FI64799B - FRENCH SURFACE THERAPEUTIC ANALYZLE - Google Patents

Description

ΪΖμΡΤ] [Bl (11) KWULUTUSJULISUU

JGBTa lj VJ UTLÄGGNI NGSSKRIFT 04/7 7 c (45) Fateaiti 10 11 1924,, c 07 C 143/80, '/ 51) Kv.lk.3 / btt.CI.3' C 07 D 307/52 FINLAND— Fl N LAND (21) PweBttltak * mu · —p * ten, », wekn * n« 753392 (22) Hak * ml * pWv * - AntAknlngadag 02.12.75 (23) AlkuptM - Glklghatsdag 02.12.75 (41) Tullut Julklsuksl - Bllvlt offantllg og> γζ

Patent * and Registry Office * (44) N «ht * iW,» noo kuLLIngluu date - 09 83

Patent · oeh rcgisterftyrelsan An * ekan uttegd oeh utUkrtftun publlcurad α (32) (33) (31) Pyydetty etuoikeus —Begird prlorltet l6.12. jb 26.09.75 USA 533352, 616331 (71) Merck & Co., Inc., 126 E. Lincoln Avenue, Rahway, New Jersey, USA (72) Helmut Hugo Mrozik, Matavan, New Jersey, USA (US) (7 ^) Oy Kolster Ab (5 * 0 Method for the preparation of therapeutically useful substituted benzene disulfonamides - Förfarande för framställning av terapeutiskt användbara substituer benzensendisulfonamider

The invention relates to a process for the preparation of therapeutically useful substituted benzenedisulfonamides of the formula

R Λ- * '\ - N

R 1 is R 1 R 2 N 2 SO 2 'SO 2 N 2' 2 wherein R is a halogenated unsaturated alkyl group containing 2 to 3 carbon atoms, and R 1 is hydrogen or methyl and R 1 and R 2 are hydrogen or benzyl, methyl or furfuryl groups.

2 i 6 4 7 9 9

Several sulfonamides, especially benzenesulfonamide compounds, have been known for several years. They have generally been prepared and studied due to their activity as antibacterial and diuretic agents, and much information has been published regarding the antibacterial and diuretic activity of sulfonamide compounds. In addition, certain benzenedisulfonamides are used as intermediates in the preparation of certain diuretics. Said diuretics have not been described to have any anthelmintic activity. The benzenedisulfonamides of the invention are novel compounds not previously described.

The compounds of the invention have potent and unexpected anthelmintic activity and are particularly active against liverworms in animals. The compounds of the invention also have potent parasiticidal activity.

Preferred compounds of the invention are those in which the halogen atoms in the R group are chlorine or fluorine or a mixture thereof.

Examples of preferred compounds of the invention are: 4-amino-6-trichlorovinyl-1,3-benzenedisulfonamide, 4-amino-6-Ca, N-difluoro-N, N-chlorovinyl-1,3-benzenedisulfonamide, 4-amino- 6- (2 <, J-dichloro-1H-fluorovinyl) -1,3-benzenedisulfonamide, 4-amino-6-trifluorovinyl-1,3-benzenedisulfonamide, 4-amino-6- (2,2-dichlorovinyl) -1 , 3-benzenedisulfonamide, 4-amino-6- (1,2-dichlorovinyl) -1,3-benzenedisulfonamide, 4-amino-6- (1,1-dibromo-1-penten-2-yl) -1, 3-benzenedisulfonamide, 4-amino-6- (3,3,3-trifluoropropynyl) -1,3-benzenedisulfonamide.

The compounds of the invention are prepared by chlorosulfonating a compound of formula R ----- NH2 to form a compound of formula R ___________NH2 C102S ----- Si - SO2Cl1 '3 64799 wherein R is as defined above, which compound is treated with ammonia or a mono- or di-lower alkylamine to form a product of formula RR,

Rr-N ° 2s Λ .. J- so ^ <s R2-82 wherein R, R1 and R2 are as defined above, or chlorosulfonating a compound of formula I! / 1

k so.nC

* 2 to form a compound of formula R> 1 ------- NH „I I | i * ·, C10-S U j ^ * 2 wherein R, R1 and R2 are as defined above, which compound is treated with ammonia or a mono- or di-lower alkylamine to form a product of formula R --- NH “R1 I! Wherein R, R 1 and R 2 are as defined above, and then, if desired, the final product thus formed is treated with alkali metal nitrite in the presence of an acid and then with a metal halide in the presence of hydrogen halide acid to give the compound, having the formula R f '·. Iial

R 1 "n 0, S 1. 0, M <8 'R 2' ^ 2 4 64799 wherein R 1 and R 2 are as defined above, after which the compound thus formed is treated with an amine of formula

, R ..

h - nc: R 4 wherein R 1 and R 2 are as defined above to give a compound of formula / '"* 3 R N" R 1 | -R4 ^ R1 ^ no „s L ...... SO„ N <"<- wherein R, R1, R2, R1 and R4 have the same meaning as above.

In a first variant of this method, the appropriately substituted aniline compound is treated with Iclorosulfonic acid. The reaction is carried out initially under cooling due to a possible exothermic reaction when the starting material and the reagent come into contact with each other. Generally, the amine is added dropwise or in small portions over 5 minutes to 2 hours to the chlorosulfonic acid while maintaining the reaction temperature at -10 to + 10 ° C. At the end of the addition, the reaction temperature is raised to 50-200 ° C over a period ranging from 15 minutes to 4 hours. A solvent can be used and is generally used only when the reaction temperature is below 100 ° C. However, it is preferable to carry out the reaction without a solvent. The product, benzenedisulfonyl chloride, is recovered from the reaction mixture in a manner known per se.

The benzenedisulfonyl chloride is then reacted with ammonia or a mono- or di-lower alkylamine to form the desired benzenedisulfonamide. The reaction can be carried out using an aqueous solution of ammonia or mono- or di-lower alkylamine, or a solution of ammonia or mono- or di-lower allylamine in any inert organic solvent such as benzene, toluene, ether, chloroform and the like; or the reaction may be carried out in liquid ammonia or amine. The reaction is somewhat exothermic and cooling is required when using an amine other than liquid ammonia. In liquid ammonia, the reaction mixture is maintained at the temperature of liquid ammonia. The product is separated and purified in a manner known per se.

The compounds of the invention may also be prepared by chlorosulfonation of an appropriately substituted O-aminobenzene sulfonamide compound followed by amination according to the following reaction scheme: y

R

i * 1, Λ

k. cio2s- ^ \ R

SO „N ^ SO-N ^" 1 R ----------- Nr2 R. - 1 '. ·' \.

'N ° 0S cn M R.

2 SO-jN. "1 R2 wherein R, R1 and R2 are as defined above. Chlorosulfonic acid is generally the preferred chlorosulfonating agent in the treatment described above. Chlorosulfonic acid is treated with ammonia or mono- or di-lower alkylamine as previously described to give the desired product. In the process described above, compounds can naturally be formed in which the -NR 1 R 2 groups in each sulfonamide unit are different.

6 64799 K '* row compounds in which R 1 and R 2 are other than hydrogen are prepared from compounds in which R 1 and R 2 are hydrogen according to the following scheme: R-. \ _ ^ NH2 '\. ^ Hal

I and I

.fJ02S - ^ \ so2N -—t no2s \ R2 ^ R ^ 'XS02N ^ R2 R3 ^ R3 \ j! / N-H ^ JJ ________ R! v 1 ^ NO_S ^ -SO_N -c '' R 4 - * / 2 2 R 2 R 2 wherein R, R 1, R 2, R 2 and R 2 are as defined above and Hal is halogen, especially chlorine or bromine.

In the process described above, the unsubstituted amino starting material is diazitized with alkali metal nitrite, especially sodium nitrite in the presence of an acid, and the diazonium salt is treated with an alkaline earth metal halide to give the 4-halogen compound. The diazotization is generally carried out in an aqueous medium at a temperature of 0 to 25 ° C, and the preferred acids are sulfuric, nitric and acetic acids.

The diazotized compound is still combined in an aqueous medium with an alkaline earth metal halide in a hydrohalic acid solution, wherein the halide of the salt and the halide of the acid are the same. The addition at 0 ° C to room temperature is carried out over a period of 5 minutes to 1 hour, and the reaction mixture is optionally stirred for a further time, suitably up to 2 hours. The halide is separated in a manner known per se.

64799

The halogen compound is converted to an R 1 -substituted amino compound by treatment with an R 1, R 2 -substituted amine. The reaction is carried out by heating to 25 ° C to 200 ° C. However, it is preferable to heat to 75-125 ° C. The reaction time is 15 minutes to 24 hours and the product is isolated in a manner known per se.

The starting materials described in the methods described above are generally known or their methods of preparation are known.

The meta-substituted aniline of the first described synthesis, wherein R is an unsaturated halogenated alkyl group having an unsaturation in the omv / position relative to the benzene ring, can be prepared according to the following reaction scheme: f3

o I

o2n \ ----- Ö-r3 02if ------ ^ ......... c = cx1x ^ I; :

'jJ

wherein V is phenyl, R 3 is hydrogen, lower alkyl or halogenated lower alkyl and X 1 and X 2 are each halogen.

The starting material in this process is m-nitro-benzaldehyde or m-nitro-phenyl-lower alkyl or -halo-lower alkyl ketone. Reagent (Ph) 3 P = CX 2 X 2 is prepared by coupling triphenylphosphine to a halogenated methane such as carbon tetrachloride, carbon tetrabromide, chloroform or bromoform. The reagent is not separated but is prepared in situ. In the preferred process, all the starting materials, triphenylphosphine, halogenated methane and benzaldehyde or ketone are combined in the same reaction vessel at room temperature to 200 ° C. Because the phosphorus reagent is prepared in situ, the starting material for the reaction is readily obtained while avoiding the problems associated with reagent storage and stability. The reaction mixture is kept at the above-mentioned temperature for 1 to 24 hours, and the product is isolated in a manner known per se. Halogenated methane is generally used in excess so that no other solvent is required, but an inert solvent may be used.

8 64799

The nitro compound obtained in the above reaction is then reduced to the corresponding amino compound using, for example, iron and hydrochloric acid or zinc and acetic acid. The amino compound thus obtained is treated with chlorosulfonic acid and then with ammonia according to the methods already described to obtain the desired product.

A variation of the above process starts from an readily available unsubstituted benzaldehyde or phenyl-lower alkyl or halogenated lower alkyl ketone: 0 R3

il I

^ I "] - c ~ r3 6 = cx1x.l

Ph p = cx.x,;! H -------- 7 R3 R3 —Lex X-, = CX ^ X2 ----------> 02N -H2 »-JL% R3 I 3 ° 2N — e = cx, x2 "I" · - ·] V — c-cx.x. | I I |; - '> if2NO2s-t ^ ^ H, N- ^' R, H ~ N ...... '· __jC = CX , X., 2: l \ i

i H

---------------------------------- ^ H2NO2S - where Ph, R1, X1 and X2 have the same meaning as above.

The benzaldehyde or ketone is treated with Ph3P = C (R) 2 - reagent according to the methods described above. The halogenated vinyl or propenyl compound thus obtained is nitrated. The nitration takes place in the p-direction to give the p-nitro compound. The reaction is carried out using an excess nitrating agent such as nitric acid or fuming nitric acid in the presence of a dehydrating agent such as concentrated sulfuric acid or acetic anhydride. The reaction mixture is maintained at 0-50 ° C for 15 minutes to 3 hours. The product is separated from the nitration reaction mixture in a manner known per se.

9,64799

The nitrated compound is then reduced to the corresponding amino compound using conventional techniques. To facilitate subsequent steps in the synthesis, the amino group is generally protected with a suitable protecting group such as acyl, preferably acetyl. The amino group is acylated with conventional acylating agents such as acid chlorides, anhydrides, carboxylic acids and the like corresponding to the desired protecting group.

The protected amino compound is then nitrated using the nitration technique described above. The recovered compound is m-nitro, a p-amino compound. After nitration, the protecting group is removed in a conventional manner. When acyl protecting groups are used, the free amine is easily recovered by acid or base catalyzed hydrolysis.

The free amine is then diazotized to give a sulfonamide group.

The amino compound is diazotized in the presence of an aqueous acid such as hydrochloric or sulfuric acid and sodium nitrite at 0-20 ° C.

The diazonium salt is then treated with a solution of sulfur dioxide and crystalline cupric chloride in acetic acid and sufficient water to obtain a solution. The reaction mixture is maintained at 0-20 ° C for 5 minutes to 3 hours. The sulfonyl chloride group thus isolated from the diazotization reaction is treated with ammonia or mono- or di-lower alkylamine as described above to give a monosulfonamide which is chlorosulfonated and aminated as described above.

Another method for preparing 3-R-aniline starting materials utilizes m-nitroaniline as a precursor. The m-nitroaniline is diazotized with mineral or organic acid, sodium nitrite and water as detailed above. The diazonium salt is then treated with an ethylene compound of the formula: R.RcC = CHX45 in the presence of crystalline cupric chloride dihydrate and acetone or other suitable non-reactive organic solvent. In the above formula, X is halogen and R 1 and is halogen or one of R 1 and R 1 may be halogen and the other hydrogen, lower alkyl or halogenated lower alkyl. The reaction is initially carried out at a temperature of -20 to + 20 ° C and then the reaction mixture is kept substantially at room temperature for 1 to 43 hours to complete the reaction.

The product obtained has the formula: 64799 10

π X

! R4R5C-C '' '' NO2

B

wherein X 1 and R 2 are as defined above. This compound is then de-hydrohalogenated to: R.RcC = C ----- \ _______ NO 4 4 5 j 2! ! 1 H ^ where R 1 and R 5 have the same meaning as above. The dehydrohalogenation is carried out using an alkali metal hydroxide or alkoxide and / or an organic base such as triethylamine in the presence of a suitable solvent such as a lower alkanol, preferably raethane or ethanol,

The nitro group is then reduced using the reduction technique described above, and the resulting amino compound is chlorosulfonated and aminated. The chlorosulfonation and amination reactions can be performed prior to the diazotization and dehydrohalogenation reaction steps.

In particular, 2- (3-aminophenyl) -1,1,2-trichlorethylene is prepared from the best known starting material 2- (3-aminophenyl) -1,1,2,2-pentachloroethane, which is dehalogenated using zinc in ethanol under the reaction conditions described above. . The above process can also be used to prepare other compounds with unsaturation at any other carbon atom using the corresponding starting materials.

The compounds of the invention are used in animal therapy.

They are effective against both adult and non-adult liverworms of the species Fasciola gigantica and Fasciola hepatica, which are common liverworms in sheep and cattle. The preferred dosage level depends on the compound used, the species of animal being treated, the viscera in question and the severity of the worm disease. In general, an effective effect is obtained when the compounds are administered in a single dose at a concentration of about 1 to 150 mg / kg of animal weight, and preferably about 1 to 50 mg / kg of animal weight. The compounds of the invention can be administered in a number of different ways depending on the animal in question, the method of treatment usually administered to that animal, the substances used and the content worm in question. The compounds are preferably administered in sufficiently effective amounts as a single or divided dose orally or parenterally when a worm infection is evident or expected in an animal.

In addition to the inactive ingredients of the composition, it may contain several other active ingredients, which may be other compounds of formula I or other known anthelmintics. Advantageous results are obtained when the compounds of formula I are combined with an anthelmintic such as 2- (4-thiazolyl) benzimidazole (thiabendazole) or (dl-2,3,5,6-tetrahydro-6-phenylimidazo [* 2,1-b] -thiazole (tetramisole) or other known anthelmintic.

The amounts of active ingredient and other ingredients in the composition will vary depending on the treatment used, the host animal and the worm disease being treated. In general, compositions suitable for oral administration will contain a total of 0.01 to 95% by weight of active compound or compounds, with the remaining concentration comprising carriers or vehicles. Various treatments may be used and each will determine to some extent the general nature of the composition. For example, the anthelmintic compounds may be administered to domestic animals in an oral dosage form such as a tablet, chew, capsule, or liquid; as a liquid oily base form suitable for parenteral administration, or the compound may be premixed and subsequently mixed with animal feed. When the compositions are in solid unit dosage forms such as tablets, capsules or chewable forms, the ingredients other than the active compounds may be any suitable non-toxic media used in the preparation of such forms, and preferably nutritionally acceptable substances such as starch, lactose, talc, magnesium stearate, vegetable gum like that. In addition, when using capsules, the active compound may be used substantially undiluted, the only external substance being the capsule body itself, which may be hard or soft or gelatin or other oral encapsulating agent. When using a dosage form for parenteral administration, the active ingredient is mixed with an acceptable oil base, preferably a vegetable oil such as peanut oil, cottonseed oil and the like. In all such forms, i. in the form of tablets, capsules, chewable forms and oil base preparations, the active compound is suitably about 5-95% by weight of the total mixture.

When the dosage unit form is in the form of a beverage, the active compound is mixed with substances which subsequently promote the suspension of the active compounds in water, such as bentonite, clays, water-soluble starches, cellulose derivatives, viscous surfactants, surfactants and the like to prepare a dry pre-beverage composition is added to the water just before use. In addition to the suspending agent, ingredients such as preservatives, anti-foaming agents or other suitable diluents or solvents may be used in the premix preparation. Such a dry product may contain up to 95% by weight of active compound, the remainder being additives. Preferably, the solid composition contains 30-95% by weight of active compound. Sufficient water must be added to the solid product to obtain the correct dosage concentration while maintaining a suitable amount of liquid for a single oral dose. Liquid beverage preparations with 10-50% by weight of dry ingredients are generally suitable, with a preferred range of 15-25% by weight.

When the compositions are intended for use in food, as food additives or food premixes, they are mixed with suitable ingredients in animal feed. For such purposes, solid orodispersible carriers are used, such as dried grain grains, corn husks, citrus flour, attapulgus clay, wheat bran, soluble molasses, corn cob flour, vegetable ingredients, soybean meal, soybean meal, soybean meal, soybean meal, The active compounds are effectively dispersed or mixed with the active solid carrier by grinding, melting or drumming. By selecting the correct diluent and varying the ratio of carrier to active agent, compositions of any desired concentration can be prepared. Food supplement preparations containing about 5-30% of active ingredient are particularly suitable for addition to the diet. The active compound 64799 is usually dispersed or mixed uniformly in the diluent, but in some cases they may be absorbed into the carrier.

These additives are added to the final animal feed in an amount sufficient to provide the final concentration desired to control or treat the worm infection via the animal feed.

The following Tables I, II and III show the therapeutic activity against some liverworm (Fasciola hepatica) of the 4-amino-unsubstituted and 4-amino-substituted compounds according to the invention and of some of the compounds known from DE-A-2,422,768. The results show that the therapeutic activity of the compounds of the present application is clearly superior to that of the compounds known from that DE application.

Table I. Therapeutic data for some of the 4-amino-unsubstituted compounds of the present invention.

4-amino-6-trikloorivinyyli-l, 3-benzenedisulfonamide

Dose

Ripe Fasciola in the rat - good activity - 6.25 mg / kg

Mature Fasciola in rat - good activity - 3.13 mg / kg s'4-amino-6- (2,2-dichloro-1-methylethenyl) -1,3-benzene] disulfonamide Mature Fasciola in rat - low activity -25 mg / kg

Mature Fasciola in rat - good activity -5 £> 4 mg / kg / 4-amino-6-trichlorovinyl-1,3-benzene-dsulfonamide Fasciola larva in sheep - active - 15 mg / kg moderately active 12.5 mg / kg weakly active 10.0 mg / kg

Mature Fasciola in sheep - active 5 mg / kg 4-amino-6-2 (2-chloro-1,2-difluoroethenyl) -1,3-benzenedisulfinamide Fasciola larva in sheep - weakly active 24.4 mg / kg ί 64799 14

Table II. Therapeutic data for some of the 4-amino-substituted compounds of the present invention.

Compound Activity against mature Fasciola hepatica

R R

3 4 Dose mg / kg -CH 3 -CH 2 active 25 active 125 moderately active 6 moderately active 3 H -CH 2 active 25 active 12 active 6 H “CH 2 active 50 H CH 2 Cl 2 H 2 - active 100 active 25 active 12.5 15; 64799

The table lii. Therapeutic data for two compounds known from DE-A-2 422 768.

4-amino-6-heptafluoropropyl-1,3-benzenedisulfonamide

Mature Fasciola in a rat with good activity 100 mg / kg

Mature Fasciola rat with good activity 50 mg / kg

Mature Fasciola in rats with low activity of 25 mg / kg

Fasciola larva in sheep good activity 75 mg / kg

Fasciola larva in sheep good activity 35 mg / kg 4-amino-6- (2,2,2-trichloro-1,1-difluoroethyl) -1,3-benzenedisulfonamide

Mature Fasciola rat with good activity 50 mg / kg

Mature Fasciola in a rat with good activity of 25 mg / kg

Mature Fasciola in rats with moderate activity 12.5 mg / kg

Examples of compositions suitable for administration to animals include:

A typical chewing composition is as follows: 4-amino-6-trichlorovinyl-1,3-benzenedisulfonamide 7.0 g

Dicalcium phosphate 1.0 g Starch 0.7 g

Guar gum 0.16 g

Talc 0.11 g

Magnesium stearate 0.028 g 64799 16

A typical beverage composition is as follows: 4-Amino-6- (tert-dichlorofluorovinyl) -1,3-benzenedisulfonamide 5.0 g

Benzalkonium chloride 5.6 ml

0.06 g of antifoam emulsion

0.3 g of hydroxyethylcellulose

Sodium phosphate 0.3 ml

Water to a volume of 30 ml

Examples of typical nutritional premixes are as follows: A. 4-Amino-6-trifluorovinyl-1,3-benzenedisulfonamide 4.5 kg

Wheat bran 41 kg B. 4-Amino-6- (1,1-dichloroprop-1-en-2-yl-1,3-benzenedisulfonamide 6.8 kg

Ground oyster shells 18 kg

Citrus flour 20 kg C. 4-Amino-6- (1,2-dichloro-3,3,3-trifluoropropenyl) -1,3 benzenedisulfonamide 4.5 kg

Corn flour 41 kg D. 4-Amino-6- (1,2-dichloro-1-propenyl) -1,3-benzenedisulfonamide 6.8 kg

Wheat bran 23 kg

Corn flour 16 kg

The above-mentioned nutritional premixes are combined with the normal diet of the animals, mixed effectively with them so that the final concentration of the active ingredient is 0.01 to 3% by weight.

Example IA

4-Amino-6- (1,2,2-trichlorovinyl) -1,3-benzenedisulfonamide 32.8 g of 2- (3-aminophenyl) -1,1,2-trichloroethylene are added dropwise with stirring to 107 ml of chlorosulfonic acid + 10 ° C. After the addition is complete, the reaction mixture is heated to 125-130 ° C and stirred at this temperature for 2 1/2 hours. It is then cooled to 20 [deg.] C. and 40.2 ml of thionyl chloride are added portionwise. The reaction mixture is then stirred at 80 ° C for 1 1/2 hours and cooled in ice to + 10 ° C. The reaction mixture is poured onto ice and 4-amino-17,64799 6- (1,2,2-trichlorovinyl) -1,3-benzenedisulfonyl chloride is extracted into methylene chloride, washed with water, dried over MgSO 4 and concentrated in vacuo to give 52 g of a brown foam. It is dissolved in 60 ml of CH 2 Cl 2 and 250 ml of liquid ammonia are added portionwise. Excess ammonia and methylene chloride are allowed to evaporate overnight. Water is added to the residue, which is carefully acidified with concentrated HCl to form an amorphous precipitate. It is extracted into ethyl acetate, washed with water, dried over MgSO 4 and concentrated in vacuo to give 45 g of a brown foam. It is extracted twice with hot benzene to leave 38.5 g of a brown substance. The residue is extracted three times with 1000 ml portions of ether and the ether solutions are concentrated in vacuo to a volume of 250 ml and the crystalline product is precipitated by careful addition of hexane to give, after filtration, 20.8 g of product; an ether complex melting at 130-135 ° C. It is boiled with 175 ml of water for 1/2 hour without allowing the compound to dissolve, then the solution is allowed to warm to room temperature, filtered, washed with water and dried in vacuo at 50 ° C to give 17.0 g of 4-amino-5- ( 1,2,2-trichlorovinyl) -1,3-benzenedisulfonamide, m.p. 188-193 ° C. A small sample is recrystallized from aqueous methanol for analysis, m.p. 205-207 ° C.

Example IB

4-amino-N, N3-dimethyl-6- (1,2,2-trichlorovinyl) -1,3-benzenedisulfonamide 10 g of 4-amino-6- (1,2,2-trichlorovinyl) -1, 3-Benzenedisulfonyl chloride prepared according to Example IA is added to 150 ml of liquid methylamine at -78 ° C. At the end of the addition, the cooling bath is removed and the excess methylamine is allowed to evaporate.

The solid residue is dissolved in water and acidified with acetic acid. The dark precipitate is collected by filtration and dried to give 7.4 g of crude product. Purification by chromatography on silica gel and crystallization from ethanol gives 1 3 2.9 g of 4-amino-N, N-dimethyl-6- (1,2,2-trichlorovinyl) -1,3-benzenedisulfonamide, m.p. 211-212 ° C.

13,64799

Example 1C

113 3 4-Amino-N, N, N, N-tetramethyl-6- (1,2,2-trichlorovinyl-1,3-benzenedisulfonamide 10 g of 4-amino-6- (1,2,2-trichlorovinyl) - 1,3-Benzenedisulfonyl chloride prepared according to Example IA is treated with 125 ml of dimethylamine The reaction mixture is further treated according to Example IB to give 5.2 g of pure 4-amino-113 3 N, N, N, N -tetramethyl-6- (1,2,2-trichlorovinyl) -1,3-benzenedisulfonamide, mp 238-239 ° C.

Example 2 4-Amino-6- (1,1-dichloropop-1-en-2-yl) sulfonamide a) 1,1-Dichloro-2-phenyl-1-propene

A mixture of 30 g of acetophenone, 420 ml of CCL4 and 196 g of triphenylphosphine is stirred at 60 ° C for 9 hours. The liquid is then decanted and the gummy residue is washed well with ether. The solutions are combined and the CCl 4 and ether are distilled off using a vigreaux short column. The residue is distilled in vacuo at 35 mm Hg and the fraction boiling at 120 ° C is collected to give 35.0 g of 1,1-dichloro-2-phenyl-1-propene.

b) 1,1-dichloro-2- (4-nitrophenyl) -1-propene

A mixture of 33 ml of concentrated H 2 SO 4 and 28 ml of concentrated HNO 3 (70%) is stirred in an ice bath while 35.0 g of 1,1-dichloro-2-phenyl-1-propene are added with a reaction mixture of 10-20 ° C: in. The temperature is allowed to rise to room temperature and vigorous stirring is continued for 1 hour. The mixture is poured onto ice, rinsed with ether, the ether extract is washed several times with water, dried over MgSO 4 and concentrated in vacuo. The vapor phase chromatogram of the crude product shows a mixture of two components, probably 1,1-dichloro-2- (4-nitrophenyl) -1-propylene (main product) and its 2-nitro isomer. The residue is distilled in vacuo at 1.0 mm Hg and the 20.9 g fraction boiling at 147-153 ° C is collected.

c) 1,1-Dichloro-2- (4-acetylaminophenyl) -1-propene 30.0 g of iron powder are added to a solution of 29.7 g of 1,1-dichloro-2- (4-nitrophenyl) -1-propene In 500 ml of 50% aqueous ethanol, and stir vigorously at reflux. A solution of 2.2 mL of concentrated HCl 19 64799 in 10.0 mL of 50% aqueous ethanol is added dropwise and the mixture is refluxed for a total of 40 minutes, filtered hot and cooled to room temperature. Add 500 mL of chloroform, basify with aqueous NaHCO 3 and separate the layers. The chloroform-alcohol layer is washed with water, dried over MgSO 4 and concentrated in vacuo to give 28.5 g of crude 1,1-dichloro-2- (4-aminophenyl) -1-propylene. It is dissolved in 145 ml of pyridine and stirred in an ice bath while 85 ml of acetic anhydride are added over a period of 5 minutes and then kept overnight at room temperature. The next morning, concentrate in vacuo and high vacuum to crystallize the residue. 30 ml of ethyl acetate are added and the slurry is stirred for 30 minutes at room temperature and for 60 minutes in an ice bath. It is then filtered, washed with a small amount of ethyl acetate and ether and dried in vacuo to give 18.0 g of 1,1-dichloro-2- (acetylamino-phenyl) -1-propene, m.p. 164.5 to 165.5 ° C.

d) 1,1-Dichloro-2- (4-acetylamino-3-nitrophenyl) -1-propene 6.0 g of 1,1-dichloro-2- (4-acetylaminophenyl) -1-propene is dissolved in 120 ml of acetic anhydrin with stirring at 50 ° C and then rapidly cooled to + 5 ° C to form a fine suspension. A mixture of 1.44 ml of acetic anhydride and 4.28 ml of concentrated HNO2, previously prepared at -20 ° C, is then slowly added over 50 minutes. The ice bath is then replaced with an oil bath and the reaction mixture is heated for 30 minutes at 50 ° C until all is dissolved and kept for another 30 minutes at 50 ° C and then all cooled in an ice bath for 2 hours. The yellow crystalline precipitate is filtered off, washed well with water and dried in vacuo to give 3.14 g of product, m.p. 142-143 ° C. The filtrate obtained above is poured into water, stirred for 1 hour, the precipitate is filtered off, washed with water and dried in vacuo to give a further 2.40 g of 1,1-chloro-2- (4-acetylamino-3-nitrophenyl) -1-propylene , sp. 139-141 ° C.

e) 1,1-dichloro-2- (4-amino-3-nitrophenyl) -1-propene

A suspension of 7.55 g of 1,1-dichloro-2- (acetylamino-3-nitrophenyl) -1-propene in 150 ml of 6N HCl is stirred and refluxed for 30 minutes. It is cooled in an ice bath, basified with 50 ml of 50% aqueous NaOH and extracted with ethyl acetate. The extract is washed with water, dried and concentrated in vacuo to give 6.6 g of crude 1,1-dichloro-2- (4-amino-3-nitrophenyl) -1-propene as a brown oil.

f) 2-Nitro-4- (1,1-dichloroprop-1-en-2-yl) benzenedisulfonamide 4.1 ml of acetic acid are saturated with SO2, 100 mg of CuCl2 · 2H2O dissolved in 2 drops of water and SCR are added. n is bubbled into a solution maintained at 10 ° C. In another flask, 500 mg of 1,1-dichloro-2- (4-amino-3-nitro-phenyl) -1-propene in 3.6 ml of concentrated HCl are stirred and heated to about 80 ° C and then rapidly cooled in ice. The suspension is stirred at 0-5 ° C while a solution of 170 mg of NaNCl 2 in 0.6 ml of water is slowly added over 30 minutes and the mixture is kept at 0 ° C for another 1 hour. 100 mg of sulfamic acid are then used to decompose the excess NaNCl 2. The reaction mixture is separated from the insoluble matter by centrifugation, and the clear solution is rapidly added to the acetic acid / SO 2 / CuCl 2 solution prepared above at 10 ° C.

The temperature is allowed to rise to room temperature over 30 minutes, the mixture is poured onto ice, extracted with methylene chloride, washed twice with water, dried and concentrated in vacuo to give 350 mg of orange crystals of 2-nitro-4- (1,1-dichloroprop-1-en-2-yl). ) -bentseenisulfonyylikloridia. It is dissolved in about 10 ml of liquid ammonia and allowed to stand overnight. Add 4 mL of water and a few drops of 2.5 HCl, allow to stand for 1 hour at room temperature, separate the solid by centrifugation, / wash with a small amount of water and dry to give 280 mg of crystalline 2-nitro-4- (1,1- dichloroprop-en-2-yl) -bentseenidisulfon-amide. A portion of this is recrystallized from benzene / hexane to give an analytical sample of the product, m.p. 149-151 ° C.

g) 2-Amino-4- (1,1-dichloroprop-1-en-2-yl) -benzenesulfonamide 1.02 g nitro-4- (1,1-dichloroprop-1-en-2-yl) -benzene -sulfonamide is dissolved in 30 ml of 50% aqueous ethanol at about 70 ° C. While stirring vigorously, 1.0 g of iron powder is added and the reaction mixture is heated to reflux. 3 drops of concentrated HCl are added and refluxing is continued for 30 minutes, the reaction mixture is filtered hot, the solution is cooled to room temperature, 60 ml of HCl and 15 ml of ethanol are added, the organic layer is washed with water, dried and concentrated in vacuo to give 935 mg of a pale oil. crystallizes from benzene / petroleum ether to give 410 mg of 2-amino-4- (d, 1-dichloroprop-1-en-2-yl) -benzenesulfonamide, m.p. 93-95 ° C.

h) 4-Amino-6- (1,1-dichloroprop-1-en-2-yl) -1,3-benzenesulfonamide 100 mg of 2-amino-4- (± -dichloroprop-1-en-2) -yl) benzenesulfonamide and 1.0 ml of chlorosulfonic acid are stirred at 5-10 ° C and then immersed in an oil bath at 100-110 ° C for 1 hour. The reaction mixture is cooled in ice, added to ice, extracted with CH 2 Cl 2, the solution is washed twice with water, dried and concentrated in vacuo to give 75 mg of crude 4-amino-6- (1,1-dichloroprop-1-en-2-yl). ) -1,3-benzenedisulfonyl chloride, which is identified by nuclear magnetic resonance and mass spectral analysis. 100 mg of this disulfonyl chloride are dissolved in 4 ml of tert-butanol and ammonia gas is bubbled into the solution for about 10 minutes at room temperature. Keep at room temperature for 15 minutes then concentrate in vacuo. The residue is dissolved in ethyl acetate, washed with dilute HCl, water, dried and concentrated in vacuo to give 87 mg of crude product which slowly crystallizes. It is recrystallized from methanol / benzene / methylene chloride to give 4-amino-6- (d, 1-dichloroprop-1-en-2-yl) -1,3-benzenedisulfonamide, m.p. 199-202 ° C. ^

Example 3 4-Amino-6- (2-chloro-1,2-difluorovinyl) -1,3-benzenedisulfonamide a) (d, 2-Difluoro-1,2,2-trichloroethyl) -benzene A solution of 86 g of N, N'-difluorostyrene in 200 ml of CCl 2 are chlorinated with chlorine at room temperature for 22 hours. The reaction mixture is washed with water and aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated by distilling off the solvent at atmospheric pressure using a vigreaux column. The liquid residue is then distilled in vacuo at 20 mm Hg to give 100 g of (1,2-difluoro-1,2,2-trichloroethyl) benzene, b.p. 96-97 ° C, N25-1, 5073.

D

64799 (b) 3- (1,2-Difluoro-1,2,2-trichloroethyl) nitrobenzene 100 g of (1,2-difluoro-1,2,2-trichloroethyl) benzene are added dropwise over 30 minutes to a vigorously stirred nitrate mixture in which is 85 ml of concentrated nitric acid in 400 ml of concentrated sulfuric acid while maintaining the temperature at 15-25 ° C by cooling in an ice bath. After the addition is complete, stirring is continued at room temperature for 5 hours. The mixture is then poured onto ice and the product is extracted with methylene chloride. The solution is washed with water and aqueous sodium bicarbonate, dried and concentrated in vacuo to a yellow oil, the oily residue is distilled in vacuo at 2.2 mm Hg to give 104 g of 3- (1,2-difluoro-1,2,2-trichloroethyl) nitrobenzene, b.p. 122-124 ° C.

c) 3- (1,2-Difluoro-1,2,2-trichloroethyl) -aniline 104.4 g of 3- (1,2-difluoro-1,2,2-trichloroethyl) -nitrobenzene are added to the solution over 10 minutes, with 325 g of crystalline stannous chloride (SnCl 2: 2Η 2 <3) in 325 g of concentrated HCl and 325 g of ethanol, while stirring vigorously and maintaining the temperature at 50 ° C. Stirring is continued for another 3 hours. Cool in ice and collect the precipitate by filtration. The solids are suspended in 500 mL of water and 500 mL of CH 2 Cl 2, the mixture is cooled in ice and basified by the addition of 50% aqueous NaOH until almost all of the solid is dissolved. The methylene chloride solution is separated, washed with water, dried over Na 2 SO 4 and concentrated in vacuo to give 75 g of 3- (1,2-difluoro-1,2,2-trichloroethyl) -aniline as a yellow oil.

d) 3- (2-Chloro-1,2-difluorovinyl) -aniline 74 g of zinc dust are added to a vigorously stirred solution of 40 g of 3- (1,2-difluoro-1,2,2-trichloroethyl) -aniline in 450 ml. in ethanol, and heated at reflux for 2 hours. Filter while hot, wash the solid residue with hot ethanol and cool the combined ethanol solution to room temperature. About 1000 mL of chloroform is added and the organic layer is washed with aqueous NaHCO 3 and water, dried over Na 2 SO 4 and concentrated in vacuo to give 23.9 g of oily 3- (2-chloro-1,2-difluorovinyl) aniline. It gives a simple peak with a retention time of 1.8 minutes at 200 ° C on a gas liquid chromatography column packed with 5% SE 3 O and the correct values for elements C, H, Cl and F in the combustion analysis.

23 64799 e) 4-Amino-6- (2-chloro-1,2-difluorovinyl) -1,2-benzenedisulfonamine 2.0 g of 3- (2-chloro-1,2-difluorovinyl) aniline are added dropwise. ml of ice-cold and well-mixed chlorosulfonic acid. 20 g of dry sodium chloride are added portionwise over 30 minutes at room temperature. The reaction flask is immersed in an oil bath and heated at 115-120 ° C for 4 hours. It is cooled in ice and added portionwise to ice water. It is treated with methylene chloride, the organic layer is washed with water, dried and concentrated in vacuo to give crude 4-amino-6- (2-chloro-1,2-difluorovinyl) -1,3-benzenedisulfonyl chloride, identified by molecular peak peak 385 in the mass spectrum. , the characteristic pattern of which corresponds to the trichloro compound. It is immediately added to the liquid ammonia and allowed to stand overnight while allowing the excess ammonia to evaporate. The residue is dissolved in a small amount of water, acidified with dilute HCl and extracted with ethyl acetate, dried and concentrated in vacuo to give 600 mg of crude 4-amino-6- (2-chloro-1,2,2-difluorovinyl) -1,3-benzenedisulfonamide. The nuclear magnetic resonance spectrum shows two simple peaks at 7.35 and 8.25 S, which correspond to this product, and represent protons at the 5- and 2-positions of the 1,3,4,6-tetrasubstituted benzene ring. This product is further purified by preparative thin layer chromatography using 2.0 mm thick layers of silica gel and benzene / ethyl acetate (1: 1) as the liquid phase to give 210 mg of pure product which gives white crystals of methylene chloride / ether, m.p. . 184-187 ° C and in a Molar ion mass 347 mass spectrometer.

Example 4 1,2-Dichloro-1- (5-amino-2,4-disulfamylphenyl) propene a) 1,1,2,2-Tetrachloro-1- (3-nitrophenyl) propane 47 g 1,1,2 2-Tetrachloro-1-phenyl-1-propane is added dropwise over 45 minutes to a well-stirred nitrate mixture of 31.2 ml of concentrated sulfuric acid and 16.9 ml of concentrated nitric acid while maintaining the temperature at 25-35 ° C. Stirring is continued for a further 3 hours at room temperature, the reaction mixture is poured into ice water, extracted with CH 2 Cl 2, concentrated in vacuo and crystallized from 125 ml of methanol to give 29 g of yellow crystals of 1,1,2,2-tetrachloro-1- (3-nitrophenyl). ) propane, m.p. 75.5 to 77 ° C.

24 64799 b) 1,2-Dichloro-1- (3-aminophenyl) -1-propene 13 g of 1,1,2,2-tetrachloro-1- (3-nitrophenyl) propane and 7.9 g of iron powder are stirred vigorously at reflux in 465 ml of 50% aqueous ethanol. 5.6 ml of a solution prepared previously from 52 ml of concentrated hydrochloric acid and 250 ml of 50% aqueous ethanol are added dropwise over 5 minutes. After stirring for a further 2 hours at reflux, the hot reaction mixture is filtered, cooled to room temperature, diluted with sufficient chloroform to double the volume of ethanol and basified with saturated aqueous sodium bicarbonate solution. The organic layer is separated, washed with water, dried and concentrated in vacuo to give a mixture of substantially pure cis- and trans-1,2-chloro-1- (3-aminophenyl) -1-propylene as a yellow oil.

c) 1,2-Dichloro-1- (5-amino-2,4-disulfamylphenyl) -1-propene 1.0 g of 1,2-dichloro-1- (3-aminophenyl) -1-propene is added dropwise To 1 ml of ice-cold chlorosulfonic acid and then y is added 13 g of dry sodium chloride in 35 minutes. The reaction mixture is heated to 125 ° C for 30 minutes and maintained at this temperature for 1 1/2 hours. It is cooled by pouring into water, extracted with methylene chloride, dried over magnesium sulfate and concentrated in vacuo to give 900 mg of crude intermediate disulfonyl chloride. It is added to liquid ammonia and allowed to stand overnight. The crude disulfonamide is separated by adding water, acidifying with dilute HCl, extracting with ethyl acetate and evaporating the extract in vacuo. Further purify by preparative thin layer chromatography using a silica gel coated plate to give 40 mg of substantially pure 1,2-dichloro-1- (5-amino-2,4-disulfampylphenyl) -1-propene.

Example 5 4-Bromo-6- (1,2,2-trichlorovinyl) -1,3-benzenedisulfonamide

Nitrosyl sulfuric acid is prepared by adding 0.51 g of powdered NaNCl 2 to 6.0 ml of cold (0 ° C) well-stirred concentrated R 2 SO 4.

2.53 g of 4-amino-6-trichlorovinyl-1,3-benzenedisulfonamide are then added portionwise, followed by 6.0 ml of glacial acetic acid. The reaction mixture is stirred for 15 minutes at 15 ° C to complete the diazotization reaction. A solution of 1.2 g of cupro bromide (¢ ^ 213 ^) in 6.0 ml of concentrated hydrobromic acid is then added dropwise and the reaction mixture is heated on a steam bath for 30 minutes after the addition is complete. The reaction mixture is added to 200 ml of cold water to give a precipitate which is collected by filtration and dried to give 1.11 g of essentially pure 4-bromo-6- (1,2, -trichlorovinyl) -1.3 g. -benzenedisulfonamide, which is recrystallized from ethyl acetate / benzene to give 0.86 g of pure product, m.p. 228-229 ° C.

Example 5A

4-Chloro-6- (1,2,2-trichlorovinyl) -1,3-benzenedisulfonamide

If cuprous chloride and concentrated HCl are used in place of cuprous bromide and concentrated HBr in the above method, 0.76 g of 4-chloro-6- (1,2,2-trichlorovinyl) -1,3-benzenedisulfonamide is obtained, which melts after recrystallization ethyl acetate / benzene at 211-213 ° C (decomposes).

Correspondingly, 4-chloro-N1, N3-dimethyl-6- (1,2,2-tri-1,3-chlorovinyl) -1,3-benzenedisulfonamide 4-amino-N, N-dimethyl-6-trichlorovinyl-1,3- benzenedisulfonamide.

Example 6 4-Benzylamino-6- (1,2,2-trichlorovinyl) -1,3-benzenedisulfonamide

A mixture of 0.31 g of 4-bromo-6-trichlorovinyl-1,3-benzenedisulfonamide and 0.76 ml of benzylamine is stirred at 100 ° C for 2 hours and then any aqueous acetic acid is added and cooled in ice. . The precipitate is collected by filtration, weighing 0.26 g after drying, and after recrystallization from ethyl acetate / benzene / petroleum ether, 0.17 g of 4-benzylamino-6- (1,2,2-trichlorovinyl) -1,3-benzenesulfonamide, m.p. . 188-190 ° C.

Example 7 4-Furfurylamino-6- (1,2,2-trichlorovinyl) -1,3-benzenedisulfonamide 4-Bromo-6-trichlorovinyl-1,3-benzenedisulfonamide and furfurylamine are reacted at 77 ° C for 10 hours above. to give 4-furfurylamino-6- (1,2,2-trichlorovinyl) -1,3-benzenedisulfonamide, m.p. 153-155 ° C.

26 64799

Example 8 4-Methylamino-6- (1,2,2-trichloronyl) -1,3-benzenesulfonamide

A mixture of 0.445 g of 4-bromo-6-trichlorovinyl-1,3-benzenedisulfonamide, 15 ml of methanol and 5-10 ml of methylamine is sealed in a steel bomb and heated at 45 ° C for 2 hours. The reaction mixture is then concentrated to a solid residue which is mixed with aqueous acetic acid. The mixture is extracted with ethyl acetate and concentrated in vacuo to give 0.3 g of an amorphous substance. Upon crystallization from aqueous methanol, 60 mg of 4-methylamino-6- (1,2,2-trichlorovinyl) -1,3-benzenedisulfonamide, m.p. 239-240 ° C (decomposes).

If the nucleophilic amino component in the previous examples is replaced by isopropylamine, di-n-butylamine, N-methylpiperazine, morpholine, thiomorpholine-1,1-dioxide or aniline, the corresponding 4-isopropylamino, 4-N, N-di-n-butyl // amino-, 4- (4-methyl-piperazinyl) -, 4- (4-morpholinyl) -, 4- (1,1'-hydroxy-4-thiomorpholinyl) - or 4-phenylamino-6-trichlorovinyl 1,3-benzenedisulfonamide.

Claims (1)

6 4 799 27! A process for the preparation of therapeutically useful substituted benzenedisulfonamides of the formula / R 3 R "T li-NSd r R 1 S -—O 2 N R 2> Sv'R 2 wherein R is a halogenated unsaturated alkyl group containing 2-3 carbon atoms and R 2 is hydrogen or methyl and R 1 and R 2 are hydrogen or benzyl, methyl or furfuryl groups, characterized in that a compound of the formula R-NH 2 C 10 2 S - SO 2 Cl is chlorosulfonated to form a compound wherein R is as defined above, which compound is treated with ammonia or with a mono- or di-lower alkylamine to form a product of formula ^ 2 R2 wherein R, R. | and R 2 is as defined above, or is chlorosulfonated to form a compound of formula 28 64799 * ΤΊτ> SO 0 N 1 to form a compound of formula ^ 2 ^ 9 JR 2 / * i C 10 2 S-1 and R 2 is as defined above, which compound is treated with ammonia or a mono- or di-lower alkylamine to form a product of formula R 2 * 2 wherein R, R and R are as defined above, and then, if desired, the resulting final product is treated with an alkali metal nitrite in the presence of an acid and then a metal halide in the presence of a hydrohalic acid to give a compound of formula * XL / R 1 ° 2S-SO 2 SO 2 NR 2 R 2 wherein R, R 1 and R 2 are as defined above, followed by the compound thus formed is treated with an amine of formula / R 3 H - N 2 R 4 6 4 7 9 9 29 wherein and R 4 are as defined above to give a compound of formula> R_ E \ 1 Γ 4 / ^ ^ NO 2 S-— SO 2 Nv <E2 wherein R, R1, R2, R1 and R2 are as defined fins the same as above. 64799 30 For example, benzene sulfonamides with the formulation of the therapeutic substituents of the formula R Ni —r 3 a -v II X / 1 ^> ° 2S -L · 2 color R is a halogen-free alkyl group, with a hydrogen atom of 2-3 cholaters, R ^ and R2 is used for the purposes of methyl or R, and R ^ and R ^ for the purposes of benzyl, methyl or furfuryl groups, kännetecknat därav, att man klorsulfonerar en förening med formuleln Ό, H? for the preparation of the formulation --- nh2 C102S I ^^ Jj S02c1 color R har samma betydelse som ovan, vilken förening behandlas med ammoniak ellon en mono-eller di-lasgre-alkyl-Amin för the formation of the formulation R - (^^. 1 - NH "'" TiOjS —L Jl — so2n <^ 1 * 2 color R, R ^ och R2 is the same as in the case of a chlorosulfoner in the form of F - m2 S02N O R2 for image of the formulation 31 64799 R --- NH? KYI 2 D! cio2s; J__εο2Ν R2 color R, och R2 har samma betydelse sora ovan, vilken förening behandlas med ammoniak eller en mono- eller di-lägre-alkyl-Amin for the image of the product with the form R NH „~ 1 i | ^ * 1> NO, S - LA SO.N color R, R1 and R2 are the same as in the case of the product, och därefter, ifall self-contained with alkali metal nitrides in the form of a ring and a dehydrator with a metal halide in the form of a halide in the form of a halogen for the form of R ", - f I --- Hal ^ RR> ^ K1 1"> no2s L U__ so2n R2 ^ R2 color R, R ^ and R2 har samma betydelse som ovan, varefter den sä bildade föreningen behandlas med en Amin med formeln