Method of obtaining derivatives of benzazepinsulfonamides or their pharmaceutically acceptable salts

专利摘要:
An antiarrhythmic agent of the formula <CHEM> or a pharmaceutically acceptable salt thereof; wherein R<1> is H, C1-C4 alkyl or C1-C4 alkoxy; X is O, -NH @- or a direct link; and R<2> and R<3>, which are the same or different, are each C1-C4 alkyl, with the proviso that when X is -NH @-, R<2> and R<3> are the same. l
公开号:SU1579456A3
申请号:SU4355570
申请日:1988-03-24
公开日:1990-07-15
发明作者:Эдвард Кросс Питер；Эдмунд Эрроусмит Джон
申请人:Пфайзер Лимитед (Фирма)；
IPC主号:

专利说明:

The invention relates to the preparation of new benzazepinsulfonamides derivatives of the general formula
gn so №JOC V NHS07CH3
CHjSOzNHu.
where K is hydrogen, methyl or methoxy,
X is —0—, —NHCO—, or a single bond,
or their pharmaceutically acceptable salts with antiarrhythmic effects.
The purpose of the invention is. development, on the basis of known methods, of a method for the preparation of new compounds with valuable pharmacological properties with increased activity with low toxicity.
Example 1. 7-Ketanesulfonamo-to-3- 2- (4-methanesulfonamidophenoxy), 2,4,5-tetrahydro-ZN-3-benzaeepine, free base or hydrochloride reed (Free base).
ate
with
4i
cl
about

Sh
but). Add 0.2 ml of methanesulfonic anhydride to a solution of 0.37 g of 7-amino-3 -Ј2- (4-aminophenoxy), 2,4,5-tetrahydro-3H-3-benzazepine in 30 ml of pyridine cooled to 0 ° and then stirred the mixture for 72 hours at room temperature. The solvent is evaporated in vacuo and the residue is treated with methylene chloride, washed with pro-10 3 times with an aqueous solution of bicarbonate and 3 times with brine. The organic layer is dried (Na2SO4), filtered and evaporated in vacuo to give an oil,
they are cast, filtered, washed with water, then dried under vacuum at 60 ° C, 110.4 g are obtained. The product is recrystallized (called from industrial methylated alcohols (1100 ml) and methanol (1320 ml), the desired compound is obtained, yield 73.5 g, so pl. 221 C.
Calculated,%: C 49.0; H 5.8; N 8.6; S 13.1;
C4oH27M30 Si HC1
Found,%: C 48.9; H 5.8; N 8.6; S 13.0.
And p and me 2,
7-Methanesulfonamides which are purified by chromatography on cof5 to-3- (4-methanesulfonamidophenethyl) -1,
ten
94564
they are cast, filtered, washed with water, then dried under vacuum at 60 ° C, 110.4 g are obtained. The product is recrystallized (called from industrial methylated alcohols (1100 ml) and methanol (1320 ml), the desired compound is obtained, yield 73.5 g, so pl. 221 C.
Calculated,%: C 49.0; H 5.8; N 8.6; S 13.1;
C4oH27M30 Si HC1
Found,%: C 48.9; H 5.8; N 8.6; S 13.0.
And p and me 2,
7-methanesulfone
silica gel flask, elution with methylene chloride containing methanol (0 to 5%), the fractions containing the product are combined and evaporated to give a semi-solid product that is triturated with ether, filtered and dried to obtain the desired compound c. as an amorphous powder, yield 0.19 g, etc., is fuzzy.
Calculated,%: C 53.0; H 6.00; N 9.3;
(2о Н 27 N У -г
Found,%: C 53.05; H 6.1; N 8.9.
Repeat the above reaction using methanesulfonyl chloride and triethylamine in ethanol at room temperature to obtain similar results,
b). 70.3 g of methanesulfonyl chloride is added dropwise over 45 minutes to a stirred solution of 83 g of 7-amino-3-2- (4-aminophenoxy) ethyl -1,2,4,5-tetrahydro-3H-3-bena- Zepin in 700 ml of N-methylmorpholine cooled to O si gives 14.6 g of methanesulfonyl chloride to heat. The solvent is decanted from the solid residue in 3000 ml of water. The aqueous solution is extracted with 2 x 500 ml of ethyl ta. The precipitate is treated with the combined organic extracts, washed with 2 x 500 ml of water, dried over MgSO4 and evaporated in vacuo. The resulting oil is treated with 500 ml of methanol containing 2.5 M sodium hydroxyl (400 ml) and stirred for 0.5 h. 400 ° C. The methanol is evaporated in vacuo and the aqueous layer is washed twice with methyl chloride. The aqueous layer was diluted with 1000 ml of water and adjusted to pH 6.5 with concentrated hydrochloric acid. The resulting precipitate grana
. The reaction mixture is to 15 and then at 2, 4,5-tetrahydro-ZN-3-benzazepine.
The target compound, so pl. 184-187 ° C, prepared according to the procedure of Example 1 (a), by acylation of the corresponding diamino-recovery by methanesulfonyl anhydride, with the exception that the reaction time is 18 hours. The solvate is analyzed and quantitated by PFR spectroscopy.
Calculated,%: C 54.1; H 6.15; N 9.4;
0
five
0
0
five
20
N
1/10 СН2С12 Found,%: С 53.9; H 6.0;
9 1, J.
Primer Zo 7-Methanesulfonamo-to-3-2- (4-methanesulfonamido-2-methoxybenzamido) This is -1,2,4,5-tetrahydro-ZN-3-benzazepine.
0.155 ml of methanesulfonyl chloride is added dropwise to a solution of 7-amino-3-2 (4-amino-2-methoxybenzamido), 2,4,5-tetrahydro-3H-3-benzazepine in pyridine, cooled to 0 ° C and the reaction mixture is stirred for another 18 h at room temperature. The solvent is evaporated in vacuo and the residue is treated with methylene chloride, washed three times with an aqueous solution of sodium bicarbonate and three times with brine. The organic layer is dried over
sodium sulfate, filtered and evaporated, an oil is obtained in which the presence of a certain amount of unreacted starting material is determined by thin layer chromatography. After that, the oil is dissolved in pyridine and treated with 0.05 ml of methanesulfonyl chloride. The reaction mixture is stirred for 72 hours at room temperature. The solvent is then evaporated off under vacuum and the residue is taken up with methylene chloride, washed three times with aqueous sodium bicarbonate and three times with brine. The organic layer is dried
3, 1579456б
over sodium sulphate, filter and produce a pervasive response.
soar get oil. Received This is defined as ERP. The concentration in the oil is then purified by the chromatic compound required to increase the silica column chromatography by 25% (then determined by eluting with methylene chloride containing from 0 to 5% methanol, the fractions containing the product and SPLR is also measured on the guinea pig's right capillary muscles incubated in saline. The muscles are stimulated at one end, evaporated in vacuo to give the title compound as a colorless foam, yield 0.32 g.
Calculated,%: C 51.7,: H, 5.9; N 11.0;
C C2 H go N4 06 S 2
Found,%: C 51.7; H 6.0; N 10.6.
II p and mep 4. 7-Methanesulfonamo-to-3-G2- (4-methanesulfonamido-Z-methylERP is also measured on the guinea pig's right capillary muscles incubated in saline. Muscles are stimulated from one end, and The benefit of the bipolar electrodes, the resulting electrogram, is recorded from the opposite end through the surface of the unipolar electrode. ERPs are determined as described above using an extrastimulation method. The time taken on the oscilloscope with a digital memory when measuring the interval between the arthactic stimulus and the peak m
- -, electrograms (i.e. time requiring phenoxy) -ethyl -1,2,4,5-tetrahydro-3H-20 s for impulse to travel along -3-benzazepine muscle muscle)
0.18 ml of methanesulfonyl chloride is added dropwise to a solution of 0.36 g of 7-amino-3- 2- (4-amino-3-methylphenoxy), 2,4,5-tetrahydro-3H-3- benz-25 zazepin in 30 ml of pyridine cooled to 0 ° C, then the mixture is stirred for 72 hours at room temperature. The solvent is evaporated in vacuo and
° B .. M THILECHLORIDE ° M 30 of the above method, as well as the corresponding result for d-sotalol, a known antiarrhythmic agent, are listed in the table.
From the results shown in Table 35, it can be seen that the compounds of this invention are more effective.
ERP for the atrium and ventricle of anesthetized or conscious dogs are also measured using an extra-stimulation technique, while the atrium or the right ventricle passes at a constant rate.
Data showing the results of ED2 and obtained using Flush are washed three times with a saturated aqueous solution of sodium bicarbonate and three times with brine. The organic layer is dried over sodium sulfate, filtered and evaporated in vacuo, an oil is obtained which is triturated with methylene chloride to obtain a solid product. Upon recrystallization of the solid product from a mixture of ethanol and ethyl acetate, the desired compound is obtained, yield 0 0.28 g, mp. 173-174 ° C.
Calculated,%: C 53.9; H 6.25; N 9.0;
CaiHs, N, 05Sa
Found,%: C 54.3; H 6.3: N 8.7.
In order to assess the effect of the compounds on atrial immunity, right guinea pig hemiatry is placed in a bath containing a physiological solution, and one end is connected to a force transducer. Tissues are stimulated at 1 Hz using an electrode field. The effective immunity period (ERP) is measured by administering premature irritation (S2) after each 8th primary irritation (Sj). S, S the combining interval is usually increased until S causes a resumption

权利要求:
Claims (2)
[1]
1. The method of obtaining derivatives of benzazepinsulfonamides of formula I
jfT (CHt -X-O-NHSOaCH3 CH3502ShD;
where R is hydrogen, methyl or methoxy; X - -0-, -NHCO- or simple
connection
or their pharmaceutically acceptable salts, characterized in that the compound of formula II
0Z teH2lrx-O-NH2
55
Htn
where X and R have reduced values, are acylated with methylsulfonyl anhydride
This is defined as ERP. The concentration of compound required to increase ERP by 25% (then determined
EPP was also measured on the right capillary muscles of the guinea pig incubated in saline. Muscles are stimulated from one end using bipolar electrodes, the resulting electrogram is recorded from the opposite end through the surface of the unipolar electrode. ERP is determined as above using an extrastimulation method. The time spent is obtained on an oscilloscope with a digital memory when measuring the interval between the artifact stimulus and the peak
The above method also corresponds to the ERP for the atria and the ventricles of anesthetized or conscious dogs using extra-stimulation techniques, while the atrium or the right ventricle is at a constant rate.
Data showing the results of ED2 and obtained using
Invention Formula
1. The method of obtaining derivatives of benzazepinsulfonamides of formula I
jfT (CHt -X-O-NHSOaCH3 CH3502ShD;
where R is hydrogen, methyl or methoxy; X - -0-, -NHCO- or simple
connection
or their pharmaceutically acceptable salts, characterized in that the compound of formula II
50
0Z teH2lrx-O-NH2
55
Htn
where X and R have reduced values, are acylated with methylsulfonyl anhydride
or methylsulfonyl halide - in the presence of an acid acceptor, followed by isolation of the target product in free form or in the form of a pharmaceutically acceptable salt.
СНз502М- N.
Examples No.
ck -80crna
H
- Q- IS02CH3 N
NHCO-O-NS02CH3
nu g h
oo
O-Q-NSOiCHj
SnT n
[2]
2. Method pop, 1, characterized in that pyridine, N-methylmorpholine, triethylamine, potassium carbonate or sodium bicarbonate is used as an acid acceptor.
/
1 CH2CH2-R
ED
45
5.6 x 10
,-eight
4.4 x 10
, -b
2.1 x 10
, -b
1.1 x 10
,-five

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法律状态:
2005-05-10| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20040325 |

优先权:

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申请号 | 申请日 | 专利标题

---

GB878707120A|GB8707120D0|1987-03-25|1987-03-25|Antiarrhythmic agents|

---