US2562208A - Fungistatic composition - Google Patents

Fungistatic composition Download PDF

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US2562208A
US2562208A US741414A US74141447A US2562208A US 2562208 A US2562208 A US 2562208A US 741414 A US741414 A US 741414A US 74141447 A US74141447 A US 74141447A US 2562208 A US2562208 A US 2562208A
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acrylic acid
acid
maleic anhydride
recrystallization
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Papa Domenick
Schwenk Erwin
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Merck Sharp and Dohme LLC
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Schering Corp
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    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/315—Zinc compounds

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  • This invention relates to a group of compounds having chemotherapeutic activity. More specifl-' cally, the invention provides a group of closely related chemical compounds which have been found to be active against a wide variety of gram negative organisms. In addition, this group of compounds is of particular interest in many of the usual types of intestinal infections.
  • An important object of the invention is to provide compounds for combating various types of gram negative organisms usually associated with intestinal infections, such compounds having low toxicity and freedom from any of the disadvantages usually associated with sulfanilamide therapy. It has also been established as an important feature of the invention that these compounds have shown activity against several organisms which are penicillin resistant.
  • the group of compounds of the invention have also been found to have a pronounced fung'istatic activity.
  • the compounds of the present invention are aroyl acrylic acids and their substitution products of the following general formula:
  • R. is a member of the group consisting of benzene, naphthalene, and their hydrogenation products, thiophene and pyridine and X is a member of the group consisting of hydrogen, halogen, nitro, amino, alkyl, hydroxyl, alkoxyl, acylamino and cycloalkyl and Y is hydrogen or a salt-forming metal.
  • aroyl acrylic acids may be substituted by a combination of two groups such as halogen and amino, halogen and nitro, alkyl and halogen, and alkyl and amino.
  • the compounds of this invention may be used in the form of the free acids or in the form of their metal salts.
  • the substances may be incorporated with inert ingredients, such as starch, in the form of tablets.
  • inert ingredients such as starch
  • other active ingredients may be incorporated in the tablets.
  • They may also be used in aqueous or oil solution employing for the former the salts, preferably the sodium salt, and for the latter preferably the free acids, or they may be administered without admixture, for example, in gelatin capsules. 7
  • fungistatic preparations for topical application,- it is advantageous to incorporate from about 2% to about 5% of the zinc salts of the aroyl acrylic acids in a cream of the vanishing type. Powder compositions containing the 2 aroyl acrylic acids or their salts may also be used effectively for this purpose.
  • the compounds of the general formula may be prepared from the appropriate aryl hydrocarbon and maleic anhydride by the Friedel-Crafts reaction.
  • the aroyl acrylic acids so obtained are usually crystallized from nonpolarsolvents in which case they are obtained as yellow crystalline substances. Recrystallization from water or mixtures of alcohol and water usually gives rise to thehydrates which are, in the majority of cases, colorless substances.
  • excess of the aryl hydrocarbon is to be avoided since addition of the aryl hydrocarbon across the double bond of the preformed aroyl acrylic acid usually occurs. This difliculty is readily overcome by using any of the usual reaction solvents such as nitrobenzene and acetylene tetrachloride, the latter being preferred.
  • An alternate method for securing certain of the aroyl acrylic acids, particularly those wherein the aryl hydrocarbon is sensitive to the above reaction conditions is to condense fi-carbethoxy acryloyl chloride with the aryl or heterocyclic hydrocarbon in accordance with the Friedel- Crafts synthesis.
  • the Perrier modification of the Friedel-Crafts synthesis has given good yields in both the fl-carbethoxy acryloyl chloride and aryl or heterocyclic hydrocarbon method or maleic anhydride procedure.
  • the acrylic acids are obtained from the corresponding aroyl propionic acids which are monobrominated a to the keto group and then debrominated.
  • EXAMPLE I p-Benzoylacrylic acid To 456 g. of anhydrous thiophene-free benzene and 98 g'. of maleic anhydride there is added gradually at about room temperature 266 g. of anhydrous aluminum chloride. It is preferable to use granular anhydrous aluminum chloride in this and subsequent examples. The reaction mixture is allowed to stand at room temperature preferably with stirring until the evolution of hydrogen chloride ceases, approximately 6-8 hours. The reaction mixture is then cautiously decomposed by the addition of ice and dilute hydrochloric acid, the excess benzene steam distilled and the residue thoroughly chilled.
  • the semi-solid or solid cake is filtered, dissolved in sodium carbonate, filtered, cooled and acidified to Congo red paper with HCl.
  • the hydrated B-benzoylacrylic acid so obtained melts at 60-61 C.
  • the anhydrous form is obtained, melting at 98-99 C.
  • EXAMPLE II p- (p-Chlorobenzo'yl) acrylic acid This compound is prepared from chlorobenzene, maleic anhydride and aluminum chloride in accordance with the procedure of Example 1. After recrystallization from aqueous ethyl alcohol, the compound melts at 153.7-154.7 C.
  • the reaction may also be carried out in excess chlorobenzene as solvent. Excessive reaction time should be avoided in order to eliminate the formation of the compound resulting from the addition of chlorobenzene across the double bond of the fl-(p-chlorobenzoyl)acrylic acid.
  • EXAMPLE III p- (p-Bromobenzoyl) acrylic acid This compound is obtained from bromobenzene in accordance with the instructions of Example II and melts at 159-160 C. after recrystallization from aqueous alcohol.
  • EXAMPLE IV 9- (p-Iodobenzoyl) acrylic acid This compound is secured from an equivalent amount of iodobenzene with maleic anhydride and aluminum chloride in accordance with the instructions of Example I.
  • Acetylene tetrachloride has been found to be the most suitable solvent
  • the fi-(p-iodobenzoyl) acrylic acid melts at 186-1865" C. after recrystallization from ethyl alcohol.
  • EXAMPLE VI p- (p-Isopropylbenzoyl) acrylic acid This compound is obtained from isopropylbenzene in accordance with the instructions of the preceding example. It is a fine yellow crystalline material melting at 103-103.5 C. after recrystallization from ethyl alcohol;
  • EXAMPLE VIII p-(2,4-dimethylbeneoyl) acrylic acid This compound is obtained from m-xylene in accordance with the instructions of Example V. After recrystallization from dilute ethanol, the compound melts at 113-114 C.
  • EXAMPLE IX [3- (a-Thenoyl) acrylic acid This compound is prepared in accordance with the instructions of Example I employing the Perrier modification. To a solution of 61 g. aluminum chloride and 24.5 g. maleic anhydride in 1'75 cc. nitrobenzene cooled to 0 C. there is added gradually with stirring 21 g. thiophene. The reaction mixture is allowed to come to room temperature and then cautiously decomposed with ice and diluted hydrochloric acid. After steam distillation, the residue is cooled thoroughly, filtered and the precipitate dissolved in sodium carbonate. Acidification gives the compound of this example which melts at 148-150 C. After recrystallization from water a pale yellow product is obtained melting at 152-153" C.
  • EXAMPLE XI fi- (Z-methyl-4-hydroarybenzoyl) acrylic acid This compound is prepared in accordance with the directions of the preceding example of using m-cresol. It is a pale yellow crystalline solid melting at 172-173 C. after recrystallization from benzene. Using acetylene tetrachloride in this reaction instead of nitrobenzene gives superior results.
  • EXAMPLE XII fi- (p-Acetylaminobenzoyl) acrylic acid To g. aluminum chloride in 200 cc. carbon disulfide there is added at orbelow 0 C. a mixture of 38 g. maleicanhydride and 50 g. acetanilid. After the addition is completed," the temperature rises to approximately 35 Caand then slowly drops back to approximately 10C; An additiona] 100 cc. of carbon disulfiide is added, the mixture stirred for hour and alter standing for 48 hours was decomposed with ice and dilute hydrochloric acid. The carbon disulilide is removed and the product which separates melts at 225-226 C. Recrystallized from dflute ethanol, the acetylamino compound is obtained as a brilliant yellow product melting at 242-24 4 C.
  • EXAMPLE XIV p-Naphthoylacrylic acid
  • 32 g. of naphthalene, g. of maleic anhydride and 65g. of aluminum chloride in about 100 cc. of benzene as solvent there was obtained a mixture of the land 2-B-naphthoylacrylic acid.
  • the separation oi! the two isomers may be carried out in accordance with J. Am. Chem. Soc. 47, 526 (1925).
  • EXAMPLE XV fi- (m-Niirobenzdyl) acrylic acid This compound may be prepared as described by Bogert and Ritter. J. Am. Chem. Soc. 47, 532 (1925). It melts at 190-l92 C. after recrystallization from alcohol.
  • EXAMPLEXXI fl- (Isopropylmethylbenzoyl) acrylic acid The compound 01 this example is obtained from p-cymene and maleic anhydride in accordance with the method of Example XVII.
  • EXAMPLE XXV fl- (2,5-diacetylaminobenzoyl) acrylic acid This compound is made by reacting 1,4-diacetylaminobenzene with maleic anhydride by the method of Example XII.
  • p- (p-chlorobenzoyl) acrylic acid in the form of the zinc salt is admixed with a vanishing cream composition consisting of 17 glyceral monostearate, 5% spermaceti, 3% lanolin, 4% mineral oil, and 71% water.
  • EXAMPLE XXV]! About 2% of the zinc salt of p-(p-iodobenzoyl) acrylic acid is admixed with a cream composition consisting of 20% stearic acid, 4% oleic acid, 1.2% potassium hydroxide, and 74.8% water.
  • EXALEPIEXXV'III An excellent iungistatic powder preparation consists of zinc p-(p-chlorobenzoyl) acrylate 20 (p-chlorobenzoyl) acrylic acid 2%, and talc 78%.
  • acid compound denotes the free acid and the metal salts thereof.
  • a fungistatic composition containing as a -major active ingredient a zinc salt of an aroyl acrylic acid.
  • a i'ungistatic composition containing as a major active ingredient a zinc salt of a fl-benzoylacrylic acid.
  • a fungistatic composition containing as a major active ingredient a zinc salt of a p- (p-chlorobenzoyl) acrylic acid.
  • a fungistatic preparation comprising a vanishing cream composition containing from about 2% to about 5% of a zinc salt of fl-(p-chlorobenzoyDacrylic acid.

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Description

Patented July 31, 1951 FUNGISTATIC COMPOSITION Domenick Papa, Brooklyn, N. Y., and Erwin Schwenk, Montclair, N. J assignors to Schering Corporation, Bloomfield, N. J a corporation of New Jersey No Drawing. Application April 14, 1947,
Serial No. 141,414
4 Claims. 1
This invention relates to a group of compounds having chemotherapeutic activity. More specifl-' cally, the invention provides a group of closely related chemical compounds which have been found to be active against a wide variety of gram negative organisms. In addition, this group of compounds is of particular interest in many of the usual types of intestinal infections. An important object of the invention is to provide compounds for combating various types of gram negative organisms usually associated with intestinal infections, such compounds having low toxicity and freedom from any of the disadvantages usually associated with sulfanilamide therapy. It has also been established as an important feature of the invention that these compounds have shown activity against several organisms which are penicillin resistant.
The group of compounds of the invention have also been found to have a pronounced fung'istatic activity.
The compounds of the present invention are aroyl acrylic acids and their substitution products of the following general formula:
where R. is a member of the group consisting of benzene, naphthalene, and their hydrogenation products, thiophene and pyridine and X is a member of the group consisting of hydrogen, halogen, nitro, amino, alkyl, hydroxyl, alkoxyl, acylamino and cycloalkyl and Y is hydrogen or a salt-forming metal. In addition to having a single substituent'as shown in the above general formula the aroyl acrylic acids may be substituted by a combination of two groups such as halogen and amino, halogen and nitro, alkyl and halogen, and alkyl and amino.
The compounds of this invention may be used in the form of the free acids or in the form of their metal salts. The substances may be incorporated with inert ingredients, such as starch, in the form of tablets. In place of or in addition to the inert ingredients other active ingredients may be incorporated in the tablets. They may also be used in aqueous or oil solution employing for the former the salts, preferably the sodium salt, and for the latter preferably the free acids, or they may be administered without admixture, for example, in gelatin capsules. 7
For use as fungistatic preparations for topical application,- it is advantageous to incorporate from about 2% to about 5% of the zinc salts of the aroyl acrylic acids in a cream of the vanishing type. Powder compositions containing the 2 aroyl acrylic acids or their salts may also be used effectively for this purpose.
The compounds of the general formula may be prepared from the appropriate aryl hydrocarbon and maleic anhydride by the Friedel-Crafts reaction. The aroyl acrylic acids so obtained are usually crystallized from nonpolarsolvents in which case they are obtained as yellow crystalline substances. Recrystallization from water or mixtures of alcohol and water usually gives rise to thehydrates which are, in the majority of cases, colorless substances. In carrying out the Friedel-Crafts reaction between the aryl hydrocarbon and maleic anhydride, excess of the aryl hydrocarbon is to be avoided since addition of the aryl hydrocarbon across the double bond of the preformed aroyl acrylic acid usually occurs. This difliculty is readily overcome by using any of the usual reaction solvents such as nitrobenzene and acetylene tetrachloride, the latter being preferred.
An alternate method for securing certain of the aroyl acrylic acids, particularly those wherein the aryl hydrocarbon is sensitive to the above reaction conditions is to condense fi-carbethoxy acryloyl chloride with the aryl or heterocyclic hydrocarbon in accordance with the Friedel- Crafts synthesis. The Perrier modification of the Friedel-Crafts synthesis has given good yields in both the fl-carbethoxy acryloyl chloride and aryl or heterocyclic hydrocarbon method or maleic anhydride procedure. In certain cases, the acrylic acids are obtained from the corresponding aroyl propionic acids which are monobrominated a to the keto group and then debrominated. These various methods are more specifically described in the following examples without being limited thereto.
EXAMPLE I p-Benzoylacrylic acid To 456 g. of anhydrous thiophene-free benzene and 98 g'. of maleic anhydride there is added gradually at about room temperature 266 g. of anhydrous aluminum chloride. It is preferable to use granular anhydrous aluminum chloride in this and subsequent examples. The reaction mixture is allowed to stand at room temperature preferably with stirring until the evolution of hydrogen chloride ceases, approximately 6-8 hours. The reaction mixture is then cautiously decomposed by the addition of ice and dilute hydrochloric acid, the excess benzene steam distilled and the residue thoroughly chilled. The semi-solid or solid cake is filtered, dissolved in sodium carbonate, filtered, cooled and acidified to Congo red paper with HCl. The hydrated B-benzoylacrylic acid so obtained melts at 60-61 C. On recrystallization from benzene, the anhydrous form is obtained, melting at 98-99 C.
In an alternative procedure, equal molecular quantities of ethyl hydrogen maleate and PC]: are warmed on the steam bath for several hours. The yellow-orange mixture is extracted with anhydrous benzene and the benzene layer treated with maleic anhydride and aluminum chloride as in the previously described method. After decomposition with ice and HCl and steam distillation the benzoylacrylic acid crystallizes out in the form of white platelets, which are dissolved in sodium carbonate filtered and reprecipitated with HCl. Recrystallized from water the acid melts at 60-605" C.
EXAMPLE II p- (p-Chlorobenzo'yl) acrylic acid This compound is prepared from chlorobenzene, maleic anhydride and aluminum chloride in accordance with the procedure of Example 1. After recrystallization from aqueous ethyl alcohol, the compound melts at 153.7-154.7 C.
The reaction may also be carried out in excess chlorobenzene as solvent. Excessive reaction time should be avoided in order to eliminate the formation of the compound resulting from the addition of chlorobenzene across the double bond of the fl-(p-chlorobenzoyl)acrylic acid.
EXAMPLE III p- (p-Bromobenzoyl) acrylic acid This compound is obtained from bromobenzene in accordance with the instructions of Example II and melts at 159-160 C. after recrystallization from aqueous alcohol.
EXAMPLE IV ;9- (p-Iodobenzoyl) acrylic acid This compound is secured from an equivalent amount of iodobenzene with maleic anhydride and aluminum chloride in accordance with the instructions of Example I. Acetylene tetrachloride has been found to be the most suitable solvent The fi-(p-iodobenzoyl) acrylic acid melts at 186-1865" C. after recrystallization from ethyl alcohol.
EXAMPLE v fl- (p-Methylbenzoyl) acrylic acid By reacting one equivalent of toluene with maleic anhydride and aluminum chloride in acetylene tetrachloride, the p-methyl derivative is obtained in excellent yield melting at 137.5- 138.5 C. after recrystallization from benzene. The use of toluene as solvent is very unsatisfactory since toluene adds readily across the double bond of the preformed p-tolylacrylic acid.
EXAMPLE VI p- (p-Isopropylbenzoyl) acrylic acid This compound is obtained from isopropylbenzene in accordance with the instructions of the preceding example. It is a fine yellow crystalline material melting at 103-103.5 C. after recrystallization from ethyl alcohol;
EXAMPLE VII B- 2,5 -dimethylbenzoyl acrylic acid By reacting p-xylene with maleic anhydride 4 and aluminum chloride in acetylene tetrachloride, the compound of this example is obtained melting at 89-90 C. after recrystallization from water.
EXAMPLE VIII p-(2,4-dimethylbeneoyl) acrylic acid This compound is obtained from m-xylene in accordance with the instructions of Example V. After recrystallization from dilute ethanol, the compound melts at 113-114 C.
EXAMPLE IX [3- (a-Thenoyl) acrylic acid This compound is prepared in accordance with the instructions of Example I employing the Perrier modification. To a solution of 61 g. aluminum chloride and 24.5 g. maleic anhydride in 1'75 cc. nitrobenzene cooled to 0 C. there is added gradually with stirring 21 g. thiophene. The reaction mixture is allowed to come to room temperature and then cautiously decomposed with ice and diluted hydrochloric acid. After steam distillation, the residue is cooled thoroughly, filtered and the precipitate dissolved in sodium carbonate. Acidification gives the compound of this example which melts at 148-150 C. After recrystallization from water a pale yellow product is obtained melting at 152-153" C.
EXAMPLE X B- (p-Hydroxybenzoyl) acrylic acid A compound under this name is described by Bogert and Ritter, J. Am. Chem. Soc. 47 532 (1925). When made according to their directions, the compound obtained is a-(p-hydroxyphenyl) S-(p-hydroxybenzoyl) propionic acid as established by analysis.
To obtain the compound of this example, the following procedure is used. To a solution of 450 cc. of acetylene tetrachloride 49 g. maleic anhydride and 128 g. aluminum chloride there was slowly added at or below room temperature 47 g. phenol. The reaction was carried out with stirring and after standing at room temperature for a short while is decomposed as indicated in the previous examples. The product obtained after purification by sodium carbonate treatment and recrystallization from water melts at 196.5- 1975 C. The melting point reported for the compound prepared by Bogert and Ritter is 136 C. identical to that of the substance shown by analysis to be a-(p-hydroxyphenyl) -/3-(p-hydroxybenzoyl) propionic acid.
EXAMPLE XI fi- (Z-methyl-4-hydroarybenzoyl) acrylic acid This compound is prepared in accordance with the directions of the preceding example of using m-cresol. It is a pale yellow crystalline solid melting at 172-173 C. after recrystallization from benzene. Using acetylene tetrachloride in this reaction instead of nitrobenzene gives superior results.
EXAMPLE XII fi- (p-Acetylaminobenzoyl) acrylic acid To g. aluminum chloride in 200 cc. carbon disulfide there is added at orbelow 0 C. a mixture of 38 g. maleicanhydride and 50 g. acetanilid. After the addition is completed," the temperature rises to approximately 35 Caand then slowly drops back to approximately 10C; An additiona] 100 cc. of carbon disulfiide is added, the mixture stirred for hour and alter standing for 48 hours was decomposed with ice and dilute hydrochloric acid. The carbon disulilide is removed and the product which separates melts at 225-226 C. Recrystallized from dflute ethanol, the acetylamino compound is obtained as a brilliant yellow product melting at 242-24 4 C.
EXAMPLE XIII (p-Aminobenzoyl) acrylic acid By the hydrolysis of the acetylamino compound described in the previous example there is obtained the compound 01' this example as a reddish solid. Its melting point is indefinite and depends to a large extent upon the rate of heating and initial bath temperature. It diazotizes readily with sodium nitrite and couples with 5- naphthol to a brilliant red dyestuil'.
EXAMPLE XIV p-Naphthoylacrylic acid By reacting in accordance with the instructions oi. Example I, 32 g. of naphthalene, g. of maleic anhydride and 65g. of aluminum chloride in about 100 cc. of benzene as solvent there was obtained a mixture of the land 2-B-naphthoylacrylic acid. The separation oi! the two isomers may be carried out in accordance with J. Am. Chem. Soc. 47, 526 (1925).
EXAMPLE XV fi- (m-Niirobenzdyl) acrylic acid This compound may be prepared as described by Bogert and Ritter. J. Am. Chem. Soc. 47, 532 (1925). It melts at 190-l92 C. after recrystallization from alcohol.
EXAMPLE XVI fi- (3-nitro-4-bromobenzoyl) acrylic acid To 63 cc. of turning nitric acid at 0 C. there is slowly added with stirring 19 g. of fi-(p-bromobenzoyDacrylic acid. The reaction mixture is allowed to stand for approximately A hour, poured into water, filtered and the precipitate recrystallized from ethanol, melting at 167-168 C.
EXAMPLE XVII p- (p-MethoxybenzoyUacrylic acid This compound is prepared from anisole. maleic anhydride and aluminum chloride in acetylene tetrachloride as solvent. The procedure used is essentially that of Example V. The compound obtained after recrystallization from benzene melts at 138-139 C.
EXAMPLEXVIII p- (p-Ethoxybenzoyl) acrylic acid Proceed as described in Example XVII using phenetole instead of anisole. After recrystallization from water the compound melts at 184.5- 185.5 C.
6 nxamnn p- (d-tetraloyl) acrylic acid This compound is obtained from tetralin and maleic anhydride as described in Example XVII. The compound of this example melts at 146.5- 14'i.5 C. after recrystallization i'rom toluene. v
EXAMPLEXXI fl- (Isopropylmethylbenzoyl) acrylic acid The compound 01 this example is obtained from p-cymene and maleic anhydride in accordance with the method of Example XVII.
EXAMPLE m1 p- (p-Cyclohezylbenzoylmcrylic acid Pherrvl cyclohexane is reacted with maleic anhydride as described in Example V. The acrylic acid of this example melts at about 182-l83 C. after recrystallization from a mixture of acetone and alcohol.
EXAMPLE XXIH p-(Acetylamino-hydrozy-benzoyl)acrylic acid This compound is made by reacting p-acetylaminophenol with maleic anhydride by the method 0! Example V.
EXAMPLE XXIV fl- (Chloro-hydroxy-benzoyl) acrylic acid This compound is made by reacting p-chlorophenol with maleic anhydride by the method oi Example V.
EXAMPLE XXV fl- (2,5-diacetylaminobenzoyl) acrylic acid This compound is made by reacting 1,4-diacetylaminobenzene with maleic anhydride by the method of Example XII.
The following are typical examples of fungistatic compositions of the invention:
About 2% of p- (p-chlorobenzoyl) acrylic acid in the form of the zinc salt is admixed with a vanishing cream composition consisting of 17 glyceral monostearate, 5% spermaceti, 3% lanolin, 4% mineral oil, and 71% water.
EXAMPLE XXV]! About 2% of the zinc salt of p-(p-iodobenzoyl) acrylic acid is admixed with a cream composition consisting of 20% stearic acid, 4% oleic acid, 1.2% potassium hydroxide, and 74.8% water.
EXALEPIEXXV'III An excellent iungistatic powder preparation consists of zinc p-(p-chlorobenzoyl) acrylate 20 (p-chlorobenzoyl) acrylic acid 2%, and talc 78%.
In the claims hereof the term acid compound denotes the free acid and the metal salts thereof.
We claim:
1. A fungistatic composition containing as a -major active ingredient a zinc salt of an aroyl acrylic acid.
2. A i'ungistatic composition containing as a major active ingredient a zinc salt of a fl-benzoylacrylic acid.
3. A fungistatic composition containing as a major active ingredient a zinc salt of a p- (p-chlorobenzoyl) acrylic acid.
7 4. A fungistatic preparation comprising a vanishing cream composition containing from about 2% to about 5% of a zinc salt of fl-(p-chlorobenzoyDacrylic acid. I
DOMENICK PAPA. ERWIN SCHWENK.
REFERENCES CITED The following references are of record in the file of this patent:
UNITED STATES PATENTS Number Name Date 1,779,258 McDermott Oct. 21, 1930 2,322,760 Lontz June 29, 1943 15 2,466,663 Russ Apr. 5, 1949 10 ment of Dermatophytosis.
8 OTHER REFERENCES 5 1945, pages 415-425. Especially page 417.
Lutz et al.-Cis and Trans B-Aroylacrylic Acids and Some Derivatives. J. Org. Chem., vol. 13 (1948), pages 284-296.
Hopkins et al.-Fungistatic Agents for Treat- J. of Investigative Dermatology, vol. 7, 1946, pages 239-253.

Claims (1)

  1. 4. A FUNGISTATIC PREPARATION COMPRISING A VANISHING CREAM COMPOSITION CONTAINING FROM ABOUT 2% TO ABOUT 5% OF A ZINC SALT OF B-(P-CHLOROBENZOYL) ACRYLIC ACID.
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3105850A (en) * 1959-06-24 1963-10-01 Spofa Vereinigte Pharma Werke Process of preparing beta-4-methoxybenzoyl-beta-haloacrylic acids
US4154817A (en) * 1974-07-02 1979-05-15 Kao Soap Co., Ltd. Smell-removing and deodorizing composition and process of using same
FR2481118A1 (en) * 1980-04-24 1981-10-30 Roussel Uclaf APPLICATION AS MEDICAMENTS OF DERIVATIVES SUBSTITUTED WITH PHENYL-4-OXO-2-BUTENOIC ACID
FR2515037A1 (en) * 1981-10-22 1983-04-29 Roussel Uclaf AS MEDICINES, CERTAIN MONO-SUBSTITUTED DERIVATIVES OF 4-PHENYL 4-OXO BUTEN-2-OIC ACID, AND THE COMPOSITIONS CONTAINING SAME
US4402978A (en) * 1980-04-24 1983-09-06 Roussel-Uclaf Gastro-protecting activity of substituted derivatives of 4-phenyl-4-oxo-2-hydroxy-butanoic acid
US4436752A (en) 1981-04-17 1984-03-13 Roussel Uclaf Treatment of gastric and gastro-duodenal disorders with derivatives of phenyl aliphatic carboxylic acids
US4473583A (en) * 1981-10-22 1984-09-25 Roussel Uclaf Compositions containing certain derivatives of 4-phenyl-4-oxobuten-2-oic acid and methods of treatment using them
US4486429A (en) * 1981-10-22 1984-12-04 Roussel Uclaf Amino derivatives of 4-phenyl 4-oxobuten-2-oic acid, pharmaceutical compositions containing them, and methods for preparing and therapeutically using them
US4594443A (en) * 1983-08-25 1986-06-10 Roussel-Uclaf Derivatives of 4-phenyl-4-oxo-buten-2-oic acid and therapeutic use thereof
WO1986006586A1 (en) * 1985-05-03 1986-11-20 Chemex Pharmaceuticals, Inc. Pharmaceutical vehicles for recucing transdermal flux
US4814348A (en) * 1983-01-24 1989-03-21 Roussel Uclaf Therapeutic compositions containing derivatives of acrylic acid having an oxygen-containing heterocycle, therapeutic treatment therewith and new compounds

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Publication number Priority date Publication date Assignee Title
US1779258A (en) * 1925-04-03 1930-10-21 Du Pont Resistant material
US2322760A (en) * 1942-02-20 1943-06-29 Du Pont Composition and method
US2466663A (en) * 1944-10-20 1949-04-05 Ward Baking Co Fungicide containing caprylic acid and its salt

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1779258A (en) * 1925-04-03 1930-10-21 Du Pont Resistant material
US2322760A (en) * 1942-02-20 1943-06-29 Du Pont Composition and method
US2466663A (en) * 1944-10-20 1949-04-05 Ward Baking Co Fungicide containing caprylic acid and its salt

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3105850A (en) * 1959-06-24 1963-10-01 Spofa Vereinigte Pharma Werke Process of preparing beta-4-methoxybenzoyl-beta-haloacrylic acids
US4154817A (en) * 1974-07-02 1979-05-15 Kao Soap Co., Ltd. Smell-removing and deodorizing composition and process of using same
US4483868A (en) * 1980-04-24 1984-11-20 Roussel Uclaf Gastro-protecting activity
DE3116416A1 (en) * 1980-04-24 1982-04-01 Roussel-Uclaf, 75007 Paris "USE OF SUBSTITUTED DERIVATIVES OF 4-PHENYL-4-OXO-2-BUTENIC ACID AS A MEDICINAL PRODUCT"
US4402978A (en) * 1980-04-24 1983-09-06 Roussel-Uclaf Gastro-protecting activity of substituted derivatives of 4-phenyl-4-oxo-2-hydroxy-butanoic acid
FR2481118A1 (en) * 1980-04-24 1981-10-30 Roussel Uclaf APPLICATION AS MEDICAMENTS OF DERIVATIVES SUBSTITUTED WITH PHENYL-4-OXO-2-BUTENOIC ACID
US4436752A (en) 1981-04-17 1984-03-13 Roussel Uclaf Treatment of gastric and gastro-duodenal disorders with derivatives of phenyl aliphatic carboxylic acids
FR2515037A1 (en) * 1981-10-22 1983-04-29 Roussel Uclaf AS MEDICINES, CERTAIN MONO-SUBSTITUTED DERIVATIVES OF 4-PHENYL 4-OXO BUTEN-2-OIC ACID, AND THE COMPOSITIONS CONTAINING SAME
US4454155A (en) * 1981-10-22 1984-06-12 Roussel Uclaf Pharmaceutical compositions containing a mono-substituted derivative of 4-phenyl-4-oxobuten-2-oic acid, and methods of using them in treating gastric and gastroduodenal ailments
US4473583A (en) * 1981-10-22 1984-09-25 Roussel Uclaf Compositions containing certain derivatives of 4-phenyl-4-oxobuten-2-oic acid and methods of treatment using them
US4486429A (en) * 1981-10-22 1984-12-04 Roussel Uclaf Amino derivatives of 4-phenyl 4-oxobuten-2-oic acid, pharmaceutical compositions containing them, and methods for preparing and therapeutically using them
US4814348A (en) * 1983-01-24 1989-03-21 Roussel Uclaf Therapeutic compositions containing derivatives of acrylic acid having an oxygen-containing heterocycle, therapeutic treatment therewith and new compounds
US4594443A (en) * 1983-08-25 1986-06-10 Roussel-Uclaf Derivatives of 4-phenyl-4-oxo-buten-2-oic acid and therapeutic use thereof
WO1986006586A1 (en) * 1985-05-03 1986-11-20 Chemex Pharmaceuticals, Inc. Pharmaceutical vehicles for recucing transdermal flux

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