DE2118193A1 - Substituted haloalkanesulfonani hde - Google Patents

Description

PATENT LAWYERS
Dr.-lng. HANS RUSCHKt QipMng.H ^ NZ A6ULAR

BERLUi 33
Auflu »te-V! Ktoria-Slf * l · OS

Minnesota Mining and Manufacturing Company, Saint Paul, Minnesota 55101, V.St.A.

SuDStitulated haloalkanesulphonanillides.

The invention relates to substituted haloalkanesulfonanilides in which the anilidophenyl and another phenyl are linked by a group consisting of -CHOH-, -CHOHCH ^ -, -C (CH,) OH- or | -C (CH) 0H- can be, and the pnenyl rings are optionally suD-Stituiert. These compounds are physiologically active, for example as anti-inflammatory agents, as agents against microorganisms or as herbicides. Certain substituted Halogex: - alkanesulfonanilides are known. Such veruindun ^ en in which the anilidriiig is bound to a phenyl ring through a carbonyl group, well-known anti-inflammatory agents (see, for example, British Patent Publication 1 198 301). In contrast to the compounds according to the invention, such compounds are highly aromatic and resonance-stabilized because the two phenyl rings are connected by the pi-electron-rich caronyl group and a longer conjugated system is thus present.

109846/193 6

_: ^ r ^, - BAOORKSINAt

«A - ■

According to the invention is a class of compounds of the formula

has been created in the R ,. a lower haloalkyl group with at least one halogen atom attached to the alpha-carbon • atom is bonded, or 2 halogen atoms, which are attached to the oeta-Kohlenstaffatöm are geounden, R "means hydrogen, a pharmaceutical compatible cation, Alley 1 with 1 or 2 carbon atoms or a member of the group π in which A

-C-A-Q

Oxygen or a carbon-carbon winding and Q is a lower alkyl radical and Y and Y ^{1 are} independently hydroxy, acetojxy, amino, halogen or alkyl or alkoxy with 1 dis> carbon atoms, η and n * are independently 0, 1 or 2 and L is -CHOH-, -CHOHCH ₂ -, -C (CH ₃ ) OH- or -C (C ^ H, -) OH- (where Cj.Hj- is a phenyl ring). The invention also provides methods for preparing and using the compounds.

The term "lower" in connection with "substituent groups" (residues) here refers to groups that contain 1 to 4 carbon atoms. ;.; .--. · "

R can be a straight or branched chain perhaloalkyl radical or a partially halogenated alkyl radical, and the halogen can be fluorine or chlorine, and preferably fluorine. As ooen ---- is indicated, R should contain at least one: halogen, · the an

, Χ.

the alpha carbon atom is bonded, or if no halogen is bound to the alpha carbon atom, at least-.ü .. halogens which are bound to the beta-carbon nature »: Me« ·· Haloalkyd radicals can either contain only one type of halogen;

ΊΟΒ8Λ6- / 1 93 p

■ - Ί> - M 29bd

■ (For example, they can be fluoroalkyl radicals) or contain mixed halogens. "When mixed halogens are present, it is advantageous to have one or more fluorine atoms per chlorine atom. A preferred class of compounds is one in which R, _{r is} perfluoroalley 1. Most preferred are compounds in which R-. Trifluoromethyl or difluoromethyl is because these compounds are generally most effective as anti-inflammatory agents.

The radical R is preferably hydrogen or a pharmaceutical compatible cation. Compounds in which H AlleyI or

0 y

"

-C-A-Q, according to the definition given above; ,, are in the ail- ^ generally less effective than the corresponding compounds in which R is hydrogen or a pharmaceutically acceptable one Cation, although it is often less than that of mammals are toxic.

Compounds in which the haloalkylsulfonamide group is Defined in meta to the L group, are currently also preferred, as are compounds in which L is -CHOH-.

It appears that the effective type of compound is the compound in which R is hydrogen and that other R groups are converted to result in the effective type of compound in vivo, and the invention is in no way intended to be limited by this theory If a compound in which R is a single group than hydrogen has a better therapeutic index (LDp- _n / ED ^ _K ) than the corresponding compound in which R is hydrogen, this compound can preferably be four denier for therapeutic treatment.

Compounds according to the invention in which R is a pharmaceutically acceptable salt represent olosse modifications of the basic active compound type. However, some compounds provide advantages, such as, for example, an improved absorption

in.q «ifi / 1 ς, ;; <ς

BATH

9 1 1 ° 1 Q

tion as well as suitable solubility and storage properties and other advantages to the knowledge of the Facumann with such Salts can be achieved.

Compounds in which η and n ^{f are} 0 (ie in which the rings, with the exception of the haloalkane sulfide and L groups, are unsubstituted) are preferred. However, if Y una / or Y ^s . Is or are halogen, this is preferably fluorine or chlorine. In addition, if Y or Y ^{1 is} hydroxy or amino, η and / or n ^! Is preferably 1.

The compounds according to the invention are acidic when R fabric is. That is why they form salts, 2.3. Compounds dex 'formula I, in which Ii is a pharmaceutically acceptable cation. These are generally alkali metal (e.g. lithium, sodium and potassium), Alkaline earth metal (e.g. barium, calcium and magnesium) and others Metal salts (e.g. aluminum, zinc and iron), ammonium and amine salts. The amine salts include the salts of aliphatic (e.g. alkyl), aromatic and heterocyclic amines, as well as those that represent a mixture of these structural types. Amines suitable for preparing the salts according to the invention can be primary, secondary or tertiary and preferably contain no more than 20 carbon atoms.

The salts according to the invention can be prepared by treating the acidic form (compounds of the formula I in which R is hydrogen) with a stoichiometric equivalent amount of a suitable 3ase under mild conditions.

Suitable bases for use in making the metal salts include metal oxides, hydroxides, carbonates, oicaroonates and alkoxides. Some salts can also be prepared aurcii cation exchange reactions (by reacting a salt according to the ¹ invention .. with an organic or inorganic salt after a cation exchange reaction). The oxy-organic amine salts include, for example, salts of the morpholine, methylcyclohexylamine, glucosamine and the like. These salts and the ammonium salts

"■ incift £ fi / i93S

BATH ORIGINAL

M 2 ^ 68

can be made by using the acidic form with the suitable organic base odex with Amnioniarjinydroxia.

The salts according to the invention are often prepared by reacting the first runnings in aqueous solution. This solution can be evaporated in order to ergeoen the δε, ΐζ of the 'compound, generally as a dry powder. In some cases it may be threader to use a non-aqueous solvent, e.g. Alkonols, acetone, etc., should be used. Di v. get: e solution is then treated in such a way that the solvent is removed, / d, eg evaporated under reduced pressure. Because many of the salts are water-soluble, they can often be used in the form of their aqueous solutions. In addition, they can be used for the production of pharmaceutical preparations in the form of capsules for oral administration.

In general, the compounds according to the invention in which R is hydrogen or alkyl and L is -CHOH- are obtained by reducing the corresponding benzopnenones according to the following equation

II

prepared, in which R., Y, Y ¹ , η and η ^{1 have} the meaning given above una M-RV, is a reducing agent or -oesteh-t from combined reagents. M ^ 'can be a complex metal hydride, such as sodium borohydride, lithium aluminum hydride, a chemical reducing agent combination, such as zinc and sodium hydroxide in "ethanol or a catalytic auction system,

10984 6/1935

BAD ORtGfNAL

· ■ O "~

M Ü'jbu

such as hydrogen and palladium on cones. Ss is been found to be tratriumoor-iya ^ ia in general is effective and sufficiently selective, and it is the preferred one Reducing agent.

The benzophehon, α ^ ε i-edusiert, is dissolved in a suitable solvent for reductions with Matriurnjorriydrla, such as in methanol, and then with a slight excess (up to 10,.>) Of Natriumuornyaria ixi iJatriumhydi- oyr.id solution treated. It is generally advantageous to do this addition below 10 ° C. in order to avoid violent e ^ -otnerrrie reactions. This reaction can take place within 15 minutes or up to several weeks at room temperature. 1 day generally provides a sufficient reaction time at this temperature or a period of time. on a small scale. Shorter reaction times are used because of the higher temperatures.

OH
ι

The compounds according to the lii-fina ^ iig, ^ ei aenen j_. -CE-CH ^ - and R is hydrogen, preferential acid condensation of alkali met all salts of
the formula ■ '

ii:

with Grignard's reagents, e.g. with Benzylmagnesiurnehloxad, in a suitable solvent such as tocrahydrofuran. Compounds according to the invention in which L -C (CH -,) OH- or -C (J ^) OH- and R is hydrogen, preferably white by reacting alkali metal salts of benzophenones of the Formula II with methyl or phenyl Grignax ^ ds reagents, e.g.

109846/1935

BAD OBIGtNAL

'with Methylmagnesiuinjodicl, Metnylmagnesiumuroiuia, Phenylmagnesiumoromid and Fiienylrnagnes lum iodide, - produced.

Usual iletiiodeii., Ur insulation of the products can be applied many. The oasis solution is generally acidified, the product is with Dläthylather, Diciilormetiian and -dei'gl. extralated. Purifying the products can aui'cii distilling, Recrystallization, elution chronology and recording unü üergl. oerkctelligt will·:. Often get four of the oils that don't work crystallize or allow to distill, but the chemical analysis and spectral analysis are used to the structures of such oils

To prepare the compounds according to the invention in which ^ R is lower alkyl, compounds of the formula I in which R is a metal ion, for example sodium or potassium, can be mixed with a stöehionietrisciien amount of alkyloromide or iodine or a dialyl sulfate in a suitable solution, like e.g. 3rd acetone, uir; be set. According to an alternative approach, di_; Metal salts of the corresponding internal benzophenones (Fci'inel II) or "Formylhalogenalkansuifonainiden (Formula III) converted into the intermediate N-alkyl compounds and these then with reducing agents or Grignard reagents to form the N-alkyl compounds of the Foi- mel I implemented.

0 I.

The compounds according to the invention in which R is -C-A-Q, are preferably made by implementing Veroinä ^ ngen of the formula I, in which R is a metal ion, with an acylating agent

of formula IV, D-C-A-Q, in which Q and A are those given above Corresponds to definitions and D is halogen, preferably fluorine, chlorine or bromine, or the residue of an anhydride, i.e. one Acyloxy group. The connections in which 0

R is -C-A-Q and L -CHOH- can also be obtained by reducing the.

10 9846/1936

around BAD ORJGlNAt

■ corresponding intermediate N-substituted benzophenones using reducing agents such as sodium borohydride or hydrogen and palladium on carbon. A wide variety of acylating agents of the formula IV can be used for the preparation of the compounds according to the invention, such as, for example, ayl halides or anhydrides, ■ halogen formates and the like. These connections are either directly available or, as in the case of certain chloroformates, are easily obtained from phosgene and the corresponding alcohol manufacturable.

The intermediate benzophenones of formula II above, in which R is hydrogen, are produced by condensation of an aminobenzophenone with a haloalkylsulfonyl halide or anhydride manufactured according to the following formula scheme:

R _x SO ₂ M

+ HX

In this formula scheme, R, n, n ¹ , Y and Y * correspond to the definitions given above and X ~ represents a halogen atom, preferably chlorine or fluorine, or the corresponding anhydride group -OSOpR (where R has the meaning given above J represents »; Approximately equivalent proportions of the reaction participants

"O G

are usually between about -15 and 150 C can lie, brought together if necessary or desired.

to stm / it 3 t

BATH ORIGINAL

If so, the implementation is carried out in a pressure vessel. the Implementation is preferably, but not necessarily, in the presence an acid acceptor, such as the alkali or alkaline earth metal carbonates and bicarbonates or a tertiary amine, such as pyridine, triethylamine or Ν, Ν-dimethylaniline. The amount of acid acceptor can be varied widely; an excess of 10 Mol- ^ ä compared to the amount of base, which is sufficient would be to bind the released strong acid (HX) is generally used.

The condensation is usually in the presence of a suitable inert organic solvent carried out. Exemplary. ' Solvents that are suitable for this purpose are methylene chloride, chloroform, carbon tetrachloride, benzene, toluene, Bis (2-methoxyethyl) ether, acetonitrile, nitromethane and the like.

After completion of the reaction, the product can if the solvent for the reaction is not miscible with water / water, it must be extracted with a dilute aqueous basic solution. The product, in the form of a salt, which is generally soluble in the aqueous layer, is made therefrom by addition a mineral acid such as hydrochloric acid or sulfuric acid and collected by filtration. According to an alternative route, the mixture obtained as the product with aqueous Hydrochloric acid can be washed, then the solvent evaporated in vacuo and the precipitate in a dilute aqueous Base solution, which is then washed with dichloromethane and treated with decolorizing charcoal. That in the form of a The salt present product is then, as described above, converted into the acidic form and isolated.

If the solvent for the reaction is miscible with water, the product is generally obtained by diluting the reaction Get mixed with water. The product, a solid substance or an oil, is separated off and purified by conventional methods.

109846/1935

BATHROOM ORIGINAL

The compounds made by the procedures below are crystalline solid substances, dia im. general through Recrystallization from aqueous alcohol, trichlorethylene, hexane, benzene-hexane mixtures and the like. Be purified. It is established been found that elution chromatography is a suitable one Represents cleaning technology.

The intermediate formylhaloalkanesulfonanilides

wherein R, Y and η have the meanings given above from known compounds by sulfonylation of the corresponding dialkoxymethylanilides according to the general method, which is used for the production of benzophenones (JI), and Stir the ^ product with aqueous acid (HCl) to form .The desired compound made in situ. The reaction conditions and the isolation and purification procedures are similar to those for the preparation of the intermediates Benzophenones are applied.

Another and preferred process for the preparation of the benzophenones of formula II in which Y or Y * is hydroxy in the cleavage of the alkoxy group from the corresponding sulfonanilides, in which Y or Y * is alkoxy. This can be more convenient Way can be made with mixtures of hydrogen iodide and acetic acid. On the other hand, other known methods of ether splitting, such as by means of hydrobromic acid-acetic acid.

If R in the compounds of formula II is hydrogen, this hydrogen is acidic in nature »Hence these compounds form slightly alkali metal, alkaline earth metal and amine salts and the like.

109846/1935

• salts. Many salts of the benzophenones can be used in a simple manner by adding the stoichiometric amount of the chosen base be prepared as a solution in an inert solvent to the acidic compound. The resulting solution is treated to remove the solvent, for example under reduced pressure Evaporated pressure.

Compounds of formula II in which R is alkyl are readily prepared by substituting the compounds of formula II in which R Represents hydrogen or a cation with an alkyl halide manufactured. This method of alkylation is as such known.

Suitable haloalkanesulfonyl anhydrides and halides (e.g. * Chlorides and fluorides) for use as starting materials in these processes are known as such, such as s -

Fluoromethanesulfonyl chloride,

Fluorochloromethanesulfonyl chloride,.

Difluoromethanesulfonyl chloride, *

Dichloromethanesulfonyl chloride, 2,2,2-trifluoroethanesulfonyl chloride, Trif luorme "thansulf onylehlorid, 1,1,2,2-tetrafluoroethanesulfonyl chloride, Bronimethanes'ulfonylehlorid,

2ί2,3,3-tetrafluoropropanesulfonyl chloride, g

2-hydroperfluoropropanesulfonyl chloride and many others' Links,

The ones used to prepare the benaophenones of formula II Aminobenzophenones are generally described in the chemical literature or can be obtained from. corresponding known substituted Nitrobensophenones by means of reduction are obtained. Very well which are not specifically described in the chemical literature ■ Nitropensophenones or aminobenzophenones are made according to processes those in the literature for the preparation of analogous compounds

109846/1935 "ί

ORIGINAL

are known. Examples of such starting materials ^; rials are:

5-amino-2-chlorobenzophenone,

j5 - Amino-4 '-f luorbenzophenone,

^ -Amino-5-bromobenzophenone,

3-amino-4'-ethylbenzophenone,

^ -Amino-2'-ethoxybenzophenone, 3-amino-4'-ethoxybenzophenone and the like.

As indicated above, the compounds according to the invention are effective anti-inflammatory agents and some compounds also have an activity against microorganisms and as herbicides. In each case, the effectiveness has been determined using recognized classification procedures. The compounds with a particular value as agents against microorganisms are those in which R is hydrogen and. R _r . Is perhaloalkyl.

The anti-inflammatory efficacy can be determined in a simple manner using specific test methods to test the ability of these compounds to counteract local edema, which is a property of the anti-inflammatory responsiveness (edema test on the rat barrel) and the occurrence of erythema due to inflammation (erythema test on guinea pigs) to counteract, Vf he demonstrated the. ^;

The edema test is carried out on adult female rats. One group of 10 rats serves as an untreated control while another group of 10 rats receives the test compounds at various times prior to inducing the edema, generally 15 minutes, one hour and / or 18 hours. The test compounds were administered as a suspension in 4% aqueous: gum arabic solution ("aeacia" solution). Edema was induced by plantar injection of 0.5 % carrageenin (0.1 ml / foot) into the right hind foot. The left hind foot received

109846/193 5

BAD OFUGlNAL

an equal volume of 0.9% physiological saline solution. 3 hours later, the volume of each hind paw was determined by plethysmography. The edema was determined in the form of the volume increase in the puss into which the edema-producing agent had been injected (volume of the "edema-forming foot" minus the volume of the "foot with physiological saline solution"). The percentage inhibition of edema formation is calculated by grading or grading the mean percentage enlargement of the edema in the edema-forming foot of the group treated with the agent and multiplying it by 100. An effective dose is one which is significant in a statistically 'M inhibition of the induced edema generally "~ to about 30-35 ^ solution of inhibition leads.

Leading publications on this method are;

1. Adamkiewicz et al., Canad.J.Biochem.Physio.J> 3, 332, 1955.

2. Selye, Brit.Med.J., 2, 1129, 1959 and

3. Winter, Proc.Soc.Exper.Biol.Med. 111, 544, 1962.

The erythema test is performed on adult albino guinea pigs of both sexes and each with a weight of 400 - 600 g carried out. The hair is from the belly of the animals with a depilatory agent in the afternoon of the day preceding the day the guinea pigs were used for testing should be removed. One group of 5 animals serves as the untreated control, while another group of 5 Animals test the compound 30 minutes before the animals are exposed to ultraviolet Directly exposed to light. To induce erythema, the animals are placed on or in a narrow animal box fixed. 3 round sections (6-8 mm in diameter) of the ventrolateral abdominal region of the animal are then made exposed to a set amount of ultraviolet radiation. .2 hours after irradiation, the erythema will be within 0-5 taking into account the intensity and completeness (full or partial circles). The highest

109846 / 193S

m 2960

rating per animal is I5. The percent inhibition will be.aaf Basis. Of the mean score for the treated group against the non-treated group is calculated. An effective dose is accepted as such if it results in a statistically significant inhibition of induced erythema, in general a 35-40 yuan inhibition.

Variations to this test include changes in the time and method of administration of the drug »

Leading publications on this method are:

1. Wilhelmi, Switzerland.Med.Wschr. 79, 577, 1949 and

2. Winder et al., Arch. Int. Pharmacodyn. II6, 36I, 1958.

The compounds according to the invention are preferably administered orally Administered. to Symptoms of Inflammatory Conditions in Mammals too mild, e.g. as 4-fold gum arabic suspensions, but can also be administered parenterally. The quantities "be ~ generally carry about 1 to 500 mg / kg body weight of the mammal to be treated.

The effectiveness of the compounds according to the invention against Microorganisms were identified using recognized classification procedures based on the methods described by Vincent, J.G. and Vincent, Helen W., Proc.Soc.Exptl.Biol.Med. 55, 162-164, 1944 and Davis, B.D. and Mingioli, E, S., Jour.Bact. 66, 129-136, 1953, written Methods are based, determined.

The following examples serve for further explanation of the invention without limiting its scope. All melting points are uncorrected. All parts are based on weight, unless otherwise stated in the examples.

109846/193 5

m 2968

example 1

3-Benzoyldifluorriietiiansulfonanilid (7.7 g, 0.025 mol) is dissolved in methanol (50 ml), the solution is cooled to below 5 ° C and treated with sodium anhydride (1.3 g, 0.030 mol) in 10% sodium hydroxide solution (25 ml ) Treated for 30 minutes. The solution is stirred at barely a temperature for 1.5 hours and then diluted with water (50 nil). The sodium salt of the substituted benzhydiol is not isolated, but the solution is mixed with 5 .iger hydrochloric acid until an acidic reaction. The solution is then extracted with dichloromethane, the extracts are dried over magnesium sulfate and the solvent is removed in vacuo, an oil being painted. The oil kristallisiex't se-ix heavily scratching and cooling to 3 ¹ - (! Phenyl-hydroxy methyl) äifluormethansulfonanilid melting at 77.5 to 79 C nacii the Umkx'istallisieren from cyclohexane.

Analjrse: füi ( G; ; j C 7th , ο Η ■ fi N Runs down 53 7th 4.2- 4.5 53 4.1 4.4 Example 2 H ₁ ^ F ₂ NO-S: cfound: '

Using actually the same procedure as in Example 1, it knows how solid 3 ^l - (phenylhydro>: methylyl) trifluoromethanesulfonanilide with a melting point of 67.5-6.9 was produced. ■

-nO

Analysis: for C ) O C ö 3, 7th / -> 4th N Calculated 50, 4th '3, 7th 4th , 2 51, , 4 J ₁₄ H ₁₂ F ₅ NO ₅ S: Found:

The following compounds are prepared from the corresponding benzophenones using the same procedure.

109846/1935

BAO ORIGINAL

Example connection. Melting point

No. ( ⁰ C)

Ί> 3 ^l - (4-chlorophenylhydroxymethyl) trifluar-

■ methanesulfonanilide 91-92 ·

.4 3 ^l - (4-methylphenylhydroxyraethyl) trifluoro-

methanesulfonanilide. 65-67

Other compounds made by the same process 'willj are in the following table with the melting point - ■ th of the intermediate benzophenone precursors.

Example benzophenone compound

No. . Melting point ^Λ

5 116-119 6th 133-136 7th 135-137 8th oil 9 oil 10 105.5-107 11 122.5-124.5 12th 118-120 13th 116.5-118.5 14th 136-137 15th 131-133 16 118-120

3 ^f - (Pheny lh? "Droxymethyl) fluoromethane lf ild

sulf onanilide

4 ^t hydroxy-3 ^f - (phenylhydroxymethyl) trifluoromethanesulfonanilide

3 ^L - (4-chloro-2-methylphenylhydroxymethyl) trifluoromethanesulfonanilide

N-methyl-3 ^t - (phenylhydroxymethyl) trifluoromethanesulfonanilide

N-Ethy1-3 ^f - (phenylhydroxymethyl) trifluoromethanesulfonanilide

^ '- (phenylhydroxymethylj ^^^ - trifluoroethanesulfonanilide

3 ^L - (4-methoxyphenylhydroxymethyl) trifluoromethanesulfonanilide

3 ^t - (4-methoxyphenylhydroxymethyl) difluoromethanesulfonanilide

3 '- (^ - Methoxyphenylhydroxymethyl) -fluoromethanesulfonani1ide

4 ⁱ - (phenylhydroxymethyl) trifluoromethanesulfonanilide

3 ^l "(2-hydroxyphenylhydroxymetnyl) trifluromethanesulfonanilide

3 ^l - (4-Methylphenylhydroxymethyl) -fluoromethanesulfonani1iQ

109846/193 5

Sorting:

Example
No. Benzophenone
Melting point
(° σ) 17th 127-129 18th 101-102 19th 72-74 20th 92-95 21st 95-97 22nd 154-136 25th 106-ιοδ 24 80-80.5 25th 99-102 26th 82-83- 27 133-13% 28 95-97 29 132-15% ' example 30th

link

5 ^f - (4-chlorophenylhydroxyBiethyl} difluoromethanesulfonanilide '

3 ^f - (3-Chlorpheny Ihy droxyme thy I) trifluoromethanesulfonanllid

5 * - (2 ^ ChlQrpher ^ lhydra: xymethyl) trif luoromethanesulfonanilide . . "

5 ^t - (2-methylpb.enylhydroxyinethyl) trifluoromethanesulfonanilide

5 - (Pfiensrliiydroxyme thyl) perf luoräthansiiironanilid

3 ^l - (4-fluorophen3rihydrofoxymethyl) trifluorine-

Metliansulfonanilid. . . . . . ■.

4 ^l -Ciilor-3 ^l - (piieny Ihy droxyrne thy 1) tri f luor-

raethansiilfonanilid -.

5 ^l - (Phenylhydroxymethyl) ^ -hydro-perfluoroethanesulfonanilide

4 * -Chlo ^ r-3 * - C phenyIhydroxymethy 1) di fluorinethanestrifonanilide . ; .

4 * -Chlor-3 * - (4-chlor pheny! Hydroxy me thy 1) trifittoraiethansulf onani Ii d

4 * -'- Chjtor- ^ ¹ - (4-fluorophenylhydroxymethyl) trifluoromethanesulfonanilide

3 ¹ - (Phenylhydroxymethyl) chloromethanesilfonanilide

5 ^f -Amino-3 ^f "* - (PhenyIhydroxymethyl) tri -

sill hair dryer

3 * - (Phenylhydroxymethyl) trifluoromethanesulfonanilide is reacted with an equimolar amount of Hatriurnhydroxid in acetone, then the solvent is removed in vacuo, and it is Katriuin-Cphenylhydroxymetliyl) trifluo ^ methänsulfonanilid obtained.

3 ¹ - 1098A6 / 1935

Example 31 ''.

3-Benzoyl trifluoromethanesulfonanilide (16.5 g, 0.050 mol) is dissolved in ethanol (250 ml) and reduced using hydrogen gas at a pressure of about 5.2 kg / cm and palladium on carbon. When the Masserstoffauf stop would take, the solution is filtered, then evaporated .The Flltrat, and it is 3 ^r - (phenylhydroxymethyl) trIfluormethansulfonanllId as an oil. The product is purified by elution chromatography as described in Example 2. . .

Example '32.

K-Äthoxycarbonyi-j-benzoyltrifluoromethanesulfonanilld (10 g, 0.025 mol.) Is dissolved in ethanol (150 ml) and 1,2-di-methoxyethane (150 ml) under a nitrogen atmosphere, and sodium; Borohydride, (0.4-7 g, 0.0125 MOl) is added and the mixture is stirred overnight at room temperature. The solvents. are evaporated and the residue is washed with 5% sodium hydroxide, 5 % hydrochloric acid and then with water. The residue is then extracted with benzene, the extracts are dried over magnesium sulphate and the solvents are removed. Removed in vacuo. The product is purified by elution chromatography on neutral aluminum oxide while bluing with hexane, hexane-benzene, benzene, chlorine than and then with ethanol. The second and third fractions will - again,. _; . chromatographed, then completely dried and give in the form of a clear oil N-ethoxycarbonyl - ^^ phenylhydroxymethylr · trifluoriaethanesilfonanilid. '. *

Analysis!

Prepare ^ t for- G ₁₇ H ₁ ^ F Ko ₅ S ι 50 # | i ^ * 0 _; 5 * 5

Cj; % H

3.9 3 Λ

Example 33

-1 - ^ - benzoyltrifluoromethanesulfonanilide is after; 103846/1035%

Procedure of Example 33, using N-propionyl-3-phenylhydr-oxymethyltrifluoromethanesulfonanilld is obtained.

Example 34

2-Benzoyl trifluoromethanesulfonanilide (27.7 g * 0.084 mole) becomes reduced by the method of Example 3I, using 2-phenylhydroxymethyltrifluoromethanesulfonanilide is obtained after purification by elution chromatography and recrystallization is obtained from trichlorethylene as a white solid substance with a melting point of 187.5-1-88.5 ° C.

Example 35

A solution of phenyl magnesium bromide in tetrahydrofuran is prepared from magnesium (1.22 g, 0.05 mol) and bromobenzene (7.85 g, 0.05 mol). A solution of sodium 3-benzoyltrifluoromethanesulfonanilide (17.6 g, 0.05 mol) in tetrahydrofuran (75 ml) is added to this solution over the course of 2 hours (at room temperature). After 3 ^s tündigem further stirring, the slurry is concentrated by evaporation in vacuo and then the residue with 10 ^ sulfuric acid (100ml) is treated. The mixture is made with diethyl ether. and dichloromethane, combine the organic layers and dry over magnesium sulfate and then concentrate by evaporation in vacuo to give an oil. The oil is purified by chromatography on silica and eluting with trichloroethane and benzene. The product is recrystallized twice from cyclohexane, and white crystals of 3- (diphenylhydr-oxymethyl) trifluoromethanesulfonanilide with a melting point of 108.5-109 * 5 ° G are exuded.

Analysis: for C ₂₀ H ₁₆ P ₃ NO ₃ S: 59 C - 4, H . Calculated Found: 50 ,.1 0 , 2 1

109846/1935

BATH ORIGINAL

Example 36 -

3-formyltrifluoromethanesulfonanilide (68th, 7 g, 0.27 mol) is in the sodium salt converted by dissolving it with 270 ml of sodium hydroxide solution Stirred and then evaporated in vacuo to a yellow-brown powder with a melting point of 226-227 ° C (decomp.).

A solution of benzyl magnesium chloride in tetrahydrofuran is prepared from magnesium (3.64 g, 0.15 mol) and benzyl chloride (19.0 g, 0> 15 mol). Sodium 3-formyltrifluoromethanesulfonanilide (13.1 g, 0.05 mol) in tetrahydrofuran (50 ml) is added to this solution. The solution is distilled and the tetrahydrofuran removed. Benzene is added and the solution is cooled and then washed with dilute sulfuric acid and the wash liquors are then extracted with dichloromethane. The benzene and dichloromethane fractions are combined and evaporated in vacuo. The residue is dissolved in dilute sodium hydroxide solution and this solution is extracted with dichloromethane, then acidified with concentrated hydrochloric acid, with 3- (2 ^ PhSiIyI-I ¹ -hydroxyethyl) trifluoromethanesulfonanilide being obtained; Repeated recrystallization from benzene and treatment with decolorizing charcoal gives white crystals with a melting point of 101.5-103.5 ° C.

% N 4.0

Analysis: for C ₁₅ H ₁₄ P ₃ NO ₃ S: 52, 2 4th H Calculated Found; 51, 9 4th ,1 , 3 Example 37

Methyl magnesium bromide (0.075 mol) in tetrahydrofuran is treated with sodium 3-benzoyl trifluoromethanesulfonanilide (16.3 g, 0.046 mol) in tetrahydrofuran. After stirring for 3 hours, the mixture is concentrated by evaporation in vacuo and the residue is treated with 10% sulfuric acid and then extracted with diethyl ether and dichloromethane. The organic

^; ■ 109846/1935

Layers are combined, dried over magnesium sulfate, filtered and evaporated in vacuo. The residue is an oil namely 3- (l'-Pheny1-1'-hydroxyethyl) trifluoromethanesulfonanilide, which can be isolated as the triethylammonium salt.

-Phenyl-1 ¹ -hydroxyäthyl) trifluorraethanesulfonanilid is dissolved in diisopropyl ether, with excess triethylamine he warms, and the white solid is recrystallized twice from a mixture of isopropanol and diisopropyl ether, with triethylammonium-3- (l'-phenyl-1 ^! -Hydroxyäthyl) ^ rIfluoromethanesulfonanilide with a melting point of -124-126 ° C is obtained.

Analysis: for / "1 ττ. TTi " ΝΤί * \ Ci (* f T / ο Kj 3 i ^ H 6th N Calculated Found: J ₁₅ N: 56, 7th 6th , 75. ' 6th , 3 56, 6th , 6

The compound of this example has been found to be an effective anti-microorganism agent, but by one Dose of 100 mg / kg is not significant as an anti-inflammatory agent is ficantly effective.

- patent claims -

109846/1935

Claims (1)

Pa t relaxed JL. Substituted halo genalkansulfonani lid, j denotes that it has the formula characterized by corresponds, in which R is a lower haloalkyl group with at least a halogen atom bonded to the alpha carbon atom is, or 2 halogen atoms attached to, the beta carbon atom are bonded, R means hydrogen, a pharmazeu-; table compatible cation, alkyl with 1 or 2 carbon atoms or a member of group u in which A is oxygen -C-A-Q: or denotes a carbon-carbon bond, Q is a lower alkyl radical, Y and Y ¹ independently of one another can be hydroxy, acetoxy, amino, halogen or alkyl or alkoxy with 1 to 3 carbon atoms, η and n ¹ independently of one another 0, 1 or 2 and L is -CHOH-, -CHOHCH ₂ -, or -C (C ₆ H ₅ ) OH-. Compound according to Claim 1, characterized in that it contains 1 carbon atom. 109846/1935 that 3>. Compound according to claim 1, characterized in that R is a fluoroalkyl group. y> - ■ - 4. Compound according to claim '$, characterized in that R " _{r is} difluoromethyl. 5. -3 ^l - (Phenylhydroxymetliyl) difluormetnansulfonanilid according to claim 4. 6. A compound according to claim 1, characterized in that R is perfluoroalkyl. j 7 '. Connection according to claim 6, characterized in that R is trifluoromethyl. ö. ^ '- XPhenylhydroxymetiiylJtriflUDrmethansulfonanilid according to claim 7 · 9. A compound according to claim 1, characterized in that R is hydrogen. 10. A compound according to claim 1, characterized in that H is a pharmaceutically acceptable cation. Ϊ1. Compound according to claim 1, characterized in that R is 0. -C-O-Q 12. N-ethoxycarbonyl - ^ - phenylhydroxymethyltrifluoromethanesulfonanilide according to claim 11. 15 · Connection according to claim 1, characterized in that L is -CHOH-. 14. Connection to. Claim 1, characterized in that 1098 46/1935 "L -CHOHCH ₂ - is. 15. 3- (2 ^f -phenyl-1 '-hydroxy ethyl) trif luoromethanesulfonanilide according to claim 16. .16. Compound according to Claim 1, - characterized in that L is -G (CH ₁ ) OH-. 17 Triethylammonium-3- (1'-phenyl-1'-hydroxyethyl) tri'luoromethanesulfonanilide according to claim Io. - - l8. Compound according to claim 1, characterized in that L is -C (CMi ^) OH-. 19. 3 "(Di phenylhydroxymethyl) trif luorrnethansulfonanilid according to claim 20. '■' ■ ch denotes j aasa man manure after / sienge of egg Dr.Ve./Br. 109846/1935