SU1433411A3 - Method of producing derivatives of 2-(1h)-quinolon or pharmaceutically acceptable salts thereof - Google Patents

Abstract

The invention relates to quinoline derivatives and, in particular, to the preparation of compounds of the general formula Hel and n where Bet is imidazolyl, non- or mono-, or disubstituted CH, CFj or CN; R is hydrogen, CH, or their pharmaceutically acceptable salts, which selectively increase the strength of the contractions of the heart and do not affect the heart rate, which can be used to treat heart failure. The goal - the creation of new, more active and low-toxic substances of the specified class. Their synthesis is carried out by cyclization of the corresponding ethoxylated imidazole in the presence of conc. with the subsequent selection of the desired product in free form or as salt. New substances are active at a dose of 0.25 mg / kg with low toxicity

Description

 s

The invention relates to a method for producing new quinalone compounds — cardiac pacemakers, which selectively increase the force of myocardial contractions, but do not affect the heart rate and plesey for the treatment and prophylaxis of cadiological diseases, in particular, heart failure.

I The purpose of the invention is to obtain BifK quinolone derivatives.

Example 1. Preparation of 6- (1-dazolyl) -8-methyl-2- (1H) -quinolone.

Trans-1-G4-n- (3-Ethoxypropenes to) -3-methylfensh1 -imidazole (2.7 g) P9 parts are added with stirring in 98% by weight sulfuric acid (cm) at. After discharge for 24 hours at room temperature (20 ° C)

tphmperature carefully drink ice (200 g) —and the resulting solution is diluted with a saturated solution of kg; sodium carbonate to pH 8; the resulting mixture is extracted with a mixture of meta-Htjji / chloroform 1: 4 by volume (7 x X 1200 cm), the extracts are combined are evaporated over MgSO4, evaporated in Kuume and a solid is obtained KttTOppe is chromatographed on a silica gel (column of Merck MK 60.9385 and | methanol / chloroform 1:19 by volume as eluant. The corresponding fractions are collected and combined and get a solid white in which is recrystallized from ethyl acetate / methanol to give 6- (1-imidazolyl) -8-methyl-2 (1H) -quinolone, t, GW1. 259-262 ° C (1.71 g).

Found,%: C 69.2; H 4.9; N 18

C ,, H ,, N, 0

Calculated,%: C 69.3; H 4.9; N 18.6.

Examples 2-11. The following compounds were prepared according to the method described in Example 1, from the appropriately substituted trans-3-ethoxyprp (Phenamides or their hydrochlorides in Examples 4 and 5) and in the presence of 98% by weight of sulfuric acid (Table 1).

Example 12. Preparation of 6- (2,4-dimethylimidazol-1-yl) -8-methyl-2- (1H) -quinolone.

Trans-1-G4-K- (3-Ethoxypropenamine-55 to) -3-methylphenyl -2,4-dimethylimidazole (3.2 g) is added in portions in 98% by weight of sulfur acid (15 cm) at 0 ° C. After you have N 16.6.

24 hours at room temperature (20 ° C), the mixture is carefully poured onto ice (150 g) and the resulting solution is alkalinized to pH 8 with a saturated aqueous solution of sodium bicarbonate. The mixture is then extracted with a mixture of methanol / chloroform 1: 9 (6 x 100 cm), the organic extracts are combined, mixed with MgSO4 and evaporated in vacuo to give a solid, which is recrystallized from a mixture of ethyl acetate / methanol and 6 are obtained (2,4- dimethylimidazol-1-yl) -8-methyl2- (1H) -quinolone, so pl. 322.5- (1.0 g). Found%:

C, 71.4; H 6.1; N 16.7 Calculated,%: C71.1; H6.0;

C, ll ,, N, 0

Examples 13-17. The following compounds were prepared according to the procedure described in Example 12 from the corresponding trans-3-ethoxypropenamide and 98% by weight of sulfuric acid (Table 2).

Example 18. Preparation of 3,4-di-hydro-8-methyl-6- (1,2,4-triazol-1-yl) -2- (1H) -quinolone.

Suspension 6 (1,2,4-triazol-1-yl) -8-methyl 2- (1H) -quinolone (Example 9) in an amount of 1.7 g in ethanol (450 cm) is hydrogenated at 60 ° C and pressure 4, 13 X 10 Pa in the presence of SG, a palladium-on-charcoal catalyst (0.35 g) for 72 hours. Then the cooled mixture is filtered through Solkafloc (a trademark of cellulose-based filtering substance) and evaporated in vacuo, resulting in solid. This substance is subjected to chromatography on silica gel (Merck, MK 60.9385, trade mark.) Using chloroform / methanol 49: 1 as eluent, then the corresponding fractions are collected, evaporated in vacuum, a solid is obtained which is recrystallized from ethyl acetate / methanol and get 3,4-dihydro-8-methyl- (1,2,4-triaz1L1-yl) -2- (1H) -quinolone, so pl. 258-259 ° C (0.266 g). ,

Found,%: C 62.9; H 5.2; N 24.4.

with "n

Calculated,%: C 63.1; H 5.3;

N 24.5.

Examples 19-23. The following

Compounds are prepared as described in Example 18 by hydrogenation of a suitably substituted quinolone in ethanol in the presence of a palladium-on-charcoal catalyst (Table 3).

Example 2D Preparation of 8-methyl-6- (2,4-dimethyl-5-nitroimidazol-1-yl) -2- (1H) -quinolone.

In a stirred solution of 8-methyl-6- (2,4-dimethylimidazol-1-yl) -2- (1H) -quinolone (0.5 g) in concentrated sulfuric acid (4 cm) at 0 ° is added concentrated nitrogen acid (1 cm). The mixture is stirred for 1 hour, carefully poured onto ice (100 g) and the solution is made alkaline to pH 8 with solid sodium carbonate. The resulting suspension is extracted with dichloromethane (3 x 100 cm), the organic phases are collected, monolithic (MgSO4), filtered, evaporated and a foam is obtained, which is dissolved with a mixture of ethyl acetate / ethyl ether, and 8-methyl-6- is obtained. (2,4-dimethyl-5-nitroimidazol-1-Sh1) - 2- (1H) -quinolone, m.p. 244-247 ° C (0.52 g).

Found,%: C 60.0; H 4.8; N 19.3

C, SH, N40,

Calculated,%: C 60.4; H 4.7; N 18,8.

 —Example 25. 3,4-Dihydro-8-m-1-6- (2,4-dimethyl-5-nitroimidazol-1-yl) -2- (1H) -quinolone monohydrate, m.p. 198-201 s are prepared, as described in Example 24, by nitration of the corresponding 3,4-dihydroquinolone.

Found,%: C 56.5; H 5.2; N 18.1.

C, yH, 6N, 0,

Calculated,%: C 56.8} H 5.4; N 17.7.

Example 26. Preparation of 8-methyl-6- (5-amino-2,4-dimeshimimidazol-1-yl) -2- (1H) -quinolone dihydrochloride 1/4 hydrate.

A suspension of 8-metsh-6- (2,4-dimesh-1-5-nitroimidazol-1-yl) -2- (1H) -quinolone (2.26 g) in ethanol (5b) is hydrogenated under pressure (4 , 13 to X 10 Pa) in the presence of a René catalyst (0.2 g) for 3 hours. The cooled mixture is then filtered through. Solkafloc (trade mark), evaporated in vacuo and a dark oil is obtained, which solidifies when rubbed with an isopropanol mixture / ethyl acetate, whereby a solid (2 g) is obtained. A small amount of this substance is dissolved in

with

d 5 0 5

0

five

0

five

0 5

ethanol, triturated with fuming hydrogen chloride and obtained after filtering 8-methyl-6- (5-ammonium-2,4-dimethylimidaeol-1-sh1) -2- (1H) -quinolone dihydrochloride 1/4 hydrate, m.p. . 223 ° C.

Found,%: C 52.3; H 5.2; N 16.1.

C, 5H, gN4-2HCl-0.25 HjO

Calculated,%: C 52.7; H 5.4; 16.2.

Example 27, Preparation of 8-Methyl-6- (5-brone-2,4-dimethylimidazol-1-yl) -2- (1H) -quinolone,

To a stirred suspension of 8-methyl-6- (2,4-dimethylimidazol-1-yl) -2- (1H) -quinolone (0.5 g) in chloroform (10 cm), N-bromosuccinimide (NBS, 0.374 g) at room temperature. After 5 min, the reaction mixture is evaporated to dryness and the residue is chromatographed on silica gel (Merck MK 60.9385, trade mark), using ethyl acetate / methanap 10: 1 as eluent. The appropriate fractions are collected and evaporated and a solid is obtained which, when recrystallized from ethyl acetate / methanol, gives 8-methy-6- (5-bromo-2,4-dimethylimidazol-1-yl) -2- (1H) 7-quinolone, m.p. 2734 (0.277 g).

Found %: C 54.2: H 4.2; N 12.7.

C, 5H, 4KzVg

Calculated,%: C 54.2; H 4.3; N 12.7.

And p im e p. 28. Preparation of 8-bromo-6- (5 4-dimethylimidazol-1 -yl) -3,4-di-hydro-2- (1H) -chinapone.

In a stirred solution of 6- (2,4-dimethylimidazol-1-yl) -3,4-dihydro-2- (1H) -quinolone (0.2 g) in concentrated sulfuric acid (5 cm) is added bromine ( 0.045 cm) and silver sulfate (0.186 g). The mixture was stirred at room temperature for 15 hours, poured into ice (20 g) and the mixture was adjusted to pH 10 with 5 M, an aqueous solution of sodium hydroxide, extracted with dichloromethane (100 cm). The organic extract is dried (MgSO4), filtered, evaporated in vacuo to give a white solid. This substance is crystallized from ethyl acetate to obtain 8-bromo-6- (2,4-dimethylimidazol-1-yl) -3, D-di-hydro-2- (1H) -quinolone (0.15 g), t. pl, 242 C.

Found,%: C 52.3; H 4.4; N 12.8.

C ,, H, 4VgMzO

51A

Calculated,% C 52.5; H 4.4; N 13.1.

PRI me R-29. 8-Methyl-6- (5-nitro 4 metipimidap-1-yl) -2- (1H) -quinolone "1/4 HjO, mp, 306-309 C, is obtained in the same way as described in example 24, by nitration of 8-methyl-6- (4-m "Tilimidazol-1-yl) -2- (1H) -quinolone (Example 6).

Found,%: C 58.3; H 4.4; N 19.8.

C, 4 n-N405

Calculated,%: C 58.2; H 4.4; N 19.4.

Example 30 Preparation of 8-methyl-6 (5-iodo-2,4-dimethylimidazol-1-yl) -2 (1H) -quinolone "0.5.

Iodine monochloride (0.406 g) is added at room temperature to the over-M (sewable solution of 8-methyl-6- (2,4-dimethylimidazol-1-yl) -2- (1H) -quinoline (0.506 g) and acetate Sodium (0.328 g) in acetic acid (10 cm) was removed for 16 h. The volatiles were removed in vacuo and the residue was separated in a mixture of 211 aqueous solutions of sodium carbonate (.) 0 cm) and dichloromethane (50 cm). In (one phase is extracted once more with dichloromethane (2 x 50 cm), the organic extracts are collected, dried (1) (MgS04), filtered and evaporated under I vacuum. The residue is chromatographed on silica dioxide (Merck, MK 60.9385, trade mark), using ethyl acetate as an eluent. The appropriate fractions are collected, evaporated and a solid is obtained, which is recrystallized from a mixture of gilatacetate / methanol and a target compound is obtained, mp 242-254 0 (0.38 g).

I Found,,%: C 46.4; H 3.7; N 11.0. I С, 5Н „Ш, 0.1 / 2. Calculated,%: C H 3.9; N 10.8.

Example 31: Preparation of 8-methyl-6- (2,4-dimethylimidazol-1-yl) -2- (1H) -quinolone methaneulphonate, copium.

A stirred solution of 8-methyl-6- (2,4-dimethylimidazol-1-yl) -2- (1H) -quinolone (365.7 g) in methanol (914 cm) at 60 ° C is treated with methanesulfonic acid (141.9 d) within 5 min. Ethyl acetate (3.3 L) was added and the solution was allowed to cool to room temperature for 1 hour, after which it was cooled on ice for 2 hours. The solid was filtered, washed with ethyl acetate (450 cm),

0

five

BUT

five

0 5

0

five

0

five

116

in vacuum under vacuum and get the target compound, so pl. 282-228 ° C.

Found,%: C 55.0; H 5.6; N 12.2.

C, 6H ,, N, 0

Calculated,%: C 55.0; H 5.5; NJ2.0.

 Example 32. Preparation of 8-methyl-6- (5-cyano-2,4-dimethylimidazol-1-yl) -2- (1H) -quinolone.1 / 4.

A mixture of 8-methyl-6- (2,4-dimethyl-5-iodim1. Schazol-1 -yl) -2- (1H) -quinolone (0., 1 g), 1 lath (0.047 g) and palladium acetate ( 0.01 g) in N-methyl-2-pyrrolidone (1 cm) is heated and stirred for 3 hours. The cooled mixture is poured into aqueous ammonia solution (10 beats, weight 0.880) and dichloromethane (50 cm) and the aqueous phase again extracted with dichloromethane (2 X 50 cm). The organic extracts are collected, dried (MgSO4), filtered, evaporated in vacuo and the residue is chromatographed on silica (Merck MK 60.9385, trade mark), using dichloromethane / methanol 19: 1 as eluent. The appropriate fractions are collected, evaporated and an oil is obtained, which crystallizes upon dissolving with diethyl ether, to give the desired compound, m.p. 334-337 C (0.03 g).

Found,%: C 68.0; H 5.1; N 20.1.

S, YN, 4MzO

Calculated,%: C 68.0; H 5.3; N 19.8.

PRI me R s 33 and 34. According to the method of example 32 using as starting compounds 6- (2-methyl-4-iodoimidazol-yl) - or 6- (4-methyl-2-iodimidazol-1-yl ) -B-methyl-2- (1H) -quinoline, copper (I) cyanide and palladium acetate and N-methyl-2-pyrolidine as the solvent, the following substances were obtained (Table 4).

Example 35. Preparation of 6- (2- iodo-4-methylimidazol-1-yl) -8-methyl-2- (1H) -quinolone.

A solution of n-butyl lithium (2.94 cm of a 1.43 M solution in n-hexane) is added dropwise to a stirred suspension of 6- (4-methyl-imidazol-1-yl) -8-methyl-2- (1H) -quinolone in the amount of 0.45 g (example 6) in tetrahydrofuran (25 cm) at -70 ° C in nitrogen. After one hour, iodine is added and the mixture is heated for 1.5 hours to room temperature.

7 | 4

temperature Then a solution of ammonium chloride (5 cm) was added and the mixture was poured into water (20 cm). The aqueous mixture is extracted with dichloromethane (3 x 50 cm), combined and the dried (MgSO4) organic extracts are evaporated in vacuo to give a residue, which is chromatographed on silica (Merck MK 60.9385, trade name). By washing with chloroform followed by combining the appropriate fractions and evaporating them, a solid is obtained, by recrystallization of which from ethyl acetate, 6- (2-iodo-4-methylimidazol-1-yl) -8-methyl-2- (1H) -quinolone is obtained, t pl. (with decomposition) 260 C (0.22 g).

Found,%: C 44.7; H 3.6; N 10.6. C, dN, N, 01 2/3

Calculated,%: C 44.6; H 3.5; N 11.1.

Example 36. 6- (4-iodo-2-metsh1I-midazol-1-sh1) -8-methyl-2- (1H) quinolone 1/3, t. Pl. 285-287 C, prepared according to the procedure of Example 12 based on trans-1-4-H- (3-ethoxypropenamide) 3-3-methylphenyl-4-iodo-2-methylimidazole in the reaction with 98% by weight sulfuric acid slot

Found,%: C 45.3; H 3.3; N 11.3.

C, H, N, 01-1 / 3

Calculated,%: C 45.3; H 3.4; N 11.3.

Receipt. trans-1-C4-c- (3-Ethoxypropamide) g-3-mets1phenyl imidazole.

trans-3-Ethoxypropenoyl chloride (3.655 g) is added dropwise while

O C in a stirred solution of 1- (4-amino-3-methylphenyl) imidazole (4.325 g) in anhydrous pyridine (30 cm), the solution is stirred at room temperature for 4 hours, then the pyridine is distilled off in vacuum and the residue is separated in a mixture chloroform (150 cm) and a saturated solution of sodium carbonate (20 cm). Then, the aqueous phase is extracted with chloroform (2 X 50 cm), the extracts are collected, dried (MgSO4) is evaporated and an oil is obtained which is chromatographed on silica (Merck MK 60.9385) using methanol / chloroform 3:97 as eluant by volume. The appropriate fractions are collected, evaporated and an oil is obtained which is triturated with ethyl acetate / simple diethyl 18

The new ester crystallizes, resulting in the target compound, tons. 141-1444 (2.75 g).

Found,%: C 69.0; H 6.4; N 24.0.

C, H7 NsOi.

Calculated,%: C 69.3; H 6.4; N 24.3.

Receive 2-11. The following compounds are prepared analogously, using the corresponding 1-substituted anilines as the starting compounds.

Oel

Hei

N - O R N

The anilines used in preparations 2, 3, 8 and 11 are known compounds. The compounds obtained are described in Table. five.

These intermediates are purified by evaporation of the pyridine solvent in vacuo, followed by chromatography of the crude hydrochloride salt on silica.

Preparation 12. 1- (4-Amino-3-methylphenyl) -imidazole.

Tin-chloride dihydrate (55.0 g is added in portions to a stirred suspension of 1- (3-methyl-4-nitrophenyl) -imidazole (10.0 g) in anhydrous ethanol (100 cm). The mixture is heated at reflux temperature for 4 hours, then cooled, basified to pH 8 with 2.5 M aqueous sodium hydroxide solution and filtered. The filtrate is evaporated in vacuo, separated in a mixture of chloroform (100 cm) and water (50 cm), then the iodine layer is extra - bathed in chloroform (3 x 50 cm). The extracts are combined, defused (MgS04), concentrated in vacuo, to obtain a solid compound, which is crystallized from ethyl acetate to yield - (4-amino-3-metilfe1shl) imidazole, mp 131-134 ° C (A, 7 g)...

Found%:

C ", H" N3

Vmsleno, N 24.3.

Receive 13-18. The following compounds are prepared analogously, using as the starting compounds the corresponding image 1 for the substituted nitrobenzene and tin dichloride derivatives.

C 69.0; H 6.4; N 24.0, Z: C 69.3; H 6.4;

Pe

A: The nitrobenzene used in the preparation of 14 is a known Q-compound. The resulting nitrobenzenes fisan in table. 6

I Comm., Inion is obtained as a mixture of the Q derivative of the preparation of 15, the mixture is separated by chromatography on silica-silica (Merck MK 60.9385) using hporoform / methanol 49: 1 as an eluant by volume. The appropriate fractions are collected, evaporated in vacuo, recrystallized and the pure product is obtained.

j Preparation 19. 6-Amino-8-1 ethyl-2- (1H) -quinolone, m.p. 290 ° C (decomposition), receive, as described

in | Example 1, by ring closure of TpaHC-N- (4-aMnHo-2-methylphenyl) -3-ethoxypropaneamide using co-centri-sulfuric acid.

Found,%: C 56.7; H 5.3; N 13.3.

SL and

,

Calculated,%: C 57.0; H 5.2; N 13.3.

Specified propenamide, so pl. 14U-142 ° C, is obtained by tin dihydrate by reduction of the corresponding 4-nitro derivative according to Preparation 12.

Found,%: C 64.8: H 7.4; N 12.2. C, g 1b-gO, -1- / 8 Calculations: leno,%: C 64.8; H 7.3; N 12.6. i

4-nitro-derivative, namely trans-H- (4-nitro-2-methylphensh1) -3-ethoxy (1

Propenamide, T. pl. 171-173 C, is obtained by reaction of 2-methyl-4-nitroaniline with trans-3-ethoxyprooenoyl chloride in accordance with the procedure described in the preparation of

Found,%: C 57, 9; H 5.8; N

.

Calculated,%: C 57.6; N 11.2.

P o luch H and e 20, 4-nitrophenyl) imidazole.

1. 11.3,

H 5.6;

1- (3-Methyl

im and yes ash / 2 co 3

-jgQ dimethylsorpamide

A mixture of 4-fluoro-2-methylnitrobenzene (15.5 g), imidazole (6.8 g) and sodium carbonate (11.1 g) is heated for 24 hours in dimethylforme- itefle. The mixture is then concentrated in vacuo, the residue is acidified to pH 1 with 4 M hydrochloric acid and the resultant solution is extracted with chloroform (2 x 25 cm). The aqueous phase is alkalinized to pH 10 with 2.5 M sodium hydroxide solution and the mixture is extracted with chloroform (3 x YuOsm. The organic extracts are dried (MgSO4), evaporated and 1- (3-methyl-4-nitrophenyl) imidazole is obtained, so pl. 12-115 with (10.0 g).

Found,%: C 58.9; H 4.4; N 20.7

S (oNch NjOi

Vyisleno,%: C 59.1; H 4.5; .N20.7.

Returns 21-25. The following compounds are prepared analogously, using the appropriately substituted fluoronitrobenzenes, the corresponding heterocyclic compounds.

3

|

N0.

SNS

and sodium carbonate as starting compounds (Table 7).

Preparation 26. Trans-1- 4-H- (3-Ethoxypropenamido) 3-Methylphenyl | -2,4-dimethylimidazole.

trans-3-Ethoxypropenoyl chloride (4.56 g) is added dropwise at 0 ° C to a stirred solution of 1- (4-amino-3-methylphenyl) -2,4-dimethylimidazole (6.5 g) in anhydrous pyridine (40 cm). The solution is stirred for 2 hours at room temperature, then the pyridine is distilled off in vacuo and the residue is separated in a mixture of chloroform (150 cm) and a saturated aqueous solution of sodium carbonate (30 cm). Then the aqueous phase is extracted with chloroform (2 x 100 cm), the organic extracts are combined, dried (MgSO4), evaporated and an oil is obtained, which is chromatographed on silica, silica (Merck MK 60.9385, trade mark) using methanol / chloroform as an eluent 1:19 by volume. The corresponding fractions {are collected, evaporated and an oil is obtained which crystallizes by rubbing it with diethyl ether, resulting in a target compound (6.3 g). Recrystallization of a small amount of the compound from ethyl acetate gives microcrystals, t, pl. 142.5-144 ,,

Found,%: C 68.5; H 7.1; N 13.9

Calculated,%: C 68.2; H 7.1; N 14.0.

Preparation 27-31. The following

Compounds are prepared as described in Preparation 25, using respectively substituted aniline (as the hydrochloride in Preparations 27 and 29) and trans-3-ethoxy-propenoyl chloride as starting compounds (Table 8).

Getting32. 1- (4-Amino-3-methylphenyl) -2,4-dimethylpimidazole.

Tin chloride dihydrate (40.7 g) is added in portions to a stirred suspension of 1- (3-methyl-4-nitrophenyl) -2,4-dimethylimidazole (8.3 g) in anhydrous | 1 ethanol (100 cm ). The mixture is heated at reflux for 4 hours, then cooled and basified to pH 8 with 2.5 M aqueous sodium hydroxide solution and filtered. The filtrate is evaporated in vacuo, separated in a mixture of chloroform (500 cm) and water (50 cm -), and the aqueous phase is further extracted with chloroform (2 x 100 cm). The organic extracts are combined, dried (MgSO4), concentrated in vacuo to give a solid (6.8 g), which is recrystallized from ethyl acetate and give 1- (4-amino-, 3-methyl-phenyl) -2.4 -dimethylimidazole, so pl. 92-9b C.

Received 33-36. The following compounds were prepared as described in Preparation 32, using the appropriately substituted nitrobenzene derivative and tin chloride dihydrate as starting compounds.

In Preparation 33, the free base is converted to the hydrochloride salt by performing reaction with hydrogen chloride in diethyl ether. The hydrochloride salt is used (Preparation 28) in the next step (Table 9).

Preparation 37. 4- (4-amino-3-methylphenyl) -1,2,4-triazole.

o

five

0

0

c 5 0

five

A solution of 4 - (, 3-methyl-4-nitrophenkl) 1,2,4-triazole (1.0 g) in acetic acid (23 cm) is hydrogenated to equip 25 ° C and pressure 4.13 x 10 Pa over the René catalyst ( 0.2 g) for 2 hours. The mixture is then filtered through Sol-kafloc (trademark of cellulose-based filtering substance), the solvent is evaporated in vacuo and the residue is separated in a mixture of chloroform (100 cm) and aqueous sodium carbonate solution (20 cm ). The aqueous phase is again extracted with chloroform (3 x X 50. Cm) the organic extracts are collected, dried (MgSO4), concentrated and an oil is obtained which is chromatographed on silica (Merck MK 60.9385, trade mark) using methanol / ethyl acetate 1 as eluent :9. The appropriate fractions are collected, evaporated and a solid is obtained which is recrystallized from ethyl acetate / hexane to give 4- (4-amino-3-methylphenyl) -, -2,4-triazap, m.p. 152- (0.67 g).

Found,%: C 62.0; H 5.6; N 31.8.

C,

Calculated,%: C 62.1; -N 5.7; N 32.2.

Getting 38. Follow the connection, so pl. 230 ° C is prepared as described in the previous preparation, using 1- (3-methyl-4-nitrophenyl) -4-trifluoromethylimidapaz and the ene / Hl catalyst as starting compounds, but instead of acetic acid, ethanol is used as a solvent. The resulting product is converted to the hydrochloride salt by reacting with hydrogen chloride in diethyl ether.

This hydrochloride salt is used in the next step (Preparation 27).

Found %: C 47.5; H 4.1; N 15.2.

C ,, H, oF, N, -HCl

Calculated,%: C 47.6; H 4.0;

N 15.1. I

Preparation 39. 1- (3-Methyl-4-nitrophenyl) -2,4-dimethylimidazole.

A mixture of 5-4 torus-2-nitrotoluene (10.3 g), 2,4-dimethylimidazole (6.36 g) and sodium carbonate (7.5 g) is heated while moving in dimethylformamide (40 cm) at 130 ° C for 40 hours. Then the cooled mixture is concentrated in vacuo, the residue

acidified to pH 10 with 4 M hydrochloric acid, the resulting solution extracted with chloroform (2 x 25 cm). to remove all neutral compounds. The aqueous phases are collected, alkalinized to pH 10 with 2.5 M piacTBopa, sodium hydroxide and the mixture is extracted with chloroform (3 x 250 cm), the organic extracts are combined, dried (MgSO4) and concentrated in vacuo to give a solid compound, which is chromatographed on a dioxide silicon (Merck MK 60.9385 trademark), using methanol / ethyl acetate 19 as the eluent. The appropriate fractions were combined, evaporated and a solid I substance (8.4 g) was obtained, which was recrystallized from ethyl acetate and 1- ( 3-methyl-A-nitrophenyl) -2,4-jElmethyl idazol, m. pl. 135.5-138 C.

Found,%: C 62.0; H 5.7; N 17.9.

С, г11 „НЗО-1

Calculated,%: C, 62.3; H 5.7;

18.2.

Preparations 40-44. The following Compounds are prepared as described in Preparation 39, using the corresponding fluorine nitrobenzene, as appropriate, using the appropriate heterocyclic compound and sodium carbonate as starting materials (Table 10),

Preparation of 45, 4- (3-Methyl-4-nitrophenyl) -1,2,4-triazole.

A mixture of 5-amino-2-nitrotoluene (2.0 g) of deformylhydrazine (1.3 g) is heated under nitrogen atmosphere for 1 hour at 200 C. Then the residue is cooled and chromatographed on silica (Merck MK 60.9385, commercial mark) using a mixture of methanol / dichloromatane Is 19 as eluent. The appropriate fractions are combined, evaporated and a solid compound (1.03 g) is obtained, which is recrystallized from ethanol to give 4- (3-metsh-1-4-nitr ) -1,2,4-triazole, so pl. 208-210 C.

Found,%: C 52.8; H 4.0; N 27.3.

CcjlleN o

Calculated C, 52.9; H 3.9;

N 27.4.

35

40

45

Paul U.E.I.E. 48. 1- (4-amino-3-trifluoromethylphenyl) 2,4-dimesh1imida3 OL ..

Ethanol (300 cm) is added to 1- (4-nitro-3-trifluoromethylphensh1) - 2,4-dimethyl-disdazole (29, Og) and the mixture is hydrogenated at 50 ° C and a pressure of 3.23 x 10 10 Pa. in the presence of 5% palladium catalyst on charcoal (2 g) for 16 hours. The mixture is then filtered through Solkafloc (trade mark), the solvent is evaporated in vacuo and a pale yellow solid is obtained (25.8 g). A small amount of recrystallized from a mixture of ethyl acetate / hexane and receive 1- (4-amino-3-trif-50 tormetgshphenyl) -2,4-dimethylimidazole, so pl. 126-7 sec.

Found,%: C 56.5; H 4.8; N 16.6. .C.,

Calculated%; C 56.5; H 4.7;

Getting 46. 4- (4-Nitro-55NJ6.5, 5.

3-trifluoromethylphenyl) -1,2,4 triazole. Preparation 49. 4- (4-Amino

Next connection, t, pl. 10.0C, 3-trifluoromethylphensh1) -1,25.4-triazole. is obtained as described in the previous report

Preparation using 4-nitro-3-trif-C9H7NjF

%; C 47.7; H 3.2; N 24.9.

tormethylaniline and 1 ,, 2-diformylhydrazcn 3 as starting compounds

 N.

0

j 0

five

five

0

five

N0

2

CPH Found,%: C 41.9; H 2.0; -N 21.7.

CqHjN FpOz

Vyisleno,%: C 41.6; H 2.1;

N 22.2;

P o luch H 47. 1- (3-Methyl-4-nitrophenyl) tetrazole.

1- (3-Methylphenyl) tetrazole (11.3 g) was carefully added at 0 ° C to fuming nitric acid (100 cm) with stirring and then the solution was heated on the steam bath for 5 minutes. The cooled solution is poured onto ice (200g) and the solid is filtered off, washed with water (100 cm) and dehydrated. After recrystallization from ethyl acetate, 1- (3-methyl-4-nitrophenyl) tetrazole is obtained. M. Pl. 166-168 ° C (9.4 g).

Found,%: C 47.0; H 3.4; N 34.5.

C,

Vyisleno,%; C, 46.8; H 3.4; , 2 ,,

1- (3-Methylphenyl) tetrazole is a known compound.

Paul U.E.I.E. 48. 1- (4-amino-3-trifluoromethylphenyl) 2,4-dimesh1imida3 OL ..

Ethanol (300 cm) is added to 1- (4-nitro-3-trifluoromethylphensh1) - 2,4-dimethyl-disdazole (29, Og) and the mixture is hydrogenated at 50 ° C and a pressure of 3.23 x 10 10 Pa. in the presence of 5% palladium catalyst on charcoal (2 g) for 16 hours. The mixture is then filtered through Solkafloc (trade mark), the solvent is evaporated in vacuo and a pale yellow solid is obtained (25.8 g). A small amount of recrystallized from a mixture of ethyl acetate / hexane and get 1- (4-amino-3-trif-0 tormetgshphenyl) -2,4-dimethylimidazole, so pl. 126-7 sec.

Found,%: C 56.5; H 4.8; N 16.6. .C.,

Calculated%; C 56.5; H 4.7;

5NJ6.5, 5.

ilfensh1) -1,25.4-triazole.

%; C 47.7; H 3.2; N 24.9.

Calculated,%: C 47.4; H 3.1; N24.6.

Getting 50 (alternative to getting 32). 1- (4-Am1sho-3-methyl-3) enyl) -2,4-dimethylimidazole. .

The following compounds are prepared as described in Preparation 48, using 1- (3-methyl-4-nitrophenyl) -2,4-dimesh-1-nmidazole in the presence of 5% palladium on charcoal catalyst H as starting compounds and ethanol as a solvent. . The crude solid compound at 78-82 s melts. After recrystallization from toluene

receive 1- (4-amino 3-methylphenyl) - 2,4-dimethylimidazole, so pl. 118-120 С

Found,%: C 71.0; H 7.6; N20.8.

Ci, H, 5N5

Calculated,%: C 71.6; H 7.5;

N 20.9.

Pr olec tion 51. 4-Nitro trifluoromethylaniline.

A solution of ammonia in water (100 cm, sp. Weight, 0.88) was added to 3-trifluoromethyl-1-4-nitrofluorobenzene (5 g) and the mixture was heated in a sealed tube at 150 ° C for 2 hours. in vacuum and get a solid yellow compound. After recrystallization of this compound from a mixture of hexane / ethyl acetate, yellow crystals of 4-nitro-3-trifluoromethylaniline are obtained, m.p. 134 C (3.5 g).

Found,%: C 41.0; H 2.4; N 13.5.

C HjNjF,

Calculated,%: C 40.8; H 2.4; , 6.:

3-Trifluoromethyl-4-nitrofluorobenzene is a known compound.

Preparation 52. trans-1-4-LN- (3-Ethoxypropanamide) 3 -3-methylphenyl 1-4-iodo-2-methylimidazole, mp, 172-174 C, is prepared according to the procedure of Preparation 1, using as starting materials, 1- (4-amino-3-methylphenyl) - 4-iodo-2-methylimidazole and trans-3-ethoxypropenoyl chloride, and anhydrous pyridine as solvent,

Found,%: C 46.8; H 4.5; N 10.1.

, vN, Oa1. .

Calculated,%: C46.7; H4.4; N 10.2.

Preparation 53. 1- (4-Amino-3-methylphenyl) -4-iodo-2-methylimidazole and further used as a crude oil are prepared by the method of preparative method for 12 s.

using 1- (3-methyl-4-nitrophenyl) -4-iodo-2-methyl-1-imidazap and tin (II) chloride dihydrate as starting materials and absol (from ethanol) as a solvent.

Preparation 54. 1- (3-Methyl-4-nitrofensh1) -4-IOD-2-methyl-imidazole 9 t. Mp, 146-148 C, prepared according to the method of preparative method 20 using 4-fluoro-2- as the starting material. methylnitrobenzene, 4-iodo-2-methylimidazole and sodium carbonate and dimethylformamide as solvent.

Found,%: C 38.5; H 3.1; N 12.4,

C, H, oN, OeI

Calculated,%: C 38.5; H 2.9; N 12.2.

Preparation of 55, 4-iodo-2-methylimidazole.

A solution of n-tubnalliti (86 cm of a 1543 M solution in n-hexane) is added dropwise at -70 ° C in nitrogen to a stirred solution of 4,5-diiod-2-methyl-dazole (20.5 g) in tetrahydrofuran (300 cm) . After 15 minutes, water (20 cm) was added and the mixture was warmed to room temperature over 1 hour. The mixture is then evaporated in vacuo to a small volume, water (50 cm) is added again, the pH is adjusted to 8 with 2M hydrochloric acid, the aqueous layer is extracted with dichloromethane (Eh 150 cm) and the combined and dried (MgSO4) extracts are evaporated in vacuum to obtain a residue that is chromatographed on silica (Merck, brand name MK 60.9385). Washing with ethyl acetate followed by combining the appropriate fractions and evaporating them gives 4-iodo-2-methylimidazole as a solid (9 g ), characterized spectrally and used without cial treatment.

Getting 56, 4,5-Diyod-2-methylimidazal,

A solution of iodine monochloride (32.5 g) in dichloromethane (100 cm) is added dropwise over 1.5 hours at -70 ° C in nitrogen to a solution of 2-methyl imidazole (8.2 g) and triethylamine (20.2 g in dichloromethane (200 cm), the mixture is stirred for another 30 minutes, then poured into water (200 cm). The precipitate formed is filtered, dried and recrystallized from a mixture of ethyl acetate and hexane to give 4,5-diiodo-2 -methylimidazole (18.5 g), characterized by spectral methods and directly used without further purification.

The following three compounds are tested:

(example 2)

dJH

Example 2 causes a maximum decrease in the QA interval, amounting to about 15 m / s at a dose of 0.5 mg / kg 2 (i.e., a 0.25 dose of IR-59.571), similarly, the compound in Example 12 causes a maximum decrease in the QA interval approximately 17 m / s at a dose of 0.25 mg / kg (i.e.

to 0.125 dose of IK-59,571 input). The compound according to example 33 is effective to the same extent.

Thus, the obtained data demonstrate significantly more you (example 12) - a low activity of the proposed compounds compared with the compound IR-:. 59,571 when administered orally to dogs that have not lost pain. This difference in activity is active.

20 VIA in oral administration confirms a significant improvement in the offerings of the compounds compared with the compound complying with European patent No. 52016 in the treatment of heart failure with congestion.

(example 33)

Structural equivalent has the formula

ethyl

 JK-59,571

Test Method

45

Four dogs were used. The results presented are the average of the values obtained for four dogs. Known compound., Pack is shown. the data of its pharmakalogi-40 :: eskoy activity, manifests itself the most effective inotropism in Vitro conditions (right atrium of the dog). As shown by experiments on dogs that have not lost pain, this compound exhibits a slight inotropic effect or does not show it at all after oral administration of a dose of 2.0 mg / kg. At the same time, three proposed compounds were tested, on the same lines with (5, those not subjected to anesthesia, using identical test methods, but with the administration of lower doses of these compounds, which, in contrast to the above, showed significant inotrpry activity even with more low doses. For example, the compound

50

55

0

five

five

0

0

five

Moreover, the compounds belong to the category of low toxicity. In particular, the compound of Example 2 was administered orally with a dose of 40 mg / kg and into an organism of rats and mice in a dose of 40 mg / kg, and animals tolerated this drug well, no deaths were detected. These doses translate into a minimum effective oral dose for dogs 640 and 160 times, respectively. When this compound is administered, it is administered in rats for 1 month as a single daily dose of 1; 3 or 10 mg / kg no significant toxicological effects were found. In addition, when administered to dogs for 1 month with a total daily dose of 0.25; 0.5 or 1.00 mg / kg no significant toxicological effects were also detected.

The test method.

Four breed dogs were used looking for her (males), not anesthetized, with normal blood pressure (Coloni Pfizer, weighing 12–16 kg). Each animal was previously subjected to surgery to prepare the right carotid loop and to insert two subcutaneous titanium pins (located in the dorsal-cervical and dorsal-lumbar regions). Carotid pulse

N k.N

SNS

250-260 (decomposition)

-N Free 69.4 (69.3) 5.0 (4.9) 18.9 (18.6) basis

SNS

-CH, Free 70.3 (70.3) 5.6 (5.5) 17.2 (17.6) basis, 295

b

N

 Mr. NzS

N

jj L: LT -GH,

Free 69.4 (69.3) 5.1 (4.9) 18.3 (18.6)

base,

253

The free 69.8 (70.3) 5.5 (5.5) .17.4 (17.6) base.

R N

Continuation of table 1

table 2

YU

23

15

sixteen

17

N,

f I

SNS

V

-SP, Free 59.6 (59.0) 4.5 (4.9) 22.5 (22.9)

base

1.0 HjO,

365-369 -CH, Free 56.2 (55.9) 4.1 (4.2) 29.8 (29.7)

base

0.5 N, 0,

267-268 -CH, Free 66.4 (66.1) 5.6 (5.6) 22.1 (22.0)

base,

273-276

nineteen

20

21

22

23

IT

CH-Nx

SNS

SNS

f

SC H.1

SNS

SNS

AxNv. 3

.СНз

-CH, Free 62.5 (62.3) 5.1 (5.3) 24.5 (24.2)

base

0.16,

334-336. -CH, Free 70.4 (70.6) 6.7 (6.7) 16.4 (16.5)

base,

260-262

-CH, Free 69.8 (69.7) 6.3 (6.3) 17.2 (17.4) base, 224-226

-CH, Free 69.3 (69.7) 6.4 (6.3) 17.4 (17.4) base, 233-235

-N free 67.1 (67.2) 6.2 (6.5) 16.7 (16.8) base 0.5

1433411

24 Continuation of table 2

Table 3

N 0

R n

177-180

Table 4

0

13

14

15

sixteen

17

18

SNS

N,

AxN- SNZ

one

SNS

1 N

SNS

i.

-jj snake

SNS

-CH, 0.25 H, j, 0 69.4 (69.1) 7.4 (7, t) 22.3 (22.0) 166

-N Free 69.0 (69.3) 6.4 (6.4) 24.1 (24.2) basis, 132

-CHj Free 70.5 (70.6) 7.0 (7.0) 22., 3 (22.4) base, 109-111, 5

-CHj Free 70.4 (70.6) 7.0 (7.0) 22.3 (22.4) base, 162-166

-CH, Free 61.9 (62.1) 5.9 (5.8) 32.1 (32.2) base ,.

122-125

-N Free 70.5 (70.6) 7.1 (7.0) 21.8 (22.4) basis, 120

Continuation of table.5

Table

Hel

Getting

t h

J3

s

СНз .cHj Free 60.9 (60.8) 5.1 (5.1) 19.1 (19.3) N rj base,

WN-H

135

, Free 61.0 (60.8) 5.1 (5.1) 19.6 (19.3) .J N base, CHS144-147

N

Vj -CH Crude CBo- No data NX.bode

SNS

solid base

Il.

-CH, Free 52.9 (52.9) 3.9 (3.9) 27.6 (27.5)

Hv,

base 116-117

SNL

ir ... jX 3 n Free 61.0 (60.8) 5.2 (5.1) 19.1 (19.4)

L j base

, 85

neg

27

28

29

CF,

one

 I

.

: N

W N

-СНз Free 56.4 (56.6) 4.9 (4.8) 12.5 (12.4) basis, 194

-CH, Free 66.3 (66.4) 6.3 (6.3) 15.3 (15.5) base, „

159-160

-CH, Free 61.8 (61.8) 6.1 (5.9) 20.9 (20.6) basis, 207-209

Table 7

.

Table 8

OE1

,

to 0

R N

thirty

31

 I-CH, Free 57.2 (57.1) 5.7 (5.5) 25.4 (25.6)

N N vbasic, 179-181

SNS td

-CHj Free 62.6 (62.5) 6.6 (6.2) 18.2 (18.2)

N And the base

IH0,5N, 0,

СНз152-153,5

Continuation of table.8 i

Table 9

Hei

ira2

Hei

t

i1

CF3

TO

ASX-Nk-A

rH

.

 V

N

TkT 3. SNZ- -CH, Free 46.6 (48.7) 3.0 (3.0) 15.5 (15.5) base,

147

-СНз Free 55.9 (55.8) 4.6 (4.8) 19.7 (19.5)

base

0.66

87-88-CH, Free 56.6 (56.9) 5.3 (5.2) 23.8 (24.1)

base,

108-110

-CH, Free 46.5 (46.8) 3.5 (3.4) 34.4 (34.2) base, 107-110

-CFj Free 50.6 (50.5) 3.6 (3.5) 15.0 (14.7) base, 169-171

Table 10

Claims (5)

Claim The method of obtaining derivatives of 2- ’(1H) -quinolone of the general formula where Het is imidazolyl, unsubstituted or substituted with 1-2 substituents selected from the group consisting of CH ^, CFj or CN; R is hydrogen or methyl, or their pharmaceutically acceptable salts, characterized in that the compound of General formula Q where Rh Het have the indicated meanings; Q is an ethoxy group, subjected to cyclization in the presence of concentrated sulfuric acid 6 by isolation of the target product in free form or in the form of a pharmaceutically acceptable salt. Table 1 neg i Example eleven eleven eleven eleven 1 ! 1 I eleven eleven 1 0) 1 . I am 1 1 g! eleven The selected form and t * pl · " ° C Found - : FROM -Η Free base 68.0 (68.2) • lt TO- -Η 250-260 (decomposition) Free 69.4 (69.3) • base -sn _er Free 70.3 (70.3) . base, 295 (calculated),% Η N ' 4.3 (4.3) 19.9 (19.9) 5.0 (4.9) 18.9 (18.6) 5.6 (5.5) 17.2 (17.6) Continuation of Table I The selected form, etc., ®С Free base, 253 Free base, 292-295 Free base, 255-259 (decomposition) Free base, 266-269 (decomposition) Free base, 318-321 Found (calculated),% FROM n N 69.4 (69.3) 69.8 (70.3) 69.9 (70.3) 61.8 (62.2) 64.1 (63.7) 5.1 (4.9) 5.5 (5.5) 5.5 (5.5) 3.8 (3.8) 4.5 (4.4) 18.3 (18.6) .17.4 (17.6) 17.3 (17.6) 26.1 (26.4) 24.8 (24.8) Free 67.9 (67.7) 5.5 (5.5) 17.4 (17.0) base 0.5 N ₂ 0,> 300 Free 67.9 (68.2) 4.2 (4.3) 19.9 (19.9) base, 244-245 table 2 At- Het R Vadeleynaya Found (calculated) measures form and i i t "pl · * FROM I n ' N ° C ί; ι ί -CH Free 56.4 (56.5) 3.5 (3.5) 14.2 (14.1) -CH base 0.25 Η ₂ 0, 294 Free 69.3 (69.3) 5.1 (4.9) 18.4 (18.7) base, 229-231 Continuation of Table 2 At- Het R Selected form, etc., ° C Found (calculated) , * measures FROM N N fifteen N—. eleven -CH Free 59.6 (59.0) 4.5 (4.9) 22.5 (22.9) base 1.0 n ₂ about, Ν — N 365-369 29.8 (29.7) 16 1 I -CH Free 56.2 (55.9) 4.1 (4.2) base SNZ 0.5 H ₂ 0, 267-268 17 -CH Free 66.4 (66.1) 5.6 (5.6) 22.1 (22.0) base, 273-276 Table 3 Example Het Selected form and mp. ° C -sleep SNZ 20 Oh -CH sun ₃ 21 CT I'm ³ -CH IX 22 Ν = η ALTx -CH SNZ 23 SNZ -H 4 SNs Free base 0.16 H ₂ 0, 334-336; Free base, 260-262 Free base, 224-226 Free base, 233-235 Free base 0.5 N ₂ 0 ABOUT Found (calculated) ^ X C Η N 62.5 (62.3) 5.1 (5.3) 24.5 (24.2) 70.4 (70.6) 6.7 (6.7) 16.4 (16.5) 69.8 (69.7) 6.3 (6.3) 17.2 (17.4) 69.3 (69.7) 6.4 (6.3) 17.4 (17.4) 67.1 (67.2) 6.2 (6.5) 16.7 (16.8) Table 4 Heterocycle CH3 ^ νΛντ CN Selected form, etc. ° C Found (calculated),% Free 65.3 (65.2) 4.5 (4.8) 20.1 (20.3) base 0.67 H ₂ 0,> 350 Free 67.5 (67.4) 4.7 (4.6) 20.9 (21.0) base 0.17 N _g O, 302-304 Table 5 Highlighted Found (calculated), Z form, etc., ° C FROM n | N Free base 185-188 64.8 (65.4) 1 5.8 (5.9) 16.3 (16.3) Free base ¹⁷⁴ 66.6 (66.4) 6.3 (6.3) 15.6 (15.5) Chloride -.-. rat, 260 59.3 (59.7) 6.3 (6.2) 13.1 (13.0) Hydrochloride, 244 58.3 (58.6) 5.8 (5.6) 13.5 (13.7) Free base 181-183 67.3 (67.3) " 6.8 (6.7) 14.6 (14.7) Free base 131-133 67.2 (67.3) > 6.7 (6.7) 14.8 (14.7) Free base 177-180 60.5 (60.5) I 5.5 (5.5) 21.9 (21.7) Continuation of Table 5 By- · Het 1 1 se! 1 1 _________! Withdrawn Found (calculated), Ζ lu- form- and - R----_ - ————- what- t. FROM n N nie t g 1 1 1 1 1 and! about 1 _____1 A ί 1 9 G ¹ ! x-C® 'ί CH3 ^ -sn _er g Free base, 163-165 61.8 (61.8) 5.8 (5.8) 20.6 (20.6) 10 -H Hydrochloride, 267 59.9 (59.7) 6.3 (6.3) 13.1 (13.1) eleven UK n Free 65.4 (65.4) 5.9 (5.8) 16.4 (16.3) base, 183-186 ► Table 6 Getting Het R Selected form and To pl · | ° C thirteen __ -sleep 0.25 N.O > = ί 166 14 Ν = ί —N Free ΑχΝ ^ base, sun ₃ 132 fifteen ^N = 1 -CHj Free Alc base, sun ₃ 109-111, 5 16 N—. ί 1 dream _? Free * Hlc CH1 base, 162-166 17 bj- ^ bj -sn _er Free "-to base, 122-125 18 Αχίκ n Free base, 120 SNZ 69.4 (69.1) 70.4 (70.6) 61.9 (62.1) 70.5 (70.6) 69.0 (69.3) 70.5 (70.6) Found (calculated), 2 7.4 (7 ,!) 6.4 (6.4) 7.0 (7.0) 7.0 (7.0) 5.9 (5.8) 7.1 (7.0) 22.3 (22.0) 24.1 (24.2) 22.3 (22.4) 22.3 (22.4) 32.1 (32.2) 21.8 (22.4) Table 7 Het but 2 Het R Selected form, etc. ⁱⁿ C Found (calculated), % FROM N N 60.9 (60.8) 5.1 (5.1) SNZ N Free base, 144-147 Free base, 189 Free base, 135 61.0 (60.8) 5.1 (5.1) 19.1 (19.3) 19.6 (19.3) Crude Free Base, Solid Free Base, 116-117 No data 52.9 (52.9) 61.0 (60.8) 3.9 (3.9) 5.2 (5.1) 27.6 (27.5) 19.1 (19.4) 56.4 (56.6) -sn ₃ Free base, 194 4.9 (4.8) 12.5 (12.4) -sn ₃ Free base, 159-160 66.3 (66.4) 6.3 (6.3) 15.3 (15.5) FROM) -CHj Free base, 207-209 61.8 (61.8) 6.1 (5.9) 20.9 (20.6) I 433411 Continuation of Table 8 Free 62.6 (62.5) 6.6 (6.2) 18.2 (18.2) base 0.5 H _t 0, 152-153.5 Table 9 Half- Het I 1 1 1 1 The selected form. And t · PL · | ° C Found (calculated) 2 reading FROM N N N = N I 1 -sn ₃ Chloride - 56.4 (56.1) rat 0.25 n _g about, 5.7 (5.8) 19.7 (19.6) -sn ₃ 263-266 Free 54.9 (54.9) 5.3 (5.1) 40.0 (39.8) base, 100-103 -sn. Free 65.0 (65.3) 6.7 (7.0) 27.5 (27.7) base, 140-142 -CHj Free 54.6 (54.9) base, 110-112 5.1 (5.1) 39.8 (40.0) Table 10 neL S'wO? R f Zola- Het R Selected form, etc. , ° C Found (calculated), % reading FROM N N Yu Ν = η st / * '*' '' -CH Free base, 147 46.6 (48.7) 3.0 (3.0) 15,5 (15,5) rV -CH _? Free 55.9 (55.8) 4.6 (4.8) 19.7 (19.5) ’ base 0.66 n ₂ about 42 ι -CH 87-88 Free base, 108-110 56.6 (56.9) 5.3 (5.2) 23.8 (24.1) N ~ n SA ~ CH, Free 46.5 (46.8) 3.5 (3.4) 34.4 (34.2) base, 107-110 _{N = r} ^CH 3 _ A.ZH, CH ₃ 44 “CF _} Free 50.6 (50.5) 3.6 (3.5) 15.0 (14.7) base, 169-171