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

N-aryl-n-fluoroalkylsulfonyl carbamates Download PDF

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US3663708A
US3663708A US719746A US3663708DA US3663708A US 3663708 A US3663708 A US 3663708A US 719746 A US719746 A US 719746A US 3663708D A US3663708D A US 3663708DA US 3663708 A US3663708 A US 3663708A
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percent
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ethoxycarbonyl
fluorine
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Joseph Kenneth Harrington
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Pbi-Gordon Corp
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Minnesota Mining and Manufacturing Co
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • 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
    • C07C311/09—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by at least two halogen atoms

Definitions

  • 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.
  • 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.
  • 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.
  • compositions of the novel, active compounds which are suitable for administration for physiological purposes.
  • processes for the preparation of the compounds of the invention for physiological purposes 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.
  • novel N-carbonylfluorocarbonsulfonanilides of the invention have the formula:
  • 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
  • Y and Y are the same or different and are hydrogen, halogen, lower alkyl, hydroxy or lower alkoxy.
  • Y or Y When either Y or Y is lower alkyl or lower alkoxy, it preferably contains not more than about 4 carbon atoms.
  • m in the foregoing formula is 2 Ge.
  • a 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • 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.
  • 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:
  • 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.
  • 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.
  • aprotic solvent suitable for the purpose are bis(2-methoxyethyl)ether, acetonitrile, acetone, methyl ethyl ketone, N,N-dimethylformamide, benzene, toluene, chloroform and the like.
  • 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.
  • 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.
  • 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:
  • Z is halogen, conveniently fluorine or chlorine, or R SO -(e.g. R,SO 0S0 R,).
  • 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.
  • the fluorocarbonsulfonanilide is isolated by known methods, e.g. by extraction using an excess of aqueous sodium hydroxide.
  • 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.
  • 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
  • halides e.g. chlorides and fluorides
  • 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:
  • 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.
  • Example 1 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.
  • 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.
  • 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.
  • Example 23 The sodium salt of 3-(4mcthoxybenzoyl)-trifluoromethanesulfonanilide is reacted with ethyl chloroformate to give N-ethoxycarbonyl-3-(4-rnethoxybenzoyl)-trifluoromethanesulfonanilide:
  • 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.
  • Example 25 The sodium salt of S-benzoyltrifluoromethanesulfonanilide was reacted with benzyl chloroformate to give N- benzyloxycarbonyl 3 benzoyltrifiuoromethanesulfonanilide:
  • Example 26 The sodium salt of 3-benzoyltrifluoromethanesulfonanilide was reacted with acetyl chloride to give N-acetyl- 3-benzoyltrifluoromethanesulfonanilide:
  • 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.
  • Example 2 8 The sodium salt of 3-benzoyldifiuoromethanesulfonanilide was reacted with methyl chloroformate to give N methoxycarbonyl 3 benzoyldifiuoromethanesulfonanilide:
  • 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.
  • 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:
  • Example 32 The sodium salt of 3-(4-methoxybenzoyl)-fiuoromethanesulfonanilide is reacted with ethyl chloroformate to 13 give N ethoxyearbonyl-3-(4 methoxybenzoyD-fluoromethanesulfonanilide:
  • This product is isolated as white crystals from ethanolwater, M.P. 6668 c.
  • 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.
  • Acompound of the formula 9. N ethoxycarbonyl 3 benzoyltrifluoromethane- 0 sulfonanilide.
  • 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
  • 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.
  • 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.
  • R is an FOREIGN T omega-hydroperfluoroalkyl radical. 733,758 10/1955 Great Bf 1mm.
  • Q is an alkyl group containing from 1 to 4 carbon atoms.

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3906027A (en) * 1972-08-05 1975-09-16 Bayer Ag N-(perfluoroalkyl-sulphonyl)-carbamic acid esters of polyalkylene oxides
US5210290A (en) * 1990-03-12 1993-05-11 Schering Aktiengesellschaft Fluorobenzenesulfonamides
CN102803208A (zh) * 2009-06-12 2012-11-28 3M创新有限公司 氟化芳香族含双(酰基)化合物和由其制备的聚酯

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3906027A (en) * 1972-08-05 1975-09-16 Bayer Ag N-(perfluoroalkyl-sulphonyl)-carbamic acid esters of polyalkylene oxides
US5210290A (en) * 1990-03-12 1993-05-11 Schering Aktiengesellschaft Fluorobenzenesulfonamides
CN102803208A (zh) * 2009-06-12 2012-11-28 3M创新有限公司 氟化芳香族含双(酰基)化合物和由其制备的聚酯
US8686179B2 (en) 2009-06-12 2014-04-01 3M Innovative Properties Company Fluorinated aromatic bis(acyl)-containing compounds and polyesters prepared therefrom
CN102803208B (zh) * 2009-06-12 2014-04-30 3M创新有限公司 氟化芳香族含双(酰基)化合物和由其制备的聚酯
US9045400B2 (en) 2009-06-12 2015-06-02 3M Innovative Properties Company Fluorinated aromatic bis(acyl)-containing compounds and polyesters prepared therefrom

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AT293424B (de) 1971-02-15

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