US3277100A - Novel substituted pyrazoles - Google Patents

Novel substituted pyrazoles Download PDF

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US3277100A
US3277100A US284374A US28437463A US3277100A US 3277100 A US3277100 A US 3277100A US 284374 A US284374 A US 284374A US 28437463 A US28437463 A US 28437463A US 3277100 A US3277100 A US 3277100A
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cyano
carbons
group
acetamido
methyl
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US284374A
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Jr Clifford L Dickinson
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EIDP Inc
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EI Du Pont de Nemours and Co
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Priority to US284374A priority Critical patent/US3277100A/en
Priority to US284323A priority patent/US3274203A/en
Priority to SE6369/64A priority patent/SE301812B/xx
Priority to CH696364A priority patent/CH454883A/en
Priority to GB22407/64A priority patent/GB1039963A/en
Priority to DK270564AA priority patent/DK116443B/en
Priority to NL6406077A priority patent/NL6406077A/xx
Priority to BE672304A priority patent/BE672304A/fr
Priority to US556540A priority patent/US3362877A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings 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
    • C07D231/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings 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
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F2/00—Processes of polymerisation
    • C08F2/38—Polymerisation using regulators, e.g. chain terminating agents, e.g. telomerisation

Definitions

  • R is methyl
  • R is alkyl of 1 through 6 carbons Where the alkyl is joined to the carbamyl nitrogen by a primary or secondary carbon of the alkyl group; alken-Z-yl of three through 6 carbons Where the alken-Z-yl group is joined to the carbamyl nitrogen by a primary or secondary carbon of the alken-2-yl group; alkoxyalkyl of 2 through 6 total carbons; hydroxyalkyl of 2 through 6 carbons; dimethylamino; or dialkylaminoalkyl where each of the alkyl groups in the dialkyl portion has 1 or 2 carbons and the remaining alkyl group has 1 through 4 carbons with a total of from 3 through 7 in the dialkylaminoalkyl group;
  • dehydropiperidyl i.e.--N
  • Y is H or CH;;; Y is H, CH C H or COOR where R is alkyl of 1 through 4 carbons; and Y is H, alkyl of 1 through 6 carbons, hydroxyalkyl of 2 through 6 carbons, trifluoromethyl, COOR Where R is alkyl of 1 through 4 carbons, dialkylaminoalkyl of 3 through 7 carbons where each of the alkyl groups in the dialkyl portion has 1 or 2 carbons and the remaining alkyl group has 1 through 4 carbons, pyrrolidinoethyl or arylalkyl of 7 through 9 carbons including such groups as benzyl, phenethyl, and 0-, mand p-tolylethyl;
  • R can be hydrogen but it is much more highly preferred that it is an acyl radical of 1 through 3 carbons such as formamido, acetamido and propionamido.
  • the alkyl or alken-2-yl group is joined to the carba-myl nitrogen by a secondary carbon of the alkyl or alken-2-yl group.
  • the compounds of this invention are generally solids. They can be used as inhibitors for vinyl polymerization but are particularly useful for their physiological characteristics.
  • the preferred compounds of Formula 1 are carbamyl pyrazoles where X is oxygen and where R and R are joined to form a piperidino ring and in particular a mono-substituted piperidyl ring where the substituent is in the para position with respect to the carbamyl nitrogen.
  • preferred compounds of this invention include the following exemplary ones:
  • cyanopyrazole 1-l (4-methylpiperidino) carbonyl-3 (5) -acetamido-4- cyanopyrazole l-N-( 4-methylpiperidino) carb onyl-3 (5 -propionamido- 4-cyan0pyrazole
  • R is alkyl of 1 through 4 carbons, such as'methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, etc.
  • R is alkyl of 1 through 4 carbons, such as'methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, etc.
  • Illustrative of these preferred compounds are the following:
  • substituted carbamyl pyrazoles of this invention can be prepared by reaction of the appropriate pyrazole with selected reactants as more fully described below.
  • One general method for the preparation of the pyrazoles of this invention can be carried out where the amine N-carboxyl chloride (e.g., N,N-dimethylcarbamoyl chloride) is available.
  • the chloride invan unreactive solvent such as ether, ethyl acetate, or benzene
  • a base such as sodium hydride or triethylamine.
  • the resulting mixture is refluxed for an extended period, say up to about 24 hours or more, .and allowed to cool.
  • the insoluble chloride e.g. sodium chloride or triethylamino hydrochloride, is filtered E and the solvent is removed from the filtrate to give the desired carbamyl or thiocarbamyl pyrazole product.
  • the same general procedure as just described is used when the pyrazole-l-carbonyl chloride is available (e.g., from pyrazole having hydrogen on nuclear nitrogen and either phosgene or thiophosgene) except that the secondary amine is reacted with the pyrazole carbonyl chloride.
  • the first method is preferred if the 3-aminopyrazoles are used since the 3-amino group would react with the phosgene or thiophosgene, whereas the second method is preferred for amines such as N-methyl-N-hydroxyethylamine where the amine substituent can also react with the phosgene or thiophosgene.
  • 'Ihe amine carbonyl chlorides such as N-piperidine carboxyl chloride are prepared by placing in a flask fitted with a DryJce condenser, mechanical stirrer and dropping funnel preferably at least 1.2 moles of phosgene in an inert solvent such as ether, tetrahydrofuran, benzene, ethyl acetate or the like.
  • an inert solvent such as ether, tetrahydrofuran, benzene, ethyl acetate or the like.
  • a solution of 1 mole of the selected amine, e.g., piperidine, and preferably, for increased yields, with 1 mole of tertiary amine such as triethylamine, in the selected solvent is added slowly with stirring and the temperature is kept below 30 C. with occasional cooling.
  • the pyrazole can be used in the above procedure in place of the amine (piperidine).
  • 3-acetamido-4-cyano-pyrazole one obtains 3'-acetamido-4-cyanopyrazole-1-carbonyl chloride.
  • the compounds of this invention have outstanding activity as analgesics, many of them exceeding codeine in potency, as shown by standard animal tests. This analgesic activity inthese compounds is particularly valuable because of significantly favorable therapeutic ratios.
  • General painkilling benefits, as well as other physiological remediation associated with aspirin, are 'believed to be obtainable according to this invention based on tests and evaluation thus far carried out.
  • the compounds of this invention exhibit outstanding anti-inflammatory and central nervous system activity.
  • a compound of this invention will be administered to the body orally, parenterally and by other methods.
  • the dosage will vary and will depend on such factors as the condition being treated; age and weight of the recipient; the responsiveness of the recipient; pn'or, concurrent and intended subsequent, medication and treatment, general health of the recipient; frequency of treatment; and of course the purpose and nature of the eifect desired.
  • the active compound will be administered in a physiologically beneficial amount. Administration can be in a single dose or in a plurality of doses over an extended period of time. It will furthermore be understood that every compound within this invention does not have an identical level of dosage requirement for therapeutic or prophylactic effectiveness and therefore experts will understand that some dosage variation between compounds can be expected for maximum benefits. It will of course also be understood that an initial dose, or first group of doses, in a course of treatment can bein greater amounts, if appropriate, for a particular medical situation and a rapid response is sought by the early administration of relatively large doses and thereafter the minimally effective dosage, or maintenance dosage, is determined.
  • a single dose will rarely exceed about 400 or SOOmilligrams of active compound within this invention, although larger amounts can be used as called for in any given situation. Extremely small doses will effect some benefit but as a practical matter a single dose of less than about 1 or 2 milligrams will seldom be used. Fortreating small animals with high physiological response and using highly active compounds, routine usage can be at much lower dosage levels however. Doses can be repeated in the same or greater or lesser amounts over a period of time as long as improvement in the recipient is observed or as long as needed under the circumstances.
  • the active compound will ordinarily be administered with a non-toxic pharmaceutical carrier in a variety of practical dosage forms.
  • These dosage forms are noval compositions comprising the non-toxic pharmaceutical carrier and a physiologically beneficial amount of one or more active compounds of this invention.
  • These highly useful dosage forms constitute an important aspect of the present invention.
  • Suitable non-toxic pharmaceutical carriers or vehicles include liquids such as water, aromatic water, alcohols, syrups, elixirs, pharmaceutical mucilages, such as acacia and tragacanth, oils such as of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, fish oil such as cod liver oil, or the like, for oral administration; water, saline, aqueous propylene glycol, aqueous polyethylene glycol, aqueous lactose, aqueous maltose, aqueous glucose (dextrose), aqueous sucrose, or the like, for administration by injection.
  • liquids such as water, aromatic water, alcohols, syrups, elixirs, pharmaceutical mucilages, such as acacia and tragacanth
  • oils such as of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, fish oil such as cod liver oil, or the like, for oral administration
  • Suitable solid carriers include soft gelatin capsules, hard gelatin capsules, slow or delayed release pills or capsules, powders, tableting vehicles and the like.
  • Suitable solid or liquid non-toxic pharmaceutical carriers are well known in the art and the selection of carrier can be from those appropriate and available in accordance with wel known prescription techniques.
  • the compositions of this invention therefore include such dosage forms as solution, suspensions, syrups, elixirs, tablets, capsules, powder packets, and the like.
  • the active ingredient of Formula 1 or 2 will be present in a physiologically beneficial amount as mentioned above.
  • the active ingredient will ordinary constitute at least about 0.01% by weight based on the total weight of the composition;
  • the concentration will ordinarily be in the range from about 0.5 to 5.0% by weight of active ingredient.
  • -For injection concentrations from 2 to 20% are satisfactory.
  • the amount of active ingredient may if desired be as much'as to or more by weight of the total. composition.
  • the active compounds of this invention can be formulated if desired with one or more pharmaceutically active materials for combination efieots, treatments and benefits.
  • Such materials include but are by no means limited to vitamins, pain killers, tranquilizers, antibiotics, antitussive agents, etc.
  • the compositions can of course contain suitable pharmaceutical modifiers such as coloring agents, sweetening or other flavoring agents, solubilizing agents, etc. as will readily occur to persons skilled in this art.
  • EXAMPLE 1 3 (5) -amino-4-cyan0-1-N,N-dimethylcarbamylpyrazole A mixture of 20.4 grams of 3-amino-4-cyanopyrazole and 9.2 grams of sodium hydride in 100 milliliters of tetrahydrofuran is stirred minutes. Dimeflhylcarbamoyl chloride (21.4 grams) is added and the mixture refluxed three hours, filtered and the filtrate evaporated to dryness. The solid remaining is recrystallized from ethyl acetate to give 6.8 grams of 3(5)-amino-4-cyano1-N,N-dimethylcarbamylpyrazole, M.P. 134-137 C.
  • the compound of this example exhibits excellent analgesic activity and is representative of the compounds of this invention in being characterized -by extremely low acute toxicity as shown in standard animal tests. In combination with its other desirable pharmacological properties, this compound is a :poor cholinesteraseinhibitor and thus can be expected to give rise to little or no undesirable side eifects.
  • the compound of this example furthermore exhibits anti-inflammatory activity.
  • the compound is formulated conveniently as an injectible solution of 0.5%, 1% and 5% by weight concentration in isotonic saline; as an injectible solution in 0.5%, 1.0% and 5% by weight concentrations in aqueous sugars including in separate solutions lactose, maltose, glucose (dextrose) and sucrose; in water in 1%, 2%, 3% and 4% by weight concentration for oral administration, with and Without a flavoring agent, a coloring agent, an 'antitussive agent, etc.; and in 25, 50, and 100 milligram amounts in standard two-piece sealed hard gelatin capsules, as Well as in soft gelatin capsules, for oral administration.- In pharmacological application it is administered in these dosage forms as dosage levels in the range of -500 milligrams.
  • EXAMPLE 2 3-acetamz'd0-4-cyan0-1-N-piperidin0carbonylpyrazole
  • a mixture of 15.7 grams (0.1 mole) of 3-acetamido- 4-cyanopyrazole and 4.7 grams of sodium hydride (53% in oil) in 200 milliliters of dimethoxy ethane is stirred and refluxed minutes.
  • Pentamethylenecarbarnoyl chloride (15.7 grams, 0.1 mole) is added in portions and the mixture is stirred and refluxed for 6 hours, then. filtered hot.
  • the precipitate that forms upon cooling is collected, yield 17.05 grams, MAP. 1-83.5-184.5 C.
  • the filtrate is concentrated to about 75 milliliters and the precipitated collected upon cooling is 7.0 grams.
  • a portion is recrystallized twice from ethyl acetate to give pure S-acetamido-4-cyano 1 N piperidino carbonylpyrazole, M.P. 183- l84 C.
  • the compound is formulated and used in 5, 10, and 25 milligram amounts in standard 2 piece hard gelatin capsules for oral administration.
  • Appropriate amounts of corn starch or lactose can be used as a filler in the capsule.
  • the compound can also be formulated as a coated or uncoated tablet containing 2.5 to milligram amounts and from 1 to 4% by weight of gelatin, from 0.5 to 1.5%
  • magnesium stearate or talc by weight of magnesium stearate or talc and a filler such as lactose or rnannitol.
  • Example No. Product 3-tormamido-4cyano-1-N,N-dimethylcarbamylpyrazole. 3-acetam1do- 1-cyano-1-N,N-dlmethylcarbamylpyrazole. 3-prop1onam1do-4-cyano-1-N,N-dimethylcarbamylpyrazole. 3-amino-4-eyano-1-N-methyl-Nethyl-N-ethylcarbarnylpyrazole. 7 3-pr0pi0riamid0-4-cyan0-1-N-methyl-N-ethylcarbamylpyrazo e.
  • 3-acetamido-4-cyano-1-N-methyl -N (penten-2-yl) carbarnylpy'razole 3-acetamido-4-cyano-1-N-methyl-N-(2-hydroxyethyl)- carbamylpyrazole. 3-propionamido-4-cyano-l-N-methy1-N-methoxymethylcarbamylpyrazole. 3-for mamido-4-cyano-1-N-methyl-N-methoxypropylthioearbamylpyrazole. 3-acetamido-4-cyano-1-N-methyl-N-diethylaminoethylcarbamylpyrazole.
  • 3-acetamido-el-cyano-l-N-pyrrolidino(thiocarbonyl) pyrazole 3-formamid0-4-cyano-l-N-piperidinocarbonylpyrazole. 3-formam1do-4-cyano-1-N-dehydropiperidin0carbonylpyrazole. 3-acetamido-4-cyano-1-N-azabicyelononylcarbonylpyrazole. 3-acetamido-4-cyano-1-N-(3,4-dimethylpiperldino) carbonylpyrazole. 3-acetamido4-eyano-1-N-p-tolylethylpiperidinocarbonylpyrazole.
  • 3-t'ormamido-d-cyano-l-N-m-methylpiperidinocarbonylpyrazole 3-acetamido-4-cyano-l-N-ptrifluoromethylpiperidinocarhonylpyrazole. 3-acetamido-4-cyano-l-N-p-ethylpiperidino(thiocarbonyl)pyrazole. 3propionamido-4-cyano-l-N-[p-(n-butyDpiperidino] (thiocarbonyDpyrazole. 3-acetamido-4-cyano-1- -o-methylplperldino(thiocarbonyDpyi-azole.
  • 3-torn1aniido-4-cyano-l-N-p-benzylpiperidinocarbonylpyrazo e 3-acetamido-4-cyano-1-N-(m-ethoxycarbonylpiperidino) carbonylpyrazole. 3-tormamido-4-cyano-1-N-(3-methyl-4-ethylpiperidino) carbonylpyrazole. 3-amino4-cyan0-1-N-[p-(n-propyl)piperidino1carbonylpyrazole. 3-acetamido-4-cyano-1-N-phenethylpiperidinocarbonylpyrazo e.
  • alkyl of 1 through 6 carbons where the alkyl is joined to the carbamyl nitrogen by a carbon selected from the group consisting of a primary and a secondary carbon of said alkyl; alken-2-yl of 3 through 6 carbons where the alken-Z-yl is joined to the carbamyl 7.
  • X is selected from the group consisting of oxygen and sul-
  • 1-N-(4-methylpiperidino) carbonyl-3 (5 -acetamidonitrogen by a carbon selected from the group consisting of a primary and a secondary carbon of said alken- 2-yl; alkoxyalkyl of 2 through 6 total carbons; dipyrazole. methylamino; and dialkylaminoalkyl where each of the 11; 3 (5)-acetamido-4-cyano-1-N,N-dimethylcarbamylalkyl groups in the dialkyl portion has 1 through 2 pyrazole.
  • a substituted piperidino group of the structure 40 References Cited by the Examiner Y3 UNITED STATES PATENTS I 2,476,986 7/1949 Martin 260310 Y1 Y1 2,817,666 12/1957 Beaver 2603 10 3,013,001 12/1961 Lynn 26087.8 wherein Y is selected from the group consisting of hy- 3,060,091 10/1962 Witkin 167-65 drogen and methyl; Y; is selected from the group con- 3,080,287 3/ 1963 Lewenstein 16 7-65 sisting of hydrogenfmethyl, ethyl and COOR where R, is alkyl of 1 through 4 carbons; and Y is selected References Cited y 'Applicant from the group consisting of hydrogen, alkyl of 1 through 6 carbons, hydroxyalkyl of 2 through 6 car- UNITED l j PATENTS bons, trifluorornethyl, CO0R where R is alkyl of 255 23333
  • each of the alkyl groups in the dialkyl portion has 1 through 2 carbons and the remaining alkyl group has 1 through 4 carbons, pyrrolidinomethyl, and hydrocarbon aralkyl of 7 through 9 carbons;
  • R is selected from the group consisting of hydrogen

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Description

United States Patent 3,277,100 NOVEL SUBSTITUTED PYRAZOLES Clifiord L. Dickinson, Jr., Wilmington, Del., assignor to E. I. du Pont de Nemours and Company, Wilmington, Del., a corporation of Delaware No Drawing. Filed May 31, 1963, Ser. No. 284,374 15 Claims. (Cl. 260-294) This invention relates to pyrazole derivatives and more particularly refers to 3-amino-4-cyano-N-carbamylpyrazoles and their preparation.
According to this invention I have discovered a narrow class of substituted pyrazoles having a most unusual combination of pharmacological properties.
I have found that this valuable combination of properties is obtained, for reasons which are not understood or yet fully explained, only with a small group of pyrazole compounds where there must be a cyano substituent in the 4-position of the pyrazole ring and also there must be an amino or acylamino substituent of 1 through 3 carbons in the 3-position (or S-position but not both the 3 and the 5; it is critical that one of these positions must be unsubstituted except for hydrogen).
Thus, the compounds ofthis invention have the formvia:
1) NC NHR;
ll if E=X I N R1 R2 which can exist as the isomeric formula 2) NC:NH-R3 NCNR1R1 I! where X is oxygen or sulfur;
R is methyl;
R is alkyl of 1 through 6 carbons Where the alkyl is joined to the carbamyl nitrogen by a primary or secondary carbon of the alkyl group; alken-Z-yl of three through 6 carbons Where the alken-Z-yl group is joined to the carbamyl nitrogen by a primary or secondary carbon of the alken-2-yl group; alkoxyalkyl of 2 through 6 total carbons; hydroxyalkyl of 2 through 6 carbons; dimethylamino; or dialkylaminoalkyl where each of the alkyl groups in the dialkyl portion has 1 or 2 carbons and the remaining alkyl group has 1 through 4 carbons with a total of from 3 through 7 in the dialkylaminoalkyl group;
and Where R and R can be joined together and together with the carbamyl nitrogen form a heterocyclic piperidyl, i,e N
dehydropiperidyl, i.e.--N
azabicyclononyl, i.e.
where Y is H or CH;;; Y is H, CH C H or COOR where R is alkyl of 1 through 4 carbons; and Y is H, alkyl of 1 through 6 carbons, hydroxyalkyl of 2 through 6 carbons, trifluoromethyl, COOR Where R is alkyl of 1 through 4 carbons, dialkylaminoalkyl of 3 through 7 carbons where each of the alkyl groups in the dialkyl portion has 1 or 2 carbons and the remaining alkyl group has 1 through 4 carbons, pyrrolidinoethyl or arylalkyl of 7 through 9 carbons including such groups as benzyl, phenethyl, and 0-, mand p-tolylethyl;
and disubstituted piperidyl of the structure Where Y and Y have the same meaning as above; and
R can be hydrogen but it is much more highly preferred that it is an acyl radical of 1 through 3 carbons such as formamido, acetamido and propionamido.
0f the compounds of Formula 1 where R is alkyl or alken-Z-yl, it is preferred that the alkyl or alken-2-yl group is joined to the carba-myl nitrogen by a secondary carbon of the alkyl or alken-2-yl group.
The compounds of this invention are generally solids. They can be used as inhibitors for vinyl polymerization but are particularly useful for their physiological characteristics.
Because of their excellent analgesic activity and other 7 desirable pharmacological properties, the preferred compounds of Formula 1 are carbamyl pyrazoles where X is oxygen and where R and R are joined to form a piperidino ring and in particular a mono-substituted piperidyl ring where the substituent is in the para position with respect to the carbamyl nitrogen. Thus, preferred compounds of this invention include the following exemplary ones:
-l-N'(4-methylpiperidino) carbonyl-3 (5 -formamido-4-.
cyanopyrazole 1-l (4-methylpiperidino) carbonyl-3 (5) -acetamido-4- cyanopyrazole l-N-( 4-methylpiperidino) carb onyl-3 (5 -propionamido- 4-cyan0pyrazole Also preferred are those compounds of Formula 1 where R is alkyl of 1 through 4 carbons, such as'methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, etc. Illustrative of these preferred compounds are the following:
The substituted carbamyl pyrazoles of this invention can be prepared by reaction of the appropriate pyrazole with selected reactants as more fully described below.
One general method for the preparation of the pyrazoles of this invention can be carried out where the amine N-carboxyl chloride (e.g., N,N-dimethylcarbamoyl chloride) is available. In this process there are brought together approximately equirnolar amounts of the pyrazole and the chloride invan unreactive solvent such as ether, ethyl acetate, or benzene, together with an equimolar amount of a base such as sodium hydride or triethylamine. The resulting mixture is refluxed for an extended period, say up to about 24 hours or more, .and allowed to cool. The insoluble chloride e.g. sodium chloride or triethylamino hydrochloride, is filtered E and the solvent is removed from the filtrate to give the desired carbamyl or thiocarbamyl pyrazole product.
The same general procedure as just described is used when the pyrazole-l-carbonyl chloride is available (e.g., from pyrazole having hydrogen on nuclear nitrogen and either phosgene or thiophosgene) except that the secondary amine is reacted with the pyrazole carbonyl chloride. .The first method is preferred if the 3-aminopyrazoles are used since the 3-amino group would react with the phosgene or thiophosgene, whereas the second method is preferred for amines such as N-methyl-N-hydroxyethylamine where the amine substituent can also react with the phosgene or thiophosgene.
'Ihe amine carbonyl chlorides such as N-piperidine carboxyl chloride are prepared by placing in a flask fitted with a DryJce condenser, mechanical stirrer and dropping funnel preferably at least 1.2 moles of phosgene in an inert solvent such as ether, tetrahydrofuran, benzene, ethyl acetate or the like. A solution of 1 mole of the selected amine, e.g., piperidine, and preferably, for increased yields, with 1 mole of tertiary amine such as triethylamine, in the selected solvent is added slowly with stirring and the temperature is kept below 30 C. with occasional cooling. When all of the amine has been added, the mixture is stirred several hours. The mixture is filtered to remove the hydrochloride and the solvent is removed from the filtrate by boiling it off. The remaining amine-N- .carboxyl chloride is distilled under reduced pressure to eifect purification.
' Alternatively, the pyrazole can be used in the above procedure in place of the amine (piperidine). By this procedure, with 3-acetamido-4-cyano-pyrazole, one obtains 3'-acetamido-4-cyanopyrazole-1-carbonyl chloride.
' As mentioned above, the compounds of this invention have outstanding activity as analgesics, many of them exceeding codeine in potency, as shown by standard animal tests. This analgesic activity inthese compounds is particularly valuable because of significantly favorable therapeutic ratios. General painkilling benefits, as well as other physiological benefication associated with aspirin, are 'believed to be obtainable according to this invention based on tests and evaluation thus far carried out.
Furthermore, the compounds of this invention exhibit outstanding anti-inflammatory and central nervous system activity.
In pharmaceutical application a compound of this invention will be administered to the body orally, parenterally and by other methods. The dosage will vary and will depend on such factors as the condition being treated; age and weight of the recipient; the responsiveness of the recipient; pn'or, concurrent and intended subsequent, medication and treatment, general health of the recipient; frequency of treatment; and of course the purpose and nature of the eifect desired.
Generally speaking, the active compound will be administered in a physiologically beneficial amount. Administration can be in a single dose or in a plurality of doses over an extended period of time. It will furthermore be understood that every compound within this invention does not have an identical level of dosage requirement for therapeutic or prophylactic effectiveness and therefore experts will understand that some dosage variation between compounds can be expected for maximum benefits. It will of course also be understood that an initial dose, or first group of doses, in a course of treatment can bein greater amounts, if appropriate, for a particular medical situation and a rapid response is sought by the early administration of relatively large doses and thereafter the minimally effective dosage, or maintenance dosage, is determined.
A single dose will rarely exceed about 400 or SOOmilligrams of active compound within this invention, although larger amounts can be used as called for in any given situation. Extremely small doses will effect some benefit but as a practical matter a single dose of less than about 1 or 2 milligrams will seldom be used. Fortreating small animals with high physiological response and using highly active compounds, routine usage can be at much lower dosage levels however. Doses can be repeated in the same or greater or lesser amounts over a period of time as long as improvement in the recipient is observed or as long as needed under the circumstances.
The active compound will ordinarily be administered with a non-toxic pharmaceutical carrier in a variety of practical dosage forms. These dosage forms are noval compositions comprising the non-toxic pharmaceutical carrier and a physiologically beneficial amount of one or more active compounds of this invention. These highly useful dosage forms constitute an important aspect of the present invention.
Suitable non-toxic pharmaceutical carriers or vehicles include liquids such as water, aromatic water, alcohols, syrups, elixirs, pharmaceutical mucilages, such as acacia and tragacanth, oils such as of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, fish oil such as cod liver oil, or the like, for oral administration; water, saline, aqueous propylene glycol, aqueous polyethylene glycol, aqueous lactose, aqueous maltose, aqueous glucose (dextrose), aqueous sucrose, or the like, for administration by injection. Suitable solid carriers include soft gelatin capsules, hard gelatin capsules, slow or delayed release pills or capsules, powders, tableting vehicles and the like. Suitable solid or liquid non-toxic pharmaceutical carriers are well known in the art and the selection of carrier can be from those appropriate and available in accordance with wel known prescription techniques. The compositions of this invention therefore include such dosage forms as solution, suspensions, syrups, elixirs, tablets, capsules, powder packets, and the like.
A vast number of suitable pharmaceutical carriers are described in Remingtons Practice of Pharmacy edited by E. W. Martin and E. F. Cook, 12th Edition, 1961, published bythe Mack Publishing Company, Easton, Pennsylvania.
, 1n these novel compositions the active ingredient of Formula 1 or 2 will be present in a physiologically beneficial amount as mentioned above. In practice this means that the active ingredient will ordinary constitute at least about 0.01% by weight based on the total weight of the composition; For oral administration in water or other liquid medium, the concentration will ordinarily be in the range from about 0.5 to 5.0% by weight of active ingredient. -For injection concentrations from 2 to 20% are satisfactory. In tablets, powders, capsules and the like the amount of active ingredient may if desired be as much'as to or more by weight of the total. composition.
The active compounds of this invention can be formulated if desired with one or more pharmaceutically active materials for combination efieots, treatments and benefits. Such materials include but are by no means limited to vitamins, pain killers, tranquilizers, antibiotics, antitussive agents, etc. The compositions can of course contain suitable pharmaceutical modifiers such as coloring agents, sweetening or other flavoring agents, solubilizing agents, etc. as will readily occur to persons skilled in this art.
This invention will be better understood by reference to the following illustrative examples in which parts and percentages given are by weight unless otherwise indicated.
EXAMPLE 1 3 (5) -amino-4-cyan0-1-N,N-dimethylcarbamylpyrazole A mixture of 20.4 grams of 3-amino-4-cyanopyrazole and 9.2 grams of sodium hydride in 100 milliliters of tetrahydrofuran is stirred minutes. Dimeflhylcarbamoyl chloride (21.4 grams) is added and the mixture refluxed three hours, filtered and the filtrate evaporated to dryness. The solid remaining is recrystallized from ethyl acetate to give 6.8 grams of 3(5)-amino-4-cyano1-N,N-dimethylcarbamylpyrazole, M.P. 134-137 C.
Analysis.C-alcd. for C- H N O: C, 46.9; H, 5.1; N, 39.1. Found: C, 47.4; H, 5.1, N, 38.8.
The compound of this example exhibits excellent analgesic activity and is representative of the compounds of this invention in being characterized -by extremely low acute toxicity as shown in standard animal tests. In combination with its other desirable pharmacological properties, this compound is a :poor cholinesteraseinhibitor and thus can be expected to give rise to little or no undesirable side eifects.
The compound of this example furthermore exhibits anti-inflammatory activity. The compound is formulated conveniently as an injectible solution of 0.5%, 1% and 5% by weight concentration in isotonic saline; as an injectible solution in 0.5%, 1.0% and 5% by weight concentrations in aqueous sugars including in separate solutions lactose, maltose, glucose (dextrose) and sucrose; in water in 1%, 2%, 3% and 4% by weight concentration for oral administration, with and Without a flavoring agent, a coloring agent, an 'antitussive agent, etc.; and in 25, 50, and 100 milligram amounts in standard two-piece sealed hard gelatin capsules, as Well as in soft gelatin capsules, for oral administration.- In pharmacological application it is administered in these dosage forms as dosage levels in the range of -500 milligrams.
EXAMPLE 2 3-acetamz'd0-4-cyan0-1-N-piperidin0carbonylpyrazole A mixture of 15.7 grams (0.1 mole) of 3-acetamido- 4-cyanopyrazole and 4.7 grams of sodium hydride (53% in oil) in 200 milliliters of dimethoxy ethane is stirred and refluxed minutes. Pentamethylenecarbarnoyl chloride (15.7 grams, 0.1 mole) is added in portions and the mixture is stirred and refluxed for 6 hours, then. filtered hot. The precipitate that forms upon cooling is collected, yield 17.05 grams, MAP. 1-83.5-184.5 C. The filtrate is concentrated to about 75 milliliters and the precipitated collected upon cooling is 7.0 grams. A portion is recrystallized twice from ethyl acetate to give pure S-acetamido-4-cyano 1 N piperidino carbonylpyrazole, M.P. 183- l84 C.
Analysis.Calcd. for C12H15N502: C, H, 5.8. Found: C, 55.2; H, 5.6.
The compound is formulated and used in 5, 10, and 25 milligram amounts in standard 2 piece hard gelatin capsules for oral administration. Appropriate amounts of corn starch or lactose can be used as a filler in the capsule.
The compound can also be formulated as a coated or uncoated tablet containing 2.5 to milligram amounts and from 1 to 4% by weight of gelatin, from 0.5 to 1.5%
6 by weight of magnesium stearate or talc and a filler such as lactose or rnannitol.
The general procedures of the above examples can be repeated using other 3-a-mino and 3-acylamino 4-cyan0 pyrazoles and appropriately substituted carbamoyl and thiocarbamoyl chlorides in place of the reactants of those examples to obtain the following listed exemplary cornpounds of this invention:
Example No. Product 3-tormamido-4cyano-1-N,N-dimethylcarbamylpyrazole. 3-acetam1do- 1-cyano-1-N,N-dlmethylcarbamylpyrazole. 3-prop1onam1do-4-cyano-1-N,N-dimethylcarbamylpyrazole. 3-amino-4-eyano-1-N-methyl-Nethyl-N-ethylcarbarnylpyrazole. 7 3-pr0pi0riamid0-4-cyan0-1-N-methyl-N-ethylcarbamylpyrazo e. 8 3amin0-4 0y8n0-1-N,N-dimethylthiocarbamylpyrazole, 9 3-tormaniido-4-cyano-l-N,N-dimethylthioearbamylpyrazo e. 10 3-acetamido-4-eyano-1-N,N-dimethylth1ocarbamylr pyrazole. 11 S-formamid0-4-cyano1-N-methyl-N-ethylcarbamylpyrazole. 12 3-acetamido-4-cyano-l-N-methyl-N-isopropy1carbamylpyrazole. 13 3-acetamido-4-cyano-l-N-methyl-N-secbutylcarbamylpyrazole. 14 3-formamido4-eyan0-1-N-methyl-N-n-hexylcarbamylpyrazole.
3-acetamido-4-cyano-1-N-methyl -N (penten-2-yl) carbarnylpy'razole. 3-acetamido-4-cyano-1-N-methyl-N-(2-hydroxyethyl)- carbamylpyrazole. 3-propionamido-4-cyano-l-N-methy1-N-methoxymethylcarbamylpyrazole. 3-for mamido-4-cyano-1-N-methyl-N-methoxypropylthioearbamylpyrazole. 3-acetamido-4-cyano-1-N-methyl-N-diethylaminoethylcarbamylpyrazole. 3-acetarmdo-Hyano-l-N-methyl-N-allylcarbamylpyrazole. a-ammot-cyano-l-N-methyl-N-(buten-2-yDcarbamylpyrazole. S-formanndoA-eyano-l-N-methyl N-ethoxypropylthiocarban ylpyrazole. 3-acetam1do-4-cyano-1-N-methyl-Ndimethylaminocarbamylpyrazole. 3-formamido-4-cyano-1-N-methyl-N-isobutylcarbamylpyrazole. 3-anuno-t-cyano-1-N-morpholinocarbonylpyrazole. 8-acetam do-4-cyano-1-N-pyrrolidinocarbonylpyrazole.
3-acetamido-el-cyano-l-N-pyrrolidino(thiocarbonyl) pyrazole. 3-formamid0-4-cyano-l-N-piperidinocarbonylpyrazole. 3-formam1do-4-cyano-1-N-dehydropiperidin0carbonylpyrazole. 3-acetamido-4-cyano-1-N-azabicyelononylcarbonylpyrazole. 3-acetamido-4-cyano-1-N-(3,4-dimethylpiperldino) carbonylpyrazole. 3-acetamido4-eyano-1-N-p-tolylethylpiperidinocarbonylpyrazole. 3-t'ormamido-d-cyano-l-N-m-methylpiperidinocarbonylpyrazole. 3-acetamido-4-cyano-l-N-ptrifluoromethylpiperidinocarhonylpyrazole. 3-acetamido-4-cyano-l-N-p-ethylpiperidino(thiocarbonyl)pyrazole. 3propionamido-4-cyano-l-N-[p-(n-butyDpiperidino] (thiocarbonyDpyrazole. 3-acetamido-4-cyano-1- -o-methylplperldino(thiocarbonyDpyi-azole. 3-torn1aniido-4-cyano-l-N-p-benzylpiperidinocarbonylpyrazo e. 3-acetamido-4-cyano-1-N-(m-ethoxycarbonylpiperidino) carbonylpyrazole. 3-tormamido-4-cyano-1-N-(3-methyl-4-ethylpiperidino) carbonylpyrazole. 3-amino4-cyan0-1-N-[p-(n-propyl)piperidino1carbonylpyrazole. 3-acetamido-4-cyano-1-N-phenethylpiperidinocarbonylpyrazo e. 3-formamido-4-cyano-1-N-(p-diethylaminoethylpiperidino)carbony1pyraz0le. 3acetamido-4cyano-1-N-(p-pyrrolidinoethylpiperldino)carbonylpyrazole. 3-acetamid0-4-cyano-l-N-(p-butoxycarbonylpiperidino) carbonylpyrazole. 3-aeetarmdo-4cyano-l-N-[3A-di(2-hydroxyethyl)piperidino]carbonylpyrazole. 3-formarm'do-4-cyano-1-N-o-tolylethylpiperidinocarbonylpyrazole.
The above examples can be repeated to obtain other compounds with the scope of this invention by appropriate selection of reactants as will be readily understood in the art.
consisting of alkyl of 1 through 6 carbons where the alkyl is joined to the carbamyl nitrogen by a carbon selected from the group consisting of a primary and a secondary carbon of said alkyl; alken-2-yl of 3 through 6 carbons where the alken-Z-yl is joined to the carbamyl 7. 1-N-(4-methy1piperidino) carbonyl-3 -formamido- 4-cyanopyrazole.
4-cyanopyrazole. 25 a 9. l-N-(4-methylpiperidino)carbonyl 3(5) propion- 7 8 The invention claimed is: 2. 'A compound as set forth in claim 1 wherein 1. A compound selected from compounds of the for- R1 mula B 15 -N NC NIP-R l H: 5 R2 1 where R is methyl and R is alkyl of 1 through 6 carbons N/ joined to the carbamyl nitrogen by a secondary carbon of 1 3:}: the alkyl, R is selected from the group consisting of A formyl, acetyl and propionyl, and X is oxygen.
10 3. A compound as set forth in claim 1 wherein A is Where a heterocyclic group as defined in claim 1. X is selected from the group consisting of oxygen and sul- A compound as set f th in claim 1 wherein A is a 4-mono-substituted piperidino group as defined in A is selected from the group consisting of claim r R 5. A compound as set forth in claim 1 wherein Ais piperidino, R is selected from the group consisting of formyl, acetyl and propionyl, and X is oxygen.
6. A compound as set forth in claim 1 wherein A is piperidino, R is selected fromrthe group consisting of wherein R is methyl; and R is selected from the group formyl, acetyl and propionyl, and X is oxygen.
8. 1-N-(4-methylpiperidino) carbonyl-3 (5 -acetamidonitrogen by a carbon selected from the group consisting of a primary and a secondary carbon of said alken- 2-yl; alkoxyalkyl of 2 through 6 total carbons; dipyrazole. methylamino; and dialkylaminoalkyl where each of the 11; 3 (5)-acetamido-4-cyano-1-N,N-dimethylcarbamylalkyl groups in the dialkyl portion has 1 through 2 pyrazole.
carbons and the remaining alkyl group has 1 through 4 carbons with a total of 3 through 7 in said dialkylaminoalkyl group;
morpholino; carbamylpyrazole. pyrrolidino; .14. 1-N=sec-butyl-N-methylcarbamyl-4 cyano 3(5)- piperidino; formamidopy-razole. dehydropiperidino; 15. 3 (5 )-acetamido-1-N-sec=butyl-N methylcarbamylazabicyclononidino; and 4-cyanopyrazole. a substituted piperidino group of the structure 40 References Cited by the Examiner Y3 UNITED STATES PATENTS I 2,476,986 7/1949 Martin 260310 Y1 Y1 2,817,666 12/1957 Beaver 2603 10 3,013,001 12/1961 Lynn 26087.8 wherein Y is selected from the group consisting of hy- 3,060,091 10/1962 Witkin 167-65 drogen and methyl; Y; is selected from the group con- 3,080,287 3/ 1963 Lewenstein 16 7-65 sisting of hydrogenfmethyl, ethyl and COOR where R, is alkyl of 1 through 4 carbons; and Y is selected References Cited y 'Applicant from the group consisting of hydrogen, alkyl of 1 through 6 carbons, hydroxyalkyl of 2 through 6 car- UNITED l j PATENTS bons, trifluorornethyl, CO0R where R is alkyl of 255 23333 et 1 through 4 carbons, dralkylammoalkyl of 3 through 7 2998426 8/1961 Dickinson.
carbons where each of the alkyl groups in the dialkyl portion has 1 through 2 carbons and the remaining alkyl group has 1 through 4 carbons, pyrrolidinomethyl, and hydrocarbon aralkyl of 7 through 9 carbons; and
R is selected from the group consisting of hydrogen,
formyl, acetyl and propionyl.
amido-4-cyanopyrazole.
10. 4-cyano-1-N,N-dimethylcarbamyl-3 (5 -formamido- 12. 4-cyano-3 (5 -formamidol-N-isopropyl-N methylcarbamylpyrazole.
13. 3(5 -acetamido-4-cyano-l-N-isopropyl-N methyl- ALEX MAZEL, Primary Examiner.
FRANK CACCIAPAGLIA, JR., Examiner.
PAUL L. SABATINE, JOSE TOVAR,
Assistant Examiners.

Claims (1)

1. A COMPOUND SELECTED FROM COMPOUNDS OF THE FORMULA
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US284323A US3274203A (en) 1963-05-31 1963-05-31 1-carbamyl and thiocarbamyl-3-amino-4-nonsubstituted and substituted pyrazoles
SE6369/64A SE301812B (en) 1963-05-31 1964-05-26
CH696364A CH454883A (en) 1963-05-31 1964-05-28 Process for the preparation of pyrazole derivatives
GB22407/64A GB1039963A (en) 1963-05-31 1964-05-29 Improvements relating to pyrazole derivatives
DK270564AA DK116443B (en) 1963-05-31 1964-05-29 Process for the preparation of 3-amino-N-carbamylpyrazole derivatives.
NL6406077A NL6406077A (en) 1963-05-31 1964-05-29
BE672304A BE672304A (en) 1963-05-31 1965-11-12
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3760084A (en) * 1972-05-01 1973-09-18 American Cyanamid Co Method of using 5-amino-1-phenyl or substituted phenyl-4-pyrazolecarbonitriles or carbox-amides
US3760083A (en) * 1972-05-01 1973-09-18 American Cyanamid Co A method for the use of 5-amino-3-ethyl-1-(m-fluorophenyl)-4-pyrazolecarboxamide
US3760082A (en) * 1972-05-01 1973-09-18 American Cyanamid Co Compositions containing 5-amino-3-ethyl-1-phenyl-4-pyrazolecarboxamides and methods of using the same

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3694456A (en) * 1970-05-08 1972-09-26 Takeda Chemical Industries Ltd 1-disubstituted aminopyrazoles
US3940484A (en) * 1971-12-07 1976-02-24 The Boots Company Limited Insecticidal compositions and methods of combatting insects using substituted imidazoles
DE2458965C3 (en) * 1974-12-13 1979-10-11 Bayer Ag, 5090 Leverkusen 3-Amino-indazole-N-carboxylic acid derivatives, process for their preparation and pharmaceuticals containing them
DE102005057894A1 (en) * 2005-12-02 2007-06-06 Basf Ag Stabilized polymerizable mixtures

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2476986A (en) * 1949-07-26 Elmobe louis martin
US2817666A (en) * 1956-10-29 1957-12-24 Monsanto Chemicals N(3-methyl-5-pyrazolone)-halo-carboxanilides
US2998425A (en) * 1959-11-02 1961-08-29 Du Pont Certain aminopyrazole carbonitriles containing a fluoroalkyl substituent
US2998426A (en) * 1959-11-02 1961-08-29 Du Pont Certain amine, cyano pyrazoles
US2998419A (en) * 1959-10-30 1961-08-29 Du Pont Certain amino, dicyano pyrazoles and process
US3013001A (en) * 1959-03-26 1961-12-12 Union Carbide Corp N-substituted pyrazole compounds and polymerization products thereof
US3060091A (en) * 1961-02-13 1962-10-23 Ciba Geigy Corp Analgesic composition consisting of morphines and amino-indanes
US3080287A (en) * 1957-08-05 1963-03-05 Lewenstein Mozes Juda Analgesic compositions

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3308130A (en) * 1962-04-26 1967-03-07 Du Pont N-disubstituted carbamyl pyrazoles

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2476986A (en) * 1949-07-26 Elmobe louis martin
US2817666A (en) * 1956-10-29 1957-12-24 Monsanto Chemicals N(3-methyl-5-pyrazolone)-halo-carboxanilides
US3080287A (en) * 1957-08-05 1963-03-05 Lewenstein Mozes Juda Analgesic compositions
US3013001A (en) * 1959-03-26 1961-12-12 Union Carbide Corp N-substituted pyrazole compounds and polymerization products thereof
US2998419A (en) * 1959-10-30 1961-08-29 Du Pont Certain amino, dicyano pyrazoles and process
US2998425A (en) * 1959-11-02 1961-08-29 Du Pont Certain aminopyrazole carbonitriles containing a fluoroalkyl substituent
US2998426A (en) * 1959-11-02 1961-08-29 Du Pont Certain amine, cyano pyrazoles
US3060091A (en) * 1961-02-13 1962-10-23 Ciba Geigy Corp Analgesic composition consisting of morphines and amino-indanes

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3760084A (en) * 1972-05-01 1973-09-18 American Cyanamid Co Method of using 5-amino-1-phenyl or substituted phenyl-4-pyrazolecarbonitriles or carbox-amides
US3760083A (en) * 1972-05-01 1973-09-18 American Cyanamid Co A method for the use of 5-amino-3-ethyl-1-(m-fluorophenyl)-4-pyrazolecarboxamide
US3760082A (en) * 1972-05-01 1973-09-18 American Cyanamid Co Compositions containing 5-amino-3-ethyl-1-phenyl-4-pyrazolecarboxamides and methods of using the same

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