New compounds

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I): wherein m = 0, 1, 2 or 3; each R1 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C6)-halogenalkoxy-group, -NR9R10, (C3-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group or (C1-C6)-alkyl; X represents -O- or CH2-, OCH2-, CH2O-, CH2NH-, NH-; Y represents nitrogen atom (N) or group CH under condition that when X represents -O- or CH2O-, CH2NH- or NH-group then Y represents group CH; Z1 represents a bond or group (CH2)q wherein q = 1 or 2; Z2 represents a bond or group CH2 under condition that both Z1 and Z2 can't represent a bond simultaneously; Q represents -O- or sulfur atom (S) or group CH2 or NH; R2 represents group of the formula: n = 0; each R4, R5, R6 and R7 represents independently hydrogen atom (H), (C1-C6)-alkyl either R4, R5, R6 and R7 represent in common (C1-C4)-alkylene chain joining two carbon atoms to which they are bound to form 4-7-membered saturated carbon ring, either each R5, R6 and R7 represents hydrogen atom, and R4 and R8 in common with carbon atoms to which they are bound form 5-6-membered saturated carbon ring; R8 represents hydrogen atom (H), (C1-C6)-alkyl or it is bound with R4 as determined above; each R9 and R10 represents independently hydrogen atom (H), (C1-C6)-alkyl; R15 represents (C2-C6)-alkyl, (C2-C6)-alkenyl, (C3-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, adamantyl, phenyl or saturated or unsaturated 5-10-membered heterocyclic ring system comprising at least one heteroatom taken among nitrogen, oxygen and sulfur atoms wherein each group can be substituted with one or more substitute taken independently among nitro-group, hydroxyl, oxo-group, halogen atom, carboxyl, (C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylcarbonyl, (C1-C6)-alkoxycarbonyl, phenyl and -NHC(O)-R17 under condition that R15 doesn't represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneiminyl group; t = 0, 1, 2 or 3; each R16 represents independently halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkyl, (C1-C)-halogenalkoxy-group, -NR18R19, (C1-C6)-cycloalkylamino-, (C1-C6)-alkylthio-, (C1-C6)-alkylcarbonylamino-group, (C1-C6)-alkyl; R17 means (C1-C6)-alkykl, amino-group, phenyl; each R18 and R19 means independently hydrogen atom (H), (C1-C6)-alkyl, or its pharmaceutically acceptable salt or solvate. Compounds of the formula (I) elicit activity of a modulating agent with respect to activity of chemokine MIP-1α receptors that allows their using in pharmaceutical composition in treatment of inflammatory diseases.

EFFECT: valuable medicinal properties of new compounds.

14 cl, 98 ex

 

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

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 8-14 kDa, characterized by a conservative fragment of four cysteines. The superfamily of chemokines can be divided into two main groups, with a characteristic structural fragments: a family of Cys-X-Cys (C-X-C) and Cys-Cys (C-C). They are distinguished on the basis of a single amino acid insertion between NH-proximal pair of cysteine residues and the identity of the sequence.

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

C-C chemokines include strong chemoattractant monocytes and lymphocytes, but not neutrophils, such as human macrophage chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (regulated by activation of factor expressed and secretory normal T-cells), eotaxin and MACR pasalnya inflammatory proteins 1α 1β (MIP-1α and MIP-1β).

Studies have shown that the actions of chemokines is mediated by subfamilies of receptors associated with G-proteins, 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 will be useful in the treatment of disorders and diseases, such as disorders and diseases indicated above.

According to the present invention, therefore, the proposed compound of General formula

where m is 0, 1, 2 or 3;

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

p is 0 or ;

X represents an oxygen atom or CH2-, OCH2-, CH2O-CH2NH-, NH-, carbonyl or sulfonyloxy group and Y represents a nitrogen atom or a group CH or C(OH), provided that when X represents an oxygen atom or CH2O-CH2NH - or-NH-group, 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 both Z1and Z2at the same time do not represent a bond;

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

R2represents a group

n is 0, 1 or 2;

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

each R4, R5, R6and R7independently 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 carbon ring, or each R5, R6and R7represents a hydrogen atom and R 4and R8together with the carbon atoms to which they are attached, form a 5-6-membered saturated carbon ring;

R8represents a hydrogen atom, a C1-C6alkyl group or it is connected with R4as defined above;

each R9and R10independently 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;

each R11and R12independently 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 a group With2-C6alkyl, C2-C6alkenyl,3-C6cycloalkyl,5-C6cycloalkenyl, substituted, phenyl or a saturated or unsaturated 5-10 membered heterocyclic ring system containing at least one heteroatom selected from nitrogen, oxygen and sulfur, where each group can be possibly ameena one or more than one Deputy, independently selected from nitro, hydroxyl, oxo, halogen, carboxyl,1-C6of alkyl, C1-C6alkoxy, C1-C6alkylthio,1-C6alkylcarboxylic,1-C6alkoxycarbonyl, phenyl and-NHC(O)-R17provided that R15does not represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneimino (1-homopiperazine) group;

t is 0, 1, 2 or 3;

each R16independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl,1-C6halogenoalkane,1-C6halogenoalkane, -NR18R19With3-C6cyclooctylamino,1-C6alkylthio, C1-C6alkylsulphonyl,1-C6alkylcarboxylic, sulfonamide (SO2NH2)1-C6alkylsulfonyl, -C(O)NR20R21, -NR22C(O)(NH)vR23, phenyl or C1-C6alkyl, possibly substituted by carboxyla or1-C6alkoxycarbonyl;

R17represents a C1-C6alkyl, amino (-NH2or phenyl group;

each R18and R19independently represents a hydrogen atom or a C1-C6alkyl group is for R 18and R19together with the nitrogen atom to which they are attached, form a 4-7-membered saturated a heterocycle;

each R20and R21independently represents a hydrogen atom or a C1-C6alkyl group, possibly substituted C1-C6alkoxycarbonyl;

v is 0 or 1;

R22represents a hydrogen atom or a C1-C6alkyl group, and

R23represents a hydrogen atom or a C1-C6alkyl group, possibly substituted by carboxyla,1-C6alkoxy or1-C6alkoxycarbonyl,

or its pharmaceutically acceptable salt or MES.

For the purposes of this description, alkyl or Alchemilla replacement group or alkyl or Alchemilla grouping in the replacement group may be linear or branched. In the definition of R15it should be noted that unsaturated 5-10 membered heterocyclic ring system may be aliphatic or aromatic.

The integer m is preferably 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-C6-, preferably C1-C4-, alkoxy (e.g. the measures methoxy, ethoxy, n-propoxy or n-butoxy), C1-C6-, preferably C1-C4-alkoxycarbonyl (for example, methoxycarbonyl or etoxycarbonyl)1-C6-preferably With1-C4-halogenated (e.g., trifluoromethyl), C1-C6-, preferably C1-C4, halogenoalkane (for example, triptoreline), -NR9R10With3-C6cyclooctylamino (for example, cyclopropylamino, cyclobutylamine, cyclopentylamine or cyclohexylamino), C1-C6-, preferably C1-C4, alkylthio (for example, methylthio or ethylthio), C1-C6-, preferably C1-C4-alkylsulphonyl (for example, methylcarbamoyl, ethylcarboxyl), n-propylboronic, isopropylcarbonate, n-butylcarbamoyl, n-internabonal or n-hexylcaine), C1-C6-, preferably C1-C4, alkylcarboxylic (for example, methylcobalamin or ethylcarbodiimide), sulfonamide,1-C6-, preferably C1-C4-, alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, n-peterculter or n-hexylsilane), -C(O)NR11R12, -NR13C(O)-(HN)pR14, phenyl or C1-C6-, preferably C1-C4-, alkyl (e.g. methyl, ethyl, n-propyl, shall sapropel, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), possibly substituted by carboxyla or C1-C6-, preferably C1-C4and alkoxycarbonyl (for example, methoxycarbonyl or etoxycarbonyl).

Most preferably, each R1independently represents halogen (in particular chlorine or fluorine), cyano, nitro, C1-C6alkoxy (in particular methoxy), C1-C6alkylsulphonyl (in particular, methylcarbamyl) or C1-C6alkylcarboxylic (in particular, methylcobalamine). Each R1in particular represents halogen or cyano.

Preferably X represents an oxygen atom or CH2- or NH-group.

The preferred combination of Y, Z1and Z2include:

YZ1Z2
SNCH2link
CHlinkCH2
SNCH2CH2
CH(CH2)2link
NCH2CH2

Q preferably represents an oxygen atom.

Each R3independently made the focus of a C 1-C6-, preferably C1-C4-, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C1-C6-, preferably C1-C4-alkoxycarbonyl (for example, methoxycarbonyl or etoxycarbonyl), -CH2OH or a carboxyl group. Preferably R3represents methyl, methoxycarbonyl, etoxycarbonyl, -CH2OH or a carboxyl group.

Each R4, R5, R6and R7independently represents a hydrogen atom or a C1-C6-, preferably C1-C4-, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), 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 carbon ring (e.g., cyclohexyl or preferably of cyclopentyl), or each R5, R6and R7represents a hydrogen atom and R4and R8together with the carbon atoms to which they are attached, form a 5-6-membered saturated carbon ring (preferably cyclopentyl).

R8represents a hydrogen atom, a C1-C6-, preferably C1-C4-, Alki is inuu group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or it is connected with R4as specified above.

Each R9and R10independently represents a hydrogen atom or a C1-C6-, preferably C1-C4-, alkyl 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 the heterocycle.

Each R11and R12independently represents a hydrogen atom or a C1-C6-, preferably C1-C4-, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), possibly substituted C1-C6-, preferably C1-C4-, alkoxycarbonyl replacement group.

R13represents a hydrogen atom or a C1-C6-, preferably C1-C4-, alkyl 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-C6-, preferably C1-C4-, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl)may Zam is on carboxyla, C1-C6-, preferably C1-C4-, alkoxy-or C1-C6-, preferably C1-C4and alkoxycarbonyl.

R15is a group With2-C6-preferably With2-C4-, alkyl (e.g. ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl or n-pentyl)2-C6-preferably With2-C4-alkenyl,3-C6cycloalkyl (for example, cyclobutyl or cyclopentyl)5-C6cycloalkenyl, substituted, phenyl or a saturated or unsaturated 5-10 membered heterocyclic ring system containing at least one heteroatom selected from nitrogen, oxygen and sulfur, where each group may be substituted by one or more (e.g. one, two, three or four) Deputy independently selected from nitro, hydroxyl, oxo, halogen (e.g. fluorine, chlorine, bromine or iodine), carboxyl, C1-C6-, preferably C1-C4-, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentile or n-hexyl), C1-C6-, preferably C1-C4-, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C1-C6-, preferably C1-C4, alkylthio (for example, methylthio or ethylthio)1-C6-predpochtitel is but C 1-C4-alkylcarboxylic (for example, methylcarbamyl, ethylcarbazole, n-propylboronic, isopropylcarbonate, n-butylcarbamoyl, n-internabonal or n-hexylcaine), C1-C6-, preferably C1-C4-alkoxycarbonyl (for example, methoxycarbonyl or ethoxycarbonyl), phenyl and-NHC(O)-R17.

Saturated or unsaturated 5-10 membered heterocyclic ring system may be monocyclic or polycyclic (e.g. bicyclic) and can contain up to four heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of ring systems that can be used include pyrrolidinyl, piperidinyl, pyrazolyl, diazolidinyl, thienyl, isoxazolyl, thiadiazolyl, pyrrolyl, furanyl, thiazolyl, indolyl, chinoline, benzimidazolyl, triazolyl, tetrazolyl and pyridinyl.

Each R16independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C3-C6cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C1-C6-, preferably C1-C4-, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C1-C6-, preferably C1-C4-alkoxycarbonyl (for example, methoxycarbonyl or etoxycarbonyl), C1-C6-, preferably C1 -C4-halogenated (e.g., trifluoromethyl), C1-C6-, preferably C1-C4, halogenoalkane (for example, triptoreline), -NR18R19With3-C6cyclooctylamino (for example, cyclopropylamino, cyclobutylamine, cyclopentylamine or cyclohexylamino), C1-C6-, preferably C1-C4, alkylthio (for example, methylthio or ethylthio), C1-C6-, preferably C1-C4-alkylsulphonyl (for example, methylcarbamoyl, ethylcarbazole, n-propylboronic, isopropylcarbonate, n-butylcarbamoyl, n-internabonal or n-hexylcaine), C1-C6-, preferably C1-C4, alkylcarboxylic (for example, methylcobalamin or ethylcarbodiimide), sulfonamide,1-C6-, preferably C1-C4-, alkylsulfonyl (for example, methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, n-butylsulfonyl, n-peterculter or n-hexylsilane), -C(O)NR21R22, -NR23C(O)-(HN)vR24, phenyl, or C1-C6-, preferably C1-C4-, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), possibly substituted by carboxyla or C1-C6-, preferably C1-C4and alkoxycarbonyl (for example, methoxycarbonyl elitextreme.com).

Preferably each R16independently represents halogen (in particular chlorine or fluorine), cyano, C1-C4alkoxy (in particular methoxy), C1-C4alkoxycarbonyl (in particular, methoxycarbonyl)1-C4halogenoalkane (in particular trifluoromethyl)1-C4alkylsulphonyl (in particular, methylcarbamyl), phenyl or1-C4alkyl (e.g. methyl or tert-butyl). Each R16represents, in particular, halogen atom or methyl group.

R17represents a C1-C6-, preferably C1-C4-, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), amino or phenyl group.

Each R18and R19independently represents a hydrogen atom or a C1-C6-, preferably C1-C4-, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R19and R20together with the nitrogen atom to which they are attached, form a 4-7-membered saturated the heterocycle.

Each R20and R21independently represents a hydrogen atom or a C1-C6-preferably With1-C4-, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tre the-butyl, n-pentyl or n-hexyl), possibly substituted With1-C6-preferably With1-C4-, alkoxycarbonyl replacement group.

R22represents a hydrogen atom or a C1-C6-preferably With1-C4-, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl).

R23represents a hydrogen atom or a C1-C6-preferably With1-C4-, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), possibly substituted by carboxyla, C1-C6-, preferably C1-C4-, alkoxy or C1-C6-, preferably C1-C4and alkoxycarbonyl.

Preferred compounds according to the invention include the following:

N-(5-chloro-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide thiophene-2-carboxylic acid,

N-[(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-methyl]-benzamide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide pyrazin-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclohexanecarbonyl to the slots,

methyl ester of N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-fallaway acid,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-ureido-ndimethylacetamide,

4-acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 1-acetyl-piperidine-4-carboxylic acid,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methoxy-benzamide,

2-acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,

2-acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide adamantane-1-carboxylic acid,

2-acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-phenyl-propionamide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-benzamide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 5-methyl-thiophene-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 1-acetyl-pyrrolidin-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 1,5-dimethyl-1H-pyrazole-3-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 5-oxo-pyrrolidin-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 1H-indole-6-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclobutanecarbonyl acid,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide pentanol acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide the Penta-4-ene acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclopentanecarbonyl acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclopropanecarboxylic acid,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methylsulfanyl-ndimethylacetamide,

2-acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-butyramide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-are the amide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2,2-dimethyl-propionamide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 5-oxo-hexanoic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-hexanoic acid amide,

2-chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,

3-chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,

DATEFORMAT (4R)-N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidin]-2-hydroxypropoxy}phenyl)-1,3-thiazolidin-4-carboxamide,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide thiophene-2-carboxylic acid,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide pyridine-2-carboxylic acid,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-isonicotinamide,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclohexanecarbonyl acid,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 5-methyl-thiophene-2-carb is a new acid,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclobutanecarbonyl acid,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide pentanol acid,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide the Penta-4-ene acid,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclopentanecarbonyl acid,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,

the hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-2,2,2-trifurcated,

4-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-3-methyl-butyric acid,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-2,2,2-succinamide acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, furan-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 1H-pyrrole-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide thiophene-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide cyclopentanecarbonyl acid

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-methyl-thiophene-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-chloro-thiophene-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-methyl-isoxazol-4-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide [1,2,3]thiadiazole-4-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-methyl-furan-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide cyclopent-1-inkarbaeva acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 2-methyl-furan-3-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-methyl-thiophene-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-nitro-1H-pyrazole-3-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide thiophene-3-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide cyclobutanecarbonyl acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-methyl-phenyl)-amide, furan-2-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 1H-pyrrole-2-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide thiophene-2-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-chloro-thiophene-2-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-methyl-isoxazol-4-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-methyl-furan-2-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide cyclopent-1-inkarbaeva acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 2-methyl-furan-Z-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-methyl-thiophene-2-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-chloro-thiophene-2-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide thiophene-3-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 2,5-dimethyl-furan-Z-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-F. the Nile)-amide cyclobutanecarbonyl acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, furan-3-carboxylic acid,

N-{2-[(3-{3-[(4-forfinal)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were}-1H-pyrrol-2-carboxamid,

N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were}-3-thiophencarboxylic,

N-{2-((3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}-2-thiophencarboxylic connection with triperoxonane acid,

N-{2-[(3-{3-[(4-forfinal)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were}-2-thiophencarboxylic,

N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-2-furancarboxylic,

N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-1-pyrrol-2-carboxamid,

N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were}-1H-pyrrol-3-carboxamide,

N-{2-[(3-{3-[(4-forfinal)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were}-2-furancarboxylic,

N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}cyclopentanecarboxylic connection with triperoxonane acid,

N-(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,

N-(2-{3-[3-(4-cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-2-ethyl-propoxy}-phenyl)-benzamide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide and

N-(2-{3-[4-(3,4-dichloro-phenylamino)-piperidine-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide.

According to the present invention, furthermore, a method for obtaining compounds of formula (I)as defined above, which compound of General formula

or its salt (e.g. salt accession acids, such as hydrochloride), where m, n, t, R1, R3, R4, R5, R6, R7, R8, R16, Q, Z1and Z2are as defined in formula (I), is subjected to the interaction with the compound of General formula

R15-CO2H (III)

or its chemically equivalent derivatives (for example, halogenosilanes or anhydrite derived), where R15is the same as defined in formula (I),

and maybe then form a pharmaceutically acceptable salt or MES, the compounds of formula (I).

The method according to the invention can easily be implemented in a solvent, for example an organic solvent such as alcohol (e.g. methanol or ethanol), a hydrocarbon (e.g. toluene), amine (e.g. triethylamine or diisopropylethylamine) or acetonitrile, at temperatures from, for example, 15°With or superior to such as a temperature in the range from 20 to 20° C.

Compounds of formulas (II) and (III) are either commercially available, are well known in the literature or can be easily obtained using known methods.

Specialists in the art it is obvious that the method according to the present invention certain functional groups such as hydroxyl or amino groups, in the original reactants or intermediate compounds may need to be protected with protective groups. Thus obtaining compounds of formula (I) may include, at a desired stage, the removal of one or more than one protective group.

The introduction of protection and removal to protect functional groups described in "Protective Groups in Organic Chemistry", edited by J.W.F.McOmine, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 2nd edition, T.W.Greene and P.G.M.Wuts, Wiley-lnterscience (1991).

The compounds of formula (I) above can be converted in their pharmaceutically acceptable salt, or a solvate, preferably salt accession acids, such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or para-toluensulfonate.

The compounds of formula (I) can exist in stereoisomeric forms. It is clear that the invention encompasses all geometric and optical isomers of compounds of formula (I) and mixtures thereof, including racemates. The use of tautomers and their mixtures is also an aspect of the m of the present invention.

The compounds of formula (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 such conditions are the following:

(1) diseases of the respiratory tract (respiratory tract), which includes chronic obstructive pulmonary disease (COPD), such as irreversible COPD, asthma, such as bronchial, allergic, endogenous, exogenous and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and hypersensitivity of the respiratory tract, bronchitis, acute, allergic, atrophic rhinitis and chronic rhinitis including caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, dry rhinitis and rhinitis medication, membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrupulously rhinitis, seasonal rhinitis, including nervous rhinitis (hay fever) and vasomotor rhinitis, sarcoidosis, exogenous allergic alveolitis and related diseases, pneumovirus and ID is optionsbuy 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, atopic dermatitis, contact dermatitis, and other eczematous dermatitises, seborrhoeic eczema, lichen planus, disease, bullous disease, congenital bullous bullosa, urticaria, angiodema, vasculitis, erythema, cutaneous eosinophilia, uveitis, alopecia areata and vernal conjunctivitis;

(4) (gastrointestinal tract) coeliac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, food allergies, which have symptoms that are not associated with the intestines, for example migraine, rhinitis and eczema;

(5) (disease of other tissues and systemic disease) multiple sclerosis, atherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus erythematosus, Hashimoto's thyroiditis, heavy psevdomatematicheskoe myasthenia gravis, diabetes type I, nephrotic syndrome, eosinophilic fasciitis, syndrome Jobe, lepromatosis leprosy, syndrome Cesari and idiopathic thrombocytopenic purpura;

(6) (allograft rejection) acute and chronic, after, for example, transplantation of kidney, Enza, liver, lung, bone marrow, skin and cornea, and chronic disease graft-versus-host;

(7) types of cancer, in particular non-small cell lung cancer (NSCLC) and squamous sarcoma;

(8) diseases in which angiogenesis is associated with elevated levels of chemokines (e.g., NSCLC), and

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

Thus, according to the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, for use in therapy.

In another aspect according to the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, in the manufacture of drugs for use in therapy.

For the purposes of this description, the term "therapy" also includes "prevention", if there is no specific guidance on the opposite. The terms "therapeutic" and "therapeutically" should be interpreted accordingly.

According to the invention is also a method of treating inflammatory disease in a patient suffering from the specified disease or having a risk of developing them, in which this patient is administered a therapeutically effective amount of the joint is of the formula (I) or its pharmaceutically acceptable salt or MES, as they are defined above.

In addition, according izobreteniya a method of treatment of diseases of the respiratory tract in a patient suffering from the specified disease or having a risk of developing them, in which this patient is administered a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt or MES, as defined above.

For the above therapeutic applications entered the dosage will undoubtedly vary depending on the compound, the route of administration, the desired treatment of the specified disease. The daily dosage of the compounds of formula (I) may be in the range of from 0.001 to 30 mg/kg

The compounds of formula (I) and their pharmaceutically acceptable salt and solvate can be used by themselves, but they are usually administered in the form of pharmaceutical compositions in which the compound of formula (I) /Sol/MES (active ingredient) is in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the method of administration of the pharmaceutical composition preferably contains 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 calculated ex the Dublin core from the whole composition.

According to the present invention also proposed a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

In addition, according to the invention, a method for preparing the pharmaceutical compositions according to the invention, in which the compound of formula (I) or its pharmaceutically acceptable salt or MES, as defined above, is mixed with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions can be entered locally (for example, in the lung and/or Airways or to the skin) in the form of solutions, suspensions, heptapteridae aerosols and dry powder drugs 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 doing, or by rectal injection in the form of suppositories or transdermal.

The invention is further explained by reference to the following illustrative examples, where spectra1H NMR (proton nuclear magnetic resonance) recorded on Varian Unity Inova 400. As internal standard used the Central peak of the solvent - CHL is Reforma-d (δ n7,27 ppm (ppm)). Mass spectra of low-resolution and accurate mass determination recorded in the system Hewlett-Packard 1100 LC-MS (liquid chromatograph-mass spectrometer)equipped with ionization chambers APCI/ESI (chemical ionization at atmospheric pressure electrospray ionization). All solvents and commercial reagents were of purification "for the laboratory, and they were used as received.

The names used for connections established using ACD/IUPAC Name Pro. In the examples used the following abbreviations:

NMP: 1-methyl-2-pyrrolidinone,

DIEA: N,N-diisopropylethylamine,

HBTU: hexaphosphate 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium,

Not: 1-hydroxybenzotriazole,

THF: tetrahydrofuran.

Example 1

N-(5-Chloro-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide

a) N-(5-Chloro-2-hydroxy-phenyl)-isobutyramide

To the flask was added 4-chloro-2-aminophenol (1.2 g, 8,39 mmol) and water (25 ml). The suspension was intensively mixed and added somelady anhydride (1.6 ml, 10.5 mmol). The mixture was heated to 60°C for 30 minutes under vigorous stirring. The emulsion was cooled, and the formed precipitate, which was collected by filtration. The solid is washed twice with water on the filter and finally dried to obtain 1.4 g (78%) specified in podzagolovke the connection in the form of a white solid.

1H-NMR (400 MHz, DMSO (dimethyl sulfoxide)-d6) δ: 10.11 (1H, s); 9.12 (1H, s); 7.94 (1 H, d, J 2.5 Hz); 6.95 (1H, dd, J 8,7; 2,6 Hz); 6.84 (1H, d, J 8.5 Hz); 2.79 (1H, p, J 6.7 Hz); 1.08 (6N, d, J 6.8 Hz).

b) N-(5-Chloro-2-oxiranylmethyl-phenyl)-isobutyramide

In a test tube was added the compound obtained in (a) (0.4 g, of 1.87 mmol), epibromohydrin (0.28 g, of 2.06 mmol), K2CO3(0.5 g, 3.7 mmol) and DMF (dimethylformamide) (2 ml). The tube was tightly closed and heated with stirring for 2 hours, 60°). The mixture is then distributed between EtOAc (ethyl acetate) 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 with getting 0,22 (44%) indicated in the subtitle compound as a white solid.

C) In a test tube was added the compound obtained in b) (0,026 g, 0.13 mmol), 3-(4-chlorphenoxy)-pyrrolidin (0.035 g, 0.13 mmol) in ethanol (2 ml). The tube was tightly closed and heated with stirring at 75°C for 3 hours. The solution was left to cool and the solvent evaporated. The crude product was purified on silica and collected purified fractions. Specified in the header connection liofilizirovanny in hydrochloride with getting to 0.055 g (84%) as a white solid. This compound was a mixture of four article is reisopera, what influenced an NMR spectrum.

1H-NMR (400 MHz, DMSO-d6) δ: 10.84-10.34 (1H, m); 9.12 (1H, s); 8.09 (1H, s); 7.36 (2H, dd, J 9,2; 1.3 Hz); 7,11-to 7.00 (3H, m); 7,00 (2H, d, J 8,8 Hz); 6.22-6.06 (1H, m); 5.22-5.10 (1H, m); 4.34 (1H, Shir. s); 4.08-3.96 (1,5H, m); 3.95-3.87 (1H, m); 3.83-3.66 (1,5H, m); 3.61-3.23 (3H, m); 2.86 (1H, Sept, J 6.6 Hz); 2.64-2.51 (1/2H, m); 2.36-2.14 (1H, m); 2.14-2.00 (1/2H, m); 1.08 (6N, d, J 6,7 Hz).

APCI-MS (MS - mass spectrometry): m/z 476,2 [MH+].

Aniline intermediate connection 1

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, obtained analogously to example 1) was dissolved in 50 ml HCl (35% in water, puriss) and boiled under reflux during the night. The product was besieged, 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: 8.39-3.31 (m, 2H); 7.31 (d, 1H); 7.01-6.98 (m, 3H); 6.94-6.91 (m, 1H); 6.75 (dd, 1H); 4.31 (m, 1H); 4.12-4.02 (m, 2H); 3.92 (dd, 1H); 2.90 (m, 1H); 2.69 (m, 1H); 2.62-2.51 (m, 2H); 2.46 (dd, 1H); 2.34 (m, 1H); 2.18 (s, 3H); 2.04-1.93 (m, 2H), 1.89-1.77 (m, 2H).

Aniline intermediate compound 2

The dihydrochloride of 1-[(2-AMINOPHENYL)oxy]-3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-propanol

Get the method described in "aniline intermediate connection 1".

APCI-MS: m/z 363, 365 [MN+].

Intermediate anilines 1 and 2, described above, used in the following example the X.

Example 2

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide thiophene-2-carboxylic acid

To a solution of 80 μl of 0.2 M 2-thiophencarboxylic acid in NMP was added HBTU (80 µl of 0.2 M/NMP), Not (80 µl of 0.2 M/NMP), DIEA (30 μl, 0.5 M/NMP) and pyridine (30 μl, 0.5 M/NMP) and stirred for 30 minutes before adding 1-[(2-AMINOPHENYL)oxy]-3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-propanol (75 µl, 0,2 M/NMP). The mixture was stirred over night at room temperature before concentrating under reduced pressure to dryness. The product is diluted with 1000 μl of dichloromethane and washed with saturated solution of NaHCO3in water (800 ml), 1,8% HCl in water (800 ml) and saturated NaCI in water.

The organic layer was concentrated under reduced pressure to dryness and used without further purification. Output 3.6 mg, 51%.

APCI-MS: m/z 473,2 [MN+].

1H-NMR (400 MHz, CD3OD) δ: 7.88-7.85 (d, 1H); 7.74-7.65 (m, 2H); 7.34-7.28 (m, 2H); 7.27-7.21 (m, 1H); 7.20-7.15 (m, 1H); 7.14-7.09 (dd, 1H); 7.06-7.00 (m, 1H); 6.96-6.91 (m, 2H); 5.18-5.12 (m, 1H); 4.39-4.30 (m, 1H); 4.19-3.24 (m, 9H); 2.66-2.11 (m, 3H).

The following compounds of examples 3-53 was obtained by methods similar to the method described in example 2.

Example 3

N-[(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-methyl]-benzamide

APCI-MS: m/z 524,3 [MN+].

Example 4

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide pyrazin-2-carboxylic what sloty

APCI-MS: m/z 469,2 [MN+].

Example 5

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclohexanecarbonyl acid

APCI-MS: m/z 473,3 [MN+].

Example 6

Methyl ester of N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-fallaway acid

APCI-MS: m/z 525,2 [MN+].

Example 7

N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide

APCI-MS: m/z 449,2 [MH+].

Example 8

N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-ureido-ndimethylacetamide

APCI-MS: m/z 463,2 [MN+].

Example 9

4-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide

APCI-MS: m/z 490,3 [MN+].

Example 10

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 1-acetyl-piperidine-4-carboxylic acid

APCI-MS: m/z 516,3 [MH+].

Example 11

N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methoxy-benzamide

APCI-MS: m/z 497,2 [MH+].

Example 12

2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide

APCI-MS: m/z 504,3 [MN+].

Example 13

2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide

APCI-MS: m/z 506,2 [MN+].

Example 14

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-guide the hydroxy-propoxy}-phenyl)-amide adamantane-1-carboxylic acid

APCI-MS: m/z 525,3 [MN+].

Example 15

2-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-phenyl-propionamide

APCI-MS: m/z 552,3 [MH+].

Example 16

N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-benzamide

APCI-MS: m/z 497,2 [MH+].

Example 17

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 5-methyl-thiophene-2-carboxylic acid

APCI-MS: m/z 487,2 [MH+].

Example 18

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 1-acetyl-pyrrolidin-2-carboxylic acid

APCI-MS: m/z 502,3 [MN+].

Example 19

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 1,5-dimethyl-1H-pyrazole-3-carboxylic acid

APCI-MS: m/z 485,3 [MH+].

Example 20

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 5-oxo-pyrrolidin-2-carboxylic acid

APCI-MS: m/z 474,2 [MH+].

Example 21

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 1H-indole-6-carboxylic acid

APCI-MS: m/z 506,2 [MH+].

Example 22

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclobutanecarbonyl acid

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

Example 23

N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide

APCI-MS: m/z 419,2 [MN+].

Example 24

(-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide pentanol acid

APCI-MS: m/z 447,3 [MN+].

Example 25

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide the Penta-4-ene acid

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

Example 26

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclopentanecarbonyl acid

APCI-MS: m/z 459,3 [MH+].

Example 27

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclopropanecarbonyl acid

APCI-MS: m/z 431,2 [MH+].

Example 28

N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide

APCI-MS: m/z 433,3 [MN+].

Example 29

N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methylsulfanyl-ndimethylacetamide

APCI-MS: m/z 451,2 [MN+].

Example 30

4-Acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide

APCI-MS: m/z 476,2 [MN+].

Example 31

N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide

APCI-MS: m/z 433,3 [MH+].

Example 32

N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide

APCI-MS: m/z 447,3 [MN+].

Example 33

N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-ndimethylacetamide

APCI-MS: m/z 435,2 [MN+].

Example 34

N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2,2-dimethyl-propionamide

APCI-MS: m/z 447,2 [MH +].

Example 35

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 5-oxo-hexanoic acid

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

Example 36

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-hexanoic acid amide

APCI-MS: m/z 461,3 [MH+].

Example 37

2-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide

APCI-MS: m/z 501,2, 503,2 [MN+].

Example 38

3-Chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide

APCI-MS: m/z 501,2, 503,2 [MN+].

Example 39

DATEFORMAT (4R)-N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-1,3-thiazolidin-4-carboxamide

APCI-MS: m/z 478,2 [MN+].

Example 40

(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide thiophene-2-carboxylic acid

APCI-MS: m/z 521,0, 523,0 [MH+].

Example 41

N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide

APCI-MS: m/z 515,2, from 517.2 [MN+].

Example 42

N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide

APCI-MS: m/z 516,2, 518,2 [MN+].

Example 43

(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide pyridine-2-carboxylic acid

APCI-MS: m/z 516,2, 518,2 [MN+].

Example 44

N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-from the nicotinamide

APCI-MS: m/z 516,2, 518,2 [MN+].

Example 45

(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclohexanecarbonyl acid

APCI-MS: m/z 521,3, 523,3 [MH+].

Example 46

N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide

APCI-MS: m/z 497,2, 499,3 [MN+].

Example 47

(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 6-methyl-thiophene-2-carboxylic acid

APCI-MS: m/z 535,2, 537,2 [MN+].

Example 48

(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclobutanecarbonyl acid

APCI-MS: m/z 493,3, 495,2 [MN+].

Example 49

N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide

APCI-MS: m/z 467,2, 469,2 [MN+].

Example 50

(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide pentanol acid

APCI-MS: m/z 495,3, 497,3 [MN+].

Example 51

(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide the Penta-4-ene acid

APCI-MS: m/z 493,3, 495,2 [MN+].

Example 52

(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclopentanecarbonyl acid

APCI-MS: m/z 507,3, 509,3 [MN+].

Example 53

N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide

APCI-MS: m/z 495,3, 497,3 [MN+].

Example 5

The hydrochloride of N-(2-{3-[3-(4-chlorphenoxy)-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-2,2,2-trifurcated

A mixture of 1-(2-aminophenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-propanol (10 mg, of 0.022 mmol), dichloromethane (3 ml) and triethylamine was cooled in an ice bath. Then solution was added triperoxonane anhydride (3,5 µl of 0.025 mmol) in dichloromethane (2 ml) and the mixture was stirred at 0°before the end of the reaction. The mixture then was diluted with dichloromethane, washed with 1 M H2SO4, water, dried over sodium sulfate and concentrated to obtain oil. This oil was then treated with 1.0 M solution of HCl in ether to obtain the product as a solid (9 mg).

APCI-MS: m/z 459, 460 [MN+].

Example 55

4-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-3-methyl-butyric acid

1 -(2-Aminophenoxy)-3-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-2-propanol (75 µl of 0.2 M/NMP) were mixed with 3-methyl-glutaric anhydride (3 equivalent, 225 ál of 0.2 M/NMP) to obtain the product containing both ester and amide. After evaporation the mixture was treated with 3 equivalents of 0.5 M LiOH in a mixture (1:4 THF/water) for two hours at 80°for hydrolysis of the ester. The reaction mixture was still diluted with water (2 ml) and the desired product was extracted with 5×500 μl of EtOAc, evaporated to dryness.

APCI-MS: m/z 539,2, 541,2 [MN+].

Example 56

N-(2-{3-[4-(3,4-is ALOR-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-succinamide acid

Received in accordance with the method described in example 55.

APCI-MS: m/z 511,2, 513,2 [MH+].

Aniline intermediate compound 3

1-(2-Amino-5-methylphenoxy)-3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-propanol

APCI-MS: m/z 377,2, 379,1 [MN+].

1H-NMR (400 MHz, CDCl3) δ: 7.26-7.21 (m, 2H); 6.79-6.74 (m, 2H); 6.67-6.62 (m, 3H); 4.83-4.76 (m, 1H); 4.15-4.06 (m,1H); 4.04-4.00 (d, 2H); 3.73-3.64 (s, 2H); 3.47-3.35 (s, 1H); 3.14-2.56 (m, 6H); 2.36-2.22 (m, 4H); 2.05-1.95 (m, 1H).

Aniline intermediate compound 4

1-(2-Amino-5-methylphenoxy)-3-[3-(4-pertenece)-1-pyrrolidinyl]-2-propanol

APCI-MS: m/z 361,1 [MN+].

1H-NMR (400 MHz, CDCls) δ: 7.00-6.94 (m, 2H); 6.81-6.76 (m, 2H); 6.67-6.62 (m, 3H); 4.81-4.74 (m, 1H); 4.15-4.06 (m,1H); 4.03-3.99 (m, 2H); 3.88-3.36 (m, 3H); 3.12-2.56 (m, 6H); 2.33-2.23 (m, 4H); 2.05-1.95 (m, 1H).

Compounds of examples 57-85 received using one of the aniline intermediates 3 and 4.

Example 57

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, furan-2-carboxylic acid

APCI-MS: m/z 471,5, 473,5 [MH+].

Example 58

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 1H-pyrrole-2-carboxylic acid

APCI-MS: m/z equal to USD 470.5, 472,5 [MH+].

Example 59

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide thiophene-2-carboxylic acid

APCI-MS: m/z 487,5, 489,5 [MH+].

Example 60

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-dryer is l)-amide cyclopentanecarbonyl acid

APCI-MS: m/z to 473.6, 475,5 [MH+].

Example 61

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-methyl-thiophene-2-carboxylic acid

APCI-MS: m/z 501,5, 503,5 [MH+].

Example 62

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-chloro-thiophene-2-carboxylic acid

APCI-MS: m/z 521,5, 532,5 [MH+].

Example 63

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-methyl-isoxazol-4-carboxylic acid

APCI-MS: m/z 486,5, 488,6 [MH+].

Example 64

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide [1,2,3]thiadiazole-4-carboxylic acid

APCI-MS: m/z 489,5, 491,5 [MH+].

Example 65

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-methyl-furan-2-carboxylic acid

APCI-MS: m/z 485,5, 487,6 [MH+].

Example 66

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide cyclopent-1-inkarbaeva acid

APCI-MS: m/z 471,6, to 473.6 [MH+].

Example 67

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 2-methyl-furan-Z-carboxylic acid

APCI-MS: m/z 485,6, 487,6 [MH+].

Example 68

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-methyl-thiophene-2-carboxylic acid

APCI-MS: m/z 501,6, 503,5 [MH+].

Example 69

(2-{3-[3-(4-Chloro-f is noxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-nitro-1H-pyrazole-3-carboxylic acid

APCI-MS: m/z 516,5, 518,5 [MH+].

Example 70

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide thiophene-3-carboxylic acid

APCI-MS: m/z 487,5, 489,5 [MN+].

Example 71

(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide cyclobutanecarbonyl acid

APCI-MS: m/z 459,5, 461,5 [MH+].

Example 72

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, furan-2-carboxylic acid

APCI-MS: m/z 455,5 [MH+].

Example 73

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 1H-pyrrole-2-carboxylic acid

APCI-MS: m/z 454,6 [MH+].

Example 74

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide thiophene-2-carboxylic acid

APCI-MS: m/z 471,5[MH+].

Example 75

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-chloro-thiophene-2-carboxylic acid

APCI-MS: m/z 505,5, are 507, 5 [MH+].

Example 76

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-methyl-isoxazol-4-carboxylic acid

APCI-MS: m/z equal to USD 470.5 [MN+].

Example 77

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-methyl-furan-2-carboxylic acid

APCI-MS: m/z 469,6 [MN+].

Example 78

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-m is Teal-phenyl)-amide cyclopent-1-inkarbaeva acid

APCI-MS: m/z 455,6 [MH+].

Example 79

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 2-methyl-furan-Z-carboxylic acid

APCI-MS: m/z 469,6 [MH+].

Example 80

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-methyl-thiophene-2-carboxylic acid

APCI-MS: m/z 485,5 [MN+].

Example 81

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-chloro-thiophene-2-carboxylic acid

APCI-MS: m/z 505,5, are 507, 5 [MN+].

Example 82

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide thiophene-3-carboxylic acid

APCI-MS: m/z 471,5 [MH+].

Example 83

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 2,5-dimethyl-furan-Z-carboxylic acid

APCI-MS: m/z 483,6 [MN+].

Example 84

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide cyclobutanecarbonyl acid

APCI-MS: m/z 443,6 [MN+].

Example 85

(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, furan-3-carboxylic acid

APCI-MS: m/z 455,5 [MN+].

Example 86

N-{2-[(3-{3-[(4-Forfinal)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were}-1H-pyrrol-2-carboxamide

APCI-MS: m/z 454,1 [MN+].

Example 87

N-{2-[(3-{3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-IU is ylphenyl}-3-thiophencarboxylic

APCI-MS: m/z 471,1 [M+H+].

Example 88

N-{2-[(3-{3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}-2-thiophencarboxylic connection with triperoxonane acid

Aniline intermediate compound 3 (60 mg, strength of 0.159 mmol), 2-thiencarbazone acid (20.4 mg, strength of 0.159 mmol) and HATU (hexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea) (72 mg, 0,191 mmol) was stirred in dichloromethane (2 ml).

Added diisopropylethylamine to pH 8. The mixture was stirred overnight and then concentrated. The residue was purified on silica (dichloromethane/methanol 98/2) followed by purification on C18 (2 g Isolute, acetonitrile/water from 20/80 to 35/65 with 0.5% triperoxonane acid) to obtain the specified title compound (75 mg, 79%).

1H-NMR (400 MHz, MeOD) δ: 7.86 (m, 1H); 7,72 (m, 1H); to 7.50 (m, 1H); 7.29 (m, 3H); 7.16 (m, 2H); 7.07 (m, 1H); 6.91 (m, 2H); 5.10 (m, 1H); 3.82-4.17 (m, 4H); 3.24-3.69 (m, 4H); 2.13-2.64 (m, 2H); 1.38 (m, 3H).

MS-APCI+: m/z 487[MH+].

Example 89

N-{2-[(3-{3-[(4-Forfinal)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were}-2-thiophencarboxylic

APCI-MS: m/z 471,1 [M+H+].

Example 90

N-{2-[(3-{3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-2-furancarboxylic

APCI-MS: m/z 456,9 [M+H+].

Example 91

N-{2-[(3-{3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-1-pyrrol-2-carboxamide

APCI-MS: m/z 456,1 [M+H+].

Example 92

N-{2-[(3-{3-[(chlorphenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were}-1H-pyrrol-3-carboxamide

APCI-MS: m/z 470,0 [M+H+].

Example 93

N-{2-[(3-{3-[(4-Forfinal)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were}-2-furancarboxylic

APCI-MS: m/z 455,1 [M+H+].

Example 94

N-{2-[(3-{3-[(4-Chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}cyclopentanecarboxylic connection with triperoxonane acid

This compound (80 mg, 86%) was obtained from aniline intermediate compound 3 (60 mg, strength of 0.159 mmol) and cyclopentanecarbonyl acid (18 μl, strength of 0.159 mmol)as described in example 88.

1H-NMR (400 MHz, MeOD) δ: 7.59 (m, 1H); 7,29 (m, 2H); 7,19 (m, 1H); 7.09 (m, 1H); 6.97 (m, 3H); 5.17 (m, 1H); 3.86-4.23 (m, 4H); 3.35-3.73 (m, 4H); 2.86 (m, 1H); 1.45 (.s, 3H).

MS-APCI+: m/z 473[MH+].

Example 95

N-(2-{3-[3-(4-Fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide

The compound was obtained by using a method similar to the method of example 88.

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

Example 96

N-(2-{3-[3-(4-Cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide

The compound was obtained by using a method similar to the method of example 88.

APCI-MS: m/z 472 [MN+].

Example 97

N-(2-{3-[4-(3,4-Dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide

The compound was obtained by using a method similar to the method of example 88.

APCI-MS: m/z 529 [MN+].

Example 98

N-(2-{3-[3-(4-Chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-IU the Il-propoxy}-phenyl)-benzamide

The compound was obtained by using a method similar to the method of example 88.

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

Example 99

N-(2-{3-[4-(3,4-Dichloro-phenylamino)-piperidine-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide

The compound was obtained by using a method similar to the method of example 88.

APCI-MS: m/z 528 [MH+].

Analysis of chemotaxis TNR-1

Introduction

In this analysis measured the chemotactic response induced by chemokine MIP-α in the human monocytic cell line 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.

Methods

Culture TNR-1 cells

Cells were quickly thawed at 37°from the frozen aliquot and resuspendable 25 cm flask containing 5 ml of RPMI-1640 medium, supplemented with Glutamax and 10% V / V heat inactivated fetal calf serum without antibiotics (RPMI + 10% HIFCS). Over 3 days the medium was discarded and replaced with fresh medium.

TNR-1 cells are usually grown in medium RPMI-1640 with the addition of 10% V / V heat inactivated fetal calf serum and glutamax, but without antibiotics. Optimal growth of the cells requires that they transferred to another environment every 3 days and that the minimum density of the subculture was 4×10+5cells/ml

Analysis of chemotaxis

Cells were removed from olby and washed by centrifugation in RPMI + 10% HIFCS + glutamax. The cells are then resuspendable at a concentration of 2×10+7cells/ml in fresh medium (RPMI + 10% HIFCS + glutamax), to which was added calcein-AM (5 ál of a solution of 1 ml with a final concentration of 5×10-6M). After a light mixing, the cells were incubated at 37°in CO2incubator for 30 minutes. Then the cells were diluted to 50 ml medium and washed twice by centrifugation at 400×g. Labeled cells are then resuspendable at a cell concentration of 1×10+7cells/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 incubator with a humidified CO2.

Chemotaxis was performed using 96-well plates to the Neuroprobe chemotaxis, equipped with an 8 μm filter (catalog number 101-8). At the bottom of the wells in triplicate was added thirty milliliters of chemoattractant with the addition of various concentrations of antagonists or media. The filter is then carefully placed on top and on the surface of the filter were added 25 μl of cells pre-incubated with the appropriate concentration of the antagonist or the media. The tablet then incubated for 2 hours at 37°C incubator with a humidified CO2. Then the cells remaining on the surface were removed by adsorption of the entire tablet was centrifuged at 2000 rpm for 10 minutes. The filter is then removed and cells that had migrated to the lower wells were counted using a fluorescence of cells associated with kalayna AM. The movement of cells was then expressed in units of fluorescence after subtracting the control of reagents and values expressed in % move by comparing the values of fluorescence with a known number of labeled cells. Effect of antagonists was calculated as % inhibition when comparing the number of transferred cells with media.

1. The compound of General formula

where m is 0, 1, 2 or 3;

each R1independently represents halogen, cyano, hydroxyl, C3-Cbcycloalkyl, C1-C6alkoxy, C1-C6halogenoalkane, C1-C6halogenoalkane, -NR9R10With3-C6cyclooctylamino, C1-C6alkylthio, C1-C6alkylcarboxylic or C1-C6alkyl;

X represents an oxygen atom or CH2, OCH2CH2O, CH2NH, NH, and

Y represents a nitrogen atom or a group CH, provided that when X represents an oxygen atom or CH2O-CH2NH - or-NH-group, then Y is a group CH;

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

Z2represents a bond or a group CH2provided that both Z1and Z2at the same time do not represent a bond;

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

R2represents a group

n is 0;

each R4, R5, R6and R7independently 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 carbon ring, or each R5, R6and R7represents a hydrogen atom, and R4and R8together with the carbon atoms to which they are attached, form a 5-6-membered saturated carbon ring;

R8represents a hydrogen atom, a C1-C6alkyl group, or it is connected with R4as defined above;

each R9and R10independently represents a hydrogen atom or a C1-C6alkyl group;

R15is a group With2-C6alkyl, C2-C6alkenyl,3-C6cycloalkyl,5-C6qi is alkenyl, of substituted, phenyl or a saturated or unsaturated 5-10 membered heterocyclic ring system containing at least one heteroatom selected from nitrogen, oxygen and sulfur, where each group may be substituted by one or more than one Deputy, is independently selected from nitro, hydroxyl, oxo, halogen, carboxyl, C1-C6of alkyl, C1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphonyl, C1-C6alkoxycarbonyl, phenyl and-NHC(O)-R17provided that R15does not represent unsubstituted 1-pyrrolidinyl, unsubstituted 1-piperidinyl or unsubstituted 1-hexamethyleneimino group;

t is 0, 1, 2 or 3;

each R16independently represents halogen, cyano, hydroxyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C6halogenoalkane, C1-C6halogenoalkane, -NR18R19C1-C6cyclooctylamino, C1-C6alkylthio, C1-C6alkylcarboxylic, or C1-C6alkyl;

R17represents a C1-C6alkyl, amino or phenyl group;

each R18and R19independently represents a hydrogen atom or a C1-C6alkyl group;

or its pharmaceutically who ielemia salt or MES.

2. The compound according to claim 1, where X represents an oxygen atom or CH2-or NH-group.

3. The compound according to claim 1, where Y represents the 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 R15is a group With2-C5alkyl, C2-C4alkenyl,3-C6cycloalkyl,3-C6cycloalkenyl, substituted, phenyl or a saturated or unsaturated 5-10 membered heterocyclic ring system containing at least one heteroatom selected from nitrogen, oxygen and sulfur, where each group may be substituted by one, two or three substituents, independently selected from hydroxyl, oxo, halogen, carboxyl, C1-C6of alkyl, C1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphonyl, C1-C6alkoxycarbonyl, phenyl and-NHC(O)-R17.

6. The compound according to claim 5, where the saturated or unsaturated 5-10 membered heterocyclic ring system containing at least one heteroatom selected from nitrogen, oxygen and sulfur, is pyrrolidinyl, piperidinyl, pyrazolyl, diazolidinyl, thienyl, thiadiazolyl, isoxazolyl, pyrrolyl, furanyl, thiazolyl, indolyl or pyridinyl.

7. The compound according to any one of claims 1 to 6, where each R 16independently represents halogen, cyano, C1-C4alkoxy, C1-C4halogenoalkane or1-C4alkyl.

8. The compound of formula (I) or its pharmaceutically acceptable salt or MES according to claim 1, chosen from:

N-(5-chloro-2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide thiophene-2-carboxylic acid,

N-[(2-(3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-methyl]-benzamide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide pyrazin-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclohexanecarbonyl acid,

methyl ester of N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-fallaway acid,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-ureido-ndimethylacetamide,

4-acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy)-phenyl)-butyramide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 1-acetyl-piperidine-4-carboxylic acid,

N-(2-{3-[3-(4-chloro-fenoc and-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methoxy-benzamide,

2-acetylamino-N-(2-[3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,

2-acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide adamantane-1-carboxylic acid,

2-acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy)-phenyl)-3-phenyl-propionamide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-benzamide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 5-methyl-thiophene-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 1-acetyl-pyrrolidin-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 1,5-dimethyl-1H-pyrazole-3-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 5-oxo-pyrrolidin-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 1H-indole-6-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclobutanecarbonyl acid,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide pentanol acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide the Penta-4-ene acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclopentanecarbonyl acid,

(2-[3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclopropanecarboxylic acid,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-isobutyramide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methylsulfanyl-ndimethylacetamide,

2-acetylamino-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-butyramide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2-methoxy-acetamide", she

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-2,2-dimethyl-propionamide,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 5-oxo-hexanoic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-hexanoic acid amide,

2-chloro-N-(2-{3-[3-(4-chloro-pheno is si)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,

3-chloro-N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,

getreportdata (4R)-N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-1,3-thiazolidin-4-carboxamide,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide thiophene-2-carboxylic acid,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-benzamide,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-nicotinamide,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide pyridine-2-carboxylic acid,

N-(2-[3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy)-phenyl)-isonicotinamide,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclohexanecarbonyl acid,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-3-hydroxy-butyramide,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide 5-methyl-thiophene-2-carboxylic acid,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy)-phenyl)-amide cyclobutanecarbonyl acid,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-propionamide,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide is etanovoi acid,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide the Penta-4-ene acid,

(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-amide cyclopentanecarbonyl acid,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenyl)-3-methyl-butyramide,

the hydrochloride of N-(2-{3-[3-(4-chlorophenoxy)-1-pyrrolidinyl]-2-hydroxypropoxy}phenyl)-2,2,2-trifurcated,

4-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy}-phenylcarbamoyl)-3-methyl-butyric acid,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-propoxy)-phenyl)-succinamic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, furan-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 1H-pyrrole-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide thiophene-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide cyclopentanecarbonyl acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-methyl-thiophene-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy} 4-methyl-phenyl)-amide 3-chloro-thiophene-2-CA is oil acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-methyl-isoxazol-4-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide [1,2,3]thiadiazole-4-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-methyl-furan-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide cyclopent-1-inkarbaeva acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 2-methyl-furan-3-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-methyl-thiophene-2-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-nitro-1H-pyrazole-3-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide thiophene-3-carboxylic acid,

(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide cyclobutanecarbonyl acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, furan-2-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 1H-pyrrole-2-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide thiophene-2-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-chloro-thiophene-2-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-methyl-isoxazol-4-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-methyl-furan-2-carboxylic acid,

(2-[3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide cyclopent-1-inkarbaeva acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 2-methyl-furan-3-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 3-methyl-thiophene-2-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 5-chloro-thiophene-2-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide thiophene-3-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide 2,5-dimethyl-furan-3-carboxylic acid,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide cyclobutanecarbonyl acids is,

(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-propoxy}-4-methyl-phenyl)-amide, furan-3-carboxylic acid,

N-{2-[(3-{3-[(4-forfinal)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were}-1H-pyrrole-2-carboxamide,

N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were}-3-thiophencarboxylic,

N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxy-2-methylpropyl)oxy]phenyl}-2-thiophenecarboxylate, connection triperoxonane acid,

N-{2-[(3-{3-[(4-forfinal)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were)-2-thiophencarboxylic,

N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-2-furancarboxylic,

N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]phenyl}-1-pyrrole-2-carboxamide,

N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were}-1H-pyrrole-3-carboxamide,

N-{2-[(3-{3-[(4-forfinal)oxy]-1-pyrrolidinyl}-2-hydroxypropyl)oxy]-4-were}-2-furancarboxylic,

N-{2-[(3-{3-[(4-chlorophenyl)oxy]-1-pyrrolidinyl)-2-hydroxy-2-methylpropyl)oxy]phenyl}cyclopentanecarboxylate, connection triperoxonane acid,

N-(2-{3-[3-(4-fluoro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,

N-(2-{3-[3-(4-cyano-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-prop is XI}-phenyl)-benzamide,

N-(2-{3-[4-(3,4-dichloro-phenoxy)-piperidine-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide,

N-(2-{3-[3-(4-chloro-phenoxy)-pyrrolidin-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide and

N-(2-{3-[4-(3,4-dichloro-phenylamino)-piperidine-1-yl]-2-hydroxy-2-methyl-propoxy}-phenyl)-benzamide.

9. The method of obtaining the compounds of formula (I) according to claim 1, wherein the compound of General formula

or its salt, where m, n, t, R1, R3, R4, R5, R6, R7, R8, R16, Q, Z1and Z2are as defined in formula (I), is subjected to the interaction with the compound of General formula

R15-CO2N (III)

or halogenoalkanes or anhydrite derivative, where R15is the same as defined in formula (I), and may then form a pharmaceutically acceptable salt 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 the compound of formula (I) or its pharmaceutically acceptable salt or MES according to any one of claims 1 to 8 in combination with a pharmaceutically acceptable adjuvant, diluent or carrier.

11. The method of preparation of the pharmaceutical composition of claim 10, wherein the compound of formula (I) in order for its pharmaceutically acceptable salt or MES according to any one of claims 1 to 8 is mixed 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 8 having the activity of a modulator of the activity of the receptor of the chemokine MIP-1α.

13. A method of treating inflammatory disease in a patient suffering from the specified disease or having a risk of developing them, in which this 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 8.

14. A method of treating respiratory disease in a patient suffering from the specified disease or having a risk of developing them, in which this 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 8.



 

Same patents:

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: pharmaceutical industry, in particular new bioactive chalcones.

SUBSTANCE: invention relates to new chalcones of formula I

, pharmaceutically acceptable salts or solvates thereof, wherein Ar is optionally substituted C5-C10-carbocycle group or 5- or 6-membered heterocycle group having sulfur atom in cycle, and Ar substituents are selected independently from Cl, Br, F, CN, SCH3 and OR10, wherein R10 is linear or branched C1-C6-hydrocarbon; R is OH or R10; R2 and R3 are independently phenyl, saturated linear or branched C1-C6-hydrocarbon, or R2 and R3 together with carbon atom attached thereto form 5- or 6-membered carbocycle group with the proviso, that in compounds where R is OH and both R2 and R3 are methyl, Ar is not phenyl, 4-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 3,4-dimethoxyphenyl, or 4-methoxyphenyl. Also disclosed are drug component for treatment or prophylaxis of neoplasm and pharmaceutical compositions with antiproliferation effect based on compounds of formula I.

EFFECT: new chalcone derivatives with value bioactive action.

26 cl, 2 tbl, 22 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to new substituted thienyl(amino)sulfonylureas of formula I ,

wherein A represents nitrogen or methane; Q represents direct bond or imino; R1 represents fluorine, chlorine, bromine, unsubstituted C1-C4-alkyl, C1-C4-alkoxyl optionally substituted with halogen, unsubstituted C1-C4-alkylthio, or di(C1-C4-alkyl)amino; R2 represents hydrogen or C1-C4-alkyl. Compounds of present invention are useful as herbicide agents.

EFFECT: new compounds with herbicide activity.

5 cl, 11 tbl, 5 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to new substituted thien-3-yl-sulfonylamino(thio)carbonyl-triazolin(thi)ons of general formula I

(wherein Q represents oxygen or sulfur; R1 represents unsubstituted alkyl; R2 represents hydrogen, halogen, unsubstituted alkyl; R3 represents hydrogen, halogen, alkyl optionally substituted with alkoxy, alkoxy or arylthio, optionally substituted with alkoxy or halogen, unsubstituted cycloalkyl or cycloalkyloxy, or unsubstituted arylalkoxy or aryloxy; R4 represents unsubstituted alkyl, alkoxy, dialkylamino, cycloalkyl) and their salts. Compounds of present invention are useful as herbicide agents. Also disclosed is herbicide composition and new synthetic intermediates for compounds of formula I.

EFFECT: new compounds and intermediates thereof with herbicide activity.

16 cl, 13 tbl, 67 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, pharmacy.

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

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

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: present invention relates to new heterocyclic derivatives having calpain inhibition activity or oxygen reactive form recovering entrapping activity of formula I

1, wherein Het represent monocyclic 5-6-membered hetericyclic radical containing 1-2 heteroatoms selected from O or N; A represents A1

2, A'1 3, A2 4, A3 5 and A4 6; X represent -(CH2)n-, -(CH2)n-CO-, -N(R45)-CO-(CH2)n-CO, -CO-N(R45)-D-CO-, -N(R45)-(CH2)n-CO-, -N(R45)-CO-C(R46R47)-CO-, -O-(CH2)n-CO-, -N(R45)-CO-NH-C(R46R47)-CO-, -CO-N(R45)-C(R46R47)-CO- or -Z-CO Y represents -(CH2)p-, C(R53R54)-(CH2)p-, C(R53R54)-CO-; R1 represents hydrogen, group CR3 or oxo; R3 represents hydrogen, monocyclic saturated 6-membered heterocycloalkylcarbonyl, wherein heterocycle contains two heteroatoms selected from nitrogen or oxygen, C1-C6-alkylcarbonyl, phenylcarbonyl or phenyl(C1-C6)-alkylcarbonyl optionally substituted with NR4R5, or R4 and R5 independently represent C1-C6-alkyl; R2 represents hydrogen, and pharmaceutical compositions containing the same.

EFFECT: new heterocyclic drugs.

18 cl, 37 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

FIELD: organic chemistry, chemical technology, biochemistry.

SUBSTANCE: invention relates to new substituted 6-sulfo-2-oxo-1,2-dihydroquinoline 4-carboxylic acids and their derivatives of the general formula (1):

eliciting physiological activity, in particular, capacity to inhibit activity of protein kinase, and also to intermediate compounds for their preparing and to the focused library, for search compound-leaders and medicinal candidates obtaining on the basis of screening combinatory libraries. In compounds of the general formula (1) R1 represents hydrogen atom or electrophilic substitute; R2 represents hydrogen atom or inert substitute; R3 represents optionally substituted hydroxyl group, optionally substituted amino-group and optionally substituted azaheterocycle; R4 represents optionally substituted amino-group and optionally substituted azaheterocycle. Also, invention relates to compounds of the general formula (1.1):

wherein R1, R2 and R3 have above given values; R5 represents hydroxyl or chlorine atom, and to their applying for preparing compounds of the general formula (1.2):

and (1.3):

wherein R1, R2 and R4 have above given values.

EFFECT: valuable medicinal and biochemical properties of compounds.

6 cl, 4 tbl, 5 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: bioactive compounds.

SUBSTANCE: invention relates to new 3-phenyl-1,2,4-benzotriazines and their derivatives of general formula 1

wherein R1 and R2 are independently fluorine or C1-C4-alkoxy, optionally substituted with halogen or tetrahydrofuryl. Compounds of present invention are useful in treatment and prophylaxis of diseases, induced by pathogenic for human and animals viruses including pathogenic for human orthopoxviruses, as well as postvaccinal sequelae.

EFFECT: compounds with improved antiviral activity.

1 cl, 12 ex, 7 tbl

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

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