US3661990A - N-alkylsulfonyl benzoylhaloalkylsulfonanilides - Google Patents

N-alkylsulfonyl benzoylhaloalkylsulfonanilides Download PDF

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Publication number
US3661990A
US3661990A US28123A US3661990DA US3661990A US 3661990 A US3661990 A US 3661990A US 28123 A US28123 A US 28123A US 3661990D A US3661990D A US 3661990DA US 3661990 A US3661990 A US 3661990A
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compounds
methylsulfonyl
benzoyltrifluoromethanesulfonanilide
alkylsulfonyl
solvent
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US28123A
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Joseph Kenneth Harrington
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Riker Laboratories Inc
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Riker Laboratories Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton

Definitions

  • This invention relates to N-alkylsulfonyl benzoylhaloalkylsulfonanilides in which the aromatic rings are optionally substituted. These compounds are active anti-inflammatory agents and some also are analgesic, antipyretic and anti-microbial agents.
  • R is alkyl or haloalkyl of one to four carbon atoms and R is chloromethyl or fiuoroalkyl of one to four carbon atoms
  • the fluoroalkyl radical having at least one fluorine .atom bonded to the alpha carbon atom or at least two fluorine atoms bonded to a beta carbon atom
  • Y and Y are the same or different and are selected from bydroxy, halogen, lower alkyl, lower haloalkyl, lower alkoxy and lower haloalkoxy
  • n and n are the same or different and are zero to three.
  • R is fluoroalkyl, it preferably has at least two fluorines bonded to the alpha carbon atom, or one fluorine bonded to the alpha carbon atom and at least two fiuorines bonded to the beta carbon atom.
  • R is fluoroalkyl, it preferably has at least two fluorines bonded to the alpha carbon atom, or one fluorine bonded to the alpha carbon atom and at least two fiuorines bonded to the beta carbon atom.
  • n is zero, the ring adjacent to the alkylsulfonamido groups is unsubstituted except for that group and the benzoyl group.
  • the second ring is unsubstituted except for the group shown in the formula and attached thereto through the carbonyl link.
  • the compounds of the invention are generally active as anti-inflammatory agents.
  • R is fluoroalkyl containing one or two carbon atoms are preferred, since such compounds are usually more active, and compounds wherein R is trifiuoromethyl or difluoromethyl are most preferred.
  • R is preferably alkyl rather than haloalkyl.
  • R is alkyl or haloalkyl of one or two carbon atoms are preferred, because as the number of carbon atoms in R increases, anti-inflammatory activity decreases.
  • R is haloalkyl
  • halogen is fluorine or chlorine.
  • R is methyl, ethyl, fiuoromethyl or chlororrrethyl are most preferred.
  • the radicals R and R may contain only fluorine or chlorine, or these halogens may both be present in one radical, or the two radicals may contain diflerent halogens.
  • R R, Y, Y, n and n are as defined hereinabove, M is a cation, eg of alkali metals, alkaline earth metals, amines or aluminum and X is halogen (preferably chlorine or fluorine, or the residue of an anhydride grouping, i.e. OSO R).
  • R and R may also be reversed in the foregoing equation.
  • R contains one or two carbon atoms and is identical with R (i.e. both are haloalkyl)
  • R contains one or two carbon atoms and is identical with R (i.e. both are haloalkyl)
  • R contains one or two carbon atoms and is identical with R (i.e. both are haloalkyl)
  • R contains one or two carbon atoms and is identical with R (i.e. both are haloalkyl)
  • a non-reactive organic solvent preferably one in which the salts of Formula II have some solubility, is used, such as 1,2-dimethoxyethane, diethyl ether, diisopropyl ether, acetone, chloroform, dichloromethane and the like.
  • the reaction temperature may vary, from the freezing point to the boiling point of the solvent used, depending upon the reactivity of the intermediate compound of Formula II and the sulfonyl halide or anhydride. In some cases the reaction proceeds at the reflux temperature of the solvent, while in others ice bath or room temperature is satisfactory.
  • the reaction product is generally isolated by filtration to remove the salt MX which is formed as a byproduct, followed by evaporation of the solvent.
  • the product is dissolved in an organic solvent such as chloroform, dichloromethane, diethyl ether and the like and washed with water and base to remove impurities such as unreacted starting material and inorganic salts.
  • the solution is dried, solvent removed in vacuo and the residue is further purified, if necessary, by conventional techniques. Usually recrystallization from ethanol or ethanol-water mixtures is satisfactory.
  • the salts of Formula II are prepared from the corresponding acid formcompound msoildgl Y.: Y..' III by adding the stoichiometric amount of a base in inert solvent solution (aqueous or nonaqueous) to the acidic compound (III). The resulting solution is treated to remove the solvent, e.g. by evaporation under reduced pressure to obtain the salt, usually as a dry powder.
  • a base e.g. by evaporation under reduced pressure to obtain the salt, usually as a dry powder.
  • Appropriate bases for use in preparing the metal salts include -metal oxides, carbonates, bicarbonates and alkoxides.
  • n, Y and Y are as previously defined and Q represents a halogen atom, preferably chlorine or fluorine, or the corresponding anhydride grouping (R being defined as above).
  • R 11, n, Y and Y are as previously defined and Q represents a halogen atom, preferably chlorine or fluorine, or the corresponding anhydride grouping (R being defined as above).
  • R 11, n, Y and Y are as previously defined and Q represents a halogen atom, preferably chlorine or fluorine, or the corresponding anhydride grouping (R being defined as above).
  • R 11, n, Y and Y are as previously defined and Q represents a halogen atom, preferably chlorine or fluorine, or the corresponding anhydride grouping (R being defined as above).
  • R 11, n, Y and Y are as previously defined and Q represents a halogen atom, preferably chlorine or fluorine, or the corresponding anhydride grouping (R being defined as above).
  • R
  • the condensation is usually conducted in the presence of an appropriate inert organic solvent.
  • Typical solvents suitable for this purpose are methylene chloride, chloro- 4 form, carbon tetrachloride, benzene, toluene, bis(2-methoxyethyl) ether, N,N-dimethylformamide, 1,2-dimethoxyethane and the like.
  • the production mixture can be extracted with a dilute aqueous base solution.
  • the product in the form of a salt which is usually soluble in the aqueous layer, is precipitated therefrom by addition of a mineral acid such as hydrochloric or sulfuric acid, and collected.
  • the product mixture can be washed with aqueous hydrochloric acid, the solvent evaporated in vacuo, and the residue dissolved in a dilute aqueous base solution which is washed with dichloromethane and treated with decolorizing charcoal.
  • the product, in the form of a salt is then isolated as described above.
  • the product is generally obtained by dilution of the reaction mixture with water.
  • the product a solid or oil, is separated and purified by conventional methods.
  • the compounds prepared according to the foregoing procedures are generally crystalline solids purified, in general, by recrystallization from aqueous alcohol, trichloroethylene, hexane, benzenehexane mixtures and the like. Elution chromatography has also been found to be a useful purification technique.
  • Suitable haloalkanesulfonylanhydrides and halides e.g. chlorides and fluorides
  • halides e.g. chlorides and fluorides
  • fiuoromethanesulfonyl chloride fiuorochloromethanesulfonyl chloride, difluoromethanesulfonyl chloride, chloromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, 2,2,2-trifluoroethanesulfonyl chloride, trifluoromethanesulfonyl chloride,
  • aminobenzophenones, IV are described in the general chemical literature or can be prepared from corresponding known substituted nitrobenzophenones by reduction. All of the nitrobenzophenones or aminobenzophenones not specifically disclosed in the chemical literature are prepared by methods known in the literature for analogous compounds. Exemplary of such starting materials are:
  • intermediates of Formula II are preferably prepared from other intermediates of Formula II.
  • 3-benzoyl-4-hydroxytrifluoromethanesulfonanilide may be prepared by reaction of 3-benzoyl-4methoxytrifluoromethanesulfonanilide with hydroiodic acid in acetic acid.
  • the compounds of the invention are as a class active anti-inflammatory agents, although some are more active than others.
  • the anti-inflammatory activity can be conveniently demonstrated using assays designed to test the ability of these compounds to antagonize 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 erytherna test).
  • Preferred compounds of the invention because of very high anti-inflammatory activity are:
  • the compounds of the invention are preferably administered orally, for example, as four percent acacia suspensions, but also may be administered parenterally. Amounts are generally about 1 to 500 mg./kg. of body Weight of the mammal to be treated.
  • the compounds of the invention are active as anti-microbial agents according to standard anti-microbial assays. Specifically, the anti-microbial activity of the compounds of the invention has been evaluated using a variation of the original agar-plate diffusion method of Vincent and Vincent (e.g., see 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).
  • Vincent and Vincent e.g., see 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.
  • EXAMPLE 3 The compounds of the invention (Formula I) are prepared according to the following general procedure: In a three-necked round-bottom flask equipped with a magnetic stirrer, a reflux condenser and an addition funnel is placed a salt of a haloalkylsulfonamidobenzophenone of Formula II (30 millimoles) in acetone (200 ml.) or other suitable solvent. To this stirred mixture is added a compound of the formula RS0 X, wherein R and X are as previously defined (about 30 millimoles). The mixture is stirred at room temperature for at least one hour, although longer reaction times and higher temperatures may increase yields or initiate sluggish reactions.
  • the solution is filtered then the solvent is removed in vacuo, and the residue is dissolved in dichloromethane or other suitable water-immiscible organic solvents, then washed with water and base.
  • the product is recovered by evaporation of the solvent and recrystallized, sublimed, distilled or chromatographed if further purification is desired.
  • n Y'n' wherein R is alkyl or haloalkyl of one to four carbon atoms and R is chloromethyl, fluoroalkyl, or chlorofluoroalkyl wherein the alkyl groups have one to four carbon atoms, the fluoroalkyl or chlorofiuoroalkyl radicals having at least one fluorine atom bonded to the alpha carbon atom or at least two fluorine atoms bonded to a meta carbon atom, Y and Y are the same or different and are selected from hydroxy, halogen, lower alkyl, lower haloalkyl, lower alkoxy and lower haloalkoxy, and n and n are the same or different and are zero to three.
  • R and R each contain only one carbon atom.
  • R is methyl or halomethyl and R is chloromethyi 10 260 556 SN 556 A 570 A 543 424 321 or a fluoromethyl containing at least one fluorine atom.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US28123A 1970-04-13 1970-04-13 N-alkylsulfonyl benzoylhaloalkylsulfonanilides Expired - Lifetime US3661990A (en)

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US2812370A 1970-04-13 1970-04-13

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US (1) US3661990A (enrdf_load_stackoverflow)
DE (1) DE2118191A1 (enrdf_load_stackoverflow)
FR (1) FR2092037B1 (enrdf_load_stackoverflow)
GB (1) GB1305680A (enrdf_load_stackoverflow)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3981914A (en) * 1971-08-03 1976-09-21 Minnesota Mining And Manufacturing Company N-alkylsulfonylperfluoroalkanesulfonanilides
US4230635A (en) * 1978-08-15 1980-10-28 Schering Corporation Substituted 4'-polyhaloisopropylsulfonanilides
US4954518A (en) * 1987-10-08 1990-09-04 Toyama Chemical Company, Ltd. 4H-1-benzopyran-4-one derivative or its salt, process for producing the same and pharmaceutical composition comprising the same as active ingredient
US5502251A (en) * 1992-05-26 1996-03-26 Bayer Ag Imides and their salts, as well as their use
WO2009073427A1 (en) * 2007-11-28 2009-06-11 E. I. Du Pont De Nemours And Company Fluorinated alkanesulfonic acid esters and amides and processes for making and using the same

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BR6794063D0 (pt) * 1966-10-21 1973-09-18 Minnesota Mining & Mfg Processo para preparar perfluoral-quilsulfonamidas n-substituidas e composicoes herbicidas e fitoreguladoras nelas baseadas
NL6904816A (enrdf_load_stackoverflow) * 1968-04-08 1969-10-10
US3576866A (en) * 1969-06-12 1971-04-27 Minnesota Mining & Mfg Benzoylhaloalkanesulfonanilides

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3981914A (en) * 1971-08-03 1976-09-21 Minnesota Mining And Manufacturing Company N-alkylsulfonylperfluoroalkanesulfonanilides
US4230635A (en) * 1978-08-15 1980-10-28 Schering Corporation Substituted 4'-polyhaloisopropylsulfonanilides
US4954518A (en) * 1987-10-08 1990-09-04 Toyama Chemical Company, Ltd. 4H-1-benzopyran-4-one derivative or its salt, process for producing the same and pharmaceutical composition comprising the same as active ingredient
US5502251A (en) * 1992-05-26 1996-03-26 Bayer Ag Imides and their salts, as well as their use
WO2009073427A1 (en) * 2007-11-28 2009-06-11 E. I. Du Pont De Nemours And Company Fluorinated alkanesulfonic acid esters and amides and processes for making and using the same

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FR2092037B1 (enrdf_load_stackoverflow) 1974-11-15
FR2092037A1 (enrdf_load_stackoverflow) 1972-01-21
GB1305680A (enrdf_load_stackoverflow) 1973-02-07
DE2118191A1 (de) 1971-10-28

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