US3308130A - N-disubstituted carbamyl pyrazoles - Google Patents

N-disubstituted carbamyl pyrazoles Download PDF

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US3308130A
US3308130A US312871A US31287163A US3308130A US 3308130 A US3308130 A US 3308130A US 312871 A US312871 A US 312871A US 31287163 A US31287163 A US 31287163A US 3308130 A US3308130 A US 3308130A
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dimethylcarbamyl
compound
carbon atoms
solution
ether
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Euclid W Bousquet
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EIDP Inc
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EI Du Pont de Nemours and Co
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Priority to CH83568A priority patent/CH461513A/de
Priority to CH28864A priority patent/CH460026A/de
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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
    • C07D231/12—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon 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
    • 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
    • C07D231/16—Halogen atoms or nitro radicals
    • 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
    • C07D231/18—One oxygen or sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • This invention relates to pyrazoles.
  • this invention relates to nuclear nitrogen substituted pyrazoles and to pharmaceutical compositions and processes utilizing as an essential active ingredient a novel pyrazole compound within the scope of this invention.
  • the compounds of this invention have outstanding activity as analgesic agents, as measured in standard animal tests. Furthermore, certain of these compounds produce antiinflammatory activity similar to that shown by adrenocortical steroids, and some have antipyretic activity.
  • R is methyl
  • R is alkyl of 1 through 6 carbon atoms, alkenyl of 3 through 6 carbon atoms, alkoxyalkyl of 2 through 6 total carbon atoms, hydroxyalkyl of 2 through 6 carbon atoms, methylalkylamino of 2 through carbon atoms, dialkylaminoalkyl where each of the alkyl groups in the dialkyl portion has 1 or 2 carbon atoms and the remaining alkyl group has 1 through 4 carbon atoms with a total of from 3 through 7 carbon atoms in the dialkylaminoalkyl group (CHA),,CN where a and A are as above; with the limitation that R is joined to the carbamyl nitrogen by a primary or secondary carbon atom; and where R and R can be joined-together and together with the carbamyl nitrogen form a heterocyclic structure from the following group:
  • dehydropiperidyl i.e.
  • Y is H,'hydroxy, alkyl of 1 through 9 carbon atoms
  • cycloalkylalkyl of 4 through 9 carbon atoms hydroxyalkyl of 2 through 9 carbon atoms, alkoxyalkyl of 3 through 9 carbon atoms, trifiuoromethyl, COOR where R is alkyl of 1 through 4 carbon atoms,
  • R is hydrogen, alkyl of lthrough 3 carbon atoms, trifiuoromethyl, fluorine, chlorine, bromine, sulfur pentafluoride or pyridyl
  • R is hydrogen, alkyl of 1 through 3 carbon atoms, trifiuoromethyl, sulfur pentafluoride, alkoxy of 1 through 3 carbon atoms, amino, cyano, fluorine, chlorine, bromine or nitro
  • R is hydrogen, alkyl of 1 through 3 carbon atoms, trifiuoromethyl, fluorine, chlorine or bromine with the limitation that when X where is sulfur or R is other than methyl R must be hydrogen; and with R R plus R containing together a maximum total of 6 carbon atoms.
  • the compounds of this invention can exist as the isomeric formula:
  • a preferred class of compounds are pyrazoles of the formula:
  • R is hydrogen or methyl
  • R is methyl, cyano, chlorine or bromine
  • Y is the same as above.
  • Another preferred class of compounds are pyrazoles of the formula:
  • R is hydrogen
  • R is cyano, chlorine or bromine
  • R is methyl
  • R is alkyl of 1 through 4 carbon atoms, alkenyl of 3 through 4 carbon atoms, or methylalkylamino where the alkyl is l or 2 carbon atoms, with the limitation that R is joined to the carbamyl nitrogen by a primary or secondary carbon.
  • disubstituted carbamyl pyrazole system has been used for the major part for the naming of exemplary compounds of the case.
  • Some of the new compounds of this invention have a bitter taste even when diluted and are effective as denaturants, e.g., in alcohol.
  • the compounds of this invention have outstanding analgesic activity as measured in standard tests.
  • Ac tivity equal to or better than that obtained with morphine has been obtained with a number of the compounds.
  • the therapeutic ratios determined in these cases were also equal to or better than those found for morphine.
  • Tests used to determine analgesic activity were the Hot Plate test described by Eddy in the Journal of Pharmacology and Experimental Therapeutics, vol. 98, pages 121437 (1950) and a modification of the method of Bass and Brook described in the Journal of the American Pharma ceutical Association, vol. 41 (10), page 569 (1952) in Which radiant heat is used to produce a response in test animals. Both of these tests are standard tests used by investigators in the field of analgesia and have been found to give indication of potential analgesic activity in man.
  • 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 amounts. 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 prophylatic eltectiveness 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 eltective 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 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 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.
  • 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 the above formulas will be present in a physiologically beneficial amount as mentioned above.
  • the active ingredient will ordinarily constitute at least about 0.0001% by weight based on the total weight of the composition.
  • concentration will ordinarily be in the range from about 05 to 10.0% by weight of active ingredient.
  • concentrations from 2 to 20% are satisfactory.
  • the amount of active ingredients may if desired be as much as 95 or 98% 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 effects, treatments and benefits.
  • Such materials include but are by no means limited to 6 vitamins, pain killers, tranquilizers, antibiotics, an-titussive 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.
  • the pyrazoles of the above formulas can be prepared by reaction of the appropriate pyrazole containing hydrogen on nuclear nitrogen with selected reactants as more fully described below.
  • an illustrative carbamylating agent is dimethylcarbamyl chloride, although other available aliphatic N-disubstituted carbamyl halides, such as Where the halogen is bromine, can be employed.
  • a further method involves the preparation of a pyrazole having a carbonyl halide or thiocarbonyl halide on nuclear nitrogen.
  • a pyrazole having a carbonyl halide or thiocarbonyl halide on nuclear nitrogen Such compounds are available by the reaction of a pyrazole having hydrogen on nuclear nitrogen and phosgene or thiophosgene as shown in the equation:
  • R R R and X have the same meaning as above.
  • the carbonyl chloride or thiocarbonyl chloride thus available can be reacted with aliphatic secondary amines (including cyclic amines) e.g. dimethylamine or piperidine to give the desired new N-disubstituted carbamyl pyrazoles as follows:
  • Particularly useful compounds and their preparation include the following: 1-dimethylcarbamyl-3,5-dimethyl 4-nitropyrazole (see Example 11) as well as similar nitro derivatives, is useful in the preparation of derivative compounds of this invention. Reduction of this compound with hydrogen in the presence of palladium-oncharcoal catalyst results in the preparation of l-dimethylcarbamyl- 4-amino-3,S-dimethylpyrazole. The latter compound is readily diazotized with nitrous acid in the presence of hydrochloric acid in the cold to give the 4-diazonium chloride of 1-dimethylcarbamyl-3,S-dimethylpyrazole.
  • the diazonium group can be replaced by halogen under procedures known to the art to give for example, the halogen derivatives of Examples 7 and 8.
  • halogen derivatives of Examples 7 and 8. By the use of a watersoluble fluoride, the corresponding fiuoro derivative, i.e., 1-dimet-hylcarbamyl-3,5-dimethyl-4-tluoropyrazole, is obtained.
  • the compound can be "used as a solvent with excellent dissolving power for polar and non-polar compounds and is useful as a reaction medium for organic reactions. It has analgesic and antipyretic activities.
  • the compound is formulated conveniently as an injectible solution of and by weight concentration in isotonic saline; as an injectible solution in 5%, 10% and 15% 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 at dosage levels in the range of 25 500 milligrams for treatment of physiological conditions as described above.
  • Example 2.1-dimethylcarbamyl-3,4- (4,5) -diethyl-5(3) A solution of 43.3 g. of 3,4(4,5)-diethyl-5(3)-methylpyrazole (obtained by the condensation of hydrazine with 3-ethylhexane-2,4-dione), 32 g. of triethylamine, and 34 g. of dimethylcarbamyl chloride in 200 ml. of benzene was allowed to stand at room temperature for 65 hours. The solution was then poured into 200 ml. of water. The benzene layer was collected and washed with two ZOO-ml. portions of water. The benzene was removed by distillation.
  • the compound of this example has analgesic activity.
  • the compound can be used as in that example.
  • This compound can be formulated in 10% by weight concentration in isotonic saline solution.
  • the compound has analgesic activity.
  • Example 4.-1-dimethylcarbamylpyrazole doNtorrm A mixture of 34 g. of pyrazole, 59 g. of dirnetbylcarbamyl chloride and 56 g. of triethylamine in 300 ml. of tetrahydrofuran was heated under reflux for 18 hours. The cooled mixture was filtered to remove triethylamine hydrochloride and the tetrahydrofuran was removed by distillation. The residual oil was freed of a small additional amount of triethylamine hydrochloride by filtration and then dissolved in 250 ml. of ether. The ether solution was washed with two 100 ml. portions of water and dried over magnesium sulfate.
  • This compound has already been described and certain utilities discussed above. It has a combination of analgesic and intiinflarnmatory properties. It can be administered suitably in capsules, by injection in aqueous medium or the like. The compound is also useful as a hydraulic fluid.
  • This compound can be formulated and used as described for the compound in Example 1.
  • Example 6.1-dimethylcarbamyl-3,4,5-trimethylpyrazole I CON(CH )2 A mixture of 50 g. of trimethylpyrazole, 53.5 g. of dimethylcarbamyl chloride, 50.5 g. of triethylamine, and 300 ml. of tetrahydrofuran was heated under reflux for 24 hours. The solid was removed by filtration and washed with petroleum ether. The solvent was removed from the combined filtrate and washings. The oil that remained was dissolved in 500 ml. of petroleum ether and washed with eight 150-ml. portions of saturated sodium chloride solution and then dried over magnesium sulfate. The drying agent and solvent were removed and the remaining oil was distilled.
  • 33.4 g. of l-dimethylcarbamyl-3,S-dimethylpyrazole 30 g. of sodium acetate, and 150 ml. of water was added 10 ml. (32 g.) of bromine over the course of five minutes. The solution was warmed at about 50 C. until the bromine color had faded and the solution was pale yellow. Crystals formed when the solution was cooled in ice. These were collected and recrystallized from ethanol/ water mixture to give 44.2 g.
  • This compound has analgesic activity and is preferably administered by injection in aqueous solution containing 1-10% by weight of this active compound and 520% by weight of propylene glycol as a solubilizing agent.
  • Example 8 -1 -dz'methy lcarbamyl-3 ,5 -dimethy l-4- chloropyrazole
  • a cold solution of 33.4 g. of l-dimethylcarbamyl- 3,5-dimethylpyrazole and 30 g. of sodium acetate in 200 ml. of water was passed in 15 g. of chlorine over the course of five minutes.
  • the solution became warm and turned orange.
  • the color had faded and when the solution was cooled in ice,,crystals formed.
  • the crude material was dissolved in petroleum ether and crystallized upon cooling to C.
  • This compound has analgesic activity and can be administered as needed for pain relief in an 8% injectible solution.
  • the compound of this example has analgesic activity and is preferably formulated using an injectible solution.
  • Example 10.1-dimethylcarbamyl-4-cyan0pyraz0le NC l N To 4.65 g. of 4-cyanopyrazole (M.P. 91-92" C., obtainable from 4-carb-oethoxypyrazole-see Jones, I. Am. Chem. Soc. 71, 3994 (1949)by reaction with ammonia to form the amide followed by dehydration) was added 2.24 g. of 53.5% sodium hydride in mineral oil, and 50 ml. of tetrahydrofuran. After hydrogen had evolved 5.38 g. of dimethylcarbamyl chloride was added and allowed to stand for 16 hours. The mixture was filtered to remove sodium chloride and solvent removed by evaporation.
  • 4-cyanopyrazole M.P. 91-92" C., obtainable from 4-carb-oethoxypyrazole-see Jones, I. Am. Chem. Soc. 71, 3994 (1949)by reaction with ammonia to form the amide followed by
  • This compound is a potent analgesic and has antiinflammatory activity. It can be formulated and used as in Example 1.
  • This compound has analgesic activity.
  • Example 12 .1-dimethycarbamyl-3,5-dimetl1yl-4- am in opyrazole CON(CH )2
  • 106 g. of 1-dimethylcarbamyl-3,5-dimethyl-4- nitropyrazole suspended in ethanol was shaken with hydrogen in the presence of palladium-on-carbon catalyst at 20-35 C., three equivalents of hydrogen were absorbed.
  • the catalyst was removed by filtration and the ethanol was removed by distillation on the steam bath.
  • the residue was crystallized from benzene/cyclohexane mixture to give 79.4 g. of l-dimethylcarbamyl-3,5-dimethy-4-aminopyrazole, MP. -108.5 C., which upon recrystallization had a melting point of 107 .9-108.9 C.
  • the analgesic activity of the 4-amino compound of this example is in the codeine range.
  • Suitable dosage forms using amounts described above include tablets, capsules, cough syrups also containing anti-tussive agents and injectible solutions.
  • Example 13.1-N,N-dimethylcarbamyl-4-chl0r0pyraz0le A mixture of 104 g. of 1-N,N-dimet'hylcarbamylpyr.- zole, 136 g. of sodium acetate trihydrate and 300 ml. of water was cooled in ice as 56 g. of chlorine was passed into it over the course of an hour. The ice bath was removed and the mixture stirred for an additional half hour. The oil layer was dissolved in 200 ml. of ether and the aqueous phase extracted with two 200-ml. portions of ether. The combined ether solutions were washed with 200 ml. of water then with two 200-ml. portions of saturated sodium chloride solution.
  • This compound has remarkable analgesic activity, approaching morphine in potency. Its outstanding antiinflammatory activity resembles that of cortison.
  • Pharmaceutical compositions containing this compound can be in the forms described in Example 1 and eleswhere above. Dosages are comparable to cortisone for inflammatory conditions. Analgesically effective dosages are in a range between those of morphine and those of codeine.
  • Example 14.1-N,N-dimethylcarbamyll-bromopyrazole To a mixture of 18.1 g. of 1-N,N-dimethylcarbamylpyrazole and 25.5 g. of potassium acetate in 200 ml. of water was added 6.7 ml. of bromine over a period of onehalf hour at room temperature. After standing overnight, the aqueous solution was saturated with sodium chloride and extracted with four -ml. portions of chloroform. The chloroform solution was dried and the solvent removed under reduced pressure. The residue was fractionated to give 16.6 g. of crude product, B.P. 99108 C./2.7 mm. The crude product crystallized from pentane when the solvent was cooled to 10 C. There was obtained 8.73 g. (31% yield) of 1-N,N-dimethylcarbamyl-4-bromopyrazole, M.P. 4648 C.
  • the infrared spectrum shows CH absorption at 3.19, 3.23 and 3.42 1. and carbonyl absorption at 5.92/.t.
  • This compound has potent analgesic and anti-inflammatory activity and for these applications can be formulated and used as described above for the compound of the preceding example
  • a mixture of 85 g. of 4-nitropyrazole, 85 g. of dimethylcarbamyl chloride, 81 g. of triethylamine and 150 ml. of benzene was heated under reflux for 6 hours.
  • To the reaction mixture was added 1350 g. of warm benzene.
  • the benzene solution was extracted with three 300-ml. portions of saturated sodium chloride solutions and then reduced to a volume of 400 ml. by distillation.
  • This compound has high analgesic activity and is preferably administered orally in tablet, syrup and capsule form. This compound is of course also useful as an intermediate in the preparation of related compounds.
  • the 4-amino compound of this example has analgesic activity and is preferably administered orally in tablet and capsule form.
  • Example 17.1,N,N-dimethylcarbamyl-4-methylpyrazole A mixture of 24.5 g. of 4-methylpyrazole (prepared by the method of Pine and Ercoli, Gazz. Chim. Ital., 81, 757 (1951)), 34 g. of dimethylcarbamyl chloride, 32 g. of triethylamine and 75 ml. of benzene was heated under reflux for 16 hours. The cooled solution was diluted with 150 ml. of benzene. The benzene solution was washed with a mixture of ml. of water and 100 ml. of saturated sodium chloride solution and then with seven 100-ml. portions of saturated sodium chloride solution.
  • the benzene solution was dried over magnesium sulfate and distilled.
  • the 1 N,N-dimethylcarbamyl-4-rnethylpyrazole boils at -136/29 mm. and weighs 30.7 g.; n,;, 1.5079.
  • the infrared shows absorption at 3.40, 5.90, 6.30, 7.23 u.
  • the proton .n.m.r. spectrum shows a pattern consistent with the structure with bands at 1- of 2.09, 2.57, 6.91 and 8.03 of intensity relationship 121:6:3.
  • the compound of this example has analgesic activity and can be administered by injection in doses on the order of codeine. It can be formulated as described in Example 1.
  • Example 18.1-N,N-dimethylcarbamyl-3 (5) chl0r0-5-(3)-methylpyrazole A mixture of 57.8 g. of 5(3)-methyl-3(5)-chloropyrazole, 59 g. of dimethylca'rbamyl chloride, 55.5 g. of triethylamine and 400 ml. of benzene was heated under reflux for 4 days. The triethylamine hydrochloride that had crystallized was removed by filtration and washed The combined filtrate and benzene wash was extracted with ten 100-ml. portions of saturated sodium chloride solution. The benzene solution was distilled to give 69.2 g. of 1-N,N-dimethy1carbamyl- 3 (5 -methyl-5 (3 -chloropyrazole, B.P. 74 0.1 mm., 71
  • This compound has analgesic activity. It can be formulated and administered in like manner to the procedure described for l-dimethylcarbamyl-3,5-dimethyl-4-bromopyrazole in Example 7.
  • Example 19.1-N,N-dimethylcarbamyl-3 A mixture of 22.0 g. of 3-methylpyraz0le, 27.0 g. of triethylamine and 28.7 g. of dimethylcarbamyl chloride The mixture was diluted with 200 ml. of benzene, and the filtrate was washed twice with ml. of saturated sodi- 'mm. that contained amine hydrochloride.
  • This compound is a useful solvent for polar compounds. It also has analgesic activity that can be utilized in standard dosage forms.
  • Example 21 -1 -dimethy lcarbamy l-3-methy l-4-chl0r0pyrazole and 1 -dimethy lcarbamy l-5-methyl-4-chl0r0pyrazole
  • a mixture of 116 g. of 3(5),4-chloropyrazole, 112 g. of dimethylcarbamyl chloride, 106 g. of triethylamine and 500ml. of benzene was heated under reflux for 48 hours. The salt that precipitated was dissolved in water and the benzene layer washed with twelve 100-ml. portions of saturated sodium chloride solution.
  • Example 22 -1 -N-methyl-N-ethy lcarbamyl-4- chloropyrazole
  • a mixture of 16.5 g. of 4-chloropyrazole-1-carbamyl chloride in 150 ml. of anhydrous ether was added a mixture of 6.1 g. of methylethylamine and 14.1 ml. of triethylamine in 25 ml. of ether at 510 C. over a period of 0.5 hours. After stirring for 1 hour at 5 C., the mixture was then refluxed for 3 hours and allowed to stand at 2426 C. for 16 hours.
  • the solid triethylamine hydrochloride was removed by filtration and washed with .two 25-ml. portions of ether.
  • This compound has good analgesic activity.
  • Example 23.1-N,N-dimethylthiocarbamylpyrazole A mixture of 27.2 grams of pyrazole, 59.5 grams of dimethylthiocarbamyl chloride, 48.5 grams of triethylamine in 250 milliliters of dry tetrahydrofuran was refluxed three hours with stirring. Triethylamine hydrochloride precipitated out about 15 minutes after start of reflux. After standing at room temperature overnight, the solid triethylamine salt was filtered off and tetrahydrofuran was removed from the filtrate. The residual oil, diluted with ether, was then successively washed till substantially neutral with water, dilute hydrochloric acid, and finally with more water.
  • the compound of this example can be formulated as an injectible solution of 5%, 10% and 15% by weight concentration in isotonic saline; as an injectible solution in 5 10% and 15 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 anti-tussive 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.
  • Analgestic activity is in the codeine range.
  • the compound has antiinflammatory activity.
  • Example 24 1-N,N-dimethyltlziocarbamyl- 4-br0m0pymz0le
  • sodium hydride in 200 milliliters of methyl ether of ethylene glycol was added 22 grams of 4- bromopyrazole.
  • 18.5 grams of dimethylth'iocarbarnyl chloride was added with slight exothermic reaction.
  • the mixture was refluxed for 20 hours, then cooled and water added.
  • the oily layer was extracted by diethyl ether and washed with water.
  • the ether solution was dried and ether evaporated. On distillation, there was obtained 20.5 grams of 1-N,N-dimethylthiocarbamyl-4-bromopyrazole, Bl. 116-8 C., at 0.6 mm.
  • the product solidified, M.P. 434 C.
  • the compound was prepared by reaction in tetrahydrofuran of bromopyrazole with dimethylthiocarbarnyl chloride in the presence of triethylamine.
  • the compound of this example has significant analgesic and antiinflammatory activity. It is conveniently formulated in 2% by weight concentration in an aqueous vehicle.
  • This compound has analgesic and antiinflammatory activity and can be administered as needed for pain relief in an 8% injectible solution.
  • This compound has analgesic activity. It can be formulated with suitable tableting adjuvtants using a conventional tableting machine with the active ingredient constituting about 45-55% by weight of the tablet. Other ingredients include gelatin, magnesium stearate and starch.
  • Examples 33-52 44 1-N,N-dimethylthiocarbamyl-3(5) ethyl-4- The theoretical amount of chloropyrazole (45 1-N,N-dimethylthiocarbamyl-3 5 -ethyl-4- bromopyrazole (46) 1-N,N-dimethylthiocarbamyl-3 (5 -ethyl-4- fiuoropyrazole 47) 1-N,N-dimethylthiocarbamyl-3,4-diethylpyrazole (48) l-N,N-dimethylthiocarbamyl-3 (5 -ethyl-4- methoxypyrazole 49) 1-N,N-dimethylthiocarbamyl-3 (5 -n-propyl-4- chloropyrazole .(50) 1-N,N-dimethylthiocarbamyl-3 5 -n-propyl-4- bromopyrazole (51 1-N,N-dimethylthiocarbamyl-3 (5 -iso
  • the pentafluorosulfur pyrazole was obtained by reacting diazomethane with pentafiuorosulfur acetylene.
  • the latter was prepared by bromination of chlorovinyl sulfur pentafluoride followed by treatment first with a base (KOH) and then with zinc.
  • the 1-N,N-dimethycarbamyl-3 (and 4)-pentafiuorosulfur pyrazole exhibit analgesic properties.
  • the invention claimed is: 1. A compound of the formula where X is selected from the group consisting of oxygen and sulfur;
  • R is methyl
  • R is selected from the group consisting of alkyl of 1 through 6 carbon atoms, alkenyl of 3 through 6 carbon atoms, alkoxyalkyl of 2 through 6 total carbon atoms, hydroxyalkyl of 2 through 6 carbon atoms, methylalkylamino of 2 through carbon atoms, dialkylaminoalkyl where each alkyl in the dialkyl portion has 1 through 2 carbon atoms and the remaining alkyl has 1 through 4 carbon atoms with a total of 3 through 7 carbon atoms in said dialkylaminoalkyl,
  • A is selected from the group consisting of H, CH and C H and wherein (CHA) has a total of 6 carbon atoms, and
  • R is selected from the group consisting of hydrogen and alkyl of 1 through 4 carbon atoms
  • R and R are separately selected from the group consisting of hydrogen and alkyl of 1 through 5 carbon atoms with the limitation that R and R together cannot exceed 5 carbon atoms, (CHA),,CN where a and A are as above; with the limitation that R is joined to the :carbamyl nitrogen by a primary or secondary carbon "atom; and where R and R together with the carbamyl nitrogen form a ring structure selected from the group consisting of rnorpholino, pyrrolidino, dihydropiperidino, azabicyclononyl and piperidino of the structure:,
  • Y is selected from the group consisting of hydrogen and methyl
  • Y is selected from the group consisting of hydrogen
  • Y is selected from the group consisting of hydrogen, alkyl of 1 through 9 carbon atoms, cycloalkylalkyl of 4 through 9 carbon atoms, hydroxy, hydroxyalkyl of 2 through 9 carbon atoms, alkoxyalkyl of 3 through 9 carbon atoms, trifluoromethyl, COOR where R is alkyl of 1 through 4 carbon atoms,
  • R and R are each separately selected from the group consisting of hydrogen and alkyl of 1 through 4 carbon atoms, dialkylaminoalky-l of 3 through 8 carbon atoms where each alkyl in the dialkyl portion has 1 through 2 carbon atoms and the remaining alkyl has 1 through 4 carbon atoms, pyrrolidinomethyl, benzyl, phenethyl, and 0-, mand p-tolylethyl, with the limitation that when Y, is CH Y and Y must be H;
  • R is selected from the group consisting of hydrogen and alkyl of 1 through 3 carbon atoms, triflu-oromethyl, fluorine, chlorine, bromine, sulfur pentafluoride and py y R is selected from the group consisting of hydrogen, chlorine, bromine, fluorine, alkyl of 1 through 3 carbon atoms, trifluoromethyl, sulfur pentafluoride, alkoxy of 1 through 3 carbon atoms, amino, cyano and nitro; and
  • R is selected from the group consisting of hydrogen, alkyl of 1 through 3 carbon atoms, trifluoromethyl, fluorine, chlorine, and bromine with the limitation that when X is sulfur, R must be hydrogen and when R is other than methyl, R must be hydrogen; with the further limitation that R R and R together have a maximum total of 6 carbon atoms.

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3362877A (en) * 1963-05-31 1968-01-09 Du Pont Use of 3-amino-n-carbamylpyrazoles as analgesic agents
US3494757A (en) * 1968-06-20 1970-02-10 Dow Chemical Co Nitrification inhibitor comprising substituted pyrazoles
US3535323A (en) * 1964-03-18 1970-10-20 Dresden Arzneimittel Amides of isoindoline-2-carboxylic acid
US3723456A (en) * 1970-10-09 1973-03-27 Bayer Ag Pyrazolo-(thiono)phosphoric(phosphonic) acid esters
US3839336A (en) * 1971-03-05 1974-10-01 Merck Patent Gmbh N-acyl-(piperazinoalkyl)-pyrazoles
US4111941A (en) * 1976-05-14 1978-09-05 The Upjohn Company Thienyl pyrazole thioamides
EP0139182A3 (de) * 1983-09-07 1985-07-03 Bayer Ag Herbizide Mittel enthaltend Photosynthesehemmer-Herbizide in Kombination mit 1,4-disubstituierten Pyrazol-Derivaten
WO2015179559A3 (en) * 2014-05-21 2016-06-09 Abide Therapeutics, Inc. Pyrazole compounds and methods of making and using same
US10266497B2 (en) 2017-05-23 2019-04-23 Abide Therapeutics, Inc. Pyrazole MAGL inhibitors
US10323038B2 (en) 2015-11-20 2019-06-18 Abide Therapeutics, Inc. Pyrazole compounds and methods of making and using same
US10385057B2 (en) 2015-11-20 2019-08-20 Lundbeck La Jolla Research Center, Inc. Pyrazole compounds and methods of making and using same
US10519134B2 (en) 2015-11-20 2019-12-31 Lundbeck La Jolla Research Center, Inc. Pyrazole compounds and methods of making and using same
US10583137B2 (en) 2015-12-02 2020-03-10 The Scripps Research Institute Triazole DAGLα inhibitors
US10927105B1 (en) 2017-05-23 2021-02-23 Lundbeck La Jolla Research Center, Inc. Pyrazole MAGL inhibitors
US11149037B2 (en) 2017-05-23 2021-10-19 H. Lundbeck A/S Pyrazole MAGL inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0014810A3 (en) * 1979-01-18 1980-11-26 Fbc Limited Pesticidal pyrazoles, their production, compositions and uses, as well as intermediates and their preparation
JPS60222479A (ja) * 1984-04-20 1985-11-07 Nippon Tokushu Noyaku Seizo Kk テトラヒドロキノリン―１―イルカルボニルイミダゾール誘導体、その製法並びに除草又は農園芸用殺菌剤

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US2075359A (en) * 1930-10-16 1937-03-30 Du Pont Insecticide
US2425320A (en) * 1942-10-23 1947-08-12 Koppers Co Inc Cleaning and pickling of metals
US2606155A (en) * 1946-11-26 1952-08-05 Koppers Co Inc Cleaning and pickling composition for metals
US2725384A (en) * 1952-08-05 1955-11-29 Eastman Kodak Co Process for preparing substituted pyrazoles
US2855342A (en) * 1955-07-27 1958-10-07 Schenley Ind Inc Analgesic compositions
US2937118A (en) * 1956-06-27 1960-05-17 Raschig Gmbh Dr F Aminopyridine compositions
US3041344A (en) * 1960-12-01 1962-06-26 Res Lab Dr C Janssen 1-(aroylalkyl)-4-piperidinecarboxamides
US3083205A (en) * 1960-08-03 1963-03-26 Res Lab Dr C Janssen N V Alkanoylamino and alkoxycarbonylamino derivatives of 1-(aroylalkyl)-4-arylpiperidines

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US2075359A (en) * 1930-10-16 1937-03-30 Du Pont Insecticide
US2425320A (en) * 1942-10-23 1947-08-12 Koppers Co Inc Cleaning and pickling of metals
US2606155A (en) * 1946-11-26 1952-08-05 Koppers Co Inc Cleaning and pickling composition for metals
US2725384A (en) * 1952-08-05 1955-11-29 Eastman Kodak Co Process for preparing substituted pyrazoles
US2855342A (en) * 1955-07-27 1958-10-07 Schenley Ind Inc Analgesic compositions
US2937118A (en) * 1956-06-27 1960-05-17 Raschig Gmbh Dr F Aminopyridine compositions
US3083205A (en) * 1960-08-03 1963-03-26 Res Lab Dr C Janssen N V Alkanoylamino and alkoxycarbonylamino derivatives of 1-(aroylalkyl)-4-arylpiperidines
US3041344A (en) * 1960-12-01 1962-06-26 Res Lab Dr C Janssen 1-(aroylalkyl)-4-piperidinecarboxamides

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3362877A (en) * 1963-05-31 1968-01-09 Du Pont Use of 3-amino-n-carbamylpyrazoles as analgesic agents
US3535323A (en) * 1964-03-18 1970-10-20 Dresden Arzneimittel Amides of isoindoline-2-carboxylic acid
US3494757A (en) * 1968-06-20 1970-02-10 Dow Chemical Co Nitrification inhibitor comprising substituted pyrazoles
US3723456A (en) * 1970-10-09 1973-03-27 Bayer Ag Pyrazolo-(thiono)phosphoric(phosphonic) acid esters
US3839336A (en) * 1971-03-05 1974-10-01 Merck Patent Gmbh N-acyl-(piperazinoalkyl)-pyrazoles
US4111941A (en) * 1976-05-14 1978-09-05 The Upjohn Company Thienyl pyrazole thioamides
US4111939A (en) * 1976-05-14 1978-09-05 The Upjohn Company Furyl pyrazole thioamides
EP0139182A3 (de) * 1983-09-07 1985-07-03 Bayer Ag Herbizide Mittel enthaltend Photosynthesehemmer-Herbizide in Kombination mit 1,4-disubstituierten Pyrazol-Derivaten
WO2015179559A3 (en) * 2014-05-21 2016-06-09 Abide Therapeutics, Inc. Pyrazole compounds and methods of making and using same
US10093630B2 (en) 2014-05-21 2018-10-09 Abide Therapeutics, Inc. Pyrazole compounds and methods of making and using same
US10323038B2 (en) 2015-11-20 2019-06-18 Abide Therapeutics, Inc. Pyrazole compounds and methods of making and using same
US10385057B2 (en) 2015-11-20 2019-08-20 Lundbeck La Jolla Research Center, Inc. Pyrazole compounds and methods of making and using same
US10519134B2 (en) 2015-11-20 2019-12-31 Lundbeck La Jolla Research Center, Inc. Pyrazole compounds and methods of making and using same
US10583137B2 (en) 2015-12-02 2020-03-10 The Scripps Research Institute Triazole DAGLα inhibitors
US10266497B2 (en) 2017-05-23 2019-04-23 Abide Therapeutics, Inc. Pyrazole MAGL inhibitors
US10927105B1 (en) 2017-05-23 2021-02-23 Lundbeck La Jolla Research Center, Inc. Pyrazole MAGL inhibitors
US11149037B2 (en) 2017-05-23 2021-10-19 H. Lundbeck A/S Pyrazole MAGL inhibitors
US11655217B2 (en) 2017-05-23 2023-05-23 H. Lundbeck A/S Pyrazole MAGL inhibitors
US12258340B2 (en) 2017-05-23 2025-03-25 H. Lundbeck A/S Pyrazole MAGL inhibitors

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