DE1470159A1 - Pyrazole derivatives, their preparation and use - Google Patents

Description

The invention relates to pyrazoles, especially pyrazoles, the are substituted on the nuclear nitrogen, and pharmaceutical preparations which contain a new pyrazole prebond according to the invention as the essential active ingredient, and their application.

The compounds according to the invention have remarkable properties as analgesics, as customary animal experiments show. In addition, certain compounds of this type have a anti-inflammatory activity similar to that of adrenocortical steroids; some have an anti-pyretic effect.

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These and other properties and applications of the compounds according to the invention are explained in more detail below.

links

The new pyrazoles produced according to the invention can be duroh the general formula

illustrate. In the formula mean

X oxygen or sulfur;

R _{1 is} methyl;

Alkyl with 1 to 6 carbon atoms, which can be substituted by a Ni ■ = tril or carbalkoxy group or a dimethyl or di-Kthylamino group, alkenyl with 2 to 6 carbon atoms, alkoxyalkyl with a total of 2 to 6 carbon atoms, where R ₁ and. R ₂ can be linked to one another to form pyrrolidyl, piperidyl,

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■ petrahydropiperidyl, azablcyclononyl, or one of duroh Nitrile, carboalkoxy, dialkylantlno, trifluoromethyl, ben- * yl. Substituted alkyl or a dialkylamino group Plperidlnoreates;

R, hydrogen, alkyl with 1 to 3 carbon atoms, trifluoromethyl. Bromine, Chlorine, Sohwsfelpentafluorld or Py-

R ^ hydrogen, chlorine, bromine, alkyl with 1 to Z> carbon atoms, Sohwefe.lpentafluorid, amino, cyano or nitro; R ^ hydrogen, alkyl with 1 to> carbon atoms, trifluoromethyl or bromine,

with the restriction that if X is sulfur or R _{2 is} a radical other than methyl, R ₅ must be hydrogen, and with the further restriction that R 1, R 1 and R ₅ together contain a maximum of 6 carbon atoms.

The oiled compounds of the invention can be used as isomers of the general formula

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1 N

C-H

If R «and Rc are the same, the above formulas are identical. However, if R 1 and R _{5 are} not the same, isomers can exist. With regard to the literature on simple pyrazoles, this is not surprising (cf. Elderfield, "Heterocyclic Compoundβ", John Wiley, NY, 1957 »Vol. V, pages 91 and 92, according to which a mixture of isomers can be obtained in syntheses). In the following description, the presence of isomers is only given in some pollen, namely in the form of 3 (5) -, 5 (3) -. The possibility for such isomers exists in all cases in which the groups on the core carbon atoms adjacent to the ring nitrogen atoms are different. For the sake of simplicity, the compounds according to the invention are generally named as 3-isomers and not as 5-isomers.

A preferred connection class are pyrazoles of the formula

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■ Ν

C «O

-S,

wherein R, a hydrogen atom or methyl,

R. denotes methyl, cyano, a chlorine atom or a bromine atom and Y, has the same meaning as above "

Another preferred class of compounds are pyrazoles of the formula

-R ₃

3
SJ

«O

R j Rp

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'ί ^! ■ -; r

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where R- is a hydrogen atom,

H, cyano «represents chlorine or bromine,

R ^ means methyl and

S ₂ alkyl with T feis 4 carbon atoms . Alkenyl with 3 to 4 carbon atoms or methylalkylamino, in which the alkyl has 1 or 2 carbon atoms, with the restriction that R is bonded to the carbamyl nitrogen atom through a primary or secondary carbon atom.

Particularly preferred compounds of the class indicated above are the following:

4-chloro-1- (4-isopropyl-1-piperidinocarbonyl) pyrazole 4-chloro-1 -y ^ T ~ (N, N-d ime thy lcarbamoy 1) -1 -piperid ino-

carbonyl ^ pyrazole

4 "chloro-1 .- (4-hydroxy-1-piperidinocarbonyl) ~ pyrazole 4-chloro-1 ~ (N ~ methyl-N-isopropylcarbaffloyl) pyrazole 4-chloro-1- (K-methyl-N-dimethylaminocarbamoyl) pyrazole

The new pyrazoles according to the invention can be obtained by reacting the corresponding pyrazole, the hydrogen on the core nitrogen with the selected reaction participants ο

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The new pyrazoles according to the invention are characterized by the presence of an amide group which is free of hydrogen atoms and which sits above carbon on the ring nitrogen, which is also hydrogen-free, ie "they have substituted the carbamyl nitrogen with two methyl groups" these compounds "in particular those which have other substituents on the pyrazole nucleus can be designated in various ways: "For example, the simple compound of the above formulas, in which R, _P Rp _P Rr and R, - are methyl, either as N, W, 5" 5-tetramethylpyrazole-carboxamide or as 1-dimethylcarbamoyl ~ 3 ₈ 5-dimethylpyrazole. In the latter designation, the carbamoyl can be simplified to Oarbamyl ο The curboxamide system may be more suitable for certain classes, but the designation system of the disubstituted carbamylpyrazoles is mainly used below to denote exemplary compounds according to the invention

Application of the connections

The new compounds according to the invention are relatively stable. . They also generally provide fluids _s in some Fälleh relatively low melting solid materials · represent the liquids are in a "broad temperature range" in general 2OO ^J C or more at Atraosphären-

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pressure, be used before, "you can on their own or together with other inert liquids as hydraulic fluids * They are particularly suitable as solvent • door polar and non-polar compounds and may be used; Reactions such as the replacement of halogen in organic compounds by the CN group of potassium cyanide, as

Reaction medium used.

Part of the new compounds according to the invention have a bitter taste even in diluted condition and they bind as denaturants, e.g. B. in alcohol, 'effective.' :., '· ■' ■

As standard experiments show, they compound "!} Vegetables of the invention have an exceptional anaetic effect. An anjsahi kit of compounds gives an effect equal to or better than old morphine. The therapeutic conditions determined in these cases are also equal to or better than those which have been found for morphine. Versuohe used to determine the analgesic activity is the experiment with the hot plate described by Eddy in "Journal of Pharmacology and Experimental Therapeutics" , Vol. 98, pages 121-137 (1950), and one modification of the method of Baas and Brook, besehrieben in "Journal of the American Pharmaceutical Association ^1" "VoI * 41 (10), page 569 (1952) to give StrahluagwHfme used

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to generate a reaction in animal experiments. Both attempts are standard experiments used by analgesic researchers; they, were designed to to give an indication of the possible analgesic activity in humans »

Of particular importance are the anti-inflammatory and. antipyretic properties which certain compounds show according to the invention. The attempt to determine the anti-inflammatory activity is the "cotton pellet granuloma" experiment, that of Meier, Schuler and DeSaulles in "Experientla", Vo'l. 6, page 4S9 (1950) generally described is. Results are obtained which are comparable to those found with cortisone and which are better than those you get with phenylbutazone, a clinically effective one anti-inflammatory agent finds. These findings point insisted that these compounds are useful in the treatment of Inflammatory diseases, for example in rheumatism Joint inflammation, bursitis and in others Diseases of "connective tissue, and in general" in treatment of lighter diseases in which cortisone is useful may be useful. By Laboratoriuras standard tests one determines the antipyretic activity which certain compounds according to the invention show »

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In pharmaceutical use, the compound is used According to the invention supplied to the body orally, parenterally and in other ways. The dosage is different and depends on factors such as the patient's condition, his age and weight, his responsiveness, the previous, simultaneous and intended subsequent medication and treatment, the general state of health of the patient, the frequency of treatment and finally the purpose and nature of the desired effect ο

Generally, the active compound will be physiological in a way The administration can be administered in a favorable amount Single dose or in several doses over a longer period of time take place. Furthermore, the dosage required for therapeutic or prophylactic effectiveness is not the same for every compound according to the invention, and a certain amount of Modification of the dose for the various compounds may be indicated. Furthermore, an initial gift or can Several initial doses in the course of a treatment can also be larger if it corresponds to a given treatment situation and a rapid response through early administration of relatively large doses is desired, and then the minimum

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Active or Aufrecbterhaltungsgabe is determined "

The single dose rarely exceeds about 400 or 500 mg of the active compound according to the invention, although larger amounts may also be indicated in given situations or 2 mg work. However, when treating small animals that are physiologically highly responsive and using very active compounds, routine use can be done at much lower dosages. The dose can be administered over a period of time in the same or higher or lower amount ₉ as long as an improvement in the patient is observed or the administration is necessary in the given case «

The active compound is usually administered along with a non-toxic pharmaceutical carrier in a variety of Formulation Forms Administered These forms represent new compositions * other than the non-toxic, pharmaceutical Carrier and a physiologically appropriate amount of one or more active compounds according to the invention contain »These valuable dosage forms represent an important embodiment of the invention =

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ORIGINAL INSPECTED

ψ ' . ·. ■ * ■■ ■■■

'Ä

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Suitable, non-toxic, pharmaceutical carriers include liquids such as v / ater, does it flavor water, alcohols, syrups, elixirs, pharmaceutical plant mucilages, like umailtrabicum and tragacanth, oils, many mineral, of animal, vegetable or artificial origin, e.g. B » Peanut oil, soybean oil, fish oil, such as cod liver oil, or the like for oral use and water, brine, aqueous milk sugar, aqueous maltose, aqueous grape sugar (dextrose), aqueous drill sugar or the like for Injections. Suitable solid carriers include white gelatin capsules, hard gelatin capsules, slow or with Delay the drug-releasing pills or pills. Capsules, powder * tablet carriers and the like. The expert knows suitable solid or liquid, non-toxic pharmaceutical carriers and can choose the carrier to be used in each case according to known principles. According to the preparation forms the invention thus includes forms such as solutions »suspensions» Syrups, elixirs, tablets, capsules, powder packs and like that

A large number of suitable pharmaceutical carriers are described by EW Kartin and E "F" Cook in "Remington's Practice of Pharmacy ¹¹ , Mack Publishing Company, Eaaton, Pa., 12th Ed., 1961"

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Preparation farms

In these new formulas, the active ingredient according to the above formulas is present in a physiologically appropriate amount. In practice this means an active ingredient. amount of usually at least about 0.0001 Jt based on the total weight of the preparation. For oral administration in water or another liquid medium, the active ingredient concentration is usually about 0.5 "to 10.0 wt »If desired, have a value as high as 95 or 98 # or more, based on the total weight of the preparation.

The active compounds of the invention can, if desired to be used to achieve combined effects with one or more other pharmaceutically active substances. Such substances include, without listing them exhaustively, vitamins, pain relievers, tranquilizers » Antlbioticaj cough suppressants (antitussives) etc. The preparations suitable pharmaceuticals can also be used in a manner known to those skilled in the art. table auxiliaries, such as colorants, one sweet or another Taste-imparting agents, solubility-imparting agents etc. contain η

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Making the connections

Wi * mentioned above "can-" to the pyrazoles of the above formulas Duroh Umaetaung dee corresponding, hydrogen at Kernet ioket off containing pyrazoles with the selected BMtktioHBteilneher, "as they are described in more detail below, create. ■ ·

The fyrazoles incorporated in the methods described here can be produced by known methods. A ß-diketone with the structure H ₅ GOCHR ₄ COR reacts with hydrazine to form a hyraxol of the formula

in the foregoing Foreel R. atells most of them the readily available »eynthetlacheη Pyrazole Waaseratoff dar »Da« Pyrazolrlngeyeteoi is etaHl »and the hydrogen in 4-Stelltmg can be done according to the above methods (or after) introduction of the carbaisyl group duroh halogen ereetate.

-yf-

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The new H-disubstituted carbainylpyrazoles and N-disubstituted thiocarbonylpyrazoles are made from available pyrazoles by implementing a disuhstituierten Carbamylohlorld or a disubstituted Thiocarbamylohlorld with a hydrogen βία nuclei ticke toff having. Pyraaol made. These The reaction can be represented as follows:

ij- ^R 3 5 Vn n ^mR 3

⁺ «Λ * ⁰ - ⁰¹ > Il J

^R 2

R ₁ , Rg, IU, R ^, Re and X have the same meaning as given above.

The reaction of disubstituted carbamyl chlorides with cyclic imines, such as ethyleneimine, is known from Annalen 566, (1950).

In the above equation, for example, the carbamylating agent is dimethyloarbamyl chloride, although others can be used available aliphatic N-substituted carbamyl halides, in which the halogen is, for example, bromine, can use

According to a further process, a pyrazole is produced which has a carbonyl halide or a thiocarbonyl halide on the nuclear nitrogen. Such connections are by implementation of a pyrazole containing hydrogen on nuclear nitrogen with phosgene or thiophosgene according to the equation.

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- ^R 3

H X-C-Cl

R ,, R ^, FL and X have the same meaning as given above.

The implementation of secondary amines with phosgene is in J. Am. Chem. Soo. £ 2. 1888 (1950).

The implementation of N-Aoyl-j ^ S-dimethyl-pyrazoles with an acid chloride or with phosgene is from Liebig's Annalen der Chemie, 65? (196S), pages 181 to 18 ?, known.

The Carbonylohlorld or Thlocarbonalohlorld available on these catfish can be combined with aliphatic sec. Amines (elnaohliesslioh cyclic amines), for example dimethylamine or piperidine, dimethylamine to form the desired new N-disubstituted carbamylpyrazoles are reacted as follows:

ι XoC-Cl

^R l * ^R 2 * ^ * ^R 4 * ^R 5 ¹ ^ ^{X have the} same meaning as given above.

The above reactions do not require any unusual reaction conditions. They are generally doors with temperatures from 0 to 100 ⁰ C and reaction times in the large

- 16 -

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ORIGINAL INSPECTED

■. j + - · ■■ · ■ ■■: ■■ · ^{: ι}

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Order carried out from 1 to 72 hours. When the reaction at a temperature above the boiling point of one of the tion participant is carried out, a sowing of Druokänlagen become necessary.

Particularly useful compounds and their preparation are Reproduced below) 1-Dimethylcarbamy1-3 »5-dimethy1-4-nitropyrazole (see Example 11) as well as similar nitroderlvates, can be used in the preparation of derivatives according to the invention. The reduction of this connection with Hydrogen in the presence of a palladium-on-charcoal catalyst leads to the formation of i-dimethylcarbamyl-4-amino-3 »5-dioethyl-pyrazzoi. The latter connection is loud βloh easily in the presence of hydrochloric acid in the cold with nitrous acid to form the 4-DiaBoniuoohloridee of 1-Dimethylonrtem, yl-3,5- <Jiti «thylpyraBol diazotleren. the Dlasoniuagruppe can be done according to methods known per se by halogen to form 8 «B. of the halogen derivative Von Examples 7 and 8 are used. When using a water-soluble fluoride, the corresponding fluorine derivatives, d, h «1-Dimethylcarbamy1-3,5-dimethyl-4-fluoropyrazole

The treatment of 4-hydroxypyraeol with dimethylcarbamylchlo-

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Using the method described above, sue leads to 1-diathy1-carbamyl-4-hydroxypyrazole. When reacting tob 1-Dimethy1-oarbemjrl-4-hydroxypyra * ol * with diazomethane, the ether, • irDiBethylcarbamyl-4-methoxypyrazole, obtained.

Dae diketone 2-ethylhexane-3,5-dione results in the implementation with hydrazine hydrate and treatment of this product with Diaethylcarbaoylchlorld in the presence of triethylairin in one inert solvent of i-dimethylcarbamyl-J-methyl-S-ieopropylpyrazole.

The following examples serve to further illustrate the new compounds according to the invention, their preparation, their usefulness and pharmaceutical preparations containing these compounds »

B β 1 a ρ 1 € 1 1

1-Dipethylcarb-yl -315-dl-thylpyraeol

/ N

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A solution of 24 g of 3 »5-dimethylpyrazole in 100 μl of tetrahydrofuran was taken with 25 g of triethylamine and then 27 g of methyl methyloarbamyl chloride, the reaction mixture was subjected to an extensive reflux treatment and then left to stand for 15 hours at room temperature. After the solvent has been removed, the residue is dried over sulfuric acid in an evacuated desiccator. The dry product is then extracted with tetrahydrofuran. When this extract is distilled, a 21 g fraction is now collected in the boiling range from 78 to 92 ° C / 0.6 to 0.9. By distilling over this section, 14.5 g of N, N, 3,5-tetramethyl-1-pyrazole-carboxamide (i-dimethylcarbamyl-315-d imctbylpyrazole) are obtained; Bp 74.5 to 77.5 ° C / 0.5 mm; n ^ ⁵ = 1,! 5006c The compound is soluble in water, alcohol and tetrahydrofuran.

Analysis ι C H

Calculated for C ₈ H ₁₃ H ₅ O 57.48 7.78. Found 57 »34 8.40

The compound can be used as a solvent with excellent dissolving power for polar and non-polar compounds and as a reaction medium for organic reactions. It has a uruigeti-scne and a nt! Pyrrol raw 3 activity,

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Easily available preparation farms of the compound and injection solutions with a concentration of 5, 10 and 15% by weight in isotonic salt solution or in aqueous sugar solutions, including finally sent solutions of milk sugar, maltose, glucose (dextrose) and cane sugar and for the Oral application solutions with a concentration of 1, 2, 3 and 4 wt can, and 25, 50 and 100 mg portions in conventional two-eight-piece, sealed hard gelatin capsules as well as in White gelatin capsules. Administration in these forms in pharmacological use for the treatment of physiological conditions such as those mentioned above, dosages in the range from 25 to 500 mg are used.

Example 2

1-Dimethylcarbamyl- 3,4- (4-5) -diethyl-5 (3) -methylpyrazole

⁰⁸ y

A solution of 43.3 g of 3 »4 (4,5) -diethyl-5 (3) -mGthylpyrezol (obtained by condensation of hydrazine with 3-ethylhexane-2,4-dione), 32 g of triethylamine and M g of dimethylcarbamyl chloride

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in 200 ml of benzene is left to stand for 65 hours at room temperature and then poured into 200 ml of water. The benzene layer is collected and washed with 200 ml portions of a filter. The benzene is distilled off. The triethylamine hydrochloride which crystallizes out in the reed oil is filtered off and entangled. The filtrate is dissolved in 300 ml of ether, washed with four 150 ml portions of water, dried over magnesium sulfate and the ether is distilled off. When distilling d «B ₍ residual oil 37» 4 g of 1-dimethylcarbamyl-3,4- (4,5) r <? Ethyl-5 (3) -methylpyrazole are obtained; boiling point 158 to 164 ° C / 26 mm Middle fraction gives the following analysis; n ^ = 1.4940.

C H _ H

Calculated for C ₁₁ H ₁ ^ N ₅ O VT7Z ¥ & ZO ₁ I.

Found 64.3 9 * 4 20 »1

The compound of this example has an analgesic activity », it can be in the form of preparations according to Example 1 how to use the connection described there.

B ice Pi e 1 \

i-Dimethylcarbamyl-3 9 5-diprop.vlpyrazole

ν CON (CH ₃ ) ₂

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Kan adds 22 g of di-methyl-carbamyl chloride and 20 g of tri-ethylamine to a solution of 30.4 g of 3,5-di-n-propylpyrazole (prepared by reacting hydrazine old Honan-4 »6-dione) in 250 μl of ether and leaves the solution Stand at room temperature for 20 hours. The triethylamine hydrochloride which precipitates out is filtered off, and the filtrate is washed with ten 100 el parts of water and dried over magnesium sulfate. The ether is distilled off and the remaining oil is subjected to distillation, 16.2 g of 1-diaethyloarbarayl-3 »5-dipropylpyrazoli boiling point 152 ° to 154 ° C./16 mm being obtained. The ultra-red spectrum of this distillate shows an impurity by some unreacted fyrazole. In another experiment, the same reaction is repeated using tetrahydrofuran as the solvent and heating the reaction mixture to reflux temperature for 1 hour. Under these conditions, i-dimethylcarbamyl-3,5-dipropylpyrasol (I _v lf-dimethyl-3,5-di-n-propylpyraaoloarboacamid) is obtained in a yield of £ 66 ι the boiling point is 162 to 163 ° C after overdistilling twice 20 mm.

« Analysis ι C H H_

Calculated for Found

This compound can be dissolved in iotonic saline in a

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Concentration of 10 Gewr, # can be used. The connection has analytical activity »

Example 4 1-Pimethylcarbamylpyrazole

Ci

CON (CH ₃ ) ₂

A mixture of 34 g of pyrazole, 59 g of dimethylcarbamyl chloride and 56 g of triethylamine in 300 ml of tetrahydrofuran is heated to reflux conditions for 18 hours. The triethylamine hydrochloride is filtered off from the cooled chamber and the tetrahydrofuran is distilled off. A small, additional amount of triethylamine hydrochloride is removed from the residual oil by filtration and then dissolved in 250 ml of ether. The ethereal solution is washed with two 100 nl portions of water and dried over magnesium sulfate * By distilling the residue after removing ether, 25 »8 g of 1-dimethylcarbamylpyrazole (ϊΤ, Ν-dimethylpyrazole carboxamide) are obtained; Bp, 102 to 109 ° C. at 17 mm., When overdistilling, 20.7 g of a material are obtained which boils at 107 to 112 ° C./18 mm; n ^ ^5r5 , 5102,

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Analysis: N_

Calculated for CgH _n N ₅ O 30.2

Found . 29.98

This connection has already been described above and discussed on the basis of certain properties. It has a combination of analgesic properties and anti-inflammatory properties o It can be easily administered in capsules, by injection in an aqueous medium, or the like. The connection is also suitable as a hydraulic medium _u

Example 5

1-Dimethylcarbamyl ^ tS-diethylpyrazole

A mixture of 83.2 g of 3,5-diethylpyrazole (obtained by reacting hydrazine with heptane-3,5-dione) ,. 86 g of dimethylcarbamyl chloride and 81 g of triethylamine in 400 ml tetrahydrofuran 14 hours d. on return flow conditions, cools down and removes the triethylarain hydrochloride Filtration »The solvent is distilled off and the

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The oil that remains left is dissolved in 500 ml of petroleum ether and washed with ten 100-ol portions of saturated atrium chloride solution. 117.5 g of 1-dimethylcarbaBtfl-3,5-diethylpyraBol (H, H-dimethyl-3,5-diethylpyraEolcarboxyamid) are obtained by distillation; Bp 130 to 132 ° C / 11 mm; n ^ ⁵ «1.4943 ^»

Analysis t Bereohnat for Found

This compound can be brought into preparation form and reacted in the same way as the compound according to Example 1.

Example 6

C. 61 .6 * H .77 V 21 . * 62 .0 θ .78 21 .5 8th .54

1-Dlmethyloarbamyl ~ 3.4 tS-trlaethylpyrazole

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A mixture of 50 g trimethylpyrazole, 53.5 g dimethylcarbamyl chloride, 50.5 g of triethylamine and 300 ml of tetrahydrofuran are heated to reflux conditions for 24 hours, and the solid is filtered off and washed with petroleum ether. The solvent is removed from the combined pest and ash. That Any remaining oil is dissolved in 500 ml of petroleum ether, washed with eight 150 ml portions of saturated sodium chloride solution and then dried over magnesium sulfate. The drying agent and the solvent are removed and the residual oil is subjected to distillation. That at 129 to 131 ° C / Material passing over 10 mm is dissolved in 400 ml of petroleum ether and mixed with five 100 ml portions of saturated sodium chloride solution washed. The solution is then dried over magnesium sulfate and freed from the solvent by distillation. The distillation of the residual oil gives 55 g of 1-dimethylcarbamyl ~ 3,4.> 5-trimethylpyrazole (N, N, 3f4,5 ~ pentamethylpyrazole carboxymide); Kpo 130 ° C / 10 mm; njp «1.5057.

Analysis: C H N_

Calculated for CqH, -N, 0 Found

59 »7 8th , 34 23 , 4 59 ,8th 8th , 55 23

The preparation and administration of this f'erbiort.irig came as in the connection of example i.

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Example 7 1-Dimethylcarbamy 1-3 τ 5-a ime thy 1-4-brornp.yrazole

Br-

H ₃ C-

H ₅

CON (CH-

Add 33.4 g of 1-dimethylcarbamyl ~ 3 »5 ~ dimethylpyrazole,
30 g of sodium acetate and 150 ml of water over the course of 5 minutes ο 10 ml (32 g) of bromine and heats the solution to around 50 ° C until the bromine color fades and the solution is pale yellow «
The solution is cooled in ice, the crystals which form are collected and recrystallized from an ethanol-water mixture, whereby 44.2 g of 1-Dimethylcarbaoiy 1-3,5 ™ dimethyl-4-bromopyrazole (N, N, 3i5-tetramethyl -4-brcmpyrazole carboxamide) in the form
colorless needles can be obtained. P, 55.5 to 56.5 ° C.
For analysis, a sample of this compound is unicrystallized from methanol-water; F. 63.5 to 64.5 ° C «

Analysis: O H Br

Calculated, for C ₈ H ₁₂ II ^ BxO 39.1 4.92 32.5 *

Found 39.3 4.9s 32.5

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The compound has analgesic activity and is preferably administered by injection of an aqueous solution » the 1 to to Gew.jG of the active compound and 5 to 20 # Contains propylene as a solubilizer.

Example 8 1 ~ Dimethylcarbamyl-3 »5-dimethyl ~ 4 ~ chloropyrazole

Cl

In a cold solution of 33.4 g of i-dimethylcarbamyl-3,5-dimethylpyrazole and 30 g of Hatriüm acetate in 200 ml of water, 15 g of chlorine are introduced in the course of 5 minutes. the Solution warms up and turns orange. At the end of the chlorine addition is the color faded; when the solution is cooled in ice, crystals form. You dissolve the raw material in Petroleum ether and cools to -80 ° C, whereupon crystallization occurs. This material once crystallized will again dissolved in petroleum ether and over a bed of acidic aluminum oxide conducted, the colored material removed. At the

Af

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Concentrate the eluate and cool in a mixture Solid carbon dioxide and acetone give 20.3 β 1-dimethyloarbatnyl-3 »5-dimethyl-4-chloropyrazoX (N, N, 3,5-tetramethyl-4-chloropyrazol-carboxaraid); P. 46 bia 54 ° C. For analysis is a sample subjected to a further crystallization at low temperature from petroleum ether j F. 53 to 54 ° C,

Analysis: Q ...... H 01

For C ₈ H ₁₂ N ₅ ClO 47.6 6.01 17.6

Found 47.5 5.75 18.1

This compound is analgesic and can be used in the form of a Solution to be injected *

Β ,, β,, 1, S ₁ ρ each 1 9

1-Dimethylcarbamyl-3-fcrifluorinethyl-5-methylpyrazole

CON (CH ₃ ),

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Kan adds to 35 g of 3-fluoromethyl-5-methylpyrazole (Fo 82 up to 87 ° C; produced by reacting 77 g of 1,1,1-trifluoropentane-2,4-dione with 25 g of hydrazine hydrate in 250 ml of tetrahydrofuran at 12 to 17 ° C, subsequent removal of the solvent. on the steam bath and cleaning by drying a solution in petroleum ether and then removing it of the solvent) 125 ml of tetrahydrofuran, 30.1 g of dimethylcarbamyl chloride and 28.3 g of triethylamine were added. That The mixture is refluxed with stirring for 48 hours, The solid triethylamine hydrochloride which precipitates is filtered off. After the tetrahydrofuran has been removed, the residual oil is diluted with ether and saturated with four 50 ml portions Washed sodium chloride solution. The essential

Solution is dried over sodium sulfate. After removal of the ether and distillation of 43 g of 1-dimethylcarbamyl-3-trifluoromethyl-5-methylpyrazole (N, N, 5 (3) -trimethyl-3 (5) -trifluormethylpyrazolcarboxamid) obtained,> corresponds to a yield of 83 $; Bp. 73 to 80 ° C / O / 65 mm “A middle fraction , ηψ = 1.4320, is analyzed from this material.

Analysis; C H

Calculated for C ₈ H ₁₀ F ₅ N ₃ O 43 * 44 4.52 found 43.17 4.43

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The compound of this example is analgesic and is preferably used in the form of an injection solution.

Example 10

1-dimethylcarbam y1-4-oyaapy ragol

NC_,

COH (CH ₃ ) ₂

For 4.65 g of 4-cyanpyrazole (P. 91 to 92 ° C; available
from 4-carboethoxypyrazole (cf. Jones, J. Am. Chem. Soc, 71 , 3994 (1949)) by reaction with ammonia to form the amide and then dehydration, 2.24 g of 53.5% sodium hydride in mineral oil and 50 ml of tetrahydrofuran are obtained added. To
The evolution of hydrogen is added to 5.38 g of dimethylcarbamyl chloride and left to stand for 16 hours, the sodium chloride mixture is filtered off and the solvent is removed by evaporation. When the solid residue is recrystallized from hexane, 6.52 g of white, needle-like crystals are formed
i-dimethylcarbamyl-4-cyanpyrazole obtained; F. 79 to 80.5 ° C "The ultrared spectrum agrees with the structure assigned to this compound"

■ - 909823/1128

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51 , 21 4th , 91 34, 13th 51 , 36 5 , 05 34, 19th

Analysis: C H

! Calculated for Found

This compound has a strong anesthetic and has a good one Anti-inflammatory power to prepare and use can be done as in example 1 »

SZ

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Example!!

1.-Piniethylcarbamyi ~ 3,5-dimethyl-4-nitropyrazole

A mixture of 35.2 g of JiS-MmethylM-nitropyrazole, 27 _{t of} 8 β diraethylcarbamyl chloride, 26.2 g of triethylamine and 300 al of tetrahydrofuran is heated to reflux conditions for 20 hours, the triethylamine hydrochloride is filtered off and the filtrate is freed from the solvent by distillation. The return

4 ■

stand is dissolved in 250 ml of ether, raise two 200 ml portions Water and then two 200 ml portions of saturated sodium chloride solution. The solution is dried over magnesium sulfate and removes the solvent. The Hestöl is distilled, with 27.7 g of i-dimethylcarbamyl ^ .S-dimethyl-4-nitropyrazole receives; Bp 138 to 144 ° C / 0.5 mm. This material solidifies on standing. The pestilence will crystallized from a dichloroethylene-cyclohexane mixture, giving 12.9 g of impure starting material, P. 110 to 116 ° C » The mother liquor from the crystallization becomes dry evaporated; the remaining pesticide is crystallized from ether at -80 ° C ο 10.4 g of 1-dioethylcarbamyl "3,5-dimethyl-4-thiitropyrazole are thereby obtained (N, N, 3 «5-tetramethyl ~ 4 ~

5 909823/1128

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ORIGINAL INSPECTED

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nitropyrazole carboxamide) obtained in the form of needles; P. bio 77.9 ° C.

The ultrarota spectrum, determined on a suepenaion in mineral oil, corresponds to the structure ascribed to the compound;

Jl 5.80, 5.87 / 1.

^ max ^

Analysis: C H N

Calculated for C ₈ H ₁₂ N ₄ O ₃ 45.3 5.71 26.4 Found 46.4 5.93 26.4

The compound has analgesic activity ■> Example 12

1 - "Whore thyloarbamy 1-3 t 5-dimethyl» 4 »aminopyrazole

CON (CH ₅ ) ₂

A suspension of 106 g of 1-dimethylcarbamyl is shaken 3 »5-dimethyl-4-nitropyrazole in ethanol in the presence of a palladium-on-carbon catalyst at 20 to 35 ° C

39

-γΐ-

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f. «ff« VI Oil

35- ■; '/ '

with hydrogen · This produces 5 equivalents of hydrogen absorbed. The catalyst is filtered off and removed the ethanol by distillation on the steam bath. The Kttek- 'stand is recrystallized from a benzene-cyclohexane Geraisch, giving 79t4 6 1-Dimethyloarbamy1-2,5-dimethy1-4-arninopyrazole, mp 105.0 to 108.5 ° C, the after Recrystallize a melting point of 107.9 to 108.9 ° C results.

Analysis: C H JK.

Calculated for C ₈ H ₁₄ N ₄ O 52.8 7.75 30.8 Found 53.0 7.91 30.8

The anaigetic activity of the 4-amino compound this Example is in the area of codeine. For suitable preparation forms using the concentrations described above * = Trationers of the active ingredient include tablets, capsules, cough syrups, which may also contain cough suppressants, and injection solutions.

Example 13

1-N, N-Diaethylcarbamyl ~ 4 ~ chloropyrazole

HC · ■ - CH Cl ₉ ClC - CH

11 ti fe n 11 it

HC N HC N

BAO ORIGINAL

SG

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In a mixture of 104 g of 1-N, N-dimethylcarbamylpyrazole, 136 g Sodium acetate trihydrate and 300 ml of Y / aseer are added with cooling 56 g of chlorine were introduced into EiB in the course of one hour. Man then removed the ice bath and stir the mixture for an additional half hour. The oil layer is dissolved in 200 ml of ether and the aqueous phase extracted with two 200 ml portions of ether, The combined ether solutions are mixed with 200 ml of water and then with two 200 ml portions of saturated sodium chloride solution washed. The ether is distilled off and the remaining oil is subjected to distillation, 83 * 3 g of one being added 128 to 139 ° C / 22 mm of boiling material can be obtained. By fractionating this distillate, 51.9 g of 1-N, N-dimethylcarbamyl-4-chloropyrazole, b.p. 138 to 142 ° C / 22 mm, obtained, which turns into a crystalline, at 50.5 to 51.5 ° C solidified melting material.

Analysis: CHN _-

Calculated for Found

This compound has remarkable analgesic activity, whose strength approaches morphine. Their exceptional anti-inflammatory activity is similar to that of the dei. Cortisone. Pharmaceutical preparations containing this compound can be used in the examples described in Example 1 and elsewhere.

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ORIGINAL INSPECTEP

41 .7 4th , 66 24 , 3 41 , 7 4th , 87 24 , 0

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NEN forms of preparation can be produced. The dosage corresponds to the treatment? des cortisone · * The ffirkdosl »* lpAnalgetlcu · lies la elapa Area «between iorphiun and codeine.

B e 1 s D 1 el 14

1 -W .l-Dlaethjloarbaajl «4« -broapjraiol

in OHOl ₃ or

Br ₂ In KOAo (H ₂ )

Su a Qeaison? O * if, 1 g I ^^ DiMtaylea ^ t ^ lp ^ va ^ ·! # 4 25.5 g Laliuoaoetat in 200 al waewer are la Terlaaf · tfta · »half an hour at room temperature (| ₉ 7 al Bfon sugesetat« Msj | let the aqueous solution stand overnight, then saturate it with sodium chloride and extract with four 150- ml portions of chloroform. The chloroform solution is dried and the solvent is removed under reduced pressure. Fractionation of the residue gives 16.6 g of crude product, b.p. 99-10 ° C. / 2.7 mm. The crude product crystallizes from fentan when the solvent is cooled to -10 ° C;

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8.73 β 1-I \ I-Dieetb, | lcarbainyl-4-broinpyra80l, P 46 to 48 ° O,

obtained, which corresponds to a yield ton 31 pounds.

The same connection is also obtained in the following way! Iu «iaer UauBf of 20.9 f 1 * f, t-BieethylearbajBQrlpyrmaoi Ib 200 al Cblorofora 15.4 tbsp bromine in 25 al Chlorofor> * ugeeet. Dia Meung is treated for 6 days rUokflue, daay alt 5 i latriuahydroayd and Bit Siawaaeer gewaaofcaa. The Ohlorofore solution is dried and the solvent is removed under reduced pressure. The residue is fractionated and the at 104 to 108 ° G / 1.5 * ■ aiedeoda fall au · Pettta »auakrietallieiert, whereby aan 8.06 g (Attabut · 25 *> 1 -», f-Diaethyloarbaayl-4-broapyraeDl, f. 45.5 to 47.5 ° 0.

pf | r O ₁ ^ O 33.0 3.7 33.6 19.3

• efnwJen 33.19 3.70 37.95

Daa Ultrarotapektrua shows a CH absorption at 3.19, 3.23 and 3.42 ^ i and Oarbony lab sorption at 5.92 μ.

The same connection is also made by implementing 4-bromopyrazole obtained with dimethyloarbamyl chloride.

The compound has a strong analgesic activity;

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and unlocking force; “It can be used for these purposes We have prepared and connected the above examples be singssttit.

Example 15

1-I.H-Dlmet hylcarbamy1-4-nitropy rmzol

° 2 ^H 1? fi ^H O ₂ M CH

H ₊ ClCOH (CH ₃ ) ² IH

A mixture of 85 g of 4-hitropyrate oil, 85 β-dimethyl carbemyl chloride, 81 g of triethylamine and 150 ml of benzene is heated to RUckflueebedlngüngen for 6 hours and 1350 g of warm benzene are added to the reaction mixture. The benzene solution is extracted with three 300 ml portions of saturated sodium chloride solution and then concentrated to a volume of 400 ml by distillation. One collects the auekrlstalll- when the solution cools down.

Eating Feetttoff and washes a little with cyclohexane Amount of colored material out. 117 g of 1-N.H-dimethylcarbarayl-4-nitropyrazole, P. obtained from 119.5 to 120.6 ° C. By concentrating the mother liquor and diluting it

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BAO ORIGINAL

ΛΟ

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with cyclohexane a second yield of 12.8 g (Po 118.5 up to 119 »5 ° C). Recrystallization from benzene provides an analysis sample, P. 120.8 to 121.6 ° C.

Analysis: C H N

Calculated for C ₆ HgN ₄ O ₅ 39.2 4.38 30.4 Found 35.3 4.31 29.9

The compound is very analgesic and is preferably administered orally in the form of tablets, syrups and capsules. This compound can of course also be used as an intermediate compound in the preparation of derivatives «

B. e 1 .β ρ i e 1 16

i-HfN-Dimethylcarbamyl-4-aminopyrazole

CH "

r \ C / - N (CH-Z) Ο

An ethanolic solution of 73 »5 g Ι-Ν, Ν-dimethylcarbamyl» 4-nitropyrazole is poured over a palladium-on-carbon

HO ~ ** 9098.23 / 1

^{Vlv BATH} ORIGINAL

_HN _ _c

^ It

HC .% "

2476-4 / 5-G ™

Catalyst shaken with hydrogen until three molar equivalents of hydrogen have been absorbed. Remove Catalyst and solvent and subject the iurUoklead? Bende oil of the distillation, 45.0 g of 1-dimethylcarbamyl-4-aminopyrasol, b.p. 127 to 128 ° 6/0 ,? mn receives from the crystals are obtained by crystallizing out of ether, which melt at 46 to 47.5 degrees Celsius.

Analysis t

Calculated for found

C. 46 ,8th H 66 H I. • 4 47
1 »ι , 4 6, 76
4n + 36 , 6
1 · «+. 6, 37
ο TU α

twice around; 7. 194 to 195 ° C (dec.).

Analyzes C H H

Calculated for C ₁₂ H ₁₃ H ₇ O ₃ 37.6 3 # 42 25.6 Found 38.0 3.59 26.0

The 4-amino compound of this example is anaetic Activity and is preferably administered orally in tablet and capsule form.

II

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Example 17 1-W «H-I) imethylcarbamyl-4-methylpyrazole

jH H ₃ C - β CH

H - 8. Λ + (ClCOH (CH ₃ ) ₂ - * H

■ Ρ

An Oemieoh of 24 # 5 g of 4-methylpyrazole (prepared according to Pino and Erooli, Gazz. Chim. Ital., 81., 757 (1951)). 34 g of dimethyl * oarbamyl chloride, 32 g of triethylamine and 75 ml of benzene are heated to reflux conditions for 16 hours. The cooled solution is diluted with 150 ml of benzene and the benzene solution is washed with a mixture of 100 ml of water and 100 ml of saturated sodium chloride solution and then with seven 100 ml portions of saturated sodium chloride solution, then dried over magnesium sulfate and distilled. 30.7 g of iN ^ -dimethylcarbamyW-methylpyrazole are obtained; Bp 135 to 136 ° C / 29 mm; nj " ⁵ --1.5079.

The ultra-red spectrum shows an absorption at 3.40, 5 * 90 6.30 and 7.23 yes. The proton n-m-r spectrum shows a diagram consistent with the structure, with bands at y <2.09 »2.57, 6.91 and 8.03 with an intensity ratio from 1: 1: 6: 3.

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Analysis: (Γ H - .H _- ^

Calculated for C ₇ H ₁₁ H ₅ O 55.0 7.26 27.4 Found 55.2 7.56 27.7

The compound of this example is analgesic and active can be injected in doses of the order of magnitude of the Codeine can be administered. It can be prepared as in Example 1.

Example 18 1-H, N ~ Dimethyloar bamyl-3 (5 ) -chloro-5 (3) -methylp.yrazole

HC C - Cl

• I Il

H ₅ CC N + ClCOH (CH ₅ ) g * HC- C - Cl HC C - CH,

Il ti Il It ->

H ₅ CC ^ Ji and / or Cl-C _v β

A mixture of 57.8 g of 5 (3) -methyl-3 (5) -chlorpyrazole, 59 g of dimethylcarbamyl chloride, 55.5 g of triethylamine and 400 ml of benzene is refluxed for 4 days. The triethylamine hydrochloride which crystallizes out is filtered off and washed with 200 ml of benzene

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ORIGINAL INSPECTED

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Washed items are extracted with ten 100 ml portions of saturated sodium chloride solution. By distilling the benzene Solution, 69.2 g of 1-H, N-dimethylcarbamyl-3 (5) -niethyl-5 (3) -chlorpyraeol are obtained {bp 74 * C / 0.1 now; n | * ■ 1.5139

Analyzes O H H Ready for O ₇ H ₁₀ H ₃ ClO 45.0 5.38 22.4

Found 45.2 5.52 22.7

The compound has analgesic activity. The preparation and administration can be carried out as in Example 7 (as for 1-prostitute t hy loarbamy 1-3, S-dimethyl - ^ - bromopyrazole) take place ·

Example 19

1-HH-Dimethylcarbamy 1-3 (5) -methylpyragol

HO — C-OBx H-C C-CH,

- - "5 ₊ O ₁₀₀ H (OH) _m " 3

A mixture of 22.0 g of 3-methylpyrazole and 27.0 g of triethylamine and 28.7 g of dimethylcarbamyl chloride is stirred for 12 hours

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INSPECTED

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heated to RUokflusabedbedingungen. The Qeeieoh is diluted with 200 ml of bensol, washed twice with 150 ml of saturated sodium chloride solution, washed over magnesium sulfate and the bensol is removed with reduced pressure. The residue is distilled through a spiral containing 30,3-oe-packed column and the fraction boiling at 124 to 125 ^ 0/25 m «is collected, 32.0 g of 1-N, H-diaethylcarbamyl-3 (5) - methylpyraeol obtains n ^ ⁵ - 1.5052.

Analysis: Calculated for Found

The preparation of the compound, which is moderately analgesic, can be done as in example 1.

Example 20

1-pimethylcarbamyl -3 t4-dimethylpyrazole

H-C-C C-CH,, H, C «C C-CH,

^ IJ ³ ♦ (H ₃ O) ₂ NCOCl> ³ j] J ^

H-C H

C. .9 H , 2 H , 4 54 »4 7th .4 2 * 7 .7 55 7th 27

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INSPECTED

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In Oemisoh 48 g of 3 (5), 4-dimethylpyra8Ol, 59 g of dimethylcarbamylohlorid, 56 g of triethylamine and 200 ml of Benaol is heated to reflux conditions for 20 hours. Sufficient water is added to the cooled mixture to dissolve the precipitated Sale, and the Benaole layer is diluted with 200 ml of acidic benzene. The benzene solution is extracted saturated with four 200-ml-Antellen Hatriumohloridlusung you · provides distillation of the benaolisohen solution an at 133-134 ⁰ O / 16 ma boiling material "the amine hydrochloride contains · Dissolve the distillate in 300 ml of ether and washed with six 100 ml portions of saturated sodium chloride solution. The ethereal solution is dried over magnesium sulfate and distilled, giving 60.6 g (73 #) 1-dimethylcarbamyl-3 »4-dimethylpyrazole, boiling point 132 ° C./16 mm; nj " ⁵ - 1.5068.

Analysis: C g N

Calculated for O ₈ H ₁₃ N ₃ O 57.5 7.85 25.1 Found 57.1 8.14 24.8

This compound is a valuable solvent for polar Links. It also represents an anaigetic and can are used in the usual forms of preparation.

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Example 21

i-Dimethyloarbamyl - ^ - methyl ^ -chlorpyrazole and 1-DlinethYlo «rbaayl-5-ethyl-» 4-cblorpyragol

Bin Gemleoh of 116 g of 3 (5), 4-chloropyrazole, 112 g Dimethy1- oarbamylchlorid, 106 g of triethylamine and 500 ml of benzene is 48 hours. Heated to RUokflussbedingungen · Dissolve the aue falling salt in Waeeer and washes the Benzolechicht twelve 100 -ml portions of saturated sodium chloride solution. By distilling the benzene solution, 123 g of a mixture of 70 i -dimethyloarbamyl ^ -nethyl ^ -chlorpyrazole and 30 i -dimethyl-oarbamyl-S-methyl- ^ - chlorpyrazole (determined on the proton nmr spectrum of the mixture) obtain.

This mixture has moderate analgesic activity.

Example 22 1- »N-methyl ~ H ~ ethylcarbamyl-4 ~ chloropyrazole

A mixture of 6.1 g of ethylethylamine and 14.1 ml of triethylamine in 25 ml of Xther at 5 to 10 ° C. is added to a mixture of 16.5 g of 4-chloropyrazole-i-carbamylohlorid in 150 tnl of anhydrous ether in the course of half an hour added. Haoh einetUndigem stirring at 5 ° C, the mixture is refluxed for 3 hours, and 16 hr. At 24 to 26 ° C allowed to stand.

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ORIGINAL INSPECTED

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The solid triethylamine hydrochloride is filtered off and washed with two 25 ml portions of ether. One distills from the Piltrat the solvent and subjects the residue to Distillation under reduced pressure. After a small forerun, 16.6 g (88 # of theory) of 1-N-methyl-N-ethylcarbamyl-4-chloropyrazole, boiling point 79 to 81 ° 0 / 0.8 mm, njp isolated.

Analysis: C H Cl N_

Calculated for C ₇ H ₁ Found:

This compound has good analgesic activity Example 25

1 -Ν, Ν-dimethylthiocarbarnylpyrazole

44 , 81 5 , 57 18.90 22nd , 40 44 , 65 5 , 41 20.65 22nd , 48

l + ClCSN (CK ^) ₂ ^(C 2 ^H !? | 5_ _t ^N

N (CH ₃ J ₂ A mixture of 27.2 g of pyrazole, 59.5 g methylthioci.rbamylchlorid, 48.5 g triethylamine in 250 ml dry tetrahydrofuran of a 5-hour reflux treatment ο About 15 minutes after the start of the reflux treatment

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triethylamine hydrochloride precipitates. The solution is left to stand at room temperature overnight, the solid triethylamine salt is then filtered off and the tetrahydrofuran is removed from the filtrate. The remaining oil, which has been diluted with ether, is then washed successively with water until it is essentially neutral, with dilute hydrochloric acid and finally with more water. After drying over dehydrated sodium sulfate, it is filtered off, the ether is removed and the mixture is distilled. Yield: 29 g (50 #) of a pale yellow, oily Ι-Ν, Ν-dimethylthiocarbamylpyrazole, boiling point 99 to 101 ° C / 1.5 mm, ηψ «1.6055.

Analysis: Calculated for C ₆ H ₉ N ₅ S: S 20.64, Found: S 20.76

Preparation forms of the compound of this example are

Injection solutions with a concentration of 5, 10 and 15 wt. # In isotonic saline solution or in aqueous sugar solutions, including separate solutions of lactose, Maltose, glucose (dextrose) and cane sugar and for oral use solutions with a concentration of 1, 2, and 4 wt. # in volume, which optionally has a taste formers, a dye, a cough suppressant, etc., and 25, 50 and 100 mg portions in conventional two-6-piece, sealed hard gelatin capsules as well as in

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Soft gelatin capsules. The analgesic activity is in the range of codeine. The compound has anti-inflammatory activity.

Example 24 1-N _> N-dimethylthiocarbamyl-4-bromopyrazole

Br-C C-H Br-C C-H

η H η η

HC N + ClCSN (CH ₅ ) ₂ ^ HC

To 3 »6 g of sodium hydride in 200 ml of methyl ether of ethylene glycol 22 g of 4-bromopyrazole are added. After the evolution of hydrogen has taken place, 18.5 g of dimethylthiocarbamyl chloride are added, a slight exothermic reaction occurs ο The mixture reflux for 20 hours, then cool and give Water too. The oily layer is extracted with diethyl ether and washed with water; the ethereal solution is dried and the ether is evaporated. After the distillation, one obtains 20.5 g of i-NiN-dimethylthiocarbamyl ^ -bromopyrazole, b.p. 116 bis 118 ° C / 0.6 mm. The product solidifies on standing, m.p. 43 bis

SO

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ORIGINAL INSPECTED

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ai

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Alternatively, the connection is established by implementing Bromopyrazole with dimethylthiocarbamyl chloride in tetrahydrofuran in the presence of triethylamine.

Analysis: C H

Calculated for C ₆ HgBrN ₅ S: 30.77 3.42 Found: 31.12 3 »66

The compound of this example has significant analgesic and anti-inflammatory activity. It is expedient to prepare a solution, $> contains the compound in an aqueous carrier containing 2 wt..

Example 25 i-NtN-dimethylthiocarbamyl ^ -chlorpyrazole

Cl-C C-H Cl-C C-H

"" + ClCSN (CH ₃ J ₂ ν ""

H-C N

14 g of sodium hydride in mineral oil are washed with benzene

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Removal of the mineral oil “30.8 g of 4-chloropyrazole are added to sodium hydride and then a benzene solution of 40 g of dimethylthiocarbamyl chloride. After the exothermic reaction has subsided, the mixture is boiled for 40 hours

Reflux, then cool it down and wash it with a sodium carbonate solution and water. After drying over sodium sulfate, the solvent is removed by evaporation, the remaining oil is diluted with ether and the precipitate which has separated out is removed. The ether is evaporated from the solution and the rest distilled yield 17 g (30 #) iN ^ ^ J-dimethylthiocarbamyl -chlorpyrazol, bp ₀₁₀₅ to 106 ° C / 0.7 mm. njp = 1.6094, m.p. 46.7 ° C (from petroleum / ether, b.p. 30 to 60 ° C).

Analysis: C H Cl S

Calculated for C ₆ H ₈ ClN ₅ Si 38.00 4.22 18.73 16.89 Found: 38.71 4.48 18.66 16.31

This compound has analgesic and anti-inflammatory activity, and it can be used in the form of a perpetual injection solution for pain relief _{or the like as needed}

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09823/1128

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Example 26 1-N, N-dimethylthiocarbamyl-4 ~ mei; hylp.yrazole

-CH H, C-C CH

Z + ClCSN (CH,), »

C »SN (CH ₃ ) ₂

A stirred mixture of 20.5 g of 4-methylpyrazole, 34 g of dimethylthiocarbamyl chloride, 28 g of triethylamine and 150 ml of dry tetrahydrofuran is boiled under reflux for 5 1/2 hours. The theoretical amount of triethylamine hydrochloride is filtered off from the cooled reaction mixture and the filtrate is evaporated in order to remove the largest amount of tetrahydrofuran. The resulting oil is dissolved in ether and the solution is washed successively with Y / ater, dilute hydrochloric acid ₉ water, aqueous sodium bicarbonate and water. The ethereal solution is then dried over sodium sulfate, decolorized with activated charcoal, filtered and the solution is distilled. An essentially colorless UI is obtained, bp 96 to 98 ° C./0.5 mm, njj ⁵ = 1.5965. This oil solidifies on standing, mp 56 to 57 ° C .; analysis, infrared and nmr spectra reveal that it is i-N, N-dimethylthiocarbamyl-methylpyrazole.

S3

... 909823/1128

INSPECTED

2476 4/5-β

Analysis t for O ₇ H ₁ 1 ^N 3 ^Sl 0 , 70 H 51 S. 99 Calculated 49 , 47 6, 55 18 27 Found: 49 6,

This compound has analgesic activity. One can using them with suitable tableting auxiliaries, prepare with a conventional tablet machine; the active ingredient makes up about 45 to 55% by weight of the tablet. Other ingredients are gelatin, magnesium stearate and starch.

Example 27 to 31

The following compounds can be prepared from the appropriately substituted pyraal and dimethylthiocarbamyl chloride using the procedure of Examples 24-26. These compounds are prepared and used in a similar manner.

example

27. i-HfN-Dimethylthiocarbainyl ^ -fluoropyrezol

28. i-NjN-Dimethylthiocarbamyl ^ -cyanpyrazole

29 o iN, N ~ dimethylthiooarbamyl-4-methoxypyrazole 3Oo 1-OS , N-dimethylthiocarbamyl-4-sthoxypyrazole

31 · i-N ^ -Dimethylthiocarbamyl ^ -trifluoromethylpyrazole,

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Example 32

Using the ,. Procedure of Example 23 and correspondingly titled Beaktlon participant in equivalent hanging, one aetet 3 (5) -Methylpyraeol (obtained by condensation ton hydrazine with 3 »Xthylhexan-2,4-dione) with Dimethylthlooarbajnylchlorid In the presence of Trläthylamin um to 1-H _t N-DiBethylthiocarbamyl-3 (5) -methylpyrazole. This product can be prepared and used as in the previous examples.

Examples 33 bla 52

The previous example 32 can be repeated to obtain the following connections, this being the case for the Reaction with Dlmethylthiocarbamylchlorid in the presence of Trläthylaain selects matching substituted pyrazole.

example

33. 1-H, M. Dimethylthiooarbaajl-3 (5) -ftthylpyra «ol

34. 1-H, H -diaethylthiocarbamyi-3 (5) -n-propylpyrazole 35-1-N, N-diaethylthioarbaa> yl-3 (5) -isopropylpyrazole

36 . 1 -H, N-Disethylt hiocarbany 1-3 (5 ) -aethy 1-4-chloropyrazole

37. 1-B, N-Dioethylthiocarbatryl-3 (5) -niethyl-4-broodpyrazole J8 »1-H _t K-Din» ethylthiocarbERyl-3 (5) -nfethyl-4-fluoropyrazole

Sf

^ - 9 0 9 8 2 3/1128

4 / 5-0 S &

example

39 * 1-1, H-DiBethylthlocerbaav 1-3 (5) -B # thjrl-4-oy * npyr * «ol

"oil

42 .. 1-W, I-Dieethyltßiocarbeay1-3 (5) -ββthyl-4-fithoxypy r · - Sol

43.1-I, I-DleethylthiocarbaiDyl-3 (5) -B © thyl-4-trifluoro-

44 "1-ll _# I-Di" ethylthlocerbyl-3 (5) -ethyl-4-cblorpyre "ol

45 · 1-I, I-methylthioarbAayl-3 (5) -Ktbyl-4-br:> fflpyrÄZOl

46. 1-1,1-Diwtby ltblooarbaey 1-3 (5) - * tby 1-4-fluoropyrazole

47.1 - », I-DiB # tbylthiooarbeeyl-3,4 ~ <Jietbylpyrezole

4Θ. 1-I, I-Din «tbjltblooarb * iiy l-3 (5) -ätbyl-4-mrt hoxypara-

49 · '1-I, I-Dl «« tbyltblecarbaey 1-3 (5) -n-propyl-4-cblor-

50 · 1- *, M-Dleetby lthl9 «erb« axl-3 (5) -D-propyl-4-bT »epyr» * ol

51. i-W.IrDleetbyltbiocarbÄey1-3 (5) -leopropyl-4-cMlor-

pyracol

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Example 53

1-N, J? -Dimetbylcarbamyl-3 (and 4) -pentafluorothio pyrazole

and

To a solution of 11.8 g (0.06 hol) of pdotafluorosulfur pyrazole and 50 ml of tetrahydrofuran is added 3.0 g at 0.5 ° C HaH (53? O in mineral oil, v / elohee in 10 ml of tetrahydrofuran is suspended · The mixture is refluxed. During this time, about 1.5 ml of hydrogen is collected over water.

7.5 g of dimethylcarbamylochloride are then added at room temperature

add, stir this mixture overnight, filter it and distill it in a molecular distillation apparatus. Man receives 8.5 g (56 ° C. yield) of carbamylated pyrazole, boiling point 70.degree

(Bath temperature) / 0.24 ■ jx. The nmr spectrum shows that it is a mixture of 3-pentafluorothio- and 4-pentafluorothio-1-dimethyloarbamylpyrazole »

909823/1128

ORIGINAL INSPECTED

2476 4 / 3-0

Analyeei 0 ^ H P _ H.

Calculated for O ₅ H ₈ P ₅ H ₅ OS * 27.17 3:04 35.82 15.85 12.09 Found: 27.99 3.06 34.81 15.74 _ 12.05

The pentafluorosulfur pyrazole is obtained by reacting diazomethane with pentafluorosulfur acetylene. The latter is produced by the bromination of chlorovinylsulfur pentafluoride and subsequent treatment with a base (KOH) and d .. a with zinc.

1-N, ir-dimethylearbamyl-3 (and 4) -pantafluorosulfurpyrazal ■ have analgesic properties.

Examples 54-79

I. Derivatives of 4-chloropyrazole-1'-carboxylic acid

Derivatives of 4-chloropyra «ol-1-carboxylic acid are passed through the following procedure. Han dissolved a solution of 0.1 UoI of the sec. Amines, ZH, and 0.1 Hol dee Triäthylamina in 200 ml Benzene and add 0.1 mol of 4-Chlorpyrazoi-i-carboxy1-chloride in portions with stirring. Stirring is continued via avenge and the precipitated triethylamine hydrochloride is filtered off

(In the case of high-boiling liquids, add 100 ml Add water and separate to remove the hydrochloride

909823/1128

OBl _GINAL

U70159

2476 4/5-β

the aqueous solution from, since other ηΓall a small amount can get into the benzene alcohol and prevent a clean distillation?) The removal of the benzene either results in a low-melting solid, which can be recrystallized from hexane or a Dl ₉ which is distilled. Apparently there is a small amount of 4-chloropyrazole »perhaps 1 to 2 g; this is removed during the distillation at about 120 ° C and 20 mm using an ultra-red heat lamp, since ea rang at βί> ^{9 ° C.}

For the meaning of Z see the first column of the following Tabel.

The following table shows the AaIn used and the properties of the tertiary fertilizers produced

900023/1128

BATH ORIGINAL

Example 54

co

co

OO

58

59 60

-H-CH ₂ CH ₂ CiI ₃

-H-CH (CHj) ₂

CH ₃ > CHCH ₂ CH ₃

-H-CH ₂ CH ^ CH ₂ 2 OCn ₃ CH ₃
Ir -H-OH ₂ CH > 2 OH, -HN (CH ₃ -Q

Kpo / (mmH _g ) nj ³ U7-149 / 20 1p5083

analysis found

48.1

127-128.5 / 6 1.5052 50.1 50.6

158-161 / 24 1.5033 50.1 50.1

145-145.5 / 17

39.5-41

48.1 48.5

about,

iff, -

6.0 6 _B 2

■ 142-U3 / 17 1.5090 47 »6 47.8 6.0 6 _S 1 cn

6.5 6.7

6.5 6.4

152-153.5 / 22 1.5241 48.1 48.1 5 * 1 5.6

152-154.5 / 10 1.5106 44.1 44.5 5.6 5.8

41.5 41.8 5.5 5.6

5.0 5.2

Aaalw

Example Z 62

63

64

CD
O in 65 Ϊ823 / ^ T
VO 66 1121 67 68 69

70

7T

GH

-u

Sop.

81 * 5-82.5

71.5-73.5

51.5-53

79.5-81. 52.0-53.5

Kp./(nhH _g )

<Z> ^CH 2 ^CH 2 ^CH 3 65.5-67

CH ₂ CH ₂ CH ₅ CH 3 39-40

49.5-52

59.0-60.0

/ V CO ₂ C ₂ H ₃

137 / 0.1

H H

SL ·. J222L. - ßSL

52.8 52.9 6.2

52.8 53.4 6.2

52.8 53.2 6.2

42.6 43.0 3.9

50.4 50.1

5.6

6.1

6.2

6.4

54.6 5 *, 6 6.7 6.9

56.4 56.9 7.1 7.2

57.9 58.6 7.5 7.5

«, I.

56.4 56.0 7.1 7.4

4.1

5.6

Example Z 72

73

co 74 O co
OO 75 Approx KJ 76 OO

78

-O

Il

OH,

- ° 2 ^H 5

<0

Smpo

5--52

Bp / (mmH _g ) 180 / 0.5

-O-

OH

"174-175 / 15

155 / 0.2

80.5-81.5

"" V - / - ^GO 2 ^C 2 ^H 5 49-52 105/0 ₉ 1

, 25

r.

Analyae

found

, 8 63.0

62.0 61.9

ν 1 51.5

179-181 / 8 1.5235 56 _Γ 4 57, Ί

57.1

50.4 50.7

47.1 46.3

about,

6.2

7 ₉ i

4.8

7.1

6.4

5.6

5.3

ϊϊ

6.0

7.8

4 _? 9

7, "

6.3

κ. 7th

* 5 f

5.3

H70159

2476 4/5-Ö

The compounds prepared according to Examples 54 to 79 can be referred to as follows:

Example urine

54 4-chloro-1- (H-methyl-H-jn-propylcarbamoyl) pyrazole '

55 4-Ctalor-1- (W-methyl-H-isopropylcarbainoyl) pyrazole

56-4 ~ chloro ~ 1- (H-methy1-H -sec.- butylcarbamoyl) pyrazole

57 4-chloro-1- (H-methyl-N-isobutylcarbaiaoyl) pyrazole j

58 4-Chloro-1- (H-methyl-N-alkylcarbamoyl) pyrazole

59 4-chloro-1- _J ^ T-methyl-H- (2-methoxyethyl) carbamoyl7 ^r '"'

pyrazole

60 4-chloro-1- (H-methyl-N-dimethylaminocarbainoyl) pyrazole

61 4-chloro-1- (1-pyrrolidinocarbonyl) pyrazole

62 4-Chloro-1- (1-piperidinocarbonyl) pyrazole

63 4-chloro-1- (2-methyl-1-piperidinocarbonyl) pyrazole

64 4-chloro-1- (3-ethyl-1-piperidinocarbonyl) pyrazole

65 4-chloro-1- (4-methyl-1-piperidinocarbonyl) pyrazole

66 4-chloro-1- (4-ethyl-1-piperidinocarbonyl) pyrazole; '

67 4-chloro-1- (4-n-propyl-1-piperidinocarbonyl) pyrazole

68 4-chloro-1- (4-n-butyl-1-piperidinocarbonyl) pyrazole j

69 4-chloro-1- (4-isopropyl-1-piperidinocarbohyl) pyrazole

70 4-chloro-1- (4-trifluoromethyl-1-piperidinocarbonyl) -

pyrazole

71 4-chloro-1- (1-ethylnipecotatocarbonyl) pyrazole

909823/1 128

4/5-G

Example name

4 -Chi or- <~ (4 · ben ^ yl-i ^ piperiduiocarbonyl) pyrazole 4-chloro-1 ~ i4 "Cyolohtixyliüethyl-1-piperidinooarbc-

nyl) pyrazole 4 ~ chloro-1- (1,2,3t6 ~ tetrahydro-1-piperldinooarbo ~

nyl) pyrazole

75 4-chloro-1 - ^ - (N, N-dimethylcarbamoyl) -1-piperidino-

carbonyl / ^ pyrazole

76 4 ~ chlorine-1 - (3-methyl-4-ethy1-1-piperidinooarbony1) -

pyrazole

77 4-chloro-1- _{/ (} / T- (3-azabicyclo- _/ / J, 2,27'-nonanocarbonyl7-

pyrazole 4-chloro ~ 1- (1-ethylisonipecotocarbonyl) pyrazole

79 4 ~ chloro «1- (4" hydroxy-1-piperidinocarbonyljpyrazole

The above compounds show nalgesic activity. Examples 80 bj s 94

By substituting other amines of the same weight and equal amounts by weight of other substituted pyrazole-1-carboxyl chlorides instead of 4-chloropyrazole-i-carboxyl chloride of Examples 54 to 79 are the following compounds here.

4-cyano-1-methyl-N-2-hexyi) carba raoyl / py resol 4-Cyar] -i - /! F-methyl ~ N- (1'-raethyl-2-pentenyl) ca:; b '

T ^ -pyrazole

909823/1128

BATH ORIGINAL

feS

2476 4 / 5-0

Example urine

82 4-BroDi-3-methyl-1 «^ f-methyl-N- (2-butoxyethyl) carb- ·

amoylj-pyrazole

83 4-trifluoromethyl-1- ^ ff-methyl-N- (2-hydroxyhexyl) -

oarbamoyl7pyrazole

84 4-methyl-1 - ^ - methyl-N- (4-diethylaminobutyl) -

oarbamoyl7-pyraBol

85 4-Amino-1 ~ ^ T- (2-äthyIcyolohexy! Methyl) -1-piperidino

carbonyl ^ pyraeol

86 4-Ieopropoxy-1- ^ T- (5-nonyl) -1-piperidinooarbonyl7 ~

pyraaol

87 4-? Luor-1 - ^ - (5-hydroxy-5-nonyl) -1-piperidlno-

oarbonyl7-pyraE0l

88 S-trifluoromethyl-i- ^ T-ipentoxybutylJ-i-piperidlno-

oarbonyj / pyraeol

89 3-0hlor-1- (1-n-butyliaonipeootooarbonyl) pyra80l

90 3-bromo-1- ^ T- (N, N-di-n-butyloarbamoyl) -1-piperi <3ino-

carbonyl / pyraeol

91 3- (4-pyridyl) -1- _J £ JT- (pyrrolidinoethyl) -1-piperidlno-

carbonyl / pyrazole

92 3-? Luoro-> 1- (M-methyl-H-eek.-butyloarbamoyl) pyresol

93 3-n-Propyl-1- (4-ieopropyl-1-piperidinooarbonyl) -

pyrazole

94 3-Bromo-5-methyl-1-H (H-dimethyloarbamoyl pyraaol

65-

909823/1128

ORIGINAL INSPECTED

fet

2476 4/5-G

Examples 95-253

The following exemplary compounds are provided for the purpose of further illustrating those within the scope of the invention

Connections indicated. These compounds can be made using the technique of the examples above, which described in more detail above, uses “An exchange of the specified groups can easily be effected by the person skilled in the art if he followed the instructions The compounds can be prepared as in example T for pharmaceutical use. The compounds are also suitable solvents for polar and non-polar compounds and can as such at room temperature and elevated temperature «like it is suitable to be used.

example link 95 1-dimethyl 96 N 97 Il 98 η 99 N 100 M. 101 N 102 H 103 η

. -4-ethylpyrazole -3 (5), 4-diethylpyrazole -3,4,5-triethylpyrazole -3 (5) -ethyl-4-methylpyrazole -3 (5) -ethyl-5 (3) -methylpyrazole -3 (5) -ethyl-4,5 (3) -dimethylpyrazole -4-ethyl-3 (5) -oethylpyraeol -4-ethyl-3,5-dimethylpyrazole

909823/1128

ORIGINAL INSPECTED

Crt

2476 4/5 -G link example 1-dimethyl 104 Il 105 It 106 Il 107 Il 108 Il 109 η 110 Il 111 Il 112 Il 113 π 114 Il 115 Il 1 4 6 1! m Il 118 Il η 9 Il 120 Il 12th

1-Diraethylcarbamyl-3 (5) -ethyl-4-methylpyrazole

-3,5-diethyl-4-methylpyrazole -3 (5) -n-propyIpyrazole -4-n-propylpyrazole
-3 (5), 4-di-n-propyIpyrazole-4-metbyl-3 (5) -n-propylpyrazole -3 (5) -methyl-5 (3) -n-propylpyrazole

-3 (5), 4 ~ d lraethyl-5- (3) -n-propyl ~ pyrazole

-3 (5) ~ isopropylpyrazole -4 ~ isopropylpyrazole

-3 (5), 4-diisopropylpyrazole -315-dü8opropy Ipyrazole -3 (5) -i8opropyl-4 "Bjethylpyrazol -3t 5} -isopropyl-5i3) -ifleihylpyra2; oI -3 (5) -isopropyl-4 _f 5 { 3) -dimethyl ~

pyrazole

-A -ethy1-3 (5) -n ~ propylpyrazole -3 (5) -ethyl-5 (3) -n-propylpyrazole -4-ethy1-3 (5) -methyl-5 (3) -n ~ propy1

pyrazole

'22 "i ^;;; ·· ■; .hyl-4" -methyl-5 (3) -n-

propyipyrazole

^f 23 "-4-s.thyl-3 (5) -isopropy Ipyrazole

124 "-3 (5) -ätby1-5 (3) -isopropylpyrazole

909823/1128

2476 4/5-G link example 1-dimethyl 125 η 126 Il 127 η 128 Il 129 Il 130 Il 131 Il 132 Il 133 Il 134 Il 135 Il 136 Il 137 Il 138 Il 139 Il 140 Il 141 It 142 Il 143

1-Dimethylcarbamyl ~ 4-ä «: hyl = .3 (5} -methyl-5 (3) -iso-

propylpyrazole

-3 (5) -ethyl-4-methyl-5 (3) -isopropylpyraz oil

-5 (5) -methyl-4-n-propylpyrazole -3,5-dimethyl-4-n-propylpyrazole -3 (5) -ethyl ~ 4-n-propylpyrazole

-3 (5) -ethyl-5 (3) -n] ethyl-4-n ~ propylpyrazole

-3 (5) -me thy l "4-isoprop, ylpyrazole

-3 (5) -ethyl ~ 4-isopropylpyrazole

-3 (5) -ethy1-5 (3) -methyl-4-ieopropylpyrazole

-5 (5) -chlorpyrazole -5 (5) -brorapyrazole -5 (5) -fluoropyrazole -4-fluoropyrazole -5 (5), 4-dichloropyrazole -3 (5), 4-dibromopyrazole -3 (5) »4-d if1uorpyrazole ™ 3 f 5-dichloropyrazole -3,5-dibromopyrazole

909823/1128

2 / / 6 4/5-G ethyl Il Example connection It 144 1-dim Il 145 Il 146 Il 147 ■ ι _m 148 Il 149 η 150 Il 151 Il 152 Il 153 Il 154 ti 155 Il 156 η 157 Il 158 159 160

i-Dimethylcarbamyi-3 ♦ 4,5-trichloropyrazole

-3 (5) -methyl-4-chloropyrazole -3 (5) -methyl-4-bromopyrazole -3 (5) -methy1-4-fluoropyrazole -3,5-dimethyl-4-fluoropyrazole -3 (5) -methyl -5 (3) -bromopyrazole -3 (5) -methyl-5 (3) -fluoropyrazole -3 (5) -ethy1-4-chloropyrazole -3 (5) -ethyl-4-bromopyrazole -3 (5) -ethyl -4-fluoropyrazole 315-die-thyl-4-ohlorpyraaoi -3 _f 5-diethyl-4-brOHipyrazole -3,5-diethy1-4-fluoropyrazole -3 (5) -ethyl-5- (3) -chlorpyrazole -3 (5) -ethyl-5 (3) -bromopyrazole -3 (5) -ethyl-5 (3) -fluoropyrazole -3 (5) -ethyl-5 (3) -meth _y l-4-chloro

pyrazole

161 "-3 (5) -ethyl-5 (3) -methyl-4-bromo-

pyrazole

162 "-3 (5) -ethyl-5 (3) -methyl-4-fluoro-

pyrazole

163 "-3 (5) -n-propyl-4-chloropyrazole

164 "-3 (5) -n-propyl-4-bromopyrazole

J- 909823/1 128

^? . H7Ö159

2476 4/5-G

example link 165 1-dimethyl 166 Il 167 Il 168 Il 169 Il 170 Il 171 Il 172 Il

1-dimethylcarbamyl = 3 (5) -n-propyl-4-fluoropyrazole

-315-di »n-propyl-4-chloropyrazole -3 »5-di-n-propyl-4-bromopyrazole -3 f5-di-n-propyl-4-fluoropyrazole -3 (5) -n-propyl-5 (3) -chlorpyrazole -3 (5) -n-propyl ~ 5 (3) -bromopyrazole -3 (5) ~ n ~ propyl-5 (3) -fluoropyrazole

~ 3 (5) -metby1-5 (3) -n-propyl-4-chloropyrazole

173 "-3 (5) -metbyl-5 (3) -n-propyl-4-bromo-

pyrazole

174 "-3 (5) -methyl-5 (3) -n-propy3-4-fluoro-

pyrazole

175 "-3 (5) -ethyl ~ 5 (3) -n-propyl-4-chloro»

pyrazole

176 "= -3 (5) -ethyl""5{3}" n-propyl-4-bromo-

pyrazole

177 "= 3 (5) -ethyl" .5 (3) -n-propyl-4-fluoro =

pyrazole

178 "" ■ 3i5) = - isopropyl-4-chloropyrazole

179 "-3 (5) -isopropyl-4-bromopyrazole

180 "-3 (5) -isopropyl-4-fluoropyrazole

181 · ⁿ ^ »S-di-isopi-opyl ^ -chlorpyrazole

182 ·· »3» 5-di-isopropyl-4-bromopyrazole

183 "" 3,5-di-isopropyl-4 "fluoropyrazole

909823/1128

4/5-G

Example connection .

184 1-Dimethylcarbamy1-3 (5) -isopropy1-5 (3) ™ chloropyrazole

185 "~ 3 (5) = isopropyl-5 (3) ~ bromopyrazole

186 "-3 (5) -isopropyl-5 (3) -fluoropyrazole

187 "" 3 (5) -methy 1-5 (3) -isopropy 1-4-

chlorpyrazole

188 »-3 (5) -methyl ~ 5 (3) -isopropyl-4 ~

bromopyrazole

189 "« ~ 3 (5) HEethy 1-5 (3) -isopropy 1-4-

fluoropyrazole

190 "-3 (5)" ethyl "5 (3) = - isopropyl-4-chloro <

pyrazole

pyrazole

192 "» 3 (5) ~ ä1: hyl-5 (3) -isopropyl-4-fluoro-

pyrazole

193 "" 3C5) -methyl-4-aminopyrazole

194 "-3 (5) = - 1; hyl-4-aminopyrazole

195 "" 3 (5) -n-propyl-4-aminopyrazole

196 "-3 (5) -i3opropyl-4-aminopyrazole

197 "-3,5-diethyl = -4-aminopyrazole

198 ^{! L} -3} 5 ~ di-n-propyl-4- "aminopyrazole" ^: 99 "-3» 5 "-diisopropyl-4 ~ -aminopyrazole 200"-3'5) -chlor-4-aminopyrasol

202 "-3 (5) - Aluor - '4 ~ aQiinopyrasol

V 909823/1128

2476 4/5-G amyl-3, S-dichloro ^ -aminopyraz oil Example connection -3 »5-dibromo-4-aminopyrazole 203 1-dimethylcarb -3 (5) -methy1-5 (3) -chlor-4 ~ amino- 204 " pyrazole 205 " -3 (5) -ethyl-5 (3) -chlor-4-amino- pyrazole 206 " "3 (5) -n-propyl-5 (3) -chloro-4 ~ amino" => pyrazole 207 " = -3 (5) -isopropyl-5 (3) -chloro-4-amino = pyrazole 208 "

209

210 211 212 213 214 215 216 217

pyrazole -3 (5) -ethyl-5 (3) -> bromo-4-aminopyrazole -3 (5) ~ n-propyl-5 (3) -bromo-4-amino-

pyrazole

-3 (5) -isopropy 1-5 (3) -bromo-4-.amino-

pyraaol

"3 (5) -methy1-5 (3) -fluoro-4-amino ~

pyrazole

-3 (5) -ethyl-5 (3) -fluoro ~ 4-amino-

pyrazole

-3 (5) -n-propyl-5 (3) -fluoro-4-amino-

pyrazole

-3 (5) -isopropyl-5 (3) -fluoro-4-aminO "

pyraz oil

pyraaol

BATH ORIGINAL

2476 4/5-G Il Il Example connection Il 218 1-dimethyl Il 219 Il 220 Il 221 Il 222 Il 223 Il 224 Il 225 Il 226 Il 227 Il 228 Il 229 Il 230 Il 231 Ä. 232 233 234 235

1-Dimethylcarbamy1-3 (5) -n-propy1-5 (3) -methyl-4-amino-

pyrazole

-3 (5) -isopropyl-5 (3) -methyl-4-atinopyrazole

-3 (5) -ethyl-5 (3) -n-propyl-4-aminopyrazole

-3 (5) -äthy1-5 (3) -ieopropyl-4-amino-

pyrazole

-4-ethoxypyrazole
-4-Ethoxy-3 (5) -methylpyrazole -3 (5) -methyl-4-methoxypyrazole -3 (5) -ethyl-4-methoxypyrazole -3 (5) -n-propyl-4-methoxypyrazole -3 (5) -isopropyl-4-methoxypyrazole -3 »5-diethyl-4-methoxypyrazole -3 (5) -ehlor-4-methoxypyrazole -3 (5)« briiuj-4-iae1; hoxypyrazole -3 (5) -methy1-5 (3) -chlor-4-met hoxy-

pyrazole

'-3 (5) -äthy1-5 (3) -chlor-4-methoxy-

pyrazole

-3 (5) -n-propyl-5 (3) -chloro-4-methoxypyrazole

-3 (55-isopropyl-5 (3) -chloro-4-methoxypyrazole

3/1128

2476 4 / 5-6

Example connection

236 1-Dimethylcarbamy1-3 (5) -ethyl-5 (3) -bromo-4-methoxypyrazole

.237 "» 3 (5) ~ n-propyl-5 (3) -bromo-4-

methoxypyrazole

238 "-> 3 (5) -isopropyl-5 (3) -bromo-4 ~

raethoxypyrazole

239 "-5 (5)" methyl- »5, (3) ~ fluoro-4-methox2

pyrazole

240 »~ 3 (5) -ethyl-5 (3) -: riuor - 4-methoxy <

pyrazole

241 "-3 (5) ~ n-propyl-5

methoxypyrazole

242 »~ 3 (5) ~ isopropyl 5 (3l ·

methoxypyrazole

243 "=» 3C5) -äthyl ^ 5 (3)

pyrazole

244 "= 3 (5) = n ~ propyl ~ 5i3l ·

methoxypyrazole

245 "~ 3C5) -isopropyl-.5 (3) -methyl ~ 4 ~

methoxypyrazole

246 »-3 (5) -ethyl ^ 5 (3} -n = -propyl-4 ~

methoxypyrazole

247 "» 3C5) »ethyl-5 (3)" isopropyl »4-

methoxypyrazole

248 η "3 (5) ° trifluoromethylpyra2ol

249 "-4-trifluoromethylpyrazole

^? V 909Ö23 / 1128

BAD ORIGtNAL

2476 4/5 ~ G

Example connection

250 1-Dime.thyloarbaiüy 1-3 (5) -trifluoromethyl-4-amino <= ·

• pyrazole

251 "-3 (5 3 ~ niethy 1-5 (3) ~ chlorine-4 - tri«

fluoromethylpyrazole

252 "- = 4-n-propoxypyrazole 255 ■ "= 4-isopropoxypyrazole

Examples 254 to 255

Using the general procedure of Examples 54-79, the following compounds:

254 4

ethylJ7 ** - earbamylpyrazole »

121 to 123 ° C / 0.3 mm-, ηψ * 1.5023

Analysis: C H

Calculated for C ^ -5H ₁₅ N ^ O ₃ Gl: 48.3 5 _S 9 Found: 48.6 6 "0

pyrazole, m.p. 70-72 ° C

Analysis; C H _-

Calculated for C ₈ H ₉ N ₄ OClI 45.2 4.3

Gefuné: 45 - 2 4.7

909823/1128

2476 4 / 5-0

Further connections, which one according to this general Process can produce are ι 4-chloro-i- ^ T-methyl-N- (methyl-2-N, N-dimethylcarbamyjfthyl ^ carbamylpyrazole,

4-Uhlor-1- ^ ir-methyl-N- (1-methyl-4-carbethoxybutylJ7-carbamylpyrazole, 4-bromo-1- ^ Tm.ethyl-H- (i-ethyl-3-oyanpropylj7 "oarbamylpyrazole and 4- Cyano-1- ^ ST-methyl-N- (l-methyl-4-H, R-diethylcarbamylbutylJ7 ^{cart) ain} y lpyrazole "

1128

BATH ORIGINAL

Claims (2)

U70159 B. Z. du Pont de Hemours and Company 2476-4 / 5-0 (P »347) claims 1. Compound of formula In what mean X oxygen or sulfur; R _{1 is} methyl; Alkyl with 1 to 6 carbon atoms, which can be substituted by a Kitrll- or Carb & lkoxygruppe or a dimethyl- or OlHthylamnogrnogruppe, alkenyl with 3 to 6 carbon atoms, alkoxyalkyl with a total of 2 to 6 carbon atoms where R ^ and R ₃ can be connected to each other under Formation of pyrrolidyl, piperldyl, tetrahydropperidyl, azatioyclononyl, or - 77 - 909823/1128 bath U70159 2476-4 / 5-α one by nitrile, carboalkoxy, diolkylamine, trifluoromethyl. Benzyl, alkyl or ο ine dialkylamino- » group substituted piperidino radicals; Hydrogen «alkyl with 1 to 3 carbon atoms, Trifluoromethyl, bromine, chlorine, sulfur pentafluoride, or pyridyl; R ^ hydrogen, chlorine, bromine, alkyl with 1 to 3 carbon atoms, sulfur pentafluoride, amino, cyano or Nitro; Re hydrogen, alkyl with 1 to 3 carbon atoms, Trifluonethyl or bromine; with the restriction that if X is sulfur or R _{2 is} a radical other than methyl 1st, R ₁ - must be hydrogen and with the further restriction that R _{1, R 1 and R 5} together contain a maximum of 6 carbon atoms. 2. Process for the preparation of compounds according to Claim 1, characterized in that a pyrazole of the general formula is used R ₄ - - 78 - 909823 / Π28 BATH ORIGINAL H70159 2476-4 / 5-0 in which R, “R ^ and R _{5 have} the meaning given above own, (a) with a disubstituted carbamyl halide or a dl-substituted thioarbamy! halide of the general formula ₁ X C-HaI in which R 1, R and X have the meaning given above and Hai means halogen or (b) initially with phosgene or thiophosgene with formation the connection in which R,., Rs, R ₅ and X have the meaning given above, and then with an aliphatic. linear or cyclic atoms of the general formula ην ' N ₈ -79- 909823/1128 2 ^ * 6-4 / 5-0 in which R ₁ and R _{2 have} the meaning given above, and if R ^ is a hydrogen atom, the compound obtained may be halogenated. Pharmaceutical ingredient consisting of a compound according to claim 1, BAO ORIGINAL - 80 - 909823 / Ί128