Method of producing sulfonamide derivative

专利摘要:

公开号:SU1591805A3
申请号:SU874202474
申请日:1987-04-30
公开日:1990-09-07
发明作者:Dzhon Edmund Errousmit；Piter Edvard Kross；Dzhoffri Noel Tomas
申请人:Pfizer Ltd；
IPC主号:

专利说明:

The invention relates to the preparation of a sulfonamide derivative, in particular 1- (4-methanesulfonamidophenoxy) 2- (p- (4-methanesulfonamidofedetil) -Cmethylamino ^ -ethane, which exhibits anti-arrhythmic activity. The goal is to develop a method of obtaining new, more active compounds. Production is carried out by acylation of the compound f-ly
SNS
- | |
^And 1 ^H ® “ ^CH 2“ ^CH 2 " ^K ~ ^CH 2" ^CH 2 ~
where K, - ΝΗ _g or NBOO ^ CH}, K ₂ - ΝΗ ₂ or MNBO ^ CH ₅ , provided that at least one of 1C and K ₂ - NG _g , compound f-ly CH ₃ 80 ₂ C1 or ( CH ₅ 50 ₂ ) ₂ 0. Semi-Invention relates to a method of obtaining a new sulfonamide derivative exhibiting antiarrhythmic activity, and can be used in medicine to increase the resistance of the heart muscle and connective tissue to the premature pathogen.
The purpose of the invention is to develop a method for obtaining new more active compounds.
Π p and me 1. A. 1- (4-Nitrophenoxy) -2- {K-methyl-P- (4-nitrophenethyl) ami_ but] -ethane.
The resulting product is isolated in free form. The process is preferably carried out in the presence of an acid acceptor - pyridine. 1 hp f-ly.
In a solution of g1-methyl-4-nitrophenethylamine (1.5 g) and 2- (4-nitrophenoxy) ethyl chloride (1.55 g) in acetonitrile (50 ml), potassium carbonate (1.25 g) and sodium iodide (1 , 2 g) and the suspension is stirred at reflux for 72 hours. After evaporation to dryness, the residual oily solid product is distributed between 2 n. an aqueous solution of sodium bicarbonate and ethyl acetate. After two additional extractions with ethyl acetate, the organic phases are combined, washed with saturated aqueous salt
, 5 and 1591805 AZ
3
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solution, dried over magnesium sulfate, filtered and. evaporated. The obtained orange solid product (2.7 g) is crystallized from ethanol, resulting in a gain of the target compound (1.9 g), melting point 74 ° C.
Found,%: N 12.15.
^C- GT ^N 'T9 *
C, 58.75; H 5.4;
Calculated,%: C 59.1; H 5.5;
N 12.2.
B. 1- (4-Aminophenoxy) -2- [Ν- (4-aminophenethyl) -Ν-methylamino)] ethane.
A solution of 1- (4-nitrophenoxy) -2- £] Chmethyl-Ν- (4-nitrophenethyl) amino] ethane (1.5 g) in ethanol (100 ml) is stirred for 16 hours at room temperature under a hydrogen pressure of 3 atm in the presence of Raney nickel ("Nikat 102 ¹ '). The reaction mixture is filtered and evaporated to dryness. The residual oil is again dissolved in ether, filtered and evaporated, and the result is a yellow solid (1.1 g), which crystallizes ethyl acetate (petroleum ether) with a bp 60-80 ° C, and the result is the target compound (0.9 g) with mp 73-74 ° C.
• Found,%: C71.3; H8.1;
• Ν 14-, 7.
ten
15
20
25
thirty
Calculated,%: C 71.55; H 8.1;
N 14.7.
B. 1- (4-Methanesulfonamidophenoxy) 2- [Ν- (4-methanesulfonamidophenethyl) -Νmethylamino] ethane (desired product).
A solution of 1- (4-aminophenoxy) -2- [D (4-aminophenethyl) -Ν-methylamino] ethane (0.75 g) and methanesulfonic anhydride (1.0 g) in anhydrous methylene chloride (50 ml) is stirred at room temperature temperature overnight. After evaporation, the resulting oil is distributed between 2 n. an aqueous solution of sodium bicarbonate and ethyl acetate. After the next two extractions with ethyl acetate, the organic phases are combined, dried over magnesium sulphate, filtered and evaporated. A colorless solid is obtained (1.2 g), which is crystallized from ethyl acetate / methanol, and the result is a target compound (0.6 g) with mp. 147-149 ° C.
Found,%: C 52.1; H 6.25;
35
40
45
50
55
N 9.45.
C ^ H ₂ .
Calculated,%: C, 51.9; H 6.15;
N9.4.
 II p m m e r 2. A. 1- (4-Methanesulfonamidophenoxy) -2- [m-metzl-P- (4nitrophenethyl) amino] ethane.
Suspension of N-methyl-4-nitrophenethylamine (1.1 g), 2- (4-methanesulfonamidophenoxy) ethyl chloride (1.5 g), sodium bicarbonate (0.5 g) and sodium iodide (0.9 g) in acetonitrile ( 100 ml) is stirred at reflux for 4 days. After evaporation to dryness, the resulting oil is distributed between 2N. sodium bicarbonate and methylene chloride. After further two extractions with methylene chloride, the organic phases are combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. A brown oil is obtained and subjected to chromatographic separation on silica gel ("Kieselgei 60") by elution with ethyl acetate, and then the corresponding fractions are recovered by evaporation, the indicated title compound is obtained as a yellow solid (0.9 g). _P
NMR spectrum · (ΟϋΟΙ ₃ ), o: 2.45 (s.,
ZN); 2.86 (m, 6H); 3.0 (s., NN); 4.2 (t., ZN); 6.86 (τ., 2H); 7.22 (d.,
2H); 7.4 (d ·, 2H); 8.15 (d, 2H).
B., 1- (4-Methanesulfonamidophenoxy) 2- [L-methyl-M- (4-aminophenethyl) amino.] - ethane.
A solution of 1- (4-methanesulfonamidophenoxy) -2- [I-methyl-H- (4-nitrophenethyl) amino] ethane (0.9 g in ethanol (100 ml) is stirred for 16 hours at room temperature under hydrogen pressure 3 atm (3.04 x ⁵ Pa) in the presence of a catalyst — Raney nickel (“Ny, cat 102"). The reaction mixture is filtered and evaporated to dryness. A solid is obtained and crystallized from toluene, to give the target compound as yellow crystals ( 0.6 g) with a melting point of 155-157 ° C.
Found,%: C 59.9; H 7.1;
N 11.2.
^C _, ^Н 25 ^М Э ° Э ·
C, 59.5; H 7.0;
N11.6.
B. 1- (4-Methanesulfonamidophenoxy) 2- [Ν- (4-methanesulfonamidophenethyl) -Ν.methylamino] ethane.
five
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In a solution of 1- (4-methanesulfonamidophenoxy) -2- £ M-methyl ~ D- (4-aminophenethyl) amino] ethane (0.15 g) in dehydrated pyridine (3 ml) methanesulfonyl chloride (35.4 μl) is added dropwise and the mixture is stirred at room temperature overnight. After evaporation, the resulting oil is distributed between 2 n. aqueous solution of bicarbonate. sodium and chloride. methylene. ^One further bare two extractions with methylene chloride are combined with organic fractions, dried over anhydrous magnesium sulfate, filtered, and evaporated. The result is a colorless solid product (0.135 g) and crystallized from a mixture of hexane-ethyl acetate, resulting in a gain of the target compound (0.1 g) with so pl. 151-152 ° C, which is identical to the product of example 1 (B).
Found,%: C51.6; H6.2;
N 9.2; 3 14.52.
C _{/ 9} N ₂₇ M ₃ 0 _5h
Calculated,%: C, 51.9; H 6.15;
N 9.4; 3 14.51.
H NMR (COCl ₃ + 1k.01480 (1 _£ ), <D: 8.6 (brs, 1H); 8.4 (brs, 1H);
7.1 (m, 4H); 6.8 (2H); 4.0 (m, 2H); 30 draft sediment. Forming a colorless "·
2.85 (with _p RN.); 2.82 (с _о ЗН); 2.80 (m, 2H); 2.65 (1m., 5H); 2.35 (s., NN).
IR spectrum (Νιι, ΐοΐ), cm ' ¹ : 3250 (s); 2950 (s); 1510 (m); 1,400 (m); 1320 (s); 1250 (m); 1225 (m); 115 (s);
1000 (m); 770 (s).
Example 3. A. 1- (4-Nitrophenoxy) -2- [N-methyl-Ν- (4-methanesulfonamidophenethyl) amino] ethane.
A solution of 11-methyl-4-methanesulfonamidophenethylamine (1.0, g), 2- (4-nitrophenoxy) ethyl bromide (1.2 g), potassium carbonate (0.67 g) and sodium iodide (0.72 g) in acetonitrile (100 ml) stirred under heating to reflux for three days. After evaporation to dryness, the residual oil is distributed between water and methylene chloride. After the next two extractions with methylene chloride, the organic phases are combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. A yellow oil is obtained and dissolved in hot methanol, cooled, and the target compound formed is crystallized out as a colorless solid (1.2 g).
NMR spectrum (CSTR, /: 2.48 (s.,
ZN); 2.82 (with., 4H); ' 2.93 (t ·, 2H); 3.02 (with., ZN); 4, 18 (t., 2H); 6.98 (d., 2H); • 7, 18 (d ·, 2H); 7.22 (d., 2H); 8.15 (d., 2H).
15
B. 1- (4-Aminophenoxy) -2-GY-Methyl1θ-(4-methanesulfonamidophenethyl) aminoD ethane, dihydrochloride.
A solution of 1- (4-nitrophenoxy) -2- £ N-methyl-Ν- (4-methanesulfonamidophenethyl) amino} ethane (1.0 g) in ethanol (50 mp) containing 5% / C (0.1 g ), stirred under a hydrogen atmosphere (50P $ _; =
= 3.45 · $ 10 Pa) c. for 4 hours. Then the reaction mixture is filtered, I evaporate the solvent, and as a result, a brown oil is obtained, which is purified by chromatographic separation in a column of silica gel ("Kiesel gel-60") by elution with methylene chloride. The corresponding 25 fractions are combined and evaporated to give a yellow oil (0.5 g), which
•but·
dissolved in ethyl acetate, and an ethereal solution of the hydrochloride is injected until the complete solid solid is washed with dry anhydrous ether and the desired compound (0.35 g) is obtained with mp. 22 ° -223 ° C.
Found,%: C 48.4; H 6.4;
N 9.0.
35
С <ί ^Η ζί ^Ν Э ° Э 2НС1-1 / 2Н ₂ O.
Calculated,%: C 48.5; H 6.3;
N 9.4.
40 B. 1- (4-Methanesulfonamidophenox) 2- £ ν (4-methanesulfonamidophenetics) -methylamino} ethane (desired product).
The indicated target compound is obtained by methylsulfonation of 1- (4-aminophenoxy) -2- £ ν-μθτηπ-Ν- (4-methanesulfonamidophenethyl) amine] ethane dihydrochloride hemihydrate (95 mg) with methyl sulfonyl chloride in pyridine according to
50 of the procedure of example 2 with the release of 30 mg, with so pl. 147-149 ° C. This compound, as confirmed by spectroscopic analysis, is identical to the product of Example 1 B.
Found,%: C 51,, 6; H 6.3;
N 9.3.
C. ^ dH 2 ₇ Ν 3О5З ₇ .
Calculated,%: C, 51.9; H 6.15;
N 9.4.
55
7
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The drug 1 - 4- [2- (methylamino), ethyl} methanesulfonanilide.
In a solution of 4 ~ G2- (methanesulfonyloxy) ethyl} methanesulfonyl anilide $
(10.3 g) in ethanol (20 ml) a solution of methylamine in industrial ethanol denatured with methyl alcohol (30 ml, 33% solution) is introduced. The mixture is heated with stirring at 85 ° C in a pressure vessel for 17 hours. After cooling, the resulting solution is evaporated to dryness, the residual evaporation product is dissolved. they are stolen in water and the resulting solution 15 is alkalinized by the addition of hydra-. and sodium oxide (1.4 g) in water (12 ml). After evaporation, a whitish solid is obtained, which undergoes chromatographic separation on 20 silica gel ("Kieselgel 60") by elution with a mixture of methylene chloride / methanol in a ratio of 3: 1. After isolating and evaporating the corresponding fractions, a whitish solid product (4.8 g) is obtained, which crystallizes from ethyl acetate / methanol mixture, and the result is the target compound (1.8 g) with m.p. 133-135 ° C.
thirty
Found,%: C 52.5; H 7.1;
N 12.2.
С Н '' оРтН ·
Calculated,%: C 52.6; H 7.2;
N 12.3. ₃₅
The drug 2 - 4- (2-chloroethoxy) methanesulfonanilide.
In a solution of 4- (2-chloroethoxy) aniline hydrochloride (9.5 g) of methanesulfonic acid anhydride (12.0 g) in chlorine methylene (100 ml) is added dropwise with cooling triethylamine (25 ml) and the mixture is stirred at room temperature temperature overnight. The resulting mixture is distributed between 2 n. 45 aqueous solution of sodium bicarbonate and methylene chloride. After further two extractions with methylene chloride, the organic phases are combined, dried over magnesium sulphate, filtered and evaporated to dryness. Semi. solid product (9.5 g) is crystallized from methanol after filtration of impurities, and as a result. get the target compound in the form of light pink crystals (5.6 g) with so pl. 111-114 ° C
NMR spectrum (С0С1 ₃ ), <Р, ppm:
2.84 (s., MN); 3.8 (t., 2C); 4.2 (t.,
2H); 6.75 (d, 2H); 7.15 (d, 2H);
9.0 (bs, 1H).
The drug 3 - 2- (4-nitrophenoxy) ethyl chloride. '
A mixture of 4-nitrophenol (139 g,
1 mol), 2- (benzosulphonyloxy) -ethyl chloride (220.5 g, 1 mol) and anhydrous potassium carbonate (138 g, 1 mol) in methyl ethyl ketone ("MEK", 1000 mp) are stirred under heating with a Reverse Refrigerator for 16 After cooling, the mixture is poured into water and the organic layer is separated.
After further two extractions with methyl ethyl ketone, the combined organic fractions are dried over Μβ3 ₄ , filtered and evaporated. The resulting solid was crystallized from ethanol to give the desired title compound (165.8 g), mp. 60 ^σ 0.
Found,%: C 47.65; H 4.0;
N 7.0.
Ο ^ Η ^ ΟΙΝΟз (I).
Calculated,%: C 47.7; H 4.0;
N7.0.
The biological activity of the compounds in free form is determined as follows.
The right atria of the guinea pigs are fixed in a bath containing a solution of physiological salt, and one end is connected to a force sensor. Tissues are stimulated by creating an electric field with electrodes at a frequency of 1 Hz. Period of effective resilience. (EKP) is measured by entering a premature stimulus (δ ₂ ) after every eighth main stimulus (5,). Merge interval. 5,5 ₂ stepT-g but increase until 3 ₂ will not cause a reproducible propagating reaction! It is defined as the EKR. Then determine the concentration required to increase the ECR by 25% (ED ₂₅ ). EKP is also measured on the right papillary muscle of the ventricle of the heart in a solution of physiological salt. Muscles are stimulated at one end with the help of bipolar electrodes, and the reproducible electrogram is recorded at the opposite end by means of a unipolar surface electro-kind. EKR determined using the method of extraneous irritant.
Using digital storage OS9
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ten
cylinder for measuring the interval. between the point of the artificially created * stimulus and the maximum point of the electrogram, determine the time of conduction, i.e. the time required for the passage of the pulse along the length of the muscle.
Atrial and ventricular heart ECRs are also measured on anesthetized or pain summarizing dogs using the external irritant method, while the atrium or right ventricle is moved at a constant rate.
The compound of formula (I) can be administered into the body, but it is usually administered in a mixture with pharmaceutical carriers, the choice of which is determined by the method of administration into the body and the practice adopted in the pharmaceutical industry. It can be introduced both into the body of sick people suffering from cardiac arrhythmia, and into the body of people who may have arrhythmia, for the purpose of prevention. It can be administered orally-5 but in the form of tablets containing medicinal bases, such as starch of lactose, or in the form of capsules, either individually or as a mixture with medicinal bases, or in the form of 30 elixirs or suspensions containing flavoring or coloring agents. It can be injected parenterally, intravenously, intramuscularly or subcutaneously. 35 For parenteral administration, it is used in the form of a sterile aqueous solution, which may contain other solutes, such as salts or glucose, in quantities sufficient to produce an iso-tonic solution.
To enter the human body for the treatment or prevention of heart diseases, such as ventricular and supraventricular flutter, oral doses of the compound of formula (I) are in the range of 1–75 mg per day from the growth of four divided doses (per day) to average adult patient (70 kg). When administered intravenously, the dose of the drug is 0.5-10 mg on demand and ί administered as a single dose. With a strong cardiac arrhythmia, intravenous administration of the drug is desirable in order to cause a rapid transition to a normal rhythm. Thus, for a typical adult patient, individual tablets or capsules should contain 1 to 25 mg of active compound in a suitable pharmaceutically acceptable carrier or drug base.
Compound (I) is tested on dogs with a minimum effective dose of 5 mg / kg, as well as a maximum dose of 10 mg / kg. In this connection does not show signs of toxicity and it can be classified as low-toxic compounds.
As a comparative compound, sotalol formulas are tested.
'he
CH ₃ 80 ₂ HH- <O-CHCHH ^ HCH (CH3) ₂
according to the specified method. Ele- receive ¹ following results: sotalol: U _{£ 2} = 7x. xy '^ m; compound (I): ED = 5x10 ^ M.
ί
Thus, the method allows to obtain a new compound that exhibits anti-arrhythmic activity in a lower dose than the known compound, and has low toxicity. .

权利要求:
Claims (2)
[1]
Claim
1. The method of obtaining the derived sulfonamide formula
ch ₃
CH ₃ -80 ₂ -HH - @ “CH ₂ -CH ₂ -K-CH ₂ -CH ₂ -0- (0 ^ -1 H50 ₂ CH ₃
characterized in that the compound of the general formula
ch ₃
^ 1 "<§ ^ CH ₂ -CH ₂ -M-CH ₂ -CH ₂ -0 ^ O) -I ₂
1591805
12
where is ΝΗ ₂ or ΝΗ3Ο ₂ ΟΗ _α ;
Kg - ΝΗ ₄ or Ш8О ₂ CH ₃ ,
provided that at least ONE of K, and K ₄ - ΝΗ ₅ , is acylated with the compound CH ^ ZO ^ C! or (CH ₃ 80g) ₂ 0
and the resulting product is isolated in free form.
[2]
2. The way pop. 1, characterized in that the process is carried out in the presence of an acid acceptor pyridine.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB868610668A|GB8610668D0|1986-05-01|1986-05-01|Anti-arrhythmia agents|LV931305A| LV5466A3|1986-05-01|1993-12-03|Satisfaction of the sulfonamide derivative|