NO744383L - - Google Patents

Description

The present invention relates to alkenesulfonamides and

preparations thereof.

The present invention relates to compounds for

reduce elevated serum lipid levels in mammals. Atherosclerosis,

which is a form of arteriosclerosis, is quickly recognized to be a

major health problem today. The disease is characterized by

deposition of lipids in the aorta and in the coronary, cerebral and peripheral arteries in the lower extremities. As the deposit increases, there is a risk of thrombus formation and occlusion. Although the causes of atherosclerosis are not fully understood, it has been observed that many people suffering from this disease exhibit elevated plasma lipid protein levels, cholesterol and triglycerides being the main components. Despite the fact that dietary habits can contribute to

lowering plasma lipoprotein levels, a number of therapeutic agents, such as oestrogens, thyroxine analogues and sitosterol preparations, have been used for this purpose. Recently, ethyl 2-(p-chlorophenoxy)-isobutyrate (clofibrate) has been shown to be an effective agent in reducing elevated triglyceride levels in humans.

The present invention also relates to certain new chemical compounds which are useful for reducing serum lipid levels in mammals. These new chemical compounds are derivatives of N-carbamoyl-2-phenylethene sulfonamide, which is also known as styrene sulfonylurea.

Arenesulfonamides, where the nitrogen atom is substituted with

a monosubstituted carbamoyl group (arenesulfonylurea derivatives),

are a well-known class of organic compounds, some of which are known to have glycochemical properties. N-(N-n-propylcarbamoyl)-p-chlorobenzenesulfonamide (chloropropamide) and. N-(N-n-butylcarbamoyl)-p-toluenesulfonamide (tolbutamide) is known to be clinically useful oral antidiabetic agents. However, there are few literature references to sulfonylurea derivatives where the nitrogen atom

in the urea group furthest from the sulfonyl group has two substituents different from hydrogen.

2-phenylethenesulfonamides, which are substituted at the nitrogen atom with a carbamoyl group (styrenesulfonylurea derivatives), are not known in the chemical or patent literature, although U.S. Pat. patent no. 2,979,437 deals with a series of aralkenesulfonylurea derivatives with hypoglycemic properties.

It is an object of the present invention to provide compounds and preparations for reducing elevated plasma lipid levels in mammals. There may be administered to a hyperlipidemic mammal an effective amount of a compound selected from 2-phenylethene sulfonamide derivatives of the formulas:

where X, A, B, Z, R 1 and R 2 are as indicated below or pharmaceutically active salts thereof. The present invention also relates to a method for the production of new sulfonamides as indicated below, where an alkenesulfonamide with the formula where X, A, B, is as indicated below, is reacted with a reagent containing a carbamoyl group which is capable of giving a group where L is equal to Z or

and if necessary

by hydrolysis of R 1 or R 2 such as alkoxycarbonylalkyl to

carboxyalkyl or demethylation of ([methoxyphenyl]alkyl)-piperidino as Z to ([hydroxyphenyl]alkyl)piperidino.

In the above formulas are:

X selected from the group consisting of hydrogen, fluorine, chlorine, bromine, trifluoromethyl, alkyl containing from 1 to 4 carbon atoms and alkoxy containing from 1 to 4 carbon atoms.; A and B are both selected from the group consisting of hydrogen, methyl, ethyl and phenyl; Z is selected from the group consisting of pyrrolidino, morpholino, thiomorpholino, 1,2,5,6-tetrahydropyridino, 1,2,3,4-tetrahydroisoquinoline, azacycloheptan-1-yl, azacyclooctan-1-yl, 3-azabicyclo- [3.2.2]nonan-3-yl, piperidino, 4-hydroxypiperidino, 4-methoxypiperidino, 4-carboxypiperidino, 4-phenylpiperidino, alkylpiperidino containing from 1 to .3 carbon atoms in the alkyl group, (phenylalkyl)piperidino containing from 1 to 5 carbon atoms in the alkyl group and ([substituted phenyl]alkyl)piperidino containing from 1 to 5 carbon atoms in the alkyl group, the substituted phenyl group being substituted with a group selected from the group consisting of hydroxy, alkyl containing from 1 to 4 carbon atoms and alkoxy containing from 1 to 4 carbon atoms; 12 o and R and R are selected from the group consisting of hydrogen, alkyl containing from 1 to 10 carbon atoms, alkenyl containing from 3 to 6 carbon atoms, cycloalkyl containing from 3 to 7 carbon atoms, phenylalkyl containing from 1 to 2 carbon atoms in the alkyl group, carboxyalkyl containing from 1 to 7 carbon atoms in the alkyl group, alkoxycarbonylalkyl containing from 1 to 2 carbon atoms in the alkoxy group and containing from 1 to 7 carbon atoms in the alkyl group, bicyclo[2.2.1]hept-2-ene-5 -ylmethyl, 7-oxabicyclo[2.2.1]heptan-2-ylmethyl, bicyclo[2.2.1]-heptan-2-ylmethyl,'phenyl and phenyl which is substituted with a group selected from the group consisting of fluorine, chloro, bromo, ritro, alkyl containing from 1 to 4 carbon atoms and alkoxy containing from 1 to 4 carbon atoms;

12

provided that R and R are not both hydrogen. However, preferred hypolipidemic agents according to the present invention are compounds of the formulas I and II, where X is selected from the group consisting of hydrogen, chlorine and methyl;

A and B are both selected from the group consisting of hydrogen, methyl and

12

ethyl; and Z, R and R are as previously stated.

Particularly preferred hypolipidemic agents according to the present invention of formula I are compounds, of formula I, where X is selected from the group consisting of hydrogen, chlorine and methyl, A and B are both hydrogen and Z is selected from the group consisting of 4-( co-phenylalkyl)-piperidino which. containing from 1 to 5 carbon atoms in the alkyl group and 4-(co-[ substituted phenyl ]alkyl)-piperidino containing from. 1 to 5 carbon atoms in the alkyl group, the substituted phenyl group being substituted with a group selected from the group consisting of hydroxy, alkyl containing from 1 to 4 carbon atoms and alkoxy containing from 1 to 4 carbon atoms. In this context, co-phenylalkyl and co-[substituted phenyl]alkyl refer to straight-chain alkyl groups with a phenyl or a substituted phenyl group on the terminal carbon atom of the alkyl group, e.g. 2-phenylethyl, 3-phenylpropyl and 5-phenylpentyl. The preferred meaning of X is hydrogen.

Particularly valuable compounds of formula I are compounds in which X, A and B each. is hydrogen and Z is 4-(co-phenylalkyl) piperidino.

Other particularly preferred hypolipidemic agents with

formula I are compounds of formula I, where X is selected from the group consisting of hydrogen, chlorine and methyl, A and B are both hydrogen and Z is 1,2,3,4-tetrahydroisoquinoline.

Particularly preferred hypolipidemic agents of formula II

are compounds of formula II, where X, A, B and R"^" are hydrogen and R 2 is either alkyl, especially n-butyl, or carboxyalkyl, especially carboxymethyl.

Other particularly, preferred hypolipidemic agents with

formula II are compounds of formula II, where X, A and B are both

12

hydrogen and R and R are both alkyl, especially n-butyl.

Compounds according to the present invention which are of particular value are: N-(N-n-butylcarbamoyl)-2-phenylethenesulfonamide, N-(N-[carboxymethyl]carbamoyl)-2-phenylethenesulfonamide, N-(4-[3-phenylpropyl]piperidinocarbonyl) -2-phenylethenesulfonamide N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-phenylethenesulfonamide.

Many of the hypolipidemic agents according to the present invention are new and thus constitute an important embodiment according to the invention. All compounds of formula I are new. Compounds of formula II are new on the condition that when 12

either R or R is hydrogen, alkyl, alkenyl, cycloalkyl, phenyl or substituted phenyl, the other of the substituents R<1> and R<2> being different from hydrogen or alkyl.

According to the present invention, the compounds of formulas I and II are synthesized. suitably from an alkenesulfonamide of formula III, where X, A and B are as indicated previously by a variety of methods. Five such methods, which in the following shall be referred to as methods A, B, C, D and E shall be discussed and described in detail.

Method A comprises the reaction of a compound of formula III with an organic isocyanate of the formula R^-N=C=0 in the presence of

a base. The reaction is usually carried out by bringing the compounds into contact with each other in a suitable solvent, usually at a temperature in the range of about 25°C to approx. 120°C, and preferably from 60°C to approx. 80°C. Suitable solvents which can be used are those which serve to dissolve at least one of the reactants and which have no adverse effect on the reactants or the product. Examples of such solvents are ethers, such as diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane; chlorinated hydrocarbons, such as chloroform, methylene chloride and 1,2-dichloroethane; lower aliphatic ketones, such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate and butyl acetate and tertiary amides, such. such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone. A variety of bases, both organic and inorganic, can be used in the process, since the primary function of the basic agent appears to be to form a salt of the sulfonamide reactant. The bases that can be used include tertiary amines, such as triethylamine, tributylamine, N,N-dimethylaniline, pyridine, quinoline, N-methylmorpholine and 1,5-diazabicyclo[4.3.0]non-5-ene; alkali metal hydroxides, such as sodium hydroxide and potassium hydroxide; alkali metal alkoxides, such. such as sodium methoxide, potassium methoxide and sodium ethoxide; metal hydrides, such as sodium hydride and calcium hydride; metal carbonates, such as sodium carbonate and potassium carbonate; and alkali metals such as sodium and potassium.

In most cases, a molar equivalent of the base is used, calculated on the sulfonamide used, but it is possible to successfully use smaller and larger amounts than a molar equivalent... Although it is usual to use a one to twofold excess of isocyanate, this is not substantially and equimolar amounts are sometimes used, particularly in cases where it is not appropriate to remove the excess of isocyanate from the product. In reality, it is possible to use an excess of sulfonamide, in which case some sulfonamide remains at the end of the reaction. When working at approx. 80°C, it is common to use reaction times of a few hours, e.g. 2 hours. A particularly suitable means of isolating the product is to add the reaction mixture to an excess of dilute aqueous acid. This causes the product to fall out, it is filtered out directly. Alternatively, it is extracted in an organic solvent that is not miscible with water, which is then separated and evaporated, yielding the impure product. In many cases the uncleaned product is quite clean, but if desired it can be further purified according to known methods.

Those skilled in the art will appreciate that it is possible to prepare a salt of the sulfonamide starting material in advance, which is then treated with isocyanate in a subsequent step. In this case, one can use the same method and the conditions indicated above in the second step of this two-step procedure.

The isocyanate starting materials used in Method A are either commercially available or can be readily prepared from the appropriate amine with phosgene using the method outlined by Shriner, Horne and Cox in Organic Synthesis, Collective Volume II, 453 (1943).

Method B comprises the reaction of a compound of formula III with a carbamoyl chloride of the formulas Z-C(=0)-Cl or R 1R 2N-C(=0)-C1, in the presence of a base. A common procedure is to add approx. 1 molar equivalent of carbamoyl chloride to a solution or suspension of sulfonamide of formula III in a suitable solvent in the presence of the base. The same solvents and bases can be used as stated above, under method A and approx. 1 molar equivalent of base is used. On the other hand, larger quantities of the base can be used in cases where an excess of base will not have an adverse effect on the reactants or products. In fact, it is common to use an excess when the base is not soluble in the reaction medium. The reaction temperature and reaction time vary due to a number of factors, such as the reactivity, the concentration of the reactants, the solubility of the reactants in the particular solvent chosen. However, it is usual to carry out the reaction in the temperature range from 40 to 120°C, and preferably from approx. 50 to approx. 80°C. In the latter temperature range, it is common to use reaction times of a few hours, e.g. 4 hours. The product can. isolated by using the methods indicated above under method A.

A variation of method B, which roughly corresponds to the Schotten-Baumann method and which is suitable in certain cases, is the addition of carbamoyl chloride to a solution of sulfonamide in water, at about ambient temperature, ie. The pH is kept in the range from

about. 7.0 to approx. 12.0 during and after the addition. At the end of the reaction, which usually requires approx. 1 hour, the reaction mixture is acidified. If the product falls out, it is filtered out. Alternatively, it can be extracted in a solvent that is not miscible with water, which is then separated and evaporated to give the impure product.

The carbamoyl chlorides used in method B are either commercial products, or they can be easily prepared by reacting the appropriate amine. with phosgene using methods outlined by Peterson in Houben-Weyl's "Methoden der Organischen Chemie", 8, 115-118 (1962).

In method C, a sulfonamide of formula III is reacted with a

1 3 4

urea derivative of formula R NH-CO-NR R , in the presence of a base, where R 3 is selected from the group consisting of alkyl containing from 1 to 6 carbon atoms, alkenyl containing from 3 to 7 carbon atoms, aryl, substituted aryl, heteroaryl and substituted heteroaryl, and R 3 is selected from the group consisting of hydrogen, cycloalkyl containing from 3 to 8 carbon atoms, benzyl, phenylethyl and R 3 , wherein each substituted group is substituted with up to three groups selected from the group consisting of of chlorine, fluorine, bromine, nitro, alkyl containing from 1 to 4 carbon atoms and alkoxy containing from 1 to 4 carbon atoms. Examples of aryl groups are phenyl and naphthyl, and examples of heteroaryl groups are pyridyl, thiazolyl, oxazolyl. and quinolyl. A particularly suitable configuration for the urea group used in this method is that where R 3 . and R 4 are both phenyl. The reaction is carried out by a o bringing the sulfonamide and urea into contact with each other using exactly the same solvent, reaction parameters, bases and reaction conditions etc. as described earlier for method A.

It is actually believed that under the influence of the base

1 3 4

the urea compound with the formula R NH-CO-NR R acts as a source of isocyanate. However, these are only theoretical considerations.

The substituted urea derivatives of the formula R NH-GO-NR R are prepared from the appropriate amine of the formula R^NH 9 and carbamoyl chloride of the formula Cl-CO-NR 2 R 4 using the procedure outlined by McManus et al. (Journal of Medicinal Chemistry, 8, 766

(1965)) and minor variations of this. The caramoyl chlorides with the 3 4 3 4 formula Cl-CO-NR R are obtained from the appropriate amine with the formula HNR R and phosgene as indicated in method B.

Method D comprises, reacting a sulfonyl isocyanate of formula IV, where X, A and B are as indicated previously, with the appropriate

12

amine of formula HZ or HNR R . The reaction is usually carried out by bringing the isocyanate into contact with the amine in a reaction-inert, organic solvent, at or at approx. ambient temperature, until the reaction is essentially complete. Reaction times of a few hours are usually used, e.g. from approx. 1 to approx. 12 hours. The same solvents can be used as stated in method A and the product is recovered according to methods mentioned above in method A.. Although the ratio between isocyanate and amine is not critical, and the use of an excess of one of the components will lead to the product, is it usual to use a small excess of amine, e.g. one-time profit.

The sulfonylis<p>cyanate starting materials are prepared from the corresponding sulfonamides of formula III, by reacting with an excess of oxalyl chloride, followed by pyrolysis of the oxamic acid chloride intermediate. Such transfers are well known in the art. See e.g. Franz and Osuch, Journal of Organic Chemistry, 29, 2592 (1964). A suitable way is in many cases to use sulfonyl isocyanate in the solvent in which it is prepared, without isolating it. If desired, oxamic acid chloride can also be treated directly with amine, and this will lead to the formation of a compound of formula I or II.

Method E involves the reaction of an amine with formula HZ

12 12 "? or HNR R with a compound of formula V, where Z, R , R , R and R 4 are as indicated previously. The reaction is usually carried out by heating the two reactants together in a reaction-inert organic solvent, which is usually a polar, organic solvent that serves to dissolve the reactants

Suitable solvents are e.g. lower alkanols, such as methanol, ethanol and n-butanol; glycols, such as ethylene glycol and propylene glycol; ethers, such as dioxane and 1,2-dimethoxyethane; acetonitrile; and tertiary amides, such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrlidone. The temperature and required reaction time to complete the transfer to the product are interdependent. At lower temperatures, a longer reaction time is required, while at higher temperatures the reaction can take place

is completed in a shorter time. Moreover, the reaction rate depends on the nucleophilicity of the amine reactant and how efficiently the group is removed. In all cases, reaction times of a few hours are used, and the turnover is usually carried out in the range from approx. 50-150°C, and preferably in the range from approx. 80 - 100°C. At approx. 100°C, a reaction time of approx. 5 hours. If desired, the starting material with formula V can be used in the form of a salt, e.g. an alkali metal salt, such as a potassium salt. Alternatively, the connection may; with formula V is introduced into the reaction medium in the form of a salt, which is then neutralized by adding an alkanoic acid, such as acetic acid. Although the reactants according to this method are usually used in equimolar amounts, the ratio between the reactants is not critical, and an excess of one of the components can usually be used. The product can be isolated by evaporating the solvent in vacuo, and then partitioning the residue between dilute, aqueous acid and an organic solvent that is immiscible with water. Evaporation of the organic solvent then gives it. unpurified product, which can be further purified according to known methods if desired.

In certain cases, method D is carried out in the absence of a solvent. In this case, the sulfonamide of formula V and the amine can be quite simply heated together until transfer to the product is essentially complete. As stated above, reaction times of a few hours can be used, e.g. about. 5 hours, and the reaction is usually carried out at a temperature in the range from approx. 50-150°C, and preferably in the range from approx. 80-100°C. This particular variant can be suitably used when the compound of formula V and the amine are in liquid phase at the reaction temperature.

Although the detailed course of method D has not been elucidated, it is assumed that some sulfonyl isocyanate of formula IV is formed

in situ during the reaction.

Preferred meanings for R 3 are alkyl containing

from 1 to 6 carbon atoms, phenyl and phenyl substituted with up to two groups selected from the group consisting of fluorine, chlorine, bromo, nitro, alkyl containing from 1 to 4 carbon atoms and alkoxy containing from 1 to 4 carbon atoms , and preferred meanings for. R 4 is hydrogen and R 3. Particularly preferred starting materials of formula V are those where R<3> and R 4 are both phenyl.

The compounds of formula IV'. is prepared by reacting the appropriate sulfonamide with formula III with a carbamoyl chloride of the formula Cl-CO-NR 3 R 4 using the method set forth in method B.

It will be understood that not all methods A, B, C and D are equally applicable when it comes to the synthesis of all compounds of formulas I and II. Methods A and C are e.g. only suitable for 1 2 preparing the compounds of formula II, where either R or R

is hydrogen. In the individual case, the person skilled in the art will choose the synthesis method that is most suitable, based on such factors as e.g. the feasibility of the chemical reactions, the availability of the starting materials, the reactivity of the starting materials, the stability of the reactants and products and in what order of magnitude the turnover is to be carried out.

A further alternative synthetic method which is particularly used for compounds of formula II. where either R 1 or R 2 is carboxyalkyl, is the hydrolysis of the corresponding compound of formula II, where either R 1 or R 2 is alkoxycarbonylalkyl. Because of the stability of the compounds of formula II and convenience of execution, the hydrolysis is usually carried out using alkaline conditions. In many cases it is simply sufficient to dissolve the ester in dilute sodium hydroxide solution, store the solution at ambient temperature for a few hours and then acidify the solution. Either the product precipitates in a form that can be filtered from, or it is extracted in a solvent that is not miscible with water, such as ethyl acetate. The solvent is then dried and evaporated to recover the impure product. A variety of co-solvents, such as lower alkanols, e.g. methanol and ethanol or acetone can be added to facilitate dissolution. In addition, a number of other bases can be used which are known to be useful for alkaline hydrolysis reactions, such as e.g. potassium oxide, calcium hydroxide, barium hydroxide, sodium carbonate and potassium carbonate. The basic agent will usually be present in an amount of at least 1 molar equivalent based on the ester used, but larger amounts, up to about 20 molar equivalents. Although the reaction is usually carried out at ambient temperature, it is possible to use temperatures in the range from approx. 0°C to approx. 100°C. The time course of the reaction varies depending on the temperature, since the reaction proceeds faster when the reaction temperature is increased. When the reaction is carried out at approx. 25 - 50°C, however, the reaction times are a few hours, e.g. overnight.

A further, alternative synthetic method used for the preparation of compounds of formula I, where Z is ([hydroxyphenyl]alkyl)piperidino. The method comprises demethylation of the appropriate compound, of formula I, where Z is the corresponding ([methoxyphenyl]alkyl)piperidino. Demethylation is carried out by known methods such as a transfer which has no adverse effect on the rest of the molecule. A particularly suitable reagent in this connection is boron tribromide and its use is indicated by Fieser and Fieser in "Reagents for Organic Synthesis", John Wiley & Sons, Inc., New York, 1967, p. 66.

As discussed earlier, the starting materials used in methods A, B, C, D and E are sulfonamides of formula III.• These sulfonamides can be prepared from ethylene derivatives of formula VI, according to one of two methods. The first of these comprises the following series of turnovers:

The reagents and conditions used in this series are, with minor variations, those indicated by Bordwell et al. (Journal of the American Chemical Society, 68, 139 (1946)) for the case where

A, B and X are all hydrogen. The series of reactions is further exemplified in U.S. Patent No. 2,979,437. The second method used for the transfer of the ethylene derivatives of formula VI to the corresponding sulfonamides of formula III comprises the treatment of the ethylene derivatives with sulfuryl chloride in N,N-dimethylformamide, followed by ammonia, using, with minor variations, the conditions indicated .by Culbertson and Dietz (Journal of the Chemical Society (London), Part C, 992 (1968)).

The ethylene derivatives of formula VI are either commercial products, or they can be prepared according to one of two general methods, both of which are well known in the field. The first method involves a Wittig reaction between a carbonyl compound of formula VII and the ylide derived from a phosphonium salt of formula ([C,HC]_PCH„B)<+>Y~, where Y is chloride or bromide as discussed by

b D6 Z

Maercker in "Organic Reactions",. IA, 270 (1965) and by Deno et al.,

in the Journal of the American Chemical Society, 87_, 2157 (1965).

The second method involves the reaction of a carbonyl compound of formula VII with a Grignard reagent of formula BCI^MgY, where Y is chloride or bromide, followed by acid catalyzed dehydration of the carbinol produced, according to the procedure indicated by Emerson in Chemical Reviews, 4_5, 347 (1949), namely:

The choice between the two methods will usually be made on the basis of such factors as the availability of the starting materials, convenient execution of the method in the relevant order of magnitude and the reactivity of the relevant starting materials.

The carbonyl compounds of formula VII are either commercial products, or they are prepared according to methods indicated in the literature. The phosphonium salts with the formula ([C,HC]_PCH0B)+Y are prepared

D 3 O Z

suitably from triphenylphosphine and the appropriate .alkyl halide according to the method indicated by Maercker, lo. ed., pp 388-393. The alkyl halides are all commercially available.

It will be seen that many of the alkenesulfonamides of formula II are useful not only as hypolipidemic agents, but also as intermediates for the preparation of hypolipidemic agents. The connections

1 2

of formula II, wherein either R or R is selected from the group consisting of phenyl and phenyl substituted with one group selected from the group consisting of fluorine, chlorine, bromine, nitro, alkyl containing from 1 to 4 carbon atoms and alkoxy which contain from 1 to 4 carbon atoms, are thus usable as starting materials

in method E as described previously. The compounds of formula II,

12

where either R or R is alkoxycarbonylalkyl are also valuable as starting materials for. the preparation by hydrolysis of the compounds of formula II corresponding to -1 2, where either R or R is carboxyalkyl.

The hypolipidemic properties of the compounds according to the present invention can be easily demonstrated by one of two methods. The first method which is mainly the method used by Newman et al. (Lipids, 8, 378 (1973)) shows the ability of the compounds

to inhibit Triton-induced hyperlipidemia in rats. A dose of 300 mg/kg of Triton WR-1339 is injected into normal male Sprague-Dawley rats that have been orally treated with the test compound.

After a further oral dose of the test compound, blood is taken from the rats via the abdominal aorta under pentobarbital anesthesia and plasma is obtained from it. the heparinized blood. The plasma cholesterol concentration is measured using the Auto-Analyser (Technicon Method N-2 4a), and the value is compared with that obtained from the control animals that have received Triton treatment but no test compound. The plasma cholesterol level for the animals that have received the test compound is found to be significantly lower than the levels for the animals that have not received the test compound.

In the second method for measuring the hypolipidemic properties of the compounds according to the present invention, normal,

adult "beagle" dogs orally, twice daily, with the test compound for a period of 6 days. During this experimental period, the dogs are fed daily at 12.oo.. On the morning of the 6th day, blood is taken from the dogs from the jugular vein and plasma cholesterol is measured according to the method adapted for the Technicon Auto-Analyser. The achieved level for a given dog is compared

with the base value for the dog determined at the beginning of the trial. It is found that the plasma cholesterol level is significantly lower at the end of the experiment compared to the base value obtained at the beginning of the experiment.

A characteristic feature of the compounds according to the present invention is the ability to form salts. Due to their acidic nature, the sulfonylurea derivatives have the ability to form salts with basic agents, and all such salts are covered by the present invention. The salts can be easily prepared by bringing the acidic and basic compounds into contact with each other, usually in a molar ratio of 1:1, either in an aqueous, non-aqueous or semi-aqueous medium. The salts are recovered either by filtration, by precipitation with a non-solvent, by evaporation of the solvent or, in the case of aqueous solutions, by lyophilization.

Basic agents which can suitably be used in salt formation belong to both the organic and inorganic types, and they can include ammonia, organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkali metal hydrides, alkali metal alkoxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal hydroxides and alkaline earth metal alkoxides. Examples of such bases are primary amines, such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine and octylamine, secondary amines, such as diethylamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines, such as triethylamine, N,N-dimethylaniline, N-ethylpiperidine, N-methylmorpholine and 1,5-diazobicyclo[4.3.0]non-5-ene; hydroxides, such as sodium hydroxide, alkoxides, such as sodium ethoxide and potassium ethoxide;

hydrides, such as calcium hydride and sodium hydride; carbonates,

such as potassium carbonate and sodium carbonate and bicarbonates such as sodium bicarbonate and potassium bicarbonate.

It will be understood that the connections.with. formula II, where R<1>or

2

R is carboxyalkyl and also has the ability to form carboxylate-

salts. These salts can be prepared in exactly the same way and by using exactly the same basic agents as described above, and these compounds are also covered by the present invention. In the case where a compound of formula II has two acidic groups, both mono- and di-salts can be prepared.

In the case of di-salts, the two cationic types can be equal

or different.

As regards the therapeutic use of a compound according to the present invention, it is preferred to use a pharmaceutically acceptable salt, salts which are different from that

which can be used for a number of other purposes. Such purposes include the isolation and purification of particular compounds and the conversion of pharmaceutically acceptable salts to non-salts or vice versa.

The hypolipidemic. properties of the alkenesulfonamides according to the present invention do. them particularly suitable and valuable for the control of hyperlipidemia in mammals, especially humans. For therapeutic use of a compound according to the present invention, the compound can be administered alone, or preferably it can be mixed with pharmaceutically acceptable. carriers or diluents. The carrier or diluent is selected on the basis of the intended mode of administration, as well as the solubility and stability of the active ingredient. When it comes to e.g. the oral route of administration, a hypolipidemic alkenesulfonamide according to the present invention can be used in the form of tablets, capsules, lozenges, powders, syrups, elixirs, aqueous solutions and suspensions, etc. according to standard pharmaceutical practice. The relative amounts of active ingredient to carrier will naturally depend on the chemical nature, solubility and stability of the active ingredient, as well as the dosage. In the case of tablets for oral use, commonly used carriers are lactose and corn starch, and lubricants, such as sterbtex K. For oral administration in capsule form, applicable diluents are lactose and dried corn starch. When aqueous suspensions are used for oral use, the active ingredient is combined with emulsifiers and suspending agents. If desired, sweeteners and/or flavorings can be added. For parenteral administration, which includes intramuscular, intra-peritoneal, subcutaneous and intravenous use, sterile solutions of the active ingredient are usually prepared and the pH of the solutions should be adjusted: and buffered. For intravenous use, the total concentration of the solvents should be controlled to make the preparation isotonic.

When the hypolipidemic compounds of the present invention are used to control, ie cure or prophylaxis, hyperlipidemia in humans, the physician will usually prescribe the daily dose. These doses will usually vary according to age, weight and the individual patient's response, as well as according to the patient's symptoms. However, an effective daily dose will in most cases be in the range from approx. 0.5 g to approx. 3.0 g

in single or divided doses. On the other hand, it may be necessary to use doses that lie outside these limits.

The following examples illustrate the invention.

Example I

N-(N-butylcarbamoyl)-1-phenylpropene-2- sulfonamide

To a mixture of 80 ml of triethylamine and 50 ml of N,N-dimethylformamide is added. 39.5 g of 1-phenylpropene-2-sulfonamide followed by 32.5 ml of n-butyl isocyanate. The mixture is heated at 85-90°C with stirring for 75 minutes. It is cooled to ambient temperature and then poured under stirring into 1 liter of 20% acetic acid. After a further 30 minutes of stirring, a precipitate forms, which is filtered off and then dissolved in 300 ml of hot acetone. The acetone is filtered off, and then allowed to cool slowly. The impure product that precipitates is filtered off, washed with aqueous acetone and allowed to dry. The acetone mother liquors are diluted with water and you get another portion of the product. This is filtered out. The two amounts are combined and then recrystallized from ethanol to give 28 g of N-(N-butylcarbamoyl)-1-phenylpropene-2-sulfonamide, m.p. 135-136°C.

Analysis:

Calculated for<c>14H2o<N>2°3<S>(<%>)<:>C 56'74'H 6'80?N 9'45

Found: (%'): C 56.64; H 6.78; N 9.27.

Example II

By proceeding as indicated in example I and reacting either 1-phenylpropene-2-sulfonamide, 2-phenylpropene-1-sulfonamide or 2,2-diphenylethene-sulfonamide with the appropriate isocyanate, the following compounds are produced:

Example III

When respectively methyl isocyanate, ethyl isocyanate, isobutyl isocyanate, n-hexyl isocyanate, n-heptyl isocyanate, n-decyl isocyanate, allyl isocyanate, 3,3-dimethylbut-2-yl isocyanate, cyclopropyl isocyanate, cyclopentyl isocyanate, cyclohexyl isocyanate, cycloheptyl isocyanate, phenyl isocyanate, p-fluorophenyl isocyanate, m-bromophenyl isocyanate, n-nitrophenyl isocyanate, p-tolyl isocyanate, p-ethylphenyl isocyanate, p-chlorophenyl isocyanate, o-chlorophenyl isocyanate, p-methoxyphenyl isocyanate, m-ethoxyphenyl isocyanate, p- butoxyphenyl isocyanate, m-methoxyphenyl isocyanate, benzyl isocyanate, 1-phenylethyl isocyanate, 2-phenylethyl isocyanate, ethoxycarbonylmethyl isocyanate and methoxycarbonylmethyl isocyanate are reacted with 2-phenylbut-l-en-l-sulfonamide, 2-( p-chlorophenyl)propene-1-sulfonamide, 2-(p-methoxyphenyl)propene-1-sulfonamide, 1-(m-chlorophenyl)propene-2-sulfonamide, 2-(p-chlorophenyl)but-l-ene-1 - sulfonamide, 1,2-diphenylethene sulfonamide, 3-phenylbut-2-ene-2-sulfonamide, 1-(p-chlorophenyl)propene-2-sulfonamide, 1-phenylpropene-2-sulfonamide, 1,2-diphenylpropene-1- sul fonamide, 1-(p-chlorophenyl)propene-2-sulfonamide, 2-(p-tolyl)propene-l-sulfonamide, 2-(p-isopropylphenyl)-propene-l-sulfonamide, 1-(p-ethoxyphenyl) propene-2-rsulfonamide, 2-phenylpropene-l-sulfonamide, 2-(p-fluorophenyl)propene-l-sulfonamide, 2,2-diphenylethylenesulfonamide, 2-(p-butoxyphenyl)propene-l-sulfonamide, 2-( p-tolyl)propene-1-sulfonamide, 1-phenylbut-1-ene-2-sulfonamide, 3-(m-chlorophenyl)but-2-ene-2-sulfonamide, 2-(p-chlorophenyl)-2-phenylethenesulfonamide , 2-(p-chlorophenyl)propene-l-sulfonamide, 2-(p-n-butylphenyl)-propene-l-sulfonamide, 2-phenylpropene-l-sulfonamide, 1-phenylpropene-2-sulfonamide, 2-(m-methoxyphenyl )propene-1-sulfonamide and 2-(p-biphenylyl)-propene-1-sulfonamide according to the method in example 1, the following compounds are produced respectively: N-(N-methylcarbamoyl)-2-phenylbut-1-ene- l-sulfonamide, N-(N-ethylcarbamoyl)-2-(p-chlorophenyl)propene-l-sulfonamide, N-(N-isobutylcarbamoyl)-2-(p-methoxyphenyl)propene-l-sulfonamide, N-(N-n -hexylcarbamoyl)-1-(m-chlorophenyl)propene-2-sulfonamide, N-(N-n-heptylcarbamoyl)-2-(p-chlorophe nyl)but-1-ene-1-sulfonamide, N-(N-decylcarbamoyl)-1,2-diphenylethylenesulfonamide,

N-N-allylcarbamoyl)-2-phenylbut-2-ene-2-sulfonamide,

N-(N-[3,3-dimethylbut-2-ylcarbamoyl)-1-(p-chlorophenyl)propene-2-sulfonamide,

N-(N-cyclopropylcarbamyl)-1-phenylpropene-2-sulfonamide,

N-(N-cyclopentylcarbamoyl)-1,2-diphenylpropene-1-sulfonamide, N-(N-cyclohexylcarbamoyl)-1-(p-chlorophenyl)propene-2-sulfonamide, N-(N-cycloheptylcarbamoyl)-2-( p-tolyl)propene-l-sulfonamide, N-(N-phenylcarbamoyl)-2-(p-isopropylphenyl)propene-l-sulfonamide, N-(N-p-fluorophenylcarbamoyl)-1-(p-ethoxyphenyl)propene^2- sulfonamide, N-(N-m-bromophenylcarbamoyl)-2-phenylpropene-l-sulfonamide, N-(N-m-nitrophenylcarbamoyl)-2-(p-fluorophenyl)propene-l-sulfonamide, N-(N-p-tolylcarbamoyl)-2,2 -diphenylethene sulfonamide, N-(N-p-ethylphenylcarbamoyl)-2-(p-butoxyphenyl)propene-l-sulfonamide, N-(N-p-chlorophenylcarbamoyl)-2-(p-tolyl)propene-l-sulfonamide, N-(N-p- chlorophenylcarbamoyl)-1-phenylbut-1-ene-2-sulfonamide, N-(N-p-methoxyphenylcarbamoyl)-3-(m-chlorophenyl)but-2-ene-2-sulfonamide, N-(N-m-ethoxyphenylcarbamoyl)-2- (p-chlorophenyl)-2-phenylethene sulfonamide, N-(N-p-butoxyphenylcarbamoyl)-2-(p-chlorophenyl)propene-l-sulfonamide, N-(N-m-methoxyphenylcarbamoyl)-2-(p-n-butylphenyl)propene-l- sulfonamide, N-(N-benzylcarbamoyl)-2-phenylpropene-1-sulfonamide, N-(N-[1-phenylethyl] carbamoyl)-2-phenylpropene-1-sulfonamide, N-(N-[2-phenylethyl]carbamoyl)-1-phenylpropene-2-sulfonamide, N-(N-[ethoxycarbonylmethyl]carbamoyl)-2-(m-methoxyphenyl) propene-1-sulfonamide and N-(N-[methoxycarbonylmethyl]carbamoyl)-2-(p-biphenylyl)propene-1-sulfonamide.

Example IV

N-(N,N-diphenylcarbamoyl)-2-phenylethene sulfonamide

To a suspension of 35 g of potassium carbonate in 500 ml of acetone, 18.3 g of 2-phenylethene sulfonamide and 35 g of N,N-diphenylcarbamoyl chloride are added. The reaction mixture is heated under reflux and stirring for 5% hour. The insoluble material is filtered from hot acetone and the acetone is concentrated to dryness in vacuo. The residue is suspended in 300 ml of ether and then filtered off. 43 g of the potassium salt of the product is obtained.

The potassium salt is dissolved in a mixture of 200 ml of acetone and

50 ml of water. The solution is acidified by using concentrated hydrochloric acid and then adding a further 50 ml of water. The solid substance that precipitates is filtered off, washed one after the other with acetone-water (1:1) and then water, and 33 g of N-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide are obtained, m.p. 185-188°C. Recrystallization of the product raises the melting point to 189-191°C.

Analysis:

Calculated for <c>2iHi8N2°3S (%): C 66'66'H 4'80'N 7.40.

Found C 66.46; H 4.82; N 7.17.

Example V

When the procedure in Example IV is repeated, except

that N,N-diphenylcarbamoyl chloride is replaced by an equimolar amount of N,N-dimethylcarbamoyl chloride, one obtains N-(N,N-dimethylcarbamoyl)-2-phenylethenesulfonamide, m.p. 160-162°C.

Analysis:

Calculated for C11<H>14<N>2°3<S>(%) : c 51',96J H 5,55} N 11,02

Found (%) : C 51.88; H 5.56; N .11,07.

Example VI

The procedure in Example IV is repeated, except that 2-phenylethenesulfonamide is replaced by an equimolar amount of 1-phenylpropene-2-sulfonamide. The product is N-(N,N-diphenylcarbamoyl)-1-phenylpropene-2-sulfonamide, m.p. 175-179°C.

Analysis:

Calculated for C 22 H 2 () N 2 O 3 S (%) : C 67.33; H 5.14; N 7,14.

Found (%): C 67.09; H 5.24; N 7.11.

Example VII

When the procedure in example IV is repeated and 2-phenylethene sulfonamide is replaced respectively with an equimolar amount of:

2-(4-biphenyl)ethene sulfonamide,

2-phenylpropene-1-sulfonamide,

2,2diphenylethylenesulfonamide,

1,2-diphenylethylene sulfonamide,

2-phenylbut-1-ene-1-sulfonamide,

1-phenylbut-1-ene-2-sulfonamide,

3-phenylbut-2-ene-2-sulfonamide,

2-(m-chlorophenyl)ethene sulfonamide,

2-(o-chlorophenyl)ethene sulfonamide,

2-(p-chlorophenyl)ethene sulfonamide,

2-(p-bromophenyl)ethene sulfonamide,

2-(m-bromophenyl)ethene sulfonamide,

2-(p-fluorophenyl)ethene sulfonamide,

2-(m-tolyl)ethene sulfonamide,

2-(p-ethylphenyl)ethene sulfonamide,

2-(p-tert-butylphenyl)ethene sulfonamide,

2-(o-methoxyphenyl)ethene sulfonamide,

2-(m-isopropoxyphenyl)ethene sulfonamide,

2-(p-butoxyphenyl)ethene sulfonamide,

2-(m-chlorophenyl)propene-1-sulfonamide,

2-(p-chlorophenyl)propene-1-sulfonamide,

2-(m-bromophenyl)propene-1-sulfonamide,

2-(p-fluorophenyl)propene-1-sulfonamide,

2-(m-tolyl)propene-1-sulfonamide,

2-(p-isopropylphenyl)propene-1-sulfonamide,

2-(p-methoxyphenyl)propenyl-1-sulfonamide,

1-(o-chlorophenyl)propene-2-sulfonamide,

1-(m-chlorophenyl)propene-2-sulfonamide,

1-(p-chlorophenyl)propene-2-sulfonamide,

1-(p-fluorophenyl)propene-2-sulfonamide,

1-(p-tolyl)propene-2-sulfonamide,

1-(m-methoxyphenyl)propene-2-sulfonamide,

1-(p-ethoxyphenyl)propene-2-sulfonamide,

2-(p-chlorophenyl)but-1-ene-1-sulfonamide,

2-(p-tolyl)but-1-ene-1-sulfonamide,

2-(m-methoxyphenyl)but-1-ene-1-sulfonamide,

1-(p-chlorophenyl)but-1-ene-2-sulfonamide,

1-(m-methoxyphenyl)but-1-ene-2-sulfonamide,

3-(p-chlorophenyl)but-2-ene-2-sulfonamide and. 1,2-diphenylpropene-1-sulfonamide,

one obtains respectively: N-(N,N-diphenylcarbamoyl)-2-(4-biphenyl)ethylene sulfonamide, N-(N,N-diphenylcarbamoyl)-2-phenylpropene-1-sulfonamide, N-(N,N- diphenylcarbamoyl)-2,2-diphenylethylene sulfonamide, N-(N,N-diphenylcarbamoyl)-1,2-diphenylethylene sulfonamide, N-(N,N-diphenylcarbamoyl)-2-phenylbut-1-ene-l-sulfonamide , N-(N,N-diphenylcarbamoyl)-1-phenylbut-1-ene-2-sulfonamide, N-(N,N-diphenylcarbamoyl)-3-phenylbut-2-ene-2-sulfonamide, N-(N, N-diphenylcarbamoyl)-2-(m-chlorophenyl)ethylene sulfonamide, N-^ (N,N-diphenylcarbamoyl)-2-(o-chlorophenyl)ethylene sulfonamide, N-(N,N-diphenylcarbamoyl)- 2-(p-chlorophenyl)ethylene sulfonamide, N-(N,N-diphenylcarbamoyl)-2-(p-bromophenyl)ethylene sulfonamide, N-(N,N-diphenylcarbamoyl)-2-(m-bromophenyl)ethene -sulfonamide, N-(N,N-diphenylcarbamoyl)-2-(p-fluorophenyl)ethene sulfonamide, N-(N,N-diphenylcarbamoyl)-2-(m-tolyl)ethene sulfonamide, N-(N,N- diphenylcarbamoyl)-2-(p-ethylphenyl)ethylenesulfonamide, N-(N,N-diphenylcarbamoyl)-2-(p-tert-butylphenyl)-ethylenesulfonamide, N-(N,N-diphenylcarbamoyl)-2-(o-methoxyphenyl )ethene sulfonamide, N-(N,N-diphenylcarbamo yl)-2-(m-isopropoxyphenyl)ethylenesulfonamide, N-(N,N-diphenylcarbamoyl)-2-(p-butoxyphenyl)ethylenesulfonamide,

N-(N,N-diphenylcarbamoyl)-2-(m-chlorophenyl)propene-l-sulfonamide, N-(N,N-diphenylcarbamoyl)-2-(p-chlorophenyl)propene-l-sulfonamide, N-(N ,N-diphenylcarbamoyl)-2-(m-bromophenyl)propene-l-sulfonamide, N-(N,N-diphenylcarbamoyl)-2-(p-fluorophenyl)propene-l-sulfonamide, N-(N,N-diphenylcarbamoyl )-2-(m-tolyl)propene-l-sulfonamide, N-(N,N-diphenylcarbamoyl)-2-(p-isopropylphenyl)propene-l-sulfonamide, N-(N,N-diphenylcarbamoyl)-2- (p-Methoxyphenyl)propene-1-sulfonamide, N-(N,N-diphenylcarbamoyl)-1-(o-chlorophenyl)propene-2-sulfonamide, N-(N,N-diphenylcarbamoyl)-1-(m-chlorophenyl) )propene-2-sulfonamide, N-(N,N-diphenylcarbamoyl)-1-(p-chlorophenyl)propene-2-sulfonamide, N-(N,N-diphenylcarbamoyl)-1-(p-fluorophenyl)propene-2 -sulfonamide, N-(N,N-diphenylcarbamoyl)-1-(p-tolyl)propene-2-sulfonamide, N-(N,N-diphenylcarbamoyl)-1-(m-methoxyphenyl)propene-2-sulfonamide, N -(N,N-diphenylcarbamoyl)-1-(p-ethoxyphenyl)propene-2-sulfonamide, N-(N,N-diphenylcarbamoyl)-2-(p-chlorophenyl)but-l-ene-l-sulfonamide, N -(N,N-diphenylcarbamoyl)-2-(p-tolyl)but-l-ene-l-sulfonamide, N-(N,N-diphenylcar bamoyl)-2-(m-methoxyphenyl)-but-l-ene-l-sulfonamide, N-(N,N-diphenylcarbamoyl)-1-(p-chlorophenyl)but-l-ene-2-sulfonamide, N- (N,N-diphenylcarbamoyl)-1-(m-methoxyphenyl)but-1-ene-2-sulfonamide, N-(N,N-diphenylcarbamoyl)-3-(p-chlorophenyl)but-2-ene-2- sulfonamide and N 2 -(N,N-diphenylcarbamoyl)-1,2-diphenylpropene-1-sulfonamide.

Example VIII

When the procedure in Example IV is repeated and the alkenesulfonamide component is respectively:

2-phenylethene sulfonamide,

1-phenylpropene-2-sulfonamide,

2-(p-methoxyphenyl)ethene sulfonamide,

2-(m-tolyl)ethene sulfonamide,

2- phenylethene sulfonamide,

1-(p-chlorophenyl).propene-2-sulfonamide,

1-(p-fluorophenyl)propene-2-sulfonamide,

3-phenylbut-2-ene-2-sulfonamide,

2- phenylethene sulfonamide,

2-(o-chlorophenyl)ethene sulfonamide,

2-(m-methoxyphenyl)propene-1-sulfonamide,

2-(p-tolyl)ethene sulfonamide,

2-(p-fluorophenyl)ethene sulfonamide,

2-phenylbut-1-ene-1-sulfonamide,

2-(p-chlorophenyl)ethene sulfonamide,

1-phenylbut-1-ene-2-sulfonamide,.

2-(p-isopropoxyphenyl)ethene sulfonamide,

2-(m-chlorophenyl)ethene sulfonamide,

2-phenylethene sulfonamide,

2-(p-chlorophenyl)ethene sulfonamide,

1,2-diphenylethene and

2-phenylethene sulfonamide,

and the carbamoyl chloride component are respectively: N-phenyl-N-(p-chlorophenyl)carbamoyl chloride,

N-phenyl-N-(p-chlorophenyl)carbamoyl chloride,

N-phenyl-N-(p-chlorophenyl)carbamoyl chloride,

N-phenyl-N-(p-chlorophenyl)carbamoyl chloride,

N,N-di(p-methoxyphenyl)carbamoyl chloride,

N,N-di-(p-methoxyphenyl)carbamoyl chloride,

N-methyl-N-(p-fluorophenyl)carbamoyl chloride,

N-methyl-N-(m-bromophenyl)carbamoyl chloride,

N-ethyl-N-(p-nitrophenyl)carbamoyl chloride,

N-(n-butyl)-N-(p-tolyl)carbamoyl chloride,

N-(n-decyl)-N-(p-ethylphenyl)carbamoyl chloride,

N-methyl-N-(p-tert-butylphenyl)carbamoyl chloride,

N-(n-propyl)-N-(m-isopropoxyphenyl)carbamoyl chloride, N-(isopropyl)-N-(p-n-butoxyphenyl)carbamoyl chloride, N-allyl-N-phenylcarbamoyl chloride,

N-benzyl-N-phenylcarbamoyl chloride,

piperidinocarbonyl chloride,

(4-=-benzylpiperidino)carbonyl chloride,

(4-[3-phenylprop-1-yl]piperidino)carbonyl chloride, (4-[3-phenylprop-1-yl]piperidino)carbonyl chloride, morpholinocarbonyl chloride and

(1,2,3,4-tetrahydroquinolino)carbonyl chloride,

respectively, the following compounds are prepared: N-(N-phenyl-N-[p-chlorophenyl]carbamoyl)-2-phenylethenesulfonamide, .N-(N-phenyl-N-[p-chlorophenyl]carbamoyl)-1-phenylpropene-2 -sulfonamide, N-(N-phenyl-N-[p-chlorophenyl]carbamoyl)-2-(p-methoxyphenyl)ethenesulfonamide, N-(N-phenyl-N- [p-chlorophenyl]carbamoyl)-2- ( m-tolyl) ethene sulfonamide, N-(N,N-di[p-methoxyphenyl]carbamoyl)-2-phenylethene sulfonamide,

N-(N,N-di[p-methoxyphenyl]carbamoyl)-1-(p-chlorophenyl)propene-2-sulfonamide, N-(N-methyl-N-[p-fluorophenyl]carbamoyl)-1-(p -fluorophenyl)propene-2-sulfonamide, N-(N-methyl-N-[m-bromophenyl]carbamoyl)-2-phenylbut-2-ene-2-sulfonamide, N-(N-ethyl-N-[p- nitrophenyl]carbamoyl)-2-phenylethenesulfonamide, N-(N-[n-butyl]-N-[p-tolyl]carbamoyl)-2-(o-chlorophenyl)ethenesulfonamide, N-(N-[n-decyl]- N-[p-ethylphenyl]carbamoyl)-2-(m-methoxyphenyl)propene-1-sulfonamide, N-(N-methyl-N-[p-tert-butylphenyl]carbamoyl)-2-(p-tolyl)ethylenesulfonamide , N-(N-[n-propyl]-N-[m-isopropoxyphenyl]carbamoyl)-2-(p-fluorophenyl)-ethylenesulfonamide, N-(N-[isopropyl]-N-[p-n-butoxyphenyl]carbamoyl) -2-phenylbut-l-ene-l-sulfonamide, N-(N-allyl-N-phenylcarbamoyl)-2-(p-chlorophenyl)-ethenesulfonamide, N-(N-benzyl-N-phenylcarbamoyl)-1- phenylbut-1-ene-2-sulfonamide, N-(piperidinocarbonyl)-2-(p-isopropoxyphenyl)ethenesulfonamide, N-([4-benzylpiperidino]carbonyl)-2-(m-chlorophenyl)-ethenesulfonamide, N-([ 4-(3-phenylprop-l-yl)piperidino]carbonyl)-2-phenylethenesulfonamide, N-([4-(3-phenylprop-l-yl)piper idino]carbonyl)-2-(p-chlorophenylethene sulfonamide,

N-(morpholinocarbonyl)-1,2-diphenylethene sulfonamide and

N-([1,2,3,4-tetrahydroisoquinolino]carbonyl)-2-phenylethenesulfonamide.

Example IX

N-(N-'Ebicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-2-phenylethenesulfonamide

To a solution of 1.8 g of 2-phenylethene sulfonamide and 4.8 g of 1,1-diphenyl-3-(bicyclo[2.2.1]hept-2-en-5-ylmethyl)urea in 20 ml of N,N- dimethylformamide is added with stirring to 0.64 g of a 56.6% dispersion of sodium hydride in mineral oil. The mixture is stirred at ambient temperature overnight and during this time a heavy precipitate forms. 200 ml of ether are then added to the reaction mixture. After stirring for 15 minutes, the precipitate is filtered off. It is dissolved in 50 ml of water and then the impure product is precipitated by acidification using concentrated hydrochloric acid. It is filtered off and recrystallized from aqueous acetone. The yield is 1.9 g (56%) of a solid, m.p. 161-163.5°C.

Analysis:

Calculated for<C>17<H>20<N>2<0>3<S>(<%>)<:>C 61.43;H 6.07; N 8.43.

Found (%) :. C 61.13; H 5.95; N 8.30.

When the above procedure is repeated and 2-phenylethene sulfonamide is replaced by an equimolar amount of 2-phenylpropene-1-sulfonamide, l-phenylpropene-2-sulfonamide, 3-phenylbut-2-ene-2-sulfonamide, 1-phenylbut-1-ene- 2-sulfonamide, 2,2-diphenylethene sulfonamide, 2-(p-chlorophenyl)ethene sulfonamide, 2-(m-tolyl)ethene sulfonamide, 2-(p-methoxyphenyl)ethene sulfonamide and 2-(p-chlorophenyl)propene- l-sulfonamide is obtained respectively N-(N-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-2-phenylpropen-l-sulfonamide, N-(N-[bicyclo[2.2. 1]hept-2-en-5-ylmethyl]carbamoyl)-1-phenylpropen-1-sulfonamide, N-(N-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-3- phenylbut-2-ene-2-sulfonamide, N-(N-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-1-phenylbut-1-ene-2-sulfonamide, N-( N- [bicyclo[2.2.1]hept-2-enr-5-ylmethyl]carbamoyl)-2,2-diphenylethenesulfonamide, N-(N-[bicyclo[2.2.1]hept-2-en-5- ylmethyl]carbamoyl)-2-(p-chlorophenyl)-ethylenesulfonamide, N-(N-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-2-(m-tolyl)-ethylenesulfonamide,

N-(N-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-2-(p-methoxyphenyl)-ethylenesulfonamide and

N-(N-[bicyclo[2.2.1]hept-2-en-5-ylmethyl]carbamoyl)-2-(p-chlorophenyl)-propene-1-sulfonamide.'

Example X

By following the procedure in example IX and using 2-phenylethenesulfonamide and 1,1-diphenyl-3-(endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)urea as starting materials, N-(N-[ endo-7-oxabicyclo[2.2.1]heptan-2-yl-methyl]carbamoyl)-2-phenylethenesulfonamide, m.p. 176-178°C.

Analysis:

Calculated for c16H2oN2°4S (%): C 57'13'H 5'99'N 8.33.

Found C 56.83; H 6.06; N 8.24.

By again following the procedure in example IX and using 2-phenylethenesulfonamide and 1,1-diphenyl-3-(exo-7-oxabicyclo[2.2.1]-heptan-2-ylmethyl)urea as starting materials, N-(N- [exo-7-oxabicyclo[2.2.1]heptan-2-yl-methyl]carbamoyl)-2-phenylethene-. sulfonamide, m.p. 150-152°C.

Analysis:

Calculated for c16H2oN2°4S (%): C 57'13; H 5'99?N 8.33.

Found (%): C 56.88; H 6.04; N 8.28.

The condensation of 1,1-diphenyl1-3-(endo-7-oxabicyclo[2.2.1]-heptan-2-yl-methyl)urea with 2-phenylpropene-1-sulfonamide, 3-phenylbut-2-ene-2 -sulfonamide, 2,2-diphenylethenesulfonamide, 2-(m-chlorophenyl)ethenesulfonamide, 2-(m-methoxyphenyl)ethenesulfonamide and 2-(p-chlorophenyl)propene-1-sulfonamide, according to the procedure in example VIII, gives: N- (N-[endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]-carbamoyl)-2-phenylpropene-1-sulfonamide, N-(N-[endo-7-oxabicyclo[2.2.1]heptane- 2-ylmethyl]-carbamoyl)-3-phenylbut-2-ene-2-sulfonamide, N-(N-[endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]-carbamoyl)-2,2- diphenylethenesulfonamide, N-(N-[endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]-carbamoyl)-2-(m-chlorophenyl)ethenesulfonamide, N-(N-[endo-7-oxabicyclo[2.2 .1]heptan-2-ylmethyl]-carbamoyl)-2-(m-methoxyphenyl)ethylenesulfonamide and

N-(N-[endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]-carbamoyl-2-(p-chlorophenyl)propene-1-sulfonamide.

Similarly, the condensation of 1,1-diphenyl-3-(exo-7-oxabicyclo 2.2.1 heptan-2-ylmethyl)urea with 1-phenylpropene-2-sulfonamide gives 1-phenylbut-1-ene-2-sulfonamide , 2-(p-chlorophenyl)ethylene-sulfonamide, 2-(p-isopropylphenyl)-ethylenesulfonamide and 1-(p-chlorophenyl)-propene-2-sulfonamide, according to the procedure in example VIII, respectively: N-(N-[ exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-1-phenylpropene-2-sulfonamide, N-(N-[exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl] -carbamoyl)-1-phenylbut-1-ene-2-sulfonamide, N-(N-[exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]-carbamoyl)-2-(p-chlorophenyl)ethylenesulfonamide ,

N-(N-[exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-2-(p-isopropylphenyl)ethylenesulfonamide, and

N-(N-[exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl]carbamoyl)-1-(p-chlorophenyl)propene-2-sulfonamide.

Example XI

[ n- t (piperidinocarbonyl)-1-phenylpropene-2- sulfonamide

A solution of 1.9 g of N-(N,N-diphenylcarbamoyl)-1-phenylpropene-2-sulfonamide and 1.7 g of piperidine in 10 ml of N,N-dimethylformamide is kept at approx. 95°C for 6 hours. It. then cool to ambient temperature and add 100 ml of ether. The mixture is extracted with 50 ml of water and the water extract is acidified by using concentrated hydrochloric acid. This causes the uncleaned product to fall out. It is filtered off, then recrystallized from a mixture of acetone and water, and 670 mg of N-(piperidinocarbonyl)-1-phenylpropene-2-sulfonamide are obtained, m.p. 159-161°C.

Analysis:

Calculated for <c>15H2oN2O3S (%): C 58'43'H 6'54?N 9.09.

Found (%)•: C 58.21; H 6.50; N 9.05.

Example XII

By following the procedure in Example XI and reacting either N-(N,N-diphenylcarbamoyl)-1-phenylpropene-2-sulfonamide or N-(N,N-diphenylcarbamoyl)-2-phenylethene sulfonamide with the appropriate amine, the following compounds are prepared :

Example XIII Reaction of the appropriate N-(N,N-diphenylcarbamoyl)alkenesulfonamide selected from those indicated in Examples IV, V and VII, with the appropriate amine, according to the procedure in Example XI, gives the following types of compounds: N-( piperidinocarbonyl)-2-(4-biphenylyl)-ethylenesulfonamide, N-(piperidinocarbonyl)-2-phenylpropene-1-sulfonamide,

N-(piperidinocarbonyl)-2,2-diphenylethylenesulfonamide,

N-(piperidinocarbonyl)-1-phenylbut-1-ene-2-sulfonamide,

N-(piperidinocarbonyl)-2-(m-chlorophenyl)ethylenesulfonamide, N-(piperidinocarbonyl)-.2-(p-methoxyphenyl)propene-1-sulfonamide, N-([4-hydroxypiperidirio]carbonyl)-2-(p -fluorophenyl)-propene-l-sulfonamide, N-([4-hydroxypiperidino]carbonyl)-2-(p-tert-butylphenyl)ethylene-sulfonamide, N-([ 4-methoxypiperidino ]carbonyl ).-l-(p -chlorophenyl)propene-2-sulfonamide, N-([4-methoxypiperidino]carbonyl)-2-(p-ethylphenyl)ethenesulfonamide, N-([ 4-phenylpiperidino ]carbonyl)-2-ferryylpropen-1- sulfonamide, N-([4-phenylpiperidino]carbonyl)-1-phenylpropene-2-sulfonamide, N-([4-phenylpiperidino]carbonyl)-2,2-diphenylethene sulfonamide, N-([4-phenylpiperidino]carbonyl) -2-(p-chlorophenyl)ethenesulfonamide, N-([4-phenylpiperidino]carbonyl)- 2-(p-tolyl)but-l-ene-l-sulfonamide, N-([4-propylpiperidino]carbonyl)-1 -phenylpropene-2-sulfonamide, N-([ 4-methylpiperidino]carbonyl)-2r-(m-bromophenyl)propene-1-sulfonamide, N-([2-methylpiperidino]carbonyl)-2,2-diphenylethylenesulfonamide, N - ([ 3-methylpiperidino ]carbonyl) -2-(p-butoxyphenyl).ethylenesulfonamide, N-([2-ethylpiperidino]carbonyl)-1-(p-chlorophenyl)propene-2-sulfonamide, N-([2-ethylpiperidino]carbonyl)-2-(m-methoxyphenyl)-but-l-en-l -sulfonamide, N-([4-benzylpiperidino]carbonyl)-2-phenylpropene-1-sulfonamide, N-([4-benzylpiperidino]carbonyl)-1-(p-chlorophenyl)propene-2-sulfonamide, N-([ 4-benzylpiperidino]carbonyl)-2-(m-bromophenyl)ethylenesulfonamide, N-([4-benzylpiperidino]carbonyl)-2-(p-fluorophenyl)ethylenesulfonamide, N-([4-benzylpiperidino]carbonyl)-1-( p-ethoxyphenyl)propene-2-sulfonamide, N-([4-benzylpiperidino]carbonyl)-2-(p-tolyl)but-1-ene-1-sulfonamide, N-([4-(2-phenylethyl)piperidino ]carbonyl)-2-phenylethenesulfonamide, N-([4-(2-phenylethyl)piperidino]carbonyl)-2-(p-chlorophenyl)ethenesulfonamide, N-([4-(2-phenylethyl)piperidino]carbonyl)-2 -(p-isopropylphenyl)propene-1-sulfonamide, N-([4-(2-phenylethyl)piperidino]carbonyl)-2-(m-isopropoxyphenyl)-ethylenesulfonamide, N-([4-(2-phenylethyl)piperidino ]carbonyl)-2-(p-fluorophenyl)ethylene sulfonamide, N-(azacycloheptan-1-ylcarbonyl)-1-phenylpropene-2-sulfonamide, N-(azacycloheptan-1-ylcarbonyl)-2 r-(o-chlorophenyl)-ethylenesulfonamide, N-(azacycloheptan-1-ylcarbonyl)-3-phenylbut-2-ene-2-sulfonamide, N-(pyrrolidinocarbonyl)-2-(m-chlorophenyl)ethylenesulfonamide,

N-(pyrrolidinocarbonyl)-2-(m-tolyl)ethylenesulfonamide,

N-(morpholinocarbonyl)-1-phenylbut-1-ene-2-sulfonamide,

N-(morpholinocarbonyl)-2-(p-chlorophenyl)propene-l-sulfonamide, N-(morpholinocarbonyl)-2-(m-isopropoxyphenyl)-ethylenesulfonamide, N-(morpholinocarbonyl)-(p-isopropylphenyl)propene-l- sulfonamide, N-.(morpholinocarbonyl)-2,2-diphenylethenesulfonamide, N-(morpholinocarbonyl)-1,2-diphenylpropene-1-sulfonamide, N-(thiomorpholinocarbonyl)-2-(p-bromophenyl)ethenesulfonamide, N -(thiomorpholinocarbonyl)-2-(p-fluorophenyl)propene-1-sulfonamide,

N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-phenylpropene-1-sulfonamide, N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-phenyl-but-l-ene-1-sulfonamide, N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-(m-chlorophenyl)ethylene sulfonamide, N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-(p-bromophenyl)ethylene sulfonamide, N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-(p-tert-butylphenyl)-ethylenesulfonamide, N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-(p-fluorophenyl)propene-1 -sulfonamide,

N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-(m-methoxyphenyl)but-1-ene-1-sulfonamide,

N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-(p-chlorophenyl)ethylene sulfonamide,

N-(N,N-dimethylcarbamoyl)-2-(p-chlorophenyl)ethenesulfonamide, N-(N,N-diethylcarbamoyl)-2-(m-tolyl)propene-1-sulfonamide, N-(N,N-diisopropylcarbamoyl) )-2-(m-isopropoxyphenyl)ethylenesulfonamide, N-(N,N-diallylcarbamoyl)-1-phenylpropene-2-sulfonamide, N-(N,N-diallylcarbamoyl)-2-(p-chlorophenyl)propene-l- sulfonamide, N-(N-[2-methylallyl]carbamoyl)-1-(p-tolyl)propene-2-sulfonamide, N-(N-[4-methylpent-3-enyl]carbamoyl)-1-( m-methoxyphenyl)but-1-ene-2-sulfonamide, N-(N-methyl-N-allylcarbamoyl)-2-(p-fluorophenyl)-ethylenesulfonamide, N-(N-methyl-N-cyclohexyl)-2- phenylethene sulfonamide, N-(N,N,dicyclohexylcarbamoyl)-3-(p-chlorophenyl)but-2-ene-2-sulfonamide, N-(N-[2-phenylethyl]carbamoyl)-1-phenylpropene-2-sulfonamide, N-(N-methyl-N-[2-phenylethyl]carbamoyl)-2-(p-chlorophenyl)-ethylenesulfonamide, N-. (4-[4-phenylbutyl]piperidinocarbonyl)-2-phenylethenesulfonamide, N-(4- [ 5-phenylpentyl ]piperidinocarbonyl)-2^-phenylethenesulfonamide, N-(3-[3-phenylpropyl]piperidinocarbonyl)-2 -phenylethenesulfonamide, N-(2-[3-phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide, N-(4-[2-(p-isopropoxyphenyl)ethyl]piperidinocarbonyl)-2-(p-chlorophenyl)-ethenesulfonamide, N- (3-[3-(p-butoxyphenyl)propyl]piperidinocarbonyl)-2-(o-tolyl)-ethylenesulfonamide, N-(3-[3-(p-isopropylphenyl)propyl]piperidinocarbonyl)-2-phenylpropene-l- sulfonamide, N-(4-[3-(p-t-butylphenyl)propyl]piperidinocarbonyl)-1-phenylpropene-2-sulfonamide, N-(4-[m-methylbenzyl]piperidinocarbonyl)-2-phenylethenesulfonamide, N-(4- [3-(m-Methoxyphenyl)propyl]piperidinocarbonyl)-2-phenylethenesulfonamide, N-(4-[3-(o-methoxyphenyl)propyl]piperidinocarbonyl)-2-phenylethenesulfonamide, N-(4-[2-(p- methoxyphenyl)ethyl]piperidinocarbonyl)-2-(p-chlorophenyl)-ethylenesulfonamide, N-(4-[4-(m-methoxyphenyl)butyl]piperidinocarbonyl)-1-(p-tolyl)propene-2-sulfonamide, N- (4-[2-phenylprop-1-yl]piperidinocarbonyl )-2-phenylethene sulfonamide and N-(4-[2-phenylbut-1-yl]piperidinocarbonyl)-2-(p-chlorophenyl)ethene sulfonamide.

Example XIV

The procedure in Example XI is repeated, except that piperidine is replaced by an equimolar amount of 4-(3-phenylpropyl)-piperidine and the N-(N,N-diphenylcarbamoyl)-1-phenylpropene-2-sulfonamide used is respectively replaced by: N-(N-phenyl-N-[p-chlorophenyl]carbamoyl)-2-phenylethenesulfonamide, N-(N-phenyl-N-[p-chlorophenyl]carbamoyl)-2-(p-methoxyphenyl)ethenesulfonamide, N-( N,N-di[p-methoxyphenyl]carbamoyl)-1-(p-chlorophenyl)propene-2-sulfonamide, N-(N-[n-butyl]-N-[p-tolyl]carbamoyl)- 2-. (o-chlorophenyl)ethenesulfonamide, N-(N-methyl-N-[p-tert-butylphenyl]carbamoyl)-2-(p-tolyl)ethenesulfonamide, N-(N-tn-propyl]-N-[m- isopropoxyphenyl]carbamoyl)-2-(p-fluorophenyl)-ethylenesulfonamide and

N-(N-benzyl-N-phenylcarbamoyl)-1-phenylbut-1-ene-2-sulfonamide.

This gives: N-([4-(3-phenylpropyl)piperidino]carbonyl)-2-phenylethenesulfonamide, N-([ 4-(3-phenylpropyl)piperidino]carbonyl)- 2r-(p-methoxyphenyl)-ethenesulfonamide ,

N-([4^(3-phenylpropyl)piperidino]carbonyl-1-(p-chlorophenyl)propene-2-sulfonamide,

N-([4-(3-phenylpropyl)piperidino]carbonyl)-2-(o-chlorophenyl)ethylene sulfonamide,

N-([4-(3-phenylpropyl)piperidino]carbonyl)-2-(p-tolyl)ethylenesulfonamide, N-([4-(3-phenylpropyl)piperidino]carbonyl)-2-(p-fluorophenyl)ethylene- sulfonamide and

N-([4r-(3-phenylpropyl)piperidino]carbonylr-1-phenylbut-1-ene-2-sulfonamide.

Example XV

N-(N-[1-Methoxycarbonylethyl]carbamoyl-2-phenylethenesulfonamide

To a solution of 3.5 g of DL-alanine methyl ester hydrogen chloride in 20 ml of N,N-dimethylformamide is added 1.05 g of a 56.6% suspension of sodium hydride in mineral oil. The mixture is stirred at ambient temperature for 15 minutes and then 3.8 g of N-(N,N-di-phenylcarbamoyl)-2-phenylethenesulfonamide is added. The entire reaction mixture is then kept at approx. 90°C for 40 minutes. After cooling to room temperature, it is diluted with an excess of ether and then extracted with water. The acidification of the water extract with dilute hydrochloric acid results in a precipitate of impure product, which is then filtered off. The ether phase is washed with dilute hydrochloric acid and a further part of the product is caused to fall out.

It is filtered off and the two portions of the product are combined. This gives 1.55 g which has a melting point of 135-139°C. The impure product is recrystallized from a mixture of acetone and hexane, and 0.70 g of N-[N-(1-methoxycarbonylethyl)carbamoyl]-2-phenylethenesulfonamide is obtained. sm.p. 138-140°C.

Analysis:

Calculated for C13H16N2°5S : C 49'94'H 5'12' N 8.96.

Found (%): C 50.06; H 5.26; N 9.32.

Example XVI

By following the procedure in Example XIV and by replacing DL-alanine methyl ester hydrogen chloride with the appropriate amino ester hydrogen chloride, the following compounds are prepared:

Example XVII

When. the procedure in example XV is repeated and the alkenesulfonamide component respectively is:

1-phenylpropene-2^sulfonamide,

2-phenylpropene-1-sulfonamide,

2-(p-chlorophenyl)ethene sulfonamide,

1,1-diphenylethylene sulfonamide,

2-(p-tolyl)ethene sulfonamide,

1-phenylpropene-2-sulfonamide,

2-phenylpropene-1-sulfonamide, • 2-(m-chlorophenyl)ethylenesulfonamide,

2r-(p-bromophenyl)ethene sulfonamide,

2-(p-fluorophenyl)ethylenesulfonamide, 3-phenylbut-2-ene-2-sulfonamide, 2-phenylbut-l-ene-l-sulfonamide, 2-(p-chlorophenyl)propene-l-sulfonamide, 2-(p -isopropylphenyl)propene-l-sulfonamide, 2-phenylpropene-l-sulfonamide, 2-(o-chlorophenyl)ethenesulfonamide, 1-phenylbut-1-ene-2-sulfonamide, 1,2-diphenylethenesulfonamide, 2-phenylethenesulfonamide,

1r-(m-chlorophenyl)propene-2-sulfonamide, 2-(m-tolyl)ethylenesulfonamide and 2-(p-isopropoxyphenyl)ethylenesulfonamide,

and the amino acid ester hydrogen chloride component is the hydrogen chloride salt of:

glycine methyl ester,

glycine methyl ester,

glycine methyl ester,

glycine methyl ester,

glycine methyl ester,

glycine ethyl ester,

glycine ethyl ester, glycine ethyl ester,

glycine ethyl ester,

glycine ethyl ester,

DL-alanine methyl ester, DL-alanine methyl ester, DL-alanine methyl ester, DL-alanine methyl ester, DL-alanine methyl ester, DL-leucine ethyl ester, DL-leucine ethyl ester, DL-leucine ethyl ester, DL-leucine ethyl ester, ;oj-aminooctanoic acid ethyl ester, (o-aminooctanoic acid ethyl ester, co-aminooctanoic acid ethyl ester and co-aminooctanoic acid ethyl ester, respectively: N-(N-[methoxycarbonylmethyl]carbamoyl)-1-phenylpropene-2-sulfonamide, N-(N-[methoxycarbonylmethyl]carbamoyl)-2-phenylpropene-1-sulfonamide, N- ( N-[methoxycarbonylmethyl]carbamoyl)-2-(p-chlorophenyl)ethylenesulfonamide, N-(N-[methoxycarbonylmethyl]carbamoyl)-1,1-diphenylethylenesulfonamide, N-(N-[methoxycarbonylmethyl]carbamoyl)-2-(p- tolyl)ethylenesulfonamide, N-(N-[ethoxycarbonylmethyl]carbamoyl)-1-phenylpropene-2-sulfonamide, N-(N-[ethoxycarbonylmethyl]carbamoyl)-2-phenylpropene-1-sulfonamide, N-(N- [ethoxycarbonylmethyl]carbamoyl) carbamoyl)-2-(m-chlorophenyl)ethenesulfonamide, N-(N-[ethoxycarbonylmethyl]carbamoyl)-2-(p-bromophenyl)ethenesulfonamide, N-(N-[ethoxycarbonylmethyl]carbamoyl)-1-(m-methoxyphenyl) propene-2-sulfonamide ,

N-(N-[1-methoxycarbonylethyl]carbamoyl)-2-(p-fluorophenyl)ethylenesulfonamide, N-(N-[1-methoxycarbonylethyl]carbamoyl)-3-phenylbut-2-ene-2-sulfonamide,. N-(N-[1-methoxycarbonylethyl]carbamoyl)-2-phenylbut-1-ene-1-sulfonamide, N-(N-[1-methoxycarbonylethyl]carbamoyl)-2-(p-chlorophenyl)propene-1-sulfonamide , N-(N-[1-methoxycarbonylethyl]carbamoyl)-2-(p-isopropylphenyl)propene-1-sulfonamide, N-(N-[1-ethoxycarbonyl-2-methylbut-l-yl]carbamoyl)-2- phenylpropene-1-sulfonamide, N-(N-[1-ethoxycarbonyl-2-methylbut-1-yl]carbamoyl)-2-(o-chlorophenyl)-ethylenesulfonamide, N-(N-[1-ethoxycarbonyl-2-methylbut -1-yl]carbamoyl)-1-phenylbut-1-ene-2-sulfonamide, N-(N-[1-ethoxycarbonyl-2-methylbut-1-yl]carbamoyl)-1,2-diphenylethenesulfonamide, N-( N-[7-ethoxycarbonylhept-1-yl]carbamoyl)-2-phenylethene sulfonamide, N-(N-[7-ethoxycarbonylhept-1-yl]carbamoyl)-1-(m-chlorophenyl)propene-2-sulfonamide, N- (N-[7-ethoxycarbonylhept-1-yl]carbamoyl)-2-(m-tolyl)ethylenesulfonamide and N-(N-[7-ethoxycarbonylhept-l-yl]carbamoyl)-2-(p-isopropoxyphenyl)-ethylenesulfonamide .

The amino acid ester hydrogen chlorides used in this example

are either commercial products or they can be prepared from the corresponding amino acids, (all of which are commercial products) by esterification. The procedures for esterification. of amino acids are indicated in Greenstein and. Winitz in the "Chemistry and the Amino-acids", John Wiley and Sons, Inc., New York-London, 1961, volume 2, pages 925-927.

Example XVIII

When the procedure in Example XIV is repeated and DL-alanine methyl ester hydrogen chloride is replaced by an equimolar amount of N-phenylglycine ethyl ester hydrogen chloride and N-p-chlorophenylglycine ethyl ester hydrogen chloride, one obtains: N-(N-phenyl-N-[ethoxycarbonylmethyl ]carbamoyl)-2-phenylethenesulfonamide and N-(N-[p-chlorophenyl]-N-[ethoxycarbonylmethyl]carbamoyl)-2-phenylethenesulfonamide.

Example XIX

N-(pyrrolidinocarbonyl)-2-phenylethenesulfonamide

A mixture of 3.4 g of N-(N-[m-chlorophenyl]carbamoyl)-2-phenyl-ethenesulfonamide and 2.15 g of pyrrolidine in 100 ml of ethanol is heated under reflux for 20 hours. The solution is cooled and then concentrated in vacuo to approx. 2 5 ml. A small amount of starting material falls out and this is filtered off. 75 ml of ether and 75 ml of water are then added to the ethanol filtrate. The layers are separated and the aqueous layer is acidified with concentrated hydrochloric acid. This causes the raw product to fall out. It is filtered off and dried and the weight is 1.5 g. The ether layer is washed with 50 ml IN hydrochloric acid, followed by 25 ml water. After drying with anhydrous sodium sulfate, the ether is evaporated in vacuo, and another portion of the product (0.70 g) is obtained. The first part of the product is crystallized from acetone, and 0.60 g of pure N-(pyrrolidinocarbonyl)-2-phenylethenesulfonamide is obtained, m.p. 201-204°C.

Analysis:

Calculated for <C>13H16N203S (%>: c 55.71; H 5.75; N 10.00

Found C 55.45; H 5.68; N 9.94.

Example XX

By following the procedure in Example XIX and by replacing pyrrolidine with the appropriate amine, the following compounds are obtained:

When N-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide is reacted with N,N-dipropylamine according to the procedure in Example XIX, the product is N-(N,N-dipropylcarbamoyl)-2-phenylethenesulfonamide,

sm.p. 128-130°C.

Analysis:

Calculated for C15<H2>2<N>2°3<S>(<%>)<:>C 58'05'H 7'15?N 9'03

Found (%) : C 57.77; H 7.09; N 8.96

Starting from N-(N-[m-tolyl]carbamoyl)-2-phenylethenesulfonamide and N,N-dibutylamine and applying the procedure in Example XIX, the product is N-(N,N-dibutylcarbamoyl)-2-phenylethenesulfonamide,

sm.p. 104-105°C.

Analysis:

Calculated for<C>17<H>26N2<0>3<S>(<%>)<:>C 60'34'H 7'74i N 8'28 Found:(%): C 60.23; H 7.58; N 8.50

Example XXI

N-(piperidinocarbonyl)-2-phenylethene sulfonamide

A suspension of 6.5 g of 2-phenylethene sulfonamide in 45 ml of oxalyl chloride is stirred and cooled under reflux for 16 hours.

It is cooled to ambient temperature, then the solid material is filtered off and washed with hexane. After dryness, the material weighs 2.2 g and has a melting point of 170-180°C.

The solid material is added in small portions with stirring at ambient temperature to a solution of 5 ml of piperidine in 15 ml of methylene chloride. The mixture is stirred. for a further 1.5 hours after completion of the addition and then evaporated to dryness in vacuo. The residue is distributed between 40 ml of water and 25 ml of ether, the layers are separated and the second layer is discarded. The aqueous layer is acidified with acetic acid and then extracted with ether. The latter ether extract is washed with water, dried with anhydrous sodium sulfate and finally evaporated to dryness in vacuo.

The remainder amounts to 0.60 g of impure product, m.p. 138-140°C. The impure product is recrystallized from a mixture of methylene chloride and ether, and a purified sample of N-(N-piperidinocarbamoyl)-2-phenyl-ethylenesulfonamide is obtained, m.p. 175-177°C. Analysis: Calculated for C14<H>18<N>2°3<S>c 57.13; H 6.17; N 9.52. Found. (%): C 57.23; H 6.11; N 9.54.

Example XXII

N-([4-carboxypiperidino]carbonyl)-2-phenylethenesulfonamide

A mixture of 5 g of N-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide and 10.3 g of ethyl isone picotate in 20 ml of N,N-dimethylformamide is kept at approx. 90°C for 40 minutes. The mixture is cooled to ambient temperature, diluted with ether and then extracted with water. The water extract is acidified with concentrated hydrochloric acid, and then extracted with methylene chloride. The dried methylene chloride is evaporated to dryness in vacuum and a viscous oil is obtained. The oil is redissolved in a small volume of tetrahydrofuran, absorbed on a column of silica gel and then eluted from the column with an excess of the same solvent. The solvent is evaporated in vacuo and the residue is dissolved in 50 ml of 0.5N sodium hydroxide solution. After 1 hour, it precipitates again by acidification and is recovered by vacuum filtration in the form of white crystals. It is then dissolved in a mixture of 100 ml of acetone and 100 ml of tetrahydrofuran and the solution is slowly concentrated so that a precipitate of the product is obtained. The solid is filtered off, triturated with acetone and pure N-([4-carboxypiperidino]carbonyl)-2-phenylethenesulfonamide is obtained, m.p. 179-181°C.

Analysis:

Calculated for<C>15<H>18<N>2°5<S>(<%>)• c 53.25; H 5.32; N 8.28. Found, (%) : C 52.93} H 5.58; N 8.04.

Example XXIII N-(4-[3-phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide

A solution of 12 g of 4-(3-phenylpropyl)piperidine and 12.5 g of the potassium salt of N-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide (prepared as indicated in Example IC) in 30 ml of N,N- dimethylformamide is heated to 75°C and then 5.7 ml of glacial acetic acid are added dropwise while stirring. The temperature increases to 90°C during the addition. The reaction mixture is kept at 85-87°C for a further 45 minutes

and then allowed to cool to ambient temperature. It is then poured into a mixture of 200 ml of IN sodium hydroxide solution and 100 g of crushed ice. A rubbery precipitate is obtained. 50 ml of ether is added and the mixture is stirred vigorously until a cloudy solution is obtained. 50 ml of hexane is added and this causes the sodium salt of the product to precipitate out. It is filtered off and washed with water followed by ether. The impure sodium salt is redissolved in a mixture of 100 ml of acetone and 50 ml of water and then 5 ml of concentrated hydrochloric acid, followed by 100 ml of water. The formed precipitate is filtered off, washed with aqueous acetone and finally recrystallized from acetone/hexane, and 6.8 g (55%) of pure N-(4-t 3-phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide are obtained,

sm.p. 131-133°C.

Example XXIV

N-( N-[ 1- carboxypropyl- l- yl] carbamoyl)- 2- phenylethene sulfonamide

To 30 ml of 1N sodium hydroxide is added 1.0 g of N-(N-[1-ethoxycarbonylprop-1-yl]carbamoyl)-2-phenylethenesulfonamide.

The mixture is stirred at ambient temperature for 30 minutes, small amounts of insoluble material are then filtered off and discarded. The filtrate is acidified with concentrated hydrochloric acid, which causes the product to precipitate. It is filtered off, washed with water, air-dried, and 6.0 g of N-(N-[1-carboxyprop-1-yl]carbamoyl)-2-phenylethenesulfonamide is obtained, m.p. 150-152°C.

Analysis:

Calculated for C13H16N2C>5S (*') : c 49/98; H 5.16; N 8.97.

Found: (%): C 49.72; H 5.20; N 8.85

Example XXV

Starting from the suitable ester' selected from the esters

in examples II, XII, XV and XVI, and by applying hydrolysis

the method in example XXIV, the following compounds are produced.

Example XXVI

By proceeding from the suitable ester, selected from the esters i

examples III, XII, XVII and XVIII, and by applying the hydrolysis method in example XXIV, the following compounds are obtained: N-(N-[carboxymethyl]carbamoyl)-2-(m-methoxyphenyl)propene-1-sulfonamide, N-(N-[carboxymethyl]carbamoyl)-2-(p-biphenylyl)propene-1-sulfonamide, N-(N,N-di[carboxymethyl]carbamoyl)-2-phenylethenesulfonamide, N-(N-[carboxymethyl ] -N-methyljcarbamoyl)-2-phenylethenesulfonamide N-(N-[carboxymethyl]carbamoyl)-1-phenylpropene-2-sulfonamide, N-(N-[carboxymethyl]carbamoyl).-2-phenylpropene-l-sulfonamide, N- (N-[carboxymethyl]carbamoyl)-2-(p-chlorophenyl)ethylenesulfonamide, N-(N-[carboxymethyl]carbamoyl)-l,l-diphenylethylenesulfonamide, N-(N-[carboxymethyl]carbamoyl)-2-(p -tolyl)ethenesulfonamide, N-(N-[carboxymethyl3 carbamoyl)-2-(m-chlorophenyl)ethenesulfonamide, N-(N-[carboxymethyl]carbamoyl)-2-(p-bromophenyl)ethenesulfonamide, N-(N-[ carboxymethyl]carbamoyl)-1-(m-methoxyphenyl)propene-2-sulfonamide, N-(N-[1-carboxyethyl]carbamoyl)-2-(p-fluorophenyl)ethylenesulfonamide, N-(N-[1-carboxyethyl] carbamoyl)-3-phenylbut-2-ene-2-sulfonamide , N-(N-[1-carboxyethyl]carbamoyl)^2-phenylbut-1-ene-1- sulfonamide, N-(N-[1-carboxyethyl]carbamoyl)-2-(p-chlorophenyl)propene-1- sulfonamide, N-(N-[1-carboxyethyl]carbamoyl)-2-(p-isopropylphenyl)propene-1-sulfonamide, N-(N-[1-carboxy-2-methylbut-l-yi]carbamoyl)-2 -phenylpropene-1-sulfonamide, N-(N-[1-carboxy-2-methylbut-1-yl]carbamoyl)-2-o-chlorophenyl)ethylenesulfonamide,.

N-(N-[1-carboxy-2-methylbut-1-yl]carbamoyl)-1-phenylbut-1-ene-2-sulfonamide,

N-(N-[1-Carboxy-2-methylbut-l-yl]carbamoyl)-1,2-diphenylethenesulfonamide, N-(N-[7-carboxyhept-l-yl]carbamoyl)-2-phenylethenesulfonamide, - N - (N-[7-carboxyhept-1-yl] carbamoyl ).-1-(m-chlorophenyl)propene-2-sulfonamide, N-(N-[7^carboxyhept-1-yl]carbamoyl-2-(m -tolyl)ethene sulfonamide, N-(N-[7-carboxyhept-1-yl]carbamoyl)-2-(p-isopropoxyphenyl)ethene sulfonamide, N-(N-phenyl-N-[carboxymethyl]carbamoyl)-2- phenylethene sulfonamide and N-(N-[p-chlorophenyl]-N-[carboxymethyl]carbamoyl)-2-phenylethene sulfonamide.

Example XXVII N-(N-[1-carboxyhept-1-yl]carbamoyl)-2-phenylethenesulfonamide

To 40 ml of N,N-dimethylformamide is added 10.05 g of ethyl 2-amiho-octanoate hydrogen chloride, followed by 2.1 g of a 56.6% dispersion of sodium hydride in mineral oil. The mixture is stirred at ambient temperature for 15 minutes and then 7.6 g of N-(N,N-diphenylcarbamoyl)-2-phenylethenesulfonamide are added. The reaction mixture is then heated at approx. 100°C for 1 hour. After cooling to ambient temperature, the mixture is diluted with an excess of ether and then extracted with water. The water extract is acidified with concentrated hydrochloric acid and an oil is separated. The overlying aqueous layer is decanted off and replaced with 50 ml of ether and 50 ml of fresh water. The ether layer is removed, dried with anhydrous sodium sulfate and then evaporated in vacuo. The rest is an oil that cannot be transferred in solid form. The oil is dissolved in acetone and 50 ml of IN sodium hydroxide is added. A heterogeneous mixture is obtained which is stirred at ambient temperature overnight. The mixture is then extracted with ether and the extract is discarded. The remaining aqueous phase is acidified with concentrated hydrochloric acid and the oil that precipitates is extracted with ether. _The ether solution is dried (Na2S04), treated with color-removing charcoal and then evaporated in a vacuum. An oil is obtained which crystallizes slowly on standing. The solid obtained by trituration with benzene is filtered off, dried and 3.0 g of N-(N-[1-carboxyhept-1-yl]carbamoyl)-2-phenylethenesulfonamide is obtained, m.p. 142-144°C.

Analysis:

Calculated for C17H24N2°5S (%): C 55'41'H 6/57; N 7.60

Found (%): C 55.86; H 6.70; N 7.37

Example XXVIII

N-( 4-[ 3-( p- hydroxyphenyl) propyl-3-piperidinocarbonyl)- 2- phenylethenesulfonamide

To a solution of 1.37 g of N-(4-[3-(p-methoxyphenyl)propyl]-piperidinocarbonyl)-2-phenylethenesulfonamide in 30 ml of methylene chloride is added 175 µl of glacial acetic acid. The mixture is cooled to -60°C and then 850 µl of boron tribromide is slowly added. The react ion mixture is then allowed to warm to ambient temperature. After

■ for a further 3 hours, it is washed with ice-cold water and then extracted with IN sodium hydroxide. The sodium hydroxide extract is washed with ether and then acidified with concentrated hydrochloric acid. A gum falls out. The overlying aqueous layer is poured off and the gum is dissolved in methylene chloride. The solvent is dried using anhydrous sodium sulphate. is evaporated in vacuum, and 0.50 g of impure product is obtained. The product is purified by dissolving it in a

small volume of acetone and reprecipitation by addition of hexane.

Finally, 0.142 g of pure N-(4-[3-(p-hydroxyphenyl)propyl]-piperidinocarbonyl)^2-phenylethenesulfonamide is obtained, m.p. 132-5°C.

Analysis:

Calculated for C23<H>28<N>2°4<S>(<%>)<:>C 64.47; H 6.59; N 6.54.

Found (%): C 64.08; H 6.97; N 6.40.

Example XXIX

Reaction of the appropriate N-([(methoxyphenyl)alkyl]piperidinocarbonyl)alkenesulfonamide with boron tribromide according to the procedure in Example XXVIII gives the following compounds: N-(4-[3-(m-hydroxyphenyl)propyl]piperidinocarbonyl)-2-phenylethenesulfonamide , N-(4-[3-(o-hydroxyphenyl)propyl]piperidinocarbonyl)-2-phenylethylenesulfonamide, N-(4-[2-(p-hydroxyphenyl)ethyl]piperidinocarbonyl-2-(p-chlorophenyl)-ethylenesulfonamide,

N-(4-[4-(m-hydroxyphenyl)butyl]piperidinocarbonyl)-1-(p-tolyl)-propene-2-sulfonamide and

N-(4-[5-(m-Hydroxyphenyl)pentyl]piperidinocarbonyl)-2-(p-bromophenyl)-ethylenesulfonamide.

Example XXX

N-(4-[3-phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide

A stirred mixture of 1.83 g of 2-phenylethene sulfonamide, 1.3 ml of oxalyl chloride and 15 ml of tetrahydrofuran is heated in an oil bath at 75-80°C for 1.5 hours under an atmosphere of nitrogen. To the solution obtained, 30 ml of xylene is added and the internal temperature is raised to 138°C within 20 minutes, while allowing tetrahydrofuran and excess oxalyl chloride to distill from the solution. During this period, two further portions and 5 ml of xylene are added. The resulting solution is kept at approx. 138°C for a further 15 minutes and then cooled to 85°C. To this xylene solution of 2-phenylethenesulfonyl isocyanate, 4.06 g of 4-(3-phenylpropyl)piperidine are added in small portions over the course of 1 minute. The reaction mixture is stirred at ambient temperature for 1.5 hours and then washed sequentially with 75 ml of 1N hydrochloric acid and two portions of 25 ml of water. To the dried and filtered xylene solution is then added 20 ml of acetone, followed by the dropwise addition of 120 ml of hexane. The precipitate that forms is removed by filtration, and 2.89 g (70% yield) of the impure product is obtained. After recrystallization from acetone/hexane, 1.07 g of the final product with melting point 125-127°C is obtained.

Example XXXI

Reaction of the appropriate alkenesulfonamide with oxalyl chloride according to the method, in example XXX gives respectively the following isocyanates: 2-(o-fluorophenyl)ethenesulfonyl isocyanate,

2-(p-chlorophenyl)ethenesulfonyl isocyanate,

2-(p-bromophenyl)ethenesulfonyl isocyanate,

2t-(m-tolyl)propene-1-sulfonyl isocyanate,

1-(p-methoxyphenyl)butene-2-sulfonyl isocyanate and

2-(p-trifluoromethylphenyl)ethenesulfonyl isocyanate.

Reaction of one of the isocyanates above with the necessary

amine, also according to the procedure in example XXX, gives respectively the following compounds: N-(4-[3-phenylpropyl]piperidinocarbonyl)-2-(2-fluorophenyl)ethenesulfonamide, N-(4-[3-(p-tolyl) propyl]piperidinocarbonyl).-2-(p-chlorophenyl)-ethylenesulfonamide,

N-(4-[5-(m-Methoxyphenyl)pentyl]piperidinocarbonyl)-2-(p-bromophenyl)-ethylenesulfonamide, N-(2-methylpiperidinocarbonyl)r-2-(m-tolyl)propene-1-sulfonamide, N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-1-(p-methoxyphenyl)butene-2-sulfonamide and

N-(N,N-dibutylcarbamoyl)-2-(p-trifluoromethylphenyl)ethylene sulfonamide.

Example XXXII

N- ( 4- [ 3- f enylpropyl 3 piperidinocarbonyl) - 2-^- f phenylethene sulfonamide A stirred mixture of 1.83 g (0.01 mol) 2-phenylethene sulfonamide, 3.45 g (0.025 mol) potassium carbonate and 4, 0 g (0.015 mol) of 4-(3-phenylpropyl)piperidinocarbonyl chloride, in 75 ml of chloroform is heated under reflux for 22 hours. The solvent is then removed by evaporation in vacuo and 75 ml of 0.5N sodium hydroxide and 35 ml of ether are added to the residue. The mixture is stirred for 1 hour and the solid material that remains undissolved is removed by filtration. This gives 1.84 g (approx. 41% yield) of the final product, as a mixture of sodium

and the potassium salts.

A 0.5 g portion of the unpurified product above is dissolved in

6 ml of acetone and 3 ml of water. The pH of the mixture is lowered to 2.0 and undissolved solids are removed by filtration. It is then recrystallized from acetone/hexane, and 0.28 g of the final product is obtained,

sm.D. 127.5-129°C.

Example XXXIII

N-(4-[3-phenylpropyl-3-piperidinocarbonyl)-2-phenylethenesulfonamide

A solution of 1>77 g (7.5 mmol) N-(N-propylcarbamoyl)-2-phenylethene sulfonamide,. 3.0 g (15 mmol) of 4-(3-phenylpropyl)piperidine and 0.86 ml (15 mmol) of acetic acid in 10 ml of N,N-dimethylformamide are heated at 100-105°C for 4 hours. The reaction solution is then cooled to 25°C and 50 ml of 1N hydrochloric acid is added, followed by 50 ml of ether. The layers. separated and into the ether phase. 50 ml IN sodium hydroxide is added. This causes the oil to appear as an intermediate phase. The three layers are separated and the aqueous phase is discarded. The ether phase is washed with water and then evaporated in vacuo, and obtain 2.3 g of a viscous liquid. The intermediate oil phase is dissolved in 25 ml of water, which is then acidified with concentrated hydrochloric acid. The acidified aqueous phase is extracted with ethyl acetate and the extracts are washed with water and then evaporated in vacuo.

This gives 0.5 g of a gummy residue.

2.3 g of the oil and 0.5 g of the gummy residue are combined and chromatographed on a column of silica gel. The first fractions are combined and evaporated in a vacuum, and 0.3 g of an oil is obtained. The latter oil is dissolved in 5 ml of acetone and 5 ml of 1N sodium hydroxide, followed by 10 ml of water. This causes the impure product to fall out as the sodium salt. The sodium salt is dissolved in 3 ml of acetone and 5 drops of concentrated hydrochloric acid are added, followed by 10 ml of water. This solution is extracted with ethyl acetate. The dried extract is evaporated in vacuo and the residue recrystallized from acetone-hexane, and 12 mg of the final product is obtained, m.p. 119-122°C. After two further recrystallizations from acetone-hexane, the product has a melting point of 127.5-129.5°C.

Example XXXIV

A dry, solid is produced. pharmaceutical preparation by mixing the following materials, in the indicated amounts by weight:

After the dried preparation is well mixed, tablets are pressed from the mixture, each. tablet is of such a size that it contains 100 mg of the active ingredient.

Tablets are also prepared which respectively contain 10, 25, 50 and 200 mg of active ingredient by choosing the appropriate amounts of N-(1,2,3,4-tetrahydroisoquinolinocarbonyl)-2-phenylethenesulfonamide. excipient mixture in each case.

Example XXXV

A dry, solid pharmaceutical preparation is prepared by mixing the following materials in the indicated amounts by weight:

The dry mixture is mixed well so that a completely uniform mixture is obtained. Soft, elastic and hard gelatin capsules containing this preparation are then produced by using sufficient materials so that in each case capsules with 250 mg of active ingredient are obtained.

Capsules are also produced which respectively contain

50, 100 and 500 mg of active ingredient by varying the amounts of sulfonamide and excipient mixture.

Example XXXVI

To a stirred solution of 4.12 g of N-(4-[3-phenylpropyl]-piperidinocarbonyl)-2-phenylethenesulfonamide in 100 ml of n-butanol is added, a solution prepared by dissolving 390 mg of potassium in 10 ml of n- butanol. • The mixture is stirred for a further 15 minutes and then the solvent is removed by evaporation in vacuo.

250 ml of diethyl ether is added to the residue and the mixture is stirred in

15 minutes. The solid is then filtered off, dried in vacuo, and the potassium salt of N-(4-[3-phenylpropyl]piperidinocarbonyl)-2-phenylethenesulfonamide is obtained.

Example XXXVII

Normal male Sprague-Dawley (Charles River) rats are fasted for 9 hours. The experimental groups, each consisting of 5 animals, are then fed overnight (15-16 hours) with ground "Purina rat chow" containing 0.2% of the test compound. The following morning, the food to which the drug has been added is removed, and after 1 hour each rat is fed orally with food containing 50 mg/kg of the test compound. After another 2 hours, each rat is administered a dose of 300 mg/kg Triton WR-1339 (oxyethylated tertiary octylphenol-formaldehyde polymer, Ruger Chemical Co., Philadelphia, Pa.) in saline by tail vein injection. After a further 2 hours, each rat is again fed orally with food containing 50 mg/kg of the test compound. After a further 4 hours, blood is taken from each rat from the abdominal aorta under pentobarbital anesthesia. The control rats are treated in the same way, except that they only receive "rat chow" and that the two additions of food do not contain the test compound. The control rats receive the same dose of Triton as the experimental animals.

Plasma is obtained from the heparinized blood samples and the plasma cholesterol concentrations are measured using an Auto-Analyser (Technicon method N-24a). The effect of the test compound is determined by comparing the plasma cholesterol levels of rats treated with the test compound and the control rats. The results are shown below in tabular form. The stated results are obtained by subtracting the plasma cholesterol concentration in treated rats from the control plasma cholesterol level and the difference is given as a percentage of the control value.

Example XXXVIII

A normal, adult "beagle" dog, weighing approx. 10 kg,

available daily at 12.oo a few days with "Purina dog chow". For the following two days, blood is taken every morning from the jugular vein and the plasma cholesterol concentration is measured according to the method adapted for use in the Technicon Auto-Analyser. The average of these values forms the baseline for the dog's plasma cholesterol level. The dog is then dosed. orally, twice daily, with the test compound. while continuing to walk the dog once a day at 12.oo with "Purina dog chow". On the morning of the 6th day after the administration of the test compound is started,

blood is drawn from the jugular vein, and the plasma cholesterol level is again measured using the Technicon Auto-Analyser. The level obtained is compared with the baseline value to determine the hypolipidemic properties of the test compound. The results appear from it. following.

The following productions illustrate the production of the starting materials.

Preparation A

1- phenylpropene- 2- sulfonamide.

To 17.5 ml of N,N-dimethylformamide, which has been cooled to 15°C, 15.5 ml of sulfuryl chloride are added dropwise with stirring over the course of 30 minutes. The temperature is kept below 25°C during the addition. The mixture is stirred for a further 30 minutes at 25°C, and then 11.3 g of 1-phenylpropene are added. The reaction mixture is heated at 90-93°C for 75 minutes. It is then poured onto 400 g of crushed ice and the product is extracted in methylene chloride. The solvent is dried using anhydrous sodium sulfate, then evaporated

in vacuum, and 18.7 g of 1-phenylpropene-2-sulfonyl chloride are obtained as a liquid.

1-phenylpropene-2-sulfonyl chloride is added to 200 ml of concentrated ammonium hydroxide. After 1 hour, the crystalline precipitate is filtered and washed successively with water and hexane. The crude product obtained is distributed between 150 ml of 1N sodium hydroxide and 50 ml of ether and two clear phases are obtained. The ether phase is removed and washed with 50 ml of water, and then the washing water is added. the original aqueous phase. The combined solution is acidified with concentrated hydrochloric acid, which causes the product to precipitate. It is filtered off and after drying, 10.9 g of 1-phenylpropene-2-sulfonamide are obtained, m.p. 138-139.5°C.

Production B

By following the procedure in Preparation A, 2-phenylpropene is reacted with sulfuryl chloride in N,N-dimethylformamide and 2-phenylpropene-1-sulfonyl chloride is obtained, which is then treated with ammonia, and gives 2-phenylpropene-1-sulfonamide, m.p. 101-102.5°C.

When 1,1-diphenylethene is reacted with sulfuryl chloride in N,N-dimethylformamide, followed by treatment with ammonia, following the procedure in preparation A, 2,2-diphenylethenesulfonamide is obtained, m.p. 134-135°C.

Analysis:

Calculated for C14H13N02S (%): C 64.86; H 5.05; N 5.40.

Found (%): C 64.73; H 5.02; N 5.26.

Manufacturing C

The procedure in preparation A is repeated, except that 1-phenylpropene is replaced by an equimolar amount of the appropriate phenylethene, phenylpropene, phenylbutene or diphenylethene derivative, and the following sulfonamides are obtained: 2-phenylbut-1-ene-1-sulfonamide,

2-(p-chlorophenyl)propene-1-sulfonamide,

. 2-(p-Methoxyphenyl)propene-1-sulfonamide, 1-(m-chlorophenyl)propene-2-sulfonamide, 2-(p-chlorophenyl)but-1-ene-1-sulfonamide, 1,2-diphenylethylenesulfonamide, 3 - phenylbut-2-ene-2-sulfonamide, 1-(p-chlorophenyl)propene-2-sulfonamide, 1,2-diphenylpropene-1-sulfonamide, 2-(p-tolyl)propene-1-sulfonamide, 2-( p-isopropylphenyl)propene-l-sulfonamide, 1-(p-ethoxyphenyl)propene-2-sulfonamide, 2-(p-fluorophenyl)propene-l-sulfonamide, 2-(p-butoxyphenyl)propene-l-sulfonamide, 1 - phenylbut-1-ene-2-sulfonamide, 3-(m-chlorophenyl)but-2-ene-2-sulfonamide, -2-(p-chlorophenyl)-2-phenylethenesulfonamide, 2r-(p-n-butyl phenyl)propene -1- sulfonamide, 2-(m-methoxyphenyl)propene-l-sulfonamide, 2-(p-biphenylyl)propene-l-sulfonamide, 2,2-diphenylethene sulfonamide,

2-(m-chlorophenyl)propene-l-sulfonamide, 2t-.(m-bromophenyl)propene-l-sulfonamide, 2-(m-tolyl)propene-l-sulfonamide,

1-(o-chlorophenyl)propene-2-sulfonamide, 1-(p-fluorophenyl)propene-2-sulfonamide, 1-(p-tolyl)propene-2-sulfonamide,

1-(m-Methoxyphenyl)propene-2-sulfonamide, 2-(p-tolyl)but-l-ene-l-sulfonamide, 2-(m-methoxyphenyl)but-l-ene-l-sulfonamide, 1-( p-chlorophenyl)but-1-ene-2-sulfonamide, 1-(m-methoxyphenyl)but-1-ene-2-sulfonamide and 3-(p-chlorophenyl)but-2-ene-2-sulfonamide.

Manufacturing D

N,N-diphenylcarbamoyl chloride is reacted with N-(endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)amine essentially as indicated by McManus et al., J. Med. Chem., 8, 766 (1965), for the preparation of 1,1-diphenyl-3-cycloheptylurea. The product is 1,1-diphenyl-3-(endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)urea, m.p. 109-111°C. Analysis:

Calculated for C20H22N2°2 (%): C 74'49'H 6'89?N 8.68.

Found (%): C 74.28; H 6.93; N 8.61.

In a similar way, N,N-diphenylcarbamoyl chloride and N-(exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)amine are reacted, and 1,1-diphenyl-3-(exo-7-oxabicyclo[2.2 .1]heptan-2-ylmethyl)urea,

sm.p. 128-130°C.

Analysis:

Calculated for C20H22N2°2 (<%>)<:>C 74'49'H 6'89; N 8.68.

Found (%): C 74.70; H 6.75; N 8.87.

Manufacturing E

Endo- and exo- isomers of N-(7-oxabicyclo[2.2.1]heptan-2-ylmethyl)amir

To a stirred solution of 212 g acrylonitrile, 272 g furan

and 50 mg of hydroquinone in 1 liter of benzene is added to a solution of 55 ml of titanium tetrachloride in 500 ml of benzene. The addition is carried out at such a rate that the internal reaction temperature does not exceed 35°C. The reaction mixture is then stirred at ambient temperature for 5 days. It is then treated with 500 ml of 0.5N hydrochloric acid. After filtration, the aqueous phase is removed and extracted with benzene; The two benzene solutions are combined, washed with water, dried with anhydrous sodium sulfate and evaporated in vacuo. This gives 156.3 g of a mixture of endo- and exo-7-oxabicyclo[2.2.1]hept-2-en-5-yl cyanide.

130 g of the mixture of isomers above is dissolved in 1 liter of acetone and hydrogenated at 3.5 kg/cm 2 in the presence of 2 g of palladium-on-barium sulfate. The catalyst is removed by filtration and the solvent is evaporated under reduced pressure. The remaining oil is subjected to fractional distillation, and 55.5 g of pure endo-7-oxabicyclo[2.2.1]heptan-2-ylcyanide are obtained, b.p. 45°C (0.1 mm Hg)

and 37.9 g of pure exo-7-oxabicyclo[2.2.1]heptan-2-ylcyanide,

k.p. 48°C (0.02 mm Hg). A small fraction weighs 14.7 g and consists of an endo-exo mixture.

Analysis:

Calculated for C_HQN0 (%): C 68.27; H 7.37; N 11.37.

Found for endo isomer %: C 67.96; H 7.21; N 11.37.

Found for % exo isomer: C 68.32; H 7.42; N 11.64.

To a stirred solution of 54.3 g of endo-7-oxabicyclo[2.2.1]-heptan-2-ylcyanide in 500 ml of methanol is added 24 ml of a suspension of Raney nickel in methanol, followed by the dropwise addition of a solution of 33, 2 g sodium borohydride in 11 ml 4N sodium hydroxide. In the last addition step, external cooling is used to keep the internal temperature at 40-50°C. At the end of the addition, the mixture is stirred for a further 20 minutes and the solid is filtered off. The filtrate is evaporated in vacuo and the residue obtained is suspended in 500 ml of 1N sodium hydroxide. . The mixture is extracted a number of times with chloroform, the combined extracts are dried and evaporated, and 55.5 g of N-(endo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)amine are obtained, b.p. 90°C (10 mm Hg).

A sample of exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl cyanide is reduced by treatment with Raney nickel and sodium borohydride in methanol as described for the endo isomer. A high yield of N-(exo-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)amine is obtained, b.p. 92-96°C (14^16 mm Hg).

Production F

4-(3-[p-Methoxyphenyl]propyl)pyridine

To a stirred solution of 3.04 g of 2-(p-methoxyphenyl)ethanol

in 10 ml of benzene, a solution of 0.72 ml of phosphorus tribromide in 10 ml of benzene is added dropwise at ambient temperature. The mixture is then heated at 60°C for 1 hour. After cooling to ambient temperature, the reaction mixture is poured onto 50 g of crushed ice. A small amount of ether is added, the organic phase is then separated, washed one after the other with. 0.5N sodium hydroxide and water and evaporated to dryness. 2.8 g of 2-(p-methoxyphenyl)-ethyl bromide is obtained as an oil.

The above oil is dissolved in 15 ml of ether, which is then added dropwise to 2 43 mg of magnesium shavings covered with 10 ml of ether.

A few crystals of iodine are added and the solvent is refluxed until almost all the magnesium has been converted. An ether solution of 2-(p-methoxyphenyl)ethylmagnesium bromide is obtained.

The Grignard solution stated above. is added dropwise at 0°C to a stirred solution of 1.04 g of 4-cyanopyridine in 15 ml of ether. After the addition, the reaction mixture is refluxed for 4 hours and then stirred at ambient temperature overnight. The reaction is stopped with ice water and the aqueous phase is acidified with concentrated hydrochloric acid. The aqueous phase is then separated and heated at 85-90°C for 1 hour.. It is cooled to ambient temperature, extracted with chloroform, followed by ether. The combined organic extracts are dried with anhydrous magnesium sulfate, then evaporated in vacuo and the product is obtained as an orange colored oil. The product is 2-(p-methoxyphenyl)ethyl-4-pyridyl ketone.

The above-mentioned ketone (800 mg) is heated under reflux for 2 hours with 850 mg of hydrazine hydrate. At this point, 1.6 g of powdered potassium hydroxide is added and reflux is continued for a further 2 hours. The reaction mixture is then cooled to ambient temperature, diluted with 20 ml of water and extracted with ether. The dried ether extract is evaporated to dryness, and 260 mg of 4-(3-[p-methoxyphenyl]propyl)pyridine is obtained.

Production G

Starting from the appropriate cyanopyridine and (hydroxy-alkyl)benzene compound and following the procedure in preparation F, the following compounds are obtained:

3-(3-phenylpropyl)pyridine,

2-(3-phenylpropyl)pyridine,

4-(2-[p-isopropoxyphenyl]ethyl)pyridine,

3-(3-[p-butoxyphenyl]propyl)pyridine,

4-(3-[p-isopropylphenyl]propyl)pyridine,

4-(3-[p-tert-butylphenyl]propyl)pyridine,

4-(m-methylbenzyl)pyridine,

4-(3-[m-methoxyphenyl]propyl)pyridine,

4-(3-[o-methoxyphenyl]propyl)pyridine,

4-(2-[p-methoxyphenyl]ethyl)pyridine,

4-(4-[m-methoxyphenyl]butyl)pyridine,

4-(3-[p-tolyl]propyl)pyridine,

4-(5-[m-methoxyphenyl]pentyl)pyridine,

4-(4-phenylbutyl)pyridine,

4-(5-phenylpentyl)pyridine,

4-(2-phenylprop-l-yl)pyridine and

4-(2-phenylbut-1-yl)pyridine.

Production H

. 4-(3-[p-Methoxyphenyl]propyl)piperidine

A solution of 2.27 g of 4-(3-[p-methoxyphenyl]propyl)piperidine in 50 ml of 1.0N hydrochloric acid is hydrogenated at 3.2 kg/cm 2 at ambient temperature in the presence of 150 mg of platinum oxide. After 20 hours, the theoretical amount of hydrogen has been absorbed and the catalyst is filtered off. The aqueous filtrate is made alkaline with 5N sodium hydroxide and then extracted with ether. The extract is dried and evaporated in a vacuum and 2.2 g of an oil are obtained. The oil solidifies slowly and 4-(3-[p-methoxyphenyl]propyl)piperidine is obtained, m.p. 65-70°C.

Production I

The hydrogenation of the pyridine derivatives indicated in preparation G, according to the procedure in preparation H, gives them. the following piperidine compounds:

3-(3-phenylpropyl)piperidine,

2-(3-phenylpropyl)piperidine,

4-(2-[p-isopropoxyphenyl]ethyl)piperidine

3-(3-[p-butoxyphenyl]propyl)piperidine,

4-(3-[p-isopropylphenyl]propyl)piperidine,

4-(3-[p-tert-butylphenyl]propyl)piperidine,

4-(m-methylbenzyl)piperidine

4-(3-[m-methoxyphenyl]propyl)piperidine,

4-(3-[o-methoxyphenyl]propyl)piperidine,

4-(2-[p-methoxyphenyl]ethyl)piperidine,

4-(4-[m-methoxyphenyl]butyl)piperidine,

4-(3-[p-tolyl]propyl)piperidine,

4-(5-[m-methoxyphenyl]pentyl)piperidine,

4-(4-phenylbutyl)piperidine,

4-(5-phenylpentyl)piperidine,

4-(2-phenylprop-1-yl)piperidine and

4-(2-phenylbut-1-yl)piperidine.

Production J

4-(3-phenylpropyl)piperidinocarbonyl chloride.

Phosgene is led down into 150 ml of dry toluene at 0°C until 17 g of gas has been absorbed. The cooling bath is removed and a solution prepared from 27.6 g of 4-('3-phenylpropyl) piperidine and 12.3 ml of pyridine and 100 ml of toluene is added dropwise to the phosgene solution with stirring over the course of 1 hour. After the addition, the reaction mixture is stored at ambient temperature for 16 hours. At this point, the reaction mixture is filtered and the filtrate is evaporated in vacuo, and 39 g of the final product are obtained in an impure state. The product is contaminated with toluene, but is sufficiently pure for coupling with alkenesulfonamides.

Claims (13)

1.'Procedure for the preparation of an N-carbamoyl-2- phenylethene sulfonamide with the formula where L is equal to Z or X is selected from the group consisting of hydrogen, chlorine and methyl; A and B are both selected from the group consisting of hydrogen, methyl and ethyl; Z is selected from the group consisting of pyrrolidino, morpholino, thiomorpholino, 1,2,5,6-tetrahydropyridino, 1,2,3,4-tetrahydro-isoquinolino, azacycloheptan-1-yl, azacyclooctan-1-yl, 3- aza-bicyclo[3.2.2]nonan-3-yl, piperidino, 4-hydroxypiperidino, 4-methoxypiperidino, 4-carboxypiperidino, 4-phenylpiperidino, alkylpiperidino containing from 1 to 3 carbon atoms in the alkyl group, (phenylalkyl)piperidino containing from 1 to 5 carbons atoms in the alkyl group and ([substituted phenyl]alkyl)piperidino containing from 1 to 5 carbon atoms in the alkyl group, the substituted phenyl group being substituted with a group selected from the group consisting of hydroxy, alkyl containing from 1 to 4 carbon atoms and alkoxy containing from 1 to 4 carbon atoms; 12 and R and R are both selected from the group consisting of hydrogen, alkyl containing from 1 to 10 carbon atoms, alkenyl containing from 3 to 6 carbon atoms, cycloalkyl containing from 3 to 7 carbon atoms, phenylalkyl containing from 1 to 2 carbon atoms in the alkyl group, carboxyalkyl which contains from 1 to 7 carbon atoms in the alkyl group, alkoxycarbonylalkyl which contains from 1 to 2 carbon atoms in the alkoxy group and which contains keeps from. 1 to 7 carbon atoms in the alkyl group, bicyclo[2.2.1]hept-2-en-5-ylmethyl, 7-oxabicyclo[2.2.1]heptan-2-ylmethyl, bicyclo[2.2.1]- heptan-2-ylmethyl, phenyl and phenyl substituted with a group selected from the group consisting of fluorine, chlorine, bromine, nitro, alkyl containing from 1 to 4 carbon atoms and alkoxy containing from 1 to 4 carbon atoms; 1 2 provided that R . and R are not both simultaneously hydrogen; under the assumption that when L is equal and A and B 1 2 and one of the substituents R or R is hydrogen, then the other is 12 of the substituents R and R different from hydrogen, alkyl, alkenyl, cycloalkyl, phenyl or substituted phenyl, characterized by an alkenesulfonamide with the formula wherein X, A and B are as defined above, or a reactive derivative thereof, is reacted with a compound containing a carbamoyl group capable of providing a grouping if necessary by hydrolysis of R 1 or R 2 such as alkoxycarbonylalkyl to carboxyalkyl or demethylation of ([methoxyphenyl]alkyl)piperidino groups such as Z to. ([hydroxyphenyl]alkyl)-piperidino. 2. Method as stated in claim 1, characterized in that a compound of formula is reacted at 25°C-120°C in the presence of a base with an isocyanate of the formula R<1>N = C 0 where X, A, B and R"'' are as stated in claim 1. 3. Procedure as stated in claim 1, characterized in that a compound of formula is reacted with a carbamoyl halide of formula 12 in the presence of a base, where X, A, B, Z, R and R are as stated in claim 1 and Hal is chlorine or bromine. 4. Method as stated in claim 1, characterized in that a compound of formula is reacted in the presence of<*>a base with a urea derivative of the formula 1 '3 where X, A, B and R are as stated in claim 1 and R is alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 7 carbon atoms, aryl, substituted aryl, heteroaryl or substituted heteroaryl, and R 4 is hydrogen, cycloalkyl of 3 to 8 carbon atoms, benzyl, phenylethyl or R 3 , each substituted group containing up to 3 of the groups Cl, Br, -NG^/alkyl containing 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms.; 5. Procedure as stated in claim 1, characterized in that a reactive derivative of the sulfonamide with the formula is reacted with an amine of the formula HZ or NHR 1 R 2, where X, A, B, Z, 12 R and R are as stated in claim 1.; 6. Procedure as stated in claim 1, characterized in that a reactive derivative of the sulfonamide with the formula is reacted with an amine with the formula HZ or HNR"<*>"R<2>12 3 where X, A, B, R , R and Z are as stated in claim 1 and R is alkyl with 1 to 6 carbon atoms, alkenyl with 3 to 7 carbon atoms, aryl, substituted aryl, heteroaryl or substituted heteroaryl and R 4 is hydrogen, cycloalkyl of 3 to 8 carbon atoms, benzyl, phenylethyl or R 3, each substituted group containing up to 3 of the group Cl, Br, -NG>2, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms. 7. Procedure as stated in claim 1, characterized in that A and B are both hydrogen and L is Z which is 4-(co-phenylalkyl)piperidino containing 1 to 5 carbon atoms in the alkyl group, or 4-(u-[substituted phenyl3alkyl)-piperidino containing 1 to 5 carbon atoms in the alkyl group, the substituted phenyl group being substituted with hydroxy, alkyl containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms. 8. Procedure as stated in claim 1, characterized in that the product X is hydrogen. 9. Procedure as specified in claim 1, characterized in that L is Z which is 4-(3-phenylpropyl)piperidino. 10. Procedure as stated in claim 1, characterized in that A and B are both hydrogen and L is Z which is 1,2,3,4-tetrahydroisoquinoline. A and B are both hydrogen,, and X is hydrogen. 12. Procedure as stated in claim 11, characterized in that R 1 is hydrogen and R 2 is n-butyl or carboxymethyl. 13. Procedure as stated in claim 1, characterized in that Z is 4-(phenylalkyl)piperidino containing 1 to 5 carbon atoms or is different from ([substituted phenyl]alkyl)piperidino.