US2562208A - Fungistatic composition - Google Patents
Fungistatic composition Download PDFInfo
- Publication number
- 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
- Authority
- US
- United States
- Prior art keywords
- compound
- acrylic acid
- acid
- maleic anhydride
- recrystallization
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 239000000203 mixture Substances 0.000 title claims description 17
- 230000001408 fungistatic effect Effects 0.000 title claims description 8
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 15
- 239000006071 cream Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical class [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 description 38
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 24
- -1 aroyl acrylic acids Chemical class 0.000 description 20
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 20
- 229940044600 maleic anhydride Drugs 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 238000001953 recrystallisation Methods 0.000 description 17
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 description 14
- 239000000155 melt Substances 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 10
- 238000002844 melting Methods 0.000 description 10
- 230000008018 melting Effects 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 239000004215 Carbon black (E152) Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 229930195733 hydrocarbon Natural products 0.000 description 7
- 150000003751 zinc Chemical class 0.000 description 7
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010022678 Intestinal infections Diseases 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 229940060367 inert ingredients Drugs 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 238000001256 steam distillation Methods 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- PLPDHGOODMBBGN-VOTSOKGWSA-N (e)-4-oxo-4-phenylbut-2-enoic acid Chemical compound OC(=O)\C=C\C(=O)C1=CC=CC=C1 PLPDHGOODMBBGN-VOTSOKGWSA-N 0.000 description 1
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 1
- AFRCOPXXVKHTOI-UHFFFAOYSA-N 2-(4-chlorobenzoyl)prop-2-enoic acid Chemical compound OC(=O)C(=C)C(=O)C1=CC=C(Cl)C=C1 AFRCOPXXVKHTOI-UHFFFAOYSA-N 0.000 description 1
- SPMMMKHRSINRIN-UHFFFAOYSA-N 2-(4-methylphenyl)prop-2-enoic acid Chemical compound CC1=CC=C(C(=C)C(O)=O)C=C1 SPMMMKHRSINRIN-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- XLYMOEINVGRTEX-ARJAWSKDSA-N Ethyl hydrogen fumarate Chemical compound CCOC(=O)\C=C/C(O)=O XLYMOEINVGRTEX-ARJAWSKDSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 150000001253 acrylic acids Chemical class 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- POJOORKDYOPQLS-UHFFFAOYSA-L barium(2+) 5-chloro-2-[(2-hydroxynaphthalen-1-yl)diazenyl]-4-methylbenzenesulfonate Chemical compound [Ba+2].C1=C(Cl)C(C)=CC(N=NC=2C3=CC=CC=C3C=CC=2O)=C1S([O-])(=O)=O.C1=C(Cl)C(C)=CC(N=NC=2C3=CC=CC=C3C=CC=2O)=C1S([O-])(=O)=O POJOORKDYOPQLS-UHFFFAOYSA-L 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- IQFVPQOLBLOTPF-HKXUKFGYSA-L congo red Chemical compound [Na+].[Na+].C1=CC=CC2=C(N)C(/N=N/C3=CC=C(C=C3)C3=CC=C(C=C3)/N=N/C3=C(C4=CC=CC=C4C(=C3)S([O-])(=O)=O)N)=CC(S([O-])(=O)=O)=C21 IQFVPQOLBLOTPF-HKXUKFGYSA-L 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- XLYMOEINVGRTEX-UHFFFAOYSA-N fumaric acid monoethyl ester Natural products CCOC(=O)C=CC(O)=O XLYMOEINVGRTEX-UHFFFAOYSA-N 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- KVEDKKLZCJBVNP-UHFFFAOYSA-N n-(4-acetamidophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(NC(C)=O)C=C1 KVEDKKLZCJBVNP-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- DLRJIFUOBPOJNS-UHFFFAOYSA-N phenetole Chemical compound CCOC1=CC=CC=C1 DLRJIFUOBPOJNS-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- 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
Definitions
- 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)
- 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)
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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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 |
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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)
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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