DK170534B1 - 7-Aminophenylpyrazolo [1,5-a] pyrimidines and their preparation and preparations containing them - Google Patents

Abstract

PROCEDURE FOR PREPARING PYRAZOLE (1,5-A) PYRIMIDINES. IT INCLUDES: A) REACTING (II) WITH DIMETHYLFORMAMIDE DIMETHYLACETHOLE AT REFLUX, TO OBTAIN A (A); B) TREAT A (A) WITH SODIUM HYDRIDE IN DIMETHYLFORMAMIDE, TO GENERATE AN ANION; C) MAKE THE ANION REACT WITH FORMULA ALKYL HALIDE (R5X), TO GIVE A (III) AND D) TREAT (III) WITH (IV) IN GLACIAL ACETIC ACID AND REFLUX, TO OBTAIN A (I). BEING: (A), N- (3- (3-DIMETILAMINO) -1-OXO-2-PROPENIL) FENIL) ALCANAMIDA; R1, H, HAL OR CIANO; R2, H OR C 1 TO 4 ALKYL; R3, (V); R5, H, C 1A 6 ALKYL AND OTHERS; R6, ALKYL, C 1 TO 6, CYCLOALKYL FROM C 3 TO 6 AND OTHERS AND X, BR O I. ARE USED AS ANSIOLYTICS AND ANTISEPTICS. *FORMULA* (Machine-translation by Google Translate, not legally binding)

Description

in DK 170534 B1

The present invention relates to novel organic compounds, [7- (3-disubstituted amino) -phenyl] -pyrazolo [1,5-a] pyrimidines, which are valuable as anxiolytic and antiepileptic agents, as well as sedative-hypnotic and skeletal muscle relaxants. . The present invention also relates to dosage unit form compositions containing these as active ingredient, and to processes for their preparation.

The novel compounds of this invention 10 have the following structural formula: 13 - R2 Is 1 - * - Ri 20 wherein R1 is selected from the group consisting of hydrogen, halogen, cyano and? Is selected from the group consisting of hydrogen and C 1 -C 4 alkyl, R 1 is "O" R 5 -NC-R 6 R 4 is selected from the group consisting of hydrogen, C 1 and C ^-Cg alkoxy, R ^ is selected from the group 3Q consisting of hydrogen, C ^-Cg alkyl, C₂-Cg alkenyl, -CH₂C = CH, C3-Cg cycloalkylmethyl, -CH₂OCH3 and -CH₂CH₂-OCH3 and R 9 is selected from the group consisting of C 1 -C 8 -alkyl, C 3 -C 8 cycloalkyl, -O-C 1 C3-dialkyl, - (CH2) n-O-C1-C3-alkyl, - (CH2) n-NH-C1-C3-35-alkyl and - (CH2) n -NC1-C3-dialkyl, where n is an integer from 1 to 3.

DK 170534 B1 2

The most preferred compounds of the present invention are those compounds of the above formula,

wherein R 1 is cyano or 0 5 II

-C-R 4, R 2 is hydrogen, R 3 is a group of the above formula, R 4 is C 1 -C 6 alkyl, R 5 is C 1 -C 8 alkyl, C 2 -C 6 alkenyl or -CH 2 C 3 CH, and R 9 is C 1 -Cg-alkyl, C3-Cg-cycloalkyl, or -O-C Ci-Cg-alkyl.

The present invention further relates to a dosage unit form composition which is characterized in that it contains from 2 to 750 mg of a compound of the invention together with a pharmaceutical carrier. Finally, the invention also relates to a process for the preparation of a compound of the invention which is characterized by the characterizing part of claim 5.

X US Patent No. 4,178,449 discloses closely related pyrazolo [1,5-a] pyrimidines having anxiolytic effect. However, these compounds have not found practical application as they cause necrosis and enlargement of the liver.

EP Patent No. 129,847 discloses closely related pyrazolo [1,5-a] pyrimidines which exhibit anxiolytic, anticonvulsant, sedative and muscle relaxant effects. However, in comparison with these known compounds, the compounds of the invention exhibit surprising improvements in these effects.

The novel compounds of the present invention can be readily prepared as set forth in the reaction scheme below: 30 DK 170534 B1 || // \ (1) DMF-acetal CH3 * \ / o (2) NaH; Rs'x \ = Y | j (X = Br, I) HNCR * (1) 10 0 / "· \ (CH3) 2NCH = CHC - / ^ y ^ = {\ r5-nc-r4 (2) + r5 o / vi II / N \ 20 f NV-N-CR * Η-h »nS-r2 ky} h2n -Ri / Nv (3) 25 LJ" ^ 1 XN ^ (4) 30 According to the above reaction scheme, a 1-acetylphenyl-3-amide (1) wherein R 9 is as defined above with dimethylformamide-dimethyl acetal at reflux to give N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl ] -alkanamide which is then reacted with sodium hydride and the resulting anion is reacted with an alkyl halide where R has the above meaning giving N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] -4-phenyl] -N-alkylalkanamide (2). This compound is then reacted with a 3-aminopyrazole (3), where and R 2 have the above meanings, in glacial acetic acid at reflux to give the product (4).

Alternatively, N- [3- [3- (dialkyl-amino) -1-oxo-2-propenyl] -phenyl] -alkanamide (5) is reacted with 3-aminopyrazole (3) to give an intermediate (6), which is reacted with a base, e.g. sodium hydride, sodium alkoxide and the like. and an R 1 halide to provide the products (4).

Now

(CH3) 2NCH = CHC-r Λ + H'N

\ = / ° H2 ^ - = r = r.J-Ri HN-C-R * (3) (5) R5 0 ^ 8

jj B "L

R ^-halide 'Ν' 'N (4) (6) 30 35 0 DK 170534 B1 5

The effective efficacy of the present compounds in standard laboratory animal experiments known to correlate well with the relief of anxietas in humans indicates that they possess action on the central nervous system at nontoxic doses and are thus valuable. as anxiolytic agents. In addition, biological data have shown that these compounds are valuable as antiepileptic agents, especially in the treatment of very severe epileptic seizures, as well as sedative-hypnotic and skeletal muscle relaxants.

The anti-anxiolytic and anti-convulsive properties of the novel compounds of the present invention have been demonstrated in an experiment which indicates anxiolytic and anti-epileptic activity by measuring the protection they provide from convulsions arising from administration. of pentylene-trazole. Single or controlled dosage amounts of the test compounds are administered orally or intraperitoneally in a 2% starch matrix containing 0.5% w / v polyethylene glycol and one drop of "Polysorbate 80" for groups of at least 4 rats. After 30 or 60 minutes, the rats are treated intravenously with pentylenetetrazole at a dose of 23 mg / kg body weight. This dose is estimated to cause clonic seizures in 99% of the unprotected rats.

It is stated [R.T. Hill and D. H. Tedeschi, "Animal Testing and Screening Procedures in Evaluating Psychotropic Drugs" in "An Introduction to Psychopharmacology" 30 Eds. R. R. Rech and KE Moore, Raven Press, New York, pp. 237-288 (1971)] that there is a great correlation between the ability of the compounds to inhibit the seizure-inducing effect of pentylenetetrazole in rats and the efficacy of these compounds as anxiolytic and anticonvulsant. vulsive agents in higher warm-blooded animals. The results of this representative compound test of the present invention are shown in Table I.

6 0 DK 170534 B1

Table I

Protection against clonic seizures induced by pentylenetetrazole ftos rats * 5 - "" * I Dose% Protected

Compound J (mg / kg) rats N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-10-yl) -phenyl] -N-ethylpropanamide | 25.0 100 N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-ethylacetamide 25.0 100 N- [3- (3-chloropyrazolo [1 5-a] pyrimidin-j-7-yl) -phenyl] -N-ethylacetamide 25.0 100 N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-propylacetamide j 6.25 100 µl [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] methylcarbamic acid, methyl ester 3.1 ii 2Q [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7--yl) -phenyl] -ethylcarbamic acid, methyl ester 12.6 75 µl in 1-butyl-N- [3- (3- cyanopyrazolo [1,5-a] -pyrimidin-7-yl) -phenyl] -acetamide 25.050 in [3- (3-cyanopyrazolo [1,5-a] pyrimidin-25β- 7-yl) -phenyl] -ethylcarbamic acid, ethyl ester 25.0 [3- (3-Chloropyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -ethylcarbamic acid, ethyl ester 25.0 3Q N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-2-propenylacetamide 25.0 100 tf- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-2-propynylacetamide 6.25 100 35 1 - * - 1-I-1 7 1707034 B1 0

Table I (continued)

Protection against clonic seizures induced by pentylenetetrazole in rats 5

Compound Dose% Protected (mg / kg) rats | N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-methylcyclobutane carboxamide 25.0 N- [3- (3-cyanopyrazolo [1, 5-a] pyrimidin-7-yl) -phenyl] -N-methylcyclopropanecarboxamide 25.0 75 N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) ) -phenyl] -N-methylacetamide 25.0 75 N- [3- (3-chloropyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-methylacetamide 12.5 3- (acetylmethylamino) -phenyl] -pyrazolo [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester 25.0 100 N- [3- (3-cyanopyrazolo [1,5-a] pyrimi - din-7-yl) -phenyl] -N-methylpropanamide 12.5 N- [3- (3-cyano-2-methylpyrazolo [1,5- a] pyrimidin-7-yl) -phenyl] -N -methyl-propanamide 25.0 100 25

Another test that has been used to assess anti-anxiolytic effects is an unconditional passive avoidance method described by JR Vogel, B. Beer and DE Clody, "A Single and Reliable Conflict Procedure for Testing Anti-Anxiety Agents ”, Psychophar macologia, 21_, 1-7 (1971). A conflict situation is induced in rats by modifying this method.

35 groups of 6 rats belonging to the tribe

Wistar, each weighing 200-240 g, is deprived of water for 48 hours and food for 24 hours. Test compounds 8 0 DK 170534 B1 are administered in single or controlled oral or intraperitoneal doses suspended in a 2% starch matrix containing 0.5% w / v polyethylene glycol and one drop of "Polysorbate 80". Control animals receive 5 matrix alone. After 30-60 minutes, each rat is placed in an individual plexiglass chamber. Water is available ad libitum from a tap located behind the chamber. A 0.7 milliampere direct current shock connection is established between the stainless steel grid 10 and the male. After drinking water 20 times without shock, the rats receive a shock for 2 seconds, and then additional shock in the ratio of 1 shock for 2 seconds for each time the rats drank 20 times. This is repeated for a total of 3 minutes. The number of shocks that each 15 rat receives in a 3 minute interval is recorded and compared with a control group. The test compounds are considered to be active if the number of shocks received by the experimental group is significantly higher than the control group of the Mann-Witney U experiment.

20 Results of this test for representative of compounds of the present invention are shown in Table II.

Table II

25 Non-conditional passive avoidance experiments in rats

Dosage

Compound (mg / kg) Result N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-ethylpropanamide 0.4 µ Active N- [3 - (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-ethylacetamide 0.8 Active N-ethyl-N- (3-pyrazolo [1,5-a ] pyrimidin-7-yl-phenyl) -acetamide 25.0 Active 9 DK 170534 B1

Table II (continued)

Non-conditioned passive avoidance test in rats in 'i' 5 Dose! Compound (mg / kg) j Result j N- [3- (3-Chloropyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-ethyl acetamide 3.1 Active 10 U- [3 - (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-propylacetamide 1,5, Active in [3- (3-cyanopyrazolo [1,5-a] pyrimidine-1 β-7-yl) -phenyl] -methylurea acid, methyl ester I 3.1 Active in [3- (3-cyanopyrazolo [1,5-a] pyrimidin-15-yl) -phenyl] -ethylcarbamic acid; methyl ester! 12.5 j Active

i

[3- (3-Chloropyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -ethylcarbamic acid, ethyl ester in 25.0 Active N- [3- (3-cyanopyrazolo [1,5 -α] pyrimidin-7-yl) -phenyl] -N-2-propenylacetamide 3.1 Active N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-2-propynylacetamide 1.5 Active N- [3- ( 3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-methylpropanamide 6.2 Active N- [3- (3-cyano-2-methylpyrazolo [1,5-a] - pyrimidin-7-yl) -phenyl] -N-methylpropanamide 25.0 Active 7- [3- (acetylmethylamino) -phenyl] - | -pyrazolo [1,5-a] pyrimidin-3-carboxylic acid, ethyl ester 25.0 Active thi- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] - N-methylacetamide 1.5 Active N- [3- (3-chloropyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-methylacetamide 3.1 Active [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-methylcyclobutanecarboxamide 25.0 Active

Another test used to determine anxiolytic activity is the measurement of the ability of the test compounds to inhibit the binding of tertiary benzodiazepines to brain-specific receptors 5 in warm-blooded animals. A modification of that of R. F.

Squires, et al., Nature, 266, No. 21, page 732 (April 1977), yogh. H. Mohler et al., Science, 198, page 849 (1977)

Albino rats, males, of the Wistar strain, each weighing 150-200 g, were purchased from Royalhart Farms. H-Me-. 3 thyldxazepam (79.9 Ci / mmol) and H-methylflunitrazepam (84.3 Ci / mmol) were purchased from New England Nuclear. The test compounds are dissolved in either dimethylformamide, acetic acid, ethanol or hydrochloric acid.

15 Whole rat cortex is gently homogenized in 20 volumes of ice-cold 0.32 M sucrose, centrifuged twice at 1000 G for 10 minutes and then recentrifuged at 30,000 G for 20 minutes to produce a crude P2 synaptosomal fraction. Either (1) resuspend the 20 P2 fraction in twice the original volume in hypotonic 50 mM tris.HCl (pH 7.4), or (2) resuspend in half of the original volume in hypotonic 10 mM tris.HCl (pH 7.4) and then the P2 fraction (-20 ° C) is frozen until used.

25 Frozen P2 preparations are thawed and resuspended four times the original homogenizing volume at the time of the experiment.

The binding assay consists of 300 Ml of the p2 ~ fraction suspension (0.2-0.4 mg protein), 100 μΐϊ-30 ter of the pharmaceutical test preparation and 100 μΐΐ-3 ter H-diazepam (1.5 nM, final concentration) or 3 H flunitrazepam (1.0 nM, final concentration) added to 1.5 ml of 50 mM tris.HCl (pH 7.4). Non-specific binding controls and total binding controls receive 35 μϋΐβΓ of diazepam (3 mM, final concentration) and 100 µL of deionized water, respectively, instead of the test compound. Incubation for 30 minutes is carried out in ice and terminated by filtration under vacuum through DK 170534 B1 11 o "Whatman GF / C" fiberglass filters. The filters are washed twice with 5 ml of ice-cold 50 mM Tris.HCl (pH 7.4) and placed in scintillation vials. After drying at 50-60 ° C for 30 minutes, 10 ml of Beckman Ready-Solv HP 5 (a pre-mix scintillation cocktail, registered trademark of Beckman Instruments, Inc., Irvine, CA 92713) is added and the radioactivity is determined by a scintillation counter .

Binding inhibition is calculated by the differences between the total binding and the binding in the presence of the test compound, divided by the total binding x 100.

The results of this representative compound test of the present invention 15 are given in Table III.

Table III

3

Inhibition of the binding of H-benzodiazepine to brain-specific receptors in rats 20

Compound% Inhibition N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7--yl) phenyl] -N-ethylpropanamide 83 N- [3- (3-cyanopyrazolo [1,5-a ] pyrimidin-7-yl) phenyl] -N-ethylacetamide 79 N- (3- (3-chloropyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-ethylacetamide 97 N - [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7- (30-yl) -phenyl] -N-propylacetamide 64 7- [3- [ethyl- (1-oxopropyl) -amino] -phenyl ] - j -pyrazolo [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester 100 in [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -1-phenyl] - methylcarbamic acid, methyl ester 87 7- [3 - [(methoxycarbonyl) methylamino] phenyl] pyrazolo [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester 9812 0 DK 170534 B1

Table III (continued) 3

Inhibition of the binding of H-benzodiazepine to brain-specific receptors in rats 5 Γ

Compound% Inhibition: [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -: - phenyl] ethylcarbamic acid, methyl ester 55 in 10 7- [3- [ethyl- (methoxycarbonyl) - amino] -phenyl] pyrazolo [1,5-a] pyrimidin-3-j-carboxylic acid, ethyl ester 99 in [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl ] -methylcarbamic acid, ethyl ester 41 Ethyl (3-pyrazolo [1,5-a] pyrimidin-7-yl-phenyl) -carbamic acid, ethyl ester 61 [3- (3-Cyanopyrazolo [1,5-a] pyrimidin-7- j-yl) -phenyl] -ethylcarbamic acid, ethyl ester 63 [3- (3-Chloro-pyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -ethylcarbamic acid, ethyl ester 78

20 I

N - [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-2-propenylacetamide 78 N- [3- (3-cyanopyrazolo [1,5-a] pyrimidine -7-yl) -phenyl] -N-2-propynylacetamide 91 N- [3- (3-cyano-2-methylpyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -propanamide 42 N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-methylpropanamide 79 N- [3- (3-cyano-2-methylpyrazolo [1,5-a ] -pyrimidin-7-yl) -phenyl] -N-methylpropanamide 95 N-methyl-N- (3-pyrazolo [1,5-a] pyrimidin-7-yl-phenyl) -acetamide 54 7- [3 - (Acetylmethylamino) -phenyl] -pyrazolo [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester 100 N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) ) -phenyl] -N-methylacetamide B1

Table III (continued) 3

Inhibition of the binding of H-benzodiazepine to brain-specific receptors in rats 5 Γ

Compound% Inhibition N- [3- (3-Chloropyrazolo [1,5-a] pyrimidin-7--yl) -phenyl] -N-methylacetamide 71 N- [3- (3-cyanopyrazolo [1,5-a ] pyrimidin-7--yl) -phenyl] -N-methylcyclobutane carboxamide 81 N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-methylcyclopropane carboxamide 83 [3 - [(cyclopropylcarbonyl) methylamino] -phenylpyrazolo [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester 95 7- [3- (acetylethylamino) -phenyl] -pyrazolo [1,5-a ] pyrimidine-3-carboxylic acid, ethyl ester 97 7- [3- (acetylamino) -phenyl] -pyrazolo [1,5-a] -20-pyrimidine-3-carboxylic acid, ethyl ester 85 7- [3 - [(methoxycarbonyl) -amino ] -phenyl] -pyrazolo [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester 76

Methyl (3-pyrazolo [1,5-a] pyrimidin-7-yl-25-phenyl) -carbamic acid, methyl ester 7- [3- (acetylpropylamino) -phenyl] -pyrazolo- [1,5-a ] pyrimidine-3-carboxylic acid, ethyl ester 97 [3- (3-chloropyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -methylcarbamic acid, methyl ester 92 7- [3 - [(cyclobutylcarbonyl) amino] ] -phenyl] -pyrazolo [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester 82

The aforementioned compounds 35 have also been found to have muscle relaxant effect during two experiments. The first experiment measures the effect of representative connections on the ability of rats to remain on an oblique wire mesh. Groups of at least 6 rats are treated orally with graduated doses of test binder or matrix and placed on a wire mesh (inclined at an angle of 60 ° from horizontal level) 65 minutes later.

The number of rats falling from the wire mesh within 30 minutes is recorded. ED ^ q (the dose required to cause 50% of the animals examined to fall) is calculated according to that of Finney D.J., in "Statistical Methods in Biological Assay", 2nd ed. Hafner, N.Y., 1964, page 454χ described linear arcsin transformation method. The compounds are dissolved or suspended in a 2% aqueous starch suspension containing 5% polyethylene glycol 400 and a drop of "Polysorbate 80" 15 and administered at a constant volume of 5 ml / kg. The results of the representative compounds in question are presented in Table IV.

Table IV

20 Effect on the ability of rats to remain on an inclined wire mesh

Compound EDCrt 25 (mg / kg) N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-ethylpropanamide 4.6 N- [3- (3 -cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-ethylacetamide 3.9

The second experiment to illustrate that the novel compounds of the present invention possess muscle relaxant properties show the effect of representative compounds on the locomotor activity of rats. Groups of 6 15 0 DK 170534 B1 rats are treated orally with matrix (5 ml / kg) or graduated doses of the test compounds. 60 minutes later, individual rats are placed in Actophotometers and the locomotor activity is measured for 5 minutes after 5 a short (30 sec) acclimation period. Counts of motor activity (number of junctions of photocells) are recorded for each rat, and the average activity counts are calculated for each treatment group. The dose resulting in a 50% reduction in the average activity counts compared to the matrix mass (MDD5q) is calculated from a linear regression equation. The test results of representative compounds are shown in Table V.

Table V

Effects on locomotor activity in rats

Compound 100 mg (kg / kg pO) N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-ethylpropanamide 2.0 N- [3- (3- cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-ethylacetamide 1.4

The novel compounds of the present invention have been found to be very valuable for mammal pharmaceutical treatment when administered in amounts ranging from ca. 0.1 mg to approx. 20.0 mg / kg body weight per day. A preferred dose regimen for optimum results will be from approx. 0.5 mg to approx. 10.0 mg / kg body weight per day. day. Dosage units are used in such a way that a total of approx. 10 to approx. 700 mg of active compound to an individual weighing approx. 70 kg, for a period of 24 hours. This dose can be adjusted to provide an optimal therapeutic response. One can, for example. administer multiple divided doses daily or the dose may be reduced proportionally to the requirements of the therapeutic situation. The compounds of this invention are preferably administered orally, but may be administered in any convenient manner, e.g. intravenously, intramuscularly or subcutaneously.

Compositions of the present invention with the desired clarity, stability and ability for parental use are obtained by dissolving from 0.10% to 10.0% by weight of active compound in a matrix consisting of a polyhydric aliphatic alcohol or mixtures thereof. Particularly preferred are glycerol, propylene glycol and polyethylene glycols. The polyethylene glycols consist of a mixture of non-volatile, normally liquid polyethylene glycols which are soluble in both water and organic liquids and which have molecular weights of. ca. 200 to 1500. Although the amount of active compound dissolved in the above matrix may range from 0.10 to 10.0 weight-20 percent, it is preferred that the amount of active compound used be from about 3.0 to approx. 9.0% by weight. Although various mixtures of the aforementioned non-volatile polyethylene glycols may be used, it is preferred to use a mixture having an average molecular weight of from ca. 200 to approx. 400th

In addition to the active compound, the parenteral solutions may also contain various preservatives which can be used to prevent bacterial and fungal contamination. The preservatives which can be used for these purposes are e.g. myristyl-γ-picolinium chloride, benzalkonium chloride, phenethyl alcohol, p-chlorophenyl-α-glycerol ether, methyl and propyl parabens and thimerosal. As a practical measure, it is also appropriate to use antioxidants. Suitable antioxidants include e.g. sodium bisulfite, sodium metasulfite and sodium formaldehyde sulfoxylate. Usually used from ca. 0.05% to approx. 0.2% concentrations of antioxidants.

17 0 DK 170534 B1

For intramuscular injection, the preferred concentration of active compound is 0.25 to 0.50 mg / ml in the final preparations. The present compounds are equally well suited for intravenous administration, whether diluted with water or diluents used in intravenous treatment, e.g. isotonic glucose, in appropriate quantities. For intravenous use, initial concentrations are down to approx. 0.05 to 0.25 mg / ml active ingredient satisfactorily.

The active compounds of the present invention may be administered orally, e.g. with an inert diluent or with an assimilable edible carrier, or they may be contained in hard or soft gelatin capsules or compressed into tablets or incorporated directly into the feed. For oral therapeutic administration, the active compounds can be incorporated with excipients and used in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, waffles and the like. The active ingredient may further be incorporated with a suitable pharmaceutical carrier or carriers known in the art to provide a delayed release tablet or capsule. Such preparations and formulations must contain at least 0.1% active compound. The percentage of the compositions and formulations may, of course, be varied and may conveniently be between ca. 2 and approx. 60% by weight of the unit dose. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.

The tablets, lozenges, pills, capsules and the like. may also contain one or more of the following ingredients: a binder such as tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate? a disintegrant, e.g. corn starch, potato starch, alginic acid and the like; a lubricant, e.g. magnesium stearate; a wetting agent, e.g.

Sodium lauryl sulfate, and a sweetening agent, e.g. sucrose, lactose or saccharin ,, or a flavoring, e.g. peppermint, winter vegetable oil or cherry flavor. When the dosage unit form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier material, e.g. fat oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For example. For example, tablets, pills or capsules may be over-10 coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetener, methyl and propyl parabens as preservatives, a dye and flavoring, e.g. cherry or orange flavor. Of course, all materials used in the preparation of any dosage unit form must be pharmaceutically pure and practically non-toxic in the amounts used.

The following examples illustrate the preparation of representative compounds of the present invention.

Example 1 N- [3- [3- (Dimethylamino) -1-oxo-2-propenyl] -phenyl] -propanamide Reflux 20 g of N- (3-acetylphenyl) -propanamide in 50 ml of dimethylformamide-dimethyl acetal for 8 hours and then evaporated. The residue is taken up in 200 ml of dichloromethane, passed through aqueous magnesium silicate, diluted with hexane and concentrated to give 21.17 g of the desired compound.

Proceeding as set forth in Example 1 and using the indicated starting materials, the amides of Examples 2-5 are set forth in Table VI.

35 19 0 DK 170534 B1

Table VI

5 Ex. Starting material Amide 2 N- (3-acetylphenyl) -ethane-N- [3- (3-dimethylamide amino) -1-oxo-2--propenyl) -phenyl] -acetamide 3 (3-acetylphenyl) - carb [3- [3- (dimethylamide acid, methyl ester amino) -1-oxo-2-propenyl] phenyl] carbamic acid, methyl ester 4 (3-acetylphenyl) carb- [3- [3 - (dimethylamino acid, butyl ester no) -1-oxo-2-propenyl] -phenyl] -carbamic acid, butyl ester 5 N- (3-acetylphenyl) - N- [3- [3- (dimethyl-butanamide) amino) -1-oxo-2-propenyl] -phenyl] -butanoamide

Example 6 N- [3- [3- (Dimethylamino) -1-oxo-2-propenyl] phenyl-N-25-ethylpropanamide

A mixture of 3.47 g of N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] propanamide and 0.68 g of 60% sodium hydride in oil in dimethylformamide is stirred for 1 hour. / 2 hours under argon, then cool in an ice bath and add a solution of 2.4 g of ethyl iodide in 10 ml of dimethylformamide in small portions. The mixture is then stirred at room temperature for 1/2 hour and extracted three times with hexane. The extracts are discarded, water is added and this mixture is extracted with dichloromethane. This extract is evaporated and the residue is crystallized from hexane to give the desired compound, mp 105-107 ° C.

DK 170534 B1 20 o

Proceeding as described in Example 6 using the compounds of Examples 1-5 and appropriate alkyl halides, the alkylated amides of Examples 7-12, 5 set forth in Table VII are prepared.

Table VII

10 Starting

Ex. material

acc. eg Alkylated amide m.p. C

2 N- [3- [3- (dimethylamino) - 110-113 -1-oxo-2-propenyl] -phenyl] -N-ethylacetamide 8 1 N- [3- [3- (dimethylamino) -1 - 148-149 -oxo-2-propenyl] -phenyl] -N - methylpropanamide 9 2 N- [3- [3- (dimethylamino) -1,110-112 -oxo-2-propenyl] -phenyl] -20 -N-propylacetamide 10 3 [3- [3- (dimethylamino) -1-oxo-93-95 -2-propenyl] phenyl] methylcarbamic acid, methyl ester 11 3 [3- [3- (dimethylamino) -1 -oxo-95-97 -2-propenyl] -phenyl] -ethyl-carbamic acid, methyl ester 12 2 N- [3- [3- (dimethylamino) -1- 146-148-oxo-2-propenyl] -phenyl] - N - methyl acetamide 30

Example 13 N- [3- (3-Cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-ethylpropanamide

A mixture of 0.54 g of 3-amino-4-pyrazole carbonitrile and 1.37 g of N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] -N-ethylpropanamide in 50 ml of glacial acetic acid Reflux DK 170534 B1 21 0 for 8 hours and then remove the solvent. The residue is partitioned between straight aqueous sodium bicarbonate and dichloromethane. The organic layer is separated, dried, passed through a layer of aqueous magnesium silicate, and hexane is added to the 5 'reflux filtrate. The mixture is then cooled and the solid collected to give 1.3 g of the desired product, mp: 161-162 ° C.

Proceeding as described in Example 13 and using appropriately substituted 10 3-amino-pyrazoles together with the indicated intermediates, the products of Examples 14-37 listed in Table VIII are prepared.

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Example 38 N- [3- (3-Chloropyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-ethylacetamide A mixture of 1.0 g of N-ethyl-N- (3-pyrazolo) - [1,5-a] pyrimidin-7-yl-phenyl) -acetamide and 4.57 g of 1-chlorobenzotriazole in 50 ml of dichloromethane are refluxed for 25 minutes, then cooled and poured into 50 ml of ice-cold 2.5 N aqueous sodium hydroxide. The mixture is filtered through aqueous magnesium silicate, precipitated with hexane and the solid collected to give 0.7 g of the desired product, mp: 157-159 ° C.

Example 39 7- [3- [Ethyl (methoxycarbonyl) amino] -phenyl] -pyrazolo [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester 12.41 g [3- [3- (dimethylamino) ) -1-oxo-2-propenyl] -phenyl] -carbamic acid, methyl ester is reacted as described in Example 6 using 9.36 g of ethyl iodide to give 13.4 g of [3- [3- thiamino) -1-oxo-2-propenyl] -phenyl] -ethylcarbamic acid, methyl ester, mp: 95-97 ° C.

2.76 g of the above ester are reacted with 1.55 g of ethyl 3-aminopyrazole-4-carboxylate as described in Example 13 to give 2.87 g of the desired product, mp: 117-119 ° C.

Example 40 [3- (3-Cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] - * -ethylcarbamic acid, methyl ester 2.76 g [3- [3- (dimethylamino) -1-oxo-2- propenyl] -phenyl] -ethylcarbamic acid, methyl ester is reacted with 1.08 g of 3-aminopyraozl-4-carbonitrile as described in Example 13 to give 2.6 g of the desired product, m.p. 164 ° C.

27 0 DK 170534 B1

Example 41 [3- (3-Cyanopyrazolo [1,5-aj pyrimidin-7-yl) -phenyl] -methylcarbamic acid, ethyl ester 5-Acetylphenyl-3-carbamic acid, ethyl ester is converted to [3- [3- (dimethylamino) ) -1-oxo-2-propenyl] -phenyl] -carbamic acid, ethyl ester in the manner described in Example 1, and this ester is then reacted with methyl iodide in the manner described in Example 6 to give [3- [ 3- (Dimethylamino) -1-oxo-2-propenyl] -phenyl] -methylcarbamic acid, ethyl ester.

2.6 g of the above ester are reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile in the manner set forth in Example 13 to give 2.09 g of the desired product, mp: 140-142 ° C .

Example 42

Ethyl (3-pyrazolo [1,5-a] pyrimidin-7-yl-phenyl) -carbamic acid, ethyl ester [3- [3- (Dimethylamino) -1-oxo-2-propenyl] phenyl] carbamic acid is reacted with ethyl iodide in the manner described in Example 6 to give [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] ethylcarbamic acid, ethyl ester.

2.9 g of the above ester are reacted with 0.83 g of 3-aminopyrazole in the manner described in Example 13 to give 2.27 g of the desired product, mp 79-81 ° C.

30

Example 43 [3- (3-Cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -ethylcarbamic acid, ethyl ester 2.0 g [3- [3- (dimethylamino) -1-oxo-2 -propanyl] -phenyl] -ethylcarbamic acid, ethyl ester is reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile as described in Example 13 to give 2.52 g of the desired product, m.p. 133-135 ° C.

Example 44 [3- (3-Chloropyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -ethylcarbamic acid, ethyl ester I, 55 g of ethyl- (3-pyrazolo [1,5-a] pyrimidine -7-yl-phenyl) -carbamic acid, ethyl ester in 50 ml of 10-dichloromethane is reacted with 1-chlorobenzotriazole for 30 minutes to give 1.29 g of the desired product, mp: 100-102 ° C.

Example 45 N- [3- (3-Cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-2-propenylacetamide II, 61 g of N- [3- (3- (dimethylamino)) -1-oxo-2-propenyl] -phenyl] -acetamide is reacted with 7.26 g of allyl bromide as described in Example 6 to give 13.34 g of N- [3- [3- (dimethylamino) - 1-oxo-2-propenyl) -phenyl] -N-2-propenylacetamide, mp: 91-94 ° C.

I, 36 g of the above intermediate are reacted with 0.54 g of 3-aminopyrazole-4-carbonitrile as described in Example 13 to give 1.0 g of the desired product, mp: 135-137 ° C.

Example 46 N- [3- (3-Cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-2-30-propynylacetamide, II, 61 g N- [3- (3- (dimethylamino) ) -1-oxo-2-propenyl] -phenyl] -acetamide is reacted with propynyl bromide as described in Example 6 to give N - [3- [3- [35 - (dimethylamino) -1-oxo-2-propenyl] phenyl] -N-2-propynylacetamide, mp: 98-101 ° C.

2.7 g of the above intermediate is reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile as described in Example 13 to give 1.90 g of the desired product, mp: 193-195 ° C.

5

Example 47 N-Butyl-N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -acetamide 11.61 g [3- [3- (dimethylamino) -1 -oxo-2-propenyl] -phenyl] -carbamic acid, methyl ester is reacted with 11.0 g of butyl iodide in the manner described in Example 6 to give 16.3 g of N-butyl-N- [3- [3- ( dimethylamino) - l-oxo-2-propenyl] phenyl] -acetamide.

2.88 g of the above intermediate is reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile in the manner described in Example 13 to give 1.61 g of the desired product, mp 146-148 ° C.

Example 48 N- [3- (3-Cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-methylcarbamic acid, butyl ester 11.61 g [3- [3- (dimethylamino) -1 -oxo-2-propenyl] -25-phenyl] -carbamic acid, butyl ester is reacted with 6.82 g of methyl iodide in the manner described in Example 6 to give 11.67 g of [3- [3- (dimethylamino) -1] -oxo-2-propenyl] -phenyl] -methylcarbamic acid, butyl ester.

3.04 g of the above ester are reacted with 1.08 g of 3-30-aminopyrazole-4-carbonitrile as described in Example 13 to give 2.3 g of the desired product, mp: 96-97 ° C.

Example 49 N- [3- (3-Chloropyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-35-methylacetamide 1.0 g N-methyl-N- (3-pyrazolo [1, 5-a] pyrimidine-7-O-yl-phenyl) -acetamide is reacted as described in Example 38 to give 1.0 g of the desired product, mp: 163-165 ° C.

Example 50 [3- (3-Chloropyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] - -methylcarbamic acid, methyl ester 1.4 g of methyl (3-pyrazolo [1,5-a] pyrimidine -7-yl-phenyl) -carbamic acid, methyl ester is reacted as described in Example 38 to give 1.42 g of the desired product, mp: 132-134 ° C.

Example 51 7- [3 - [(Cyclopropylcarbonyl) methylamino] -phenylpyrazolo-[1,5-a] pyrimidine-3-carboxylic acid, ethyl ester N- (3-Acetylphenyl) -cyclopropane carboxamide is prepared by reaction of m-aminoacetophenone, diisopro -pylethylamine and cyclopropane carboxylic acid chloride in dichloromethane.

This compound is then converted to N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] -phenyl] -cyclopropane carboxamide in the manner described in Example 1 and then alkylated as described in Example 6 using methyl iodide to give 10.17 g of N- [3- (3-dimethylamino) -1-oxo-2-propenyl) phenyl] -N-methylcyclopropane carboxamide, mp: 120-122 ° C.

0.54 g of this compound is reacted as described in Example 13 with 3-aminopyrazole-4-carbonitrile to give 1.08 g of the desired product, mp: 178-30-180 ° C.

Example 52 $ 7- [3 - [(Cyclopropylcarbonyl) methylamino] -phenylpyrazolo [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester 0.73 g of ethyl 3-aminopyrazole-4-carboxylate and 1.36 g N- [3 - [(3- (dimethylamino) -1-oxo-2-propenyl] -phenyl] -N-methylcyclopropane carboxamide is reacted as described in Example 13 to give 0.52 g of it. desired product, mp: 122-124 ° C.

Example 53 N- [3- (3-Cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] - N-methylcyclobutane carboxamide m-Aminoacetophenone, cyclobutane carboxylic acid chloride and diisopropylethylamine in dichloromethane are reacted to give N - (3-acetylphenyl) -cyclobutancarboxamid.

This compound is then converted to N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] -phenyl] -cyclobutane carboxamide, mp: 155-157 ° C, in the same manner as described in Example 1 and further alkylated as described in Example 6 using methyl iodide to provide 8.32 g of N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] -N-methylcyclobutane carboxamide, m.p. : 117--119 ° C.

0.54 g of 3-aminopyrazole-4-carbonitrile is reacted with 1.43 g of the above product in the same manner as described in Example 13 to give 1.3 g of the desired product, mp: 157-158 ° C.

Example 54 7- [3 - [(Cyclobutylcarbonyl) amino] phenyl] pyrazolo [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester 0.78 g of 3-amino-4-carboethoxypyrazole and 1.36 g of N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] -cyclobutane carboxamide is reacted as described in Example 13 to give 1.52 g of the desired product, m.p.: 123 -125 ° C.

35

Claims (11)

0 DK 170534 B1 Patent claims. A compound, characterized in that it has the formula XN x 10 wherein R 1 is selected from the group consisting of hydrogen, halo, cyano and n, R 1 is selected from the group -c-r 4 consisting of hydrogen and C C 1 -C 4 alkyl, R 1 is R 5 -NC-R 6 R R is selected from the group consisting of hydrogen, C ^-Cg-alkyl and C ^-Cg alkoxy, Rg is selected from the group consisting of hydrogen, C ^-Cg alkyl, C₂-Cg alkenyl, -CH₂ -C = CH, C3-C8-cycloalkylmethyl, -CH2OCH3 and -CH2CH2OCH3, and Rg is selected from the group consisting of C1-C5-C5 alkyl, C3-C8-cycloalkyl, -O-C1- alkyl, -NH-C1-C3-alkyl, -N-C1-C3-dialkyl, - (CH2) n-O-C1-C3-alkyl, - (CH2) -NH-C1-C3-alkyl and - (CH 2) n ~ NC 1 -C 3 dialkyl, where n is an integer from 1 to 3. A compound according to claim 1, characterized in that R is cyano or O, R 2 is hydrogen, R 3 is a group of the formula referred to in claim 1, R 2 is C 1 -C 8 alkyl, C 2 "C 6 alkenyl or -CH 2 C = CH, 3 g R claim 1, and R 9 is C 1-6 -C 8 alkyl, C 3 -C 8 cycloalkyl or -OC 2 -C 8 alkyl. 0 DK 170534 B1 Compound according to claim 2, characterized in that it is selected from the group consisting of N- [3- (3-cyanopyrazolo [1,5-a] -pyrimidin-7-yl) -phenyl] -5-N-ethylpropanamide , N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-ethylacetamide, N- [3- (3-cyanopyrazolo [1,5-a] pyrimidine) -7-yl) -phenyl] -N-propylacetamide, [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -methyl-carbamic acid, methyl ester, 7- [3 - [(methoxycarbonyl) methylamino] -phenyl] -pyrazolo [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester, [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) - phenyl] -15-ethylcarbamic acid, methyl ester, ethyl (3-pyrazolo [1,5-a] pyrimidin-7-yl-phenyl) -carbamic acid, ethyl ester, [3- (3-chloropyrazolo [1,5-a ] pyrimidin-7-yl) -phenyl] -ethyl-carbamic acid, ethyl ester, N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-2-propenylacetamide, N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] - N-2-propynylacetamide and N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -25-N-methylacetamide. Dosage unit form composition, characterized in that it contains from 2 to 750 mg of a compound according to claim 1 together with a pharmaceutically acceptable carrier. A process for preparing a compound of formula I3 · 35 0 DK 170534 B1 wherein R is selected from the group consisting of hydro-10 gene, halogen, cyano and &quot; is selected from the -or4 group consisting of hydrogen and C R-is R5-NC-R Ré R R is selected from the group consisting of hydrogen, C C-Cg-alky ^ C C-Cg-alkoxy, Rg is selected from the group consisting of hydrogen, C ^-Cg-alkyl, C₂-Cg-alkenyl, -CH₂C = CH, Cg-Cg-cycloalkylmethyl, -Cl 2 OCH 3 and -C 1 C 1 -C 3 OCH 3, and R 9 is selected from the group consisting of C 1 -C 8 alkyl, C 8 -C 8 cycloalkyl, -OC 2 -C 8 alkyl, -NH-15-C 1 -C 3 - alkyl, -N-C1-C3 dialkyl, - (CH2) n -O-C1-C3 alkyl, (CH2) n "NH" Cl "C3" alkyl ° g where n is an integer from 1 to 3, characterized in that (a) is reacted with 1-acetylphenyl-3-amide of the formula UQ with dimethylformamide, dimethylacetal at reflux to give N- [3- [3- (dimethylamino) -1-oxo-30-2-propenyl] -phenyl] alkanamide, (b) reactes N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] -phenyl] alkanamide with sodium hydride to provide an anion, B1 (c) reactes the produced anion with an alkyl halide of formula R R-X wherein X is Br or I to provide N- [3- [3- (dimethylamino) -1-oxo-2- propenyl] -phenyl] -N - alkyl-alkanamide of formula 5 (ch3) 2nch = chc- / 'S, o r5-nc-r4 (d) react N - [3- [3- (dimethylamino) -1 -oxo-2-propenyl] -phenyl] -N-alkylalkanamide having a 3-aminopyrazole of the formula 15 at HN V2 h2nL = ^ 1_Ri 20. glacial acetic acid at reflux which gives the desired products. 25 30