专利摘要:
The invention relates to substituted nitriles, in particular, the preparation of phenylacetonitrile derivatives of the general formula @ where R 1 -R 5 are the same or different H, a lower alkoxy group A-CR 6 (CN) - (CH 2 ) M —NR 7 - (CH 2 ) N - or - (CH 2 ) N —NR 7 - (CH 2 ) M -CR 6 (CN) - with R 6 - H- or i-C 2 -C 12 -alkyl, R 7 = HC 1 -C 6 = alkyl, M and N are the same or different integers 2 or 3 XYC (O) -N (Z) 2 , with one ZH = or ISO-C 1 -C 4 -alkyl, cyclohexyl, cycloalkyl (lower), and the other ZH or both Z form a 5-6-membered nitrogen-containing heterocycle: YH = C 1 -C 4 - alkyl, or hydrates, or dihydrates, their oxalates, or citrates, which affect the blood supply to the heart. The goal is to create new, more active substances of the specified class. The synthesis is carried out by reacting a compound of the formula 1, in which instead of the XO-N (O) 2 group there are -YC (O) -OR 8 , where R 8 -H or lower alkyl, with the compound HN-ZZ-ON (O) 2 ( Z — see above) followed by separation of the base, the desired salt, or the desired hydrates. Unlike verapamil, new substances have a direct effect on the coronary vessels or reduce blood pressure with a negative inotropic effect. 6 tab.
公开号:SU1508956A3
申请号:SU853955485
申请日:1985-09-11
公开日:1989-09-15
发明作者:Ляйнерт Херберт;Кампе Вольфганг;Штрайн Клаус;Мюллер-Бекманн Бернд;Барч Вольфганг
申请人:Берингер Маннхайм Гмбх (Фирма);
IPC主号:
专利说明:

This invention relates to a process for the preparation of new phenylacetonitrile derivatives of the general formula
OXOlSSOo
where R ,, R, R, R, R - the same or different, hydrogen, lower alkoxygroup,
A has the following meanings:
C.N R, C- (CH2) m-N- (CH2) OR
R.

cm
CCH VN-fcH VC
Where
Rg is normal or iso-C-C-alkyl.
S - linear C4-C5-alkyl5 pit - the same or different
2 or 3,
- group of formula
X
-Y-C-ISIZZ 1
11 o
1508956
once water. The methylene chloride phase is dried over sodium sulfate and evaporated. . For further purification, the residue is chromatographed on silica gel (220 g silica gel-BO, solvent (eluent): methylene chloride (4% methanol). The resulting column fractions are evaporated, the residue is dissolved in methanol and the solution is mixed with a methanol solution of 0.8 g of oxalic dihydrate acids. The solution is evaporated and the residue is treated with diisopropyl ether. 3.75 g (87% of theory) are obtained crystal 15
fishing with m.p. 124-125 s (decomposition).
Where one of Z is linear or branched C, -C4-alkyl, cyclohexyl, lower alkyl cyclohexyl, cyclohexyl lower a; lkyl, and the other Z hydrogen or both radicals Z together form a heterocyclic nitrogen-containing cycle with 5-6 carbon atoms;
Y is linear C, –C 4 –alkyl, or hydrates, or dihydrates of their oxalates, or citrates, which exhibit pharmacological activity and can be used in medicine.
The purpose of the invention is to search for new derivatives of phenylacetonitrile, which, as compared with compounds that are similar in structure, exhibit higher activity.
The invention is illustrated by the examples below.
Example 1 2-methoxy-4-1-cyano-1- / methylethyl / - -4 - / - N-methyl-N- / 2 - / 3-dimethoxyphenyl oxalate dihydrate / -ethyl / aminobuty | / -phenoxy-N- - / nitrooxyeth1 / -acetamide.
3 g of 2-methoxy-4- (1-cyano-1 / methyl-ethyl / -4- / N-methyl-N- / 2- / 3,4-dimethoxy phenyl / ethyl / aminobutyl) / phenoxyacetic acid is dissolved in a mixture of 60 ml of methylene chloride and 1.27 ml of triethylamine. It is added with stirring and with a solution of 1 ml of ethyl chloroformate in 30 ml of methylene chloride. After the addition is complete, stir for further 45 min at -15 ° C and then add 1.6 g of nitroxyethylammonium nitrate. Then, with stirring and at -15 ° C, a solution of 2.75 ml is added dropwise.
triethylamine in 25 ml of methylene chloride. Stir for another 30 minutes at -15 ° C, dilute the reaction solution with 50 ml of methylene chloride and wash several times
0
five
0
five
5 Q
0
five
fishing with m.p. 124-125 s (decomposition).
Similarly, the following compounds are prepared.
Example 2. Oxalate 2-Mitoxy-1. -4- / 1-cyano-1- / methyletsh1 / -4-N-methyl-M- / 2- / 3,4-dimethoxyphenylAethyl / -minobutyl / / -phenoxy-K- / 2-nitroxypro- d-acetamide, m.p. 115-116 0 (decomposition).
PRI me R 3. Oxalate 2-methoxy- -4- / 1-cyano-1- / methylethyl / -4- / K-methyl-K- / 2- / 3,4-dimethoxyphensh1 / -ethyl / - -aminobutyl / / -phenoxy-K- / 3-nitrocoxibutyl-2 / -acetamide, m.p. 136-137 ° C (decomposition).
Example 4. 2-Methoxy-4- / 1- -cyano-1- / methylethyl / -4- / N-methyl-L-; - (2- (3,4-dimethoxyphenyl) -ethyl) -aminobutyl / -phenoxy- (1-methyl-3-nitroxypropyl-2) -acetamide.
Example 5. 2-Methoxy-4- / 1- -cyano-1- / methylethyl / -4- / N-MeTmi- / 2- - / 3,4-dimethoxyphene1 / -ethyl / -amino-butyl / phenoxy N- [1,3-bis-nitroxy-cyclohexyl-2] -acetamide.
Example 6. 2-Metoxy-4- (1-cyano-1- / methylether1 / -4- .. - / N-methyl-N- / 2- (3,4-dimethoxyphenkene) dihydrate. -ethyl (-aminobutyl) / / -phenoxy-N- -bis- / nitrooxyethyl / -acetamide-oxalate, m.p. 105-107 C (decomposition).
Example 7. 2-methoxy- -4- (1-cyano-1- / methylethyl) -4- (K-methyl- (2- (3,4-dimethoxyphenyl) -eth-1 (-1-α-aminobutyl)) hydrate phenoxy-N, N-bis-2- -nitroxypropyl / acetamide oxalate, m.p. 118-120 s (decomposition).
2-methoxy-4- (1-cyane-1- / methyl-ethyl / -4- / N-methyl-N- / 2- / 3,4-dime-trxyphenyl) -ethyl / -aminobutyl is required as a starting material. // phenoxyacetic acid is obtained as follows.
1-stage. 3-Methoxy-4-benzyloxy and-isopropyl benzyl cyanide.
150 g of 3-methoxy-4-benzyloxybenzyl cyanide together with 470 ml of 50% sodium hydroxide solution, 76 ml of 2-bromopropane and 6 g of benzyltributyl ammonium bromide are stirred for 5 hours at 55 C. Then the reaction
Valy from the catalyst and evaporated. This gives 36 g (97% of theory) of “i-isopropyl- (b // N-methyl-K-homoboatryl / -amino-y-propyl / -3-methoxy-4-oxyphenylacetonitrile as an oily product.
4-stage. 2-Methyl-4- (1-cyano-1- / methylstil / -4- / ethyl mixture) The mixture is poured into 4 liters of water and the extract with JQ-methyl-N- [2- (3,4-dimethoxyphenyl) -ethsh1 / -aminobutyl // - phenoxyacetic acid.
Route several times with methylene chloride. The combined methylene chloride phases are dried over sodium sulfate and evaporated, and the residue is distilled under high vacuum. This gives 155 g (90% of theory) of 3-methoxy-4-benzyloxy - (/ - isopropyl benzyl cyanide, bp 184-186 C / 6 "mm Hg, mp 68-70 C.
Stage 2, ui-isopropyl-oi, - / (N- -methyl-N-homoveratryl) -amino-propyl / -3-methoxy-4-benzo-1oxyphenyl-acetonitrile.
36.6 g of 3-methoxy-4-benzyloxy- (-isopropylbenzyldianide) is dissolved in 150 ml of absolute dimethylformamide. To the resulting solution, add 30.3 g of (K-methyl-K-homoboratryl) -amino-chloro-propane and 5.7 g of 55% sodium hydride are added to the mixture under stirring for 1 hour. After the addition is complete, the mixture is stirred for 2 hours at 50 ° C and then the reaction mixture is poured into 4 liters of water. The mixture is extracted several times with methylene chloride - The single methylene chloride phases are over sodium sulfate and evaporated to dryness. The chromatograph remains to be purified. irate on a silica gel column (1.2 kg silica gel, solvent (eluent): methylene chloride / 2% methanol). After evaporation of the column fractions, 45 g (70% of theory) of oL-isopropyl-o / K-methyl-N- are obtained homoveratryl / - - amino - propyl / - 3-methoxy-4-benzyloxyphenylacetonitrile as an oily product.
Stage 3: about-Isopropyl-c / / N-methyd-N-hematover-y-amino-J-propyl / -3-methoxy-4-hydroxyphenylacetonitrile. 45 g S-Isopropyl-ot- / / N-me. Tyl-H-homoveratril / -amino-2-misc) 1 / - -3-methoxy-4-benzyloxyphenylacetone-nitrile is dissolved in 400 ml of methanol and, after adding 4 g of Pd / C (10%) as a catalyst, is hydrogenated . After uptake, the calculated amount of hydrogen is filtered off from the catalyst and evaporated. This gives 36 g (97% of theory) of “i-isopropyl- (b // N-methyl-K-homoboatryl / -amino-y-propyl / -3-methoxy-4-oxyphenylacetonitrile as an oily product.
4-stage. 2-methoxy-4- / 1-cyano-1- / methylstil / -4- / LQ -methyl-N- / 2- / 3,4-dimethoxyphenyl / 0 ethyl ester
five
0
-Ensh1 / -aminobutyl // - phenoxyacetic acid.
34.5 g of oi-Isopropyl - (,, - // N-methyl--N-hemovalent / -amino-) l-propyl / -3-5 methoxy-4-hydroxyphenylacetonitrile
dissolved in 200 ml of dimeshmformamide and, with stirring at room temperature, mixed with 3.5 g of sodium hydride (55%). Stir additionally for another 15 minutes and then a solution of 9.8 ml of bromoacetic acid ethyl ester in 50 ml of dimethylformamide is added dropwise. The temperature should not exceed 30 ° C. At the end of the addition, it is stirred, for another 1 hour, the reaction mixture is poured into 4 liters of water and extracted repeatedly with methylene chloride. The combined methylene chorland phases are dried via sodium sulfate and then evaporated. The chromatographic purification unit is a silica gel column. (1.2 kg silica gel; eluent: methylene chloride / 3% methanol). After evaporation of the column fractions, 33.3 g (81% of theory) of 2-methoxy-4- - 1-cyano-1- / methylethyl / -4- / N-metsh1- -M- / 2- / 3 ethyl ester are obtained. , 4-dimethoxyphenyl (-ethyl) -aminobutyl / -phenoxyacetic acid as an oily product.
5th stage. 2-Methoxy-4- (1-cyano- -1 - / - methylethyl / -4- / N-metssh-1-M- / 2- (3,4-dimethoxyphenyl) -ethyl / -aminobutsh1 / / -phenoxyacetic acid.
Ethyl 2-methoxy-4- (1-cyano-1- / methylethyl) -4- (N-methyl-N- / 2- (3,4-dimethoxyphenyl) -ethyl) -aminobutyl / / α-phenoxyacetic acid is dissolved in 150 ml of ethanol. To the solution n is added dropwise with stirring and at room temperature 125 ml of 1N. sodium hydroxide solution. At the end of the addition, stirring is continued for another 1 hour at room temperature and the alcohol is then evaporated. Then 125 ml of 1N is added. hydrochloric acid is extracted several times with methylene chloride. The combined methylene chloride phases are dried over sulfa5
0
five
five
volume and evaporate. Get 29.5 g (94% of theory) 2-methoxy-4- - / 1-cyano-1- / methylethyl / -4- / N-methyl- -Y- / 2- / 3,4-dimethoxyphenyl / - ethyl (-aminobutyl) -phenoxyacetic acid as an oily product.
Example 8. 2-methoxy-5- (1-cyano-1- / methylethyl) -4- (N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminobutyl) oxalate oxalate hydrate / -phenoxy- / nitrooxyethyl / -acetamide.
4.5 g of 2-methoxy-5- / 1-cyano-1- / methylethyl / -4- / H-methyl-H- / 2- / 3, 4-dimethoxyphenyl / ethyl / aminobutyl // - fe - Noxyacetic acid is dissolved in a mixture of 80 ml of methylene chloride and 1.9 ml of triethylamine. Under stirring and at -15 ° C, a solution of 1.35 ml of ethyl chloroformate in 30 ml of methylene chloride is added dropwise to the solution obtained. At the end of the addition, the mixture is stirred for an additional 45 minutes at -15 ° C and then 2.3 g of nitrooxyethylammonium nitrate are added. Then with stirring and at -15 ° C, a solution of 3.8 ml of triethylamine in 25 ml of methylene chloride is added dropwise. The mixture is further stirred for 30 minutes at -15 ° C, the reaction mixture is diluted with 50 ml of methylene chloride and washed several times with water. The methylene chloride phase is dried over sodium sulfate and evaporated. The residue to be purified is chromatographed on a column of silica gel (250 g of sily gel, eluent: methylene chloride / 3% methanol).
The resulting column fractions are evaporated, the residue is dissolved in methanol and the solution is mixed with a methanol solution of 1.25 g of oxalic acid dihydrate. The solution is evaporated and the residue is treated with diisopropyl ether. Obtain 4.9 g (78% of theory) of crystals with so pl. 127- (decomposition).
Similarly, the following c-solids are obtained.
Example 9. 2-methoxy-5- (1-cyano-1- (methylethyl) - (1-methyl-H- (2- (3,4-dimethoxyphenyl) -ethyl) -aminobutyl) -phenoxy- H - - / 2-nitrooxypropyl / -acetamide, m.p. 132-134 ° C (decomposition).
Example 10. 2-methoxy-5- (1-cyano-1- (methyl-ethyl) -4- (N-methyl-N- (2- (3,4-dimethoxy phenyl) ethyl) -butythyl) oxalate dihydrate / -phenoxy-N
0
five
0
five
0
five
0
five
- / 3-nitrooxybutyl-2 / -acetamide, so pl. 123-125 C (decomposition).
Example 11. 2-methoxy-5- (1-cyano-1- / methylethyl) - -4- (K-methnc-H- (2- (3,4-dimethoxyphenyl) -ethyl) -aminobutyl) oxalate hydrate / -phenoxy-N- - / 2-methyl-3-nitrooxypropyl-2 / -atseta-midy, so pl. 125-127 C (decomposition).
Example 12. 2-methoxy-5- (1-cyano-1- / methylethyl / - -4-N-methyl-H - / - 2- (3,4-dimethoxyfenyl) -ethyl / -aminobutyl / oxalate oxalate hydrate / -phenoxy-K- - / 1, 3-bis-nitrooxycyclohexyl-2 / - -acetamide, so pl. 140-142 ° C (decomposition).
Example 13. 2-methoxy-5- (1-cyano-1- / methylethyl) -4- [N-methyl-N- [2- [3,4-dimethoxyphenyl] -ethyl] -aminobutyl oxalate oxalate hydrate (-phenoxy-H, K-V.-bis- / nitrooxyethyl) -acetamide, m.p. 105-107 C (decomposition).
Example 14. 2-methoxy-5- (1-cyano-1- / methylstil / - -4- (N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminobutyl) oxalate hydrate -phenox; i-H, L- -bis- (2-nitrooxypropyl) -acetamide, mp. 118-120 C (decomposition).
Necessary as a starting material 2-methoxy-5- / 1-cyano-1- - / metSH1Etsh1 / -4- / N-methyl-N- / 2- / 3,4-dimethoxyphenyl / -tsh1 / aminobutyl / / - phenoxyacetic acid is prepared analogously to 2-methoxy-4- / 1-cyano-1- - / methylethyl / -4- / M-metsh-1-Y- / 2- / 3,4-dimethoxyphenyl / -ethyl / aminobutyl / / -phenoxyacetic acids, but instead of 3-methoxy-4-benzyloxybenzyl cyanide, 3-benzyloxy-4-methoxybenzyl cyanide is used as a starting material and is reacted with a 2-nitroxypropyl ammonium nitrate.
Example 15. 2-methoxy-4- / 2- / M-methyl-L- / 4-cyano-4- / methylethyl (-4- / 3,4-dimethoxyfenyl) -butyl / -aminoethyl / oxalate oxalate hydrate / -phenoxy- / nitroo-etsh1 / -acetamide.
I.
3 g of 2-methoxy-4- / 2- / M methyl-L- - / 4-cyano-4- / methylethyl / -4- / 3,4-dimethoxyphenyl / -butyl / -aminoethyl / / phenoxyacetic acid solution in a mixture of 60 ml of methylene chloride and 1.3 ml of triethylamine. To the resulting solution, while stirring and adding dropwise, a solution of 1 ml of this, co-dimethyl ester in 30 ml of methylene chloride. At the end of the addition, stir further.
45 min at -IS C, 1.6 g of nitrooxyethylammonium nitrate are added and then a solution of 2.9 ml of triethyl amine in 30 ml of methylene chloride is added dropwise. The mixture is further stirred at -15 ° C for another 30 minutes, the reaction solution is diluted with 50 ml of methylene chloride and washed several times with water. The methylene chloride phase is dried over sodium sulfate and evaporated. The residue is purified by chromatography on a silica gel column (220 g of silica gel, eluent methanol / 4% methylene chloride),
The resulting column fractions are evaporated, the residue is dissolved in meta.
The solution is mixed with a methanol solution of 850 mg of oxalic acid dihydrate. The solution is evaporated and the residue is treated with diisopropyl ether. Obtain 3.7 g (85% of theory) of crystals with so pl. 132 ° C (decomposition).
The following compounds are prepared in a similar manner.
Example 16. Oxalate hydrate of 2-methoxy-4- / 2- / N-methyl-N- / 4-cyano-4- / methylethyl / -4- / 3,4-dimethoxyphenyl / -butyl / -aminoethyl / -phenoxy-N- / 2- -nitroxypropyl / acetamide, m.p. 135 136 ° С (decomposition).
Example 17. Oxalate hydrate of 2-methoxy-4- (2- (N-methyl-K-) (4-cyano-4- / meth-ethyl / -4- / 3,4-dimethoxyphenyl) -butyl / -aminoet- Il / -phenoxy N- - / 3-nitroxybutyl-2- / acetamide, so pl. 132-134 C (decomposition).
Example 18. Oxalate hydrate of 2-methoxy-4- / 2- / N-methyl-N- (4-cyano-4- / methylethyl) -4- / 3,4-dimethoxyphenip / -butyl / -aminoethyl / / -phenoxy- -N- / 2-methyl-3-nitro ooicpr opil / 2 / -aceamide, so pl.
Prime
ch-4- / 2- / N-methyl-N- / 4-cyano-4- / methylethyl / -4- / 3,4-dimethoxyphenyl / -butyl / -aminoethyl / / -phenoxy-L- / 1,3- -bis-nitroxycyclohexyl-2 / -acetates da, so pl. 90-92 0 (decomposition).
 Example 20. 2- methoxy-4- (2- (N-methyl-H-) / 4-cyano-4- (meth- ethyl) -4- (3,4-dimethoxyphene-1 / -butyl) -aminoethyl / oxalate oxalate hydrate / -phenoxy- -N, N-bis- / nitroxyethyl / -detamide,
122-124 with (decomposition), p 19. Oksalat 2-method. Pl. 110-112 ° C (decomposition).
Example21. Oxalate dihydrate 2-methoxy-4- / 2- / N-methyl-M- / 4-cyano-4- / methyl-ethyl / -4 / 3,4-dimethoxyphenyl / -butyl / -minoethyl / / -phenoxy
t
ten
25
zo
508936 O
-N, N-bis- / 2-nitroxypropyl / acetamide, so pl. 110-112 ° C (decomposition).
Example 22. 2-methoxy-4- / 2- / N-methyl-N- / 4-cyano-4- / methylethyl / -4- / 3,4,5-trimethoxyphenyl / -butyl / oxalate dihydrate -aminoethyl / / -phenoxy- -M- / nitrooxyethyl / -acetamide, m.p. 128-130 ° C (decomposition).
Example 23. 2-methoxy-4- / 2- / N-methyl-M- / 4-cyano-4- / - methylethyl (-4- / 3,4,5-trimethoxy-phenyl) -butyl / oxalate dihydrate -aminoethyl / -phenoxy-N- - / 2-nitrooxypropyl / -acetamide, m.p. 135-136 ° C (decomposition).
Example 24. 2-methoxy-4- (2- / N-metsish-1- / 4- / 4-cyano-4- (methylstil) -4- / 3,4,5-trimethoxyphenyl) -butyl oxalate dihydrate -aminoethyl / / -phenoxy-20 -Y- / 3-nitroxybutyl-2 / -acetamide, m.p. 123-124 ° C (decomposition).
PRI mme R 25. Oxalate 2-methoxy-4- / 2- / K-methyl-N- / 4-cyano-4- / metsh-ethyl / -4- / 3,4,5-trimethoxyphenyl (-but-tsh1 / -aminoethyl) -phenoxy-L- (1,3-bis-nitroxycyclohexyl-2) -acetamide.
15
about
five
0
five
0
five
m.p. 147-149 ° C (decomposition).
2-methoxy-4- (2- (N-methyl--H- (4-cyano-4- / methylethyl) -4- (3,4-dimethoxyphenyl) -butyl) -amino ethyl / i-phenoxyacetic acid is prepared as follows.
1-stage, about-Isopropyl- "C- / / N- -methyl-N- / 2 - / - 3-methoxy-4-benzyloxy, si / -ethyl / / -amino-y-propyl / -3, 4-dimethoxyphenylacetonitrile.
48.5 g of ".-Isopropyl-3,4-dimethoxyphenylacetonitrile is dissolved in 200 ml of dimethylformamide-a. To the resulting solution was added 40.8 g of N- -methyl-N- / 2- (3-methoxy-4-benzyloxy) -ethyl / -M- / y-chloropropyl / -amine and the solution was heated to 50 ° C. . 8.15 g of sodium hydride (55%) are added thereto over 1 hour. After the addition is complete, the mixture is stirred for an additional 3 hours at 50 ° C, the reaction mixture is poured into 4 liters of water, and extracted several times with methylene chloride. The combined methylene chloride phases are washed with water, dried over sodium sulfate and evaporated. Purification residue is chromatographed on a silica gel column (1.8 kg silica gel, eluent: methylene chloride / 3% methanol).
After evaporation of the column fractions, 52.8 g (86% of theory) of o-isopropyl-cch - / / meths1-M- / 2- / 3-methoxy-4-benzyloxy / -ethyl // - amino-) C are obtained -propyl / -3,4-dimerK Siphenylacetone-nitrile in the form of an oily product.,
2-stage. o -Isopropyl-oi - // N- -methyl-N- / 2- / 3-methoxy-4-hydroxyphenyl / - -ethyl // - amino-) C-propyl / -3,4-dimethoxyphenylacetonitrile.
47.9 g of o6-isopropyl-1) - // N-methyl- -Y- / 2- (3-methoxy-4-benzyloxy) -ethyl / -amine-J-propyl / -3,4-dimethoxyphenyl- acetonitrile is dissolved in 400 ml of methanol and, after addition of 2 g of Pd / C (10%) as a catalyst, is hydrogenated. After uptake, the calculated amount of hydrogen is filtered off from the catalyst and evaporated. Receive 38 g (95% of theory)
(3,4-dimethoxyphenyl) -butyl / -amino-ethyl // - phenoxyacetic acid.
36,5 ethyl ester of 2-methoxy-4- - / 2- / N-methyl-N- / 4-cyano-4 / -methyl-ethyl / -4- / 3,4-dimethoxyphenyl / -butyl / - -amino-phenyl-acetic acids are dissolved in 150 lL of ethanol. 140 ml of 1N is added dropwise to the resulting solution at room temperature with stirring. sodium hydroxide solution. Stir additionally for another 1 h, then add 140 ml of 1N. hydrochloric acid and alcohol are evaporated. The aqueous phase is extracted with methylene chloride. The methylene chloride phase is dried over sodium sulfate and. evaporated. 33.7 g (97% of theory) of 2-g-4 / .2- / N-methyl-N- / 4-cyano-4 are obtained.
oi-isopropyl-oi - // N-methyl-N- / 2- / 3-metoc-20 - / methylethyl / -4- / 3,4-dimethoxyphenyl / - si-4-oxy / -ethyl // - amino - -propyl / - -butylamino-ethyl / phenoxyacetic acid-3,4-dimethoxynphenylacetonitrile as an oily product.
ST Stage 2-methoxy-4- [2- (Y-methyl-H- [4-cyano-4- (meth- TILEH]) -4- [3,4-dimethoxyphenyl] -butyl] -aminoethyl] ethyl ester / -phenoxyacetic acid.,
37.7 g (5 -isopropyl-o.-V / N-methyl-ZO
-N- (2- (3-methoxy-4-oxy) / -ethyl // - amino-propyl / -3,4-dimethoxyphenyl acetonitrile is dissolved in 200 ml of absolute dimethylformamide and mixed with stirring with 3.7 g sodium hydride (55%). Stir further for another 15 minutes and then a solution of 10.7 g of bromoacetic acid ethyl ester in 100 ml of dimethylformamide is added dropwise. The temperature should not exceed 30 ° C. At the end of the addition, it is stirred further. For another 1 hour, the reaction mixture is poured into 4 liters of water and extracted several times with methylene chloride.
The combined methylene chloride phases are washed with water, dried over sodium sulfate and evaporated. Purification residue is chromatographed on a silica gel column (1.2 kg silica gel, eluent methylene chloride / 3% methanol). After evaporation of the column fractions, 36.6 g (81% of theory) of ethyl, 2-methoxy-4- - / 2- (K-methyl-N- / 4-diano) -methylethyl / - -4- / 3, 4-dimethoxyphenylbutyl / -amino-ethyl // phenoxyacetic acid as | oily product.
4-stage. 2-Methoxy-4- / 2- / - -methyl-L- / 4-cyano-4- / methylethyl / 4- /
Lots in the form of an oily product. Used in the first stage, N- -methyl-H / 2 - / - 3-methoxy-4-benzyloxy / - 25-ethyl / -Y- / X-chloropropyl / -amine was prepared as follows.
148 g of 3-methoxy-4-benzyloxybenzo cyanide is dissolved in 2.5 liters of methanol and, after the addition of 350 ml of liquid ammonia and 16 g of Rene nickel, is hydrogenated at 100 ° C and a pressure of 80 atm. The hydrogenation is exhausted after 4 hours. The catalyst is filtered off and evaporated, and the residue is purified by silica gel column chromatography (1.6 kg silica gel, eluent: methylene chloride / 5% isopropylamine).
After evaporation of the column fractions, 126 g (84% of theory) of 3-methoxy-4-benzyloxy-α-phenylethyl-amine are obtained. It is dissolved in 500 ml of toluene and after the addition of 48.5 ml of benzaldehyde it is heated with a water separator. At the end of the water separation, cool down to room temperature and add 46 ml of dimethyl sulfate. The mixture is then refluxed for 30 minutes. Cool to room temperature. This forms
5Q two layers The upper toluene layer is separated and discarded. The bottom layer is mixed with 500 ml of 80% ethanol and then boiled under reflux for 30 minutes. The alcohol is then distilled off and the residue is treated with methylene chloride. The methylene chloride phase is extracted with concentrated hydrochloric acid and then discarded.
35
40
55
- / methylethyl (-4- / 3,4-dimethoxyphenyl) - - butylaminoethyl // phenoxyacetic acid
Lots in the form of an oily product. Used in the first stage, N- -methyl-N / 2 - / - 3-methoxy-4-benzyloxy / - -ethyl / -Y- / X-chloropropyl / -amine was prepared as follows.
148 g of 3-methoxy-4-benzyloxybenzo cyanide is dissolved in 2.5 liters of methanol and, after the addition of 350 ml of liquid ammonia and 16 g of Rene nickel, is hydrogenated at 100 ° C and a pressure of 80 atm. The hydrogenation is exhausted after 4 hours. The catalyst is filtered off and evaporated, and the residue is purified by silica gel column chromatography (1.6 kg silica gel, eluent: methylene chloride / 5% isopropylamine).
After evaporation of the column fractions, 126 g (84% of theory) of 3-methoxy-4-benzyloxy-α-phenylethyl-amine are obtained. It is dissolved in 500 ml of toluene and after the addition of 48.5 ml of benzaldehyde it is heated with a water separator. At the end of the separation, the water is cooled to room temperature and 46 ml of dimethyl sulfate are added. The mixture is then refluxed for 30 minutes. Cool to room temperature. This forms
two words The upper toluene layer is separated and discarded. The bottom layer is mixed with 500 ml of 80% ethanol and then boiled under reflux for 30 minutes. The alcohol is then distilled off and the residue is treated with methylene chloride. The methylene chloride phase is extracted with concentrated hydrochloric acid and then discarded.
20
25
The aqueous phase is made alkaline, with cooling, with a concentrated solution of sodium hydroxide, and an oil is liberated. It is dissolved in methylene chloride, the methylene chloride phase is dried over sodium sulfate and evaporated. 106 g (80% of theory), 3-methoxy-4-benzyloxy-) L-phenyl-N-methylethylamine are obtained in the form of an oily product.
It is dissolved in 500 ml of dimethylformamide and, after addition of 132 g of potash and 52 ml of 1-bromo-3-chloropropane, is stirred for 5 hours at room temperature. After that, the reaction mixture is diluted with methylene chloride and the insoluble residue is sucked off. The filtrate is diluted with water and extracted several times with methylene chloride. The methylene chloride phases are combined, dried over sodium sulfate and evaporated. The residue for purification is chromatographed on a silica gel column (1.2 kg silica gel, eluent methyl methylene chloride / 3% methanol). After evaporation of the column fractions .48.5 g (36% of theory) of N-methyl-K- - / 2- / 3-methoxy-4-benzyloxy (-ethyl) -N- / y-xpropyl / -amine are obtained. as a loose product.
Example 26. Oxalate 2-methoxy-5- / 2- / N-methyl-N- / 4-cyano-4- / methyl-Etil / -4- / 3,4-dimethoxyphenyl / -butyl / - -aminoethyl // - phenoxy-K- / nitrooxyethyl / -acetamide.
. 4.5 g of 2-methoxy-5- / 2-.N-methyl-N- / 4- -cyano-4- / methylethyl / -4- / 3,4-dimethoxyphenyl / -butsh1 / -aminoethyl // -Phenoxyacetic acid is dissolved in a mixture of 80 ml of methylene chloride and 1.9 ml of triethanolamine. Under stirring and at -15 ° C, a solution of 1.4 ml of ethyl chloroformate in 30 ml of methylene chloride is added dropwise to the resulting solution. After the addition is complete, stir for another 45 minutes at -15 ° C, add 2.3 g of nitrooxyethyl ammonium nitrate, and then a solution of 3.8 ml of triethylamine in 30 ml of absolute methylene chloride is added dropwise. Stir for 30 minutes at -15 ° C, dilute the reaction solution with 50 ml of methylene chloride and wash several times with water. The methylene chloride phase is dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel column for further purification (220. g silica gel, eluent {
methylene chloride / 3% methanol). The column fractions are evaporated, the residue is dissolved in methanol and the solution is mixed with a methanol solution of 1.2 g of oxalic acid hydrate. The solution is evaporated and treated with dizropropyl ether. Obtain 4.5 g (74% of theory) of crystals with so pl. 128130 ° C (decomposition).
The following compounds are prepared in a similar manner.
Example 27. 2-methoxy-5- (2- (N-methyl-L- / 4-cyano-4- / methylethyl) -4- (3,4-dimethoxyfenyl) -butyl / -aminoethyl / oxalate oxalate hydrate / -phenoxy-N- - / 2- nitrooxypropyl / -acetamide, so pl. 133-135 ° C (decomposition).
Example 28. 2-methoxy-5- (2- (K-methyl-N- / 4- -cyano-4- / methylethyl) -4- (3,4-dimethoxyphenyl) -butyl / -aminoethyl / oxalate oxalate dihydrate / -phenoxy- -N- / 3-nitroxybutyl / -acetonetamide, m.p. 123-125 ° C
Example 29. 2-methoxy-4- / 2- / №-methyl-L- / 4-cyano-4- / methylethyl / -4- / 3,4-dimethoxyphenyl / -butyl / -aminoethyl / oxalate oxalate hydrate / -phenoxy-N- - / 2-methyl-3-nitrosoxypropyl / 2 / -aceta-mas- 30 MIDa, mp. 128-130 C (decomposition).
Example 30. Oxalate hydrate of 2-methoxy-5- [2- (N-methyl-N- (4-cyanoG- -4- / methylethyl) -4- (3,4-dimethoxyphenyl) -butyl) -aminoethyl / / -phenoxy-N- - / 1, 3-bis-nitroxycyclohexyl-2 / - -acetamide, so pl. 143-145 ° C (decomposition) ..
 Example 31. 2-methoxy-5- (2- (M-methyl-M- (4-cyano-4- / methylethyl) - 4- (3,4-dimethoxyphenyl) -butyl) -aminoethyl oxalate oxalate hydrate // - phenoxy-N- -bis- / nitrooxyethyl / -acetamide, m.p. 110-112 C (decomposition).
Example 32. 2-methoxy-5- (2- (N-methyl-N- / 4-cyano-4- - / methylethyl) -4- (3,4-dimethoxyphenyl) -butyl) -aminoethyl oxalate oxalate hydrate // -phenoxy-N-bis- / 2- -nitroxypropyl / -acetamide, so pl. 118-120 ° C (decomposition).
35
40
45
50
Required as source
2-methoxy-5- (2- (N-methyl-N- - / 4-cyano-4- / methylethyl) -4- (3,4-dimethoxyphenyl) -butyl / -aminoethyl // - fe- Noxyacetic acid is prepared analogously to 2-methoxy-4- / 2- / N-I-N- / 4- -cyano-4- / methylethyl / -4- / 3,4-dimethoxyphenyl / -butyl / -aminoethyl // - phenoxy - acetic acid.
0
Required as source
2-methoxy-5- (2- (N-methyl-N- - / 4-cyano-4- / methylethyl) -4- (3,4-dimethoxyphenyl) -butyl / -aminoethyl // - fe- Noxyacetic acid is prepared analogously to 2-methoxy-4- / 2- / N-I-N- / 4- -cyano-4- / methylethyl / -4- / 3,4-dimethoxyphenyl / -butyl / -aminoethyl // - phenoxy - acetic acid.
The following compounds are prepared in a similar manner.
Example 33. Oxalate 3- / 2- / N- -methyl-N- / 4-cyano-4-dodecyl-4- / 3,4-dimethoxyphenyl / -butyl / -aminoethyl // - phenoxy-N-nitroxyethyl / -acetamide, so pl. 134-136 C (decomposition).
Example 34. 3- / 2- / N-methyl-N- / 4-cyano-4-dodecyl-4- / 3,4-Dimethoxyphenyl / -butyl / -amino-ethyl // - phenoxy-K- / 2-nitrooxypropsh1 / - -acetamide, m.p. 140-142 C (decomposition).
Example 35 3- (2- (H-methyl-H-) / 4-cyano-4-dodecyl-4- (3,4,5-trimethoxyphene 1) -butty1 /.- amo-noethyl / -phenoxy-H oxalate oxalate hydrate - (2-nitroxyethyl) - -acetamide, m.p. 127-129 ° C (decomposition).
P p i. meper 36. Oxalate 3- / 1-cyano-1-hexyl-4- / N-methyl-N- / 2- / 3-methoxy-xiphenyl / -ethyl / -aminobutyl // - phenoxy- -Y - / 2-nitrooxypropyl / -acetamide, so pl. 134-136 C.
Example 37. Oxalate 3- / 1-cyane- 1 -hexyl-4- (N-methyl-N- / 2- (3-methoxyphenyl) -ethyl / -aminobutyl // - phenoxy- -Y- / nitroxyethyl / -acetamide 5 oil.
Example 46. Citrate hydrate 4- / nitrooximeshch1 / -piperid1-1 amide 2-methoxy-5- (1-cyano-1- / metSch1-ethyl / -4- / K-methyl-H- / 2- / 3,4-dimethoxyfe) Example 38. Oxal dihydrate-30 nyl / -ethyl / -aminobutsch1 // - phenoxy-axust 2-methoxy-5- / 1-cyano-1- / methylethyl / - -4- / N-methyl-N- / 2- / 3,4 -dimethoxyphenyl / -ethyl / -aminobutyl / -phenoxy-L- [2,2- -dimethyl-3-nitroxypropyl] / 1 / -acetamide, m.p. 140 ° C (decomposition).
Example 39. 2-methoxy-5- [2 - / - methyl-K- [4-cyano-4- [methylethyl] -4- [3,4-dimethoxyphenyl] -butyl] aminoyl oxalate dihydrate oxalate // -phenoxy-N- - / 2,2-dimesh1-3-nitrooxy 1propyl-1 / - -acetamide, so pl. 140 ° C (decomposition).
Example 40. 2-methoxy-4- (1-cyano-1- / methyl-ethyl) -4- (N-methyl-N- / 2- (3,4-dimethoxy-diphenyl) -ethn-1-amnobutyl oxalate dihydrate // - phenoxy- -Y- / 2,2-dimethyl-3-nitrosoxypropyl-1 / - -acetamide, so pl. 140 ° C (decomposition).
Example. 41. The 2-methoxy-5- (2- (N-methyl-N- (4-cyano-4- (methylethyl) -4 (3,4-dimethoxyphenyl) -butyl) aminoethyl (/ - phenoxy-K- - / Z-nitrooxypropyl / 1 / -acetamide, mp 132-135 C (decomposition).
Example 42. Hydrate, citrate 4- / O.-nitroxyethyl / -piperidylamide 2-methoxy-5- / 2- / M-methyl-N- / 4-cyano-4- / methylethyl / -4- / 3.4 -dimethoxyphenyl / - -butyl / -aminoethyl // - phenoxyacetic
35
40
45
Noah acid, so pl. 142-145 C (decomposition).
Example 47. Citrate hydrate 4- / N-nitroxyethyl / -piperidylamide 2-methoxy-5- / 1-cyano-1- / methylethyl / - -4- / N-metsh-1- / 2- / 3,4-dimethoxyf - Nile / -ethyl / -aminobutyl / / -phenoxyacetic acid, m.p. 144-146 C (decomposition).
Example 48 Citrate hydrate 2-methoxy-5- (2- / YM) ethyl-K- (4-cyano-4- (methyl) ethyl-4- (3,4,5-trimethoxyphenyl) -butyl / -aminoethyl // - phenoxy- -N- / 3-nitroxy-propyl-1 - / - acetamide, m.p. 141-142.C (decomposition).
PRI me R 49. Citrate 4- / nitrooxymethyl / -pyperidyl ina 2-methoxy-5- / 2- / N-methyl-N- / 4-cyano-4 / metsh1ethyl / -4-3,4 , 5-trimethoxy-50 Phenyl - / - butyl / -aminoethyl // - phenoxy-acetic acid, so pl. 139-142 ° С (decomposition).
Example 50, citrate 4- / c | 6-yl-hydroxyethyl / -piperidylamide 2-methoxy-4- / 2- / N-methyl-H- / 4-cyano-4- / metsh1Etil / -4- / 3.3 , 5-trimethoxyphenyl / -butyl- / aminoethyl // - phenoxy-sucroic acid, m.p. 143-144 C decomposition).
55
acids, so pl. 142-145 ° C (decomposition).
Example 43. Citrate hydrate 4- / nitrooxymethyl / -piperidylamide 2-methoxy-5- / 2- (N-methyl-N- / 4-cyano-4- / methylethyl / -4- / 3,4-dimethoxyphenyl (-b) for type / - aminoetyl // - phenoxyacetic acid, m.p. 146-147 ° C (decomposition).
Example 44i Citrate 4- / nitrate ooxymethyl / -PIP yridylamide 2-methoxy-4- / 2- / Y-metsh-1-Y- / 4-cyano-4- / methylethyl / -4- / 3,4-dimethoxyphene- 5 nil / -bootsh1 / -aminoethyl // - phenoxyacetic acid, m.p. 144-146 ° C (disintegration). .
Example 45. Citrate hydrate 4- / N-nitro-oxyetyl / -piperidylamide 2-methoxy-4- / 2- / K-metSH1-N- / 4-cnano-4- / methylstil / -4- / 3,4 -dimethoxyphenyl / -butyl / -aminoethyl // - phenoxyacetic acid, m.p. 143-144 C (decomposition).
0
Example 46. Citrate hydrate 4- / nitrooximeshch1 / -piperid1-1 amide 2-methoxy-5- (1-cyano-1- / metSch1-ethyl / - -4- / K-methyl-H- / 2- / 3,4-dimethoxyfenyl / -ethyl / -aminobuty1 / - phenoxyux
five
0
five
Noah acid, so pl. 142-145 C (decomposition).
Example 47. Citrate hydrate 4- / N-nitroxyethyl / -piperidylamide 2-methoxy-5- / 1-cyano-1- / methylethyl / - -4- / N-metsh-1- / 2- / 3,4-dimethoxyf - Nile / -ethyl / -aminobutyl / / -phenoxyacetic acid, m.p. 144-146 C (decomposition).
Example 48 Citrate hydrate 2-methoxy-5- (2- / YM) ethyl-K- (4-cyano-4- (methyl) ethyl-4- (3,4,5-trimethoxyphenyl) -butyl / -aminoethyl // - phenoxy- -N- / 3-nitroxy-propyl-1 - / - acetamide, m.p. 141-142.C (decomposition).
PRI me R 49. Citrate 4- / nitrooxymethyl / -pyperidyl ina 2-methoxy-5- / 2- / N-methyl-N- / 4-cyano-4 / metsh1ethyl / -4-3,4 , 5-trimethoxy-0 Phenyl - / - butyl / -aminoethyl // - phenoxy-acetic acid, so pl. 139-142 ° С (decomposition).
Example 50, citrate 4- / c | 6-yl-hydroxyethyl / -piperidylamide 2-methoxy-4- / 2- / N-methyl-H- / 4-cyano-4- / metsh1Etil / -4- / 3.3 , 5-trimethoxyphenyl / -butyl- / aminoethyl // - phenoxy-sucroic acid, m.p. 143-144 C decomposition).
five
17
EXAMPLE 51 Citrate 4- / nitrooxymethyl / -piperidylamide 2-methoxy-4- / 2- (K-methyl-M- / 4-cyano-4- / methylethyl) -4- / 3, 4,5-trimethoxyphenyl / -butyl / -aminoethyl // - phenoxy-acetic acid, so pl. 142-144 ° C (decomposition).
Example 52. Citrate hydrate 4- / nitrooximeshch1 / -piperidylamide- -2-methoxy-4- / 1-cyano-1- / methylethyl / -4- / N-methyl-K / 2- / 3.4-3.4 -dimethoxy-phenyl / -ethyl / aminobutyl // - phenoxy-acetic acid, so pl. 145-147 ° C (decomposition).
Example 53. Citrate hydrate 4- / o6-nitroxyethyl / -piperidylamide 2-methoxy-4g / 1-cyano-1 / methylethyl / - -4 / N-methyl-N- / 3,4-dimethoxyphenyl / - ethyl / aminobutyl / -phenoxyacetic acid, so pl. 143-145 ° C (decomposition).
Example 54. Hydrate, oxalates of 3- / 2- / H-methyl-N- / 4-cyano-4-hexyl-4/3-methoxyphenyl / -butyl / aminoethyl / / -phenoxy-N- / nitroxyethyl / - -acetamide, so pl. 134-135 ° C (decomposition) ..
Example 55. 3- / 2- / Н-methyl-Н- / 4-cyanohexyl- -4- / 3-methoxy-phenes 1 / -butyl / -amino-ethyl / / -phenoxy-N- / 2-nitrooxypro oceanate hydrate -: drank / -acetamide, so pl. 136-137 ° С (operation).
Example 56-. Oxalate 2-methoxy-4- (2- (N-methyl-N- (4-cyano-4- / metsch1-ethyl) -4- (3,4-dimethoxyphene-1 / -butyl) -aminoethyl) - phenoxy -Y- / S /, / + / - 2-nitrooxypropyl / -acetates yes, so pl. 134-135 With (decomposition).
Example 57. 2-methoxy-4- / 2 - / - M-methyl-N- / 4-cyano-4- / methylethyl / -4- / 3,4-dimethoxyphenyl-by-I / aminoethyl oxalate oxalate hydrate -N- / R / - - / 2-nitrooxypropyl-acetamide, m.p. 126-128 ° C (decomposition). ; Example 58. 2-methox-4- / 2- (N-methyl-M- / 4-cyano- / methi; l-ethyl) -4- (3,4-dimethoxyphenyl) -butyl / -minoethyl // - - Phenoxy-N- / metschI- / 2- -nitroxycyclohexyl // - citrate, so pl. 144-146 ° C (decomposition).
Example 59. Citrate hydrate 2-methoxy-5- / 1-cyano-1- / methylstil / - -4- / N-methyl-N- / 2- / 3,4-dimethoxyphenol / -THYL / -aminobutyl / / -phenoxy-N- - / massI / 2-nitroxycyclohexyl //
-acetamide, cue).
m.p. 142-143 ° C (decomposition
-,

/ -
ten
15
20
25
508956
Example 60. Citrate hydrate 2-methoxy-5- (2- (N-methyl-N- / 4-cyano-4- / methylethyl) -4- (3,4-dimethoxyphenyl) -butyl / -aminoethyl / / -phenoxy-N- - / methyl- / 2-nitroxycyclohexl1 / - acetamide, so pl. 80 ° C (decomposition). Required as a source material, phenoxyacetic acid is prepared in a manner similar to the examples described.
Elemental analysis and the output of the proposed compounds in examples 1-60 are given in table.1.
Pharmacological studies.
A test for an effect similar to nitrate carried out on anesthetized rats.
The principle of action of all organic nitrates is the cleavage of the nitro group, which, through various intermediate stages, contributes to the formation of SMR in the vessel wall and the expansion of the corresponding areas supplied by this vessel, resulting in increased blood supply and the heart is less stressed.
.In order to prove denitration, which is the principle of action of all organic nitrates, the denitration rate is evaluated in relation to the rate of the known therapeutically used nitrate, isosorbium dinitrate (ISDN). For this, the rats are sacrificed under the action of anesthesia, and the liver is refunded with an equimolar ISDN solution of appropriate concentration or test substances for 4 minutes, and the amount of nitrate released in the persulfate is determined. The values indicate relative denitration compared to the ISDN metabolite - 1S-5-MN, the denitration of which is about 1. High values mean fast denitration, small values mean slow denitration: 50. Rapid cleavage of the nitro group means therefore short, slow denitration, but a longer effect is considered to be desirable.
Ca-antagonistic test. action
This test is verified in comparison with verapamil. Isolated spontaneously atrial dysplasia
thirty
35
40
45
55
The test substances in various concentrations are added to guinea pigs, and based on the concentration curves, the concentration that causes a 30% recovery of the contractile force of the heart and the concentration that causes inhibition of the atrial frequency is determined. The ratio of the two ends of the actions indicates whether the substance provides a stronger recovery of frequency and contractility. As a reduction in the frequency of atria is considered desirable in the function of contraction of the heart, which is not affected by the effect of concentration (substance),
The results are presented in table 2.
As can be seen from the data of Table 2, verap is mil as a Ca-antagonist does not show denitrization without a nitrate group. In contrast, when using ISDN, no significant effect of contractility or frequency is found up to the solubility limit of 1 mmol. The substances studied show relative denitration, which is clearly below the denitrization of ISDN, thus revealing a longer duration of action than with this substance. ,
Verapamil in a concentration that is 2.2 times less causes 30% inhibition of atrial contractility as a heart rate. In the proposed substances, the ratios of the ratios are shifted in favor of the stronger ones, which reduce the average.
frequency or less reduction of contractility. Thus, the proposed compounds are intrinsic and Ca-antagonistic effect and actin. The effect that ISDN exhibits.
Tests illustrating the biological effect of the compounds on mean arterial blood pressure and on the rate of increase in pressure in the left ventricle.
After anesthesia using sodium pentobarbital, normal blood pressure rats are implanted into the femoral artery (for measuring blood pressure) and into the femoral vein (for 55 Pressure, measuring probe for electrovaginal injection of the test compounds). In addition, a catheter is inserted through the artery of the carotis into the left ventricle of the heart from a micro-magnetic flowmeter around the aorta to continuously measure the flow of blood through the heart and subcutaneous electrodes for ECG measurements. Test
five
0
five
0
five
com Millar. With this catheter, the pressure in the left ventricle and, in particular, the pressure increase rate dp / dt can be measured. Before administration of the test compound, the autonomic nervous system is blocked by administering propranolol (1 mg / kg, intravenously) and atropine (1.5 mg / kg, intravenously, followed by a long infusion at a rate of 40 µg / kg / min.). Thereafter, the test compound is infused. In the case of most compounds, in the first 10 minutes, 1 mg / kg is poured, and in the next 10 minutes, another 2 mg / kg is poured. In some cases, only half of the indicated dose is infused, i.e. 0.5 mg / kg in the first 10 minutes and 1 mg / kg in the second 10 minutes.
The results are presented in Table 3, which provides data on the effect of the compounds obtained on blood pressure and the rate of pressure increase (measured 10 at 50 mm Hg) in the left ventricle of the heart, denoted dp / dt /. A decrease in the rate of increase in pressure means a negative, and an increase is a positive inotropic effect. In Table 3 of this report, also the number of experimental suture (p) on which the experiments were performed, the baseline values of pressure and values after infusion of 1 and 3 mg / kg ( i.e., 10 and 20 minutes after the start of the infusion, respectively. .. The values shown are mean values, (i) mean the mean deviation from the mean value.
As follows from the data, all
0
blood pressure and decrease the rate of pressure increase, i.e. have a negative inotropic effect. / The observed effect in the case of all compounds is dose dependent. With the introduction of 3 mg / kg, the effect is higher than after the infusion of 1 mg / kg.
In a surgical procedure, dogs are implanted with a catheter in the aorta for continuous measurement of blood pressure, catheter B, a femoral vein for intravenous administration of test compounds, a catheter in the right atrium for continuous measurement of blood in it.
Pressure measuring probe of an electromagnetic flowmeter around the aorta for continuous measurement of blood flow through the heart and subcutaneous electrodes for ECG measurements. Test
21
compounds begin no earlier than .8-10 days after surgery. To this end, dogs are placed in a special cell-catheter, and an electromagnetic measuring probe and ECG electrodes are connected to the appropriate recording systems. After the animals become accustomed to the laboratory conditions, the initial values of the measured parameters are recorded and after that the test compounds are administered intravenously in increasing doses. The interval between the two injections is 15 minutes. In addition to the oral administration of the compounds, blood MSf. To do this, they are suspended in methylcellulose (1% suspension) and using gastric
15
the probe is injected directly into the suspension. 20 Dose, 1 mg / kg reduces the blood flow for a long time in the stomach.
This bl.4 shows the results, hemodynamic effect, obtained with the introduction of verapamil to awake dogs.
As can be seen, depending on the dose, a decrease in systolic and diastolic blood pressure occurs. In the right atrium at doses of 0.2 mg / kg, there is no significant statistical change in blood pressure (wilcoxon test). At doses of 0.7 and 2 mg / kg, an increase in blood pressure occurs in the right atrium. This increase indicates a negative foreign effect of verapamil. The peripheral vascular resistance (calculated as the ratio of mean arterial blood pressure to the heart volume at a given time and given as a percentage of the initial value, taken as 100%) does not change significantly. The PQ-time obtained from ECG data, starting with a dose of 0.7 mg / kg, increases significantly. In the case of maximum doses administered in individual cases, signs of respiratory blockage are observed. volume of the third degree. Heart rate has a slight upward trend.
Table 5 shows the hemodynamic effect for compound 16 on. waking dogs, which shows that the proposed compound in terms of systolic and diastolic to equal pressure is comparable to verapamil, however, in the case of use
0895622
Nor does compound 16 show a decrease in peripheral vascular resistance, the magnitude of which depends on the dose.
In addition, there is a decrease in blood pressure in the right atrium. And only at the maximum dose of compound 16, as in the case of verapamil, an increase in blood pressure occurs in the right atrium.
Table 6 shows the hemodynamic effect for compound 45, from which it can be seen that this compound has an effect on systolic and diastolic blood pressure at the same level as verapamil, but unlike verapamil when using
ten
five
0
five
0
treatment in the right atrium.
Thus, the proposed compounds exhibit antagonistic action (like verapamnlu), directly affect the coronary vessels, or reduce blood pressure, providing a negative inotropic effect. But unlike verapamil, it acts as typical organic nitrates — isosorbium dinitrate, which reduces preload (blood pressure in the right atrium).
Thus, the proposed compounds not only reduce blood pressure, increase PQ - time, but also reduce blood pressure in the right atrium.
权利要求:
Claims (2)
[1]
Invention Formula
f A process for the preparation of phenylacetonitrile derivatives of the general formula
45
rhokog
CEN
same or different
hydrogen, lower alkoxy;
has the following meanings:
R7
C - ((SNG OR "6
CSN
- (C% VN- (CH2)
Re
RR, de Rg - normal or isotope C -C-apcnp., Linear C -C-alkyl type - the same or different, 2 or 3} X is a group of the formula
-Y-C - NZZ,
11 o
de one of Z is linear or branched C, -C-alkyl, cyclohexyl, lower alkyl cyclohexyl, cyclohexyl-lower alkyl, and the other Z. hydrogen or both radicals Z together form a heterocyclic nitrogen-containing



53.93. H 6.5 N 7.86
54.13 N 6.44 N 7.8
,
[2]
2. Нг04-0,5ИГ.О (699,7)
C 56.6 H 6.72 N 8.01
C 56.44 H 6.87 N 8.01
CrHr04 (704.8)
C 57.94 H 6.86 N 7.95
C 57.47 H 7.0 N 7.87
CrH2.04 (704.8)
C 57.94 H 6.86 N 7.95
C 57.91 H 7.06 N 7.93
C5, (791.8)
C 54.6, H 6.24 N 8.84
C 54.49 H 6.32 N 8.79
 (801.8) C 50.93 H 6.4 N 8.73 C 51.23 H 6.21 N 8.58. (821.8) C 53.26 N 6.58 N 8.63 C 53.02 N 6.47 N 8.47. (694.7)
C 55.32 N 6.67 N 8.06 C 55.24 N 6.75 N 8.09
cycle with 5-6 atoms
carbon,
Y is linear C, -C-alkyl, or hydrates, or dihydrates of their oxalates, yl-and citrates, characterized by the formula
so that the connection is about
where, A, Y have the indicated values}.
R, g is hydrogen, or lower alkyl, is reacted with a compound of the formula
HN2ZONO,
where Z has the indicated value, with the subsequent allocation of the target product in free form, or in the form of hydrates, or dihydrates of their oxalates, or citrates.
Table 1
87 5 T 51 56 62 60 52
78
25 15089562
Continuation of table 1
9 . (708.8)
Calculated: C 55.9 N 6.83 N 7.91 59 Found: C 55.65 N 6.81 N 7.75
10C ,, (740.8) Calculated: C 55.1 H 7.1 N 7.652 Found: C 55.4 H 6.87 N 7.58
   (722.8)
Calculated: C 56.6 AND 6.97 N 7.75 63 Found: C 56.73 H 7 N 7.71
12Cj H NgO -CiH O -HjO (809.8) Calculated: C 53.39 H 6.35 N8.65 Found: C 53.58 H 6.41 N 8.41
13 Cj.H45N50j,. (783.8)
Calculated: C 52.1 N 6.3 N 8.9466
Found: C 52.02 H 6.32 N 8.72; C H204-H O (811.8)
Calculated: C, 53.26; H, 6.58; N, 8.6352
Found: C, 53.42; H, 6.75; N, 8.48.
15C3oH42N; Og-C, iHj, 04. (694.7).
Calculated: C 55.32 H 6.67 N 8.0585
Found: C 55.18 H 6.56 N 7.91
16C, NN Ov-CgNeO ,. HgO (708.7) .57 Calculated: C 55.9 N 6.83 N
Found: C, 55.94; H, 6.71; N, 7.85.
17C5jH46N40e.C, Hi04. (722.8)
Calculated: C 56.5 N 6.97 N 7.75 65. Found: C 56.5 N 6.75 N 7.82
18C. (722.8)
Vyisleno: C 56.5 N 6.97 N 7.7561
Found: C 56.37 H 6.87 N 7.64
19C, H4, N50 ,, - CrH ,, 07 (791.8)
Calculated: C 54.6 N 6.24 N 8.84 55 Found: C 54.72 N 6.89 N 8.92
20C, .jH45N504-C- HjO + HgO (787.8)
Calculated: C 52.1 N 6.3 N 8.9454
Found: C 52.1 H 6.26 N8.72
21C H gNjOj, - CrHg04-2HgO (829.8) Calculated: C 52.1 H 6.7 N 8.4460 Found: C 52.23 H 6.61 N 8.29
22C3 ,, - C, H 04-2Hj, 0 (742.7)
- Calculated: C 53.5 N 6.78 N 7.566
Found: C 53.71 N 6.92 N7.69
23C j2.H46N40 ,, - (756.7)
Calculated: C 53.9 N 6.9 N 7.459
Found: C 54.15 H 6.8 N 7.54
, eN40, C2 H 04 2HaO (770.8)
Calculated: C 54.5 N 6.9 N 7.2 51. Found: C 54.47 H 6.71 N 7.4
- CrHg.04 (821.8)
Calculated: C 54.08 II 6.25 N 8.521 57 Found: C 53.95 H 6.38 N 8.31
26C, (676.7}
Calculated: C 56.8 N 6.55 N 8.28 74 Found: C 56.97 N 6.59 N 8.28
271508956 28
Continuation of table 1
I.:....LI.
Sz,, H204. (708.7)
Calculated: C 55.9 N 6.83 N 7.94 69 Found: C 55.75 H 6.61 N 7.81
Cj H 6N40a-C H 04 HjO (740.8)
Calculated: C 55.1 N 7.1 N 7.656
Found: C 55.13 N 6.93 N 7.57
. C. (722.8)
Calculated: C 56.5 H 6.97 N 7.75 54 Found: C 56.54 H 6.84 N 7.68
0.4 H4TNs04-C2H204-HjO (809.8)
Calculated: C 63.39 N 6.45 N 8.6571
Found: C 53.18 H 6.3 N 8.5
  (783.8)
Calculated: C 52.1 N 6.3 N 8.9461
Found: C 51.96 N 6.19 N 8.83
,, GjHeO.HgO (811.8) Calculated: C 53.26 N 6.58 N 8.6369 Found: C 53.5 N 6.69 N 8.57
. C, gIl5gN407 0.5 C ,, Ng07-NgO (745.9)
Calculated: C 62.8 N 8.27 N 7.5155
Found: C 62.62 H 8.7 N 7.63
G, gHgoN70T C H204-IUQ (804.9)
Calculated: C, 61.2 N, 7.9 N, 6.9959
Found: C, 61.42; H, 7.91; N, 6.99
. C gHgoN Og. (820.9)
Calculated: C 59.97 H 7.85 N 6.82 57 Found: C 59.85 H 7.95 N 6.9
, gN406-C;, H 04-H; iO (690.7)
Calculated: C 59.4 N 7.29 N 8.1163
Found: C 59, 7.29 N 7.93
S.N StsOb-SN O -NgO (676.7)
Calculated: C 58.67 N 7.15 N 8.2858
Found: C 58.68 H 7.33 N 8.43
 C;,. 0 11264 2NeO (754.8.).
Calculated: C 55.69 AND 7.21 N 7.4553
Found: C 55.55 H 6.97 N 7.29 C2 2H48N40g CiH204-2H5.0 (754.8)
Calculated: C 55.6U, H 7.24 N 7.45 59. Found: C 55.83 H 7.28 N 7.33
C, 3H4eN40s; C Ha04-2H20 (754.8)
Calculated: C 55.69 H 7.21 N 7.45-59.
Found: C 55.48 N 6.94 N 7.28
Cj, H44N40g C2H.i04-2H20 (726.8) Calculated: C 54.54 H 6.84 N 7.7145 Found :. C 54.87 H 6.76 N 7.82
C, H55040-C HgO HaO (867.9)
Vyisleno: C 56.93 H, 6.99 N, 6.4870
Found: C 57.07 H 7.2 N 6.42
C, H aN40a C6Hg07-H20 (850.9)
Calculated: C, 56.4 H, 6.87 N, 6.5866
Found: C 56.64 H 7.06 N 6.58
. SbNdot- (850,0)
Calculated: C 65.46 H 6.87 N 6.58 63 Found: C 56.4 H 6, 78 N 6.4
3
I
29150895630
Continuation of table 1
- T -; -
-
. (867.9)
Calculated: C 56.93 H 6.99 N 6.48 61 Found: C 56.84 H 6.82 N 6.3
C H eN Oe-CgHgO H O (850.9)
Calculated: C 56.46 And 6.87 N 6.5855
Found: C 56.24 H 6.86 N 6.46 C H5 N40a.SbK804-NgO (864.9)
Calculated: C 56.93 H, 6.99 N, 6.4859
Found: C 56.67 H 6.94 N 6.29 C 5 5goMcho CgHgO HgO (880.9)
Calculated: C 55.9 N 6.9 N 6.3651
Found: C 56.34 H 6.96 N 6.28 C ,, 6H5., N40 ,. CgHeO HgQ (894.98)
Calculated: C, 56.37; H, 6.98; N, 6.2650
Found: C 56.67 H 7, 14 N 6.2 SzbN5gM40 ,. SbNZO.NgO (894.98)
Calculated: C, 56.37; H, 6.98; N, 6.2658.
Found: C 56.29 H, 7.18 N 6.12
C jHsoN Og-CgHeO - (880.9).
Calculated: C 55.9 N 6.9 N 6.3659
Found: C 55.74 N 6.84 N 6.27
C H gN Oe CgHgO HeO (850.9)
Calculated: C 56.76 H 6.07 N 6.58. 63
Found: C 56.36 H 6.7 N 6.73
 CjyHsoN Oe. CgHaOj. (864.9)
Calculated: C 56.93 H 6.99 N 6.7863
. Found: C 56.74 H 6.84 N 6.41
C ,,, H4, H70b-C-H From (658.7)
Included: C 60.17 H 7.04 N 8.558
Found: C 59.85 H 7.21 N 8.7
C ,,, H46N406 C2Hi04 H20 (690.7)
Calculated: C 59 H 7.29 .N 8.11 -55
Found: C 58.84 H 7.2 N 8.21
C, 08-C.2.11 04-24,2.0 (726.8)
Calculated: C, 54.54; H, 6.94; N, 7.7157
Found: C 54.5 N 6.72 N 7.88
C, H N Og-C2 Hj, 04 2H20 (726.8)
Calculated: C 54.54 N 6.94 N 7.7155
Found: C 54.47 H 6.81 N 7.57
CjjHsoN Og. With NvOt-NgO (864.9)
Calculated: C 56.93 H 6.99 N 6.48 51 Found: C 56.85 H 7.03 N 6.64
CjsHs N Og. CfcHgO. HjO (864.9)
Calculated: C, 56.93 H, 6.99; N, 6.7859
Found: C 56.97 H 6.85 N 6.49
C55H5OH408-CbH807-NgO (864.9)
Calculated: C 56.93 H, 6.99 N, 6.4856
Found: C 57.1 N 6.96 N 6.45
311508956
table 2
The continuation of the table.2.
 The doses tested were 0.5 mg / kg for the first 10 minutes and 1 mg / game for the second 10 minutes.
Systolic blood pressure, mm Hg. Diaatolic blood pressure, -mmHg The pressure in the right atrium, mm Hg Peripheral resistance, PQ-time, ms Heart rate
129 ± 4. 125 ± 5 130 ± 4.5 120 ± 4.2 108 ± 5.3 75 + 3.7
58 + 3
57 ± 3 58 ± 3 60 ± 3 59 + 4 47 ± 3
31 ± 3
2.7 ± 0.5 2.4 ± 0.8 2.8 ± 0.6 2.5iO, 6 3.2 + 0.7 7.8 ± 0.9 9.7 ± 0.9
100 137
104 ± 2.4 96 + 5.0 103 ± 5.8 102 ± 5.7 115 + 11.0 100 ± 8.3 148. 142148175230
78 ± 6.2 83 ± 6.2 84 ± 6.9 83 + 7.2 91 + 7.4 90 + 7.4 72 + 2.5
Note. The mean values of 10 experiments + are given (mean error.
Values obtained 15 minutes after the administration of the substance
31 ± 3
Indicator
Dose of the tested compound, mg / kg
Baseline values
0.01
1 Systolic
blood
pressure,.
mmHg. 14814141i5 I42t5 13815 124 ± 3 120t3 109 ± 5
Diastolic blood pressure
mmHg.66i260t362 ± 3 61 ± 2 59 ± 2 52 ± .1 39 ± 3
Right pressure
atria4,4iO, 7 3.8tO, 8 2.9 + 0.7; 2.7tO, 7 2, OtO, 6 3.9 ± 0.4 8.5 ± 0.9
Peripheral vascular resistance 10094t289 + 4 88 + 3 76 ± 3. 68 + 3 64 ± 8 PQ - time,
me137-135128132151201
Frequency core reductions79 + 481 + 59014, 92 + 6 104 + 5 104 + 6 90 + 2
Note. The mean values of 10 runs are given ± mean error.
Values obtained 15 minutes after the administration of the substance.
Table of indicators Test doses, mg / kg
Original T 3
value.
Systolic. .
pressure, mm Hg 152.5 + 4.6 148.3 + 4.6 150.8 + 5.1 I 27.5i7.4
Diastolic
pressure, mm Hg 70.8 + 1.5 67.5 + 4.1 72.5 + 3.8. 48, S6,0
Right pressure
atria 5.9 + 0.5 4.5 + 0.3 5.2 + 0.6. 8.9 + 1.1
PQ-time 130140160190
Heart rate,
abbreviations 83 + 8 81 + 6 105 + 4 72 + 13
Note. The mean values from 6 experiments + average value are given,
Values obtained 15 minutes after the administration of the substance.
Compiled by S. Polkova Editor N. Kishtulinets Tekhred L. Serdyukova Proofreader T. Paliy
Order 5553/58 Circulation 352 Subscription
VNSHSHI of the State Committee for Inventions and Discoveries at the State Committee on Science and Technology of the USSR 4/5, Moscow, Zh-35, Raushsk nab. 113035
Production and publishing plant Patent, Uzhgorod, st. Gagarin, 101
Table 5
0.02
0.07
0.2
0.7
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同族专利:
公开号 | 公开日
IL76327D0|1986-01-31|
CS652285A2|1987-07-16|
HU195644B|1988-06-28|
CS255894B2|1988-03-15|
HUT38302A|1986-05-28|
ZA856942B|1986-05-28|
ES8604861A1|1986-03-16|
FI853343L|1986-03-13|
JPS6185355A|1986-04-30|
DE3433383A1|1986-03-20|
EP0175249A3|1987-08-19|
EP0175249A2|1986-03-26|
AU4709985A|1986-03-20|
AU562730B2|1987-06-18|
DK413685A|1986-03-13|
US4612313A|1986-09-16|
CA1248533A|1989-01-10|
GR852167B|1986-01-03|
FI853343A0|1985-08-30|
IL76327A|1989-06-30|
ES546908A0|1986-03-16|
DD237504A5|1986-07-16|
DK413685D0|1985-09-11|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题

FR2663M|1961-04-01|Knoll Ag|Phenylacetonitriles substituted with basic groups.|
US4340603A|1980-08-13|1982-07-20|Interx Research Corporation|Novel inotropic prodrugs|
DE3144150A1|1981-04-10|1982-12-09|Basf Ag, 6700 Ludwigshafen| -CYAN-1, -DIPHENYL-AZAALKAN DERIVATIVES, THEIR PRODUCTION AND THE MEDICINAL PRODUCTS CONTAINING THEM|US4612329A|1984-10-17|1986-09-16|Hokuriku Pharmaceutical Co., Ltd.|Pharmaceutical alpha-aminoalkyl-alpha-alkylphenylacetonitriles|
DE3642331A1|1986-12-11|1988-06-23|Basf Ag|BASICLY SUBSTITUTED PHENYL ACETONITRILES, THEIR PRODUCTION AND THE MEDICINAL PRODUCTS CONTAINING THEM|
GB8717068D0|1987-07-20|1987-08-26|Fujisawa Pharmaceutical Co|Nitric ester derivative|
NL9001955A|1990-09-05|1992-04-01|Cedona Pharm Bv|NEW THIAZOLIDINE DERIVATIVES.|
US6263940B1|1999-04-21|2001-07-24|Axon Corporation|In-line continuous feed sleeve labeling machine and method|
TW200821303A|2006-08-08|2008-05-16|Speedel Experimenta Ag|Organic compounds|
PT2170050E|2007-06-20|2014-09-04|Milestone Pharmaceuticals Inc|Short acting phenylalkylamine calcium channel blockers and uses thereof|
法律状态:
优先权:
申请号 | 申请日 | 专利标题
DE19843433383|DE3433383A1|1984-09-12|1984-09-12|NEW PHENYL ACETONITRILE DERIVATIVES|
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