NO135286B - - Google Patents

Description

Analogy method in the production of

therapeutically active benzenesulfonylureas

connections.

The present invention relates to an analogous process for the preparation of N-aralkyl-N'-(benzenesulfonyl)-urea compounds, and the pharmaceutically acceptable salts thereof which have valuable pharmaceutical properties, e.g. anti-arrhythmic activity and anti-angina activity.

The compounds produced according to the present invention are those which have the following structural formula:

and the non-toxic pharmaceutically acceptable salts thereof, i.e. alkali metal, alkaline earth metal and ammonium salts,

where X represents hydrogen or methyl, X"^" represents hydrogen or methoxy, Y represents lower alkyl, lower alkoxy or halogen, Y"'" represents hydrogen, lower alkyl or lower alkoxy, and R represents hydrogen or methyl, provided that when Y is p-chloro, X, X"<*>", Y"<*>" and R cannot all simultaneously denote hydrogen atoms.

The term "halogen" as used herein includes all halogens, but chlorine and bromine are preferred, and the term "lower alkyl" includes the straight, cyclic and branched hydrocarbyl radicals having up to 6 carbon atoms, with methyl being preferred. In those compounds where a phenyl ring is substituted with any radical among alkyl, halogen, alkoxy and hydroxy radicals, such substituents may be placed in the ortho or meta positions, but it is preferred to have a single substituent in the para position on the phenyl ring. In a preferred group of compounds prepared according to the present invention, X is hydrogen, Y is lower alkyl, halogen, hydroxyl or hydrogen, while Y is methyl or halogen and X is hydrogen , methyl- or halogen:.

In the particularly preferred compounds prepared according to the present invention, X is methyl, R is hydrogen or methyl, and X"'", Y and Y"*" are all hydrogen. A particularly preferred compound because of its very valuable pharmaceutical properties are l-(α-methyl-phenethyl)-3~(p-tolylsulfonyl)-urea. It has been found that the i-isomer having the (d-a-methyl-phenethyl) group is more effective than. the isomer having the (1-a-methyl-phenethyl) group.

The analogy method according to the invention is characterized by the fact that

1) a reactive derivative of a carbamic acid of general formula

preferably

where X and Y are - as defined above, and either Q is hydrogen and Z is alkoxy or -NH2, or Q and Z together represent an additional N-C bond.,

traded with. an amine of general formula

where X''"-, Y"*" and R are as defined above.

It should be noted, however, that when the reactive derivative is an isocyanate (ie when Q and Z together represent an additional N-C bond), and a compound where Y or Y^ is a hydroxyl group is desired, the hydroxyl group must be protected during the reaction and then released. The protected group is preferably one that can be removed under mild conditions and especially by mild hydrogenation, i.e. a benzyloxy-carboxyl group or a benzyl group.

It is advantageous to react -the reactive derivative

of the carbamic acid ester with equivalent or slightly excess amounts of the amine according to analogous methods in the art, e.g. as stated in J. Org. Chem., 23, p. 927 (1958).

2) A reactive derivative of a carbamic acid of the formula

preferably where X"^ and Y are as defined above, and either Q"*" is a hydrogen atom or a methyl group and Z is alkoxy or -NfU, or Z and Q together represent an additional C-N bond, react with a sulfonamide of the formula

or with, a reactive derivative thereof, where X and Y are as defined above..

It should be noted that when the reactive derivative is an isocyanate (ie when Q"*" and Z together represent an additional N-C bond), and a compound where Y or Y"<*>" is a hydroxyl group is desired, the hydroxyl group must be protected' during the reaction, i.e., as described under the first embodiment, and then released.

■When a reactive derivative of the sulfonamide is used, the reactive derivative is preferably an alkali metal salt, e.g., the sodium salt..'.•/-..."■

The above-described reaction between a reactive

- derivative of a carbamic acid and an amino compound, (or a ■ reactive derivative thereof) is carried out, preferably by heating a-v the reactants together, e.g. by melting them, or by heating them in the presence of an inert organic solvent

agent, e.g. benzene, toluene, xylene, dimethylformamide or acetonitrile. The reaction is preferably carried out at a temperature of 80°C - 180°C, preferably from 80°C - 155°C, preferably at the reflux temperature of the solvent (when such is used).

After condensation, the solvent (if present) can be removed by distillation or filtration and the product dissolved in a suitable solvent, e.g. hot alcohol or ether.. Purification is then carried out by standard methods and, if desired, the product is converted to its alkali metal, alkaline earth metal or ammonium salt by standard methods.

The second embodiment of this method is carried out particularly conveniently either by condensing the sodium salt of the sulfonamide with a urea compound:

or by condensation of the sulfonamide with an isocyanate: 3) A reactive derivative of an acid of the formula is reacted with a urea compound of general formula 11 where R, X, Y, X and Y are as defined above, and where p is 1 or 2. The reactive derivative of the acid may be an acid halide, preferably the chloride. Thus, this reaction is "preferably carried out either by reaction of an acid chloride of formula with a urea compound of formula /' or by reaction of an acid chloride of formula with a hydroxylurea compound of formula

The reaction can e.g. is carried out in an inert organic solvent such as a hydrocarbon solvent, preferably at the solvent's reflux temperature.

h) ' One reduces a compound with a general formula

where X, Y, X and Y are as defined above, W is a hydrogen or halogen atom or a diazonium group, W 2 is a hydrogen or halogen atom or a diazonium group, R 2 is a group suitable for removal by hydrogenolysis, or a hydrogen atom-, n is 0 or 1, M is one of the following groups: where R"^" is a hydrogen atom, a methyl group, or a group suitable for removal by hydrogenolysis, and L is a methylene group or a group of the formula

where B is an oxygen or sulfur atom, the compound of formula IA being different from the desired compound in at least one structural feature.

Many of the transformations or eliminations that take place in these processes can be carried out by catalytic hydrogenation. E.g. a compound of formula I can be obtained by catalytic hydrogenation of a compound of formula IA

■1 2

where W is a hydrogen atom or a halogen atom, and W is a hydrogen or halogen atom.

Method alternative k- can be exemplified by the following turnovers (i) - (Vi):

(i) Reduction of a compound of formula

where R"*" represents a hydrogen atom or a methyl group or a group suitable for removal by hydrogenolysis, and R represents a hydrogen atom or a group suitable for removal by hydrogenolysis, at least one of R-^ and R 2 represents a group suitable for to be removed by hydrogenolysis, by catalytic hydrogenation, preferably using palladium on charcoal, to remove any of the eliminable groups by hydrogenolysis. At least one of R and R preferably represents a benzyl, benzyloxy or benzyloxycarbonyl group. (ii) ■ Reduction of a compound by. formula where B is oxygen or sulphur. The reduction can be carried out by catalytic hydrogenation, e.g. over palladium or a Raney-nickel alloy. A mercapto group BH can also be removed with zinc in the presence of an organic acid such as acetic acid. (iii) Reduction of a compound of formula

12

where one of W and W represents a halogen atom, and the other represents hydrogen or halogen, to eliminate and/or W 2 , preferably by catalytic hydrogenation.

(iv) • Reduction of a compound with .formula

to open the cyclopropane ring, or of a compound of formula to open the aziridine ring. The latter method gives compounds in which R is H. This reduction is also often carried out by catalytic hydrogenation.'(v) Reduction of a compound containing a cation of the general formula

where one of W and W represents a diazonium group, and the other represents a hydrogen atom or a diazonium group, using a reducing agent known to remove diazonium groups, preferably hypophosphoric acid.

(vi) Reduction of a compound of formula

preferably by catalytic hydrogenation, or by means of Raney nickel alloy and alkali.

5) A compound of general formula

1 1

where X, X , Y, Y and R are as defined above, and m is 0

or 1, is oxidized, preferably with hydrogen peroxide.

6) Man in a connection with general formula

where X, X"*", Y, Y^ and R are as defined above, and A represents sulphur, an imino group or an iminol ether group, the substituent converts A to an oxy group by hydrolysis when A is an imino or iminol ether group, or by reaction with quicksilver or solvoxyd when A is sulphur.

7) That a compound of the formula

wherein X and R have the previously indicated meanings, Y is the group Y as previously defined or a hydroxy or

leave 1

amino group, X is the group X as previously defined or la 1

a hydroxy group and Y is the group Y as previously defined or a hydroxy group, is reacted with an O-methylating agent when X la is a hydroxy group, mqd an O-(lower alkylating) agent when Y<a>or Y<la>is a hydroxy group , and with a

diazotizing agent followed by a halogenating agent when Y is an amino group.

A compound of formula I prepared by any of the foregoing methods may then be converted to a pharmaceutically acceptable salt by standard methods, e.g. by. reaction with an alkali metal hydroxide such as sodium hydroxide.

The compounds of formula I and their pharmaceutically acceptable salts are often used in medicine in levorotatory form, although either the dextrorotatory form or a racemic mixture can be used. In practice, it is preferred to prepare the optically active compounds by using the optically active reactants (e.g. d-amphetamine) in process 1) or 2) above. When a racemic mixture is obtained, however, the mixture can be easily separated into the optically active isomers by standard methods.

The method of treating live mammals for cardiac arrhythmias is carried out by administering a therapeutically effective amount of 1-(α-methyl-phenethyl)-3-benzenesulfonylurea of formula I, or a pharmaceutically acceptable salt thereof. The therapeutically effective amount of a compound can be determined from methods well known in the art. One such laboratory method is the test, which is carried out on dogs, and where arrhythmia is induced with the help of digitalis. In this test, mixed-breed dogs are sedated, regardless of sex,

intravenously with. 35 mg/kg pentobarbital sodium. A femoral vein and a femoral artery are provided with cannulae for drug introduction and recording of the systemic pressure, respectively. The dog is also prepared for registration of a lead(II) core electrocardiogram.

After a stabilization period during which the systemic blood pressure and the electrocardiogram are followed, a dose of 35/ug/kg digitalis is given i.v. If no conduction abnormality appears in the form of nodal or ventricular arrhythmia, a second dose of 35/Ug/kg digitalis is given. This dose of digitalis is given every 15 minutes, until the arrhythmia develops and lasts for at least 30 minutes. The drug to be tested is given there after i.v. in an attempt to normalize the abnormal electrocardiogram. Quinidine or propanolol are used as reference standards.

On this basis, trials and other trial methods, e.g. electrically induced fibrillation, it has been determined that compounds according to the present invention induce an anti-arrhythmic effect in small mammals at 2-50 mg/kg body weight. It has also been found that the compounds according to the present invention are particularly suitable for providing protection against and for reversing ventricular arrhythmia.

Particularly suitable as an anti-arrhythmic agent is the compound 1-(cc-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea which has been found to be particularly suitable for the treatment of supra-ventricular arrhythmia. As can be seen from the results shown in Table I, this compound is particularly effective at a dose level of 5 mg/kg body weight. Another particularly effective compound is 1-methyl-1-(a-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea. Both of these compounds are more effective in the (d-α-methyl-phenethyl) form, which for l-(d-α-methyl-phenethyl)-3~(p-tolylsulfonyl)-urea is the levorotatory form and for 1-methyl-l- (d-a-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea is the dextrorotatory form.

The method of preventing the symptoms of angina pectoris (ie, severe sub-sternal pain, shortness of breath and hypoxic changes in a "limb-lead" electrocardiogram, eg S-T segment depression, as well as other well-known factors associated with angina pectoris) is carried out by administering a therapeutically effective amount of 1-(α-methyl-phenethyl)-3-benzenesulfonylurea of formula I, or a pharmaceutically acceptable salt thereof. The therapeutically effective dose for the treatment of angina pectoris is determined by modified methods according to Rona and Stahton for inducing cardiac necrosis in rats, and is as follows: Only male Charles River rats weighing no less than 200 g are used. The animals are conditioned for at least one week for which medicine is given. Animals of comparable age and body weight are separated into control and experimental groups and given standard laboratory food. and water ad libitum. The disease-causing agent is 80 mg/kg diiso-proterenol (hereinafter referred to as ISU) injected subcutaneously once, per day for 2 days~. The control group receives a subcutaneous injection of the same volume of physiological saline.

The experimental group receives an appropriate dose of the test compound intraperitoneally or orally 2 days before the ISU injection is initiated. The ISU injection is started on the third day of the drug regimen, and both agents are given to the respective groups for the following two days. The drug to be tested is given as two equal doses every day.

On the third and fourth day, 30 minutes were given before and 30 minutes after the ISU. A fourth group of rats receives ISU, subcutaneously, plus 250 µg/kg nitroglycerin as a drop of solution on the oral mucosa, 30, 60 and 90 minutes after initiation of ISU. The nitro-glycerin group reveals the sensitivity of a given rat litter to this standard anti-anginal agent. The initial and final body weights of all animals are noted, and they are then euthanized 2h hours after the second ISU injection. The heart of each animal is removed, dried with absorbent paper, weighed and assessed for degree of necrosis. Four areas of the heart are examined for lesions, namely the apex of the heart, the intraventricular septum, the left ventricle and the right ventricle. The following grading system with degrees from 0 to h is used:

0 = no lesions, -

1=spots at the apex of the heart and farthest into the left ventricle,

2=clearly defined areas of necrosis at the apex of the heart,

3=significant infarct-like necrosis in the left ventricle, which

extends to the intraventricular septum,

h = significant infarct-like necrosis involving both ventricles and the intraventricular septum.

Intermediate values can also be given, namely 0.5, 1.5,

2.5 and 3.5. An average necrosis number for each group is determined, and the percentage protection is calculated.

By processing this data using modern statistical analysis methods, a complete assessment is obtained. By using these methods, a program has been prepared which calculates the heart weight as a percentage of the body weight, in addition to the mean value, the variance, the standard deviation and the standard error which refer to these percentage figures. One-way analysis of the variance of the necrosis numbers within the different groups is carried out for statistical assessment.

On the basis of these tests and-by comparison with known compounds which are suitable for the treatment of angina; pectoris, the compounds of the present invention have been found to exhibit anti-anginal activity (in small mammals) within a dosage range of 10 to 50 mg/kg body weight, with 20 mg/kg being the preferred oral dose.

Correspondingly, the dosage range for prevention of loss of glutamine oxalotransaminase enzyme activity in heart tissue is measured according to well-known methods. By means of these methods, it was determined that the compounds according to the present invention were effective (on small mammals) in the range of 10 to ^0 mg/kg body weight (oral), with 20

mg/kg as the preferred dose.

The maximum dose of the compounds according to the present invention will of course depend on the severity of the disease, the stage of, and the individual characteristics of each individual case and will be determined by the treating diagnostician using well-proven standard parameters for this purpose.

From the results of the experiments for the determination of- (a) anti-arrhythmic activity, (b) anti-anginal activity and (c) prevention of loss of glutaminox.lotransaminase enzyme activity in cardiac tissue, it is clear that l- (a-methyl-phenethyl)-3-(p-tolylsulfonyl)-

urea is a particularly effective and desirable compound for treat-

of such conditions in mammals. This compound has such an outstanding therapeutic index, and such excellent usage properties that it,

in comparison with most of the other compounds of formula I, comes in a class of its own.

Also when its usage characteristics are compared with the usage characteristics

of known compounds that have excelled in the described area, it is quite clear that 1-(α-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea is a particularly useful therapeutic agent. It should also be noted that the levorotatory form of this compound is better than both the dextrorotatory form and the racemic mixture of this compound. Thus, among the compounds according to the present invention, 1-(d-α-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea (ie the compound prepared in example 1) is particularly desirable for the therapeutic purposes indicated above. Another compound which has been found to be particularly suitable for the aforementioned therapeutic purposes is 1-methyl-1-(a-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea.

In the following table, the mentioned compound 1-(d-α-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea is compared with a number of other compounds produced according to the invention as well as nitroglycerin and propranolol. The compounds are compared with respect to MED^Q, which indicates a 5% reduction in electrical change in the cardiac muscle of dogs under ischemia or a 30% reduction in the degree of isoproterenol-induced transmural cardiac necrosis in rats.

It appears that all compounds exhibit a significant effect. With. with respect to nitroglycerin and propranolol, it is noted that the compounds produced according to the present method show significant advantages compared to these compounds, because nitroglycerin cannot be used prophylactically and has a very short duration (15 min.), while propranolol can induce heart failure in weak hearts. The compounds produced according to the present method can be used prophylactically, they have a long duration (approx. h hours) and very low toxicity. They thus show significant advantages compared to nitroglycerin and propranolol.

In order to exercise their function as therapeutically useful compounds, the compounds are preferably administered as pharmaceutical preparations, i.e. in admixture with an acceptable pharmaceutical carrier suitable for enteral or parenteral administration, said carrier normally making up the main part of the mixture. Such preparations can be solid dosage forms such as e.g. tablets, capsules and suppositories, or liquid preparations such as e.g. elixirs, emulsions and injectable preparations in ampoules. By. in the preparation of pharmaceutical preparations, such substances can be used which do not react with the active substance, such as e.g. water, gelatin, lactose, starch, magnesium stearate, calcium carbonate, talc, vegetable oils, benzyl alcohols, rubber, polyalkylene glycols, petroleum jelly and the like. The pharmaceutical preparations preferably contain between 0.1 and 50% by weight of active ingredient.

The following examples illustrate the preparation of the compounds according to the present invention.

Example 1

1-(d-α-methyl-phenethyl)-3-(β-tolvolsulfonyl)-urea

5 g of d-amphetamine in 35 ml of toluene is added slowly with stirring to 7.5 g of ethyl-N-p-toluenesulfonyl carbamate in 75 ml of toluene. The mixture is refluxed for 3 hours, the solvent is removed in vacuo, and the residue is dissolved in hot alcohol. The hot alcohol solution is transferred with good stirring into 10 ml of 5% hydrochloric acid, and the product is filtered off, washed with water and recrystallized from acetone. 1-(d-α-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea is obtained, m.p. l80° - l8l°C ,

fal26 -33° (C = 2%, dioxane).

D

Example 2

1-(d-α-methyl-phenethyl) 3-(p-tolylsulfonyl)-urea

To a solution of 7 g of d-amphetamine in 200 ml of toluene is added dropwise, with stirring, a solution of 9.8 g of p-methylphenethylsulfonyl isocyanate in 75 ml of toluene. The mixture is heated on a steam bath for 30 minutes, cooled and the residue is filtered off, washed with water and recrystallized from acetone. 1-(d-α-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea is obtained, m.p. 180°- 181°C,

[α] 26 -33° (C = 2%, dioxane).

D

Example ^

d- 1- methyl- l-( a- methyl- phenethyl)- 3-( p- tolylsulfonyl)- urea

A solution of 80 g of d-deoxyephedrine in 1 liter of dry benzene is cooled to 10°C, and 56 P p-toluenesulfonyl isocyanate in 200 ml of dry benzene is added with good stirring for 15 minutes. •The temperature of the mixture is brought to approx. 30°C, and the stirring is continued without stirring until it drops to room temperature. The mixture is heated to 65° - 70° C for 2 hours, cooled to 10°C, and successively extracted with 350 ml cold 5% hydrochloric acid,

50 ml of the same solution, 50 ml of water and 20 ml of 5% sodium bicarbonate. The benzene is evaporated in vacuo, and the slightly rubbery residue is recrystallized from 100 ml of acetonitrile. The yield of the white crystalline product in this example

is 70 g, m.p. 1^5° - 1^9°C,

fal<26>+13.2° (C =25?, ethanol).

D

♦

The following compounds can be prepared, by to replace amphetamine or deoxyephedrine and the carbamate or isocyanate reactants in the preceding examples 1 to 3 with suitable reactants, and by using the previously described method, the following is obtained:

1-(a-methyl-phenethyl)-3-(m-tolylsulfonyl)-urea,

sm.p. 1^7° - 1^9°C,

/aj<26>+3.9° (C =2%, dioxane):,

D

1-(a-methyl-phenethyl)-3-(3,^-dimethyl-benzenesulfonyl)-urea, m.p. 177° 178°C,

fa]<26>~ h, 2° (C = 1%, dimethylformamide); 1-(a-methyl-phenethyl)-3-(p-methoxybenzenesulfonyl)-urea, m.p. 139° - 1^1°C,

fal<26>-5.6° (C = 1$6, acetone)-,

D

1-(α-methyl-phenethyl)~3-(p-ethylbenzenesulfonyl)-urea,

sm.p. 162° - ■163°C ,

fal 26 -6.5° (C =1%, dimethylformamide)* and

D

1-(α-methyl-phenethyl)~3-(p-tolylsulfonyl)-urea,

sm.p. 158° - 159°C,

(race food).

Example h

1-( d- a- methyl- phenylethyl)- 3-( toluene- m- sulfonyl)- urea

To a solution of 1.0 g of d-amphetamine in 10 ml of dioxane, 2.0 g of toluene-m-sulfonylurea is added. The mixture is refluxed for 2 hours and 150 ml of water is then added slowly with stirring to precipitate l-(d.-q-methyl-phenylethyl)-3-(toluene-m-sulfonyl)-urea.

This compound is filtered off, washed with water and recrystallized from acetone, m.p. l<1>+7° - 1^9°C,

fal<26>+3.9° (C = 2%, dioxane).

UJD

Example 5

l-( q-methvl-^ .^-- dimethoxyphenylethyl.) - 3-( p- tolylsulf onyl)- urea

A mixture of 2.2 g of q<->methyl-3,^-dimethoxyphenylethyl isocyanate and 1.7 g of toluene-p-sulfonamide in 30 ml of toluene is heated on a water bath for 3 hours. The mixture is worked up as described in example 1, and 1-(α-methyl-3, h-dimethoxyphenylethyl)-3-(p-tolylsulfonyl)-urea is obtained,

sm.p. lk6° - 1^7°C, [α]<26>-7.6° (C = 1%, ethanol).

D

Example 6

l-( d.- a- methyl- ph enethyl) - 3- Cp-tolylsulf onyl) - urea

A solution of h.2 g of 1-(d-α-methyl-phenethyl)-1-benzyl-3-(p-tolylsulfonyl)-urea in alcohol is hydrogenated at 70°C under pressure (3 atm.) in the presence of 0.5 g 10% palladium on charcoal. When no more hydrogen is absorbed, the mixture is filtered, the palladium charcoal is washed with hot alcohol, and the hot-alcohol solution is concentrated and transferred into 10 ml of 5% hydrochloric acid. The precipitate, 1-(d-a-methyl-phenethyl)~3-(p-tolylsulfonyl)-urea, is purified as described in example 1.

Sm.p. 180° - 181°C, [ al26 -3.3° (C = 2%, dioxane).

J. D

Example 7

1-(S-methyl-phenethyl)-1-methyl-3-(p-tolylsulfonyl)-urea

A solution of 3.8 g of 1-(a-thiobenzoylethyl)-1-methyl-3-(p-tolyl-sulfonyl)-urea in 100 ml of 10% sodium hydroxide solution is heated on a steam bath, and 10 g of Raney nickel alloy is added slowly while stirring. The mixture is heated and stirred for a further 1 hour, filtered and transferred to an excess.

(100 ml) of dilute (kN) succinic acid. The product, 1-(α-methyl-phenethyl)-1-methyl-3-(p-tolylsulfonyl)-urea is filtered off, washed with water and recrystallized from acetone.

M.p.lhk°-lk7°C, fall 26+13.6°-(C =2%, ethanol).

D

Example 8

l-( q- methyl- ph enethyl) - l- methyl- 3-(- p- tolylsulf onyl) - urea

To a solution of 3.8 g of 1-(1-phenyl-1-mercaptopropyl-2)-1-methyl-3-(p-tolylsulfonyl)-urea in 20 ml of acetic acid and 10 ml of water, 1 g of zinc stbv is added. The mixture is then heated in a water bath. for 1 hour, filtered and transferred to 100 ml of water. The precipitate is filtered off, washed with water, dried and recrystallized from acetone. 1-(α-methyl-phenethyl)-1-methyl-3-(p-tolylsulfonyl)-urea is obtained, m.p. lhh° - 1>+70C ,

lal26 +13.6° (C = 2%, ethanol).

D

Example 9

1-( d- a- methyl- phenethyl)- 3-( v - tolylsulfonyl)- ure a

3.6 g of 1-(d-a-methyl-p-chlorophenethyl)-3-(p-tolylsulfonyl)-urea are dissolved in 100 ml of a hot 10% sodium hydroxide solution, and the mixture is heated on a steam bath, while 5 g Raney -nickel alloy is slowly added while stirring. The mixture is heated and stirred for a further 1 hour, filtered and then poured into an excess (100 ml) of 3-N hydrochloric acid. The compound formed, 1-(d-α-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea, is filtered off, washed with water and recrystallized in acetone. Sm.p. l80°- l8l°C, fa]<26>-,3.3° (C 1

TS

dioxane). D

Example 10

1-(q-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea

A solution of 3.3 g of 1-(2-phenylcyclopropyl)-3~(p-tolylsulfonyl)-urea in 20 ml of acetic acid is hydrogenated over 0.5 g of 5% palladium charcoal. When no more hydrogen is absorbed, the mixture is filtered and poured into 100 ml of water, the precipitate is filtered off, washed with water and recrystallized from acetone. 1-(α-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea is obtained, m.p. 180° - 181°C.

The same compound can be obtained by hydrogenation of 1-(1-phenylpropylene)-3-(p-tolylsulfonyl)-urea.

Example 11

1-(d-α-methyl-phenethyl)-3-(P-tolylsulfonyl)-urea

A solution of 3.0 g of l-(d-a-methyl-phenethyl)-3~(p-tolylthio)-urea in 10 ml of acetic acid, 8 ml of water and '5 ml of hydrogen peroxide is refluxed for 2 hours and then diluted with 80 ml of water. The mixture is cooled and filtered, and the solid is washed with water and recrystallized from acetone to give 1-(d-a-methyl-phenethyl)-3-(p-tolyls-ulfonyl)- urea, mp 180° - 181°C, £a}<26>-3.3° (C = 2%, dioxane).

D

Example 12

1-(g-methyl-phenethyl)-^-(p-tolylsulfonyl)-urea

A solution of 3.6 g of 1-(α-methyl-phenethyl)-3-(p-tolylsulfonyl)-guanidine in 50 ml of 5% sodium hydroxide solution is refluxed until no more ammonia evaporates. The solution is transferred into an excess (25 ml) of dilute (kN) hydrochloric acid, cooled and filtered. The product, 1-(g<->methyl-phenethyl)-3-(p-tolylsulfonyl)-urea, is washed with water and recrystallized from acetone, m.p. 180° - 181°C.

Example 13

1-(g-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea

3.5 g of 1^(<g->methyl-phenethyl)-3-(p-tolylsulfonyl)-thio-urea are refluxed in 50 ml of benzene with. 5>0 g mercuric oxide. After 2 hours, the solution is filtered and cooled, and the resulting 1-(g<->methyl-phenethyl)-3-(p-tolylsulfonyl)-urea is filtered off and recrystallized from acetone, m.p. l80° - l8l°C.

Example ih -

1-( d- g- methyl- phenethyl)- 1- methyl- 3 - ( p- tolylsulfonyl)- urea v

3.6 g of 1-(d-g<->methyl-p-aminophenylethyl)-1-methyl-3-(p-.tolylsulfonyl)-urea is added to 30 ml >+N hydrochloric acid, and the mixture is cooled with stirring to 0 ° - 5°C. A solution of 0.75 g of sodium nitrite in 5 liters of water is slowly added drop by drop while stirring until there is a small excess of nitrite in the mixture. Then, 20 ml of 30% phosphorus underacidification is added, and the mixture is allowed to stand at room temperature overnight. The solid is filtered off, washed with water and recrystallized in acetone, whereby 1-(d-g<->methyl-phenethyl)-1-methyl-3-(p-tolylsulfonyl)-urea is obtained, m.p.

lkh° - 1^7°C, fa] 26 +13.6° (C •= 2%, ethanol).

D

Example 15

1-(g-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea

A solution of 3.6 g of m,m<1->epithio-1-(a-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea in 100 ml of a 10% sodium hydroxide solution is heated on a steam bath, and 10 g of Raney nickel alloy are added slowly while stirring. The mixture is heated and stirred for a further 1 hour and then poured into an excess (100 ml) of hB hydrochloric acid. The compound obtained, 1-(α-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea is filtered off, washed with water and recrystallized in acetone. Sm.p. 178° - 180°C.

Example 16

1-( d- a- methyl- phenethyl)- 1- methyl- 3-( P- chlorobenzenesulfonyl)- urea

3.5 g of 1-(d-α-methyl-phenethyl)-1-methyl-3-sulfanilyl urea are diazotized. The formed diazonium solution is added dropwise over the course of 10 minutes and while stirring to a solid (90°C) solution of 2.1 g of cupric chloride in 1-0 ml of concentrated hydrochloric acid and 20 ml of water. The mixture is then stirred for a further 15 minutes at 90°C and cooled. The compound obtained, 1-(d-q<->methyl-phenethyl)-1-methyl-3-(p-chlorobenzenesulfonyl)-urea is separated, washed thoroughly with water, washed and recrystallized in acetone. Sm.p. 165° - 168°C,

fal26 -5.8° (C = 2%, dioxane).

D

Example 17

1-(a- methylphenethyl)- 3-(P- methoxybenzenesulfonyl)- urea

3.3 g of 1-(q<->methyl-phenethyl)-3-(p-hydroxybenzene-sulfonyl)-urea are suspended in 50 ml of 5% sodium hydroxide solution, and the mixture is heated on a steam bath. 1.5 g of dimethyl sulphate is then added dropwise. stir, and the mixture is heated for another half hour. The mixture is then dressed, filtered and transferred in an excess. (25 ml) of dilute C+N) hydrochloric acid and cool. The product, 1-(q<->methyl-phenethyl)-3-(p-methoxybenzenesulfonyl)-urea, is filtered from,

washed with water and recrystallized from acetone. Sm.p.

139° - 1M-1°C, Tal<26>-5.6° (C = 1%, acetone).

D

1-(α-methyl-3β-dimethoxyphenylethyl)-3-(p-tolylsulfonyl)-urea, m.p. lk6° - 1<>>+7°C, [ f6 - 7, 5° (C=1%. y ethanol) can be prepared accordingly.

Example 18

, 1-(d-g-methyl-phenethyl)-3-(p-toluenesulfonyl)-urea

A solution of 1.9 g of p-toluenesulfonyl chloride in 50 ml of petroleum ether is added to a solution of 1.9 g of 3-hydroxy-l-(d-g-meth<y>l-phenethyl)-urea in 100 ml of petroleum ether. The mixture is boiled with reflux and stir for 2 hours, dress and extra-

here with 2N NaOH. The liquid extract is acidified with acetic acid, and the product, l-(d-a-methyl-phenethyl)^-(p-toluene-sulfonyl)urea, is precipitated. The precipitate is filtered off, washed with water and recrystallized from acetone, m.p. 180° - 181°C,

B] 26 -33° (C = 2%, dioxane).

Example 19-

1-(d-α-methyl-phenethyl)-3-(p-toluenesulfonyl)-urea

A solution of 1.9 g of p-toluenesulfonyl chloride in 50 ml of petroleum ether is added to a solution of 2.1 g of N-(d-α-methyl-phenethyl)-urea in 100 ml of petroleum ether. The mixture is heated under reflux and stirred for 2 hours, cooled and extracted with 2N sodium hydroxide solution. The aqueous extract is acidified with acetic acid, and the compound formed, l-(d-q<->methyl-phenethyl)-3-(p-toluenesulfonyl)-urea is precipitated. The compound is filtered off, washed with water and recrystallized in acetone, m.p. 180° - 181°C, f<q>7<26>-33° (C = 2%, dioxane)...

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Claims (7)

1. Analogy method for the preparation of anti-arrhythmic and anti-angina active compounds with the general formula: where X- denotes hydrogen or methyl, X' denotes hydrogen or methoxy, Y denotes lower alkyl, lower alkoxy or halogen, Y denotes hydrogen, lower alkyl or lower alkoxy, and R denotes hydrogen or methyl, provided that when Y is p-chloro , X, X"1", Y"*" and R cannot all at the same time denote hydrogen atoms, and pharmaceutically acceptable salts thereof, characterized by: 1) a reactive derivative of a carbamic acid with general mel ;preferably ;where X and Y are as defined above, and either one is Q hydrogen and Z is alkoxy or -NH , or Q and Z together represent an additional N-C bond, is reacted with an amine of the general formula; where X<1>, Y<1> and R are as defined above, or; 2) a reactive derivative of a carbamic acid of the formula 11rJ-where X and Y are as defined above, and either is U a hydrogen atom or a methyl group and Z is alkoxy or -NH^, or Z and Q together represent an additional C-N bond, is reacted with a sulfonamide of the formula ;or with a reactive derivative thereof, where X and Y are like those defined above, or; 3) a reactive derivative of an acid of the formula is reacted with a urea compound of the general formula; where R, X, Y, X^ and Y<1> are as defined above, and where p is 1 or 2, or; 4) one reduces a compound of general formula where X, Y, X"*" and Y are as defined above, V<p>~ is a hydrogen or halogen atom or a diazonium group, V<v>is a hydrogen or halogen atom or a diazonium group, R 2 is a group suitable for 1 åo to be removed by hydrogenolysis, or a hydrogen atom, n is 0 or 1, M is one of the following groups: where is a hydrogen atom, a methyl group, or a group suitable for removal by hydrogenolysis, and L is a methylene group or a group of the formula where B is an oxygen or sulfur atom, the compound of formula IA being different from the desired compound in at least one structural feature, or 5) a compound of general formula where X, X<1>, Y, Y1 and R are as defined above, and m is O or 1, oxidized, or 6) one in a connection with general formula where X, x\ Y, Y"1" and R are as defined above, and A represents sulfur, an imino group or an iminol ether group. converts the substituent A into an oxy group by hydrolysis when A is an imino or iminol ether group, or by reaction with mercury solv or solvoxide: when A is sulphur, or 7) that. a compound of the formula . wherein X and R have the meanings previously indicated, Y3 is the group Y as previously defined or a hydroxy or amino group, leave 1 X is the group X- as previously defined or a hydroxy group let 1 and Y is the group Y as previously defined or a hydroxy group pe, ...is traded with. an O-methylating agent when X leaves a hydroxy group, with an O-r (lower alkylating) agent when Y a or Y leaves a hydroxy group, and with a diazotizing agent followed by a halogenating agent when Y is an amino group. 2. Process according to claim 1, for production of l-.(d-a-methyl-phenethyl)-3-(p-tolylsulfonyl)-urea, characterized in that a) d-amphetamine is reacted with p-tolylsulfonyl isocyanate, or b) d-amphetamine is reacted with a lower alkyl ester of N-p-tolylsulfonylcarbamic acid, or c) d-amphetamine is reacted with p-tolylsulfonylurea, or d) N-(d-a-methylphenethyl)-urea is reacted with p-tolylsulfonyl chloride, or e) N-(d-a-methylphenethyl)-urea is reacted with p-tolylsulfonamide, or f) a lower alkyl ester of N-(d-a-methylphenethyl)-carbamic acid is reacted with p-tolylsulfonamide, or g) (d-a-methylphenethyl)-isocyanate is reacted with p-tolylsulfonamide. 3. Process according to claim 1 for production of d-1-methyl-1-(a-methylphenethyl)-3-(p-tolylsulfonyl)-urea, characterized by a) d-desoxyef edrine is reacted with p-tolylsulfonyl isocyanate, or b) d-deoxyephedrine is reacted with a lower alkyl ester of N-p-tolylsulfonylcarbamic acid, or c) d-deoxyephedrine is reacted with p-tolylsulfonylurea, or d) N-methyl-N-(d-a -methylphenethyl)-urea is reacted with p-tolylsulfonyl chloride, or e) .N-methyl-N-(d-a-methylphenethyl)-urea is reacted with p-tolylsulfonamide, or f) a lower alkyl ester of N-methyl-N-( d-α-methylphenethyl)-carbamic acid is reacted with p-tolylsulfonamide•