FI83324C - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA / 7- (3-DISUBSTITUERAD AMINO) FENYL / PYRAZOLO / 1,5-A / PYRIMIDINER. - 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

1 83324

The invention relates to the preparation of novel organic compounds which are [7- (3-disubstituted amino) phenyl] pyrazolo. The invention relates to the preparation of new organic compounds which are [7- (3-disubstituted amino) phenyl] pyrazolo [1,5-a] pyrimidines and which are useful as anxiolytic and antiepileptic agents as well as sedatives and hypnotics and skeletal-10 muscle relaxants.

The invention relates to a process for the preparation of therapeutically useful [7- (3-disubstituted amino) phenyl] pyrazolo [1,5-a] pyrimidines of the formula (Ia), 20 5x I -3 yS —--- Rl N 1

O

Wherein R 1 is hydrogen, halogen, cyano or -C-R 4; R4 is (C1-C6) alkoxy; R2 is hydrogen or (C1-C3) -alkyl; R5 is hydrogen, (C1-C6) -alkyl, (C2-C6) -alkenyl or -CH2C5CH; and R6 is ( C3-C3) -alkyl, (C3-C6) -cycloalkyl or -O- () -alkyl.

EP 129 847 discloses compounds of the same type having an N-methylacetamide group in the meta position of the phenyl ring and a benzene group in the 3-position of the pyrazolene-30. U.S. Patent No. 4,178,449 describes compounds having a CF 3 group at the meta position of the phenyl ring and carboxylic acid ethyl ester, cyano, halogen and the like groups at the 3-position of the pyrazole ring.

The compounds known from the above-mentioned U.S. Patent Publication 35a have good anxiolytic activity. However, these compounds have been shown to cause adverse side effects (2,83324) (necrosis and hepatic dilatation). The compounds known from said EP were also toxic. Surprisingly, it was found that the compounds of the present application, in particular the pyrazolo (1,5-α] pyridines substituted in the 7-position by phenyl-N-ethylacetamide-5 and in the 3-position by a cyano group, are not toxic to the liver.

The most preferred compounds of formula (Ia) are 0

II

those wherein Rx is cyano or -C-R4; R 2 is hydrogen, R 4 is alkyl-10 (C 1 -C 6); and R 5 is alkyl (C 1 -C 6), alkenyl (C 2 -C 6) or -CH 2 C =CH.

The compounds of formula (Ia) may be used in mammals to treat a state of pain or a fall disease or to provide a sedative or hypnotic effect or to relax skeletal muscle.

Compounds of formula (Ia) shall be prepared according to the invention in such a way that a) 20-N-acetylphenyl-3-amide of formula (I)

CH3-C V__V

0

II

H-N-C-R 9 is reacted with dimethylformamide dimethyl acetal under reflux to give N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] alkanamide; B) N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] alkanamide is reacted with sodium hydride to give the anion; c) reacting the resulting anion with an alkyl halide of formula R 5 -X wherein X is Br or I to give N- [3- [3-dimethylamino) -1-oxo- 2-propenyl] phenyl] -N-alkyylialkaaniamidi

II

3,83324 H / T, n, (CH3) 2NCH = CHCl2 - (R) -5-NC-R6 d) N- [3- [3-dimethylamino) -1-oxo-2-propenyl] phenyl ] -N-alkylalkanamide is reacted with a 3-aminopyrazole of formula (III),

/OF

Η-ΓΤ Vi- R, J (III) H2N_L = _L_R1 15 by heating in glacial acetic acid under reflux to give the desired end product.

The novel compounds of formula (Ia) can be readily prepared according to the following reaction scheme: (1) DMF

CfI3_C \ / (2) NaH; R -X

\ _r ^ / (X = Br, I) I 0

'IV

H-N-C-R, 6 \! mr ~ \ (CH) NCH = CHC // \\ \ = / o I «r5-nc-r6 RO (II) 30 O VJ J11 r ^ VN-c-R_6__ Hr v_r2 ^ H2N_I -J-Ri -R2 ( IM) 35 JI - Ri ^ NT 1 (Ia) 4 83324

According to the above reaction scheme, 1-acetylphenyl-3-amide (I) in which R 6 is the same as above is reacted with dimethylformamide dimethyl acetal by heating under 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 wherein R 5 is the same as above to give N- [3- [3- (dimethylamino) -1-oxo- 2-Propenyl] phenyl] -N-alkylalkanamide (II). This compound is then reacted with 3-aminopyrazole (III) in which R 1 and R 2 are the same as above by heating under glacial acetic acid under reflux to give the product (Ia).

Alternatively, N- [3- [3- (dialkylamino) -1-oxo-2-propenyl] phenyl] alkanamide (V) is reacted with 3-aminopyrazole (III) to give intermediates (VI) which are reacted with a base such as sodium hydride, sodium alkoxide and the like and R 5 halide to give the products (ia).

.N n t-y H-n / CN-R2 25 (CH3) 2NCH = CHC_y / \) h, H-1 ~ I ^ \ = J (III) o

II

,, HN-C-R, (V) 6 'f H ° 30 · 5 f ^>, - N-C-R6

fjp-c-Rs- (CJJ

R 2 -halogen I 35 (Ia) (VI)

II

5,83324

The efficacy of the novel compounds of the present invention in standard experiments using laboratory animals known to provide relief for pain in humans demonstrates that they have CNS activity at non-toxic doses and are therefore useful as anxiolytic agents. In addition, biological results have shown that these compounds are useful as antiepileptic agents, especially in the treatment of falls, as well as sedatives, hypnotics, and skeletal muscle relaxants.

The analgesic and anticonvulsant properties of the novel compounds of the present invention have been demonstrated in an experiment showing anxiolytic and antiepileptic activity by measuring the protective effect they provide against anticonvulsants caused by the administration of pentylenetetrazole. Test compounds were administered in single or stepwise doses orally or intraperitoneally in a 2% aqueous suspension of starch containing 0.5% (v / v) polyethylene glycol and one drop of polysorbate 80 for groups of at least 4 rats. After 30 or 60 minutes, rats were administered intravenous pentylenetetrazole at a dose of 23 mg / kg body weight. These 25 doses were estimated to cause jerky seizures in 99% of unprotected rats. It is presented in [R.T. Hill and D. H. Tedeschi, "Animal Testing and Screening Procedures in Ecaluating Psychotropic Drungs," in An Introduction to Psychopharmacology, edited by R.R. Rech and 30 K.E. Moore, Raven Press, New York, pp. 237-288 (19719)] that there is a high degree of correlation between the ability of compounds to inhibit the disease-inducing effect of pentylenetetrazole in rats and the anxiolytic and anticonvulsant efficacy of said compounds in higher warm-blooded animals. The results of this experiment performed on representative compounds of the present invention are shown in Table I.

β 83324

Table I

Protection against convulsions induced by pentylenetetrazole in rats Compound 1 Dose% by weight of rotazine ir / kg of protection "Z" 3- (i-cyanopyrazole / 1,5-a-pyrimidin-7-yl) -25 .0,100 phenyl-7-N-ethylpropanamide N - [- 3- (3-cyanopyrazolyl] -1,5-pyrimidin-7-yl) -25.0 100 10 phenyl N-ethylacetanide]

N.-7- 3- (3-Cyclopyrazolo [1,5-a] pyrimidin-7-yl) -, 25.0 100 L

ι I

phenyl N-N-ethylacetamide N-Z "3- (3-cyanopyrazolo / 1,5-pyridin-7-yl) -6,25,100 phenyl-N-propylacetamide '. , 1- [3- (3-Cyano-pyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] - / 3,1-methyl-carbamic acid methyl ester / 3- (3-cyano-pyrazolo / 1,5-a-pyrimidin-7-yl) - 12,6 75 20 phenyl Ethyl carboxylic acid methyl ester N-butyl-N- [SO-cyanopyrazolo] -1'-7-pyrimidin-7'-yl} phenyl 7-acetamide 25.0 50- [3- (3-cyanopyrazolo) (1,5-a-pyrimidin-7-yl) -1 25 Ethyl ethyl ethyl carboxylic acid ester 25.0 25 ("SP-chloropyrazolo] -1,5-α-pyrimidin-7-yl) phenyl ethyl ethyl carbamic acid ethyl ester 25.0 25 N-3- (3-cyanopyrazolo)" a Pyrimidin-7-yl) -phenyl 7-N-2-propenylacetamide 25.0 100 l N- [3- (3-cyanoprazole [1,5-a] pyrinidin-7-yl) -1-phenyl ι propynylacetainide 6> 25 100 ιu- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl)] 9C A 50 phenyl JN-methylcyclobutanecarboxamide 33 '35 M - f 3- (3 - r, y <i nopyr rnt no 1 o / 1,5 - a / pyrimyl clin-7-yl 1, i) Ö 75 • phenyl-7-N-methylcyclopropanecarboxamide

II

7,83324 ϋ-Ζ "3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) 25.0 75 phenyl N, N-methylacetamide Nf 3- (3-chloropyrazolo) -1H-pyrimidin-4-yl ) - 12.5 50 5 phenyl 7-N-methylacetamide 7-L 3- (α-methylimethylamino) phenyl] pyrazolo [1,5-a] pyrimidine-3-carboxylic acid ethyl ester 25.0 100 N- / 3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) 12,5 50 phenyl N, N-methylpropanamide NZ "3- (3-cyanomethylpyrazolo [1,5-a] pyrimid. 25.0 100

-7-yl) phenyl-7-N-methylpropanamide I

Another experiment used to evaluate the relief effects of pain states in a method based on unconditional passive avoidance has been proposed by J.R. Vogel, B. Beer, and D.E. Clody, in "A Simple and Reliable Conflict Procedure for Testing Anti-Anxiety Agents", Psychopharmacologia, 21, 1-7 (1971). 20 Conflict is caused in rats by a modification of this method.

Groups of 6 native Wistar rats, each weighing 200-240 g, were left without water for 48 hours and without food for 24 hours. Test compounds were administered in simple or staggered, oral or intraperitoneal doses, suspended in a 2% aqueous starch suspension containing 0.5% (v / v) polyethylene glycol and one drop of polysorbate 80. Control animals received 30 vehicle alone. . After 30-60 minutes, each rat was placed in a separate plexiglass chamber. Water was available at will from the water tap located at the back of the chamber. A 0.7 milliamp DC shock current was generated between the stainless steel riti-35 floor and the faucet. After a 20-licking drink with no shock, a 2-second shock was administered and then 8,83324 shocks were induced with a 2-second £ shock for every 20 lickings. This was continued for a total of 3 minutes. Within 3 minutes of each rat, the same number of shocks was recorded and this was compared to the ver-5 tail group. Test compounds were considered active if the number of shocks obtained by the test group was significantly higher than in the Mann-Witney U test of the control group. The results of this experiment with typical compounds of this invention are shown in Table II.

10 Table II

Unconditional passive avoidance test in rats

Compound Dose Result (ng / kg) N- [3- (3-cyanopyratolo [1,5-a] pyrimidin-7-yl) - active phenyl N, N-ethylpropanamide 20 NZ ~ 3 - (3-Cyanopyrazol-1,5-a-pyrimidin-7-yl) -active phenyl 8-N-ethylacetamide N-ethyl-N- (3-pyrazolo [1,5-a] pyrimidin-7-yl active · 25.0

phenyl) acetamide I

! N- {3- (3-chloropyrazolo [1,5-a] pyrimidin-7-yl) - active and

o -I

phenyl-N-ethylacetamide;

ϋ - / - 3- (3-Cyanopyrazole 10Z: 1,5-α-pyrimidin-7-yl) - active J

Phenyl-7-propylacetamide (5'-3- (3-cyanopyrazolo) -1,5-pyrimidin-7-yl) -phenylphenylmethylcarbamic acid methyl ester 3,1- [3- (3-methylpyrritrate). o 1 o / ~ 1,5-α-pyrimidin-7-yl) - active ioc

phenyl-7-ethylcarbamic acid methyl ester 'J

2- [3- (3-Chloro-pyrazolo [1H-pyrimidin-7-yl] -phenyl) -ethyl} -carbamic acid ethyl ester 25.0-Active N-β- (3-cyanopyrazolo [η 1,5-a] pyrimidin-7 -yl) - active

”I

phenyl-7-N-2-propenylacetamide! 3.1- and 9,83324 N4- [3- (3-cyanopyrazolo / 1,5-a] pyrimidin-7-yl) -1,5-active phenyl] -N-2-propynylacetamide N - [- 3 - ( 3-Cyanopyrazolor 1,5-pyridin-7-yl) -5,2-active phenyl N-methylpropanamide:

5 J

N - [(3- (3-cyano-2-methylpyrazolo) -1,5-pyrimidin-7-yl] phenyl) phenyl] -N-methylpropanamide 7- (3- (acetylmethylamino) phenyl) phenyl Pyrazolo [T1,5-a 7- and 25,0 active pyrimidine-3-carboxylic acid ethyl ester 10 Hf 3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -1,5 active phenyl N-methylacetamide N- [-Z'3- (3-chloropyrazolo [1,5-a] pyrimidin-7-yl) -3,1-active phenyl 7-N-methylacetamide N- [3- (3-yl, mopyrazolo) (5- (7-pyrimidin-7-yl) phenyl] -N-methylcyclobutanecarboxamide .25.0 active and ___ ί-- '

Another assay used to determine anxiolytic activity is to measure the ability of test compounds to inhibit the binding of tritium-treated benzodiazepines to brain-specific receptors in warm-blooded animals. In this case, a modification of the method proposed by R.F. Squires, et al., 25 in Nature ,. 266, no. 21 p. 732 (April 1977) and H. Mohler et al. in Science 198, p. 849 (1977).

Male albino rats (Wistar strain, each weighing 150-200 g) were obtained from a facility called Royalhart Frams. 3H-methyldiazepam (79.9 Ci / mmol) and 3H-methyl-flunitrazepam (84.3 Ci / mmol) were obtained in New England

From a facility called Nuclear. Test compounds were dissolved in either dimethylformamide, acetic acid, ethanol or hydrochloric acid.

The entire cortex of rats was carefully homogenized to 35 volumes of ice-cold 0.32 M sucrose solution, centrifuged twice at 1000 g for 10 minutes 10,83324, and then centrifuged again at 30,000 g for 20 minutes to obtain a crude P2 synaptosomal fraction. The P2 fraction was either: (1) resuspended in twice the original volume of hypotonic 50 mM Tris.HCl (pH 7.4), or (2) resuspended in half the original volume of hypotonic 10 mM Tris.HCl (pH 7.4), and then cooled (-20 ° C) until use. The cooled P2 preparations were thawed and resuspended to four times the original homogenization volume at the time of the experiment.

The binding sample consisted of 300 μΐ suspension of P2 fraction (0.2-0.4 mg protein), 100 μΐ test drug, and 100 μΐ 3H-diazepam (1.5 nM, final concentration) or 3H-flunitrazepam (1.0 nM , final concentration), which sample was added to 1.5 ml of 50 mM

Tris.HCl (pH 7.4). Instead of the test compound, 100 μit diazepam (3M, final concentration) and 100 20 μΐ deionized water were added to the non-specific binding control samples and to the total binding control samples, respectively. The 30 minute incubation was performed on ice and terminated by vacuum filtration through Whatman GF / C glass fiber filters. The filters were 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 Readv-Solv ™ HP (high performance pre-prepared scintillation cocktail mix, trademark registered to Beckman Instruments, Inc., Irvine, CA 92713) was added and the radioactivity was determined in a scintillation counter. .

Binding inhibition was calculated by dividing the difference between total binding and binding in the presence of test compound by 100 times total binding.

The results of this experiment with typical compounds of the present invention are shown in Table III.

Il il 83324

Table III

Inhibition of 3H-benzodiazepine binding to brain-specific receptors in rats 5

Compound Prevention in% ---------- Hf 3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) -83 phenyl 7-N-ethylpropanamide 10 Nf 3- (3-cyanopyrazolo) 5- (7-pyrimidin-7-yl) phenyl] -79 N-ethylacetamide N - 3- (3-chloropyrazolo [1,5-a] pyrimidin-7-yl) phenyl N-Ethylacetamide N - ['3- (3-cyanopyrazolo-1-5-pyrimidin-7-yl) phenyl] -64 N-propylacetamide 7-7 3- [ethyl (1-oxopropyl) amino] phenyl] pyrazolo-100 [1,5-a] pyrimidine-3-carboxylic acid ethyl ester 20 7 3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl i-87-methylcarbamic acid methyl ester 7-7 3-7 (methoxycarbonyl) methylamino] phenyl-pyrazolo-98

C 1,5-a-Pyrimidine-3-carboxylic acid ethyl ester I

25 3- (3-Cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl} ethylcarbamic acid methyl ester [3- (3-7) ethyl (methoxycarbonyl) amino] phenyl] pyrazolo [3- 99 71,5-α-Pyrimidine-3-carboxylic acid ethyl ester 30 L 7 3- (3-Cyanopyrazolo-1,5-pyrimidin-7-yl) phenyl 7- (4-methylcarbamic acid ethyl ester 1) ethyl (3-pyrazolo-1,5-yl a 7-Pyrimidin-7-yl-phenylcarbamine 61-acid ethyl ester 35 7 3- (3-cyanopyrazolo-7,5-pyrimidin-7-yl) -phenyl-7-ethylcarbamic acid ethyl ester 1 i 12 83324 f 3- (3-Cone-pyrazolo) 1,5-a-Pyrimidin-7-yl i-phenyl] -78-ethylcarbamic acid ethyl ester N-7 3- (3-cyanopyrazolo [5,5-a] pyrimidin-7-yl) phenyl] -78N-2-propenylacetamide N-7 3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N1- [2-propynylacetamide N-7 3- (3-cyano-2-methylpyrazolo] 1,5-a 7-pyrimidin-7-yl) -42-phenylpropion-N-7- 3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-methylpropane mide N-7 3- (3-cyano-2-methylpyrazolo [1,5-a] pyrimidin-95-7-yl) phenyl] N-methylpropopropamide N-methyl-N- (3-pyrazolo [1.5] -7-pyrimidin-7-ylphenyl] -54-acetamide 1- [3- (acetylmethylamino) phenyl] pyrazolo [1,5-a] pyridine-3-carboxylic acid ethyl ester H- [3- (3- cyanopyrazolo [71,5-a] pyrimidin-7-yl) phenyl] -NN-methylacetamide

NrC 3- (3-Chloropyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-methylacetamide N-7 3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl i] - 81 hl-methylcyclobutanecarboxamide N - [- 3- (3-cyanopyrazolo] 1,5-a-pyrimidin-7-yl] phenyl] -83β-methylcyclopropanecarboxamide 7-73- [cyclopropylcarbonyl) methylamino] -7-phenyl] 1,5-a-Pyrimidine-3-carboxylic acid ethyl ester 7- [3- (acetylethylamino) phenyl] pyrazolo [1,5-a] 97,7-pyrimidine-3-carboxylic acid ethyl ester 7- [3- (acetylamino) phenyl] pyrazolo] a 7-pyrimidine-3-carboxylic acid ethyl ester 7-7 3-7 (methoxycarbonyl) amino-7-phenylpyrazolo [1,5-a] pyrimidine-3-carboxylic acid ethyl ester

II

13,83324 Methyl (3-pyrazolo [1,5-a] pyrimidin-7-yl] -phenyl} -carbamic acid methyl ester 7- [3- (acetylpropylamino) phenyl] pyrazolo [1,5-a] 97-Pyrimidine-3-carboxylic acid ethyl ester [3- (3-chloro-pyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -7-29

methyl carbamic acid methyl ester I

Ί-L 3 -C (cyclobutylcarbonyl) amino / phenyl] pyrazolo-82

10f.S-α-Pyrimidine-3-carboxylic acid ethyl ester I

I____ The compounds of this invention have also been shown to have skeletal muscle relaxant Akti-15 activity in two experiments. Another experiment measures the effect of typical compounds on the ability of rats to remain on a sloping screen. Groups of at least 6 rats were orally dosed with test compounds or vehicle and placed 65 minutes later on a wire mesh screen (angle of inclination 60 ° to the horizontal). The number of rats that fell from the sieve within 30 minutes was recorded. The ED50 (the dose required to cause 50% of the animals tested to fall off the screen) was calculated by D.J.

- 25 according to the Finney * linear arsine conversion method, "Statistical Methods in Biological Assay", 2nd edition, Hafner NY, 1964, p. 454. The compounds were dissolved or suspended in a 2% aqueous starch suspension containing 5% polyethylene glycol. 400 and a drop of polysorbate 80, and 30 were given a constant volume corresponding to 5 ml / kg. The results of typical compounds of this invention are shown in Table IV.

35 14 83324

Table IV

Effect on the ability of rats to remain on a sloping sieve 5

Compound ED50 __ (mg / kg) N- [3- (cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-ethylpropanamide 4.6 10 N- [3- (3-cyanopyrazolo [1 5-a] pyrimidin-7-yl) -phenyl] -N-ethylacetamide 3.9

Another experiment to shed light on the fact that the novel compounds of the present invention have skeletal muscle relaxing properties demonstrates the effect of typical compounds on exercise activity in rats. A group of 6 rats was treated orally with vehicle or in divided doses of test compounds. 60 minutes later, private rats were placed in actophotometers and exercise activity was measured for 5 minutes after a short (30 second) exercise period. Exercise activity number (number of photocell beam cross-sections) was recorded for each rat and average activity numbers were calculated for each treatment group. The dose that caused a 50% reduction in mean activity numbers compared to the vehicle-treated group (MDD50) was calculated from a linear regression equation. The test results for type-30 compounds are shown in Table V.

35 15 83324

Table V

Effects on exercise activity in rats

Compound MDD50 5__ (mg / 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 10

The novel compounds of the present invention have been found to be very useful in the treatment of mammals when administered in amounts ranging from about 0.1 mg to about 20.0 mg / kg of body weight per day. The recommended dosage regimen for optimal results would be between about 0.5 mg and about 10.0 mg / kg body weight per day. Dosage units are used so that the active compound is administered to a subject weighing from about 10 to about 700 mg per about 70 kg of body weight within 24 hours. This dosage regimen may be modified to achieve the optimal therapeutic effect. For example, several sub-doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. The compounds of this invention are preferably administered orally, but may be administered by any suitable route, such as intravenously, intramuscularly or subcutaneously.

The compositions of the present invention having the desired brightness, stability and suitability for parenteral use are obtained by dissolving 0.10 to 10.0% by weight of the active compound in a carrier which is a polyhydric aliphatic alcohol or a mixture thereof. Particularly satisfactory are glycerol, propylene glycol, and polyethylene glycols. Polyethylene glycols consist of a mixture of non-volatile, normally liquid polyethylene glycols which are soluble in both water and organic liquids and have molecular weights of about 83324 to about 200 to 1500. Although the amount of active ingredient dissolved in the above carrier may vary from 0.10 - 10.0% by weight, it is preferred that the amount of active compound used is between about 3.9 and about 9.0% by weight. Although blends of the aforementioned non-volatile polyethylene glycols may be used, it is preferred to use a blend having an average molecular weight of from about 200 to about 400.

In addition to the active compound, parenteral solutions can also contain various preservatives which can be used to prevent bacterial and fungal contamination. Preservatives used for these purposes include, for example, myristyl-gamma-picolinium chloride, benzalkonium chloride, phenethyl alcohol, p-chlorophenyl-alpha-glycerol ether, methyl and propyl parabens and thimerosal. For practical reasons, it is also suitable to use antioxidants. Suitable antioxidants include, for example, sodium bisulfite, sodium metabisulfite and sodium formaldehyde sulfoxylate. Generally, concentrations of antioxidant ranging from about 0.05% to about 0.2% are used.

For intramuscular injection, the preferred concentration of active compound is 0.25 to 0.50 mg / ml of the final compositions. The novel compounds of the present invention are equally suitable for administration intravenously diluted with water or diluents used for intravenous treatment, such as isotonic glucose in appropriate amounts. For intravenous use, satisfactory initial concentrations of active agent of less than about 0.05-0.25 mg / ml are satisfactory.

The active compounds of the present invention may be administered orally, for example, with an inert diluent or an assimilable edible carrier 35, or may be enclosed in hard or soft shell gelatin capsules or compressed into tablets, or incorporated directly into an edible diet. When the drug i7 83324 is administered orally, the active compounds can be mixed with excipients and used in the form of tablets, drills, capsules, elixirs, suspensions, syrups, ointments and the like. In addition, the active ingredient may be mixed with a suitable pharmaceutical carrier or carriers known to provide a delayed release tablet or capsule. Such compositions and preparations should contain at least 0.1% of active compound. The percentage composition of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of a unit dose. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.

Tablets, cachets, pills, capsules, and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dipotassium phosphate; a disintegrant such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a wetting agent such as sucrose, lactose or saccharin may be used or flavoring agents such as peppermint, gaulter oil or cherry seasoning. If the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other agents may be present as coatings or otherwise to modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a coloring agent, and a flavoring such as cherry or orange flavoring. Each substance used to prepare its dosage unit form must, of course, be pharmaceutically pure and substantially non-toxic in the amounts used.

The following non-limiting examples illustrate the preparation of typical compounds of the present invention.

Example 1 N- [3- [3-dimethylamino) -1-oxo-2-propenyl] phenyl] propanamide

A mixture of 20 g of N- (3-acetylphenyl) propanamide in 50 ml of dimethylformamide dimethylacetal was heated under reflux for 8 hours and then evaporated. The residue was taken up in 200 ml of dichloromethane, passed through aqueous magnesium silicate, diluted with hexane and evaporated to give 21.17 g of the desired compound.

Following the procedure of Example 1 and using the starting materials shown, the amides of Examples 2-5 shown in Table VI were prepared.

Table VI

20__

Eg_Starting material__Amide_2 N- (3-acetylphenyl) -N- [3- (3-dimethylamino) -1-ethanamide oxo-2-propenyl) phenyl] acetamide 25 3- (3-acetylphenyl) carbo- [3- [3 - (dimethylamino) -1-bamic acid methyloxo-2-propenyl] phenyl] ester carbamic acid methyl ester 4- (4-acetylphenyl) carbo- [3- [3- (dimethylamino) -1-bamic acid butyloxy] 2-Propenyl] phenyl] ester carbamic acid butyl ester N- (3-acetylphenyl) -N- [3- [3- (3-dimethylamino) butanamide 1-oxo-2-propenyl] phenyl] - butanamide

II

i9 83324

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

A mixture of 3.47 g of N- [3- [3- [3- (dimethyl-5-amino) -1-oxo-2-propenyl] phenyl] propanamide and 0.68 g of a 60% oil dispersion of sodium hydride in dimethyl in lyformamide, stirred for 0.5 h under argon, then cooled in an ice bath and a solution of 2.4 g of ethyl iodide in 10 ml of dimethylformamide was added in small portions. The mixture was then stirred at room temperature for 0.5 hours and extracted 3 times with hexane. The extracts were discarded, water was added and this mixture was extracted with dichloromethane. This extract was evaporated and the residue was crystallized from hexane to give the desired compound, m.p. 105-107 ° C.

Following the procedure of Example 6, using the compounds of Examples 1-5 and the appropriate alkyl halides, the alkylated amides of Example 7-12 shown in Table VII were prepared.

20

Table VII

Eg starting material Alkylated amide mp ° C

EXAMPLES ____________ 7 2 N- [3- [3- (dimethylamino) -1-oxo-110-113 2-propenyl] phenyl] -N-ethylacetamide 8 1 N- [3- [3- (dimethylamino) -1-oxo-148-149 30 2-propenyl] phenyl] -N-methylpropanamide 9 2 N- [3- [3- (dimethylamino) -1-oxo-110-112 2-propenyl] phenyl] -N -propylacetamide 35 20 83324 10 3 [3- [3- (dimethylamino) -1-oxo-2- 93-95 propenyl] phenyl] methylcarbamic acid methyl ester 11 3- [3- [3- (dimethylamino) - 1-Oxo-2-95-97 5 propenyl] phenyl] ethylcarbamic acid methyl ester 12 2 N- [3- [3- (dimethylamino) -1-oxo-146-148 2-propenyl] phenyl] -N-methyl- ___ acetamide_ | _ 10

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 50 in glacial acetic acid, was heated to reflux for 8 hours and then the solvent was removed. The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was separated, dried, passed through a pad of aqueous magnesium silicate, and hexane was added to the refluxing filtrate. The mixture was then cooled and the solid collected to give 1.3 g of the desired product, m.p. 161-162 ° C.

Following the procedure of Example 13 and using appropriately substituted 3-aminopyrazoles in combination with said intermediates, the products of Examples 14-37 shown in Table VIII were prepared.

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Example 38 N- [3- (3-Chloro-pyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-ethyl-acetamide

A mixture of 1.0 g of N-ethyl-N- (3-pyrazo-5-holo [1,5-a] pyrimidin-7-ylphenyl) acetamide and 4.57 g of 1-chlorobenzotriazole in 50 ml of dichloromethane was heated using a reflux condenser for 25 minutes, then cooled and poured into 50 ml of ice-cold 2.5 N aqueous sodium hydroxide solution. The mixture was filtered through aqueous magnesium silicate, mixed with hexane and the solid collected to give 0.7 g of the desired product, m.p. 107-159 ° C.

Example 39 7- [3- [Ethyl (methoxycarbonyl) amino] phenyl] py-15-racolo [1,5-a] pyrimidine-3-carboxylic acid ethyl ester 12.41 g portion [3- [3- (dimethylamino) 1-Oxo-2-propenyl] phenyl] carbamic acid methyl ester was reacted as described in Example 6 using 9.36 g of ethyl iodide to give 13.4 g of [3- [3- (dimethylamino) -1-oxo-2- propenyl] phenyl] ethylcarbamic acid methyl ester, m.p. 95-97 ° C.

A 2.76 g portion of the above ester was 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, m.p. 117-119eC.

Example 40 [3- (3-Cyano-pyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -ethylcarbamic acid methyl ester 2.76 g portion [3- [3- (dimethylamino) -1-30-oxo-2-propenyl ] phenyl] ethylcarbamic acid methyl ester was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile as described in Example 13 to give 2.6 g of the desired product, m.p. 162-164 ° C.

35 26 83324

Example 41 [3- (3-Cyano-pyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -methyl-carbamic acid ethyl ester 1-Acetyl-phenyl-3-carbamic acid ethyl ester 5 was converted to [3- [3- (dimethylamino) -1- oxo-2-propenyl] phenyl] carbamic acid ethyl ester by the method of Example 1 and this ester was then reacted with methyl iodide, then by the method of Example 6 to give [3- [3- (dimethylamino) -1-oxo-2-10 propenyl] phenyl] methylcarbamic acid ethyl ester.

A 2.6 g portion of the above ester was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile according to the procedure of Example 13 to give 2.09 g of the desired compound, m.p. 140-142 ° C.

15 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 was reacted with ethyl iodide before according to the method of Example 6, to give [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] ethylcarbamic acid ethyl ester.

A 2.9 g portion of the above ester was reacted with 0.83 g of 3-aminopyrazole according to the procedure of Example 13 to give 2.27 g of the desired product, m.p. 79-81eC.

Example 43 [3- (3-Cyano-pyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -ethylcarbamic acid ethyl ester 30 g (2.0 g) of [3- [3- (dimethylamino) -1-oxo-2] -propenyl] phenylethylcarbamic acid ethyl ester was 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.

li 35 27 83324

Example 44 [3- (3-Chloro-pyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -ethylcarbamic acid ethyl ester 1.55 g portion of ethyl- (3-pyrazolo [1,5-a] -). 5 Pyrimidin-7-yl-phenyl) -carbamic acid ethyl ester was reacted in 50 ml of dichloromethane with 1-chlorobenzotriazole for 30 minutes to give 1.29 g of the desired product, m.p. 100-102 ° C.

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

A 1.36 g batch of the above intermediate was reacted with 0.54 g of 3-aminopyrazole-20-carbonitrile as described in Example 13 to give 1.0 g of the desired product, m.p. 135-137eC.

Example 46 N- [3- (3-Cyanopyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-2-propynylacetamide 25 A batch of 11.61 g of N- [3- [3- (Dimethylamino-1-oxo-2-propenyl] phenyl] acetamide was reacted with propynyl bromide as described in Example 6 to give N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] -N-2-propynylacetamide, mp 98-101 ° C.

A 2.7 g portion of the above intermediate was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile as described in Example 13 to give 1.90 g of the desired product, m.p. 193-195eC.

35 28 83324

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

A 2.88 g portion of the above intermediate was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile by the method of Example 13 to give 1.61 g of the desired product, m.p. 146-148 ° C.

Example 48 N- [3- (3-Cyano-pyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -N-methyl-carbamic acid butyl ester A batch of 11.61 g of [3- [3- (dimethylamino) - 1-Oxo-2-propenyl] phenyl] carbamic acid butyl ester was reacted with 6.82 g of methyl iodide by the method of Example 20 6 to give 11.67 g of [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] methylcarbamic acid bytyl ester.

A 3.04 g portion of the above ester was reacted with 1.08 g of 3-aminopyrazole-4-carbonitrile by the method described in Example 13 to give 2.3 g of the desired product, m.p. 96-97eC.

Example 49 N- [3- (3-Chloropyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-methylacetamide 30 1.0 g portion of N-methyl-N- (3-pyrazolo [1,5-a] Pyrimidin-7-yl-phenyl) -acetamide was reacted as described in Example 38 to give 1.0 g of the desired product, m.p. 163-165 ° C.

35 29 83324

Example 50 [3- (3-Chloro-pyrazolo [1,5-a] pyrimidin-7-yl) -phenyl] -methyl-carbamic acid methyl ester 1.4 g portion of methyl- (3-pyrazolo [1,5-a] -). 5-Pyrimidin-7-yl-phenyl) -carbamic acid methyl ester was reacted as described in Example 38 to give 1.42 g of the desired product, m.p. 132-134 ° C. Example 51 7- [3 - [(Cyclopropylcarbonyl) methylamino] phenyl] phenyl] pyrazolo [1,5-a] pyrimidine-3-carboxylic acid ethyl ester N- (3-acetylphenyl) cyclopropanecarboxamide was prepared by carrying m-aminoacetophenone, di -isopropylethylamine and cyclopropanecarboxylic acid chloride to react in dichloromethane.

This compound was then converted to N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] cyclopropanecarboxamide by the method of Example 1 and then alkylated by the method of Example 6 using methyl iodide to give 10.17 g of N- [3- (3-dimethylamino) oxo-2-propenyl) phenyl] -N-methylcyclopropanecarboxamide, m.p. 120-122 ° C.

A 0.54 g portion of this compound was reacted with 3-aminopyrazole-4-25 carbonitrile as described in Example 13 to give 1.08 g of the desired product, m.p. 178-180 ° C.

Example 52 7- [3 - [(Cyclopropylcarbonyl) methylamino] phenyl] pyrazolo [1,5-a] pyrimidin-3-carboxylic acid ethyl ester A batch of 0.73 g of ethyl 3-aminopyrazole-4-carboxylate and 1, 36 g of N- [3 - [(3-dimethyl) -1-oxo-2-propenyl] phenyl] -N-methylcyclopropanecarboxamide were reacted as described in Example 13 to give 0.52 g of the desired product, m.p. 122-124 ° C.

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Example 53 N- [3- (3-Cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-methylcyclobutanecarboxamide m-aminoacetophenone, cyclobutanecarboxylic acid 5 chloride and diisopropylethylamine were reacted in dichloromethane to give N- (3-asetyylife-phenyl) cyclobutanecarboxamide.

This compound was then converted to N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] cyclobutanecarboxamide, m.p. 155-157 ° C, according to the method of Example 1, and this was further alkylated by the method of Example 6 using methyl iodide to give 8.32 g of N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] -phenyl] -N-methylcyclobutanecarboxamide, m.p.

117-119 ° C.

A 0.54 g portion of 3-aminopyrazole-4-carbonitrile was reacted with 1.43 g of the above product according to the procedure of Example 13 to give 1.3 g of the desired product, m.p. 157-158 ° C.

Example 54 7- [3 - [(Cyclobutylcarbonyl) amino] phenyl] pyrazolo [1,5-a] pyrimidine-3-carboxylic acid methyl ester 0.78 g batch of 3-amino-4-carboethoxypyrazole 25 sols and 1.36 g of N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] cyclobutanecarboxamide was reacted as described in Example 13 to give 1.52 g of the desired product, m.p. 123-125 ° C.

Il

Claims (14)

31 83324 A process for the preparation of therapeutically useful [7- (3-disubstituted amino) phenyl] pyraz-5 Solo [1,5-a] pyrimidines of formula (Ia), O II c-R / r r | 1 6 o ff 15 where I *! is hydrogen, halogen, cyano or -C-R4; R 4 is (C 1 -C 6) alkoxy; R 2 is hydrogen or (C 1 -C 6 alkyl); R 5 is hydrogen, (C 1 -C 6) alkyl, (C 2 -C 6) alkenyl or -CH 2 C 5 CH 4; C 6) -cycloalkyl or -O-C 1 -C 4 -alkyl, characterized in that a) 1 H -cyl-3-amide of the formula (I) cH 3 -I- (T) (i) R6 is reacted with dimethylformamide dimethylacetal under reflux to give N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] alkanamide; b) reacting N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl] alkanamide with sodium hydride to give the anion; C) reacting the resulting anion with an alkyl halide of formula R 5 -X wherein X is Br or I to give N- [3- [3-dimethylamino) -1- oxo-2-propenyl] phenyl] -N-alkylalkanamide 5 "M (CH3) 2NCH = CHC- <y (II) l5-nc-r6 d) N- [3- [3-dimethylamino) -1-oxo-2 -propenyl] phenyl] -N-alkylalkanamide is reacted with a 3-aminopyrazole of formula (III), H-ftT NS- r 15 2 (III) H2nJ -: - Rx by heating in glacial acetic acid under reflux to give the desired end product. . Process according to Claim 1, characterized in that N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl-N-ethylpropanamide is prepared. Process according to Claim 1, characterized in that N-3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl-N-ethylacetamide is prepared. Process according to Claim 1, characterized in that N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-propylacetamide is prepared. Process according to Claim 1, characterized in that [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] methylcarbamic acid methyl ester is prepared. Process according to Claim 1, characterized in that 7- [3 - [(methoxycarbonyl) methylamino] phenyl] pyrazolo [1,5-a] pyrimidin-3-yl 33,83324 carboxylic acid ethyl ester is prepared. Process according to Claim 1, characterized in that [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] ethylcarbamic acid methyl ester is prepared. Process according to Claim 1, characterized in that ethyl (3-pyrazolo [1,5-a] pyrimidin-7-yl-phenyl) -carbamic acid ethyl ester is prepared. Process according to Claim 1, characterized in that [3- (3-chloropyrazolo [1,5-a] pyrimidin-7-yl) phenyl] ethylcarbamic acid ethyl ester is prepared. Process according to Claim 1, characterized in that N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-2-propenylacetamide is prepared. Process according to Claim 1, characterized in that N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-2-propynylacetamide is prepared. Process according to Claim 1, characterized in that N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl] phenyl-N-methylacetamide is prepared 25 34 8 3 3 2 4