|Publication number||US2319481 A|
|Publication date||May 18, 1943|
|Filing date||May 31, 1941|
|Priority date||May 31, 1941|
|Publication number||US 2319481 A, US 2319481A, US-A-2319481, US2319481 A, US2319481A|
|Inventors||William B Stillman, Albert B Scott, Clampit James Marion|
|Original Assignee||Norwich Pharma Co|
|Export Citation||BiBTeX, EndNote, RefMan|
|Referenced by (21), Classifications (5)|
|External Links: USPTO, USPTO Assignment, Espacenet|
Patented May 18, 1943 Norwich Pharmacal Company, Norwich, N. Y., a corporation of New York No Drawing, ApplioationMay 31, 1941,
Serial No. 396,152 r I Chin's. (Cl. 161-83) The present invention relates primarily to antiseptics, i. e.compounds which restrain or inhibit the growth of putrefactive micro-organisms, and is concerned more particularly with'antiseptics oi the iuran series-specifically nitrofurans.
Antiseptics are, of course, known. However, they are frequently bound up with undesirable characteristics, such as toxicity, tendency toward they are applied, lack oi. stability, insolubility, etc. These undesirable characteristics are, in general, ascribable to the presence conventional.
T undue irritation of or injury to tissue to which ly in most antiseptics, of toxic heavy metals (e. g.
mercurials), phenolic hydroxyl groups e. 3. antiseptics of the phenol type), halogens (iodineor the like), etc. a
A desideratum relative to antiseptics is that they shall be free of defects of known substances of the character above outlined, i. e. that the antiseptics shall be non-toxic, relatively non-irritant, non-corrosive, stable and soluble, without however, sacrificing relative antiseptic activity.
A primary object of this invention therefore is to provide a new series of organic antiseptics which shall fulfill the above characterized desideratum. a i 1 The invention is based upon the surprising and unexpected discovery that the nitrof-urans comprise compounds which possess marked antiseptic activity without entailing the prejudicial characteristics of toxicity, undue irritativeness,
, etc., to which reference has above been made.
More specifically stated, it has been found that outstanding antiseptic activity of useful character can be realized from a wide variety of furan compounds provided that these compounds contain 9. nitro group in an a-position, i. e. in the 2- or fi-position in the furan ring. It is within the scope of the present invention that these nitroiuran compounds may be substituted in at least one of the remaining alpha (2 or 5) and beta positions 3 and 4 by hydrogen, or an alkyl, hydroxyalkyl, acyloxyalkyl, oximidoalkyl, semicarbozonoalkyl, hydrazonoalkyl, diacyloxyalkyl, carbo'xyalkenyl, carbalkoxyaikenyl, acyl, carbalkoxy, halogeno-carbalkoxy, carbamyl, or dialkyicarbamyl radical or the like.
The preperred derivatives of nitrofuran within the scope of the present invention mayconveniently be represented by the following chemical formula:
Nov-UR 0 wherein R represents the aforementioned wide variety of substituents of which the following speciflc ones may be cited by way of example:
CH=CHCOOCaHa 00cm, oocnn; cocam, V
. COOCHa, COOCaI-Is, COOCHaCHaCl,
The organic antiseptics according to the present invention may be used, severally or in admixture, for example as constituents of aqueous antiseptics, antiseptic tinctures, antiseptic creams and ointments, deodorants and other pharmaceutical preparations. In some cases, the compounds of the present invention may impart. preservative and/or bactericidal properties to the preparations into which they are incorporated.
An advantageous characteristic of the nitrofurans which come within the purview of this invention is; their solubility in simple solvents frequently used in pharmaceutical preparations, e. 8. water, oil, etc. The solubilities are, in general, of a magnitude to make it possible to use aqueous solutions as well as ointments of essentially, oiLv,
base in actual practice and in making tests of the character hereinafter set forth. By way of illustration, aqueous antiseptic preparations and antiseptic ointments may be produced as follows, according to the present invention:
Preparation of 2-formyl-5-nitr0furan (ii-acetate and aqueous antiseptic solution A nitrating mixture of 60 cc. acetic anhydrlde and 27 cc. fuming nitric acid (sp. gr. 1.5) is stirred at --5 C. while a solution of 16 grams of furfural diacetate in cc. of acetic anhydride is added dropwise. Stirring is continued 1 hour after addition is complete, and the mixture poured onto 250 grams of crushed ice. The oil is separated, more is obtained by ether extraction of the aqueous layer, and the final ether solution containing all the oil is washed thoroughly with sodium bicarbonate and then twice with water. The ether is removed and an equal volume of pyridine is added. Vigorous reaction occurs. The solution is then poured onto ice, diluted to one liter, and chilled. The solid product is filtered and recrystallized twice from petroleum ether. White crystals M. P. 91-92 C. Yield=4 grams or An aqueous antiseptic solution is readily prepared by dissolving 1 gram in one liter of hot water and filtering. This solution will give a cup plate zone of 8 mm. (F. D. A. method- Staph. aureus).
Preparation of antiseptic ointments containing nitrofuran stearate, the nitroi'uran can be incorporated into the glyceryl monostearate.
ANTISEPTIC ACTIVITY OF NITROFURANS The nitrofuran derivatives above indicated as coming within the purview of this invention, and
many others, have been prepared and subjected, among other things, to a test for inhibitory antiseptic activity according .to the standard cup plate method (described in Circular No. 198, U. S. Department of Agriculture, Food and Drug Administration, December 1931), and .have been found to be excellent antiseptics.
The following Table I sets forth the results obtained according to the said standard cup plate method (F. D. A. Circular 198) with aqueous solutions of representative compounds according to this invention in connection with Staphylococcus aureus. The cup plate results shown are expressed in terms of mm. of clear zone (1. e. zone in which the growth of bacteria is inhibited), and show the penetration as well as the inhibitory action on Staphylococcus aureus. The Kolmer test on Staph. aureus, also shown in Table I, represents the maximum dilution at v which the antiseptic still inhibits the growth of the bacteria.
Tenn 1 Cup plate antiseptic tests and Kolmer test for inhibitory action Staph. aumn cup Staph. Compound Gonc. i K aureua (aqueous) 81; f Kolmer antiseptic dilution action) LIT". 1 Zearbcthoxy-5-nitrofuran. 1: 500 4. 0 m
2 t 1:. 1 f H880 it? 1 -ace y m ro uran mm 12.0 1 Z-butyryl-S-mtroluran. 1:2500 9. 0 1:5000 1.0 9
2 lormyl 5 nitrofuran diacetate 121000 8.0
2-ethyl-5-nitroiuran 1:500 11.0
2-propyl-5-nltroluran l: 1750 3. 0
N0te.--See Circular No. 198, U. S. Department 01 Agriculture, December 1931, Methods of Testing Antiseptics."
These results compare very favorably with the activity against Staphylococcus aureus in many of the best known prior art antiseptics.
THE amrsnprrc ACTIVITY IN DEODORANT CREAMS An important characteristic of the antiseptics of the present invention is their property of remalning effective in a deodorant cream with petrolatum or other ointment or cream base.
The following table sets forth results as to antiseptic activity obtained by the standard cup plate method (F. D. A. Circular 198) on Staphylococcus aureus with the following illustrative nitrofmran antiseptics in a deodorant cream containing a petrolatum base.
TABLE II Cup plate antiseptic tests on deodorant creams PERSISTENCE OF ACTIVITY IN DEODORANT CREAMS In the deodorant use of an antiseptic cream the ability of the antiseptic to remain active is of considerable importance. When deodorant creams with a petrolatum base containing nitroiuran antiseptics are spread on parchment and immersed in a broth inoculated with a mixed culture (Staph. aureus plu organisms from the human axilla), the persistence of antiseptic ac- -500,000 organisms. at 37 C.,- the, tube is observed for bacterial iuracrylate.
9,810,401 tion is remarkable. This is shown in Table III."
In this test for persistence of antiseptic action, 0.25 g. of the deodorant cream are spread evenlyover a 25 sq. cm. strip or parchment paper. The parchment paper is then placed in a culture tube containing 10 cc. of artificial perspiration (culture broth) which has been inoculated with,
a mixed culture (Staph. aureus plus organisms from the human axilla), using approximately Alter, hours incubation growth, the paper is transferred to a fresh tube.
incubatedand' the transfer-process repeated until bacterial growth occurs. The tubesare incu-' bated at '37? C. torso-hours atterthe transfer and observed for delayed-growth. The persistcream is measured by the number of transfers possible before growth is observed. vA "+-sign TAIL: III
A Third I transfer Second transfer First Cone. transfer Compound 48 hrs.
Per 2-carbethoxy-5- nitroiuran. 2-ocetyl-5-nitro ursn. Ethyl b-nitrollllllll llllll'll illi l iii llllllil iliillll llil llH-l IHH+|++ ii-nitro-iuracryllc acid.
FUNGISTATIC ACTION 'ence of antiseptic emciency oithedeodorant 01' Laboratory and Clinical Medicine, 25, 1199-1204 (1940). Tsar: V Trmn blue irritation studies (rabbit) toxicity (intraperitoneal) Sate concentration Toxicity Outta peritoneal) Solub. (up fmmflon) Compound in water mm Saline tro- Rat Rabbit tum 2 carbcthoxy 5 nlfloluranufleu 115000 1:5000 1:250 800 700 Ethyl 5 nitroiurscrylate 1:30) 1:3(1!) 1:250 850 500 2-scetyl-5-nitro- 1:3(1) 1:300 1:1000 200 50 'z-rropionyl-fin ttoluran lzfill) 121000 1:250 250 100 z-but'yryld-nitmiuran .mooo 1:1000 300 150 lti axlrn uin soluhillty.-
' a 1 NITROFURANS IN OINTMENTS The intravenous dye test for vascular permeability due to irritants is a well known laboratory method of testing for irritation. See, for example, A method for the quantitative estimation of chemical irritation," J. H. Weatherby, Journal Still another important characteristic of nitrofuran's .within thescope of this invention is the property which they exert, when incorporated into ointments, "of imparting high antiseptic which is exhibited thereby. Results obtained with some of the more active nitrofuran antiseptics, when tested at a concentrationof 1:500 in a cream with a petrolatumbase, are shown in Table IV. The cup plates were incubated 48 hours at room temperature.
TABLE IV Funaistatic action of deodorant creams (petrolatum base) Trichophyton room-sum cup plate zone Concentration in Compound cream v bl'm. 2-csrbethox -5-nitroflzran 2-scetyl-5n troi'uran l8 Dibutyl B-nitroiuramide intravenous Trypan blue.
NON-IRRITANT AND NON-TOXIC CHARA C- TER OF NI'I'ROFURAN ANTISEPTICS The relatively non-irritant and non-toxic standard irritation. Toxicity was obtained by intraperitoneal administration of the solid compound in a gelatin capsule. The toxicity is' given as the level at which 50% of the test animals die.
power (as shown in tests according to the aforementioned standard cup plate method) while involving an extremely and unusually low toxicity (as determined in tests on laboratory animals); r
Thus, nitrofurans such, for example, as 2- acetyl- 5-nitrofuran and 2-propionyl-5-nitrofuran in a petrolatum base ointment at an antiseptic concentration of 1.:1000 produce, in the cup. platetest, clear zones of 10 mm. or more.
The corresponding toxicity in the rat (level at Goodresults are also obtainable, for example,
with 2 ethyl-5-nitrofuran and 2-propyl-5-nitro- Among the new compoundsdeveloped in this work the most active, usefulv antiseptics are 2-formyl-5-nit-rofuran semicarbazone, 2-propionyl-5-nitrofuran, 2-butyryl-5-nitrofuran and 2-ethyl-5-nitrofuran. In the preparation of one of these new compounds. namely, 2-propionyl-5- nitrofuran, the nitration step is typical of the procedure used on all of the nltrofuran antiseptics."
One mole of aluminum chloride is mixed with l250cc. carbon disulfide and one mole of propionyl chloride in a 3-neck, 3-liter flask. A solution of 74 cc. of furan in 250 cc. carbon disulfide is added slowly. Temperature is held at 10 C. At the end of the addition, the mixture is stirred 1 hour at room temperature and then poured onto cracked ice. The carbon disulfide is distilledofl' and the residue steam distilled. The
distillate is made alkaline, extracted with ether and the ether extract washed and dried. Propionyl furan, B. P. 81.2 C. Yield=50 grams of propionyl furan in 50 cc. acetic anhydride is run in slowly at 5 C., the mixture stirred for /2 hour and poured onto cracked ice. The product is extracted twice with ether (150 cc.) and 50 cc. pyridine added to the ether extract. The solution is warmed to start the reaction and diluted with water when reaction is complete.
2-pro- White crystals M. P.
An aqueous antiseptic solution can be prepared from 2-propionyl-5-nitrofuran by dissolving 1 gram in 600 cc. of hot water and filtering. This solution will give a cup plate zone of 16.5 (Staph. aureus) and 16.0 mm. (Bact. typhosum).
It is apparent from the foregoing that the present invention makes available a new series of organic antiseptics which are non-corrosive and practically non-irritant. These new antiseptics do not contain a heavy metal, such as mercury, nor do they contain the phenolic hydroxyl group. The new antiseptics possess lower toxicity than commonly used antiseptics. They are sufilciently soluble and stable to be of practical use in aqueous antiseptics, in antiseptic tinctures, in antiseptic creams and ointments, in deodorants, etc.
It will of course be understood that the antiseptic action of the furan derivatives according to the present invention is not limited to the bacteria above employed by way of example but that such antiseptic action extends also to various other bacteria such as Bact. typhosum, etc.
Having described the invention, what is claimed is:
1. A pharmaceutical preparation having bacteria-growth inhibiting properties and containing, as the essential active ingredient, a nitrofuran of the formula of the formula rim-l "-0 0x 0 wherein X represents alkyl.
3. A pharmaceutical preparation having bacteria-growth inhibiting properties and containing as the essential active ingredient, a nitrofuran of the formula Nol L000):
wherein X represents alkyl.
4. A pharmaceutical preparation having bacteria-growth inhibiting properties and containing as the essential active ingredient, a nitrofuran of the formula wherein Y represents acyloxy.
5. A pharmaceutical preparation having bacteria-growth inhibiting properties and comprising an aqueous solution containing, as the essential active ingredient, a nitrofuran of the formula NoJL R wherein R represents a member of the group consisting of hydrogen and the alkyl-hydroxyalkyl, acyloxyalkyl, oximidoalkyl, semicarbazonoalkyl, hydrazonoalkyl, diacyloxyalkyl, carboxyalkenyl, carbalkoxyalkenyl, acyl, carbalkoxy, halogenocarbalkoxy, carbamyl and dialkylcarbamyl radicals.
6. A deodorant composition containing, as the essential active ingredient, a nitrofuran of the formula Nor-l LB wherein R represents a member of the group consisting of hydrogen and the alkyl, hydroxyalkyl, acyloxyalkyl, oximidoalkyl, semicarbazonoalkyl, hydrazonoalkyl, diacyloxyalkyl, carboxyalkenyl, carbalkoxyalkenyl, acyl, carbalkoxy, halogeno-carbalkoxy, carbamyl and dialkylcarbamyl radicals,
'7. A pharmaceutical preparation having bacteria-growth inhibiting properties and comprising the ointment base having homogenously dispersed therethrough, as the essential active ingredient, a nitrofuran of the formula No l 1R wherein R represents a member of the group consisting of hydrogen and the alkyl, hydroxyalkyl, acyloxyalkyl, oximidoalkyl, semicarbazonoalkyl, hydrazonoalkyl, diacyloxyalkyl, carboxyalkenyl, carbalkoxyalkenyl, acyl, carbalkoxy, halogenocarbalkoxy, carbamyl and dialkylcarbamyl radicals.
WILLIAM B. STILLMAN.
ALBERT B. SCOTT.
J. MARION CLAMPIT.
|Citing Patent||Filing date||Publication date||Applicant||Title|
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|US2847424 *||Jul 3, 1953||Aug 12, 1958||Norwich Pharmacal Comopany||Halogenated esters of nitrofurfuryl alcohol|
|US2890982 *||Oct 30, 1956||Jun 16, 1959||Norwich Pharma Co||Method of combatting helminthiasis using nitro-furyl-acrylate derivatives|
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|US3470096 *||Aug 24, 1965||Sep 30, 1969||Nalco Chemical Co||Synergistic mixtures for control of slime-forming bacteria and other deleterious micro-organisms and processes using same|
|US3723477 *||May 15, 1970||Mar 27, 1973||Morton Norwich Products Inc||4-fluoro-3-methylphenyl 5-nitro-2-furyl ketone|
|US3910839 *||Nov 2, 1972||Oct 7, 1975||Kemira Oy||Slime inhibitor for use in industrial water recirculating systems|
|US4564362 *||Jul 7, 1983||Jan 14, 1986||Burnhill Michael S||Vaginal device|
|US4601714 *||Mar 7, 1984||Jul 22, 1986||Burnhill Michael S||Vaginal device|
|US5112382 *||May 24, 1990||May 12, 1992||Rohm And Haas Company||Halopropargyl compounds, compositions, uses and processes of preparation|
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|DE1119295B *||Feb 12, 1959||Dec 14, 1961||Norwich Pharma Co||Verfahren zur Herstellung von 5-Nitro-furfuryliden-(2)-derivaten|
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|U.S. Classification||424/76.8, 549/482, 549/481, 514/471|