DE2456947A1 - NEW ALKENSULPHONAMIDES, THEIR PRODUCTION AND THE MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Description

The present invention is concerned with compounds that reduce increased serum lipid content in mammals. Atherosclerosis, a form of arteriosclerosis, is increasingly recognized as a major health problem » The disease is characterized by the deposition of lipids in the aorta and in the coronary arteries and. the cerebral as well as peripheral arteries of the lower. Extremities. As the deposit increases, there is a risk of

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Thrombus formation and occlusion. While the origin of the Atherosclerosis is not fully understood, yet it has been observed that numerous patients suffer from the disease have increased lipid protein concentrations in the plasma, with cholesterol and iriglycerides being the main components. The lipoprotein content in the plasma can be reduced by means of suitable nutrition, but various types of food also become earthed therapeutic agents such as estrogens, thyroxine analogs and sitosterol supplements used for this purpose. Recently, ethyl 2- (p-chlorophenoxy) isobutyrate (Clofibrate) to be effective. Triglyceride reducing agent found in humans.

The present invention relates to certain novel chemical compounds which help reduce serum lipid levels Mammals are useful. These new chemical compounds are derivatives of N-carbamoyl-2-phenylethensulfonamide, which is also known as styrenesulfonylurea »

The arene sulfonamides, which are monosubstituted on the nitrogen atom by a Carbamoyl group are substituted (arene sulfo = nylureas), are a known class of compounds, and some representatives are known to have hypoglycemic properties. For example, N- (N-n ~ propylcarbamoyl) -pchlorobenzenesulfonamide (Chlorpropamlde) and N- (N-n-rButylcar = bamoyi) -p-toluenesulfonamide (tolbutamide) as oral antidiabetic agents in clinical use. Few, from literature known works, however, deal with sulfonylureas ^ in which the nitrogen atom of the urea radical 2 removed from the sulfonyl group is different from hydrogen Carries substituents.

Substituted by a carbamoyl group on the nitrogen atom

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2-Phenyläthensulfonarnide (styrenesulfonylureas) are from Little known in the chemical or patent literature, although US Pat. No. 2,979,437 from 1961 already has one Range of aealkene sulfonylureas, mixed with hypogly-k & mix Has described properties.

The aim of the invention is to provide compounds and medicaments for reducing increased lipid content in the Mammalian plasma. To do this, "one administered a hyperlipidemic Mammal an effective amount of a 2-Pb.enyl =

ethensulfonamide derivative of iOrmeln:

ι 0

.C = C-SO ₉ -NH-CZ

(D

C = C-SO ₂ -NH-C-NR ¹ R ² ι j

AWAY

(ID

1 2

wherein X, A, B, Z ,, R and R have the meanings given below or a pharmaceutically active salt thereof.

The invention also relates to a method for producing the new sulfonamides, in which one is an alkene sulfonamide of the Formula:. .

C-SO-NH,

II ²²

AWAY

III

wherein X, A and B have the meaning given below, with an Oarbamoylgruppe providing reagent, wel-

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—A—

ches is capable of forming a group -CL, in which L is Z or -N ^ "2, reacts and optionally hydrolyzes R or R in the form of alkoxycarbonylalkyl radicals to carboxyalkyl radicals or demethylates the (/ methoxyphenyly'alkyl) piperidino radical Z to (/ hydroxyphenyl7alkyl) piperidino radical *

In the above formulas, 1 denotes hydrogen, fluorine, chlorine, bromine, the trifluoromethyl radical, an alkyl radical having 1 to 4 carbon atoms or an alkoxy radical having 1 to 4 carbon atoms. A and B are each hydrogen, the methyl, ethyl or phenyl radical. Z denotes the pyrrolidino-, morpholino-, thiomorpholino-, 1,2,5 »6-tetrahydropyridino-, 1,2,3,4-tetrahydroisoquinolino ~, azacycloheptan-1-yl-, azaeyclooctan-1-yl-, 3- Azabicyclo / 5.2e_27nonan-3-yl--, Piperi = dino-, 4-Hydroxypiperidino-, 4-Methoxypiperidino-, 4-Garboxy = piperidino-, 4-Phenylpiperidino- or an alkylpiperidino = radical with 1 to 3 carbon atoms in the alkyl radical, a (phenylalkyl) -piperidino radical with 1 to 5 carbon atoms in the alkyl portion or a (/substituiert7Ph.enyl7alkyl )pipe=ridino radical with 1 to 5 carbon atoms in the alkyl portion, where the phenyl radical is represented by hydroxyl, alkyl with 1 to 4 carbon atoms or alkoxy with 1 to 4 Carbon atoms sub-

1 2

is established. R and R each represent hydrogen, an alkyl radical having 1 to 10 carbon atoms, and an alkenyl radical 3 to 6 carbon atoms, cycloalkyl radical with 3 to 7 carbon atoms, phenylalkyl radical with 1 to 2 carbon atoms in Alkyl moiety, carboxyalkyl moiety with 1 to 7 carbon atoms in the alkyl moiety, alkoxycarbonylalkyl moiety with 1 to 2 carbon atoms in the alkoxy portion and 1 to 7 carbon atoms in the alkyl portion, the bicyclo / 2.2.j [7hept-2-en-5-ylmethyl-, 7-0xabicyclo / 2 * .2..l7b-eptan-2-ylmethyl- or bicyclo / 2 ".2.j7heptan ~ 2-ylmethyl radical, the phenyl or one by fluorine, chlorine, bromine, the nitro group, an alkyl radical with 1 to 4 carbon atoms

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men or alkoxy radical; with 1 to 4 carbon atoms substituted phenyl, with the]
de consist of hydrogen.

1 2

th phenyl radical, with the proviso that R and E do not

The preferred hypolipidemic agents according to the present invention are the compounds of the formula I and II, wherein X is hydrogen, chlorine or the methyl radical, A and B are hydrogen, the methyl or ethyl radical
have the above meaning.

12th

represent the methyl or ethyl radical and Z, R and R represent the

Particularly preferred hypolipidemic agents according to the present invention are compounds of the formula I, wherein X is hydrogen, Chlorine or the methyl radical, A and B "hydrogen and Z a 4- (vö-phenylalkyl) -piperidino radical with 1 to 5 carbon atoms in the alkyl moiety or a 4 - (^ - / substituted phenyl7alkyl) piperidino radical with 1 to 5 carbon atoms in the alkyl moiety, the substituted phenyl radical being substituted by the hydroxyl group, an alkyl radical having 1 to 4 carbon atoms or alkoxy radical is substituted with 1 to 4 carbon atoms, represent »Under u-phenylalkyl- and υ- / substituted Phenyl.7alkyl radicals are straight-chain alkyl radicals with a Phenyl or substituted phenyl radical on the terminal carbon atom understood, for example the 2-phenylethyl, 3-phenylpropyl and 5-phenylpentyl radical. X is preferably hydrogen. Particularly valuable compounds of the formula I are those in which X, A and B are hydrogen and Z is the 4- (<5c-phenylalkyl) piperidino radical.

Other particularly preferred hypolipidemic agents of the formula I are those in which X = hydrogen, chlorine or the methyl radical, A and B = hydrogen and Z = 1,2,3,4-Tetrahy represent droisochinolinorest.

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Particularly preferred hypolipidemic agents of Formula II

1 2

are those in which X, A, B and H are hydrogen and R is an alkyl radical, in particular the n-butyl radical, or a carboxy = alkyl radical, in particular the arboxymethyl radical.

Further particularly preferred hypolipidemic agents of the formula II are those in which X, A and B are hydrogen and R and R are an alkyl radical, in particular the n-butyl radical.

Individual connections of particular interest are:

N- £ N-n-butylcarbamoyl) ~ 2-phenylethensulfonamide, N- (N- / C * arboxymet hyl / carbamoyl) -2-phenylät hensulfonamid,

N- (4- / 3-Phenylpropyl7piperidinocarbonyl) -2-phenyläthensulfona ^ ■

N- (1,2,3,4-i'etra hydroisoquinolino carbonyl) -2-phenylethensul-

ifonamido

Many of the hypolipidemic agents of the invention are new and represent an important embodiment of the invention. In particular, all compounds of the formula I are new die Compounds of the formula II are also new, provided

1 2
that if one of the radicals R or R is hydrogen, an alkyl, alkenyl, cycloalkyl, phenyl or substituted phenyl radical

1 ρ

is of the type indicated, the other radical R or R is hydrogen or an alkyl radical of the type mentioned is different.

The compounds of formulas I and II are made from an alkene sulfonamide of the formula III, in which X, A and B are as defined above, according to one of several possible Methods synthesized. Five methods, referred to below as A, B, C, D., and E, are now detailed explained.

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¹¹ do

AWAY

Method A consists in reacting a compound of the formula III with an organic isocyanate of the formula R-N = G = O in the presence of a base. The reaction is usually carried out by putting the reagents in a suitable Solvent at a temperature of usually from about 25 to about 120 ° C, and preferably from about 60 to about 80 ° C brings into contact with each other. Suitable solvents are those that dissolve at least one of the reactants, and do not react in an unfavorable way with the other or the product. Examples of such solvents are Ethers such as diethyl ether, tetrahydrofuran ,. 1,2-dimethoxyethane, the chlorinated hydrocarbons such as chloroform, Methylene chloride and. 1_, 2-dichloroethane, the lower aliphatic Ketones such as acetone, methyl ethyl ketone and methyl iso = butyl ketone, esters such as ethyl acetate and butyl acetate, tertiary Amines such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and IT-methylpyrrolidone. Numerous both organic and inorganic Bases can be used because apparently the main * Function of the basic agent in the formation of salts with the sulfonamide consists. Useful bases include tertiary amines such as triethylamine, tributylamine, Ν, Ν-dimethylaniline, pyridine, Quinoline, N-methylmorpholine and 1,5-diazabicyclo ^? O3o07-non-5-en, Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium methylate, potassium methylate and sodium ethylate, metal hydrides such as sodium hyaride and calcium hydride, metal carbonates such as sodium carbonate

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and potassium carbonate and alkali metals such as sodium and potassium. In most cases a molar equivalent of base is used, based on the sulfonamide, but smaller or larger amounts can also be used with success. Although the Reaction is usually favored by a one to two-fold excess of isocyanate, this is not a critical factor, and occasionally equimolar amounts are used, especially in those cases in which the removal of the excess isocyanate from the product is awkward. In fact, you can also use an excess of sulfonamide work, and in this case remains after implementation some sulfonamide back. If you work at about 80 C, then used reaction times of a few, for example 2 hours, are usually used. A particularly cheap way to isolate the product consists in adding the reaction mixture to excess dilute aqueous acid. That falls here ■ Product off, it is filtered off directly. In the other case one extracts into an organic one that is immiscible with water Solvent, which is then separated from the aqueous phase and evaporated, leaving the crude product behind. In In many cases the crude product is essentially pure, but if necessary it can be further purified by known methods will.

As the expert will recognize, you can first use a salt of the Form the starting sulfonamide, which is then treated with the isocyanate in the next stage. In this case, meet the conditions discussed above for the second stage of this two-stage process.

The isocyanates used as the starting material in Method A are either commercially available or they can be readily obtained are produced by reacting the corresponding amine

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with phosgene according to the method of Shriner, Hörne and Cox, Organic Synthesis, Anthology II, 453 (1943) «

Method B consists in implementing a compound of the Formula III with a garbamoyl chloride of the formula Z-C (= O) - Cl or R R N-C (= O) -C1 in the presence of a base. With a typical The procedure is about 1 mole equivalent of the carbamoyl chloride to a solution or suspension of the sulfonamide of the formula III in a suitable solvent in the presence added to the base. The same solvents are suitable and bases mentioned in connection with Method A, and usually about 1 mole equivalent of base is used. However, larger amounts of base can be used if excess base does not adversely affect the reactants or products. Indeed, one usually cooperates an excess if the base is not soluble in the reaction medium. Reaction temperature and reaction time vary in Dependence on various factors "such as reactivity and concentration of the reagents and their solubility in the selected solvent system. Usually the implementation will, however in the temperature range from about 40 to 120 ° G and preferably from about 50 to about 80 ° G. With the latter Temperatures are typically used with reaction times of a few, for example 4 hours. The product can then be isolated as described in connection with Method A. will.

A variant of method B, which comes close to the Schotten-Baumann process and is very useful in special cases, consists in adding the garbamoyl chloride to a solution of the sulfonamide in water at around room temperature, the pH being during and maintained in the range of about 7 »0 to about 12.0 after the addition. After implementation _>

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-1U-

which typically takes about an hour, the reaction mixture acidified. If the product precipitates, it is filtered off. Otherwise it will turn into something immiscible with V / ater extracted organic solvent, which is then separated from the aqueous phase and evaporated, the Crude product remained

The carbamodichlorides used in Method B are either commercially available or they can easily be prepared by reacting the corresponding amine with phosgene, wherein one is those of Peterson in Houben-Weyl's "Methods of Organic Chemie, "8, 115-118 (1962) uses methods described.

When carrying out method C, a sulfonamide of the formula III is ^{reacted with a urea derivative of the formula R 1} NH-CO-NR ⁵ R ⁴ "in the presence of a base, where in the last-mentioned formula R ^ is an alkyl radical with 1 to 6 carbon atoms, alkenyl radical with 3 to 7 carbon atoms, an aryl or substituted aryl radical, heteroaryl or substituted heteroaryl radical and R is hydrogen, an Oycloalkylrest with 3 to 8 carbon atoms, the benzyl or phenethyl radical or

represent a radical R, each substituted radical being represented by up to 3 substituents in the form of chlorine, fluorine, bromine, the nitro group, alkyl radicals with 1 to 4 carbon atoms or Alkoxy radicals with 1 to 4 carbon atoms can be substituted. Typical examples of aryl radicals are phenyl and Naphthyl radical, typical examples of heteroaryl radicals of the pyridyl, thiazolyl, oxazolyl and quinolyl radical. One special appropriate configuration of the urea content is occurs when R and R each denote phenyl. The reaction is carried out by taking sulfonamide and urea brings into contact with each other, whereby the same solvents, reaction parameters, bases and reaction ratios,

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mentioned in connection with method A. It is assumed that, under the influence of the base, the urea of the formula R ¹ NE-GO-NR ⁵ R ⁴ reacted as an isocyanate donor. However, this is a theoretical consideration which is in no way intended to restrict the course of the reaction. ·

The substituted ureas of the formula R NH-CO-NR ⁵ R ⁴ 'are obtained from the corresponding amine R NH ₉ and carbamoyl chloride of the formula Cl-CQ-ITR R by the method of McManus et al., Journal of Medicinal Chemistry, &, (1965) 766 or "variants thereof produced" The carbamoyl chlorides. of the formula Cl-CO-NR ⁵ R ⁴ are made from the amines of the formula HNR ^ R ⁴ and. Phosgene as described in connection with method B is formed.

Method D consists in converting a sulfonyl isocyanate of the formula IV, in which X, A and B have the above meaning

sit, with the corresponding amine of the formula HZ or HNR R The reaction is usually carried out by using the isoeyanate and amine in an inert organic solvent in contact at or near room temperature brings about until essentially complete implementation has taken place has ο Usually reaction times of a few, for example about 1 to about 12 hours, are used. To carry out This procedure uses the same solvents as described in Method A and the product will also isolated as described in connection with method A The ratio of isocyanate to amine is not critical, and when using an excess of one or other component the product is formed; usually one works with a small excess of amine, for Example with a simple excess.

The sulfonyl isocyanates used as starting material are

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produced from the corresponding sulfonamide of the formula III by reaction with an excess of oxalylchloride and subsequent pyrolysis of the oxamic acid chloride. Such implementations are known, see zwr. Example Franz and Osuch, Journal of Organic Chemistry, £ 9, 2592 (1964). It is often advisable to continue using sulfonyl isocyanate in the solvent in which it was prepared without isolation. In addition, the Oxamidsäure- chloride can be treated v / ground optionally directly with the amine, thereby attaining to the compounds of Jj ¹ Ormel I or II.

, V-C = C

(IV) j

Method E consists in converting an amine of the formula

12th

HZ or HNR R with a compound of the formula V in which Z, R, R, R and R are as defined above. Usually, the two reactants are heated together in an inert organic solvent, which is generally a polar organic solvent which dissolves the reactants.

ϊ /

C = C-SO ₀ -NH-C-ST

(V)

Suitable solvents are, for example, lower alkenols such as methanol, ethanol and n-butanol, glycols such as ethylene

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glycol and propylene glycol, ethers such as dioxane and 1,2-dimeth = oxymethane, acetonitrile and tertiary amides such as N, N-dimethyl = formamide, Ν, Ν-dimethylacetamide and N-methylpyrrolidone. temperature and reaction time for complete implementation are interdependent. .At lower temperatures longer reaction times are required, while the reaction time is shorter at higher temperatures. In addition, the ' The rate of reaction depends on the nucleophilic character of the amine used and the effect of the leaving group. Response times of a few are usually found in each pail Hours and the reaction is normally carried out at from about 50 to about 150.degree. C., and preferably in the range of about 80 to 100 ° C. At about 100 ° G, a reaction time of about 5 hours is usual. If desired, one can use the parent compound Use V in the form of a salt, for example an alkali metal salt such as the potassium salt. Furthermore can the compound of formula V "in the form of a salt in the Introduce the reaction medium, which is then neutralized with an alkanecarboxylic acid such as acetic acid. Become common In this method, the starting materials are combined in equimolar amounts, but the ratio is the reactant is not critical and both components can be used successfully in excess. The product can be isolated by distilling off the solvent in vacuo and then the residue between dilute aqueous acid and a water-immiscible organic solvent. When the organic evaporates Solvent is then obtained the crude product, which can optionally be further purified by known methods can.

In certain cases, method E is used in the absence of a For this purpose, the sulfonamide is carried out using solvents Formula V and the amine are simply heated together until the

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Conversion to the product is essentially complete. As already indicated, the reaction times are a few hours, for example about 5 hours, and the reaction usually takes place at a temperature of about 50 to about 150 ° G and preferably in the range of about 80 to about 100 ° C. This process variant is recommended when the compound of formula V and the amine are liquid at the reaction temperature Phase present «.

Although the mechanism on which method E is based is not is known, it is believed that there is some sulfonyl isocyanate which formed formula IV in situ in this reaction

Preferred substituents H are alkyl radicals with 1 to 6 carbon atoms, the phenyl radical and up to 2 of the substituents fluorine, chlorine, bromine, nitro, alkyl with 1 to 4 carbon atoms and phenyl radicals substituted by alkoxy with 1 to 4 carbon atoms. Preferred substituents R are hydrogen or R. Particularly preferred starting materials of the formula V are those in which R and R each have the Means phenyl radical.

The compounds of the formula IV are prepared by reacting the corresponding sulfonamide of formula III with a garbamoyl chloride of the formula Cl-OO-NR R, using of the procedure discussed in method B.

As will be readily apparent to those skilled in the art, not all methods A, B, C and D are equally applicable to the synthesis of all compounds of formulas I and II can be used »For example, methods A and G are only suitable for the production of compounds of formula II, in which either R or R is hydrogen. In individual cases, the person skilled in the art would select the synthesis

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Choose the method that is most suitable, taking into account factors such as the ease of the chemical Reactions, the accessibility of the starting materials and their reactivity, the stability of the reagents and products and the size of the reaction batch.

Another process- especially used for the production of Compounds of the formula II -suitable in which either

12th
R or R denotes a carboxyalkyl radical, consists in the hydrolysis of the corresponding compound of the formula II

/ ". 1 2
which R or R is an alkoxycarbonylalkyl radical ο This hydrolysis is usually carried out under basic conditions. In many cases it is sufficient to simply dissolve the ester in dilute sodium hydroxide solution, let the solution stand for a few hours at room temperature and. then to acidify. Either the product then precipitates in such a form that it can be filtered off, or it is extracted with a water-immiscible solvent such as ethyl acetate. The solvent is then dried and evaporated to give the crude product. In order to promote the solution, numerous water-miscible cosolvents such as lower alkanols, for example methanol and ethanol or acetone, can be added. Various other known bases are also suitable for carrying out the alkaline hydrolysis, for example potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate and potassium carbonate. The basic agent is usually present in an amount of at least 1 molar equivalent based on the ester used, but larger amounts of up to about 20 molar equivalents can also be used. Although the reaction is usually carried out at room temperature, temperatures in the range from about ½ to about 100 ° C. can also be used. The timing of the reaction depends on the temperature,

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because the reaction proceeds faster with increasing keäktion temperature. If the reaction is carried out at temperatures of about 25 to 50 ⁾ C, reaction times of several hours are usually used, for example overnight «

A further synthesis is used to prepare the compounds of Formula I, in which Z denotes the (/ hydroxyphenyl7alkyl) piperidino radical, applied «This method consists of demethylation a corresponding compound '= of the formula I, in which Z denotes the (/ methoxyphenyl7alkyl) piperidino radical. Demethylation takes place according to methods known per se which do not adversely affect the molecule. A particularly suitable one The reagent for this reaction is boron tribromide, its Use of Fieser and Fieser in "Reagents for Organic Synthesis," John Wiley & Sons, Inc., New York, 1967, p. 66 is discussed.

As already mentioned, the starting materials of methods A, B, C, D and E are sulfonamides of formula III. These sulfonamides can be prepared from the ethene derivatives of formula VI by one of two methods. The first method includes the following Stages:

VI

AWAY

C ■ C-SO-Na I · I ³ Λ Β

- V

s C-SO ₀ -NH ₀

IJ ²²

AWAY

III

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Output _n ngsmaterialien and iteaktionsbedingungen correspond, with small modifications the of Borwell et al (Journal of .the American Chemical Society, 63, (1946) 139) "for those described .Fälle in which A, - B and X vi / on Hydrogen The implementation of this reaction step sequence is also described in US Pat. No. 2,979,457. The second process for converting the ethene derivatives of the formula VI into the corresponding sulfonamides of the formula III consists in treating the ethene derivative with sulfturyl chloride in N, N-dimethyl = formamide , with subsequent reaction with ammonia, using the conditions of Culbertson and Dietz (Journal of the Chemical Society (London), Part C, (1968) 992) with minor modifications.

The athenene derivatives of the formula VI are either commercially available or can be prepared by one of two general methods known per se. The first method consists in a Wittig reaction between an carbonyl compound of the formula VII and the ylide of a phosphonium salt of the formula (/ G ₆ E ^ J PGH ₂ B) ⁺ X ", where Y is chloride or bromide (see Maercker in" Organic Reactions, "14» 270 (1965) and Deno et al., In Journal of the American Chemical Society, 87, (1965) 2157)

AWAY

VII

VI

The second method consists in reacting a carbonyl compound of the formula VII with a Grignard reagent of the formula BCH ₂ MgY, in which Ϊ denotes chloride or bromide with

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subsequent acid-catalyzed hydration of the resulting Garbinols as prescribed by Emerson, Chemical Reviews, 45, (1949) 347)

^ T ^- C = O + CH ₂ MgY ν

AWAY

AWAY

VII

VI

The person skilled in the art makes the choice between these two methods due to the availability of the starting materials, the feasibility on the intended scale and the reactivity the respondent.

The carbonyl compounds of the formula VII are either commercially available or can be prepared by processes known from the literature getting produced. The phosphonium salts of the formula (/ CgHj ^ PCHijB) ^ * "are expediently made from triphenylphosphine and the corresponding alkali halide according to the instructions of Maercker, loc. cit. S 388-393 formed. All eligible Alkyl halides are commercially available.

Numerous alkene sulfonamides of formula II are not only available as hypolipidemic agents useful but also as intermediates for the manufacture of hypolipidemic agents. So are

1 2

Compounds of the formula II in which either R or R denotes Phenyl radical or one by fluorine, chlorine, bromine, nitro, alkyl with 1 to 4 carbon atoms or alkoxy with 1 to 4 carbon atoms Substituted phenyl radical, useful as starting materials in method E. Furthermore, connec-

1 2 '

fertilize the formula II, wherein one of the radicals R or R a Alkoxycarbonylalkyl radical is useful as starting materials

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for the preparation of the corresponding compounds of the formula II,

1 ?
where R or R is a carboxyalkyl radical «

The Hypolipidemic Properties of the Present Compounds can be demonstrated by two methods. In the first method, which is essentially that of Newmann et al (Lipids, 8, (1973) 378) is the method used, it shows Ability of the compounds to inhibit Triton-induced Hyperlipidemia in rats. Male Sprague-Dawley rats. 300 mg / kg Triton WR-1339 are injected, with the animals had been treated orally with the 'fixed connection. After another oral administration of the test compound, the animals become bleeding via the abdominal aorta under anesthesia with pentobarbital and the plasma is extracted from the heparinized blood won. The cholesterol concentration in the plasma is with an auto-analyzer (Technicon method N-24a) and the value is compared with the value that was used for comparison animals after treatment with Triton, but without test compound, results. The level of cholesterol in plasma is at the animals treated with the test compound were noticeably lower than in the untreated animals.

In the second method of measuring hypolipidemic properties the test compound is administered orally to normal adult beagle dogs twice a day for 6 days. During the test period, the animals are fed once a day at noon. On the morning of the 6th day, the Dogs are exsanguinated via the thrombus and the cholesterol content of the plasma is determined in the Technicon Auto-Analyzer. The value obtained in this way is compared with the basic value that was determined at the start of the test. At the end of the test is the cholesterol level is much lower than at the beginning of the test.

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A characteristic property of the compounds according to the invention is their ability to form salts. Due to their acidic nature, the sulfonylureas can form salts with basic substances, and all salts represent a further embodiment of the invention _o The salts can be easily and conveniently prepared, for example by simply adding acidic and basic components, usually in a molar ratio of 1: 1 , in aqueous, non-aqueous or partially aqueous medium, as required, brings into contact with one another. The salts are either filtered off or precipitated with a non-solvent solvent, or isolated by evaporation of the solvent or, in the case of aqueous solutions, obtained by lyophilization.

Basic agents suitable for salt formation can be organic or inorganic in nature * These 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 hydrides and alkaline earth metal alkoxides. Specific Examples of such bases are the 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, Ν, Ν-dimethylaniline, N-ethylpiperidine, N-methylmorpholine and 1,5-diazobicyclo / 4 »3o07non ~ 5-en, hydroxides such as sodium hydroxide, alkoxides such as sodium ethylate and Potassium ethylate, hydrides such as calcium hydride and sodium hydride, Carbonates such as potassium carbonate and sodium carbonate and bicarbonates such as J-sodium bicarbonate and potassium bicarbonate.

The "compounds of the formula II in which one of the radicals R or

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R is a arboxyalkyl radical, carboxylate salts can also be used form. These salts, which can be prepared in the same way and with the same basic agents, represent Another embodiment of the invention. Has a If the formula II joins two acidic groups, so can both the mono-like the disalts are produced. In the case of disalts, the two cations can be the same or different.

The pharmaceutically acceptable salts are preferred for therapeutic use; for numerous other purposes, η however, different salts can also be produced therefrom. These purposes include the isolation and purification of certain Compounds and the implementation of pharmaceutically acceptable salts with their .non-salt-like counterparts.

Due to the hypolipidemic properties "are those according to the invention Alkene sulfonamides particularly suitable and valuable for combating hyperlipidemia in mammals, in particular in humans. For therapeutic use, the compound can be used alone or, preferably, in admixture with pharmaceutical approved carriers or diluents will. The carriers or diluents are chosen according to the route of administration, solubility and Stability of the active ingredient chosen. The hypolipidemic alkene sulfonamides according to the invention can be administered orally in the form of tablets, capsules, troches, powders, syrups, elixirs, aqueous solutions and suspensions and such as can be given. The quantity ratio of active ingredient to the carrier depends of course on the chemical nature, the solubility and stability of the active ingredient and the intended dosage. ' In the range of tablets for oral Use is usually used as a carrier lactose and corn starch and lubricants, for example · Sterotex K. Zur oral administration in capsules are suitable as a dilution

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medium lactose and dry corn starch. With use of aqueous suspensions for oral Ver'abrei ^c Wlf "d of the active ingredient with an emulsifier and üuspendiermitteln combined. If necessary, can be added sweeteners and / or flavoring agents. For parenteral administration, which includes intramuscular, intraperiotoneale, subcutaneous and intravenous administration, is prepared usually sterile solutions of the active ingredient, the pH of the solution having to be adjusted and buffered accordingly.For intravenous use, the total concentration of the solute should be adjusted so that the preparation is isotonic.

Will the hypolipidemic compounds of the invention to combat, the hi (eats for the cure or prophylaxis of the Hyperlipidemia used in humans, the daily dose is usually prescribed by the doctor. These doses vary depending on the age, weight and reaction of the patient as well as the Severity of his symptoms. In most cases, however, the daily dose will range from about 0.5 to about 3.0 grams be. This amount can be ■ Ί all at once or in portions administered. Occasionally it may also be necessary to use dosages outside these limits.

example 1 N- (N ~ butylcarbomoyl) -1-phenylpropene-2-sulfonamide

To a mixture of 80 ml of triethylamine and 50 ml of N, N-dimethylformamide 39 »5 g of 1-phenylpropene-2-sulfonamide and then 3 ~ 2.5 ml of n-butyl isocyanate added. The mixture is under Stirring heated to 85 to 90 ° C for 75 minutes, then to room temperature cooled and, while stirring, in 1 liter of 20% acetic acid poured. After stirring for 1/2 hour, the precipitate formed is filtered off and then poured into 300 ml of hot acetone solved. The solution is filtered and the piltrate becomes

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slowly cooled. The crude product which separates out is filtered off, washed with aqueous acetone and left to dry. The mother liquors are diluted with water, a second product fraction precipitating which is filtered off. The two fractions are combined and recrystallized from ethanol to give 28 g of N- (N-butylcarbamoyl) -1-phenylpropene-2-sulfonamide, mp 135-136 ° C is obtained.

Analy se: Ber ,. for G ₁ .H ₂₀ IT ₂ O ₅ S: G: 56.74; H: 6.30; N: 9.45 Found 1o _o: C: 56.64; H: 6.78; N: 9.27 f *.

Example 2 -

According to the procedure of Example 1 by reacting 1-phenylpropene-2-sulfonamide, 2-phenylpropene-1-sulfonamide or 2,2-diphenylethene sulfonamide with the corresponding Isoeyan & t the compounds of the following formula are obtained:

■: r

= C-SP ₂ -NH ~ CZ AB

509824/1018

Analyst '

F .. ( ⁰ C.)

(Z)

CJ CO CO

■ Q OO

! Waterst,
j water st.

.'What 3 first,
ft'ethyl

Hethyl
ff ethyl
Ethyl
Water st.
Via ssLiyss t.
Afc thy Ϊ

-Hethyl

Wa ase; rs t. Ae thyl

J ^ e thyl 'water t.

Wa s & erj5 1 ..Wa sse,] ea t.

Whats rs t. Water t.
Water !. methyl
7 / asse rfft. We thyl
Wasserqt. "Fcfethyl. '

What sers t. What s-era-t.
Wa s se rs t.Was se rat.1

phenyl
phenyl

Wassejegt.
-Wa & sLergt.

N-3Lsopropylamino 191-192

N-propylamino '190-192

K-heptadecylaniino * 118.5-122

) l-propylamino 176-178

N-Cyclohexylamino * '155-158

N- ^ yclohexylamino '142-146

N-Isopropylamino 163-165

N- (ni-tolyl) amino '137-139

K-propylaraino. 103-105

N- (A thoxycarbonyl-

"methyl) amino. 172-174

N- (IrAdamanty1) amino 186-187.5

ii- (tert-t-butyl) amino. . 181-182

N- (1-adamantyl) amino 168-170

K-Cftthoxycarbonyl-

jaethyl) amino 181-182

N- (1-fttethoxycarbonyl-

": -pheny lit thyl) amino 168-170

N- (H ^ jethoxycarbonyl-

3-me thy lbut-1-yl) amino '156-158

K -isopropylamino. 209-210

N-propylamino. _ 184-186

55.31 6.4.3

55.31
68.26
55.31
59160
59.60
55.31
61.81
56J73

50.00
63.32
74

l ¹⁵

51.23
51 _? 88

54.23
62.78
62.78

9.82
43
88
6188
6.43
5.49
60

5.16
6.71

⁶ I ⁸⁰
7OO

5.56
5.99

• «

6.26
5.85
5 _; 85

9.92
9I92
5.69
9.92
8 69

8 69

9 92
8.48
9.45

8.97
7.7.7

9.45
7 _; * 48

8.59

7.91
8.'14
8 J14

55.48 55.61 68.18 55.22 59.91 59.52 55.23 61 94 56 ^ 3

50.12 63.29 56.48 64 ^ 23

51 j 61

7.56. 51.76

54.12 62 44 62.56

6.39 6.51 10.12 6.40 7

7 6

5 6.98

5.13 6.81

6 6.86

5.59 5.90

6.25 5 5.89

9.65 10.19 5.66 9 8.62 8'79 9.81 8

Example III

If you use 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, m-nitrophenyl isocyanate, p-tolyl isocyanate, p-ethylphenyl iso = cyanate, p-chlorophenyl isocyanate, o-chlorophenyl isocyanate, p ~ Heth = oxyphenyl isocyanate, m-ethoxyphenyl isocyanate, p-butoxyphenyliso = cyanate, m-methoxyphenyl isocyanate, benzyl isocyanate, 1-phenyl = ethyl isocyanate, 2-phenylethyl isocyanate, ethoxycarbonylmethyl = isocyanate or lethoxycarbonylmethyl isocyanate according to the specification of Example 1 with 2-phenylbut-1-en-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-en-1-sulfonamide, 1,2-Diphenyläthensul = phonamide, 3-phenylbut-2-ene-2-sulfonamide, i- (p-chlorophenyl) -propene-2-sulfonamide, 1-phenylpropene-2-sulfonamide, 1,2-diphe = nylpropene-1-sulfonamide, 1- (p-chlorophenyl) propene-2-sulfonamide, 2- (p-tolyl) propene-1-sulfonamide, 2- (p-isopropylphenyl) propene-1-sulfonamide, 1 ~ (p-ethoxyphenyl) propene-2-sulfonamide, 2-phenyl = propene-1-sulfonamide, 2- (p-fluorophenyl) propene-1-sulfonamide, 2,2-diphenylethensulfonamide, 2- (p-butoxyphenyl) prop'en-1-sul = phonamide, 2- (p ^ tolyl) propene-1-sulfonamide, 1-phenylbut ~ 1-en-2-sulfonamide, 3- (m-chlorophenyl) but-2-en-2-sulfonamiä, 2- (p-chlorophenyl) -2-phenylethensulfonamide, 2- (p-Chlorophenyl) propene-1-sulfonamide, 2- (p-n-Butylphenyl) propene-1-sulfonamide, 2-Phe = nylpropene-1-sulfonamide, 1-phenylpropene-2-sulfonamide, 2- (m ~ Methoxyphenyl) propene-1-sulfonamide or 2- (p-biphenyl) propene-1r ' sulfonamide, the following compounds are obtained:

509824/1018

^: 2Λ56,947

N- (N-Hethylaarbamoyl) ~ 2-phenylbut: -l ~ en <-l-sulfonamide;.,
. N- (N ~ y | thylcarbamoyl) -2- (p-chloro: phenyl) propene'-1-sulfonate nitride-, N- (N-3sobutylcarbamoyl) -2- (p-methoxyphenyl) propene; -l-sulfonamide ( -en ^: -l-sulfonamide v, N- (N-0ecylcarbamoyl) -l _l 2-diphenylether ^ sulfonamide->, ·

JN-N-Allylcarbatnoyl) -2-phenylbut-2-ene-2-sulfonamidi »,

.N- (N- [3,3- ^ imethylbut-2-yl3carbamoyl) -l- (p-chloro-phenyl) propene.? -2-sulfone-. amide ^, ·. ·

N- (N- £ yclopropylcarbatnoyl) -l-phenylpropene-T-2-sulfoiiamide-! _I.

!! - (N-cyclopentylcarbamoyl) -1,2-diphenylpropent; '- l ~ sulfonamid ^, N- (N-iyclohexylcarbanioyl) ~ 1 (p-chloro-phenyl) propenc.-2-sulf onaiaid ?,

• N- (N- £ yclopheptylcarbamoyl) -2- (p-tolyl) propeni \ -l-sulfonamide i.,

• N- (K-phenylcarbamoyl} -2 - '(p-isopropylphenyl) propene.: - l-sulfonaraid': »,

N- (N-p-fluoro-: phenylcarbatnoyl) -1- (Tj »- & tho>: yphenyl) propenfc-2-sulfonaraidti ,,

• N- (N-ra-ßromcpheny.lcarbamoyl) -2-pheny.lpropen'2-l-sulfonamIdo,
N .- (N.-J2, -Nitrophenylcarbamoy 1) -2- (p-fluoro-; phenyl) propen \ -l-sulfonamide f.

. '. N- (Nj- £ - ^: r.olylcarbamoyl) -2 _t 2-diphenylethene> sulfonamide ..,
jW- (Nj-: P.-ethylphenylcarbaraoyl) - 2- (p-butoxyphenyl) propene. ^ - l '^> sulfonamld ~ _t N- (Np-chloro-phenylcarbamoyl) -2- (p-tolyl) propene-1 -sulf onamid ^,

• N- (li-p- ^: chlorophenylcarbamoyl) -l-phenylbut-l-ene ⁱ : -2-sulfonamide> ₉ '

. N- (N-p-Wethoxyphenylcarbamoyl) -3- (m-chloriphenyl) but - 2 - ene-2 - sulfonamidfi !, Nj- (N-m- ^ thoxyphenylcarbamoyl) -2- (p-chlorophenyl) -2 ~ -phenylathenc: suli onamid.- :, N- (N-p-ßutoxyphenylcarbamoyl) -2- (p-chloro ^. Phenyl) propenti-l ~ sulfonamldvi, N- (N-m-ftethoxyphenylcarbamoyl) -2- (p-n-butylphenyl) propene '.- l ~ sulfonamide -, N- (iM5enzylcarbamoyl) -2-phenylpropene ^ -l-sulfonamide m,

N- (N- [1-bhenylethyl] carbamoyl) -2-phenylpropcni -l-sulfonamide-λ,

· »- N- (N-t2-P) hcnylethyl] carbamoyl) -l-phenylpropenü ⁱ -2-sulfonamide; -,

~ 509824/1018 _ORJfmiÄ1

ORIGINAL INSPECTED

N- (N- / Athoxycarbonylinethyl7carbanoyl) -2 - (m-ineth.oxypheny _r l) -propene-1-sulfonamide and

N- (N- / methoxycarbonylmethyl7carbamoyl) -2- (p ~ biphenylyl) -propene-1-sulfonaniido

Example IV N- (N _y N-Diphenylcarbamoyl) -2-phenylethensulfonamide

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 ΪΓ, Ν-diphenyl = carbamoyl chloride. admitted «. The reaction mixture is refluxed for 5 1/2 hours while stirring. Insoluble parts are filtered hot from the acetone, then the piltrate is concentrated to dryness in vacuo «The residue is in Suspended 300 ml of ether and filtered off. This gives 43 g of the potassium salt of the product.

The potassium salt is dissolved in a mixture of 200 ml of acetone and 50 ml of water, the solution is acidified with concentrated hydrochloric acid, then another 50 ml of water are added. The pesticide which separates out is filtered off and washed successively with acetone / water (1: 1) and then with water. This gives 33 g ($ 87) of N- (N, N-diphenylcarbamoyl) · 2-phenylethensulfonamide from 1 * 185 - 188 ° C. The melting point is increased to 189 to 191 ° G by recrystallization »

Analysis; Ber. for C ₂₁ H ₁₈ N ₂ O ₅ S: C: 66.66; H: 4.8Q;

N: Τ »40? Δ Gefc: C: 66.46; H: '4.82; N: 7 * 17 f ° o

Example V

If the procedure of Example IV is repeated, but "replacing the !!, N-Diphenylcarbamoylchlcrids with an equimo-

«YTchlorlare Amount of N, IT-dimethyl ca rbamoTl ^ d, this is how that is obtained

509 82 4/1018

N- (N, N-dimethylcarbamoyl) -2-phenylethensulfonamide from P. - 162 ° G.

Analysis: Ber. for C ₁₁ H ₁₄ N ₂ O ₃ S: C: 51 _S 96; H: 5.55; N: 11.02; Found _o: G: 51.88; H: 5.56; N: $ 11.07 »

Example YI

The procedure of Example IV is repeated, but below Replacement of the 2-phenylethensulfonamide by an equimolar amount of 1-phenylpropene-2-sulfonamide. The product obtained is N ~ (N, N-diphenylcarbamoyl) - * 1-phenylpropene ~ 2 ~ sulfonamide from 175 - 179 ° C ..

Analysis : Calc. For C ₂₂ H ₂₀ N ₂ O ₃ S: C: 67.33; H: 5.14; N: 7 »14 $ Found: C: 67.09; H: 5.24; N: 7j11 $ o

Example VII

If the procedure of Example IV is repeated replacing the 2-phenylethylene with an equimolar amount:

2- (4-biphenyl) ethensulphonamide, 2 ~ phenylpropene-1-sulphonamide, 2,2-diphenylethensulphonamide, 1,2-diphenylethensulphonamide. 2 ~ phenylbut-1-en-1 ~ sulfonamide, 1-phenylbut-1-en-2-sulfonamide, 3-phenylbut-2-en-2-sulfonamide, 2- (m-chlorophenyl) ethensulfonamide, 2- (o- Chlorophenyl) ethensulphonamide, 2- (p-chlorophenyl) ethensulphonamide, 2- (p-bromophenyi) ethensulphonamide, 2- (m-bromophenyl) ethensulphonamide, 2- (p-fluorophenyl) ethensulphonamide, 2- (m-Iolyl) ethensulphonamide - (p-ethylphenyl) ethensulfonamide,

5 0 9 8 2 4/1018

2- (p-tert-Βυ tylphenyl) ethensulfonaiiiid, 2 ~ (o-methoxyphenyl) ethensulfonamide, 2- (m-13opropoxyphenyl) ethensulfonamide, 2- (p-butoxyphenyl) ethensulfonamide, 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-Tolyr) propene ~ 1-sulfonamide, 2- (p-isopropylphenyl) propene-1-sulfonamide, 2- (p-methoxyphenyl) propene-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) propen- 2-s'ulfonamid, ^ 1- (p-ethoxyphenyl) propene-2-sulfonamide, 2- (p-chlorophenyl) but-1-en-1-sulfonamide, 2- (p-Tolyl) but-1-en-1-sulfonamide, 2- (m-methoxyphenyl) but-1-en-1-sulfonamide, 1- (p-chlorophenyl) but-1-en-2-sulfonamide, • j - (m-Met hoxyphenyl) but-1-en-2-sulfonamide, 3 - (. P-Chlorophenyl) but-2-en-2-sulfonamide and 1,2-diphenylpropene-1-sulfonamide,

so you get

N- (N, N-diphenylcarbamoyl) -2- (4-biphenyl) äthensulfonamid, N- (N, N-diphenylcarbamoyl) -2-phen _y lpropen-1-sulfonamide, N- (N, N-diphenylcarbamoyl) -2 , 2-diphenylethene-sulfonamide, N- (N, N-diphenylcarbamoyl) -1,2-diphenylethene-sulfonamide, N- (N, N-diphenylcarbamoyl) -2-phenylbut-1-en-1-sulfonamide, - (N, N-Diphenylcarbamoyl) -1-phenylhut-1-en-2-sulfonamide,

509824/1018

- J) U-

N ~ (N, N-Diphenylcarbamoyl) -3-phenylbut-2-en-2-sulfonamide, N- (N, N-diphenylcarbamoyl) -2- (m-chlorophenyl) ethene sulfonamide, N- (N, N-diphenylcarbamoyl) -2- (o ~ dhloii) h9nyl) ethene sulfonamide ,. N- (N, N-diphen, ylcarbamoyl) -2 ~ (p-chlorophenyl) ethene sulfonamide, N- (N, N-diphenylcarbamoyl) -2- (p - bromophenyl) ethene-suifonamide, 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) ethene sulfonamide,

N- (N, N-diphenylcarbamoyl) -2- (p-tert-butylphenyl) ethene sulf onamid,

N ~ (N, N-diphenylcarbamoyl) -2- (o-methoxyphenyl) ethene sulfonamide,

N- (N, N-diphenylcarbamoyl) -2- (m-isopropoxyphenyl) ethensulf onamid,

N- (N, N-diphenylcarbamoyl) -2- (p-butoxyphenyl) ethene sulfonami d,

N- (N, N-diphenylcarbamoyl) -2- (m-chlorophenyl) propene-1-

sulfonamide,

N- (N, N-diphenylcarbamoyl) -2- (p-chlorophenyl) propene-1-

sulfonamide,

N- (N, N-diphenylcarbamoyl) -2- (m-bromophenyl) propene-1-

sulfonamide

N- (N, N-diphenylcarbamoyl) -2- (p-fluorophenyl) propene-1-

sulfonamide,

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

N- (N, N-diphenylcarbamoyl) -2- (p-isopropylphenyl) propene-1-

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,

509824/1018

N- (N, N-DiphenylGarbamoyl) ^ ~ (m-methoxypb.enyl) propene ~ 2'-

sulfonamide,

N- (N, N-DiphenylGarbamoyl) - "1- (p-eth.oxyphenyl) propene-2-

sulfonacid,

N- (N, N-DiphenylcarbaTnoyl) -2- (p-chlorophenyl) but-1-en-1-

sulfonamide,

N- (N, N-diphenylcarbamoyl) -2- (p-tolyl) but-1-en-1- "

sulfonamide,

N- (N, N-Oiphenylcarbamoyl) ~ 2- (m-methoxyphenyl) but - 1-en ~ 1 · -

.sulf onamide,

N- (N, N-diphenylcarbaemoyl) -1- (p-chlorophenyl) but ~ 1-en-2-

sulfonamide,

N- (N, N-diphenylcarbamoyl) -1 - '(m-methoxyphenyl) but-1-en-2-

sulfonamide, ■

N- (N, N-diphenylcarbamoyl) -3- (p-chlorophenyl) but-2-en-2-

sulfonamide, or _o

N- (N, N ~ diphenylcarbamoyl) -1,2-diphenylpropene ~ 1-sulfonamide

Example VIII ..

Repeating the procedure of Example IV with the following Alkene sulfonamide

2-phenylenesulfonamide, 1 ~ phenylpropene-2-sulfonamide, 2- (p ~ methoxyphenyl) ethensulfonamide, 2- (m-tolyl) ethensulfonamide,

2 ~ Phenylethensulfonamid, ·

1- (p-Chlorophenyl) propene-2-sulfonamide, 1- (pi ^I luophenyl) propene-2-sulfonamide, 3-phenylbut-2-en-2-sulfonamide, 2-ph.enylethensulfonamide, 2- (o- Chlorophenyl) ethensulfonamide, 2- (m-methoxyphenyl) propene-1-sulfonamide, 2- (p-tolyl) ethensulfonamide, 2- (p-fluorophenyl) ethensulfonamide, 2-phenylbut-1-en-1-sulfonamide,

509 8 2 4/10 1 8

2- (p ~ chlorophenyl) ethene sulfonami;:,

1-Phenylbut ~ 1-en ~ 2 ~ sulfonamide,. .

2- (p ~ isopropoxyphenyl) ethensulfonamide, 2- (m-chlorophenyl) ethensulfonainide, 2-phenylethensulfonamide, 2- (p-chlorophenyl) ethensulfonamide, 1,2-Mphenyläthen and 2-phenylenesulfonamide,

and the following carbamoyl chloride:

N ~ phenyl ~ N- (p-chlorophenyl) carbamoyl chloride, N-phenyl-N- (p-chlorophenyl) carbamoyl chloride, N-phenyl-N-Cp-chlorophenylJcar-bamoylchloride, N-phenyl-N-ip-chlorophenyl carbamoyl chloride, N, N-Di (p-methoxyphenyl) ca rbamoy1c hlο rid, N ^ -DiCp-methoxyphenylJcarbamoylchlorid, N-methyl-N-Cp-fluorophenyl / carbamoyl chloride, N-methyl-IT- (in - bromophenyl) carbamoyl chloride, N-ethyl-N-Cp-nitrophenylicarbamoyl chloride, N- (n-butyl) -N- (p-tolyl) carbamoyl chloride, N- (n-Deeyl) -N- (p-Ethylphenyl) carbamoyl chloride, N-methyl-N- (p-tert-butylphenyl) carbamoyl chloride, N- (n-Porpyl) -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-yl7piperidino) carbonyl chloride, (4- / 3-phenylprop-1-yl / piperidino) carbonyl chloride, Morpholinocarbonyl chloride and (1,2,3,4-tetrahydroquinolino) carbonyl chloride,

this is how you get:

509824/1018

N- (üT-Ph.enyl-N- / p-chlorophenyl7carbamoyl) -2-ptienyl-ether-

sulfonamide,

N ~ (N-phenyl-N- / p-chlorophen.yl7oarbamoyl) -1-phLenyl-propen-

sulfonamide,

N- (N-phenyl-N- / p-chlorophenyl / carbamoyl) -2- (p-methoxyphenyl) -

ethensulfonamide,

N- (N-phenyl-N- / p-chlorophenyl7carbanioyl) -2- (m-tolyl) -

ethensulfonamide,

N-CüTjN-Di / p-methoxypb.enyl / carbaEoylJ - ^ - phenyläthen-

sulfonamide ,.

K- (iT, N-Di _i / p-methoxyphen ^ _i l7carbainoyl) -i- (p-chloroph.enyl) -

propene-2-sulfonamide,

N- (N-Met hyl-N - ^ / p-f luo rphenyl7carbamoyl) -1 - (p-f luo rphenyl) -

propene-2-sulfonamide,

2-sulfonamide,

N- (N-ethyl-N- / p-nitrophenyl7carbamoyl) -2-pb.enyl-ethene-

sulfonamide,

N- (N- / n-butyl7-N ~ / p-tolyl) carbampyl) -2- (o-! Chlorophenyl) -

ätaensulfonamid,

N- (N- / n-Decy3 / -N- / p-ethylphenyl7carbamoyl) -2 - (m-metlioxyp! Aenyl)

propene-1-sulfonamide,

N- (N-Metb.yl-N- / p-tert-butylpb.enyl7carb'amoyl) -2- (p-tolyl) -

ethensulfonamide,

N- (N / n-Propyl7 N / m-is opropoxypb.enyl.7 ^c arbamoyl) -2- (pf luo r =

phenyl) ethensulfonamide,

N- (N- / Isopropyl7-N- _i / pn-butoxyphenyl7 ^car ^ ^amo yl) "* 2-phenyl but-

1-en-1-3ulf.onamide,

N- (N-allyl-N-phenylcarbamoyl) -2- (p-chlorophenyl) -ethen-

sulfonamide,

N- (N-Benzyl-N-phenylcarbamoyl) -i-phenylbut-1-en-2-3ulphonamide, N- (piperidinocarbonyl) -2- (p-isopropoxyphenyl) ethensulfo-

. . namid,

N - (/ 4-Benzylpiperid ino7carbonyl) -2- (m-chlorophenyl) -ethen-

sulfonamide,

N - (/ 4- (3-phenylpro p-1-yl) pipe ridino7carbonyl-2-phenyleth-. sulfonamide,

N - (/? - (3-Phenylprop-1-yl) piperidino7 ^carbon yl ~ 2 ^> - (p-chlorophenyl) ethensulfonamide,

N- (Morpholinocarbonyl) -1,2-diphenyläthensulfonamid respectively. ,> 2,3,4 ~ ietrahydroisoquinolino7 ^carbo & yl) -2-phenyl- ·

ethensulfonamide,

509824/1018

Example IX

N- (H- / bicyclo / 2.2.i7hept-2-en -5-.ylmeth.vl7carbamoyl) - 2-phenylethensulfona in i d

To a solution of 1.8 g of 2r-Phehyläthensulfonamid. and 4.8 g of 1,1-diphenyl-5- (bicyclo / 2.2cj7!: ^ie P ^i; -2-en-5-ylmethyl) urea in 20 ml of Ν, Ν-dimethylformamide are 0.64 g with stirring a 56 _S 6 $ dispersion of sodium hydride in mineral oil. The mixture is stirred overnight at room temperature during which time a heavy precipitate also forms. Then 200 ml of ether are added and, after stirring for 15 minutes, the precipitate is filtered off. It is then dissolved in 50 ml of water and the crude product is precipitated by acidification with concentrated hydrochloric acid. It is filtered off and recrystallized from aqueous acetone, yield 1.9 g ($ 56), mp 161-163.5 ° C. _O

Analysis; Ber. for C ₁₇ H ₂₀ N ₂ O ₃ S: C, 61.43; H; 6.07; N: 8.43 # o Found: C: 61.13; H: 5.95; N: $ 8.30,

Repeat the above procedure. Replacement of the 2-Phe = nyläthensulfonamids by an equimolar amount of 2-phenyl = » propene-1 ~ sulfonamide, 1-phenylpropen-2-sulfonamide, 3-phenylbut ~ 2 ~ en ~ 2 ~ sulfonamide, 1 ~ phenylbut-1-en-2-sulfonamide, 2,2-diphe » nyläthensulfonamid, 2- (p-chlorophenyl) ethensulfonamid, 2- (m-tolyl) ethensulfonamid, 2- (p-methoxyphenyl) ethensulfonamide or 2- (p-chlorophenyl) propene-1-sulfonamide, the Links;

N- (N- / bicyclo / 2.2.j7nept-2-en-5-ylmethyl7carbamoyl) -2-

phenylpropene ~ 1-sulfonamide,

"N- (N- / bicyclo / 2.2.j7hept-2-en-5-ylmethyl7carbamoyl) -1-

phenylpropene-1-sulfonamide,

N- (N- ^ Sicyclo _i /2.2 ₀ j7hept-2-en-5-ylmethyl7'carbamoyl) -3-

phenylbut-2-en-2-sulfonamide,

N- (N- / Bicycl0 / 2.2.j7hept-2-en-5-ylmethyl7carbamoyl) -1-

phenylbut ~ 1-en-2-sulfonamide,

509824/1018

ir- (N- / bicyclo / 2.2.i7hept-2-eri-5-ylmethyl7carbainoyl) - «2.2-

diphenylethensulfonamide,

yy7y) (p-ehlorphenyl) ethensulfonamide,

5yy7yi) (m-tolyl) ethensulfonamide,

. 2oJl7hept-2-en-5-ylmethyl7carbamoyl) -2- '

(p-meth.oxypb.enyl) ate hensulfonamide

N- (N- / Bicyclo / 2.2 .j ^ hept ~ 2.-en-5-ylmethyl7carbamoyl) ~ 2-

(p-chlorophenyl) propene-1-sulfonamide.

Example X ,

If the procedure of Example IX is repeated using 2-phenylethensulfonamide and 1,1-diphenyl-3-(endo-7-oxa-bicyclo / 2 * .2o _< i / heptan-2-ylmethyl) urea as starting materials, one obtains the N- (N- _i / endo-1-0x _< abicyclo / 2.2 _e 27heptan-2 «rylmethyl7carbamoyl) -2-phenylethensulfonamide from i ¹ . 176 178 ° C.

Analysis: Ber. for C ₁₆ H ₂₀ N ₂ O ₄ S; C: 57.13; H: 5.99; N: 8.33 ^ »Found: · C: 56.83; H: 6.06; N: $ 8.24 "

In addition, using 2-phenylethensulfonamide and 1,1-diphenyl-3- (exo ^ -oxabicyclo /? Ο2oj7heptan-2-ylmethyl) urea as starting materials, the compound N- (N- / exo- 7-Oxabicyclo / 2O2 _e J _i 7-heptan-2-ylmethyl7carbamoyl) -2-phenylethensulfpnamide from IO 150-152 ° C. ■ "■ ■

Analysis; Ber _o for: C ₁₆ H ₂₀ N ₂ O ₄ S: C: 57.13; H: 5.99; N: 8

Found: C. 56.88; H: 6 _f 04; N: 8.28 ^.

The condensation of 1,1-I) iphenyl-3- (endo-7-oxabicyclo- ·

/2*.2oj/heptan-2-ylmethyl) urea with 2-phenylpropen-1-sul = phonamide, 3-phenylbut-2 ~ ene ~ 2-sulfonamide, 2,2-diphenylethene =

509 824/1018

sulfonamide, 2 ~ (m-chlorophenyl) ethensulfonamide, 2- (m-methoxy = phenyl) ethensulfonamide respectively. 2- (p-Chlorophenyl) propene-1-sul = fonainid by the method of Example JX. delivers the ver bindings:

N ~ (N ~ / endo-7-0xabicyclo / 2.2oj7heptan ~ 2-ylmethyl7-carbamoyl) -2-phenylpropene-1-sulfonamide,

N- (N- / endo-7-0xabicyclo / 2.2.j7heptan-2-ylmethyl7-carbamoyl) -3-phenylbut ~ 2-en-2-sulfonamide,

(/ y / J [7P carbamoyl) -2,2-diphenylethene sulfonamide,

N- (N- / endo-7-0xabicyclo / 2.2c _t i7heptan ~ 2-ylmethyl7-carbamoyl) -2- (m-chlorophenyl) ethensulfonamide,

N- (N- / endo-7-oxabicyclo / 2.2 _e j7jieptan-2-ylm-e.thyl7-carbamoyl) -2- (m-methoxyphenyl) ethensulfonamide and

N- (N ~ / endo-7-oxabicyclo / 2.2oj7heptan-2-ylmethyl7-carbamoyl) -2- (p-chlorophenyl) propene-1-sulfonamide _{or the like}

The condensation of 1,1-diphenyl-3- (exo-7-oxabicyclo- / 2 "> 2" j / heptan-2-ylmethyl) urea with 1-phenylpropene ~ 2-sulfonamide, 1-phenylbut ~ 1-en-2-sulfonamide, 2 ~ (n-chlorophenyl) ethensulfonamide, 2- (p-isopropylphenyl) ~ ethene = sulfonamide respectively. 1 ~ (p-chlorophenyl) propene-2 ~ sulfonamide according to the regulation of example (X to the connections:

N- (N- / exo-7-0xabicyclo / 2.2.j7heptan-2-ylmethyl7-carbamoyl) -1-phenylpropene-2-sulfonamide,

N- (N- / exo-7-0xabicyclo / 2.2.J_7h-eptan-2-ylmethyl7-carbamoyl) -1-phenylbut-1-en-2-sulfonamide,

N- (N- / exo-7 ~ 0xabicyclo / 2 \ 2.i / heptan-ylmethyl7-carbamoyl) -2- (p-chlorophenylthene sulfonamide,

N- (N- / exo-7-0xabicyclo / 2.2cJ ^ heptan-2 ~ ylmethyl7-carbamoyl) -2- (p-isopropylphenyl) sthensulfonamide,

N- (N- / exo-7-0xabicyclo / 2.2ci7heptan-2-ylmethyl7-carbamoyl) -1- (p -chlorophenyl7propene-2-sulfonamide β

509824/1018

Example XI N ~ (piperidinocarbonyl) -1-pbien.ylpropen-2-5ulfonamide

A solution of 1.9 g of N- (N, N-diphenylcarbamoyl) -1-phenylpro = pen-2-sulfonamide and 1.7 g of piperidine in 10 ml of dimethylformamide is kept at about 95 ° C. for 6 hours. Then the solution was cooled to room temperature and 100 ml of ether were added. The mixture is extracted with 50 ml of water, the aqueous extract is acidified with concentrated hydrochloric acid. The crude product precipitates. It is filtered off and umkriställisiert from a mixture of acetone and water, wherein 670 mg of N- (piperidinocarbonyl) -1-phe "nylpropen-2-sulfonamide, melting at 159 - 161 ° C are obtained.

Analysis; J3er. for G ₁₅ H ₂₀ N ₂ O ₃ S: C: 58.43; H: 6.54; N: 9 »O9 #. "Found: C; 58.21; H: 6.50; N: $ 9.05.

Example XII . . -

The procedure of Example XI is repeated with reaction of N ~ (N, N-diphenylcarbamoyl) -1 ~ phenylpropene ~ 2-sulfonamide with the appropriate amine, the following compounds obtain:

C - SO ₂ - NH - C - Z

509824/1018

analysis

• P. (° C.) Ber "( 'S) N Found (96) N I. A. B Z 175-177 C. H 8.38 G H 8.10 1 Water st. Water st. N- (Bicyel0 / 2 *. 2, jJ- 61.07. 6.58 61.24 6.77 CO
I. heptan-2-ylmethyl) -
QTTii no 143-144.5 8.14 8.06 Water st. , CLlU. (JL XJL V
• water st. N-methyl ~ N- (2-phe =
nylethyl) amino
Water st. 4-benzylpiperidino 175-177 62.78 5.85 7.29 62.77 5.39 7.16 Water st. Water st. 1,2,5,6-Tetrahydro = 170-172 65.61 6.29 9.59 65.66 6.45 9.56 Water st. pyridino 57.53 5.52 57.55 5.58 Water st. 4-propylpiperaldino 146-148 8.33 8.17 Water st. Water st. 2-ethylpiperidino 138-140 60.70 7.19 8.69 60.48 'S, 67 3.65 water. Water is. N ~ (azacycloheptane 128-129 '. 59.61 6.88 ■ 9.09 59.51 6.35 9.04 Water ο 1-yl) amino 58.43 6.54 58, 20 6.51 Water st. 2- (2-hydroxyethyl) - 130-181.5 8.23 3.25 Water st. piperidino 56.79 6.55 56.38- 6.49 Water st. 2-methylpiperidino 138-140 9.09 9.32 Water st β Water st. N, N-Di (2-methyl = 157.5- 58.43 6.54 8.28 58.00 6.46 3.29 Water st. prop-1-yl) amino 158.5 60.34 7.74 60.17 7.68 Water st. N, N-diisopropyl = 168.169 9.03 8.91 CTi Water st. amino 58.00 7.15 57.60 7.08 CO Water st. N- (Azacyclooctane-1-
yl) amino
Water st. Thiomorpholines 107-109 8.69 3.63 Water st. Water st. 3,5-dimethylpipe = 163-166 59.61 6.88 8.97 59.45 6.79 3.93 Water « ridino 149.151 50.00 5.16 8.69 49.95 5.25 8.56 Water « Water st. N-Benzyl-N-Ethyl = 59.61 6.88 59.64 6.88 amino 79-80 8.14 8.13 Water st. Water st. 4-methylpiperidino 62.78 5.85 62.66 .5.32 Methyl piperidino 169-171 9.09 9.07 Water ο Water st. N, N-Di (ethoxycar = 159-161 58.43 6.54 9.09 58.09 6.40 9.05 Water st. bonylmethyl) amino 112-114 58.43 6.54 7.03 58.21 6.50 7.02 Waterst, 51.25 5.57 51.10 5.60

1,2,3,4-tetrahydro =

isoquinoline »

Pyrrolidino

Morpholines)

Ν, Ν-diethylamino. 4-phenylpiperidino . 4- (3-phenylpropyl)

piperidino. 4-methoxypiperidino . + Ν, Ν-didecylamino . N- (ethoxycarbonyl =

methyl) -N-benzyl =

amino
. N- (ethoxycarbonyl =

methyl) -N-methyl =

amino
• 4- (3-phen, ylpropyl) -

piperdidino
. ' 3j4-dichloro-piperi =

dino

ο 4- (3-Z4-Methoxyphe = ■ nyl7propyl) -piperi =

dino

. Morpholino
. 1,2,3,4-tetrahydro =

iäochinolino. Pyrrolidino. Ν, Ν-diethylamino

This compound was isolated as the sodium salt and analyzed.

Water st. Methyl' Hydrogen
Water st.
Water ο
Water ο
Water st. methyl
methyl
methyl
Water st
Water st 50982 Water st.
Water st.
Water ο
Water st. Vva s se rs t
Water st
Water st
Water st -P- / 1018 Water st.
Water st.
Water st. JBeFthylj; ·
Water st
Water st Water st.
Water st. • water st
■ water st Water ο
Water st. Water st
Water st

147-148.5. 64.03 5.66 7.86 64.01 5.67 7.89

151-153
145-147
122-124
135-137
131.5-133

57.13
54.19
56.73
64.78
66.97

154.5-156.5 55.55
154-157 65.87
130-133 59.69

6.17
5.85
6.74
5.98
6.84

6.22

9.34
5.51

9.52
9.03
9.45
7.56

6.79

8.64
5.30
6.96

126-123 51.51 5.56 8.58 129-131 67.57. 7.08 ■ 6.56 195-197 46.27 4.44. 7.71 214-216 62.09 6.25 6.03 174-176
165-167 199
113-11.5

56.92
54.14

56.39
64.90
66.68

6.09 5.89 6.80 6.28 7.11

9.47 8.93 9.36 7.41 6.92

55.59 6.22 3.54 66.11 9.12 5.29 59.54 5.53 6.89

51.62 5.50 3.46

67.70 7.22 6.32

46.32 x 4.39 7: 6i

62.13 6.46 5.9y

CD CjD

Example XIII

When converting the corresponding N- (N, N-diphenylcarbamoyl) alkene sulfonamids (see Examples IV, V and VII) with the appropriate Amiη following the procedure of Example XI, the following compounds are obtained:

K sulfonamide, * -

N ~ (jpiperidinocarbonyl) -2-phenylpropene> -.1-sulfonamid ', N - ({iiperidinocarbonyl) -2,2-diphenylcithenc sulfonainid',

N- (piperidinocarbonyl) -l-phenylbut-l-eii (-2-sulfonamide « _t .. ./-

N - * (fiperidinocarbonyl) -2- (m-chloro < phenyl) dthent: - sulfonamides,. ■.

■ ·

K- (piperidinocarbonyl) -2- (p-methoxyphenyl) propene ~ l ~ sulfonamidi ,, -

_c N - ([4-HydroxypiperidinoJcarbonyl) -2- (o-fluorophenyl ^ ~ propem-1-sulfonamide;

N- ([4-Hydroxypiperidino] carbonyl) -2- (o-tert-butyl- _ phenyl) dithem.sulfonamidf.,

N - ([4-ϊtetl · oxypiperidxno] carbonyl) -l- (p-chloro-phenyl) propenii-2-sulfonamide >,

N- ([4-Hethoxypiperidino] carbonyl) -2- (jd- £ ethylphenyl) h sulfonamides ;, ·

N - ([A-phenylpiperidino] carbonyl) -2-phenylpropene-1-sulfonamid_,

N - ([4-phenylpiperidino] carbonyl) -l-phenylpropeni - 2-sulfonamide-,

N - ([4-Phenylpiperidino] carbonyl) -2,2-diphenylathene sulfonainide !,

N - ([A-phenylpiperidino] carbonyl) -2- (p -chloro> phenyl) -Shf. sulfonamid.,

N - ([A-ehenylpiperidino] carbonyl) -2- (p-tolyl) but-len <.- 1-sulfonamidr. _t

IJ- (14-Propylpiperidlno] carbonyl) ~ 1-phenylpropene '-2-sulfonamidi,

N-C [A-methylpiperidino] carbonyl) ~ 2- (m-bron phenyl) -propene -l-sulfonaraid- »

509824/1018 original inspected

ι.

N - ([2 ~ Hethylpiperidino] carbonyl) - * 2,2-diphenylathene · '~ sulfonamides,.

N-Ci 3HHe thy! .Piperidino J carbonyl) -2- Cp_-butoxyphenyl) dtthen isulfonamidf.,

• N- (12-jfthylpip.eridinoJ carbonyl) -l- (p-chloruphenyl) -propeni-2-sul-phonamidi, · ■.

N-C.I-2-Ethylpiperidino] carbonyl) -2-Ga-methoxyph (enyl) -but-1-en : -l-sulfonamide> i,

N- C [A-benzylpiperidinoJ carbonyl) ~ 2-pheny! Propene'-1-sulf onaraid-,

N -C [4-Benzylpiperidino] carbonyl) -1- (p -chloriphenyl) -propene »-2-sulfonamidf.,. ':

N- C [4-Benzylpiper idinoj carbonyl) -2-Cm-brotu '. iphenyl) -

: sulfonainide> '.,' ♦

N - ([4-Senzylpiperidino] carbonyl) -2- (p-fIvorjphenyl) - '· ii * then> .sulfonamidv-, ■

N-CI ^ -ßenzylpiperidino] carbonyl) -l-Cp- ^ thoxyphenyl) -propem-2-sulfonamidt., . ' ·

N -C [4-Benzylpiperidino] carbonyl) -2-Cp7tolyl ") but-lenc.-1-sulf onamid '·, · "". "

_> N-Cl ^/ »- (2-phenyl ^ thyl) piperidino] carbonyl) -2-phenyl- • l ^ isulphonamide. ,

N- ([4- C2-ehenylethyl) piperidino] carbonyl) -2-Cp.-chloro / .ph "erjyl) 4then". Sulfonamide ;,

N -C [4- (2-phenylethyl) piperidino] carbonyl) -2-C-pisopropylphenyl) propene •. -1-sulfonamide .,

N-C [^ - C2- | henylAth ^ l) piperidino] carbonyl) -2-Cm-. isopropoxyphenyl) ethers sulfonamide ',.

N-C [4-C2-phenylethyl) piperidino] carbonyl) -2-Cpf luor..phenyl) Ätheni.sulf onaraid j,

NC (^ zacycloheptan-l-ylcarbonyl) -l-phenylpropent-2-sulfonaraid '., - ^ ₁ . ., ._. ■

N-0 ^ zacycloheptan-l-ylcarbonyl) -2-Co-chlori phenyl) -Athen ' sulfonamides,. "

N - (^ zacycloheptan-1-ylcarbonyl) -3-phenylbut-2-eni-2-su If onamid ■ -., -

N- (Byrrolidinocarbonyl) -2- (m-chloruphenyl) © thentsulfonamide j,

N-Cpyrrolidinocarbonyl) -2- (m-tolyl) ethem sulfonamidi, N- (rtorpholinocarbonyl) -l-phenylbut-1-eni "-2-sulfonamidr _t

N- (Horpholinocarbonyl) -2- (p-chloro ^ phenyl) propem -Irsulf.onamid .,

50 98 24/1018

ORIGINAL INSPECTED

N- (^ orphollnocarbonyl) -2- (ra-isopropoxypheny 1) - ^ then ■.-Sulfonamide, ',

N- (morpholinocarbonyl) - (p-isopropylphenyl) propene ^ -1-sulfonaraide, '"

li- (fiorpholinocarbonyl) -2,2-diphenylSTtheni sulfonamide.,

• N- (jHorpholino <iarbonyl) -l, 2-diphenylpropene. -1-sulfone amidj,

N-CThIotaorpholJ.nocarbonyl) -2- (j> -brom./phen.yl) AtheiiL.-sulfonamid., . .

N-CThiomorpholinocarbonyl) -2- (p-fluorophenyl) propent - 1-sulfonamidc, ■ '

N -. ( _{1,2 f} S, A-Tetrahydroisoquinolinocarbonyl) -2-phenyl-. "propenu-1-sulf onamldt. ',

N- (1,2,3, A-ITetrahydroiso ^ hnolinocarbonyl) - ^ - phenylbut-1-en ^ -l-sulfonamidf ', ··. "■

N- (1,2,3, A-TctrahydroisoChinolinocarbony ^^ - Cachlor. phenyl) e> theni sulfonamides,

N- (1,2,3, A-tetrahydroisoohinolinocarbonyl) -2- (pbromo-jphenyl) Athent: sulfonaiiiid ₁ :, *

N- (1,2,3,4-Te _> trahydroisoquinolinocarbonyl) -2- (p-tert-butylphenyl) Äthencsulfonamid / ..,

N- (1,2,3,4-tetrahydroisotfiinolinocarbonyl) -2- (p-

fluorophenyl) propeni -1-sulfonamide < ,;. ·

N- (1,2,3,4-pet ^ ahydroisoquinolinocarbonyl) -2- (in-

methoxyphenyl) but-l-enc-l-sulfonamide ..,

N- (1,2,3, A-fTe ^ rahydroiso ^ / jinolinocarbonyl) -2- (pchlorophenyl) ethene sulfonamide ■.,

N- (N, N-ßimethylcarbainoyl) -2- (p ^ -chlorphenyl) -4-thenvsulfonamide,

. N- (N, N- ^ l ^ thylcarbamoyl) -2- (m-tolyl) propem -1-sulfonamidt,

N- (N, N-J> isopropylcarbanioyl) -2- (m-isopropoxyphenyl) -cithen .sulfonamides,

N- (N, N-j) .iallylcarbamoyl) -l-phenylpropene-2-sulfonamidc ,

N- (N, JM-Jjiallylcarbamoyl) -2- (D-chloro (.phenyl) propenf - _# 1-sulfonamidc,

N- (N- [2-f / ethylallyl] carbamoyl) -l- (p-tolyl) propene -2-sulfonamidc,

N- (N- [4- ^ ethylpent-3-enyl] carbamoyl) -1- (m-methoxyphenyl) but-1-eni -2-sulfonaraid,

ORIQINALINSPECTED

509824/1018

24569 ^ 7

N- (N-iiiethyl-K-allylcarbainoyl) -2 ~ (p-iiuor phenyl) -i sulfonamides,

N- Qi-Hethyl-K-cyclohexyl) -2-phenylathencsulfonaraidc ·,

N ^ (N.N ^ tolcyclohexylcarbainoyl) -3- (p-chloro (phenyl) but-2-eni_-2-sulfonamide «., ·

N- (N- [2-phenylt: thyl] carbamoyl) -1-phenylpropen., -2-sulfonamide .,

N- (N-Methyl-N- [2-phenylethyl] carbamoyl) -2- (p -chlorochl) ^ th 3ul £ onaniid (,

N -. (4- [4-? ⁾ Henylbutyl] piperidinocarbonyl) -2-phenyl © then'- ^> sulfonamid_, * ·

jH- (4- {5-phenylpentyl] piperidinocarbonyl) -2-phenylate must: -. sulfonamides,

N- (3- [3-t * henylpropy lJpiperidinocarbonyD ^ -phenyl ^ 'thent'.sulfonamid,., .

N- (2- [3-phenylpropyl] piperidinocarbonyl) .- 2-phenylethene sulfonic acid ,

N- (4- [2- (p-3sopropoxyphenyl) ethyl] piperidinocarbonyl) -2- " Qp-chlorophenyl) Athene sulfonamidt,

.N- (3- [3- (p-Butoxyphenyl) propyl] piperidinocarbonyl) -2- ^ otolyl) ^ thensulfonanad

N- (3- [3- (p-Isopropylphenyl) propyl] piperidinocarbonyl) -2 phenylpropeni-l-sulfonamide. ,

N- (4- [3- (p-J-Futylphenyl) propyl] piperidinocarbonyl) -lphenylpropent.-2-sulfonamide , ·

N- (4- [m ^ ethylbenzyl] piperidinocarbonyl) -2-phenyldthenosulfonamide «., ·

N- (4- [3- (nt-ifethoxyphenyl) propyl] piperidinocarbonyl) -2-phenyl then sulfonamide <,

N- (4- f 3- (p-'1ethoxyphenyl) propyl] piperidinocarT3onyl) -2-hl ^ hm sulf onamidi,

N- (4- [2- (p-iiethoxyphenyl) ^ thyl] piperidinocarbonyl) -2- (Pj-chlorv phenyl) ithen> sulfonaraid; . '

N- (4- [4- (ra-ftethoxyphenyl) butyl] piperidinocarbony I) -I- »P-tolyl) propenf -2-sulfonamide-,

N ^ (4- [2-phenylprop-1-ylJpiperidinocarbonyl) ~ 2-phenyl- ^: dtheni.sulfonaraidi. lind

N -> (4- [2-Phenylbut-1-yl] piperidinocarbonyl) -2- (p -chlorophenyl) a * theni sulf onamidt,

509824/1018

Example XIV

The procedure of Example XI is repeated, but the piperidine used there is replaced by an equimolar amount 4 ~ (3-Phenylpropyl) piperidine and the N ~ (N, N-diphenylcarba = moyl) -1-phenylpropene-2-sulfonamide

K- (N - phenyl-N / p-chlorphenyl7 ^Gar bamoyl) -2-phenyläthensulfonamid,

N- (N-phenyl-N- / p-chlorophenyl7carbäffloyl) -2- (pmethoxyphenyl) ethensulfonamide,

Cj ^ pypy /
phenyl) propene-2-sulfonamide,

N- (NTZH-BUtVlZ-Ii-Zp-tolyl7carbamoyl) -2- (o-chlorophenyl) ethensulfonamide,

N- (N-methyl-N-Zp-tert ~ butylphenyl7carbamoyl) -2- (p ~ tolyl) ethensulfonamide,

N- (N-Zn-Propyl7-N-ZS-iscpropoxyphenyl7carbamoyl) -2 (p-fluorophenyl) ethensulfonamide and

N- (N-Benzy1-N-phenylcarbamoyl) -1-phenylbut ~ 1 ~ en-2 ~ sulfonamide

replaced.

This gives you the connections

N- (Z4- (3-phenylpropyl) piperidino7 ^carbon y ¹ ) ~ 2-phenylethensulfonamide,

N- (Z4- (3-phenylpropyl) piperidino7carbonyl) -2- (p-met hoxyphenyl) ethensulfonamide,

N- (Z4- (3-phenylpropyl) piperidino7carbonyl-1- (p-chlorophenyl) propene-2-sulfonamide,

N- (Z - (3-phenylpropyl) piperidino7 ^car carbonyl) -2- (o-chlorophenyl) äthensulfonamid,

- N- (Z4 (3 ~ phenylpropyl) piperidlno7 ^car konyl) -2- ·. / p-tolyl) ethene sulfonamide, ........

N- (/ J (3 ~ phenylpropyl) piperid ino7 ^{carbo 'a} yl) -2 ~ (p-fluorophenyl) äthensulfonamid "" and

N- (Z4- (3-phenylpropyl) piperidino7carbonyl-1 ~ phenylbut-1-en-2-sulfonamide.

509824/1018

Example XV '

N- (N- / T-methoxy carbonylät h.yl7carbamoyl) -2-phenyläthensulfonamid

1.05 g of a 56.6% suspension of sodium hydride in mineral oil are added to a solution of 3.5 g of DL-alanine methyl ester hydrochloride in 20 ml of dimethylformamide. The mixture is stirred at room temperature for 15 minutes, then 3.8 g of N- (N, N-diphenylcarbamoyl) -2-phenylethensulfonamide are added. The reactant mixture is then kept at about 90 ° C. for 40 minutes. After cooling to room temperature, it is diluted with excess ether and then extracted with water. When the aqueous extract is acidified with dilute hydrochloric acid, the crude product precipitates, it is filtered off. It is filtered off and the two fractions are combined. This gives 1.55 g of product. From the mp 135-139 ° G ₀ The crude product is recrystallized from a mixture of acetone and hexane, 0.70 g of N- / N * - (1-methoxycarbonylethyl) -2-carbamoyl7 phenyläthensulfonamid mp 133 - 14O ⁰ C are obtained.

Analysis; Ber _c for C ₁₅ H ₁₆ N ₂ O ₅ S: C, 49.94; H: 5.12; N: 8.96 ^ ₀ FFEF ": C: 50.06; H: 5.26; N: 9.32 <fo _o

Example XVI

If the procedure of Example XV is repeated, but below Replacement of the DL-alanine methyl ester hydrochloride by the corresponding one Amino ester hydrochloride, the following compounds obtain:

CH = CH-SO ₂ -NH-CZ

509824/1018

analysis

F. (° C.) Ber. (#) '' Sef. (#)

GHN CHN

N-d-A'thoxycarbonyl-127-129 54.23 6.26 7.92 54.23 6.29 7.93

2-methylprop-1-yl) ~ amino

N- (i-ethoxycarbonyl-2-

methylbut-1-yl) amino 126-128 55.43 6.56 7.61 55.52 6.54 7.48

N- (1-ethoxycarbonyl-pent-81-83 55.43 6.56 7.61 55.25 6.49 7.77

* "1-yl) amino

co N- (5-ethoxycarbonyl-pent-97-99 55.43 6.56 7.61 55.50 6.56 7.65

co 1-yl) amino

-p- N- (1,3-dimethoxycarbonyl = 120-122 50.00 5.25 7.29 49.89 5.22 7.11

^ "" Prop-1-yl) amino

Ξ N-d-ethoxycarbonyl-prop-149-151 52.92 5.92 8.23 52.69 5.89 8.23

- »1-yl) amino

⁰⁰ N- (3-ethoxycarbonyl-prop-120-122 52.92 5.92 8.23 52.76 5.90 8.28

T-yl) amino

■ 4? -

The procedure of Example XV is repeated with the following Alkenesulfonamide

1-phenylgropen-2-sulfonamide, 2-phenylpropene-1-sulfonamide, 2- (p ~ chlorophenyl) ethensulfonamide, 1,1-diphenylethensulfonamide, 2- (p-tolyl) ethene sulfonamide, 1 ~ phenylpropene-2- sulfonamide, 2-phenylpropene-1-sulfonamide, 2- (m-chlorophenyl) ethensulfonamide, 2- (p ~ bromophenyl) ethensulfonamide,. 1- (m-methoxyphenyl) propen-2-sulfonamide, ^2- (p ~ Pluorphenyl) äthensulfonamid, 3-phenylbut-2 ~ en-2-sulfonamide, 2-phenylbut-1-en-1-sulfonamide, 2- ( p ~ chlorophenyl) propene-1-sulfonamide, 2 ~ (p ~ isopropylphenyl) propene-1-sulfonamide, 2-phenylpropene-1-sulfonamide, 2- (o-chlorophenyl) ethensulfonamide, 1-phenylbut-1-en-2- sulphonamide, 1,2-diphenylethensulphonamide, 2-phenylethensulphonamide, 1- (m-chlorophenyl) propene-2'-sulphonamide, 2- (m-tolyl) ethensulphonamide and 2- (p-isopropoxyphenyl) ethensulphonamide,

and the following amino acid ester hydrochloride

Glycine methyl ester, Glycine methyl ester, glycine methyl ester, glycine methyl ester,

509824/1 01

Glycine methyl ester,

Glycine ethyl ester, _

Glycine ethyl ester, / 40034 /

Glycine ethyl ester, glycine ethyl ester, glycine ethyl ester, DL-alanine methol ester, DL-alanine methyl ester,

DL-alanine methyl ester, ^

DL-Alaninemethylester, DL-Alaninemethylester, DL-Leucinäth _v lester, DL-Leucinäthylester, DL-Leucinäthylester, DL-Leucinäthylester, to-Aminooctansäureäthylester, to-Aminooctansäureäthylester, ö-Aminooctansäureäth ^ lester and ω-Aminoäthylester,

this is how you get the connections:

N_ (N_Methoxycarbonylmethyl7carbamoyl) -1-phenylpropene-2-sulfonamide,

N- (N- ^ Me t hoxyca rb onylme t hyl7carbamoyl) -2-phenylpropene-1-sulfonamide,

N- (N- / methoxycarbonylmethyl7 ^{cari: iamo} yl) ~ 2- (p-chlorophenyl) ethensulfonamide, N- (N- / methoxycarbonylmethyl / carbamoyl) -1,1-diphenylethensulfonamide,

N-ÖH- / Methoxycarbonylmethyl7carbamoyl) -2- (p-tolyl) -äthensulfonamid,

N- (N- / ethoxycarbonylmethyl / carbamoyl) -1-phenylpropene-2-sulfonamide,

N- (N- / ethoxycarbonylmethyl / .carbamoyl) -2-phenylpropene-1-sulfonamide,

5 0 9 8 2 4/10 18 '

N- (N ~ / EthoxyearbonylEiethyl7carbamoyl j —2— (in— chlorophenyl) ethensulfonamide,

( _/ yyy7 bromophenyl) ethensulfonumide,

N- (N- / Ä "t hoxyca r bony Im ethyl7carbamoyl) -1- (mmethoxyphenyl) propene-2-3ulf onamid,

CZyyy fluorophenyl) ethensulfonamide,

N- (N- / T-methoxycarbonylethyl7carbanioyl) -3-pfcienylbut 2-en ~ 2-sulf onaznid, - "- ^"

IT- (N- / T-Met hoxycärbonylät hyl / carbainoyl) -2-phenylbut 1-en-1-sulfonamide, '

N- (N- / 1-Met hoxycarbonylät hyl / carbamoyl) ~ 2- (p-chlorophenyl) propen-1-3ulfonamid, ■

N- (N- / T-methoxycarbonylethyl7carbamoyl) -2- (pi3opropylphenyl) propene-1-sulfonamide, -

. N- (Ν- / ΐ-Αΐ1ιοχ ^ θ3Γ ^ οη ^ Ί-2-ηθΐ hylbu t-1 2-phenylprop8n-1-aulf onarnid,

N- (N- / T-ethoxycarbonyl-2-methylbut-1 ~ yl7carbamoyl) -2 ~ (o-chlorophenyl) ethane sulf onamid,

N- (N- _J / T-ethoxycarbonyl-2-metbylbut-1-yl7carbamoyl) -1-phenylbut-1-en-2-sulfonamide,

N- (N- / T-ethoxycarbonyl-2-methylbut-T-yl7cai * bamoyl) -1,2-diphenylethensulfonamide,

N- (N- / T-ethoxycarbonylhept-i-yl / carbamoyl) -2-phenyl ~ ethensulfonamide,

N- (N- / 7-Ätb.oxycarbonylhept-1-yl7carbamoyl) -. 1- (m ~ chlorophenyl) propene-2-sulfonamide,

N- (N- / 7-ethoxycarbonylhept-1-yl7carbamoyl) -2- (mtolyljäthensulfonamid and

N- (N- / 7-Ethoxycarbonylhept-1-yl7carbamoyl) -2- (pisopropoxyphenyl) ethensulfonamide. ■

The amino acid ester hydrochlorides used in this example are either commercial products or they can be obtained from the corresponding acids (all of which are commercially available) are represented by esterification. Method of esterification of amino acids are from Greenstein and Winitz in the "Chemistry of the Amino-acids," John Wiley and Sons, Inc., New York-London, 1961 ,. Vol. 2, pp. 925-927.

50 9 824/1018

Example XVIII

Repeating the procedure of Example XV, with the replacement of the DL-alanine methyl ester hydrochloride with an equimolar amount of N-Phenylglycinäthylester hydrochloride or Np-chloro ptien3 = ^r lglycinäthylester hydrochloride, one obtains the compounds

N- (N-phenyl-N- / athoxycarbonylmethyl7carbamoyl) -2 ~ phenylethensulfonamide and

N- (N- _/ / p-chlorophenyl7-N- / athoxycarbonylmethyl7-carbamoyl) ~ 2-phenylethensulfonamide <>

Example XIX N- (Pyrrolidinocarbonyl) -2-phenylethensulfonamide

A mixture of 3 »4 g (N- (N- / m ~ chlorophenyl7carbamoyl) -2-phenylethensulfonamide and 2.15 g of pyrrolidine in 100 ml of ethanol is refluxed for 20 hours. Then the solution will be cooled and concentrated in vacuo to approx. 25 ml. A small amount of starting material precipitates and separates off will. 75 ml of ether and 75 ml of water are added to the ethanol filtrate added, the phases are separated and the aqueous phase is acidified with concentrated hydrochloric acid. Included the crude product precipitates. It is filtered off and, after drying, weighs 1.5 g. The ether phase is mixed with 50 ml of hydrochloric acid and then washed with 25 ml of water. After drying over anhydrous sodium sulfate, the ether is removed in vacuo.

distilled inan, with a second product fraction of 0.70 g

The first fraction is recrystallized from acetone and gives 0.60 g of pure N- (pyrrolidinocarbonyl) -2-phenyl = ethensulfonamide of ¹ . 201 - 204 ° C.

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Analysis: Ber. for Gef .:

C: 55.71 * H: 5.75; N: 10.00? Ί < G: 55.45; N: 5.68; N: 9.9496-

Example XX

If the procedure of Example XIX is repeated while replacing the pyrrolidine with the corresponding amine, the following are obtained Get connections:

509824/1 0.1 8 ,.

analysis

Be iv (fl) Gef

F. - ( ⁰ C.) CH - N C HN

Ν, Ν-dibutylamino 104-105.5 60.34 7.74 8.28 60.60 7.50 8.32

ttorpholino. '176-179 52.70 5.44 9.46 52.63 5.37 9.48

1,2,3,4-tetrahydro 165-167 63.15 5.30 8.18 63.00 5.35 8.26

isoquinolino

3-azabicyclo / 5.2.27- 181-184 61.06 6.63 8.38 .61.08 6.66 8.32

_o nonan-3-yl

co Ν, Ν-diethylamino 110-113 55.31 6.43 9.92 55.28 6.29 9.80

NJ I

** 3-Hydroxypiperidino 160-165 54.19 5.85 9.03 54.43 5.94 9.24. ^

Q N, N-Diheptylamino 65.37 9.06 6.63 65.88 8.84 6.71

'./ird -N- (N, N-diphenylcarbamoyl) -2-phenylethensulfonamide with Ν, Ν-Dipropylamine implemented according to the method of Example XIX, so one obtains the N- (N, N-dipropylcarbamoyl) -2-phen ^ lat.hen = sulfonamide with a temperature of 128 - 130 ° G.

Analysis: Ber. for 0 H ₂₂ N ₂ O, S: C: 58.05; H: 7.15; N: 9.03 # o Found: "C: 57.77; H: 7.09; N: 8.96 ^.

If one goes from N- (N- / m-Tolyl7carbamoyl) -2-phenylethensulfonamide and Ν, Ν-dibutylamine, is obtained by the method of Example XIX the N- (N, N-dibutylcarbamoyl) -2-phenylethensulfo = namide with a temperature of 104 ~ 105 ° C.

Analysis: Ber <. for G ₁₇ H ₂₆ N ₂ O ₅ S: G: 60.34; H: 7.74; N: $ 8.28. Found: C: 60.23; H: 7.58; N: 8.50 ^.

Example XXI . ■

N ~ (piperidinocarbonyl) -2-phenylethensulfonamide

A slurry of 6.5 g of 2-phenylethensulfonamide in 45 ml Oxalyl chloride is refluxed with stirring for 16 hours. Then it is cooled to room temperature, after which it is the solid is filtered off and washed with hexane. After drying, the product weighs 2.2 g and has a melting point 170 to 180 ° G. "

The above solid is added in small portions with stirring at room temperature to a solution of 5 ml of piperidine in 15 ml Methylene chloride added. After finished? That will be an encore The mixture was stirred for a further 1.5 hours and then concentrated to dryness in vacuo. The residue is between 40 ml of water and 25 ml of ether are distributed, the layers are separated and the ether layer is discarded. The aqueous layer is acidified with acetic acid and then extracted with ether. The-

50 9824/1018

this ether extract is washed with water, dried over anhydrous sodium sulfate and concentrated to dryness in vacuo. This gives 0 _s 60 g of residue as a crude product with a melting point of 133 140 ° G. This is recrystallized from a mixture of methylene chloride and ether, 'wobe? ^a 9aS pure N- (N ~ Piperiäino-car = bamoyl) -2-phenyläthensulfonamid mp 175 - 177 ° C is obtained.

Analysis: Ber. for C ₁₄ H ₁₈ N ₂ O ₃ S: G: 57.13; H: 6.17; N: $ 9.52. Found:. ■ C: 57.23; H: 6.11; N: $ 9.54.

Example XXII

N - (/ 4 * -Carboxypiperidino7oarbonyl) -2-phenylethensulfonamide

A mixture of 5 g of N- (N, N-diphenylcarbamoyl) -2-phenylethene = sulfonamide and 10.3 g of ethyl isonipecotet in 20 ml of dimethylformamide is kept at about 90 ° C. for 40 minutes. Then the mixture is cooled to room temperature, diluted with ether and extracted with water. The aqueous extract is acidified with concentrated hydrochloric acid and then extracted with methylene chloride. The dried methylene chloride is evaporated in vacuo, leaving a viscous oil. This is redissolved in a little tetrahydrofuran, absorbed on a column of silica gel and then eluted with an excess of the same solvent. The solvent is evaporated off in vacuo and the residue is dissolved in 50 ml of 0.5N sodium hydroxide solution. After an hour it is again precipitated by acidification, then the white ones. Crystals · sucked off. They are then dissolved in 100 ml of acetone and 100 ml of tetrahydrofuran and the solution is slowly concentrated so that the product precipitates. The Peststoff is filtered off and triturated with acetone to thereby give the pure N - (/ 4 Carboxypiperidino7 ^c ar, t) onyl) -2-phenyläthensulfonamid of J ?. 179 ■ - 131 ° G.

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Analysis; Boron, for everyone C ₁₅ H ₁₈ N ₂ O ₅ S: C; 53.25; H: 5.32; N: 8.28? B. Found: G: 52.93; H: 5.58; N: 8

Example XXIII

N- (4 ~ / ^ -Pb.e nylpropyl7piperidino carbonyl) -2-phenylethensulfonaniid

A solution of 12 g of 4- (3-phenylpropyl) piperidine and 12.5 g of the potassium salt of N- (N, IT-diphenylcarbamoyl) -2- <phenyl = ethensulfonamide (for preparation see Example IV) in 30 ml of dimethylformamide is brought to 75 C., then 5.7 ml of glacial acetic acid are added dropwise with stirring. " During the addition, the temperature rises to 90 0" Poured into 200 ml of sodium hydroxide solution and 100 g of crushed ice · A gummy precipitate forms. -50 ml of ether are added and the mixture is stirred vigorously until a cloudy solution is obtained, then 50 ml of hexane are added, whereupon the sodium salt is added The product is filtered off and washed with water and then with ether. The crude sodium salt is dissolved in a mixture of 100 ml of acetone and 50 ml of water, then 5 ml of concentrated hydrochloric acid and 100 ml of water are added The precipitate is filtered off, washed with aqueous acetone and finally recrystallized from acetone / hexane, whereby '6.8 g ($ 55) of pure N- (4- / 5-phenylpropyl7piperidinocarbonyl) -2-phenylethensulfonamide of P. 131-133 ° C receives.

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Example XXIV

N- (N- / T ~ arboxyprop-1-yl7carbamo.yl) -2-phenylethensulfonamide

1.0 g of N- (N- / T-ethoxy-carbonylprop-1-yl7carbamoyl) -2-phenylethensulfonamide is added to 30 ml of 1N sodium hydroxide solution. The mixture is stirred at room temperature for 30 minutes, then the small amount of insoluble material is filtered off and discarded. The filtrate is concentrated with. Hydrochloric acid acidified, whereby the product precipitates. Ea is filtered off, washed with water / ash and dried in the air, with 6.0 g of N- (N- / T-carboxyprop-1-yl7carbamoyl) -2-phenylethensulfonamide from Έ ¹ . 150 - 152 ° C.

Analysis: Ber. for C ₁₅ H ₁₆ N ₂ O ₅ S: C: 49 * 98; H: 5.16; N: $ 8.97. Found: C: 49.72; H: 5.20; N: 8.85 # c

Example XXV

If one starts from a corresponding ester according to Examples II, XII, XV or XVI, one obtains when using the Hydrolysis according to Example XXIV the following compounds:

C = C-SO ₀ -NH-CZ I ²

AWAY

5098 2 4/1018

analysis

AWAY. H H

H H

N- (1-carboxy-2-phenylethy3) amino

N- (carboxymethyl) amino

HCH, N- (carboxymethyl) - -v amino

H H N- (i-carboxyethyl) amino

H H N- (1-CarbOxy-3-methylbut-1-yl) amino

H H N- (1,3-dicarboxyprop-1'-yl) amino

H H N- (i-Carboxy ~ 2-methylprop-1-yl) amino

H H N- (3-carboxyprop-1-yl) amino

H H N- (1-carboxypent-1-yl) amino

H H, N- (5-carboxypent-1-yl) amino

H H N ~ (1-carboxy-1-methylbuΐ-1-yl) amino +

HH N- (1-carboxyhept-1 ~ yl) amino

H H N- (carboxymethyl) -n-benzylamino

P; ( ⁰ C) 167.5-169

182-183

183-185

155-156

162-164

170-171

155-157

133-135

140-142

154-155 * 5

130-133

142-144

127-128

57.75 4.85 7.48 57.64 4.84 7.22

46.48 4j26 9.86 46.69 4.33 9.86

48.32 4.73 9.39 47.99 4.79 9.29

48.32 4.73 9.39 48.31 4.71 9.14

52.92 5.87 8.23 52.56 5.75 8.02

47.19 4.53 7.86 46.98 4.51 7.79

51.52 '5.56 8.58 51.33 5.74 8.47

49.98 5.16 8.97 49.82 5.22 8.82

52.92 5.92 8.23 58.85 6.00 8.22

52.92 5.92 8.23 53.07 5.98 8.17

50.40 5.92 7.83 50.69 5.71 7.87

55.41 6.57 -7.60 55.86 6.70 7.37 57.75 4.85 7.48 57.40 $ 4.82, 20

+ This compound was isolated and analyzed as a monohydrate.

Example XXVI

Starting from the corresponding ester (see Examples III, XII, XVII and XVIII) one obtains by the hydrolysis process of example 2 [XIV the following compounds:

N- (N- ^ üarboxymethyl7carbamoyl) -2 ~ (m-methoxyphenyl) - propene-1-sulfonamides

N- (N- / Öarboxymethyl7carbamoyl) -2- (p-biphenyl) -propen-1-sulfonamide,

N- (N, N-di / carboxymethyl7carbamoyl) -2-phenylethensulfonamide,

N- (N- / Öarboxymethyl7-N-methyl) carbamoyl) -2-phenylethensulfonamide,

N- (N- / Üarboxymethyl / carbamoyl) -1-phenylpropen-2-aulfonamide,

N- (N- / Öarboxymethyl7carbamoyl) -2-phenylpropen-1-aulfonamide,

N- (N- / arboxymethyl7carbaiaoyl) -2- (p-chlorophenyl) ethensulf onamid, ~ "

N ~ (N- / Üarboxymethyl7carbamoyl) -1, 1-diphenylethensulfonamide,

N- (N- / Öarboxymethyl7carbamoyl) -2- (p-tolyl) ethensulf onamid,

N- (N- / Üarboxyme thyl7ca rbamoyl) -2- (m-chlorophenyl) ethene sulf onamid, "*"

N- (N- / Öarboxyme thyl7carbamoyl) -2- (p-bromophenyl) -äthensulfonamid,

N- (N- / Üarboxymethyi7carbamoyl) -1- (m-methoxyphenyl) -propene-2-sulfonamide,

N - (- / T-carboxyethyl-carbamoyl) -2- (p-fluorophenyl) -ethensulf onamid, ~~

N- (N- / T-carboxyethyl7carbamoyl) -3 ~ phenylbut-2-en-2-sulfonamide,

U- (U _ ^ / T-.Garboxyäthyl7carbanioyl) -2-phenylbut-1-en-1-sulfonamide,

509824/1018

N ~ (N- / i-Carboxyäthy3 ^ carbamoyl) -2- (p - chlorophenyl) -propen-1-sulfonamide,

N- (N- / T-carboxyethyl7ca rbamoy1) -2- (p-isopropylphenyl) -propen-1-sulfonamide,

N- (N- _/ / T-carboxy-1-nethylbut-1-yl7carbamoyl) -2-phenylpropene-1-sulfonainide,

N- (N- / T ^ carboxy-2-methylbut ~ 1-ya / carbampyl) -2 - (ochlorphenyl) ethensulfonamide,

N-CN-ZT-Carboxy ^ -methylbut-i-yl / carbamoylJ-i-phenylbut-1-en-2-sulfonamide,

N- (N - / - f-carboxy-2-methylbu1; -1-ryl7carbainoyl) -1,2-diphenylethensulfonamide, ·

N- (N- / 7-Garboxyhept-1-yl7carbamoyl) -2 ~ phenylethensulfonamide, '; "

N- (N-ZT-carboxyhept-1-yl / arbamoyl) -1- (m-chlorophenyl) propene-2-sulf onamid, "" · "■■.

N- (N- / 7-rCarboxyhept-1-yl7carbamoyl) -2- (m-tolyl) -ethensulfonamide,

N- (N- / 7-carboxyh.ept-1-yl7carbamoyl) -2- (p-i8opropoxyphenyl) ethensulfonamide,

N- (N-phenyl-N- / carboxymethy _i 17carbamoyl) -2-phenylethensulfonamide and

N- (N- / p-Ghlorpb.enyl7carboxymethyl7carbamoyl) -2-phenylethensulfonamidο .

Example XXYII

N- (N ~ / T ~ carboxyhept-1-yl / carbamoyl) -2 ~ pb-enylethensulfonamide

10.05 g of ethyl 2-aminooctanoate hydrochloride are added to 40 ml of dimethylformamide and then 2.1 g of a 56.67% dispersion of sodium hydride in mineral oil were added. The mixture will stirred at room temperature for 15 minutes, then 7.6 g of N- (N, N-diphenylcarbamoyl) -2-phenylethensulfonamide are added. The reaction mixture is then heated to approx. 100 ° C for 1 hour, then allowed to cool to room temperature. The mixture is then diluted with excess ether and extracted with water. When acidifying the aqueous

5 0 9 8 2 A / 1 0 1 8

-6ο-

Extract with concentrated hydrochloric acid separates an oil away. The supernatant aqueous phase is decanted off and replaced with 50 ml of ether and 50 ml of fresh water. the .Aether phase is removed, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue is obtained an oil that cannot be converted into a solid. The oil is dissolved in acetone, then 50 ml of 1N sodium hydroxide solution are added. admitted. A heterogeneous mixture forms which is stirred overnight at room temperature will. Then the mixture is extracted with ether, the extract is discarded. The remaining aqueous phase is acidified with concentrated hydrochloric acid and the oil that separates out is extracted into ether. · The ethereal solution is dried over sodium sulfate, treated with decolorizing charcoal and concentrated in vacuo. An oil is obtained which slowly crystallizes when standing. The solid obtained in this way is triturated under benzene, filtered off and dried, 3 »0 g of N ~ (N- / T-carboxyhept-1-yl7-carbamoyl) -2-phenylethensulfonamide received from the MP 142 - 144 ° C.

Analysis: Ber. for C ₁₇ H ₂₄ N ₂ O ₅ S: G: 55.41; H: 6.57; N: $ 7.60. Found: G: 55.86; H: 6.70; N: $ 7.37.

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Example XXVIII

IT- (4- / 5- (p-Hydrox.yph.enyl) propyl7piperidinocarbonyl) -2-phenylethensulfoaamide

To a solution of 1.37 g of N- (4- / 3- (p-methoxyphenyl) propyl / -piperidinocarbonyl) -2-phenylethensulfonamide in 30 ml of methylene chloride, 175 μl are added as jissy. The mixture is cooled to -60 ° G, then 850 μl BoYitribromide is slowly added. The reaction mixture is then allowed to warm to room temperature. After a further 3 hours, it is washed with ice-cold water and extracted with 1N sodium hydroxide solution. The sodium hydroxide extract is washed with ether and washed with. concentrated hydrochloric acid acidified, with, one obtains a gummy precipitate. The supernatant aqueous phase is poured off and the gum is dissolved in methylene chloride. The solvent is dried with anhydrous sodium sulfate and then distilled off in vacuo, giving 0.50 g of crude product. This is cleaned by dissolving it in a little acetone and precipitating the spring with hexane. Finally, 0.142 g of pure N- (4- / p-hydroxyphenyl) obtained - · propyl7piperidinocarbonyl) -2-phenyläthensulfonamid, mp 132-135 °. G. ·

Analysis: Ber. for C ₂₅ H ₂₈ H ₂ O ₄ S: C: 64.47; H: 6.59; N: 6 Found: G: 64.08; H: 6.97; N: 6

Example XXIX ■

If one puts the corresponding N - (/ methoxyphenyl) alkyl7piperidino carbonyl) alkene sulfonamide following the procedure of Example XXVIII with boron tribromide, the following compounds are obtained: ·

N- (4- / m-hydroxyphenyl) propyl7piperidinocarbonyl) -2-phenylethensulfonamide, '

509 824/1018

N "(4- / ~ o-hydroxyphenyl) propyl / pipe rid inocarbonyl) -2-phenylethensulfonamide, N- (4- / 2-Hydroxyphenyl) aryl / pipe rid inocarbonyl-2 ~ (p-chlorophenyl ether sulfonamide, N- (4- / 4- (m-Hydroxyphenyl) bu tyl7pipe radinocarbonyl) -1- (p-tolyl) propene-2-sulfonamide and N- (4- / 5- (m-hydroxyphenyl) pentyl / piperidinocarbonyl) -2- (p-bromophenyl) ethensulfonamide

Example 30

N- (4- / 3-phenylprop.yl7pipe ridinocarbonyl) -2-phenylethensulfonamide

A mixture of 18.3 g of 2-phenylethensulfonamide, 1.3 ml of oxalyl chloride and 15 ml of tetrahydrofuran is heated to 75 to 80 ° C. in a nitrogen atmosphere for 1.5 hours in an oil bath while stirring. 30 ml of xylene are added to the solution thus obtained and the internal temperature is increased to 138 ° 0 in the course of 20 minutes, tetrahydrofuran and excess oxalyl chloride being allowed to distill off from the solution. During this period, two additional 5 ml portions of xylene are added. The resulting solution is kept at approx. 138 ° C for 15 minutes and then cooled to 85 ° 0. 4-06 g of 4- (3-phenylpropyl) piperidine are added in small portions over the course of one minute to the xylene solution of the 2-phenylethensulfonyl isocyanate. The reaction mixture is stirred at "room temperature for 1.5 hours, then washed successively with 75 ml of 1N hydrochloric acid and twice with 25 ml of water each time. 20 ml of acetone are then added to the dried and filtered xylene solution, then 120 ml of hexane are added dropwise. The precipitate which forms is filtered, thus obtaining 2.89 g (7O ^a / o yield) of crude After recrystallization from acetone / hexane gives 1.07 g of the title compound i \. 125 - 127 ° 0th

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Example XXXI

By reacting the corresponding alkene sulfonamide with oxalyl chloride the following isocyanates are obtained by following the procedure of Example XXX:

2- (o-fluorophenyl) ethensulfonyl isocyanate, 2- (p-chlorophen, yl) ethensulfonyl isocyanate, 2 - (p-bromophenyl) ethensulfonyl-isocyanate, 2- (HL-ToIyI) propene-.1-sulfonyl-isocyanate, 1 ~ (p-methoxyphenyl) butene-2-sulfonyl isocyanate, and 2- (p-Trifluoromethylphenyl) ethensulfonyl isocyanate. ·

When reacting the above isocyanates with the corresponding Amines, also according to the procedure of Example XXX, the following connections result:

N- (4- / 5-Phenylpropyl7piperidinocarbonyl) -2- (2-fluorophenyl) -äthensulfonamid,

N- (4- / 3- (p-tolyl) propyl7piperidinocarbonyl) -2- (p-chloro- ' phenyl) ethensulfonamide, '.

N- (4- / 5- (m-methoxyphenyl) pentyl7piperidinocarbonyl) - '2 - (p-bromophenyl) ethensulfonamide,

N- (2-methylpiperidinocarbonyl) -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) ethensulfonamide.

Example XXXII -

H- (4- / 5-phenylpropyl7piperidinocarbonyl) -2-phen.yläthensulfonamid '

A mixture of 1.83 g (0.01 mol) of 2-phenylethene sulfonamide, 3.45 g (0.025 moles) potassium carbonate and 4.0 g (.0.01-5 moles)

509 8 2.4 / 1Q1 8

4- (3-phenylpropyl) piperidinocarbonyl chloride in chloroform is refluxed for 22 hours with stirring the solvent evaporated in vacuo and the residue is with 75 ml of Ü, 5N sodium hydroxide solution and 35 ml of ether offset. The mixture is stirred for 1 hour, then undissolved solid is filtered off. This gives 1.84 g (approx. 41 $ yield) of the title compound as a mixture of their sodium and potassium salts.

0.5 g of the above crude product in 6 ml of acetone and 3 ml 'v / ater resolved. The pH of the mixture is lowered to 2.0, then undissolved solid is filtered off. It is recrystallized from acetone / hexane, 0.28 g of the Title compound of mp 127.5-129 ° 0 is obtained.

Example XXXIII

N- (4- / 3-phenylpropyl7piperidinocarbonyl) -2-phenylethene sulfonamide

A solution of 1.77 g (7.5 millimoles) of N- (N-propylcarbamoyl) -2-phenylethensulfonamide, 3.0 g (15 millimoles) 4- (3-phenylpropyl) piperidine and 0.86 ml (15 millimoles) acetic acid in 10 ml of dimethylformamide is heated to 100 to 105 ° 0 for 4 hours. The reaction mixture is then cooled to 25 ° G and 50 ml of 1N hydrochloric acid and then 50 ml of ether are added. The phases are separated and 50 ml become the ether phase In sodium hydroxide solution added. This creates an intermediate phase an oil, the 3 layers are separated and the aqueous layer is discarded. The ether phase becomes with Washed with water and concentrated in vacuo to give 2.3 g of a viscous liquid. The intermediate layer off The oil is dissolved in 25 ml of water, then acidified with concentrated hydrochloric acid. The acidified aqueous phase is with

5 0 9 8 2 4/1018

Ethyl acetate extracted and the extracts with l / i / water washed and concentrated in vacuo. This gives 0.5 g of a rubbery residue.

The 2.3 g of oil and 0.5 g of the gummy residue are combined and lychromatographed on a column of silica gel. The first few fractions are combined and concentrated in vacuo, 0.3 g of an oil being obtained. This is dissolved in 0.5 ml of AGeton, then 5 ml of sodium hydroxide solution and then 10 ml of water are added. The crude product precipitates out as the sodium salt. That. The sodium salt is dissolved in 3 ml of acetone, then 5 drops of concentrated hydrochloric acid and 10 ml of water are added. This solution is extracted with ethyl acetate. The dried extract is concentrated in vacuo and the residue is recrystallized from acetone / hexane, 12 ml of the title compound vom.l · ¹ . 119 - 122 ° C can be obtained. -After two more recrystallizations from acetone / hexane, the product melts at 127.5 to 129.5 ° C.

Example XXXIV

A dry solid pharmaceutical preparation is produced by mixing the following substances in the specified Weight quantities:

N- (1,2,3,4-tetrahydroisoquinino = 50 linocarbonyl) -2-phenylethene = sulfonamide

Sodium citrate 25

Alginic acid 10

Polyvinyl pyrrolidone 10

Magnesium stearate. . 5 ·

50 9 82 4/1018

After careful mixing, the mixture turns into tablets punched out, each tablet having a size such that it contains 100 mg of active ingredient.

With a corresponding change in the amount of active ingredient by weight and diluents are also tablets containing 10, 25, 50 and 200 mg of N- (1,2,3,4-tetrahydroisoquinolinocarbonyl) -. 2-phenylethensulfonamide manufactured.

Example XXXV

A dry solid pharmaceutical preparation is made by combining the following substances in the specified amounts by weight generated:

N- (4-, | / 3-Phenylpropy! ^ Piperidino carbonyl) - 25O ₉ O 2-phenylethensulfonamide

Lactose 190.2

dried corn starch 50.0

"Sterotex K" (hydrogenated vegetable oil) 9.8

The dry mixture is carefully agitated so that one Maintains a completely uniform mixture. Soft elastic and hard gelatin capsules are filled with it, whereby you do so much of the mixture is filled in so that each capsule contains 250 mg of active ingredient.

By changing the proportions of sulfonamide and diluent, capsules with 50, 100 and 500 mg Active ingredient manufactured.

Example XXXVI

To a solution of 4.12 g of N- (4- / 3-I ⁾ henylpropyl7piperidino = carbonyl) -2-phenylethensulfonamide in 100 ml of n-butanol

509824/1018

a solution is added with stirring, which is obtained by dissolving 39 for potassium had been prepared in 1 ml of n-butanol. That G-emisch is stirred for a further 15 minutes, then the solvent distilled off in vacuo. 250 ml of diethyl ether are added to the residue, and the mixture is then stirred for 15 minutes. The solid is then filtered off and dried in vacuo.

inan ._ _

net, where the potassium salt of N- (4- / 3-phenylpropyl / piperidino =

carbonyl) -2-phenylethensulfonamides

Example XXXVII .

Normal male Sprague-Dawley rats (Charles River) will be Starved for 9 hours. Test groups of 5 animals each then ground overnight (15-16 hours) with minced meat Purina rat chow fed 0.2 ^ 5 of the test compound contains. The following morning, the Deprived of food and then gavaged 50 ml / kg of the test compound to each rat. After two more hours administration of 300 mg / kg Triton WR-1339 takes place (Oxyethylated tert-octylphenol / JiOrmaldehyd-Polymer, Manuf. Ruger Chemical Co., Philadelphia, Pa.) In saline by injection into the tail vein ", after a further 2 hours a second gavage administration of 50 ng / kg of test compound. After 4 hours, the rats are over the Abdominal aorta bled under pentobarbital anesthesia. the Control animals are treated in the same way, but only receive rat chow and the two doses by means of the Gastric tubes do not contain a fixed connection. The depth of comparison receive the same amount of Triton as the test animals.

The plasma is obtained from the heparinized blood samples and the oholesterin concentration is determined by means of the auto-analyzer

509824/1018

lysers (Technicon method N-24a). The activity of the The most beneficial compound is determined by looking at the amount of cholesterol in the plasma of the treated had compared with the amount of cholesterol in the comparison animals. The results shows the following table. The values given have been calculated by subtracting the cholesterol concentration in the treated rats from the cholesterol concentration the comparison animals, the difference being given as a percentage of the comparison value.

Test compound $ cholesterol decrease

N- (N-n-butylcarbamoyl) -2- (p-chloro = 8 phenyl) ethensulfonamide

N- (piperidinocarbonyl) -2-phenyl = 5

ethensulfonamide

509824/1018

-ί> 9_

Cholesteiin.-

N- (N- [(£ arboxymethyl] carbamoyl) -2-pheny1-iithene-sulfonamides

N- (W-Cyclohexyl carbamoy 1) -2-phenyl "then λ-sulfonamide?

a *

N_ (N- [Athoxycarbönylmethyl] carbamoyl) -2-phenylä'thenusülf onamid 5 »

N- (N, N-fii [n-butyl] carbamoyl) -2-phenylethene-sulfonamides

N- (4-eenzylpiperidinocarbonyl) -2-phenyla "th ~ eni.sulfonaniid, ^

U- (N-n-propylcarbamoy 1) -1, l-diphenyljithene— sulfonamides

N- (N- ^ lIy lcarbamoyl) -2-phenylätthen ^ sulfon— amidi ..

N- (H- | J <ethyl-N- [2-phenyl thyl] carbamoyl) -2-phenyl-thentesulfonamide c

N- (lzacyci oheptylcarbonyl) -2-phenylähene τ sulfonamides.

N- (N, N-fiii [2-methylprop-1-yl] carbamoyl) -2- phenyl-phenosulfonamide ". . .

N- (ftorpholinocarbonyl) -l-phenylproρenί.-2-sulfonamide · · ·

• N- (N- [I-A thoxycarbony 1-2-methy lprop-1-yl] - carbamoyl) -2-phenyl3kthenc sulfonamides. '

N- (4- [3-ifthenylpropyl] piperidinocarbonyl) - 2-phenylathene sulfonamidt

Il

Il

Il

• 14

9 5 5

12th

-.16

15th

* 30

20 31

'509824/1018

ORIGINAL INSPECTED

-7C-

XXXVIII

A normal adult beagle dog weighing about 10 kg is fed Purina dog food once a day for several days at 12 noon. On two consecutive mornings, the dog will be bled from the jugular vein and the plasma oholesterol levels will be decreased
measured by a method suitable for the Technicon Auto-Analyzer. The mean value of these concentrations represents the base value for the cholesterol content in the plasma of this dog. The dog then receives the test compound orally twice daily. continuing once a day at 12 noon
is fed Purina dog food. On the morning of the 6th day after the start of administration of the test compound, the
Dog in turn is bled from the Tirosselader and again the cholesterol concentration in the plasma is measured with the Technicon
Auto-analyzer measured. The value is compared with the base value for the purpose of determining the hypolipidemic properties of the test compound. The results are shown in the table below;

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co> σ

link

N- (N- / n-i3utyl7carbainoyl) -2-pb.enylethensulfonamide. N- (N- / m-Tolyl7 ^c a ^r t) amoyl) -2-phenylethensulfonamide

N- (N- / n-Buty: i7carbamoyl) -1-phenylpropene-2-sulfo ~ namid

Il

N * - (1 »2,3» 4-tetrahydroisoquinolinocarbonyl) -2-phenylethensulfonamide

Il

Il Il

N- (4- / 3-Phenylpropyl7piperidinooarbonyl) -2-phenyl-ethensulf onainid

It Il Il Il

N- (N- / Üarboxymethyl7 ^{car1:) a} i ^DO yl) ~ 2-phenylethensulfonamide "

Amount of gholesterol in plasma (m g / 100 ml)

F - female

M = male.

gender Reason- After u-ta'U ^ er lot of ' value administration (mg./kg. ) Dog 296 the i'tiütiv & rb. 25th P. 143 202 25th M. 149 ■ 132 25th P. 135 129 .25. ■ M 157 94 .25 P. 130 136 25th .M. 176 128 25 · P. 155 138 25th M. 137 34 . 2.5 ■ .M 159 128 2.5 M. 160 146 1 P. 190 157. ι 1 ■ · Μ. 120 H3 3 Ul P. 150 • 114 ι Ul • ρ 152 125 VJl M. 123 127 5 M. 170 '106 1 P. 180 1-56 1 P. 170 157 1 M. 150 ■ 141 1 M. 140 113 VJl P. 150 113 VJl ■ ρ 140 210 ■ 5 M. 170 140 ^ 5 M. ¹⁶ .7 pounds ; CD

The following preparations serve to illustrate the preparation of some of the starting materials of the preceding examples.

Preparation A; 1-phenylpropene-2-sulfonamide

To 17 »5 ml of dimethylformamide of 15 ° G are added with stirring in the 15.5 ml of sulfuryl chloride were added dropwise over the course of 30 minutes. The temperature is kept below 25 G during the addition. Then the mixture is stirred for a further 30 minutes at 25 G, then 11.3 g of 1-phenylpropene are added. That The reaction mixture is heated to 90 to 93 ° G for 75 minutes, then poured onto 400 g of crushed ice, whereupon the product is extracted in methylene chloride. The solvent is dried with anhydrous sodium sulfate and then in vacuo distilled off, 18.7 g of 1-phenylpropene-2-sulfonyl chloride as a liquid.

The 1-phenylpropene-2-sulfonyl chloride is concentrated to 200 ml Ammonium hydroxide added. After one hour, the crystalline precipitate formed is filtered off and washed successively with water and hexane. The thus obtained Crude product is between 150 ml in sodium hydroxide solution and 50 ml of ether distributed, two clear phases being obtained. The ether phase is removed and washed with 50 ml of water washed, then the washing solution is added to the original aqueous phase. The combined solution is concentrated with Hydrochloric acid acidified, whereupon the product precipitates. It is filtered off and 10.9 g are obtained after drying 1-phenylpropene-2-sulfonamide from I \ 138 to 139.5 °. G.

Preparation B;

According to the instructions for preparation A, 2-phenylpropene is used with

50982 4/1018

Sulfuryl chloride reacted in dimethylformamide, whereby the 2-phenylpropene-i-sulfonyl chloride is obtained. This provides the Treat the 2-phenylpropene-i-sulfonamid'vom with ammonia J ?. 101-102.5 ° C

1,1-Diphenylethene is substituted with sulfuryl chloride in dimethylformamide around and then treated with ammonia after According to the procedure of preparation A, the 2,2-diphenyl = ethensulfonamide is obtained from P. 134 - 135 ° C.

Analysis: Calculation for C ₁₄ Hu ₅ NO ₂ S: G: 64.86; H: 5.05; N: 5.40 # _o Found: C: 64.73; H: 5.02; -N: 5.26 ^ _O

Preparation G:

The procedure of preparation A is repeated, but below Replacement of 1-phenylpropene with an equimolar amount of the corresponding phenylethene, pnenylpropene, phenylbutene or diphenylethene, the following sulfonamides being obtained:

2-phenylbut-1-en-1-sulfonamide, 2- (p-Chlorophenyl) propene-1-sulfonamide, 2- (p-Met hoxyphenyl) propene-1-sulfonamide, 1- (m-chlorophenyl) propene-2-sulfonamide, 2- (p-chlorophenyl) but-1-en-1-sulfonamide, 1,2-Diphenyläthensulfonamid, 3-phenylbut-2-en-2-sulfonamide, 1- (p ~ chlorophenyl) propene-2-sulfonamide, 1,2-diphenylpropene-1-sulfonamide, 2- (p-Iolyl) propene-1-sulfonamide, 2- (p-isopropylphenyl) propene-1-sulfonamide, 1- (p-ethoxyphenyl) propene-2-sulfonamide, 2- (p-fluorophenyl) propene-1-sulfonamide, 2- (p-butoxyphenyl) propene-1-sulfonamide, - 1-phenylbut-1-en-2-sulfonamide,

509824/1018

3- (m-chlorophenyl) but-2-en-2-sulfonamide, 2- (p-chlorophenyl) -2-phenylethensulfonamide, 2- (pn-butylphenyl) propene-1-sulfonamide, 2- (m-methoxy phenyl) propene-1-sulfonamide, 2- (p-biphenylyl) propene-1-sulfonamide, 2,2-diphenylathene-sulfonamide, 2- (m-chlorophenyl) propene-1-sulfonamide, 2- (m-bromophenyl) propene-1- sulfonamide, 2- (m-tolyl) _propen-1-sulfonamide, 1- (o ~ chlorophenyl) propene-2-sulfonamide, 1- (p-i'luorophenyl) propene-2-sulfonamide, 1- (p- Tolyl) propene-2-sulfonamide, 1- (m-methoxyphenyl) propene-2-sulfonamide, 2- (p-Iolyl) but-1-ene-1-sulfonamide, 2- (m-methoxyphenyl) but-1-ene -1-sulfonamide, 1- (p-chlorophenyl) but-1-en-2-sulfonamide, 1- (m-methoxyphenyl) but-1-en-2-sulfonamide and 3- (p ~ chlorophenyl) but-2- en-2-sulfonamide

Preparation D:

N, N-diphenylcarbamoyl chloride is treated with N- (endo_7-0xabicyolo- / 2.2. _- 17'heptan-2-ylmethyl) amine essentially by the method of McManus et al., J. Laed. Chem., 8, (1965) 766 for the preparation of 1, i-diphenyl-3-cycloheptylurea. The product obtained is 1,1-diphenyl-3- (endo-7-oxabicyclo / 2.2.j7keptan-2-ylmethyl) urea, melting at 109-111 ° C,

Analysis: At ·., For G ₂₀ H ₂₂ N ₂ O ₂ : G: 74.49; H: 6.89; 'N: 8.68? $. Found: G: 74.28; H: 6.95; N: $ 8.61. '

In an analogous way one obtains from Ν, Ν-diphenylcarbamoyl chloride and N- (exo-7-0xabicyclo / 2.2.J ^[7b-e P ^{'t-2-ylmethyl)} amine to 1,1-diphenyl-3- (exo 7-oxabicyclo / 2o2.j [7heptan-2-ylmethyl) urea from b \ 128 - 130 ° C.

509824/1018

analysis: Ber. for C ₂₀ H ₂₂ N ₂ O ₂ : G: 74.49; H: 6.89; N: $ 8.68. Found: C.:74.70; H: 6.75; N: $ 8.87.

Preparation: .. · ...

End and ego isomers of N- (7-

heptan-2-ylmethyl) amine ^;

A solution of 55 ml of titanium tetrachloride in 500 ml of benzene is added with stirring to a solution of 212 g of acrylonitrile, 272 g of iurane and 50 mg of hydroquinone in 1 liter of benzene. The addition is carried out at such a rate that the internal temperature does not exceed 35.degree. The reaction mixture is then stirred for 5 days at room temperature and then treated with 500 ml of 0.5N hydrochloric acid. After the filtration, the aqueous phase is separated off and extracted with benzene. The two benzene solutions are then combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. This gives 156.3 g of a mixture of endo- and exo-7-oxabicyclo / 2.2._1 _j 7hept-2-en-5- ylcyanido

130 g of this isomer mixture are dissolved in 1 liter of acetone and hydrogenated at 3.5 kg / cm pressure in the presence of 2 g of palladium-barium sulfate. The catalyst is filtered off, then the solvent is evaporated off under reduced pressure <, - The remaining oil is fractionally distilled, 55.5 g of pure enäo ~ 7-0xabicyclo / 2.2cj_7h ^e P "fcan-2-ylcyanid, Kp _{0 1} = 45 ° C and 37 * 9 g of pure exo-7-0xabicyclo / 2.2c_l7heptan-2-ylcyanid, bp _{0 Q2} = '48 G is obtained, furthermore a small fraction of 14.7 g is obtained from the exo and endo mixture .

To alyse: Ber. for G ₇ H ₉ NO: G: 68.27; H: 7.37; N: -11.37 $.

Found for endo isomer: G67.96; H: 7 _S 21; N: $ 11.37.

- Found for exo isomer: G: 68.32; H: 7.42; N: $ 11.64.

50982A / 1018

To a solution of 54.3 g of endo-7-oxabicyclo / 2.2 <._ 1_7 ^{1: le} P ^{'ta: 1} - "2-ylcyanid with stirring 24 ml of a slurry of Raney nickel in 500 ml of methanol was added in ^methanol! , then a solution of 33.2 g of sodium borohydride in 11 ml of 4N sodium hydroxide solution is added dropwise. During the latter addition, external cooling is carried out in order to keep the internal temperature at 40 to 50 ° C. After the addition has ended, the mixture is stirred for a further 20 minutes The solids are then filtered off. The filtrate is concentrated in vacuo and the residue is suspended in 500 ml of sodium hydroxide solution. The mixture is extracted several times with chloroform, then the combined extracts are dried and concentrated, whereby 55.5 g of N- ( endo-7-0xabicyclo / 2 ".2.j7heptan-2- * yl = methyl) amine from Kp-J ₀ = 90 0.

A sample of the exo-7-0xabicyclo / 2 \ 2.j7heptan-2-r-ylinethylcyanideS is made with Eaney-Nic ^ cel and sodium borohydride in methanol, such as described using the example of the endo isomer, reduced. Included you get that in high yield

heptan-2-ylmethyl) amine of bp _1. ^ ₆ = 92 - 96 ° G.

Preparation ff: 4 ~ (3- / p-methoxyphenyl7propyl) pyridine

To a 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 room temperature. The mixture is heated to 60 for 1 hour. After cooling to room temperature, the mixture is poured onto 50 g of crushed ice. Then a little ether is added, the org ^ ical phase is separated, washed successively with O, 5N sodium hydroxide ^ WSSC Le ^ ^{e: i} Uend evaporated to dryness!. 2.8 g of 2- (p-methoxyphenyl) ethyl bromide are obtained in the form of an oil.

509824/1018

This oil is dissolved in 15 ml of ether, the solution becomes too 243 mg magnesium shavings, which are covered with 10 ml ether, added dropwise. A few crystals of iodine are added, then the solvent is refluxed until practically all Magnesium reacted. You get a. Ether solution of 2- (p'-methoxyphenyl) ethenemagnesium bromide.

This Grignard solution becomes 1.04 g at 0 ° G with stirring 4-cyanopyridine in 15 ml of ether was added dropwise. After the addition the reaction mixture is refluxed for 4 hours and then stirred overnight at room temperature. Then it will be the reaction is stopped with ice water and the aqueous phase is acidified with concentrated hydrochloric acid. The watery Phase is separated off and heated to 85 to 90 ° C. for 1 hour. After cooling to room temperature, extraction is carried out with chloroform and then with ether. The united organic Extracts are dried over anhydrous magnesium sulfate and concentrated in vacuo, · v / o if the product is an orange Receives oil. It consists of 2- (p-methoxyphenyl) ethyl-4-pyridyl ketone.

800 mg of this ketone are refluxed with 850 mg of hydrazine hydrate for 2 hours. At this point, 1.6 g of potassium hydroxide powder are added, and the mixture is then refluxed for a further 2 hours. The reaction mixture is then cooled to room temperature, diluted with 20 ml of water and extracted with ether. After drying, the ether extract is concentrated to dryness, 260 mg of 4- (3- / p-methoxypheny _- 17- * propyl) pyridine remaining.

Preparation G; '

According to the instructions for preparation F , one obtains from the

509824/1018

Speaking cyanopyridine and (hydroxyalkyl) - benzene following Products:

3- (3-phenylpropyl) pyridine, '

2- (3-phenylpropyl) pyridine, 4- (2- / p-1.3opropoxyphenyl7ethyl) pyridine, 3- (3- / p-Butoxypnenyl7prop.yl) pyridine, 4- O-Zp-Isopropylphenyl / propyl) pyridine, 4- (3- / p-tert-ethylphenyl7propyl) pyridine, 4- (m-methylbenzyl) pyridine, 4- (3- / m-methoxyphenyl7propyl) pyridine, 4- (3- / p-methoxyphenyl7propyl) pyridine, 4- (2 ~ / p ~ methoxyphenyl7ethyl) pyridine, 4- (4- / m-methoxyphenyl7butyl) pyridine, 4- (3- / p-Tolyl7propyl) pyridine, 4- (5- / m-methoxyphenyl7pentyl) pyridine, 4- (4-phenylbutyl) pyridine, 4- (5-phenylpentyl) pyridine, 4- (2-phenylprop-1-yl) pyridine and.

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

Preparation H: 4- (3- / p-methoxyphen.yl7p ^ opyl) piperidine

A solution of 2.27 g of 4- (3- / p-methoxyphenyl7propyl) piperidine in 50 ml of 1, on-dalzoic acid is at low temperature and 3 »16 kg / cm Pressure hydrogenated in the presence of 150 mg of platinum oxide. To. The theoretical amount of hydrogen was absorbed for 20 hours and the catalyst was filtered off. The PiItrat was made basic with 5N sodium hydroxide solution and then extracted with ether. The extract was dried and concentrated in vacuo leaving 2.2 g of an oil which slowly solidified. The 4- (3- / p-methoxy = phenyl7propyl) pipe ridin from the i ?. 65 - 70 ° G obtained.

5098 24/1018

Preparation I:

If the pyridine derivatives listed in preparation G are hydrogenated according to the instructions for preparation H, the following are obtained Pyridine compounds:

3- (3-phenylpropyl) piperidine, 2- (3-phenylpropyl) piperidine, 4- (2- / p-Isoprppoxyphenyl7.ät hyl) ^piperidine; 3- (3- / p-Butoxyphenyl7propyl) piperidine, 4- (3- / p-Isopropylphenyl7propyl) piperidine, 4- O-Zp-tert-butylphenyl / prop / l) piperidine, 4- (m-methylbenzyl) piperidine, 4 - (3- / m-methoxyphenyl7propyl) piperidine, 4- (S- ^ o-methoxyphenyl / propyl) piperidine, 4- (2- / p-methoxyphenyl7ethyl) piperidine, 4- (4 ~ _- / m-methoxyphenyl7butyl) piperidine, 4- (3-Zp-iolyl7propyl) piperidine, 4- (5- / 5-methoxyphenyl) pentyl) piperidine, 4- (4-phenylbutyl) piperidine, 4- (5-phenylpentyl) piperidine, 4- (2-phenylprop- i-yl) piperidine and 4- (2-phenylbut-1-yl) piperidine.

Preparation J: 4- (3-phenylpropyl) piperidinocarbonyl chloride

Phosgene is introduced into 150 ml of dry toluene at 0 ° G, until 17 g of gas have been absorbed. The cooling bath is then removed and the phosgene solution is added while stirring A solution was added dropwise over the course of 1 hour, consisting of 27 »6 g 4- (3-phenylpropyl) piperidine, 12th, 3 ml pyridine and 100 ml Toluene had been prepared. After the addition has ended, the mixture is left to stand for a further 16 hours at low temperature.

., 50982A / 1018

■ -30-

Then, Ji is filtered, ¹ Utrat is concentrated in vacuo to give 39 g of iitelverbindung be obtained as a crude product. This product is contaminated with toluene, but sufficiently pure for coupling with alkene sulfonamides.

509824/1018

Claims (5)

Claims. 1. A composition for lowering elevated lipid content in the blood of mammals ·, of a pharmaceutically acceptable l'räger and an N-üarbamoyl-2-phenyläthensulfonamid, characterized in that it comprises sleeves as sulfonamide is a compound of Fo X , ^ O .C = C-SO ₀ -NH-CL AB or contains a pharmaceutically acceptable salt thereof, where in the above formula L is the remainder. Z or -N-Cx » ² X hydrogen, chlorine or the methyl radical, A and B hydrogen, the methyl or ethyl radical, Z the pyrrolidino, morpholino, thiomorpholine, 1,2,5 »6-tetrahydropyridino, 1» 2,3, 4- 'i ¹ etrahydropyridino-, 1, 2,3, 4-tetrahydroisochino = lino-, azacycloheptan-1-yl, azacyclooctan-i-yl-, 3-aza = bicyclo / 3.2._27nonan-3-yl-, piperidino-, 4-Hydroxypiperi = dino, 4-methoxypiperidino, 4-carboxypiperidino or ■ 4-phenylpiperidino, ⁷ diIt 1 to 3 carbon atoms in the alkyl portion, a (phenylalkyl) -piperidino radical with 1 to 5 carbon atoms in the alkyl portion or a (/ sub = substituted phenyl7alkyl) piperidino radical with 1 to 5 carbon atoms in the alkyl moiety, the substituted phenyl radical by the hydroxyl group, alkyl with 1 to 4 carbon atoms or alkoxy with 1 to 4 carbon atoms may be substituted, and R and R are hydrogen, alkyl radicals with 1 to 10 carbon atoms, alkenyl radicals with 3 to 6 carbon atoms, cycloalkyl radicals with 3 to 7 / ~ an alk, 7 "lpiperid.inorest ORIGINAL INSPECTED 509824/1018 Carbon atoms, phenylalkyl radicals with 1 to 2 carbon atoms in the alkyl portion, carboxyalkyl radicals with 1 to 7 carbon atoms in the alkoxy portion, alkoxycarbonylalkyl radicals with 1 to 2 carbon atoms in the alkoxy portion and 1 to 7 carbon atoms in the alkyl portion, de »bicyclo- / 2.2., I7hept-2 -en-5-ylmethyl-, 7-uxabicyclo / 2.2. jjhe ^ tan 2-ylmethyl, bicyclo _i /2.2o _i i7heptan-2-ylmethyl radical, phenyl, or a substituted phenyl radical, substituted by fluorine, chlorine, bromine, the nitro group, alkyl with 1 to 4 carbons carbon atoms or alkoxy may be substituted with 1 to 4 carbon atoms, provided that R and
not both represent hydrogen. 2. Means according to claim 1, characterized in that A and B consist of hydrogen and L is a radical. Z in JiOrm of a 4 - (<w-phenylalkyl) piperidino radical with 1 to 5 carbon atoms in the alkyl moiety or one 4 - ("- / substituted Phenyl7alkyl) piperidino radicals with 1 to 5 carbon atoms in the alkyl moiety, the phenyl radical of which is replaced by the Hydroxyl group, alkyl having 1 to 4 carbon atoms or Alkoxy is substituted by 1 to 4 carbon atoms, represents. 3. Agent according to claim 2, characterized in that X is hydrogen. 4. Means according to claim 3, characterized in that Z denotes the 4- (3-phenylpropyl) piperidino radical. 5. Means according to claim 1, characterized in that A and B is hydrogen and Z is the 1,2,3,4-tetrahydroisoquinoline radical means. ORIGINAL INSPECTED ■ 50.9824 / 1018 6. Means according to claim 1, characterized in that L a remnant of the Pormel C ^ ₂ and A, B and X represent hydrogen. 7. Composition according to claim 6, characterized in that R is hydrogen
means. Hydrogen and R the η-butyl or carcoxymethyl radical 8. N-Garbamoyl-2-phenylethensulfonamide of the jormel X> _t O C = C-SO ₀ -NH-CL AB wherein L is a radical Z or -N. ₉ , X! Hydrogen, chlorine . ^ R or the methyl radical, A and B hydrogen, the methyl or ethyl radical, Z the pyrrolidino, morpholino, thiomorpholino, 1,2,5, S-tetrahydropyridinq, 1,2,3 ,, ^ tetrahydropyridino- , ^J \, 2,3j 4-l ¹ etrahydroisoquinolino-, azacycloheptan-T-yl-, azacyclooctan-i-yl-, 3-azabicyclo / 3.2.27nonan-3-yl-, piperidino-, 4-hydroxypiperidino-, 4 -Methoxypiperidino, 4-carboxypiperidino or 4-phenylpiperidino, an alkylpiperidino with 1 to 3 carbon atoms in the alkyl part, a (phenylalkyl) -piperidino with 1 to 5 carbon atoms in the alkyl part or a (/ substituted phenyl7-alkyl) piperidino with 1 to 5 carbon atoms in the alkyl moiety, the substituted phenyl radical being substituted by hydroxyl, alkyl with 1 to 4 carbon atoms or alkoxy with 1 to 4 carbon atoms 12th
can, and R and R hydrogen, alkyl radicals with 1 to ORIGINAL IMSPECTED 509824/1018, · -8t- 2 4 5 6 9 A 7 Carbon atoms, -alkenyl res te- with 3 to 6 carbon atoms, cyeloalkyl residues with 3 to 7 carbon atoms, phenylalkyl residues with 1 to 2 carbon atoms in the alkyl portion, carboxyalkyl residues with 1 to 7 carbon atoms in the alkyl portion, alkoxycarbonylalkyl residues with 1 to 2 carbon atoms in the alkoxy portion and 1 to 7 carbon atoms in the alkyl part, the bicyclo-. /^.J/b-ept^-en-S-ylmethyl-, 7-0xabieyclo / 2.2oj7-heptane-2.ylmethyl ~ or bicyclo / 2.2 _e j7n ^e P ' ^tan - ² -y ^lme = tjiyl radical, the phenyl radical or a phenyl radical substituted by fluorine, chlorine, bromine, the nitro group, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, provided that 1 2
that R and R do not both consist of hydrogen and with the further proviso that if L ■ - ^ ' ^! C-d2 loading 1 2 interprets and A and B and one of the radicals R or R vVas- 12th mean hydrogen, the other radical R or R is hydrogen, alkyl, alkenyl, cycloalkyl, phenyl or substituted Phenyl must be different. 9 «sulfonamide according to claim 8, characterized in that A and B denote hydrogen and L denotes a radical Z in Ji'orm a 4 - ("- Phenylalkyl) piperidino radical with 1 to 5 carbon atoms in the alkyl moiety or a 4 - (^ - ^ iubstituted PhenylJ-alkyl) piperidino radical with 1 to 5 carbon atoms in the alkyl moiety, the phenyl radical being represented by hydroxyl, alkyl having 1 to 4 carbon atoms or Alkoxy is substituted by 1 to 4 carbon atoms, represents. 10c sulfonamide according to claim 9i, characterized in that that X is hydrogen. 11. sulfonamide according to claim 3, characterized in that that Z denotes the 4- (3-phenylpropyl) piperidino radical. 509824/10 18 -8B- 12. dulfonamid.nach claim 8, characterized in that that A and B are hydrogen and Z is the 1,2,3,4-tetrahydroisoquinolino radical means. / 13. Sulphonamide according to claim S, characterized in that L is a radical ~ ^N: C; r2 ^{and A} » ^{B and x are} hydrogen. 14o sulfonamide according to claim 13, characterized in that R ^{1 is} hydrogen and
methyl radical means. 1 2 that R is hydrogen and R is the η-butyl or Garboxy- 15 sulfonamide according to claim 8, characterized in that that Z a. 4- (Phenylalkyl) -pipiridino radical with 1 to 5 carbon atoms' in the alkyl portion or one of (/ substituted phenyljalkyl) piperidino radicals different Rest is. 16. Process for the preparation of an N-Garbamoyl-2-phenyl = ethensulfonamides according to claim 8, characterized in that that one has an alkene sulfonamide of the formula wherein X, A and B have the meaning given in claim 8 own, or a reactive derivative thereof, with a reagent which provides a carbamoyl group and which leads to the formation of a - C - L group 5 0 9 8 2 4/1018 1 ? is able to convert and optionally R or R hydrolyzed in the form of alkoxycarbonylalkyl radicals to give urboxyalkyl radicals or radicals Z in the form νοη / χ / hydroxyphenyl7alkyl) piperidino radicals demethylated. 17 · The method according to claim 16, characterized in that a compound of the formula - ^ j? —V // Vy — C = C- C = C-SOoNH, (III) AWAY in the presence of a base at 25 to 120 G with an isocyanate the formula R ¹ - N = C = 0 wherein X, A, B and R have the meaning given in claim 8, is reacted. 18. The method according to claim 16, characterized in that there is a compound of the formula C = C-SO ₂ -NH ₂ (III) AWAY in the presence of a base with a garbamoyl halide of the formula «2
ZC (= O) -Ct or R ¹ RN-GC = O) -HaI 1 2 converts, where in the above formulas X, A, B, Z, R and R have the meaning given in claim 8 and Hai Called chlorine or bromine ί / "". (/ methoxyphenyl7alkyl) piperidino radicals to 509824/1018: 19 · The method according to claim 16, characterized in that one compound of the formula "- C = C-SO ₉ -NH ₀ »ι * * - AWAY (HD i - ■! with a urea of the formula R ¹ NH-OONR ⁵ E ⁴ ", wherein in these" .Formulas X, A, B_ and R have the meaning given in claim 8, R is an alkyl radical with 1 to 7 carbon atoms, alkenyl radical with 3 to 7 carbon atoms, aryl radical, a substituted aryl radical, heteroaryl or substituted heteroaryl radical and R ^ represent hydrogen, a cycloalkyl radical with "3 to 8 carbon atoms, the benzyl or phenylethyl radical or a radical R, where each substituted radical represents up to 3 of the substituents chlorine, May have bromine, nitro, alkyl with 1 to 4 carbon atoms or alkoxy with 1 to 4 carbon atoms. 20. The method according to claim 16, characterized in that the sulfonamide in junction of the reactive derivative the formula C = C-SO ₀ -N = C = O ti ^ AWAY with an AmIn of the formula HZ or " HNR ¹ R ² 1 ? converts, where in the above formulas X, A, B, Z ,. R and R have the meaning given in the claim * 50 9 82 47 1018- -38- 21. The method according to claim 16, characterized in that the sulfonamide is in the form of the reactive derivative the .formula AWAY with an amine of the formula HZ or HNR ¹ R ² 1 2 Reacts., where in the above formulas X, A, B, R, R and 2 have the meaning given in claim 8 and R an alkyl radical with 1 to 6 carbon atoms, alkenyl radical with 3 to 7 carbon atoms, aryl radical or substituted aryl radical, heteroaryl or substituted Heteroaryl radical and R is hydrogen, a cycloalkyl radical with 3 to 8 carbon atoms, the benzyl or phenyl • z. represent ethyl radical or the radical R, each substituted Remainder by up to 3 of the substituents chlorine, bromine, nitro, alkyl with 1 to 4 carbon atoms or Alkoxy can be substituted with 1 to 4 carbon atoms. For: Pfizer Inc. Dr. Saint Beil Lawyer 5 0 9 8 2 4/1018