US3663708A - N-aryl-n-fluoroalkylsulfonyl carbamates - Google Patents

Abstract

N-CARBONYLFUOROCARBONSULFONANILIDES OF THE GENERAL FORMULA:

(Y''-PHENYL)-CO-(Y-PHENYLENE)-N(-SO2-RF)-CO-A(-Q)M

WHEREIN RF IS A FLUORCARBON GROUP HAVING 1 TO 4 CARBON ATOMS, HAVING EITHER AT LEAST ONE FLUORINE ATOM ATTACHED TO THE ALPHA CARBON ATOM OR IF THERE IS NO FLUORINE ATOM ATTACHED TO THE ALPHA CARBON ATOM, HAVING AT LEAST TWO FLUORINE ATOMS ATTACHED TO THE HTE BETA CARBON ATOM, A IS -O-,-S-,-N< OR A SINGLE CARBON-CARBON BOND, Q IS A HYDROCARBON GROUP CONTAINING UP TO 14 CARBON ATOMS, M IS 1 OR 2 AND Y ANDY'' ARE THE SAME OR DIFFERENT AND ARE HYDROGEN, HALOGEN, LOWER ALKYL, HYDROXY OR LOWER ALKOXY. THESE COMPOUNDS HAVE VALUABLE PHYSIOLOGICAL ACTIVITY AS ANTI-INFLAMMATORY AGENTS.

Description

United States Patent 3,663,708 Patented May 16, 1972 ABSTRACT OF THE DISCLOSURE i-AQu R SG N wherein R is a fluorocarbon group having 1 to 4 carbon atoms, having either at least one fluorine atom attached to the alpha carbon atom or if there is no fluorine atom attached to the alpha carbon atom, having at least two fluorine atoms attached to hte beta carbon atom, A is O-, S, -N or a single carbon-carbon bond, Q is a hydrocarbon group containing up to 14 carbon atoms, m is 1 or 2 and Y and Y are the same or different and are hydrogen, halogen, lower alkyl, hydroxy or lower alkoxy. These compounds have valuable physiological activity as anti-inflammatory agents.

DETAILED DESCRIPTION The invention relates to N-carbonylfluorocarbonsulfonanilides which have valuable physiological activity. Steroids having cortisone-like activity have heretofore been used for treatment of inflammatory, e.-g. arthritic conditions. While these are effective, they have certain undesirable side effects, particularly on the endocrine system. Consequently, there is a need for effective antiinflammatory agents which are free of such disadvantages.

The novel and efficacious compounds of the present invention are non-steroidal in character, and their use does not entail side effects peculiar to steroid therapy. Of particular value in the anti-inflammatory compounds of the present invention is their relatively low toxicity, and they are well-tolerated by the gastrointestinal tract. A number of the new compounds also have anti-pyretic and analgesic activity. The physiological activities of these compounds have been elucidated by means of mammalian animal tests.

The present invention contemplates providing a novel class of physiologically active compounds, especially compounds with anti-inflammatory activity. The invention further aims to provide compositions of the novel, active compounds which are suitable for administration for physiological purposes. Within the purview of the invention are processes for the preparation of the compounds of the invention for physiological purposes. Still other objects of the invention will become apparent to those skilled in the art from reading the following disclosure.

The novel N-carbonylfluorocarbonsulfonanilides of the invention have the formula:

R 8 OzN @EEJ,

wherein R is a fluorocarbon group having from 1 to 4 carbon atoms, having either at least one fluorine atom attached to the alpha carbon atom or if there is no fluorine atom attached to the alpha carbon atom, having at least two fluorine atoms attached to the beta carbon atom, A is a connecting group selected from the class consisting of 0--, S, N and a single carbon-carbon bond; Q is a hydrocarbon group containing up to 14 carbon atoms; m is 1 or 2 corresponding to the valence bonds of A to which it is attached; and Y and Y are the same or different and are hydrogen, halogen, lower alkyl, hydroxy or lower alkoxy. When either Y or Y is lower alkyl or lower alkoxy, it preferably contains not more than about 4 carbon atoms. When m in the foregoing formula is 2 Ge. when a is --N the two Q groups in the molecule can be the same or different.

R, in the formula can be branched or straight chain fluorocarbon radical. A preferred class of the compounds of the invention are those in which R, is a perfluorocarbon radical, such as a perfluoroalkyl group.

Q can be acyclic (straight chain or branched) or cyclic (aromatic or aliphatic) or a mixture of acyclic and cyclic structures.

As noted previously, the products of the present invention are active anti-inflammatory agents and some also are analgesic and anti-pyretic agents. The anti-inflammatory activity can be conveniently demonstrated using assays designed to test the ability of these compounds to antag-l onize the local edema which is a characteristic of the antiinflammatory response (rat foot edema test) and to inhibit the onset of the erythematous manifestation of inflammation (guinea pig erythema test).

The edema test is performed on adult rats of either sex. One group of 10 rats serves as the non-medicated controls, while other groups of 10 rats receive the test compound at various times prior to the induction of the edema, usually 15 minutes, one hour and/or 18 hours. The test compound is administered as a suspension in 4 percent aqueous gum acacia (which contains 0.9 percent NaCl). Edema is induced by the plantar injection of 0.5 percent carrageenin (0.1 ml./foot) into the right hind foot. The left hind foot receives a like volume of 0.9 percent saline. One hour later, the volume of each hind foot is determined plethysmographically by measuring the volume of mercury displaced. The edema is expressed as the percent increase in the volume of the edemogen injected foot (volume of the edemogen foot" less the volume of the saline foot," divided by the latter, times The percent inhibition is calculated by dividing the mean percent increase in the edema of the edemogen foot of the medicated group by the mean increase in the nonmedicated group times 100. An active dose is taken to be that dose giving a statistically significant inhibition of the induced edema, usually about 30-35 percent inhibition.

Leading references to this method are: (l) Adamkiewicz et al., Canad. J. Biochem. Physio. 33:332, 1955; (2) Selye, Brit. Med. J. 2:1129, 1949; and (3)- Winter, Proc. Soc. Exper. Biol. Med. 111:544, 1962.

The erythema test is performed on adult, albino guinea pigs of either sex, weighing 400-600 g. Hair is removed from the animals by a depilatory mixture the afternoon of the day prior to the day on which they are to be used. One group of five animals serves as non-medicated controls, while another group of five receives the test compound minutes prior to direct exposure to ultraviolet light. For induction of erythema, the guinea pig is restrained on a small animal board. Three circular sections (6-8 mm. in diameter) of the ventro-lateral abdominal area of the animal are then exposed to a controlled amount of ultraviolet radiation. Two hours after exposure, the erythema is scored 0-5 on the basis of its intensity and completenesss (full or partial circles). The maximal score per animal is 15. The percent inhibition is calculated on the basis of the mean score for the medicated group versus the non-medicated group. An active dose is taken to be that dose giving a statistically significant inhibition of the induced erythema, usually -40 percent inhibition. Modifications of this test include variation in the time and method of drug administration.

Leading references to this method are: (1) Wilhelm, Schweiz, Med. Wschr. 25 :577, 1949; and (2) Winder et al., Arch. Int. Pharmacodyn, 116:261, 1958.

In the rat foot edema test, the following compounds of the invention have been found to be eflective anti-inflammatory agents (i.e. to have significant activity) at oral dosage levels of 150 mg./ kg. or less in single doses:

N-ethoxycarbonyl-3 -benzoyltri1fluoromethanesulfonanil ide,

N -methoxycarb onyl-3 -benzoyltrifluorom ethanesul fonanilide,

N-butoxyc arbo nyl-3-benzoyltrifluorornethanesulfon anilide,

N-2-methylpropoxycarbonyl-3-benzoyltrifluoromethanesulfonanilide,

N-ethoxycarbonyl-3- (4-chlorobenzoyl tri-fluoromethanesulfonanilide,

N-ethoxycarbonyl-li- (4-methoxybenzoyl trifluoromethanesulfonanilide,

N-phenoxycarbonyl-3 -benzoyltrifiuoromethanesulfonanilide,

N-benzyloxycarbo nyl-3-benzoyltrifluoromethanesulfonanilide,

N-acetyl-3 -benzoyltrilluoromethanesulfonanilide,

N,N-dimethyl-N'-trifiuoromethanesulfonyl-N- 3-benzoylphenyl urea N-methoxycarbon yl- 3 -benzoyldi lluoromethanesulfonanilide,

N-ethoxycarbonyl-3-benzoyldifluoromethanesulfonanilide,

N-ethoxyca rbo nyl-3- 4-methoxybenzoyl) difluoromethanesulfonanilide,

N-ethoxycarbonyl-3-benzoylfiuoromethanesulfonanilide,

N-ethoxycarbonyl-Ii- 4-methoxybenzoyl fluoromethanesulfonanilide, and

N-octyloxycarbonyl-3-benzoyltrifluoromethanesulfonanilide.

Aspirin, which is very widely used as an anti-inflammatory agent, is only marginally active at 150 rug/kg. orally in the rat foot edema test.

In the guinea pig erythema test, the following compounds of the invention has been found to be effective at dosage levels of 150 mg./kg. or less orally in single doses:

N-ethoxycarbonyl-3-benzoyltrifiuoromethanesulfonanilide,

N-methoxycarbonyl-3-ben zoy1trifluoromethanesulfonanilide,

N-Z-methylpropoxycarbonyl-3-benzoyltrifiuoromethanesulfonanilide,

N-phenoxycarbonyl-3-benzoyltrifluoromethanesulfonanilide.

N-benzyloxycarbonyl-3-benzoyltrifluoromethanesulfonanilide, and

N-ethoxycarbonyld -benzoyldifluoromethanesulfonanilide.

4 Other compounds of the invention, which are active at somewhat higher doses in the above tests, include:

N-ethozycarbonyl-B-benzoylperfluorobutanesulfonanilide,

N-ethoxycarbonyl-3- [4-(2-methyl-2-propyl) -benzoyl] trifluoromethanesulfonanilide,

N-ethoxycarbonyl-3-benzoyl-5-propoxytrifluoromethanesul fonanilide,

N-ethoxycarbonyl-3(4-fluorobenzoyl) -difluoromethanesulfonilide,

N-thiophenoxycarbonyl-3-benzoyltri iluorornethanesulfonanilide,

N-ethoxycarbonyl-3-benzoyl-4-chlorotrifluoromethanesult'onanilide,

N-ethoxycarbonyl-3-benzoyl-l 1,2,2-tetrafluoroethanesulfonanilide,

N-ethoxycarbonyl'3-benzoyl-2,2,2-trifiuoroethanesulfonanilide,

N-ethoxycarbonyl-3-benzoyl-1, 1,3 -trihydropertluoropropanesulfonanilide,

N-ethoxycarbonyl-4-chloro-3 (4-chlorobenzoyl -trifiuoromethanesulfonanilide, and

N-ethoxycarbonyl-4-chloro-3 4-methyl'benzoyl -trifluo romethanesulfonanilide.

The compounds of the invention are all relatively nontoxic, e.g. their acute LD levels when administered orally have been found to be generally greater than 1000 mg./ kg. in rats.

The compounds of the invention are prepared by the reaction of a fluorocarbonsulfonanilide of the formula:

11 I}; C also: it

with an acylating agent of the formula:

(III) 0 BrQJAQ In these formulae R Y, Y, A, Q and m are as previously defined. M represents hydrogen or an alkali metal, such as sodium or potassium or a tertiary ammonium cation, such as triethylammonium, pyridinium or N,N- dimethylanilinium and R represents a halogen or the residue of an anhydride, i.e. an acyloxy group. A wide variety of acylating agents of Formula III can be used in preparing the compounds of the invention, including acyl halides or anhydrides, haloformates, thiol haloformates, carbamyl halides and the like. These compounds are either available directly or, in the case of certain chloroformates or thiol chloroformates are easily pgepared from phosgene and the appropriate alcohol or t iol.

In carrying out this condensation, it is generally satisfactory to employ substantially equivalent quantities of the reactants, usually but not necessarily in the presence of an aprotic solvent. Some solvents suitable for the purpose are bis(2-methoxyethyl)ether, acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, benzene, toluene, chloroform and the like.

When M is hydrogen, the reaction is preferably carried out in the presence of a proton acceptor. The amount of proton acceptor can be varied widely, although the amounts routinely employed are sulficient to bind all of the acidic hydrogen of the sulfonanilide reactant. Some examples of proton acceptors which may be used include alkali metal salts, such as the sodium or potassium carbonates, bicarbonates and acetates and also tertiary amines, such as triethylamine, pyridine and N,N-dimethylaniline.

The condensation is most often carried out in the temperature range of about 0 to C., but this may be lowered or raised if desired. When the sulfonanilide reactant is used in the form of its preformed alkali metal salt, the reaction proceeds to completion in 24 hours or less at lower temperatures, e.g. to 50 C.

The precursor fluorocarbonsulfonanilides are prepared by reaction of the corresponding fluorocarbonsulfonic anhydride or fluorocarbonsulfonyl halide with a solution of the selected aminobenzophenone and a SllfliClCl'lt quantity of an acid acceptor in an inert organic solvent as follows:

lL msmz NE E;

o JL/W RISOANH Q HZ where Z is halogen, conveniently fluorine or chlorine, or R SO -(e.g. R,SO 0S0 R,). Among the suitable solvents are glyme, benzene, chloroform, methylene chloride and the like. The reaction is advantageously carried out at 15 C. to +l50 C. but these temperatures may be raised or lowered if desired. The reaction is carried out under pressure where gaseous reactants are involved or where the reaction is slow under ordinary conditions.

After completion of this reaction, the fluorocarbonsulfonanilide is isolated by known methods, e.g. by extraction using an excess of aqueous sodium hydroxide. In this case the aqueous extract is washed with organic solvents and, if deired, treated with charcoal to remove impurities. Subsequent acidification of the aqueous extract with mineral acid then afiords the product as an oil or solid which is distilled, sublimed, chromatographed or recrystallized as required to give pure product. When water-soluble solvents are used, the reaction mixture can be poured directly into an aqueous mineral acid. The product is then isolated by extraction techniques and purified as above.

An additional method of obtaining the precursor sulfonanilides of the compounds of the invention in which Y is hydroxy is by cleavage of the alkoxy group of the comparable sulfonanilide precursors in which Y is alkoxy. This can be done conveniently with hydrogen iodideacetic acid mixtures.

Suitable fluorocarbonsulfonylanhydrides and halides (e.g. chlorides and fluorides) for use in these precedures are known to the art (e.g. see US. Pat. 2,732,398). The aminobenzophenones used in producing the fluorocarbonsulfonanilide precursors are described in the general chemical literature or can be prepared from the corresponding known substituted nitrobenzophenones by reduction. Among them are:

6 4-amino-l-chlorobenzophenone, 3-amino-4'-fluorobenzophenone, 3-amino-S-bromobenzophenone, 3-amino-4'-ethylbenzophenone, 3-amino-2'-ethoxybenzophenone, 3-amino-4'-ethoxybenzophenone, etc.

The acylating agents of Formula III are well known. Among these are acetic anhydride, butyryl chloride, N,N- diethylcarbamoyl chloride, 4-phenylphenylacetyl chloride, phenylthiochloroformate, carbobenzoxy chloride, naphthoyl chloride and isopropyl chloroformate.

The following examples are given for the purpose of further illustrating the present invention, but are not intended in any way to be limiting of the scope thereof. All parts are by weight unless otherwise specified in the examples. The solvent mentioned in the table of Examples 2-17 in the column headed Product is the solvent used for recrystallization.

PREPARATION OF THE PRECURSOR FLUORO- CARBO'NSULFONANILIDES Example 1 Preparation of 3-benzoyltrifluoromethanesulfonanilide Into a round bottom, 3-neck, 1000 ml. flask equipped with stirrer, condenser, addition funnel, internal thermometer and nitrogen sweep was charged 3-aminobenzophenone (59.8 g., 0.304 mole), triethylamine (50.4 ml.) and chloroform (400 ml). Trifluoromethanesulfonic anhydride was added slowly to the stirred mixture at l025 C. (ice-bath cooling). After stirring at room temperature for two hours, the solution was washed with dilute hydrochloric acid and then extracted with 10 percent aqueous sodium hydroxide. The aqueous extract was washed with chloroform until the washes were clear, clarified with charcoal, and acidified to pH 1 with concentrated hydrochloric acid. The product was collected by filtration, washed with water and dried. Recrystallization from hexane afforded analytically pure product, M.P. 99-10l C.

Analysis.Calcd. for c u rmo s (percent): C, 51.1; H, 3.1. Found (percent): C, 51.3; H, 3.2.

The following table summarizes the preparation of a number of other precursor compounds of the invention. Unless otherwise specified, the general method of Example 1, i.e. reaction of the fluorocarbon sulfonic anhydride with the primary arylamine in the presence of an acid acceptor, was utilized in each.

TABLE I Ex. No. Structure Product Analysis (percent) 2 0 White leaflets M.P. 136-137" C. For CHHwFaNOsS: Gale. 0, 51.1; H, 3.l. Found: C,

H (I; (ethanol/water). 50.7; H, 3.2. cmsom- Q 3 H White crystals M.P. 98-100 C. For CuHroFsNOsS: Cale. C, 61.1; H, 3.1. Found: C,

C F S 03N (water). 51.0; 11,3.1.

Light yellow needles M.P.l25125.5 For Cis'HnFaNOrS: Cale. C, 50.2; H, 3.4. Found: C,

O H II C. (ethanol/water). 50 3, H, 3.4. C F35 OzN- C- OOHs TABLE I-Contlnued Ex. N0. Structure Product Analysis (pereent) 5 0 White crystals M.P. 129.5l31.5 C. For CmHuFaNO S: Cale. C, 52.5; H, 3.5. Found: C,

II If (ctlmnohwater). 52.6; H, 3.5. C F38 02N -C (j (ll White crystals M.P. 139-141 C. For cu'ugcmmoasz Cale. C, 46.1; H, 2.5. Found; C,

H i) l (ethanol/water). 46.4; H, 2.6.

7 0 Light yl-llow nPvdh-s M.P. 123.5- For Cl-IIIDC1F3NOJSI Cale. G, 46.1; H, 2.5. Found: C,

U 125.5 0. (ethanol). 46.3;11, 2.6. U.- 0 F13 OzN-@ @-c1 8 H White crystals M.P. 99-102" C. For CuHuClFsNOaS: Cale. C, 46.2; H, 2.5. Found: C,

C F; S 0:N- (ethanol/water). 46.2; H, 2.6.

9 0 White crystals M.P. 145-147" C. For CuHoClFsNOssz Cale. C, 46.1; H, 2.5. Found: C,

H I] (ethanol/water). H, .5. C FsS OzN- -C C 10 0 Pale yellow needles M.P. 144.5-146" For CuHuClFaNmS: Gale. 0, 46.2; H, 2.5. Found: C,

H El (3. (trichloroethylene). 46.3; H, 2.6. C F 8 O2N -C 11 0 White crystals M.P. 156158 For cu mFaNofi: Cale. C, 48.8; H, 2.9. Found: C

H I; (brichloroethylene). C FuS O2N C- 12 0 White crystals M.P. 99-1005 For CuHuFaNozs: Cale. C, 54.1; H,3.6; N,4.5. Found:

(trlchloroethylone). C, 53.9; H, 3.6; N, 4.4. C FaHS O2NH C- 13 0 White crystals M.P. 118-120 For CwlImFgNOfiiCalc. C,62.8;H,3.9;N,4.2. Found:

1| (C(Jh-hexano). C, 52.6; H, 3.9; N, 4.2. C FzlI S OzNH- -0- OCH:

14 0 White crystals M.P. 11125-119 C FOICnlIQFNOzS.CILIC.C,57.3;1 ,4.1;N,4.9. Found:

U (Cl-CHg-CHaCl-h97lan8). C, 57.6; H, 4.1; N, 6.2. ClIzF S OxNII- O C 15 O Crystals M.P. 11654185 C. otha- For C H FNmS: Cale. C, 55.8; S, 4.4. Found: C,

11 nol/water). 56.3; H, 4.6. CII F S OzNII- C- OCH:|

16 0 Tan crystaJs M.P. 106408 For C H ClFgNOgS-l Cull Cale. C, 47.7; H, 2.9; N,

(oyclohexane). 3.7. Found: 6, 47.5; H, 2.7; N, 4.0.

17 White powder M.P. 134-136 C.

(bunzeuehuxuno).

For HoIMNOES: Cale. C, 48.4; H, 2.6; N, 4.0. Found:

C, 48.9; H, 2.8; N, 4.1.

I This ll)HIIOXYLSU!)SULUUI] compound was prepared by cleavage of the corresponding 4-mut|loxyl-substitutcd compound with hydrogen iodide and acetic acid.

9 PREPARATION on THE COMPOUNDS on THE INVENTION Example 18 Preparation of N-ethoxycarbonyl 3 benzoyltrifiuoromethanesulfonanilide ems om Ethyl chlorofonmate (3.24 g., 0.0298 mole), 3-benzoyltrifluoromethanesulfonauilide sodium salt (10.59 g., 0.0302 mole, prepared by reacting the sulfonanilide with aqueous sodium bicarbonate then removing the water) and reagent grade acetone (45 ml.) were combined in a 100 ml., 3-neck, round bottom flask fitted with magnetic stirrer, condenser and nitrogen sweep. The mixture was stirred at room temperature for 24 hours. The sodium chloride precipitate was removed by filtration, and crude product was obtained on solvent evaporation. Two recrystallizations from 95 percent ethanol afiorded white analytically pure product for biological testing, M.P. 131.5-133 C.

Analysis.-Calcd. for C H F NO S (percent): C, 50.8; H, 3.5. [Found (percent): C, 50.6; H, 3.5.

Similarly, other compounds of the invention can be prepared by reacting the precursor compounds of the foregoing examples with ethyl chloroformate utilizing the general method of the previous example.

The following examples show the specific preparations of a number of other compounds of the invention utilizing the same general method, i.e. reacting the acid anion of the precursor fluorocarbonsulfonanilide H o msom g with various chlorofonmates, acid chlorides or carbamyl chlorides. The reactions were generally carried out at ambient temperature and pressure in the presence of acetone.

Example 19 The sodium salt of 3 'benzoyltrifluoromethanesulfonanilide was reacted with methyl chloroformate to give N methoxycarbonyl 3 benzoyltrifluoromethanesulfonanilide:

This product is isolated from methanol as white crystals, M.P. 129-131 C.

Analysis.-Calcd. for c,.,H,,F,No,s (percent): C, 49.6; H, 3.1; N, 3.6. Found (percent): C, 49.5; H, 3.3; N, 3.7.

I 6-0 (CHghCHa The sodium salt of 3 benzoyltrifluoromethanesulfonanilide was reacted with iso-butyl chloroformate to give N (2 methylpropoxycanbonyl) 3 benzoyltrifiuoromethanesulfonanili de This product is isolated from ethanol as white crystals, M.P. 65.5-68 C.

Analysis.--Calcd. for C 'H F NO S (percent): C, 53.1: H, 4.23; N, 3.3. Found (percent): C, 53.1; H, 4.3; N, 3.2.

Example 22 The sodium salt of 3 (4 chlorobenzoyl) trifiuoromethanesulfonanilide is reacted with ethyl chloroformate to give N-ethoxycarbonyl-3-(4-chlorobenzoyl)-trifiuorome thanesulfonanilide cmsoiN This product is isolated from ethanol as white crystals, M.P. 125.5"-127.7 C.

Analysis.Calc. for C H CIF NO S (percent): C, 46.9; H, 3.0; N, 3.2. Found (percent): C, 47.1; H, 3.1; N, 3.2.

Example 23 The sodium salt of 3-(4mcthoxybenzoyl)-trifluoromethanesulfonanilide is reacted with ethyl chloroformate to give N-ethoxycarbonyl-3-(4-rnethoxybenzoyl)-trifluoromethanesulfonanilide:

O -OCZH! This product is isolated from ethanol as white crystals, M.P. -82 C.

Analysis.Calc. for C H RNO S (percent): C, 50.3; H, 3.7. Found (percent): C, 50.3; H, 3.8.

Example 24 The sodium salt of 3-benzoyltrifluoromethanesulfon anilide was reacted with phenyl chloroformate to give N- phenoxycarhonyl 3 benzoyltrifluoromethanesulfonanilide:

This product is isolated from benzene-hexane as white crystals, M.P. 82.5 -84 C.

Analysis.-Calc. for C H F NO S (percent): C, 56.2; H, 3.14; N, 3.12. Found (percent): C, 56.5; H, 3.2; N, 3.2.

Example 25 The sodium salt of S-benzoyltrifluoromethanesulfonanilide was reacted with benzyl chloroformate to give N- benzyloxycarbonyl 3 benzoyltrifiuoromethanesulfonanilide:

O -OCH This product is isolated from ethanol as white crystals, M.P. 83.5-85 C.

Analysis.Calc. for C= H F N0 S (percent): C, 57.0; H, 3.5; N, 3.0. Found (percent): C, 57.2; H, 3.5; N, 2.8.

Example 26 The sodium salt of 3-benzoyltrifluoromethanesulfonanilide was reacted with acetyl chloride to give N-acetyl- 3-benzoyltrifluoromethanesulfonanilide:

C F SOnN This product is isolated from ethanol as white crystals, M.P. 95 -97 C.

Analysis.Calc. for C H F N0 S (percent): C, 51.8; H, 3.3. Found (percent): C, 51.4; H, 3.4.

Example 27 The sodium salt of 3-benzoyltrifluoromethanesulfonanilide was reacted with N,N-dimethylcarbamyl chloride to give N,N-dimethyl-N'-trifiuoromethanesulfonyl-N'-(3- benzoylphenyl) urea O w ah This product is isolated from ethanol as white crystals, M.P. l33.5-136.5 C.

Analysis.Calc. for C11H15F3N304S (percent): C, 51.0; H, 3.75; H, 7.0. Found (percent): C, 51.0; H, 3.9; H, 6.9.

Example 2 8 The sodium salt of 3-benzoyldifiuoromethanesulfonanilide was reacted with methyl chloroformate to give N methoxycarbonyl 3 benzoyldifiuoromethanesulfonanilide:

O -OOH:

This product is isolated from ethanol as white crystals, M.P. -98" C.

Analysis.-Calcd. for C H F N0 S (percent): C, 51.8; H, 3.6; N, 3.8. Found (percent): C, 51.8; H, 3.7; N, 3.8.

Example 29 The sodium salt of 3-benzoyldifluoromethanesulfonanilide was reacted with ethyl chloroformate to give N- ethoxycarbonyl-3-benzoyldifluoromethanesulfonanilide 0 1-0 CaHs This product is isolated from ethanol as white plates, M.P. 97.5-99.5 C.

Analysis.-Calcd. for C17H15FzN05S (percent): C, 53.3; H, 3.94; N, 3.65. Found (percent): C, 53.0; H, 4.0; N, 3.6.

Example 30 The sodium salt of 3-(4-methoxybenzoyU-difluoromethanesulfonanilide was reacted with ethyl chloroformate to give N-ethoxycarbonyl-B-(4-methoxybenzoyl)-difiuoromethanesulfonanilide lide was reacted with ethyl chloroformate to give N-ethoxycarbonyl-3-benzoylfluoromethanesulfonanilide:

0 (i l-0C2!! CIIzFSOzN This product is isolated from ethanol as white crystals, M.P. 93.596 C.

Analysis.-Calcd. for C H FNO S (percent): C, 55.8; H, 4.42; N, 3.84. Found (percent): C, 55.8; H, 4.5; N, 3.9.

Example 32 The sodium salt of 3-(4-methoxybenzoyl)-fiuoromethanesulfonanilide is reacted with ethyl chloroformate to 13 give N ethoxyearbonyl-3-(4 methoxybenzoyD-fluoromethanesulfonanilide:

O 0 CzHs CHgFSOg Example 33 The sodium salt of S-benzoyltrifluoromethanesulfonanilide is reacted with n-octyl chloroformate to give N- octyloxycarbony1-3-benzoyltrifluoromcthanesulfonanilide:

This product is isolated as white crystals from ethanolwater, M.P. 6668 c.

Analysis.-Calcd. for c n F No s (percent): C, 56.8; H, 5.4; N, 2.9. Found (percent): C, 56.7; H, 5.1; N, 2.8.

Other examples of the preparation of compounds of the 15 invention from the corresponding sulfonanilides and acylating agents are shown in the following table. The sulfonanilides are first converted to the sodium salt by reaction with sodium hydroxide and removal of water. The dry salt is then reacted with the acylating agent as 20 previously described.

TABLE 11 Ex. No. Sulfonanilide Acylating agent Product 34.--" CIFQSOZNH H E ClC-O-CaHs c-oc,n.

C4FIS OzN C N O 35--.; C F53 OzNH u (1? E- clc-s-(Mh c-s-ctn.

C F: S OzN 1 f OCuH7 1) (Bo l-I7 36.-.: H(CF1)2SO2NH O A ClC-O (32H: /COC2H w M OaN i Br 0 37....*. 0 ms omn ClC CH /C CH C F S OaN 38....J. C2F S OzNH CI} ClI-OCzHs C-O CzHs 39...: C F38 OzNH C2FsSOzN TOT 1 H O 0 0 ClO-S 0-5..

TAPLE Il-Continucd ulfonanilitle Acylatlng rlgcnt Product 48..... crtsonvn if f c1o-octrn coc=n,

c r; s on/ Cl c1 CIA@ CI What is claimed is: 8. A compound according to claim 1 wherein R is CF;.

1. Acompound of the formula 9. N ethoxycarbonyl 3 benzoyltrifluoromethane- 0 sulfonanilide. IL 0 10. A method for relieving inflammation in a mammal which comprises administering orally to said mammal an msom effective dose less than the toxic amount of a compound of the formula: l l I \X \X H C-AQ||| wherein R is a fluorocarbon group having from 1 to 4 I carbon atoms, having at least one fluorine attached to the C alpha carbon atom or if there is no fluorine attached to 1M5 i it the alpha carbon atom, having at least two fluorine atoms attached to the beta carbon atom, Q is a hydrocarbon Y group containing up to 14 carbon atoms and Y and Y are the same or dilferent and are hydrogen, halogen or hydroxy or lower alkyl or lower alkoxy having from 1 wherein R is a fluorocarbon group from 1 to 4 carbon ig 232 22 3 3 of the formula atoms, having at least one fluorine atom attached to the alpha carbon atom or if there is no fluorine atom attached to the alpha carbon atom, having at least two fluorine (5-0-Q atoms attached to the beta carbon atom, A is O, Q RISOZN/ is a hydrocarbon group containing up to 14 carbon atoms, and Y and Y are the same or different and are hydrogen, C 40 halogen or hydroxy, or lower alkyl or lower alkoxy havii ing from 1 to 4 carbon atoms.

11. A method according to claim 10 which comprises wherein R; is a fluorocarbon group having from 1 to 4 fig ig ga g fi fi 3 benzoylmfiuom' carbon atoms, having at least one fluorine atom attached 12. A method awarding to claim 10 which comprises to the alpha carbon atom or if there is no fluorine atadministering N sthoxycarbonyl 3 benzoyltrifluorm tached to the alpha carbon atom, having at least two methancsulfonanilide fluorine atoms attached to the beta carbon atom, and Q is a hydrocarbon group containing upto 14 carbon atoms. References Cited pesfiuigmzfigiyriound according to claim 2 wherein R, 18 UNITED STATES PATENTS 4. N methoxycarbonyl 3 benzoyltrifluoromethane- 2,809,990 10/1957 Brown 260--534 sulfonanilide.

5. A compound according to claim 2 wherein R is an FOREIGN T omega-hydroperfluoroalkyl radical. 733,758 10/1955 Great Bf 1mm.

6. A compound according to claim 2 wherein Q is OTHER REFERENCES alkyl' Roberts and Caserio Basic Princi ples of Orgamc Acompound ofthe formula Chemistry, W. A. Benjamin, Inc., New York, N.Y., p.

0 664 (1965). UFZSOZN/ LORRAINE H. WEINBERGER, Primary Examiner I. F. TERAPANE, Assistant Examiner 0 8 US. Cl. X.R.

wherein Q is an alkyl group containing from 1 to 4 carbon atoms.

260- 455 A, 463, 470, 544 C, 553 A, 553 D, 556 F; 424- 322 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,663, 708 Dated May 16 1972 Inventor(s) Joseph Kenneth Harrington It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below: Column 2, line 28, for "a" read --A-- Columns l5l6, Example 43, "Cl-C-N" should read --Cl-C-N- Column 17, line 26, after "fluorine" insert --atom-- Signed and sealed this 31st day of October 1972.

(SEAL) Attest:

EDWARD M.FLEICHER,JR. ROBERT GO'ITSCHALK Attesting Officer Commissioner of Patents ORM PO 1050(10 USCOMM'DC 603764 69 u s GOVIINMENT PRINTING OFFICE: I919 o--:s5s34v