3 carbalkoxy-5-(-aminoacyl)-5h-dibenz [b, f] azepine with antiarrhythmic action


C07D223/24 - with hydrocarbon radicals, substituted by nitrogen atoms, attached to the ring nitrogen atom

 

(57) Abstract:

The invention relates to 3-carbalkoxy-5-( -aminoacyl)-5H-dibenz/b, f/azepine, in particular compounds of the General f-crystals

,

where Y = -C(O)-(CH2)m-OTHER2(HCl)n; X = -(CH2)2-; and R1= R2= CH3m=n=1 or 2= m and n=1; b) R1= CH3, R2= C2H5or C2H4OH; m=n=1; R1=C2H5; R2=H or CH3, m=1, n=0 or 1; R1=R2=C2H5, m=1, n=0 or 1; d) R1=C2H5, R2=n-C3H7n-C4H9, m=1, n=0 or 1; f) R1=C2H5, R2=n-C6H13, cyclohexyl, n-C4H9m= n= 1; W) R1=C2H5, R2=C2H4OH, m=n=1 or m=2, n=1;C) R1= ISO-C3H7; R2=C2H5or tert-C4H9, m=1, n=0 or 1; R1=C2H4OH, m=1, n=0 or 1; R1=ISO=-C3H7, R2=CH3, m=1, n=0; l) R1=R2=C2H5, m=2, n=1; m) R1=C2H5, R2=C6H5CH2, m=1, n=0; n) R1=C2H5, R2=C6H5(CH2)2m=n=1; R1=C2H5, R2=CH3, m=1, n=0 or 1; p) R1= R2= C2H5

The invention relates to new chemical compounds of a number of dibenz/b, f/azepine, namely 3-carbalkoxy-5-(-aminoacyl)-5H-dibenz/b, f/azepine General formula

< / BR>
where (a) R1=R2=CH3X=-CH2-CH2-, m=n-1;

b) R1=R2=CH3X=-CH2-CH2-, m=2, n=1;

in R1=CH3, R2=C2H5X=-CH2-CH2-, m=n=1;

g) R1=CH3, R2=C2H5OH, X=-CH2-CH2-, m=n=1;

d) R1=C2H5, R2=H, X=-CH2-CH2-, m=1, n=0 or 1;

e) R1=C2H5, R2=CH3X=-CH2-CH2-, m=1, n=0 or 1;

W) R1=R2=C2H5X=-CH2-CH2-, m=1, n=0 or 1;

C) R1=C2H5, R2=n-C3H7X=-CH2-CH2-, m=1, n=0 or 1;

and R1=C2H5, R2=n-C4H9X=-CH2-CH2-, m=1, n=0 or 1;

K) R1=C2H5, R2=tert-C4H9X=-CH2-CH2-, m=n=1;

l) R1=C= , X=-CH2-CH2m=n=1;

n) R1=C2H5, R2=CH2CH2OH, X=-CH2-CH2-, m=n=1;

o) R1=C2H5, R2=CH2CH2OH, X=-CH2-CH2-, m=2, n=1;

p) R1=ISO-C3H7, R2=C2H5X=-CH2-CH2-, m=1, n=0 or 1;

R) R1=ISO-C3H7, R2=tert-C4H9X=-CH2-CH2-, m=1, n=0 or 1;

(C) R1=ISO-C3H7, R2=CH2CH2OH, X=-CH2-CH2-, m=1, n=0 or 1;

t) R1=ISO-C3H7, R2=CH3X=-CH2-CH2-, m=1, n=0;

u) R1=R2=C2H5X=-CH2-CH2-, m=2, n=1;

f) R1=C2H5, R2=C6H5CH2X=-CH2-CH2-, m=1, n=0;

x) R1=C2H5, R2=C6H5CH2X=-CH2-CH2-, m=n=1;

C) R1=C2H5, R2=CH3X=-CH=CH-, m=1, n=0 or 1;

h) R1=R2=C2H5X=-CH=CH-, m=n=1,

that possess antiarrhythmic activity and can be used in medicine.

The aim of the invention is the finding in a series of dibenz/b,f/azepine new compounds with higher antiarrhythmic activity, nacetyl-10,11-dihydro-5H-dibenz/b,f/ azepine (Ia).

A mixture of 2.4 g (0,006 mol) of 3-carbomethoxyamino-5-chloroacetyl-10,11-dihydro-5H-dibenz/b, f/azepine and 1.2 g (0.04 mol) of methylamine in 30 ml of toluene is heated in a steel cylinder (shaking occasionally) for 3 hours at a bath temperature of 40-50oC, and then 4 hours at 150-155oC. After cooling, the reaction mixture is precipitation, which is a mixture of original substances and hydrochloride of methylamine (chromatogram in acetone). The precipitate is filtered off, the toluene solution is evaporated to dryness to remove excess dimethylamine), the residue is dissolved in toluene and the addition of an ethereal solution of hydrogen chloride receive hydrochloride. Weight 1.2 g (46%); so pl. 254-256oC (from ethanol). Found, 61,15; N 5,98; N 11,38; Cl 8,58; C19H21N3O3HCl. Calculated C 60,70; H Of 5.89; Cl 9,40; N 11,18.

Example 2. 3 Carbomethoxyamino-5-(-methylamino)-propionyl 10, 11-dihydro-5H-dibenz/b,f/azepine (IB).

A mixture of 3.6 g (0.01 mol) of 3-carbomethoxyamino-5- (b-chloropropionyl)-10,11-dihydro-5H-dibenz/b, f/azepine, a solution of 3 g (0.1 mol) of methylamine in 15 ml of ethanol and 15 ml of toluene is heated in a steel container for 3 hours at a bath temperature of 40-50oC and then 4 hours at 130-140oC. After cooling the reaction mixture is distilled off, the excess methylamine and solvents, Maslenitsa base, dissolving it in toluene and the addition of an ethereal solution of hydrogen chloride allocate hydrochloride. Yield 2.5 g (69%); so pl. 182-183oC (from isopropanol).

Found, Cl 9,89; N 11,40.

C18H23N3O3HCl.

Calculated Cl RS 9.69; N 11,48.

Example 3. 3 Carbomethoxyamino-5-acylaminoacyl-10,11-dihydro-5H-dibenz/b,f/azepine (Ie).

A mixture of 7 g (0.02 mol) of 3-carbomethoxyamino-5-chloroacetyl-10, 11-dihydro-5H-dibenz(b,f)azepine and 25 g (0.18 mol of water 33%) solution of ethylamine are stirred while heating to 120 ml of toluene while gradually raising the temperature to 50oC for 1 h, the Original product is not fully dissolved, add 30 ml of ethanol and continue stirring while boiling for another 4 hours After cooling, the reaction mass is separated toluene layer is washed twice with water, distilled toluene and the residue is dissolved in 20 ml of isopropanol. The addition of isopropanol saturated with hydrogen chloride, allocate hydrochloride.

Weight of 5 g(63%); so pl. 241 to 243oC (from isopropanol). The white crystalline substance, soluble in water, when heated in spirits.

Found, C 61,07, 61,20; H 6,38; 6,40; Cl Is 9.09; 9,29.

C20H23N3O3HCl.

You,f/azepine (Iك).

The mixture 2,04 g (0,006 mol) of 3-carbomethoxyamino-5-chloroacetyl-10, 11-dihydro-5H-dibenz/b, f/azepine and 1.83 g (0.03 mol) of ethanolamine and 70 ml of toluene was stirred at 50-60oC for 40 min and then heated for another 3 hours at the boil. The reaction mixture is cooled, poured toluene with oily layer, the latter is washed twice with water, dissolved in toluene. The solution is dried with magnesium sulfate, the addition of ether saturated with hydrogen chloride, isolated chlorhydric.

The mass of 1.13 g (50%); so pl. 220oC (decomp. from ethanol). The white crystalline substance, soluble in water, when heated in spirits.

Found, C 57,33; 57,47; H 6,04; 6,03; Cl 9,26; 9,16.

C20H23N3O4HCl.

Calculated C 57,93; H 6,14; Cl 9,00.

Example 5. 3 Carbamaxepine-5-aminoacetyl-10,11-dihydro-5H-dibenz/b, f/azepine (Ia).

A mixture of 1.75 (0,005 mol) of 5-chloroacetyl-3-carbamaxepine-10, 11-dihydro-5H-dibenz/b,f/azepine and a solution of 1.7 g (0.1 mol of ammonia in 50 ml of ethanol is heated under pressure in steel cylinders (shaking occasionally) for 3 h at 56-58oC, then at a bath temperature of 140-150oC for another 4 h After cooling the reaction mixture, the solution is evaporated, the residue is dissolved in 120 ml of 5% hydrochloric acid. The acidic solution by"ptx2">

Found, C 67,62; H 6,38; N 12,11.

C19H21N3O3.

Calculated C 67,23; H 6,23; N 12,38.

From the alcoholic solution of the base by the action of ethereal solution of hydrogen chloride allocate hydrochloride, T. pl. 230-242oC (from ethanol).

Found, Cl 8,89; 8,59; N 10,98; Br11.01.

C19H21N3O3HClH2O.

Calculated Cl 9,00; N 10,67.

Example 6. 3 Carbamaxepine-5-(methylamino)-acetyl-10,11-dihydro-5H-dibenz/b,f/azepine (S).

To a stirred suspension of 108 g (0.3 mol 3-carpetcleaning-5-chloroacetyl-10,11-dihydro-5H-dibenz/b, f/azepine in 1500 ml of ethanol was added for 30 min at 15-20oC 700 g of an aqueous solution of methylamine (38%), heated for 0.5 h the mixture on a water bath to 50oC, kept at this temperature for 4 h and 1 h at 80oC. After cooling the mixture to 30oC added thereto under stirring 1900 ml of water and cooled water 3 tsp Loose sediment base is filtered off, washed with water, dried. Exit 98 g (83.2% of theory); so pl. 167-168oC (from acetone).

Found, C 68,15; H 6,63; N 11,83.

C20H23N3O3.

Calculated C 67,97; H 6,56; N 11,89.

The addition to the solution of the base aceton> Example 7. 3 Carbamaxepine-5-(ethylamino)acetyl-10,11-dihydro-5-N-dibenz-/b,f/azepine (If).

To a suspension of 72 g (0.2 mol) of 3-carbamaxepine-5-chloroacetyl=10, 11-dihydro-5H-dibenz(b,f)azepine in 1000 ml of ethanol is added with stirring 150 g (1 mol) of 30% aqueous solution of ethylamine. The mixture is heated 1 h at 60oC and then 4 h at 70-75oC. the Cooled mixture is then poured into 2500 ml of a mixture of ice water. Fell when standing base is filtered off, washed with water and dried. The output 71 g (98% of theory); so pl. 157-160oC (from acetone).

Found, C 68,65; H 6,98; N 11,24.

C21H25N3O3.

Calculated C 68,64; H 6,86; N 11,44.

The addition to the solution of the base in isopropanol solution of hydrogen chloride in isopropanol receive hydrochloride; so pl. 224-231oC.

Example 8. 3 Carbamaxepine-5-(n-propylamino)-acetyl-10,11-dihydro-5H-dibenz/b,f/azepine (Z).

To a suspension of 36 g (0.1 mol) 3-carbamaxepine-5-chloroacetyl-10, 11-dihydro-5H-dibenz/b, f/azepine in 250 ml of ethanol was added 20 g (0.33 mol) of n-Propylamine, the mixture is heated under reflux for 5 h, distilled 80-100 ml of ethanol, filtered. Fell when standing crystals of the base is filtered off and washed with a small quantity with the/SUB>N3O3.

Calculated C 69,27; H 7,13; N Br11.01.

The addition to the solution of the base in acetone solution of hydrogen chloride in n=propanol obtained chlorhydrate; so pl. 198-201oC (propanol).

Example 9. 3 Carbamaxepine-5-(n-butylamino)-acetyl-10,11-dihydro-5H-dibenz/b,f/azepine (AI).

To a suspension of 36 g (0.1 mol) 3-carbamaxepine-5-chloroacetyl-10,11-dihydro-5H-dibenz/b, f/azepine in 250 ml of ethanol was added 30 g (0.4 mol) of n-butylamine and the mixture is heated 4 hours at the boil under reflux. Drove about 50 g of ethanol, filtered. From the filtrate upon standing in the refrigerator falls crystals Foundation. Yield 33 g (83.4% of theory); so pl. 184-188oC.

Found, C 69,64; H 7,53; N 10,55.

C23H29N3O3.

Calculated C 69.85 Mm; H 7,39; N To 10.62.

The addition to the solution of the base in acetone solution of hydrogen chloride in isopropanol receive hydrochloride; so pl. 178-180oC (from isopropanol).

Example 10. 3 Carbamaxepine-5-(tert-butylamino)acetyl-10,11=dihydro-5H-dibenz/b,f/azepine (VBE).

To a suspension of 36 g (0.1 mol) 3-carbamaxepine-5-chloroacetyl-10, 11-dihydro-5H-dibenz/b,f/azepine added 22 g (0.3 mol) of tert=butylamine. The mixture is heated 5 hours at Keego the original substance). Transparent filtrate is mixed with a double volume of water deposited precipitate is filtered off (29 g). The residue purified by dissolving it in 20 ml of 1N. hydrochloric acid and 250 ml of ethanol and after the addition of filtration of ammonia. The resulting substance (27 g) dissolved again in a mixture of 70 ml of 1N. hydrochloric acid and 150 ml of ethanol, the solution is filtered and evaporated in vacuum to dryness. To the residue was added 200 ml of acetone, the mixture is boiled for 30 minutes under reflux and filtered. From the filtrate upon standing falls 13 g (28.9% of theory) of the hydrochloride with so pl. 182-186oC.

Found, C 61,50; H 7,18; Cl A 7.92; N Being 9.61.

C23H29N3O3HClH2O.

Calculated C 61,39; H 7,16; Cl 7,88; N 9,34.

Example 11. 3 Carbamaxepine-5-(n-hexylamino)-acetyl-10,11-dihydro-5H-dibenz/b,f/azepine (Il).

A mixture of 36 g (0.1 mol) 3-carbamaxepine-5-chloroacetyl-10,11-dihydro-5H-dibenz/b,f/azepine, 250 ml of ethanol and 35 g (0.35 mol) of n-hexylamine heated 4 hours at the boil under reflux, after which the reaction mixture is evaporated to dryness in vacuum. The residue is dissolved in 200 ml of chloroform, the solution is shaken several times with an equal volume of water, after which the chloroform layer is dried with magnesium sulfate and evaporated to dryness. The residue is dissolved in 250 ml isoprodol Foundation. The output of 18.5 g (43,7% of theory); so pl. 121-123oC.

Found, C 70,81; H A 7.85; N 9,95.

C25H33N3O3.

Calculated C 70,99; H A 7.85; N 9,92.

To isopropanolate stock solution after separation of the base is added a solution of hydrogen chloride in isopropanol. Precipitated hydrochloride is recrystallized from acetone. Yield 12 g (26.1% of theory); so pl. 200-210oC.

Found, C 65,50; H 7,30; Cl 7,72; N 9,16.

C25H33N3O3HCl.

Calculated C 65,27; H 7,45; Cl 7,71; N 9,13.

Example 12. 3 Carbamaxepine-5(cyclohexylamino)acetyl-10,11-dihydro-5H-dibenz/b,f/azepine (Ei).

A mixture of 36 g (0.1 mol) 3-carbamaxepine-5-chloroacetyl-10,11-dihydro-5H-dibenz/b,f/azepine, 250 ml of toluene and 30 g (0.3 mol) of cyclohexylamine heated 4 hours at the boil under reflux, after which the hot solution is filtered from the hydrochloride of cyclohexylamine. Toluene filtrate is washed several times with water, dried with sodium sulfate, the solvent is evaporated in vacuum. The residue is dissolved in a mixture of 100 ml of 2n. hydrochloric acid and 50 ml of ethanol. Fell when standing, the crystals are filtered and cleaning boiled with 400 ml of acetone. Yield 27 g (56,7%); so pl. 182-188oC.

Found, 7,45; N 8,83.

Example 13. 3 carbamaxepine-5-(b - acetylamino)-acetyl-10, 11-dihydro-5H-dibenzo/b,f/azepine (In).

To a suspension of 36 g (0.1 mol) 3-carbamaxepine-5-chloroacetyl-10, 11-dihydro-5H-dibenz/b,f/azepine in 200 ml of ethanol was added 19 g (0.32 mol) ethanolamine, heat a mixture of 4 hours at the boil under reflux, filtered, the solvent is distilled off and the oily residue is dissolved in 100 ml of acetone. To the acetone solution was added a solution of hydrogen chloride in isopropanol to pH 2-3 and leave in the refrigerator for crystallization. The crystals are filtered, washed with a small amount of cold acetone and dried. The yield 25 g (59,5% of theory); so pl. 204-208oC. After recrystallization from a mixture of isopropanol to acetone yield 15 g; so pl. 219-224oC.

Found, to 59.82; H 6,30; Cl 8,48; N9,81;

C21H25N3O4HCl.

Calculated C To 60.6; H 6,24; Cl 8,44; N 10,01.

Example 14. 3 Carbamaxepine-5-(b-acetylamino)-propionyl 10,11-dihydro-5H-dibenz/b,f/azepine (A).

A mixture of 3.7 g (0.01 mol) of 3-carbomethoxyamino-5- (b-chloropropionyl)-10,11-dihydro-5H-dibenz/b, f/azepine, 3 g (0.05 mol) of ethanolamine and 70 ml of ethanol is heated at 40-50oC for 1.5 h, and then heated for another 4 hours at the boil, the eye is), it is dried, dissolved in toluene, and the addition of ether saturated with hydrogen chloride, receive hydrochloride. Yield 2.6 g (60%); so pl. 186-187oC (from isopropanol).

Found, Cl 7,70,7,98; N 9,90,10,02.

C22H27N3O4HCl.

Calculated Cl 8,17; N 9,68.

Example 15. 3 Carisoprodolsoma-5-acylaminoacyl-10,11-dihydro-5H-dibenz(b,f)azepin (IR).

A mixture of 3.75 g (0.01 mol) of 3-carisoprodolonline-5-chloroacetamido-10,11-dihydro-5H-dibenz/b,f/ azepine, 10 g (0.04 mol) of an aqueous solution (33%) of ethylamine in water and 35 ml of toluene is heated under stirring while raising the temperature for two hours before the 50oC and then at this temperature and continue stirring for another 5 hours After cooling the reaction mass to room temperature, separating the toluene solution is washed with water, dried and the toluene is distilled off. The oily residue is dissolved in 20 ml of isopropanol, heated with charcoal, filtered and cooled in the refrigerator, roll a basis weight of 2.35 g (61%); so pl. 152-153oC (from toluene).

Found, 69,22; 69,37; H 7.23 Percent; 7,17.

C22H27N3O3.

Calculated C 69,26; H 7,13.

The base is dissolved in Toole and the addition of essential rest is 0,16; 60,16; H Of 6.96; 7,21; Cl 7,50; 7,43.

C22H27N3O3HClH2O.

Calculated C 60,61; H 6,93; Cl 8,13.

Example 16. 3 Carisoprodolonline-5-tertbutylamine-acetyl-10,11-dihydro-5H - dibenz/b,f/azepine (Ip).

A mixture of 3.7 g (0.01 mol) of 3-carisoprodolonline-5-chloroacetyl-10,11-dihydro-5P-dibenz/b,f/ azepine, 3.6 g (0.05 mol) of tert=butylamine and 30 ml of ethanol is heated, gradually increasing the temperature of the mixture to a boil (about 40 min). When this precipitate gradually dissolved, the mixture is boiled for 4 h, the solvent is distilled off, the oily residue is washed with warm water, roll a crystalline precipitate of the base, the mass of 3 g (75%); so pl. 154-156oC (from toluene).

Found, C 67,61; H 7,53; N 9,84.

C24H21N3O3H2O.

Calculated C 67,35; H To 7.77; N 9,83.

The base is dissolved in isopropyl alcohol and adding ether saturated hydrogen chloride allocate hydrochloride; so pl. 185-187oC (from isopropanol). The white crystalline substance, soluble in water and alcohol.

Found, C Totals 62.52, 62,41; H 7,31; 7,22; Cl 7,21.

C24H31N3O3HClH2O.

Calculated C 62,12; H 7,16; Cl Of 7.64.

Example 17. 3 Carisoprodolsoma-5(b-about the Ino-5-chloroacetamido-10,11-dihydro-5H-dibenz/b, f/azepine in 60 ml tool added 3.0 g (0.05 mol) of ethanolamine, the reaction mixture is stirred for 40 minutes at 35-40oC, then boil for another 4 hours Cooled to room temperature, poured toluene with oily mass, after the last two processing water zakristallizuetsya. The precipitate is filtered off, washed with water, obtain 2.5 g (57%) of the Foundation with so pl. 138-140oC (from ethyl acetate).

Found, N 10,96; 10,11.

C22H27N3O4.

Calculated, N 10,57.

The base is dissolved in 100 ml of toluene and addition of ether saturated with hydrogen chloride, allocate hydrochloride. Output 2 g; so pl. 160oC (decomp).

Found, C 6,38; 60,71; H 6,92; 6,95; Cl Of 7.90; 7,80; N Of 9.30; 9,34.

C22H27N3O4HCl.

Calculated C 60,89; H 6,50; Cl 8,16; N 9,68.

Example 18. 3 Carisoprodolsoma-5-methyliminodiacetic-10,11-dihydro-5H-dibenz/b,f/azepine (It).

Put 18 g (about 0.05 mol) of 3-carisoprodolsoma-5-chloroacetyl-10,11-dihydro - 5H-dibenz/b,f/azepine and 300 ml of ethanol (96%) in a three-neck flask with a capacity of 2 liters and under stirring at room temperature add 100 ml of 38% aqueous solution of methylamine (about 1.2 mol). Gradually heating on the water is. Hledat mixture until 30oC, add 750 ml of cold water, leave overnight, then added with stirring 400 ml of water, separated oily residue is washed with water, dissolved in 80 ml of acetone, the solution is filtered and allowed to crystallize by cooling. Yield 11 g (60% of theory); so pl. 150-152oC.

Found, C 68,70; H 6,95; N 11,32.

C21H25N3O3.

Calculated C 68,62; H 6,86; N 11,38.

Example 19. 3 Carbamaxepine-5-(b-ethylenepropylene)-10,11-dihydro-5H-dibenz/b,f/azepine (IV).

Suspended 37,3 g (0.1 mol) 3-carbamaxepine-5-(b-chloropropionyl)-10,11-dihydro-5H-dibenz/b, f/azepine in 250 ml of 96%alcohol, add 150 ml of a 33%aqueous solution of ethylamine in water and stirred the mixture for 6 h at 50-60oC. Evaporated volatile components of the mixture in vacuum to dryness, the residue is dissolved in 300 ml of 1N. HCl, treated with the solution at room temperature with charcoal, filtered and precipitated base by addition of concentrated ammonia solution. The precipitate is washed with water, extracted with ether, dried and added a solution of HCl in isopropanol to pH 2. Falls crystalline hydrochloride of 3-carbamaxepine-(5-b-ethylamino-propionyl)-10,11-dihydro-5H-dibenzazepine. Yield 3.6 g; so pl. 150oC.

Example 20. 3 Carbamaxepine-5-benzylaminocarbonyl-10,11-dihydro-5H-dibenz/b,f/azepine (F).

Suspension 18 g (0.05 mol) of 3-carbamaxepine-5-chloroacetyl-10,11-dihydro-5H-dibenz/b, f/azepine in 120 ml of ethanol, was added 20 g (about 0.2 mol) of benzylamine and heat the mixture for 5 h in a boiling water bath. After an hour comes complete dissolution of the precipitate, and does not drop the hydrochloride of benzylamine. Leave the mixture overnight in the refrigerator, the precipitated crystals of the base is filtered off and washed with water and ethanol. The basis of poorly soluble in dilute acid. So pl. 155-157oC.

Found, C 72,63; H 6,53; N 9,77.

C26H27N3O3.

Calculated C 72,70; H 6,34; N 9,78.

Example 21. 3 Carbamaxepine-5-(b-phenylethylamine)-10,11-dihydro-5H-dibenz/b,f/azepine (Ix).

To a suspension of 18 g (0.05 mol) of 3-carbamaxepine-5-chloroacetyl-10,11-dihydro-5H-dibenz/b, f/azepine in 150 ml of ethanol was added 6 g (about 0.06 mol) of triethylamine and 12 g (0.1 mol) b=phenethylamine and the mixture is heated 8 hours at the boil under reflux. The reaction mass is mixed with 800 ml of water, the separated oil is separated, dissolved in 150 ml of acetone, acidified by acid reaction by addition of 10 m the ptx2">

Found, N 8,46; Cl 7,55;

C22H29N3O3HClH2O.

Calculated N 8,44; Cl 7,38.

Example 22. 3 Carbamaxepine-5-methylaminomethyl-5H-dibenz /b,f/azepine (C).

To a suspension of 12 g (0,033 mol) of 3-carbamaxepine-5-chloroacetyl-5H-dibenz/b, f/azepine in 150 ml of ethanol is added 50 ml of approximately 35%aqueous solution of methylamine (approximately 0.5 mol MCH3NH2) and stirred the mixture for 5 h at 50-60oC. the Resulting light yellow solution is evaporated in vacuo to half volume, add excess water discharged oily base extracted with chloroform (250 ml), the organic layer washed with water, dried with sodium sulfate, the solvent is distilled off in vacuum. The remaining crystals melt at 143-153oC. Output 7,22,

The base is dissolved in isopropanol and adding HCl solution in isopropanol precipitated hydrochloride, which is filtered off, washed with a small amount of acetone and dried. Yield 6 g (46% of theory); so pl. 263-270oC.

Found, N 10,90; Cl 9,02;

C20H21N3O3HCl.

Calculated N 10,33; Cl 9,14.

Example 23. 3 Carbamaxepine-5-acylaminoacyl-5H-dibenz/b, f/azepine (C).

In the conditions of example 22 from theory) of the hydrochloride of 3-carbamaxepine-5-acylaminoacyl-5H-dibenz(b,f)azepine, so pl. 234-240oC.

Found, C Totals 62.52; H 6,36; N 10,42, Cl 8,57.

C21H23N3O3HCl.

Calculated C 62,76; H Of 6.02; N 10,46.Cl 8,82.

The results of pharmacological tests of the compounds I.

For testing has been used aqueous solutions of clorhidrato, and in those cases, when the selection of the crystal clorhidrato was difficult to apply the solutions of bases in the calculated quantity of hydrochloric, sulfuric or other acceptable acid.

The synthesized compound I showed in experiments on various models determine the antiarrhythmic action of the high activity and good tolerability. The activity of compound I compared to the activity of bonnechere hydrochloride of 3-carbamaxepine-5-dimethylaminoacetyl-10,11= dihydro-5H-dibenz/b,f/azepine).

Method of aconitine arrhythmia in rats. The study was performed according to the method of Femera. Control preparations were injected for 2 min intravenously or 60 min oral to aconitine (50 µg/kg). The current dose is the dose that reduces arrhythmia in the middle to separate cases of ventricular extrasystoles.

Method for the determination of acute toxicity. Used rats of both sexes: the drug was administered inside the animal investigated 3 4 dosage for every 10 animals (LD50he counted on Lichfield-Wilcoxon signed).

Method two-stage ligation of the coronary artery in dogs (Harris). Studies conducted on animals weighing 7-20 kg Under Nembutal anesthesia did the ligation of the coronary artery. The analyte was injected inwardly at 24 h after ligation on a background of reception of gastric arrhythmias.

Test data presented in the table.

As can be seen from the presented data, the compounds Ia, d, e, f, h, C exceed bonnekor on antiarrhythmic index. Compound Ia, e, W, C, m, n, R, C have a lower value of U73(i.e., more active) than bonnekor on the model of aconitine arrhythmia. Compounds Ia, b, C, d, e, l, n, o, R, p, s, t, u, f, x, C have a lower toxicity than bonnekor. The comparison of activity of substances by introducing them orally and intravenously (index suction) shows that the compounds Iك, d, e, g, h, I, K, m, n, p, t, u, f, h have greater bioavailability than bonnekor.

3 Carbalkoxy-5-( -aminoacyl-5H-dibenz[b,f]-azepine General formula

< / BR>
where R1R2CH3X CH2CH2-, m n 1;

R1R2CH3X-CH2CH2-, m 2, n 1;

R1CH3, R2UB>2
CH2-, m n 1;

R1WITH2H5, R2N, X IS CH2- CH2-, m is 1, n is 0 or 1;

R1WITH2H5, R2CH3X CH2CH2-, m is 1, n is 0 or 1;

R1R2WITH2H5X CH2- CH2-, m is 1, n is 0 or 1;

R1WITH2H5, R2THE H3H7X-CH2CH2-, m is 1, n is 0 or 1;

R1WITH2H5, R2H-C4H9X-CH2CH2-, m n1;

R1WITH2H5, R2tert-C4H9X-CH2CH2-, m n 1;

R1WITH2H5, R2THE H6H13X-CH2CH2-, m n1;

R1WITH2H5X CH2CH2-, m n1;

R1WITH2H5, R2CH2CH2HE, X-CH2CH2-, m n1;

R1WITH2H5, R2CH2CH2HE, X-CH2CH2-, m 2, n 1;

R1ISO-C3H7, R2WITH2H5X-CH2CH2-, m is 1, n is 0 or 1;

R1ISO-C3H7, R2tert-C4H9X-CH2CH2-, m is 1, n is 0 or 1;

R1ISO-C3H7, R2CH2CH5HE, X-CH2CH2-, m is 1, n is 0 or 1;

R1from> X CH2- CH2-, m 2, n1;

R1WITH2H5, R2- C6H5CH2X-CH2CH2-, m 1, n 0;

R1WITH2H5, R2- C6H5CH2CH2X-CH2CH2-, m n 1;

R1WITH2H5, R2CH3X CH=CH-, m is 1, n is 0 or 1;

R1R2WITH2H5X-CH=CH-, m n 1,

possessing antiarrhythmic action.

 

Same patents:

- aminopropionic)-5h-dibenz[b, f] azepine with antiarrhythmic activity" target="_blank">

The invention relates to new chemical compounds of a number of dibenz (b, f) azepine, namely 3-carbalkoxy-5- (-aminopropionic)-5H-dibenz (b, f) azepine General formula

where (a) X=-CH2-CH2-, R1=R2=CH3, R3=H, n=1;

b) X=-CH2-CH2-, R1=CH3, R2=CH2CH2OH, R3=H, n=1;

C) X=-CH2-CH2-, R1=C2H5, R2=R3=H, n=1;

g) X=-CH2-CH2-, R1=C2H5, R2=CH3, R3=H, n=0 or 1;

d) X=-CH2-CH2-, R1=R2=C2H5, R3=H, n=1;

e) X=-CH2-CH2-, R1=C2H5, R2=H-C3H7, R3=H, n=1;

W) X=-CH2-CH2-, R1=C2H5, R2=R3=CH3n=1;

C) X=-CH2-CH2-, R1=R2=R3=C2H5n=1;

and) X=-CH2-CH2-, R1=C2H5, R2and R3together = -(CH2)2O(CH2)2-, n=1;

K) X=-CH2-CH2-, R1=ISO-C3H7, R2=CH3, R3=H, n=0;

l) X=-CH2-CH2-5, R2=CH3, R3=H, n=0;

n) X=-CH=CH-, R1=R2=C2H5, R3=H, n=1,

that possess antiarrhythmic effect and can find application in medicine

Hypotensive agent // 2084225

The invention relates to new derivatives of diazepinone having valuable properties, in particular derivatives of diazepinone General formula (I)

< / BR>
where B is one of the divalent residues and) g)

< / BR>
and

X, l, m, n and R1R7have the following meanings:

X Gruppen or, if B denotes the divalent residue (a), a nitrogen atom,

l integer 1, 2 or 3,

m is an integer 1 or 2,

n is an integer of 1 to 4,

R1a hydrogen atom or an unbranched or branched alkyl with 1 to 6 carbon atoms,

R2a hydrogen atom, an unbranched or branched alkyl with 1 to 8 carbon atoms, unbranched or branched alkenyl with 4 to 6 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, unsubstituted or substituted by alkyl with 1 to 3 carbon atoms, substituted, phenyl, unsubstituted or substituted by one or two methyl groups or methoxypropane or one halogen atom, or phenylalkyl with 1 to 3 carbon atoms in the alkyl part, unsubstituted or substituted at the fragrance stands or methoxy group or a halogen atom,

R3and R4the same or the difference is,

R5a hydrogen atom or a chlorine or methyl,

R6and R7the same or different and denote hydrogen atoms or alkali with 1 to 3 carbon atoms, and, in addition, R7may also indicate a halogen atom,

mixtures of their isomers or their individual isomers and their salts, mainly their physiologically tolerated acid additive salts, in particular with pharmacological action

The invention relates to medicine, namely, neurology

The invention relates to organic chemistry, specifically to new biologically active compounds derived from polyunsaturated fatty acids, hydroxypregnenolone fatty acids and prostaglandins of General formula I:

< / BR>
where R the rest prostaglandin formula:

< / BR>
where one of the two groups at C-9 atom (R1or R2) a hydrogen atom, and the other hydroxyl (R2or R1or R1and R2together form a keto or hydroxyimino; and where one of the two groups at C-11 of the atom (R3or R4) a hydrogen atom, and the other hydroxyl (R4or R3or R3and R4together form a keto or hydroxyisopropyl; provided that R3and R4do not form a keto or hydroxyisopropyl when R1and R2together form a keto or hydroxyimino; and where one of the two groups at C-15 atom (R5or6) a hydrogen atom, and the other (R6or R5) hydroxyl or fluorine atom; the symbolrepresents a single or a CIS-double bond; or R is the residue of a prostaglandin of the formula:

represents a single or double bond, provided that R7or R8do not form a hydroxyl, when the C-10 and C-11 atoms connected by a double bond, or provided that if7or R8hydroxyl, C-12 and C-13 atoms are connected by the TRANS-double bond; and where one of the two groups at C-15 atom (R9or R10) a hydrogen atom, and the other (R10or R9) hydroxyl;

or R the rest of the prostaglandin type I formula:

< / BR>
where the group Q at C-5 of the atom the atom is iodine or bromine, the symbolrepresents a single or double bond, provided that Q is bromine or iodine, when the C-5 and C-6 atoms connected by a double bond;

or R residue of the unsaturated fatty acids of the formula:

< / BR>
where a 0 6, f 1 6, 1 7, provided that the total carbon chain length from 18 to 22 carbon atoms;

or R residue hydroxy acid of the formula:

< / BR>
where m 1 7 x 0 4, k 0 4, n is 0 to 3, provided that the total carbon chain length from 18 to 22 carbon atoms, and str is

The invention relates to gastroenterology

The invention relates to new heterocyclic compounds having valuable biological properties, in particular to derive dipyrido-diazepine General formula (I)

(I) where Z is oxygen, sulfur, group NCN иNOR9where R9lower alkyl;

R1hydrogen, hydroxyl, lower alkyl, lower alkenyl, lower alkenylacyl, lower alkoxyl, lower alkanoyl, lower dialkylaminoalkyl, lower alkoxyalkyl, lower alkylthiomethyl, benzyl;

R2hydrogen, lower alkyl, lower foralkyl, lower cycloalkyl, lower cycloalkenyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, cyano, phenyl, benzyl, lower alkoxybenzyl, methylsulphonyl;

R3hydrogen, hydroxyl, halogen, nitro, lower alkyl, lower alkoxy, amino, lower mono - or dialkylamino, lower alkynylamino, pyrrolidin-1-yl, pyrrolin-1 - yl, tetrahydropyridine-1-yl, morpholine-1-yl, piperidine-1-yl, methoxyphenylethylamine, methoxybenzylamine;

R4hydrogen, halogen, lower alkyl, nitro, amino;

R5hydrogen, hydroxyl, halogen, lower alkyl, lower alkoxy, trihalomethyl, lower oxyalkyl, cyano;

R8hydrogen, lower alkyl; and when Z is oxygen or sulfur, R2hydrogen, lower alkyl, lower alkenyl, lower quinil, lower alkoxyalkyl, lower alkylthiomethyl, lower alkanoyl, phenyl, benzyl, lower alkoxybenzyl; R3, R4, R5, R6, R7and R8a hydrogen atom or one of the substituents R3, R4, R5, R6, R7and R8the lower alkyl and the other substituents are hydrogen, or one of the substituents R3, R4, R5and R7the halogen and the other substituents R6and R8hydrogen, or one of the substituents R3, R4and R7nitro, and the remaining substituents R5, R6and R8hydrogen, or one of zamestitelei R3, R5and R6is hydroxyl, and the other substituents R4, R7and R8hydrogen, or one of the substituents R3, R4and R7amino and the other substituents R5, R6and R8hydrogen, or one of the substituents R3and R5alkoxy, and the other substituents R4, R6, R7and R8hydrogen, or R5lowest oxyalkyl or cyano, and R3, R4, R6, R7and R8hydrogen, or R7azido, and R3, R4, R5, R6and R83, R4and R5means butyl, and the other substituents R6, R7and R8mean hydrogen, and R6, R7and R8independently of one another denote hydrogen or lower alkyl, provided that at least one of them means hydrogen, or one of the substituents R6, R7and R8means butyl, and the other substituents R3, R4and R5mean hydrogen, R1does not mean hydrogen, lower alkyl, lower alkenyl, benzyl, lower alkanoyl, lower alkoxyalkyl and lower alkylthiomethyl, and their hydrates and pharmacologically tolerable salts have valuable biological properties, particularly an inhibitory effect on reverse transcriptase of the virus HIV-1, so that they can be used for prevention or treatment of AIDS

The invention relates to medicine and can be used to treat conditions involving increased adhesion - aggregation of platelets and for preservation of platelet-rich plasma

FIELD: veterinary science.

SUBSTANCE: a sow should be twice injected with oxytocin and, additionally, intramuscularly about 2-4 h after afterbirth detachment one should introduce clathroprostin at the dosage of 1 ml. The innovation suggested is very efficient in preventing metritis-mastitis-agalactia and endometritis in sows, as well.

EFFECT: higher efficiency of prophylaxis.

1 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

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

13 cl, 1 tbl, 30 ex

FIELD: medicine, cardiology.

SUBSTANCE: patient with stenocardia should be introduced with efficient quantity of omapathrylate or its pharmaceutically acceptable salt either separately or in combination with another pharmaceutically active agent. Another pharmaceutically active substance could be represented by organic nitrate, beta-adrenergistic blocking agent, blocking agent of calcium supply or antithrombocytic preparation. It is suggested to apply omapathrylate or its pharmaceutically acceptable salt to prepare medicinal preparations for treating and/or decreasing stenocardial symptoms.

EFFECT: higher efficiency.

16 cl, 2 dwg, 2 ex, 8 tbl

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

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

17 cl, 70 ex

FIELD: organic chemistry, medicine, pharmacy.

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

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

20 cl, 6 tbl, 192 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical tricyclic antidepressants combined with selective reverse serotonin capture inhibitors. Anxious version of subpsychotic level depressive syndrome of endogenous genesis being treated, intravenous drop-by-drop infusion of 2.-4.0 ml of 1% amitriptiline solution per 200 ml of physiologic saline is applied in 12-14 procedures combined with selective reverse serotonin capture inhibitor given per os, Zoloft is per os administered as the inhibitor at a dose of 50-100 mg. Then, supporting Zoloft therapy is applied at a dose of 100 mg during 3 months. Atypic version of depressive syndrome of subpsychotic level and endogenous genesis is treated with intravenous drop-by-drop infusion of 1.25% Melipramine solution at a dose of 2.0-4.0 ml per 200 ml of power supply source in 12-14 infusions combined with a reverse serotonin capture inhibitor. Paxyl is taken at a peroral dose of 40-60 mg as the inhibitor. Then, supporting Paxyl therapy is applied at a dose of 40-60 mg during 3 months.

EFFECT: enhanced effectiveness of treatment; reduced risk of complications; accelerated depressive syndrome relief.

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to method for production of synthetic chlorophyll (Chl) or bacteriochlorophyll (Bchl) derivatives of general formula I , wherein X is O;. Claimed method includes interaction under anaerobic conditions of Chl, Bchl derivatives containing COOCH3-group in C-132-position and COOR3-group in C-172-position in presence of tetraethyl orthotitanate. Further compounds of formula I wherein R1 and R2 are different radicals are obtained in aproton solvent such as peroxide-free tetrahydrofurane and dimethyl formamide, and compounds of formula I wherein R1 and R2 are the same ones are produced by using R1OH as a solvent. Derivatives of present invention are useful as stabilizers, linkage/spacer for binding another acceptable molecules to Chl/Bchl macrocycle.

EFFECT: simplified method for production of various chlorophyll or bacteriochlorophyll derivatives.

13 cl, 3 ex, 2 tbl, 8 dwg

FIELD: animals science.

SUBSTANCE: the present innovation deals with intramuscular injection of sodium salt preparation cloprostenol 30-45 min before placing at the dosage of 750 mcg/animal. The method provides increased reproductive function, enhances sexual reflex, increases the volume of ejaculate, concentration, activity and quality of spermatozoa.

EFFECT: higher efficiency of breeding.

2 ex, 3 tbl

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