US3676463A - Oxobenzofuran carboxamides - Google Patents

Oxobenzofuran carboxamides Download PDF

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US3676463A
US3676463A US81162A US3676463DA US3676463A US 3676463 A US3676463 A US 3676463A US 81162 A US81162 A US 81162A US 3676463D A US3676463D A US 3676463DA US 3676463 A US3676463 A US 3676463A
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dihydrobenzofuran
oxo
carboxanilide
compound
mole
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US81162A
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Saul P Kadin
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Pfizer Corp Belgium
Pfizer Corp SRL
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Pfizer Corp Belgium
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/56—Unsaturated compounds containing hydroxy or O-metal groups containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms

Definitions

  • ABSTRACT [22] Filed: Oct. 15, 1970 A series of novel 2-oxo-2,3-dihydrobenzofuran-3-carboxa- PP N03 81,162 mides have been prepared, including their pharmaceutically acceptable salts. These compounds are useful in therapy as 52 us. Cl ..260/343.3 424/279 mn'semidal anti-inflammawry Alternate methmis [51] Int. Cl.
  • This invention relates to various new and useful 2-oxobenzofuran carboxamidesin the field of medicinal chemistry. More particularly, it is concerned with a novel series of 2-oxo- 2,3-dihydrobenzofuran-3-carboxamides, which are of especial value in view of their unique chemotherapeutic properties.
  • CONHR and the base salts thereof with pharmacologically acceptable cations wherein X and Y are each a member selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl and alkoxy each having from one to five carbon atoms, trifluoromethyl and trifluoromethoxy; and R is a member selected from the group consisting of naphthyl, phenyl and mono and di-substituted phenyl wherein each substituent is chosen from the group consisting of fluorine, chlorine, and bromine, alkyl having up to four carbon atoms, alkoxy and thioalkoxy each having up to three carbon atoms, trifluoromethyl and trifluoromethoxy.
  • X and Y are each a member selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl and alkoxy each having from one to five carbon atoms, trifluoromethyl and trifluoromethoxy
  • R is a member selected from the
  • the product Upon completion of the reaction, the product is easily recovered from the spent reaction mixture by pouring same into an excess of ice-water containing a slight excess of acid, such as hydrochloric acid, whereby the desired carboxamide compound readily precipitates from solution and is subsequently collected by such means as suction filtration and the like.
  • acid such as hydrochloric acid
  • Another method for preparing the instant compounds of this invention involves reacting a 2,3-dihydrobenzofuran-2- one in the form of an alkali metal or alkaline-earth metal salt with an appropriate 1,1,3-trisubstituted urea of the formula (R' NCONHR, wherein R is an aryl group such as phenyl, pchlorophenyl, p-bromophenyl, p-nitrophenyl, pacetylaminophenyl, p-tolyl, p-anisyl, a-naphthyl, [ax-naphthyl, and the like.
  • This reaction is preferably carried out in the presence of a reaction-inert polar organic solvent medium.
  • Typical organic solvents for use in this connection include the N,N-dialkyl lower alkanoamides like dimethylformamide, dimethylacetamide, diethylforrnamide and diethylacetamide, as well as lower dialkyl sulfoxides such as dimethyl sulfoxide, diethyl sulfoxide and di-n-propyl sulfoxide, etc. It is desirable that the aforesaid solvent for this reaction be present in sufficient amount to dissolve each of the previously mentioned starting materials. In general, the reaction is conducted at a temperature that is in the range of from about 20 C. up to about ISQ for a period of about to about 10 hours.
  • Recovery of the desired product from the reaction mixture is then most conveniently accomplished by first diluting the reaction solution with water and then adjusting the pH of the resulting aqueous solution to at least about pH 8.0, followed by subsequent extraction of the basic aqueous solution with any water-immiscible organic solvent in order to remove minor amounts of unreacted or excess starting material that might possibly be present at this stage.
  • Isolation of the desired 2-oxo-2,3-dihydrobenzofuran-3-carboxamide'from the basic aqueous layer is then effected by the addition thereto of a dilute aqueous acid solution, wherein the acid is present in such amount that it will cause precipitation of the desired 2- oxobenzofuran carboxamide to occur from the aqueous solution.
  • the relative amounts of reagents employed are such that the molar ratio of the 2,3-dihydrobenzofuran-2-one to the l,l-diaryl-3-(monosubstituted)urea is desirably in the preferred range of from about 1:1 to about 1:3, although substantially equimolar ratios will still cause equally satisfactory results to be achieved.
  • the two major type starting materials required for this reaction viz., the 2,3-dihydrobenzofuran-2-ones and the l,l-diaryl-3-(monosubstituted)ureas, are both readily available to those skilled in the art.
  • the 2,3-dihydrobenzofuran-2-ones which are also used as starting materials in the previously described isocyanate method, are, for the most part, well-known in the chemical prior art and/or can easily be synthesized in every case from more readily available materials in accordance with standard organic procedures that are commonly described therein [e.g., see Elderfield et al., in Heterocyclic Compounds," Vol.
  • the 1,1- diaryl-3-(monosubstituted)ureas are all readily prepared from common organic reagents by employing standard procedures well known in the art, e.g., the desired 1,] ,S-trisubstituted urea may be prepared from the corresponding disubstituted carbamyl chloride [(R) NCOCl] and the appropriate amine (RNH in accordance with the general procedure of Reudel, as described in Recueil des Travaux Chimiqucs des Pays-Bus, Vol. 33,- p. 64 I914).
  • the chemical bases which are used as reagents in this invention to prepare the pharmaceutically acceptable salts of same are those which form non-toxic salts with the many herein described acidic 2-oxo-2,3-dihydrobenzofuran-3-carboxamides, such as 2'-fluoro-2-oxo-2,3-dihydrobenzofuran-3-carboxanilide, for example.
  • These particular non-toxic base salts are of such a nature that their cations are essentially non-toxic in character over the wide range of dosage administered. Examples of such cations include those of sodium, potassium, calcium and magnesium, etc.
  • salts can easily be prepared by simply treating the aforementioned 2-oxo-2,3- dihydrobenzofuran-3-carboxamides with an aqueous solution of the desired pharmacologically acceptable base, i.e., those oxides, hydroxides or carbonates which contain pharmacologically acceptable cations, and then evaporating the resulting solution to dryness while under reduced pressure.
  • the desired pharmacologically acceptable base i.e., those oxides, hydroxides or carbonates which contain pharmacologically acceptable cations
  • they may also be prepared by mixing lower alkanolic solutions of the said acidic compounds and the desired alkali metal alkoxide together, and then evaporating said resulting solution in the same manner as before. ln either case, stoichiometric amounts of reagents must be employed in order to ensure completeness of reaction, with consequent maximum production of yields of the desired pure product.
  • the 2-oxo-2,3-dihydrobenzofuran- 3-carboxamide compounds of the present invention are all 'readily adapted to therapeutic use as anti-inflammatory agents, particularly in view of their ability to reduce the swelling and relieve the pain caused by arthritic and other inflammatory disorders that are normally associated with such basic ailments as rheumatoid arthritis and the like.
  • 2-oxo-5-chloro-2,3-dihydrobenzofuran-3-carboxanilide a typical and preferred agent of the present invention, exhibits remarkable activity in the standard carrageenin-induced rat foot edema test [described by C.A. Winter et al., Proc. Soc. Exp. Biol., Vol.
  • none of these compounds cause any substantial side effects to occur in the subjects to whom they are so administered, i.e., no problems of toxicity or of a harmful pharmacological nature, either gross or microscopic, are encountered when said compounds are administered for the aforestated purposes in the manner described as indicated above.
  • the herein described 2-oxo-2,3-dihydrobenzofuran-3- carboxamide anti-inflammatory agents can be administered to an afflicted subject via either the oral or parenteral routes of administration.
  • these compounds are most desirable administered in doses ranging from about 100 mg. up to about 1,000 mg. per day, although variations will still necessarily occur depending upon the weight of the subject being treated.
  • a dosage level that is in the range of from about 1.6 to about 16 mg. per kg. of body weight per day is most desirably employed in order to achieve effective results.
  • dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful or deleterious side effects to occur provided that such higher dose levels are first divided into several smaller doses that are to be administered throughout the day.
  • novel compounds of the invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like.
  • Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
  • Such oral pharmaceutical compositions can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for just such a purpose.
  • the therapeutically effective compounds of this invention are present in such dosage forms at concentration levels ranging from about 0.5 to about percent by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
  • tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hardfilled gelatin capsules; preferred materials in the connection would also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
  • the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
  • solutions of these particular 2-oxo-2,3-dihydrobenzofuran-3-carboxamides in either sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions of the corresponding water-soluble alkali metal or alkaline-earth metal salts previously enumerated.
  • aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • These particular solutions are especially suitable for intravenous, intramuscular and subcutaneous injection purposes.
  • a general procedure employed for detecting and comparing the anti-inflammatory activity of the compounds of the present invention is, as previously indicated, the standard carrageenin-induced rat foot edema test using the aforementioned technique of CA. Winter et al. In this test, anti-inflammatory activity is determined as the inhibition of edema formation in the hind pawof male albino rats (weighing 150-190 g.) in response to a subplantar injection of carrageenin. The carrageenin is injected as a 1 percent aqueous suspension (0.05 ml.) 1 hour after oral administration of the drug, which is normally given in the form of an aqueous solution.
  • Edema formation is then assessed 3 hours after the carrageenin injection by measuring the volume of the injected paw initially as well as at the 3-hour mark. The increase in volume: three hours after carrageenin injection constitutes the individual response.
  • Compounds are considered'active if the response between the drug-treated animals (six rats/group) and the control group (i.e., animals receiving the vehicle alone) is deemed to be significant on comparison with results afforded by standard compounds like acetylsalicylic acid at 100 mg./kg. or phenylbutazone at 33 mg./kg., both by the oral route of administration.
  • reaction mixture was diluted with 200 ml. of ice water and treated with a few sodium bisulfite crystals to remove the dark color. It was-then extracted with 40 ml. of chloroform, followed by three-100 ml. portions of diethyl ether. The combined ether layers were saved, dried over anhydrous magnesium sulfate and subsequently evaporated to dryness while under reduced pressure. In this manner, a 24 g. (94 percent) yield of 2-hydroxy-5-chlor0phenylacetic acid was obtained as residue in the form of a yellow crystalline solid, m.p. 128-130 C.
  • a solution consisting of 24.68 g. (0.129 mole) of 4,5- dichloro2-methyl-anisole dissolved in ml. of chloroform was then treated at reflux temperature with 20.6 g. (0.129 mole) of bromine (6.9 ml.) dissolved in 50 ml. of chloroform.
  • the bromine solution was added in a drop-wise manner during the course of a 1.5-hour period and upon completion of same, refluxing was continued for an additional hour.
  • EXAMPLE V The procedure described in Example IV was repeated using 1.33 g. (0.010 mole) of o-tolyl isocyanate in place of 1.19 g. (0.010 mole) of phenyl isocyanate.
  • the corresponding final product thus obtained was 2-methyl-2- oxo-2,3-dihydrobenzofuran-3-carboxanilide (0.85 g.), m.p. 164-1 65 C. after recrystallization from benzene.
  • EXAMPLE VI The procedure described in Example IV was repeated using 1.49 g. (0.010 mole) of o-methoxyphenyl isocyanate (i.e., oanisyl isocyanate) in place of 1.19 g. (0.010 mole) of phenyl isocyanate.
  • the corresponding final product thus obtained was 2'-methoxy-2-oxo-2,3- dihydrobenzofuran-3-carboxanilide (1.05 g.), m.p. 142-l43 C. after recrystallization from ethyl acetate.
  • EXAMPLE VIII The procedure described in Example VII was repeated using 3.38 g. (0.020 mole) of 5-chloro-2,3-dihydrobenzofuran-2-one, 2.62 g. (0.022 mole) of phenyl isocyanate and 2.22 (0.022 mole) of triethylamine in 10 ml. of dry dimethylformamide.
  • the corresponding final product thus obtained was 2-oxo-5-chloro-2,3-dihydrobenzofuran-3- carboxanilide, m.p. l86-l88 C. after recrystallization from benzene.
  • the resulting mixture was poured into 20 ml. of ice water and thereafter treated with ml. of IN aqueous potassium hydroxide and 5 ml. of dry ethyl acetate.
  • the basic aqueous layer which separated at this point was then saved and added to an ice-water mixture containing 5 ml. of concentrated hydrochloric acid, whereupon a cream-colored crystalline precipitate soon formed.
  • the latter material was subsequently collected on a filter funnel and air-dried to constant weight to give 0.568 g. (38%) of 2-0xo-5,6-dichloro-2,3- dihydrobenzofuran-3-carboxanilide, m.p. 2 l 0-2 1 2 C.
  • EXAMPLE XI The procedure described in Example X was repeated using 3.38g. (0.0022mole) of p-chlorophenyl isocyanate and 2.22 g. (0.0022 mole) of triethylamine in 10 ml. of dimethylformamide, together with 3.38 g. (0.0020 mole) of 5-chloro-2,3- dihydrobenzofuran-2-one also dissolved in 10 ml. of dimethylformamide.
  • the corresponding final product thus obtained was 4-chloro-2-oxo-5'chloro-2,3- dihydrobenzofuran-3-carboxanilide, m.p. 222223 C. after recrystallization from isopropanol.
  • the potassium and lithium salts are also prepared as are the alkali metal salts of all the other acidic 2- oxo-2,3-dihydrobenzofuran-3-carboxamides of this invention,
  • EXAMPLE XV The calcium salt of 2-methyl-2-oxo-2,3-dihydrobenzofuran-3-carboxanilide is prepared by dissolving said compound in water containing an equivalent amount in moles of calcium hydroxide and then freeze-drying the mixture.
  • the corresponding magnesium salt is also prepared in a similar manner, as are all the other alkaline-earth metal salts not only of this particular compound, but also of those acidic 2-oxo- 2,3-dihydrobenzofuran-3-carboxamides previously described in the examples immediately preceding Example XlV.
  • EXAMPLE XVl A dry solid pharmaceutical composition is prepared by blending the following materials together in the proportions by weight specified below:
  • a dry solid pharmaceutical composition is prepared by combining the following materials together in the proportions by weight indicated below:
  • X and Y are each a member selected from the group consisting of hydrogen, fluorine, chlorine, bromine, alkyl and alkoxy each having from one to five carbon atoms, trifluoromethyl and trifluoromethoxy; and R is a member selected from the group consisting of naphthyl, phenyl and monoand di-substituted phenyl wherein each substituent is chosen from the group consisting of fluorine, chlorine, and bromine, alkyl having up tofour carbon atoms, alkoxy and thioalkoxy each having up to three carbon atoms, trifluoromethyl and trifluoromethoxy.
  • each chlorine and R is fluorophenyl.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Furan Compounds (AREA)
US81162A 1970-10-15 1970-10-15 Oxobenzofuran carboxamides Expired - Lifetime US3676463A (en)

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JP (1) JPS5527060B1 (cs)
BE (1) BE773913A (cs)
DE (1) DE2150901A1 (cs)
FR (1) FR2110447B1 (cs)
GB (2) GB1337506A (cs)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3862133A (en) * 1973-04-30 1975-01-21 Goodrich Co B F Gamma-lactones of o-hydroxyphenylacetic acids
DE2713584A1 (de) * 1976-04-09 1977-10-20 Ciba Geigy Ag Oxothiaverbindungen
DE3038593A1 (de) 1979-10-15 1981-04-23 Pfizer Inc., New York, N.Y. Neue entzuendungshemmende und immunregulatorische pyridine und pyrimidine
US4396621A (en) * 1976-04-09 1983-08-02 Ciba-Geigy Corporation Certain 2-oxo-2,3-dihydro-3-benzothiophene-carboxamides and their pharmaceutical compositions

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2750990B1 (fr) * 1996-07-09 1998-11-06 Hoechst France Procede de preparation de l'enol-lactone de l'acide 2-oxocyclohexylidene acetique et application a la preparation de la 2-coumaranone

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2757178A (en) * 1952-05-03 1956-07-31 American Cyanamid Co Chloro-phthalides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2757178A (en) * 1952-05-03 1956-07-31 American Cyanamid Co Chloro-phthalides

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3862133A (en) * 1973-04-30 1975-01-21 Goodrich Co B F Gamma-lactones of o-hydroxyphenylacetic acids
DE2713584A1 (de) * 1976-04-09 1977-10-20 Ciba Geigy Ag Oxothiaverbindungen
US4396621A (en) * 1976-04-09 1983-08-02 Ciba-Geigy Corporation Certain 2-oxo-2,3-dihydro-3-benzothiophene-carboxamides and their pharmaceutical compositions
DK152046B (da) * 1976-04-09 1988-01-25 Ciba Geigy Ag Analogifremgangsmaade til fremstilling af 2-oxo-2,3-dihydrobenzo(b)thiophencarboxamider eller salte deraf med baser
DE3038593A1 (de) 1979-10-15 1981-04-23 Pfizer Inc., New York, N.Y. Neue entzuendungshemmende und immunregulatorische pyridine und pyrimidine

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GB1337506A (en) 1973-11-14
JPS5527060B1 (cs) 1980-07-17
DE2150901A1 (de) 1972-04-20
FR2110447B1 (cs) 1975-02-07
BE773913A (fr) 1972-04-14
GB1337507A (en) 1973-11-14
FR2110447A1 (cs) 1972-06-02

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