[go: up one dir, main page]

US3274203A - 1-carbamyl and thiocarbamyl-3-amino-4-nonsubstituted and substituted pyrazoles - Google Patents

1-carbamyl and thiocarbamyl-3-amino-4-nonsubstituted and substituted pyrazoles Download PDF

Info

Publication number
US3274203A
US3274203A US284323A US28432363A US3274203A US 3274203 A US3274203 A US 3274203A US 284323 A US284323 A US 284323A US 28432363 A US28432363 A US 28432363A US 3274203 A US3274203 A US 3274203A
Authority
US
United States
Prior art keywords
methyl
acetamido
carbons
alkyl
grams
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US284323A
Inventor
Jr Clifford L Dickinson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
EIDP Inc
Original Assignee
EI Du Pont de Nemours and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by EI Du Pont de Nemours and Co filed Critical EI Du Pont de Nemours and Co
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 DK270564AA priority patent/DK116443B/en
Priority to NL6406077A priority patent/NL6406077A/xx
Priority to GB22407/64A priority patent/GB1039963A/en
Priority to BE672304A priority patent/BE672304A/fr
Priority to US556540A priority patent/US3362877A/en
Application granted granted Critical
Publication of US3274203A publication Critical patent/US3274203A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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

  • This invention relates to pyrazole derivatives and more particularly refers to 3-amino-N-carbarnylpyrazoles of outstanding pharmaceutical properties.
  • the compounds of this invention are particularly valuable for their remarkable analgesic activity. This activity is combined with significantly high therapeutic ratios. Their outstanding and unusual combination of physiologically beneficial properties is particularly useful since the compounds so far have not shown any evidence of being addicting.
  • 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-Z-yl group; alkoxyalkyl of 2 through 6 total carbons; hydroxyalkyl of 2 through 6 carbons; dimethyl amino; 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
  • 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;
  • R is hydrogen; halogen such as fluorine, bromine and most preferably chlorine; alkyl of 1 through 3 carbons and preferably methyl; or trifiuoromethyl.
  • alkyl or alken-2-yl group is joined to the carbamyl nitrogen by a secondary carbon of the alkyl or alken-Z-yl group.
  • the compounds of this invention are generally solids. They can 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:
  • this latter compound can be prepared by refluxing the 3-aminopyrazole in 98100% formic acid for at least 10 hours, removing the formic acid, and boiling the resulting product in water for 4 or more hours.
  • the 3- acetamidopyrazoles and 3-propionamidopyrazoles are prepared by heating the 3-aminopyrazole with the appropriate anhydride for an hour, removing the excess anhydride and acid, and boiling the product for 4 or more hours.
  • the 4-alkyl-3-aminopyrazoles can be prepared by condensing 1 mole of the appropriate nitrile (propionitrile for methyl as the 4-alkyl) with 1 mole of ethyl formate using .1 mole of sodium ethoxide in ethanol to give the sodium salt of 2-formylpropionitrile.
  • This lattercompound is condensed with a mole of hydrazine hydrochloride by heating under reflux to obtain 3-amino-4-methylpyrazole.
  • 3-amino-4-trifluorornethylpyrazole is prepared by treatting a solution of 3-aminopyrazole-4-carboxylic acid in hydrogen fluoride with sulfur tetrafluoride at 200 C. for at least 6 hours.
  • One general method for the preparation of the pyrazoles of this invention can be carried out Where the amine- N-carbonyl chloride e.g., N,N-dimethylcarbamoyl chloride) is available. In this process there are brought together approximately equimolar amounts of the pyrazole and the chloride in an 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.
  • an unreactive solvent such as ether, ethyl acetate, or benzene
  • the insolube chloride e.g., sodium chloride or triethylamine hydrochloride
  • 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 methd is preferred for amines such as N-methyl-N-hydroxyethylamine where the amine substituent can also react with the phosgene or thiophosgene.
  • the amine carbonyl chlorides such as N-piperidine carboxyl chloride are prepared by placing a flask fitted with a Dry Ice 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 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 pyrazole can be used in the above procedure in place of the amine (piperidine).
  • the amine piperidine
  • 3-acetamidopyrazole one obtains 3- acetamidopyrazole-l-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 in these compounds is particularly valuable because of significantly favorable therapeutic ratios.
  • General painkilling benefits, as Well as other physiological beneficiation 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; prior, concurrent and intended subsequent, medication and treatment, general health of the recipient; frequency of treatment; and of course the purpose and nature of the effect 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 be in 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 500 milligrams 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. For treating 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 novel 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 t e 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 Well 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 ordinarily 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.
  • the amount of active ingredient may if desired be as much as 90 to 95% 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 eflects, 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 -ace tamz'd0-4 -brm0-1 -N ,N -dimethylcarbamylpyrazole A mixture of 10.2 grams of 4-bromo-3-acetamidopyrazole and 2.3 grams of sodium hydride in 100 milliliters of tetrahydrofuran is stirred and refluxed 15 minutes. N,N-dimethylcarbamoyl chloride (5.6 grams) is added and the mixture refluxed two hours. The mixture is filtered and the filtrate concentrated to give 13.6 grams of 3 (5 -acetamido-4-bromo-1-N,N-dimethylcarbamylpyr. azole. Recrystallization from benzene gives a melting point of 124-125 C.
  • the 3 (5 -acetamido-4-bromo-1-N,N-dimethylcarbamylpyrazole of this example exhibits an outstanding combination of pharmacological properties including analgestic and anti-inflammatory activity.
  • the compound is formulated conveniently as an injectible solution of 1%, 2%, 5% and 10% by weight concentration in a mixture of 10% ethanol and 20% propylene glycol in isotonic saline; and in 5,10, and 25 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 at dosage levels in the range of 5100 milligrams.
  • N-methyl-N-n-hexylcarb 3-acetamido-4-bromo-1-N-methylamoyl chloride. N-n-hexylcarbamylpyrazole.
  • N-methyl-N-methoxy- 3-acetamidotbromo-l-N-methylethylcarbamoyl chloride N-methoxyethylcarbamylpyrazo e.
  • Examples 1-15 can be repeated using a similar amount of corresponding thiocarbamoyl chloride reactant in place of the indicated carbamoyl chloride reactant to obtain the corresponding thiocarbamylpyrazole products.
  • EXAMPLE 16 3 -acetamid0-1 -N ,N -dimethy lcarbamylpyrazole
  • a mixture of 12.5 grams of 3-acetamid0pyraz-ole and 4.7 grams of sodium hydride (53%) in milliliters of the dimethyl ether of ethylene glycol are stirred and refluxed 30 minutes.
  • N,N-Dimethylcarbamoyl chloride (10.7 grams) is added and the mixture refluxed overnight.
  • the mixture is filtered and the filtrate evaporated to dryness.
  • the solid remaining is recrystallized from benzene to give 12.5 grams of 1-N,N-dimethylcarbamyl- 3-acetamidopyrazole, M.P. 122-124" C.
  • the compound is formulated and used in 25, 50 and 100 milligram amounts in standard two pieced hard gelatin capsules for oral administration.
  • the compound is formulated conveniently as injectible solutions of 5 and 10% 7
  • EXAMPLE 17 3-amin0-1-N,N-dimethylcarbwmylpyrazole
  • a mixture of 17.0 grams of 1-N,N-dimethylcarbamyl- 3 5 -(p-dimethylaminobenzalamino pyrazole, 12.5 grams of 2,4-dinitrophenylhydrazine, and 0.5 grams of p-tolu enesulfonic acid in 200 milliliters of ethanol are refluxed 30 minutes, cooled in ice, and filtered.
  • the filtrate is concentrated, dissolved in 150 milliliters of water, treated with decolorizing charcoal, and extracted overnight with chloroform in a continuous extractor.
  • the chloroform extract is concentrated to give 6.4 grams of 3(5)-amino- 1-N,N-dimethylcarbamylpyrazole, M.P. 5962 C., which upon recrystallization from cyclohexane has a melting point of 63-64 C.
  • This compound can be formulated in 10% by weight concentration in isotonic saline solution. Dosage of 50- 100 milligrams as needed can be administered for analgesic and anti-inflammatory treatments.
  • EXAMPLE 18 1-N,N-dimethylcarbamyl-3-formamidopyrazole A solution of grams of 3-aminopyrazole in 50 milliliters of 98% formic acid is heated under reflux overnight (16 hours). The formic acid is removed under reduced pressure (7 mm.) and the residue is refluxed in 100 milliliters of water for six hours. This is cooled and the precipitate of 3-formamidopyrazole is collected to yield 10.0 grams, M.P. 160161 C.
  • the compound of this example has significant analgesic and anti-inflammatory activity. It is conveniently formulated in 2% by weight concentration in water together with a flavoring agent and can be taken orally in doses of from 10 to 50 milligrams each every 4 to 6 hours as needed as a codeine substitute for relief from pain.
  • It can also be formulated as a tablet containing from 2.5 to 50 milligram amounts, from 14% by weight of gelatin and from 0.5 to 1.5% by weight of a lubricant such as magnesium stearate or talc, and mannitol as a filler.
  • a lubricant such as magnesium stearate or talc, and mannitol
  • EXAMPLE 5 3-acetamid0-1 -N -piperidinocarbonylpyrazol e
  • a mixture of 12.5 grams (0.1 mole) of 3-acetamidopyrazole and 4.7 grams of sodium hydride (53% in oil) in 200 milliliters of dimethoxy ethane is stirred and refluxed for 30 minutes.
  • Pentamethylenecarbamoyl chloride (15.7 grams, 0.1 mole) is added in portions, and the mixture is refluxed 8 hours with stirring.
  • the hot reaction mixture is filtered and the precipitate Washed with ethyl acetate.
  • the filtrate is cooled in ice and the precipitate is collected, yield 4.4 grams, M.P. 188-197 C.
  • the precipitate first obtained is washed with water to remove the sodium chloride and dried, yield 14.3 grams, M.P. 202-204 C. A portion of the latter is recrystallized twice from dioxane to give pure 3-acetarnido-l-N-piperidinocarbonylpyrazole, M.P. 207.5208.5 C.
  • This compound can be formulated and used in 5, 10 and 50 milligram amounts in standard two piece hard' gelatin capsules containing corn starch as a diluent.
  • Example Product Product 3-amin0-4-ehloro-1-N,N-dimethylcarbamylpyrazole. 3-amino4-fluoro-1-N-methy1-N-ethylcarbamylpyrazole. 3-amino-4-trifluoromethyl-l-N-methyl-N- (buten-2yl)- carbamylpyrazole. 3-amino-4-ethyl-1-N-methyl-N-(5-hydroxypentyl) carbamylpyrazole. 3-amino-4-methyl-1-N,N-dimethylthioearbamylpyrazole. 3-amino-4-chloro-l-N-methyl-N-ethylthioearbamylpyrazole.
  • 3-amino-1-N-morpholinocarbonylpyrazole 3-acetamido-l-N-py'rrolidinocarbonylpyrazole. 3-f0rmamido-l-N-piperidinocarbonylpyrazole. 3-formamido-1 N-dehydropiperidinocarbonylpyrazole. 3-acetamido-1 N -dehydropiperidinocarbonylpyrazolc. 3-formamido-l-N-azabicyclononylcarbonylpyrazole.
  • Y is selected from the group consisting of hydrogen 'and methyl
  • Y is selected from the group consisting of hydrogen, methyl, ethyl and -COOR where R is alkyl of 1 through 4 carbons
  • Y is selected from the group consisting of hydrogen, alkyl of 1 through 6 carbons, hydroxyalkyl of 2 through 6 carbons, trifluorornethyl, -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 through 2 carbons and the remaining alkyl group has 1 through 4 carbons, lpyrrolidinomethyl, and hydrocarbon aralkyl of 7 through 9 carbons;
  • R is selected from the group consisting of hydrogen
  • R is selected from the group consisting of hydrogen
  • R is methyl and R is alkyl of 1 through 6 carbons joined to the carbamyl nitrogen by a secondary carbon of the alkyl, R is selected from the group consisting of formyl, acetyl and propionyl, R is chlorine, and X is oxygen.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

United States Patent I-CARBAMYL AND ThrdcARBAMvL-s-AMINo-4- NONSUBSTITUTED AND SUBSTITUTED PYRAZ- OLIES Clifiord L. Dickinson, Jr., Wilmington, Del., assignor to E. I. du Pont de Nemonrs and Company, Wilmington,
DeL, a corporation of Delaware No Drawing. Filed May 31, 1963, 'Ser. No. 284,323 19 Claims. (Cl. 260-294) This invention relates to pyrazole derivatives and more particularly refers to 3-amino-N-carbarnylpyrazoles of outstanding pharmaceutical properties.
The compounds of this invention are particularly valuable for their remarkable analgesic activity. This activity is combined with significantly high therapeutic ratios. Their outstanding and unusual combination of physiologically beneficial properties is particularly useful since the compounds so far have not shown any evidence of being addicting.
The compounds of this invention have the formula:
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-Z-yl group; alkoxyalkyl of 2 through 6 total carbons; hydroxyalkyl of 2 through 6 carbons; dimethyl amino; 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 structure from the following group:
morpholino, i.e.,N
pyrrolidyl, i.e.,N
p peridyl, i.e.,N
dehydropiperidyl, i.e.,-N
3,274,203 Patented Sept. 20, 1966 mono-substituted piperidyl of the structure 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 ptolylethyl;
and disu'bstit-uted piperidyl of the structure where Y and Y have the same meaning as above;
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; and
R is hydrogen; halogen such as fluorine, bromine and most preferably chlorine; alkyl of 1 through 3 carbons and preferably methyl; or trifiuoromethyl.
Of 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 carbamyl nitrogen by a secondary carbon of the alkyl or alken-Z-yl group.
The compounds of this invention are generally solids. They can can be used as inhibitors for vinyl polymerization but are particularly useful for their physiological characteristics.
Because of their excellent analgesic activity and other 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:
1-N-(4-methylpiperidino) carbonyl-3 (5) formarnido-4-chloropyrazole 1-N-(4-methylpiperidino carbonyl-3 (5 formamido-4-methylpyrazole l-N- 4-methylpiperidino carb onyl-3 5 acetamido-4-chloropyrazole l-N- (4 methylpiperidino) carbonyl-3 (5 acetamido-4-methylpyrazole 1-N-(4-methylpiperidino) carbonyl-3 (5 propionamido-4-chloropyrazole l-N- (4-methylpiperidino) carbonyl-3 (5 propionamido-4-methylpyrazole 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:
1-N,N-dimethylcarbamyl-3 (5 -formamidopyrazole 3 (5 -acetamido-1-N,N-dimethylcarbamylpyrazole 1 N methyl N isopropylcarbamyl 3(5) formamidopyrazole 3(5) acetamido 1 N methyl N isopropylcarbamylpyrazole 1 N sec butyl N methylcarbamyl 3(5) formanidopyrazole I :2 3(5) acetamido 1 N sec butyl N methylcarbamylpyrazole The substituted carbamyl pyrazoles of this invention can be prepared by reaction of the appropriate pyrazole with selected reactants as more fully described below.
When the starting material is a 3-formamidopyrazole compopnd, this latter compound can be prepared by refluxing the 3-aminopyrazole in 98100% formic acid for at least 10 hours, removing the formic acid, and boiling the resulting product in water for 4 or more hours. The 3- acetamidopyrazoles and 3-propionamidopyrazoles are prepared by heating the 3-aminopyrazole with the appropriate anhydride for an hour, removing the excess anhydride and acid, and boiling the product for 4 or more hours.
The 4-alkyl-3-aminopyrazoles can be prepared by condensing 1 mole of the appropriate nitrile (propionitrile for methyl as the 4-alkyl) with 1 mole of ethyl formate using .1 mole of sodium ethoxide in ethanol to give the sodium salt of 2-formylpropionitrile. This lattercompound is condensed with a mole of hydrazine hydrochloride by heating under reflux to obtain 3-amino-4-methylpyrazole.
3-amino-4-trifluorornethylpyrazole is prepared by treatting a solution of 3-aminopyrazole-4-carboxylic acid in hydrogen fluoride with sulfur tetrafluoride at 200 C. for at least 6 hours.
One general method for the preparation of the pyrazoles of this invention can be carried out Where the amine- N-carbonyl chloride e.g., N,N-dimethylcarbamoyl chloride) is available. In this process there are brought together approximately equimolar amounts of the pyrazole and the chloride in an 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 insolube chloride, e.g., sodium chloride or triethylamine hydrochloride, is filtered ofi 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 methd is preferred for amines such as N-methyl-N-hydroxyethylamine where the amine substituent can also react with the phosgene or thiophosgene.
The amine carbonyl chlorides such as N-piperidine carboxyl chloride are prepared by placing a flask fitted with a Dry Ice 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 effect purification.
Alternatively, the pyrazole can be used in the above procedure in place of the amine (piperidine). By this procedure, with 3-acetamidopyrazole, one obtains 3- acetamidopyrazole-l-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 in these compounds is particularly valuable because of significantly favorable therapeutic ratios. General painkilling benefits, as Well as other physiological beneficiation 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; prior, concurrent and intended subsequent, medication and treatment, general health of the recipient; frequency of treatment; and of course the purpose and nature of the effect 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 be in 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 500 milligrams 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. For treating 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 novel 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 t e 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 Well 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 5 by E. W. Martin and E. F. Cook, 12th edition, 1961, published by the Mack Publishing Company, Easton, Pennsylvania.
In 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 ordinarily 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 90 to 95% 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 eflects, 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 -ace tamz'd0-4 -brm0-1 -N ,N -dimethylcarbamylpyrazole A mixture of 10.2 grams of 4-bromo-3-acetamidopyrazole and 2.3 grams of sodium hydride in 100 milliliters of tetrahydrofuran is stirred and refluxed 15 minutes. N,N-dimethylcarbamoyl chloride (5.6 grams) is added and the mixture refluxed two hours. The mixture is filtered and the filtrate concentrated to give 13.6 grams of 3 (5 -acetamido-4-bromo-1-N,N-dimethylcarbamylpyr. azole. Recrystallization from benzene gives a melting point of 124-125 C.
Analysis.Calcd. for C H N O Br: C, 34.9; H, 4.0. Found: C, 35.6; H, 4.0.
The 3-acetamido-4-bromopyrazole is obtained by the following procedure:
A solution of 16.6 grams of 3-aminopyrazole in 75 milliliters of acetic acid and 40 milliliters of acetic anhydride is heated under reflux for one hour. The solvent is removed under reduced pressure, 200 milliliters of water added, and the solution refluxed four hours and cooled. The precipitate of 3-acetamidopyrazole is collected, yield 21.3 grams, M.P. 222.5223.5 C.
Analysis.-Calcd. for C H N O: C, 48.0; H, 5.6; N, 33.6. Found: C, 48.2; H, 5.8; N, 34.0.
To a stirred mixture of 3.0 grams of 3-acetamidopyrazole and milliliters of water is added 4.0 grams of bromine. After three hours, the solution is made neutral with 10% sodium hydroxide and after some time a precipitate of 3-acetamido-4-bromopyrazole is collected (yield 3.3 grams). It is recrystallized from ethyl acetate, M.P. 144.5145.5 C.
Analysis.C-alcd. for C H N OBr: C, 29.4; H, 3.0; Br, 39.2. Found: C, 30.7; H, 2.8; Br, 37.5.
The 3 (5 -acetamido-4-bromo-1-N,N-dimethylcarbamylpyrazole of this example exhibits an outstanding combination of pharmacological properties including analgestic and anti-inflammatory activity. The compound is formulated conveniently as an injectible solution of 1%, 2%, 5% and 10% by weight concentration in a mixture of 10% ethanol and 20% propylene glycol in isotonic saline; and in 5,10, and 25 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 at dosage levels in the range of 5100 milligrams.
The general procedure of the preceding example is exemplary compounds of this invention:
113x Amine-N-carbonyl-chloridc Product 2. N -methylN-ethylcarb- 3-acetamido-4-bromo-1-N-methylamoyl chloride. N -ethylcarbamylpyrazole.
3. N -methyl-N-isopropyl- 3-acetamido-4-bromo-1-N-methylcarbamoyl chloride. N-isopropylcarbamylpyrazole.
4-- N-methyl-N-secbutyl- 3-acetamido-4-bromo-1-N-methylcarbamoyl chloride. N-sec-butylcarbarnylpyrazole.
5. N-methyl-N-n-hexylcarb: 3-acetamido-4-bromo-1-N-methylamoyl chloride. N-n-hexylcarbamylpyrazole.
6. N-methyl-N- (penten-2 yl) 3-acetamido--bromo-l-N-methylcarbamoyl chloride. N (1p enten-2-yl) carbamylpyram e.
7. N-methyl-N- (2-hydr0xy- 3-acetamido-4-bromo-1-N-n1ethylethyD-carbamoyl chlor- N -(2-hydroxyethyl) carbamylide. pyrazole.
8.- N-methyl-N-methyoxy- 3acetamidoA-bromo-LN-methylmethylcarbamoyl chlor- N -methoxymethylcarbamylide. pyrazole.
9.-... N-methyl-N-methoxy- 3-acetamido-4bro1no-1-N-methylpropylcarbamoyl chlo- N-methoxypropylcarbamylride. pyrazole.
10.... Nmethyl-N-dimethyl- 3-acetamido-4-bromo-1-N-methylaminocarbamoyl chlo- N -dimethylaminocarbamylride. pyrazole.
11.-.. N-methyl-N-diethyl- B-acetamido-4-bromo-1-N-methylaminoethylcarbamoyl N -diethylaminoethylcarb amylchloride. pyrazole.
l2. N-methyl-N-n-propyl- 3-acetamido-4-bromo-1-N-methylcarbamoyl chloride. N-n-propylcarbamylpyrazole.
13. N -methyl-N-isobutyl- 3-acetarnido-4-bromo-1-N-methylcarbamoyl chloride. N-isobutylcarbsmylpyrazole.
14. N-methyl-N-allylcarb- 3-acet:amido-4-brorn0d-N-methylamoyl chloride. N-allylcarbamylpyrazole.
15 N-methyl-N-methoxy- 3-acetamidotbromo-l-N-methylethylcarbamoyl chloride. N-methoxyethylcarbamylpyrazo e.
The preceding Examples 1-15 can be repeated using a similar amount of corresponding thiocarbamoyl chloride reactant in place of the indicated carbamoyl chloride reactant to obtain the corresponding thiocarbamylpyrazole products.
Similarly, the preceding procedures can be repeated using the corresponding 4-chloro, 4-fluoro, 4-alkyl and 4-trifluoromethylcarbarnoyl and thiocarbamoyl chloride reactants in place of the indicated carbamoyl rand thiocarbamoyl chloride reactant to obtain the corresponding carbamylpyrazole and thiocarbamylpyrazole products.
Similarly, the preceding examples can be repeated using corresponding carbamoyl and thiocarbamoyl chloride reactants having only hydrogen in the 4-position to obtain the corresponding 4-unsubstituted carbamylpyrazole and thiocarbamylpyrazole products, as illustrated by the following:
EXAMPLE 16 3 -acetamid0-1 -N ,N -dimethy lcarbamylpyrazole A mixture of 12.5 grams of 3-acetamid0pyraz-ole and 4.7 grams of sodium hydride (53%) in milliliters of the dimethyl ether of ethylene glycol are stirred and refluxed 30 minutes. N,N-Dimethylcarbamoyl chloride (10.7 grams) is added and the mixture refluxed overnight. The mixture is filtered and the filtrate evaporated to dryness. The solid remaining is recrystallized from benzene to give 12.5 grams of 1-N,N-dimethylcarbamyl- 3-acetamidopyrazole, M.P. 122-124" C.
Analysis.Calcd. for C H N O C, 49.0; H, 6.2; N, 28.6. Found: C, 48.0; H, 6.2; N, 28.8.
The compound is formulated and used in 25, 50 and 100 milligram amounts in standard two pieced hard gelatin capsules for oral administration. The compound is formulated conveniently as injectible solutions of 5 and 10% 7 EXAMPLE 17 3-amin0-1-N,N-dimethylcarbwmylpyrazole A mixture of 17.0 grams of 1-N,N-dimethylcarbamyl- 3 5 -(p-dimethylaminobenzalamino pyrazole, 12.5 grams of 2,4-dinitrophenylhydrazine, and 0.5 grams of p-tolu enesulfonic acid in 200 milliliters of ethanol are refluxed 30 minutes, cooled in ice, and filtered. The filtrate is concentrated, dissolved in 150 milliliters of water, treated with decolorizing charcoal, and extracted overnight with chloroform in a continuous extractor. The chloroform extract is concentrated to give 6.4 grams of 3(5)-amino- 1-N,N-dimethylcarbamylpyrazole, M.P. 5962 C., which upon recrystallization from cyclohexane has a melting point of 63-64 C.
Analysis.-Calcd. for C H N O: C, 46.7; H, 6.5; N, 36.4. Found: C, 47.1; H, 6.4; N, 36.2.
This compound can be formulated in 10% by weight concentration in isotonic saline solution. Dosage of 50- 100 milligrams as needed can be administered for analgesic and anti-inflammatory treatments.
EXAMPLE 18 1-N,N-dimethylcarbamyl-3-formamidopyrazole A solution of grams of 3-aminopyrazole in 50 milliliters of 98% formic acid is heated under reflux overnight (16 hours). The formic acid is removed under reduced pressure (7 mm.) and the residue is refluxed in 100 milliliters of water for six hours. This is cooled and the precipitate of 3-formamidopyrazole is collected to yield 10.0 grams, M.P. 160161 C.
A mixture of 5.7 grams of 3-formamidopyrazole, 2.4 grams of sodium hydride (53% in mineral oil) and 5.3 grams of N,N-dimethylcarbamoyl chloride is stirred and heated under reflux overnight. The mixture is filtered and the filtrate is.evaporated to dryness. The residue is recrystallized from benzene to give 5.25 grams of 1-N,N- dimethylcarbamyl-3-forrnamidopyrazole, M.P. 75-78 C.
The compound of this example has significant analgesic and anti-inflammatory activity. It is conveniently formulated in 2% by weight concentration in water together with a flavoring agent and can be taken orally in doses of from 10 to 50 milligrams each every 4 to 6 hours as needed as a codeine substitute for relief from pain.
It can also be formulated as a tablet containing from 2.5 to 50 milligram amounts, from 14% by weight of gelatin and from 0.5 to 1.5% by weight of a lubricant such as magnesium stearate or talc, and mannitol as a filler.
By the foregoing procedures the following examplary compounds can be obtained:
Product 3-acetamido-4-methyl-l-N-methyl-N-ethylthiocarbamylpyrazole. 3-propionamido-1-N,N-dimethylcarbamylpyrazole. 3-propionamide-1-N,N-dimethylthiocarbamylpyrazole. 3-pro1l)ionamidoi-bromo-l-N ,N-dimethylcarbamylpyrazo e. 3-propionamido--chloro-1-N,N-dimethy1carbamylpyrazo e. 3-propionamidoi-methyl-l-N,N-dimethylcarbamylpyrazole. 3-propionamido-4-trifiuoromethyl-l-N-methyl-N-secbutylcarbamylpyrazole 3-formarriidoA-chlor0-l-N-methyl-N-n-propylearbamylpyrazo e.
43 3-f0rmamido-4chloro-1-N -methyl-N-11-pr0py1thiocarbamylpyrazole.
44 3-formaniid -4-methyl-l-N-methyl-N-n-propylcarbamylpyrazo e.
45 3 iormamido-4-bromo'1-N-methyl-N-n-propylcarbamylpyrazole.
46 3-formamido-4-bromo-1-N-methyl-N-isopropylcarbamylpyrazole.
47 3-formamido-4ch1oro-1-N-methyl-N-isopropylcarbamylpyrazole.
48 3-acetamido-4-chloro-1-N-methyl-N-methoxyethylcarbamylpyrazole.
49 3-formamido4-chlor0-l'N-methyl-N-dimethylaminocarbamylpyrazole.
50 3-forn1amidoi-bromo-l-N-methyl-N-1sobutylcarbamylpyrazole.
51 3-propionamido--methyl-l-N-methyl-N-allylcarbamylpyrazole.
52 3-arm'no-4-n-propyl1N-methyl-N-diethylaminoethylcarbamylpyrazole.
EXAMPLE 5 3 3-acetamid0-1 -N -piperidinocarbonylpyrazol e A mixture of 12.5 grams (0.1 mole) of 3-acetamidopyrazole and 4.7 grams of sodium hydride (53% in oil) in 200 milliliters of dimethoxy ethane is stirred and refluxed for 30 minutes. Pentamethylenecarbamoyl chloride (15.7 grams, 0.1 mole) is added in portions, and the mixture is refluxed 8 hours with stirring. The hot reaction mixture is filtered and the precipitate Washed with ethyl acetate. The filtrate is cooled in ice and the precipitate is collected, yield 4.4 grams, M.P. 188-197 C. The precipitate first obtained is washed with water to remove the sodium chloride and dried, yield 14.3 grams, M.P. 202-204 C. A portion of the latter is recrystallized twice from dioxane to give pure 3-acetarnido-l-N-piperidinocarbonylpyrazole, M.P. 207.5208.5 C.
Analysis.-Calcd. for C H N O C, 55.9; H, 6.8. Found: C, 56.0; H, 7.0.
This compound can be formulated and used in 5, 10 and 50 milligram amounts in standard two piece hard' gelatin capsules containing corn starch as a diluent.
The preceding example is repeated substituting other substituted pyrazoles and substituted carbamoyl and thiocarbamoyl chlorides for the reactants of that Example to obtain the following compounds:
Example Product Product 3-amin0-4-ehloro-1-N,N-dimethylcarbamylpyrazole. 3-amino4-fluoro-1-N-methy1-N-ethylcarbamylpyrazole. 3-amino-4-trifluoromethyl-l-N-methyl-N- (buten-2yl)- carbamylpyrazole. 3-amino-4-ethyl-1-N-methyl-N-(5-hydroxypentyl) carbamylpyrazole. 3amino-4-methyl-1-N,N-dimethylthioearbamylpyrazole. 3-amino-4-chloro-l-N-methyl-N-ethylthioearbamylpyrazole. 3-formamide-4-ehloro-1-N-methyl-N-cthylcarbamylpyrazole. 3-formamido-4-bromo-1-N-methyl-N-diethylaminocthylcarbamylpyrazole. 8-formamid0-4-methyl-l-N-methyl-N-ethoxypropylthiocarbamylpyrazole. 3-acetamido-4-ehloro-1-N,N-dimethylcarbamylpyrazole. 3-aeetamidot-methyl-l-N,N-dimethylcarbamylpyrazole. 3-acetamido-4-chloro -1-N,N -dimethylthiocarbamy1pyrazole. 3-acet1amido-4-methyl-1-N,N-dimethylthiocarbamylpyrazo e. 3-acetlamido-4-chloro1-N-methyl-N-ethylcarbamylpyrazo e. 3-acetamido-4-chloro-1-N-methyl-N-ethylthiocarbamylazole. 3acetiamidoAmethyI-I-N-methyI-N-ethy1carbamylpyrazo e.
3-amino-1-N-morpholinocarbonylpyrazole. 3-acetamido-l-N-py'rrolidinocarbonylpyrazole. 3-f0rmamido-l-N-piperidinocarbonylpyrazole. 3-formamido-1 N-dehydropiperidinocarbonylpyrazole. 3-acetamido-1 N -dehydropiperidinocarbonylpyrazolc. 3-formamido-l-N-azabicyclononylcarbonylpyrazole.
3-acetamido-1-N-(3,4-di111ethylpiperidino)-carb0nylpyra- Example Product 71 3-acetamidoA-methyl-l-Npyrrolidinocarbonylpyrazole.
72 3-formamid0-4-chloro-l-N-p-methylpiperidino (thiecarbonyDpyrazole.
73 B-propiouamido-4-isopr0pyl-l-N-p-isopropylpiperidinocarbonylpytazole.
74 3-arnino-4-fiuoro-1-N-[p-(n-propyl)piperidino]- carbonylpyrazole.
75 3-acetamido-4-ethy1-l-N-phenethylpiperidinocarbonylpyrazole.
76 3-formamido-4-chloro -1-N -(p-diethy1amin0ethylpiperidino)carbonylpyrazole.
77 3-acetarnidoAbromo-l-N-(p-pyrrolidinoethylpiperidino)- carbonylpyrazole.
78 3-acetamido i-methyl-l-N-(p-butoxycarbonylpiperidino)- carbonylpyrazole.
79 3-acetarnido-4-chloroJ-N-[3,4-di(2-hydroxyethy1)- piperidino]carbcnylpyrazole.
80 3-formamido-4-bromo-1-N-o-toly1ethylpiperidinocarbonylpyrazole.
The above examples can be repeated to obtain other compounds within the scope of this invention by appropriate selection of reactants as will be readily understood in the art.
The invention claimed is:
1. A compound selected from compounds of the formula where X is selected from the group consisting of oxygen and sulfur; A is selected from the group consisting of wherein R is methyl; and R is selected from the group 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 nitrogen by a carbon selected from the group consisting of a primary and a secondary carbon of said alken- 2-yl; alkloxyalkyl of 2 through 6 total carbons; dimethylamino; and dialkylarninoalkyl 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 with a total of 3 through 7 in said dialkylaminoal'kyl morpholino;
pyrrolidino;
piperidino;
dehydropiperidino;
azabicyclononidino; and
a substituted piperidino group of the structure wherein Y is selected from the group consisting of hydrogen 'and methyl, Y is selected from the group consisting of hydrogen, methyl, ethyl and -COOR where R is alkyl of 1 through 4 carbons; and Y is selected from the group consisting of hydrogen, alkyl of 1 through 6 carbons, hydroxyalkyl of 2 through 6 carbons, trifluorornethyl, -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 through 2 carbons and the remaining alkyl group has 1 through 4 carbons, lpyrrolidinomethyl, and hydrocarbon aralkyl of 7 through 9 carbons;
R is selected from the group consisting of hydrogen,
formyl, acetyl, propionyl; and
R is selected from the group consisting of hydrogen,
chlorine, bromine, fluorine, alkyl of 1 through 3 carb ons, and trifluoromethyl. 2. A compound as set forth in claim 1 wherein where R is methyl and R is alkyl of 1 through 6 carbons joined to the carbamyl nitrogen by a secondary carbon of the alkyl, R is selected from the group consisting of formyl, acetyl and propionyl, R is chlorine, and X is oxygen.
3. A compound as set forth in claim 1 wherein /R1 A is N where R is methyl and R is alkyl of 1 through 6 carbons joined to the carbamyl nitrogen by a secondary carbon of the alkyl R is selected from the group consisting of formyl, acetyl and propionyl, R is methyl, and X is oxygen.
4. A compound as set forth in claim 1 wherein A is a heterocyclic group as defined in claim 1.
5. A compound as set forth in claim 1 wherein A is a 4-mono-substit-uted piperidino group as defined in claim 1.
6. A compound as set forth in claim 1 wherein A is piperidino, R is selected from the group consisting of formyl, acetyl and propionyl, R is chlorine, and X is oxygen.
7. A compound as set forth in claim 1 wherein A is piperidino, R is selected from the group consisting of formyl, acetyl and propionyl, R is methyl, and X is oxygen.
8. 1-N-(4 methylpiperidino)carbonyl-3(5)-formamido- 4-chloropyrazole.
9. 1-N-(4-methylpiperidino)carbonyl-3 (5 -formamido- 4-methylpyrazole.
10. 1-N-(4-methylpi-peridino) carbonyl-3 (5 -acetarnido- 4-chloropyrazole.
11. 1-N-(4-methylpiperidino)carbonyl-3 (5 -acetamido- 4-methylpyrazole.
12. 1 N-(4-methylpiperidino)carbonyl-3 (5)-propionamido-4-chloropyrazole.
13. 1 N-(4-methylpiperidino)carbonyl-3(5)-propionamido-4-methylpyrazole.
15. 3 (5 -acetamido-1-N,N-dimethylcarbamylpyrazole.
14. 1-N,N-dimethylcarbamyl-3 (5 -formamidopyrazole.
16. "1-N-methyl-N-isopropylcarbamyl-3 5 -formamidopyrazole.
17. 3 (5) -acetamido-1-N-methy1-N-isopropyl-oarbamylpyrazole.
18. 1 N-sec-butyl-N-methylcarbamyl-3(5)-formamidopyrazole.
3,2 74, 2O 3 1 1 1 2 19. 3(5) acetamido-1-N-sec-butyl-N-methyl-carbamyl- References Cited by the Applicant PYraZole- UNITED STATES PATENTS 2,998,419 8/1961 Dickinson et a1.
efmnces Cted by the Exammer 2,998,425 8/1961 Dickinson (31; n1.
UNITED STATES PATENTS 5 2,998,426 8/1961 Dickinson et 211. 2,476,986 7/1949 Martin 260-310 2,817,666 12/1957 Beaver 260-310 ALEX MAZEL, Primary Examiner- 3,013,001 12/1961 Lynn 26087.7 FRANK CACCIAPAGLIA, JR., HENRY R. JILEs, 3,060,091 10/1962 Witkin 16765 10 Examiners.
3,080,287 3/ 1963 Lewenstein 167- 65 PAUL SABATINE, JOSE TOVAR, Assistant Examiners.

Claims (1)

1. A COMPOUND SELECTED FROM COMPOUNDS OF THE FORMULA
US284323A 1963-05-31 1963-05-31 1-carbamyl and thiocarbamyl-3-amino-4-nonsubstituted and substituted pyrazoles Expired - Lifetime US3274203A (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
US284374A US3277100A (en) 1963-05-31 1963-05-31 Novel substituted pyrazoles
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
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
GB22407/64A GB1039963A (en) 1963-05-31 1964-05-29 Improvements relating to pyrazole derivatives
BE672304A BE672304A (en) 1963-05-31 1965-11-12
US556540A US3362877A (en) 1963-05-31 1966-06-10 Use of 3-amino-n-carbamylpyrazoles as analgesic agents

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US284374A US3277100A (en) 1963-05-31 1963-05-31 Novel substituted pyrazoles
US284323A US3274203A (en) 1963-05-31 1963-05-31 1-carbamyl and thiocarbamyl-3-amino-4-nonsubstituted and substituted pyrazoles
US556540A US3362877A (en) 1963-05-31 1966-06-10 Use of 3-amino-n-carbamylpyrazoles as analgesic agents

Publications (1)

Publication Number Publication Date
US3274203A true US3274203A (en) 1966-09-20

Family

ID=27403460

Family Applications (3)

Application Number Title Priority Date Filing Date
US284323A Expired - Lifetime US3274203A (en) 1963-05-31 1963-05-31 1-carbamyl and thiocarbamyl-3-amino-4-nonsubstituted and substituted pyrazoles
US284374A Expired - Lifetime US3277100A (en) 1963-05-31 1963-05-31 Novel substituted pyrazoles
US556540A Expired - Lifetime US3362877A (en) 1963-05-31 1966-06-10 Use of 3-amino-n-carbamylpyrazoles as analgesic agents

Family Applications After (2)

Application Number Title Priority Date Filing Date
US284374A Expired - Lifetime US3277100A (en) 1963-05-31 1963-05-31 Novel substituted pyrazoles
US556540A Expired - Lifetime US3362877A (en) 1963-05-31 1966-06-10 Use of 3-amino-n-carbamylpyrazoles as analgesic agents

Country Status (5)

Country Link
US (3) US3274203A (en)
CH (1) CH454883A (en)
DK (1) DK116443B (en)
GB (1) GB1039963A (en)
SE (1) SE301812B (en)

Cited By (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
US4051252A (en) * 1974-12-13 1977-09-27 Bayer Aktiengesellschaft 3-aminoindazole-1 and 2-carboxylic acid derivatives
WO2007063031A3 (en) * 2005-12-02 2007-07-19 Basf Ag Stabilized polymerizable mixtures

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
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
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

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
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
US2998425A (en) * 1959-11-02 1961-08-29 Du Pont Certain aminopyrazole carbonitriles containing a fluoroalkyl substituent
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
US2998426A (en) * 1959-11-02 1961-08-29 Du Pont Certain amine, cyano pyrazoles
US2998425A (en) * 1959-11-02 1961-08-29 Du Pont Certain aminopyrazole carbonitriles containing a fluoroalkyl substituent
US3060091A (en) * 1961-02-13 1962-10-23 Ciba Geigy Corp Analgesic composition consisting of morphines and amino-indanes

Cited By (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
US4051252A (en) * 1974-12-13 1977-09-27 Bayer Aktiengesellschaft 3-aminoindazole-1 and 2-carboxylic acid derivatives
WO2007063031A3 (en) * 2005-12-02 2007-07-19 Basf Ag Stabilized polymerizable mixtures

Also Published As

Publication number Publication date
US3277100A (en) 1966-10-04
US3362877A (en) 1968-01-09
CH454883A (en) 1968-04-30
SE301812B (en) 1968-06-24
DK116443B (en) 1970-01-12
GB1039963A (en) 1966-08-24

Similar Documents

Publication Publication Date Title
US3687965A (en) Novel 5-(n-substituted aminomethyl)-2-oxazolidinones and their process of preparation
US4385057A (en) Diphenylbutyl-piperazinecarboxamides in pharmaceutical compositions and methods
US4093734A (en) Amino-benzoic acid amides
US3665009A (en) 1-carbamolypyrazole-4-sulfonamides
US3308130A (en) N-disubstituted carbamyl pyrazoles
US3577415A (en) 1-substituted-3-substituted phenoxypyrrolidines
US3274203A (en) 1-carbamyl and thiocarbamyl-3-amino-4-nonsubstituted and substituted pyrazoles
US4518712A (en) Piperazine derivative and analgesic composition containing the same
JPH0723364B2 (en) Novel 1-piperazine carboxamide derivative
US3966957A (en) Method for controlling emesis with N-(1-substituted-3-pyrrolidinyl)benzamides and thiobenzamides
US3927011A (en) 2-Aminoalkyl-1-(pyridylcarbonylphenyl)imidazole compounds
US3517007A (en) 5 - acetamido - 4 - pyrimidinecarboxamides,5 - acetamido - 4 - pyrimidinecarboxylic acid hydrazides and related compounds
JPH0723365B2 (en) Novel piperazine carboxamide compounds with phenoxyalkyl or thiophenoxyalkyl side chains
US3407193A (en) Substituted biurets
US3474090A (en) 3-aminoalkyl-1,3-benzodiazepin-2-ones
US3760074A (en) Pharmaceutical compositions containing a 5-phenyl-7-bromo-1h-1,5-benzodiazepine-2,4-(3h,5h)-dione
US3663564A (en) Urazoles and their production
US4065451A (en) 1,3-Dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one, substituted diamino acetate esters and their acid salts
US3133924A (en) Amino-substituted cyclobutane carboxamides
US3636111A (en) Carbamoyl oximes
US4247705A (en) 4-Substituted 2-iminoimidazolidine compounds
US3376306A (en) 1-carboxamido-3-amino-1, 2, 4-triazoles and a process for their preparation
DE69404322T2 (en) 3-ARYL-4-ALKYL AND 4,5-DIALKYL-4H-1,2,4-TRIAZOLES, USED AGAINST MEMORY DISORDERS
US3465080A (en) Therapeutic compositions containing morpholinoalkylene - indoles and methods of administering such in the treatment of depression
US3987175A (en) Derivatives of phenoxy isobutyric acid having hypolipemizing and hypocholesterolemizing action