US3716555A - New 5-nitrofuryl derivatives - Google Patents

New 5-nitrofuryl derivatives Download PDF

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Publication number
US3716555A
US3716555A US00084512A US3716555DA US3716555A US 3716555 A US3716555 A US 3716555A US 00084512 A US00084512 A US 00084512A US 3716555D A US3716555D A US 3716555DA US 3716555 A US3716555 A US 3716555A
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United States
Prior art keywords
pyrazole
furyl
cyano
carbon atoms
nitro
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Expired - Lifetime
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US00084512A
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English (en)
Inventor
G Howarth
J Gainer
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Novartis Corp
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Ciba Geigy Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • compositions containing these compounds relate 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a carboxylic acid anhydride such as acetic anhydride
  • 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.
  • 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.
  • mice The toxicity of the compounds of the invention as demonstrated for example in mice is of favorable low order.
  • 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.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising an antimicrobially effective proportion of an active compound of the invention and a pharmacologically acceptable solid carrier or liquid diluent.
  • compositions according to the invention contain at least one active compound of the invention as active substance together with a conventional pharmaceutical carrier.
  • a conventional pharmaceutical carrier 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.
  • 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 ste
  • 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.
  • 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.
  • 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-hydroxydiphenyl
  • 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.
  • 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.
  • the product was 4-cyano-5-(l-ethoxyethylideneamino)-l-methy1-3-(5-nitro-2-furyl)-pyrazo1e, having melting point 160C.
  • 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.
  • 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.
  • 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.
  • 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;
  • R is alkyl having from one to three carbon atoms.
  • a compound according to claim 1 which is 4- cyano-S -ethoxymethyleneamino-1-methyl-3-(5-nitro-2 -furyl)-pyrazole.
  • a compound according to claim 1 which is 4- cyano-S-ethoxymethyleneaminol Z-hydroxyethyl )-3- (S-nitro-2-furyl)-pyrazole.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Earth Drilling (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Catalysts (AREA)
US00084512A 1969-10-28 1970-10-27 New 5-nitrofuryl derivatives Expired - Lifetime US3716555A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB5266369 1969-10-28
GB4305670 1970-09-09
GB4305570 1970-09-09
GB4305470 1970-09-09

Publications (1)

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US3716555A true US3716555A (en) 1973-02-13

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US00084512A Expired - Lifetime US3716555A (en) 1969-10-28 1970-10-27 New 5-nitrofuryl derivatives
US00084531A Expired - Lifetime US3755324A (en) 1969-10-28 1970-10-27 3-(5-nitro-2-furyl)-1h-pyrazolo{8 3,4{9 pyrimidins-4(5h)-ones

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US00084531A Expired - Lifetime US3755324A (en) 1969-10-28 1970-10-27 3-(5-nitro-2-furyl)-1h-pyrazolo{8 3,4{9 pyrimidins-4(5h)-ones

Country Status (17)

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US (2) US3716555A (enrdf_load_stackoverflow)
AT (7) AT304517B (enrdf_load_stackoverflow)
BE (1) BE758050A (enrdf_load_stackoverflow)
BG (1) BG17005A3 (enrdf_load_stackoverflow)
CH (5) CH549598A (enrdf_load_stackoverflow)
DE (2) DE2064874A1 (enrdf_load_stackoverflow)
DK (1) DK130589B (enrdf_load_stackoverflow)
FR (1) FR2070170B1 (enrdf_load_stackoverflow)
GB (1) GB1326360A (enrdf_load_stackoverflow)
HK (1) HK52076A (enrdf_load_stackoverflow)
IE (1) IE34623B1 (enrdf_load_stackoverflow)
IL (1) IL35542A (enrdf_load_stackoverflow)
KE (1) KE2638A (enrdf_load_stackoverflow)
NL (1) NL7015412A (enrdf_load_stackoverflow)
NO (1) NO130007B (enrdf_load_stackoverflow)
RO (1) RO56795A (enrdf_load_stackoverflow)
SE (2) SE383747B (enrdf_load_stackoverflow)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3980794A (en) * 1974-05-13 1976-09-14 Eli Lilly And Company Method for promoting growth of poultry with 3-(5-nitro-2-imidazolyl)pyrazoles
US4093812A (en) * 1975-03-25 1978-06-06 Byk Gulden Lomberg Chemische Fabrik Gmbh (Nitrofuryl)pyrazoles, their synthesis and use, and compositions containing them
US5977118A (en) * 1995-03-10 1999-11-02 Sanofi 6-substituted pyrazolo[3,4-d]pyrimidin-4-ones and compositions and methods of use thereof

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3888887A (en) * 1972-01-14 1975-06-10 American Home Prod Derivatives of 3-amino-2-halo-2-cyclohexen-1-one
AR204665A1 (es) * 1974-05-13 1976-02-20 Lilly Co Eli Procedimiento para preparar compuestos de 3-(5-nitroimidazol-2-il)pirazolo(3,4d)pirimidina
US4044130A (en) * 1974-07-03 1977-08-23 Ciba-Geigy Corporation Compositions for the control of microorganisms
DE2747531A1 (de) * 1977-10-22 1979-04-26 Basf Ag Substituierte 3-aminopyrazole
US4282361A (en) * 1978-03-16 1981-08-04 Massachusetts Institute Of Technology Synthesis for 7-alkylamino-3-methylpyrazolo [4,3-d]pyrimidines
RU2006134021A (ru) 2004-02-27 2008-04-10 Ф.Хоффманн-Ля Рош Аг (Ch) Производные гетероарил-конденсированного пиразола
JP2007523938A (ja) 2004-02-27 2007-08-23 エフ．ホフマン−ラ　ロシュ　アーゲー ピラゾールの縮合誘導体
BRPI0508107A (pt) 2004-02-27 2007-07-17 Hoffmann La Roche derivados de indazol e composições farmacêuticas contendo os mesmos
CA2620105A1 (en) 2005-08-25 2007-03-01 F. Hoffman-La Roche Ag P38 map kinase inhibitors and methods for using the same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3414580A (en) * 1963-07-24 1968-12-03 Heyden Chem Fab Method for the production of substituted 5-aminopyrazoles

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR4032E (fr) * 1902-10-22 1905-05-03 Francois Louis Dit Amedee Gira Appareil pour la commande automatique des registres de tirage des générateurs, pouvant assurer aussi la fumivorité
CH398626A (de) * 1960-05-11 1966-03-15 Ciba Geigy Verfahren zur Herstellung neuer Pyrazolopyrimidine
AT229863B (de) * 1961-10-11 1963-10-25 Norwich Pharma Co Verfahren zur Herstellung des neuen 2-(5-Nitro-2-furyl)-imidazo-[1,2-a]-pyridins bzw. -pyrimidins
US3335141A (en) * 1964-08-17 1967-08-08 Norwich Pharma Co 4-substituted-1-alkyl-6-(5-nitro-2-furyl)-1h-pyrazolo[3, 4-d]pyrimidines
FR206F (enrdf_load_stackoverflow) * 1965-07-20

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3414580A (en) * 1963-07-24 1968-12-03 Heyden Chem Fab Method for the production of substituted 5-aminopyrazoles

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3980794A (en) * 1974-05-13 1976-09-14 Eli Lilly And Company Method for promoting growth of poultry with 3-(5-nitro-2-imidazolyl)pyrazoles
US4093812A (en) * 1975-03-25 1978-06-06 Byk Gulden Lomberg Chemische Fabrik Gmbh (Nitrofuryl)pyrazoles, their synthesis and use, and compositions containing them
US5977118A (en) * 1995-03-10 1999-11-02 Sanofi 6-substituted pyrazolo[3,4-d]pyrimidin-4-ones and compositions and methods of use thereof

Also Published As

Publication number Publication date
NL7015412A (enrdf_load_stackoverflow) 1971-05-03
DK130589C (enrdf_load_stackoverflow) 1975-08-18
AT305994B (de) 1973-03-26
KE2638A (en) 1976-06-11
AT303714B (de) 1972-12-11
SE402591B (sv) 1978-07-10
BG17005A3 (bg) 1973-04-25
AT304518B (de) 1973-01-10
DK130589B (da) 1975-03-10
CH549598A (de) 1974-05-31
RO56795A (enrdf_load_stackoverflow) 1974-08-01
DE2064874A1 (de) 1972-06-29
FR2070170B1 (enrdf_load_stackoverflow) 1974-02-22
CH549597A (de) 1974-05-31
US3755324A (en) 1973-08-28
AT299179B (de) 1972-06-12
BE758050A (fr) 1971-04-27
IL35542A (en) 1975-04-25
IE34623B1 (en) 1975-06-25
DE2052719A1 (de) 1971-09-16
HK52076A (en) 1976-08-27
AT304519B (de) 1973-01-10
IL35542A0 (en) 1971-04-28
GB1326360A (en) 1973-08-08
AT304517B (de) 1973-01-10
CH549599A (de) 1974-05-31
CH548412A (de) 1974-04-30
CH572053A5 (enrdf_load_stackoverflow) 1976-01-30
FR2070170A1 (enrdf_load_stackoverflow) 1971-09-10
AT303715B (de) 1972-12-11
SE383747B (sv) 1976-03-29
NO130007B (enrdf_load_stackoverflow) 1974-06-24
IE34623L (en) 1971-04-28

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