Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3716555 A
Publication typeGrant
Publication dateFeb 13, 1973
Filing dateOct 27, 1970
Priority dateOct 28, 1969
Also published asDE2052719A1, DE2064874A1, US3755324
Publication numberUS 3716555 A, US 3716555A, US-A-3716555, US3716555 A, US3716555A
InventorsJ Gainer, G Howarth
Original AssigneeCiba Geigy Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
New 5-nitrofuryl derivatives
US 3716555 A
Abstract
Compounds of the class of 4-cyano-5-alkoxymethylenamino-3-(5-nitro-2-furyl)-pyrazole have antimicrobial properties and are active ingredients in pharmaceutical compositions and animal feedstuff compositions; an illustrative example is 4-cyano-5-ethoxymethylenamino-1-methyl-3-(5-nitro-2-furyl)-pyrazole.
Images(5)
Previous page
Next page
Description  (OCR text may contain errors)

United States Patent Howarth et al.

[ 51 Feb. 13, 1973 S-NITROFURYL DERIVATIVES Inventors: Graham Arton Howarth, Wilmslow; James Gainer, Tyldesley, both of England Assignee: Ciba-Geigy Corporation, Ardsley,

Filed: Oct. 27, 1970 Appl. No.: 84,512

Foreign Application Priority Data Sept. 9, 1970 Great Britain ..43,056/70 US. Cl ..260/3l0 R, 260/45.8 NZ, 260/347.7,

424/273, 99/2 N Int. Cl. ..C07d 49/18 Field of Search ..260/3 10 [56] References Cited UNITED STATES PATENTS 3,414,580 l2/l968 Hohn ..260/310 Primary Examiner-Harry l. Moatz Attorney-Karl F. Jorda and Bruce M. Collins ABSTRACT 5 Claims, No Drawings DETAILED DESCRIPTION The present invention relates to nitrofuryl derivatives, in particular, to derivatives of 3-(5-nitro-2-furyl)- pyrazole which compounds have antimicrobial properties. It further relates to pharmaceutical and animal feedstuff compositions containing these compounds and to methods for the treatment of a mammal suffering from microbial infections, particularly of urinary tract infections, comprising administering to said mammal an effective amount of such compound. The invention also provides methods for protecting organic material susceptible to microbial attack with an effective amount of a compound according to the invention.

More particularly, the present invention relates to compounds of the formula I wherein R is alkyl having from one to five carbon atoms, carbalkoxy having from one to five carbon atoms in the alkyl moiety, or hydroxyalkyl having from two to five carbon atoms;

R, is hydrogen, alkyl having from one to five carbon atoms which may be unsubstituted or substituted partially or completely by chloro or bromo; cycloalkyl having from five to seven carbon atoms in the carbocyclic ring, aralkyl having up to twelve carbon atoms, or alkenyl having from two to four carbon atoms; and

R is alkyl having from one to three carbon atoms.

Examples of alkyl groups having from one to five carbon atoms are methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiarybutyl and n-pentyl groups. If R, is an alkyl group then it preferably contains from one to three carbon atoms. Cycloalkyl of from five to seven carbon atoms embraces cyclopentyl, cyclohexyl and cycloheptyl groups, whereby the cyclohexyl group is preferred. By the term aralkyl is meant for example the benzyl group and other groups consisting of an aryl and an alkyl moiety, such as phenylethyl, naphthylrnethyl and the like. Alkenyl containing from two to four carbon atoms embraces the vinyl, allyl, Z-methallyl, but-2 -enyl and but-3-enyl group.

Compounds of formula I are produced by treating a compound of the formula II wherein R is as defined in formula I, with a compound of the formula wherein R and R are as defined in formula I, and removing the alkanol produced during the reaction by chemical or physical means as the reaction proceeds. The reaction is advantageously carried out at the reflux temperature of the reaction mixture.

The removal of alkanol as the reaction proceeds may be done by chemical means, for example by conducting the reaction in the presence of a carboxylic acid anhydride, such as acetic anhydride, or by physical means, for example by distilling off the alkanol as formed. If the reactants are liquid, the reaction may be carried out in the absence of solvent; if both the reactants are solid, or if desired in any case, the reaction may be carried out in the presence of any anhydrous non-reactive solvent.

The starting compounds of formula II are prepared by reacting the corresponding nitrofuryl-nitrilimine which in one of its canonical forms may be represented by the formula III.

(III) with malononitrile, where R has its previous significance.

The nitrofurylmitrilimine of formula III may conveniently be generated, as required, during the course of the reaction with malononitn'le, by treating with a base the corresponding nitrofuryl-a-halo-hydrazone having the formula IV OzNl J-C-halogen 0 t NHR (IV) The process may, if desired, be effected in the presence of a conventional base or other hydrogen halide acceptor. The halogen present in the halohydrazone of formula IV is preferably chlorine or bromine.

The compounds of the invention have valuable antimicrobial properties, and in particular have antibacterial, antimycoplasmal, anthelminthic, antiprotozoal, coccidiostatic, trypanocidal and antimalarial activity of value in human or veterinary medicine. The compounds are particularly valuable in the treatment of infections of the intestinal and urinary tracts.

Their antimicrobial activity is demonstrated in a number of conventional pharmacological tests. Thus it is shown that, for example, 4-cyano-5-ethoxymethyleneamino-l methyl-3-(S-nitro-Z-furyl)- pyrazole has in vitro an excellent growth inhibiting effeet against staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, Salmonella typhi and others if added in amounts of about 1 to about 10 'y/ml to the bacterial culture.

The toxicity of the compounds of the invention as demonstrated for example in mice is of favorable low order.

For their intended internal use, for example for the treatment of intestinal and urinary tract infections, the active compounds are administered in dosages depending on the kind of infection, the species and the age, weight and particular condition of the individual being treated. in general the daily dosage upon oral application will vary from about i to 100 mg/kg for mammals. The compounds may also be used to protect a high molecular weight hydrophobic or other organic material susceptible to bacterial or other microbial deteroriation by contacting the organic material with, impregnating in or otherwise treating with, the compounds in amounts up to about 5 percent by weight. The compounds also find application as growthpromoting additives to animal feedstuffs, to which they may be added in proportion of from 5 to 500 parts per million.

Accordingly, the invention also provides a pharmaceutical composition comprising an antimicrobially effective proportion of an active compound of the invention and a pharmacologically acceptable solid carrier or liquid diluent.

The pharmaceutical compositions according to the invention contain at least one active compound of the invention as active substance together with a conventional pharmaceutical carrier. The type of carrier actually used depends to a great extent on the intended application; for external use, for example in disinfecting healthy skin, disinfecting wounds and in treating dermatoses and affections of the mucous membranes caused by bacteria, ointments, powders and tinctures are used in particular. The ointment bases may be anhydrous, for instance they can consist of mixtures of wool fat and soft paraffin, or they can consist of aqueous emulsions in which the active substance is suspended. Suitable carriers for powders are, for instance, ricc starch and other starches; the bulk weight of the carriers may be made lighter, if desired, for example by adding highly dispersed silicic acid, or may be made heavier by adding talcum. The tinctures may contain at least one active ingredient in aqueous ethanol, in particular 45 percent to 75 percent ethanol, to which percent to percent of glycerol may be added, if desired. Solutions prepared from polyethylene glycol and other conventional solubility promoters, and also, optionally, from emulsifying agents, may be used with particular advantage in disinfecting healthy skin. The content of active ingredient in pharmaceutical compositions for external application is preferably in the range of from 0.1 percent to 5 percent.

Gargles or concentrates for their preparation, and tablets for slow dissolution in the mouth, are suitable for the disinfection of the mouth and throat. The former are preferably prepared form alcoholic solutions containing 1 percent to 5 percent of active substance to which glycerol or flavorings may be added. Lozenges, that is solid dosage units, preferably have a relatively high content of sugar or similar substances and a relatively low content of active substance, for instance 0.2 percent to 20 percent by weight, as well as the usual conventional additives such as binding agents and flavorings.

Solid dosage units, in particular tablets, dragees (sugar coated tablets) and capsules, are convenient for use in intestinal disinfection and for the :oral treatment of urinary tract infections. These units preferably contain from 10 percent to percent of the active compound to enable the administration of daily doses of from 0.1 to 2.5 grams to adults, or of suitable reduced doses to children to be made. Tablets and dragee cores are produced by combining the active compounds with solid, pulverulent carriers such as lactose, saccharose, sorbitol, maize starch, potato starch or amylopectin, cellulose derivatives or gelatines, preferably with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weight. Dragee cores may then be coated, for example with concentrated sugar solutions which can also contain gum arabic, talcum and/or titanium dioxide, or they may be coated with a lacquer dissolved in volatile organic solvents or mixture of solvents. Dyestuffs can be added to these coatings, for instance to differentiate between varying dosages. Soft gelatine capsules and other closed capsules consist, for example, of a mixture of gelatines and glycerol and may contain, for example, mixtures of the active compound with polyethylene glycol. Hard gelatine capsules contain, for example, granulates of an active substance with solid pulverulent carriers, for instance lactose, saccharose, sorbitol, mannitol, starches (such as potato starch, maize starch or amylopectin), cellulose derivatives of gelatins, and magnesium stearate or stearic acid.

In all forms for administration the active compounds can be present as solo active ingredients or they can also be combined with other known pharmacologically active, and especially antibacterial and/or antimycotically or other anti-microbially active substances, for example to broaden the range of application. They can be combined for example, with 5,7-dichloro-2-methyl-8- quinolinol or other derivatives of 8-quinolinol, with sulfamerazine or sulfafurazole or other derivatives of sulfanilamide, with chloramphenicol or tetracycline or other antibiotics, with '3,4,5-tribromosalicylanilide or other halogenated salicylanilides, with halogenated carbanilides, with halogenated benzoxazoles or benzoxazolones, with polychloro-hydroxy-diphenylmethanes, with halogen-dihydroxy-diphenyl sulphides, with 4,4 -dichloro-Z-hydroxydiphenylether or 2',4,4'- trichloro-Z-hydroxydiphenylether or other polyhalogenhydroxydiphenylethers, or with bactericidal quaternary compounds or with certain dithiocarbamic acid derivatives such as tetramethylthiuram disulphide. Also, carriers which themselves have favorable pharmacological properties may be used, for instance sulphur as a powder base or zine stearate as a component of ointment bases.

i The invention also provides a method of protecting an organic material susceptible to bacterial or other microbial attack which comprises treating the material with an active compound of the invention. The organic material may be, for instance, a natural or synthetic polymeric material, a proteinaceous or carbohydrate substance, or a natural or synthetic fiber or textile material formed therefrom.

The invention also provides an animal feedstuff composition comprising an active compound of the invention in an amount sufficient to promote the growth of the animal fed with the composition.

The following examples will serve to further illustrate the nature of the present invention, however, they should not be construed as a limitation on the scope thereof.

EXAMPLE 1 1 Milliliter of acetic anhydride and 12 milliliters of triethyl orthoformate were added to 1.0 gram of 5- amino-4cyano- 1 -methyl-3 5-nitro-2-furyl )-pyrazole, and the mixture was refluxed for 5 hours. After this period of heating, the excess ethyl orthoformate and acetic anhydride were removed by distillation under reduced pressure. The crude residue was recrystallized and the product was 4-cyano-5-ethoxymethyleneamino-l -methyl-3-( 5-nitro-2-furyl pyrazole.

EXAMPLE 2 A mixture of 5 grams of 5-amino-4-cyano-l-(2- hydroxyethyl)-3-(5-nitro-2-furyl)-pyrazole, 70 milliliters of triethyl orthoformate and 5 milliliters of acetic anhydride was heated under reflux for 4 hours and cooled. The crystalline solid was collected, washed with ether and dried. Recrystallization from ethyl acetate gave 4-cyano-5-ethoxymethyleneamino-l-(2- hydroxyethyl)-3-(5-nitro-2-fury1)-pyrazole, having melting point 1 16C.

EXAMPLE 3 The procedure described in Example 2 was carried out using 5-amino-4-cyano-l-methyl-3-(5-nitro-2-furyl)-pyrazole and triethyl orthoacetate as starting materials the reaction conditions being the same.

The product was 4-cyano-5-(l-ethoxyethylideneamino)-l-methy1-3-(5-nitro-2-furyl)-pyrazo1e, having melting point 160C.

EXAMPLE 4 The procedure described in Example 2 was carried out using 5-amino-4-cyano-l-methyl-3-(5-nitro-2-furyl)-pyrazole and triethyl orthopropionate as starting material, the reaction conditions being the same.

The product was 4-cyano-5-( l-ethoxypropylideneamino)-l-methy1-3-(5-nitro-2-furyl)-pyrazole, having melting point 161C.

EXAMPLE 5 PREPARATION OF TABLETS 100 g of 4-cyano-S-ethoxymethyleneamino-1- methyl-3-(5-nitro-2-furyl)- pyrazole are mixed with 60.0 g of maize starch and 35.0 g of lactose, the mixture is moistened with a solution of 5.0 g of gelatin and 3.0 g of glycerol in 70.0 g of water and granulated through a sieve. The granulate is mixed with a mixture of 15.0 g of talcum, 10.0 g of maize starch and 2.0 g of magnesium stearate. The resulting mixture is pressed into 1,000 tablets, each containing 100 mg of active substance. 1f desired, the tablets can be grooved for better adaption of the dosage.

EXAMPLE 6 Preparation of Dragees Composition 1 4-Cyano-S-ethoxymethylenenamino- 1.

for 1,000 dragees Magnesium stearate T al- 0t W White dragee coating Shellac Su ar 5 T cum 3 Gum arabic Colloidal silicon dioxide Titanium dioxide one:

Composition 1 is granulated in the heat with composition Il through a sieve of 1.2 mm mesh diameter. The dried granulate is mixed with composition 11] and the resulting mixture is pressed into 1,000 dragee cores. These are then coated with composition 1V and dried. The dragees obtained weight 255.0 mg and contain 100 mg of active substance.

EXAMPLE 7 Preparation of a Syrup The active substance and the colloidal silicon dioxide are passed through a sieve of 1.2 mm mesh diameter (1).

The p-hydroxybenzoic acid esters, the citric acid and the sodium cyclamate are dissolved in the given amount of boiling distilled water; the glycerol is then added to this solution (11). The sodium carboxymethyl cellulose and the sugar are thoroughly mixed (lll).

Composition 111 is then added at C to Solution 11 under stirring until complete dissolution of 111. The viscous, slightly turbid liquid is cooled to room temperature, filtered, if necessary, and mixed with composition I. Water is added to the resulting mixture up to the prescribed weight of 1,155.0 g and the syrup obtained is homogenized.

What is claimed is:

l. A compound of the formula 1 OzNI 0N wherein R, is alkyl having from one to five carbon atoms, carbalkoxy having from one to five carbon atoms in the alkyl moiety or hydroxyalkyl having from two to five carbon atoms,

R is hydrogen,a1ky1 having from one to five carbon atoms which may be unsubstituted or substituted partially or completely by chloro or bromo;

cycloalkyl having from five to seven carbon atoms in the carbocyclic ring, benzyl, phenylethyl, naphthylmethyl, or alkenyl having from two to four carbon atoms; and

R is alkyl having from one to three carbon atoms.

2. A compound according to claim 1 which is 4- cyano-S -ethoxymethyleneamino-1-methyl-3-(5-nitro-2 -furyl)-pyrazole.

3. A compound according to claim 1 which is 4- cyano-S-ethoxymethyleneaminol Z-hydroxyethyl )-3- (S-nitro-2-furyl)-pyrazole.

4. A compound according to claim 1 which is 4-

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3414580 *Jul 2, 1964Dec 3, 1968Heyden Chem FabMethod for the production of substituted 5-aminopyrazoles
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3980794 *Mar 14, 1975Sep 14, 1976Eli Lilly And CompanyMethod for promoting growth of poultry with 3-(5-nitro-2-imidazolyl)pyrazoles
US4093812 *Mar 23, 1976Jun 6, 1978Byk Gulden Lomberg Chemische Fabrik GmbhMicrobiocides, disinfectants
US5977118 *Mar 26, 1997Nov 2, 1999Sanofi6-substituted pyrazolo[3,4-d]pyrimidin-4-ones and compositions and methods of use thereof
Classifications
U.S. Classification548/365.7, 549/482, 523/122, 524/103
International ClassificationC07D498/04, C07D487/04
Cooperative ClassificationC07D487/04
European ClassificationC07D487/04