US3308130A - N-disubstituted carbamyl pyrazoles - Google Patents

Description

United States Patent 3,303,130 N-DISUBSTITUTED QARBAMYL PYRAZOLES Euclid W. Bousquet, Wilmington, Del., assignor to E. I. du Pont de Nemours and Company, Wilmington, Del., a corporation of Delaware No Drawing. Filed Oct. 1, 1963, Scr. No. 312,871 6 Claims. (Cl. 260-294) This application is a continuation-in-part of my copending applications Serial No. 190,212, filed April 26, 1962; Serial No. 158,102, filed December 8, 1961; Serial No. 158,136, filed December 8, 1961, all three now abandoned; the two latter applications each being continu ations-in-part of my application Serial No. 103,219, filed April 17, 1961 (now abandoned) which in turn is a continuation-in-part of my application Serial No. 78,342, filed December 27, 1960 (now abandoned).

This invention relates to pyrazoles.

More specifically, 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.

The above and other properties and utilities possessed by the compounds of this invention will be elaborated .upon more fully hereinafter.

COMPOUNDS The new pyrazoles of this invention can be illustrated by the general formula:

U\IRa where X is oxygen or sulfur;

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:

morpholino, i.e.

L pyrrolidyl, i.e.

piperidyl, i.e.

dehydropiperidyl, i.e.

azabicyclononyl, i.e.

mono-substituted piperidyl of the structure where Y is H or CH Y is H, CH C H or COORg where R is alkyl of 1 through '4 carbon atoms;

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,

Y and Y have the same meaning as above; 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; and 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:

R4- 5l-R X H 3 1NON L E/ In the instances where R and R are the same, these formulas are identical. However, where R and R are not the same, isomers are capable of existence. This is not surprising in view of the literature on simple plyrazoles (see Elderfield, Heterocyclic Compounds, John Wiley, New York, 1957, vol. V, pages 91-92, showing that a mixture of isomers may result from synthetic procedures). In the detailed description that follows in only some instances has the presence of isomers been indicated, namely, as 3(5)-, 5 (3)-. The possibility of such isomers exists in all instances where .the groups on the nuclear carbons adjacent to the annular nitrogens are different. For simplicity, the compounds of this invention are generally named as the 3-isomer rather than as the S-isomer.

A preferred class of compounds are pyrazoles of the formula:

a where R is hydrogen or methyl; R is methyl, cyano, chlorine or bromine; and Y is the same as above.

Another preferred class of compounds are pyrazoles of the formula:

where R is hydrogen;

R is cyano, chlorine or bromine;

R is methyl; and

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.

Particularly preferred compounds from the above classes are the following:

tem may be better adapted to certain classes, the disubstituted carbamyl pyrazole system has been used for the major part for the naming of exemplary compounds of the case.

COMPOUND UTILIZATION The new compounds of this invention are relatively stable. They are generally liquid, although some are relatively low=melting solids. They have a wide range as liquids, generally of 200 C. or more at atmospheric pressure. They can be used by themselves or with other inert liquids, for hydraulic fluids. They are particularly useful as solvent for polar and non-polar compounds and can be used as the reaction medium for such reactions as replacement of halogen in organic compounds by the CN group of potassium cyanide.

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.

Of particular importance in the present invention are the antiinflammatory and antipyretic properties shown by certain of these compounds. The test used to determine the antiinfiammatory activity was the Cotton Pellet Granuloma test generally described by Meier, Schuler and De Saulles in Experiential, vol. 6, page 469 (1950). Results have been obtained which are comparable to those found with cortisone and better than those found with phenylbutazone, a clinically effective antiinfiarm matory agent. These findings suggest that these com pounds may be useful in the treatment of inflammatory diseases such as rheumatoid arthritis, bursitis, and other diseases of connective tissue and in general in treatment of ailments in which cortisone is useful. Antipyretic activity as shown by certain compounds of this invention was determined by standard laboratory tests.

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 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. 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 by E. W. Martin and E. F. Cook, 12th edition, 1961, published by the Mack Publishing Company, Easton, Pennsylvania.

COMPOSITIONS In these novel compositions the active ingredient of the above formulas 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 0.0001% by weight based on the total weight of the composition. For oral adminstration in Water or other liquid medium, the concentration will ordinarily be in the range from about 05 to 10.0% 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 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.

PREPARATION OF. COMPOUNDS As mentioned above, 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.

Pyrazoles used in the processes as herein described are available by methods of the chemical literature. Thus, a beta-diketone of the structure R COCHR COR reacts with hydrazine to yield a pyrazole of the formula:

N R1 H where R R R R R and X have the same meaning as above.

In the preceding equation 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. Such compounds are available by the reaction of a pyrazole having hydrogen on nuclear nitrogen and phosgene or thiophosgene as shown in the equation:

R4 H-Ra ml N X is... 11T

where 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:

R2 where R R R R R and X have the same meaning as above.

The preceding reactions make no unusual requirements in the way of condiitons. In general, they are conducted at temperatures of 0-100 C. for times of the order of 172 hours. Pressure equipment may be necessary when the reaction is conducted above the boiling point of one of the reactants.

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. By the use of a watersoluble fluoride, the corresponding fiuoro derivative, i.e., 1-dimet-hylcarbamyl-3,5-dimethyl-4-tluoropyrazole, is obtained.

When 4-hydroxypyrazole is treated with dimethylc-arbamyl chloride by the method previously described, there is obtained 1-dimethylcarbamyl-4-hydroxypyrazole. Reaction of 1-dimethylcarbamyl-4-hydroxypyrazole with diazomethane results in the formation of the ether, l-dimethylcarb-amyl-4-methoxypyrazole.

The diketone 2-methylhexane-3,5-dione on reaction with hydrazine hydrate and treatment of this product with dimethylcarbamyl chloride in the presence of triethylamine in an inert solvent gives 1-dimethylcarbarnyl-3- methyl-5-isopropylpyrazole.

The following examples illustrating the novel compounds of this invention, their preparation, their usefulness, and pharmaceutical compositions containing the novel compounds, are given in addition to those given above to more clearly explain my invention.

Example 1.1-dim'ethylcarbamyl-3,5-dimethylpyrazole oH CH i oloomorrm i H3O H3O o ON(C Ha To a solution of 24 g. of 3,5-dimethylpyrazole in 1 ml. of tetrahydrofuran was added 25 g. of triethylamine and then 27 g. of dimethylcarbamyl chloride. The reaction mixture was refluxed for one hour and then allowed to stand at room temperature for 15 hours. The residue, after removal of the solvent, was dried over sulfuric acid in an evacuated desiccator. This dry product Was then extracted with tetrahydrofuran. On distillation of this extract, a 21-g. fraction, B.P. 7892 C./0.60.9 mm., was collected. Redistillation of this cut gave 14.5 g. of N,N,3,5 tetramethyl-l-pyrazolecarboxamide (also named 1-dimethyloarbamyl-3,S-dimethylpyrazole), B.P. 74.577.5 C./0.5 mm.; n 1.5006. This compound is soluble in water, alcohol, and tetrahydrofuran.

Analysis-Calcd. for C l-1 N 02 C, 57.48; H, 7.78. Found: C, 57.34; H, 8.40.

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 triethylam-ine hydrochloride that crystallized in the residual oil was removed by filtration and discarded. The filtrate was dissolved in 300 ml. of ether and washed with four 150-ml. portions of water and dried over magnesium sulfate. The ether was removed by distillation and the residual oil was distilled to give 37.4 g. of l-dimethylcarbamyl 3,4-(4,5 -diethyl-5 (3 -methylpyrazole, B.P. 158-164" C. at 26 mm. The center fraction had n 1.4940 and the following analysis:

Analysis.-Calcd. for C H N O: C, 63.2; H, 9.2; N, 20.1. Found: C, 64.3; H, 9.4; N, 20.1.

The compound of this example has analgesic activity. Formulated as described for the compound of Example 1, the compound can be used as in that example.

To a solution of 30.4 g. of 3,5-di-n-propylpyrazole (prepared from the reaction of hydrazine with nonane- 4,6-dione) in 250 ml. of ether was added 2.2 g. of dimethylcarbamyl chloride and 20 g. of triethylamine. The solution was allowed to stand at room temperature for 20 hours. The triethylamine hydrochloride that had precipitated was removed by filtration and the filtrate was washed with ten -ml. portions of water and dried over magnesium sulfate. The ether was removed by distillation and the oil that remained was distilled to give 16.2 g. of 1-dimethylcarbamyl-3,5-dipropylpyrazole, B.P. 152- 154 C. at 16 mm. The infrared spectrum of this distillate indicated some unreacted pyrazole contaminated the product. In another experiment the same reaction was repeated, using tetrahydrofuran as the solvent and the reaction was carried out by heating the reaction mixture at reflux temperature for 17 hours. Under these conditions, a 68% yield of 1-dimethylcarbamyl-3,5-dipropylpyrazole, alternately named N,N-dimethyl-3,5-di-npropylpyrazolecarboxamide, was obtained which after two distillations boiled at 162-16? C. (20 mm.).

Analysis.-Calcd. for C H N O: C, 64.6; H, 9.48; N, 18.8. Found: C, 66.4; H, 9.73; N, 19.6.

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. Distillation of the residue after removal of ether gave 25.8 g. of l-dimethylcarbamylpyrazole, alternately named N,N-dimethylpyrazolecarboxamide, B.P. 102109 C. at 17 mm. Resdistillation gave 20.7 g. of material boiling at 107-112 C. at 18 mm.; 11 1.5102.

Analysis.Calcd. for C H N O: N, 30.2. Found: N, 29.98. i

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.

| comma A mixture of 83.2 g. of 3,5-diethylpyrazole (obtained by reaction of hydrazine with heptane-3,5-dione), 86 g. of dimethylcarbamyl chloride, and 81 g. of triethylamine in 400 ml. of tetrahydrofuran was heated under reflux for 14 hours. The mixture was cooled and the triethylamine hydrochloride was removed by filtration. The solvent was removed by distillation and the oil that remained was dissolved in 500 ml. of petroleum ether and washed with ten 100-ml. portions of saturated sodium chloride solution. Distillation gave117.5 g. of l-dimethylcarbamyl-3,S-diethylpyrazo-le, also named .N,N-dimethyl-3,S-diethylpyrazolecarboxamide, B.P. 130-132 C. at 11 mm.; 11 1.4943.

Analysis.Calcd. for C H N O: C, 61.6; H, 8.77; N, 21.5. Found: C, 62.0; H, 8.78; N, 21.54.

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. The material that boiled at 129l31 C./ mm. was dissolved in 400 ml. of petroleum ether and washed with five IOO-ml. portions of saturated sodium chloride solution. The solution was then dried over magnesium sulfate and freed of solvent by distillation. Distillation of the remaining oil gave 55 g. of 1 dirnethylcarbamyl 3,4,5 trimethylpyrazole, also named N,N-3,4,5-pentamethylpyrazolecarboxamide, B.P. 130 C./10 mm.; 11 1.5057.

Analysis.Calcd. for C H N O: C, 59.7; H, 8.34; N, 23.1. Found: C, 59.8; H, 8.55; N, 23.4.

Example 7.-1-dimethylcarbamyl-3,5-dimethyl- 4-br0m0pyraz0le Br HCH; rnol ON(CHa)2 To 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. of 1-dirnethylcarbamyl-3,5- dimethyl-4-bromopyrazole as colorless needles, M.P. 55.5-56.5 C. A sample of this compound which can also be named N,N,3,5-tetramethyl-4-bromopyrazolecarboxamide was prepared for analysis by crystallization from methanol/water M.P. 63.564.5 C.

Analysis.Calcd. for C H N BrO: C, 39.1; H, 4.92; Br, 32.5. Found: C, 39.3; H, 4.91; Br, 32.5.

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 To 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. At the end of the addition of the chlorine, 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 once crystallized material was redissolved in petroleum ether and passed over a bed of acid alumina which removed colored material. When the eluate was concentrated and cooled in solid carbon dioxide-acetone mixture, 20.3 g. of 1-dimethylcarbamyl-3,5-dimethyl-4-chloropyrazole, alternately named N,N,3,5-tetramethyl-4-chloropyrazolecarboxamide, M.P. 46-54 C., was obtained. A sample was prepared for analysis by an additional crystallization at low temperature from petroleum ether. It melted at 53-54 C.

Analysis.Calcd. for C H N ClO: C, 47.6; H, 6.01; Cl, 17.6. Found: C, 47.5; H, 5.75; Cl, 18.1.

This compound has analgesic activity and can be administered as needed for pain relief in an 8% injectible solution.

Example 9.1-dimetl1ylcarbamyl 3 trifluoromethyl-S- methylpyrazole "-01";

H OlN solvent) was added 125 ml. of tetrahydrofuran, 30.1 g. of dimethylcarbamyl chloride, and 28.3 g. of triethylamine. The mixture was refluxed with stirring for 48 hours. The solid triethylamine hydrochloride precipitate was removed by filtration. The residual oil, after removal of the tetrahydrofuran, was diluted with ether and this was washed with four 50-ml. portions of saturated sodium chloride solution. The ether solution was dried over sodium sulfate. After removal of the ether and distillation there was obtained 43 g. (83% yield) of l-dimethylcarbamyl- 3-trifiuoromethyl-S-methylpyrazole, B.P. 73-80 C./ 0.65 mm., of which a center fraction of 11 1.4320 was analyzed. This compound can also be named N,N,5(3)- trimethyl-3 (5 -trifluoromethylpyrazolecarboxamide.

Analysis.-Calcd. for C H F N O: C, 43.44; H, 4.52. Found: C, 43.17; H, 4.43.

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. After recrystallization of the solid residue from hexane, 6.52 g. of white needle-like crystals, M.P. 7980.5 C. of 1-dimethylcarbamyl-4-cyanopyrazole was obtained. The infrared spectrum was in agreement with the assigned structure.

Analysis.Calcd. for C H N O: C, 51.21; H, 4.91; N, 34.13. Found: C, 51.36; H, 5.05; N, 34.19.

This compound is a potent analgesic and has antiinflammatory activity. It can be formulated and used as in Example 1.

Example 11.1 dimethylcarbamyl-3,5-dimethyl-4-nitr0- pyrazole H-on domom):

A mixture of 35.2 g. of 3,5-dimethyl-4-nitropyrazole, 27.8 g. of dimethylcarbamyl chloride, 26.2 g. of triethylamine, and 300 ml. of tetrahydrofuran was heated under reflux for 20 hours. The triethylamine hydrochloride was removed by filtration and the filtrate was freed of solvent by distillation. The residue was dissolved in 250 ml. of ether and extracted with two 200-ml. portions of water and then two 200-ml. portions of saturated sodium chloride solution. After the solution was dried over magnesium sulfate the solvent was removed. The residual oil was distilled to give 27.7 g. of l-dimethylcarbamyl-3,5-dimethyl-4-nitropyrazole, B.P. 138-144 C./ 0.5 mm. This material solidified when allowed to stand. The solid was crystallized from dichloroethylene-cyclohexane mixture to give 12.9 g. of impure starting material, M.P. 110-116" C. The liquors from this crystallization were evaporated to dryness and the solid that remained was crystallized from ether at 80 C. to give 10.4 g. of 1 dimethylcarbamyl 3,5 dimethyl-4-nitropyrazole as needles, M.P. 77-77.9 C. A mineral oil suspension had an infrared spectrum indicative of the assigned structure, having A 5.80, 5.87 for the compound, alternately named N,N,3,5 tetramethyl-4-nitropyrazolecarboxamide.

12 Analysis.-Calcd. for C H N O C, 45.3; H, 5.71; N, 26.4. Found: C, 46.4; H, 5.93; N, 26.4.

This compound has analgesic activity.

Example 12 .1-dimethycarbamyl-3,5-dimetl1yl-4- am in opyrazole CON(CH )2 When 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.

Analysis-Calcd. for C H N O: C, 52.8; H, 7.75; N, 30.8. Found: C, 53.0; H, 7.91; N, 30.8.

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. The ether was removed by distillation and the oil that remained was distilled to give 83.3 g. of material boiling at 128-139 C./22 mm. Fractionation of this distillate gives 51.9 g. of 1-N,N-dimethylcarbamyl-4-chloropyrazole, B.P. 138- 142/ 22 mm. that solidifies to a crystalline material melting at 50.5-51.5".

Analysis.Calcd. for C H N ClO: C, 41.7; H, 4.66; N, 24.3. Found: C, 41.7; H, 4.87; N, 24.0.

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 same compound was also obtained as follows: To a solution of 20.9 g. of 1-N,N-dimethylcarbamylpyrazole in 200 ml. of chloroform was added 15.4 ml. of bromine in 25 ml. of chloroform. The solution was refiuxed for 6 days, then treated with 5% sodium hydroxide and washed with ice water. The chloroform solution was dried and the solvent removed under reduced pressure. The residue was fractionated and the portion boiling at 104-108" C. at 1.5 mm. was crystallized from pentane to give 8.06 g. (25% yield) of l-N,N-dimethylcarbamyl-4- bromopyrazole, M.P. 45.5-47.5" C.

, Analysis.-Calcd. for C H BrN O: C, 33.0; H, 3.7; Br, 33.6; N, 19.3. Found: C, 33.19; H, 3.70; Br, 37.95; N, 20.0.

The infrared spectrum shows CH absorption at 3.19, 3.23 and 3.42 1. and carbonyl absorption at 5.92/.t.

The same compound'is also obtained by reaction of 4-bromopyrazole with dimethylcarbamyl chloride.

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. When the solution cooled a solid crystallized which was collected and washed free of a small quantity of colored material with cyclohexane to give 117.7 g. of 1-N,N-dimethylcarbamyl-4-nitropyrazole, M.P. 119.5-120.6. A second CH lur C1CON(CH3)2 crop of 12.8 (M.P. 1185-1195") was obtained by conv centrating the liquors and diluting them with cyclohexane. Recrystallization from benzene gave an analytical sample, M.P. 120.8-l2l.6.

Analysis.Calcd. for CsH N O C, 39.2; H, 4.38; N, 30.4. Found: C, 35.3; H, 4.31; N, 29.9.

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.

Example 1 6.1-N,N-dimelhylcarbamyl-4-aminopyrazole OQNCCH H2 H2NC CH II II II N HG N N O N o o monm Al mony,

with 200 ml. of benzene.

14 Analysis.Calcd. for C H N O C, 37.6; H, 3.42; N, 25.6. Found: C, 38.0; H, 3.59; N, 26.0.

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.

Analysis.Calcd. for C H N O: C, 55.0; H, 7.26, N, 27.4. Found: C, 55.2;-H, 7.56; N, 27.7.

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

Analysis.Calcd. for C H N C10; C, 45.0; H, 5.38; N, 22.4. Found: C, 45.2; H, 5.52; N, 22.7.

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 (5) 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.

Example 20.-1-dimethylcarbamyl-3,4-dimethylpyraz0le HzC-C-.CC H

ll 3 aC)zNCOCl H-O N A mixture of 48 g. of 3(5),4-dimethylpyrazole, 59 g. of dimethylcarbamyl chloride, 56 g. of triethylamine, and 200 ml. of benzene was heated under reflux for hours. Enough water was added to the cooled mixture to dissolve the precipitated salt and the benzene layer was diluted with 200 ml. of additional benzene. The benzene solution was extracted with four 200-ml. portions of saturated sodium chloride. Distillation of the benzene solution gave material boiling at 133134/ 16 The distillate was dissolved in 300 ml. of ether and washed with six 100-ml. portions of saturated sodium chloride solution. The ether solution was dried over magnesium sulfate and distilled to give 60.6 g. (73%) of l-d-imethylcarbamyl-3,4-dimethylpynazole, B.P. 132/16 mm. 11 1.5068.

Analysis.Calcd. for C H N O: C, 57.5; H, 7.85; N, 25.1. Found: C, 57.1; H, 8.14; N, 24.8.

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 To 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. The solvent was removed from the filtrate by distillation and the residue distilled under reduced pressure. After a small forerun there was isolated 16.6 g. of l-N-methyl-N- ethylcarbamyl-4-chloropyrazole, B.P. 7981 C. at 0.8 mm. (88% theory, 11 1.5149).

16 Analysis.Oalcd. for CqH10C1N3OZ C, 44.81; H, 5.37; Cl, 18.90; N, 22.40. Found: C, 44.63; H, 5.41; Cl, 20.63; N, 22.48.

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. After drying over anhydrous sodium sulfate, filtration and removal of ether, 29 grams (50%) of a pale yellow, oily 1-N,N-dimethylthiocarbamylpyrazole, B.P. 99-101" C./1.5 mm. (12 1.6055), was collected from distillation.

Analysis-Called. for C H N S: S, 20.64. Found: S, 20.76.

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 To 3.6 grams of sodium hydride in 200 milliliters of methyl ether of ethylene glycol was added 22 grams of 4- bromopyrazole. After hydrogen had evolved, 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. On standing, the product solidified, M.P. 434 C.

Alternatively, the compound was prepared by reaction in tetrahydrofuran of bromopyrazole with dimethylthiocarbarnyl chloride in the presence of triethylamine.

Arzalysis.Calcd. for C H BrN S: C, 30.77; H, 3.42. Found: C, 31.12; H, 3.66.

The compound of this example has significant analgesic and antiinflammatory activity. It is conveniently formulated in 2% by weight concentration in an aqueous vehicle.

1 7 Example 25 .-1 -N ,N -dimethy lthiocarbamyl 4-chloropyrazole Sodium hydride (14 grams) in mineral oil was washed with benzene to remove the mineral oil. To the sodium hydride was added 30.8 grams of 4-chlolopyrazole: and then a benzene solution of 40 grams of dimethylthiocarbamyl chloride. After the exothermic reaction subsided the mixture was refluxed for 40 hours, then cooled and washed with sodium carbonate solution and water. After drying over sodium sulfate, the solvent was removed by evaporation and the residual oil diluted with ether, and a precipitate which formed was removed. The ether was evaporated from the solution and the residue distilled to give 17 grams (30%) of 1-N,N-dimethylthiocarbarnyl- 4-chloropyrazole, boiling at 105-6 C. at 0.7 mm.; n 1.6094, M.P. 46.7 (from petroleum ether B.P. 30- 60 C.).

Analysis.-Calcd. for C H ClN S: C, 38.00; H, 4.22; Cl, 18.73; S, 16.89. Found: C, 38.71; H, 4.48; CI, 18.66; S, 16.31.

This compound has analgesic and antiinflammatory activity and can be administered as needed for pain relief in an 8% injectible solution.

Example 26.1-N,N-dimethylthiocarbamyl- 4-methylpyrazole A stirred mixture of 20.5 grams of 4-methylpyrazole,--

34 grams of dimethylthiocarbamyl chloride, 28 grams of triethylamine, and 150 milliliters of dry' tetrahydrofuran was refluxed for hours. triethylamine hydrochloride was removed by filtration from the cooled reaction mixture and the filtrate concentrated by evaporation to remove most of the tetrahydrofuran. The resulting oil was dissolved in ether and washed successively with water, dilute hydrochloric acid, water, aqueous sodium bicarbonate, and water. The ether solution was then dried over sodium sulfate, decolorized with decolorizing charcoal, filtered, and distilled. Av substantially colorless oil was obtained, B.P. 96-8 C./0.5 mm., n 1.5965, which on standing solidified, M.P. 56-7" C., and was identified as 1-N,N-dimethy1thiocarbamyl-4- methylpyrazole by analysis, infrared, and n.m.r. spectra.

Analysis.-Calcd. for C7H11N3SI C, 49.70; H, 6.51; S, 18.99. Found: C, 49.47; H, 6.55; S, 19.27.

This compound has analgesic activity. It can be formulated with suitable tableting adjuvtants usinga 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 27-31 (27) 1-N,N-dimethylthiocarbamyl-4-fluoropyrazole (28) 1-N,N-dimethylthiocarbamyl-4-cyanopyrazole (29) 1-N,N-dimethylthiocarbamyl-4-methoxypyrazole (30) 1-N,N-dimethylthiocarbamyl-4-ethoxypyrazole 1 8. (3 1 1-N,N-dimethylthiocarbamyl-4-trifluoromethylpyrazole Example 32 Using the procedures of Example 23 and substituting appropriate reactants in equivalent amounts, 3(5)-methylpyrazole (obtained by condensation of hydrazine with 3-ethylhexane-2,4-dione) is reacted with dimethylthiocarbamyl chloride in the presence of triethylamine to obtain 1 N,N-dimethylthiocarbamyl-3(5)-methylpyrazole. This product can be formulated and used as in the preceding examples.

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 -isopropyl-4- chloropyrazole 5 2) 1-N,N-dime-thylthiocarbamyl-3 5 -isopropyl-4- methylpyrazole Example 53.1-N;N-dimethylcarbamyl-3 (and 4 pentafluorothiopyrazole To a solution of 11.8 g. (0.06 mole) of pentafluorosulfur pyrazole and 50 ml. of tetrahydrofuran was added at 05 C., 3.0 g. of NaH (53%)'in mineral oil suspended in 10 ml. of tetrahydrofuran. The mixture was heated to reflux. During this time about 1.5 ml. of H was collected over water. Dimethylcarbamyl chloride (7.5 g.) was then added at room temperature. This mixture was stirredovernight, filtered and distilled through a molecular still. There was obtained 8.5 g. (56%) of carbamylated pyrazole, B.P. 70 C. (pot. temp.)/0.24 The n.m..r. spectrum showed this was a mixture of 3-pentafluorothioand 4-pentafluorothio-l-dimethylcarbamyl pyrazole.

and

Analysis.--Calcd. for C H F N OS: C, 27.17; H, 3.04; F, 35.82; N, 15.85; S, 12.09. Found: C, 27.99; H, 3.06; F, 34.81;N, 15.74; S, 12.05.

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.

Examples 5479 I 01 l (EMN Cl (I) Derivatives of 4 chloropyrazole 1 carboxylic +Z N N aczd.-Der1vat1ves of 4-chlor0pyrazole-1-carboxy11c acid \I/ N/ were prepared by the following procedure. A solution of 0.1 mole of the secondary amine, ZH, and 0.1 mole of triethylamine was dissolved in 200 ml. of benzene, and ()1 Z 0.1 mole of 4-chloropyrazole-l-carboxyl chloride was added in portions with stirring. Stirring was continued See the first column below for the 11162111118 of overnight, and the precipitate of triethylamine hydrochloh following table ShOWS the am employed and ride was filtered off. (In the case of high-boiling liquids, properties of the compounds produced:

Analysis Ex. Z M.P. B.P./mm. 11

C c H H caled. found caled. found (i311; 54 -NCHzCH CH 147-149/20 1. 5083 47.4 48.1 5.0 5.2

(1H5 55 N-CH(CH3)1 142-143/17 1.5090 47.6 47.8 5.0 5.1

(IJH: CH: 55 -N0HOH,0H 127128.5l6 1.5052 50.1 50.6 5.5 5.7

57 NCH2CH(CH:)1 158-161/24 1.5033 50.1 50.1 6.5 6.4

(1H5 58 NCH2CH=CH 152-153.5/22 1.5241 48.1 48.1 5.1 5.5

(IJHa 59 NCH2CH1OCH3 152-154.5/10 1.5105 44.1 44.5 5.5 5.

(DI-Ia 60 NN(CH 1454455117 41.5 41.3 5.5 5.6

65- -OCH; 79.5-81 52.8 53.2 0.2 0.4

66..-.-- N CHzGHa 52.0-53.5 54.6 54.5 6.7 5.9

67- N GH CHZOHB 55.5-57 55.4 55.9 7.1 7.2

68.....- N CI-I CI-I CH CH 39-40 57.9 58.6 7.5 7.5

(3H5 69-.." OUH 49. 5-52 56.4 56.0 7.1 7.4

l CH3.

(244) l-dimethylcarbamyl-3 (5 -n-propyl-5 (3 -methyl- 4-methoxypyrazole (245 l-dimethyloarbamyl-3 (5 -isopropyl-5 (3 -methyl- 4-methoxypyrazole (246) 1-dimethylcarbamyl-3 (5 -ethyl-5 (3 -n-propyl- 4-methoxypyrazole (247) l-dimethylcarbamyl-3 5 -ethyl-5 (3 isopropyl- 4-methoxypyrazole (248 1-dimethylcarbamyl-3 (5 -trifluoromethylpyrazole (249 1-dimethylcarbamyl-4-trifluoromethylpyrazole (250) 1-dimethylcarbamyl-3 (5 -trifluoromethyl-4- aminopyrazole (25 1 l-dimethylcarbamyl-3 (5 -methyl-5 3 -chloro- 4-trifluoromethylpyrazole (252) 1-dimethylcarbamyl-4-n-propoxypyrazole (253 1-dimethyloarbamyl-4-isopropoxypyrazole Examples 254-255 Using the general procedures of Examples 54-79 the following compounds were obtained:

(254) 4-chloro-1-[N-methyl-N-(1-methyl-2-carboethoxyethyl)]carbamylpyrazole, B.P. l21-123/ 0.3 mm.; n 1.5023.

Analysis.Calcd. for C H N O Cl: C, 48.3; H, 5.9.

Found: C, 48.6; H, 6.0.

(255 4-chloro-1- [N-methyl-N-(Z-cyanoethyl) ]carbamylpyrazole, M.P. 7 -72 Analysis.Calcd. for C H N OCl: C, 45.2; H, 4.3

Found: C, 45.2; H, 4.7.

Further compounds that can be prepared according to this general procedure are 4-chloro-1- [N-methyl-N- (methyl-2-N,N-dimethylcarbamylethyl) ]carbamylpyrazole,

4-chlorol [N-methyl-N- 1-methyl-4-carbethoxybutyl) carbamylpyrazole,

4-bromo- 1- [N-methyl-N- 1-ethyl-3 -cyanopropyl) 1- carbamylpyrazole, and

4-cyano-l-[N-methyl-N-( 1-methyl-4-N,N-diethylcarbamylbutyl) ]carb amylpyrazole.

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,

where a is an integer of 1 through 5,

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,

where a and A are as above and 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:,

where 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 carbon atoms; and

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,

where 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.

2. 4-chloro-1-(4-isopropyl-l-piperidinocarbonyl)pyrazole.

3. 4 chloro 1-[4-(N,N-dimethylcarbamoyl)-l-piperidinocarbonyflpyrazole.

l4. 4 chloro-l-(4-hydroxy-l-piperidinocarbonyl)pyraz- 15. 4 chloro-l-(N-mcthyl-N-isopropylcarbamoyl)pyraz- 6. 4 chloro-1-(N-methyl-N-dimethylaminocarbamoyl) pyrazole.

(References on following page) 29 v 30 References Cited by the Examiner 2,937,118 5/ 1960 Haxthausen et a1. 16765 UNITED STATES PATENTS 3,041,344 6/1962 Ianssen 260-294 6/1933 Salzberg et aL 26o 243 5 3/ 963 n n 0 9 3/ 1937 Sqlzberg et a1. 167-22 5 ALEX MAZEL, Primary Examiner. 8/1947 H111 252149 1952 Hill 252 149 RIZZO, m 11/1955 Burness 260-310 HENRY R. JILES, J. TOVAR, Assistant Examiners. 10/1958 Wagner et a1. 167-65

Claims (1)

1. A COMPOUND OF THE FORMULA