Aromatic heterocyclic compounds as anti-inflammatory agents

 

The invention relates to compounds of formula (I)in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and so on, in secondary or tertiary amino group in which the nitrogen atom of the amino group is covalently bonded to groups selected from C1-C3alkyl and C1-C5alkoxyalkyl; R1has a value selected from a range of (a) branched or unbranched3-C10alkyl, and so on, (b)3-C7cycloalkyl and so on , or tetrahydropyranyl group; R2pre is using halogenated; R3choose from a range that includes (a) phenyl, naphthyl and heterocyclic group that represents pyridinyl, and so on, (b) branched or non-branched (C1-C6)alkyl which may be partially or fully halogenated and which may be substituted by phenyl group; R4and R5mean morpholine; X denotes Oh, and their physiologically acceptable salts and acids. Method for obtaining compounds of formula (I). Also proposed pharmaceutical composition inhibiting the production of cytokines, including connection on p. 1 or its pharmaceutically acceptable derivatives as active substances and conventional adjuvant. Methods of treatment of inflammatory and autoimmune diseases, which include the introduction of a patient in need of treatment a therapeutically effective amount of the compounds on p. 1. The technical result - aromatic heterocyclic compounds as anti-inflammatory agents. 5 C. and 12 C.p. f-crystals, 3 tables.

Description text in facsimile form (see graphic part).

Claims

1. Aromatic geterotsiklicheskie the compounds of formula (I)

L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain;

in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography;

Q has a value selected from a range that includes (a) phenyl, naphthyl, pyridine, imidazole, Piran, which optionally is substituted by one to three groups selected from the series comprising halogen atoms, With1-C6alkyl, C1-C6alkoxy, mono - or di-(C1-C3alkyl) amino group; b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine, piperidine, piperazine and 1-oxo-thiazolidin, which is optional substituted with one to three groups selected from a range that includes With1-C6alkyl, C1-C6alkoxy and C1-C3alkoxy-C1-C3alkyl; C) a secondary or tertiary amino group in which the nitrogen atom of the amino group is covalently bonded to groups selected from the series, including1-C3alkyl and C3-C10alkyl which may be partially or fully halogenated; (b)3-C7cycloalkyl selected from a range, including cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, which may be partially or fully halogenated and which may be substituted by one to three C1-C3alkyl groups, or tetrahydropyranyl group;

R2has a value selected from a range, including branched or unbranched C1-C6alkyl which may be partially or fully halogenated;

R3choose from a range that includes (a) phenyl, naphthyl and heterocyclic group, which represents a pyridinyl; where phenyl, naphthyl or heterocyclic group is optionally substituted by one to five groups selected from a range that includes branched or unbranched1-C6alkyl, phenyl, naphthyl, panels1-C5alkyl. halogen atom, a C1-C3alkyloxy, amino, mono - or di(C1-C3)alkylamino, phenylamino, NH2C(O), mono - or di(C1-C3)alkylamino-carbonyl, amino (C1-C5) alkyl, mono - or di(C1-C3)alkylamino(C1-C5)alkyl and R4-C1-C5

each of R4and R5means morpholine;

X denotes O, and

their physiologically acceptable acids or salts.

2. Connection on p. 1, in which AG2denotes naphthyl.

3. Connection on p. 1, in which Ar1denotes the pyrazole; Ar2represents 1-naphthyl; L denotes a saturated or unsaturated branched or unbranched carbon With1-C6a circuit in which one or more methylene groups are optionally independently replaced by O, NH or S; and in which the linking group is optionally substituted by oxopropoxy; R1has a value selected from a range, including branched or unbranched1-C4alkyl, cyclopropyl and cyclohexyl which may be substituted With one1-C3alkyl group; R3has a value selected from a range, including branched or unbranched1-C4alkyl, phenyl, pyridinyl, each optionally substituted as described in paragraph 1.

4. Connection on p. 2, in which L denotes propoxy, ethoxy or methoxy, and each of these radicals optionally substituted by one exography.

5. Connection on p. 4, in which L oboznachaet the sludge or propyl, each optionally substituted with one exography.

7. Connection on p. 2, in which L denotes a3-C5acetylene, which is optionally substituted by one exography.

8. Connection on p. 2, in which L denotes methylaminopropyl, which is optionally substituted by one exography.

9. Connection on p. 1, selected from the range includes the following products:

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-yl-ethoxy)naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-(CIS-2,6-DIMET-Immortalis-4-yl)ethoxy)naphthalene-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-(TRANS-2,6-di methylmorpholin-4-yl)ethoxy)naphthalene-1-yl]urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-(2-(methoxymethyl)morpholine-4-yl )ethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-yl)-2-oksidoksi)naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-yl)-2-methylethoxy)naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-yl)-1-methylethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-thiomorpholine-4-ylethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-Pyr-[4-(2-morpholine-4-ylethoxy)-3-methylnaphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-(morpholine-4-ylcarbonyl)ethoxy)naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-(tetrahydro-Piran-4-yl)ethoxy)naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-(1-exoterra-hydrotype-3-yl)ethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(3-morpholine-4-ylpropyl)naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(morpholine-4-ylmethyl)naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-pyridine-4-yl-ethyl) - naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(3-(morpholine-4-yl) propyne-1-yl) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(3-(tetrahydro-Piran-2-yloxy) propyne-1-yl) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(3-(tetrahydro-Piran-2-yloxy)buten-1-yl) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(3-(piperidine-1-yl)propyne-1-yl) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(3-(2-methoxy-methylmorpholin-4-yl)propyne-1-yl) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(pyridin-4-yl-methoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pain-4-yl-propoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-imidazol-1-yl-ethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-(3,4-DIMET oksifenil)ethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(pyridin-4-yl-methylamino)naphthalene-1-yl] urea;

1-[5-isopropyl-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-yl-ethoxy) naphthalene-1-yl] urea;

1-[5-cyclohexyl-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-yl-ethoxy) naphthalene-1-yl] urea;

1-[5-(2,2,2-triptorelin)-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-ylethoxy) naphthalene-1-yl] urea;

1-[5-(1-methylcyclopropyl-1-yl)-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-ylethoxy)naphthalene-1-yl] urea;

1-[5-(1-methylcyclohex-1-yl)-2-phenyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-ylethoxy) naphthalene-1-yl]urea;

1-[5-tert-butyl-2-methyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-ylethoxy)naphthalene-1-yl] urea;

1-[5-tert-butyl-2-(4-chlorophenyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-ylethoxy)naphthalene-1-yl] urea;

1-[5-tert-butyl-2-butyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-ylethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-(4-methyl-3-carbamylethyl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-ylethoxy)naphthalene-1-yl] urea;

1-[5-tert-butyl-2-(4-methyl-3-(morpholine-4-yl)were)-2H-pyrazole-3-yl]-3-[4-(2-morpholine is folin-4-ylethoxy)naphthalene-1-yl] urea;

1-[5-tert-butyl-2-(3-dimethylaminomethylphenol)-2H-pyrazole-3-yl]3-[4-(2-morpholine-4-ylethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-(2-chloropyridin-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-ylethoxy) naphthalene-1-yl] urea;

1-[5-tert-betel-2-(2-methylpyridin-5-yl)-2H-pyrazole-3-yl]-3[4-(2-morpholine-4-ylethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-(2-methoxypyridine-5-yl)-2H-pyrazole-3-yl]-3[4-(2-morpholine-4-ylethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-(pyridin-3-yl)-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-ylethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-pyridine-4-ylethoxy)naphthalene-1-yl] urea;

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazole-3-yl]-3-[4-(2-(TRANS-2,6-dimethylmorpholine-4-yl)ethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazole-3-yl]-3-[4-(3-morpholine-4-ylpropyl-1-yl)naphthalene-1-yl] urea and its physiologically acceptable acid or salt.

10. Connection on p. 9, which is selected from a range that includes the following products:

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-ylethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-(1-Osotimehin-4-yl) ethoxy) naphthalene-1-yl] urea;

1-[5-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazole-3-the-morpholine-4-ylethoxy) naphthalene-1-yl] urea and

1-[5-tert-butyl-2-methyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-ylethoxy) naphthalene-1-yl] urea.

11. Connection on p. 9 representing 1-[5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl]-3-[4-(2-morpholine-4-ylethoxy)naphthalene-1-yl] urea and its physiologically acceptable salt.

12. A method of treating inflammatory diseases which comprises the administration to a patient in need of such treatment, a therapeutically effective amount of the compounds under item 1.

13. The method according to p. 12, in which the inflammatory disease belongs to the group comprising rheumatoid arthritis, multiple sclerosis, Guillain-Barre syndrome-Strole, Crohn's disease, ulcerative colitis, psoriasis, the disease is graft versus host disease, systemic lupus erythematosus and insulin-dependent diabetes mellitus.

14. A method of treating an autoimmune disease, which comprises administration to a patient in need of such treatment, a therapeutically effective amount of the compounds under item 1.

15. The method according to p. 14, in which an autoimmune disease refers to groups that include toxic shock syndrome, osteoarthritis, diabetes, and inflammatory diseases of the digestive tract.

16. The pharmaceutical composition inhibiting the production of cytokines, including saedii.

17. A method of obtaining a connection on p. 1 of formula (I)

in which X denotes O, and AG1, AG2, L and Q have the meanings specified in paragraph 1, including (a) the reaction of aminoheterocycles formula (II) Ar1-NH2with phenylpropanol obtaining urethane compounds of the formula (V)

(b) reaction of a carbamate of the formula (V) from step (a) with arylamino formula (IV)

obtaining the compounds of formula (I).

 

Same patents:

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc

The invention relates to new derivatives of 2-aminopyridine F.-ly (1) where denotes unsubstituted or substituted phenyl, pyridyl, thienyl, thiazolyl, hinely, cinoxacin-2-yl or Antonelliana derivatives; D is unsubstituted or substituted phenyl, pyridyl, thienyl, pyrimidyl, indolyl, thiazolyl, imidazolyl, hinely, triazolyl, oxazolyl, isoxazolyl or Antonelliana derivatives, provided that C and D are not simultaneously have the following values: S - phenyl, and D is phenyl, S - phenyl, and D - pyridyl, With - pyridyl and D - phenyl, - pyridyl and D - pyridyl; R1- R4- hydrogen, NO2or NH2

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

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The invention relates to amino acid derivatives of the formula I

< / BR>
or its non-toxic salt or its hydrate, the pharmaceutical composition having inhibitory effect on calcium channel iv-type; the inhibitor calcium channel N-type; a pharmaceutical composition for prevention and/or treatment of cerebral infarction and pharmaceutical compositions for the treatment of pain

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc

The invention relates to derivatives of cyclic amines and their use as pharmaceuticals, particularly to a compound represented by the General formula (I), its pharmaceutically acceptable acid additive salts or its pharmaceutically acceptable C1-C6alcaldicios salt, R1-phenyl, C3-8-cycloalkyl, aromatic heterocycle with 1-3 heteroatoms selected from O, S, N, or combinations thereof, and these groups may be condensed with benzene ring or an aromatic heterocyclic group with heteroatoms, selected from O, S or N, or combinations thereof, and may also have different substituents

The invention relates to new salts of pyridinium General formula (I) or their pharmaceutically acceptable salts, where R1is-R4- R5or-N(R7)N(R7R9, R4choose from the group of-N(R7R6O-, N(R7R6N(R7), -OR6O-,

-OR SIG6N(R7)-, where R6- alkyl, R5choose from the group of alkyl, aryl, including heteroaryl, -COR7, -SO2R7and-COR10where R7Is H, alkyl or aryl, including heteroaryl, R2Is F, Cl, Br, J, alkyl, aryl, including heteroaryl, formyl, acyl, C(O)NR7R10or C(O)or SIG7, m = 0, 1, or 2, R3selected from the group comprising R7OR7N(R7)(R10) and CH(R7)C(O)R8, R8is R7OR7and NR7R10, R9is hydrogen, alkyl, aryl, including heteroaryl, -C(O)R10, -SO2R10, -C(S)OTHER10, -C(NH)NH(R10), -C(O)OTHER10, R10- H, alkyl, or aryl, including heteroaryl, and in each case, it is not necessarily different from R7X represents an ion halogen provided that 1) when two alkyl groups are the same carbon or nitrogen, they are not necessarily linked together with the formation of a cyclic structure, and (2) nitrogen heteroaryl ring R1

The invention relates to new N-phenylamine and N-pyridylamine derivative of the formula I

< / BR>
in which X denotes O or S;

R1and R2which may be identical or different, denote hydrogen, (C1-C6)alkyl or (C3-C8)cycloalkyl or R1and R2together with the carbon atom to which they are attached, form a (C3-C8)cycloalkyl;

R3means (C6-C12)aryl, optionally substituted by one or more radicals Y, which may be the same or different;

Y represents halogen;

R4and R5represent hydrogen;

Ar denotes one of the following groups or WITH:

< / BR>
T represents hydrogen or (C1-C6)alkyl;

T3and T4which may be identical or different, denote (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)allylthiourea;

R6and R7each denotes hydrogen or R6and R7together represent a bond;

Z denotes either (I) the divalent group-CHR9- in which the R11-, in which R10and R11together they form a bond that Z represents the group-CH=CH-, or R10and R11that may be the same or different, have the meanings indicated above for R9or (III) a divalent group-CHR12-CHR13-CH2-, in which R12and R13together they form a bond, Z represents-CH=CH-CH2-, or R12and R13that may be the same or different, have the meanings indicated above for R9,

as well as their additive salts with pharmaceutically acceptable acids or bases, and method of production thereof, pharmaceutical compositions and drug manifesting gipolipedimecescoe and antiatherosclerotic action based on them

The invention relates to new derivatives of 1-[(1-substituted-4-piperidinyl)methyl]-4-piperidine F.-ly (I), where Ar is a group of the formula (Ar-1) or (Ar-2), where R1is a halogen, R2represents hydrogen or lower alkyl, R3represents hydrogen, lower alkyl or lower alkanoyl, R4represents hydrogen or lower alkyl, R5and R6are the same or different and represent hydrogen or lower alkyl, n is 1, 2 or 3, And represents a group of formula (a-1), (a-2) or (a-3): -Z-N(Q1)(Q2) (A-1), where Z represents-CO -, - CS-or-SO2-, Q1and Q2are the same or different and represent hydrogen, lower alkyl, cycloalkyl, unsubstituted or substituted phenyl or phenyl(lower alkyl), or Q1and Q2together with the nitrogen atom form a pyrolidine, piperidine, hexahydroazepin, morpholino, thiomorpholine or pieperazinove ring; -CO-R7(A-2), where R7represents hydrogen, lower alkyl, lower alkoxy, lower alkoxycarbonyl, substituted lower alkyl; -(CH2)p-CH(R8)-COR9(A-3), where p has a value 0, 1, 2, 3, 4 5; R8represents hydrogen or lower alkyl; R9is

The invention relates to the field of organic chemistry and relates to compounds of formula (I) and their pharmaceutically acceptable salts and difficult ether derivatives

< / BR>
where Ar represents a phenyl group which may be optionally substituted from 1 to 3 substituents selected from the group consisting of halogen atoms and triptorelin groups having antifungal activity

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc
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