DK144270B - ANALOGY PROCEDURE FOR THE PREPARATION OF N-CARBAMOYL-2-PHENYLETHENSULPHONAMIDES - Google Patents

Description

(19) DENMARK (¾4 * f \ BR /

(12) SUBMISSION WRITING (id. 144270 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 6299/74 (51) lnt.CI.3 C C 143/833 (22) Filing date 4 dec. 1974 C 07 D 227/04 (24) Race day Dec 4 1974 C 07 D 295/20 (41) Aim. available Jun 6 1975 (44) Submitted Feb 1 1982 (86) International application # - (86) International filing day - (85) Continuation day - (62) Master application no -

(30) Priority 5 · Dec. 1973, 422088, US

(71) Applicant PFIZER INC., New York, US.

(72) Invented Gerald Fagan Holland, US.

(74) Associate Engineer Hofman-Bang & Boutard.

(54) Analogous process for the preparation of N-carbamoyl-2-pheylethylenesulfonamides.

The invention relates to an analogous process for the preparation of novel N-carbamoyl-2-phenylethenesulfonamides of the general formula I of claim 1. These compounds are derivatives of N-carbamoyl-2-phenylethenesulfonamide, also known as styrene-sulfonylurea, and are useful. to reduce serum lipid levels in mammals.

i) Atherosclerosis, which is a form of arteriosclerosis, is increasingly recognized as a predominant health problem in our day.

The disease is characterized by the deposition of lipids in the aorta, and in the coronary, cerebral and peripheral arteries of the lower extremities. As the deposits increase, there is a risk of thrombus formation and occlusion. Although the origin of atherosclerosis is not fully understood, it has been observed that many people suffering from this disease exhibit elevated plasma lipid protein levels, of which cholesterol and triglycerides are major components. Although dietary habits may help lower plasma lipoprotein levels, several therapeutic agents such as estrogens, thyroxine analogs and sitosterol preparations have been used for this purpose. Recently, ethyl 2- (p-chlorophenoxy) -isobutyrate (clofibrate) has been shown to be an effective means of reducing elevated triglyceride levels in humans.

Arenesulfonamides, substituted on the nitrogen atom by a monosubstituted carbamoyl group (arensulfonylureas), are a well-known class of organic compounds, some of which are known to have hypoglycemic properties. Eg. are N- (N-n-propylcarbamoyl) -p-chloro-benzenesulfonamide (chloropropamide) and N- (N-n-butylcarbamoyl) -p-toluene-sulfonamide (tolbutamide) are clinically useful oral anti-diabetic agents. However, there are few references in the literature to sulfonylureas in which the nitrogen atom in the urea portion, which is farthest from the sulfonyl group, carries two substituents which are different from hydrogen.

2-Phenylethenesulfonamides, substituted on the nitrogen atom by a carbamoyl group (styrenesulfonylureas) are not well known in the chemical or patent literature, although the disclosure to U.S.A. U.S. Patent No. 2,979,457, issued April 11, 1961, discloses a variety of aralkensulfonylureas having hypoglycemic properties.

The object of the present invention is to provide a process for the preparation of novel compounds which are useful agents for reducing elevated plasma lipid levels in mammals. A hyperlipidemic mammal may be administered an effective amount of a compound selected from 2-phenylethenesulfonamide derivatives of the general formula: S / R 11 β-CH = C-SO 2 -NH-C-N x 1 in which X, R, R and R are as defined in the preamble of claim 1, or pharmaceutically acceptable salts thereof.

The process according to the invention is characterized by the characterizing part of claim 1.

Particularly preferred hypolipidemic agents of formula I are those wherein R is hydrogen and -NR R is 4- (u'-phenylalkyl) piperidino having 1-5 carbon atoms in the alkyl moiety. In this context, u-phenylalkyl represents straight-chain alkyl groups having a phenyl group on the terminating carbon atom of the alkyl group, e.g. 2-phenylethyl, 3-phenylpropyl and 5-phenylpentyl. The preferred value of X is hydrogen. A particularly valuable compound of formula I is that wherein X and R are both hydrogen and -NR R is 4- (3-phenylpropyl) -piperidino, because of its very high activity as shown by the last four values of the table in the following Example 23.

Other particularly preferred hypolipidemic agents of formula I are those wherein R is hydrogen and -NR R is 1,2,3,4-tetrahydroisoquinolino.

Particularly preferred are also the hypolipidemic agents of formula I, wherein 2, X, R and R are all hydrogen and R is either alkyl of 1-4 carbon atoms, especially n-butyl, or 1-carboxyalkyl of 2-5 carbon atoms, especially carboxymethyl.

Also particularly preferred are the hypolipidemic agents of Formula I wherein X and R are both hydrogen, R and R are each alkyl of 1-4 carbon atoms, especially n-butyl.

Individual compounds of particular value are: N- (Nn-butylcarbamoyl) -2-phenylethenesulfonamide, N- (N- / carboxymethyl7carbamoyl) -2-phenylethenesulfonamide, N- (4- / 3-phenylpropyl7piperidinocarbonyl) -2-phenylethenesulfonamide and N- (1,2,3,4-tetrahydroisoquinolinocarbonyl) -2-phenylethenesulfonamide,

In the process of the invention, the compounds of formula I are synthesized from an alkenesulfonamide of formula

(v A-ch = c-so2-NH2 III

wherein X and R are as previously defined, by one of several methods, four such methods, hereinafter referred to as Methods A, B, C and D, will now be discussed and described in detail.

Method A consists in reacting a compound of formula III with 2 an organic isocyanate of formula R -N = C = 0 in the presence of a base.

The reaction is usually carried out by contacting the reagents in a suitable solvent at a temperature in the range 25 - 120 ° C, and preferably 60 - 80 ° C. Suitable solvents which may be used are those which will serve to dissolve at least one of the reactants and which will not adversely affect either the reactants or the product. Examples of such solvents are ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane; chlorinated hydrocarbons such as chloroform, methylene chloride and 1,2-dichloroethane; lower aliphatic ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters such as ethyl acetate and butyl acetate; and tertiary amides such as N-, N-dimethylformamide, Ν, Ν-dimethylacetamide and N-methylpyrrolidone. A wide variety of bases of both organic and inorganic type can be used in the process of the invention, as it is found that the primary function of the basic agent is to form a salt of the sulfonamide reactant. Bases which may be used include tertiary amines such as triethylamine, tributylamine, N, N-dimethylaniline, pyrridine, quinoline, N-methylmorpholine and 1,5-diazabicyclo / 5.3.07non-5-ene; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal oxides such as sodium methoxide, potassium methoxide and sodium methoxide; metal hydrides such as sodium hydride and calcium hydride; metal carbonates such as sodium carbonate and potassium carbonate; and alkali metals such as sodium and potassium. In most cases, a molar equivalent base, based on the sulfonamide used, is used, but smaller and larger amounts than a molar equivalent can be used ¥ 5 144270 successfully. Although it is common to add a double or triple excess of isocyanate, this is not necessary and sometimes equimolar amounts are used, especially in cases where it would be inappropriate to remove the excess isocyanate from the product. In fact, it is possible to use an excess of sulfonamide, in which case some sulfonamide remains at the end of the reaction. When operating at about 80 ° C, reaction times of some hours, e.g. two hours. A particularly convenient way of isolating the product involves adding the reaction mixture to an excess of dilute aqueous acid. If this causes the product to precipitate, it is filtered out directly. Alternatively, it is extracted into a water-immiscible organic solvent, which is then separated and evaporated to leave the crude product. In many cases, the raw product is essentially pure, but if desired, it can be further purified by well known methods.

As will be appreciated by one of ordinary skill in the art, it is possible in advance to form a salt of the starting sulfonamide which is then treated with the isocyanate in a subsequent step. In this case, the same method and conditions as discussed above are applicable in the second step of this two step process.

The starting isocyanates used in Method A are either commercial products or are readily prepared by reacting the appropriate amine with phosgene by the method set forth by Shriner, Horne and Cox in Organic Syntheses, Collective Vol. II, 453 (1943).

Method B consists of reacting a compound of formula III with a carbamoyl chloride of formula R R N-C (= O) -C1, in the presence of a base. In a typical procedure, approximately a molar equivalent of the carbamoyl chloride is added to a solution or suspension of the sulfonamide of formula III in a suitable solvent in the presence of the base. The same solvents and bases listed above under Method A are useful in this process and are usually used around a molar equivalent base. On the other hand, larger amounts of base can be used in cases where the excess base will not adversely affect the reactants or products. When the base is not soluble in the reaction medium, an excess is usually used. The reaction temperature and reaction time vary depending on a number of factors, such as the reactivity and concentrations of the reagents and the solubility of the reagents in the particular chosen solution system. However, the reaction is usually carried out in the temperature range of 40 - 120 ° C, and preferably at 50 - 80 ° C. At the latter temperatures, reaction times of a few hours are typically used, e.g. four hours. The product can be isolated by the same methods as described above under Method A.

An alternative variation of Method B, which is an approximate Schotten-Baumann procedure, and which is appropriate in some cases, consists in adding the carbamoyl chloride to a solution of the sulfonamide in water at about room temperature, keeping the pH within the range of about 7.0 to about 12.0 during and after the addition. At the end of the reaction, which typically takes about one hour, the reaction mixture is made acidic. If the product is precipitated, it is filtered out. Alternatively, it can be extracted into a water-immiscible organic solvent, which is then separated and evaporated to leave the crude product.

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

Method C consists of reacting a sulfonyl isocyanate of the formula

X. _ ^ R

CH = C-SO2-N = C = O (XV) wherein X and R are as previously defined, with the appropriate amine of the formula HNR ^ R ^. The reaction is usually carried out by contacting the isocyanate in a reaction inert organic solvent at about room temperature until the reaction is substantially complete. Reaction times of a few hours are usually used, e.g. from about 1 hour to about 12 hours. The same solvents listed in Method A are useful in the present process and the product is recovered by methods discussed above under Method A. Although the ratio of isocyanate to amine is not critical and the use of an excess of one of the components will successfully lead to the product, it is usual to use a small excess of the amine, e.g. the double amount.

The starting sulfonyl isocyanates are prepared from the corresponding sulfonamide of formula III by reaction with an excess of oxalyl chloride, followed by pyrolysis of the oxamic acid chloride intermediate thus obtained. Such transformations are well known in the art; see e.g. Franz and Osuch, Journal of Organic Chemistry, 29. 2592 (1964). In many cases, it is an appropriate procedure to use the sulfonyl isocyanate in the solvent in which it is prepared, without isolation. Furthermore, if desired, the oxamic acid chloride can be treated directly with the amine and this will successfully lead to the formation of a compound of formula I.

1 9

Method D consists of reacting an amine of the formula HNR R with a compound of the formula? s / r3., (v, y-CH = C-SO 2 -NH-CN (V) • 1 Λ -pj wherein X, R, R, R, R 5 and R 4 have the meaning previously defined. The reaction is carried out usually by heating the two reactants together in a reaction inert organic solvent which is usually a polar organic solvent which serves to dissolve the reactants.

Suitable solvents are e.g. lower alkanols such as methanol, ethanol and n-butanol: glycols such as ethylene glycol and propylene glycol ethers such as dioxane and 1,2-dimethoxyethane; acetonitrile; and tertiary amides such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and N-methyl-pyrrolidone. The reaction temperature and time required to complete the conversion to the product are related. At lower temperatures, longer periods are required, while the reaction at higher temperatures is completed in a shorter time. Furthermore, the rate of reaction depends on the nucleophilicity of the reactant and the efficiency of the leaving group.

In any case, reaction times of a few hours are usually used and the reaction is usually carried out at temperatures in the range of about 50 to about 150 ° C, preferably 80-100 ° C. At about 100 ° C

A reaction time of about 5 hours is usually used. If desired, the starting compound of formula V can be used in the form of a salt, e.g. an alkali metal salt such as the potassium salt. Alternatively, the compound of formula V may be introduced into the reaction medium in the form of a salt which is then neutralized by the addition of an alkanoic acid such as acetic acid. Although the reactants in this method are usually combined in equimolar amounts, the reactant ratio is not critical and an excess of one or the other component can be successfully used. The product can be isolated by evaporation of the solvent in vacuo and subsequent partitioning of the residue between dilute aqueous acid and a water-immiscible organic solvent. Evaporation of the organic solvent then yields the crude product, which if desired can be further purified by well known methods.

In some cases, method D is performed in the absence of a solvent.

In this case, the sulfonamide of formula V and the amine is simply heated until the conversion to the product is substantially complete. As indicated above, reaction times of a few hours, e.g. about 5 hours, and the reaction is usually carried out at a temperature in the range of about 50 to 150 ° C, and preferably at 80-100 ° C. This particular variation is convenient when the compound of formula V and the amine is in the liquid phase at the reaction temperature. .

Although the detailed process of Method D has not been clarified, it is believed that some sulfonyl so cyanate of Formula IV is formed in situ during the course of the reaction.

3

Preferred values for R are alkyl of 1-6 carbon atoms, phenyl and substituted phenyl of up to two substituents selected from fluoro, chloro, bromo, nitro, alkyl of 1-4 carbon atoms and alkoxy of 1-4 carbon atoms, and preferred values of R ^ is hydrogen and the same as 3 R. Particularly preferred starting materials of formula V are those wherein R 4 and R are both phenyl.

The compounds of formula V are prepared by reacting the appropriate sulfonamide of formula III with a carbamoyl chloride of formula 3a C1-C0-NR2 R using the procedure described in method B.

9 U4270

As will be appreciated by one skilled in the art, not all methods A, B, C and D are equally applicable to the synthesis of all the compounds of formula I. method A is only suitable for the preparation of compounds of formula I wherein R 1 is hydrogen. In each case, one skilled in the art will select the most appropriate synthesis method on the basis of such factors as e.g. the feasibility of the chemical reactions, the availability of the starting materials, the reactivity of the starting materials, the stability of the reagents and products and the scale at which the reaction is to be carried out.

A further alternative synthesis method used specifically for 2 of the compounds of formula I wherein R is carboxyalkyl is the hydrolysis of the corresponding compound of formula II, 2 wherein R is alkoxycarbonylalkyl. Due to the stability properties of said compounds of formula II and ease of work, the present hydrolysis is usually carried out using basic conditions. In many cases it is sufficient simply to dissolve the ester in dilute sodium hydroxide solution, store the solution at room temperature for a few hours, and then make the solution acidic. Either the product is precipitated in a filterable form or it is extracted into a water-immiscible solvent such as ethyl acetate. The solvent is dried and evaporated to recover the crude product. However, a variety of water miscible auxiliary solvents such as lower alkanols, e.g. methanol and ethanol, or acetone, to help with the solution. Furthermore, various other bases known in the art are useful for alkaline hydrolysis reactions, e.g. potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate and potassium carbonate are equally useful. The basic agent will usually be present in an amount of at least one molar equivalent suitable for the ester used, but larger amounts of up to about 20 molar equivalents can be used. Although the reaction is usually carried out at room temperature, it is possible to use temperatures in the range of from about 0 to about 100 ° C. The time course of the reaction varies depending on the temperature as the reaction proceeds faster as the reaction temperature increases. However, if the reaction is carried out at 25-50 ° C, reaction times of several hours are usually used, e.g. overnight.

144270 ίο

As discussed above, the starting reagents used in Methods A, B, C and D are sulfonamides of formula III. These sulfonamides can be prepared from ethene derivatives of formula VI by two methods. The first of these comprises the following sequence of reactions: X--aH = CHR -► X ^ -CH = é-SO3Ua

WE

R V R

* <Q> -CH = 0-SO2-NB2 <- * \) -

III

The reagents and conditions used in this reaction sequence are those described with minor variations by Bordwell et al.

(Journal of the American Chemical Society, 68, 139/1946?) For the case in which R and X are both hydrogen. The embodiment of this reaction sequence is further exemplified in U.S. Patent No. 2,979,437 to the other method used to convert the ethene derivatives of formula VI to the corresponding sulfonamides of formula III in treating said ethylene derivatives with sulfuryl chloro. Ride in Ν, Ν-dimethylformamide, followed by ammonia, using the conditions specified by Culbertson and Dietz (Journal of the Chemical Society / London7, Part C 992/19687 / and minor variations thereof).

The ethylene derivatives of formula VI are either commercial products or they can be prepared by two general methods, both of which are well known in the art. The first method comprises a Wittig reaction between an aldehyde of formula VII and the ylide derived from a phosphonium salt of formula (/ GgH in "Organic Reactions", 14, 270 (1965), and by Deno et al., in the Journal of the American Chemical Society, 87, 2157 (1965).

11 144270

Ο-01 «, ®-Γ« 6Η5> 3 - '^ -CH = I = H R

VII VI

The second method consists of reacting an aldehyde of formula VII with a Grignard reagent of formula RCH 2 MgY wherein Y is chloride or bromide, followed by acid-catalyzed dehydration of the thus-formed carbinol according to procedures disclosed by Emerson in Chemical Reviews. 45, 347 (1949), that is:

R

VI1 VI

The choice of these two methods will usually be made by one of ordinary skill in the art on the basis of such factors as the availability of the starting materials, the ease of execution of the process at the intended scale, and the reactivity of the particular reactants.

The aldehydes of formula VII are either commercial products or are prepared by published literature methods. Phosphoniums all of the formula (/ Cgΐί ^ 7 3PCE2R) + Y ~ are conveniently prepared from triphenylphosphine and the appropriate alkyl halide in accordance with procedures disclosed by Maercker, loc, cit., Pages 388-393. The alkyl halides are all commercially available.

As will be appreciated by those skilled in the art, many of the alkenesulfonamides of formula I are useful not only as hypolipidemic agents but also as intermediates for the preparation of hypolipidemic agents.

Thus, those compounds of formula I wherein R is alkoxycarbonylalkyl are valuable as starting materials for preparation. 2 gene of the corresponding compounds of formula I wherein R is carboxylalkyl by hydrolysis.

12 146270

The hypolipidemic properties of the compounds of the process according to the invention are easily detected by two methods.

In the first method, which is essentially the method used by Newman et al. (Lipids, 8, 378 [1973]) »demonstrated the ability of the compounds to inhibit Triton-induced hyperlipidemia in rats. A 300 mg / kg "Triton WR-1339" dose is injected into normal Sprague-Dawley male rats that have been orally treated with the test compound. After further oral dosing with the test compound, the rats are blood drained via the abdominal aorta under pentobarbital anesthesia and plasma is prepared from the heparinized blood. The plasma cholesterol concentration is measured using an Auto-Analyzer (Technicon Method N-24a), and the value is compared with that obtained from control animals who received the "Triton" treatment but no test compound. The plasma cholesterol level in the animals given the test compound is found to be significantly lower than in the animals that did not receive the test compound.

By the second method of measuring the hypolipidemic characteristics of the compounds, normal adult beagle dogs are orally dosed twice daily with the test compound for a period of 6 days. During the trial period the dogs are fed once daily at. 12 noon. On the morning of the sixth day, the dogs are bloodstained from the jugular vein and the plasma cholesterol content is measured by the method adapted for use with the Technicon Auto-Analyzer. The level achieved in a given dog is compared to the basic value of the dog that was determined at the start of the test. The plasma cholesterol level is found to be substantially lower at the end of the test compared to the baseline value obtained at the beginning of the test.

A characteristic feature of the compounds of the invention is their ability to form salts. Due to their acidic nature, sulfonylureas have the ability to form salts with basic agents, and all of these salts should be considered to be within the scope of the invention. The salts can be prepared easily and conveniently e.g. by simply contacting the acidic and basic units, usually in a 1: 1 molar ratio, in an aqueous, non-aqueous or partially aqueous medium, as needed. The salts are recovered by filtration, by precipitation with a non-solvent, by evaporation of the solvent or in the case of aqueous solutions by lyophilization.

13 144270

Basic agents which can be suitably used for salt formation can: be of both organic and inorganic type, and include ammonia, organic amines, alkali metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, alkali metal hydrides, alkali metal alkoxides, o alkaline earth metal hydroxides, , alkaline earth metal hydrides and alkaline earth metal alkoxides. Re-. present examples of such bases are primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine and octylamine; secondary amines such as diethylamine, N-methylaniline, morpholine, pyrrolidine and piperidine; tertiary amines such as triethylamine, Ν, Ν-dimethylaniline, N-ethylpiperidine, N-methyl-morpholine and 1,5-diazobicyclo [4 »3.0] non-5-ene; hydroxides such as sodium hydroxide; alkoxides such as sodium ethoxide and potassium ethoxide; hydrides such as calcium hydride and sodium hydride; carbonates such as potassium carbonate and sodium carbonate; and hydrogen carbonates, such as sodium bicarbonate and potassium hydrogen carbonate.

As will be appreciated by one of ordinary skill in the art, those compounds of formula 2I wherein R is carboxyalkyl have the additional ability to form carboxylate salts. These salts, which can be formed in exactly the same manner and using exactly the same basic agents as described above, are also within the scope of the invention. In those cases where a compound of formula I has two acidic groups, both mono- and disalts can be prepared. For the disalts, the two cations may be the same or different.

The hypolipidemic properties of the alkenesulfonamides prepared by the process of the invention make them particularly useful and valuable in controlling hypolipidemia in mammals, especially humans. For therapeutic use, the compound may be administered alone or may preferably be admixed with pharmaceutically acceptable carriers or diluents. This carrier or diluent is selected based on the intended route of administration as well as the solubility and stability of the active ingredient.

When the hypolipidemic compounds prepared by the method of the invention are used for control, i.e. cure or prophylaxis, of hyp erlipidememia in man, the daily doses will usually be determined by the physician. Furthermore, these doses will vary according to the individual patient's age, weight and reaction, as well as the severity of the patient's symptoms. However, in most cases an effective daily dose will range from about 0.5 to about 3.0 g in single or divided doses. On the other hand, doses outside these limits may need to be used in some cases.

The following examples serve to illustrate the method of the invention.

EXAMPLE 1 N- (N-Butylcarbamoyl) -1-nhenylpropene-2-sulfonamide

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

Analysis calculated for: C ^ I ^NgO ^S (%): C 56.74 '; H, 6.80; N, 9.45; found: (%): 056.64; H, 6.78; N, 9.27.

EXAMPLE 2

According to the procedure of Example 1 and by reacting 1-phenyl-propene-2-sulfonamide with the appropriate isocyanate, the following compounds are prepared: 8 / R1 ^ \ -CH = i-S02-HH-BK ^ 2 144270 16 mo \ O o \ sf <μ sc \ ο \ or »vo hon cn o vo 'ί ^ ιλ o \ J5 r · r · f «Ar> r * iN t * · ί * rs o> o <Acoco σ \ ^ θ \ Γ * co f * g -1.

U \ Η MH Ο »π II ΙΛ Ό Ov O Ά jj co tn η ο -τ ha to co m av ri * 'EC * - * ·>» ·· - »sf Λ O · -» »7 * *» < "*

(D \ D \ 0 O N | Λ ΙΛ vO VO ΙΛ ΙΛ 'O

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(ri to H CO N <f CM 03 CO CO fti VO CM

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OUT

m r-i iH tO o r-l O N -f in CO CO CO

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O CM CM H VO 0 \ M-NNO CM O CO

o cvcnfvTco c-- co co r- co r- m ^ H i—! tn r — I r — i H i — i r — i ft i r — i i— {* i

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A mixture of 1.8 g of phenylethenesulfonamide, 3.5 g of potassium carbonate and 1.6 g of N, N-dimethylcarbamoyl chloride in 75 ml of acetone was heated under reflux and stirring for 2 hours. The reaction mixture was cooled to room temperature and filtered. The collected solid was stirred with 50 ml of water and a small amount of insoluble material was removed by filtration and discarded. The filtrate was acidified with concentrated hydrochloric acid and the precipitated solid was separated by filtration. The solid was recrystallized from acetone to give 93 mg of the above compound, m.p. 160-162 ° C. Adding an equal volume of hexane to the mother liquor from the recrystallization gave an additional 150 mg of the above compound, m.p. 160-162 ° C.

Analysis calculated for C C ^H ^N₂S (%): C, 51.96; H, 5.55; N, 11.02 Found (° / o): C, 51.88; H, 5.57; N 11.07 Example 4 N- (piperidinocarbonyl) -1-phenylpropene-2-sulfonamide

A solution of 1.9 g of N- (N, N-diphenylcarbamoyl) -1-phenylpropene-2-sulfonamide and 1.7 g of piperidine in 10 ml of Ν, Ν-dimethylformamide is maintained at about "95 ° C for 6 hours. It is then cooled to room temperature and 100 ml of ether is added. The mixture is extracted with 50 ml of water and then the aqueous extract is stained with concentrated hydrochloric acid. This causes the crude product to precipitate. It is then filtered off and recrystallized from a mixture of acetone and water to give 670 mg of N- (piperidinocarbonyl) -1-phenylpropene-2-sulfonamide, m.p. 159-161 ° 0o

Analysis calculated for (%); C, 58.43; H, 6.54; N, 9.09; found (%): C, 58.21; H, 6.50; N, 9.05.

Example 5 18 144270

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Example 6 20 144270 N- (N- / T-methoxycarbonyletyl) carbamoyl) -2-phenylethenesulfonamide

To a solution of 3.5 g of DL-alanine methyl ester hydrochloride in 20 ml of Ν, Ν-dimethylformamide is added 1.05 g of a 56.6% suspension of sodium hydride in mineral oil. The mixture is stirred at room temperature for 15 minutes and then 3.8 g of N- (N, N-diphenylcarbamoyl) -2-phenylethenesulfonamide is added. The entire reaction mixture is then kept at ca. 90 ° C for 40 minutes. After being cooled slowly to room temperature, the reaction mixture is diluted with an excess of ether and then extracted with water. Acidification of the aqueous extract with dilute hydrochloric acid results in precipitation of the crude product which is filtered off. The ether phase is washed with dilute hydrochloric acid, which causes an additional amount of product to precipitate. It is filtered off and the two product volumes are combined. This gives 1.55 g of solid with a melting point of 135-139 ° C. The crude product is recrystallized from a mixture of acetone and hexane to give 0.70 g of N- / N- (1-methoxycarbonylethyl) carbamoyl7-2 -phenylethene sulfonamide, m.p. 138-L40 ° Co.

Analysis calculated for C ^ HH ^ gN₂S (%): C, 49.94; H, 5.12; N, 8.96; found (%): C, 50.06; H, 5.26; N, 9.32.

EXAMPLE 7

According to the procedure of Example 6, and the DL-alanine methyl ester hydrochloride used therein is replaced by the appropriate amino ester hydrochloride, the following compounds are prepared: ^ R1

CU- ~ -Cn-SO2-NH-C -N

144270 21 _Analysis _, _ ~ ._1_2 -, o *: calculated - 'the lunette' NR R_ J- W c _li_ __N_ · C_ _H_ _N_ N- (1-ethoxycarbonyl-127-129 54.23 6.26 7.91 ' 54.23 629 29.93 2-Mechylprop-1-yl) -amine

1- (1-echoxycarbonyl-126-128 55.43 6.56 7.61 55.52 6.54 7.48 2- methylbut-1-yl) -amino-Kd-ethoxycarbonyl-81-83 55.43 6 56 7.61 55.25- 6.49 7.77 pent-1-yl) amino N- (1-ethoxytronbonyl) 149-151 52 ^ 92 5.92 8.23 52.69 5 89-β-prop-1-yl) amino EXAMPLE 8 N- (Pyrrolidinecarbonyl) -2-phenylethensulfonamide

A mixture of 3.4 g of N- (N- / m-chlorophenyl7carbamoyl) -2-phenylethenesulfonamide and 2.15 g of pyrrolidine in 100 ml of ethanol is heated at reflux for 20 hours. The solution is cooled and then concentrated in vacuo to ca. 25 ml. A small amount of starting material is precipitated and it is filtered off. 75 ml of ether and 75 ml of water are then added to the ethanolic filtrate. The layers are separated and the aqueous layer acidified with concentrated hydrochloric acid. This causes the crude product to precipitate. It is filtered off and weights 1.5 g after drying. The ether layer is washed with 50 ml of 1N hydrochloric acid followed by 25 ml of water. After drying over anhydrous sodium sulfate, the ether is evaporated in vacuo to give another product (0.70 g). The first product is recrystallized from acetone to give 0.60 g of pure N- (pyrrolidinecarbonyl) -2-phenylethensulfonamide, m.p. 201-204 ° C.

Analysis - Calculated for C-HH H g ^O₂S (%): C, 55.71; H, 5.75; N, 10.00.

found (94): C, 55.45; H, 5.68; N, 9.94.

EXAMPLE 9

According to the procedure of Example 8, and substituting the pyrrolidine for the appropriate amine, the following compounds are prepared: 0 0 Ί r ± il / µl / R1 2 J 2 -Cl 2 = C 1 -SO 2-2 K-C-N 2 g

R

- Analysis S] rmln2 __, SS9PMt (»- fuflrtp * (%) NR R_ M.p. (* C) CHN c H s N, JJ-jd ibu tylamino 104-105.5 60.34 7.74 8.23 60.60 7.50 .8, -32 rooTpholino 176-179 52.70 5.44 * 9.46 52.63 5.37 = 9.48 1.2,3,4-tetrahydro-165-167 63.15 5 8.18 63.00 5., 8.26 isoquinoli.no '* 7 ^ 3 -, S-Diethylamino 110-113 55.31 6.43 9.92 55.23 6.29 9T80 When N- (N N-diphenylcarbamoyl) -2-phenylethensulfonamide is reacted with Ν, Ν-dipropylamine according to the procedure of Example 8, the product is N- (N, N-dipropylcarbamoyl) -2-phenylethensulfonamide, mp 128-130 ° C.

Analysis - "Calculated for (%): C, 58.05; H, 7.15; N, 9.03.

found (%): C, 57.77; H, 7.09; N, 8.96.

From N- (N- / m-tolyl7carbamoyl) -2-phenylethensulfonamide and N, N-dibutylamine and using the procedure of Example 8, the product is N- (N, N-dibutylcarbamoyl) -2-phenylthensulfonamide, m.p. 104-105 ° Co.

Analysis - Calculated for C CHHggNNgO ^S (%): C, 60.34; H, 7.75; N, 8.28 found (#): C, 60.23; H, 7.58; N, 8.50.

EXAMPLE 10 N- (Piperidinocarbonyl) -2-phenylethensulfonamide

A slurry of 6.5 g of 2-phenylethenesulfonamide in 45 ml of oxalyl chloride is stirred and heated under reflux for 16 hours. It is cooled to room temperature and then the solid which is washed with hexane is filtered off. After drying, the solid weighs 2.2 g and has a melting point of 170-180 ° C.

144270 23

The above solid is added in small portions with stirring at room temperature to a solution of 5 ml of piperidine in 15 ml of methylene chloride. The mixture is stirred for an additional 1.5 hours after completion of the addition and then evaporated to dryness in vacuo. The residue is partitioned between 40 ml of water and 25 ml of ether, the layers are separated and the ether layer is discarded. The aqueous layer is acidified with acetic acid and then extracted with ether. The latter ether extract is washed with water, dried over anhydrous sodium sulfate and finally evaporated to dryness in vacuo. The residue is 0.60 g of crude product, m.p. 138-140 ° C. The crude product is recrystallized from a mixture of methylene chloride and ether to give a pure sample of N- (N-piperidinocarbonyl) -2-phenylethensulfonamide, sinP · 175-177 ° C.

Analysis - calculated for C 14 H 13 N 2 O 3 S (%): C, 57.13; H, 6.17; N, 9.52 (%): C, 57.23; H, 6.11; N, 9.54.

EXAMPLE 11 N_ (4,3-Phenylpropyl7PiPeridinocarbonyl) 2-Phenylethensulfonamide

A solution of 12 g of 4- (3-phenylpropyl) piperidine and 12.5 g of the potassium salt of N- (N, N-diphenylcarbamoyl) -2-phenylethenesulfonamide (prepared as described in Example 4) in 30 ml of Ν, Ν-dimethylformamide Heat to 75 ° C and then 5.7 ml glacial acetic acid is added dropwise with stirring. The temperature is raised to 90 ° C during the addition. The reaction mixture is kept at 85-87 ° C for an additional 45 minutes and then allowed to cool to room temperature.

It is poured onto a mixture of 200 ml of 1 N sodium hydroxide solution and 100 g of crushed ice. A rubbery precipitate is formed. A 50 ml portion of ether is added and the mixture is stirred vigorously until a cloudy solution is obtained. Then a 50 ml portion of hexane is added which causes the sodium salt of the product to precipitate. It is filtered off and washed with water followed by ether. The crude sodium salt is redissolved in a mixture of 100 ml of acetone and 50 ml of water, and then 5 ml of concentrated hydrochloric acid is added followed by 100 ml of water. The precipitate formed is filtered off, washed with water in acetone and finally recrystallized from acetone / hexane to give 6.8 g (55%) of pure N- (4- / 3-phenylpropyl7-piperidinocarbonyl) -2-phenyl-ethenesulfonamide, snip . 131-133 ° C.

EXAMPLES 1-2 N- (N- / T-Carboxyprop-1-yl7carbamoyl) -2-phenylethenesulfonamide

To 30 ml of 1N sodium hydroxide solution is added 1.0 g of N- (N- / 1-ethoxy-carbonyl pr op-1-yl7carbamoyl) -2-phenylethensulfonamide. 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 acidified with concentrated hydrochloric acid which causes the product to precipitate. It is filtered off, washed with water and air dried to give 6.0 g of N- (N- / 1-carboxyprop-1-yl7carbamoyl) -2-phenylethensulfonamide, m.p. 150-152 <>

Analysis - Calculated for C 13 H 16 N 2 O 5 S W · c 4-9.98; H, 5.16; N, 8.97.

found (%): C, 49.72; 5.20; N, 8.85.

EXAMPLE 13

From the appropriate ester selected from those of Examples 2, 5, 6 and 7 and using the hydrolysis procedure of Example 12, the following compounds are prepared: R 0 \ R1 3 ~ J> - CH = C-SO 2 -3MH-CU <^ 2 144270 25 -1? .., and list e .__ R NRXR ^ _ Mp. (° C) CHNCH y H · N- (1-carboxy-2- 167.5-169 57.75 4.85 7.48 57.64 4.84 7.22 phenylethyl) amino f 7 Ιί N- (carboxymethyl) - 182-183 46.48 4 26 9.86 46.69 4.33 9.86 amino - - CH, - (earboxynethyl) - 183-185 48.32 4, / 3 9.39 * 47.99 4.79 <>, 29 3 amino * 7 1 '7 H N- (1-carboxyethyl) - 155- 156 48.32 4.73 9.39 48.31 4.71 9.14 amino H N- (1-carboxy-3-methylbut-1-yl) amino 162-164 52.92 5.87 8.23 52 56 5.75 8. 02 H N- (1-carboxy-2- 155-157 51.52 5.56 8.58 51.33 5.74 8.47 methylprop-1-yl) - amino H-N- (1-carboxypent-140-142 .52.92 5.92 8.23 58.85 '6.00 8.22 l-yl) araino' '*' H N- (1-earbxy-2 130-133 50.40 5.92 7.83 '50.69 5., 71 7,, 87 ylbut-1-yl) amino * H jj- (1-carboxyhept-1- 142-144 55, 41 6.57 7.60 55.36 6.70 7.37 yl) amino

This material is isolated and analyzed as a monohydrate.

EXAMPLE 14 N- (4-β-phenylpropylpiperidinocarbonyl) -2-phenylethenesulfonamide

A stirred mixture of 1.83 g of 2-phenylethanesulfonamide, 1.3 ml of oxalyl chloride and 15 ml of tetrahydrofuran is heated in an oil bath at 75-80 ° C for 1.5 hours under an atmosphere of nitrogen. To the solution obtained is added 30 ml of xylene and the internal temperature is raised to 138 ° C over 20 minutes, while the tetrahydrofuran and the excess oxalyl chloride are allowed to distill out of the solution. During this time, 2 additional 5 ml portions of xylene are added. The resulting solution is maintained at ca. 138 ° C for an additional 15 minutes and then cooled to 85 ° C. To this xylene solution of 2-phenylethenesulfonyl isocyanate, 4.06 g of 4- (3-phenylpropyl) piperidine is added in small portions over 1 minute. The reaction mixture is stirred at room temperature for 1.5 hours and then washed successively with 75 ml of 1N hydrochloric acid and two 25 ml portions of water. To the dried and filtered xylene solution is then added 20 ml of acetone followed by the dropwise addition of 120 ml of hexane. The resulting precipitate is removed by filtration to give 2.89 g (70% yield) of crude product. After recrystallization from acetone / hexane, 1.07 g of the above compound is obtained with a melting point of 125-127 ° C.

EXAMPLE 15 N- (4- [5-phenylpropyl] piperidinocarbonyl) -2-phenylethenesulfonamide

A stirred mixture of 1.83 g (0.01 mole) of 2-phenylethenesulfonamide, 3.45 g (0.025 mole) of potassium carbonate and 4.0 g (0.015 mole) of 4- (3-phenylpropyl) piperidinocarbonyl chloride in 75 ml of chloroform heated at reflux for 22 hours. The solvent is then removed by evaporation in vacuo and to the residue is added 75 ml of 0.5N sodium hydroxide solution and 35 ml of ether. The mixture is stirred for 1 hour and the solid which remains undissolved is removed by filtration.

This gives 1.84 g (about 41% yield) of the above compound as a mixture of its sodium and potassium salts.

A 0.5 g portion of the above crude product is dissolved in 6 ml of acetone and 3 ml of water. The pH of the mixture is lowered to 2.0 and the undissolved solid is removed by filtration. It is then recrystallized from acetone / hexane to give 0.28 g of the above compound, mp 127.5-129 ° C.

Example 16 N- (4- [3-phenylpropyl) piperidinocarbonyl) -2-phenylethenesulfonamide

A solution of 1.77 g (7.5 millimoles) of N- (N-propylcarbamoyl) -2-phenylethensulfonamide, 3.0 g (15 millimoles) of 4- (3-phenylpropyl) piperidine and 0.86 ml (15 acetic acid in 10 ml of N, N-dimethylformamide is heated to 100-105 ° C for 4 hours. The reaction solution is then cooled to 25 ° C and 50 ml of 1N hydrochloric acid is added followed by 50 ml of ether. The layers are separated and to the ether phase is added 50 ml of 1 N sodium hydroxide solution. This causes an oil to appear as an intermediate phase. The three layers are separated and the aqueous phase is discarded. The ether phase is washed with water and then evaporated in vacuo to give 2.3 g of a viscous liquid. The intermediate oil phase is dissolved in 25 ml of water, which is then acidified with concentrated hydrochloric acid. The acidified aqueous phase is extracted with ethyl acetate and the extracts are washed with water and then evaporated in vacuo. This gives 0.5 g of a rubbery residue.

The 2.3 g of oil and the 0.5 g of gummy residue are combined and chromatographed on a column of silica gel. The first few fractions are combined and evaporated in vacuo to give 0.3 g of an oil.

This latter oil is dissolved in 5 ml of acetone and 5 ml of 1 N sodium hydroxide solution is added followed by 10 ml of water. This causes the crude product to precipitate as its sodium salt. The sodium salt is dissolved in 3 ml of acetone and 5 drops of concentrated hydrochloric acid are added followed by 10 ml of water. This solution is extracted with ethyl acetate. The dried extract is evaporated in vacuo, the residue is recrystallized from acetone / hexane to give 12 mg of the above compound, m.p. 119-122 ° C. After two further recrystallizations from acetone / hexane, the product has a melting point of 127.5-129.5 ° C.

EXAMPLE 17

To a stirred solution of 4.12 g of N- (4- [3-phenylpropyl] piperidino-carbonyl) -2-phenylethenesulfonamide in 100 ml of n-butanol is added a solution prepared by dissolving 390 mg of potassium in 10 ml of n-butanol. The mixture is stirred for a further 15 minutes and then the solvent is removed by evaporation in vacuo. To the residue is added 250 ml of diethyl ether and the mixture is stirred for 15 minutes. The solid is filtered off and dried under vacuum to give the potassium salt of N- (4- [3-phenylpropyl] piperidinocarbonyl) -2-phenylethenesulfonamide.

EXAMPLE 18

Normal Sprague-Dawley (Charles River) male rats are fasted for 9 hours. Sample groups consisting of 5 animals are then fed overnight (15-16 hours) with ground "Purina" rat feed containing 0.2% of the test compound. The following morning, the treated feed is withdrawn and after 1 hour each rat is dosed with an oral administration containing 50 mg / kg of the test compound. After a further two hours, rat nerve was administered a 300 mg / kg dose of "Triton WR-1339" (oxyethylated tertiary-octylphenyl formaldehyde polymer,

Ruger Chemical Co., Philadelphia, Pa.) In physiological saline solution by injection into the tail vein. After a further 2 hours, each rat is given a different oral administration containing 50 mg / kg of the test compound. After a further 4 hours, each rat is blood-drained via the abdominal aorta under pentobarbital anesthesia · Control rats are treated in the same way except that they receive rat food alone and that the two oral doses do not contain a test compound. The control rats receive the same dose of "Triton" as the test animals.

Plasma is prepared from the heparinized blood samples and plasma cholesterol concentrations are measured using "Auto-Assays" (Technicon method N-24a). The activity of a test compound is assessed by comparing plasma cholesterol levels from rats treated with the test compound and control rats. The results are tabulated below. The reported results are calculated by subtracting the plasma cholesterol concentration in treated rats from the concentration in the control rats and expressing the difference as a percentage of the control value.

144270 29

Test compound% Decrease in cholesterol concentration N- (N, n-butylcarbamoyl) -2- (p-chlorophenyl) ethensulfonamide 8 N- (piperidinocarbonyl) -2- (phenylethenesulfonamide) N- (N- ^ carboxyme -thyl] carbamoyl) -2-phenylethensulfonamide 8 N- (N-cyclohexylcarbamoyl) -2-phenylethene sulfonamide 14 N- (N-one thoxycarbonylmethyl (c) arbamoyl) -2.-phenylethensulfonamide 9 N- (N, N -dien-butyl (arbamoyl) -2-phenylethensulfonamide 5 N- (4-benzylpip eridino carbonyl) -2-phenylethesulfonamide 5 N- (Nn-propylcarbamoyl) -1,1-diphenylethene sulfonamide 12 N- (N-allylcarbamoyl) -2-phenylethenesulfonamide 21 N- (N-methyl-N-2-phenylethyl-carbamoyl) -2-phenylethenesulfonamide 13 N- (1-azacycloheptylcarbonyl) -2-phenylethenesulfonamide 16 N- (N , N-di 2-methylprop-1-yl3carbamoyl) -2-phenylethensulfonamide N- (morpholinocarbonyl) -1-phenylpropen-2-sulfonamide 8 N- (N- 1 -ethoxycarbonyl-2-methylprop-1-yl] ] -c-arbamoyl) -2-phenylethenesulfonamide N- (4- (3-pb.enylpropyl) piperidinocarbonyl) - ^ - phenylethenesulfonamide 30 "17" 20 "31, n 1442 70 do EXAMPLE 19

A normal adult beagle dog, weighing about 10kg, is fed with "Purina" dog food once daily at. 12 noon for several days. The dog is then blood drained two consecutive mornings from the jugular vein and plasma cholesterol concentrations are measured by the method adapted for use in "Technicon Auto-Analyzes". The average of these values represents this dog's baseline plasma cholesterol level. The dog is then dosed orally twice daily with the test compound, while continuing to be fed "Purina" dog food once daily at 10am. . 12 noon. In the morning of the sixth day after the start of the test compound administration, the dog is again blood drawn from the jugular vein and again the plasma cholesterol level is measured using "Technicon Auto-Analyzes". The level thus obtained is compared with the baseline level for determining the hypolipidemic properties of the test compound. The results are given below.

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The following preparations are set forth to illustrate the source of certain starting materials used in the foregoing examples.

Preparation A

1 Phenylpropene-2-sulfonamide

To 17.5 ml of Ν, Ν-dimethylformamide, cooled to 15 ° C, is added dropwise with stirring over 30 minutes to 15.5 ml of sulfuryl chloride. The temperature is kept below 25 ° C during the addition. The mixture is stirred for an additional 30 minutes at 25 ° C and then 11.3 g of 1-phenylpropene is added. The reaction mixture is heated to 90-93 ° C for 75 minutes. It is then poured onto 400 g of crushed ice and the product is extracted into methylene chloride. The solution is dried over anhydrous sodium sulfate and then evaporated in vacuo to give 18.7 g of 1-phenylpropene-2-sulfonyl chloride as a liquid.

The 1- Phenylpropene-2-sulfonyl chloride is added to 200 ml of concentrated ammonium hydroxide. After one hour, the crystalline precipitate formed is filtered off and washed sequentially with water and hexane. The crude product thus obtained is partitioned between 150 ml of 1 N sodium hydroxide solution and 50 ml of ether, giving two clear phases. The ether phase is removed and washed with 50 ml of water, then the wash water is added to the original aqueous phase. This combined solution is acidified with concentrated hydrochloric acid, which causes the product to precipitate. It is filtered off and, after drying, gives 10.9 g of 1-phenylpropene-2-sulfonamide, mp 138-139.5 ° C.

Preparation B

According to the procedure of Preparation A, 2-phenylpropene is reacted with sulfuryl chloride in Ν, Ν-dimethylformamide to form 2-phenylpropene-1-sulfonyl chloride, which is then treated with ammonia to form the 2-phenylpropene-1-sulfonamide, m.p .: 101 -102.5 ° C.

When 1,1-diphenylethene is reacted with sulfuryl chloride in N, N-dimethylformamide followed by treatment with ammonia according to the procedure of Preparation A, 2,2-diphenylethenesulfonamide is obtained, mp: 134-135 ° C.

33 1A4270

Analysis calculated for CC HH ^NO₂S (%): C; 64.86; H, 5.05; N, 5.40.

Found: (90s C, 64.73; H. 5.02; N, 5.26.

PREPARATION C

N- (N, N-diphenylcarbamoyl) -2-phenylethenesulfonamide

To a suspension of 35 g of potassium carbonate in 500 ml of acetone is added 18.3 g of 2-phenylethenesulfonamide and 35 g of N, N-diphenylcarbamoyl chloride. The reaction mixture is heated under reflux and stirring for 5 1/2 hours. The insoluble material is filtered from the hot acetone and the acetone is then concentrated to dryness in vacuo. The residue is slurried in 300 ml of ether and then filtered off to give 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 using concentrated hydrochloric acid and then an additional 50 ml of water is added. The precipitated solid is filtered off and washed successively with acetone / water (1: 1) and with water. This gives 33 g (87%) of N- (N, N-diphenylcarbamoyl) -2-phenylethensulfonamide, m.p. 185-188 ° C. Recrystallization of the product raises the melting point to 189-191 ° C.

Analysis calculated for C ^ forH ^ gO₂S (%): C, 66.66; H, 4.80; N, 7.40; found (%) ·. C, 66.46; H, 4.82; N, 7.17.

PREPARATION D

The procedure of Preparation C is repeated except that the 2-phenylethenesulfonamide used therein is replaced by an equimolar amount of 1-phenylpropene-2-sulfonamide. The product is N- (N, N-diphenylcarbamoyl) -1-phenylpropene-2-sulfonamide 175-179 ° C.

Analysis calculated for (90: C, 67.33; H, 5.14; N, 7.14; Found (90: C, 67.09; H, 5.24; N, 7.11).

144270 34

PREPARATION B

4- (5- [p-Methoxyphenyl] propyl) pyridine

To a stirred solution of 3.04 g of 2- (p-methoxyphenyl) ethanol in 10 ml of benzene is added dropwise a solution of 0.72 ml of phosphorus tribromide in 10 ml of benzene at room temperature. The mixture is then heated to 60 ° C for one hour. After being cooled to room temperature again, the reaction mixture is poured onto 50 g of crushed ice. A small amount of ether is added and then the organic phase is separated, washed sequentially with 0.5 N sodium hydroxide solution and water and evaporated to dryness. This gives 2.8 g of 2- (p-methoxyphenyl) ethyl bromide as an oil.

The above oil is dissolved in 15 ml of ether which is then added dropwise to 243 mg of magnesium chips covered with 10 ml of ether. A few crystals of iodine are added and then the solution is heated at reflux until almost all the magnesium has reacted. This gives an ether solution of 2- (p-methoxyphenyl) ethylmagnesium bromide.

The Grignard solution described above is added dropwise at 0 ° C to a stirred solution of 1.04 g of 4-cyanpyridine in 15 ml of ether.

After the addition is complete, the reaction mixture is heated under reflux for 4 hours and then stirred at room temperature overnight. The reaction is quenched with ice water and the aqueous phase is acidified with concentrated hydrochloric acid. The aqueous phase is then separated and heated to 85-90 ° C for one hour. It is cooled back to room temperature and extracted with chloroform followed by ether. The combined organic extracts are dried over anhydrous magnesium sulfate and then evaporated in vacuo to give the product as an orange oil. The product is 2- (p-methoxyphenyl) ethyl-4-pyridyl ketone.

The ketone (800 mg) described above is heated under reflux for 2 hours with 850 mg of hydrazine hydrate. At this point, 1.6 g of powdered potassium hydroxide is added and heating under reflux is continued for an additional 2 hours. The reaction mixture is then cooled to room temperature, diluted with 20 ml of water and extracted with ether. The dried ether extract is evaporated to dryness to give 260 mg of 4- (3β-p-methoxyphenylpropyl) pyridine.

PREPARATION F

4- (5- / p-Methoxyphenyl7nropyl) piperidine

A solution of 2.27 g of 4 (3- / p-nithoxyphenyl) propyl) pyridine in 50 ml of 1.0N hydrochloric acid is hydrogenated at 3 »16 kp / cm at room temperature in the presence of 150 mg of platinum oxide. After 20 hours, the theoretical amount of hydrogen has been absorbed and the catalyst is filtered off. The aqueous filtrate is basified with 5N sodium hydroxide solution and then extracted with ether. The extract is dried and evaporated in vacuo leaving 2.2 g of an oil. The oil solidifies slowly to give 4- (3- / p-methoxyphenyl-7-propyl) -piperidine, m.p. 65-70 ° C.

PREPARATION G

4- (2-Phenylpropyl) niperidinocarbonyl chloride

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

Claims (2)

144270 36 An analogous process for the preparation of N-carbamoyl-2-phenylethensulfonamides of the general formula R n / r 1 / N) -CH = C-SOO-NH-CN / I , R means hydrogen or methyl, R means hydrogen or alkyl of 1-4 carbon atoms, and R means alkyl of 1-4 carbon atoms, alkenyl of 3-5 carbon atoms, cycloalkyl of 3-7 carbon atoms, phenylalkyl of 1-2 carbon atoms in the alkyl moiety. , 1-carboxyalkyl of 2-5 carbon atoms or 1- (alkoxycarbonyl) alkyl of 1-2 carbon atoms in the alkoxy moiety and 1-4 carbon atoms in the alkyl moiety, or R and R together with the nitrogen atom to which they are attached, means piperidino, morpholino, 1,2,3,4-tetrahydroisoquinolino, azacycloheptan-1-yl or 4- (ω-phenylalkyl) piperidino having 1-5 carbon atoms in the alkyl moiety, p 1 where R when R and R are both hydrogen, cannot be alkyl, alkenyl or cycloalkyl, or pharmaceutically acceptable salts thereof, characterized by, (a) that a phenylethenesulfonamide of formula ΧΧ / = Λ R Wherein X and R are as defined above, reacted with an isocyanate of formula r 2 -n = c = o 2 wherein R is as defined above, or (b) a phenylethenesulfonamide having the above Formula III is reacted with a carbamoyl chloride of the formula r10 R \ y> NC-C1 12. wherein R and R are as defined above, however, R cannot be hydrogen, or (c) a reactive derivative of the phenylethensulfonamide III with the formula IV Xv R i ^ ch = c-so2-n = c = o iv wherein X and R have the above meaning are reacted with an amine of the formula ^ R1 HN <: ^ R2 1 2 wherein R and R have the above meaning or (d) a reactive derivative of the phenylethenesulfonamide III of formula V i