a risk of a specified disease in which the patient is administered a therapeutically effective amount of the compounds of formula (I'), (I'), (I") or (I') or its pharmaceutically acceptable salt or MES, as defined previously.

This invention also provides a method of treating respiratory disease in a patient suffering from the specified disease or having a risk of a specified disease in which the patient is administered a therapeutically effective amount of the compounds of formula (I'), (I'), (I") or (I') or its pharmaceutically acceptable salt or MES, as defined previously.

For the above-mentioned therapeutic applications of the introduced dose will, of course, vary depending on the connection method of maintaining the desired treatment and the disorder. Daily dose of the compounds of formula (I'), (I'), (I") or (I"') can be in the range from 0.001 mg/kg to 30 mg/kg

The compounds of formula (I'), (I'), (I") or (I"') and f is rmaceuticals acceptable salt and solvate can be used by themselves, but, as a rule, are introduced in the form of a pharmaceutical composition where the compound of formula (I'), (I'), (I") or (I")/Sol/MES (active ingredient) is together with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the method of administration of the pharmaceutical composition preferably includes from 0.05 to 99 wt.% (percent by weight), more preferably from 0.05 to 80 wt.%, even more preferably from 0.10 to 70 wt.%, and even more preferably from 0.10 to 50 wt.% the active ingredient, all percentages by weight based on the weight of the entire composition.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I), (I'), (I") or (I') or its pharmaceutically acceptable salt or MES, as defined previously, together with a pharmaceutically acceptable adjuvant, diluent or carrier.

This invention also provides a method of preparing pharmaceutical compositions according to this invention, in which a mixed compound of formula (I), (I'), (I") or (I') or its pharmaceutically acceptable salt or MES, as defined earlier, with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical composition can be injected locally (for example in the lungs and/or Airways or to the skin) in the form of solutions, suspe is si, heptapteridae aerosols and chemicals in the form of a dry powder; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous injection, or by rectal injection in the form of suppositories or transdermal.

This invention also further illustrated by reference to the following illustrative examples, in which1H NMR spectra were recorded using a Varian Unity Inova 400. The Central peak of the solvent of chloroform-d (δn7,27 million-1) was used as internal standard. Mass spectra of low-resolution and accurate mass determination were recorded on the system liquid chromatograph-mass spectrometer (LC-MS) on a Hewlett-Packard 1100, equipped with ionization chambers chemical ionization at atmospheric pressure (APCI)/electrospray ionization (ESI). All solvents and commercially available reagents were of laboratory purity and were used as purchased. The nomenclature used for the connection was established using ACD/IUPAC Name Pro.

Example 1

The hydrochloride of N-(2-{3-[3R,S-(4-Chlorphenoxy)pyrrolidin-1-yl]-2R,5-hydroxypropoxy}phenyl)ndimethylacetamide

(1) tert-Butyl ether 3-hydroxypyrrolidine-1-carboxylic KIS is the notes

The solution pyrrolidin-3-ol (16,25 g, 186,5 mmol) and di-tert-butyl-dicarbonate (40,7 g, 186,5 mmol) in anhydrous tetrahydrofuran (THF) (50 ml) under nitrogen atmosphere was stirred over night. Concentration under reduced pressure and purification by flash chromatography on silica (EtOAc:heptane, 7:3) was allowed to get to 31.9 g (91%) indicated in the subtitle of the connection.

1NAMR (400 MHz, DMSO-d6): δ to 4.87 (d, 1H, J=3,4 Hz), is 4.21 (bs, 1H), 3,31-up 3.22 (m, 3H), 3,10 (d, 1H, J=11.5 Hz)and 1.83 (m, 1H), 1,72 (m, 1H), of 1.39 (s, 9H).

Chemical ionization at atmospheric pressure mass spectrometry (APCI-MS): m/z 132 [MN+-56]

(2) 3-(4-Chlorphenoxy)pyrrolidin

Tributyl ether 3-hydroxypyrrolidine-1-carboxylic acid (2.1 g, 9.9 mmol) and triphenylphosphine (2,59 g, 9.9 mmol) was dissolved in anhydrous THF (35 ml) under nitrogen atmosphere. The solution was cooled to 0°and was added 4-chlorophenol (1.28 g, 9.9 mmol)dissolved in anhydrous THF (10 ml), and then diethylazodicarboxylate (DEAD) (1,55 ml, 9.9 mmol). After 15 minutes the ice bath was removed and the reaction mixture was stirred over night. The reaction mixture was concentrated under reduced pressure and the residue was stirred with simple ether. The solid triphenylphosphine oxide was filtered. The solution was washed three times with sodium hydroxide (1 M) and concentrated. The product is protected by butyloxycarbonyl (SIDE), was purified by flash chromatography dioxide on the silicon, using as eluent a mixture of EtOAc/heptane. It was dissolved in dichloromethane (35 ml) and triperoxonane acid (17 ml). The reaction mixture was stirred at room temperature overnight, concentrated and purified by flash chromatography on silica (Meon:CHCl3:NH3, 100:100:1) to obtain specified in the subtitle compound (1,72 g, 88%).

1H-NMR (400 MHz, DMSO-d6): δ 7,30 (d, 2H, J=8,9 Hz)6,91 (d, 2H, J=8,9 Hz), 4,82 (m, 1H), 3,03 (dd, 1H, J=12,3, a 5.4 Hz), 2,82 (m, 3H), 1,99 (m, 1H), 1,72 (m, 1H).

APCI-MS: m/z 198 [MH+].

(3) the Hydrochloride of N-(2-{3-[3R,S-(4-Chlorphenoxy)pyrrolidin-1-yl]-2R,S-hydroxypropoxy}phenyl)ndimethylacetamide

A solution of 3-(4-chlorphenoxy)-pyrrolidine (0,059 g, 0,298 mmol) and N-acetyl-2-(2,3-epoxypropoxy)aniline (0,062 g, 0,299 mmol) in EtOH (1.5 ml, 99.5%pure) was stirred for 3 hours at 75°in a sealed vial. The solvent is evaporated after the reaction, and the residue was purified on silica (CH2Cl2:MeOH, 98:2 to 97:3) to give 88 mg of the free amine specified in the connection header. The amine was dissolved in a mixture of Meon:water 1:1 (30 ml)and the solution was acidified with 2 M hydrochloric acid. The methanol is evaporated and the remaining aqueous solution liofilizirovanny to obtain 92 mg (70%) indicated in the title compound as a white solid.

APCI-MS: m/z 405,2 407,2 [MN+] isotopic pattern]

Example 2

The hydrochloride of N-(5-chloro-2-{3-[3R,S-(4-chlorphen the si)pyrrolidin-1-yl]-2R,S-hydroxypropoxy}phenyl)ndimethylacetamide

(1) N-(5-Chloro-2-hydroxyphenyl)ndimethylacetamide

A solution of 4-amino-2-chlorophenol (2.0 g, a 13.9 mmol) and acetanhydride (1.77 g, 17.3 mmol) in water (40 ml) was carefully stirred for 5 minutes. The reaction mixture was then heated with stirring to 60°C for 30 minutes and then allowed to cool. Formed pink solid and the precipitate was collected by filtration, washed twice with water and dried to obtain 1.8 g (70%) indicated in the subtitle of the connection.

1H-NMR (400 MHz, DMSO-d6): δ to 10.09 (1H, s); a 9.25 (1H, bs); to 7.93 (1H, s); 6,93 (1H, dd, J of 8.8 and 2.7 Hz); at 6.84 (1H, d, J 8.6 Hz); of 2.09 (3H, s).

APCI-MS: m/z of 186.0 [MH+].

(2) N-(5-Chloro-2-oxiranylmethyl)ndimethylacetamide

A solution of N-(5-chloro-2-hydroxyphenyl)ndimethylacetamide (0,499 g, 2.68 mmol), K2CO3(0,60 g, 4.35 mol) and epibromohydrin (0,405 g, 2,95 mmol) in dimethylformamide (DMF) (5 ml) was heated under stirring at 50°C for 2 hours. This mixture is then distributed between EtOAc and water 40+40 ml of the Organic phase is washed twice with water and once with brine and finally concentrated in vacuo to obtain the crude product. The crude product was purified on silica (heptane:EtOAc, 1:1) obtaining of 0.43 g (66%) of a white solid.

1H-NMR (400 MHz, CDCl3):δ 8,46 (1H, d, J 2.3 Hz); of 7.90 (1H, bs); 6,98 (1H, dd, J of 8.7 and 2.4 Hz); 6,83 (1H, d, J 8,8 Hz); 4,36 (1H, dd, J 11,5 2,4 Hz); of 3.94 (1H, dd, J 11,6, 6,0 Hz); 3,41-to 3.36 (1H, m); of 2.97 (1H, dd, J of 4.7 and 4.2 Hz); 2,80 (N, dd, J 4,6, and 2.6 Hz); of 2.23 (3H, s)

(3) the Hydrochloride of N-(5-Chloro-2-{3-[3R,S-(4-chlorphenoxy)pyrrolidin-1-yl]-2R,S-hydroxypropoxy}phenyl)ndimethylacetamide

Was obtained in a manner analogous to the method described in Example 1, stage (3).

Example 3

N-(2-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

Received in accordance with the methods described in Example 1. Purified and isolated as the free amine with 73% yield by chromatography on a column of C18(H2O:CH3CN, buffer 0.1 M NH4OAc, gradient from 30% to 95% CH3CN).

APCI-MS: m/z 453, 455 [MN+].

1H-NMR (400 MHz, CDCl3): δ to 7.32 (d, 1H), 7,01 (d, 1H), 6,85-8,80 (m, 2H), 6,78-6,69 (m, 3H), or 4.31 (m, 1H), 4,15-4.09 to (m, 1H), 4,18-3,18 (bs, 3H), 2.91 in (m, 1H), 2,71 (m, 1H), 2,62-2,52 (m, 3H), 2,35 (m, 1H), 2,05-of 1.93 (m, 2H,), 1,89-to 1.77 (m, 2H).

Example 4

The dihydrochloride of 1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanol

N-(2-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide (1,418 g of 3.13 mmol) was dissolved in 50 ml HCl (35%/aq., puriss) and boiled under reflux during the night. The product was besieged and was filtered and dried to obtain 0,835 g (65%) specified in the connection header.

APCI-MS: m/z 411,413 [MH+].

1H-NMR (400 MHz, CDCl3): δ 8,39-of 3.31 (m, 2H), 7,31 (d, 1H), 7,01-6,98 (m, 3H), 6,94-6,91 (m, 1H), 6.75 in (dd, 1H), or 4.31 (m, 1H), 4,12-was 4.02 (m, 2H), 3,92 (dd, 1H), 2,90 (m, 1H), 2,69 (m, 1H), 2,62 is 2.51 (m, 2H), 2,46 (dd, 1H), of 2.34 (m, 1H), 2,18 (s, 3H), 2,04-of 1.93 (m, 2H), 1,89-to 1.77 (m, 2H).

Example 5

Hydrochlor is d N-(2-{3-[3-(3,4-dichlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

Received in accordance with the methods described in Example 1, to obtain 68 mg (68%) indicated in the title compound as a white solid.

APCI-MS: m/z 439, 441 [MH+].

Example 6

Methyl ester 2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxypropoxy}benzoic acid

(1) Methyl ester 2-oxiranemethanol acid

Was obtained analogously to the method described in Example 2, stage (2).

1H-NMR (400 MHz, CDCl3): δ 7,81 (1H, dd, J of 7.7 and 1.7 Hz); 7,46 (1H, dt, J of 7.7 and 1.7 Hz); 7,05-6,98 (2H, m); 4,33 (1H, dd, J 11,3, 3,0 Hz); 4,11 (1H, dd, J 11,3, 4,8 Hz); 3,90 (3H, s); 3,43-3,37 (1H, m); 2,93-2,90 (2H, m).

(2) Methyl ester 2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxypropoxy}benzoic acid

Was obtained analogously to the method described in Example 1, stage (2). Allocated in the form of a free amine.

1H-NMR (400 MHz, CDCl3): δ 7,81 (1H, dd, J of 8.1, 1.8 Hz); 7,46 (1H, dt, J of 7.8 and 1.7 Hz); 7.03 is-6,91 (4H, m); 6,86-PC 6.82 (2H, m); 4,28-4,10 (3H, m); 4,08-4,00 (1H, m); 3,88 (3H, s); 2,92-2,84 (1H, m); 2,83 was 2.76 (1H, m); 2,66 of $ 2.53 (2H, m,); the 2.46 (1H, t, J 10,2 Hz); a 2.36 (1H, t, J 10,2 Hz); 2,02-of 1.92 (2H, m); 1,86-of 1.74 (2H, m); and 1.63 (1H, bs)

APCI-MS: m/z 404,2 [MH+].

Example 7

Methyl ester 2-(2-{3-[4-(3,4-divergence)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid

(1) Methyl 2-[(2-hydroxybenzoyl)amino]-2-methylpropanoate

To a solution of 2-(chlorocarbonyl)phenylacetate (20 mmol, of 3.96 g) in toluene (50 ml) was added N-ethyl-N,N-Diisopropylamine (22 mmol, 2,84 g) and 2-methylalanine (22 mm is l, of 2.27 g). After stirring the reaction mixture at room temperature overnight the mixture was diluted with 250 ml of toluene and washed with 1.8% aq. HCl (250 ml) and feast upon. aq. NaCl (250 ml). The organic phase was dried over Na2SO4and concentrated under reduced pressure. The residue was dissolved in Meon (50 ml) was added 3 drops of conc. H2SO4. The mixture was boiled under reflux for 2 hours and concentrated under reduced pressure. The residue was dissolved in 250 ml of EtOAc and washed the feast upon. aq. NaHCO3(250 ml) and feast upon. aq. NaCl (250 ml). The organic phase was dried over Na2SO4and concentrated under reduced pressure. Remaining in the crude substance was used without further purification.

APCI-MS m/z: 238 [MN+].

(2) Methyl 2-methyl-2-{[2-(2-oxiranylmethyl)benzoyl]amino}-propanoate

A solution of methyl 2-[(2-hydroxybenzoyl)amino]-2-methylpropanoate, K2CO3(20 mmol, of 2.68 g) and 2-(chloromethyl)oxirane (22 mmol, 2,03 g) in acetonitrile (60 ml) was stirred while boiling under reflux overnight. The reaction mixture was diluted with EtOAc and washed with 1.8% aq. HCl (250 ml) and feast upon. aq. NaCl (250 ml). The organic phase was dried over Na2SO4and concentrated under reduced pressure. The residue was purified on a column of C18(H2O:CH3CN, 0.1 M buffer NH4OAc, gradient 10% to 95% CH3CN) obtained with the eat indicated in the subtitle compound (244 mg, 5%, two-stage).

APCI-MS: m/z 294 [MN+].

1H-NMR (400 MHz, CDCl3): δ to 8.40 (s, 1H), 8,14 (dd, 1H), 7,41 (dt, 1H), 7,07 (t, 1H), 6.90 to (d, 1H), of 4.44 (dd, 1H), 4,07 (dd, 1H), 3,74 (s, 3H), of 3.45 (m, 1H), equal to 2.94 (dd, 1H), 2,84 (dd, 1H), 1,64 (d, 6H).

(3) Methyl ester of 2-(2-{3-[4-(3,4-divergence)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methyl-propionic acid

Toluene solution of 4-(3,4-divergence)piperidine (0,03 ml, 0.5 M) was mixed with a toluene solution of methyl 2-methyl-2-{[2-(oxiranylmethyl)benzoyl]amino}of propanoate one (0.03 ml, 0.5 M). The mixture was diluted to 0.20 ml of toluene and 0.05 ml of methanol. The reaction mixture was stirred over night at 100°in sealed vessels. The product was concentrated in vacuo and used without any treatment.

APCI-MS: m/z 507 [MN+].

1H-NMR (400 MHz, CDCl3): δ 8,13 (s, 1H), of 7.90 (dd, 1H), 7,33 (dt, 1H), 7,07-of 6.96 (m, 2H), 6.89 in (d, 1H), 6.73 x of 6.68 (m, 1H), 6,58-6,55 (m, 1H), 4,77-4,72 (m, 1H), 4,49 (bs, 1H), 4,20 is 4.13 (m, 2H), 3,69 (s, 3H), to 3.58-3,44 (m, 2H,), 3,39-3,26 (m, 4H), of 2.54-2.40 a (m, 2H), 2,13-2,04 (m, 2H), 1,60 (d, 6N).

Example 8

N-[2-({(1R,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopent}oxy)phenyl]ndimethylacetamide and

N-[2-({(1S,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopent}oxy)phenyl]ndimethylacetamide

(1) N-[2-(2-cyclopenten-1 yloxy)phenyl]ndimethylacetamide

To a suspension of sodium hydride (60%). in paraffin; 297 mg, the 7.43 mmol, 1.1 equiv.) in DMF (3 ml) dropwise at 0°C was added a solution of 2-acetamidophenol (1,02 g of 6.75 mmol, 1.0 equiv.) in DMF (12 ml). Ceres minutes via a syringe was added harcelement-2-ene (R.Moffett, Organic Synthesis, Wiley: New York 1963, Collect. Vol.IV, p.238-241) (762 mg, 0.76 to ml, the 7.43 mmol, 1.1 equiv.) and stirring continued over night. For water treatment was followed by flash chromatography on silica gel (heptane/ethyl acetate, 2:1, then 1:1) to give 992 mg (68%) indicated in the subtitle compound as a dark yellow oil.

1H-NMR (400 MHz, CDCl3): δ 8,35 (1H, d, J 8.0 Hz), 7,73 (1H, bs), 7,00 (1H, td, J of 7.9, 1.5 Hz), 6.90 to-6,95 (2H, m), 6,17 (1H, m), 5,95 (1H, m), are 5.36 (1H, d, J 5,9 Hz), 2,59 (1H, m), of 2.38 (2H, m), 2,17 (3H, s), of 1.97 (1H, m).

MS-ESI+: m/z 218,1 [MH+].

(2) N-{2-(6-Oxabicyclo[3.1.0]Gex-2-yloxy)phenyl}ndimethylacetamide

It chilled in an ice bath to a solution of N-[2-(2-cyclopenten-1 yloxy)phenyl]ndimethylacetamide (149 mg, 686 μmol, 1.0 equiv.) in dichloromethane (4 ml) was added meta-chloroperbenzoic acid (85%; 146 mmol, 1.1 equiv.). After stirring overnight at slow warming to ambient temperature the reaction mixture was diluted with tert-butylmethylamine ether, then washed the feast upon. a solution of sodium bisulfate, 5%. sodium hydroxide and brine and dried over sodium sulfate. Evaporation of the solvent and flash chromatography on silica gel (ethyl acetate/heptane, 2:3, then ethyl acetate) allowed us to obtain 93 mg (58%) indicated in the subtitle compound as a mixture of TRANS (secondary) and Cys (main) diastereoisomeric epoxides in the form of a pale yellow oil. The ratio of CIS/TRANS was is defined as 2:1 by 1H-NMR.

1H-NMR (400 MHz, CDCl3): δ 8,39 (1H [A]m), a 8.34 (1H [V], d, J 8.2 Hz), to $ 7.91 (1H, [A], bs), to 7.59 (1H, [], bs), 6,92-7,25 (3N [A]+3H [IN], m), 4,89 (1H [V], d, J 5.2 Hz), of 4.77 (1H, [A], td, J of 8.0, 1.3 Hz), 3,66 (1H [IN], m)to 3.64 (1H [IN], m), 3,60 (1H, [A], m)of 3.54 (1H [A], m)of 2.23 (1H [V], d, J 8,4 Hz), of 2.21 (3H, [A], s), 2,19 (3N [], s), 2,10 (2N [A], m), 1,72-1,92 (m), 1,53-1,63 (m) (2N [AND]+3H [IN]). (A = trance = Cys)

MS-ESI+: m/z 234,1 [MN+].

(3) N-[2-({(1R,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopent}oxy)phenyl]ndimethylacetamide and

N-[2-({(1S,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopent}oxy)phenyl]ndimethylacetamide

N-{2-(6-oxabicyclo[3.1.0]Gex-2-yloxy)phenyl}ndimethylacetamide (racemic mixture of TRANS and CIS diastereoisomers) (87 mg, 373 mmol, 1.0 equiv.) and 4-(3,4-dichlorophenoxy)piperidine (92 mg, 394 μmol, of 1.06 equiv.) was dissolved in 2 M lithium perchlorate in acetonitrile (3 ml) and heated in a sealed tube overnight at 85°C. Water processing and flash chromatography of the crude material on silica gel (heptane/ethyl acetate/methanol/ammonia =1:3:0:0 then 0:90:10:1, then 0:80:20:3) led to the separation of the two diastereoisomeric additional products to obtain 24 mg (14%) diastereoisomer (1S,2S,3R) (eluted first) and 75 mg (42%) aliremove second diastereoisomer (1R,2S,3R).

For diastereoisomer (1S,2S,3R):

1H-NMR (400 MHz, CDCl3): δ of 8.27 (1H, dd, J of 7.6 and 1.7 Hz), to $ 7.91 (1H, s), 7,29 (1H, d, J a 8.9 Hz), 6,88-to 7.00 (4H, m), of 6.73 (1H, dd, J of 8.9 and 2.8 Hz), of 4.45 (1H, m), 4,28 (1H, hept, J 3.6 Hz), 4,18 (1H, dd, J7,1, 4.6 Hz), 2,87 (3H, m), 2,71 (1H, q, J 7.5 Hz), of 2.15 (3H, s), 2,11 (1H, m), 1,78-2,02 (7H, m).

MS-APCI+: m/z 479,1 [MN+].

For diastereoisomers (1R,2S,3R):

1H-NMR (400 MHz, CDCl3): δ 8,20 is 8.25 (2H, m), 7,29 (1H, d, J a 8.9 Hz), 6,91-to 7.00 (4H, m), 6,74 (1H, dd, J of 8.9 and 2.8 Hz), 4,46 (1H, bq, J 4.8 Hz), the 4.29 (1H, m), 4,13 (1H, d, J 7.2 Hz), 2,95 (2H, m), 2,84 (2H, m), of 2.50 (2H, m), 2,15 (3H, s), 1.93 and-2,07 (5H, m), equal to 1.82 (2H, m), 1,58 (1H, m).

MS-APCI+: m/z 479,1 [MN+].

Example 9

N-[2-({(2,3-TRANS)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclohexyl}oxy)phenyl]ndimethylacetamide

(1) N-[2-(2-cyclohexen-1 yloxy)phenyl]ndimethylacetamide

2-Cyclohexanol (491 mg, of 0.49 ml, 5.00 mmol, 1.0 equiv.), 2-acetamidophenol (756 mg, 5.00 mmol, 1.0 equiv.) and triphenylphosphine (1.44 g, of 5.50 mmol, 1.1 equiv.) was dissolved in THF (10 ml) and kept at ambient temperature in a water bath. After adding dropwise diethylazodicarboxylate acid (871 mg, 0,78 ml, 5.00 mmol, 1.0 equiv)dissolved in THF (3 ml), the reaction mixture was stirred over night. Extraction processing and flash chromatography on silica gel (heptane/tert-butyl methyl ether =1:1) allowed to obtain 224 mg (19%) indicated in the title compound as a yellow oil.

MS-ESI+: m/z 232,2 [MN+].

(2) N-[2-(7-oxabicyclo[4.1.0]hept-2-yloxy)phenyl]ndimethylacetamide

To a solution of N-[2-(2-cyclohexen-1 yloxy)phenyl]ndimethylacetamide (76 mg, 329 μmol, 1.0 equiv.) in dichloromethane (5 ml) at 0°With added meta-chlorbenzoyl acid (85%; 121 mg, 559 mmol, 1.7 equiv.). Peremeci is the W continued throughout the night, while the reaction mixture gave the opportunity to slowly warm to room temperature. The heterogeneous mixture was diluted with ethyl acetate and washed the feast upon. sodium sulfite, 5% sodium hydroxide and brine. Drying over sodium sulfate, evaporation of the solvent and flash chromatography on silica gel allowed to obtain 59 mg (73%) indicated in the title compounds as a mixture of diastereoisomers (ratio A:B = TRANS:CIS =5:31H-NMR]).

1H-NMR (400 MHz, CDCl3): δ 8,35 (1H [A]+1H [In], m), 8,02 (1H [A], bs), of 7.70 (1H [], bs), 6,95? 7.04 baby mortality (3N [A]+3H [IN], m)to 4.62 (1H, [A], dd, J 8.4 and, of 5.5 and 2.1 Hz), 4,55 (1H [IN], dd, J 7,5, 6,7 Hz), 3,30-to 3.36 (2H [A]+1H [IN], m), 3,19 (1H [V], t, J 3.6 Hz), 1,26-2,23(1 [A]+10H [IN], m).

LC/S-ESI+: m/z 248,1 [MN+(A)], 248,2 [MN+(C)].

(3) N-[2-({2,3-TRANS)-3-(4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclohexyl}oxy)phenyl]ndimethylacetamide

Diastereoisomer a mixture of N-[2-(7-oxabicyclo[4.1.0]hept-2-yloxy)phenyl]ndimethylacetamide (59 mg, 239 μmol, 1.0 equiv.) and 4-(3,4-dichlorophenoxy)piperidine (56 mg, 239 μmol, 1.0 equiv.) was dissolved in 2 M lithium perchlorate in acetonitrile (2 ml) and heated in a sealed tube overnight at 85°C. Water processing and flash chromatography on silica gel (heptane/ethyl acetate/methanol =50:100:3) allowed us to obtain 86 mg (75%) as a yellow oil is then reduced to diastereoisomeric the ratio of 69:31=And:(1H-NMR). Could not observe any separation diastereoisomers on columns with obrasheniyashi. The relative stereochemistry of the primary and secondary diastereoisomers respectively were unable to determine due to the complex spectrum of the mixture.

1H-NMR (400 MHz, CDCl3): δ 9,48 (1H [AS], bs), a 9.25 (1H [], bs), 8,46 (1H [A]+1H [V], t, J 9.1 Hz), 7,22-to 7.32 (2H [A]+1H [IN], m), 6,93-was 7.08 (4H [A]+5N [IN], m), 6,72-6,76 (1H [A]+1H [IN], m), 4,08-4,30 (3H [A] +3H [IN], m), 3,55-of 3.64 (2H) [A]+1H [B], m), 2,96-of 3.07 (2H [A]+2N [V], m), 2,71 (2N [A]+3H [IN], m), 2,19 (3N [A], s)of 2.16 (3H [], s), 1,47-2,37 (1 [A]+10H [IN], m).

MS-ESI+: m/z 493,1 [MN+(a,b)].

The following compounds were obtained using methods similar to those described in the previous Examples.

Example 10

N-(5-chloro-2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 473,1 475,1 [MN+].

Example 11

N-(3-Acetyl-2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide

APCI-MS: m/z 495,1 497,1 [MN+].

Example 12

N-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide

APCI-MS: m/z 453,1 455,1 [MN+].

Example 13

N-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide

APCI-MS: m/z 457,1 459,1 [MN+].

Example 14

1-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)propan-2-ol

APCI-MS: m/z 421,1 423,1 [MN+].

Example 15

1-(7-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}indol-1-yl)alanon

APCI-MS: m/z 463,1 465,1 [MN+].

Example 16

N-(4-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-is]-2-hydroxypropoxy}biphenyl-3-yl)ndimethylacetamide

APCI-MS: m/z 515,1 517,1 [MN+].

Example 17

N-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide

APCI-MS: m/z 457,1 459,1 [MN+].

Example 18

N-(2-[3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide

APCI-MS: m/z 453,1 455,1 [MN+].

Example 19

N-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 439,1 441,1 [MN+].

Example 20

N-(5-Chloro-2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 439,1 441,1 [MN+].

Example 21

N-(3-Acetyl-2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide

APCI-MS: m/z 461,1 [MH+].

Example 22

N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide

APCI-MS: m/z 419,1 [MH+].

Example 23

N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide

APCI-MS: m/z 423,1 [MH+].

Example 24

1-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)propan-2-ol

APCI-MS: m/z 387,1 [MH+].

Example 25

1-(7-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}indol-1-yl)alanon

APCI-MS: m/z 429,1 [MH+].

Example 26

N-(4-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)ndimethylacetamide

APCI-MS: m/z 481,1 [MH+].

Example 27

N-(2{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide

APCI-MS: m/z 423,1 [MN+].

Example 28

N-(2{3-[3-(4-Chloro what enocsi)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide

APCI-MS: m/z 419,1 [MN+].

Example 29

N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 405,1 [MH+].

Example 30

N-(5-Chloro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 423,1 [MH+].

Example 31

N-(3-Acetyl-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide

APCI-MS: m/z 445,3 [MH+].

Example 32

N-(2-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide

APCI-MS: m/z 403,3 [MH+].

Example 33

N-(5-fluoro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 407,1 [MH+].

Example 34

1-[3-(4-Pertenece)pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)propan-2-ol

APCI-MS: m/z 371,1 [MH+].

Example 35

1-(7-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}indol-1-yl)alanon

APCI-MS: m/z 413,1 [MH+].

Example 36

N-(4-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)ndimethylacetamide

APCI-MS: m/z 465,3 [MH+].

Example 37

N-(4-fluoro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 407,1 [MH+].

Example 38

N-(2-(3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide

APCI-MS: m/z 403,1 [MH+].

Example 39

N-(2-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 389,1 [MH+].

Example 40

N-(5-Chloro-2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxyp is poxy}phenyl)ndimethylacetamide

APCI-MS: m/z 441,1 [MH+].

Example 41

N-(3-Acetyl-2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide

APCI-MS: m/z 463,3 [MH+].

Example 42

N-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide

APCI-MS: m/z 421,1 [MH+].

Example 43

N-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide

APCI-MS: m/z 425,1 [MN+].

Example 44

1-[3-(3,4-Divergence)pyrrolidin-1-yl]-3-(1H-indol-7-yloxy)propan-2-ol

APCI-MS: m/z 389,1 [MN+].

Example 45

1-(7-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}indol-1-yl)alanon

APCI-MS: m/z 431,1 [MN+].

Example 46

N-(4-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)ndimethylacetamide

APCI-MS: m/z 483,3 [MN+].

Example 47

N-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide

APCI-MS: m/z 425.1 [MN+].

Example 48

N-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide

APCI-MS: m/z 421,1 [MN+].

Example 49

N-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 407,1 [MN+].

Example 50

N-(5-Chloro-2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 487,1 489,1 [MN+].

Example 51

N-(3-Acetyl-2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide

APCI-MS: m/z 509,3 511,1 [MN-].

Prima is 52

N-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide

APCI-MS: m/z 467,1 469,1 [MN+].

Example 53

N-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide

APCI-MS: m/z 471,1 473,1 [MN+].

Comparative Example 54

1-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-3-(1H-indol-7-yloxy)propan-2-ol

APCI-MS: m/z 435,1 437,1 [MN+].

Example 55

1-(7-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}indol-1-yl)alanon

APCI-MS: m/z 477,1 479,1 [MN.

Example 56

N-(4-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)ndimethylacetamide

APCI-MS: m/z 429,1 431,1 [MN-]

Example 57

N-(243-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide

APCI-MS: m/z 471,1 473,1 [MN+].

Example 58

N-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide

APCI-MS: m/z 467,1 469,1 [MN-]

Example 59

N-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 453,1 455,1 [MN-]

Example 60

N-(5-Chloro-2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 453,1 455,1 [MN-]

Example 61

N-{3-Acetyl-2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide

APCI-MS: m/z 475,3 [MN+].

Example 62

N-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide

APCI-MS: m/z 433,1 [MN+].

Example 63

N-(243-[4-(4-Chlorphen the si)piperidine-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide

APCI-MS: m/z 437,1 [MN+].

Comparative Example 64

1-[4-(4-Chlorophenoxy)piperidine-1-yl]-3-(1H-indol-7-yloxy)propan-2-ol

APCI-MS: m/z 401,1 [MN+].

Example 65

1-(7-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}indol-1-yl)alanon

APCI-MS: m/z 443,1 [MN+].

Example 66

N-(4-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)ndimethylacetamide

APCI-MS: m/z 495,3 [MN+].

Example 67

N-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide

APCI-MS: m/z 437,1 [MN+].

Example 68

N-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide

APCI-MS: m/z 433,1 [MH+].

Example 69

N-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 419,1 [MH+].

Example 70

N-{5-Chloro-2-[3-(8-chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy}phenyl}ndimethylacetamide

APCI-MS: m/z 448,1 of 450.1 [MN-]

Example 71

N-{3-Acetyl-2-[3-(8-chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-5-were}ndimethylacetamide

APCI-MS: m/z 470,1 [MH+].

Example 72

N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-4-were}ndimethylacetamide

APCI-MS: m/z 428,1 [MH+].

Example 73

N42-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-5-forfinal}ndimethylacetamide

APCI-MS: m/z 432,1 [MH+].

Example 74

1-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-3-(1H-indol-7-yloxy)propan-2-ol

APCI-MS: m/z 396,1 [MN-]

Use the 75

1-{7-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]indol-1-yl}alanon

APCI-MS: m/z 438,1 [MN-]

Example 76

N-{4-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]biphenyl-3-yl}ndimethylacetamide

APCI-MS: m/z 490,1 [MN-]

Example 77

N-(2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-4-forfinal}ndimethylacetamide

APCI-MS: m/z 432,1 [MN-]

Example 78

N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-5-were}ndimethylacetamide

APCI-MS: m/z 428,1 [MN-]

Example 79

N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]phenyl}ndimethylacetamide

APCI-MS: m/z 414,1 [MN+].

Example 80

N - (5-Chloro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy}phenyl}ndimethylacetamide

APCI-MS: m/z 432,1 [MN-]

Example 81

N-{3-Acetyl-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-5-were}ndimethylacetamide

APCI-MS: m/z of 454.3 [MN-]

Example 82

N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-4-were}ndimethylacetamide

APCI-MS: m/z 412,1 [MN-]

Example 83

N-[5-fluoro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy}phenyl}ndimethylacetamide

APCI-MS: m/z 416,1 [MH-]

Example 84

1-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-3-(1H-indol-7-yloxy)propan-2-ol

APCI-MS: m/z 380,1 [MH-]

Example 85

1-{7-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]indol-1-yl}-e is anon

APCI-MS: m/z 422,1 [MH-]

Example 86

N-{4-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]biphenyl-3-yl}ndimethylacetamide

APCI-MS: m/z 474,3 [MH-]

Example 87

N-{4-fluoro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy}phenyl}ndimethylacetamide

APCI-MS: m/z 416,1 [MN+].

Example 88

N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-5-were)ndimethylacetamide

APCI-MS: m/z 412,1 [MN+].

Example 89

N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-phenyl}ndimethylacetamide

APCI-MS: m/z 398,1 [MH+].

Example 90

N-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 453, 455 [MH+].

Example 91

Methyl ester 3-(2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid

APCI-MS: m/z 482, 484 [MN+].

Example 92

1-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-3-(2,6-dimethoxyphenoxy)propan-2-ol

APCI-MS: m/z 456, 458 [MH+].

Example 93

1-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-3-(2-methoxyphenoxy)propan-2-ol

APCI-MS: m/z 426, 428 [MH+].

Example 94

2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide

APCI-MS: m/z 467, 469 [MH+].

Example 95

1-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he

APCI-MS: m/z 452, 454 [MH+].

Example 96

1-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)alanon

APCI-MS: m/z 438, 440 [MH+].

Por the measures 97

Methyl ester 3-(2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid

APCI-MS: m/z 418 [MN+].

Example 98

1-(2,6-Dimethoxyphenoxy)-3-[3-(4-pertenece)pyrrolidin-1-yl]propane-2-ol

APCI-MS: m/z 392 [MN+].

Example 99

1-[3-(4-Pertenece)pyrrolidin-1-yl]-3-(2-methoxyphenoxy)propan-2-ol

APCI-MS: m/z 362 [MH+].

Example 100

Methyl ether (2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid

APCI-MS: m/z 447 [MH+].

Example 101

Methyl ether (2-{3-[3-(4-chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid

APCI-MS: m/z 491 [MH+].

Example 102

Methyl ester 2-(2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid

APCI-MS: m/z 475 [MH+].

Example 103

2-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide

APCI-MS: m/z 403 [MH+].

Example 104

1-(2-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)alanon

APCI-MS: m/z 404 [MH+].

Example 105

1-(2-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he

APCI-MS: m/z 388 [MH+].

Example 106

1-(2-{3-[3-(4-Pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)alanon

APCI-MS: m/z 374 [MH+].

Example 108

Methyl ester 3-(2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid

APCI-MS: m/z 436 [MN+]./p>

Example 109

1-[3-(3,4-Divergence)pyrrolidin-1-yl]-3-(2-methoxyphenoxy)propan-2-ol

APCI-MS: m/z 380 [MH+].

Example 110

Methyl ether (2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid

APCI-MS: m/z 465 [MH+].

Example 111

2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide

APCI-MS: m/z 421 [MN+].

Example 112

1-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)alanon

APCI-MS: m/z 422 [MH+].

Example 113

1-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he

APCI-MS: m/z 406 [MN+].

Example 114

1-(2-{3-[3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)alanon

APCI-MS: m/z 392 [MN+].

Example 115

N-(2-{3-[4-(3,4-Dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 452,1 [MN+].

Example 116

Methyl ester 3-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid

APCI-MS: m/z 434 [MH+].

Example 117

1-[3-(4-Chlorphenoxy)-pyrrolidin-1-yl]-3-(2,6-dimethoxyphenoxy)-propan-2-ol

APCI-MS: m/z 408 [MH+].

Example 118

1-[3-(4-Chlorphenoxy)-pyrrolidin-1-yl]-3-(2-methoxyphenoxy)-propan-2-ol

APCI-MS: m/z 378 [MN+].

Example 119

Methyl ether (2-(3-[3-(4-Chlorphenoxy)-pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid

APCI-MS: m/z 463 [MH+].

Example 120

Methyl ester 2-(-{3-[3-(4-Chlorphenoxy)-pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid

APCI-MS: m/z 491 [MH+].

Example 121

2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide

APCI-MS: m/z 419 [MH+].

Example 122

1-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)alanon

APCI-MS: m/z 420 [MH+].

Example 123

1-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he

APCI-MS: m/z 404 [MH+].

Example 124

1-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)alanon

APCI-MS: m/z 390 [MH+].

Example 125

N-(2-{3-[3-(4-Cianfrocca)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 396 [MH+].

Example 126

Methyl ester 3-(2-{3-[3-(4-cianfrocca)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid

APCI-MS: m/z 425 [MH+].

Example 127

Methyl ether (2-{3-[3-(4-cianfrocca)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid

APCI-MS: m/z 454 [MH+].

Example 128

2-{3-[3-(4-Cianfrocca)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide

APCI-MS: m/z 410 [MH+].

Example 129

4-{1-[2-Hydroxy-3-(2-propionyloxy)propyl]pyrrolidin-3-yloxy}benzonitrile

APCI-MS: m/z 395 [MH+].

Example 130

N-(2-{2-Hydroxy-3-[3-(4-methoxyphenoxy)pyrrolidin-1-yl]propoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 401 [MH+].

Example 131

N-(4-Chloro-2-{3-[4-(3,4-dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 486 [MH+].

Example 132

Methyl ester 3-(2-{3-[-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid

APCI-MS: m/z 468, 470 [MH+].

Example 133

1-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-3-(2-methoxyphenoxy)propan-2-ol

APCI-MS: m/z 412, 414 [MH+].

Example 134

Methyl ether (2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid

APCI-MS: m/z 497, 499 [MH+].

Example 135

Methyl ester 2-(2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid

APCI-MS: m/z 525, 527 [MH+].

Example 136

2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide

APCI-MS: m/z 453, 455 [MH+].

Example 137

1-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)alanon

APCI-MS: m/z 454,456 [MH+].

Example 138

1-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he

APCI-MS: m/z 438, 440 [MH+].

Example 139

1-(2-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)alanon

APCI-MS: m/z 424,426 [MH+].

Example 140

N-(2-{3-[4-(3,4-Divergence)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 421 [MH+].

Example 141

Methyl ester 3-(2-{3-[4-(3,4-divergence)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid

APCI-MS: m/z 450 [MH+].

Example 142

2-{3-[4-(3,4-Divergence)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide

APCI-MS: m/z 435 [MH+].

Example 143

1-(2-{3-[4-(3,4-Divergence)piperidine-1-yl]-2-hydroxypropoxy}phenyl)p is opan-1-he

APCI-MS: m/z 420 [MH+].

Example 144

Methyl ether (2-{3-[4-(3,4-divergence)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid

APCI-MS: m/z 479 [MH+].

Example 145

N-(2-(3-[3-(3,4-Diferenciate)piperidine-1-yl]-2-hydroxypropoxy)phenyl)ndimethylacetamide

APCI-MS: m/z 435 [MH+].

Example 146

N-(2-{3-[4-(4-Pertenece)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 403 [MH+].

Example 147

Methyl ester 3-(2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid

APCI-MS: m/z 432 [MH+].

Example 148

1-(2,6-Dimethoxyphenoxy)-3-[4-(4-pertenece)piperidine-1-yl]propane-2-ol

APCI-MS: m/z 406 [MN+].

Example 149

1-[4-(4-Pertenece)piperidine-1-yl]-3-(2-methoxyphenoxy)propan-2-ol

APCI-MS: m/z 376 [MH+].

Example 150

1-(2-{3-[4-(4-Pertenece)piperidine-1-yl]-2-hydroxypropoxy}phenyl)alanon

APCI-MS: m/z 388 [MN+].

Example 151

2-{3-[4-(4-Pertenece)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide

APCI-MS: m/z 417 [MH+].

Example 152

1-(2-{3-[4-(4-Pertenece)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he

APCI-MS: m/z 402 [MN+].

Example 153

Methyl ether (2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid

APCI-MS: m/z 461 [MH+].

Example 154

N-(2-{3-[3-(4-Forfinancial)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 417 [MH+].

Example 155

Methyl ester 3-(2-(3-[3-4-forfinancial)piperidine-1-yl]-2-hydroxypropoxy)phenyl)propionic acid

APCI-MS: m/z 446 [MH+].

Example 156

1-[3-(4-Forfinancial)piperidine-1-yl]-3-(2-methoxyphenoxy)propan-2-ol

APCI-MS: m/z 390 [MH+].

Example 157

1-(2-{3-[3-(4-Forfinancial)piperidine-1-yl]-2-hydroxypropoxy)phenyl)alanon

APCI-MS: m/z 402 [MN+].

Example 158

Methyl ester 2-(2-{3-[3-(4-forfinancial)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid

APCI-MS: m/z 503 [MN+].

Example 159

2-{3-[3-(4-Forfinancial)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide

APCI-MS: m/z 431 [MH+].

Example 160

1-(2-{3-[3-(4-Forfinancial)piperidine-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)alanon

APCI-MS: m/z 432 [MH+].

Example 161

N-(2-{3-[4-(4-Acetylaminophenol)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 442 [MH+].

Example 162

N-(4-{1-[3-(2-Acetylphenol)-2-hydroxypropyl]piperidine-4-yloxy}phenyl)ndimethylacetamide

APCI-MS: m/z 427 [MH+].

Example 163

N-(4-Cyano-2-{3-[4-(3,4-dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 477 [MH+].

Example 164

Methyl ester 3-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid

APCI-MS: m/z 448 [MH+].

Example 165

1-[4-(4-Chlorphenoxy)-piperidine-1-yl]-3-(2-methoxyphenoxy)propan-2-ol

APCI-MS: m/z 392 [MH+].

Example 166

1-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)alanon

APCI-MS: m/z 404 [MH+].

Example 167

Marked the th ether 2-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid

APCI-MS: m/z 505 [MH+].

Example 168

2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide

APCI-MS: m/z 433 [MH+].

Example 169

1-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)alanon

APCI-MS: m/z 434 [MH+].

Example 170

1-(2-{3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he

APCI-MS: m/z 418 [MH+].

Example 171

Methyl ether (2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid

APCI-MS: m/z 477 [MH+].

Example 172

N-(2-{3-[3-(4-chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 433 [MH+].

Example 173

Methyl ester 3-(2-{3-[3-(4-chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid

APCI-MS: m/z 462 [MH+].

Example 174

1-(2-{3-[3-(4-Chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)alanon

APCI-MS: m/z 418 [MN+].

Example 175

2-{3-[3-(4-Chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide

APCI-MS: m/z 447 [MH+].

Example 176

1-(2-{3-[3-(4-Chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-he

APCI-MS: m/z 432 [MH+].

Example 177

N-[2-({(1R,2R)-2-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-1-hydroxycyclopent}methoxy)phenyl]ndimethylacetamide

Example 178

The hydrochloride of methyl(2S,4R)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-[(4-Chlorobenzyl)oxy]-2-pyrrolidinecarboxylic

Note the market 179-189

Educt:

A) (3,4-Dichlorophenyl)piperidine-4-ylamine

In a nitrogen-filled reaction vessel was dissolved tert-butyl ether 4-oxo-piperidine-1-carboxylic acid (2,46 g, 12.3 mmol) and 3,4-dichlorophenylamino (1.0 g, 6,17 mmol) in dichloromethane (28 ml) and acetic acid (2,12 ml). At room temperature was added triacetoxyborohydride sodium (3,67 g, 17.3 mmol). The reaction mixture was stirred overnight and then poured into a solution of sodium bicarbonate (5%). The aqueous phase three times was shaken with ethyl acetate (EtOAc). The combined organic phase was dried over sodium sulfate, evaporated and purified by flash chromatography (EtOAc:heptane 3:7) to obtain 1.7 g, 81% purified compounds. Specified in the title compound, protected by butyloxycarbonyl (SIDE), was dissolved in dichloromethane (26 ml) and triperoxonane acid (13 ml) and stirred at room temperature for 3 h, evaporated and dissolved in diethyl ether and sodium hydroxide (1 M). The organic layer was separated and the aqueous phase is twice washed with simple ether. The combined organic layer was washed with a small amount of brine, dried over sodium sulfate and evaporated obtaining of 1.15 g (76%) specified in the connection header.

1H-NMR (400 MHz, DMSO-d6): δ then 7.20 (d, 1H, J=8,9 Hz), 6.73 x (d, 1H, J=2.7 Hz), is 6.54 (dd, 1H, J=8,8, 2.7 Hz), 5,95 (d, 1H, J=8.1 Hz), up 3.22 (m, 1H), 2.91 in (bd, 2H, J=12,6 Hz), of 2.51 (m, 2), 2,02 (bs, 1H), 1,81 (bd, 2H, J=12,4 Hz), 1,18 (m).

APCI-MS: m/z 245 [M+].

B) (4-Chlorophenyl)piperidine-4-ylamine

Synthesized as (A), from tert-butyl ether 4-oxo-piperidine-1-carboxylic acid (3,59 g, 18.0 mmol), 4-chlorpheniramine (1,15 g, 9.0 mmol) and triacetoxyborohydride sodium (5.34 g, to 25.2 mmol) in dichloromethane (40 ml) and acetic acid (3.1 ml). Remove protection conducted in dichloromethane (37 ml) and triperoxonane acid (18 ml). Output 1.5 g, 79%.

1H-NMR (400 MHz, DMSO-d3): δ 7,40 (d, 2H, J=8,9 Hz), 6,55 (d, 2H, J=8,9 Hz), 5,62 (d, 1H, J=8.1 Hz), 3,18 (m, 1H), 2,92 (bd, 2H, J=12,6 Hz)of 2.50 (m, 2H), 1,99 (bs, 1H), equal to 1.82 (d, 2H, J=a 12.7 Hz), of 1.18 (m, 2H).

APCI-MS: m/z 211 [MH+].

In) (4-Forfinal)piperidine-4-ylamine

Synthesized as (A), from tert-butyl ether 4-oxo-piperidine-1-carboxylic acid (3,59 g, 18.0 mmol), 4-ftorhinolona (1.0 g, 9.0 mmol) and triacetoxyborohydride sodium (5.34 g, to 25.2 mmol) in dichloromethane (40 ml) and acetic acid (3.1 ml). Remove protection conducted in dichloromethane (37 ml) and triperoxonane acid (18 ml). Output 1.1 g, 63%.

1H-NMR (400 MHz, DMSO-d6): δ 6,85 (t, 2H, J=9.0 Hz), 6,51 (dd, 2H, J=9,1, 4.6 Hz), 5,27 (d, 1H, J=8,2 Hz), 3,13 (m, 1H), 2,89 (bd, 2H, J=12,5 Hz), 2,48 (m, 2H), 1,80 (bd, 2H, J=12.3 Hz), 1.14 in (m, 2H).

APCI-MS: m/z 195 [MH+].

G) (3,4-Differenl)piperidine-4-ylamine

Synthesized as (A), from tert-butyl ether 4-oxo-piperidine-1-carboxylic acid (3,59 g, 18.0 mmol), 3,4-dipertanyakan (1,16 g, 9.0 mmol) and triacetoxy the reed sodium (5.34 g, of 25.2 mmol) in dichloromethane (40 ml) and acetic acid (3.1 ml). Remove protection conducted in dichloromethane (37 ml) and triperoxonane acid (18 ml). Yield 1.26 g, 66%.

1H-NMR (400 MHz, DMSO-d6): δ 7,05 (dt, 1H, J=10,8, 9,2 Hz), 6,50 (ddd, 1H, J=14,1, 7,0, 2,8 Hz), 6,32 (bd, 1H, J=9,20 Hz), 5,64 (d,1H, J=8,14 Hz), 3,17 (m, 1H), 2,90 (bd, 2H, J=12,6 Hz)of 2.50 (m, 2H), 2,00 (bs, 1H), 1,81 (bd, 2H, J=12,6 Hz)of 1.16 (m, 2H).

APCI-MS: m/z 213[MH+].

Example 179

N-(2-{3-[4-(3,4-Dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}-4-were)ndimethylacetamide

APCI-MS: m/z 466 [MH+].

Example 180

N-(2-{3-[4-(4-Chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 418 [MH+].

Example 181

N-(4-Chloro-2-{3-[4-(4-chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 452 [MH+].

Example 182

N-(2-{3-[4-(4-Chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-cyanophenyl)ndimethylacetamide

APCI-MS: m/z 443 [MH+].

Example 183

N-(2-{3-[4-(4-Chloroaniline)-1-piperidinyl]-2-hydroxypropoxy}-4-were)ndimethylacetamide

APCI-MS: m/z 432 [MH+].

Example 184

N-(5-Chloro-2-{3-[4-(4-foronline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 436 [MN+].

Example 185

N-(5-Chloro-2-{3-[4-(3,4-diptiranjan)-1-piperidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 454 [MH+].

Example 186

N-(5-Cyano-2-{3-[4-(4-foronline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 427 [MH+].

Example 187

N-(5-Cyano-2-{3-[4-(3,4-diptiranjan)-1-piperidinyl]-2-hydroxyp is epoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 445 [MN+].

Example 188

N-(2-{3-[4-(4-Foronline)-1-piperidinyl]-2-hydroxypropoxy}-4-were)ndimethylacetamide

APCI-MS: m/z 416 [MH+].

Example 189

N-(2-{3-[4-(3,4-Diptiranjan)-1-piperidinyl]-2-hydroxypropoxy}-4-were)ndimethylacetamide

APCI-MS: m/z 434 [MH+].

Example 190

N-(2-{3-[3(S)-{4-Parfenov)propman-1-yl]-2-(R)-hydroxypropoxy)ndimethylacetamide

1) 3-(S)-(4-Chlorphenoxy)pyrrolidin CF3COOH

To a solution of triphenylphosphine (4,2 g, 16,02 mmol) in THF (75 ml) at 0°With added diethylazodicarboxylate (2,52 ml)over 15 min was added 4-chlorophenol (2,05 g, 16,02 mmol)and after 10 min was slowly added tert-butyl ester 3-hydroxy-pyrrolidin-1-carboxylic acid (3.0 g, 16,02 mmol) in THF (20 ml). After the addition the ice bath was removed and the reaction mixture is maintained at room temperature during the night. The solvent was removed in vacuum and the residue was stirred with diethyl ether, the solid triphenylphosphine was filtered. The residue was purified by flash chromatography (0-0,5% Meon in CHCl3) obtaining specified in the subtitle compound (3,65 g, 76%)which was dissolved in dichloromethane (60 ml), and added triperoxonane acid (15 ml). The reaction mixture for 30 min was maintained at room temperature. The solvent was removed in vacuum. The residue was dissolved in dichloromethane, was added diethyl ether and hexane. Solid ve is estvo was filtered with getting 3,70 g, 97%indicated in the subtitle of the connection.

1H-NMR (CDCl3, 400 MHz): δ and 10.20 (s, 1H), 9,99 (s, 1H), 7,25 (d, J 8,8 Hz, 2H), 6,78 (d, J 8,8 Hz, 2H), 4,99 (m, 1H), 3,41 (m, 4H), 2,30 (m, 1H), measuring 2.20 (m, 1H).

APCI-MS: m/z 198 (MH+).

2) N-(2-{3-[3(S)-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-(R)-hydroxypropoxy)ndimethylacetamide

A mixture of 3-(S)-(4-chlorphenoxy)pyrrolidine CF3COOH (312 mg, 1.0 mmol), N-acetyl-2-(2,3-epoxypropoxy)aniline (207 mg, 1.0 mmol), K2CO4(560 mg) in EtO (10 ml) was stirred at 65°C for 4 h the Solvent was removed in vacuum. The residue was distributed between ethyl acetate and water. The organic layer was washed with an aqueous solution NHCl, then water. The organic layer was dried over Na2SO4, filtered, concentrated. The residue was purified by flash chromatography (0-3% Meon in CHCl3with a mixture of diastereoisomers (310 mg, 77%). Diastereoisomers were separated by high-performance liquid chromatography (HPLC) to obtain N-(2-{3-[3(S)-(4-chlorphenoxy)pyrrolidin-1-yl]-2-(R)-hydroxypropoxy)ndimethylacetamide (57 mg).

1H-NMR (CDCl3, 400 MHz): δ at 8.36 (m, 1H), of 8.25 (s, 1H), 7,25 (m, 2H), 6,99 (m, 2H), 6,93 (m, 1H), 6.75 in (m, 2H), 4,80 (m, 1H), 4,08 (m, 2H), 3.96 points (m, 1H), 3,11 (dd, J 5,9, and 10.5 Hz, 1H), 3,01 (m, 1H), 2,82 (m, 2H), at 2.59 (m, 1H), of 2.51 (dd, J 3.2, and 12.0 Hz, 1H), to 2.29 (m, 1H), 2,19 (s, MN), a 2.01 (m, 1H). APCI-MS: m/z 405 (MH+).

Example 191

The hydrochloride of N-(2-{3-[3S-(4-chlorphenoxy)pyrrolidin-1-yl]-2S-hydroxypropoxy}phenyl)ndimethylacetamide

The reaction is carried out is similar to Example 190.

1H-NMR (CDCl3, 400 MHz): δ 8,35 (m, 1H), compared to 8.26 (s, 1H), 7,24 (m, 2H), 6,99 (m, 2H), 6,92 (m, 1H), 6.75 in (m, 2H), 4,80 (m, 1H), 4,12 (m, 2H), 3,95 (m, 1H), 2.95 and (m, 2H), 2,80 (m, MN), 2,52 (dd, 3,4, and 12.2 Hz, 1H), 2,30 (m, 1H), 2,19 (s, 3H), 2,01 (m, 1H).

APCI-MS: m/z 405 (MH*).

Example 192

N-(2-{3-[3(R)-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-(S)-hydroxypropoxy}phenyl)ndimethylacetamide

The reaction was carried out analogously to Example 190.

1H-NMR (CDCl3, 400 MHz):δ at 8.36 (m, 1H), of 8.25 (s, 1H), 7,25 (m, 2H), 6,99 (m, 2H), 6,93 (m, 1H), 6.75 in (m, 2H), 4,80 (m, 1H), 4,08 (m, 2H), 3.96 points (m, 1H), 3,11 (dd, J of 5.9, 10.5 Hz, 1H), 3,01 (m, 1H), 2,82 (m, 2H), 2,59 (m, 1H), of 2.51 (dd, J 3.2, and 12.0 Hz, 1H), to 2.29 (m, 1H), 2,19 (s, MN), a 2.01 (m, 1H).

APCI-MS: m/z 405 (MH+).

Example 193

N-[5-Chloro-2-({(2S)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide

The reaction was carried out analogously to Example 190.

1H-NMR (CDCl3, 400 MHz): δ to 8.45 (m, 1H), at 8.36 (br. S, 1H), 7.23 percent (m, 2H), 6,95 (m, 1H), 6,85 (m, 1H), 6.75 in (m, 2H), 4,80 (m, 1H), 4,07 (m, 2H), 3,91 (m, 1H), 2.95 and (m, 2H), 2,80 (m, 3H), 2.49 USD (dd, J 3.2, and 12.0 Hz, 1H), 2,30 (m, 1H), 2,19 (s, 3H), 2,03 (m,1H).

APCI-MS: m/z 439 (MH+).

Example 194

N-[5-chloro-2-({(2R)-3-[(3R)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide

The reaction was carried out analogously to Example 190.

1H-NMR (CDCl3, 400 MHz): δ to 8.45 (m, 1H), at 8.36 (br. S, 1H), 7.23 percent (m, 2H), 6,95 (m, 1H), 6,85 (m, 1H), 6.75 in (m, 2H), 4,80 (m, 1H), 4,07 (m, 2H), 3,91 (m, 1H), 2.95 and (m, 2H), 2,80 (m, 3H), 2.49 USD (dd, J 3.2, and 12.0 Hz, 1H), 2,30 (m, 1H), 2,19 (s, 3H), 2,03 (m, 1H).

APCI-MS: m/z 439 (MH+).

Example 195

N-[5-Chloro-2-({(2S)-3-[(3R)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}OK and)phenyl]ndimethylacetamide

The reaction was carried out analogously to Example 190.

1H-NMR (CDCl3, 400 MHz): δ to 8.45 (m, 1H), 8.34 per (br. S, 1H), 7,22 (m, 2H), 6,94 (m, 1H), 6,85 (m, 1H), 6.75 in (m, 2H), 4,80 (m, 1H), 4,08 (m, 2H), 3,90 (m, 1H), 3,11 (dd, J of 5.9, 10.5 Hz, 1H), to 3.02 (m, 1H), 2,81 (m, 2H), 2,58 (m, 1H), 2.49 USD (dd, J 3.5-inch, 12.1 Hz, 1H)that is 2.30 (m, 1H), 2,18 (s, 3H), 2,01 (m, 1H).

APCI-MS: m/z 439 (MH+).

Example 196

N-[5-chloro-2-({(2R)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide

The reaction was carried out analogously to Example 190.

1H-NMR (CDCl3, 400 MHz): δ to 8.45 (m, 1H), 8.34 per (br. S, 1H), 7,22 (m, 2H), 6,94 (m, 1H), 6,85 (m, 1H), 6.75 in (m, 2H), 4,80 m. 1H), 4,08 (m, 2H), 3,90 (m, 1H), 3,11 (dd, J of 5.9, 10.5 Hz, 1H), to 3.02 (m, 1H), 2,81 (m, 2H), 2,58 (m, 1H), 2.49 USD (dd, J 3.5-inch, 12.1 Hz, 1H), 2,30 (m, 1H), 2,18 (s, 3H), 2,01 (m, 1H).

APCI-MS: m/z 439 (MH+).

Example 197

N-(2-{3-[3-(4-Chlorphenoxy)-pyrrolidin-1-yl]-2-hydroxypropoxy}-4,5-differenl)ndimethylacetamide

1) 4,5-Debtor-2-NITROPHENOL

In the flask was dissolved 3,4-diferena (3,10 g, with 23.7 mol) in acetic acid (15 ml). To the stirred solution was added dropwise a solution of fuming HNO3(1.25 g, 29.7 mmol) in acetic acid (6 ml). The temperature was maintained below 50°throughout the addition. After complete addition, the mixture was stirred for another one hour. The reaction mixture was then poured into a mixture of ice-water, causing the precipitation of a yellowish solid. The solid is collected by filtration and dried. The solid was purified on silica (EtOAc 5:1) to obtain specified in the subtitle compound (2,05 g, 50%) as a yellow oil, which upon standing crystallized.

1H-NMR (400 MHz, CDCl3): δ 10,61 (1H, s); 8,00 (1H, dd, J of 9.6 and 8.2 Hz); 7,00 (1H, dd, J of 10.4, 6.8 Hz).

2) N-(4,5-Debtor-2-hydroxyphenyl)ndimethylacetamide

To the flask was added the product obtained in stage (1) (0,59 g, 3,37 mmol), and acetic acid (10 ml). The solution was heated under stirring to 90°and added tin (powder, 1,60 g, 13.5 mmol). The flask was corked and was heated with stirring for a further one hour and the hot solution was filtered through celite. The filter is then washed with another 10 ml of hot acetic acid. To the filtrate was added water (25 ml) and acetamiprid (0.5 ml, of 5.29 mmol)and the resulting mixture was heated under stirring at 60°C for 20 minutes. The mixture was allowed to cool and was distributed between EtOAc and water. The organic phase was collected and washed with water and brine. The organic phase was evaporated to obtain 0,63 g (100%) specified in the subtitle compound as a solid substance.

1H-NMR (400 MHz, DMSO-d6): δ of 10.25 (1H, s); 9,31 (1H, bs); 7,88 (1H, dd, J 12,8, 7.9 Hz); 6,83 (1H, dd, J 12,1, 7,7 Hz); of 2.08 (3H, s).

3) N-(4,5-Debtor-2-oxiranylmethyl)ndimethylacetamide

To the vessel was added the compound obtained in stage (2) (0.4 g, 2,137 mmol), epibromohydrin (0.35 g, 2.55 mmol), K2CO3(0.6 g, 4.4 mmol) and DMF (2 ml). The corked vessel and heated with stirring for 2 hours, 60°). The mixture is then distributed between EtOAc and water and the organic phase is washed twice with water and once with brine, and finally evaporated to obtain a brown solid. The crude epoxide was purified on silica to obtain 0.27 g (52%) indicated in the subtitle compound as a slightly pink solid.

1H-NMR (400 MHz, CDCl3): δ of 8.37 (1H, dd, J 12,2, 8,8 Hz); a 7.85 (1H, bs), is 6.78 (1H, dd, J 11,2, 7,1 Hz); 4,34 (1H, dd, 11,5, 2,2 Hz); 3,90 (1H, dd, 11,6, 6.3 Hz); 3,40-to 3.36 (1H, m); 2,98 (1H, t, J 4.5 Hz); of 2.81 (1H, dd, J of 4.7, and 6.3 Hz); 2,22 (3H, s).

4) N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4,5-differenl)ndimethylacetamide

To the vessel was added the compound obtained in stage (3) (0,059 g, 0.24 mmol), 3-(4-chlorphenoxy)pyrrolidin (0,048 g, 0.24 mmol) and ethanol (2 ml, 99.5%pure). The corked vessel, and the contents were heated with stirring to 75°C for 2 hours. The crude solution was evaporated and the resulting oil was purified on silica to the specified in the title compound, which liofilizirovanny as hydrochloride. Specified in the title compound was obtained as a white solid (0.075 g, 65%). This compound was a mixture of four stereoisomers, which had effect on the NMR spectra.

1H-NMR (400 MHz, DMSO-d6): δ 10,78-10,30 (1H, m); of 9.30 (1H, s); 8,07 (1H, dd, J 12,8, and 9.3 Hz); 7,40-7,34 (2H, m); 7.23 (1H, dd, J 12,7, 7.5 Hz); 7,05-6,99 (2H, m); to 6.19 (1H. bs); 5,23-5,11 (1H, m); of 4.35 (1H, bs); 4,08-3,97 (1,5H, m); 3.96 points-are 3.90 (1H, m); 3,84-3,70 (1,5H, m); 3,63 is 3.23 (4H, m); 2,66 is 2.00 (5H, m).

APCI-MS: m/z 411,1 [MlH+].

Example 198

N-{5-X is the PR-2-[2-hydroxy-3-(3-phenoxypyridine-1-yl)propoxy]phenyl}ndimethylacetamide

The compound was obtained analogously to Example 197.

1H-NMR (400 MHz, DMSO-d6): δ 10,80-10,36 (1H, m); 9.26 (1H, s); to 8.14 (1H, s); to 7.32 (2H, t, J 8.35 Hz); 7,11-to 6.95 (5H, m); of 6.31-of 6.02 (1H, m); 5,24-5,12 (1H, m); 4,37 (1H, bs); 4,10-3,97 (1,5H, m); 3.95 to 3,88 (1H, m); 3,84-3,68 (1,5H, m); 3,64-3,26 (4H, m); 2,65-2,52 (0,5H, m); 2,35-2,02 (4,5H, m).

APCI-MS: m/z 405,2 [MH+].

Example 199

N-(5-Chloro-2-{2-hydroxy-3-[3-(4-nitrophenoxy)pyrrolidin-1-yl]propoxy]phenyl)ndimethylacetamide

The compound was obtained analogously to Example 197.

1H-NMR (400 MHz, DMSO-d6): δ 10,95-10,48 (1H, m); 9,26 (1H, s); 8,24 (2H, d, J 9.6 Hz); 8,13 (1H, bs); 7.23 percent-7,17 (2H, m); 7,12-7,02 (2H, m); of 6.20 (1H, bs); 5,43-and 5.30 (1H, m); to 4.38 (1H, m); 4,18-4,06 (0,5H, m); 4,05-of 3.97 (1H, m); 3.95 to a 3.87 (1H, m); 3,86-3,72 (1,5H, m); 3,69-of 3.27 (4H, m); 2,73-2,60 (0,5H, m); 2,46-2,08 (4,5H, m).

APCI-MS: m/z of 450.1 [MH+].

Example 200

N-(5-Acetyl-2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

The compound was obtained analogously to Example 197.

APCI-MS: m/z 481,2, 483,2 [MN+].

Example 201

Methyl ester of 4-acetylamino-3-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoic acid

The compound was obtained analogously to Example 197.

APCI-MS: m/z 497,1, 499,2 [MH+].

Example 202

N-(3-{3-[3-(3,4-Dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}naphthalene-2-yl)ndimethylacetamide

The compound was obtained analogously to Example 197.

APCI-MS: m/z 489,2, 491,2 [MH+].

Example 203

N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-cyanophenyl)ndimethylacetamide

Indicated the data in the title compound was obtained in accordance with the method in Example 197.

APCI-MS: m/z 430,2 [MN+].

Example 204

Methyl ester of 4-acetylamino-3-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoic acid

The compound was obtained analogously to Example 197.

APCI-MS: m/z 463,2 [MH+].

Example 205

N-(3-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}naphthalene-2-yl)ndimethylacetamide

Specified in the title compound was obtained in accordance with the method in Example 197.

APCI-MS: m/z to 455.2 [MH+].

Example 206

N-(5-Cyano-2-[3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

Specified in the title compound was obtained in accordance with the method in Example 197.

APCI-MS: m/z 478,2, 480,1 [MH+].

Example 207

N-(2-{3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-triptoreline)ndimethylacetamide

Specified in the title compound was obtained in accordance with the method in Example 197.

APCI-MS: m/z 521,1, 523,2 [MH+].

Example 208

Triptorelin N-(5-chloro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

Specified in the title compound was obtained in accordance with the method in Example 197.

APCI-MS: m/z 423,1, 424,9 [MH+].

Example 209

Triptorelin N-(5-acetyl-2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

1) N-(5-Acetyl-2-oxiranylmethyl)ndimethylacetamide

To a solution of 4-acetyl-2-NITROPHENOL (0.50 g, was 2.76 mmol) in THF (2 ml) was added 10% Pd/C (0.15 g). The resulting mixture was first made H2when the pressure 1,01325×105PA (1 ATM.) for 5 hours, then filtered through celite and evaporated to obtain 0,63 g of red oil. Was added water (20 ml) and acetamiprid (0.35 g, 3,44 mmol)and the mixture was thoroughly stirred for 5 minutes. The reaction mixture was then heated with stirring to 60°C for 30 minutes and then allowed to cool. Formed red solid, and the precipitate was collected by filtration, washed with water and dried to obtain 0.27 g (1,40 mmol) of N-(5-acetyl-2-hydroxyphenyl)ndimethylacetamide. It was dissolved in DMF (5 ml). Added K2CO3(0.34 g, 2.45 mmol) and epibromohydrin (0.21 g, 1.54 mmol)and the resulting mixture was heated under stirring at 50°C for 3 hours. The mixture was distributed between EtOAc and water 40+40 ml of the Organic phase is washed twice with water and once with brine and finally concentrated in vacuo to obtain a red oil. The crude product was purified on silica (heptane/EtOAc, 1:2-1:4) to obtain 110 mg (16%) indicated in the subtitle of the connection.

1H-NMR (400 MHz, CDCl3): δ 9,03 (1H, d, J 1.9 Hz), 7,81 (1H, bs), 7,74 (1H, dd, J to 8.6, 2.3 Hz), of 6.96 (1H, d, J 8.6 Hz), 4,48 (1H, dd, J of 11.3, 2.4 Hz), 4,00 (1H, dd, J of 11.4, 6.4 Hz), 3,45 is 3.40 (1H, m), 2,99 (1H, t, J 4.4 Hz), and 2.79 (1H, dd, J 4,7, and 2.6 Hz), at 2.59 (3H, s), and 2.26 (3H, s).

2) Triptorelin N-(5-acetyl-2-{3-[3-(4-chlorphenoxy)Pirro is one-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

Specified in the title compound was obtained in accordance with the method described in Example 197.

APCI-MS: m/z 447, 449 [MH+].

Example 210

N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)methanesulfonamide

1) of the Dihydrochloride of 1-(2-aminophenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-propanol

A mixture of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide (0.95 g, 2.34 mmol) and concentrated hydrochloric acid (25 ml) was heated (100-105° (C) for 3 hours, then was allowed to stand at room temperature overnight. The mixture was concentrated under reduced pressure to one third of its volume, podslushivaet saturated sodium bicarbonate. The resulting suspension was extracted twice with ethyl acetate. The organic extracts were dried, the solvent evaporated under reduced pressure to obtain a pale brown oil. The oil was dissolved in minimum amount of methanol, diluted with ethyl ether, and the product was besieged by adding ethyl ether saturated with HCl. The product was filtered to obtain specified in the subtitle product (0,93 g, 91.2 per cent).

APCI-MS: m/z 363 [MH+] for the free base.

2) N-(2-{3-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)metenkephalin

Methanesulfonanilide (35 mg, 0.3 mmol) was added to a cooled (0° (C) peremeshivaemogo mixture of the above amine (110 mg, 0.25 mmol) and pyridine (0.4 ml) in anhydrous dichloromethane (10 ml). The mixture was then stirred at room temperature for 1.5 hours, then concentrated. The residue was distributed between ethyl acetate and water. The organic phase was concentrated, and the residue was purified by flash chromatography (silica gel, dichloromethane-methanol, 25:1) to obtain the specified title compound (68 mg, 61.8 percent) in the form of foam.

1H-NMR (400 MHz, CDCl3): δ 7,51 (dd, 1H, J=1.4 and 8.0 Hz), 7,22 (m, 2H), 7,10 (m, 1H), 7,68 (m, 1H), 6,92 (d, 1H, J=9.0 Hz), 6,76 (m, 2H), 5,78 (very bs, 1H), 4,80 (m, 1H), 4,20 (m, 1H), 4,08 (m, 1H), 3,98 (m, 1H), and 3.16 (m, 1H), 3,01 (m, 1H), 2,96 (s, 3H), 2,89 (m, 2H), 2,74 (m, M), 2,68 (dd, 1H, J=4.0 and a 12.2 Hz), 2,3 (m, 1H), and 2.02 (m, 1H).

13C-NMR (400 MHz, CDCl3): δ 155,9, 149,4, 129,4, 126,9, 125,8, 125,77, 125,75, 122,29, 122,26, 122,17, 115,5, 113,52, 113,50, 76,52. 76,49, 72,15, 72,09, 67,18, 67,08, 60,24, 60,07, 57,96, 57,94, 53,18, 52,98, 39,1, 31,92, 31,90.

APCI-MS: m/z 441 [MN+].

Example 211

N-(5-chloro-2-[3-[3,4-dichlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy]phenyl)urea

1) N-(5-Chloro-2-hydroxyphenyl)urea

A solution of potassium cyanate (6,14 g of 75.6 mmol) in water (50 ml) was added dropwise to a stirred suspension of 2-amino-4-chlorophenol (5,00 g, 34.8 mmol) in a mixture of acetic acid (350 ml) and water (250 ml) and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture three times was extracted with ethyl ether. The ether extracts were combined and concentrated to Vya is anyone oils. To the above oil was added 10% solution of sodium bicarbonate (250 ml). The solid product was filtered and repeatedly washed with water and recrystallized (toluene containing a small amount of methanol) to obtain specified in the subtitle compound (3,27 g, 50.4 percent).

1H-NMR (400 MHz, DMSO-d6): δ a 10.1 (s, 1H), 8,07 (d, 1H, J=2.2 Hz), of 8.04 (s, 1H), 6.75 in-is 6.78 (m, 2H), 6,29 (bs, 2H).

13C-NMR: δ 156,0, 144,1, 130,0, 122,5, 120,2, 117,5, 115,2.

2) N-[5-Chloro-2-(2-oxiranylmethyl)phenyl]urea

A suspension of N-(5-chloro-2-hydroxyphenyl)urea (53 mg, 0.28 mmol), cesium carbonate (92 mg, 0.28 mmol) and epibromohydrin (49 mg, 0.36 mol) in anhydrous DMF (0.6 ml) was stirred at room temperature for 24 hours. The mixture is then distributed between ethyl acetate and water. The organic phase was three times washed with water, dried and concentrated to a solid residue. The crude product was recrystallized (ethyl ether and heptane) to obtain specified in the subtitle compound (18 mg, 26.5 per cent).

1H-NMR (400 MHz, DMSO-d6): δ to 8.20 (d, 1H, J=2.2 Hz), 8,00 (s, 1H), 7,00 (d, 1H, J=8,8 Hz), to 6.88 (dd, 1H, J=2.4 and 8.6 Hz), 6,40 (bs, 2H), and 4.40 (dd, 1H, J=2.2 and 12.0 Hz), 3,90 (dd, 1H, J=6.6 and 12.0 Hz), 3,37 (m, 1H), 2,88 (t, 1H, H=4,8 Hz), is 2.74 (m, 1H).

3) N-(5-Chloro-2-[3-[3,4-dichlorophenoxy)-1-pyridinyl]-2-hydroxypropoxy]phenyl)urea

The solution specified in the subtitle compound (2) (16 mg, 0.07 mmol) and 3-(3,4-dichlorophenoxy)pyrrolidine (17 mg, 0.07 to which mol) in absolute ethanol (1 ml) was stirred for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography (dichloromethane-methanol, 15:1) to obtain the specified title compound (11 mg, 33%).

1H-NMR (400 MHz, DMSO-d3): δ 8,18 (d, 1H, J=2.6 Hz), 7,94 (s, 1H), and 7.5 (d, 1H, J=0.0 Hz), 7,16 (d, 1H, J=2.1 Hz), 6,82-6,98 (m, MN), 6,33 (bs, 2H), to 4.98 (m, 1H), 4,90 (m, 1H), 3,85-4,07 (m, 3H), 2,63-of 2.93 (m, 5H), 2.21 are 2,30 (m, 1H), 1.74 (m, 1H).

APCI-MS: m/z 198 [MH+].

Example 212

2,2,2-Triptorelin 1-(3-(2-[(aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(4-chlorphenoxy)pyrrolidine

1) N-(2-Hydroxyphenyl)urea

A solution of potassium cyanate (3.94 g, to 48.6 mmol) in water (30 ml) for 15 min was added to a suspension of 2-aminophenol (2,41 g, 22,1 mmol) in 50% aqueous acetic acid (160 ml). The resulting solution was allowed to stand at room temperature overnight and then was extracted with ethyl ether (3 times). The combined organic extracts were concentrated to a small volume and poured into a cooled saturated aqueous sodium bicarbonate. The solid was filtered and washed with water to obtain specified in the subtitle compound (1,61 g, 47.9 per cent).

1H-NMR (400 MHz, DMSO-d6): δ 9,88 (s, 1H), of 7.97 (s, 1H), 7,80 (bd, 1H), 6.77 (m, 1H), of 6.68 (m, 1H), 6,17 (s, 2H).

2) N-[2-(2-Oxiranylmethyl)phenyl]urea

The solution epibromohydrin (0,94 g, at 6.84 mmol) in anhydrous DMF (2 ml) was added dropwise to a stirred suspension of N-(2-Ki is roxiprin)urea (0.65 g, 4,27 mmol) and cesium carbonate (2,22 g, at 6.84 mmol) in DMF (8 ml). After 2 hours the mixture was distributed between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with water (3 times), dried and concentrated. Semi-solid residue was dissolved in a mixture of dichloromethane/ethyl ether, filtered and added heptane to turbidity. After standing at room temperature overnight, the solid was filtered to obtain specified in the subtitle compound (0.28 g, 32%).

1H-NMR (400 MHz, DMSO-d6): δ 8,07 (m, 1H), 7,82 (s, 1H), 6,97 (m, 1H), 6,85 (m, 2H), 6,24 (bs, 2H), 4,37 (dd, 1H, J=2,5 and 11.6 Hz), with 3.89 (dd, 1H, J=6,4 and 11.6 Hz), to 3.38 (m, 1H), 2,87 (t, 1H, J=4,6 Hz)of 2.75 (dd, 1H, J=2.6 and 5.2 Hz).

APCI-MS: m/z 209 [MH+].

2) 2,2,2-Triptorelin 1-(3-{2-[(aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(4-chlorphenoxy)pyrrolidine

A solution of N-[2-(2-oxiranylmethyl)phenyl]urea (78 mg, and 0.37 mmol) and 3-(4-chlorphenoxy)pyrrolidine (70 mg, 0.36 mmol) in absolute ethanol (4 ml) was heated at the boil under reflux for 2.5 hours. The mixture was then concentrated and the residue was purified by HPLC to obtain specified in the title compound (102 mg, 54.5 per cent).

1H-NMR (400 MHz, DMSO-d6+D2O): δ 7,98 (bd, 1H, J=7,2 Hz), was 7.36 (d, 2H, J=8,8 Hz), 6,95-7,02 (m, 3H), to 6.88 (m, 2H), 5,15 (bd, 1H). 4.26 deaths (m, 1H). The remaining 10 aliphatic protons appear as a complex, overlapping multi the years between δ 2,04 and 4.04.

APCI-MS: m/z 406 [MH+] 408 [MH++2] free base.

Example 213

2,2,2-Triptorelin 1-(3-{2-[(aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(3,4-dichlorophenoxy)pyrrolidine

A solution of N-[2-(2-oxiranylmethyl)phenyl]urea (described in example 212, step (2); 69 mg, 0.33 mmol) and 3-(3,4-dichlorophenoxy)pyrrolidine (77 mg, 0.33 mol) in absolute ethanol (4.5 ml) was heated at 70°C for 2 hours. The residue after solvent evaporation was purified by HPLC to obtain specified in the title compound (133 mg, 72.3 per cent).

1H-NMR (400 MHz, DMSO-d6+D3O): δ of 7.96 (bd, 1H, J=7.4 Hz), 7,54 (bd, 1H, J=9.0 Hz), 7,27 (bs, 1H), 6,84-7,00 (m, 4H), 5,20 (bd, 1H), 4.26 deaths (m, 1H). The remaining 10 aliphatic protons appear as a complex overlapping multiplets between δ 2.05 and a 4.03.

APCI-MS: m/z 439,9 [M], 442 [M+2] for the free base.

Example 214

2,2,2-Triptorelin 1-(3-{2-[(aminocarbonyl)amino]-4-chlorophenoxy}-2-hydroxypropyl)-3-(4-chlorphenoxy)pyrrolidine

A solution of N-[2-(2-oxiranylmethyl)phenyl]urea (described in example 212, step (2); 47 mg, 0.22 mmol) and 3-(4-chlorphenoxy)pyrrolidine (41 mg, 0.2 mmol) in absolute ethanol (3 ml) was heated at 70°C for 1.5 hours. The solvent is then evaporated and the residue was purified by HPLC to obtain specified in the title compound (67 mg, 60,9%).

1H-NMR (400 MHz, CD3OD): δ of 8.04 (s, 1H), 7,31 (d, 2H, J=8.6 Hz), 6,94-6,98 (m, 4H), 5,20 (bs, 1H), however, 4.40 (m, 1H). The remaining 10 aliphatic protons appear as a complex overlapping multiplets between δ 2,25 and 4.13.

APCI-MS: m/z 440,1 [M] and 442,1 [M+2] for the free base.

Example 215

The hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N-utilmately

The ethereal solution of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)urea [obtained from hydrochloride (110 mg, 0.25 mmol) by treatment with 1 M NaOH and extraction of simple ether] was treated utilitarianism (16 μl, 0.2 mmol) in a sealed vessel for 15 h at ambient temperature. After evaporation and purification by flash chromatography on silica (EtOAc/Meon/ 100/5) the appropriate fractions were acidified using 1 M HCl and liofilizirovanny from acetic acid to obtain specified in the title compound as a white amorphous solid (35 mg, 37%). The substance is a mixture of two diastereoisomeric pairs.

APCI-MS: m/z 434 [MH+].

Example 216

The hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N'-metalmachine

To a solution of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)urea [obtained from hydrochloride (44 mg, 0.1 mmol) by treatment with 1 M NaOH and extraction of simple ether] in dichloromethane (DHM) (3 ml) was added di(tert-butyl)tricarbonate (26 mg, 0.1 mmol)and the solution ostavlala 15 minutes Added methylamine (2 M in DHM, 100 μl, 0.2 mmol)and the solution was left to stand over night. After evaporation the crude product was purified by preparative RP-HPLC, using as mobile phase acetonitrile and water containing 0.1% triperoxonane acid (TFU). The appropriate fraction was concentrated in vacuo and was extracted with 1 M NaOH and simple ether. The residue of the organic phase was acidified using 1 M HCl and liofilizirovanny from acetic acid to obtain specified in the title compound as a white amorphous solid (15 mg, 30%). The substance is a mixture of two diastereoisomeric pairs.

APCI-MS: m/z 420 [MH+].

Example 217

(2S,4S)-1-{3-[2-(Acetylamino)phenoxy]-2-hydroxypropyl}-4-(4-chlorophenoxy)-2-pyrrolidinecarbonyl acid; compound with triperoxonane acid

(1) of the Hydrochloride of methyl-(2S,4S)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(4-chlorophenoxy)-2-pyrrolidinecarboxylic

Methyl(2S,4S)-4-(4-chlorophenoxy)-2-pyrrolidinecarboxylic (370 mg, 1.0 mmol) and N-[2-(2-oxiranylmethyl)phenyl]ndimethylacetamide (207 mg, 1.0 mmol)dissolved in tert-butanol (7 ml), was stirred in a sealed vessel at 100°With during the night. Treatment of the crude material by flash chromatography on silica (DHM/Meon 100/2), acidification of the corresponding fractions of 1 M HCl and lyophilization from acetic acid has asanee in the subtitle compound as a white amorphous solid (360 mg, 72%). The substance is diastereoisomer mixture.

APCI-MS: m/z 463 [MH+].

2) (2S,4S)-1-{3-[2-(Acetylamino)phenoxy]-2-hydroxypropyl}-4-(4-chlorophenoxy)-2-pyrrolidinecarbonyl acid; compound with triperoxonane acid. Connection (1) (50 mg, 0.1 mmol) was dissolved in acetonitrile (2 ml) and water (3 ml). Added dissolved in water (0.5 ml) hydrate of lithium hydroxide (8 mg, 0.2 mmol). The reaction was terminated after 0.5 h, which was determined by analytical HPLC. The mixture was acidified TFU and purified by preparative RP-HPLC, using as mobile phase acetonitrile and water containing 0.1% TFU. The appropriate fraction was concentrated in vacuo and the residue liofilizirovanny from acetic acid to obtain specified in the title compound as a white amorphous solid (27 mg, 48%). The substance is diastereoisomer mixture.

APCI-MS: m/z 449 [MN+], 431 [MN+]lactone, a small number].

Example 218

Ethyl (2S,4S)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(3,4-dichlorophenoxy)-2-pyrrolidinecarboxylic; salt triperoxonane acid

1) Methyl-(2S,4S)-4-(3,4-dichlorophenoxy)-2-pyrrolidinecarboxylic

The compound was obtained in analogy to Example 217(2) of the methyl ester of N-BOC-CIS-4-hydroxy-L-Proline and 3,4-dichlorophenol.

1H-NMR (400 MHz, DMSO-d3): δ for 9.64 (bs, 2H); 7,58 (d, 1H); to 7.25 (d, 1H); 6,94 (dd, 1H); 5,24 (m, 1H; of 4.66 (dd, 1H); 3,76 (s, 3H); 3,55 (dd, 1H); 3,47 (d, 1H); 2,67-of 2.58 (m, 1H); of 2.38 (d, 1H).

APCI-MS: m/z 290, 292 [MN+isotopic pattern].

2) Ethyl-2S,4S)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(3,4-dichlorophenoxy)-2-pyrrolidinecarboxylic; salt triperoxonane acid

The compound was obtained in analogy to Example 217 of the compounds (1) (404 mg, 1.0 mmol) and N-[2-(2-oxiranylmethyl)phenyl]ndimethylacetamide (207 mg, 1.0 mmol), except that the solvent used was ethanol. Happened transesterification, and after processing and purification of the specified connection was allocated in the form of a white solid (209 mg, 33%).

The substance is diastereoisomer mixture.

APCI-MS: m/z 511, 513 [MN+isotopic pattern].

Example 219

N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide; salt triperoxonane acid and

N-[2-({(2R)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide; salt triperoxonane acid

1) [(2S,4S)-4-(4-Chlorphenoxy)pyrrolidinyl]methanol

Methyl(2S,4S)-4-(4-chlorophenoxy)-2-pyrrolidinecarboxylic (obtained from the methyl ester of CIS-4-hydroxy-L-Proline according to Example 217(2)) (850 mg, of 3.32 mmol) in anhydrous THF (20 ml) was added over 40 min to a mixture of lithium aluminum hydride (505 mg, 13.3 mmol) in anhydrous THF (10 ml) at 0°C in argon atmosphere. PEFC is stirring over night at room temperature was added decahydrate sodium sulfate (1 g), followed by adding dropwise water (0.5 ml), sodium hydroxide (15% wt./about., 0.5 ml) and water (1.5 ml). Filtration and evaporation was possible to obtain a syrup, which was purified by flash chromatography on silica gel (dichloromethane/methanol/concentrated ammonia 100/20/1 with getting listed in the subtitle compound (0,60 g, 79%).

1H-NMR (400 MHz, CDCl3): δ 7,22 (m, 2H), 6,78 (m, 2H), 4,79 (m, 1H), 3,62 (m, 2H), 3,39 (m, 1H), 3,23 (bd, 1H), 3,14 (dd, 1H, J 5.0 Hz, and 12.2 Hz), 2,28 (m, 1H), 1,72 (m, 1H).

APCI-MS: m/z 228 [MH+].

2) N-[2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide; salt triperoxonane acid and

N-[2-({(2R)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide; salt triperoxonane acid

[(2S,4S)-4-(4-Chlorphenoxy)pyrrolidinyl]methanol (380 mg, 1,67 mmol) and N-[2-(2-oxiranylmethyl)phenyl]ndimethylacetamide (414 mg, 2.00 mmol) was dissolved in tert-butanol (5 ml) and stirred in a sealed vessel at 100°C for 3 hours the Solution was concentrated and the residue was purified by flash chromatography on silica gel (dichloromethane/methanol 13/1) and subsequent preparative RP-HPLC, using as mobile phase a mixture of acetonitrile/water containing 0.1% triperoxonane acid. The appropriate fractions liofilizirovanny with getting listed in the title compounds (epimer A: 248 mg, 27%, the epimer B: 115 mg, 13%; stereochemistry in epimeres center is not defined).

p> Epimere And:

1H-NMR (400 MHz, MeOD): δ of 7.82 (dd, 1H, J 1.3 Hz, 8.0 Hz), 7,31 (m, 2H), 7,14 (m, 1H),? 7.04 baby mortality (m, 1H), of 6.96 (m, 3H), 5,20 (m, 1H), and 4.40 (m, 1H), 4,11 (bd, 2H), 3,79-of 4.05 (m, 5H), to 3.73 (dd, 1H, J 5.2 Hz, 12,5 Hz), of 3.43 (dd, 1H, J of 2.6 Hz, 13.0 Hz), 2,80 (m, 1H), 2,18 (s, 3H), 2,12 (m, 1H).

APCI-MS+: m/z 435 [MN+].

The epimer B:

1H-NMR (400 MHz, MeOD): δ 7,79 (dd, 1H, J 1.3 Hz, 7.9 Hz), 7,32 (m, 2H), 7,14 (m, 1H),? 7.04 baby mortality (m, 1H), 6,97 (m, 3H), by 5.18 (m, 1H), 4,49 (m, 1H), 3,83-4,19 (m, 7H), of 3.69 (dd, 1H, J 4.8 Hz, 13,2 Hz), 3.34 (m, 1H), of 2.72 (m, 1H), 2,18 (s, 3H), 2,07 (m, 1H).

APCI-MS+: m/z 435 [MN+].

Example 220

The hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxy-2-methylpropoxy}phenyl)ndimethylacetamide

1) N-{2-[(2-Methyl-2-propenyl)oxy]phenyl}ndimethylacetamide

Connection (1,74 g, 85%) was obtained from 3-chloro-2-methylpropene (1,09 g, to 11.9 mmol) and 2-acetamidophenol (1.50 g, 9,92 mmol) by analogy with the compound described in Example 8 (1).

1H-NMR (400 MHz, CDCl3): δ at 8.36 (dd, 1H, J 1.7 Hz, 7.8 Hz), 7,80 (bs, 1H), 6,98 (m, 2H), 6.87 in (dd, 1H, J 1.6 Hz, 7.9 Hz), to 5.08 (s, 1H), 5,04 (s, 1H), 4,51 (s, 2H), of 2.21 (s, 3H), of 1.85 (s, 3H).

2) N-{2-[(2-Methyl-2-oxiranyl)methoxy]phenyl}ndimethylacetamide

The compound (0.56 g, 65%) was obtained from N-{2-[(2-methyl-2 - propenyl)oxy]phenyl}ndimethylacetamide (800 mg, 3.90 mmol) and meta - chloroperbenzoic acid (80%, 1.10 g, with 5.22 mmol) by analogy with the compound described in Example 8 (2).

1H-NMR (400 MHz, CDCl3): δ at 8.36 (m, 1H), 8,01 (bs, 1H), 7,01 (m, 2H), 6,91 (m, 1H), 4,07 (m, 2H), 2,96 (d, 1H, J 4.8 Hz), and 2.79 (d, 1H, J 4.8 Hz), 2,22 (s, 3H), 1,49 (s, 3H).

3) of the Hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxy-2-METI is propoxy}phenyl)ndimethylacetamide

Specified in the title compound (255 mg, 110%) was obtained from N-{2-[(2-methyl-2-oxiranyl)methoxy]phenyl}ndimethylacetamide (123 mg, 0,577 mmol) and 3-(4-chlorphenoxy)pyrrolidine (100 mg, 0,506 mmol) by analogy with the compound described in Example 1 (3).

1H-NMR (400 MHz, MeOD):δ to 7.61 (m, 1H), 7,29 (m, 2H), 7,18 (m, 1H), 7,10 (m, 1H), of 6.96 (m, 3H), by 5.18 (m, 1H), 3,91-4,22 (m, 4H), 3,37 is 3.76 (m, 4H), 2,66 (m1/2N), is 2.37 (m, 1H), 2,25 (m1/2H)to 2.15 (m, 3H), of 1.45 (m, 3H).

APCI-MS+: m/z 419 [MH+].

General methods and acquisition of the initial substances for Examples 221-230

Getting epoxides:

A) N-(2-[[2S*,3S*)-3-Methyloxirane]methoxy}phenyl)ndimethylacetamide

1) N-{2-[(E)-1-Propyloxy]phenyl}ndimethylacetamide

A heterogeneous mixture of commercially available 1-chloro-2-butene (Aldrich, predominantly TRANS) (453 mg, of 0.49 ml, 5.00 mmol), 2-acetamidophenol (756 mg, 5.00 mmol) and potassium carbonate (691 mg, 5.00 mmol) in acetone (10 ml) was heated to the temperature of reflux distilled during the night. After evaporation of the solvent the residue was washed with ethyl acetate and water. Washing the organic phase with water, 5%. sodium hydroxide and brine and evaporation of the solvent allowed to obtain the crude material which was purified by flash chromatography on silica gel (heptane/EtOAc=3:2). The output 732 mg (71%) of a brownish-yellow solid. The TRANS-CIS=81:19 ratio (defined by1H-NMR; 400 MHz, CDCl3):

APCI-MS+: m/z 206,1 [MH+].

2) Meta-chloroperbenzoic to the slot (70 percent; 270 mg, 1.92 mmol, 2.0 equiv.) added to cooled in an ice bath to a solution of compound (1) (112 mg, 546 μmol)dissolved in dichloromethane (3 ml), and stirred without further cooling during the night. After adding ethyl acetate, and the mixture was washed a feast upon. sodium sulfite, 5%. sodium hydroxide and brine. Drying over sodium sulfate, evaporation of the solvent and flash chromatography on silica gel allowed to obtain 86 mg (71%) of product as a beige solid in the ratio of TRANS:CIS 83:17, which was determined by means of1H-NMR.

1H-NMR (400 MHz, CDCl3; shows only the signals of the main isomer): δ 8,35 (1H, m), of 7.90 (1H, br.s), 7,00 (2H, m), to 6.88 (1H, m), 4,30 (1H, dd, J 11,4, 2,5 Hz), of 3.96 (1H, dd, J of 11.4, 5.7 Hz), is 3.08 (2H, m), of 2.21 (3H, s), of 1.40 (3H, d, J 5.2 Hz).

APCI-MS+: m/z 222,1 [MN+].

B) N-(2-{[(2S,3R)-3-Methyloxirane]methoxy}phenyl)ndimethylacetamide

1) N-[2-(2-Butenyloxy)phenyl]ndimethylacetamide

A mixture of 1-bromo-2-butyne (1.39 g, 10.4 mmol), 2-acetamidophenol (1,58 mg, 10.4 mmol), anhydrous potassium carbonate (1.44 g, 10.4 mmol) and sodium iodide (30 mg) in butanone (50 ml) was heated overnight to a temperature of reflux distilled. After filtration of the reaction mixture, the filtrate evaporated and the resulting residue was washed with ethyl acetate. The resulting solution was washed with 5%. sodium hydroxide, brine and water, dried over sodium sulfate and evaporated. The crude material paracrystal obyvali from a mixture of heptane/methyl tert-butyl ether (MTB) (1:1) obtaining of 1.57 g (74%) of light brown needle-shaped crystals.

APCI-MS+: m/z to 204.1 [MN+].

2) N-{2-[(Z)-2-Butenyloxy]phenyl}ndimethylacetamide

A mixture of alkyne (1) (357 mg, of 1.76 mol) and 5% Pd/BaSO4(22 mg) in pyridine (2.0 ml) was first made in the course of 2 hours and 30 minutes under atmospheric pressure at room temperature. At this time the starting material was completely consumed, but some excess recovery to the corresponding alkane was observed using LC/MS. The reaction mixture was filtered on celite, which was thoroughly washed with ethyl acetate. After that, the filtrate washed with 1 N. HCI for acidification of the reaction mixture and, finally, washed with brine until neutral pH. Drying over sodium sulfate, evaporation of the solvent allowed to obtain 318 mg (88%) of the crude material, which contained in addition to the desired Z-olefin are also a number of E-olefin and the corresponding alkane as by-products. The ratio defined by1H-NMR (400 MHz, CDCl3), was E:Z:alkane =83:10:7. The crude material was used in the next stage without additional purification.

APCI-MS+: m/z 206,1 [MN+].

3) Olefin (2) (310 mg and 1.51 mmol) was dissolved in dichloromethane (10 ml), at 0°With added meta-chloroperbenzoic acid (80%; 587 mg of 2.72 mmol, 1.8 equiv.). After stirring over night at room temperature was followed by evaporating the solvent and washing the resulting residue this is lacerata, washing the feast upon. sodium sulfite, 5% sodium hydroxide and brine and drying over sodium sulfate. Evaporation of the solvent and flash chromatography on silica gel (ethyl acetate/heptane =2:1 followed by ethyl acetate) allowed us to obtain 269 mg (81%) of the epoxide in the ratio E:z average of 82:18 (defined by1H-NMR), in the form of a white powder.

1H-NMR (400 MHz, CDCl3; shows only the signals of the main isomer): 5 of 8.37 (1H, dd, J of 7.5, 2.1 Hz), 7,81 (1H, br.s), 7,02 (2H, m), 6,91 (1H, dd, J of 7.4 and 1.7 Hz), 4,32 (1H, dd, J 11,1, 3.6 Hz), a 4.03 (1H, dd, J 11,1, 6,9 Hz)to 3.33 (1H, dt, J of 7.0, 4.0 Hz), 3,24 (1H, dt, J 9,9, 5,5 Hz), of 2.21 (3H, s)to 1.38 (3H, d, J 5.7 Hz),

APCI-MS+: m/z 222,1 [MN+].

C) N-{2-[(1R,2S,5R)*-6-Oxabicyclo[3.1.0]Gex-2-yloxy]phenyl}ndimethylacetamide

1) (2-Cyclopenten-1 iloxi)(triisopropyl)silane

A solution of 2-cyclopentenone (.Alder, F.H.Flock, Chem. Ber. 1956, 89, 1732.) (2,31 g, 27.5 mmol), (triisopropyl)chlorosilane (5.30 g, 5,9 ml, 27.5 mmol), imidazole (of 2.06 g, 30.2 mmol) in DMF (50 ml) was stirred at room temperature for 3 h and for a further one hour at 50°C. Then the solution was diluted with ethyl acetate, 4 times washed with water and dried over sodium sulfate. Evaporation of the solvent was allowed to get 6,32 g (96%) salelologa ether 513/13 in the form of a colourless liquid. In accordance with1H-NMR spectrum of a significant impurity is not detected.

1H-NMR (400 MHz, CDCl3): δ 5,88 (1H, m), USD 5.76 (1H, m), to 4.98 (1H, m), 2,48 (1H, m), 2,27-2,17 (2H, m), of 1.70 (1H, m), 1,12-1,05 (N, m.

2) Triisopropyl[(1R,2R,5R)*-6-oxabicyclo[3.1.0]Gex-2-yloxy]silane

Meta-chloroperbenzoic acid (70%; 5,41 g, 21.9 mmol, 1.7 equiv.) added to cooled in an ice bath to a solution of compound (1) (3,10 g, 12.9 mmol)dissolved in dichloromethane (25 ml), and stirred without further cooling for a further 90 minutes After filtering the reaction mixture, evaporation of the filtrate the residue was dissolved in ethyl acetate, washed with a feast upon. sodium sulfite, 5%. sodium hydroxide and brine and dried over sodium sulfate. Evaporation of the solvent allowed to obtain the crude material in the form of a mixture diastereoisomeric epoxides in respect of TRANS/CIS average of 78:22 (1H-NMR). Separation by flash chromatography on silica gel (heptane/ethyl acetate =95:5, followed 90:10) allowed us to obtain 1.65 g (50%) of the desired TRANS-epoxide (1R,2R,5R)* as aliremove first diastereoisomer. The total yield of both diastereoisomeric epoxides amounted to 2.86 g (87%).

1H-NMR (400 MHz, CDCl3): δ 4,39 (1H, d, J 3.4 Hz), 3,54 (1H, d, J 2.5 Hz), 3,37 (1H, d, J 2.5 Hz), was 1.94 (1H, m), 1,84 (dtd, J 13,7, 9,3, 1.1 Hz), 1.60-to 1.55V (2H, m), 1,13-1,04 (21H, m).

3) [(1S,2R,5R)*-6-Oxabicyclo[3.10]hexane-2-ol

To a solution of salelologa ether (2) (280 mg, of 1.09 mmol) in THF (2.0 ml) was added tetrabutylammonium fluoride (1.0 M in THF; 1.2 ml, 1.20 mmol). After stirring for 3 h at room temperature the mixture was diluted what dilatatum, washed with brine and dried over sodium sulfate. Chromatographic filtration on silica gel (heptane/tert-butyl methyl ether 2:1 followed by ethyl acetate) allowed us to obtain 79 mg (72%) as a pale yellow oil.

1H-NMR (400 MHz, CDCl3): δ 4,36 (1H, d, J 5.1 Hz), 3,55 (1H, s), 3,42 (1H, d, J 1.5 Hz), 1,99 (1H, m), of 1.84 (1H, dddd, J 13,9, 10,1, 9,0, 1.1 Hz), 1,69-of 1.53 (3H, m).

4) Specified in the title compound was obtained in accordance with the General Protocol (I)below.

1H-NMR (400 MHz, CDCl3): δ scored 8.38 (1H, m), to $ 7.91 (1H, br.s), 7,02-6,98 (2H, m), 6,94 (1H, m), 4,78 (1H, td, J of 8.0, 1.2 Hz), 3,61 (1H, m), of 3.54 (1H, d, J 2.7 Hz), of 2.21 (3H, s), of 2.21 (1H, m), 2,10 (1H, dt, J of 12.8, 12.0 Hz), of 1.76 (1H, dtd, J 14,3, 10,4, 1,4 Hz), 1,58 (1H, m).

APCI-MS+: m/z 234,1 [MH+].

General Protocol (I) to obtain N-{2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]Gex-2-yloxy]phenyl}acetamido

Stage 1 - accession Mitsunobu (Mitsunobu):

It chilled in an ice bath to a solution of epoxy alcohol 546/16 (1.0 equiv.), triphenylphosphine (1.2 equiv.) and 2-NITROPHENOL (1.0 equiv.) in anhydrous THF (2 mg/mmol) was added dropwise diethyldithiocarbamate acid (1.2 equiv.). Stirring was continued overnight without further cooling. Water main processing with subsequent flash chromatography on silica gel (typical eluent:heptane/ethyl acetate =1:1) allowed us to obtain 2-nitrophenolate esters, which are often contained equimolar amount of side ol the product diethyl-1,2-hydrazodicarboxylate.

Stage 2 - hydrogenation:

A mixture of 2-nitrophenolate esters obtained in stage 1, aminobutiramida(ethyl)amine (2.0 equiv.), anhydrate acetic acid (2.0 equiv.) and 5%. Pt/C (10 mg/mmol) in ethyl acetate (10 ml/mmol) was first made during 1 h under atmospheric pressure at room temperature. In the case of non-halogenated aromatic compounds can be used Pd/C and shorter times of reaction, usually about 5 minutes After that, the catalyst was filtered using a filter funnel, filled with telicom, and washed with ethanol. The filtrate was evaporated and the residue was subjected to water main processing. Subsequent flash chromatography on silica gel (typical eluent:ethyl acetate/heptane =2:1) allowed to obtain the appropriate acetamide with typical outputs 50-70% (stage 2).

G) N-{5-Chloro-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]Gex-2-yloxy]phenyl}ndimethylacetamide

Received in accordance with the Protocol (I).

1H-NMR (400 MHz, CDCl3): δ of 8.47 (1H, d, J 2.5 Hz), 7,89 (1H, br.s), 6,97 (1H, dd, J of 8.8, 2.5 Hz), 6,85 (1H, d, J 8,8 Hz), 4,74 (1H, td, J of 8.0, 1.3 Hz), to 3.58 (1H, m), of 3.56 (1H, m), of 2.21 (1H, m), of 2.21 (3H, s), is 2.09 (dt, J 13,0, 7,4 Hz), of 1.76 (1H, dtd, J 14,3, 10,1, 1.3 Hz), and 1.56 (1H, m).

MS-APCI+: m/z 268,0 [MN+].

E) N-{4-fluoro-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]Gex-2-yloxy]phenyl}ndimethylacetamide

Received in accordance with the Protocol (I).

1H-NMR (400 MHz, CDCl3): δ 8,23 (1H, dd, J 10,7, 2,8 Hz), to 7.99 (1H, br.s), 6,89 (1H, dd, J9,0, 5,5 Hz), 6,69 (1H, ddd, J 11,1, 9,0, 3.1 Hz), 4,70 (1H, t, J 7.8 Hz), of 3.56 (2H, s), of 2.21 (1H, dd, J 14,7, and 8.4 Hz), of 2.21 (3H, s), 2,08 (1H, dt, J 13,0, 8,2 Hz), a 1.75 (1H, dtm, J 14,3, 9.5 Hz).

APCI-MS+: m/z 252,1 [MH+].

General Protocol (II) to attach aminocyclo to substituted 2-(aryloxyalkyl)oxirane

Equimolar amount of aminocyclo and epoxide, dissolved in a saturated solution LiClO4in acetonitrile (1 ml/100 mmol), was heated to 100°C in a sealed tube. Typical reaction times ranged from 3 h to epoxides with an open circuit to 18 h for oxabicyclo[3.1.0]hexanol. After cooling to ambient temperature the reaction mixture was diluted with ethyl acetate and subjected to water treatment. The crude products are usually received with the quantitative outputs and purified by flash chromatography on silica gel (typical eluent: ethyl acetate/methanol =80:20).

Examples 221-230 below was received in accordance with the General protocols (I) and (II).

Example 221

N-(2-{(1S*2R,3S*)-3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)ndimethylacetamide

1H-NMR (400 MHz, CDCl3): δ to 8.20 (1H, d, J 7.4 Hz), 8,07 (1H, br, s), 7,21 (2H, m), 7,01-of 6.96 (2H, m), 6,92 (1H, dm, J 7.4 Hz), 6,77 (2H, dm, J is 8.8 Hz), of 4.77 (1H, m), of 4.54 (1H, br q, J 4.8 Hz), is 4.15 (1H, m), 3.04 from-only 2.91 (3H, m), of 2.81 (1H, q, J 6.8 Hz), 2,62 (1H, quint, J 7,3 Hz)to 2.29 (1H, m)of 2.16 (3H, s), 2,13-1,90 (5H, m), and 1.63 (1H, m),

MS-APCI+: m/z431,2 [MH+].

Example 222

N-(2-{(1R*,2R*, 3S*)-3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hidroxizina is nilakshi}phenyl)ndimethylacetamide

1H-NMR (400 MHz, CDCl3): δ compared to 8.26 (1H, m), of 7.90 (1H, br, d, J 9.5 Hz), 7,20 (2H, m), 6,97 (2H, m), to 6.88 (1H, br, d, J 7,3 Hz), 6,76 (2H, m), was 4.76 (1H, m), 4,50 (1H, m), is 4.21 (1H, dt, J 14,1, 5,5 Hz), 3.00 and-2,89 (3H, m), 2,67-2,54 (2H, m), 2,28 (1H, m), of 2.15 (3H, s), 2,11 (1H, m)of 1.97 (2H, m), of 1.87 (2H, m).

MS-APCI+: m/z 431,2 [MH+].

Example 223

N-(2-{(2R*,3R*)-3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxyethoxy}phenyl)ndimethylacetamide

1H-NMR (400 MHz, COCl3): δ of 8.27 (1H, dd, J of 7.6, 1.6 Hz), 8,07 (1H, br.s), 7,30 (1H, d, J 8,8 Hz),? 7.04 baby mortality-6,92 (4H, m), 6,74 (1H, dd, J of 8.8, 2.9 Hz), 4.26 deaths (1H, m)to 4.23 (1H, dd, J of 9.9, 2.7 Hz), 4,06 (1H, m), of 3.96 (1H, dd, J 9,9, 8.0 Hz), 2,86-2,72 (3H, m), 2,58 (1H, m), 2,47 (1H, m)to 2.18 (3H, s), 1,99 (2H, m), of 1.80 (2H, m), of 1.12 (3H, d, J 6.9 Hz).

MS-APCI+: m/z 469,1 [MH+].

Example 224

N-(2-{(1S*,2R*,3S*)-3-[4-(4-Chlorophenoxy)piperidine-1-yl]-2-hydroxycyclopent}phenyl)ndimethylacetamide

1H-NMR (400 MHz, CDCl3): δ compared to 8.26 (1H, m), to 8.20 (1H, br.s), 7,19 (2H, m), 7,02 (2H, m), to 6.95 (1H, m), at 6.84 (2H, m), of 4.49 (1H, q, J 5.2 Hz), or 4.31 (1H, m), is 4.15 (1H, m), 2,95 (2H, q, J 7.8 Hz), 2,87 (1H, m), of 2.51 (2H, br.q, J 10,2 Hz), are 2.19 (3H, s), 2,10-of 1.95 (5H, m)to 1.86 (2H, m), 1,60 (1H, m).

MS-APCI+: m/z 445,0 [MH+].

Example 225

N-(2-{(2R*,3S*)-3-[4-(3,4-Dichlorophenoxy)piperidine-1-yl]-2-hydroxyethoxy}phenyl)ndimethylacetamide

1H-NMR (400 MHz, CDCl3): δ of 8.47 (1H, br.s), at 8.36 (1H, dd, J of 7.2, 1.3 Hz), 7,32 (1H, d, J 9,0),? 7.04 baby mortality-6,93 (4H, m), of 6.75 (1H, dd, J 9,0, 2,9 Hz), 4,34 (1H, m), 4,11 (1H, m), of 3.96 (1H, dd, J 10,5, 5,2 Hz), 3,66 (1H, m), 3.00 and is 2.80 (2H, m), a 2.71 (2H, m), 2,42 (1H, m), are 2.19 (3H, s), is 2.05 (1H, m), 1,94-of 1.81 (2H, m), a 1.08 (3H, d, J 6,7 Hz).

MS-APCI+: m/z 466,9 [MH+].

Example 226

N-(2-{(2R*,3R*)-3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxyethoxy}phenyl)AC the Tamid

1H-NMR (400 MHz, CDCl3): δ a 8.34 (1H, t, J 4.5 Hz), 8,18 (1H, br.s), 7,22 (2H, m), of 6.99 (2H, m), 6,93 (1H, m), 6,76 (2H, m), 4,78 (1H, m), 4,20 (1H, m), 4,07 (1H, dt, J 10,1, 2,9 Hz), 3,95 (1H, dd, J a 10.1 and 8.2 Hz), 3.15 in (0,5H, dd, J 10,7, 6,1 Hz), 2,97-2,94 (1,5H, m), 2,89 (0,5H, q, J and 7.6 Hz), 2,82 (0,5H, dd, J of 10.5, 2.5 Hz), 2,73 (0,5H, qm, J 7.5 Hz), 2,65 (0,5H, m), 2,58 (1H, m), and 2.26 (1H, m), a 2.01 (1H, m), of 1.09 (3H, manifests itself as a dd, J 6,7, the 1.7 Hz).

MS-APCI+: m/z 419,1 [MH+].

Example 227

N-(24(2R*,3S*)-3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxyethoxy}phenyl)ndimethylacetamide

1H-NMR (400 MHz, CDCl3): δ 8,48 (1H, m), of 8.37 (1H, m), 7,22 (2H, m),? 7.04 baby mortality-6,93 (3H, m), 6,77 (2H, m), 4,80 (1H, m), of 4.12 (1H, m), of 3.97 (1H, dd, J 10,5, a 5.3 Hz), the 3.65 (1H, m), 3,09 (0,5H, dd, J 10,3, 6,0 Hz), 3,06-2,99 (1,5H, m), 2,94 (0,5H, q, J 8.0 Hz), 2,87-2,67 (2,5H, m in), 2.25 (1H, m), 2,02 (1H, m), of 1.05 (3H, manifests itself as a dd, J 6,7, 5,2 Hz).

MS-APCI+: m/z 418,9 [MH+].

Example 228

N-(2-{(1S*,2R*,3S*)-3-[4-(3-Chlorophenoxy)piperidine-1-yl]-2-hydroxycyclopent}phenyl)ndimethylacetamide

1H-NMR (400 MHz, CDCl3): δ of 8.25 (1H, m), 8,17 (1H, br.s), 7,18 (1H, t, J 8.1 Hz), 7,01 (2H, m), 6,97-of 6.90 (3H, m), 6,79 (1H, dm, J 9.0 Hz), 4,48 (1H, q, J 5.5 Hz), 4,34 (1H, hept., J 3.5 Hz), 4,15 (1H, dd, J 7,2, 5,5 Hz), 2,95 (2H, q, J 7.4 Hz), 2,87 (1H, m), 2,52 (2H, br.q, J 9.6 Hz), 2,19 (3H, s), 2,09-1,94 (6N, m)to 1.86 (2H, m)to 1.59 (1H, m).

MS-APCI+: m/z 445,1 [MH+].

Example 229

N-[5-Chloro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclopent}oxy)phenyl]ndimethylacetamide

1H-NMR (400 MHz, CDCl3): δ scored 8.38 (2H, m), 7,31 (1H, d, J 8.7 Hz), of 6.99 (1H, d, J 8,8 Hz), to 6.95 (1H, dd, J of 8.8, 2.6 Hz), 6,86 (1H, d, J 8,8 Hz), to 6.75 (1H, dd, J of 8.8, 2.9 Hz), to 4.38 (1H, q, J 4.0 Hz), or 4.31 (1H, hept., J of 3.7 Hz), 4,10 (1H, dd, JȤ a 7.6 Hz)of 3.00 (1H, q, J 7,1 Hz), 2.91 in-2,82 (1H, m), 2,53 (2H, m), 2,17 (3H, s), 2,08-of 1.93 (5H, m), of 1.85 (2H, m), 1,60 (1H, m).

MS-APCI+: m/z 513,1 [MH+].

Example 230

N-[4-fluoro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclopent}oxy)phenyl]ndimethylacetamide

1H-NMR (400 MHz, CDCl3): δ 8,58 (1H, br.s), 8,19 (1H, dd, J 10,9, and 3.2 Hz), 7,31 (1H. d, J 8,8 Hz), 7,00 (1H, d, J 2.9 Hz), 6.89 in (1H, dd, J 9,0, 5,2 Hz), to 6.75 (1H, dd, J 9,0, 2,9 Hz), to 6.67 (1H, td, J of 8.8, 3.1 Hz), 4,35-the 4.29 (2H, m), 4.09 to (1H, dd, J of 7.8, 5.0 Hz), 3.04 from (1H, q, J 7.8 Hz), is 2.88 (2H, m), 2,54 (2N, m)to 2.18 (3H, s), of 2.08 (5H, m), of 1.85 (2H, m), of 1.61 (1H, m).

MS-APCI+: m/z 497,2 [MH+].

Obtaining initial substances for Examples 231-248

A) (S*R*)-1-(3,4-Dichlorobenzyl)-2,5-dimethylpiperazine

A solution of 1,2-dichloro-4-chloromethylbenzene (1.1 ml, 7,89 mmol) in DMF (5 ml) was added to 2,5-dimethylpiperazine (1.0 g, 8,77 mmol)dissolved in DMF (25 ml). The reaction mixture was stirred overnight, then poured into a mixture of EtOAc and sodium carbonate (5%). The aqueous phase is twice washed with EtOAc and the combined organic phase is repeatedly washed with brine and dried over sodium sulfate. After evaporation the crude material was dissolved in methanol. Dibenzylamine piperazine was not dissolved. The filtrate was filtered through a short column of silica using as eluent methanol, and evaporated to obtain the pure product. Output 812 mg, 38%.

1H-NMR (400 MHz, DMSO-d6): δ 7,56 (d, 1H, J=8.1 Hz), 7,52 (d, 1H, J=1.8 Hz), 7,20 (dd, 1H, J=8,2, 1.8 Hz), of 3.97 (d, 1H, J=14.1 Hz), 3.04 from (d, 1H, J=142 Hz), was 2.76 (dd, 1H, J=11,9, 3.0 Hz), 2,59 (m), 2,48 (dd, 1H, J=11,9, and 2.6 Hz), is 2.37 (t, 1H, J=10,8 Hz), 2,12 (m), 1,89 (s)of 1.57 (t, 1H, J=10.4 Hz), and 1.00 (d, 1H, J=6,1 Hz)of 0.82 (d, 1H, J=6.3 Hz).

APCI-MS: m/z 273 [M+].

B) (S*R*)-1-(4-Chlorobenzyl)-2,5-dimethylpiperazine

Synthesized in the same way as (A), from 1-chloro-4-chloromethylbenzene (1.27 g, 7,89 mmol) and 2,5-dimethylpiperazine (1.0 g, 8,77 mmol) in DMF. Output 701 mg, 37%.

1H-NMR (400 MHz, DMSO-d6): δ of 7.36 (d, 2H, J=8,4 Hz), 7,30 (d, 2H, J=8,4 Hz), of 3.97 (d, 1H, J=a 13.9 Hz), 3,01 (d, 1H, J=13,8 Hz)of 2.75 (dd, 1H, J=11,9, 3.0 Hz), 2.57 m (m, 1H, J=10,8, and 2.6 Hz), 2,47 (dd, 1H, J=10,9, and 2.6 Hz), a 2.36 (dd, 1H, J=11,6, 10.1 Hz), 2,10 (m, 1H), of 1.88 (bs, 1H), 1,53 (t, 1H, J=10.5 Hz), a 1.01 (d, 3H, J=6,1 Hz)to 0.80 (d, 3H, J=6.4 Hz).

APCI-MS: m/z 239 [MH+].

C) 1-(3,4-Chlorobenzyl)piperazine

3,4-chlorobenzylchloride (170 mg, 0,872 mmol) was added to a solution of piperazine (150 mg, of 1.74 mmol) and triethylamine (1 ml) in DMF (10 ml) at room temperature. After 2 h, the solution was concentrated in vacuum. The resulting residue was ground into powder in a simple ether and the resulting solid is washed with water and then dissolved in methanol and evaporated with toluene to obtain 89 mg of the product as a solid.

APCI-MS: m/z 245, 247 [MH+].

1H-NMR (400 MHz, CD3OD) δ 7,41 (d, 1H, J=2.0 Hz), 7,37 (d, 1H, J=8,2 Hz), 7,13 (dd, 1H, J=8,2, J=2.0 Hz), and 3.5 (s, 2H), 3,05 (m, 4H), 2.57 m (m, 4H).

G) 1-(4-Chlorobenzyl)piperazine

Received by analogy with (C) above.

Example 231

The dihydrochloride of N-(2-{3-[4-(3,4-dichlorobenzyl)-1-piperazinil]-2-hydroxyp is epoxy}phenyl)ndimethylacetamide

A solution of N-acetyl-2-(2,3-epoxypropoxy)aniline (87,53 mg, 0,422 mmol) and 1-(3,4-Chlorobenzyl)piperazine in ethanol (10 ml, 99.5%pure) was boiled under reflux for 3 hours. The solvent is kept under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (dichloromethane/methanol 20:1) to obtain specified in the connection header in the form of a resin. Adding 1.0 M ethereal HCl solution allowed to obtain 78 mg of a white solid product (40%).

APCI-MS: m/z 452, 454 [MN+].

1H-NMR (400 MHz, CD3OD) δ 8,0 (1H, dd, J=1,53 Hz, J=8,01 Hz), and 7.5 (1H, d, J=1,91 Hz), was 7.45 (1H, d, J=8,2 Hz), 7.23 percent (1H, dd, J=6,1 Hz, J=2.1 Hz), 6.89 in-was 7.08 (4H, m), is 4.15 (1H, m), 3,9-4,1 (2H, m), of 3.48 (2H, S), 2,45-2,60 (10H, m), 2,17 (3H, S).

Examples 232-248 synthesized in accordance with Example 231 from the original substances (a)to(G)above

Example 232

N-(2-{3-[4-(3,4-Dichlorobenzyl)-1-piperazinil]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide

APCI-MS: m/z 470 [MN+].

Example 233

N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 480 [MN+].

Example 234

N-(5-chloro-2-{3-[4-(3,4-dichlorobenzyl)-1-piperazinil]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 486 [MN+].

Example 235

N-(5-Chloro-2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 480 [MH+].

Example 236

N-(2-{3-[4-(3,4-DIH orbenin)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}-4-were)ndimethylacetamide

APCI-MS: m/z 494 [MH+]

Example 237

N-(2-{3-[4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide

APCI-MS: m/z 498 [MH+].

Example 238

N-(2-{3[(S*R*)-4-(3,4-Dichlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 480 [MH+].

Example 239

N-(2-{3[(S*R*)-4-(4-Chlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 446 [MH+].

Example 240

N-(5-Chloro-2-{3-[(S*R*)-4-(3,4-dichlorobenzyl)-2,5-dimethylpiperazine]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 514 [MH+].

Example 241

N-(5-Chloro-2-{3-[(S*R*)-4-(4-Chlorobenzyl)-2,5-dimethylpiperazine]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 480 [MH+].

Example 242

1-(5-Chloro-2-{3-[4-(4-chlorobenzoyl)-1-piperazinil]-2-hydroxypropoxy}phenyl)-1-alanon

APCI-MS: m/z 451 [MH+].

Example 243

N-(5-Cyano-2-{3-[(S*R*)-4-(3,4-dichlorobenzyl)-2,5-dimethylpiperazine]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 505 [MH+].

Example 244

N-(2-{3-[(S*R*)-4-(4-Chlorobenzyl)-2,5-dimethylpiperazine]-2-hydroxypropoxy}-5-cyanophenyl)ndimethylacetamide

APCI-MS: m/z 471 [MH+].

Example 245

N-(5-Chloro-2-(3-[4-(4-Chlorobenzyl)-1-piperazinil]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 452 [MH+].

Example 246

N-(4-Chloro-2-{3-[4-(4-Chlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 460 [MH+].

Example 247

N-(2-{3-[4-(4-Chlorobenzoyl)-1-piperazinil]-2-hydroxypropoxy}-5-cyanophenyl)ndimethylacetamide

APCI-MS: m/z 457 [MH+].

Example 248

N-(2-{3-[4-(4-Chlorobenzoyl)-1-piperazinil]-2-hydroxypropoxy}-4-were)ndimethylacetamide

APCI-MS: m/z 446 [MH+].

Example 249

N-[5-Chloro-2-({(1R,2S,3R)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxycyclopent}oxy)phenyl]ndimethylacetamide

MS-APCI+: m/z 464,9 [MH+].

[α]22=-47,6 (CH2With2).

Example 250

N-{2-[(2S)-(3-{(3S)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-forfinal}ndimethylacetamide

APCI-MS: m/z 423,1 [M+].

Example 251

The hydrochloride of N-[2-({(2S)-3-[(3S)-3-(4-chlorbenzyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide

1) 3-(4-Chlorbenzyl)pyrrolidin

To a solution of 3-(4-Chlorobenzyl)-2-pyrrolidinone (420 mg, 2 mmol) in anhydrous THF (25 ml) and in the atmosphere N2in parts under stirring was added alumoweld lithium (al) (190 mg, 5 mmol) for two minutes. The temperature was increased to 60°C, and stirring was continued for 2.5 hours the Mixture was extinguished 200 μl of water, 200 μl of 5 M NaOH and 600 μl of water. Solid salts of Li and Al was filtered and the filtrate evaporated to obtain a colorless oil (387 mg, 99%).

APCI-MS: m/z 196, 198 [MH+].

2) (2S)-1-[3-(4-Chlorobenzyl)-1-pyrrolidinyl]-3-(2-nitrophenoxy)-2-propanol

A solution of the compound (1) (387 mg, 2 mmol) and (2S)-2-[(2-nitrophenoxy)methyl]oxirane (390 mg, 2 mmol) in ethanol (6 ml) was boiled under reflux to complete the reaction (2 h), which was determined by LC-MS. The solution is tel evaporated to obtain an orange oil (650 mg, 83%)which was used without further purification.

APCI-MS: m/z 391, 393 [MH+].

3) (2S)-1-(2-Aminophenoxy)-3-[3-(4-Chlorobenzyl)-1-pyrrolidinyl]-2-propanol

To a solution of compound (2) (650 mg, 1,67 mmol) in ethanol (10 ml) at 60°C was added a mixture of dihydrate of tin chloride (II) (2.25 g, 10 mmol) and 35% hydrochloric acid (2.5 ml). The temperature is quickly increased to 75°C. the Mixture was stirred at 60°C for another 30 min After evaporation of the solvent the residue was extracted with 5 M NaOH and simple ether. The organic phase is washed with water, dried and evaporated. The residue was purified by RP-HPLC with acetonitrile and water containing 0.1% TFU as mobile phase. The desired fraction was evaporated and the residue was extracted with 1 M NaOH and simple ether. Specified in the subtitle compound was obtained from the organic phase in the form of a colorless oil (400 mg, 66%).

APCI-MS: m/z 361, 363 [MH+].

4) To a solution of compound (3) (400 mg, 1.1 mmol) in DHM (10 ml) was added acetamide (200 μl, 2.1 mmol)and the mixture was left overnight. After evaporation the residue was dissolved in methanol and was added 1.5 M sodium methoxide in methanol (2 ml). The mixture was left for 2 h, evaporated and washed with ether and water. From the organic phase obtained mixture of two diastereoisomers. Diastereoisomers were separated by HPLC on a chiral column using as mobile phase a mixture of isohexane, 2-propanol and m is canola. Selected enantiomers was dissolved in methanol (1 ml)were acidified using 1 M hydrochloric acid (1 ml), diluted with water and liofilizirovanny with getting listed in the title compounds as white amorphous solids (156 mg 173 mg).

Absolute stereoisomeric was not defined.

APCI-MS: m/z 403, 405 [MH+].

Example 252

N-(5-Chloro-2-{3-[3-(4-chlorbenzyl)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide; salt triperoxonane acid,

1) 3-(4-Chlorbenzyl)pyrrolidin-2-he

To the flask was added Diisopropylamine (3,22 g of 31.8 mmol) and anhydrous THF (60 ml). The contents of the flask maintained under nitrogen atmosphere and then cooled to -76°C. To the cooled solution was added dropwise n-utility (n-BuLi, 32 mmol, 20 ml, 1.6 M in hexane). After complete addition the solution was stirred for 10 minutes, was added dropwise a solution of 1-trimethylsilylpropyne-2-it (of 5.00 g of 31.8 mmol, obtained in accordance with methods from the literature) in anhydrous THF (5 ml). The solution is then stirred for a further 20 minutes via syringe over 5 minutes was added a solution of 4-chlorobenzylchloride (5,13 g, 32 mmol) in THF (5 ml). The resulting mixture was stirred at -76°C for 1 hour and then it was allowed to reach ambient temperature and was stirred overnight. Was added water (40 ml)and the mixture was thoroughly stirred for 60 mine is. The phases were separated and the organic phase was washed with brine and finally evaporated to obtain an oil, which crystallized upon standing. The solid was ground into powder with a mixture of heptane:EtOAc 2:1 and filtered to obtain partially purified solid. The solid was purified on silica (gradient dichloromethane (DHM) with subsequent DHM:Meon from 99:1 to 98:2 to 97:3) to obtain 1.3 g (20%) specified in the subtitle of the connection.

1H-NMR (400 MHz, CDCl3) δ: 7,27 (2H, d, J 8,4 Hz); 7,16 (2H, d, J 8,4 Hz); 5,43 (1H, bs): 3,31-3,13 (3H, m); 2,74-2,61 (2H, m); 2,20-2,12 (1H, m); a 1.88-1.77 in (1H, m).

2) 3-(4-Chloranil)pyrrolidin

In a flask was dissolved the compound obtained in (a) (0.20 g, 0.95 mmol)in anhydrous THF (10 ml). Small portions over 10 minutes was added LiAIH4(0.17 g, a 4.53 mmol). After complete addition the mixture was heated to 60°C for approximately 3 h in nitrogen atmosphere, and the reaction was monitored using LC-MS, and the reaction mixture is extinguished after the reaction. Before quenching the reaction mixture was allowed to reach ambient temperature and carefully was added dropwise water (0,160 ml). Was added dropwise NaOH (10% solution in water, 0.16 ml), and finally, another portion of water (of 0.48 ml). The mixture was stirred for 1 hour and then filtered. The filtrate was concentrated in vacuum to obtain specified in the subtitle compound (,18 g, 97%) as a colourless oil.

APCI-MS: m/z 196,1 [M+H].

3) N-(5-Chloro-2-{3-[3-(4-chlorbenzyl)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide; salt triperoxonane acid

Specified in the title compound was obtained in accordance with the method described in Example 1 (3) from the compound obtained in (2).

1H-NMR (400 MHz, DMSO) δ: to 9.93-9,62 (1H, m); 9,12 (1H, s); 8,11 (1H, s); 7,38 (2H, d, J 8,9 Hz); 7.29 trend-of 7.23 (2H, m); 7,13-7,02 (2H, m); 6,11-of 6.02 (1H, m); 4,29-4,16 (1H, bs); 4,05-of 3.95 (1H, m); 3.95 to a 3.87 (1H, m,); 3.75 to a 3.50 (2H, m); 3,40-up 3.22 (3H, m); 2,91-to 2.65 (3H, m); 2,62-2,52 (1H, m); a 2.13 (3H, s); 2,11-of 1.94 (1H, m); 1,81-of 1.55 (1H, m).

Example 253

Triptorelin N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-were)-1-pyrrolidinecarboxamido

1) 2-[(5-Methyl-2-nitrophenoxy)methyl]oxirane

A mixture of 5-methyl-2-NITROPHENOL (7.7 g, 50 mmol), potassium carbonate (13.8 g, 0.1 mmol) and epibromohydrin (of 8.25 ml, 0.1 mmol) was dissolved in DMF (100 ml) and stirred for 2-3 h at 100°C in nitrogen atmosphere. The mixture was diluted simple ether (0.5 l) and was extracted with water to pH=7. The organic phase was evaporated, and the residue was purified by flash chromatography on silica (DHM) obtaining specified in the subtitle compound as a yellow solid (8.65 g, 83%).

1H-NMR (400 MHz, CDCl3): δ 7,80 (d, 1H); 6,91 (s, 1H); 6,86 (d, 1H); 4,39 (dd, 1H); 4,15 (dd, 1H); 3.43 points-3,37 (m, 1H); of 2.93 (dd, 1H); 2,89 (dd, 1H); to 2.42 (s, 3H).

2) 1-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-3-(5-methyl-2-nitrophenoxy)-2-propanol

A mixture of compound (1) (1,05 g, 5.0 mmol) and 3-(4-chlorphenoxy)- pyrrolidine (988 mg, 5.0 mmol) in ethanol (12 ml) was boiled under reflux for 2 hours the Solvent is evaporated to obtain the crude product as an orange oil which was used without further purification.

APCI-MS: m/z 407, 409 [MN+].

3) 1-(2-Amino-5-methylphenoxy)-3-[3-(4-chlorphenoxy)1-pyrrolidinyl]-2-propanol

To a stirred solution of compound (2) (2.1 g, 5.0 mmol) in ethanol (10 ml) at 50°With added chloride dihydrate tin (II) (5.6 g, 25 mmol) in 35% hydrochloric acid (6 ml). Started exothermic reaction and the temperature was rapidly increased to 75°C. the Mixture was maintained at 60°C for 0.5 hours, the Cooled mixture was podslushivaet 1 M sodium hydroxide (180 ml) and was extracted with simple ether, the organic phase is washed with water, dried and evaporated to obtain specified in the subtitle compound as a pale yellow oil (1,34 g, 71%).

NMR: Due to a mixture of two diastereoisomeric pairs merging results in parts of the protons.

1H-NMR (400 MHz, CDCl3): δ of 7.23 (d, 2H); 6,77 (d, 2H); 6,67-of 6.65 (m, 1H); 6,64-6,63 (m, 1H); of 4.83 was 4.76 (m, 1H); 4,14-4,06 (m, 1H); 4,01 (d, 2H); 3,71 (bs, 2H); to 3.41 (bs, 1H); 3,10 (dd, 0,5H); 3,01-2,90 (m, 1,75H); 2,87-2,70 (m, 2,7H); 2,66-to 2.57 (m, 1,5H); 2,28 (h, 1H); of 2.25 (s, 3H); 2.06 to 1,95 (m, 1H).

APCI-MS: 377, 379 [MN+].

4) Triptorelin N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropan and}-4-were)-1-pyrrolidinecarboxamido

A solution of the compound (3) (75 mg, 0.2 mmol) and di(tert-butyl)tricarbonate (53 mg, 0.2 mmol) in DHM (3 ml) was stirred for 1 h at ambient temperature. Added pyrrolidine (33 μl, 0.4 mmol) and stirring was continued for 1 h the Reaction was completed, which was determined by LC-MS. Added TFU (1 ml)and the solution was left for 1 h Volatile part evaporated and the crude product was purified by preparative RP-HPLC, using as mobile phase acetonitrile and water containing 0.1% TFU. The desired fraction was concentrated in vacuo and the residue liofilizirovanny obtaining specified in the title compound as a white amorphous solid (85 mg, 72%).

NMR: Due to a mixture of two diastereoisomeric pairs merging results in parts of the protons. Data obtained from the free base.

1H-NMR (400 MHz, CDCl3): δ 8,03 (dd, 1H); from 7.24 (d, 2H); 6,94 (bs, 1H); 6,82-6,74 (m, 2H); is 6.78 (d, 2H); 6.73 x of 6.68 (m, 1H); 4,85 was 4.76 (m, 1H); 4,11-of 3.94 (m, 3H); 3,52-of 3.42 (m, 5,6H); 3,11 (dd, 0,5H); 3,05 of 2.92 (m, 0,45H); 2,95 (d, 1H); 2,87-of 2.72 (m, 2,5H); 2,62-2,52 (m, 1,4H); 2,37-of 2.21 (m, 0,7H); to 2.29 (s, 3H); 2,08-1,90 (m, 4,6N).

APCI-MS: m/z 474, 476 [MH+].

Example 254

Triptorelin N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-hydroxyphenyl)ndimethylacetamide

To a stirred solution of the free base of the compound in Example 265 (3) (128 mg, 0.29 mmol) in DHM (4 ml) at room temperature in an atmosphere of N2 doba is Lyali 1 M tribromide boron in DHM (of 0.58 ml, of 0.58 mmol). The heterogeneous mixture was stirred overnight and poured into methanol. After evaporation the crude product was purified by RP-HPLC, using as mobile phase acetonitrile and water containing 0.1% TFU. The desired fraction liofilizirovanny obtaining specified in the title compound as a white amorphous solid (113 mg, 73%).

APCI-MS: m/z421, 423 [MH+].

Example 255

N-[2-({(2S)-3-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl}oxy)-4-forfinal]ndimethylacetamide; salt triperoxonane acid

1) (2S)-2-[(5-fluoro-2-nitrophenoxy)matid]oxiran

To the flask was added (R)-glycidol (0,994 g, a 13.4 mmol) and triphenylphosphine (3,52 g, 13,4 mol), and THF (20 ml, dried over molecular sieves), and 5-fluoro-2-NITROPHENOL (2.10 g, a 13.4 mmol). The mixture was stirred to obtain a homogeneous solution. The solution was cooled in an ice bath, is added dropwise over several minutes was added diethylazodicarboxylate (DEAD, 2,11 ml of 13.4 mmol). After complete addition, the flask was allowed to reach room temperature and was stirred for another 2 hours. The solvent was removed in vacuo and to the residue was added chloroform (5-10 ml). The precipitate (PPg3O) was removed by filtration, and the solid was washed with additional chloroform (5-10 ml). The filtrate was applied to a column for flash chromatography (SiO2, heptane:ethyl acetate 4:1) and PTS who attended with getting 2,02 g (71%) indicated in the subtitle compound as a crystalline substance after concentration of the purified fractions.

1H-NMR (400 MHz, CDCl3) δ: of 7.97 (1H, dd, J of 9.3, 6.0 Hz); 6,86 (1H, dd, J of 10.0, 2.5 Hz); 6,80-6,74 (1H, m); of 4.44 (1H, dd, J 11,4, and 2.6 Hz); 4,12 (1H, dd, J 11,2, 5,1 Hz); 3,44-to 3.38 (1H, m); 2,95 (1H, t, J 4.5 Hz); 2,90 (1H, dd, J 4,8, 2,6).

2) (2S)-1-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-3-(5-fluoro-2-nitrophenoxy)-2-propanol

To the vessel was added 4-(3,4-dichlorophenoxy)piperidine (0,123 g, 0.5 mmol) and the compound obtained in stage (1) (0,106 g, 0.5 mmol), and ethanol (99.5%pure, 3 ml). The vessel tightly corked, and the contents were heated at 65°With stirring for 3 hours and the reaction was monitored using LC-MS. The vessel was allowed to cool and the solvent is evaporated, which resulted in obtaining oil, which was purified on silica (as a stepped gradient DHM followed DHM:Meon from 99:1 to 98:2 to 97:3). Evaporation of the purified fractions allowed to obtain 0,22 g (96%) indicated in the subtitle compound as oil.

APCI-MS: m/z 459,1 [M+H].

3) N-[2-({2S)-3-[4-{3,4-Dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl}oxy)-4-florfenicol: salt triperoxonane acid

The compound obtained in stage (2) (0,22 g, 0.48 mmol), was dissolved in ethanol (99.5%pure, 7 ml) and heated under stirring to 60°C. was Added a solution of SnCl2×2H2O (0.56 g, 5 equivalents) in concentrated hydrochloric acid (0.63 ml) and stirred at 60°C for 1 hour. The mixture then was allowed to cool. The solution is selecively by adding an excess of 2 M NaOH, and the solution was extracted with diethyl ether (3×50 ml). The combined ethereal solutions were washed with brine and evaporated. The resulting oil was dissolved in THF (8 ml) was added water (8 ml) followed by the addition of acetanhydride (50 l, 0.52 mmol). The mixture was stirred at 40°C for 15 minutes. The organic solvent was removed in vacuo, and the residue was extracted with EtOAc (3×30 ml). The combined organic phases were washed with brine and concentrated in vacuum. The residual oil was purified by preparative HPLC to obtain 55 g (20%, purity 98%) indicated in the title compound in the form of triptoreline and after lyophilization of the purified fractions in the form of a white solid.

APCI-MS (m/z): 471,0, 472.0 M., 473,0 and 474,0 [M+H].

Example 256

The hydrochloride of N-(2-(3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4,6-differenl)ndimethylacetamide

1) 3,5-Debtor-6-NITROPHENOL

To a stirred solution of 2,3,4-cryptomaterial (5 g, 28,23 mmol) in anhydrous methanol (70 ml) was added sodium (0,68, 29,46) in anhydrous methanol (30 ml). The solution was stirred until consumption of all source materials (˜2 h). After the concentrate was added water and the solution was extracted with simple ether, dried over Na2SO4, filtered and concentrated to a yellow residue (4,65 g). To the yellow solution of the residue in dichloromethane (140 ml) was added tribromide boron (1 M in dichlor is Tanya, 40 ml) and stirred at room temperature overnight. Then added water and the solution was stirred for another 30 minutes the Organic phase was separated and the aqueous phase was extracted with simple ether. The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuum to obtain a brownish residue. The residue was washed with a simple ether and washed with 2 M sodium hydroxide and water. Water flushing and washing with sodium hydroxide were combined and neutralized 6 M HCl and was extracted with simple ether, dried over Na2SO4and was evaporated to obtain a yellow residue, which was purified by flash chromatography on silica gel using as eluent a mixture of EtOA:heptane 1:2 to give the desired 2 g, 11,42 mmol.

Gas chromatography (GC)-MS: m/z 175 (M+).

1H-NMR (400 MHz, CD3OD) δ million-1, 6,63 of 6.68 (1H, m), 6,60 is 6.67 (1H, dt).

2) 2-[(3,5-Debtor-2-nitrophenoxy)methyl]oxiran

To a mixture of 3,5-debtor-6-NITROPHENOL (100 mg, 0,571 mmol) and potassium carbonate (349 mg) in DMF (5 ml) was added epibromohydrin (80 mg, 0,582 mmol) and stirred at 70°C for 3 hours was Added water and ethyl acetate, the organic phase was separated, dried and concentrated. The resulting residue was purified by chromatography (ethylacetate 1:3) to give 161 mg (0,696 mmol) of the desired product in the form of solid substances is TBA.

GC-MS: m/z 231 (M+).

3) 1-[3-(4-Chlorophenoxy)-1-pyrrolidinyl]-3-(3,5-debtor-2-nitrophenoxy)-2-propanol

A solution of 3-(4-chlorphenoxy)pyrrolidine and 2-[(3,5-debtor-2-nitrophenoxy)methyl]oxirane (50 mg, 0,216 mmol) in ethanol was boiled under reflux for 3 hours. The solvent is kept under reduced pressure, and poluchennyi the resulting residue was purified by column chromatography on silica gel (dichloromethane/methanol 20:1) to give 45 mg (0,105 mmol) specified in the connection header in the form of solids.

4) of the Hydrochloride of N-(2-(3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy)-4,6-differenl)ndimethylacetamide

The platinum oxide on carbon was added to a solution of 1-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-3-(3,5-debtor-2-nitrophenoxy)-2-propanol (40 mg, 0,0932 mmol) in ethanol, and the mixture was first made in the course of 4 hours at a pressure of 1,01325×105PA (1 ATM). The mixture was filtered through Celite and washed several times with hot ethanol and the combined filtrate was concentrated in vacuum. The resulting yellow residue was washed with dichloromethane and to the solution was added acetanhydride. The solution was stirred at room temperature for 2 hours, then concentrated. Adding 1.0 M ethereal solution of hydrogen chloride was allowed to receive 20 mg specified in the header of the product as a solid.

APCI-MS: m/z 441 [MH+].

Note the p 257

N - [2-({(2S)-3-[(2S,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl]-2-hydroxypropyl}oxy)-4-forfinal]ndimethylacetamide; salt triperoxonane acid

Specified in the title compound was obtained in accordance with the method described in the following Example 260.

1H-NMR (400 MHz, DMSO-d6) δ: of 9.89 (1H, bs); 9,05 (1H, s); 7,79 (1H, dd, J of 8.8, 6.6 Hz); 7,37 (2H, d, J 9.6 Hz); 7,00-6,94 (3H, m); 6.75 in (1H, dt, J to 8.6, 2.6 Hz); 6,00 (1H, bs); 5,17-5,10 (1H, m); 4,32-4,20 (1H, m); of 4.05 (1H, dd, J 10,1, 4.6 Hz); of 3.97 (1H, dd, J 9,9, 5.7 Hz); 3,78-3,50 (3H, m); 3,47 (1H, t, J and 11.6 Hz); 3,17 (1H, t, J 13.3 Hz); and 2.83 (1H, p, J 6.9 Hz); 2,07 (3H, s); 1,90 and 1.80 (1H, m); of 1.42 (3H, d, J 6.4 HZ).

Example 258

The hydrochloride of N-[2-({(2S)-3-[(3R)-3-(4-chlorbenzyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide

Was obtained using the method described in Example 251.

Example 259

N-{2-[(2R)-(3-{(3S)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-forfinal}ndimethylacetamide

APCI-MS: m/z 423,1 [M+].

Example 260

N-[2-({(2S)-3-[(2R,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide; salt triperoxonane acid

1) 1-(tert-Butyl) 2-methyl (2S,4R)-4-hydroxy-1,2-pyrrolidinecarboxylic

In the flask was dissolved hydrochloride (2S,4R)-4-hydroxyproline (5.4 g, 30 mmol) in a mixture of THF (200 ml), water (170 ml) and NaOH (30 ml, 2 M in water, 60 mmol). To this emulsion was added di-tert-BUTYLCARBAMATE (Re2O, is 6.54 g, 30 mmol) and the mixture was thoroughly stirred for 1 hour. Added a simple ether (100 ml) and the phases of the awali the opportunity to split. The aqueous phase was extracted with an additional number of ordinary ether (100 ml). The aqueous phase was removed and the combined organic phases are washed with 1 M HCl (aq.) and potassium carbonate (feast upon., aq.) and brine. The extract was dried Na2SO4and concentrated in vacuo to obtain a residue, which was purified on silica (stepwise gradient of heptane:EtOAc 5:1 to 3:1 to 1:1, stains visualized using the I2/Meon). Pair purified fractions were concentrated in vacuum with the receipt of 4.2 g (57%) indicated in the subtitle compound as a colourless oil.

1H-NMR (400 MHz, CDCl3) δ: 4,50 (1H, bs); 4,45 is 4.35 (1H, m); 3,74 (3H, s); of 3.64 (1H, dd, J 11,7, a 4.3 Hz); 3,59-of 3.42 (1H, m); 2,35-of 2.20 (1H, m): 2,14-2,03 (1H, m); of 1.97 (1H, dd, J 23,3, and 3.7 Hz); 1.44MB (N, d, J 18,9 Hz).

2) 1-(tert-Butyl) 2-methyl (2S,4S)-4-(4-chlorophenoxy)-1,2-pyrrolidinecarboxylic

In a flask was dissolved the compound obtained in stage (1) (2,54 g of 10.3 mmol), triphenylphosphine (2,71 g of 10.3 mmol) and 4-chlorophenol (1,33 g of 10.3 mmol) in THF (50 ml, dried over molecular sieves) under stirring with a magnetic stirrer. The flask was cooled in an ice bath and to this stirred solution is added dropwise over several minutes was added diethylazodicarboxylate (DEAD, 1.8 g, or 10.3 mmol). The reaction mixture was allowed to stand over night, allowing the ice to melt and the reaction mixture to reach room temperature. Dissolve Italy evaporated, and the residue was treated with simple ether (30 ml), allowing the phosphine oxide to precipitate. The solid was removed by filtration, and the filtrate was concentrated in vacuum. The residue was purified on silica (stepwise gradient of heptane:EtOAc 8:1 to 6:1 to 3:1. Spots on thin-layer chromatography (TLC) and visualized with the use of reagent Sabaha (Seebach)). Concentrated purified fractions allowed to obtain of 2.51 g (68%) indicated in the subtitle compound as a colourless viscous oil.

1H-NMR (400 MHz, CDCl3) δ: 7,26-7,20 (2H, m); 6,77-6,70 (2H, m); a 4.86 (1H, bs); 4,55 (1/2H, dd, J to 8.6, 2.6 Hz); 4,43 (1/2H, dd, J 7,6, 3,9 Hz); 3,84-of 3.60 (5H, m); 2,53-of 2.36 (2H, m); 1,47 (N, d, J 18.2 Hz).

3) tert-Butyl (2S,4S)-4-(4-chlorophenoxy)-2-(hydroxymethyl)-1-pyrrolidinecarboxylic

In a flask was dissolved the compound obtained in stage (2) (0,951 g, to 2.67 mmol)in THF (10 ml, dried over sieves). The solution was cooled in an ice bath and added LiBH4(0.09 g, 4.07 mmol). The mixture was stirred overnight, allowing ice to cool and the solution to reach room temperature. The crude mixture was then distributed between EtOAc (100 ml) and water (100 ml). The aqueous phase was removed and the organic solution was washed with 0.5 M HCl (aq.), NaHCO3(feast upon., aq.) and brine. The solution is evaporated to obtain an oil, which, apparently, was contaminated with inorganic salts. Dissolution in DHM and the filtration is through Celite® allowed to get 0,82 g (94%) indicated in the subtitle compound as a colourless oil.

1H-NMR (400 MHz, DMSO-d6) δ: 7,33 (2H, d, J 9.5 Hz); to 6.95 (2H, d, J 9,5); 4,96 (1H, bs); 4,71 (1H, bs); 3,84-3,55 (3H, m); of 3.32 (2H, bs); 2,29-2,07 (2H, m); 1,41 (N, s).

4) tert-Butyl(2S,4S)-4-(4-chlorophenoxy)-2-{[(methylsulphonyl)oxy]methyl)-1-pyrrolidinecarboxylic

In a flask was dissolved the compound obtained in stage (3) (0,82 g, 2.5 mmol), in dichloromethane (10 ml, dried over molecular sieves). The flask was cooled on ice and out of the syringe was added triethylamine (0,69 ml, 5.0 mmol). Dropwise over several minutes added methanesulfonamide (0,30 ml, 3,86 mmol) and the resulting mixture was stirred overnight, allowing the ice to melt. To the mixture was added DHM (60 ml) and the solution washed with 1 M HCl (aq.), NaHCO3(feast upon., aq.) and brine. The solution is evaporated to obtain 0,876 g (86%) indicated in the subtitle compound as a yellow oil, which was used in the next stage without any further purification.

1H-NMR (400 MHz, DMSO-d6) δ: to 7.35 (2H, d, J 9.4 Hz); 6,99 (2H, d, J 9.4 Hz); 5,07-free 5.01 (1H, m); 4,37 (1H, dd, J 8,9 and 4.2 Hz); 4,20-of 4.05 (2H, m); 3,71 (1H, dd, J 11.8 in, 5.0 Hz); of 3.32 (2H, s); 3.15 in (3H, s); 2,07 (1H, d, J 14.4 Hz); 1,41 (N s).

5) tert-Butyl(2R,4S)-4-(4-chlorophenoxy)-2-methyl-1-pyrrolidinecarboxylic

In a flask was dissolved the compound obtained in stage (4) (0,876 g of 2.16 mmol)in THF (10 ml, dried over sieves). The reaction is th mixture was kept in an inert atmosphere and then cooled in an ice bath. Using a syringe for 15 minutes was added LiB(Et)3N (1 M triethylborohydride lithium in THF, 9 ml, 9 mmol). The ice bath was removed and the mixture was stirred over night. The crude mixture was distributed between EtOAc (100 ml) and water (100 ml). The aqueous phase was removed and the organic phase is washed with 1 M HCI (aq.), NaHCO3(feast upon., aq.) and brine. The solution is evaporated and the residue was purified on silica (gradient heptane:EtOAc 10:1 to 5:1 to 4:1 to 2:1. The TLC spots were visualized using reagent Sabaha (Seebach)) to obtain the 0,401 g (60%) indicated in the subtitle compound as a colourless oil.

1H-NMR (400 MHz, DMSO-d6) δ: 7,33 (2H, d, J 8.7 Hz); of 6.96 (2H, d, J 8.7 Hz); 5,00-4,94 (1H, m); the 3.89 (1H, bs); to 3.64 (1H, dd, J 12,5, 5,2 Hz); 3,38 (1H, d, J and 12.2 Hz); 2,41-of 2.28 (1H, m); 1,79 (1H, d, J of 13.7 Hz); 1,40 (N, s); of 1.23 (3H, d, J 6.6 Hz).

6) (2R,4S)-4-{4-chlorphenoxy)-2-methylpyrrolidine; salt triperoxonane acid

In a flask was dissolved the compound obtained in stage (5) (0,390 g, 1.25 mmol), in dichloromethane (DHM, 15 ml). To this solution was added TFU (triperoxonane acid, 6 ml) and the mixture was allowed to stand for 3 hours, after which volatiles were removed in vacuum. The residue is evaporated twice with DHM, getting mentioned in the subtitle compound as oil.

APCI-MS (m/z): 212 [M+H].

7) N-[2-({(2S)-3-[(2R,4S)-4-(4-Chlorophenoxy)-2-methylpyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide; salt tripto the acetic acid

Specified in the title compound was obtained in accordance with the method described in Example 255, since the substances obtained in stage (6), and (2S)-2-[(2-nitrophenoxy)methyl]oxirane. Connection received from 25% of output.

1H-NMR (400 MHz, DMSO-d6) δ: 9,88 (1H, bs); of 9.02 (1H, s); 7,89 (1H, d, J 7.7 Hz); 7,37 (2H, d, J 7.7 Hz); 7,09-to 6.88 (5H, m); of 6.02 (1H, bs); 5,18-5,11 (1H, m); 4,34-4,22 (1H, m); was 4.02 (1H, dd, J 10.2 and, of 4.3 Hz); of 3.94 (1H, dd, J of 9.8, 5.7 Hz); of 3.77-3,30 (4H, m); 3,19 (1H, t, J is 10.7 Hz); 2,84 (1H, p, J 6,7 Hz); of 2.09 (3H, s); 1,91-of 1.81 (1H, m); 1,43 (3H; J 6.4 Hz).

APCI-MS (m/z): 419,2 [M+H].

Example 261

N-{2-[(2S)-(3-{(3R)-3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-forfinal}ndimethylacetamide

APCI-MS: m/z 423,1 [M+].

Example 262

Triptorelin N'-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-were)-N,N-dimethylation

Specified in the title compound was obtained by analogy with the methods described in Example 253, starting with the compound (3) (75 mg, 0.2 mmol) and dimethylamine (2 M in THF, 200 μl, 0.4 mmol). The substance was obtained as a white amorphous solid (73 mg, 65%).

1H-NMR (400 MHz, Meon-d4): δ rate of 7.54 (dd, 1H); 7,51 (d, 2H); 7,16 and to 7.15 (d, 2H); 7,05 (bs, 1H); of 6.96 (bd, 1H); 5.40 to to 5.35 (m, 1H); 4,54-to 4.46 (m, 1H); 4,27 (d, 2H); 4,16 of 3.56 (m, 6H); 3,20 (bs, 6H); 2,84 at 2.59 (m, 1H); 2,59 is 2.44 (m, 1H); of 2.50 (s,3H).

APCI-MS: m/z448, 450 [MH+].

Example 263

N-(2-{3-[3-(4-Chloroanilino)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

1) tert-Butyl-3-hydroxy-1-pyrrolidinecarboxylic

To rest the ru 3-hydroxy-1-pyrrolidine (871 mg, 10 mmol) in THF (30 ml) was added di(tert-butyl)dicarbonate (2,18 g, 10 mmol) in THF (2 ml)and the reaction mixture is maintained under stirring at room temerature for the night. The solvent was removed in vacuum and the residue was purified by flash chromatography (0-2% Meon in CHCl3) obtaining specified in the title compound (1.7 g).

1H-NMR (CDCl3, 400 MHz): δ of 4.45 (m, 1H); 3,55-of 3.25 (m, 4H); 2,18-of 1.85 (m, 3H); 1,45 (s, 9H).

APCI-MS: m/z 166 (M-Side).

2) tert-Butyl-2-oxo-1-pyrrolidinecarboxylic

Oxide chromium (vi) (800 mg, 8.0 mmol) was added to pyridine (1.6 ml) in CH2Cl2(10 ml) and the resulting solution was stirred for 15 min at room temperature. Solution was added tert-butyl 3-hydroxy-1-pyrrolidinecarboxylic (374,5 mg, 2.0 mmol) in CH2Cl2(5 ml) followed by immediate addition of acetanhydride and the reaction mixture is maintained at room temperature for 15 minutes After adding ethyl acetate mixture decantation and filtered through a short column of silica gel. The filtrate was concentrated to obtain specified in the subtitle product (193 mg) and used directly in the next stage.

3) tert-Butyl 3-(4-chloroanilino)-1-pyrrolidinecarboxylic

tert-Butyl-2-oxo-1-pyrrolidinecarboxylic (190 mg, of 1.02 mmol), 4-Chloroaniline (64 mg, 0.5 mmol) and acetic acid (184 mg) was mixed in dihormati the e (5 ml). Added triacetoxyborohydride sodium (326,5 mg)and the reaction mixture is maintained under stirring at room temperature over night. After adding aq. NaHCO3the reaction mixture was diluted by adding ethyl acetate. Two layers were separated. The organic layer was dried over Na2SO4, filtered, concentrated. The residue was purified by flash chromatography (0-15% ethyl acetate in petroleum spirit 40-60) obtaining specified in the subtitle product (140 mg).

1H-NMR (CDCl3, 400 MHz): δ to 7.18 (m, 2H); 6,50 (m, 2H); 3,99 (m, 1H); 3,70 (m, 2H); 3.46 in (m, 2H); 3,20 (m, 1H); to 2.18 (m, 1H); to 1.87 (m, 1H); 1,45 (s, 9H).

APCI-MS: m/z 197(M-Side).

4) N-(4-Chloranil)-3-pyrrolidinone (2×CF2COOH)

To a solution of tert-butyl 3-(4-chloroanilino)-1-pyrrolidinecarboxylic (130 mg, 0,438 mmol) in CH2CI2(5 ml) was added CF3COOH (1 ml). After 30 min the volatiles were removed in vacuum to obtain specified in the subtitle product (186 mg), which was used in the next stage.

5) N-(2-{3-{3-(4-Chloroanilino)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

A mixture of N-(4-chlorophenyl)-3-pyrrolidinone (2×CF3COOH) (186 mg, 0,438 mmol), N-[2-(2-oxiranylmethyl)phenyl]ndimethylacetamide (91 mg, 0,438 mmol) and K2CO3(200 mg) in ethanol (6 ml) kept under stirring at 65°for 2.5 hours Volatiles were removed in vacuum. The residue was distributed between e what racedata and aq. a solution of NH4Cl. The organic layer was washed with water, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (0-3% Meon in CHCl3) obtaining specified in the header of the product (70 mg).

1H-NMR (CDCl3, 400 MHz): δ 8,35 (m, 1H); 8,21 (br.s, 1H); for 7.12 (m, 2H); 7,01 (m, 2H); 6,92 (m, 1H); 6.48 in (m, 2H); 4,13-to 3.92 (m, 4H); 3,84 (br.s, 1H); 2,99 (m, 1H); 2,87-of 2.30 (m, 6H); to 2.18 (s, 3H); of 1.66 (m, 1H).

APCI-MS:m/z446(MH+).

Example 264

The hydrochloride of N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-1-methylpropyl)oxy]phenyl}ndimethylacetamide

1) N-{2-[(1-Methyl-2-propenyl)oxy]phenyl}ndimethylacetamide

The compound (557 mg, 40%) was obtained from 3-chloro-1-butene (747 ml, 7,42 mmol) and 2-acetamidophenol (1,02 g of 6.75 mmol) analogously to the compound described in Example 8 (1).

1H-NMR (400 MHz, CDCl3): δ of 8.37 (m, 1H), 7,80 (bs, 1H), 6,94 (m, 3H), to 5.93 (m, 1H), 5.25 in (m, 2H), 4,84 (m, 1H), of 2.21 (s, 3H), 1,49 (d, J 6.3 Hz, 3H).

2) N-{2-{1-(2-Oxiranyl)ethoxy]phenyl}ndimethylacetamide

The compound was obtained from N-{2-[(1-methyl-2-propenyl)oxy]phenyl}ndimethylacetamide (549 mg, to 2.67 mmol) and meta-chloroperbenzoic acid (80%, 923 mg, 4,28 mmol) analogously to the compound described in Example 8 (2). Purification was performed on silica gel using as eluent a mixture of petroleum ether/ethyl acetate 10/15. It is possible to obtain the separation of the two diastereoisomeric pairs.

Diastereoisomer 1: (53 mg, 9%), Rf=0,27.

Diastereoisomer 2: (406 mg, 69%), Rf=0,0.

1H-NMR (400 MHz, CDCl3): δ 8,39 (m, 1H), 8,01 (bs, 1H), 7,00 (m, 3H), 3,98 (m, 1H), 3,24 (m, 1H), equal to 2.94 (t, J 4.5 Hz, 1H), 2,71 (dd, J 2.6 Hz, J 4.5 Hz, 1H), of 2.23 (s, 3H), 1,47 (d, J 6.3 Hz, 3H).

3) of the Hydrochloride of N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl)-2-hydroxy-1-methylpropyl)oxygenic}ndimethylacetamide

Specified in the title compound (230 mg, 100%) was obtained from diastereoisomer 2 N-[2-(1-oxiranylmethyl)phenyl]ndimethylacetamide (123 mg, 0,557 mmol) and 3-(4-chlorphenoxy)pyrrolidine (100 mg, 0,506 mmol) analogously to the compound described in Example 1 (3).

1H-NMR (400 MHz, MeOD): δ 7,86 (m, 1H), 7,30 (m, 2H), to 7.09 (m, 2H), 6,97 (m, 3H), to 5.21 (m, 1H), 4,51 (m, 1H), 3,83-4,22 (m, 3H), 3,37-3,62 (m, 4H), 2,68 (m, 1/2H)a, of 2.38 (m, 1H), and 2.27 (m, 1/2H), 2,19 (m, 3H), 1,32 (m, 3H).

MS-APCI+: m/z 419 [MH+].

Example 265

The hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-methoxyphenyl)ndimethylacetamide

1) 1-[3-(4-Chlorophenoxy)-1-pyrrolidinyl-3-(5-methoxy-2-nitrophenoxy)-2-propanol

Specified in the subtitle compound was obtained analogously to Example 253 (2) of 2-[(5-methoxy-2-nitrophenoxy)methyl]oxirane (320 mg, 1.6 mmol) and 3-(4-chlorphenoxy)pyrrolidine (365 mg, 1.6 mmol). The crude product was obtained as a yellow oil (580 mg) and used without further purification.

APCI-MS: m/z 423, 425 [MH+].

2) 1-(2-Amino-5-methoxyethoxy)-3-{3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-propanol

Specified in the subtitle compound was obtained in analogy to Example 253 (3) from the compound (1) (290 mg, 0.7 mmol). Neocide the Noah compound was obtained as a colourless oil (233 mg, 85%) and used without further purification.

APCI-MS: m/z 393, 395 [MN+].

3) of the Hydrochloride of N-(2-{3-{3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-methoxyphenyl)ndimethylacetamide

To a solution of compound (2) (157 mg, 0.4 mmol) in pyridine (3 ml) was added acetamide (1 ml). The mixture was stirred for 1 h at ambient temperature. After evaporation the residue was dissolved in methanol (ml) and was added 1.5 M sodium methoxide in methanol (1 ml). The mixture was left overnight at ambient temperature. After evaporation the residue was washed with a simple ether and water. Free base specified in the title compound was obtained from the organic phase in the form of a colorless oil (171 mg, 98%). The free base (43 mg) was dissolved in methanol (5 ml), acidified using 1 M hydrochloric acid to pH<2, was diluted with water (50 ml) and liofilizirovanny. Specified in the title compound was obtained as a white amorphous solid (30 mg, 64%).

APCI-MS: m/z 435, 437 [MN+].

Example 266

N-(2-[3-(4-Chlorobenzoyloxy)pyrrolidin-1-yl]-2-hydroxypropoxy)phenyl)ndimethylacetamide; salt triperoxonane acid

1) tert-Butyl ether 3-{4-chlorobenzoyloxy)pyrrolidin-1-carboxylic acid

A solution of tert-butyl 3-hydroxy-1-pyrrolidinecarbonyl acid (0.27 g, 1.44 mmol) in anhydrous THF (4 ml) was added dropwise to a cooled (0° (C) stirred suspension of sodium hydride(0,078 g, 2,17 mmol, approximately 50% suspension in oil) in THF (10 ml). After 30 min the solution was added 4-chlorobenzylamino (0.36 g, of 1.74 mmol) in THF (2 ml) and the resulting suspension was stirred at room temperature (K.T.) during the night. The reaction mixture of raspredelyali between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with saturated aqueous sodium chloride, dried and concentrated. The residue was subjected to flash chromatography (heptane-ethyl acetate, 6:1) to obtain specified in the subtitle compound mpem-butyl ether 3-(4-chlorobenzoyloxy)pyrrolidin-1-carboxylic acid in the form of oil (0,30 g, 66,8%).

1H-NMR (CDCl3): δ 7,30 (m, 4H), of 4.49 (bs, 2H), 4,11 (m, 1H), of 3.45 (m, 4H), 1,90-of 2.08 (m, 2H), of 1.46 (s, 9H).

2) 3-(4-Chlorobenzoyloxy)pyrrolidin

A solution of tert-butyl methyl ether 3-(4-chlorobenzoyloxy)pyrrolidin-1-carboxylic acid (0.28 g, 0.9 mmol) in aqueous 90% formic acid (7.5 ml) was stirred at (0°C) for 30 min, then at room temperature overnight. The solvent was removed under reduced pressure, and the residue was treated with saturated aqueous potassium carbonate and was extracted twice with n-butanol. The combined organic extracts were concentrated, and the residue was purified by flash chromatography (SiO2, dichloromethane-methanol-ammonium hydroxide, 8:8:1 then 50:10:1) to obtain the specified in the subtitle compound 3-(4-chlorobenzoyloxy)pyrrolidine (0,13 g, 70%).

1H-NMR (DMSO-d6): δ 7,32-7,41 (m, 4H), 4,42 (s, 2H), was 4.02 (m, 1H), 3,18 (bs, 3H), 2,75-of 2.86 (m, 3H), 2,68 (m, 1H), 1,66-of 1.81 (m, 2H).

APCI-MS: m/z 212 [MH+].

3) N-(2-[3-(4-Chlorobenzoyloxy)pyrrolidin-1-yl]-2-hydroxypropoxy)phenyl)ndimethylacetamide; salt triperoxonane acid

A solution of 3-(4-chlorobenzoyloxy)pyrrolidine (0,050 g, 0.24 mmol) and N-(2-oxiranylmethyl)ndimethylacetamide (0,049 g, 0.24 mmol) in absolute ethanol (3 ml) was heated in a sealed tube at 70°C for 2 hours the Product was purified by HPLC to obtain specified in the connection header (0,60 g, 47%).

1H-NMR (CD3OD): δ a 7.85 (m, 1H), 7,35 (m, 4H), 7,12 (m, 1H), 7,02 (d, 1H, J=8 Hz), of 6.96 (m, 1H), 4,56 (m, 2H), 4,39 (m, 2H), of 4.05 (d, 2H, J=5,9 Hz), 3,85 (m, 2H), 3,48 (m, 4H), 2,10-to 2.55 (m, 5H).

APCI-MS: m/z 419 [MH+] 421 [MN+2].

Example 267

N-(2-{3-[3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxy-2-methylpropoxy}phenyl)ndimethylacetamide

The compound was obtained by using a method similar to the method of Example 270, which follows.

APCI-MS: m/z 419 [MH+].

Example 268

N-(2-{(1S,2R,3S)*-3-[(3S)-3-(3,4-Divergence)pyrrolidin-1-yl]-2-hydroxycyclopent}-5-chlorophenyl)ndimethylacetamide (diastereoisomer mix)

Received by analogy with the following Example 271 N-{5-chloro-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]Gex-2-yloxy]phenyl}ndimethylacetamide (5.3 mg, 20 mmol) and (3S)-3-(3,4-divergence)pyrrolidine (4.0 mg, 20 µmol).

MS-APCI+:m/z467[M+].

Example 269

N-[2-({(2R,3S)*-3-[(3S)-3-(4-Chlorphenoxy)pyrrole the Nile]-2-hydroxybutyl}oxy)-4-were]ndimethylacetamide (diastereoisomer mix)

Received by analogy with the following Example 271 N-(4-methyl-2-{[(2S,3R)*-3-methyloxirane]methoxy}phenyl)ndimethylacetamide (4,7 mg, 20 mmol) and (3S)-3-(4-chlorphenoxy)pyrrolidine (4.0 mg, 20 µmol).

MS-APCI+: m/z 433 [M+].

Example 270

The hydrochloride of N-{2-[(3-{4-[(3,4-dichlorophenyl)oxy]-1-piperidinyl}-2-hydroxy-2-methylpropyl)oxy]-4-forfinal}ndimethylacetamide

1) N-[4-fluoro-2-(2-methylacrylate)phenyl]ndimethylacetamide

3-Chloro-2-methylpropene (1,36 g, 15 mmol) was added to a mixture of 5-fluoro-2-NITROPHENOL (of 1.57 g, 10 mmol), potassium carbonate (2.76 g, 20 mmol), tetrabutylammonium hydrosulfate (0,068 g, 0.2 mmol) and acetonitrile (30 ml) and the mixture is boiled under reflux for 18 h the Cooled reaction mixture was diluted with toluene and washed with 5% aqueous potassium carbonate, dried and evaporated. Part of the residue (0,631 g, 3 mmol), dithionite sodium (1.04 g, 6 mmol) in EtOH-THF-H2About (2:1:1.3 ml) was heated at 75°C for 4 h the Mixture was distributed between dichloromethane and 15% aqueous potassium carbonate, and the organic solution was dried and concentrated. The obtained residue was diluted with methanol (1.5 ml) and subjected to interaction with acetanhydride (1.5 ml) at 50°C for 2 min, and allowed him to reach room temperature for 20 min, then was added pyridine (4 ml)and the solution was again heated at 50°C for 3 min, cooled and concentrated. The substance was purified by chromatography on silicagel is e (petroleum ether-ethyl acetate 2:1) to give 95 mg specified in the subtitle of the connection.

1H-NMR (300 MHz, CDCl3): δ of 8.28 (dd, 1H), 7.62mm (bs, 1H), 6,70-6,60 (m, 2H), 5,07 (dd, 2H), 4,49 (s, 2H), measuring 2.20 (s, 3H), of 1.84 (s, 3H).

2) N-(4-fluoro-2-{[(2-methyl-2-oxiranyl)methyl]oxy}phenyl)ndimethylacetamide

Specified in the subtitle compound was obtained from N-[4-fluoro-2-(2-methylacrylate)phenyl]ndimethylacetamide same way as described in Example 8 (2).

1H-NMR (300 MHz, CDCl3): δ 8,31 compared to 8.26 (dd, 1H), 7,79 (bs, 1H), 6.75 in-6,65 (m, 2H), 4,14 (d, 1H), 3,97 (d, 1H), 2,93 (d, 1H), 2,80 (d, 1H), of 2.21 (s, 3H), 1,50 (s, 3H).

APCI-MS: m/z 240 [MN+].

3) of the Hydrochloride of N-[2-[(3-{4-[(3,4-dichlobenil)oxy]-1 - piperidinyl}-2-hydroxy-2-methylpropyl)oxy]-4-forfinal}ndimethylacetamide

A solution of 4-(3,4-dichlorophenoxy)piperidine (36 mg, 0,146 mmol), N-(4-fluoro-2-{[(2-methyl-2-oxiranyl)methyl]oxy}phenyl)ndimethylacetamide (35 g, 0,146 mmol) in EtOH (1 ml, 95%) was stirred for 2.5 h at 77°in a sealed vessel. The solvent is evaporated, and the residue was purified on silica (dichloromethane-methanol, 15:1, containing 1% NH4OH (25%)) to give 45 mg of the corresponding free amine specified in the connection header.

1H-NMR of the corresponding free amine specified in the connection header.

(400M Hz, CDCl3): δ compared to 8.26 is 8.22 (dd, 1H), 7,89 (bs, 1H), 7,31 (d, 1H), 7,01 (d, 1H), 6,77-of 6.65 (m, 3H), 4,30 (m, 1H), 3,80 (dd, 2H), 2,93-of 2.81 (m, 2H), to 2.67 (d, 1H), 2,63 is 2.51 (m, 2H), 2,45 (d, 1H), 2,19 (s, 3H), 1,96 (m, 2H)and 1.83 (m, 2H), 1,62 (bs, 1H), 1,31 (s, 3H).

4) of the Hydrochloride of N-2-[(3-{4-[3,4-dichlorophenyl)oxy]-1 - piperidinyl}-2-hydroxy-2-methylpropyl)oxy]-4-FPO is phenyl}ndimethylacetamide

The solution of the free amine in methanol (10 ml) was acidified with HCl (conc., 0,020 ml) to pH 3 and concentrated. The residue three times evaporated with toluene to obtain specified in the title compound hydrochloride as a white powder.

APCI-MS: m/z 485, 487 [MN+].

Example 271

N-(2-{(1S,2R,3S)*-3-[(3S)-3-(4-Chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}-4-forfinal)ndimethylacetamide (diastereoisomer mix)

N-{4-fluoro-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]Gex-2-yloxy]phenyl}ndimethylacetamide (5.0 mg, 20 mmol) and (3S)-3-(4-chlorphenoxy)pyrrolidin (3.9 mg, 20 µmol) was dissolved in 2 M solution LiClO4in acetonitrile (0.2 ml) and heated in a sealed tube to 100°C. Dilution with ethyl acetate, neutral water treatment and evaporation of the solvent allowed to obtain the crude product which was used without further purification.

MS-APCI+: m/z 449 [M+].

Example 272

N-(5-Chloro-2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 441,1 [MN+].

Example 273

N-(5-Chloro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 423,1 [MN+].

Example 274

N-(4-Cyano-2-{3-[4-(3,4-dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)ndimethylacetamide

APCI-MS: m/z 477 [MN+].

Example 275

N-(4-Hydroxy-2-{(1S,2R,3S)*-3-[(3S)-3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)ndimethylacetamide (diaster izomera mix)

1) N-{4-methoxy-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]Gex-2-yloxy]phenyl}ndimethylacetamide (32 mg, 122 μmol) and (3S)-3-(4-chlorphenoxy)-pyrrolidin (24 mg, 122 μmol) was dissolved in 2 M solution LiClO4in acetonitrile (1 ml) and heated in a sealed tube to 100°C. Dilution with ethyl acetate, neutral water treatment and evaporation of the solvents allowed to obtain 62 mg (110%) of the crude product of accession, which reacts with borrisrandom (1 M in CH2Cl2, and 0.37 ml, 371 mmol) in dichloromethane (1 ml) at room temperature over night. The reaction mixture was extinguished with methanol (1.0 ml), and the volatile components evaporated. The remaining crude material was subjected to reverse-phase HPLC to obtain 30 mg (54%) indicated in the title compound in the form of diastereoisomeric mixture.

MS-APCI+: m/z 447,1 [MN+].

2) Separation of diastereoisomers.

Described earlier stage (1) diastereoisomer the mixture was subjected to chiral-phase HPLC (stationary phase: Chiralpak AD; mobile phase: isohexane/isopropanol/methanol/diethylamine=80:16:4:0,1), where the compound of Example 276 was eluruumis the first and the compound of Example 277 was eluruumis second stereoisomer. Determination of the absolute configuration of the corresponding stereoisomer below the selected optional and can be used interchangeably.

Example 276

N-(4-Hydroxy-2-{(1S,2R,3S-3-[(3S)-3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)ndimethylacetamide

1H-NMR (400 MHz, CDCl3; HE-protons neglected): δ 8,02 (1H, s), 7,49 (1H, d, J 8,4 Hz), 7,17 (2H, d, J 8.9 in Hz)of 6.71 (2H, d, J 8,8 Hz), to 6.43 (1H, s), 6,34 (1H, d, J 7.2 Hz), was 4.76 (1H, m), 4,39 (1H, m), 4.09 to (1H, m), 3,10-2,95 (3H, m), 2,89 (1H, m), 2,77 (1H, m), 2,24 (1H, m), of 2.08 (3H, s), 2,10-of 1.84 (3H, m), of 1.75 (1H, m)to 1.59 (1H, m).

MS-APCI+: m/z 447,1 [MH+]

[α]22=+49,5 (CH2With2).

Example 277

N-(4-Hydroxy-2-{(1R,2S,3R)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)ndimethylacetamide

1H-NMR (400 MHz, CDCl3; HE-protons neglected): δ of 7.75 (1H, s), 7,60 (1H, d, J 8,4 Hz), 7,19 (2H, d, J 8,3 Hz), 6.73 x (2H, d, J 8.6 Hz), to 6.57 (1H, s), 6,38 (1H, d, J 8,4 Hz), of 4.77 (1H, m), 4,43 (1H, m), is 4.21 (1H, m), 3,09-to 2.94 (3H, m), 2,79 (1H, m), 2,68 (1H, m), 2,28 (1H, m), of 2.08 (3H, s), 2.05 is-1,90 (3H, m), of 1.86 (1H, m), 1,53 (1H, m).

MS-APCI+: m/z 447,1 [MH+].

[α]22=-45,2 (CH2C2).

Diastereoisomer Examples 278 and 279 were obtained using methods similar to the methods used to obtain the compounds of Examples 221-230, and shared in accordance with the order, as described in Example 275 above. The absolute configuration of the respective isomers is determined optionally in accordance with the fact, as mentioned above, and therefore it is interchangeable.

Example 278

N-[2-({(1S,2R,3S)-3-[(3S)-3-(4-Chlorphenoxy)pyrrolidinyl]-2-hydroxycyclopent}oxy)phenyl]ndimethylacetamide

Isomer, eluruumis first.

MS-APCI+: m/z 431,1 [MH+].

[α]22=+72,2 (CH2With2).

Example 279

N-[2-{(1R,2S,3S)-3-[(3S)-3-(4-Chlorphenoxy)pyrrolidinyl]-2-hydroxycyclopent}oxy)phenyl]ndimethylacetamide

Isomer, eluruumis second.

MS-APCI+: m/z 431,1 [MH+].

[α]22=-51,4(CH2C2).

Diastereoisomer Examples 249 280 and received using methods similar to the methods used to obtain the compounds of Examples 221-230, and shared in accordance with the order, as described in Example 275 above. The compound of Example 280 is an isomer, eluruumis first, whereas the compound of Example 249 is an isomer, eluruumis second. The absolute configuration of the respective isomers is determined optionally in accordance with the fact, as mentioned above, and therefore it is interchangeable.

Example 280

N-[5-Chloro-2-({(1S,2R,3S)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxycyclopent}oxy)phenyl]ndimethylacetamide

MS-APCI+: m/z 464,9 [MH+].

[α]22=+53,0 (CH2With2).

Example 281

N-{5-Chloro-2-[((1S,2R,3S)*-3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxycyclopent)oxy]phenyl}ndimethylacetamide (racemic mixture)

Was obtained analogously to Example 271 N-{5-chloro-2-[(1R,2S,5R)*-6-oxabicyclo[3.1.0]Gex-2-yloxy]phenyl}ndimethylacetamide (5.3 mg, 20 μmol) and 1-(4-Chlorobenzyl)-4-piperidylamine (4.5 mg, 20 µmol).

MS-APCI+: m/z 492 [M+].

Example 282

N-[2-({(2S)-3-[(3S)-3-(4-Chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)-4-hydroxyphenyl]ndimethylacetamide

1) (2S)-2-[(5-Methoxy-2-nitrophenoxy)methyl] oxirane

Specified in the subtitle compound recip is whether the conditions Mitsunobu (Mitsunobu) of R-(+)-glycidol (198 mg, 1 mmol), 5-methoxy-2-NITROPHENOL (169 mg, 1 mmol), triphenylphosphine (263 mg, 1 mmol) and DEAD (157 μl, 1 mmol), using as a solvent of anhydrous THF. The crude substance was purified by flash chromatography on silica, using as mobile phase a mixture of ethyl acetate and heptane. The required fractions were combined to obtain the crude product as white crystals (175 mg). The product was contaminated restored DEAD in a molar ratio of 1:1, which is equivalent to yield 100 mg (44%) of the desired product

1H-NMR (400 MHz, CDCl3): δ 8,00 (d, 1H); 6,60 (d, 1H); 6,55 (dd, 1H); at 6.4 (bs, 1H, reset. DEAD); to 4.41 (dd, 1H); 4,22 (q, 4H, reset. DEAD); 4,13 (dd, 1H); to 3.89 (s, 3H); 3,44-3,39 (m, 1H); 2,95 (dd, 1H); 2,92 (dd, 1H); of 1.29 (t, 6H; reset. DEAD).

APCI-MS: m/z 226 [MN+].

2) (2S)-1-[(3S)-3-(4-Chlorphenoxy)pyrrolidinyl]-3-(5-methoxy-2-nitrophenoxy)-2-propanol

Specified in the subtitle compound was obtained analogously to Example 1(2) (1) (169 mg, 0.43 mg) and (3S)-3-(4-chlorphenoxy)pyrrolidine (85 mg, 0.43 mmol). The product was obtained as a yellow oil and used without further purification.

APCI-MS: m/z 423, 425 [MN+].

3 (2S)-1-(2-Amino-5-methoxyphenoxy)-3-[(3S)-3-{4-chlorphenoxy)pyrrolidinyl]-2-propanol

Specified in the subtitle compound was obtained analogously to Example 253 (3) (2) (0.43 mmol). The resulting product (colorless oil, 163 mg) was a mixture of desired product and vosstanovlenie what about DEAD in a molar ratio of 5:1. The substance used as such.

1H-NMR (400 MHz, CDCl3): δ of 7.23 (d, 2H); 6,77 (d, 2H); to 6.67 (d, 1H); of 6.49 (d, 1H); 6,41 (bs, reset. DEAD); to 6.39 (dd, 1H); a 4.83-of 4.77 (m, 1H); 4,22 (q, reset. DEAD); 4,14-4,07 (m, 1H); 4,01 (d, 2H); of 3.75 (s, 3H); 3,01-only 2.91 (m, 2H); 2,88-of 2.72 (m, 3H); 2,62 (dd, 1H); 2,29 (Gex., 1H); 2.06 to a 1.96 (m, 1H); of 1.29 (t, reset. DEAD).

APCI-MS: m/z 393, 395 [MN+].

4) N-[2-({(2S)-3-[(3S)-3-(4-Chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)-4-hydroxyphenyl]ndimethylacetamide

To a solution of compound (3) (157 mg) in a mixture of acetonitrile (10 ml) and water (2 ml) was added acetamide (1 ml)and the mixture was stirred at ambient temperature overnight. Added a 1.5 M sodium methoxide in methanol (1 ml), and stirring was continued for 1 h After evaporation the residue was washed with a simple ether and water. Specified in the subtitle product was obtained from the organic phase in the form of a colorless oil (155 mg).

1H-NMR (400M Hz, CDCl3): δ 8,18 (d, 1H); to 7.95 (bs, 1H); from 7.24 (d, 2H); is 6.78 (d, 2H); 6,56-of 6.52 (m, 2H); 4,85-4,78 (m, 1H); 4,22 (q, reset. DEAD); 4,10-was 4.02 (m, 2H); 4,00-to 3.92 (m, 1H); of 3.78 (s, 3H); 3,00-only 2.91 (m, 2H); 2,87-by 2.73 (m, 3H); 2,53 (dd, 1H); 2,36 was 2.25 (m, 1H); 2,17 (s, 3H); 2,07 of 1.99 (m, 1H); of 1.29 (t, reset. DEAD).

APCI-MS: m/z 435, 437 [MN+].

5) N-[2-({(2S)-3-[(3S)-3-(4-Chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)-4-hydroxy(renilla

Specified in the title compound was obtained in analogy to Example 254 (4) (150 mg). The product obtained after lyophilization, was a white amorphous solid 101 mg, 57%).

1H-NMR (400 MHz, CDCl3+1 drop DMSO-d6): δ to 8.7 (bs, 1H); 8.34 per (s, 1H); 8,73 (d, 1H); 7.18 in (d, 2H); 6.73 x (d, 2H); 6,40 of 6.31 (m, 2H); 4,99-is 4.93 (m, 1H); 4,4-1,9 (bm, 6H); or 4.31-to 4.23 (m, 1H); 3,88-of 3.78 (m, 2H); 3,39-of 3.25 (m, 2H); 2,4-2,2 (m, 2H); 2,07 (s, 3H).

APCI-MS: m/z 421, 423 [MN+].

Analysis of chemotaxis TNR-1

Introduction

The analysis measures the chemotactic response induced by the chemokine MIP-1α in cell lines of human monocytes TNR-1. Compounds of the Examples were evaluated for their ability to inhibit the chemotactic response to a standard concentration of the chemokine MIP-1α.

Ways

Cell culture TNR-1

Cells were quickly thawed at 37°from the frozen aliquot and resuspendable in the flask height 25 cm, containing 5 ml of RPMI-1640 medium, supplemented Glutanax and 10% heat inactivated fetal calf serum without antibiotics (RPMI+10% FFTS). On day 3 the medium was removed and replaced with fresh medium.

Cells TNR-1, as expected, were grown in medium RPMI-1640, supplemented with 10% heat inactivated fetal calf serum and glutamicum, but without antibiotics. Optimal growth of cells required to be replanted every 3 days and that the minimum density of the subculture was 4×105cells/ml

Analysis of chemotaxis

Cells were removed from the flask and washed by centrifugation in RPMI+10% FFTS + glutamax. Cells then resuspendable 2×107cells/the l in fresh medium (RPMI+10% FFTS + glutamax), to which was added calcein-AM (5 ál of a solution of 1 ml with a final concentration of 5×10-6M). After careful mixing, the cells were incubated at 37°in CO2incubator for 30 minutes. Cells were diluted to 50 ml medium and washed twice by centrifugation at 400×g. Labeled cells are then resuspendable to the concentration of cells 1×107cells/ml and incubated with an equal volume of antagonist MIP-1α (final concentration of 10-10M to 10-6M) for 30 minutes at 37°C in humidified CO2the incubator.

Chemotaxis was performed using 96-well chemotactic tablets Neuroprobe, using 8 μm filters (cat. No. 101-8). Thirty microlitres chemoattractant, supplemented with various concentrations of antagonists or solvent, was added to the lower wells in three Parallels. The filter was then carefully placed on the surface and then the surface of the filter were added 25 μl of cells, preincubating with the appropriate concentration of antagonist or solvent. The tablet then incubated for 2 hours at 37°C in humidified CO2the incubator. Cells remaining on the surface was then removed by adsorption, and the entire tablet was centrifuged at 2000 rpm for 10 minutes. The filter was then removed and cells, which migirov is whether at the bottom of the hole, quantitatively determined by fluorescence associated with cells calcein AM. The migration of cells was then expressed in units of fluorescence after subtracting the fluorescence of control (reagent), and values were normalized to % migration by comparing the fluorescence values with values known for the number of labelled cells. The effect of the antagonist was calculated as % inhibition, when the number of migrating cells was compared with the solvent.

The example of the pharmaceutical composition

Injection

The following ingredients were mixed in the usual way for solution for injection containing 5 mg/ml of active compound. For this purpose, 1 ml of 0.9%sodium chloride solution was added to 5 mg of active compound, the resulting mixture was solubilizers with shaking and were ampliroll.

The connection according to the invention5 mg
A solution of sodium chloride at 0.9%1 ml

1. The compound of General formula

where R represents a group

where m is 0, 1, 2 or 3;

each R1independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-C6C is cloaker, C1-C6alkoxy, C1-C6alkoxycarbonyl, C1-C6halogenoalkane, C1-C6halogenoalkane, -NR9R10With3-C6cyclooctylamino, C1-C6alkylthio, C1-C6alkylsulphonyl, C1-C6alkylcarboxylic, sulfonamide,1-C6alkylsulfonyl, -C(O)NR11R12, -NR13C(O)-(NH)pR14, phenyl or C1-C6alkyl, possibly substituted by carboxyla or C1-C6alkoxycarbonyl;

p is 0 or 1;

X represents an oxygen atom or sulfur, or CH2CH(CH3), Co2CH2O, CH2NH, NH or carbonyl group;

Y represents a nitrogen atom or a group CH or C(OH), provided that when X represents an oxygen atom or sulfur or a group CH2O, CH2NH or NH, then Y is a group CH;

Z1represents a bond or a group (CH2)qwhere q is 1 or 2;

Z2represents a bond or a group CH2provided that Z1and Z2both simultaneously represent a bond;

Q represents oxygen atom or sulfur, or a group CH2or NH;

R2represents a group

where n is 0, 1 or 2;/p>

each R3independently represents a C1-C6alkyl, C1-C6alkoxycarbonyl, -CH2OH or a carboxyl group;

R4, R5, R6and R7each independently represents a hydrogen atom or a C1-C6alkyl group, or R4, R5, R6and R7together represent a1-C4alkylenes chain linking the two carbon atoms to which they are attached, with the formation of a 4-7-membered saturated carbocycle, or R5, R6and R7each represents a hydrogen atom, and R4and R8together with the carbon atoms to which they are attached, form a 5-6-membered saturated carbocycle;

R8represents a hydrogen atom, a C1-C6alkyl group or is linked to R4as defined above;

R9and R10each independently represents a hydrogen atom or a C1-C6alkyl group, or R9and R10together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle;

R11and R12each independently represents a hydrogen atom or a C1-C6alkyl group, possibly substituted C1-C6alkoxycarbonyl;

R13represents a hydrogen atom is or C 1-C6alkyl group;

R14represents a hydrogen atom or a C1-C6alkyl group, possibly substituted by carboxyla, C1-C6alkoxy or C1-C6alkoxycarbonyl;

R15is carboxyl, C1-C6alkylsulphonyl, C1-C6alkoxycarbonyl,1-C6alkoxycarbonyl1-C6alkyl or the group-NR17R18, -NHSO2CH3, -NHC(O)CH3, -C(O)NR17R18, -NHC(O)NR17R18, -OC(O)NR17R18, -OCH2C(O)NR17R18, -NHC(O)OR17'or17";

t is 0, 1, 2 or 3;

each R16independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, C1-C6halogenoalkane, C1-C6halogenoalkane, -NR19R20With3-C6cyclooctylamino, C1-C6alkylthio, C1-C6alkylsulphonyl,1-C6alkylcarboxylic, sulfonamide (SO2NH2), C1-C6alkylsulfonyl, -C(O)NR21R22, -NR23C(O)(NH)vR24, phenyl or C1-C6alkyl, possibly substituted by carboxyla or C1-C6alkoxycarbonyl;

R17and R18each independently researched the mo represents (1) hydrogen atom, (2) a 5-6-membered saturated or unsaturated ring which may contain at least one heteroatom selected from nitrogen, oxygen and sulfur, and the ring possibly substituted by at least one Deputy, selected from halogen, methyl and trifloromethyl, or (3) C1-C6alkyl group, possibly substituted by at least one Deputy, selected from halogen, trifloromethyl, carboxyl, C1-C6alkoxycarbonyl and 5-6-membered saturated or unsaturated ring which may contain at least one heteroatom selected from nitrogen, oxygen and sulfur, and the ring possibly substituted by at least one Deputy, selected from halogen, methyl and trifloromethyl, or R17and R18together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle;

R17'represents a hydrogen atom or a C1-C6alkyl group, possibly substituted by carboxyla or C1-C6alkoxycarbonyl;

R17"defined as R17above, except that R17"does not represent a hydrogen atom;

R19and R20each independently represents a hydrogen atom or a C1-C6alkyl group, or R19and R20together with the nitrogen atom to which they are connected is ineni, form a 4-7-membered saturated a heterocycle;

R21and R22each independently represents a hydrogen atom or a C1-C6alkyl group, possibly substituted C1-C6alkoxycarbonyl;

v is 0 or 1;

R23represents a hydrogen atom or a C1-C6alkyl group, and

R24represents a hydrogen atom or a C1-C6alkyl group, possibly substituted by carboxyla, C1-C6alkoxy or C1-C6alkoxycarbonyl,

or its pharmaceutically acceptable salt or MES.

2. The compound according to claim 1, where X represents an oxygen atom or CH2The co2CH2Oh, NH or carbonyl group.

3. The compound according to claim 1 or 2, where Y represents a nitrogen atom or a group CH.

4. The compound according to any one of claims 1 to 3, where Q is an oxygen atom.

5. The compound according to any one of claims 1 to 4, where R15represents a C1-C4alkoxy, C1-C4alkylsulphonyl, C1-C4alkoxycarbonyl1-C4alkyl, -NHC(O)CH3, -C(O)NR17R18, -NHSO2CH3or-NHC(O)NR17R18.

6. The compound according to any one of claims 1 to 5, where each R16independently represents halogen, cyano, hydroxyl, C1-C4alkoxy, C1-C4alkoxycarbonyl, C1-C4halogenoalkane, C1-C4alkylsulphonyl, phenyl or C1-C4alkyl.

7. The compound of formula (I'), or its pharmaceutically acceptable salt, or MES as defined in claim 1, chosen from:

the hydrochloride of N-(2-{3-[3R,S-(4-chlorphenoxy)pyrrolidin-1-yl]-2R,S-hydroxypropoxy}phenyl)acetamide", she

the hydrochloride of N-(5-chloro-2-{3-[3R,S-(4-chlorphenoxy)pyrrolidin-1-yl]-2R,S-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

dihydrochloride of 1-(2-aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanol,

the hydrochloride of N-(2-{3-[3-(3,4-dichlorophenoxy)-1-pyrrolidinyl)-2-hydroxypropoxy}phenyl)acetamide", she

methyl ester 2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxypropoxy}benzoic acid,

methyl ester 2-(2-{3-[4-(3,4-divergence)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid,

N-[2-({(1R,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopent}oxy)phenyl]acetamide", she

N-[2-({(1S,2S,3R)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-2-hydroxycyclopent}oxy)phenyl]acetamide", she

N-[2-({(2,3-TRANS)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclohexyl}oxy)phenyl]acetamide", she

N-(5-chloro-2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)and is etamide,

N-(3-acetyl-2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide,

N-(4-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)acetamide", she

N-(2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide,

N-(2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-chloro-2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy} phenyl)acetamide", she

N-(3-acetyl-2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide,

N-(4-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)acetamide", she

N-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide,

N-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(4-chlorphenoxy)PI is Raiden-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-Chloro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(3-acetyl-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(5-fluoro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(4-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)acetamide", she

N-(4-fluoro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-chloro-2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(3-acetyl-2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide,

N-(4-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)acetamide", she

N-(2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide,

N-(2-{3-[3-(3,4-divergence)Pyrrhus is lidin-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-chloro-2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(3-acetyl-2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide,

N-(4-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)acetamide", she

N-(2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide,

N-(2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-chloro-2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(3-acetyl-2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-forfinal)ndimethylacetamide,

N-(4-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}biphenyl-3-yl)acetamide", she

N-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-Ki is oxypropane}-4-forfinal)ndimethylacetamide,

N-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-were)ndimethylacetamide,

N-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

methyl ester 3-(2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-3-(2,6-dimethoxyphenoxy)propan-2-ol,

1-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-it,

1-(2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ethanone,

methyl ester 3-(2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-(2,6-dimethoxyphenoxy)-3-[3-(4-pertenece)pyrrolidin-1-yl]propane-2-ol,

1-[3-(4-pertenece)pyrrolidin-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

methyl ester (2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

methyl ester (2-{3-[3-(4-chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

methyl ester 2-(2-{3-[3-(4-FPO is phenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid,

2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)ethanone,

1-(2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propane-1-it,

1-(2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ethanone,

methyl ester 3-(2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-[3-(3,4-divergence)pyrrolidin-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

methyl ester (2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)ethanone,

1-(2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propane-1-it,

1-(2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ethanone,

N-(2-{3-[4-(3,4-dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

methyl ester 3-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-3-(2,6-dimethoxyphenoxy)propan-2-ol,

1-[3-(4-chlorphenoxy)pyrrolidin-1-the l]-3-(2-methoxyphenoxy)propan-2-ol,

methyl ester (2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

methyl ester 2-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid,

2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)ethanone,

1-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propane-1-it,

1-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ethanone,

N-(2-{3-[3-(4-cianfrocca)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

methyl ester 3-(2-{3-[3-(4-cianfrocca)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

methyl ester (2-{3-[3-(4-cianfrocca)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

2-{3-[3-(4-cianfrocca)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

4-{1-[2-hydroxy-3-(2-propionyloxy)propyl]pyrrolidin-3-yloxy}benzonitrile,

N-(2-{2-hydroxy-3-[3-(4-methoxyphenoxy)pyrrolidin-1-yl]-propoxy}phenyl)acetamide", she

N-(4-Chloro-2-{3-[4-(3,4-dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

methyl ester 3-(2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydrox is propoxy}phenyl)propionic acid,

1-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

methyl ester (2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

methyl ester 2-(2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid,

2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)ethanone,

1-(2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)propane-1-it,

1-(2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ethanone,

N-(2-{3-[4-(3,4-divergence)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

methyl ester 3-(2-{3-[4-(3,4-divergence)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

2-{3-[4-(3,4-divergence)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[4-(3,4-divergence)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-it,

methyl ester (2-{3-[4-(3,4-divergence)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

N-(2-{3-[3-(3,4-diferenciate)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxyprop is si}phenyl)acetamide", she

methyl ester 3-(2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-(2,6-dimethoxyphenoxy)-3-[4-(4-pertenece)piperidine-1-yl]propane-2-ol,

1-[4-(4-pertenece)piperidine-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

1-(2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ethanone,

2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-it,

methyl ester (2-{3-[4-(4-pertenece)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

N-(2-{3-[3-(4-forfinancial)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

methyl ester 3-(2-{3-[3-(4-forfinancial)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-[3-(4-forfinancial)piperidine-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

1-(2-{3-[3-(4-forfinancial)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ethanone,

methyl ester 2-(2-{3-[3-(4-forfinancial)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid,

2-{3-[3-(4-forfinancial)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[3-(4-forfinancial)piperidine-1-yl]-2-hydroxypropoxy)-6-methoxyphenyl)ethanone,

N-(2-{3-[4-(acetylaminophenol)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(4-{1-[3-(2-acetylphenol)-2-hydroxypropyl]-piperidine-4-yloxy}phenyl)acetamide", she

N-(4-cyano-2-{3-[4-(3,4-dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

methyl ester 3-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propionic acid,

1-[4-(4-chlorophenoxy)piperidine-1-yl]-3-(2-methoxyphenoxy)propan-2-ol,

1-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ethanone,

methyl ester 2-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)-2-methylpropionic acid,

2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-6-methoxyphenyl)ethanone,

1-(2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-it,

methyl ester (2-{3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}benzoylamine)acetic acid,

N-(2-{3-[3-(4-chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

methyl ester 3-(2-{3-[3-(4-chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy} phenyl)propionic acid,

1-(2-{3-[3-(4-chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)ethanone,

2-{3-[3-(4-chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}-N,N-dimethylbenzamide,

1-(2-{3-[3-(4-chlorphenoxy)piperidine-1-yl]-2-hydroxypropoxy}phenyl)propane-1-it,

N-[2-({(1R,2R)-2-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-1-hydroxycyclopent}methoxy)phenyl]acetamide", she

hydrochloride of methyl(2S,4R)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-[(4-Chlorobenzyl)oxy]-2-pyrrolidinecarboxylic,

N-(2-{3-[4-(3,4-dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[4-(4-chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(4-Chloro-2-{3-[4-(4-chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(4-chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-cyanophenyl)ndimethylacetamide,

N-(2-{3-[4-(4-chloroanilino)-1-piperidinyl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(5-chloro-2-{3-[4-(4-foronline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-chloro-2-{3-[4-(3,4-diptiranjan)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-cyano-2-{3-[4-(4-foronline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-cyano-2-{3-[4-(3,4-diptiranjan)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(4-foronline)-1-piperidinyl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[4-(3,4-diptiranjan)-1-piperidinyl]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[3(S)-(4-chlorphenoxy is)pyrrolidin-1-yl]-2-(R)-hydroxypropoxy}phenyl)acetamide", she

the hydrochloride of N-(2-{3-[3S-(4-chlorphenoxy)pyrrolidin-1-yl]-2S-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[3(R)-(4-chlorphenoxy)pyrrolidin-1-yl]-2-(S)-hydroxypropoxy}phenyl)acetamide", she

N-[5-chloro-2-({(2S)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide", she

N-[5-chloro-2-({(2R)-3-[(3R)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide", she

N-[5-chloro-2-({(2S)-3-[(3R)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide", she

N-[5-chloro-2-({(2R)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide", she

N-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-4,5-differenl)ndimethylacetamide,

N-{5-chloro-2-[2-hydroxy-3-(3-phenoxypyridine-1-yl)propoxy]phenyl}acetamide", she

N-(5-chloro-2-{2-hydroxy-3-[3-(4-nitrophenoxy)pyrrolidin-1-yl]propoxy}phenyl)acetamide", she

N-(5-acetyl-2-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

methyl ester of 4-acetylamino-3-{3-[3-(3,4-dichlorophenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoic acid,

N-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}-5-cyanophenyl)ndimethylacetamide,

methyl ester of 4-acetylamino-3-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}benzoic acid,

N-(5-cyano-2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxyp is poxy}phenyl)acetamide", she

N-(2-{3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxypropoxy}-5-triptoreline)ndimethylacetamide,

trifenatate N-(5-chloro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

trifenatate N-(5-acetyl-2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)methanesulfonamide,

N-(5-chloro-2-[3-[3,4-dichlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy]phenyl)urea

2,2,2-trifenatate 1-(3-{2-[(aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(4-chlorphenoxy)pyrrolidine,

2,2,2-trifenatate 1-(3-{2-[(aminocarbonyl)amino]phenoxy}-2-hydroxypropyl)-3-(3,4-dichlorophenoxy)pyrrolidine,

2,2,2-trifenatate 1-(3-{2-[(aminocarbonyl)amino]-4-chlorophenoxy}-2-hydroxypropyl)-3-(4-chlorphenoxy)pyrrolidine,

the hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N'-utilmately,

the hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-N'-metalmachine,

(2S,4S)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(4-chlorophenoxy)-2-pyrrolidinecarboxylic acid; compound with triperoxonane acid,

ethyl-(2S,4S)-1-{3-[2-(acetylamino)phenoxy]-2-hydroxypropyl}-4-(3,4-dichlorophenoxy)-2-pyrrolidinecarboxylic; salts of triperoxonane the th acid,

N-[2-({(2S)-3-[(2S,4S)-4-(4-chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide; salt triperoxonane acid,

N-[2-({(2R)-3-[(2S,4S)-4-(4-chlorophenoxy)-2-(hydroxymethyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide; salt triperoxonane acid,

the hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxy-2-methylpropoxy}phenyl)acetamide", she

N-(2-{(1S*,2R*,3S*)-3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)acetamide", she

N-(2-{(1R*,2R*,3S*)-3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)acetamide", she

N-(2-{(2R*,3R*)-3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxyethoxy}phenyl)acetamide", she

N-(2-{(1S*,2R*,3S*)-3-[4-(4-chlorophenoxy)piperidine-1-yl]-2-hydroxycyclopent}phenyl)acetamide", she

N-(2-{(2R*,3S*)-3-[4-(3,4-dichlorophenoxy)piperidine-1-yl]-2-hydroxyethoxy}phenyl)acetamide", she

N-(2-{(2R*,3R*)-3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxyethoxy} phenyl)acetamide", she

N-(2-{(2R*,3S*)-3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxyethoxy}phenyl)acetamide", she

N-(2-{(1S*,2R*,3S*)-3-[4-(3-chlorophenoxy)piperidine-1-yl]-2-hydroxycyclopent} phenyl)acetamide", she

N-[5-chloro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclopent}oxy)phenyl]acetamide", she

N-[4-fluoro-2-({(1S,2R,3S)*-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxycyclopent}is XI)phenyl]acetamide", she

dihydrochloride of N-(2-{3-[4-(3,4-dichlorobenzyl)-1-piperazinil]-2-hydroxypropoxy} phenyl)acetamide", she

N-(2-{3-[4-(3,4-dichlorobenzyl)-1-piperazinyl]-2-hydroxypropoxy}-4-forfinal)ndimethylacetamide,

N-(2-{3-[4-(3,4-dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-chloro-2-{3-[4-(3,4-dichlorobenzyl)-1-piperazinil]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-chloro-2-{3-[4-(3,4-dichlorobenzyl)-2,5-dimethyl-1-piperazinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(3,4-dichlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-(2-{3-[4-(3,4-dichlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydro-ciprodex}-4-forfinal)ndimethylacetamide,

N-(2-{3-[(S*R*)-4-(3,4-dichlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[(S*R*)-4-(4-Chlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-chloro-2-{3-[(S*R*)-4-(3,4-dichlorobenzyl)-2,5-dimethylpiperazine]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-chloro-2-{3-[(S*R*)-4-(4-Chlorobenzyl)-2,5-dimethylpiperazine]-2-hydroxypropoxy}phenyl)acetamide", she

1-(5-chloro-2-{3-[4-(4-chlorobenzoyl)-1-piperazinil]-2-hydroxypropoxy}phenyl)-1-ethanone,

N-(5-cyano-2-{3-[(S*R*)-4-(3,4-dichlorobenzyl)-2,5-dimethylpiperazine]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[(S*R*)-4-(4-Chlorobenzyl)-2,5-dimethylpiperazine the]-2-hydroxypropoxy}-5-cyanophenyl)ndimethylacetamide,

N-(5-chloro-2-{3-[4-(4-Chlorobenzyl)-1-piperazinil]-2-hydroxypropoxy}phenyl)acetamide", she

N-(4-chloro-2-{3-[4-(4-Chlorobenzyl)-2,5-dimethyl-1-piperazinil]-2-hydroxypropoxy}phenyl)acetamide", she

N-(2-{3-[4-(4-chlorobenzoyl)-1-piperazinyl]-2-hydroxypropoxy}-5-cyanophenyl)ndimethylacetamide,

N-(2-{3-[4-(4-chlorobenzoyl)-1-piperazinil]-2-hydroxypropoxy}-4-were)ndimethylacetamide,

N-[5-chloro-2-({(1R,2S,3R)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxycyclopent}oxy)phenyl]acetamide", she

N-{2-[(2S)-(3-{(3S)-3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-forfinal}ndimethylacetamide,

the hydrochloride of N-[2-({(2S)-3-[(3S)-3-(4-chlorbenzyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide", she

N-(5-chloro-2-{3-[3-(4-chlorbenzyl)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)ndimethylacetamide; salt triperoxonane acid,

trifenatate N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-were)-1-pyrrolidinecarboxamido,

trifenatate N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-hydroxyphenyl)ndimethylacetamide,

N-[2-({(2S)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-hydroxypropyl}oxy)-4-forfinal]ndimethylacetamide; salt triperoxonane acid,

the hydrochloride of N-(2-(3-(4-chlorphenoxy)pyrrolidin-1-yl)-2-hydroxypropoxy)-4,6-differenl)ndimethylacetamide,

N-[2-({(2S)-3-[(2S,4S)-4-(4-chlorophenoxy)-2-methylpyrrolidinyl]-2-hydro is sapropel}oxy)-4-forfinal]ndimethylacetamide; salt triperoxonane acid,

the hydrochloride of N-[2-({(2S)-3-[(3R)-3-(4-chlorbenzyl)pyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]acetamide", she

N-{2-[(2R)-(3-{(3S)-3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-forfinal}ndimethylacetamide,

N-[2-({(2S)-3-[(2R,4S)-4-(4-chlorophenoxy)-2-methylpyrrolidinyl]-2-hydroxypropyl}oxy)phenyl]ndimethylacetamide; salt triperoxonane acid,

N-{2-[(2S)-(3-{(3R)-3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-forfinal} ndimethylacetamide,

trifenatate N'-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-were)-N,N-dimethylation,

N-(2-{3-[3-(4-chloroanilino)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

the hydrochloride of N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-1-methylpropyl)oxy]phenyl}acetamide", she

the hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}-4-methoxyphenyl)acetamide", she

N-(2-[3-(4-chlorobenzoyloxy)pyrrolidin-1-yl]-2-hydroxypropoxy)ndimethylacetamide; salt triperoxonane acid,

N-(2-{3-[3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxy-2-methylpropoxy}phenyl)acetamide", she

N-(2-{(1S,2R,3S)*-3-[(3S)-3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxycyclopent}-5-chlorophenyl)ndimethylacetamide (diastereoisomeric mixture),

N-({(2R,3S)*-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxybutyl}oxy)-4-were]ndimethylacetamide the (diastereoisomeric mixture),

the hydrochloride of N-{2-[(3-{4-[(3,4-dichlorophenyl)oxy]-1-piperidinyl}-2-hydroxy-2-methylpropyl)oxy]-4-forfinal}ndimethylacetamide,

N-(2-{(1S,2R,3S)*-3-[(3S)-3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}-4-forfinal)ndimethylacetamide (diastereoisomeric mixture),

N-(5-chloro-2-{3-[3-(3,4-divergence)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(5-chloro-2-{3-[3-(4-pertenece)pyrrolidin-1-yl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(4-cyano-2-{3-[4-(3,4-dichloraniline)-1-piperidinyl]-2-hydroxypropoxy}phenyl)acetamide", she

N-(4-hydroxy-2-{(1S,2R,3S)*-3-[(3S)-3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)ndimethylacetamide (diastereoisomeric mixture),

N-(4-hydroxy-2-{(1S,2R,3S)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)acetamide", she

N-(4-hydroxy-2-{(1R,2S,3R)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidin-1-yl]-2-hydroxycyclopent}phenyl)acetamide", she

N-[2-({(1S,2R,3S)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxycyclopent}oxy)phenyl]acetamide", she

N-[2-({(1R,2S,3R)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxycyclopent}oxy)phenyl]acetamide", she

N-[5-chloro-2-({(1S,2R,3S)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxycyclopent}oxy)phenyl]-acetamide", she

N-{5-chloro-2-[((1S,2R,3S)*-3-{[1-(4-Chlorobenzyl)-4-piperidinyl]amino}-2-hydroxycyclopent)oxy]phenyl}ndimethylacetamide (racemic mixture) and

< num="2140"> N-[2-({(2S)-3-[(3S)-3-(4-chlorphenoxy)pyrrolidinyl]-2-hydroxypropyl} oxy)-4-hydroxyphenyl] ndimethylacetamide.

8. The method of obtaining the compounds of formula (D) according to claim 1, wherein the compound of General formula

where R is as defined in formula (I'), is subjected to the interaction with the compound of General formula

where Q, R2, R4, R5, R6, R7and R8such as defined in the formula (I'),

and maybe after that carry out the conversion of the compounds of formula (I') into another compound of formula (I') and, if desired, receive a pharmaceutically acceptable salt or MES the compounds of formula (I').

9. The method of obtaining the compounds of formula (I') according to claim 1, wherein the compound of General formula

where R, R4, R5, R6, R7and R8such as defined in the formula (I'), is subjected to the interaction with the compound of General formula

where L1represents a hydrogen atom or an activating group, and Q and R2such as defined in the formula (I'),

and maybe after that carry out the conversion of the compounds of formula (I') into another compound of formula (I') and, if desired, receive a pharmaceutically acceptable the ol or MES the compounds of formula (I').

10. Pharmaceutical composition having the activity of a modulator of the activity of the receptor of the chemokine MIP-1αcontaining compound of the formula (I'), or its pharmaceutically acceptable salt, or MES according to any one of claims 1 to 7, together with a pharmaceutically acceptable adjuvant, diluent or carrier.

11. The method of preparation of the pharmaceutical composition of claim 10, wherein mixing the compound of the formula (I'), or its pharmaceutically acceptable salt, or MES according to any one of claims 1 to 7 with a pharmaceutically acceptable adjuvant, diluent or carrier.

12. The compound of formula (I'), or its pharmaceutically acceptable salt, or MES according to any one of claims 1 to 7 for use in therapy.

13. The compound of formula (I'), or its pharmaceutically acceptable salt, or MES according to any one of claims 1 to 7 for use in the manufacture of drugs for use in therapy.

14. The compound of formula (I'), or its pharmaceutically acceptable salt, or MES according to any one of claims 1 to 7 for use in the manufacture of drugs for the treatment of diseases or conditions of the person, which is useful modulation of activity chemokine receptor.

15. The compound of formula (I'), or its pharmaceutically acceptable salt, or MES according to any one of claims 1 to 7 for use in the manufacture of drugs for the treatment of rheumatoid arthritis.

16. The compound of formula (I'), and its pharmaceutically acceptable salt, or MES according to any one of claims 1 to 7 for use in the manufacture of drugs for the treatment of chronic obstructive pulmonary disease.

17. The compound of formula (I'), or its pharmaceutically acceptable salt, or MES according to any one of claims 1 to 7 for use in the manufacture of drugs for the treatment of asthma.

18. The compound of formula (I'), or its pharmaceutically acceptable salt, or MES according to any one of claims 1 to 7 for use in the manufacture of drugs for the treatment of multiple sclerosis.

19. A method of treating inflammatory disease in a patient suffering from the specified disease or having a risk of a specified disease in which the patient is administered a therapeutically effective amount of the compounds of formula (I'), or its pharmaceutically acceptable salt, or MES according to any one of claims 1 to 7.

20. A method of treating respiratory disease in a patient suffering from the specified disease or having a risk of a specified disease in which the patient is administered a therapeutically effective amount of the compounds of formula (I'), or its pharmaceutically acceptable salt, or MES according to any one of claims 1 to 7.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds. Invention describes compounds or their salts of the general formula (I): A-B-N(O)s (I) wherein s = 2; A means R-T1- wherein R represents radical of a medicinal substance under condition that a medicinal substance by the formula R-T1-Z or R-T1-OZ wherein Z represents hydrogen atom (H) or (C1-C5)-alkyl is taken among paracetamol, salbutamol, ambroxol, alendronic acid,, cetirizine, ampicillin, aciclovir, doxorubicin, simvastatin, diphylline, tacrine, clopidogrel, dimethylomeprazol, diclofenac, ferulic acid, enalapril, propranolol, benfurodil hemisuccinate, tolrestate or sulindac; T1 means (CO), oxygen atom (O) or NH; B means TB-X2-O- wherein TB means bivalent radical R1B-X-R2B wherein R1B and R2B are similar or different and represent linear or branched (C1-C6)-alkylenes and X represents a bond, oxygen (O), sulfur (S) atom or NR1C wherein NR1C represents hydrogen atom (H) or linear or branched (C1-C6)-alkyl; corresponding precursor B is represented by the formula -TB-X2-OH wherein TB means (CO) and free valence in TB represents -OZ wherein Z is determined above, or TB means oxygen atom (O), and free valence in TB represents hydrogen atom (H) under condition that in the formula (I) when X2 in precursor B represents linear or branched (C2-C20)-alkylene then a medicinal substance by the formula R-T1-Z or R-T1-OZ used in the formula (I) doesn't belong to the following substances: enalapril (ACE inhibitors) and diclofenac (NSAID). Also, invention describes pharmaceutical compositions for using in cases of oxidative stress and 4-nitroxybutanoic acid 4'-acetylaminophenyl ester. Invention provides preparing novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of medicinal substances and compositions.

7 cl, 8 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new N-(2-arylpropionyl)-sulfonamides of the formula (1): wherein R2 means phenyl, thiophenyl optionally substituted with 1-3 substitutes taken independently among halogen atom, (C1-C4)-alkyl, phenyl, phenoxy-group, benzyl, benzoyl, (C1-C7)-acyloxy-group, 2-thienoyl or 1-oxo-2-isoindolyl; R means linear or branched (C1-C16)-alkyl, trifluoromethyl, cyclohexyl, o-tolyl, 3-pyridyl, p-cyanophenylmethyl, p-aminomethylphenylmethyl, 2-cyano-1-propyl, alkoxyethylene group CH3-(CH2)ni-(OCH2CH2)mi- wherein ni and mi mean a whole number from 1 to 3, or the group P1P2N-CH2-CH2- wherein P1 and P2 represent independently hydrogen atom (H), (C1-C3)-alkyl, benzyloxycarbonyl, α-, β- or γ-pyridocarbonyl, carboxycarbonyl or carbalkoxycarbonyl; or R1 and P2 in common with nitrogen atom to which they are bound form morpholino-group; R' means hydrogen atom (H) or linear or branched (C1-C3)-alkyl, or their salts with strong or mean bases. Compounds of the formula (1) show inhibitory activity with respect to chemotaxis and degranulation of neutrophiles induced with interleukin-8 and can be used in pharmaceutical composition used for prophylaxis and treatment of tissue injures.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 dwg, 2 tbl, 18 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to a method for preparing {2-[4-(α-phenyl-p-chlorobenzyl)piperazine-1-yl]ethoxy}acetic acid (cetirizine) of the formula (I): (I).

Method involves hydrolysis of compound of the formula (II): (II)

wherein R1 and R2 represent independently (C1-C4)-alkyl that can be substituted with phenyl, (C2-C4)-alkenyl or cyclohexyl; or R1 and R2 in common with adjacent nitrogen atom form morpholine group. Hydrolysis is carried if necessary in the presence of interphase catalyst. Cetirizine is used as a component in anti-allergic pharmaceutical compositions. Also, invention describes a method for preparing intermediate compounds of the formula (II).

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

5 cl, 25 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

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

22 cl, 1 tbl, 2 sch, 78 ex

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

The invention relates to the derivatives of benzosulfimide formula (I):

< / BR>
where X represents a nitro-group, a cyano or halogen; Y1represents a secondary or tertiary amino group; Y2represents nitrogen or NH group; Z represents oxygen, sulfur, -N-CN or CH-NO2; and R1and R2that may be the same or different, are each independently saturated or unsaturated linear or branched alkyl group containing from 2 to 12 carbon atoms, saturated or unsaturated alicyclic group containing from 3 to 12 carbon atoms, phenyl, unsubstituted or substituted by one or more substituents, which represents a1-C4alkyl group, nitro, cyano, trifluoromethyl, carboxy and halogen, benzyl group or phenylethylene group, or Y1means tertiary amino group and R1form a morpholine or homopiperazin and Y2represents nitrogen and R2forms homopiperazin, except for derivatives, for which X is a nitro-group, Y1represents a secondary amino group (-NH-), Y2represent the group, includes m-toluyl, phenyl and cyclooctyl, and with the exception of N-[(2-cyclooctylamino-5-cyanobenzoyl)sulfonyl] N'-Isopropylamine, or its pharmacologically acceptable salt

The invention relates to new unsaturated derivatives of hydroximino acid formula

< / BR>
where R1means phenyl, optionally substituted by 1-3 substituents selected from the group comprising FROM1-2alkoxygroup, halogen, or represents a 6-membered unsaturated heterocyclic group containing one nitrogen atom as a heteroatom, and R2means hydrogen or R1together with R2form5-7-cycloalkyl group, Y represents hydrogen, a hydroxy-group,3-22-alkanoyloxy, X means halogen, a hydroxy-group or amino group, R3represents a group of formula-NR4R5where R4and R5mean independently from each other hydrogen, C1-5is an alkyl group, or R4and R5form with the adjacent nitrogen atom a 5 - or 6-membered saturated heterocyclic group which may contain an oxygen atom and may be condensed with a benzene ring, in addition, its geometrical and/or optical isomers and/or pharmaceutically acceptable acid salt additive
The invention relates to an anhydrous crystalline form of the hydrochloride R(-)-M-(4,4-di(3-methyltin-2-yl)but-3-enyl)-nicotinebuy acid, free from associated organic solvent (1), which is nephroscopes and thermally stable under normal storage conditions

The invention relates to the chemistry of fluorine-containing nitrogenous heterocycles, namely to a new connection, 2-trifluoromethyl-3-heptafluoroisopropyl-4,4-bystreptomyces-dalidio-2 formula (THBI)

with growth stimulating activity against pathogenic fungi Verticillium dahlia, Fusarium oxysporium, Thialaviopsis basicola, Risoctonia solani, and ergotaminum strain of ergot, which can find application in biotechnology

The invention relates to a new group of individual chemical compounds - cyclic amino compounds represented by the following formula:

< / BR>
where R1represents a phenyl group which may be optionally substituted by at least one Deputy, which represents a halogen atom; R2represents a C1-C8aliphatic acyl group or (C1-C4alkoxy) carbonyl group; and R3represents a saturated cyclic amino group which has from 2 to 8 carbon atoms in one or more cycles, with the highest nitrogen cycle has from 3 to 7 atoms in the cycle, and the specified saturated cyclic amino group substituted by a group having the formula-S-S-R4where R4and X have the meanings as defined below, and the said saturated cyclic amino group attached via its cyclic nitrogen atom adjacent to the carbon atom that is attached to the substituents R2and R1; R4represents a phenyl group which may be optionally substituted by at least one Deputy, selected IGP and nitro groups; WITH1-C6alkyl group which may be optionally substituted by at least one Deputy, selected from the group consisting of amino groups, carboxyl groups, (C1-C4alkoxy)carbonyl groups, substituents having the formula-NH-A1(where a1represents an-amino acid residue), and substituents having the formula-CO-AND2(where a2represents an-amino acid residue); or (C3-C8cycloalkyl group, and X represents a sulfur atom, sulfinol group or sulfonyloxy group, and the above-mentioned cyclic aminecontaining group may be optionally additionally substituted by a group having the formula = CR5R6where R5and R6are the same or different, and each independently represents a hydrogen atom, a carboxyl group, (C1-C4alkoxy)carbonyl group, karbamoilnuyu group, (C1-C4alkyl) karbamoilnuyu group or di-(C1-C4alkyl)karbamoilnuyu group; or their pharmacologically acceptable salts, pharmaceutical composition having inhibitory action in Rel is the prevention of disease, selected from the group consisting of embolism and thrombosis in a warm-blooded animal

The invention relates to new derivatives of biphenylamine formula (I)

< / BR>
where a IS-O-CmH2m-X1-

or denotes the formula (II)

,

where X1oxygen,

or formula (III)

< / BR>
R1- cycloalkyl with 5-7 carbon atoms, Ar1, CR4R5AG2, (CH3)2R6, R2is hydrogen, alkyl, hydroxyl, halogen, O - alkyl, R3is hydrogen, alkyl, R4- alkyl, trifluoromethyl, CH2HE, R5is hydrogen, alkyl, trifluoromethyl, or R4and R5may together form alkylene, R6- CH2OH, CONR7R8CH2R7R8provided that R1means associated through alkylene unsubstituted phenyl residue, or their acid additive salts with pharmacologically acceptable acids

The invention relates to new chemical compounds with biological activity, in particular to new derivatives of phenylaniline, their tautomers and stereoisomers, including mixtures thereof, and their salts, pharmaceutical compositions with anti-thrombotic and anti antiaggregatory action

The invention relates to new derivatives of N-(3-hydroxy-4-piperidinyl) (dihydro-2H-benzopyran or dihydrobenzoic) carboxamide, having valuable pharmaceutical properties, namely activity to stimulate gastrointestinal peristalsis

The invention relates to the synthesis of biologically active compounds, namely, salts of nitrogen-containing heterocyclic derivatives and 5-hydroxynicotinic acid of General formula:

< / BR>
where X 0(1a), CH2(1B), NH(1B)

The invention relates to new N-substituted azaheterocyclic carboxylic acids f-crystals (I) or their salts, in which R1and R2independently represent a hydrogen atom, halogen atom, trifluoromethyl, C1-C6-alkyl or C1-C6-alkoxy: Y is the grouporin which only the underlined atom participates in the cyclic system; X is a group-O-, -S-, -CR7R8, -CH2-CH2-, -CH=CH-CH2-, -CH2-CH=CH-, -CH2CH2CH2-, -CH=CH-, -NR9-(C= O)-, -O-CH2-, -(C= O)- or -(S=O)-, where R7, R8and R9independently represent a hydrogen atom or a C1-C6-alkyl; z = 1, 2, or 3; m = 1 or 2, n = 1 when m = 1 and n = 0 when m = 2; R4and R5each represents a hydrogen atom or, when m = 2, can both work together to develop a bond; R6is hydroxyl or C1-C8-alkoxygroup, or its pharmaceutically acceptable salt, provided that is not included compound 10-(3-(3-carbomethoxy-1-piperidyl) propyl) phenothiazines and 10-(3-(3-carborexics-1-piperidyl) propyl) phenothiazines

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