US3290213A - Antibacterial nitrofurfurylidene derivatives and methods of using same - Google Patents

Antibacterial nitrofurfurylidene derivatives and methods of using same Download PDF

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US3290213A
US3290213A US208575A US20857562A US3290213A US 3290213 A US3290213 A US 3290213A US 208575 A US208575 A US 208575A US 20857562 A US20857562 A US 20857562A US 3290213 A US3290213 A US 3290213A
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nitrofurfurylidene
hydrazide
hydroxybenzoic acid
compound
antibacterial
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US208575A
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Carron Maurice Claude Ernest
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Lab Robert Et Carriere SA Des
LABORATORIES ROBERT ET CARRIERE SA
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Lab Robert Et Carriere SA Des
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/70—Nitro radicals
    • C07D307/71—Nitro radicals attached in position 5
    • C07D307/72—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2
    • C07D307/74—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2 by hydrazino or hydrazono or such substituted radicals
    • C07D307/75—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2 by hydrazino or hydrazono or such substituted radicals having carboxylic acyl radicals or their thio or nitrogen analogues directly attached to the hydrazino or hydrazono radical, e.g. hydrazides

Definitions

  • the present invention provides, as a new such derivative, the S-nitrofurfurylidene hydrazide of 4-hydroxy-benzoic acid; this compound has the formula:
  • This compound is prepared, in accordance with a feature of the invention, by reacting S-nitnofurfural with 4-hydroxybenzhydr-azide.
  • the reaction is conveniently effected in water or aqueous dimethyl formamide at temperatures between room temperature and the boiling point.
  • the compound of the invention has a bactericidal effect on a number of bacilli. This effect has been established by comparing the diameter of the inhibition circles produced in a culture of a given bacillus on agar-agar, under the effect of a known volume of solution containing a predetermined amount of the compound. The solution is introduced into small pits formed in the agar-agar.
  • the new compound was compared, on the one hand, with iodochlor-ohydroxyquine, a conventional intestinal antiseptic, and, on the other hand, with the corresponding Z-hydroxy compound.
  • the quantity of solute poured into each pit was 0.075 ml. After incubation for 18 hours in an oven at 37 C., the diameter of the inhibiton zones was measured.
  • the most active compound is the S-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid, which in one case (that of B. typhosum) has an effect not shared by the two comparison compounds.
  • the bacteriostatic power of the new compound was also tested by determining the lowest dose capable of inhibiting the development of the microorganism in question, when inoculated into a peptonised meat broth incubated at a temperature of 37 C. It was thus established that the 4-hydroxybelnzoic acid hydrazide exerts a powerful bacteriostatic activity in these circumstances.
  • the majority of Gram-negative bacilli, particularly those of the colityphosum-dysenteriae group, were found to be greatly affected by the new nitrofurfurylidene compound. The same is true with staphylococci.
  • B. proteus and B. pyocyaneus are scarcely affected by the new compound.
  • the two comparison products i.e. iod-ochlorohydroxyquine and the S-nitrofurfurylidene hydrazide of Z-hydroxybenzoic acid
  • the product of the invention exerts a bacteriostatic effect in a concentration of 1 to 500,000
  • the 2-hydroxy isomer acts only in a concentration of 1 to 50,000 and iodochlorohydroxyquine only at 1 in 10,000.
  • the new compound is therefore 10 times as active on bacillus dysenteriae as its isomer and 50 times as active as iodochlorohydroxyquine.
  • the bacteriostatic effect of the compound of the invention on the anaerobic organisms, B. Putrificus, B. Perfringens and vibrion septique, is also greater than that of the two comparison compounds.
  • the S-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid has a bactericidal action on B. coll, B. typhosum and staphylococci, which are dead at the end of 8 hours of contact with a 1225,000 solution of the hydrazide in polyethylene glycol 300. Under the same conditions, iodoc'hlorohydroxyquine and the Z-hydroxy isomer have no bactericidal action.
  • the new compound has a very low toxicity, both when administered internally (by gastric probe as a suspension in aqueous agar) and when administered locally in the mouse, the LD 50 being at least 4.75 g./kg.
  • a study of the chronic toxicity in the rat revealed no toxic effects (on general behaviour, globule count, leucocyte distribution, or the viscera), and the stomach and intestine revealed no deterioration, which shows good acceptance by the mucous membrane.
  • EXAMPLE I 13 g. (0.1 mol) of 4-hydroxybenzhydrazide were dissolved in a boiling mixture of 100 ml. of water and an equal volume of dimethylformamide. 15.5 g. (0.11 mol.) of S-nitrofurfural dissolved in 31 ml. of dimethylform amide were added to this hot solution, and the mixture was stirred and brought to the boiling point.
  • the mixture was then allowed to stand for fifteen hours.
  • the precipitate was separated, washed twice with 100 ml. of water, and recrystallised by dissolving it in 250 ml. of hot pyridine and pouring this solution into 250 ml. of water.
  • the S-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid obtained was washed with water and methanol and was dried at a moderate temperature. It weighed 23 g. (83.7% yield), and melted at 298 C. The percentage nitrogen determined by the micro-Dumas method was 15.41% (theory 15.27%).
  • the hydrazide is separated, washed with water and dried in an oven at 50 C. There are thus obtained 30 g. of the hydrazide (a yield of 88%), which is purified by crystallisation from pyridine or fl-methoxyethanol.
  • the bactericidal effects of the new compound described above make it suitable for therapeutic use both internally and externally.
  • the invention includes within its scope pharmaceutical compositions comprising the 5- nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid in association with a pharmaceutical carrier.
  • compositions may be used in a form suitable for oral administration in the treatment of intestinal infec tions of microbial origin. Suitable compositions may also be used in proctology (suppositories), gynaecology (ovules), and dermatology (ointments). The new compositions are especially valuable for local application in cases of staphylococcal and streptococcal infection.
  • composition for example, be made as follows:
  • Each pill contains 0.10 g. of active substance.
  • Mucilaginous granules The following products are mechanically mixed:
  • This mixture is continuously stirred. There may be added thereto various medicaments such as anti-inflammatory agents, vasoconstrictors, and local anaesthetics. After these optional additions, the preparation is poured into suppository moulds. The further operations are performed by the usual methods.
  • Ovules 50 kg. of polyethylene glycol 1500 are melted on the water bath, and 0.250 kg. of S-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid is addedthereto. The mixture is stirred until it is completely dissolved, filtered and poured into an ovule mould.
  • a daily dose of 0.1 to 1.0 g. is generally ade-- quate, an amount between 0.4 and 0.6 g. being preferred.
  • a dose of 0.2 to 0.9 g. per 24 hours is ordinarily satisfactory.
  • a pharmaceutical composition comprising the 5- nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid in association with a significant amount of a pharmaceutical carrier.
  • a method of treating a subject having an infection caused by a microorganism selected from the group consisting of E. coli, B. zyphosum, B. dysenteriae, and Staphylococcus aureous which comprises administering to the infected subject an amount of S-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid sufiicient to control the infection, but in an amount insufiicient to cause toxic symptoms in said infected subject.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Description

United States Patent 67,839 6 Claims. (Cl. 167-55) This invention relates to nitrofurfurylidene derivatives having bactericidal properties.
The present invention provides, as a new such derivative, the S-nitrofurfurylidene hydrazide of 4-hydroxy-benzoic acid; this compound has the formula:
This compound is prepared, in accordance with a feature of the invention, by reacting S-nitnofurfural with 4-hydroxybenzhydr-azide. The reaction is conveniently effected in water or aqueous dimethyl formamide at temperatures between room temperature and the boiling point.
The compound of the invention has a bactericidal effect on a number of bacilli. This effect has been established by comparing the diameter of the inhibition circles produced in a culture of a given bacillus on agar-agar, under the effect of a known volume of solution containing a predetermined amount of the compound. The solution is introduced into small pits formed in the agar-agar.
The new compound was compared, on the one hand, with iodochlor-ohydroxyquine, a conventional intestinal antiseptic, and, on the other hand, with the corresponding Z-hydroxy compound.
In these experiments, the compounds under test were used as solutions having a weight concentration of 0.1% in polyethylene glycol 300 or dimethylformamide. It was established that the solvent did not by itself exert any inhibiting effect on the bacillus under the conditions of the experiment.
The quantity of solute poured into each pit was 0.075 ml. After incubation for 18 hours in an oven at 37 C., the diameter of the inhibiton zones was measured.
The following table shows the diameters of the inhibition circles:
It will be noted that the most active compound is the S-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid, which in one case (that of B. typhosum) has an effect not shared by the two comparison compounds.
The bacteriostatic power of the new compound was also tested by determining the lowest dose capable of inhibiting the development of the microorganism in question, when inoculated into a peptonised meat broth incubated at a temperature of 37 C. It was thus established that the 4-hydroxybelnzoic acid hydrazide exerts a powerful bacteriostatic activity in these circumstances. The majority of Gram-negative bacilli, particularly those of the colityphosum-dysenteriae group, were found to be greatly affected by the new nitrofurfurylidene compound. The same is true with staphylococci. On the other hand, B. proteus and B. pyocyaneus are scarcely affected by the new compound.
Under the same conditions, the two comparison products, i.e. iod-ochlorohydroxyquine and the S-nitrofurfurylidene hydrazide of Z-hydroxybenzoic acid, prove to be considerably less effective. Thus, in the case of the bacillus dysenteriae, the product of the invention exerts a bacteriostatic effect in a concentration of 1 to 500,000, while the 2-hydroxy isomer acts only in a concentration of 1 to 50,000 and iodochlorohydroxyquine only at 1 in 10,000. The new compound is therefore 10 times as active on bacillus dysenteriae as its isomer and 50 times as active as iodochlorohydroxyquine.
In the case of staphylococci, it has been observed that the new product is 10 times as active as its Z-hydroxy isomer and 5 times as active as iodochlorohydroxyquine.
The bacteriostatic effect of the compound of the invention on the anaerobic organisms, B. Putrificus, B. Perfringens and vibrion septique, is also greater than that of the two comparison compounds.
The S-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid has a bactericidal action on B. coll, B. typhosum and staphylococci, which are dead at the end of 8 hours of contact with a 1225,000 solution of the hydrazide in polyethylene glycol 300. Under the same conditions, iodoc'hlorohydroxyquine and the Z-hydroxy isomer have no bactericidal action.
When administered by a gastric probe in a dosage of mg./ kg. in the form of a suspension in sugar syrup (at a concentration of 5 mg. per ml.), the S-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid considerably reduces the normal intestinal flora or the mouse, while under the same conditions iodochlorohydroxyquine produces only a very slight effect.
Finally the new compound has a very low toxicity, both when administered internally (by gastric probe as a suspension in aqueous agar) and when administered locally in the mouse, the LD 50 being at least 4.75 g./kg. A study of the chronic toxicity in the rat revealed no toxic effects (on general behaviour, globule count, leucocyte distribution, or the viscera), and the stomach and intestine revealed no deterioration, which shows good acceptance by the mucous membrane.
The following examples are illustrative of the process by which the new com-pound may be prepared.
EXAMPLE I 13 g. (0.1 mol) of 4-hydroxybenzhydrazide were dissolved in a boiling mixture of 100 ml. of water and an equal volume of dimethylformamide. 15.5 g. (0.11 mol.) of S-nitrofurfural dissolved in 31 ml. of dimethylform amide were added to this hot solution, and the mixture was stirred and brought to the boiling point.
The mixture was then allowed to stand for fifteen hours. The precipitate was separated, washed twice with 100 ml. of water, and recrystallised by dissolving it in 250 ml. of hot pyridine and pouring this solution into 250 ml. of water.
The S-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid obtained was washed with water and methanol and was dried at a moderate temperature. It weighed 23 g. (83.7% yield), and melted at 298 C. The percentage nitrogen determined by the micro-Dumas method was 15.41% (theory 15.27%).
3 EXAMPLE 11 16.7 g. of S-nitrofurfural were added to a suspension of 18 g. of 4-hydroxybenzhydrazide in 1000 ml. of Water. On stirring heating occurs with formation of a yellow precipitate. The reaction is completed by heating for 15 minutes on a water bath.
After cooling, the hydrazide is separated, washed with water and dried in an oven at 50 C. There are thus obtained 30 g. of the hydrazide (a yield of 88%), which is purified by crystallisation from pyridine or fl-methoxyethanol.
The bactericidal effects of the new compound described above make it suitable for therapeutic use both internally and externally. The invention, therefore, includes within its scope pharmaceutical compositions comprising the 5- nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid in association with a pharmaceutical carrier.
The compositions may be used in a form suitable for oral administration in the treatment of intestinal infec tions of microbial origin. Suitable compositions may also be used in proctology (suppositories), gynaecology (ovules), and dermatology (ointments). The new compositions are especially valuable for local application in cases of staphylococcal and streptococcal infection.
Practical forms of composition may, for example, be made as follows:
These components are completely mixed, passed through a -mesh Tyler screen, and made into tablets by double compression. These tablets are thereafter coated, by the method usually adopted in the manufacture of pills with gummy and gelatinous syrup, with a powder consisting of a mixture of calcium carbonate and talc, and finally with a simple syrup to render them completely smooth.
Each pill contains 0.10 g. of active substance.
Mucilaginous granules The following products are mechanically mixed:
S-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid 1 Carob bean albumen flour 30 Citric acid 3 Icing sugar 66 litres of water are gradually added, with mixing in such a Way as to obtain a homogeneous paste, which is granulated, dried at 50 C., and perfumed.
Suppositories 19 kg. of excipient based upon hydrogenate whale oil (Imhausen type) are melted on a water bath. Into the liquid excipient is gradually introduced, with stirring, a mixture, rendered completely homogeneous by passage through a grinding machine, of
Molten excipient 1 5-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid 0.660
This mixture is continuously stirred. There may be added thereto various medicaments such as anti-inflammatory agents, vasoconstrictors, and local anaesthetics. After these optional additions, the preparation is poured into suppository moulds. The further operations are performed by the usual methods.
Ovules 50 kg. of polyethylene glycol 1500 are melted on the water bath, and 0.250 kg. of S-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid is addedthereto. The mixture is stirred until it is completely dissolved, filtered and poured into an ovule mould.
Ointment There is melted on the water bath, a mixture consisting of:
Kg. Cetyl alcohol 1.80 Propylene glycol 13.200 Polyethylene glycol 4000 19 Polyethylene glycol 1500 19 Polyethylene glycol 300 26.600) Essence of lavender 0.400i
To the fused mixture is added 0.600 kg. of 5-nitrofur-- furylidene hydrazide of 4-hydroxybenzoic acid, and the: mixture is stirred until it is completely dissolved, filtered,, and poured into ointment tubes.
When administered orally in the treatment of intestinala infections a daily dose of 0.1 to 1.0 g. is generally ade-- quate, an amount between 0.4 and 0.6 g. being preferred. For rectal or vaginal administration a dose of 0.2 to 0.9 g. per 24 hours is ordinarily satisfactory.
Clinical trials have shown that the new compound gives favourable results in the treatment of intestinal and rectal infections which do not respond to treatment with sulphonamides or antibiotics, in the treatment of infections of the genitalia, and in the treatment of infected eczemas.
I claim:
1. The S-nitrofurfurylidene hydrazide of 4-hydroXybenzoic acid of formula:
2. A pharmaceutical composition comprising the 5- nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid in association with a significant amount of a pharmaceutical carrier.
3. A method of treating a subject having an infection caused by a microorganism selected from the group consisting of E. coli, B. zyphosum, B. dysenteriae, and Staphylococcus aureous, which comprises administering to the infected subject an amount of S-nitrofurfurylidene hydrazide of 4-hydroxybenzoic acid sufiicient to control the infection, but in an amount insufiicient to cause toxic symptoms in said infected subject.
4. A method according to claim 3 in which 0.1 to 1 g. of the said hydrazide is administered orally every day.
5. A method according to claim 3 in which 0.2 to 0.9 g. of the said hydrazide is administered every day by the rectal route.
6. A method according to claim 3 in which 0.2 to 0.9 g. of the said hydrazide is administered every day by the vaginal route.
References Cited by the Examiner Ivanov, Chem. Abst., vol. 53, 1959, page 15038i.
Journal-Modern Drug Encyclopedia, Seventh Edition, 1958, Drug Publications, Inc., New York, NY. pages 481-482.
Koschucharov-Pharmazie, vol. 15 (1960) pages 492- 497 (abstracted in Chem. Abst., vol. 56, 1962, page 11712f).
Zhelyazkov-Farmatsiya, vol. 90, 1960, pages 11-19 (167-531). (Abstracted in Chem. Abstract, vol. 55, 1961, age 3547A.)
SAM ROSEN, Primary Examiner.
FRANK CACCIAPAGLIA, JR., Examiner.

Claims (1)

  1. 3. A METHOD OF TREATING A SUBJECT HAVING AN INFECTION CAUSED BY A MICROORGANISM SELECTED FROM THE GROUP CONSISTING OF E. COLI, B. TYPHOSUM, B. DYSENTERIAE, AND STAPHYLOCCOCCUS AUREOUS, WHICH COMPRISES ADMINISTERING TO THE INFECTED SUBJECT AN AMOUNT OF 5-NITROFURFURYLIDENE HYDRAZIDE OF 4-HYDROXYBENZOIC ACID SUFFICIENT TO CONTROL THE INFECTION, BUT IN AN AMOUNT INSUFFICIENT TO CAUSE TOXIC SYMPTOMS IN SAID INFECTED SUBJECT.
US208575A 1961-07-12 1962-07-09 Antibacterial nitrofurfurylidene derivatives and methods of using same Expired - Lifetime US3290213A (en)

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FR867839A FR1427M (en) 1961-07-12 1961-07-12 Antiseptic drug based on nitro furan derivative.

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GB (1) GB962706A (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3376296A (en) * 1965-12-17 1968-04-02 Salsbury Lab Ortho-nitrobenzoic acid, 5-nitrofurfurylidene hydrazide
US3764694A (en) * 1969-05-21 1973-10-09 Sterling Drug Inc Anticoccidiosis method and compositions
US4093746A (en) * 1976-04-23 1978-06-06 Marxer S.P.A. Method of and fodder for rearing white-meat calves for slaughter
US4093747A (en) * 1976-04-23 1978-06-06 Marxer S.P.A. Method of and fodder for pig-raising

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1070318B (en) * 1976-04-23 1985-03-29 Marxer Spa USE OF NIFUROXAZIDE AS A FOOD DITIVE IN THE BREEDING OF POULTRY FROM MEAT, IN PARTICULARLY CHICKENS AND GUINEA
FR2636743B1 (en) * 1988-09-20 1993-01-08 Sat Cie OPTICAL FIBER CABLE
CN109053650A (en) * 2018-08-20 2018-12-21 黄石法姆药业股份有限公司 A kind of synthetic method of 4- hydroxyl -2`- (5- nitrofuran methene)-phenylhydrazide

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2416234A (en) * 1945-08-28 1947-02-18 Eaton Lab Inc Series of nitrofuran compounds
US2416236A (en) * 1945-08-28 1947-02-18 Eaton Lab Inc Series of nitrofuran compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3376296A (en) * 1965-12-17 1968-04-02 Salsbury Lab Ortho-nitrobenzoic acid, 5-nitrofurfurylidene hydrazide
US3764694A (en) * 1969-05-21 1973-10-09 Sterling Drug Inc Anticoccidiosis method and compositions
US4093746A (en) * 1976-04-23 1978-06-06 Marxer S.P.A. Method of and fodder for rearing white-meat calves for slaughter
US4093747A (en) * 1976-04-23 1978-06-06 Marxer S.P.A. Method of and fodder for pig-raising

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FR1427M (en) 1962-08-06
GB962706A (en) 1964-07-01
BR6240925D0 (en) 1973-05-24

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