Derivatives arylsulfonamides, mixtures of isomers, or individual isomers and their physiologically tolerated additive salts with bases, and a pharmaceutical composition having antidromically activity

 

(57) Abstract:

Usage: in the pharmaceutical industry. The essence of the invention: derivatives of arylsulfonamides formula I, where R1- benzyl, thienyl, chloranil, tetramethylene, pentamethylene, phenyl, possibly substituted by halogen atom, nitro, stands, metaxylem or trifluoromethyl, or disubstituted by chlorine atoms or metaxylem, R2is hydrogen or methyl, R3pyridyl, R4and R5is hydrogen or together denote a carbon-carbon bond, R6is hydroxyl or methoxyl, A group of formula 2-4, where R7and R8is hydrogen or together denote a methylene or ethylene, X Is N-methylaminopropyl or sulfur atom, and the group CHR7associated with a group NR2, B is a carbon-carbon bond or unbranched alkylene with 2-4 carbon atoms, mixtures of isomers, individual isomers and their physiologically tolerated additive salts with bases, if R6means a hydroxyl and a pharmaceutical composition having antidromically activity, containing an effective amount of the compounds of formula I, where R2-the hydrogen atom at the specified values of R1, R3, R4, R5, R6, R7, R8, A B and X, P the new derivative arylsulfonamides, having, in particular, valuable pharmacological properties, more particularly to a derivative of arylsulfonamides General formula (I)

< / BR>
where R1benzyl, thienyl, chloranil, tetramethylene pentamethylbenzyl, phenyl, unsubstituted or monosubstituted by a halogen atom, a nitro-group, stands, metaxylem or trifluoromethyl, phenyl, disubstituted by chlorine atoms or methoxypropane,

R2a hydrogen atom, methyl,

R3pyridyl,

R4and R5hydrogen atoms or together denote a carbon-uglerodnoi communication,

R6hydroxyl, methoxyl,

A group of the formula

< / BR>
where R7and R8a hydrogen atom or together denote a methylene or ethylene group

X N-methyl-aminogroup or sulfur atom, and the group-CHR7associated with the group-NR2-,

B a carbon-carbon bond or unbranched Allenova group with 2-4 carbon atoms,

their mixtures, isomers or individual isomers and physiologically tolerated additive salts with bases, if R6means hydroxyl, which in particular have antithrombine action.

It is known to use derivatives arylsulfonamides, for example 3-(4-(2-benzene-sulphonamido-ethyl)-benzoyl)propionic to the tsya obtain new derivatives arylsulfonamides with improved antirabicakim action.

The problem is solved derived arylsulfonamides the above formula (I), mixtures of isomers, or individual isomers and its physiologically tolerated additive salts with bases, if R6means hydroxyl.

New derivatives of arylsulfonamides can be obtained by known methods, some of which are described in the examples of the preparation of derivative arylsulfonamides.

A further object of the invention is a pharmaceutical composition having antidromically activity, which, in addition to the pharmaceutically acceptable carrier contains as active substances derived arylsulfonamides General formula (Ia)

< / BR>
where R1thienyl, chloranil, tetramethylene, pentamethylene, phenyl, unsubstituted or monosubstituted by a halogen atom, stands or trifluoromethyl, or disubstituted by chlorine atoms or metaxylem,

R2a hydrogen atom,

R3pyridyl,

R4and R5hydrogen atoms or together denote a carbon-carbon bond,

R6hydroxyl or methoxyl,

A group of the formula

< / BR>
R7and R8a hydrogen atom or together denote a methylene or ethylene,

X N-methyl-aminogroup OSVETLENIE alkylen with 2-4 carbon atoms,

in an effective amount.

The proposed pharmaceutical composition is prepared by known methods, for example, by mixing the ingredients, if necessary, under heating.

As mentioned above, the new compounds of formula (I) exhibit an antithrombotic effect, which is confirmed by the results of the next experiment, in which we investigated the following new compounds And Method, and a known compound Z:

And 6-(2-(4-toluensulfonate)indan-5-yl)-6-(3-pyridyl)-Gex-5-ANOVA acid

B 6-(4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl)-6-(3-pyridyl)Gex-5-ANOVA acid

6-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-6-(3-pyridyl)-hexanoic acid

G 6-(4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl)-6-(3-pyridyl)hexenoic acid

D 6-(4-(2-(4-triftormetilfullerenov)ethyl)phenyl)-6-(3-pyridyl)Gex-5-ANOVA acid

E 6-(4-(2-(4-bromobenzonitrile)ethyl)phenyl)-6-(3-pyridyl)-Gex-5-ANOVA acid

W 6-(4-(2-(4-forbindelseshandtering)ethyl)phenyl)-6-(3-pyridyl)-Gex-5-ANOVA acid

C 6-(4-(2-(4-toluensulfonate)ethyl)phenyl)-6-(3-pyridyl)-Gex-5-ANOVA acid

And 6-(4-(2-(2,3,4,5,6-pentamethyldiethylenetriamine)ethyl)phenyl)-6-(3-pyridyl)-Gex-5-ANOVA acid

To 6-(4-(2-(4-b is Teal)phenyl)-7-(3-pyridyl)-hept-6-ANOVA acid

M 6-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-6-(3-pyridyl)-Gex-5-ANOVA acid

N 6-(2-(4-bromobenzonitrile)indan-5-yl)-6-(3-pyridyl)-Gex-5-ANOVA acid

6-(2-(4-perbincangannya)indan-5-yl)-6-(3-pyridyl)-Gex-5-ANOVA acid

Paragraph 6-(2-(2-thiophenesulfonyl)indan-5-yl)-6-(3-pyridyl)-Gex-5-ANOVA acid

R 6-(2-benzosulfimide-indan-5-yl)-6-(3-pyridyl)-Gex-5-ANOVA acid

6-(2-(2,5-dichlorobenzenesulfonyl)indan-5-yl)-6-(3-pyridyl)-Gex-5-ANOVA acid

T methyl ester 6-(2-(4-forbindelseshandtering)indan-5-yl)-6-(3-pyridyl)-Gex-5-ene acid

7-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-7-3-pyridyl)-hept-6-ANOVA acid

F. 5-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-5-(3-pyridyl)-Penta-4-ANOVA acid

X methyl ester 5-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-5-(3-pyridyl)-Penta-4-ene acid

C 6-(1-(4-(2-(4-chlorobenzenesulfonamide)ethyl) - naphthyl))-6-(3-pyridyl)-Gex-5-ANOVA acid

H 6-(5-(2-(4-forbindelseshandtering)ethyl)-N-methyl-pyrrol-2-yl)-6 -(3-pyridyl)Gex-5-ANOVA acid

W 6-(5-(2-(4-globesaltysailor)ethyl-thiophene-2-yl)-6-(3-pyridyl)Gex-5-ANOVA acid

Y 6-(2-(4-chlorobenzenesulfonamide)-1,2,3,4-tetrahydronaphtyl-6-yl)-6 -(3-Pirie known from EP 0 194 548, C 07 C 143/79, 1986).

Technique

By the method of born and Cross (J. Physiol. 170, 397 (1964)) in platelet-rich plasma of healthy subjects measure platelet aggregation. To ensure anticoagulation activity to blood add sodium citrate (3,14%) in a volume ratio of 1:10.

Induced collagen aggregation

The decrease in optical density of a suspension of platelets photometrically measured and recorded after adding the caller aggregation substance. Angle of inclination of the density curve conclude on the rate of aggregation. The point of the curve, which has the highest light transmission, is used to determine the optical density.

The amount of collagen choose the minimum possible to get irreversibly passing the curve. Use trading collagen foreign companies Gormonami, DE.

Before adding collagen plasma together with a test compound are incubated at 37oC for 10 minutes

On the obtained measurement data graphically determine the effective dose ED50relating to 50% increase change in optical density, i.e. the latency of the aggregation.

Below are your results:

Studied Conn>/BR>AND 0.62

TO 2,6

L 1.5

M 0,56

N 0,4

ABOUT 1,8

P 2,0

P 1,9

WITH 2.0

T 1,0

IN 2.2

F 1,8

X 2.0

C 1,8

H 1,1

W 1,2

SHCH 1,9

Z (known) 3,0

New connections belong to the category of low-toxic substances.

Required to obtain the appropriate action dosage, it is 2-4 times daily 0.3 to 4 mg/kg, preferably 0.3 to 2 mg/kg of body weight. The new compounds of the formula I, if necessary in combination with other active substances, it is possible to develop together with one or more inert conventional carriers and/or diluents, such as, for example, corn starch, milk sugar, raw sugar, microcrystalline cellulose by stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, mixture of water and ethanol, or glycerol, or sorbitol, or polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or girasolereale substances, as, for example, utverzhdennym fat or suitable mixtures in normal Galenika preparations, such as tablets, pills, capsules, powders, suspensions or suppositories.

The following examples of posn is sulfonylamino)ethyl)phenyl)-6-(3-pyridyl)-Gex-5-ANOVA acid

2-(p-chlorobenzenesulfonamide)ethylbenzene

To a mixture of 150 ml of telengard and 150 ml of water are added to 30.3 g of 2-phenethylamine, 12 g of sodium hydroxide and 0.5 g of tetrabutylammonium bromide. Stirring, to this mixture portions add 65,5 g of acid chloride of 4-chlorobenzenesulfonate. After 30 min the organic phase is separated, concentrated and the residue is recrystallized from toluene.

Output: 65 g (88% of theoretical)

melting point: 90oC.

b) 4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl-3-pyridylketone

To 100 g of trichloride aluminium slowly added to 25.5 ml of dimethylformamide so that the temperature did not exceed 70oC. To this mixture was added to 35.6 g of the hydrochloride of the acid chloride of nicotinic acid and 49 g of 2-(4-chlorobenzenesulfonamide)telebasel and heated for 2 h to 100oC. the Reaction mixture is poured on ice, neutralized and extracted with ethylenchloride. The organic phase is concentrated and the residue is subjected to chromatography on cynicalliberal column using as eluent a mixture of telengard and ethanol in a ratio of 40:1.

Output: 16.7 g (25% of theoretical),

melting point: 150-152oC.

C20H17ClN2O3S (400,91)

pyridyl)Gex-5-ANOVA acid

To a suspension of 6.7 g of bromide 4-carboxybutyl-triphenylphosphane and 4.5 g of tert. -butyl potassium in 100 ml of tetrahydrofuran at 0oC is added 4.0 g of 4-(2-(4-chlorobenzenesulfonamide)ethyl)-phenyl-3-pyridylketone and within 2 hours mix. The reaction mixture is decomposed by the addition of ice water and washed with toluene. The aqueous phase is acidified and extracted with ethylenchloride. The organic extract is concentrated and the residue is subjected to chromatography on cynicalliberal column using as a mixture of telengard and ethanol in a ratio of 20: 1. Containing the product fraction is concentrated, the residue is dissolved in ethyl ether, acetic acid and adding 2 ml of cyclohexylamine allocate cyclohexylammonium salt.

Yield: 1.9 g (36% of theoretical),

melting point: 95oC (decomposition).

C25H25ClN2S x 1/2 cyclohexylamine (534,61)

calculated: C 62,91; H 5,94; N 6,55

found: C 62,80; H 6,03; N 6,72

Example 2

6-(1-(4-(2-(4-chlorobenzenesulfonamide)ethyl)naphthyl)-6 -(3-pyridyl)Gex-5-ANOVA acid

a) 1-(2-(p-chlorobenzenesulfonamide)ethyl)naphthalene

Obtained from 1-(2-amino-ethyl)naphthalene and the acid chloride of 4-chlorobenzenesulfonate analogously to example 1A. Purification of the crude product is of Trenchard and cyclohexane in the ratio 2:1.

Yield: 92% of theoretical,

melting point: 98-99oC

C18N16ClNO2S (345,87)

calculated: C 62,51; H of 4.66; N 4,05

found: C 62,39; H to 4.68; N 3,86

b) 4-(2-(4-chlorobenzenesulfonamide)ethyl) - naphthyl-3-pyridyl-ketone

Obtained from hydrochloride of the acid chloride of nicotinic acid and 1-(2-(p-chlorobenzenesulfonamide)ethyl) - naphthalene analogously to example 1B. Purification of the crude product is carried out by chromatography on cynicalliberal column using as eluent ethylthiourea and complex ethyl ester of acetic acid in the ratio of 5:1.

Output: 22% of theoretical,

resin, the value of Rf: 0,41 (silica gel; a mixture of telengard and ethyl ester of acetic acid 3:1)

C24H19ClN2O3S (450,96)

calculated: C 63,92; H 4,25; N 6,21

found: C 64,54; H 4,43; N 6,01

in) 6-(1-(4-(2-(4-chlorobenzenesulfonamide)ethyl) - naphthyl-6-(3-pyridyl)Gex-5-ANOVA acid

Obtained from 4-(2-(4-chlorobenzenesulfonamide)ethyl-naphthyl-3-pyridylketone and bromide 4-carboxyvinyltransferase analogously to example 1B, but without education cyclohexylamine salt.

Yield: 43% of theoretical,

resin, Rf-value:the value of 0.52 (silica gel; telengard/BR>
found: C 64,91; H 5,35; N 5,20

Example 3

6-(5-(2-(4-forbindelseshandtering)ethyl)-N-methyl-pyrrol-2-yl)-6 -(3-pyridyl)Gex-5-ANOVA acid

a) 5-(2-(4-forbindelseshandtering)ethyl)-N-methyl-pyrrol-2-yl-3-pyridyl-ketone

To a solution of 14.1 g of 2-(2-(4-forbindelseshandtering)-ethyl)-N-methyl-pyrrole in 100 ml of toluene and 50 ml portions of dimethylformamide is added 9.8 hydrochloride of the acid chloride of nicotinic acid. Refluxed for 2 h, the reaction mixture is poured on ice, neutralized and extracted with ethylenchloride. The crude product is subjected to chromatography on cynicalliberal column using as eluent a mixture of telengard and ethanol in a ratio of 20:1.

Yield: 4.6 g (24% of theoretical),

melting point: 140oC

C19H18FN3O3S (387,44)

calculated: C 58,90; H to 4.68; N 10,85

found: C 58,62; H to 4.52; N 10,70

b) 6-(5-(2-(4-forbindelseshandtering)ethyl)-N-methyl-pyrrol-2-yl)-6 -(3-pyridyl)Gex-5-ANOVA acid

Obtained from 5-(2-(4-forbindelseshandtering)ethyl)-N-methylpyrrole-2-yl-3-pyridylketone, and bromide 4-carboxyvinyltransferase analogously to example 1B), the crude product is purified by recrystallization from a mixture of water and isopropanol is B>4S (471,56)

calculated: C 61,13; H 5,56; N 8,91

found: C 61,23; H 5,72; N 9,00

Example 4

6-(5-(2-(4-chlorobenzenesulfonamide)ethyl)thiophene-2-yl)-6-(3-pyridyl)Gex-5-ANOVA acid

a) 2-(2-(p-chlorobenzenesulfonamide)ethyl)thiophene

Is obtained analogously to example 1A from 2-(2-amino-ethyl)-thiophene, and the acid chloride of 4-chlorobenzenesulfonic acid.

Yield: 69% of theoretical,

melting point: 93oC

C12H12ClNO2S2(301,83)

calculated: C 47,75; H 4,01; N WITH 4.64

found: C 47,75; H 3,88; N 4,45

b) 5-(2-(4-chlorobenzenesulfonamide)ethyl)thiophene-2-yl)-3-pyridylketone

To a suspension of 20 g of aluminium chloride and the hydrochloride of the acid chloride of nicotinic acid in 150 ml of telengard drops added a solution of 15 g of 2-(2-(4-chlorobenzenesulfonamide)ethyl)thiophene in 50 ml of telengard. Heated for 90 min to 50oC, the reaction mixture is poured on ice, the precipitate is sucked off and recrystallized from methanol.

Yield: 3.7 g (17% of theoretical),

melting point: 154-160oC

C18H15ClN2O3S0,5 HCl (is 317.1)

calculated: C 68,17; H 7,43; N 9,39

found: C 68,27; H 7,31; N 8,99

7-(4-(2-amino-ethyl)phenyl)-7-(3-pyridyl)heptane acid

Yield: 96% of teoreticheskoj schiano: C 73,59; H 8,03; N 8,58

found: C 73,48; H 8,00; N OF 8.37

d) 6-(4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl)-6-(3-pyridyl)hexanoic acid

to 1.9 g of 6-(4-(2-amino-ethyl)phenyl)-6-(3-pyridyl)-hexanoic acid are suspended in 150 ml of dioxane and added 20 ml of a 5% potassium carbonate solution. To this mixture at room temperature was added 1.54 g of acid chloride of 4-chlorobenzenesulfonic acid in 20 ml of dioxane. After 5 h and evaporated on a rotary evaporator to dryness, the residue is absorbed in a small amount of sodium liquor and precipitated by dilute acetic acid. The precipitate is collected, dried and subjected to chromatography on cynicalliberal column using as eluent of chloroform and methanol in a ratio of 10:1.

Yield: 1.8 g (61% of theoretical,

resin, the value of Rf: to 0.48 (silica gel; chloroform/methanol=10:1)

C25H27ClN2O4S (487,03)

calculated: C 61,65; H 5,59; N 5,79

found: C 61,59; H of 5.40; N 5,74

Similarly receive the following connections:

6-(4-(2-(4-forbindelseshandtering)ethyl)phenyl)-6-(3-pyridyl)hexanoic acid

Yield: 11% of theoretical,

resin, the value of Rf: of 0.53 (silica gel; chloroform/methanol=10:1)

C25H27FN2O4S (470,60)iridis)-hexanoic acid

Output: 12% of theoretical,

resin, the value of Rf: of 0.55 (silica gel; chloroform/methanol=10:1)

C26H29N2O4S (466,60)

calculated: C 66,93; H 6,48; N 6,00

found: C 66,81; H to 6.57; N 5,94

6-(4-(2-(4-bromobenzonitrile)ethyl)phenyl)-6-(3-pyridyl)hexanoic acid

Yield: 24% of theoretical,

resin, the value of Rf: 0,34 (silica gel; chloroform/methanol:1)

C25H27BrN2O4S (531,50)

calculated: C 56,50; H 5,12; N 5,27

found: C 56,41; H 5,31; N 5,17

Example 11

5-(4-(2-(4-forbindelseshandtering)ethyl)phenyl)-5-(3-pyridyl)pentane acid

Is obtained analogously to example 10D) of 5-(4-(2-amino-ethyl)phenyl)-5-(3-pyridyl)pentanol acid and the acid chloride of 4-fermentolisate.

Yield: 28% of theoretical,

resin, the value of Rf: 0,33 (silica gel; chloroform/methanol=10:1)

C24H25FN2O4S (456,50)

calculated: C 63,14; H 5,52; N 6,94

found: C 63,04; H ceiling of 5.60; N 5,96

Example 12

5-(4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl)-5-(3-pyridyl)pentane acid

Is obtained analogously to example 10D) of 5-(4-(2-amino-ethyl)-phenyl-5-(3-pyridyl)pentanol acid and the acid chloride of 4-chlorobenzenesulfonate.

Yield: 21% of those who about: C 60,94; H 5,33; N OF 5.92

found: C 61,01; H 5,35; N 5,70

Example 13

7-(4-(2-(4-toluenesulfonylamino)ethyl)phenyl)-7-(3-pyridyl)heptane acid

Is obtained analogously to example 10D) and 7-(4-(2-amino-ethyl)-phenyl)-7-(3-pyridyl)heptane acid and the acid chloride of 4-toluenesulfonic acid.

Yield: 78% of theoretical,

resin, the value of Rf: of 0.42 (silica gel; chloroform/methanol=10:1)

C27H32N2O4S (480,60)

calculated: C 67,47; H of 6.71; N OF 5.83

found: C 67,34; H of 6.71; N 5,74

Example 14

7-(4-(2-(4-forbindelseshandtering)ethyl)phenyl)-7-(3-pyridyl)heptane acid

Is obtained analogously to example 13 from 7-(4-(2-amino-ethyl)phenyl)-7-(3-pyridyl)heptane acid and the acid chloride of 4-fermentolisate.

Yield: 66% of theoretical,

resin, the value of Rf: of 0.20 (silica gel; chloroform/methanol=10:1)

C26H29FN2O4S (484,6)

calculated: C 64,44; H 6,03; N 5,72

found: C 64,48; H of 5.99; N 5,72

Example 15

Methyl ester 5-(4-2-(4-chlorobenzenesulfonamide)ethyl)phenyl)-5-(3-pyridyl)pentanol acid

2.0 g 5-(4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl)-5-(3-pyridyl)pentanol acid are dissolved in 30 ml of methanol and add 3 ml of thionyl chloride at 0oC. Dissolve the column with silica gel.

Yield: 1.1 g (53% of theoretical),

resin, the value of Rf: of 0.65 (silica gel; chloroform/methanol=95:5)

C26H29ClN2O4S (501,1)

calculated: C 62,33; H of 5.83; N 5,59

found: C 62,36; H 6,01; N 5,42

Example 16

Methyl ester 5-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-5-(3-pyridyl)-Penta-4-ene acid

3.7 g of 5-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-5-(3-pyridyl)Penta-4-ene acid are dissolved in 30 ml of methanol, which introduced dried hydrogen chloride. The solution is stirred overnight and then evaporated on a rotary evaporator. Cooling with ice, adding an aqueous solution of potassium carbonyl allocate base is extracted with methylene chloride. The solution is evaporated on a rotary evaporator and the residue is subjected to chromatography on a column with silica gel.

Yield: 2.5 g (52% of theoretical),

resin, the value of Rf: of 0.53 (silica gel; toluene/dioxane/ethanol and acetic kislota:1:1:0,6)

C26H25ClN2O4S (497,01)

calculated: C 62,80; H 5,10; N the ceiling of 5.60

found: C 62,67; H 5,39; N 5,40

Similarly receive the following connection:

Methyl ester of 7-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-7-3-pyridyl)-hept-6-ene acid

Yield: 73% of theorems28H29ClN2O4S (525,06)

calculated: C 64,05; H 5,56; N 5,33

found: C 64,45; H x 6.15; N OF 5.05

Example 17

5-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-5-(3-pyridyl)-Penta-4-ANOVA acid

Obtained from the methyl ester 5-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-5-(3-pyridyl)Penta-4-ene acid by hydrolysis of sodium lye.

Output: 95% of theoretical,

melting point: 94-114oC

C25H23ClN2O4S (482,98)

calculated: C 62,20; H 4,80; N 5,80

found: C 62,14; H 4,70; N 5,81

Similarly receive the following connection:

7-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-7-(3-pyridyl)-hept-6-ANOVA acid

Yield: 94% of theoretical,

melting point: 66-90oC

C27H27ClI2O4S (511,03)

calculated: C 63,50; H and 5.30; N 5,50

found: C 63,65; H of 5.29; N 5,30

Example 18

(Z)- and (E)-6-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-6-(3-pyridyl)Gex-5-ANOVA acid

to 1.9 g of methyl ester of 6-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-6-(3-pyridyl)Gex-5-ene acid is subjected to chromatography on cynicalliberal column using as eluent a mixture of telengard, ethyl ester acetic acid and glacial acetic acid in calagione example 17 hydrolyzing sodium lye.

(Z-6-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-6-(3-pyridyl)-Gex-5-ANOVA acid

Yield: 200 mg (10% of theoretical),

Melting point: 70-100oC

C26H25ClN2O4S (497,01)

calculated: C 62,83; H 5,07; N 5,64

found: C 62,72; H 5,24; N 5,47

(E)-6-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-6-(3-pyridyl)-Gex-5-ANOVA acid

Yield: 400 mg (20% of theoretical),

Melting point: 75-103oC

C26H25ClN2O4S (497,01)

calculated: C 62,83; H 5,07; N 5,64

found: C 62,75; H 5,14; N 5,43

Example 19

6-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-6-(3-pyridyl)-hexanoic acid

3.0 g of 6-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-6-(3-pyridyl)Gex-5-ene acid are dissolved in 50 ml of 0.3 N sodium liquor and subjected to hydrogenation of 1 g of palladium on coal at 40oC and 3.5 bar within 60 minutes Then the catalyst is sucked off and the pH of the filtrate set 4-5. The isolated product is separated and absorb in chloroform. The organic extract is washed with water, dried and concentrated. The mixture is then subjected to chromatography on cynicalliberal column using as eluent a mixture of telengard, ethyl ester acetic acid and glacial acetic acid in the ratio of 70:30 PM:Oia: 85-100oC

C26H27ClN2O4S

calculated: C 62,58; H the 5.45; N 5,61

found: C 62,54; H the 5.45; N 5,79

Example 20

7-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-7-(3-pyridyl)-heptane acid

Is obtained analogously to example 19 by restoring 7-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-7-(3-pyridyl)hept-6-ene acid using platinum on coal.

Output: 40% of theoretical,

resin, the value of Rfbe : 0.3 (silica gel; telengard ethyl ester of acetic acid/acetic acid=10:3:0,5)

C26H29ClN2O4S (501,03)

calculated: C 62,32; H of 5.83; N 5,59

found: C 62,56; H 6,00; N 5,32

Example 21

5-(2-(benzosulfimide)indan-5-yl)-5-(3-pyridyl)pentane acid

Obtained from 5-(2-(4-chlorobenzenesulfonamide)indan-5-yl)-5-(3-pyridyl)Penta-4-ene acid analogizes example 19 by catalytic hydrogenation in the presence of platinum as a catalyst.

Yield: 37% of theoretical,

melting point: 80-110oC

C25H25ClN2O4S (485,00)

calculated: C 61,91; H 5,19; N 5,77

found: C 61,85; H 5,33; N 6,05

Example 22

7-(2-(benzosulfimide)indan-5-yl)-7-(3-pyridyl)heptane acid

Polychaets the project analogously to example 21.

Output: 10% of theoretical,

melting point: 60-75oC

C27H29ClN2O4S (513,05)

calculated: C 63,21; H 5,69; N 5,46

found: C 63,43; H 5,88; N 5,63

Example 23

3-(2-(4-toluensulfonate)indan-5-yl)-3-(3-pyridyl)prop-2-ANOVA acid

a) Ethyl ester of 3-(2-(4-toluensulfonate)indan-5-yl)-3-(3-pyridyl)prop-2-ene acid

To a suspension of 9.6 g of tert.-the butyl potassium in 100 ml of tetrahydrofuran and 25 ml of dimethylformamide at 5oC add 9,84 g teeterboro ether phosphonooxy acid. Stirred for 30 min at 0oC and added 15.5 g of 2-(4-toluensulfonate)indan-5-yl-3-pyridylketone. Then for 5 h refluxed. The solution serves on ice water and extracted 4 times with methylene chloride. Then dried, evaporated on a rotary evaporator and the residue is subjected to chromatography on cynicalliberal column using as eluent a mixture of telengard and ethyl ester of acetic acid in the ratio 9:1.

Output: 17,2 g (93% of theoretical),

the value of Rf: 0,46/of 0.35 (silica gel; telengard ethyl ester acetic acid 1:1)

b) 3-(2-(4-toluensulfonate)indan-5-yl)-3-(3-pyridyl)-prop-2-ANOVA acid

4,2 N sodium liquor for 30 min refluxed. The cooled solution is washed three times with 50 ml of methylene chloride and acidified with. The residue is washed, dried and recrystallized from n-butanol.

Yield: 2.3 g (58% of theoretical),

melting point: 228-230oC

C23H22N2O4S (422,5)

calculated: C, compared with 65.38; H 5,24; N 6,63

found: C 65,32; H 5,17; N 6,48

Example 24

3-(2-(4-(toluensulfonate)indan-5-yl)-3-(3-pyridyl)propanoic acid

Is obtained analogously to example 19 from 3-(2-(4-toluensulfonate)indan-5-yl)-3-(3-pyridyl)prop-2-ene acid with subsequent deposition of dioxane by adding simple diisopropyl ether.

Yield: 74% of theoretical,

melting point: 85-97oC

C23H22N2O4S0,8 dioxane (424,51)

calculated: C 63,57; H is 6.19; N 5,66

found: C 63,39; H 6,30; N 5,62

Example 25

6-(4-(2-(4-forbindelseshandtering)ethyl)phenyl)-6-(3-pyridyl)-Gex-5-ANOVA acid

3.1 g of 6-(4-2-amino-ethyl)phenyl)-6-(3-pyridyl)Gex-5-ene acid is obtained analogously to example 10 g) in 150 ml of dioxane is stirred with 5 ml saturated potassium carbonate solution. Then add 2.9 g of acid chloride of 4-forbindelsesteknologi acid and at room temperature is stirred luxusni acid absorb, dry and thicken. The residue is subjected to chromatography on cynicalliberal column using as eluent a mixture of chromatography and methanol in a ratio of 20:1.

Yield: 0.5 g (10% of theoretical),

resin, the value of Rf: of 0.55 (silica gel; chloroform/methanol=10,1)

C25H25FN2O4S (470,6)

calculated: C 64,09; H 5,38; N 5,98

found: C 63,77; H 5,59; N 6,00

Similarly receive the following connections:

6-(4-(2-(4-toluensulfonate)ethyl)phenyl)-6-3-pyridyl)Gex-5-ANOVA acid

Yield: 13% of theoretical,

resin, the value of Rf: 0.5 (silica gel; chloroform/methanol=10:1)

C26H28N2O4S (464,6)

calculated: C 67,22; H 6,07; N 6,03

found: C 67,06; H 6,21; N 5,86

6-(4-(2-(4-bromobenzonitrile)ethyl)phenyl)-6-(3-pyridyl)-Gex-5-ANOVA acid

Output: 20% of theoretical,

resin, the value of Rf:of 0.4 (silica gel; chloroform/methanol=10:1)

C25H25BrN2O4S (529,5)

calculated: C 56,71; H amounts to 4.76; N OF 5.29

found: C 56,72; H 4,58; N 5,12

Example 26

7-(4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl)-7-(3-pyridyl)-hept-6-ANOVA acid

Obtained from 4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl-3-pyridylketone analogously to example is l=5:1)

C26H27ClN2O4S (499,02)

calculated: C 62,58; H the 5.45; N 5,62

found: C 62,48; H of 5.40; N 5,62

Example 27

Diethylamid 6-(4-(2-(4-globesaltysailor)ethyl)phenyl)-6-(3-pyridyl)-Gex-5-ene acid

1.0 g 6-(4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl)-6-(3-pyridyl)Gex-5-ene acid are dissolved in 15 ml of tetrahydrofuran and stirred for 15 min with 0,49 g carbonyldiimidazole. Then add 1 ml of diethylamine and heated for 2 h under reflux. Then concentrated and the residue is absorbed in ethyl ether, acetic acid and dried. Finally subjected to chromatography on cynicalliberal column using as eluent ethyl ester of acetic acid.

Yield: 0.6 g (54% of theoretical),

oil, the value of Rf:to 0.23 (silica gel; ethyl ester of acetic acid)

C29H34ClN3O3S (540,12)

calculated: C 64,48; H 6,34; N 7,78

found: C 64,42; H 6,60; N 7,52

Similarly receive the following connection:

Benzylated 6-(4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl)-6-(3-pyridyl)-Gex-5-ene acid

Yield: 51% of theoretical,

resin, the value of Rf: of 0.37 (silica gel; ethyl ester of acetic acid)

C32H32ClNl-4-chlorobenzenesulfonamide)ethyl)phenyl)-6-(3-pyridyl)Gex-5-ANOVA acid

2.0 g 6-(4-(2-(4-chlorobenzenesulfonamide)ethyl)-phenyl)-6-(3-pyridyl)Gex-5-ene acid is stirred over night in 10 ml of 4 N sodium liquor, 100 ml of methylene chloride, 80 mg of chloride designed and 0.85 grams of methyliodide. Then the organic phase is separated and the aqueous phase by acidification brought to pH 5. The isolated product is separated, absorb in methylene chloride, dried and concentrated. The residue is subjected to chromatography on a column of silica gel using ethylthiourea/methanol 97:3.

Output: 0,43 g (21% of theoretical),

melting point: 121-125oC

C26H27ClN2O4S (499,02)

calculated: C 62,58; H the 5.45; N 6,61

found: C 62,53; H 5,54; N OF 5.53

Example 29

E - and Z-6-(4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl)-6-(3-pyridyl)Gex-5-ANOVA acid

a) 4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl-3-pyridyl-ketone

156 g of 4-(2-acetylamino)phenyl-3-pyridylketone for 16 h heated in 800 ml of 6 N hydrochloric acid. The solution is concentrated and the residue is absorbed in a mixture of 200 ml of water and 500 ml of dioxane. By adding 10 N sodium liquor set the value of pH 8-10. Then add drops of the solution of 126 g of acid chloride of 4-chlorobenzenesulfonic acid in 150 ml of dioxane and 10N sodium liquor on when the precipitate is sucked off. Released crude product is recrystallized from toluene.

Output: 148 g (65% of theoretical),

melting point: 159-160oC

C20H17ClN2O3S (400,91)

calculated: C 59,92; H 4,28; N 6,99

found: C 60,00; H 4,10; N 6,91

E-6-(4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl)-6-(3-pyridyl)Gex-5-ANOVA acid

222 g of bromide 4-carboxybutyl-triphenylphosphane suspended in 2000 ml of tetrahydrofuran and cooled to -20oC. To this suspension was added 156 g of tert.-the butyl potassium and then 155 g of 4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl-3-pyridylketone. Stirred for 90 min, and the temperature allowed to rise to 10oC. the Reaction mixture is poured into 5000 ml of ice water. The aqueous phase is washed with ethyl ether, acetic acid and then adding citric acid to establish a pH value of 5. The precipitate is sucked off and recrystallized from a mixture of water and ethanol.

Output: 140 g (75% of theoretical),

melting point: 159-160oC

C25H25ClN2O4S (485,00)

calculated: C 61,91; H 5,20; N 5,78

found: C 61,67; H is 5.06; N 5,70

in) Z-6-(4-(2-(4-chlorobenzenesulfonamide)ethyl)phenyl)-6-(3-pyridyl)Gex-5-ANOVA acid

The original solution of example 31B) showauthor on cynicalliberal column using as eluent a mixture of telengard and ethyl ester of acetic acid in the ratio 6:4+3% acetic acid. The first fraction is collected, concentrated and the residue is recrystallized from ethyl ester of acetic acid/simple ethyl ester.

Yield: 7.8 g (3% of theoretical),

melting point: 94-95oC

C25H25ClN2O4S (485,00)

calculated: C 61,91; H 5,20; N 5,78

found: C 61,66; H 5,23; N BY 5.87

Example 30

6-(2-(4-chlorobenzenesulfonamide)-1,2,3,4-tetrahydronaphtyl-6-yl)-6 -(3-pyridyl)Gex-5-ANOVA acid

a) Hydrochloride of 2-amino-6-bromo-1,2,3,4-tetrahydronaphthalene

55.8 g of titanium chloride at 0oC gently drops added to 700 ml of dimethyl ether of ethylene glycol. Then the portions of the gain of 22.3 g of sodium borane and then a solution of 33.5 g of 6-bromo-2-oximino-1,2,3,4-tetrahydronaphthalene in 250 ml of dimethyl ether of ethylene glycol. Stir for 4 h at room temperature, serves the reaction mixture on ice, addition of concentrated ammonia establish the pH of the mixture and filtered over kieselgur. The filtrate is extracted with methylene chloride. The extract is concentrated, to the residue was added a simple ether and adding isopropanole secrete hydrochloric acid hydrochloride.

Yield: 20.2 g (55% of theoretical),

melting point: 237oC

C10
the 5.25 g of 2-Amino-6-bromo-1,2,3,4-tetrahydronaphthalene dissolved in 75 ml of dioxin and water in the ratio 2:1. At 0oC add 44 ml of 1N sodium lye and then 4.8 g of di-tert.-BUTYLCARBAMATE. Stir for 12 h at room temperature, the reaction mixture is thickened, add water and extracted with ethyl ester of acetic acid. The extract is concentrated and the residue is recrystallized from petroleum ether.

Output: 5.2 g (80% of theoretical),

melting point: 111oC

C15H20BrNO2(326,23)

calculated: C 55,23; H 6,18; N 4,29

found: C 55,08; H 6,29; N 4,51

a) 2-tert.-butoxycarbonylamino-6-bromo-1,2,3,4-tetrahydronaphtyl-6-and-3-pyridinemethanol

3.25 g of 2-tert.butoxycarbonylamino-6-bromo-1,2,3,4-tetrahydronaphthalene dissolved in 50 ml of absolute tetrahydrofuran and cooled to -70oC. add Drops of 8.8 ml of n-utility in hexane (2.5 M) and stirred for further 90 min at -50oC. Then at -70oC drops are added to 1.1 g of pyridine-3-alleged and for a further 60 min mix. The reaction mixture is poured on ice and extracted with ethyl ester of acetic acid. The organic phase is washed with water, dried, concentrated and the residue is recrystallized from cyclohexane/er>C

C21H26N2O3(354,45)

calculated: C 71,16; H 7,39; N OF 7.90

found: C 70,96; H 7,46; N 7,86

g) 2-(4-chlorobenzenesulfonamide)-1,2,3,4-tetrahydronaphtyl-6-yl-3-pyridylketone

of 1.75 g of 2-tert.butoxycarbonylamino-1,2,3,4-tetrahydronaphtyl-6-yl-3-pyridinemethanol in 30 ml of chloroform for 1 h at room temperature stir from 17.5 g of manganese dioxide. The suspension is filtered, the filtrate concentrated, and the residue for 1 h at 40-50oC is stirred in 10 ml of 2N hydrochloric acid. Then the addition of concentrated ammonia is alkalinized and the aqueous phase is extracted with ethyl ether acetic acid. The extract is washed with water, concentrated and the residue is dissolved in 20 ml of methylene chloride. To this solution at 0oC add 0,86 g of acid chloride of 4-chlorobenzenesulfonic acid and then 1 g of triethylamine and stirred for 2 h at room temperature. The reaction mixture is poured on ice and extracted with methylene chloride. The extract is washed with water, dried, concentrated and the residue is recrystallized from ethyl ester of acetic acid/petroleum ether.

Yield: 1.2 g (57% of theoretical),

melting point: 170-172oC

C22H19ClN2O3S (426,92)

calculated: C 61,89; H 4,49; N 6,56<5-ANOVA acid

Is obtained analogously to example 31B) of 2-(4-chlorobenzenesulfonamide)-1,2,3,4-tetrahydronaphtyl-6-yl-3-pyridylketone and bromide 4-carboxybutyl-triphenylphosphane.

Yield: 63% of theoretical,

melting point: 172oC

C27H27ClN2O4S

calculated: C 63,46; H 5,33; N 5,48

found: C 63,42; H 5,41; N 5,43

Similarly to the above examples get the following connections:

6-(4-(2-(4-methoxybenzenesulfonamide)ethyl)phenyl)-6-3-pyridyl)Gex-5-ANOVA acid

melting point: 104-106oC

C26H28N2O5S (480,58)

calculated: C 64,98; H by 5.87; N OF 5.83

found: C 64,90; H of 6.02; N OF 5.99

6-(4-(2-(3,4-dimethoxybenzenesulfonamide)ethyl)phenyl)-6-(3-pyridyl)Gex-5-ANOVA acid

Yield: 18% of theoretical,

resin, the value of Rfof 0.36 (silica gel; dichloromethane/ethyl ester acetic acid 6:4+3% acetic acid)

C27H30N2O6S (510,61)

calculated: C 63,51; H of 5.92; N 5,49

found: C 63,21; H 5,79; N 5,33

6-(4-(2-(4-triftormetilfullerenov)ethyl)phenyl)-6-(3-pyridyl)Gex-5-ANOVA acid

melting point: 140-143oC (ethyl ester of acetic acid/ petroleum ether)

C26H25F3N2O4S phenyl)-6-(3-pyridyl)Gex-5-ANOVA acid

C23H23ClN2O4S2(491,03)

calculated: C, 56.26 vertical; H 4,72; N 5,70

found: C 55,96; H 4,70; N 5,79

6-4-(2-(phenylmethanesulfonyl)ethyl)phenyl)-6-(3-pyridyl)-Gex-5-ANOVA acid

C26H28N2O4S (464,58)

resin, the value of Rf: of 0.64 (silica gel; ethyl ester of acetic acid)

calculated: C 67,22; H 6,07; N 6,03

found: C 67,27; H 6,22; N 5,88

The following examples illustrate possible forms of implementation of the proposed pharmaceutical composition.

Example 31

Tablets with 100 mg of the compound of example 1 as an active substance

Composition:

1 tablet contains:

active substance 100.0 mg

lactose 80.0 mg

corn starch 34,0 mg

polyvinylpyrrolidone 4.0 mg

magnesium stearate 2.0 mg

total: 220,0 mg

Preparation:

The active ingredient, lactose and starch are mixed and uniformly moistened with an aqueous solution of polyvinylpyrrolidone. The wet mass is passed through a sieve of the size of cells 2.0 mm, dried in a multistage drying Cabinet at a temperature of 50oC, and then pass through a sieve of the size of the cells is 1.5 mm then add the magnesium stearate and mix. The finished mass is pressed into tablets.

drezon.

Example 32

Capsules of hard gelatin containing 150 mg of the compound of example 1 as an active substance

1 capsule contains:

the active substance of 150.0 mg

dried corn starch, about 180,0 mg

lactose powder, about a 87.0 mg

the stearate 3.0 mg

total: about 420,0 mg

Preparation:

The active substance is mixed with the excipients, the resulting mass is passed through a sieve of the size of cells of 0.75 mm, and using a suitable device stirred to obtain a homogeneous mass.

The finished mass is fed into capsules of hard gelatin size 1.

The content of one capsule: about 420 mg

The shell of a capsule: Capsule is made of hard gelatin size 1.

Example 33

Suppositories containing 150 mg of the compound of example 1 as an active substance

1 suppository contains

the active substance of 150.0 mg

polyethylene glycol (molecular weight 1500) 550,0 mg

polyethylene glycol (molecular weight 6000) 460,0 mg

the monostearate polyethylenimine 840,0 mg

total: 2000,0 mg

Preparation:

The polyethylene glycol monostearate and polyethylenimine melted, the active substance homogen the P> Example 34

The suspension containing 50 mg of the compound of example 1 as an active substance

In 100 ml of suspension contains

active compound 1.0 g

sodium carboxymethyl cellulose 0,2

methyl ester of p-oksibenzoynoy acid 0.05 g

complex propyl ester of p-oksibenzoynoy acid 0.01 g

glycerin 5.0 g

70% solution of sorbitol 50.0 g

aroma 0.3 grams

distilled water to 100.0 ml

Preparation:

Distilled water is heated to a temperature of 70oC. it at stirring dissolved complex of methyl and propyl esters of p-oksibenzoynoy acid, glycerin and sodium carboxymethyl cellulose. Cooled to room temperature, while stirring add the active ingredient and mix to obtain a homogeneous dispersion. Then add a solution of sorbitol and aroma, and the suspension is stirred when removing the air.

5 ml suspension containing 50 mg of active substance.

Example 35

Tablets containing 150 mg of the compound of example 1 as an active substance

Composition:

1 tablet contains:

the active substance of 150.0 mg

lactose powder 89,0 mg

corn starch 40,0 mg

colloidal the>Preparation:

The active substance is mixed with the lactose, corn starch and silicic acid. The resulting mixture is moistened 20% aqueous solution of polyvinylpyrrolidone and pass through a sieve of the size of the cells is 1.5 mm

The resulting granulate is dried at a temperature of 45oC, and after that it again crushed by passing through the same sieve, add magnesium stearate and mix.

The resulting mass is pressed into tablets.

The weight of one tablet: 300 mg

the punch diameter: 10 mm, flat

Example 36

Coated tablets containing 75 mg of the compound of example 1 as an active substance

1 tablet contains:

the active substance of 75.0 mg

calcium phosphate 93,0 mg

corn starch of 35.5 mg

polyvinylpyrrolidone 10.0 mg

oksipropilmetiltselljuloza 15,0 mg

the stearate 1.5 mg

total: 230,0 mg

Preparation:

The active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, oksipropilmetiltselljulozy and half the specified amount of magnesium stearate. Using the appropriate apparatus produce extruded billet with a diameter of approximately 13 mm, which with the help of other suitable I. From the obtained granulate using an appropriate apparatus is pressed tablets of the desired shape.

The weight of one tablet uncoated: 230 mg

The punch diameter: 9 mm, curved

Thus obtained tablets provide a thin coating mainly consisting of oksipropilmetiltselljulozy. The finished tablets with coating, polished using beeswax.

The weight of one coated tablets: 245 mg.

1. Derivatives arylsulfonamides General formula I

< / BR>
where R1benzyl, thienyl, chloranil, tetramethylene, pentamethylene, phenyl, unsubstituted or monosubstituted by a halogen atom, a nitro-group, stands, metaxylem or trifluoromethyl or disubstituted by chlorine atoms or metaxylem;

R2a hydrogen atom or methyl;

R3pyridyl;

R4and R5hydrogen atoms or together denote a carbon-carbon bond;

R6hydroxyl or methoxyl;

A group of the formula

< / BR>
< / BR>
or

< / BR>
where R7and R8a hydrogen atom or together denote a methylene or ethylene;

X N-methyl-aminogroup or sulfur atom, and the group-CHR7- associated with a group-NR2-, and B a carbon-carbon bond or nerazvit the portable additive salts with bases, if R6means hydroxyl.

2. Pharmaceutical composition having antidromically activity containing the derived arylsulfonamides as an active substance in a mixture with a pharmaceutically acceptable carrier, characterized in that the quality of the derived arylsulfonamides it contains a compound of General formula (Ia)

< / BR>
where R1thienyl, chloranil, tetramethylene, pentamethylene, phenyl, unsubstituted or monosubstituted by a halogen atom, stands or trifluoromethyl or disubstituted by chlorine atoms or metaxylem;

R2' the hydrogen atom;

R2pyridyl;

R4and R5hydrogen atoms or together denote a carbon-carbon bond;

R6hydroxyl or methoxyl;

A group of the formula

< / BR>
< / BR>
or

< / BR>
where R7and R8a hydrogen atom or together denote a methylene or ethylene;

X N-methyl-aminogroup or sulfur atom, and the group-CHR7- associated with a group and B is a carbon-carbon bond or unbranched alkylene with 2 to 4 carbon atoms,

in an effective amount.

Priority signs.

12.05.89 R1thienyl, phenyl, unsubstituted or monosubstituted by a halogen atom, nitrogroup the l;

R2a hydrogen atom;

R3pyridyl;

R3and R4hydrogen atoms or together form a carbon-carbon bond;

R6hydroxyl, methoxyl;

A group of the formula

< / BR>
< / BR>
or

< / BR>
where R7and R8a hydrogen atom or together form a methylene or ethylene;

X N-methyl-aminogroup or sulfur atom, and the group-CHR7- associated with a group-NR2or

B a carbon-carbon bond or unbranched alkylene with 2 to 4 carbon atoms;

28.09.89 R1chloranil, tetramethylene, pentamethylene, phenyl, monosubstituted by trifluoromethyl.

 

Same patents:

The invention relates to the field of chemistry of biologically active substances, which may have application in medicine

The invention relates to the field of organic chemistry and relates to a method of obtaining new derivatives of imidazole

The invention relates to novel condensed heterocyclic compounds or their salts

The invention relates to 5,6-disubstituted-3 - pyridylmethylamine compounds of the formula I

< / BR>
where Z is hydrogen, halogen;

Z1represents hydrogen, halogen, cyano and nitro;

X represents Cl, Br, J, or R3SO3;

R3represents C1-C4-alkyl or phenyl, are not necessarily substituted with one to three C1-C4-alkoxygroup, C1-C4- alkyl groups, nitro groups: cyano groups or halogen atoms;

Y and Y1each independently represents OR4, NR4R5or, if they are taken together, YY1represent-O-, -S - or;

R4and R5are each independently hydrogen, C1-C4-alkyl, does not necessarily substituted C1-C4- alkoxygroup, or phenyl, does not necessarily substituted with one to three C1-C4-alkyl groups, C1-C4- alkoxygroup or halogen atoms; or phenyl, does not necessarily substituted with one to three C1-C4-alkyl groups, C1-C4- alkoxygroup atoms or halogen;

R6represents hydrogen or C1- C4- alkyl;

Q is

The invention relates to a derivative of bis-benzo - or benzopyrano-piperidine, piperidylidene and piperazine, which are particularly useful as antagonists of platelet-activating factor and antihistamine, and their pharmaceutical compositions, methods of use of these derivatives and to the method of production thereof

The invention relates to imidazolium and pyridium derived phenylsilane 1,4-dihydropyridines, to the way they are received and containing pharmaceutical compositions

The invention relates to polycyclic aminecontaining compounds, to their optically pure enantiomers, the way they are received, to Farmaceutici on their basis, as well as to new intermediate compounds for the synthesis of polycyclic compounds

The invention relates to new biologically active compounds, in particular to new pyridone derivative exhibiting analgesic activity

The invention relates to the synthesis of biologically active compounds, namely, salts of nitrogen-containing heterocyclic derivatives and 5-hydroxynicotinic acid of General formula:

< / BR>
where X 0(1a), CH2(1B), NH(1B)

The invention relates to a derivative of quinone f-ly Ior its pharmacologically acceptable salts, where R1heteroalkyl group, in which heteroalkyl is a five - or six-membered cycle, containing as the heteroatom nitrogen and the alkyl portion contains 1 to 10 carbon atoms, B is carboxyl or protected carboxyl group, R3,R4,R5the same or different from each other and each represents a hydrogen atom, a hydroxyl group, a C1-C8alkyl, C1-C8alkoxy, C1-C8alkoxy, C1-C10alkyl, C1-C8alkoxy, C1-C8alkoxy, C3-C7cycloalkyl C1-C8alkoxy, thio C1-C8alkyl, thio C1-C8alkyl, except when R3and R4each is simultaneously the lowest C1-C8alkoxygroup, or a group represented by the formula IIwhere R3,R4,R5have the meanings specified above, X and Y are the same or different and each represents a hydroxyl or C1-C8alkoxy

The invention relates to new chemical compounds with biological activity, in particular derivatives pyridyl General formula I

_where And communication, cycloalkenes and cycloalkylcarbonyl groups, each with 3-4 carbon atoms in which one methylene group can be replaced dichloromethylene group, an unbranched Allenova group with 2 or 3 carbon atoms, which may be single or multiply unsaturated group-R7CR8-, -O-R7CR8- or-NR9where R7is a hydrogen atom, hydroxyl, phenyl or an alkyl group with 1-3 carbon atoms; R8is a hydrogen atom or an alkyl group with 1-3 carbon atoms and R9is a hydrogen atom, an alkyl group with 1-3 carbon atoms or phenyl; X is carbonyl, thiocarbonyl or sulfonylurea group;

R1is an alkyl group with 1-4 carbon atoms, unsubstituted or substituted phenyl group, cycloalkyl group with 5-7 carbon atoms, phenyl, naphthyl, biphenylyl, diphenylmethyl, indolyl, Tieni the group, in which the phenyl nucleus may be mono-, di - or tizamidine identical or different substituents from the group comprising fluorine, chlorine or bromine, alkoxy with 1-4 carbon atoms and an alkyl with 1-4 carbon atoms, and one of the substituents can also mean trifluoromethyl, carboxyl, amino - or nitro-group;

R2is a hydrogen atom or alkyl with 1-4 carbon atoms;

R3- pyridyl;

R4and R5is a hydrogen atom or together denote a further carbon-carbon bond;

R6is hydroxyl or alkoxygroup with 1-3 carbon atoms;

n = 2,3 or 4,

mixtures of their isomers or individual isomers and their physiologically tolerable additive salts (if R6means a hydroxyl group), which have valuable pharmacological properties, particularly an antithrombotic effect

The invention relates to substituted pyridine deoxyadenosyl acids, in particular to the new 3R,5S-(+)-7-[4-(4-forfinal)-2,6-aminobutiramida 5-methoxymethyl-PI - Reid-3-yl]-3,5-deoxyadenosine acid in Erythro-(E)-configuration in the form of a physiologically tolerable salt of the metal, which serves as an inhibitor of the biosynthesis of cholesterol
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