Derivatives oxadiazole

 

(57) Abstract:

The invention relates to new derivatives of oxadiazole General formula I, in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen; Z denotes a radical of the formula II, R1means phenyl radical, which is optionally substituted directly or through alkylene bridges with the number of carbon atoms from 1 to 4 once, twice or three times by one or more substituents from the series halogen, C1-C4-alkyl, CF3, -NR5R6, NO2, -OR7. Derivatives oxadiazole General formula I can be used as drugs when neurodegenerative diseases and ischemia of the brain of different origin. These include, for example, epilepsy, hipocresia, hypoxia, anoxia, brain trauma, brain swelling, amiotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease. 7 C.p. f-crystals, 6 PL.

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The invention relates to new nitrogen-containing heterocyclic compounds with biological activity, in particular derivatives oxadiazole.

Known derivatives oxadiazole with activity, neuroprotective is the breaking of oxadiazole, possessing neuroprotective effect.

The problem is solved proposed derivatives oxadiazole General formula (I)

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in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen;

Z denotes a radical of the formula

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in which S1and S2mean radicals of the formula

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in which V denotes oxygen, sulfur; and D mean the same or different C1-C10-alkylene bridges, which are, respectively, can be singly or multiply substituted by such substituents as =0, 1,3-dioxolane or 1,3-dioxane.

S1and S2mean radicals of the formula

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in which V and V have the above values, a U mean WITH3-C6-cycloalkyl group or6-C10-aryl group which may be substituted one or more times WITH1-C4-alkyl, -NR5R6;

S1and S2mean radicals of the formula

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in which b and D have the above meanings and both groups D and both radical R4may be the same or different;

S1and S2mean radicals of the formula

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S1and S2mean radicals of the formula

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moreover, D has the above meanings and both groups D and both radical R4may be the same or different;

S1and S2mean radicals of the formula

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where E means NR7(n, m=2 or 3 and n+m>2);

S1and S2mean radicals of the formula

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in which V and D have the above values and W stands for a radical of the formula

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optionally substituted C1-C4-alkyl, in which E denotes NR7a n, m, l=0,1 or 2, or W means is attached through the carbon atom 5, 6-membered heterocycle containing one or more heteroatoms from the series nitrogen, oxygen, which may optionally be substituted by benzyl or1-C4-alkyl;

S1and S2mean radicals of the formula

-V-W

in which V and W have the above meanings;

S1and S2mean radicals of the formula

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which has the above meanings and both Deputy R7may be the same or different;

S1and S2mean radicals of the formula

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in which the substituent R7
S3and S4mean radicals of the formula

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in which b and D have the above meanings and both groups D and both Deputy R4can be identical or different;

S3and S4mean radicals of the formula

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in which V and D have the above meanings;

S3and S4mean radicals of the formula

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in which D has the above meanings, and both groups D and both Deputy R4can be identical or different;

Q means a condensed, one unsaturated 5-membered cycle which may contain one or more heteroatoms from the series oxygen;

S5means a radical of the formula

-D-R4< / BR>
in which D has the above meanings;

R1means phenyl radical, which is optionally substituted directly or through alkylene bridges with the number of carbon atoms from 1 to 4 once, twice or three times by one or more substituents from the series halogen, C1-C4-alkyl, -CF3, -NR5R6, -NO2, -OR7,

or Deputy formula

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where, V or D have the above zacharovannye value;

R1means phenyl-C1-C6-alkyl, preferably phenyl-C1-C4-alkyl, phenyl-C2-C6alkenyl;

R1means a radical of the formula M-, and M is 5, 6-membered heterocycle attached via a C - or N-atom, which contains one heteroatom from the series nitrogen, oxygen or sulfur;

R1means3-C7-cycloalkenyl radical;

R1means, optionally substituted C1-C4-alkyl, preferably the stands, norbornane, norbornene radical, preferably an adamantane or noradsanta radicals;

R1means optionally substituted radical of the formula

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R2and R3denote identical or different radicals such as hydrogen, halogen, -OR7C1-C10-alkyl;

R4means amine of the formula-NR5R6;

R4means N-oxide of the formula

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R5means hydrogen, C1-C10-alkyl;

R6means hydrogen, C1-C10-alkyl;

R6means6-C10-aryl, preferably phenyl;

R7means hydrogen, C1-C4-alkyl;

if necessary, in the form of their racemates, their enantiomer the acids.

Preferred compounds of General formula (I)

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in which X and Y denote oxygen or nitrogen, and X and Y cannot be both at the same time oxygen or nitrogen,

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Z denotes a radical of the formula in which

S1and S2mean radicals of the formula

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in which V denotes oxygen, sulfur, and D mean the same or different WITH1-C4-alkylene bridges, which can be substituted with such substituents as =0;

S1and S2mean radicals of the formula

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in which V and V have the above significance, a U mean WITH3-C6-cycloalkyl or6-C10-aryl group which may be substituted by such substituents as1-C4-alkyl, -NR5R6;

S1and S2mean radicals of the formula

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in which b and D have the above meanings and both groups D and both the radical R4can be identical or different;

S1and S2mean radicals of the formula

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in which V and D have the above meanings;

S1and S2mean radicals of the formula

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in which V and U have the above values

S1and S24can be identical or different;

S1and S2mean radicals of the formula

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where E means NR7(n, m=2 or 3 and n+m>2);

S1and S2mean radicals of the formula

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in which V and D have the above values, a W stands for a radical of the formula

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if necessary WITH1-C4-alkyl, in which E denotes NR7, n, m, l=0, 1, or 2, or W means attached through a carbon atom 5, 6-membered heterocycle containing one or more heteroatoms from the series nitrogen, oxygen, which optionally may be substituted by benzyl or1-C4-alkyl;

S1and S2mean radicals of the formula

-V-W

in which V and W have the above meanings;

S1and S2mean radicals of the formula

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which has the above meaning and the substituents R7can be identical or different;

S1and S2mean radicals of the formula

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in which the substituents R7can be identical or different;

S3and S4mean radicals of the formula

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where, V and D have the above meanings;

S3and S4and Deputy R4can be identical or different;

S3and S4mean radicals of the formula

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in which V and D have the above meanings;

S3and S4mean radicals of the formula

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in which D has the above meanings and both groups D and both Deputy R4may be the same or different;

Q means a condensed, one unsaturated 5-membered heterocycle containing one or more heteroatoms from the series oxygen;

S5means a radical of the formula

-D-R4,

in which D has the above meanings;

R1means phenyl radical, which is optionally substituted one or more times by one or more substituents such as halogen, preferably fluorine, chlorine or bromine, WITH1-C4is an alkyl radical, -CF3, -NR5R6, -NO2, -OR7or one radical of the formula

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where, V and D have the above meanings;

R1means phenyl radical which can be substituted by the Deputy formula

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where, V and U have the above meanings;

R1means phenyl radical, which is substituted replaces>WITH4-alkyl, preferably benzyl, phenyl-C2-C4alkenyl;

R1means a radical of the formula M-, and M is 5 or 6-membered heterocycle attached via a C - or N-atom, which contains one heteroatom from the series nitrogen, oxygen or sulfur;

R1means3-C7-cycloalkyl, preferably cyclopropyl or cyclopentyl;

R1means, optionally substituted C1-C4the alkyl preferably the stands, norbornane-norbornene radical, preferably an adamantane or noradsanta radicals;

R1means, optionally substituted one or more times by halogen, hydroxy-group or a methoxy group, the radical of the formula

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R2and R3denote identical or different radicals such as hydrogen, the hydroxy-group, halogen, preferably fluorine, chlorine or bromine, WITH1-C4-alkyloxy, preferably methoxypropan,1-C4-alkyl;

R4means-NR5R6,

R4means N-oxide with the formula

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R5means hydrogen, C1-C4-alkyl,

R6means hydrogen, C1-C4-alkyl;

R6means phenyl radical,

Especially preferred derivatives of oxadiazole General formula (I)

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in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen,

Z denotes a radical of the formula

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in which S1means a radical of the formula

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in which V denotes oxygen, sulfur, and b and D indicate the same or different WITH1-C4-alkylene, bridges, which can be substituted with such substituents as =0;

S1means a radical of the formula

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in which V and D have the above meanings;

S1means a radical of the formula

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in which V has the above meanings and U mean WITH3-C6-cycloalkyl or phenyl group which may be substituted WITH1-C4-alkyl;

S1means a radical of the formula

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in which b and D have the above meanings and both groups D and both Deputy R4the same or different;

S1means a radical of the formula

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in which D has the above meanings and both groups D and both mean NR7(with n, m=2 or 3 and n+m>2);

S1means a radical of the formula

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in which V and D have the above values, a W stands for a radical of the formula

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optionally substituted C1-C4-alkyl, in which E denotes NR7, n, m, l=0, 1, or 2,

or W means attached through a carbon atom a 5 - or 6-membered heterocycle which contains one or more heteroatoms from the series nitrogen, oxygen and which is optionally substituted by benzyl or1-C4-alkyl;

S1means a radical of the formula

-V-W

in which V and W have the above meanings;

S2means a radical of the formula

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in which V and D have the above meanings;

S4means a radical of the formula

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in which V and D have the above meanings;

Q means a condensed, one unsaturated 5-membered heterocycle containing one or more heteroatoms from the series oxygen;

S5means a radical of the formula

-D-R4,

in which D has the above meanings;

R1means benzyl or phenyl radical, the latter can be singly or multiply substituted by one or more of the Deputy is>
;

R1means phenyl radical substituted by a radical of the formula

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in which V denotes oxygen and D means WITH1-C4is an alkyl bridge;

R1means 5 - or 6-membered heterocycle attached via a carbon atom or nitrogen, which contains one heteroatom from the series nitrogen, oxygen or sulfur;

R1means cyclopropyl, checkpointer or cyclohexyl;

R1means norbornane, norbornene, adamantane or noradsanta, optionally substituted metal group;

R1means a radical of the formula

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R1means-CH=CH-phenyl;

R2means hydrogen, fluorine, chlorine, bromine, C1-C4-alkyloxy,1-C4-alkyl or hydroxy-group;

R3means hydrogen;

R4means-NR5R6;

R4means N-oxide of the formula

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R5means hydrogen, C1-C3-alkyl;

R6means hydrogen, C1-C3-alkyl, benzyl or phenyl;

R7means hydrogen, C1-C4-alkyl, benzyl;

if necessary, in the form of their racemates, their enantiomers, in the form of Stereolab or mixtures thereof, and optionally their pharmacologically-besouro X and Y denote oxygen or nitrogen, moreover, X and Y cannot be both at the same time oxygen or nitrogen;

Z denotes a radical of the formula

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in which S1means a radical of the formula

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in which V denotes oxygen, sulfur, means-CH2and D denotes one of the groups-CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2- (CH3)N-, -CH2-CO-, -CH2-CH2-CO-;

S1means a radical of the formula

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in which V and D have the above meanings;

S1means radicals piperazine-1-yl, 4-methylpiperazin-1-yl;

S1means a radical of the formula

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in which V and D have the above values, and

W stands for a radical of the formula

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optionally substituted C1-C4is an alkyl group or

W means attached through a carbon atom a 5 - or 6-membered heterocycle containing nitrogen, which is optionally substituted by benzyl or C1-C4-alkyl;

R1means a radical of the formula

-V-W,

in which V and W have the above values

S2means a radical of the formula

-(CH2)a 0.1-O-(CH2)2,3-R4,

Q means a condensed, one-time Genaside the formula

-D-R4,

in which D has the above meanings;

R1means radicals cyclopropyl, cyclopentyl, benzyl or phenyl, the latter may be singly or multiply substituted by one or more substituents, such as fluorine, chlorine, bromine, C1-C4-alkyl, -CF3, -NMe2, -NO2or7;

R1means phenyl substituted by a radical of the formula

-O-(CH2)2,3-R4,

R1means furan, thiophene, pyridine or pyrrole;

R1means norbornane, norbornene, adamantane or noradsanta;

R1means-CH=CH-phenyl;

R2means hydrogen, fluorine, chlorine, bromine, C1-C4-alkyloxy,1-C4-alkyl or hydroxy-group;

R3means hydrogen;

R4means-NR5R6or N-oxide of the formula

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R5means hydrogen, C1-C3-alkyl;

R6means hydrogen, C1-C3-alkyl, benzyl or phenyl;

R7means hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl;

if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and mixtures thereof, and optionally their pharmacologically b is Roy

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X and Y mean nitrogen or oxygen, and X and Y cannot both be oxygen or nitrogen,

Z denotes a radical of the formula

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in which S1means a radical of the formula

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in which V denotes oxygen, sulfur, means-CH2and D means one of isgroup-CH2,-CH2-CH2-,-CH2-CH2-CH2-,-CH2- (CH3)N-,-CH2-CO-,-CH2-CH2-CO-;

S1means a radical of the formula

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in which V and D have the above meanings;

S1means radicals piperazine-1-yl, 4-methylpiperazin-1-yl;

S1means a radical of the formula

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in which V and D have the above values and W stands for a radical with the formula

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optionally substituted C1-C4is an alkyl group, or W means attached through a carbon atom a 5 - or 6-membered heterocycle containing nitrogen, which may be optionally substituted benzyl or1-C4-alkyl;

S1means a radical of the formula

-V-W,

in which V and W have the above meanings;

Q means a condensed, one unsaturated 5-membered heterocycle that contains one heteroatom from the series achene;

R1means radicals cyclopropyl, cyclopentyl or phenyl, and the phenyl cycle can be singly or multiply substituted by one or more substituents, such as fluorine, chlorine, bromine, C1-C4is an alkyl radical, -CF3, -NMe2, -NO2or7;

R1means furan, thiophene, pyridine or pyrrole;

R1means norbornane, norbornene, adamantane or noradsanta;

R1means-CH=CH-phenyl;

R2means hydrogen, fluorine, chlorine, bromine, C1-C4-alkyloxy,1-C4-alkyl or hydroxy-group;

R3means hydrogen;

R4means, -NR5R6or N-oxide of the formula

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in which R5means hydrogen, C1-C3-alkyl;

R6means hydrogen, C1-C3-alkyl, benzyl or phenyl;

if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and mixtures thereof, and, if appropriate, their pharmaceutically safe salts with acids.

Next are of great interest compounds of General formula (I)

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in which X and Y represents oxygen or nitrogen, and X and Y cannot be both at the same time oxygen or nitrogen which V denotes oxygen, sulfur and D denotes one of the groups-CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2- (CH3)N-,-CH2-CO-, -CH2-CH2-CO-;

S1means radicals piperazine-1-yl, 4-methylpiperazin-1-yl;

S1means a radical of the formula

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in which V and D have the above values and W stands for a radical of the formula

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or W means attached through a carbon atom a 5 - or 6-membered heterocycle containing nitrogen, which is optionally substituted methyl group;

S1means a radical of the formula

-V-W,

in which V and W have the above meanings;

Q means a condensed, one unsaturated 5-membered heterocycle that contains one heteroatom from the series oxygen;

S5means a radical of the formula

-D-R4,

in which D has the above meanings;

R1means phenyl radical, which is optionally substituted one or more times by one or more substituents such as fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CF3or7;

R1means furan, thiophene or pyridine;

R2means hydrogen, fluorine, chlorine, P>5R6or N-oxide with the formula

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R5means hydrogen, methyl, ethyl, n-propyl, isopropyl;

R6means hydrogen, methyl, ethyl, n-propyl, isopropyl, benzyl or phenyl;

R7means hydrogen, methyl or ethyl;

if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and mixtures thereof, if appropriate, their pharmaceutically safe salts with acids.

Of particular importance are further compounds of General formula (I)

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in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen;

Z denotes a radical of the formula,

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in which S1means a radical of the formula

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in which V denotes oxygen and D represents one of the groups-CH2-, -CH2-CH2-, -CH2- (CH3)N-,-CH2-CH2-CO-;

S1means radicals of N-piperazinil;

S1means a radical of the formula

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in which V and D have the above values, a W stands for a radical of the formula

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or W means attached through a carbon atom a 5 - or 6-membered heterocycle containing nitrogen, optionally substituted methyl group;

S1means radical forma unsaturated 5-membered heterocycle, containing as heteroatoms oxygen;

S5means a radical of the formula

-D-R4,

in which D has the above meanings;

R1means phenyl radical which can be substituted one or more times by one or more substituents such as fluorine, chlorine, bromine, methyl radical, -CF3the hydroxy-group, methoxypropyl or atelocerata;

R1means furan, thiophene or pyridine;

R2means hydrogen, fluorine, chlorine or methyl;

R3means hydrogen;

R4means-NR5R6;

R5means hydrogen, methyl, ethyl, n-propyl, isopropyl;

R6means hydrogen, methyl, ethyl, n-propyl, isopropyl, benzyl or phenyl;

optionally in the form of their racemates, their enantiomers, in the form of their diastereomers and mixtures thereof, if appropriate, their pharmaceutically safe salts with acids.

Especially preferred according to the invention compounds of General formula (I)

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in which

X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen;

Z denotes a radical of the formula

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in which S1means one has radical/SUB>-CH2-CO-R4;

S1means one of the radicals-O-CH2-W or-O-W, in which W means attached through a carbon atom a 5 - or 6-membered heterocycle comprising the nitrogen atom, which is optionally substituted methyl group;

Q means a condensed, one unsaturated 5-membered heterocycle containing, as heteroatom oxygen;

S5means a radical of the formula-CH-R4;

R1means phenyl radical which can be substituted one or more times by one or more substituents such as fluorine, chlorine, bromine, methyl, -CF3the hydroxy-group, methoxypropyl or atelocerata;

R1means thiophene;

R2means hydrogen, fluorine, chlorine or methyl;

R3means hydrogen;

R4means-NR5R6;

R5means hydrogen, methyl, ethyl, isopropyl;

R6means hydrogen, methyl, ethyl, isopropyl, benzyl or phenyl;

optionally in the form of their racemates, their enantiomers, in the form of their diastereomers or mixtures thereof; optionally, their pharmaceutically safe salts with acids.

Under alkyl groups or alkilani (and in the case when they are svetlanna or unbranched alkyl groups with carbon atoms of 1 to 10, preferably the number of carbon atoms from 1 to 4, as example can be mentioned methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl. To denote methyl, ethyl, butilkoi or tert-butilkoi groups are used and abbreviations Me, Et, Bu and tBu.

Substituted alkyl groups, unless otherwise agreed upon (and in the case when they are an integral part of other substituents) may have, for example, one or more substituents from the following series of halogen, hydroxy-, mercapto-, C1-C6-alkyloxy-, amino-, alkylamino, dialkylamino-, cyano-, nitro-group, =O, -Cho, COOH, -COO-C1-C6-alkyl, -S-C1-C6-alkyl.

Under alkenylamine groups (and in the case when they are an integral part of other substituents) understand branched or unbranched alkeneamine group with the number of carbon atoms from 2 to 10, preferably, with the number of carbon atoms from 2 to 3, containing at least one double bond, for example, and the above-mentioned alkyl groups, if they contain at least one double bond, such as vinyl (provided that do not form volatile enamines or anglefire), propanil, the network (and in the case if they are an integral part of other substituents) may have one or more substituents from the following series of halogen, hydroxy-, mercapto-, C1-C6-alkyloxy-, amino-, alkylamino, dialkylamino-, cyano-, nitro-group, =O, -Cho, -COOH, -COO-C1-C6-alkyl and-S-C1-C6-alkyl.

Under alkenylamine groups (and, in the case when they are an integral part of other substituents) understand alkyline group with the number of carbon atoms from 2 to 10, which contain at least one triple bond, for example, ethinyl, propargyl, butynyl, pentenyl, hexenyl.

Substituted alkyline group, if it is not otherwise specified, (and in the case when they are an integral part of other substituents) may have one or more substituents from the series halogen, hydroxy-, mercapto-, C1-C6-alkyloxy-, amino-, alkylamino, dialkylamino-, cyano-, nitro-group, =O, -Cho, -COOH, -COO-C1-C6-alkyl, -S-C1-C6-alkyl.

Under cycloalkenyl radicals with the number of carbon atoms from 3 to 6 understand cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl which may be substituted by branched or unbranched alkyl group with chisor, chlorine, bromine or iodine.

Under the aryl understand aromatic cyclic system containing from 6 to 10 carbon atoms, which, if not specified otherwise, may have substituents from the series of C1-C6-alkyl, C1-C6-alkoxygroup, halogen, hydroxy-, mercapto-, amino-, alkylamino, dialkylamino-group, CF3-, cyano-, nitro-group, -Cho, -COOH, -COO-C1-C6-alkyl, -S-C1-C6-alkyl. The preferred aryl radical is phenyl.

As an example, attached through a carbon atom a 5 - or 6-membered heterocycles, which contain heteroatoms such as nitrogen, oxygen or sulfur, can be called a furan, tetrahydrofuran, 2-methyltetrahydrofuran, 2-hydroxymethylene, tetrahydrofurane-butyrolactone, Piran, Piran, dioxolan, tetrahydropyran, dioxane, thiophene, dihydrothiophene, tolan, ditiolan, pyrrole, pyrrolin, pyrrolidine, pyrazole, pyrazoline, imidazole, imidazoline, imidazolidine, triazole, tetrazole, pyridine, piperidine, pyridazine, pyrimidine, pyrazin, piperazine, triazine, the tetrazine, morpholine, thiomorpholine, oxazol, isoxazol, oxazin, thiazole, isothiazol, thiadiazole, oxadiazole, pyrazolidine, and the heterocycle may be substituted as specified in refinements.

+channel site 2 binding site of the histamine H1 receptor, 5-hydroxytryptamine 1A receptor, 5-hydroxytryptamine 2A receptor, the Sigma receptor. In addition, these compounds find antagonistic activity at AMPA-receptor.

The neuroprotective effect of the compounds according to the invention was confirmed in animals. Based on these results, the compounds according to the invention can be used in neurodegenerative diseases, and ischemia of the brain of different origin.

Compounds according to the invention can be obtained by using known methods, among others, as described below.

In the first stage, the nitrile of General formula (I), based on methods known from the literature (L. F. Tietze, T. Eicher, "Reaktionen und Sinthesen im Organisch-this trade Praktikum und Forschungslaboratorium", 2nd ed. 1991, Georg Thieme Verlag Stuttgart, New York, page 340), by reaction with hydroxylamine in turn amidoxime General formula (2) (scheme 1). The reaction of this amidoxime (2) under alkaline conditions, the reaction with derivatives of benzoic acid, substituted nucleophilic groups of the General formula (3) are oxadiazole General formula (4). Production is using appropriate protective groups.

As a reason suitable the alcoholate of alkaline or alkaline earth metals, for example, methanol, ethanol, isopropanol, n-, sec - and tert-Putilkovo alcohol. Suitable alkali and alkaline earth metals are lithium, sodium, potassium, magnesium, calcium. The sodium methylate, sodium ethylate, isopropylate sodium tert-butyl potassium and potassium methylate especially preferred as bases. In addition, according to the invention are suitable such grounds as hydrides of alkali and alkaline earth metals.

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in which L' = tsepliaeva groups, such as chlorine, bromine or alkoxygroup;

L = tsepliaeva group, for example, chlorine, bromine, iodine, methanesulfonyl;

Nu = -OH, -SH, -NH2=VH, according to the above clarification, or

Nu = -B-OH-B-SH, -B-NH2=B-VH according to the above clarifications,

Sn= S1S2S3S4or S5according to the above clarifications.

Modification of side chain in the formation of derivative oxadiazole General formula (Ia') occurs according to the scheme 1 in the final reaction of the compound (4) with electrophilic compounds of General formula (5). For this to oxadiazole (4) after adding one base in an inert restoreselection, after 15 to 30 minutes, heated at the back of distillation during the time from 4 to 12 hours, preferably from 6 to 8 hours. After cooling to room temperature the greater part of the solvent is distilled off in vacuo, and the product after washing and drying purified by crystallization or chromatography. According to the invention is used as a basis hydrides of alkali and alkaline earth metals. Preferred hydrides of sodium, lithium, potassium, magnesium, calcium. Suitable inert solvents are dimethylformamide, methylene chloride, and cyclic ethers such as tetrahydrofuran or, preferably dioxane. Along with this, as a reason to use the alcoholate of alkali and alkaline earth metals, such as methanol, ethanol, isopropanol, n-, sec-, tert-butanol. Suitable such alkaline and alkaline earth metals, such as lithium, sodium, potassium, magnesium and calcium. Use sodium methylate, sodium ethylate, isopropylate sodium tert-butyl potassium and potassium methylate. According to the invention also apply hydroxide of alkali and alkaline earth metals lithium, sodium, potassium, magnesium and calcium, however, the preferred sodium hydroxide, potassium hydroxide, lithium hydroxide and hydro is inogo cycle, contained in the formula (Ia1have a heteroaromatic cycle, get a similar way.

The reaction of aromatic nitrides with the General formula (6) with electrophilic compounds of General formula (5) gives according to the scheme 2 aromatic cyanides, substituted side chain Sn(n=1, 2, 3, 4), General formula (7). This nitrile (6) after adding a base in an inert solvent at room temperature or under heating, preferably from 40 to 80odeprotonated and finally add the electrophiles (5). The resulting solution over time from 0.25 to 2 hours, heated from 40 to 80oafter cooling to room temperature the solvent is distilled off in vacuum. This product after washing and drying without further purification directly injected into the following stages. According to the invention as a base use hydrides of alkali and alkaline earth metals, preferably sodium hydride, lithium, potassium, magnesium and calcium. Suitable inert solvents are dimethylformamide, methylene chloride, and cyclic ethers such as tetrahydrofuran, preferably dioxane.

< / BR>
in which L' = tsepliaeva group, for example chlorine, bromine, alkoxygroup;

L = tsepliaeva g, or

Nu = -B-OH-B-SH, -B-NH2=B-VH according to the above clarifications;

Sn=S1S2S3S4or S5according to the above clarifications.

These NITRILES make known (L. F. Tietze, T. Eicher, "Reactions and syntheses in the organic chemistry lab and in research laboratories", Georg Thieme Verlag, Stuttgart, 2nd ed., 1991, page 340) in the aromatic amidoxime General formula (8). In an alkaline environment, these amidoxime when reacted with derivatives of carbonic acids (9) form oxadiazole formula (Ib'). To do this, dissolve amidoxime (8) with derivatives of carboxylic acids (9) in an inert solvent, preferably an alcohol, particularly preferably in ethanol, and when exposed to the heated base. After cooling to room temperature the greater part of the solvent is distilled off in vacuum and the product after washing and drying cleaned by crystallization or chromatography. As a reason suitable the alcoholate of alkaline or alkaline earth metals, methanol, ethanol, isopropanol, n-, sec - and tert-Putilkovo alcohol. Suitable alkali and alkaline earth metals are: lithium, sodium, potassium, magnesium, calcium. As grounds particularly preferred methylate is rmula (Ib), which, instead of the phenyl cycle contained in the formula (Ib'), contain heteroaromatic cycle, get a similar way. Oxadiazole General formula (Ib) having a functional group in the side chain, get with the use of suitable protective groups.

Derivatives oxadiazole General formula (10), which have aromatic cycle side chain, substituted tsepliaeva group, make according to the invention by reaction with nucleophiles of General formula (11) compounds of General formula (I') (see scheme 3).

Scheme 3:

< / BR>
in which L = tsepliaeva group, for example chlorine, bromine, iodine, methanesulfonyl,

S' = -B-V-D-V-D and V, V and D above clarifications,

Sn= S1S2S3S4or S5have vysheotmechennye values.

For this connection (10) is dissolved in an inert solvent and, after the addition of the nucleophile (11) heated for from 0.5 to 2 hours, preferably from 1 to 1.5 hours at a temperature of from 50 to 120oC. After cooling to room temperature the greater part of the solvent is distilled off in vacuo, and the product after washing and drying purified by crystallization or chromatography.

Suitable inert dissolved is respectfully dioxane.

Oxadiazole General formula (I), which, instead of the phenyl cycle contained in the formula (I'), contain heteroaromatic cycle, get a similar way and manner. Synthesis of oxadiazoles General formula I, having the functional groups in the side chains is carried out with use of suitable protective groups.

Below are some detailed descriptions of the synthesis of illustrating the invention, however, the subject invention is not limited to them.

Example 1: 5-{ 2-[2-(N, N-dimethylamino)ethyl]oxymethyl-phenyl}-3-phenyl-1,2,4-oxadiazol

< / BR>
a) Obtaining amidoxime benzoic acid:

14 g of hydroxylamine hydrochloride dissolved in 50 ml of water and with stirring and cooling with ice add 16,8 g hydrogencarbonate sodium. To this mixture add a solution of 10.3 g of the nitrile of benzoic acid in 100 ml of ethanol and 3 hours of heat at the back of distillation. In conclusion, the ethanol is distilled off in vacuum and the residue is 2 times extracted with diethyl ether. The combined ether phases are dried over sodium sulfate and the solvent is distilled off. The residue (13,4 g = 98.5% of theoretical.) without further purification enter in the cyclization reaction.

b) Obtain 5-(2-hydroxymethyl-phenyl)-3-phenyl-1,2,4-oxadiazole:

1,36 g amidoximes 15 minutes. In conclusion, the type of 2.68 g of phthalide under stirring and heated 15 hours at the back of distillation. Dark red solution is dried in vacuum and the residue is dissolved in water. It neutralizes 2N hydrochloric acid and extracted with dichloromethane. The organic phase is dried over sodium sulfate, the solvent is distilled off and chromatographic on silica gel with dichloromethane/methanol (98: 2).

Yield 1.2 g (48% of theory.).

C) Obtain 5-{2-[2-(N,N-dimethylamino)ethyl]oxymethyl-phenyl}-3-phenyl-1,2,4-oxadiazole:

1 g of 5-(2-hydroxymethyl-phenyl)-3-phenyl-1,2,4-oxadiazole dissolved in 20 ml of dimethylformamide (DMF) and add 0.2 g of sodium hydride (60% in oil). Then stirred for 30 minutes at 20-23oWith and add pre-mixed for 30 minutes a mixture of 2-N,N-dimethylaminoethoxide and 0.22 g of sodium hydride (60% in oil) in 20 ml of DMF. This mixture is heated at 100oC for 5 hours, then the solvent is distilled off in vacuum. The residue is dissolved in water, acidified with 2N hydrochloric acid and extracted with ether acetic acid. The aqueous phase is alkalinized with sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over sodium sulfate, the solvent is distilled off in vacuum and chromatographic on siliya. Yield 0.07 g (5% of theory.). Melting point: 107oC (decomp.)

Example 2: 5-{2-[2-(N,N-dimethylamino)ethyl]oxy-phenyl}-3-phenyl-1,2,4-oxadiazol

< / BR>
a) Obtaining 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole:

6.8 g amidoxime betinov acid and 15.2 g of methyl ester of salicylic acid dissolved in 150 ml of anhydrous ethanol, add 2.3 g of sodium and 3 times heated for 25 minutes (with 5-minute breaks) in a microwave power of 400 watts. The reaction mixture was reduced tol/3volume in vacuo and to the residue water is added. Upon cooling, the addition of 2N hydrochloric acid to establish a pH of 8-9, the formed precipitate is sucked off and washed with water. For complete removal of the water it is dissolved in dichloromethane and dried over sodium sulfate and the solvent is distilled off. Output: 12,9 g (92% of theory. in terms of amidoxime benzoic acid). Melting point: 156-158oC.

b) Obtain 5-{2-[2-(N,N-dimethylamino)ethyl]oxy-phenyl}-3-phenyl-1,2,4-oxadiazole:

of 2.38 g of 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole dissolved in 100 ml of anhydrous dioxane and add 0.3 g of 80% suspension of sodium hydride in oil and 15 minutes at a temperature of 25-30oWith the mix. To this solution was added 60 ml of anhydrous dioxane, which is the solution stirred for 15 minutes at a temperature of 25-30oC. the combined solution is heated 8 hours at the back of distillation, left overnight and evaporated in vacuum. To the residue add water and 20 ml of 1 N sodium hydroxide and spend

extraction of acetic ether. The organic phase is dried over sodium sulfate, the solvent is evaporated in vacuum and the residue chromatographic on silica gel with acetic ether/isopropanol (70: 30, to which is added a 2.5% 25% ammonia solution). Thus obtained base is dissolved in anhydrous ethanol, acidified with a solution of model HC1 in ether and planted diethyl ether. The residue is recrystallized from anhydrous ethanol and diethyl ether. Yield: 2.2 g (64% of theoretical.), melting point: 186-187oC.

Example 3: 3-{2-[2-(N,N-dimethylamino)ethyl]oxy-phenyl}-5-phenyl-1,2,4-oxadiazol:

< / BR>
a) Obtaining 2-[2-(N, N-dimethylamino)ethyloxy]-(nitrile benzoic acid):

of 23.8 g of 2-hydroxy (nitrile benzoic acid) mixed with 6.0 g of 80% suspension of sodium hydride in oil and 200 ml of dioxane for 30 minutes at 60oC. To this solution was added 100 ml of anhydrous dioxane, to which was added 28.8 g of the hydrochloride of 2-(N,N-dimethylamino)ethylchloride and 6.0 g of 80% suspension of sodium hydride in oil. This solution is stirred for 3 the TT and then the solvent is evaporated in vacuum. To the residue is added water and 1N sodium hydroxide and extracted with diethyl ether. The organic phase is dried over sodium sulfate, and the solvent is evaporated in vacuum. Output: 19,6 g (52% of theory.).

b) Obtain 2-[2-(N,N-dimethylamino)ethyloxy](amidoxime benzoic acid):

14 g of hydroxylamine hydrochloride are dissolved in 100 ml of water and rationed when shuffle add to 16.8 g hydrogencarbonate sodium. To this mixture add a solution 19,0 g 2-(N,N-dimethylamino)ethyloxy-(nitrile benzoic acid in 150 ml of ethanol and heated for 5 hours back by distillation. Then the ethanol is evaporated in vacuum and the residue is 2 times extracted with diethyl ether. The combined ether phases are dried over sodium sulfate and the solvent evaporated. The residue (16 g is equal to 72% of theory.) used in the cyclization reaction without further purification.

C) Obtaining 3-{2-[2-(N,N-dimethylamino)ethyl]oxy-phenyl}-5-phenyl-1,2,4-oxadiazole:

of 4.46 g of 2-(N, N-dimethylamino)ethyloxy-(amidoxime benzoic acid) and 5,44 g of methyl ester of benzoic acid are dissolved in 150 ml of absolute ethanol, add 2.3 g of sodium and heated 2 times in 11 minutes (with interval of 5 minutes) in a microwave power of 300 watts. The reaction mixture vyparivat in vacuum, to the residue dog is evaporated in vacuum, and the rest chromatographic on silica gel with acetic ether/isopropanol (70: 30, adding 2.5% of 25% ammonia solution). Thus obtained base is dissolved in anhydrous ethanol, acidified with a solution of model HC1 in ether and planted diethyl ether. The residue is recrystallized from anhydrous ethanol and diethyl ether. Yield: 2.5 g (36% of theory.). Melting point: 174-175oC.

Example 4: 5-{2-[2-(morpholino)ethyl]oxy-phenyl}-3-phenyl-1,2,4-oxadiazol

< / BR>
of 2.38 g of 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole dissolved in 100 ml of anhydrous dioxane and stirred with 0.3 g of 80% suspension of sodium hydride in oil for 15 minutes at 25-30oC. To this solution was added 75 ml of absolute dioxane, to which was added and 3.72 g of the hydrochloride of 2-(morpholino)ethylthiourea and 0.6 g of 80% suspension of sodium hydride in oil. This solution is stirred for 15 minutes at 25-30oC. These combined solutions are heated for 6 hours at 100oAnd finally the solvent is evaporated in vacuum. To the residue add water and 20 ml of 1N sodium hydroxide and extracted with acetic ether. The organic phase is dried over sodium sulfate, the solvent is distilled off under vacuum and the residue chromatographic on silica gel with acetic EF is dissolved in anhydrous ethanol, acidified with ethereal solution model HC1 and planted diethyl ether. The residue is recrystallized from anhydrous ethanol and diethyl ether. Yield: 1.9 g (49% of theory.). Melting point 194-195oC.

Example 5: 5-{ 2-[2-(4-methylpiperazin-1-yl)ethyl] oxy-phenyl}-3-phenyl-1,2,4-oxadiazol

< / BR>
a) Receiving 5-[2-(2-bromacil)hydroxy-phenyl]-3-phenyl-1,2,4-oxadiazole:

1.85 g of 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole dissolved in 80 ml of methyl ethyl ketone and add 5 ml of 1,2-dibromethane, 6 g of potassium carbonate and 0.1 g of potassium iodide. The mixture is heated for 12 hours at the back of distillation and after cooling the precipitate is filtered off. The organic phase is separated from the solvent in vacuo and chromatographic on silica gel first with toluene and then dichloromethane as eluent. Yield: 2.3 g (86% of theory.).

b) Obtaining 5-{2-[2-(4-methylpiperazin-1-yl)ethyl]oxy-phenyl}-3-phenyl-1,2,4-oxadiazole:

1,72 g of 5-[2-(2-bromacil)hydroxy-phenyl]-3-phenyl-1,2,4-oxadiazole dissolved in 50 ml of anhydrous dioxane and add 2 g of N-methylpiperazine. The solution is heated for 1 hour at the back of distillation and then the solvent is distilled off in vacuum. The remainder chromatographic on silica gel with dichloromethane/methanol (90:10). The base thus obtained, dissolve lizovyvatj of anhydrous ethanol and diethyl ether. Exit; 1.7 g (78% of theory.). Melting point: 251-253oC.

Example 6: 5-phenyl-3-[2-(4-methylpiperazin-1-yl)-phenyl]-1,2,4-oxadiazol

< / BR>
a) Obtaining 1-(2-cyanophenyl)piperazine:

(similar to G. E. Martin, R. J. Elgin, J. R. Mathiasen, C. C. Davis, J. M. Kesslick, J. Med. Chem. 32 (1989), 1052-1056)

b) Obtaining 1-(2-cyanophenyl)-4-methylpiperazine:

of 7.48 g of 1-(2-cyanophenyl)piperazine are dissolved in 30 ml of formaldehyde and 30 ml of formic acid is heated for 1 hour at the back of distillation. The solvent is evaporated in vacuum and the residue is dissolved in ether and add water. Alkalinized 20% sodium hydroxide solution, saturated with potassium carbonate and extracted with ether. The organic phase is dried over sodium sulfate and vacuum distilled off the solvent. For cleaning chromatographic on silica gel with acetic ether/isopropanol (70:30, adding 1% 25% ammonia solution). Yield: 6.7 g (83% of theory.).

C) Obtaining amidoximes carried out according to the method described in example 3b.

g) Receiving 1,2,4-oxadiazoles carried out according to the method described in example 3b.

Example 7: 3-phenyl-5-[2-(piperazine-1-yl)-phenyl]-1,2,4-oxadiazol

< / BR>
a) Obtaining 2-(piperazine-1-yl)-(methyl ester of benzoic acid):

(similar is-oxadiazole:

To 1,36 g amidoxime benzoic acid and of 2.34 g of maleinate 2-(piperazine-1-yl)-(ethyl ester of benzoic acid) is added to 0.92 g of sodium in 100 ml of anhydrous ethanol and 6 times in 30 minutes (with breaks for 5 minutes) heated in a microwave oven with a power of 350 watts. After cooling, the solvent is distilled off in vacuum. The residue is extracted with dichloromethane from water. The organic phase is dried over sodium sulfate and the solvent is distilled off in vacuum. The remainder chromatographic on silica gel with acetic ether/isopropanol (70:30 adding 5% 25% ammonia solution). Yield: 90 mg (3% of theoretical.). Melting point: 254-255oC.

Example 8: 5-{2-[2-(N,N-dimethylamino)ethyl]oxy-phenyl}-3-(4-hydroxyphenyl)-1,2,4-oxadiazol

< / BR>
a) Obtaining 2-[2-(N, N-dimethylamino)ethyl] oxy(methyl ester of benzoic acid):

15.2 g of methyl ester of salicylic acid dissolved in 200 ml of anhydrous acetonitrile, add 4.4 g of 60% suspension of sodium hydride in oil is added and stirred for 60 minutes at room temperature. To this solution was added 200 ml of absolute acetonitrile is added to 17.4 g of the hydrochloride of 2-(N,N-dimethylamino)ethylchloride and 5.2 g of 60% suspension of sodium hydride in oil. This solution is stirred for 60 minutes at Italy in vacuum. To the residue water is added and extracted with acetic ether. The organic phase is dried over sodium sulfate, the solvent is distilled off in vacuum and the residue chromatographic on silica gel with acetic ether/methanol (1:1). Obtain 14.6 g of a yellow oil (65% of theory. ).

b) Obtain 2-[2-(N,N-dimethylamino)ethyl]oxy-(benzoic acid):

4.4 g of 2-[2-(N,N-dimethylamino)ethyl]oxy(methyl ester of benzoic acid) is heated with 30 ml of 5N hydrochloric acid for 15 minutes in a microwave oven with a power of 300 watts. Then extracted with acetic ether, the aqueous phase is evaporated and recrystallized from acetonitrile/ether. Output: 4.2V g (86% of theory.)

C) Obtain 5-{2-[2-(N,N-dimethylamino)ethyl]oxy-phenyl}-3-(4-hydroxyphenyl)-1,2,4-oxadiazole;

of 2.45 g of 2-[2-(N, N-dimethylamino)ethyl] oxy-(benzoic acid), 1,91 g of the hydrochloride of N-ethyl-(N-dimethylaminopropyl)carbodiimide and catalytic amounts of hydroxybenzotriazole are dissolved in 50 ml of DMF. After 15 minutes add 1.52 g of 4-hydroxy(amidoxime benzoic acid) and heated for 15 minutes in a microwave oven at a power of 700 watts. The solvent is distilled off, the residue is dissolved in acetic ether, washed with water, dried over sodium sulfate and the solvent is distilled off in vacuum. The remainder of the filter isoC (decomp.).

Example 9: 5-{2-[(carboxamido)methyl]oxy-phenyl}-3-phenyl-1,2,4-oxadiazol

< / BR>
3.57 g of 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole dissolved in 70 ml of anhydrous DMF and stirred with 0.6 g of 60% suspension of sodium hydride in oil for 30 minutes at a temperature of 25-30oC. To this solution was added 1.4 g of amide 2-Chloroacetic acid and stirred for 2 hours at 100oC. then the solvent is distilled off in vacuum. To the residue add water and sucked off. The precipitate is boiled successively in methanol and ethyl ester of acetic acid. Output: 3/3 g (75% of theory.). Melting point: 249-251oC.

Example 10: 5-{2-[2-(carboxamido)ethyl]oxy-phenyl}-3-phenyl-1,2,4-oxadiazol

< / BR>
a) Obtaining 5-{2-[2-[1,3-dioxane-2-yl)ethyl]oxy-phenyl}-3-phenyl-1,2,4-oxadiazole:

4.1 g of 5-(2-hydroxyphenyl)-3-phenyl-1,2,4-oxadiazole dissolved in 60 ml of anhydrous DMF and add 0,688 g of 60% suspension of sodium hydride in oil. To this mixture of 3.15 g of 2-(2-bromacil)-1,3-dioxane and stirred for 4 hours at 100oC. After cooling, the solvent is distilled off in vacuo and to the residue water is added. It is extracted with acetic ether, the organic phase is dried over sodium sulfate and vacuum distilled off the solvent. About the CLASS="ptx2">

b) Obtain 5-{2-[2-(carboxyl)ethyl]oxy-phenyl}-3-phenyl-1,2,4-oxadiazole:

2.5 g 5-{2-[2-(1,3-dioxane-2-yl)ethyl]oxy-phenyl}-3-phenyl-1,2,4-oxadiazole dissolved in 50 ml of acetone and 0oTo add drops of a solution of chromium oxide (VI) in 30% sulfuric acid. Then for 20 hours stirred at 20-23oWith and added under cooling at 5oWith 25 ml of isopropanol. The mixture is introduced into a suspension of 100 ml dichloromethane and 100 ml of water and separate the organic phase. The aqueous phase is again extracted with dichloromethane and the combined organic solutions again with water. Dried over sodium sulfate, the solvent is distilled off in vacuum and chromatographic on silica gel with dichloromethane/ethyl ether acetic acid (97:3). The product is recrystallized from ethyl ester of acetic acid. Output: 0,23 g (11% of theory.). Melting point: 170-171oC.

C) Obtain 5-{ 2-[2-(carboxamido)ethyl]oxy-phenyl}-3-phenyl-1,2,4-oxadiazole:

0.8 g of 5-{2-[2-(carboxyl)ethyl]oxy-phenyl}-3-phenyl-1,2,4-oxadiazole dissolved in 40 ml of anhydrous dichloromethane and cooled tooC. To this solution add 2 ml of oxalicacid dissolved in 5 ml of anhydrous dichloromethane and stirred for 1.5 hours at 20oC. the Solvent is distilled in vacuumer, while the reaction volume will not become alkaline. Leave on for 14 hours, add water, separating the resulting precipitate and dichloromethane phase and the organic phase is dried over sodium sulfate. After removal of the solvent receive the remainder of 0.7, This residue chromatographic on silica gel with dichloromethane/methanol (98:2) and the product is recrystallized from acetic ester. Yield: 0.24 g (33% of theory.). Melting point: 137-138oC.

By analogy with the above-described method, and examples of the syntheses were obtained including the following compounds (see table.1 and 2).

It has been unexpectedly found that compounds corresponding to the invention exhibit an affinity for various receptors or activity on different types of receptors and exhibit a neuroprotective effect.

Experiments in vivo and in vitr showed that damage cells and stopping their operation occurring in the brain as a result of hypoglycaemia, hypoxia, anoxia, global or focal cerebral ischemia, traumatic brain injury, cerebral edema and increased intracranial pressure partly associated with increased synaptic activity and power in connection with the release of transmitters. Along with glutamate, histamine and St. especially calcium ions and sodium.

It is known that after systematic reception of glutamate is the destruction of neurons in the brain of mice (S. M. Rothman, T. W. Olney, Trends in Neurosciences, 10 (1987) 299). This result allows us to conclude that glutamate plays a role in neurodegenerative diseases (R. Schwarcz, B. Meldrum, The Zancet 11 (1985) 140). In addition, it is known that substances such as quisqualate acid, kainic acid, botanova acid, glutamic acid, N-methyl-D-aspartic acid (NMDA) and a-amino-3-hydroxy-5-methyl-4-isooxazolyl acid (AMPA) are exogenous, respectively, endogenous neurotoxins. Brain damage that can be induced by such substances, comparable with lesions that arise in connection with epilepsy and other neurodegenerative diseases such as Huntington's disease or Alzheimer's disease. Substances and ions, which inhibit the activity of glutamate receptors and associated with this receptor ion channel, such as competing and non-competing antagonists of excitatory amino acids, protects brain cells from hypoxic and ischemic damage. These results indicate that glutamate receptors play an important role in the transmission of isemi the technology at the neural cell patch-clamp method) (M. L. Mayer, L. Vyklicky, G. L. Westbrook, J. Physiol. 415 (1989) 329-350). Testing was performed at a concentration of test substance 100 μm (see table.3).

Evidence of affinity to the place of connection "Na+the channel site" were thus obtained, as described by G. W. Brown (J. Newrosci. 6 (1986) 2064).

Testing was conducted in a typical way, when the concentration of the test substance 10 μm (see table.4).

Cell damage during hypoglycaemia, hypoxia, anoxia and ischemia lead to a result of insufficient supply to low energy output, as, for example, glucose in neurons.

The influence of antagonists histamine receptors in violation absorption 2-deoxyglucose induced by hypoxia and hypoglycemia was studied in the rat "Hippocampus Slice" drugs (S. Shibata, S. Watanase, Neuroscience Letters 151 (1993) 138). Adding histamine is further exacerbated by the decrease in the absorption of 2-deoxyglucose induced ischemia. It has been shown that antagonists of the histamine H1 receptor improves the absorption of 2-deoxyglucose, lowering which induced ischemia, whereas antagonists histamine H2 receptor does not have influence. Protective effect of antagonists of the histamine H1 receptor can be eliminated with the help of histamine. E. ucirvine ischemia.

Excessive neural activity combined with a massive increase in neurotransmitters can lead to neural degeneracy in animal models of transient cerebral ischemia (A. Benveniste, H. Drejer, A. Schousboe, N. H. Diemer, J. Neurochem. 43 (1984) 1369). Neural activity can also be inhibited by substances that bind neurotransmitters with receptors such as 5-hydroxytryptamine (serotonin) (R. Andrade, R. A. Nicoll, Soc. Neurosci. Abstr. 11 (1985) 297). In addition, it has been shown that administration of 5-hydroxytryptamine agonists in animal models of occlusion of middle cerebral artery leads to the reduction of infarction area (J. H. M. Pren, C. Backhauss, C. Karkoutly, J. Nuglisch, B. Peruche, C. Rossberg, J. Krieglstein, Eur. J. Pharmacol. 203 (1991) 213).

As test systems for evidence of affinity to the following receptors have been studies on the binding of receptors, based on the following works: histamine H1 (H1) receptor (S. Dini al. Agents and Actions 33 (1991) 181); 5-hydroxytryptamine 1A (HT1A) receptor (M. D. Hall et al., J. Neurochem. 44 (1985) 1685); 5-hydroxytryptamine 2A (NTA) receptors (Leysen J. H. and al., Mol. Pharmacol. 21 (1982) 301). Testing was carried out typically at a concentration of test substance 10 M

Table 5 shows the magnitude of the braking on the above-mentioned institutions after transient focal ischemia. Takahashi and researcher. managed, for example, to prove when researching a potential ligand of the Sigma receptor in a model of transient focal ischemia reduction infarction space.

As a test system for the proof of the affinity of the compounds of the invention, the Sigma-receptor studies have been conducted linking of the receptor, according to (E. W. Karbon, K. Naper, M. J. Pontecorv Eur. J. Pharmacol. 193 (1991) 21). Testing was conducted in a typical way when the concentration of the test substance 10 M Values of inhibition are shown in table 6.

Evidence of neuroprotective action in vivo obtained on the model of stroke in rats. For this induce permanent focal cerebral ischemia in the operating occlusion of the Arteria cerebri media (MCAO) (relying on the work of A. Tamura, D. I. Graham, J. McCulloch, and G. M. Teasdale, J. Cereb. Blood Metab. 1 (1981) 53-60). Using 5-{2-[2-(N,N-dimethylamino)ethyl]oxy-phenyl}-3-phenyl-1,2,4-oxadiazole (example 2) has been clearly and significantly reduce the affected area.

The above results prove that the derivatives of oxadiazole General formula I can be used neurodegenerative diseases and ischemia of the brain of different origin. These include, napresne Huntington, Alzheimer's disease, hypotension, heart attack, increased intracranial pressure, ischemic and associated with hemorrhage palsy, global cerebral ischemia, cardiac arrest, diabetic polyneuropathy, tinnitus, perinatal asphyxia, psychosis, schizophrenia, depression and Parkinson's disease.

Compounds of General formula (I) is used alone or in combination with other compounds conforming to the invention, optionally in combination with other farmacologicos active substances. Appropriate forms for application are, for example, tablets, capsules, suppositories and solutions, especially solutions for injection ('s.c. i.v., i.m.) and infusion-syrups, emulsions or dispersible powders. Moreover, the share of the pharmaceutically active substance is from 0.1 to 90 wt.%, preferably from 0.5 to 50 wt.% of the total composition, i.e. in amounts which are sufficient to achieve the dosage intervals below. Appropriate tablets receive, for example, by mixing one or more active substances with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, raspylyeniya and gelatin, lubricating means such as magnesium stearate or talc and/or tools to achieve the effect of prolongation such as carboxymethylcellulose, acetated cellulose or polyvinyl acetate. Tablets can also consist of many layers.

Accordingly, it is possible to obtain tablets with the coating of the cores obtained analogously to the tablets with substances that are usually used for coating tablets such as kollidon or shellac, gum Arabic, talc, titanium dioxide or sugar. To achieve the effect of prolongation or to avoid incompatibility of the core may also consist of several layers. Similarly, for the effect of prolongation can serve as a shell bean, consisting of several layers, and use the same excipients, which are mentioned above and used for tablets.

Syrups active compounds, if necessary combination of active substances, relevant to the invention may contain sweeteners such as saccharine, cyclamate, glycerol or sugar, as well as tools that enhance the taste, such as aromatic substances such as vanillin or orange extract. In addition, they may contain auxiliary substances for the treatment the condensation products of fatty alcohols with ethylene oxide, or protective substances such as p-hydroxybenzoate.

Injection and infusion solutions prepared in the usual way, such as adding isononanol, preserving drugs such as p-hydroxybenzoates, or stabilizers such as alkali metal salts with ethylenediaminetetraacetic acid, optionally using emulsifying means and/or dispersing means, and using water as a diluent, if necessary, organic solvents can be used as intermediaries for the dissolution or auxiliary solvents, and fill the injection bottles or ampoules or infusion bottles.

It is possible to produce a capsule containing one or several active substances, where necessary, the combination of active substances, with the active substances are mixed with inert carriers such as lactose or sorbitol, and sealed in a gelatin capsule.

Suitable candle can, for example, be manufactured when mixing with established media such as neutral fats or polyethylene glycol, and optionally their derivatives. As auxiliary substances may be mentioned, oils), vegetable oils (such as peanut butter, Kungaeva oil), mono - or polyfunctional alcohols (e.g. ethanol, glycerol), substance-media such as the grinding of rocks (for example, kaolin, alumina, talc, chalk), grinding of synthetic inorganic materials (highly disperse silicic acid and silicates), sugars (cane, milk or grape sugar), emulsifying means (for example, lignin, spent sulfite liquor, methylcellulose, starch and polyvinylpyrrolidone) and additives to improve processing (for example, magnesium stearate, talc, stearic acid and acrylourethane).

The application is carried out in the usual way, preferably by parenteral, especially intravenous infusion.

In the case of oral administration, tablets can, of course, contain, along with the aforementioned substances-carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with other substances, fillers such as starch, preferably potato starch, gelatin and the like. In addition, can be shared tools to improve processing in pelletizing such as stearate vspomogatelny substances can be added taste enhancers or colorants.

In the case of parenteral use use solutions of the active ingredients with suitable liquid materials-carriers.

Dosing with intravenous administration is from 1 to 1000 mg per hour, preferably from 5 to 500 mg per hour. However, if necessary it is possible deviation from these quantities, depending on body weight, respectively, form of application, the individual susceptibility to the drug, type of dosage form and time, respectively, of the interval between meals. Thus, in some cases, it is sufficient application in fewer than the minimum amount, while in other cases it is necessary to exceed the upper limit. In the case of the use of large quantities is recommended to carry out a larger number of doses per day.

In addition, compounds with the General formula (I), respectively, and their salts with acids, can be combined with active ingredients other series.

The following examples illustrate the invention, but are not limited to:

Examples of pharmaceutical forms

A) Tablet - a tablet

Active ingredient: 100 mg

Milk sugar - 140 mg

To the s active ingredient, milk sugar and part of the corn starch are mixed together. The mixture is sieved, and then moisturize with a solution of pyrrolidone in water, knead, granularit wet and dried. The granulate, the remainder of the corn starch and the magnesium stearate is sifted and mixed together. From the mixture is pressed to tablets of suitable weight and shape.

B) Tablet - a tablet

Active substance - 80 mg

Milk sugar - 55 mg

Corn starch - 190 mg

Microcrystalline cellulose 35 mg

Polyvinylpyrrolidone 15 mg

The sodium carboxymethyl starch - 23 mg

Stearate of marnia - 2 mg - 400 mg

Pulverized active ingredient, part corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed with each other, the mixture is sieved and with the remnants of starch and water is processed into a granulate which is dried and sieved. To this add natrocarbonatite starch and magnesium stearate are mixed and the mixture is pressed to tablets of suitable size.

C) Ampoule solutions

Active ingredient: 50 mg

Sodium chloride 50 mg

Aqua for injection with 5 ml

The active substance is dissolved when self is the solution is filtered in the absence of pyrogens, and the filtrate under aseptic conditions is poured into ampoules, which are then sterilized and zapravljajut. Capsules contain 5 mg, 25 mg and 50 mg of active substance.

1. Derivatives oxadiazole General formula (I)

< / BR>
in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen;

Z denotes a radical of the formula

< / BR>
< / BR>
< / BR>
in which S1and S2mean radicals of the formula

< / BR>
in which V denotes oxygen, sulfur;

B and D indicate the same or different C1-C10-alkylene bridges, which can be singly or multiply substituted by such substituents as = O, 1,3-dioxolane or 1,3-dioxane;

S1and S2mean radicals of the formula

< / BR>
in which V and V have the above meanings;

and U mean WITH3-C6-cycloalkyl group or6-C10-aryl group, which respectively may be substituted one or more times WITH1-C4-alkyl, -NR5R6;

S1and S2mean radicals of the formula

< / BR>
in which b and D have the above meanings and both groups D and both radical R4may be the same or different;

S1and S2mean radicals of the formula

< / BR>

S1and S2mean radicals of the formula

< / BR>
moreover, D has the above meanings and both groups D and both radical R4may be the same or different;

S1and S2mean radicals of the formula

< / BR>
in which E is NR7(n, m= 2 or 3 and n+m>2);

S1and S2mean radicals of the formula

< / BR>
in which V and D have the above values and W stands for a radical of the formula

< / BR>
< / BR>
optionally substituted C1-C4-alkyl, in which E is NR7and n, m, l= 0, 1, or 2, or W means is attached through the carbon atom 5, 6-membered heterocycle containing one or more heteroatoms from the series nitrogen, oxygen, which may optionally be substituted by benzyl or1-C4-alkyl;

S1and S2mean radicals of the formula

-V-W,

in which V and W have the above meanings;

S1and S2mean radicals of the formula

< / BR>
which has the above meanings and both Deputy R7may be the same or different;

S1and S2mean radicals of the formula

< / BR>
in which the substituent R7may be the same or different;
S3and S4mean radicals of the formula

< / BR>
in which b and D have the above meanings and both groups D and both Deputy R4can be identical or different;

S3and S4mean radicals of the formula

< / BR>
in which V and D have the above meanings;

S3and S4mean radicals of the formula

< / BR>
in which D has the above meanings and both groups D and both Deputy R4can be identical or different;

Q means a condensed, one unsaturated 5-membered cycle which may contain one or more heteroatoms from the series oxygen;

S5means a radical of the formula

-D-R4,

in which D has the above meanings;

R1means phenyl radical, which is optionally substituted directly or through alkylene bridges with the number of carbon atoms from 1 to 4 once, twice or three times by one or more substituents from the series halogen, C1-C4-alkyl, -CF3, -NR5R6, -NO2, -OR7or Deputy formula

< / BR>
where, V or D have the above meanings;

R1means phenyl, z is o phenyl, which is replaced by the Deputy formula

< / BR>
in which V and D have the above meanings;

R1means phenyl-C1-C6-alkyl, preferably phenyl-C1-C4-alkyl, phenyl-C2-C6alkenyl;

R1means a radical of the formula M-, and M is a 5,6-membered heterocycle attached via a C - or N-atom, which contains one heteroatom from the series nitrogen, oxygen or sulfur;

R1means3-C7-cycloalkenyl radical,

R1means, optionally substituted C1-C4-alkyl, preferably the stands, norbornane, norbornene radical, preferably an adamantane or noradsanta radicals;

R1means optionally substituted radical of the formula

< / BR>
R2and R3denote identical or different radicals such as hydrogen, halogen, -OR7WITH1-C10-alkyl;

R4means amine of the formula-NR5R6;

R4means N-oxide of the formula

< / BR>
R5means hydrogen, C1-C10-alkyl;

R6means hydrogen, C1-C10-alkyl;

R6means6-C10-aryl, preferably phenyl;

R7OZNA is their diastereomers or mixtures thereof, and also, if appropriate, their pharmaceutically safe salts with acids.

2. Derivatives oxadiazole General formula (I) according to p. 1, in which X and Y denote oxygen or nitrogen, and X and Y cannot be both at the same time oxygen or nitrogen,

Z denotes a radical of the formula

< / BR>
< / BR>
< / BR>
in which S1and S2mean radicals of the formula

< / BR>
in which V denotes oxygen, sulfur, and D mean the same or different WITH1-C4-alkylene bridges, which can be substituted with such substituents as = O;

S1and S2mean radicals of the formula

< / BR>
in which V and V have the above significance, a U mean WITH3-C6-cycloalkyl or6-C10-aryl group which may be substituted by such substituents as1-C4-alkyl, -NR5R6;

S1and S2mean radicals of the formula

< / BR>
in which b and D have the above meanings and both groups D and both the radical R4can be identical or different;

S1and S2mean radicals of the formula

< / BR>
in which V and D have the above meanings;

S1and S2mean radicals of formula

< / BR>
in which D has the above meaning, and both groups D and both the radical R4can be identical or different;

S1and S2mean radicals of the formula

< / BR>
in which E is NR7(n, m= 2 or 3 and n+m>2);

S1and S2mean radicals of the formula

< / BR>
in which V and D have the above values, a W stands for a radical of the formula

< / BR>
< / BR>
if necessary, replaced WITH1-C4-alkyl, in which E is NR7, n, m, l= 0, 1, or 2, or W means attached through a carbon atom 5,6-membered heterocycle containing one or more heteroatoms from the series nitrogen, oxygen, which optionally may be substituted by benzyl or1-C4-alkyl;

S1and S2mean radicals of the formula

-V-W,

in which V and W have the above meanings;

S1and S2mean radicals of the formula

< / BR>
which has the above meaning and the substituents R7can be identical or different;

S1and S2mean radicals of the formula

< / BR>
in which the substituents R7can be identical or different;

S3and S4oznachaet radicals of the formula

< / BR>
in which b and D have the above meanings and both groups D and both Deputy R4can be identical or different;

S3and S4mean radicals of the formula

< / BR>
in which V and D have the above meanings;

S3and S4mean radicals of the formula

< / BR>
in which D has the above meanings and both groups D and both Deputy R4may be the same or different;

Q means a condensed, one unsaturated 5-membered heterocycle containing one or more heteroatoms from the series oxygen;

S5means a radical of the formula

-D-R4,

in which D has the above meanings;

R1means phenyl radical, which is optionally substituted one or more times by one or more substituents, such as halogen, preferably fluorine, chlorine or bromine, WITH1-C4is an alkyl radical, -CF3, -NR5R6, -NO2, -OR7or one radical of the formula

< / BR>
where, V and D have the above meanings;

R1means phenyl radical which can be substituted by the Deputy formula

< / BR>
where, V and U of July

< / BR>
in which V and D have the above meanings;

R1means phenyl-C1-C4-alkyl, preferably benzyl, phenyl-C2-C4alkenyl;

R1means a radical of the formula M-, and M is 5 or 6-membered heterocycle attached via a C - or N-atom, which contains one heteroatom from the series nitrogen, oxygen or sulfur;

R1means3-C7-cycloalkyl, preferably cyclopropyl or cyclopentyl;

R1means, optionally substituted C1-C4-alkyl, preferably the stands, norbornane-norbornene radical, preferably an adamantane or noradsanta radicals;

R1means, if necessary, one or more times substituted by halogen, hydroxy-group or a methoxy group, the radical of the formula

< / BR>
R2and R3denote identical or different radicals, such as hydrogen, the hydroxy-group, halogen, preferably fluorine, chlorine or bromine, C1-C4-alkyloxy, preferably methoxypropan,1-C4-alkyl;

R4means-NR5R6,

R4means N-oxide with the formula

< / BR>
R5means hydrogen, C1-C4-alkyl;

>means hydrogen, C1-C4-alkyl,

if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and mixtures thereof, and, if appropriate, their pharmaceutically safe salts with acids.

3. Derivatives oxadiazole General formula (I) according to p. 1, in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen; Z denotes a radical of the formula

< / BR>
< / BR>
in which S1means a radical of the formula

< / BR>
in which V denotes oxygen, sulfur, and b and D indicate the same or different WITH1-C4-alkylene bridges, which can be substituted with such substituents as = O;

S1means a radical of the formula

< / BR>
in which V and D have the above meanings;

S1means a radical of the formula

< / BR>
in which V has the above meanings and U mean WITH3-C6-cycloalkyl or phenyl group which may be substituted WITH1-C4-alkyl;

S1means a radical of the formula

< / BR>
in which b and D have the above meanings and both groups D and both Deputy R4the same or different;

S1means a radical of the formula

and various;

S1means a radical of the formula

< / BR>
in which E is NR7(n, m= 2 or 3 and n+m>2);

S1means a radical of the formula

< / BR>
in which V and D have the above meanings, and W stands for a radical of the formula

< / BR>
optionally substituted C1-C4-alkyl, in which E is NR7, n, m, l= 0, 1, or 2, or W means attached through a carbon atom a 5 - or 6-membered heterocycle which contains one or more heteroatoms from the series nitrogen, oxygen and which is optionally substituted by benzyl or C1-C4-alkyl;

S1means a radical of the formula

-V-W,

in which V and W have the above meanings;

S2means a radical of the formula

< / BR>
in which V and D have the above meanings;

S4means a radical of the formula

< / BR>
in which V and D have the above meanings;

Q means a condensed, one unsaturated 5-membered heterocycle containing one or more heteroatoms from the series oxygen;

S5means a radical of the formula

-D-R4,

in which D has the above meanings;

R1means benzyl or phenyl radical, the latter can be the 1-C4-alkyl, -CF3, -NMe2That is been certified with qi net2, -NO2or-or SIG7;

R1means phenyl radical substituted by a radical of the formula

< / BR>
in which V denotes oxygen and D means WITH1-C4is an alkyl bridge;

R1means 5 - or 6-membered heterocycle attached via a carbon atom or nitrogen, which contains one heteroatom from the series nitrogen, oxygen or sulfur;

R1means cyclopropyl, cyclopentyl or cyclohexyl;

R1means norbornane, norbornene, adamantane or noradsanta optionally substituted methyl group;

R1means a radical of the formula

< / BR>
R1means-CH= CH-phenyl;

R2means hydrogen, fluorine, chlorine, bromine, C1-C4-alkyloxy,1-C4-alkyl or hydroxy-group;

R3means hydrogen;

R4means-NR5R6;

R4means N-oxide of the formula

< / BR>
R5means hydrogen, C1-C3-alkyl;

R6means hydrogen, C1-C3-alkyl, benzyl or phenyl;

R7means hydrogen, C1-C4-alkyl,

if necessary, in the form of their racemates, their enantiomers, in the form of Stereolab ilenia General formula (I), according to p. 1, in which X and Y denote oxygen or nitrogen, and X and Y cannot be both at the same time oxygen or nitrogen; Z denotes a radical of the formula

< / BR>
< / BR>
in which S1means a radical of the formula

< / BR>
in which V denotes oxygen, sulfur, means-CH2and D denotes one of the groups-CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2- (CH3)N-, -CH2-CO-, -CH2-CH2-CO-;

S1means a radical of the formula

< / BR>
in which V and D have the above meanings;

S1means radicals piperazine-1-yl, 4-methylpiperazin-1-yl;

S1means a radical of the formula

< / BR>
in which V and D have the above values, a W stands for a radical of the formula

< / BR>
optionally substituted C1-C4is an alkyl group or

W means attached through a carbon atom a 5 - or 6-membered heterocycle containing nitrogen, which is optionally substituted by benzyl or1-C4-alkyl;

S1means a radical of the formula

-V-W,

in which V and W have the above meanings;

S2means a radical of the formula

-(CH2)a 0.1-O-(CH2)2,3-R4,

Q oznachaet islord;

S5means a radical of the formula

-D-R4,

in which D has the above meanings;

R1means radicals, cyclopropyl, cyclopentyl, benzyl or phenyl, the latter may be singly or multiply substituted by one or more substituents, such as fluorine, chlorine, bromine, C1-C4-alkyl, -CF3, -NMe2, -NO2or7;

R1means phenyl substituted by a radical of the formula

-O-(CH2)2,3-R4,

R1means furan, thiophene, pyridine or pyrrole;

R1means norbornane, norbornene, adamantane or noradsanta;

R1means-CH= CH-phenyl;

R2means hydrogen, fluorine, chlorine, bromine, C1-C4-alkyloxy,1-C4-alkyl or hydroxy-group;

R3means hydrogen;

R4means-NR5R6or N-oxide of the formula

< / BR>
R5means hydrogen, C1-C3-alkyl;

R6means hydrogen, C1-C3-alkyl, benzyl or phenyl;

R7means hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,

if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and mixtures thereof, as well as the s (I), according to p. 1, in which X and Y denote the nitrogen or oxygen, and X and Y cannot both be oxygen or nitrogen, Z denotes a radical of the formula

< / BR>
in which S1means a radical of the formula

< / BR>
in which V denotes oxygen, sulfur, means-CH2and D denotes one of the groups-CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2- (CH3)N-, -CH2-CO-, -CH2-CH2-CO-;

S1means a radical of the formula

< / BR>
in which V and D have the above meanings;

S1means radicals piperazine-1-yl, 4-methylpiperazin-1-yl;

S1means a radical of the formula

< / BR>
in which V and D have the above values and W stands for a radical with the formula

< / BR>
optionally substituted C1-C4is an alkyl group, or W means attached through a carbon atom a 5 - or 6-membered heterocycle containing nitrogen, which may be optionally substituted benzyl or1-C4-alkyl;

S1means a radical of the formula

-V-W,

in which V and W have the above meanings;

Q means a condensed, one unsaturated 5-membered heterocycle that contains one geteroyadernye value;

R1means radicals cyclopropyl, cyclopentyl or phenyl, and the phenyl cycle can be singly or multiply substituted by one or more substituents, such as fluorine, chlorine, bromine, C1-C4is an alkyl radical, -CF3, -NMe2, -NO2or7;

R1means furan, thiophene, pyridine or pyrrole;

R1means norbornane, norbornene, adamantane or noradsanta;

R1means-CH= CH-phenyl;

R2means hydrogen, fluorine, chlorine, bromine, C1-C4-alkyloxy,1-C4-alkyl or hydroxy-group;

R3means hydrogen;

R4means-NR5R6or N-oxide of the formula

< / BR>
R5means hydrogen, C1-C3-alkyl;

R6means hydrogen, C1-C3-alkyl, benzyl or phenyl;

R7means hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl,

if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and mixtures thereof, and, if appropriate, their pharmaceutically safe salts with acids.

6. Compounds of General formula (I) according to p. 1, in which X and Y represents oxygen or nitrogen, and X and Y cannot be abcal formula

< / BR>
in which V denotes oxygen, sulfur, and D denotes one of the groups-CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2- (CH3)N-, -CH2-CO-, -CH2-CH2-CO-;

S1means radicals piperazine-1-yl, 4-methylpiperazin-1-yl;

S1means a radical of the formula

< / BR>
in which V and D have the above values and W stands for a radical of the formula

< / BR>
or W means attached through a carbon atom a 5 - or 6-membered heterocycle containing nitrogen, which is optionally substituted methyl group;

S1means a radical of the formula

-V-W,

in which V and W have the above meanings;

Q means a condensed, one unsaturated 5-membered heterocycle that contains one heteroatom from the series oxygen;

S5means a radical of the formula

-D-R4,

in which D has the above meanings;

R1means phenyl radical, which is optionally substituted one or more times by one or more substituents such as fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CF3or7;

R1means furan, thiophene or pyridine;

R4means-NR5R6or N-oxide with the formula

< / BR>
R5means hydrogen, methyl, ethyl, n-propyl, isopropyl;

R6means hydrogen, methyl, ethyl, n-propyl, isopropyl, benzyl or phenyl;

R7means hydrogen, methyl or ethyl,

if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and mixtures thereof, if appropriate, their pharmaceutically safe salts with acids.

7. Compounds of General formula (I) according to p. 1, in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen; Z denotes a radical of the formula

< / BR>
in which S1means a radical of the formula

< / BR>
in which V denotes oxygen and D represents one of the groups-CH2-, -CH2-CH2-, -CH2- (CH3)N-, -CH2-CH2-CO-;

S1means radicals of N-piperazinil;

S1means a radical of the formula

< / BR>
in which V and D have the above values, a W stands for a radical of the formula

< / BR>
or W means attached through a carbon atom a 5 - or 6-membered heterocycle containing nitrogen, optionally substituted methyl group;

S1means a radical of the formula

S5means a radical of the formula

-D-R4,

in which D has the above meanings;

R1means phenyl radical which can be substituted one or more times by one or more substituents, such as fluorine, chlorine, bromine, methyl radical, -CF3the hydroxy-group, methoxypropyl or atelocerata;

R1means furan, thiophene or pyridine;

R2means hydrogen, fluorine, chlorine or methyl;

R3means hydrogen;

R4means-NR5R6;

R5means hydrogen, methyl, ethyl, n-propyl, isopropyl;

R6means hydrogen, methyl, ethyl, n-propyl, isopropyl, benzyl or phenyl,

if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers and mixtures thereof, if appropriate, their pharmaceutically safe salts with acids.

8. Compounds of General formula (I) according to p. 1, in which X and Y denote oxygen or nitrogen, and X and Y cannot both be oxygen or nitrogen; Z denotes a radical of the formula

< / BR>
in which S1means one of the radicals-O-CH2-CH2-R4, -O-CH2-C(CH3)H-R4, -OSUB>2-W or-O-W, in which W means attached through a carbon atom a 5 - or 6-membered heterocycle comprising the nitrogen atom, which is optionally substituted methyl group;

Q means a condensed, one 5-membered heterocycle containing, as heteroatom oxygen;

S5means a radical of the formula-CH-R4;

R1means phenyl radical which can be substituted one or more times by one or more substituents, such as fluorine, chlorine, bromine, methyl, -CF3the hydroxy-group, methoxypropyl or atelocerata;

R1means thiophene;

R2means hydrogen, fluorine, chlorine or methyl;

R3means hydrogen;

R4means-NR5R6;

R5means hydrogen, methyl, ethyl, isopropyl;

R6means hydrogen, methyl, ethyl, isopropyl, benzyl or phenyl,

if necessary, in the form of their racemates, their enantiomers, in the form of their diastereomers or mixtures thereof, if appropriate, their pharmaceutically safe salts with acids.

 

Same patents:

The invention relates to compounds of formula (I) R4-A-CH(R3)N(R2)B-R1where a is optionally substituted phenyl group, provided that the group-CH(R3)N(R2)B-R1and-OR4are in the 1,2-position relative to each other on the carbon atoms of the ring, and provided that the atom of the ring, in anthopology towards OR4- joined the group (and therefore in the 3-position relative to the-CHR3NR2-linking group) is unsubstituted; In - pyridyl or pyridazinyl; R1located on the ring In the 1,3 - or 1,4-position relative to the-CH(R3)N(R2)-linking group and represents carboxy, carbarnoyl or tetrazolyl, or R1represents a group of formula СОNRaRa1where Rais hydrogen or C1-6alkyl, and Ra1- C1-6alkyl, or R1represents a group of formula CONHSO2Rbwhere Rb- C1-6alkyl, trifluoromethyl, or a 5-membered heteroaryl selected from isooxazolyl and thiadiazolyl, optionally substituted C1-6the alkyl or C1-4alkanolamines; R2- C1-6alkyl; R3is hydrogen; R4- C1-4alkyl, C3-7cycloalkyl,1-3alkyl or their pharmaceutically acceptable salt or in vivo hydrolyzable esters

The invention relates to a new method of obtaining isoxazolidinone the compounds of formula (II) in which R represents an optionally substituted aromatic hydrocarbon group or its salt, by reacting the compounds of formula (1) or its salt with the compound of the formula (2) in the presence of an inorganic base in an aqueous solvent with getting aspartates the compounds of formula (3), which interacts with acetic anhydride using dimethylaminopyridine as a catalyst in the presence of base followed by heating for decarboxylation to obtain the compounds of formula (4), to which is added p-toluensulfonate acid to obtain oxazolidinedione derivative of the formula (5)which then restores the tetrahydrofuran in the presence of NaBH4and methanol to obtain oxazolidinones the compounds of formula (6) and its further interaction with methylchloride in the presence of triethylamine to obtain methanesulfonate derivative of the formula (7), which interacts with the compound of the formula (8) in the presence of potassium carbonate to obtain benzylidene derivative of the formula (9), which is further restored in an atmosphere of hydrogen for the floor is warping with obtaining the compounds of formula (11)

The invention relates to new compounds of the formula (I) or their salts, where X, Y independently is hydrogen, halogen; Z is oxygen; Q is chosen among the Q1-Q9described in the claims and containing heterocycles with nitrogen, and sulfur; Ar is pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl, or pyridyl, pyrimidyl, pyridazinyl, triazolyl, thiazolyl, isothiazole or phenyl substituted with up to five substituents, when Q - Q3or Q6substituted phenyl is excluded

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

The invention relates to derivatives of N-sulfanilimide formula I, where R1and R2denote hydrogen, halogen, C1-4alkyl, C1-4alkoxycarbonyl or phenyl which can be substituted one to three times, equal or different residues from the group comprising halogen, C1-4alkyl, trifluoromethyl; R3- halogen, cyano, trifluoromethyl; R4- 4-isoxazolyl, pyrazolyl, which may be substituted with halogen, C1-4the alkyl, amino group, cycloalkyl, as well as their acid-salt additive

The invention relates to new derivatives of 4.1-benzoxazepin-2-she is of the formula (I), where R1lower alkyl, substituted by at least one optionally substituted hydroxyl group, R2and R3independently of one another is hydrogen or phenyl, which is substituted by 1-3 substituents selected from the group consisting of lower C1-C4alkoxygroup; X is a bond, methylene group or a linking group with a chain length of 1-7 atoms, selected from the group consisting of -(CH2)m-E-(CHR6)n-, where m and n = 1 or 2 independently from each other: E-bond or an oxygen atom, -NR5-, -CONR7-, where R5-methylsulphonyl, R6and R7independently of one another(i) hydrogen, (ii) lower alkyl, which is not substituted or substituted by substituents selected from the group consisting of piperidine, indolyl, possibly esterified carboxypropyl, (iii) benzyl, Y is optionally substituted carbarnoyl and/or the substituents on the N atom of carbamoyl, taken together, form a ring which may be substituted, or tetrazolyl, or piperidine, and the ring And is substituted by 1-3 substituents selected from the group consisting of atoms of Halogens or their salts

The invention relates to arylalkylamines formula I, where In - unsubstituted pyridyl, pyrazinyl, isoxazolyl or thienyl; Q - CH2; X - CH2or S; R1and R2each - H; and R3- OR5; R4OA; R5- Or cycloalkyl with 4-6 C atoms; And the alkyl with 1-6 C-atoms, and their physiologically acceptable salts

The invention relates to the use as a medicinal substance medications for the treatment of diseases associated with impaired venous function and/or inflammatory edema tricyclic derivatives of 1,4-dihydro-1,4-dioxo-1H-naphthalene and its new compounds of General formula I, where a is either a sulfur atom, oxygen or the radical R3N, where R3is a hydrogen atom, a C1-C5-alkyl; R1is either1-C5-alkyl, or phenyl ring, unsubstituted or substituted by one or more groups selected from methyl, methoxy, fluorine, chlorine, or 5-6-membered heteroaromatic ring having one or more heteroatoms selected from oxygen, sulfur, nitrogen, unsubstituted or substituted group selected from chlorine, bromine, nitro, amino, acetamido, acetoxymethyl, methyl, phenyl; R2is a hydrogen atom, halogen, C1-C5-alkyl, hydroxy, and methoxy; and pharmaceutically acceptable salts

The invention relates to a derivative of piperazine and piperidine derivatives of General formula (a) where And denotes a heterocyclic group with 5-7 atoms in the ring containing 1-2 heteroatoms from the group O, N and S; R1denotes hydrogen or fluorine; R2denotes oxoprop or1-4alkyl and p = 0 or 1; Z represents carbon or nitrogen, and the dotted line represents a simple bond when Z is nitrogen, and simple or double bond when Z is carbon; R3and R4independently of one another denote hydrogen or C1-4alkyl; n = 1 or 2; R5stands WITH1-4alkoxy, C1-4alkyl, halogen or hydroxy, and q = 0 or 1; Y represents phenyl, substituted by 1-2 substituents from the group of hydroxy, halogen, C1-4alkoxy, cyano, aminocarbonyl, di-C1-4alkylamino-carbonyl; furyl or thienyl and their salts

The invention relates to the derivatives of thiophene of the General formula I, in which R1is the formula A1- X1- R3; R2is perhaps the formula A2- X2- R4; ring b is 4-10-membered nitrogen-containing cycloalkyl ring or 5 - or 6-membered nitrogen-containing unsaturated heterocycle; Ar represents an aryl ring or heteroaryl ring; A1, A2and A3may be the same or different and each represents a bond or lower alkylenes group; X1and X2may be the same or different and each represents a bond or a formula-O-, -S-; R3and R4may be the same or different, and each represents a hydrogen atom, cyclic aminogroup or a lower alkyl group, aryl group or aracelio group, or its pharmaceutically acceptable salt

The invention relates to new chemical compound is 2-(N-morpholin)-4-methylpyridine, which can be used as inhibitors of acid corrosion of steel by acid treatment of wells or refineries

The invention relates to derivatives of 5-phenyl-3-(piperidine-4-yl)-1,3,4-oxadiazol-2(MN)-it General formula I, in which R1is a group (C1-C4)alkyl or the group (C3-C7)cycloalkenyl; X1is a hydrogen atom or halogen or the group (C1-C4)alkoxy or or1and X1together, the group of the formula-och2O-, -O(CH2)2-; -O(CH2)2O - or-O(CH2)3O-; X2is a hydrogen atom or amino group; X3is a hydrogen atom or halogen; R2is a hydrogen atom or a possibly substituted group (C1-C6)alkyl, or a phenyl group(C1-C4)alkyl which may be substituted on the phenyl ring, or a phenyl group(C2-C3)alkenyl, or group of phenoxy(C2-C4)alkyl or cyclo(C3-C7)alkylaryl, or group of 2,3-dihydro-1H-inden-1-yl or 2,3-dihydro-1H-inden-2-yl, or gruppa General formula -(CH2)nFROM a-Z, in which n = 1 to 6, a Z - group piperidine-1-yl or 4-(dimethylamino)piperidine-1-yl

The invention relates to new isoxazol derivative of General formula I, where R1denotes optionally substituted C6-C14airgroup or 5-6-membered heterocyclic group containing one heteroatom selected from nitrogen, oxygen, sulfur; R2denotes a hydrogen atom, halogen atom, optionally substituted C1-C6alkyl group, a C2-C6alkenylphenol group2-C6alkylamino group3-C10cycloalkyl group3-C10cycloalkenyl group, cyano, carboxitherapy,1-C7alkanoglu,2-C7alkoxycarbonyl group or optionally substituted carbamoyl; R3denotes optionally substituted by an amino group or a saturated 5-6-membered heterocyclic group containing a nitrogen atom; X represents an oxygen atom or a sulfur atom; n denotes an integer from 2 to 6, and their pharmaceutically acceptable salts

The invention relates to new chemical compounds, in particular derivatives (1,2,3-triazolyl)-1,2,5-oxadiazole General formula I, where R = NH2or< / BR>
and, if R1= N, R2lowest hydroxyalkyl, or, if R1- lower alkyl, lower hydroxyalkyl, aryl, R2= N, the lower hydroxyalkyl or a radical of General formula-C(O)R3where R3= HE, NH2, lower alkyl or lower alkoxyl, potentiating NO-dependent activation of the soluble form of guanylate cyclase (RGC)

The invention relates to a new derivative of bisexuality and its pharmaceutically acceptable salts, are useful as pharmaceuticals, in particular as a hypoglycemic drugs (drugs that increase insulin sensitivity), and containing pharmaceutical compositions
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