US2675404A - Therapeutic salts of vanillic acid esters - Google Patents
Therapeutic salts of vanillic acid esters Download PDFInfo
- Publication number
- US2675404A US2675404A US275690A US27569052A US2675404A US 2675404 A US2675404 A US 2675404A US 275690 A US275690 A US 275690A US 27569052 A US27569052 A US 27569052A US 2675404 A US2675404 A US 2675404A
- Authority
- US
- United States
- Prior art keywords
- salt
- vanillate
- soluble
- water
- solution
- 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
Links
- 150000003839 salts Chemical class 0.000 title claims description 28
- 230000001225 therapeutic effect Effects 0.000 title description 9
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical class COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 title 1
- -1 ALKALI METAL SALT Chemical class 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 14
- 229910052783 alkali metal Inorganic materials 0.000 claims description 13
- BVWTXUYLKBHMOX-UHFFFAOYSA-N methyl vanillate Chemical compound COC(=O)C1=CC=C(O)C(OC)=C1 BVWTXUYLKBHMOX-UHFFFAOYSA-N 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 241000282414 Homo sapiens Species 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 9
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 9
- MWAYRGBWOVHDDZ-UHFFFAOYSA-N Ethyl vanillate Chemical compound CCOC(=O)C1=CC=C(O)C(OC)=C1 MWAYRGBWOVHDDZ-UHFFFAOYSA-N 0.000 description 8
- 150000003863 ammonium salts Chemical class 0.000 description 8
- 241000223205 Coccidioides immitis Species 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 150000001340 alkali metals Chemical class 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- 241000228404 Histoplasma capsulatum Species 0.000 description 4
- 206010020144 Histoplasmosis disseminated Diseases 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 201000003486 coccidioidomycosis Diseases 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- WKOLLVMJNQIZCI-UHFFFAOYSA-M vanillate Chemical compound COC1=CC(C([O-])=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-M 0.000 description 2
- 241000223203 Coccidioides Species 0.000 description 1
- 201000002563 Histoplasmosis Diseases 0.000 description 1
- 101100161752 Mus musculus Acot11 gene Proteins 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007775 late Effects 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
- C07C69/92—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring with etherified hydroxyl groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Patented Apr. 13, 1954 THERAPEUTIC SALTS F VANILLIGACID ESTERS.
IrwinA'. Pearl,Appleton, Wis., assignor to The "Institute of P'aper Chemistry, Appleton, 'Wis.,
a corporation 'of Wisconsin No .Drawing. Application March 8,1952, Serial No. 275,690
' Claims;
In general, "the present invention relates to products which are effective against histoplasma capsulatum and coccidioi des immitis and, more particularly,'the invention relates to water soluble salts of alky1 vanillates which are therapeutically effective against disseminated histoplasmosis and coccidioidomycosis.
In recent years,investigations have shown that the lower-alkyl (less than eight carbon atoms) vanillates are effective against histoplasma capsulatum and coccidioides immitis so that certain infections such as disseminated histo-plasmosis and coccidioidomycosis may be effectively treated through the use of ethyl vanillate and other lower alkyl vanillates. Indeed, several-"case histories have dramm'atically illustrated the general effectiveness of these lower alkyl vanillates against disseminated histop-lasmosis.
However, since the lower alkyl vanillates .are
not water-soluble, it has been'necessary to dissolve the alkylvanillates in olive oil, a 40 per cent solution usually being'prepared, in order to administer the lower alkylvanillates to human beings. The olive oil-vaniliate solution then. has been given orally. Suchadministration of the vanillates has been necessary because, as pointed has'been a relatively smallmargin between therapeutically effective doses of the loweralkyl vanillates and the doseswhich are toxic. "The problem, therefore, has-been to .broaden. the margin. so as to make possible establishment of higher levels of thea'lkyl'vanillatesin the human system while at the same time keeping the amounts ofvanillates administered to human beings below toxic levels.
Accordingly, an object of the present invention is to provide new compounds which may be injected into the human system in a manner such that increased amounts of the alkyl vanillates may be introduced into the human system without causing toxicity. As will appear hereinafter, this and other objects of the invention are accomplished by the formation of an alkali metal salt of the lower alkyl (less than eight carbon atoms) vanillates which is water soluble and which will 2 break up in the human system so as'to free the alkyl vanillates from the alkali metal 'so that it may be therapeutically effective'against histoplasmosis and coccidioidomycosis. As used herein, the term alkali metal shall consist of sodium, potassium, lithium and ammonium.
'In preparing the salts of the invention, an alkali 'metal lower alk'ylate (one to four carbon atoms) is usuallyjpreparecl and the alkylate is then combined with a lower alkyl vanillate, causing a precipitate to :be formed. However, the am.- monium salt is usually made by'introducing ammonia gas into a lower alkyl vanillatesolution,
thereby producing a precipitate. The precipitate comprises an alkali metal salt of the alkyl vanillate. The mixture is .filtered and the precipitate washed with an alcohol andthen with ether. After washing, the precipitate is dried and may then be dissolved .in distilled water and used against histoplasma capsulatum and coccidioides immitis.
The salts of potassium and lithium are not generally satisfactory for therapeutic use in human beings and therefore, for such therapeutic purposeathe lower alkylvanillate salts of sodium and ammonium are preferred. The alkali metal salts are solubleinwater, as indicated, but the alkali metal separates from the alkyl vanillate when neutralized. Accordingly, when an alkali metal .salt of a lower alkyl vanillate is introduced intramusculaizly, intravenously, or subcutaneously into human beings, the lower valkyl vanillate separates .fromthe alkali metal and is in a free form to act against histo plasma-capsulatum and coccidioides .immitis.
Ithas been found that of the lower alkyl vanil- 1 lates, .iso-butyl vanillate. is particularly effective um saltsof these alk'yl vanillates. are preferably made for. .use treating human beings.
As a specific example of the preparation of the salt of the invention, a solution of sodium ethylate was first prepared by placing 42.7 grams of metallic sodium. in 2500 cc. of absolute ethanol under reflux conditions. After reflux, the solution was cooled and was then mixed with a cold solution (15 C.) of iso-butyl vanillate which had been dissolved in 1250 cc. of absolute ethanol. Mixing of the two solutions was accomplished by stirring and, after a few minutes of stirring, the mixture became thick with fine white needles of the sodium salt of iso-butyl vanillate. The cooled mixture was filtered and the precipitate washed with cold anhydrous ethanol and then with large volumes of absolute ether. After washing with the ether, the sodium salt of isobutyl vanillate was dried. The salt was relatively stable and was very soluble in water, the salt giving a clearsolution having a pH between and 11. It was found that the iso-butyl vanillate precipitated from an aqueous solution by the addition of acid to the point where the solution was substantially neutral. I
As another example of the preparation of a salt of the invention, a solution comprising 340 grams of iso-butyl vanillateand 1500 cc. of absolute ether was prepared. The solution was prepared. in a flask and dry ammonia gas was bubbled into the flask until it became almost solid with a white granular precipitate. The precipitate was filtered and thoroughly washed with cold C.) anhydrous ether and then air dried. In this manner; 89 grams of the am- .monium salt of iso-butyl vanillate was prepared,
the salt having a slight ammoniacal odor and being soluble in water. The aqueous solution had a pl-I-of about 9.
trate again treated with the ammonia gas.
Finally, 364 grams of pure ammonium salt of isobutyl vanillate was obtained.
The ammonium salt is somewhat more satisfactory for use in the treatment of human beings because of its lower pH and, consequently, lower alkalinity. Y
The ammonium salt of ethyl vanillate was prepared by preparing a solution ofBOO grams. of ethyl vanillate in 1500 cc. of absolute ether. This solution was then treated with dry ammonia gas and the precipitate recovered as inv the previous example.
' The ammonium salt of n-propyl vanillate was made by first preparing a cold solution of 300 grams of n-propyl vanillate in 1500 cc. of absolute ether. This solution was also treated with dry ammonia gas until the flask containing the solution became solid with the ammonium salt of n-propyl vanillate. The salt was filtered and washed with absolute ether and air dried. The filtrate was again treated with ammonia gas to recover additional amounts of ammonium salt n-propyl vanillate. V
The lithium and potassium salts of the lower alkyl vanillates may be prepared by first preparing a solution of potassium or lithium ethylate, this being accomplished by placing 1.9 moles and combined with a cold solution comprising about two moles of a lower alkyl vanillate and 1250 cc. of absolute ethanol. When these solutions are combined, the potassium or lithium salt will precipitate and may be recovered by filtering. A more pure salt may be had by washing the filtered salt with ether and air drying the product.
In the foregoing, I have disclosed certain products which have unusual value in the treatment of disseminated histoplasmosis and coccidioidomycosis. These products may be easily administered to human beings and higher efiective therapeutic levels may be achieved in the human body without danger of toxicity.
The various products which are believed to be new are set forth in the following claims.
I claim:
1. An alkali metal salt of a lower alkyl vanillate, said salt being in crystalline form and being soluble in water in amounts suflicient to provide a therapeutically active composition.
2. The sodium salt of a lower alkyl vanillate, said salt being in crystalline formandbeing soluble in water in amounts suflicient to provide a therapeutically active composition.
3. The ammonium salt of a lower alkyl vanillate, said salt being in crystalline form and being soluble in water in amounts sufficient to provide a therapeutically active composition.
4. An alkali metal salt of ethyl vanillate, said salt being in crystalline form and being soluble in water in amounts sufficient to provide a therapeutically active composition.
5. An alkali metal salt-of iso-butyl vanillate, said salt being in crystalline form and being soluble in water in amounts sufficient to provide a therapeutically active composition.
6. An alkali metal salt of n-propyl vanillate, said salt being in crystalline form and being soluble in water in amounts sufficient to provide a therapeutically active composition.
7. A therapeutic compound comprising the'sodium salt of iso-butyl vanillate, said salt being in crystalline form and being soluble in water in amounts suflicient to provide a therapeutically active composition. a
8. A therapeutic compound comprising the ammonium salt of iso-butyl vanillate, said salt being in crystalline form and being soluble in water in amounts suflicient to provide a therapeutically active composition.
9. A therapeutic compound comprising the sodium salt of n-propyl vanillate, said salt being in crystalline form and being soluble in water in amounts sufiicient to provide a therapeutically active composition, a
10. A therapeutic compound comprising the ammonium saltof n-propyl vanillate, said salt being in crystalline form and being soluble in water in amounts sumcient to provide a therapeutically active composition.
References Cited in the file of this patent .Tiemann et al., Ber. Deut. Chem., 10, 59-60 (1877).
Claims (1)
1. AN ALKALI METAL SALT OF A LOWER ALKYL VANILLATE, SAID SALT BEING IN CRYSTALLINE FORM AND BEING SOLUBLE IN WATER IN AMOUNTS SUFFICIENT TO PROVIDE A THERAPEUTICALLY ACTIVE COMPOSITION.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US275690A US2675404A (en) | 1952-03-08 | 1952-03-08 | Therapeutic salts of vanillic acid esters |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US275690A US2675404A (en) | 1952-03-08 | 1952-03-08 | Therapeutic salts of vanillic acid esters |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2675404A true US2675404A (en) | 1954-04-13 |
Family
ID=23053407
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US275690A Expired - Lifetime US2675404A (en) | 1952-03-08 | 1952-03-08 | Therapeutic salts of vanillic acid esters |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2675404A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5686406A (en) * | 1994-06-24 | 1997-11-11 | Rhone-Poulenc Chimie | Vanillic acid ester perfuming agents |
-
1952
- 1952-03-08 US US275690A patent/US2675404A/en not_active Expired - Lifetime
Non-Patent Citations (1)
| Title |
|---|
| None * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5686406A (en) * | 1994-06-24 | 1997-11-11 | Rhone-Poulenc Chimie | Vanillic acid ester perfuming agents |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0001584B1 (en) | Hydroxydiphosphonic acids, process for their preparation and their use as complex-forming agents | |
| DE2534390A1 (en) | 1,3-DI-AMINOALKANE-1,1-DIPHOSPHONIC ACIDS | |
| US2675404A (en) | Therapeutic salts of vanillic acid esters | |
| US2144552A (en) | Alkanol-amine salt of mandelic acid | |
| DE1168441B (en) | Process for the production of a polyaminopolyacetic acid and its complex metal compounds | |
| US2767207A (en) | Beta (n-propylamino)beta, beta-dimethyl ethyl benzoate and its water-soluble salts | |
| US3899521A (en) | Complex compounds of aspartic acid with a rare earth metal and zinc | |
| US2850426A (en) | Anthelmintic piperazine-phosphoric acid compositions and method of combatting helminth infestations therewith | |
| DE2050072C3 (en) | Aluminum tri-3-acetyl-18 betaglycyrrthetinate, process for its preparation and pharmaceutical preparations containing it | |
| DE829166C (en) | Process for the preparation of N- (p-arsenosobenzyl) glycine amide and its salts | |
| DE2606298A1 (en) | DERIVATIVES OF 2-IMINO- AND 2-THIOXO- 5-CARBOXYALKYLBARBITURIC ACID, THEIR SALT, THEIR MANUFACTURING PROCESS AND PHARMACEUTICAL AGENTS | |
| DE2636346C2 (en) | Anhydrous sodium acetylsalicylic acid in the form of plate-like crystals, processes for its preparation and medicinal products containing it | |
| IE34307B1 (en) | New 1-alkyl-6-azauracil compounds and preparations which contain a 1-alkyl-6-azauracil compound as an active ingredient | |
| US2261188A (en) | Stabilized form of vitamin b6 and process of preparing the same | |
| GB1569380A (en) | Pharmaceutical compositions comprising substituted phenyl-amino-alcohol and process for preparing these compositions | |
| DE2745084A1 (en) | 5-Keto-piperazine-2,2-di:phosphonic acid derivs. - useful as chelating agents e.g. in water treatment, for providing trace elements and treating metabolic disorders | |
| DE913171C (en) | Process for the preparation of amine salts of penicillin | |
| US2104738A (en) | Bismuth allantoinate and process of making it | |
| US3681437A (en) | Citrates of 5-(z-dimethylaminoethoxy)carvacrol acetate | |
| CH613952A5 (en) | Process for the preparation of N,N'-bis(3-picolyl)-4-methoxy-isophthalamide | |
| DE1107230B (en) | Process for the preparation of bispenicillin compounds of sulfonamides | |
| DE2351859A1 (en) | SALT OF POLYSULFUR ACID ESTERS OF GLYCOPEPTIDES WITH AMINO ACIDS | |
| DE865453C (en) | Process for the preparation of non-hygroscopic choline salts | |
| US2351844A (en) | Chlorocaffeine nitrate and nitrite and process of making them | |
| US3312701A (en) | 3-chlorophyridazone-(6)-1-acetic acid diallylamide |