Novel sulfonamides, a processes for their preparation and pharmaceutical compositions containing these new sulfonamides

The present invention relates to novel 2-phthalimidoethane- sulfone-N-arylamides. These novel compounds are represented by formula I

wherein n = 1 - 4 and

R _] _ is hydrogen or an alkyl or hydroxyalkyl group having

1 - 6 carbon atoms

R ₂ is a)

wherein

R3 and R can be similar or different and mean hydrogen, an alkoxy, carbalkoxy or alkyl group with 1 - 4 carbon atoms, halogen, trifluoromethyl or a nitrogroup or a group of the formula

-N

wnerein

R5 and R5 can independently of each other mean hydrogen or an alkyl group with 1.- 4 carbon atoms, but if n = 1,

R _] _, R3 and R cannot at the same time mean hydrogen atoms,

b )

wherein

Z = 0 , N or S .

Examples of prefered compounds of the invention are those of the formula I wherein n = 1 - 4 and R _] _ is hydrogen

wherein

R3 is hydrogen, an alkoxy, alkox carbonyl or alkyl group comprising 1 - 4 carbon atoms, halogen, trifluoro- methyl or a nitro group or a group of the formula

/ ^R = ^ ^R 5 / «5

-N -S0 ₂ N or -CON

\ _D \ n \ „

H ^R 6 ^R 6

wherein

R5 and Rg can independently of each other mean hydrogen or an alkyl group with 1 - 4 carbon atoms, and

R4 is hydrogen or halogen.

Still more prefered are compounds of formula I wherein n = 1 - 3 and

R]_ is hydrogen or metyl or hydroxyethyl

wherein

R _] is a methoxy, metoxylcarbonyl or methyl, Cl, F, trifluoromethyl or a nitrogroup or a group of the formula

/ ^R 5 ^ ^R5 ^ ^R 5

-N ; -S0 N or -CON

\ « \ _n

^R e Rβ \ „ ^R 6

wherein

R5 and Rg each are hydrogen or methyl and

R4 is hydrogen or chlorine.

Prefered compounds of the invention are

2-Phthalimidoethanesulfone-N-(4-methoxybenzyl)-amide, 2-Phthalimidoethanesulfone-N-(4-methylbenzyl)-amide, 2-Phthalimidoethanesulfone-N-(4-nitrobenzyl)amide, 2-Phthalimidoethanesulfone-N-methyl-N-benzylamide, 2-Phthalimidoethanesulfone-N-furfurylamide, 2-Phthalimidoethanesulfone-N-(4-carbomethoxybenzyl)amide, 2-Phthalimidoethanesulfone-N-(benzyl)ethanolamide, 2-Phthalimidoethanesulfone-N-(4-carboxamidobenzyl)amide, 2-Phthalimidoethanesulfone-N-(3-dimethylaminebenzyl)amide, 2-Phthalimidoethanesulfone-N-(2,4-dichlorobenzyl)amide, 2-Phthalimidoethanesulfone-N-(3-trifluoromethylbenzyl.)amide , 2-Phthalimidoethanesulfone-N-(4-fluorobenzyl)amide, 2-Phthalimidoethanesulfone-N-(3-phenyl)propylamide, 2-Phthalimidoethanesulfone-N-[3-(4-chlorophenyl)propyl]amide , 2-Phthalimidoethanesulfone-N-[2-(4-dimethylsulfonamidophenyl ) ethyl]amide,

2-Phthalimidoethanesulfone-N-[2-(3-dimethylaminephenyl)et hyl] amide,

2-Phthalimidoethanesulfone-N-[3-(4-dimethylaminephenyl)pr opy a ide,

2-Phthalimidoethanesulfone-N-(4-methoxybenzyl)amide, 2-Phthalimidoethanesulfone-N-(4-methoxybenzyl)amide, 2-Phthalimidoethanesulfone-N-(4-methylbenzyl)amide 2-Phthalimidoethanesulfone-N-(3,4-dichlorobenzyl)amide, 2-Phthalimidoethanesulfone-N-(4-chlorobenzyl)amide.

The present invention relates also to the process for preparing these novel compounds. The process is characterized in that

1) a phthalimidoethanesulfonylchloride of formula II

is reacted with an a ine of formula III

NH-(CH ₂ 5 _n -R ₂ (III)

wherein n, R^ and R ₂ are the same as above.

2) a phthalimidoethanesulfonamide of formula IV

wherein Rj_ is the same as above, is alkylated with a suitable alkylating agent containing the group -(CH ₂ ) _n -R , wherein n and R are the same as above,

3 ) a Dhthali idoethanesulfonamide of formula V

(CH λ«)n-R~ λ (V)

wherein n and R are the same as above, is alkylated with a suitable alkylating agent containing the group R _] _ defined above,

4) a phthali ide of formula VI

or a salt thereof is reacted with a compoud of formula VII

X-CH ₂ CH ₂ S0 ₂ ϊN- ¹ (CH ₂ ) _n -R ₂ (VII)

wherein n, R _] _ and R are the same as above and X is an interchangeable group such as e.g. halogen, or

5) a phthalic anhydride of formula VIII

or the equivalent acid is reacted with an amide of formula IX

H ₂ N-CH ₂ CH ₂ S0 ₂ N-(CH ₂ ) _n -R ₂ ^' (IX)

wherein n, R _j _ and R ₂ are the same as above.

The Finnish patent publication FI 67214 describes certain taurinealkylamide derivatives and their antiepileptic properties It was now surprisingly been found that the corresponding aryl derivative possesses antiarrhythmic properties.

The antiarrhythmic effect of the compounds was studied in vitro on a spontaneously beating rat atrium preparation when arrhythmi was induced by aconitine (Holland W.C. & Burn J.H., Br. Med. J. , vol. 1, 1031, 1958) as well as in situ by the raising fibrillati level electrically induced in a cat heart (Szekeres L & Papp JGy Handbook of Experimental Pharmacology, vol. XVI/3, 131, 1975). The effects of the seven compounds found most effective in the in vitro test compared to quinidine and lidocaine are shown in table I. In the in vitro test 20 compounds were more effective than quinidine. In the in situ test some of the compounds were more effective than quinidine and lidocaine. 2-Phthalimidoethane sulfone-N-(3-dimethylaminebenzyl)amide had an effect which increased considerably when the dose was increased to 6 mg/kg i. in the in situ test. With this dose the effect on the atrium was + 183 ± 10 % (p < 0.01) and on the ventricle it was + 68 ± 9 % (p < 0.01), whereas with quinidine with the same dose it was + 53 ± 5 % (p < 0.01) and + 36 ± 6 % (p < 0.01) and with lidocai with a dose of 10 mg/kg i.v. it was + 90 ± 17 % (p < 0.01) and + 49 ± 14 % (p < 0.05) .

Only quinidine and 2-phthalimidoethanesulfone-N-(3-dimethylamine benzyDamide were statistically significantly effective in raisi the fibrillation level in an electrically stimulated cat ventric

Table 1

The effect of test compounds on arrhythmia induced by aconitine in a spontaneously beating atrium preparation of a rat heart and the ability to raise the fibrillation level of electrical stimulation in situ in the atrium and ventricle of a cat heart.

Table 1

Aconitine arrhythmia in Change in fibrillation vitro relia¬ level from control valu bility in situ with a dose of

^EC 50 interval 4 mg/kg i.v.

Compound N (μM) (95 %) N atrium ventricle

2-Phthalimidoethane- sulfone-N-

3-(4-chlorophenyl)- propylamide 8 0.6 (0.4-0.8)

3-( henyl) ropyl¬ amide 8 1.4 (0.9-2.1)

(2,4-dichloro- - - be zyl)amide 6 1.7 (0.9-3.1) 5 +17±15% + 4±13%

(3,4-dichloro- benzyl)amide 6 1.9 (0.8-4.5) 5 +72±19% +25±13%

(4-chlorobenzyl)- a ide 6 2.2 (1.1-4.2) 5 +57±17% +10± 8%

(3-dimethylamine- benzyl)amide 6 2.2 (0.5-9.3) 5 +30± 7% +38±11%

(3-trifluoromethyl- benzyl)amide 6 2.4 (0.9-6.4) 5 +26±15% +20±16% benzylamide 6 3.8 (2.6-6.5)

isopropylamide 2) 6 25.7 (19.8-33-5) 5 +42± 6% +15±1Q% Quinidine 8 20.3 (13.7-30.3) 20 +36± 6% +25± 8% Lidocaine 6 234.0 (182-314) 8 +27±16% +25±11%

1) Chemical Abstracts, Vol. 41 (1947) 6527 - 6529

2) Fl-patent 67214

The effect of the compounds on the contraction and frequency of the heart was studied using a spontaneously beating rat atrium preparation of a rat heart. Spraque-Dawley female rats

(180 - 200 g) were decapitized and the atrium from the animals' hearts was prepared in oxidized Tyrode-solution (+30°C). The atri was fixed to an isometric sensor and allowed to stabilize for

15 minutes with a 0.5 g weight in carbogen (0 95% + C0 5%)

- oxidized Tyrode-solution (+30°C). After the addition of the test compound the contraction and frequency were registered for a period of 13 minutes.

The effect of come effective contraction increasing compounds in comparison to g-strophanthin is shown in table 2. Especially the dimethylaminebenzyl derivatives were found to increase contraction. A decrease in contraction frequency was also observed by the most effective doses. It is also known that in a spontaneously beating rat atrium preparation these parameters affect each other.

Table 2

The effects of certain compounds on the contraction and frequency of a spontaneously beating atrium preparation of a rat heart in vitro (10 minutes after the administration of the test compoun are shown in Table 2. The results are given as percentages of the values before the administration of the active substance (± SE).

Table 2

Contr¬ Frequ¬

Concen¬ action ency tration as % of as % of

Compound N uM control control

2-Phthalimidoethanesulfone-N-

(3-dimethylaminebenzyl)amide 8 8 10 150±16 91±3

8 40 177±16 78±3

2-(4-dimethylaminephenyl)■ 8 10 147± 9 82±3 ethylamide 4 40 213±38 71±5

3-(4-dimethylaminephenyl)■ 6 10 91± 9 84±3 propylamide 6 40 131± 8 83±3

3-( henyl)propylamide 10 121±12 87±3

3-(4-chlorophenyl) ropyl¬ amide 4 10 92±12 87-3

isopropylamide 4 10 89±14 95±3

g-strophanthin 6 10 127± 7 90±3

Solvent control (DMSO) 8 _ 85± 8 94±4

1) FI 67214

The effect of the compounds on the contraction and frequency of the heart of an anaesthetized dog in vivo was studied with 2-phthalimidoethanesulfone-N-(3-dimethylaminebenzyl)amide, using mexilethine as reference substance.

Dogs (10 - 20 kg) of both sexes were anaesthetized with Nembutal (35 mg/kg i.v.). The test animals were breathing spontaneously an their chests were not incised. The pressure in the left ventricle was measured with a catheter led into the heart through the

arteria carotis. The maximun rate of increase (dP/dt _max ) of pressure in the left ventricle was used as indication of the contraction of the heart. The systemic blood pressure was measur from the arteria femoralis using a pressure sensor.

The test compound (0.5 - 6 mg/kg i.v.) brought about a significa increase in contration without affecting heart frequency. Immedi ately after the test compound was injected a considerable drop in blood pressure was observed but was so brief that it does not account as reflex for the increase in the contraction of the heart. The reference substance mexilethine brought about a statistically significant decrease in the contraction of the heart, frequency and blood pressure with the same concentrations (table 3).

Table 3

The effect of 2-phthalimidoethanesulfone-N-(3-dimethylamine- benzyl)amide (320) and mexilethine (MEX) on the contraction of the heart (dP/dt _max ), frequency and systemic blood pressure in anaesthetized dogs. The table shows the perσentual changes compared to the state existing before the injection of the active substance (± Se, N = 5) .

TABLE 3

It has -also been found that the compounds according to the invention lower the blood pressure of anaesthetized cats quite considerebly and for a long period. Cats (2.5 - 3.5 kg) of both sexes were anaesthetized with chloraloseurethane (50 + 300 mg/kg i.v.). Blood pressure was measured from the arteria femoralis using a pressure sensor. The results are shown in table -4.

Table 4 The effect of certain compounds on the average blood pressure of anaesthetized cats. The results are given as percentages of the value before the administration of the test compound (± SE, N = 5)

Dose Change in (mg/kg) blood Duration

Compound i.v. pressure (%) (min)

2-Phthalimidoethanesulfone-N-

(4-chlorobenzyl)amide 2 -33±4 7

4 -52±6 17

(3-dimethylaminebenzyl)- 2 -40±3 4 a ide 4 -42±3 6

(3,4-dichlorobenzyl)-amide 2 -49±4 6

4 -56±6 13

(2,4-dichlorobenzyl)-amide 2 -30±5 4

4 -56±3 16

(3-trifluoromethylbenzyl)- 2 -34±5 5 amide 4 -43±5 7

isopropylamide D 2 -22±3 4

4 -44±5 6

1) Fl-patent No. 67214

The compounds according to the invention can be prepared according to the following examples.

Example 1

2-Phthalimidoethanesulfone-N-(4-methoxybenzyl)-amide

To a mixture of 30 ml methylenechloride and 6 ml of an 6M aqueous potassium carbonate 0.01 moles of 4-methoxybenzylamine was added at 0 - 5°C. Phthali idoethanesulfonylchloride

(0.01 moles) was added within 5 minutes. The mixture was stirred for 30 minutes after which 25 ml of water was added. The layers were separated, the organic phase was washed with water, dried and the solvent was distilled off. The product was crystallized from aqueous ethanol.

Yield: 2.9 g (78 %; theor. 3.7 g) m.p. : 122 - 124°C.

Example 2

2-Phthalimidoethanesulfone-N-(4-methylbenzyl)-amide

This compound has prepared in accordance with example 1 from 4-methylbenzylamine. The yield was 1,9 g (53 %; theor. 3.6 g). m.p. : 150 - 151°C.

Example 3

2-Phthalimidoethanesulfone-N-(4-nitrobenzyl)amide

The compound was prepared in accordance with example 1 from 4-nitrobenzylamine. The yield was 2.7 g (69 %; theor. 3.9 g). m.p. : 197 - 199°C.

Example 4

2-Phthalimidoethanesulfone-N-methyl-N-benzylamide

The compound was prepared in accordance with example 1 from N-methylbenzylamine. The yield was 2.6 g (72 %; theor. 3.6 g) m.p. : 160 - 162 ⁾ < ⁰ C.

Example 5

2-Phthalimidoethanesulfone-N-furfurylamide

The compound was prepared in accordance with example 1 from furfurylamine. The yield was 2.7 g (81 %; theor. 3.34 g) m.p. : 134 - 136°C

Example 6

2-Phthalimidoethanesulfone-N-( -carbomethoxybenzyl)amide

The compound was prepared in accordance with example 1 from methyl-4-aminomethylbenzoate. Yield: 3.0 g (75 %; theor. 4.02 g) m.p.: 172 - 174°C.

Example 7

2-Phthalimidoethanesulfone-N-(benzyl)ethanolamide

The compound was prepared in accordance with example 1 from N-benzylethanolamine. Yield: 2.0 g (52 %; theor. 3.9 g) m.p.: 92 - 94°C.

Example 8

2-Ph.thalimidoethanesulfone-N-(4-carboxamidobenzyl)amide

The compound was prepared in accordance with example 1 from 4-aminomethylbenzamide. Yield: 2.3 g (58 %; theor. 3.9 g) m.p. t 173 - 174°C.

Example 9

2-Phthalimidoethanesulfone-N-(3-dimethylaminebenzyl)amide

The compound was prepared in accordance with example 1 from 3-dimethylaminobenzylamine. Yield: 1.8 g (45 %; theor. 3.9 g) m.p. : 116 -118°C.

Example 10

2-Phthalimidoethanesulfone-N-(2,4-dichlorobenzyl)amide

The compound was prepared in accordance with example 1 from 2,4-dichlorobenzylamide. Yield: 2.9 g (71 %; theor. 4.1 g) m.p. : 161 - 163°C.

Example 11

2-Phthalimidoethanesulfone-N-(3-trifluoromethylbenzyl)ami de

The compound was prepared in accordance with example 1 from 3-trifluoromethylbenzylamine. Yield: 3.24 g (79 %; theor. 4.1 g) m.p.: 134 - 135°C.

Example 12

2-Phthalimidoethanesulfone-N-(4-fluorobenzyl)amide

The compound was prepared in accordance with example 1 from 4-fluorobenzylamine. Yield: 2.9 g (81 %; theor. 3.6 g) m.p.: 163 - 164°C.

Example 13

2-Phthalimidoethanesulfone-N-(3-phenyl)propylamide

The compound was prepared in accordance with example 1 from 3-phenylpropylamine. Yield 3.0 g (81 %; theor. 3.7 g) m.p.: 117 - 119°C.

Example 14

2-Phthalimidoethanesulfone-N-[3-(4-chlorophenyl)oropyl]am ide

The compound was prepared in accordance with example 1 from

3-(4-chlorophenyl)propylamine. Yield: 2.5 g (61 %; theor. 4.06 g) m.p. : 151 - 152°C.

Example 15

2-Phthalimidoethanesu.lfone-N-[2-(4-dimethylsulfonamidoph enyl)- ethyl3amide

The compound was prepared in accordance with example 1 from N,N-dimethyl-4-(2-aminoethyl)benzenesulfonamide. Yield: 2.3 g (49 %; theor. 4.65 g)

Example 16

2-Phthalimidoethanesulfone-N-[2-(3-dimethylaminephenyl)et hyl3amide

The compound was ^* prepared in accordance with example 1 from 2-(3-dimethylaminophenyl)ethylamine. Yield: 1.5 g (37 %; theor. ^~ 4.0 g) m.p.: 86 - 90°C.

Example 17

2-Phthalimidoethanesulfone-N-[3-(4-dimethyIaminephenyl)pr opyl3amid

The compound was prepared in accordance with example 1 from 3-(4-dimethylaminophenyl)propylamine. Yield: 1.8 g (43 %; theor. 4.15 g) m.p.: 90 - 94°C.

Example 18

2-Phthalimidoethanesulfone-N-(4-methoxybenzyl)amide

To a mixture consisting of 2-phthalimidoethanesulfonamide (0.01 moles), 50 ml toluene, 50 ml concentrated potassium- hydroxide solution and 0.1 g tetrabutylammonium hydrogensulphate was added 0.012 moles of 4-methoxybenzylbromide. The mixture was stirred for 30 hours. The layers were separated and the organic layer was washed with water. The yield was 1.8 g (48 %; theor. 3.7 g) .

The melting point at the product was equal to that given in example 1.

Examples 19

2-Phthalimidoethanesulfone-N-(4-πtethoxybenzyl)amide

Potassium salt of phthalimide (0.01 moles) and N-(4-methoxybenzyl)

2-bromethanesulfonamide (0.06 moles) were dissolved in 70 ml of dimethylformamide. The solution was heated at a temperature of 105 - 110°C for 7 hours. To the cooled solution was added

150 ml of water and the solidified oil formed was separated.

The product was crystallized form aqueous ethanol. The yield was 1.9 g (51 %; theor. 3.7 g).

The melting point of the product was equal to that given in example 1.

Example 20

2-Phthalimidoethanesulfone-N-(4-methylbenzyl)amide

A solution of phthalic anhydride (0,01 moles) and N-(4-methyl- benzyl)-2-aminoethanesulfonamide (0.015 moles) was heated at a temperature of 130 - 140°C for 2 hours. The mixture was cooled and dissolved in a small amount of hot ethanol. The product crystallized during the cooling of the ethanol solution. The ield was 1.7 g (47 %; theor. 3.6 g).

When phthalic acid (0.01 moles) was used as starting material, the mixture was heated for 2 hours at about 200°C and sulfon- amide was used in excess (0.03 moles). The yield was 1,1 g (30 %; theor. 3.6 g) .

In both cases th melting point of the product was the same as that given for the product in example 2.