FI89487C - Process for the preparation of therapeutically active 4 - / (substituted) alkylcarbonyl / -4,5-dihydro- and -4,5,6,7-tetrahydro-7 - / (substituted) phenyl / pyrazolo- / 1,5- a / pyrimidine-3-carbonitriles - Google Patents

Description

1 8 9 4 7

Process for the preparation of therapeutically active 4 - [(substituted) alkylcarbonyl] -4,5-dihydro- and 4,5,5,7-tetrahydro-7 - [(substituted) phenyl] pyrazolo [1,5-a] - for the preparation of pyramidine-3-carbonitriles 5

Divided separated from patent application 874547

The invention relates to a process for the preparation of new therapeutically active 4 - [(substituted) alkylcarbonyl] -4,5-dihydro- and -4,5,6,7-tetrahydro-7 - [(substituted) phenyl] pyrazolo [1, For the preparation of 5-α] -pyrimidine-3-carbonitriles of formula 15

Rs_ J.- I CN

20 \ S

N 2 -O 2 = C-CH 2 -N 2 -N-N-R 10 wherein R 7 is a mono- or di-substituent which is hydrogen, lower C 1-5 alkyl, lower C 1-3 alkoxy, halogen, nitro or trifluoromethyl ; R 4 and R 5 are both hydrogen or C 1-3 alkyl; and R 10 is C 1-3 alkyl or benzyl, which may be substituted on the phenyl ring by C 1-3 alkyl, C 1-4 alkoxy, chlorine, fluorine or trifluoromethyl; as well as their pharmacologically acceptable acid addition salts. The process according to the invention is characterized in that the amine of formula 35- ^

R 10 "N / NH (1) 2 89487 wherein R 10 is as defined above is reacted with a compound of formula R 7

J

1_ / Nv r4— (2) R5 _J ^ J = -L cn

10 N

o = c-ch2x wherein R7, R4 and R7 are as defined above and X is chlorine or iodine.

U.S. Pat. No. 4,448,962 discloses compounds of the same type but containing a 10-membered ring, while compounds of formula 3 contain a 9-membered ring structure. The compounds of the present invention are useful in the treatment of cognitive and closely related problems not disclosed in said U.S. publication.

The process of the present invention 4 - [(substituted) alkylcarbonyl] -4,5-dihydro- and 4,5,6,7-tetrahydro-7 - [(substituted) phenyl] pyrazolo-25 [1,5-a] - for the preparation of pyrimidine-3-carbonitrile compounds is illustrated by the following reaction scheme: I Ν ** Ε07 is Lv. J toluene

^ T

ϋ, Λ-Ζ NH * JL. OF

10 \ _ / R ·. r2 C 1> ·> * - - 35

0 = C (CHI> n X

<2> Ψ I, i 3 89487

O

, 0 = 1¾ 10 / \ C = C- (CH2, n-N2 / Z-S) 0 <3) 15

According to the above reaction scheme, the amine (1) in which Z and R 10 are as described above is reacted with a haloalkanoyl-4,5-dihydro- or -4,5,6,7-tetrahydro-7-substituted phenylpyrazolo [1,5-a] ] pyrimidine-20-dine-3-carbonitrile (2), wherein n, R 7, R 2, R 4 and R 5 are as described above, X is a halide such as chlorine or iodine, and an alkali carbonate in toluene at reflux temperature to give the products ( 3).

FI-A-87459 discloses an invention 25 which relates to novel organic compounds which are useful as intermediates in the process of the present invention for the preparation of compounds of formula 3. In particular, FI publication 87459 relates to a process for the preparation of new 4,5-dihydro- and 4,5,6,7-tetrahydropyrat-30 Solo [1,5-a] pyrimidines, which are also useful as sedatives, antihypertensives and agents, used to treat aging boredom, perceptual problems, and similar neurological behavioral problems, 35 and as antidepressants in mammals. These compounds have the formula 4 89487 J3

Ra N ^ N-R

46 "2 K2 5 (I) Κ5" \ ν ^ -R1 R6 wherein 10 symbol --- denotes an alternative single or double bond between the C6 and C7 positions; R3 is hydrogen, chlorine, carbamoyl, carboxyl, C1.3- alkoxy-O-carbonyl, cyano, -CO-CH 2, -COC (CH 3) 3 or R 2, R 2, R 4, R 5 and R 6 may each be hydrogen or C 1-3 alkyl; R 3 is hydrogen, C 1-4 alkyl , wherein R 7 and R 6 may be V = T 1 and R 8 are the same or different and are each hydrogen, halogen, C 1-3 alkyl, nitro, C 1-3 alkoxy, trifluoromethyl, acetylamino or N -alkylacetylamino in which the alkyl group contains 1 to 3 carbon atoms, or R 3 is a monovalent 3-pyridyl or 4-pyridyl radical, each pyridyl radical being optionally substituted by a C 1-4 alkyl radical.

These as intermediates in the process of the present invention are novel 4 - [(substituted) alkylcarbonyl] -4,5-dihydro- and -4,5,6,7-tetra-hydro-7 - [(substituted) phenyl] of formula 3. ] 4,5-dihydro- and 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidines useful for the preparation of pyrazolo [1,5-a] pyrimidine-3-carbonitriles are obtained as crystalline substances, which are colorless to yellow in color and have characteristic melting points and absorption spectra. They are usually soluble in organic solvents such as lower alkanols,

I: I

5 89487 to chloroform, tetrahydrofuran. N, N-dimethylformamide, dichloromethane, acetone and the like but are usually insoluble in water.

The following reaction schemes and Examples 1-63 illustrate the preparation of 4,5-dihydro- and 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine derivatives of formula I used in the process of the invention. The method is described in more detail in F1 patent application 874547.

In Scheme 1, compounds of formula I wherein the symbol --- denotes a double bond are denoted by the formula

Ia and the compounds of the formula I, respectively, in which the symbol --- denotes a single bond, are denoted by the formula Ib.

15 Scheme 1 2 N 2T "^ 2 | NaBH3CH-acetic acid __ 20 r5- ^ 3 | Rl II 1

N I

III

\ / 25 Ia

NaBH4-tetrahydrofuran, methanol * 3

Ib λ R4 - '^ N' ^ V * (C2H5) 3SiHCF3CO2H__ or H2 / catalyst / solvent ^ 5— \ / 1

35 B

Ia

V

6 89487 + r6x r3 i λ N i 5 R4 “f '^ Vr2 I_ R3

R5 \ y-L (? I λ N

h R4T Γ V2 10 lb ** \ J == ^ l

+ R6X - f I

R6 wherein Rx, R2, R3, R4, R5 and R6 are as defined above and X is halogen.

The pharmacological activity of the compounds prepared according to the present invention is demonstrated in the following experiments.

20 The test used to evaluate analgesic effects is the method of unconditional, passive avoidance described in Vogel, JR, Beer, B. and Clody, DE, "A Simple and Reliable Conflict Procedure for Testing Antianxiety Agents". Psycho-25 Pharmacology 21 (1971) 1-7. A conflict situation is caused in rats according to a variation of this method as follows.

Groups of eight common male Wistar rats, each weighing 200 to 240 30 g, were not given water for 48 hours. The test compounds were administered as single or divided oral doses suspended in a mixture of 2% starch and 5% polyethylene glycol in distilled water and one drop of polysorbate-80. Control animals received 35 excipients alone. At 60 minutes, each rat was placed in a single tray of 7,848,47 clear plastic. Tap water was available from an ad libitum nozzle located in a black box some distance from the main compartment. A 0.7 milliampper AC, 5-pulse electric current was placed between the stainless steel mesh floor and the faucet. After each 20 electric shock-free water runs, rats were given a two-second electric shock. The ratio of the 20 electric shock-free water consumption to the subsequent two-second electric shock 10 was included in the total time of three minutes. The number of electric shocks received by each rat over three minutes was recorded and compared to the control group. Test compounds are considered to be effective if the amount of electric shocks received by the test group is significantly greater than the Mann-VJhitney U test of the control group. Ts. test compounds are considered to be effective if the test shows that the treated rat withstands slightly more than twice the amount of electric shock compared to the untreated rat. The results obtained from this in vivo experiment using representative active compounds of formula 3 are given in Table I.

TABLE I

Conflict method in rats 25 Result

Dose (electric shock

Compound (mg / kg) amount / 3 min) 4,5-dihydro-4 - [(4-methyl-1-piperazinyl) acetyl] -7- [3- (trifluoromethyl) phenyl] pyrazolo [ 1,5-a] pyrimidine-3-carbonitrile, dihydrochloride 4 - {[4- (2-cyclohexylethyl) -1-piperazinyl] acetyl} -4,5-dihydro-7- [3- (trifluoromethyl) ) phenyl] pyrazolo [1,5-a] pyrimidine-3-: 40 carbonitrile 25 18.0 β 39487

Another assay used to determine the analgesic effect is an assay that measures the ability of a test compound to inhibit the binding of triturated benzodiazepine to receptors specific to the mammalian brain. A method was used which was a variation of the method described in Squires, R. F. et al. Nature 266 (21) (April 1977) 732, and Mohler, H. et al. Science 198 (1977) 849.

Male albino rats (of the Wistar genus, each weighing 150-200 g) were obtained from Royalhart Farms. 3H-methyldiazepam (79.9 Ci / mmol) and 3H-methylflunitrazepam (84.3 Ci / mmol) were obtained from New England Nuclear. Test compounds were dissolved in dimethylformamide, acetic acid, ethanol or hydrochloric acid. The following method was followed.

The whole cortex of rats was gently homogenized to 20 volumes of ice-cold 0.32 M sucrose, centrifuged twice at 1,000 g for 10 minutes, and then again at 30,000 g for 20 minutes to form an unprocessed β2 synaptosomal fraction. The P2 fraction was either (1) resuspended in hypotonic 50 mM Tris-HCl (pH 7.4) at twice the original volume, or (2) resuspended in hypotonic 10 mM Tris-HCl (pH 7.4) 7.4), which was half the original volume, and cooled (-20 ° C) until used.

Frozen P2 preparations were thawed and resuspended to four times the homogenization volume at the time of the experiment.

The binding assay consisted of 300 slices of P2 fraction suspension (0.2-0.4 mg protein), 100 slices of test drug and 100 slices of 3H-diazepam (1.5 nM, final concentration) or 3H-flunitrazepam (1.0 nM, final concentration) added to 1.5 ml of 50 nM Tris.HCl (pH 7.4 7.4). Nonspecific binding controls and total siS 9 89437 accumulation controls received 100 μΐ diazepam (final concentration 3 μΜ) and 100 μΐ deionized water instead of test compound, respectively. The samples were incubated on ice for 30 minutes and the incubation was terminated by vacuum filtration through a glass fiber filter. The filters were washed twice with 5 ml of ice-cold 5 mM Tris-HCl (pH 7.4) and placed in ampoules for scintillation counting. After drying at 50-60 ° C for 30 minutes, 10 ml of diluent was added and the radioactivity was determined with a liquid scintillation counter.

Binding inhibition was calculated as the difference between total binding and binding in the presence of test compound divided by total binding multiplied by 100.

A physiological effect can be demonstrated by a test compound that inhibits 3 H-benzodiazepine binding by 12% or more. Such an in vitro effect is biologically relevant when the test compound also shows a statistically significant sedative effect in in vivo experiments.

The results of this in vitro experiment using representative compounds of formula 3 are given in Table II.

TABLE II

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

Compound Contraception% 4,5-Dihydro-4 - [(4-methyl-1-piperazinyl) acetyl] -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3- carbonitrile 41 4,5-Dihydro-4 - {[4- (phenylmethyl) -1-Piper-35-azinyl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3 -carbonitrile 17 4 {[4- (3,4-dichlorophenyl) -1-piperazinyl] -40 acetyl} -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5- a] pyrimidine-3-carbonitrile, hydrochloride 12 10 89 487

Table II (continued)

Compound Contraception% 5__ 4 - [(dihexylamino) acetyl] -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 24 10 4,5-dihydro 4 - ({4- [2- (4-morpholinyl) -2-oxoethyl] -1-piperazinyl} acetyl) -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] -Pyrimidine-3-carbonitrile 4- [2- (3-cyano-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidin-4 (5H) -yl] -2-oxoethyl } -N- (1-methylethyl) -1-piperazineacetamide 41 20 4,5-dihydro-4 - ({4- [2-oxo-2- (1-pyrrolidinyl) ethyl] -1-piperazinyl} acetyl) -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 33 25 4 - {[4- (2-cyclohexylethyl) -1-piperazinyl] acetyl] -4.5 -dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyramidine-3-carbonitrile, dihydrochloride 14 30 4- (2- {3-cyano-7- [3- (trifluoromethyl)) Phenyl] -pyrazolo [1,5-a] pyrimidin-4 (5H) -yl} -2-oxoethyl) -1-piperazinecarboxylic acid, ethyl ester 45 35 4- {C 4- (2-furanylcarbonyl) -1-pipe Racinyl] acetyl} -4,5-dihydro-7 - [(3-trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile, hydrochloride 12 40 4,5-dihydro-4- (1 -piperazinylacetyl) -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 4- (2- {3-cyano-7- [3- (trifluoromethyl) phenyl) ] pyrazolo [1,5-a] pyrimidin-4 (5H) -yl} -2-oxoethyl) -N-phenyl-1-piperazinecarboxamide 24 50 N- (5-chloro-2-methoxyphenyl) -4- ( 2- (3-Cyano-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidin-4 (5H) -yl} -2-oxoethyl) -1-piperazineacetamide 15, 55

Table II (continued)

Compound Contraception% 5 _______________________________________________ ______________ 4.5.6.7-Tetrahydro-4 - [(4-phenylmethyl-1-piperazinyl) acetyl] -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] -10 Pyrimidine-3-carbonitrile 14 4.5.6.7-Tetrahydro-4 - {[4- (phenylmethyl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyramidine - 15 3-carbonitrile, dihydrochloride 12

Certain of the novel compounds of the invention are effective antihypertensive agents when administered to mammals in non-toxic doses. The antihypertensive effect of these compounds was examined according to the method described in Chan, P. S. and Poorvin, D. W., "Clinical and Experimental Hypertension", 1 (6) (1979) 817-830, as follows.

Male Okamoto rats, 16 weeks old and naturally hypertensive, with a mean arterial blood pressure of 160 ± 1.5 mmHg are used in the experiment. 1-3 rats are used for the test compound. The rat is administered by gavage a test compound suspended in 2% pre-cooked starch at a concentration of 50 mg / ml, at a dose of 100 mg / kg body weight or less, together with 0.9% sodium chloride, which was 25 ml / kg body weight. Another similar dose of test compound without sodium chloride is administered 24 hours later. 28 hours after the initial 35 doses, mean arterial blood pressure is measured

By the method of Chan and Poorvin vide supra. The procedure is repeated, if necessary, in the second and third rats.

The results of this experiment using representative compounds prepared in accordance with the present invention are shown in Table III.

12 39 4 87

TABLE III

Reduction of mean arterial blood pressure in rats with naturally high blood pressure 5 Compound VKVP / mmHg 4,5-dihydro-4 - {[4- (phenylmethyl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [ 1,5-a] pyrimidine-3-carbonitrile 120 4,5-dihydro-4 - {[4- (phenylmethyl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [1 , 5-a] pyrimidine-3-carbonitrile, dihydrochloride 137 4 - ({4 - [(4-chlorophenyl) phenylmethyl] -1-piperazinyl} acetyl) -4,5-dihydro-7- [3-20 ( trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 134 4,5-dihydro-4 - [(4-phenyl-1-piperazinyl) acetyl] -7- [3- (trifluoromethyl) phenyl] - Pyrazolo [1,5-a] pyrimidine-3-carbonitrile 137 4 - {[4- (3-chlorophenyl) -1-piperazinyl] acetyl} -4,5-dihydro-7- [3- (trifluoromethyl) - Phenyl] pyrazolo [1,5-a] pyramidine-3-30 carbonitrile 124 4,5-Dihydro-4 - {[4- (2-pyrimidinyl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) tert-carbonyl] pyrazolo [1,5- -a] Pyrimidine-3-carbo-127-nitrile 4 - {[4- (4-fluorophenyl) -1-piperazinyl] acetyl} -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] Pyrazolo [1,5-a] pyrimidine-3-carbon-40-nitrile 130 4- (3- {4 - [(4-chlorophenyl) methyl] -1-piperazinyl} -1-oxopropyl) -4,5- Dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-45-di-3-carbonitrile 138 4,5-dihydro-4 - ({4- [2- (4-morpholinyl) -2- oxoethyl] -1-piperazinyl] acetyl] -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 129

II

Table III (continued) 13 89 4 87

Compound VKVP / mmHg 5- [2- (3-cyano-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidin-4 (5H) -yl} -2 -oxo-ethyl) -N- (1-methylethyl) -1-piperazine-acetamide 129 10 4 - ({4- [bis (4-fluorophenyl) methyl] -1-piperazinyl} acetyl) -4,5- Dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 121 15 4- (2- {3-cyano-7- [3- (trifluoromethyl)) -phenyl] pyrazolo [1,5-a] pyrimidin-4 (5H) -yl} -2-oxoethyl) -N-phenyl-1-piperazinecarboxamide 125-20 N- (5-chloro-2-methoxyphenyl) -4 - (2- {3-cyano-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidin-4 (5H) -yl} -2-oxoethyl) -1-piperazineacetamide 139 25 4.5 - dihydro-4 - {[4- (2-propenyl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3- carbonitrile 139 30 4 - [(4-cyclobutyl-1-piperazinyl) acetyl] -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyramidine-3-carbonitrile '124 35 4,5-dihydro-4 - {[4- (1-methylethyl) -1- piperazinyl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 139 40

The novel compounds of formula 3 have the ability to enhance nerve function in warm-blooded animals with behavioral neurological problems, including impaired perception associated with decreased nerve function as seen in brain dysfunction, aging, boredom, and the like.

One useful in vivo test associated with impaired nerve function is the oxygen deficiency test for passive avoidance 14 6 9 437. This experiment is used to determine the impairment of oxygen deficient memory loss in drug-treated mice compared to saline-treated control animals that have not received drug.

The method of passive walk-avoidance in one experiment is used in one experiment. Groups of 25 Swiss-Webster, middle-aged mice (9 months old) are placed one at a time in the anterior compartment of a two-compartment box and allowed to spontaneously roam the rear compartment. As soon as the mouse enters the rear compartment, the door closes automatically and a weak electric shock (0.4 mA for four seconds) is applied to the mouse legs. After the electric shock, the mice are placed in the first 15 oxygen-free environments (0% oxygen) for 12 seconds, which quickly causes unconsciousness. They are then placed in a low-oxygen environment (15% oxygen) for four minutes, which prolongs the oxygen-poor state, keeping the mouse unconscious. All experiments are performed 24 hours later 20 and in all cases the mice have fully recovered from the previous anoxic / low oxygen treatment. All test compounds are administered intraperitoneally at a dose of 10 to 200 mg / kg 30 minutes before training for the experiment. Control animals are given 25 injections intraperitoneally of saline alone at 0.01 ml / g body weight.

The latency time, which is the time before the mouse goes to the back tray, was recorded at both training and experimental events. The better the mouse remembers receiving an electric-30 rope, the more reluctantly it goes into the back compartment and the longer the latency phase, which is the time before going back to the compartment. A 30% improvement (extended latency) over saline controls is considered effective. The result of this experiment, which was performed with a representative compound of formula 3, is shown in Table IV.

h i is 89437

TABLE IV

Oxygen-induced memory loss test for passive avoidance

Dose Improvement Compound (mg / kg)% 4,5-dihydro-4 - {[4- (phenylmethyl) -1-piperazinyl] acetyl} -7- [3-10 (trifluoromethyl) phenyl] pyrazolo-100 65 [ 1,5-a] Pyrimidine-3-carbonitrile The compounds of this invention are useful as antidepressants in warm-blooded animals, as shown in the following experiments. First, the antidepressant properties of these compounds were tested by measuring their ability to counteract depression induced in animals by administering them with tetrabenazine methanesulfonate. Each test compound was orally administered to 10 mice at a dose of 25 mg / kg body weight. Thirty minutes later, each mouse was administered intraperitoneal tetrabenazine methanesulfonate at a dose of 39 mg / kg body weight, a dose known to significantly reduce the exploratory behavior of normal mice. Thirty minutes later, the exploratory behavior of mice was studied according to the method described in Greenblatt, E. and Österberg, A. C., "Toxicology and Applied Pharmacology" 7 (1965) 566-578. Compound 30 is considered effective if three or more of the ten mice are protected from tetrabenazine-induced effects.

The results of experiments with representative compounds of formula 3 are shown in Table V.

16 S 9 4 e 7

TABLE V

Tetrabenazine - induced depression

Compound Result 4,5-dihydro-4 - {[4- (phenylmethyl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbo - nitrile effective 4,5-dihydro-4 - ({4 - [(3-methoxyphenyl) methyl] -15-piperazinyl} acetyl) -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyramidine -3-carbonitrile effective 4,5-dihydro-4 - ({4 - [(3-methoxyphenyl) methyl] -201-piperazinyl} acetyl) -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] ] pyrimidine-3-carbonitrile, dihydrochloride effective 4 - {[4- (1,3-benzodioxol-5-ylmethyl) -1-25-piperazinyl] acetyl} -4,5-dihydro-7- [3- (trifluoromethyl) phenyl ] pyrazolot 1,5-a] -pyrimidine-3-carbonitrile effective The efficacy of the compounds of this invention as antidepressants was further demonstrated in the following experiment measuring the ability of a test compound to inhibit the binding of 3H-imipramine to human platelet membranes.

35 Platelet membranes were obtained using a method

described in Wennogle, L. P. et al., Pharmac. Biochem. Behav. 15 (1981) 975. Fresh human platelet concentrate (less than 48 hours old) was obtained from the New York Blood Center. These concentrates were prepared in citrate-dextrose anticoagulant using standard methods. Platelets were washed twice by centrifugation (2,500 x G, 10 minutes) in 50 volumes of anti-protease buffer containing 0.005 M Tris-potassium chloride, 0.12 M sodium chloride, 0.05 M

li 17 89487

Tris, pH 7.5, 0.025 units / ml aprotinin, 0.05 pg / m pepstatin, 2 x 10-5 bacitracin, 3 mM ethylenediaminetetraacetic acid and 1.0 mM ethylene glycol bis (δ-aminoethyl ether) -N, N'-tetraacetic acid. An-5 tiproteases have been shown to inhibit the disruption of 3 H-imipramine receptors [Wennogle, L. P. et al., (Vide supra)]. All methods were performed at 0 ° C using plastic laboratory vessels throughout the preparation of platelet membranes. Platelets were resuspended in 20 volumes of pus-10 discipline and sonicated three times using ten second intervals on a Branson sonicator (cell crusher 350) at setting 6 (3/4 inch standard end piece) keeping the sample on ice throughout the procedure. The platelet membranes were then washed twice at 18,000 x G for 20 minutes with 50 volumes of anti-protease buffer and resuspended at 3.0 mg protein / ml using Bradford protein assay and bovine gamma globulin as a standard. The membranes were used immediately or stored frozen in liquid nitrogen.

The method of replacing the binding of 3 H-imipramine to human platelet membranes was performed essentially as described in Paul, S. M. et al., Life Sci. 26 (1980) 953 is described in the following variations. Membranes (0.3 mg protein) were suspended in antiprotease buffer 25 with both 3.0 mM 3H-imipramine (New England Nuclear) and replacement drug or buffer in a total volume of 250 in glass test tubes. The samples were incubated for 90 minutes at 100 ° C, then diluted to 5 ml in a solution of 0.12 M sodium chloride, 0.005 M potassium chloride, 0.05 M Tris, pH 7.5 (wash buffer), and filtered. immediately through GF / B Whatman filters and washed twice with 5 ml of wash buffer. Filters were counted in a liquid scintillation counter after the addition of a Beckman HP Scintillant. 35 liquids.

ie 0 94 8 7 Non-specific binding of 3H-imipramine was determined as the fraction of radioactivity (usually 35%) that was not replaced by 10 M desmethylimipramine. Specific binding was defined as the subtraction if this non-specific level was subtracted from the total 3 H-imipramine binding values measured by incubation in the absence of 3 H-imipramine replacement drug. Compounds were tested in a parallel assay in test tubes at a concentration of 10 μΜ. Compounds that inhibited binding by more than 50% were considered effective.

The results of this experiment performed with representative compounds of the present invention are shown in Table VI.

15 TABLE VI

Binding of 3H-imipramine to human platelet membranes

Compound Contraception% 20'-4,5-dihydro-4 - ({4 - [(3-methoxyphenyl) methyl] -1-piperazinyl} acetyl) -7- [3- (trifluoromethyl) phenyl] pyrazolo [ 5-a] Pyrimidine-3-carbonitrile 78 4 4 - {[4- (1,3-benzodioxol-5-ylmethyl) -1-piperazinyl] acetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 81 30 4 - ({4- [2- (dimethylamino) ethyl] -1-piperazinyl} acetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile, dihydrochloride 72 35 4 - ({4- [3- (dimethylamino) propyl] -1-piperazinyl} acetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 89 40 4- (3- {4 - [(4- chlorophenyl) methyl] -1-piperazinyl-1-oxopropyl] -4,5-dihydro-7- [3-trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile, dihydrochloride 85 i 19 89 4 8 7

Table VI Current)

Compound Contraception% 5 '4 - ({4 - [(4-chlorophenyl) methyl] -1-piperazinyl} acetyl) -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyramidine -3-carbonitrile 84 10 4,5-Dihydro-4- {1-oxo-3- [4- (phenylmethyl) -1-piperazinyl] propyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [1 3,5-a] Pyrimidine-3-carbonitrile 80,6 4,5,6,7-Tetrahydro-4 - {[4- (3-phenoxypropyl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) ) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 57-20 7- (2,5-dichlorophenyl) -4,5-dihydro-4- [1-oxo-3- [4- (phenylmethyl) - 1-Piperazinyl] propyl] -pyrazolo [1,5-a] pyrimidine-3-carbonitrile 79 25 The low oxygen survival test is a useful in vivo test to measure the efficacy of drugs acting on the central nervous system to increase survival in a low oxygen environment to a known parasympathetic. compared to the substance, physo-30 stigimin. This experiment shows an increased survival of animals in a low-oxygen environment after drug treatment compared to saline-treated control animals.

Extensive studies have shown that in conditions with only 10% oxygen, only 5 to 20% of control mice survived after 5 minutes, whereas 60 to 80% of physostigmine-treated mice survived. The drugs were tested by injecting groups of mice intraperitoneally 30 minutes to 40 minutes before being placed in a low-oxygen environment, and survival was measured. The principle of this experiment is that drugs that increase survival in low oxygen conditions without associated depression or side effects of sedatives do so by increasing brain metabolism, i.e., improving energy supply relative to need and thus maintaining normal brain function under conditions of decreased energy metabolism. Given that the brain is dependent on a constant supply of energy, drugs with this property can have many far-reaching therapeutic indications, such as being able to help recover from stroke and injuries where the injury has occurred inside the head, and they reduce the detrimental effects of CNS disorders associated with aging. For example, deficiencies in energy metabolism have been thought to contribute significantly to neurochemical and neurophysiological disorders associated with aging and boredom in the elderly.

In the low oxygen survival test, groups of 20 Royal Hart mice (6 weeks old) were injected intraperitoneally with 20 saline test compounds at various doses ranging from 1 to 200 mg / kg 30 minutes before being placed in the low oxygen mixture ( 10% oxygen, 90% carbon dioxide), and survival was measured after five minutes.

A control group of 20 mice was injected intraperitoneally with saline (0.01 ml / g body weight) and the procedure was performed as described above.

Another group of 20 mice was injected intraperitoneally with 0.125 mg / kg of physostimine in saline and the procedure was performed as described above.

The results of this experiment, which were performed on representative compounds of formula 3, are shown in Table VII.

2i 39 48 7

TABLE VII

Low oxygen survival test

Dose Selviy-

Compound (mg / kg)% 5 _____ 4,5-dihydro-4 - {[4- (phenylmethyl) -10 40 1-piperazinyl] acetyl} -7- [3-100 48 (trifluoromethyl) phenyl] pyrazolo [1 , 5-a] pyrimidine-3-carbonitrile 7- (4-chlorophenyl) -4,5-dihydro-4-10 50 {[4- (phenylmethyl) -1-piperazinyl] -100 82.5 acetyl} pyrazolo [1 , 3,5-a] pyramidine-3,3-carbonitrile 7- (4-chlorophenyl) -4,5-dihydro-4-10,500 [(4 - {[2- (trifluoromethyl) phenyl] -100,90 methyl} -1- piperazinyl) acetyl] -20 pyrazolo [1,5-a] pyrimidine-3-carbonitrile 7- (2,5-dichlorophenyl) -4 - {[4- (2,5-dimethylphenyl) -1 -piperazinyl] -2008025acetyl} -4,5-dihydropyrazolo [1,5-a] pyrimidine-3-carbonitrile 4,5-dihydro-4 - ({4- [4- (2-oxo-1-pyrrole). 100 68 lidinyl) -2-butynyl] -1-piperazinyl} acetyl) -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 4.5- dihydro-5-methyl-4 - {[4- (phenylmethyl-43-yl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3 -k arbonitrile, dihydrochloride 40 4,5-Dihydro-6-methyl-4 - {[4- (phenylmethyl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [1, 5-a] Pyrimidine-3-carbonitrile, dihydrochloride 45 4,5,6,7-Tetrahydro-4 - {[4- (phenylmethyl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) ) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 50

Table VII (continued) 22 8 9 4 8 7

Dose Selviy-

Compound (mg / kg)% 5 ____________________________ 4.5-dihydro-4 - {[4- (phenyl] methyl) -1,100,8 1-piperazinyl] acetyl} -7 - [(3- (trifluoromethyl) phenyl] pyrazolo-10 [ 1,5-a] pyramidine-3-carbonitrile hydrochloride 4,5-dihydro-4 - ({4 - [(3-trifluoro-100-methylphenyl) methyl] -1-piperazinyl} acetyl) -7- [3 - (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 4,5-dihydro-4 - ({4 - [(3-trifluoromethylphenyl) methyl] -1-piperazinyl } acetyl) -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile, dihydrochloride 7- (3-chlorophenyl) -4 - ({4 - [(3 (chloro (100-phenyl) methyl] -1-piperazinyl} -50,7-acetyl) -4,5-dihydro-6-methylpyrazolo [1,5-a] pyrimidine-3-carbon-30-nitrile, dihydrochloride 7- (4-chlorophenyl) -4 - ({4 - [(3-chlorophenylphenyl) methyl] -1-piperazinyl} -100 62 acetyl) -4,5-dihydro-6-methylpyrat-35 Solo [1, 5-a] pyrimidine-3-carbonitrile, dihydrochloride 7- (3-chlorophenyl) -4,5- dihydro-6,200 73 methyl-4 - [(4 - {[3- (trifluoromethyl) -40 phenyl] methyl} -1-piperazinyl) acetyl] pyrazolo [1,5-a] pyramidine-3-carbonitrile 4- [(4-benzoyl-1-piperazinyl) -100,945 acetyl] -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 4.5 - dihydro-4 - {[4- (2-phenylethyl) -1,106,50-1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile, dihydrochloride I.

Table VII (continued) 23 8 9 4 8 7

Dose Selviy-

Compound (mg / kg)% 5-4 - ({4- [bis (4-fluorophenyl) methyl) -1,50,5-piperazinyl) acetyl] -4,5-dihydro-7- [3- (trifluoromethyl) phenyl -10 [alpha] pyrazolo [1,5-a] pyrimidine-3-carbonitrile, dihydrochloride 7- (2,5-dichlorophenyl) -4,5-dihydro-100,704 4 - [(4-phenyl-1-piperidinyl) weapon -15 style] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 7- (2,5-dichlorophenyl) -4,5-dihydro-100 50 4 - {[4- (phenylmethyl) -1-piperidine-20] methyl] acetyl} pyrazolo [1,5-a] pyramidine-3-carbonitrile

The novel compounds of the present invention which are effective in treating depression and / or relieving pain in warm-blooded animals are administered in amounts of about 0.1 to 35.0 mg / kg of body weight per day. The preferred dosage regimen for optimal results would be about 0.5 to 20.0 mg / kg body weight per day, and dosage units are used such that the total amount of active compound, from about 35 mg to about 1.4 g, is administered to a subject weighing about 70 kg. , Within 24 hours.

Certain of the compounds of the present invention have been found to be useful as agents for the treatment of perceptual and similar neurological behavioral problems in mammals when administered in amounts of about 5 to 200 mg / kg body weight per day. The preferred dosage regimen for optimal results would be about 10 to 50 mg / kg body weight per day, and such dosage units are used to administer a total amount of about 700 mg to about 3.5 g of active compound to a subject weighing about 70 kg over 24 hours.

24 8 9 4 8 7

The following non-limiting Examples 1-63 illustrate the preparation of 4,5-dihydro- and 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidines useful as intermediates in the process of the invention, Examples 1-18 illustrate the preparation of starting materials . Examples 64-78, 172, 174, 175, 177, 178, 188 and 189 also illustrate the preparation of starting materials. Examples 79 to 171, 173, 176, 179 to 187 and 190 to 192 illustrate the process of the invention for 4 - [(substituted) alkylcarbonyl] -4,5-dihydro- and 10 -4,5,6,7-tetrahydro-7- to prepare [(substituted) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitriles. Example 1 7- [3- (Trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carboxamide A mixture of 3.0 g of 7- [α, α, α-trifluoro-m-tolyl li) pyrazolo [1,5-a] pyrimidine-3-carbonitrile (prepared as described in U.S. Patent No. 4,236,005) and 150 ml of concentrated sulfuric acid were stirred at room temperature for four hours. The solution was then carefully poured into ice water while stirring. The white precipitate formed was collected, washed with water and then with saturated sodium bicarbonate until neutral. The solid was heated with one liter of isopropyl alcohol and filtered. The white solid was dried in vacuo to give the product of the example as a colorless solid; mp. 256-258 ° C.

Example 2 7- (2,5-Dichlorophenyl) -2-methylpyrazolo [1,5-a] pyrimidine-3-carboxamide 30 A mixture of 31.0 g of 2 ', 5'-dichloroacetophenone and 25 ml of N, N-dimethylformamide dimethyl acetal , was heated on a steam bath for six hours, then evaporated to dryness in vacuo. The residue was suspended in hexane and filtered to give 35.3 g of 2 ', 5'-di-35 chloro-3-dimethylaminoacrylophenone as orange crystals; mp. 83-85 ° C.

25 8 948 7

A mixture of 12.2 g of 3-amino-4-cyano-5-methylpyrazole and 24.4 g of 2 ', 5'-dichloro-3-dimethylaminoacrylophenone in 250 ml of glacial acetic acid was heated on a steam bath for four hours. hours. The mixture was cooled to give 21.28 g of 7- (2,5-dichlorophenyl) -2-methylpyrazolo [1,5-a] pyrimidine-3-carbonitrile as off-white crystals.

The above product (21.28 g) was dissolved in concentrated sulfuric acid and the solution was stirred for five hours. 10 The solution was carefully poured onto ice. The resulting precipitate was collected by filtration, washed with water and air-dried to give the title product as colorless crystals; mp. 234-236 ° C.

Other pyrazolo [1,5-a] pyrimidine-1-carboxamides prepared from the corresponding pyrazolo [1,5-a] pyrimidine-3-carbonitriles as described in Example 1 are listed in Table 1.

Pyrazolo [1,5-a] pyrimidine-3-carbonitriles were prepared by the methods described in U.S. Patent Nos. 4,178,449, 4,236,005 and 4,281,000 by reacting the appropriate 3- (dimethylamino) acrylophenone intermediate with an appropriately substituted 3- with aminopyrazole-4-carbonitrile.

26 8 9 4 8 7

table 1

Pyrazolo [1,5-a] pyrimidine-3-carboxamides 5 Γ I3 6 I 3 2 * H2504 - j_3 - * ^ s) -— C = N> -ί — CO — NH 2 N NT X N ^ 10 i

For example, the compound R2 R3 Sp. ° Cj »-------—- 3 7-phenylpyrazolo [1,5-a] -H 236-pyrimidine-3-carboxamide <238.5 20 4 2-methyl-7-phenylpyrazolo- ('| 1 233- [1,5-a] pyrimidine-3-CH2,235 carboxamide 5 7- (3-pyridinyl) pyrazolo-1H-285-25 [1,5-a] pyrimidine-3,286 carboxamide 6 7- (4 -pyridinyl) pyrazolo-1H-[394- [1,5-a] pyrimidine-3-396-carboxamide | 7- 7- (3-fluorophenyl) pyrazolo-H247- [1,5-a] pyrimidine-3 - 249 carboxamides 35 _________

Example 8 40 Phenyl- {7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidin-3-yl} methanone

A reaction mixture of 1.87 g of (3-amino-1H-pyrazol-4-yl) phenylmethanone and 2.43 g of 3-dimethylamino-1- [3- (trifluoromethyl) phenyl] -2-propen-1- on 25 ml of 27 89487 glacial acetic acid, was heated at reflux for six hours, after which the solvent was removed in vacuo to give a crystalline residue. This residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then poured through a thin layer of aqueous magnesium silicate. Addition of hexane to the eluate at reflux resulted in crystallization. After cooling, the desired product was recovered as crystals; mp. 148-150 ° C.

Example 9

Phenyl- [7- (4-pyridinyl) pyrazolo [1,5-a] pyrimidin-3-yl] methanone

Following the general procedure of Example 8 and reacting (3-amino-1H-pyrazol-4-yl) phenylmethanone with 3-dimethylamino-1- (4-pyridinyl) -2-propen-1-one gave the desired product; mp. 185-186 ° C.

Example 10 7- (3-Chlorophenyl) pyrazolo [1,5-a] pyrimidine-3-20 carbonitrile

A mixture of 50.0 g of 3'-chloro-3-dimethylamino-acrylophenone, 25.0 g of 3-aminopyrazole-4-carbonitrile and 500 ml of glacial acetic acid was heated at reflux for two hours. Upon heating, the mixture became a solution and a precipitate formed after the mixture was at reflux for one hour. The reaction mixture was filtered and the crystals were collected and triturated in finely saturated aqueous sodium bicarbonate solution, filtered, washed with water and then dried to give 49.0 to 30 g of the product of the example as colorless crystals; mp. 238-240 ° C.

Example 11 7- (3-Nitrophenyl) pyrazolo [1,5-a] pyrimidine-3-carbonitrile

A mixture of 24.4 g of 3-dimethylamino-3'-nitro-35 acrylophenone, 13.0 g of 3-aminopyrazole-4-carbonitrile and 28 8 9 4 S 7 120 ml of glacial acetic acid was heated at reflux for seven hours and then stirred at room temperature. at 16 hours. The precipitate was collected, triturated in saturated aqueous sodium bicarbonate solution, filtered and washed with water. The solid was then finely triturated in acetonitrile, filtered and dried to give the desired product; mp. 244-246 ° C.

Example 12 N- [3- (3-Cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-methylacetamide

A mixture of 540 mg of 3-aminopyrazole-4-carbonitrile, 1.23 g of N- {3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl} -N-methylacetamide and 50 g of ml of glacial acetic acid, was heated at reflux for eight hours, after which the solvent was removed. The residue was partitioned between saturated sodium bicarbonate solution and dichloromethane. The organic layer was separated, dried, poured through an aqueous magnesium silicate layer, and hexane was added to the refluxing filtrate to crystallize the product. The mixture was cooled and the solid was collected to give the desired product; mp. 195-197 ° C.

Example 13 N- [3- (3-Cyano-pyrazolo [1,5-a] pyrimidin-7-yl) -25-phenyl] -acetamide

A mixture of 6.0 g of 3-aminopyrazole-4-carbonitrile, 13.0 g of N- {3- [3- (dimethylamino) -1-oxo-2-propenyl] phenyl} acetamide and 100 ml glacial acetic acid, was heated at reflux for four hours. Upon standing at room temperature, a precipitate formed. The precipitate was isolated, washed with hexane and then ether and dried. The solid was recrystallized from acetonitrile-N, N-dimethylformamide to give the title product; mp. 252-254 ° C.

I: 29 89437

Example 14 7- (3-Chlorophenyl) -5-methylpyrazolo [1,5-a] pyramidine -3-carbonitrile

A mixture of 50.0 g of 3-chloroacetophenone and 75.0 ml of N, N-dimethylacetamide dimethyl acetal was stirred and heated at reflux for 16 hours. The mixture was evaporated in vacuo to give an oil. The oil was finely ground in hexane while cooling in an ice bath. The formation of crystals was achieved by rubbing. The crystals were collected by filtration to give 60.2 g of 1- (3-chlorophenyl) -N- (dimethylamino) -2-buten-1-one as red crystals; mp. 38-40 ° C.

A mixture of 30.0 g of the above compound, 14.48 g of 3-aminopyrazole-4-carbonitrile and 200 ml of glacial acetic acid was stirred and heated at reflux for two hours to form a solid. The mixture was allowed to stand at room temperature for 16 hours, after which it was filtered. The white crystalline precipitate was triturated with sodium bicarbonate to neutralize the mixture and then filtered. The crystals were washed with copious amounts of water and then dried to give the product of the example as white crystals; mp. 218-220 ° C.

Example 15 7- (4-Chlorophenyl) -5-methylpyrazolo [1,5-a] pyrimidine-3-carbonitrile

A mixture of 25.0 g of 4-chloroacetophenone and 40 ml of N, N-dimethylacetamide dimethyl acetal was stirred and heated at reflux for three to 30 hours. The mixture was evaporated in vacuo to give a red solid. The solid was triturated in n-hexane and filtered. The solid was washed with n-hexane and dried to give 15.6 g of 1- (4-chlorophenyl) -3- (dimethylamino) -2-buten-1-one as red crystals; mp. 103-105 ° C.

30 8 9 4 8 7

A mixture of 15.6 g of the above compound, 7.53 g of 3-aminopyrazole-4-carbonitrile and 150 ml of glacial acetic acid was stirred and heated to reflux for 15 minutes. The mixture became a solution and a precipitate formed during heating at reflux. The mixture was filtered to give a light brown solid. The solid was triturated with saturated sodium bicarbonate solution until the pH was 7-8, then collected by filtration-10 miles and dried to give 17.2 g of crude product. 1 g of the product was finely ground in water and the mixture was stirred for two hours at room temperature. The mixture was filtered and the solid dried to give the desired product as brown crystals; mp. 285-287 ° C.

Example 16 5-Methyl-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile

A mixture of 20.0 g of 3-trifluoromethylacetophenone and 20 ml of N, N-dimethylacetamide dimethyl acetal was stirred and heated at reflux for three hours. The mixture was evaporated to dryness in vacuo to give a red solid. The solid was triturated in n-hexane and filtered. The solid was washed with n-hexane and dried to give 18.0 g of 3- (dimethylamino) -1- [3- (trifluoromethyl) phenyl] -2-buten-1-one as red crystals; mp. 71-73 ° C.

A mixture of 18.0 g of the above compound, 7.56 g of 3-aminopyrazole-4-carbonitrile and 150 ml of glacial acetic acid was stirred and heated at reflux for 16 hours. The reaction mixture was evaporated to dryness in vacuo to give yellow-white crystals. The crystals were triturated with saturated aqueous sodium bicarbonate solution, and then the mixture was filtered. The crystals were washed with water and dried. The solid was dissolved in 80 ml of hot ethanol and cooled in an ice bath while scrubbing to effect crystallization. The product was collected by filtration and drying to give the product as pale cream crystals; mp.

153-155 ° C.

Example 17 7- (3-Chlorophenyl) -6-methylpyrazolo [1,5-a] pyrimidine-3-carbonitrile

A mixture of 75.0 g of m-chloropropiophenone and 200 ml of N, N-dimethylformamide dimethyl acetal was stirred and refluxed for 16 hours. The mixture was evaporated in vacuo to give a black oil. The oil was subjected to Kugelrohr distillation at 0.5 mmHg and the fractions boiled at 110 ° C were removed. The residue from the distillation was collected to give 35.0 g of 3'-chloro-3-15 dimethylamino-2-methylacrylophenone as a black oil.

A mixture of 25.0 g of the above compound, 11.88 g of 3-aminopyrazole-4-carbonitrile and 250 ml of glacial acetic acid was stirred and refluxed for three hours. The reaction mixture was evaporated to dryness in vacuo to give a dark brown solid.

The solid was triturated with saturated aqueous sodium bicarbonate and then the mixture was filtered to give the title product as white crystals; mp. 206-208 ° C.

Example 18 7- (4-Chlorophenyl) -6-methylpyrazolo [1,5-a] pyramidine-3-carbonyltril

A mixture of 50.0 g of p-chloropropiophenone and 200 ml of N, N-dimethylformamide dimethyl acetal was stirred and refluxed for 28 hours. The reaction mixture was evaporated in vacuo to give a yellow oil. The oil was subjected to Kugelrohr distillation. The oil remaining from the distillation was collected and triturated in hexane to give crystals. The solid 35 was collected by filtration to give 32 8 9 4 3 7 21.5 g of 4'-chloro-3-dimethylamino-2-methylacrylophenone as yellow crystals; mp. 45-47 ° C.

A mixture of 21.5 g of the above compound, 10.368 g of 3-aminopyrazole-4-carbonitrile and 250 ml of glacial acetic acid was stirred and heated at reflux for 24 hours. The mixture was evaporated to dryness in vacuo to give brown crystals. The solid was triturated with saturated aqueous sodium bicarbonate to adjust the pH to 7-8, and then the mixture was filtered. The solid was washed with water and dried to give the desired product as light brown crystals; mp. 154-157 ° C.

Example 19 4,5-Dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile

To a solution of 6.0 g of 7- (α, α, α-trifluoro-m-tolyl) pyrazolo [1,5-a] pyramidine-3-carbonitrile (U.S. Patent 4,236,005, Example 3) in 100 ml of glacial acetic acid , 3.0 g of sodium cyanoborohydride were gradually added at room temperature in the presence of nitrogen. The mixture was stirred at room temperature for two hours. The precipitate was collected by filtration, washed with water and then dissolved in dichloromethane. The organic solution was neutralized with saturated sodium bicarbonate solution, then dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give the desired product as a white solid. The product was recrystallized from isopropyl alcohol; mp. 175-177 ° C.

Following the general procedure of Example 19 and reacting the appropriate pyrazolo [1,5-a] pyrimidine derivative with sodium cyanoborohydride, the dihydro products of Examples 20-38 listed in Table VII were obtained.

I! 33 3 9 4 8 7

Example 39 4,5-Dihydro-4-methyl-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyriridine-3-carbonitrile

A mixture of 1.5 g of 4,5-dihydro-7- [3- (tri-5-fluoromethyl) phenyl] pyrazolo [1,5-a] pyramidine-3-carbonitrile (Example 19) and 220 mg of 60% sodium hydride as a mineral oil dispersion in 50 ml of N, N-dimethylformamide was stirred at room temperature in the presence of nitrogen for 3.5 hours. 1 ml of iodomethane was then added and the reaction mixture was stirred in the presence of nitrogen for 16 hours.

The mixture was evaporated to dryness in vacuo to give an oil. The oil crystallized from n-hexane on trituration to give the product which was recrystallized from ethyl acetate / hexane (1: 4) to give the desired product as yellow crystals; mp. 120-122 ° C.

Example 40 4,5,6,7-Tetrahydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carboxamide

A solution of 3.44 g of 4,5-dihydro-7- [3- (tri-fluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carboxamide (Example 24) in 40 ml trifluoroacetic acid, stirred in the presence of nitrogen and heated to 60 ° C in an oil bath. Then, 5.0 ml of triethylsilane was added, and the mixture was stirred at 60 ° C for 24 hours.

The reaction mixture was cooled and carefully poured into a beaker containing 25% aqueous potassium hydroxide solution and crushed ice. The precipitated product was extracted into chloroform. The chloroform was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give crystals which were recrystallized from toluene / hexane to give the desired product: m.p. 152-154 ° C.

34 8 9 4 8 7

Example 41 4,5,6,7-Tetrahydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyridine-3-carbonitrile

A mixture of 1.0 g of 4,5,6,7-tetrahydro-7- [3-5 (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carboxamide, 0.44 g of potassium carbonate and 10 ml of ethyl chloroformate in 30 ml of p-dioxane, was heated at reflux for three hours. The mixture was evaporated to dryness in vacuo. The residue was extracted with dichloromethane and the combined extracts were filtered and then evaporated to give 0.6 g of an oil. The oil was triturated with ether / hexane to give 250 mg of a white solid. The solid was subjected to preparative thick layer chromatography using chloroform / ethanol (10: 1). The product with an Rf value of 0.64 was collected and isolated to give the product of the example as a white solid; mp. 183-185 ° C.

Example 42

Phenyl- [4,5,6,7-tetrahydro-7- (4-pyridinyl) pyraz-20 Solo [1,5-a] pyrimidin-3-yl] methanone to a 20.0 g portion of phenyl- [7- (4-Pyridinyl) pyrazolo [1,5-a] pyrimidin-3-yl] methanone (prepared as described in Example 9), suspended and stirred in 100 ml of glacial acetic acid in the presence of nitrogen, was gradually added. 5 g of sodium cyanoborohydride and during this addition another 50 ml of glacial acetic acid were added. After 3 hours, the solution was evaporated to dryness in vacuo. The residue was dissolved in dichloromethane and treated with saturated sodium bicarbonate until basic. The organic layer was separated and dried over anhydrous sodium sulfate. Evaporation gave a gummy solid. The solid was recrystallized from isopropyl alcohol to give the desired product as a pale yellow solid; mp. 186-189 ° C.

35 89437

Example 43 7- (3-Fluorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidine-3-carbonitrile to a portion of 5.0 g of 7- (3-fluorophenyl) -5 5 , 5-dihydropyrazolo [1,5-a] pyrimidine-3-carbonitrile (prepared as described in Example 23) in 50 ml of trifluoroacetic acid and stirred in the presence of nitrogen and heated to 60 ° C, 7.2 ml of triethylsilane were added. . Heating was continued for four hours, then the mixture was stirred at room temperature for 16 hours.

The mixture was carefully poured into an ice-cooled beaker containing 150 ml of water and 40 g of potassium hydroxide. The precipitate formed was collected, washed with water and dried. The solid was dissolved in dichloromethane and filtered through aqueous magnesium silicate. Evaporation of the filtrate gave a white solid. Recrystallization from isopropyl alcohol gave the desired product; mp. 146-148 ° C.

Example 44 7- (3-Chlorophenyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyramidine-3-carbonitrile To a portion of 8.0 g of 7- (3-chlorophenyl) -4,5- dihydropyrazolo [1,5-a] pyrimidine-3-carbonitrile (prepared as described in Example 30) in 65 ml of trifluoroacetic acid, stirred in the presence of nitrogen and heated to 55 ° C, was added 7, 3 ml of triethylsilane. The reaction mixture was stirred and heated at 60 ° C for 7.5 hours. The mixture was then carefully poured into an ice-cooled beaker containing 100 ml of 25% aqueous potassium hydroxide. The formed precipitate was collected by filtration and dissolved in chloroform. The chloroform solution was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 6.8 g of white crystals. The crystals were finely ground 36,8487 in ether. The ether was collected and crystals formed. The crystals were washed with ether to give 2.8 g of white crystals. The crude product (2.8 g) was chromatographed on liquid chromatography using silica gel column-5 and eluting with 5% ethyl acetate / chloroform. The fraction containing the desired product was collected and evaporated in vacuo to give crystals; mp. 148-150 ° C.

Example 45 7- (3-Chloro-phenyl) -4,5,6,7-tetrahydro-5-methyl-pyrazolo [1,5-a] pyrimidine-3-carbonitrile

To an unweighted amount of 7- (3-chlorophenyl) -5-methylpyrazolo [1,5-a] pyrimidine-3-carbonitrile (prepared as described in Example 14) in a stirred mixture of 1 liter of tetrahydrofuran and 1 liter of methyl alcohol in the presence of nitrogen, 20.0 g of sodium borohydride was gradually added. The mixture was stirred for eight hours at room temperature, then allowed to stand for three days to give two layers. The top layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give a yellow oil. The oil was dissolved in 250 ml of chloroform and filtered through aqueous magnesium silicate and evaporated to a yellow oil. The oil was triturated with ether and crystals formed on trituration. The crystals were collected to give the desired product as white crystals; mp. 192-195 ° C.

Example 46 7- (4-Chloro-phenyl) -4,5,6,7-tetrahydro-5-methyl-pyrazolo [1,5-a] pyrimidine-3-carbonitrile to give 17.2 g of 7- (4- chlorophenyl) -5-methylpyrazolo [1,5-a] pyrimidinecarbonitrile (prepared as described in Example 15) in a stirred mixture of 1 liter of tetrahydrofuran and 1 liter of I:: 37 δ 9 4 8 7 10.0 g of sodium borohydride. The mixture was heated at 55 ° C for six hours and then evaporated in vacuo to give a gummy solid. The solid was triturated in ether, then taken up in talc by filtration to give the desired product as white crystals; mp. 215-217 ° C.

Example 47 4,5,6,7-Tetrahydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile To a stirred mixture of 14.0 g of 5-methyl- 7- [3- (Trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile (prepared as described in Example 16) in 250 ml of glacial acetic acid was added in the presence of nitrogen to 29.5 g of sodium cyanoborohydride. The mixture was heated at 55-60 ° C in a water bath for 16 hours, then evaporated in vacuo to give a white solid. The solid was triturated in saturated sodium bicarbonate to neutralize the mixture to pH 7-8. The crystals were collected by filtration and dissolved in 200 ml of absolute ethanol by heating on a steam bath. The solution was evaporated in vacuo to give 10.1 g of white crystals. Crude product for chromatography on Waters Prep. A 500A Liquid Chromatograph using a silica gel column and eluting with ethyl acetate / hexane (35:65) and the two peak fractions were collected. The fraction of the second peak was evaporated in vacuo to give the product of the example as white crystals; mp. 192-194 ° C.

Example 48 4,5,6,7-Tetrahydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile

A mixture of 1.5 parts of 4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrrolo Solo [1,5-a] pyramidine-3-carbonitrile, 50 parts of ethyl acetate, 10 parts of parts of acetic acid-35 poa and 0.2 parts of 5% palladium / carbon catalyst, 38 8 9 4 8 7 were shaken in a Parr hydrogenator under a hydrogen pressure of about 207 kPa for 4.5 hours. The reaction mixture was filtered and the mother liquor was concentrated to remove the solvent. The resulting yellow oil was crystallized by trituration with ether. The crystalline product was recrystallized from ethyl acetate by adding hexane. The product, 4,5,6,7-tetrahydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile, melted at 181-183 ° C.

Example 49 4,5,6,7-Tetrahydropyrazolo [1,5-a] pyrimidine-3-carboxamide

To a stirred mixture of 4.0 g of pyrazolo [1,5-a] pyrimidine-3-carbonitrile in 200 ml of methyl alcohol was added, in the presence of nitrogen at room temperature, three sodium borohydride buttons in one portion. The mixture was stirred for several hours and then allowed to stand at room temperature. The product was collected by filtration to give 1.75 g of 4,5,6,7-tetrahydropyrat-Solo [1,5a] pyrimidine-3-carbonitrile; mp. 206-207 ° C. The above product (1.75 g) was dissolved in concentrated sulfuric acid and stirred for 16 hours. The reaction mixture was carefully poured onto ice and weakly basified with ammonium hydroxide. The precipitate was collected by filtration to give the product of the example as colorless crystals; mp. 247-248 ° C.

Example 50 4,5,6,7-Tetrahydro-2-methylpyrazolo [1,5-a] pyrimidine-3-carbonitrile

A stirred mixture of 7.32 g of 5-amino-3-methyl-pyrazole-4-carbonitrile and 10.0 g of malonaldehyde-bis (dimethyl acetal) in 50 ml of glacial acetic acid was heated at reflux for eight hours. The reaction mixture was cooled and evaporated in vacuo. The residue was partitioned between saturated sodium bicarbonate and dichloromethane. The organic layer was dried over anhydrous 39,8487 sodium sulfate and poured through magnesium silicate. The eluent was evaporated to give 7.65 g of 2-methylpyrazolo [1,5-a] pyrimidine-3-carbonitrile; mp. 179-181 ° C.

To a stirred mixture of 5.0 g of the above product in 250 ml of methyl alcohol in the presence of nitrogen was added sodium borohydride. The mixture was stirred at room temperature for several hours and then concentrated. The residue was recrystallized from dichloromethane / -10 n-hexane to give the desired product as colorless crystals; mp. 170-172 ° C.

Example 51 4.5.6.7-Tetrahydro-2-methylpyrazolo [1,5-a] pyrimidine-3-carboxamide A dose of 1.0 g of 4,5,6,7-tetrahydro-2-methylpyrazolo [1 The 1,5-a] pyrimidine-3-carbonitrile was dissolved with stirring in 5.0 ml of concentrated sulfuric acid. The mixture was stirred for six hours at room temperature, then poured onto ice. This mixture was basified with concentrated ammonium hydroxide and then filtered to give the product of the example as a colorless solid; mp. 234-236 ° C.

Example 52 4.5.6.7-Tetrahydro-2-methyl-5,7-dipropylpyrazolo [1,5-a] pyrimidine-3-carbonitrile

A stirred mixture of 4.88 g of 5-amino-3-methylpyrazole-4-carbonitrile and 6.25 g of 4,6-nonanedione in 50 ml of glacial acetic acid was heated at reflux for ten hours. After maintaining the reflux at-30 ° C, the reaction mixture was treated as described in Example 50 to give 7.80 g of 2-methyl-5,7-dipropylpyrazolo [1,5-a] pyramidine-3-carbonitrile; mp. 73-74 ° C.

To a 2.0 g portion of the above compound, which was in 80 ml of methyl alcohol in the presence of nitrogen, 0.33 g of sodium borohydride was gradually added while stirring the solution. After 1 hour, the solvent was evaporated and the residue partitioned between saturated sodium bicarbonate and dichloromethane and purified as described hereinabove to give the product of the example; mp. 98-99 ° C.

Example 53 4,5,6,7-Tetrahydropyrazolo [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester A stirred mixture of 10.88 g of 5-amino-4-pyrazolecarboxylic acid ethyl ester, 11.51 g of malonic aldehyde bis (dimethyl acetal) and 100 ml of glacial acetic acid, was heated under reflux for 16 hours, then treated as described in Example 50 to give 7.8 g of pyrazolo [1,5-a] pyrimidine-3-carboxylic acid ethyl ester.

To a stirred mixture of 5.0 g of the above product in 200 ml of ethyl alcohol and 100 ml of methyl alcohol was gradually added about 1.0 g of sodium borohydride in the presence of nitrogen at room temperature.

The reaction mixture was stirred for 16 hours and then evaporated in vacuo. The residue was partitioned between saturated sodium bicarbonate solution and dichloromethane. The organic layer was poured through a short column of aqueous magnesium silicate and n-hexane was added to the eluent to crystallize the product. Recrystallization from dichloromethane / hexane gave the desired product; mp. 158-159 ° C.

Example 54 Phenyl- (4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl) -methanone

A mixture of 1.87 g of (3-amino-1H-pyrazol-4-yl) phenylmethanone (prepared in U.S. Patent Application Serial No. 612,811, filed May 24, 1984, as described 35), 1.64 g of malonaldehyde bis (dimethyl acetal) ) and 41 6 9 4 8 7 25 ml of glacial acetic acid, was heated at reflux for six hours. The solvent was evaporated and the solid was treated as described in Example 50 to give 1.70 g of phenylpyrazolo [1,5-a] pyrimidin-3-ylmethanone; mp. 174-175 ° C.

A mixture of 3.07 g of the title compound (prepared as described above), 60 ml of N, N-dimethylformamide and 600 mg of 10% palladium / carbon catalyst was hydrogenated at an initial hydrogen pressure of 103 kPa until hydrogen was no longer absorbed. The resulting mixture was filtered to remove the catalyst and evaporated to dryness. The crude product was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution, and after separation, the organic layer was dried over anhydrous sodium sulfate and poured through a short column of aqueous magnesium silicate. The eluent was heated to reflux on a steam bath with the gradual addition of n-hexane. When crystallization was observed, the solution was cooled and the solid was collected by filtration to give the desired product; mp. 173-174 ° C.

Example 55 2-Furanyl- (4,5,6,7-tetrahydro-pyrazolo [1,5-a] pyrimidin-3-yl) -methanone A mixture of 7.08 g of (3-amino-1H-pyrazol-4 - yl) -2-furanylmethanone (prepared as described in U.S. Patent Application Serial No. 612,811, filed May 24, 1984), 8.20 g of malonaldehyde bis (dimethylacetal) and 100 ml of glacial acetic acid, were heated at reflux for eight hours. The solvent was evaporated and the solid was treated as described in Example 50 to give 4.92 g of 2-furanylpyrazolo [1,5-a] pyrimidin-3-ylmethanone; mp. 222-224 ° C.

A mixture of 1.0 g of the above compound-35, 100 ml of N, N-dimethylformamide and 500 mg of 10% 42 8 9 4 8 7 palladium / carbon catalyst was hydrogenated and isolated as described in Example 54 and There was thus obtained 2-furanyl- (4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-ylmethanone, mp 138-139 ° C.

Example 56 2,2-Dimethyl-1- (4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl) -1-propanone A mixture of 25.0 g of pivaloylacetonitrile in 50 ml in N, N-dimethylformamide dimethyl acetal, was stirred at room temperature for eight hours in the presence of argon, after which the solvent was evaporated and n-hexane was added to the residue with stirring. The product was collected by filtration to give 34.6 g of 2 - [(dimethylamino) methylene] -4,4-dimethyl-3-oxopentanenitrile. A mixture of 18.0 g of the above compound, 15.0 g of aminoguanidine nitrate, 250 ml of ethyl alcohol and 11.0 ml of 10 N sodium hydroxide was heated under reflux for eight hours. The solvent was evaporated and water was added to the residue to give an oily precipitate which was crystallized by trituration. The precipitate was partitioned between saturated sodium bicarbonate and dichloromethane and treated as described in Example 50 to give 9.69 g of product. 1.33 g of this material was recrystallized from dichloromethane / hexane to give 1.02 g of 1- (3-amino-1H-pyrazol-4-yl) -2,2-dimethyl-1-propanone; mp. 159 - 160 ° C.

A stirred mixture of 3.34 g of the above compound (prepared as described above), 3.50 g of malonaldehyde bis (dimethyl acetal) and 100 ml of glacial acetic acid was heated at reflux for eight hours. The reaction mixture was cooled and evaporated in vacuo and partitioned and treated as described hereinabove to give 3.19 g of 2,2-dimethyl-1-pyrazolo [1,5-a] pyrimidin-3-yl-1-propanone; mp. 130 -35 131 "C.

I: 43 8 9 4 8 7

A mixture of 2.0 g of the above compound, 40 ml of N, N-dimethylformamide and 400 mg of 10% palladium / carbon catalyst was hydrogenated and isolated as described in Example 54 to give 2,2-dimer. -5-style-1- (4,5,6,7-tetrahydropyrazolo [1,5-a] pyrimidin-3-yl-1-propanone, mp 169-170 ° C.

Example 57 4,5-Dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carboxylic acid 3.37 g of 4,5-dihydro-7- [3 - (Trifluoromethyl) -phenyl] pyrazolo [1,5-a] pyrimidine-3-carboxylic acid ethyl ester (prepared as described in Example 22) was added to a solution of 1.4 g of potassium hydroxide in 100 ml of ethanol. The mixture was heated to reflux for 5 hours, cooled to room temperature and evaporated to dryness in vacuo. The residue was dissolved in water and the solution was neutralized to pH 7.0 with concentrated hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 2.5 g of the desired product as a white solid; mp. 175-177 ° C.

Example 58 7- (2,5-Dichlorophenyl) -4,5-dihydropyrazolo [1,5-a] pyrimidine-3-carbonitrile A mixture of 98.3 g of 2 ', 5'-dichloro-3-dimethyl liaminoacrylophenone and 43.5 g of 3-aminopyrazole-4-carbonitrile in 1 liter of glacial acetic acid were heated under reflux for 6 3/4 hours. The reaction mixture was cooled and diluted, and the precipitate thus obtained was collected, washed with water and dried in vacuo to give 107.6 g of 7- (2,5-dichlorophenyl) pyrazolo [1,5-a] pyrimidine-3-carbonitrile as pale yellow crystals; mp. 202-204 ° C.

To a stirred mixture of 59.7 g of the above product in 600 ml of glacial acetic acid was added nitrogen 1 44 89 487 of the above product in 600 ml of glacial acetic acid, in the presence of nitrogen gradually added about half of 25.9 g of sodium cyanoborohydride. The mixture was then heated on a steam bath with constant stirring until a solution was obtained. The heat was removed, the remaining sodium cyanoborohydride was added in the presence of nitrogen and the reaction mixture was stirred for an additional 2.5 hours. The resulting yellow precipitate was collected by filtration, washed with water and then neutralized by washing with saturated sodium bicarbonate solution. The precipitate was dried in vacuo to give 41.1 g of the product of the example as a pale yellow solid; mp. 222-223 ° C.

Example 59 7- (4-Chloro-phenyl) -4,5-dihydro-pyrazolo [1,5-a] -15-pyrimidine-3-carbonitrile

A mixture of 87.0 g of 4'-chloro-3-dimethylaminoacrylophenone and 44.9 g of 3-aminopyrazole-4-carbonitrile in 500 ml of glacial acetic acid was heated at reflux for 5.5 hours and the precipitated product was taken up. 20 by filtration, washed with water and dried to give 87.7 g of a solid. The above filtrate was diluted with water to further precipitate 13.6 g of a solid. The combined products (101.3 g) were combined with 1 liter of absolute alcohol and the mixture was heated to boiling point, after which the mixture was filtered hot to give 79.7 g of 7- (4-chlorophenyl) -pyrazolo [1,5-a] pyrimidine-3- carbonitrile; mp. 244-245 ° C.

To a stirred mixture of 46.8 g of 7- (4-chloro-30-phenyl) pyrazolo [1,5-a] pyrimidine-3-carbonitrile in 2 liters of glacial acetic acid was added in the presence of nitrogen and on a steam bath, gradually heating to 30.0 g. g of sodium cyanoborohydride and heating and stirring were continued until all the solid had dissolved. The heating was removed and stirring was continued. A solid formed which was collected by filtration. The solid was washed with water, then aqueous ammonia and once more with water. The solid was dried in vacuo to give 29.1 g of the product of the example as a white solid; 5 sp. 208-209 ° C.

Example 60 3-Chloro-4,5-dihydro-7- [3- (trifluoromethyl) phenylpyrazolo [1,5-a] pyrimidine

To a stirred mixture of 13.3 g of 3-chloro-10- 7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine in 150 ml of glacial acetic acid was gradually added in the presence of nitrogen at room temperature. 02 g of sodium cyanoborohydride. The mixture was stirred for 24 hours, then evaporated in vacuo to give an oil. The oil was dissolved in dichloromethane and washed with saturated sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and the filtrate evaporated in vacuo to give an oil which was then triturated in hexane. The formed crystals were collected by filtration to give 6.7 g of the desired product as yellow crystals; mp. 89-92 ° C. Example 61 4,5-Dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine To a stirred mixture of 25.0 g of 7- [3- (trifluoromethyl) ) phenyl] pyrazolo [1,5-a] pyrimidine in 250 ml of glacial acetic acid, 14.92 g of sodium cyanoborohydride were gradually added in the presence of nitrogen at room temperature. The resulting solution was stirred for 24 hours, after which it was evaporated in vacuo to an oil. The oil was dissolved in chloroform and washed with saturated sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give a semi-solid which was chromatographed on a silica gel column using ethyl acetate (25%) and hexane 46 89487 (75%) as the solvent system. The product fraction was collected and evaporated to give 6.2 g of the desired product as orange crystals; mp. 61-64 ° C.

Example 62 5- (2,4-Dichlorophenyl) -4,5,6,7-tetrahydro-6-methylpyrazolo [1,5-a] pyrimidine-3-carbonitrile

A mixture of 50.0 g of 2,5-dichloroacetophenone and 50 ml of N, N-dimethylacetamide dimethyl acetal was stirred and refluxed for 12.5 hours. The mixture was then cooled and evaporated in vacuo to give an oil which was crystallized by trituration to give a dark red solid. This was collected and washed with hexane / ether to give 58.8 g of 1- (2,5-dichlorophenyl) -3- (dimethylamino) -2-but-15 en-1-one as a red solid.

A mixture of 58.8 g of the above product and 24.5 g of 3-aminopyrazole-4-carbonitrile in 400 ml of glacial acetic acid was heated at reflux for about five hours. The reaction mixture was cooled and diluted with water, and the resulting precipitate was collected by filtration. This was washed several times with water and dried to give 68.5 g of 7- (2,5-dichlorophenyl) -5-methylpyrazolo [1,5-a] pyrimidine-3-carbonitrile as a pale yellow solid; mp. 229-230 ° C.

To a stirred mixture of 68.5 g of the above product in 1 liter of glacial acetic acid and heated on a steam bath was gradually added 28.4 g of sodium cyanoborohydride in the presence of nitrogen. Heating and stirring were continued for about six hours, after which an additional 21.6 g of sodium cyanoborohydride was added and heating and stirring were continued for 5.5 hours. The reaction mixture was filtered hot to remove insoluble matter totaling 23.1 g (A). The filtrate was cooled in an ice bath to crystallize a solid, and the solid was collected by filtration and washed with water to give I: - 47 89 487 219.9 g of (B). The filtrate from (B) was diluted with water to give a further precipitate which was collected after standing to give 19.07 g of (C).

A mixture of 10.0 g of (A), 10.0 g of 5 (B) and 10.0 g of (C) was stirred in 150 ml of methanol and In 500 ml of tetrahydrofuran in the presence of nitrogen and then 12.44 g of sodium borohydride were gradually added. The mixture was heated to reflux for seven hours and then filtered hot. The filtrate was cooled to room temperature, and water was added to separate the oil, which was extracted into chloroform. The organic layer was separated, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo to give an off-white solid which was triturated with ether / hexane to give 19.4 g of the product of the example as a white solid; mp. 184-185 ° C.

Example 63 7- (3,4-Dichlorophenyl) -4,5-dihydropyrazolo-20 [1,5-a] pyrimidine-3-carbonitrile

A mixture of 50.0 g of 3,4-dichloroacetophenone and 75 ml of N, N-dimethylformamide dimethyl acetal was heated at reflux for six hours, then allowed to cool for 15 hours. The crystalline precipitate was collected by filtration, washed with hexane and dried. Upon addition of hexane to the above filtrate, some additional product precipitated which was collected by filtration. The precipitates were combined, washed with hexane and dried in vacuo to give 55.0 g of 3 ', 4'-dichloro-3-dimethylaminoacrylophenone as bright yellow crystals.

A mixture of 55.0 g of the above product and 24.3 g of 3-aminopyrazole-4-carbonitrile in 500 ml of glacial acetic acid was heated at reflux for 35 hours. The reaction mixture was allowed to stand at room temperature for 48 hours. The separated solid was collected by filtration, washed with water, then aqueous ammonia and once more with water. The product was dried in vacuo to give 62.5 g of 7- (3,4-dichlorophenyl) -5-pyrazolo [1,5-a] pyrimidine-3-carbonitrile as pale yellow crystals.

A 25.0 g portion of the above product was then combined with one liter of glacial acetic acid, and to this mixture was gradually added an excess of sodium borohydride. The mixture was stirred for two days in the presence of nitrogen while maintaining the temperature with a steam bath. The solid precipitated from solution was recrystallized from ethanol to give 12.0 g of 7- (3,4-dichlorophenyl) -4,5-dihydropyrazolo [1,5-a] pyramidine-3-carbonitrile as a pale yellow solid; mp. 254-256 ° C.

Example 64 4- (Chloroacetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile A dose of 8.3 g sodium cyanoborohydride was gradually added to a solution of 20 g of 7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile (U.S. Patent 4,178,449) in 400 ml of glacial acetic acid at ice bath temperature. and in the presence of nitrogen with stirring. The reaction was stirred in an ice bath for 45 minutes, then at room temperature for three hours, 1.7 g of sodium cyanoborohydride was added and stirring was continued for another two hours.

The precipitate was collected, washed with water and saved.

The glacial acetic acid solution was concentrated to half volume and diluted with 250 mL of water. The resulting precipitate was collected, washed twice with water, combined with the above precipitate and dissolved in 600 ml of dichloro-35 methane. This solution was washed twice with saturated aqueous sodium bicarbonate, dried, filtered and concentrated to a pale yellow solid. This solid was recrystallized from hot isopropanol to give 14.8 g of 4,5-dihydro-7- [3- (tri-5-fluoromethyl) phenyl] pyrazolo [1,5a] pyramidine-3-carbonitrile.

A mixture of 2.9 g of the above compound and 3.4 g of chloroacetic anhydride in 100 ml of toluene was heated at reflux with stirring for 5 hours. The reaction was cooled, 1 g of chloroacetic anhydride was added, the mixture was stirred for 48 hours at room temperature, then heated at reflux for 5 hours and allowed to stand overnight at room temperature. The mixture was then concentrated in vacuo over 15 steam baths. The residue was suspended in ether and the white crystals were collected, washed with ether and dried, yielding 1.1 g of the desired intermediate, m.p. 179-181 ° C.

Example 65 4- (3-Chloro-1-oxopropyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyramidine-3-carbonitrile

To a stirred mixture of 4.5 g of 4,5-dihydro-7- [3-trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-25-3-carbonitrile and 3.6 g of 1, 8-Bis (dimethylaminonaphthalene, N, N, N ', N'-tetramethyl-1,8-naphthalenediamine in 120 ml of dry tetrahydrofuran was added dropwise in the presence of nitrogen to a solution of 3.9 g of 3-chloropropionyl chloride In 30 ml of tetrahydrofuran, the mixture was stirred for one hour, heated at reflux for 4 hours, then allowed to stand overnight, filtered and the filtrate evaporated in vacuo over a steam bath, the residue triturated in ether, filtered, washed with ether, dried and solid. the material was then heated to a solution in 25 mL of acetone / 89487 ril and filtered, and on storage in the refrigerator, a solid formed which was collected, washed with ether and dried to give 3 g of the desired product, mp 183-185 ° C.

Example 66 4- (Chloroacetyl) -7- (3-chlorophenyl) -4,5-dihydropyrazolo [1,5-a] pyrimidine-3-carbonitrile A 23.4 g portion of 7- (3-chlorophenyl) pyrazolo [1,5-a] pyrimidine-3-carbonitrile and 11.7 g of sodium cyanoborohydride in 500 ml of glacial acetic acid were reacted as described in Example 1 to give 18.4 g of 4,5-dihydro-7 - (3-chlorophenyl) pyrazolo [1,5-a] pyramid-3-carbonitrile.

An 18.1 g portion of the above compound and 15 g of chloroacetic anhydride in 200 ml of toluene were reacted as described in Example 1 to give 15 g of the desired intermediate, m.p. 196-198 ° C.

Example 67 4,5-Dihydro-4- (iodoacetyl) -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyramidine-3-carbonitrile

A mixture of 1.8 g of 4- (chloroacetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile and 825 mg of sodium iodide in 25 ml of acetone, stirred in the presence of nitrogen at reflux for two hours, then cooled and filtered. The filtrate was evaporated, the residue triturated in ether, filtered, washed with ethers and dried. The solid was heated to a solution in 10 mL of ethyl acetate, filtered, cooled, and after 1 h, 20 mL of hexane was added and the reaction mixture was recooled. The solid was collected, washed with hexane and dried, yielding 1.3 g of the desired intermediate, m.p. 158-160 ° C.

I; si 89 48 7

Example 68 4- (Chloroacetyl) -4,5,6,7-tetrahydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyramidine-3-carbonitrile a portion of 4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile in 90 ml of trifluoroacetic acid was stirred in the presence of argon and heated to 60-65 ° C.

A 10.8 ml portion of triethylsilane was added and the mixture was stirred at 60-65 ° C for 5.5 hours, then allowed to stand at room temperature overnight. The mixture was poured into 300 ml of 25% aqueous potassium hydroxide solution containing crushed ice, and extracted three times with chloroform. The extracts were combined, washed with saturated sodium chloride, dried, concentrated to 200 mL and filtered through aqueous magnesium silicate. The solvent was evaporated and the residue triturated with ether and dried to give 5.9 g of 4,5,6,7-tetrahydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-20. ne-3-carbonitrile.

A mixture of 5.9 g of the above compound and 10.2 g of chloroacetic anhydride in 60 ml of toluene was stirred in the presence of argon at reflux for 18 hours, then the solvent was removed in vacuo on a steam bath. The residual oil was dissolved in 25 ml of chloroform, filtered through aqueous magnesium silicate and concentrated to an oil. The oil was added to ether and the solid was collected to give the desired intermediate, m.p. 157-159 ° C.

Example 69 4- (Chloroacetyl) -7- (3-fluorophenyl) -4,5-dihydropyrazolo [1,5-a] pyrimidine-3-carbonitrile 7- (3-fluorophenyl) pyrazolo [1,5-a] α] pyrimidine-3-carbonitrile was reacted as described in Example 66 to give 6 g of the desired intermediate, m.p. 190-193 ° C.

52 89487

Example 70 4- (Chloroacetyl) -4,5-dihydro-7- (3-nitrophenyl) pyrazolo [1,5-a] pyrimidine-3-carbonitrile 7- (3-nitrophenyl) pyrazolo [1,5-a] -pyramidine-3-5 carbonitrile was reacted as described in Example 66 to give 0.9 g of the desired intermediate, m.p. 164-167 ° C.

Example 71 4- (Chloroacetyl) -7- (4-chlorophenyl) -4,5-dihydro-10 pyrazolo [1,5-a] pyrimidine-3-carbonitrile 7- (4-chlorophenyl) pyrazolo [1,5-a] pyramidine The 3-carbonitrile was reacted as described in Example 66 to give 12.44 g of the desired intermediate, m.p. 198-199 ° C.

Example 72 4- (Chloroacetyl) -7- (2,3-dichlorophenyl) -4,5-dihydropyrazolo [1,5-a] pyramidine-3-carbonitrile 7- (2,5-dichlorophenyl) pyrazolo [1 The 1,5-a] pyrimidine-3-carbonitrile was reacted as described in Example 66 to give 39.3 g of the desired intermediate, m.p. 235-236 ° C.

Example 73 4- (Chloroacetyl) -4,5-dihydro-6-methyl-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 6-methyl-7- (3- (Trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile was reacted as described in Example 66 to give 39.3 g of the desired intermediate, mp 178-182 ° C.

Example 74 4- (Chloroacetyl) -4,5-dihydro-5-methyl-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile 5-methyl- 7- [3- (Trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile was reacted as described in Example 66 to give 6.2 g of the desired intermediate, m.p. 160-163 ° C.

Example 75 4- (Chloroacetyl) -7- [3-chlorophenyl) -4,5-dihydro-56-methyl] pyrazolo [1,5-a] pyramidine-3-carbonitrile 7- (3-chlorophenyl) - 4,5-Dihydro-6-methylpyrazolo [1,5-a] pyrimidine-3-carbonitrile was reacted as described in Example 66 to give 12.5 g of the desired intermediate, m.p. 132-135 ° C.

Example 76 4- (Chloroacetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carboxylic acid, ethyl ester 15 g A portion of ethyl (ethoxymethylene) cyanoacetate was carefully poured into a solution of 50 ml of 85% hydrazine hydrate in 115 ml of water. The mixture was stirred for one hour, then cooled in an ice bath. The formed crystals were collected, dissolved in dichloromethane, filtered through aqueous magnesium silicate, the filtrate was cooled in an ice bath, and hexane was added. The resulting crystals were collected (40.9 g).

The above crystals and 62.7 g of 3-dimethylamino-3 '- (trifluoromethyl) acrylophenone in 250 ml of acetic acid were stirred and heated at reflux for 16 hours and then evaporated to an oil. The oil was dissolved in 500 mL of dichloromethane and washed with aqueous sodium bicarbonate. The organic layer was then dried, filtered and evaporated to an oil. This oil was dissolved in isopropanol with a steam bath and then placed in an ice bath overnight. Filtration gave 67.1 g of white crystals.

The above crystals, 67.1 g, were dissolved in 250 ml of glacial acetic acid, and in the presence of nitrogen, 35.5 g of sodium cyanoborohydride was added. The mixture was stirred for three hours 54 8 9 4 8 7 and then evaporated to an oil. The oil was dissolved in dichloromethane, washed with aqueous sodium bicarbonate and a solid formed on standing. The solid was dissolved in 500 ml of isopropanol while heating, then cooled to give 50.3 g of a solid.

6.8 g of the above-mentioned solid and 4.0 g of 1,8-bis (dimethylamino) naphthalene, N, N, N ', N'-tetramethyl-1,8-naphthalenediamine, which were 100 In 10 ml of dry tetrahydrofuran, 4.50 g of chloroacetyl chloride in 100 ml of dry tetrahydrofuran were added dropwise over two hours under a nitrogen atmosphere. The mixture was stirred overnight and then filtered. The filtrate was evaporated to a semi-solid 15 and this was crystallized from ether to give 5.0 g of the desired intermediate, m.p. 141-142 ° C.

Example 77 4- (Chloroacetyl) -7- (4-chlorophenyl) -4,5-dihydro-6-methylpyrazolo [1,5-a] pyrimidine-3-carbonitrile 20 g of 10 g portion of 7- (4- chlorophenyl) -4,5-dihydro-6-methylpyrazolo [1,5-a] pyrimidine-3-carbonitrile and 9 g of 1,8-bis (dimethylamino) naphthalene, N, N, N ', N'-tetramethyl -1,8-Naphthalenediamine in 300 ml of dry tetrahydrofuran was stirred in the presence of nitrogen and 6 ml of chloroacetyl chloride in 70 ml of dry tetrahydrofuran was added over 15 minutes with stirring. The mixture was stirred at reflux for 5.5 hours, then at room temperature overnight and then filtered. The filtrate was concentrated to an oil. The oil was triturated with ether, the solid collected and dried to give 10 g of the desired intermediate, m.p. 138-140 ° C.

55 89 4 8 7

Example 78 7- (4-Chloro-phenyl) -4- (iodo-acetyl) -4,5-dihydro-pyrazolo [1,5-a] pyrimidine-3-carbonitrile

A mixture of 15.67 g of 4- (chloroacetyl) -7- (4-5 chlorophenyl) -4,5-dihydropyrazolo [1,5-a] pyrimidine-3-carbonitrile and 15.61 g of potassium iodine in 150 ml acetone, heated and stirred at reflux for 6.5 hours and then filtered. The filtrate was evaporated and the residue was triturated with ether to give 4.51 g of the desired intermediate.

Example 79 4,5-Dihydro-4 - [(4-methyl-1-piperazinyl) acetyl] -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile A mixture of containing 1.3 g of N-methylpiperazine, 4.4 g of 4- (chloroacetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile and 1.5 g of sodium carbonate in 75 ml of toluene, was heated at reflux for four hours, then allowed to stand at room temperature overnight. The mixture was treated with 30 ml of 1 N sodium hydroxide and the phases were separated. The aqueous phase was extracted twice with chloroform. The organic phases were combined, washed with water, dried, filtered and concentrated. The residue was heated to solution in 50 mL of ethyl acetate, filtered and cooled. The crystalline solid was collected, washed with ethyl acetate and hexane and dried to give 1.8 g of the desired product, m.p. 178-180 ° C.

Following the general procedure of Example 79 and using the intermediates of Examples 67-78 and the indicated piperazines, the products of Examples 80-139 in Table 2 were obtained.

56 89487

(NC-HCNCTiCNLncN U OCOOOcOr-COO-H

o (NHHHHHHCN

I I I I I I I I

• omcnor-ocoo

a oaor-coc'-oof-H

CO (ΝΗΗΗΗΗΗΓΊ Ή

II -HI

'-' '—I I -Η H I I Ή O II

• HI I -H H fH -H --- -Η Ϊ ^ Η H - v -H I

HO Η -Η -Η -H CO -H H S 0 CO H H If)

> i H H> 1 I H -H I -H μ H H 4-> (S) μ H H * I

> i 0 Η> ι Η> ι μ I —- μ (0> i-H Q) + -> (0 SH 0

C CO> ·. C ¢ 0 S μ Η-Η-μ M tH iH CO (0 μ S μ IH

• H-μ> iQ) μ μ η ΐΗ · Η ο) μ μ <u μ ο) μ μ ηθ co co chm 11 c rnb, ca ο) h · —i sh aa) hh co μ μ H - μ Ε Ο HS 0 HEC -HQ- HEC Η μ to> i co hh (U-HJ3 η μ xi a-ho h .-. A-ho> << o μα μππ αμμ ίπομ ι μ χ) ν · η ι μ χι> ι μ ο .—> to sh -η -η ο (0 S ε <ο η ο μ> ιη η ο μ μ> ·.

α · π μ S η ο, ο χ μ · ΗΛ: ι 3 co g> ι ι 3 co <ua η η οιμμ ι η ι ο) μ ι.-ή λ; h s ^ -ή λ: co ι — ι a Sh α α) μ ηήπ e o co -η μι co c -h μι <o h

I tn · Η E · Η I -H I - 31 H -H ΓΟ μ 0) H -H CO - H

hc ah g ι — ι μ -h -h hh> ι μ ι <a μ S μ ι -h tn ia) ιμο · πμ c πμο S μ h μ - s μ η hs - μ -Η Η Οΰ Η -ν Η> ι · Η · Η μ -ν G 0) · Η · Η μ C> ι C · Η • Η - - HI 3 μ I Ή>. μ -Η 0) 1 -Η απ Η 0) I * Η Q) Η Η · Η -H Ή <0> ι CO Ό C -Ρ Ό ΕΓΟ-Η HSH Ε 00 Η C Η Η> 1 Η · Η · Η μ X μ ι—. -Η 0) —-H -H L_J XJ α S -Η · Η Ljfl Η - Η> ι> .μ η -η ι ο) ι ε μ ι ε η ι -η ιμμ ηι · η co η μ μ Νμ > ι μ ne c- η · ηγο · η ϊη ε h <u η ίπΐ ^ ε μ η μ 0) μ · η> .μ ι - ι μ ι »ι-ιμ> ι ι · η ιΕ · η ϊη ι η co S η e ο) c μ - -η -ηοϊη χ ι> ι c ομ - hc ι ο μ μ sg • heo α) ι c η μ a otsa α) μ>. -πμο m μ>, ο) μο η · η λ Eron> ι ό ι μ ι ι η ό α η ο λ ι ό a ao) J3 ϊη μ μ —1— -η> ί> ι'— ι ο) ---.-. -> ι. — ι S 3 μ η> ι.—. η ε μ> ιΟ 10 · Η I Ό G XI (0 Ε · Η (0 · ΗΛ (0 S Η (0 O XI <0 α Η (0 cox nr - η α) -η ι ι η ι η - η ι c η. * co η ι ι μ α; 0) η ι> ιΐΕ μ Όιη roSiin S Τ3 m 0) · ηι, * τ3 m Hoi μμοο Son -hi - S - 5>, ι - μ μη οι - ι 3 co - · η ι C μ μ μ ιο Η., ρ, _ι c ιη η · η μ ι Η ιη Η · η η ι ι μ -η ο) ό> ί ο-1—1 ία) .— ι α) -.—> μ ^ η ό *! -. η η η ο * μ c μ> ια ο o 'ο to ο μ · ^ ο ο ι c ο ^ ο> ι · η c' —1 - Ή · Η .C r-ι Η I Η -ν '( 0 Η · Η I Η ΟΓΟ-Η CO I Η> ι ί4 Ή ή ι η μ · η <0 λ; - ο w .—, ο μ - ο η -. Η μ ο co μ η I 00 Ό Ο Ό IHH C0 I -Η (!) Ο Ή 10 AC I Τ3 GH C0 A * wT3 ^ 1 η ο ι ιο Ό η μ Ν 'η μ οπμ h r- η α) πμ φι-η I ι Ε Η ΙΟ - I> Η <0 ltH (0 H> i (0 Ό I Ε X)> ι (0 £ 00 Ε 0) Or-H J * - η χ>> ι μ OS μ α:> .μ ι ο · η ι S μ Ο --ή μ μ ι μ in · .—. - μ> ι μ c>. ιμ> ι ν <μ μ η μ> ι πιμ ο τ3 - η ι ο <ν ο) α ό -η α ν <ο) α - ό>. - (a) α a * ts> ι 3> ιΗ Οι —Η Η - ^ C0 .—. (!) ι— · '—- C0 .—. ΓΟίμα Η Ο) η> ιΐα Ε-1 £ Η. — Ι * —1 HO t _. (0H χ: μ · Η> —1 (0 -Η W .c> - (0 -H C0 0 .—> • ΗΪΗ (0 ItHO) I Η Ή 10 HI ι—- HI · Η (0 I π-1 HI μ (0 Ό> (1 Ό'ίμμ 'ΐ-ΗίΗ' Όμ & ι '»-HS' Φ'ΟΙ 'i- HS 'ΦΌΙ I μ ΙΟ ^ + J (ö -ν' Η IQ) S -ν> HS. I ΙΟ ι — IH S ^> ι ΙΟ ιο α) ν -νθ) μ ν sc ιο ac wsc -hio - - hsc ^.

- CO H IC0> 1 l> iQ) --HQ) l> i <D l-H I> .11 l-HH

(0. — Ι ί1 ιο ft c μ o1 ομ ^ ΰμ ^ ΰμ το -

I I

H -H · Η I

G -Η μ μ ι -H

• H H Oi OOh

H ίΗ I -H o -H -H -H IHO CO S

CO -H H HH COH -H I H H μ ^ 1-H

μ co μ> ι x> i μ -h> i. * h ch-h oh

(0 μ O> i H O S O H * H »—I 0) O H H S

μ c o co to co μ to oshcatosh λ ω ^ jc n <no> 0) πμ ι μ a) μ η> .μ is i. * S> ica a λ a; c ό c eg a: c c ί1 c πομ co x O-H I 10) -0) IQ) I Q) o) -0) -HQ) IQ)

ιέ ft. 2 oo-Q (NX) Roxo ^ μχιημ hoezjC

Go

-J E

Go HO H <N CO N1 IO VO r-

<COOO CO CO CO CO CO CO CO

57 ω li 57 89 4 87 OCOCOPO'P'fin

U ooinoc ^ cvricovD

0 P 1 “I p 1 — I p r-It — I rH

I I I I I I I I

• σΐο-ίοσίοοιηοοΜ1

01 ['-inOlOUDTfOOiO

C / 3 '—I p i — I t — I 1 — I rH i— (I — I

I I I

I Ρ I r — 1 I r-. I

1-1 E 0 I I P CO P 0

Ή · Η I H M I — I P I '—1 p I P

Ρ P 0 0) Ρ> <I ΙΟ I> i ^ 0

ίρ> ι Ή W ap> i0 I—. rH ^ f> ι Ρ CO I

> iQj Ρ Ρ p> i CP -HO "-'- P rH + J -HI

Pi— '> i (0 Q> i -HO H CO - · 03> i (0 (Or-,

Q) (0> i P I C (fl CO> i -P ICO> i p -P-H

(01 -P> i HO) + J-P> i (0 if (0 -P> i (0 rH

(Oin 0) a IP (0 (0 CP I <-1 0) a P>, Λ * (0l-1 ^ · ~ · -H Ρ Ρ P> 1 Il-rl-rl (fl I-1 Q) > 1 Ή • rl rH (OP Ή * H rH 0> 1 (0 Qi 'Hi — II — I (0 -rl Ql C Ή

rH I-1 f — l rH rH rH * rl Qj Ql -P <—I> —I> 1 * H I-1 I — I · Η 03 P

> 1 Ο P> 1> 1> 1 * rl * rl I — t (0 Ή> 1> 1 * H * H> 1 a Ρ P

> 1 P rH> 1 Ph> iP Ql * H P rH> 1 C P P> 1 I · - p

CO> 1 C 4-> P 4-> IH a)> 1 C Ρ P> iC HHP

rH (0> 1 0) 0) 03 P rH> i a> 1 Q3 (0 * H> 1 0) I Η Ή

COP CP SEC I> 1 -PC Ρ P C CP -> | C

P (0 -P ^ -P-P0 '-'C QiU ^ 10 0 P P> 1 0

(OP (0 -P -P P P J3 P 0) P I P -P Η PO (0 -P -P HPO

P> 1 P P rH> 1 O P rH P H rp rH POP PrHrH> 1 G) P

0 Q (0> i · Ρ> i 3 (0 ίΡ '-'- Ρ lPP> 1 Q 10 (0> i -P> 1 E (0 a l-ι P> i -HCHX> ι Ρ P ^ Ρ P> 1 -PXP>, -PC -P Jd -pp d) PP a) pi cpp -P> ipp α I q) pp ojpi apaa) p p-pco p> tpp Sp o> i oo aop poco

1> i -PEP "- P I Ό> i P> 1P -P E Ρ I -PEP PCI

p> 1 a p c I p p p p c> 1 a) c pip a p c co p p

1C IPO ^ <^ C EOJO Ό E Ο P r— 'C IPO AIP C

P 0) P O .Q * —1 I P P E «O P P £ 3 O P P P O .Q O P P

PP ICP ICOP PPP PPP 3 Ρ P I 3 P PPP

> 1— ^ P (0 (O '-' Ό> <P (0> 0 (0 P SO ~ P (0 0))

Sp ρρλ iip aojd a 3 a: p Sp ρ p. * E ~ p

Cpp ppi ο> E ι 3 ι I p I PCE ppi iiE

03> <P> 1 P CO (flip CH P 00 NPO Pd) P> iPC0 (NCOP

P> 1P SP IX rH p - PI WPI PPP> ι Ρ I '—- «- · Ph I Ρ PC - POP> 1 IP p IPP' -> 1 C - PII> 1 omo) ic ipa - ^ pc -i * jc I pa <dic - <f o- a —- £ P POOP P>, r-1 i_j ρ P> - | ^ -P 00 PI — I POOP i — i | r-, 1— 1 PP p I —1 P> P> i (0 <PP 'Pip I — I> t (0 P 1—1 P p p- (0

IPC P I Ό I a 1 I I Ό I 00 Ό I> 1 I P I Ό IP I

O O OhP ii Oin ifrop ^ pp n p in oc ^ p ii pin I 3 £ 1 O I E IP - I p E I I E 103 - 3 ι E ι> i - 03 OPP pop oap Oi P O (- P OEp pop O Sp

P Ρ P (0 JbdPP P r — IP Ρ Γ "- P pip p-r | P PPP ppi — I

O OPJd ι Ό> ι ΌΡΟ Ό I> ι Ό 'p> ι ΌΡΟ · Ό> ι Ό03Ο 3> ι ρ ι co> ι a> ι ρ ρ> ίρ a> ι · Ηα> ιΟρ> ι a> ι ( ορ Ε <£ pm '-'. Cr-I £> 0 ΛΡγ-ι £ Ργπ £ 30 - £ r-, £ (0 ο Ρ ^ II Ρ (0 Ρ> 1 (0 Ρ> 1 (0 Ρ> 1 (0 Ρ Ρ (0 I Ρ (0 Ρ ι — ι (0 Ό I Ρ ^ f Ό I Ό C Ρ Ό> 1 I Ό> ι I ΌΡΡ Ί'ΌΙ ΌΡΡ ι οο C <—ι ι ιη ι ρ ( 0 ι Pin ι ρ in iPto> —ι ι ιη ι ρ co ιη> —ι ρ «-ρ ιη - LO (0 ρ ιη α) - ιη φ - ιη ρ ρ 'Pin - ιη> ιΡ -IP I -Ρ V Ρ> 1 ι Ο Ρ -COP - Ρ> 1 I -Ρ -> ι> ι ^ ό -ϊ> —ι1 Titoa if co '^ ι ίο ι — 11 rf ^ a ^ ff --1 "cf ca

3 P IP

3 C Ρ ρ P

X P P E I O I

PPP I> 1 P P 311 P

(0 (0P P> 1 P P p p CO

• ρ P> 1 Ρ P (0> 1P> 1P PPP Ρ P P

-— co> 1 op p ap ap pppop op UCO> i CI> i I> 1 P> 1> 1 3> i P> 1 (NO) dl P> i 0) (N> 1 OH> 1 P> i > 1 P> i 03> i

a Ρ X C Λ C · ~ τΌ -rPCPC EC

OP ι I 03 I IP IP I QJ Q) I QJ l 0)

«A 2 OOP Z ρ Ό PC oo E P Tf p CMP

D

E

Dp co σι Ο ρ oh co ^ f in <coco co σ 'σι σι σ' en σι ei ω 58 89487 COlDr-IrHOCMf-CTl U rfrfC> COr ~ l \ OC> t> ° r ~ I H H H H H (N t—)

I I I I I I I I

• νο <ησ> σ> ο ^ <^ ΐΓ) Γν a rf ^ criNHinocs

C / 3 H H 1-HtHrHCNiH

I III

I r — I ι — I, —ι r—, Ή Η II μ -Η μ • H Η II I · Η r — I I -rl H I Ή I I μ μ

Ή N '-> 0 Ηί · Ηι — I Ή' Ή II '-'> —1 ι -'- ιΟ> 1 N

NN Ή I — I Ή Η Ή Η · Η -rl U Ζ N -Η -Η H H NN

N C H o H ΝΉ SH Ή N I μ H H rl o CC

Cd) N CO NN μ SS h aH O) N μ NW HO) • H4H N μ N μ μ μ N N ii ii rH - tn -PN μ CO H-4 co ^ c ia c oh φ-μ-Η hs ή μ ή aio μ- 'μ-h · η μ · η ε co ui chn hoc -h μ <o μ <ohh co N mh omeon μ se o co n μ h μ μ> Ί rH μa μ μ λ j * μ and> · qj ν · η and μa m sh cd n -h co - · ιοομ ομμ co-h g μ μ co - an · η a μ · η μ-h μ cm ι o (O a) co ό μ o <ö μ · η · η μ-h • h οι μ d) h uin ϋ ts 3 λ; h, * μ ό 3 x d> μ ο, φ c a e μ a n ani ι h ι ^ o ε -h hi a n ιεμ

I · Η -H -H S -H -H CO ^ 4H CO -H I (0 rH H CO μ N rH -H -H

μ μ caca μ ι · η-hi h <n μ o-hi ac ι μ c ιοο ια) ιμ · Η μ μ μ n ι α) μμ · π id)> - 00 1-13X3 ηηη-η η c Ν μ c ω μ μ c μ μ μ · η3Λ η Η μ Ι- ^ rH II · Η Ν ^ μ μ -Η (0 Ν ^ Η I μ Η Η μ Η μ (0 ^ -Η · Η ι — ι C0 · Η CI * Η d) rH · Η a I · Η ι— '· Η · Η Ν Η (0

Η · Η X · Η rH · Η Η> -> Ό H C0 Ό Ε> 1 C I 00 Ό · Η Η · Η Ν · Η X

Ν μ I H S μ ι-ΗΙ-Η Η ι—> · Η μ Ν Η Η ι— -Η Η Ν ^ μ μ I

αμοο n ν μ n ν ε ο ι ε μι · π ^ ι ε n ν μ <ι> μ co Ο ^ ι Ν μ η Ν ι · η μ ν μ ο ^ ιο ι sh ν μ μ ε ^ -ι μι · Η cq) c μομ μιμ 3 cc μ ο ι μ μ mc ~ ι μ aco CSEO QJ μ 5η Ο Ν μ ιη (0 ΐ '-' ^ ι d) eoh co c 1—1 · η a-HXi ε ό a ε μ a μ ^ μ ο μ ae · η and μ ι- · μ ο ι * η ομμ ^> ν — ι ι η * - * · η ^ ι * <ι) μηπ ^ μ μ s ι η c ν ό μοιο · η £ m ^ ν (ο μ ι a 3 *; 5η co -ποιο νν ό ΗΙ · Η a CX Η Ή IIHC Η ΟΝ / Η 3 3ί CI μ Ε 0 Ε ι rH 1 Ν Ό m ιμιη ^ μ a ιμιη N μ ι 0) ΟΕ ιβ μ · π «μη s 1 - 04 ¢ 0 ιόι end) 'Νμ ο μ μ μ • Η Ό μ' - '• HI CinrH 1—1 (0 rH CO Η Η • - 'W tH GHIH Ό μ

μ N N ι μ · η φνΐ — ι ι ίο ι — ι ι — ι'Ei 1 (0'— ι d) μ -π μ n N

s £ α μ c μ ^ ο ^ ή ο ι · η ο μ μ e oi a Ν * Η ι — ι> —ι - '· Η Ή I Η Η-' Ή HS μ H * —- * · Η rH · Η - · Η 3 · Η ι — ι μ ο ο 'ι η μ ~ ο' -Ι-πο ι ν μ ^ η ο μι · π μ ό <ο 0) ιι ι coo ο-neo ίΝω -ha N ι ν wo co ό μιι emin ** -> μ Ο Η μ υ ^, μ Ci-iS li> ιμ θ '- "H imin Η' 'ι ι ε η ν (0 ι e co ιοιομ ι c to hie * α) ό h ον-η j <Ν μ oh μ (Old) oh μ * ν μ h μ - 'ι - μιμ —- a ν μ co ν Nm μ μ co ν ιιμ en ι ι—> ο ι ^ ο ό ^ Ν> -> oa Όμa tn -η Όμa 'ί'-Ν · η ι— «ο 3 C0 · Η rH N · Η a I μ ι—> Ν <0 r — ι I rl S n (0 < —Ι ^ · Η Οι Χ3 · ΗγΗ Εη '—ι rH O £ 3 Η 1—1 ^ ι a · Η JC μ * Η C0 ι — 1 Ν £ μ Ή' - 'rH ι — ι ι — ι μ ο IN C0 · Η Ν <0 * rri O rH · Η 0) Η ^ ο μ · Η 0) Η ΙΝ <0 ΙΝ «• ^ Νμ os ι ι ω s ό a> 1 ihh) oas s ι Ί'Νμ ^ μ ιο ιμιη C044N ι-ΗΝ n ο Ε ι · ΗΝ ^ μίη —- 0) μ m (ϋ ι wOC inQjC - co ι mac - ^ d) '- · 0) μ ICON -ϋ) μ lid) viQ) ι μ μ * iq) ΐ (θμ ICON ^ (0 a ^ 31-1 ^ μμ if μ μ ro - ^ τμμ <i to> - «^ fioa

^ III

3 -H I -Η μ · Η -H

3 C * H μ ι — ΙΌ μ X Ή rH N I Ή Ν Ή * Η Ή Ο

μ · Η Ν Ν I · Η Ή rH Ν I Η rH I μ I * Η 3 I

(0 co Ν -η e -η η —ι ι 5η μ n s o n s μμ μ- ^ • μ μ μ μ Ν μΝ ΟίΝΝιΰΐΝμίΝμΝ μμμ - (0 0) ι N a ΟΝ μιμ Ε · πμ μ- ^ μ ΟΝ ι μ μ

μ E 0 N 0 OC0 μ μ Ο) ι H d) SH d) o ID H1 SN

es o -Hca μ μμ oho hno ano μμ —nn a ό-ho aa; c esi »- Sib iNcoc«; c ωαμ oh ιεμ ι ια) in. * ιμ ^ ΗΝΛ: id) hujo a coioaiN ^ ja ^ co zqjo -—Co ^ and ληε

O

a ε O h m oo σι o μ es co

<cocn cr · σι σι O O O O

E * W μ μ μ μ ι 59 89 487 o es vo h vo σν o O ΗΟΟνΟνΟνΟιΟιΟΟ ·

° CS C '' H H r-I H H I — I

i i i i i i i i

oomoinov ^ r ^ co aoc ^ vovoiniopco CO (N r-H H ι — I i— (i — I i — I

I - I

OI I -rl -rl en p i — i h e i

Il -PO) Ή · Η · Η I II

O '—1 (0 Oi »H> ι · Η f — I I · Η I — I O

M Η PH P Ό 3h Pi — I · Η H I

UH> i a Sni a> h ip i a)> i ho o <- · a ι p ο ε ε e o a>. tP co ε ι

H tp - H Q) H H H Q) P H C>, P H I — I

H C -HI εθ HP 4-1X3 Oili CIO HIO

> i <0 H - '-'CO iP - tp I * H HP iP I

ip H H> i H HP in a HÄH H - H CO tp iP P

C -— Η ip * —I H 10 C I — 1 HHH IHH Pa C '

H H H C ip P 0) 10 iPO H - H H 10 · -. dl H

CO H H O ip ip> i HI ip I H H Cp H PH H i—> P P HP ca '-'in cinp h tp p oh ^ o ίο ipp - a) q) o I- o * p> ipp a tp ih

P P H H o H HP O 'H Hvf Η> ι O H H tp O' O

0 o c h co p ho i-o- · Hie p ε c ac - cn

QEO iPAid) P> i ^ 0 P - 0 OHO iO ^ P

Η Η Λ> 1 O P Ο P H IH Ο Η P ε P P HHH 1 (0

app PICO O H H H O O H P HOP I - H O 'P

10 (0 OJN φ Η Ό H ICO H> i 10 H 3 (0 - Η Η ΙΪΡ ho jc ε I h ä I h op. * Tp. * Ϊρηλ: hhh oa 1 HI H -— ιΗ I in pp (0 IPI> ι HI HCpp P - - h co ph ip co * p Ό po 'o co eh co ipipP oh

HHI OH> i —- O 'Η ΪΡ ip W-C0I OPl ip P H> i H

HPH 3> iP - · I C Pa * —1 (0 H HPH CO C P iP H

ip P C HiPO I — O Hi—. I - C ^ C Ο ε O h ip h iP wH HI V »ΗΛ Ό H -S 'H H I l H a Η P ΌΡΗ

P I H H * i — i HP I H * —IH H S ’(Ο Η Ο P P I O H

0Γ0Ό PKO —- ip (0 P - ipO 1-0-1 Ό PO (0 inenp

H i— * H Pina I ip X 'iP I> 1H VH I H a 3 Λ! * (0 P

h I ε ——a 'tfpi o <p vf c ε ι ο ε ιηι o <—ή

iP C '' H I O '(0 I O CO I O IHH V »I H CS H CO I H C

iplP COIP - CO I —CO - COP I - p '- H I —HO

CO O tp * —1 C H H (0 H H (0 H P 0 H in I P H H SP

λ; p a iHH h - c η—. Hioa pna o <p c h ip p Ο Ό ι — ι M3 ip iPHH iPH ip P r-ι Ό ip ι — ι 1 — I wH N C (0

PiPIO I H Η Η 3ίΗΗ ip O (0 iPiplO P-1 I H iP H

OPi η ε co CiPO C ip h Cai PPI I no ccoi h H in C H X OipH OppH oh m coin o <> - <h opco a: ό * ορό h c ε h e h na ^ pen * ιιε Hoi

O i. I H (0 ipp HHH H H P H I H P (0 H O tv H HPH

p co in.—. > <a p p co p p in p p h 0-1-1 pip poc

O I'O (0 - (0 O P tp OPH 010 PHO Ό - ip oa-H

e es o 'h iioa; oioa oioc o - h ihh tp na 3 h h H - I O CO I H HP 1—1 HPO Η Η Ο Γ- 'ip O pH I—. H a ι ι - co vin c Λίοιο JdOP achco -ipco h jp io h - h

O 'HP I' H I a ι I a P liPP Ifi CP Q ip I I Η ε 1 — I H (0 CS H H CO H in COHIO CO tp (0 ΉΙ0 IPm CO H H

ν 'fpp —-i — ι co w a' ^ aJ <'-'PP inenp mo - ^: p P

liP> 1 lOP I I H III lOtp 'PtP' C0H lipiP

p a o 'η ίο r * η ι — ι r * h co tp ε a o <(oa o <io <- p a I— *

3 H I H H

3 C I H H p HHH

λ; ηα; ηηο HtPH

PH O> 1 iP P I H H I H iP iP> 1

(0 CO Pip> 1 M H H H HIHiP C iP

-HP OP COOPiP> 1 PHipCO O CO

'-'ίο ho a' h o ip> 1 OHipp a p p jd h oohoco co oipcoc o c es o iPH PaipHP P HiPPO P o a entp pa> iA; c c. * e c p a p

OH I iP (OlOPIO 0) IOOI I I

AIO. CSCO ϋΡΟΟΟΡ P O 'H P z CS Z

id D

d E

Oho * p vo o- oo en o h <CO Ο Ο Ο Ο Ο Ο Η ι — ι

E-l Cl3 Η Η Η Η Η ι — I i-H pH

60 8948 7 mt ^ c ^ ocN ^ r-ir ^ U νοιηοοσννο ^^ νο

° »—I

11 * 11 * 11 • Oinc ^ coo ^^ if) QI ^ omcocovo ^ co ^ o

CO ίΗι-ΗιΗτΗιΗ ^ Γ-Ι »—I

l I I r — 1 |

^ -H r — i I (0 I -HI O I

• H C * H Ή I i-H £ β - "“ o.

II rH · Η »—H I Ό in I · Η · Η pH · Η · Η 4-> I -Η · Η

Ο ^ τΗ> 1 O I ** Η Η? ΙΗ H f t0 Γ ^ 1 Η pH

• CO Ή> ι Ό> ι Η m Μ · Η> ι MC> ι · ιΗ Μ μ Μ Ν Μ Η Ο Ρ MCO -1— 'MN Ρ Μ Ν Μ tn Ν Ν Μ Μ Μ 0) Ε MW Ο W Ρ μ Ρ CL Ν Ρ μ S-μ Ε · η tn-μ im Sh) 4j + j oj * j to ->>, <u + ->

C tO M μ P <0 r-, 0 C E M (OEM μ M C E P

• h μ h> i to μ m tn -h m c μ -h c a) h -h -h c co> h n cl μ N m ρ tn μ o ο) μο cl n tn u o p cl> 1--. a) a> ito pox cl oxmnpox (0 OC <0 CL> —i SL lö 3 μ M 3 μ cl c 10 3 μ μμ α) ΐ mm ρ> ι μ m <o clm (o itu μ m <o 0 ) TO Pin CLM 0) CL OP * IP Jtf MP φρλ;

CL> 1 - - I> 1 03 ι — ι CL M I M Ml IM CL ‘H I

m £ im h> (OM m μη ι μ n - m m μη

CL M U1> - <I C '-'M CL P I i — i P I M Sm CL Ρ I

I T3 * —1 O '' Q) M N I -—-- M M -— M M> 1M I '—- M

Ml M M P M M N Ml C MIC> iPM MIC

Iin 10 M - -M> i P in M> ιηΜ> ΦΉ in M

i-1 * M * 3 * W> i M M> 1 Q) i — i> -> -H> i i —'M CL E μ 1—1 * —1 M

• rlT'M IP> 1M M Ctn MIT3 PITO OMP ΜΙΤΟ

Ml M - (0 P> 1 μ -μ (0 MC ^ M (1)> M μμ · Η M Dv M

> ι · μ M μ O)> i P tn—> i I E E I E CLOC> i I E

Sm μ M> 1 M P M PM> 1 o M - o M M 3 O> i O M

pmp> i cl mojc <0 m m ρμμ -μμμ en m x ρμμ

ο)> ι μ ν ^> ι ε ο μ sh <dto> i mto> jk ρ μ α) το N

E> 1 C CM N M X 0) N M E> 1 CL N N CL OMfO E> iCL

- co o) m ρμμ clpm - jo -. nx <-ι c μ jk - cm P 0) XP> 1 0) 0 (0 M 0) μ M (0 (0 C (0 (0 0) PIM <0 (0 Μρμ o> i E 3X cl E p Μμι ο) μι pwn Μμι> ι m (0 μρ imi I mm> iPin p pm ill> iPin S μ ϋ PO) mpnm μ c> iU> po) - nnM n 0) * coi m tn ^ mi too cpm μΡΜ we cpm a) 3 n cio i μ mp 3 xo) i 1—1 oi · -> ti -μ a) · * —1

P M I II — 1 ^ iPC M M μ P f- O ON O Tf C-. M P O

M P M n M 1— '--— M> i P (0 M - M M - M i — ι l Ό M * M

μ ι C —m ρ ι m n m jk μ vo o x io o> —ί-- · μ μιοο

On-μ ι> Μ ι no ρμι o 'tn -μ -tn ime o * tn O ^ m to N p Tjti — ι-μ 3 P n Onp τοιηρ ^ mm Oinp Ρ I TO ICM IlE and w IM - (0 I - (0 I SL M - (0 o) jk to p OM μ onm οι m jk ^ μ m vr μ o NN jk · * ι <μ p ι ι E μιηρ μ ι μ Mnc ι ι> ι - ι N μ p cl ιι> ι

O - M OPM Ό »m> i 3»; * —Ι -μ n - CL 04 - CL Ό 0) «- <^ J1 - CL

3 '- -μ μ> ι (0 C> i M CL> ι ι ι -μ -—M i — ι -—- -μ ι — ι> i tn (0 M ι — ι Ei —1 m> i χ μ o xmi — i tn o- to 'mp l_jmm xioi> - mm ι> 1 CL -μ Q) XM> 1 (0 ι ι m ι> ιΜ ι> ιΜ · μ nin ι Sh ** n ι το α μ το> ιΐ ^ o ε ^ nn ^ nn op- nn μριη ιμ (0 ιριη —μ-μ ^ + j wj pn imm pn

0) - n CLJK m Φ> «—ΙΌ μ ^ o) C 0) C in N> -i w <d C

ι «m -il - tn m ι n n itno) itno) -NO itno) Τ 'O μ ^ TMn i ^ lO1 — ι vi £ CL (0 P ^ (0 P> J C M vf 10 P

- I

3 M -μ 3 CM μ JK M Ml Oi pm ι -μ N m ι -μ O m -μ ι m (0 tn -μ m N m ι -μ m mm tn m mm mp μΝ tn N OM μ n jk n jkm μ n

- (0 ON P Ν · μ mm ON m N on ON

μ otn c pm jkn otn τo tn c N Otn

OIO) MP Q) 0) N NN MP IP Q) CL MP

a jk c x en tn p jk c mc po jkc OM 10) ι IP 13 l CL) '0) ιμ 10) sk cl ^ x z mo) 2 x nx (N x n α ^ x

LK

X

X E

2 m oi n in m o- co σν

<tn —I M M M M M M M

EL U) M ι — I M M M M M M

I: 6i 89 487 tncomoo ^ o-oi U PCO ^ fCOPCPt ^ C '' o pr-I Ρ Ρ Ρ Ρ Ρ ι— (

I I I I I I I I

• cocM-tfcricocoinco a rHco ^ r ^ Ot ^ ot ^ CO p i — I i — I i— (t— <i — I <—I I — i I I I I I (0

i-l I I ι I — 1 c — 1 I — I I

Q) I—. I I — I I -HI I (0 (0 P in a-H I * H * H (D l Ή O * H I I r — l -.

• H f — III — i C4 p 4-1 r — and — l P LO I IT) ι — la> 1 Q) (0 0> 1 P <0 So> 1 'P'> 4> - 'ι S ε ι cs ω ι cw sh to ρ popcpm η-p Jd in ρ pc> - λ; · - · α) p

ια) P «. 4-10) O '(0 (0 Q) i OO GO

- 44 P P CO P P + jp 4-IO CP '-'CO

P - P S'— 1 V4 (0 P 0) '—1 (0 S "-Ή 0) 0 Ρ P

Ρ Ρ P CO P · - 'P GO pa IO 4-1 CO P <0

> iHP Q) ι-H —- Ρ Ρ I H 0) 0 ^ Cfl l-P S P

> 1> 4 P 4-IO I Ρ P N o ap ^ -, + J n (0 S> 4 atpp w ω MNP '-'to -ho> -ρ (ο wp ca

Ο Ρ P IP> ->> 4 P ip atp IP I> 4 0) O

PQJ-H Tf (0> PCP ^ <0 I JZ> 4 ^ a 44 pa ε c * - * p ι * hc * - 'p fp ή ial— * · -' ή ό ή Ή ο co ο> ps ΙΌ 0 <- 44 P ps co ρ X) ia ρ xi ia - ι p ph iho £

ϋ O P 'f p <- <(0 P -M <- P in H Ό Ή TJI> 1 o -H

03 (0 IP IP (0 I -H Η'-H> 4> 4 I> 4 H Ό cp * oh ** a) * oh s ό · pj: s op * i 0) 44 I ppp I a I PS SlP-HP PO) Iin 44 -P CO OS O-PCO OS P - Ρ Ό0) O 10 ^ 'IPI> iP P a I> iP QJ-PP ICO> 4 <0 CO Ρ Ρ XC 0) · Ρ Ό I · Ρ Λ Q) · Ρ ε HC in CO · Ρ χ: ι—> · Ρ 1-4 I · ρ '-' —- c · ρ (0 H Cp '—ι C · ρ cö Η' 'Cp 0 - ι — ι> —ι ρ * Ρ * —ι ι - '»-4 II -Ρ Ό (0 · Ρ XI · Ρ Ό (0 · Ρ Ρ> 4.0 Ρ <· Ρ · Ρ Ό Η · Ρ τ * Ρ Ρ Μ1 (Ο Ρ I ι- “» Η · Ρ ι— '· Ρ I ι — ι · Ρ HC Ρ I Ρ Ρ I> 4 * Ρ' —1 ι — I * Ρ in ρ ρ ό · ρό m · Ρ ρ SOiO -> 4 | 4 in Cn w · - cp ρ ν ι · ρ ήρ ι ρ · ρ ήρ Spa; · ρ Cp ρ 'Cp iSp I CP ε> 4 · Ρ in> 4 ε ίρ · Ρ G · Ρ IHC · Ρ · Ρ · Ρ ** + J Ρ

ι ρ INC 'S-ρ iSc ο) Ρ co Cp-PC icoc io) C

ι * -> P —'CO ^ <PP —CO Ρ 0 I SO) 0 - P 0 - COO

O -P> 1 Ρ Ρ Λ I 0) Cp -P -P and -PO -PC Ρ Λ · Ρ (0 X -Ρ (0 X) ρ hah co ρ - ε a hcop phc q) <op hpp η - p Ό ΪΡ1—> tppio P> —ι. CpPiO OJC-P PPlO ΪΡ 0) ¢ 0 Cp-P (0> 1> 4 (0 SOJi H-P10 S <0 * 31 -P P CD * sajc SH ϋ xpi cpi tpHi cpi p ό pai c-pi cfpi

co a) m Q) fl) co ίΡίΡΐη o) Q) co 44 ^ p o-pco o) aco 0) iP (O

ρ ω 'nai ctp' pai ιιε oai 4411 n c 1

0) P (0 H p * P p 0) C Η · Ρ · Ρ * P Ό * Γ '' · Ρ H I * P * P Ρ · Ρ * P P * P

+ j o) 1 — ι1— 'pac pa) · -, t4ac ^ -ip ^: ^ ic pic pcoc O P -P O O I -Ρ · Ρ 44 O O I · ρ CO - ΪΡ -Ρ ι -P 0 - -p O P -p

3 I ip ip O P * P P - 'P O P * P * P * P a Ό -' * P Ο · Ρ P O 10 * P

E4 rv CP ο ΡΙΌ O-PO PI Ό X) PI — I Ι-ΡΌ ΡΡΌ ΡΡΌ '> 1 CO Jd - -p OPCO dd - -p> —i fp (0 inpp jcCp-p Λ! 0) · ρ cd c ρ ι η ε pSp ι · ρ ε ιίρι 'cp ε ιίρε iaG - · ρ co' ί'Ρ-ρ jdSio ί> ρ · ρ '-' Pin <ncp-p ^ a-ρ ^ · ρ · ρ ιηιοΡ Cp Ρ -'ΡΡ '-Sp wQj. wPP ^ ορ ^ ap 'Ρ Cp ι Cp Cp iq) Cp iSCp icop io> Cp iPCp i i Cp ΙΌ a cp p a o-Ga p-ca co> -> c ^ Ga ipaa cppa

- I I

3 P H -P

3 C -Ρ Ρ P * P

X -P I P O I O P I

P -P -P s 3 I -P -P 31 S -P I -P

(0C0 C0-P S P - P CO P—> 4 C0-P -PP

• r-> P ddp CO P P S -Cd P 44 PP CO Jd P P> 4 '—1 (0 O ^ t P -P P S OP IPPP O> 1 O Cp P C Cp C MScdpS Cp Cp C CS Oco

cn 0) coa 0) PCpPOS ^ Cp Cp 0) Q) a PP

a ho X) '-'PC ε c cocpx) po x c OP IP I 10) 0) 10) P0) 0) l lp 10) east coa 2 n e λ (n p X3PGZ coa ^ xi

CD

D

H G

DPO P CM CO in co o

<C0CM CM CM CM CM CM CM CM

E4 [i) P p p p p p p p 62 & 9 4 8 7 ^ o- in m (N τί t-η U (HiocococN ^ inn

° »H * H * H | H i— (r-H Q \ r-H

I I I I I I I I

• ηνΟ (Ν) ηΗ (Ντίσι

Q tHiOCOOOCS ^ CTiCN

ΙΛ H ι — I H i — 1 H H rH

I I I I I

~ Il H I Sh OPI

Il · Η H H I 01 ι — ι> ί IH Q) r — i • —ή ή ie -h a: ® ci ^ o a-h

• Hio Sh -H -H Ό OI <00 <- CO -H H

HP> ί I HH I Hln PH IHQ, Sh> i> 1 CO> ι TO ΚΙ I 01 '30 n ® I Sh SH a 0) H SH' O EH HO) lp H c CO HO -PE ^ HI · - 1 lP O Sh 10

• HP HOI dl H 10 N O (N (0 Ola - H

0) Ό H-P EP --101 wH p Xr ^ H · - H

H SH Sh ® I SH H-P 10 I SH O-H HHH

«O x: Sh p m- a hio -a-oi ^ a ih shh h

PH H Sh · - I — 1 Sh p 1 —'H 1 — rH> <SH pH H

0) Ό dia -—- (O Sh Sh ή (0 ή H 1 — i Sh H SH P

ai h Eo li h a ip ih ia oi h h

H l / l H HP ^ in <0 i-. r? SH - <3 <SH 'S'O Ed) H

a 'H TO TO 1' (OH ia I Sh Ip H EC

Ι ^ ίΗ I> i Oh (OH O'— 'O-P oa H H 0

Hip 1D £ H pi—- '-ΪΗ H PH Pd) H P. H pH P Xl

I - '-P -H H TO O H> iH TO H Ό 01 H O -H H> iOP

- HH NOH SHH HCH ShSH Sh (0H ShHH C 3 (0 HHC w | H £ 0 SH 0) H £ SH Är-iH JO Sh H OJHÄ H Si OI in P HO) Sh H p HH hhp H>, phhi Sh Sh Λ -31 Ή TO HC —- H TO 0) TO HH TO CH whn

Sh C P · - ‘h i (0 HHH ιοί i Sh h ι h h i P i

ιαΐ (0 ή ι c in p 0) h C in ia h in> 1 G in m c ^ h H

inPil ι <—> O 'Sh H Sh O ί — .η' CO '-PO' - • '-' C I H I ^ H JO ^ a (0 Sh Xl ^ H H TJI H Xl ^ (0 X)> —1 I H

Hpcn I H P II—. P-PP I H H I01P IpP in H

0 O ι - Sh (0 '-'H 0) 0) 10 - Sh P - H ® -'OI® * - Ό cooh h sh a: h h a e a; h Sh -p h ® a: h a a; i i h

a: H c H-PI HSH H H I H C H HPl H H I H N E

oash snoin Sh Sh apn sh h e> id) n Snan hi h

HHH ShOII ShH I O I ShOIO> <a I Shii Sh-- ’P

TO TO Ό C (0 H CO) H3H C-PX1 CH H CH H Sh h Sh 01 hr al r-ι c I ι hc αΐιορ oiac oiic hha reduced hhh sand hhhhp π) m ii hhh OISh · -> H H H H H HH HHH H 0) XHHHHHHE (0 C <Np PSHO phh Sh P Ό pai PIT3 pho ihi QI ^ Sh OShh oh h Sh hh onn o - ho Sh h in oi in

Xl I a O C E OShh O ~ E Oai oh E O> 1 E ι CO

01 I (η ι · “> HHH H P 0) I H H I H HHH H H H O ® H

p niio asoip asc + j -pnp ajhc a: sh p ajoip p.-.---

O 'Ή | H H HHH C --1 H I H H H E 'O H O

e h h m ό ίο a o ai e oiia το - h o e a to h a shhh

H '—'— I' lp. — ι IHO Λ N ι — ι IHO I O '—1 I H' - 'xl Sh O

ι Sh h in oi io ιηιοχι ι ι ® in h h in xi io in> i <o h> i to Sh -—- 'ai' PP ^ Oi 'ShE' P ι '> h ι Ό C H

'- • PO nh in NO® ^ P in co Sh H (M®in n C m ih® h oi hwas' z ax -—1 to '^ ep ^ a;' - oi »noip ie / ίο iih ι h ι ι ι — ι ι dl Sh ihh ihh * h> tf®0) [Η HI — I [—an - ^ 1 JC '—1 C— H Ci NHU [HWI — I oa

3 H I H I

3 C ι Sh H HHH

Ai h Oi Sh Sh i hhh h ph 01 in -PH h Sh h Shh Sh Sh ®0) -PI Q1HH O 0) ShShSH Sh Γ-l-P CH E Sh Sh 0) Ai H CSh 0) 0)

- ® 0) 0 h Sh Sh -P Oh (0C -P -P

P X10) TO G -P C -P Sh PO C C

oi oi ia; h ιοί o οι oish 3x1 o oi a n O H in H E Xl EC HP J3 Xl

OH 'H Sh' H I I I Q) I ® I I

«A htOShinh Z Z ΓΊ h (NA; z z & o

-1 E

S3 H CO en O H (N n ^ tn <o) <n (N n n n n n n

E- * W H i ~ l 1 — I H H r — i H H

63 89 487 σ> vo · ** σ »U o x> tn cn ° r-l H i— (t — t

I I I I

• 00 ^ (N 0-

Λ t'- VO IT) (S

(/} iH r * H r — t r — I

I-I

H I I

i — I I I — i I I — v I

> 1 r — I -rl · Η -HI I I- '

> 1 · Η rl ^ rt O μ H

CH> 1> 1> (H φ H

• rt> (S Ql O O.> 1 cn>, + j> - <C co -h> λ μ ca> to h μ Acma) ωι co to ta) M ft tom -! -> M hha) r ^ -H (0> 1 I - 'a * rt r — t · ι-1 <- (lt a * rt rl f — t H r — t 1—1 Q) r — i -rt r-1 a> ι · Η o ah I> 1 μ> 1 rH "rl r — I> 1? 1 rt 4-> + J CO a> i> i4->

I φ H -rt (Λ I> 1 + -> CU

- EC Cfl-P h c Φ E

• rl -r10 + J (0 I φ E -H

H μ X) (0 1-1 H H μ

> i0 It μ ίμ H Ό HO

> iD (H Q) and H H H ίμ 3

PHJ! a- ~> ϊμΗ E> iH

Φ H I H -H> 1> 1 (0 C <4-1 • rt · Η Γ0 an P S * rt QJ * rt co μ ι ι ίμ φ μ co h μ

>; + J-r (r- (S E d) X -r-μ H

0 - C IC Ή E O IttC

μ I -rl -HO) H H X) I H

ΰη · Η h <w ίμ μ μ> -> γο-h> -f1— 'Ό> 1 .—- -rl> (0 (0 ^ <Ό £ I -rl> 1 H Ό C 3 X 1 I - rl

IC-'E -PH -H Q) HI <* C- E

N I -rt Φ> i E (W W n II -H

- -hae> i (0 - · -hio ^ μ li — t ίμ I μ * HI 1-t Ή μ · Η> (ίμ a ^ φ co ^ μ c ό ha 1 -1> (r — I -— g XI — I —- · Η> 1> 1l-1 μ (0 I— '-rl 0' -n I -rl x;> (to

1 (1) 1 I μ X) I fOd -rt + j I

i E m Ο μ -μ d Din II - 13 (0 I I E 1 (0-

0) ooh oha; o h sincl

μ μ I I— μ M-ι I μ I μ -r-.u_j Ο Π ^ Ο Ό H 00 Ό r ~>>, · μο

3 ίμ H H> i 1-1 I> | Ha IHH

H x: H O X! 4J-rl XlHr-. O ίμ O

h> co · μ —-rc -Η> ιίθ e co Ό ^ μ Ό I · Η O> ii OC μ I μ (0 I co η I μ to μ -μ ίο uo Φ μ m> - «Ό md - χιιομ - C0> i -IH - (/) Η ΐμ> (m · ίο aoe ^ (0 <—I coooa

3 H

3 C I H H

X -H H H H

μπω η ίμ ρμ <o co XH> 1> 1 • ο μ ο fx co to - (0 μ Η> ι μ μ μ το Η μ cc CNO)> 1> 1 <D Φ Φ a χ:> 1 ε ό λ ο η ι μ ι ι ι X a 2 Φ 2 2 2 * 2 J Ε! 3 Η <Ω f- 00 σ> <(0 ΓΟ 00 00 C0 Ε-> ω η τ — ι t — tr — t 64 69487

Example 140 4,5-Dihydro-4 - [(4-methyl-1-piperazinyl) acetyl] -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile, dihydrochloride 5,5-Dihydro-4 - [(4-methyl-1-piperazinyl) acetyl] -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3- the carbonitrile was dissolved in hot ethyl acetate and treated with dilute alcoholic hydrochloric acid. On cooling, a solid formed which was collected, washed with ether and dried.

This solid was heated to boiling point in 60 mL of acetonitrile, filtered and the filtrate was diluted with 60 mL of ether and placed in the refrigerator. The solid was collected, washed with ether and dried to give 600 mg of the desired product, m.p. 198 ° C (completely).

Following the general procedure of Example 140 and using various organic and inorganic solvents, the products of Examples 141-158 in Table 3 were obtained.

i ..

e5 894 8 7 VO CO CS (S (N n O 'O (s es es esvOTjifo ° es es es esescses II iiiii • Τί VO O ooh in a es es es es no Ti en en rs es es escseses ii ή i I III r ** i | · Η I ri

I — I O i — I O Ή O Ή O -H

Hl a H P S 'I I H P Si H I Hl Ή O Ή H H Ό rP d)' ^> ιΌ> ι O ΙΟ -H tP 0

> ιΗΌ a> i> i C H H H tp> i P (0 'I Ό> i rH

> iO-H I! P JO Ή - "H H C JO d) P H Ti O H CO -H

C (I) ^ rl CH W-H-H | P d) H lllfflO I H P H (0 Ό

• H -PO I d) Ό -P H H tp H Ό (0 P H m 0 O CO P H

co (0 h> -, m <o pp ρ c r- 'i> ip -hmhp ιο ρ pp and · η - * p S p -h-Hv haohp and ra po (Q ΪΡ OH -H -H <UPH (OH -HH> -i H S '<0 OP> irl pap ϊρ hh ante p? Ph sp h and Sp ρ ρ od)' —ό ippp-H -neo ra Sp h Sh op pp ό an o an pp p Pph a -h jo pph c> iP tu a Pp · η · ηρ • HH O d) PP Ipp Q) Q) P · Η> ι Ό (0 r—> JO QH Ό a pp h ε o) -p ^ 0 (0 a ε p cnc> i to · η-hi>, pp i no e -h '3 and -hhh p <u jo h ό h pp jo

H C -H-HC '-'Hl a P C (0 VH H Pp 1C

Id) 'H P 0 -HIW00 100 pm ^ H Pp' ^ Q)

m H -H> ι O O H -H I H 3 J3 0) H -H pp C H -H H -H

Ή <—I Pp 3 P ri P Ή IHP a * —IH Sv d) * —I H 'H

H * H * H C H (0 riPC '> * P ίΟ · Η Pp · Η C H H H H

> 1H -H Q) lp JA -P wH -H -H AND a ΪΡ -H -H m -H! P H -H

Pp Si P lp -Hl Oi -H H P I IPP tn -HP C Pp P

p Sv p h p en Eero pppeo hop php h Pp p d) P -H tnPI 'H> 1 ^ 1 IE Ή (0 Si H ΌΡΗ

E d) c and ^ -h -h ie pih ^ .pC pppc Hd) C

• h e o oic hcv-h to bring h po <upo eeo

H H JO Ρ00Η Slip E ν-Ή H O JO a <U JO H H JO

fP P P d) 1H> i 0 PP ^ i h Pp 3 P H EP PPP

PpOiO E i Ό GP a HM3 PpH (0 anto Pp O (0 c 3 ji itp-H o ό ι-i HiH cp a; ip and aoa: (Uhi eniE * p Pp <0 So E 0) hi Hoi ihi ipipen '-rn.p HjOi PpP-h ippcn i 3 en es h en

d) - H I 1—1 H P p H in C Ό P H P I H H I wd I

P lp H I H Pp O-ο> (UPpPP pwH HP H lp H

0 "Spc ^ ppa o i h pc a oic pp h c Ti p c 3 -— 'h p-- Pp r — i h m i — i h -h r — i oen-H> i p h ^' -r h

E-1 WJI-H -rP (0 Λ Ό P Ό (0 H i — 1 H tnPH P-1 I H

Ι00Ό ld) l h vf H -H oil A I O AND Ό Ι00Ό

Ti i — i -h Ti tn in Ό i o Ό o in m h tp h d) i h Ti / h

i i E i (0 'i --n en -h Hvv Ό i E JOenE iiE

ONH O Ή H VOHPP A vf h 10 h o -—- H OC ^ H

plp p H · —1 * H <0 O lii — 1 v ^ pp HIP plp

Oh> i oho os Pp P h en ^ o 'Ό Pp JA n- Pp ό m pp tp-na pp Pp h pp s <and w-hh en pp a ppia Si ha jo h> —i jo> 1 ο h • -pao * —i höh wjOr-> tnor-- jo h H Pp (0 HC to Ό I d) <—lp ΙΪΡΙΟΌ IH (0 IP (0 H Pp ra

Ό ίΡ I Ό H P H Ί1 KIHO vf SPH Ti Ό I 'ί-ΌΙ O S I

i pm I to (0 P ή <ο, _ι: ρ -vp epi in ^ ppm i pm ind) 'inppo SC Hl) po -nin' <—> jo in d)> 'tO H v O SH IH Si HI (0 SH l 'H IHH' (OH Tf (0u_i τί pa JA ^ HC Ό τί ra a JA TiTjii — I Ti Ό 1 τί ra -

•B

AND

AND

1 p (0 0) 3E (po ov co esTico

Ph h es h h es es es en d) to a o) o

PA

PA H 03 JA • J I JA

Dhph es tn τί in vo p.

<to to τί τί Ti Ti Ti Ti Ti

H U E H H H H H H H

ee 89 487

10 Cv tH 00 Cv CO

O in oo (n in en o

o (N (N es CM H CM

I I I I II

• M1 in en in in in a in oo h in en o

CO CM (S 09 O '! M (M

i il i i I i — i I w i — i I Ή I r — i

Il I O -HO -H -H O CO P -H

Ή CU (Dll ·! I H tl HH h PCD Hl

t M-l (Oi — i Ό iv b ^ tJ Cv Cv Ό (OM Cv O H

^ V - H 10 -H> 1 -H S> 1 M> 1 Sh O

H H H 1-iHX; H e JC G C £ Φ Q <I CO H

H H H H ^ * rl Si Q) Ή Ή 0) Ή a '0 H (0 M

Cv Cv H H NO CV P TD (OHO H-H Cl CO H O

Cv CV M Cv C G - p ^ v aH IQ p (0 H

CPP 5h <D H H * (OH- I Cv Cv (0MJ *

H <D H CP H 10 H H M H H H Si .C M Si O

CO eeh - hp Sh il) Sh ieha) am p-πο co-hh m Sh q, Sh --va> td a - <ο <0 U £ 3 PHHMPH -HP -H HP HH>, momo cv m <d <up am hh - - an .e 0) 3 (0 h> iP aep ι ε p cv hhi cm h

an X 0) P H H H H H H H H H H SO

• h p i a a) e a m e i m e p> i-h ic a H 00 H E 0 100 I—> 0 0 0)> i H -—- Q)

IMI a-Hi3 H3X) H DO E P M H PH

HP H I M M I H M H H M H Q) P H '-' H

I —- C H O (0 i — i P (0> i P (0 HEH Jv H H

1—1 I H I 3 X H H X> iH Ä> iH C Cv H H

H 00 H - H I H M I P M I Cv M O P fv M

Hl —'TD H P 00> iP00 dJPOO C O £ 3 0)> iP

S I h H H I Sv I E vv I 0) 3 M H P H

Sitvg> i M H P I H - I H P H (0 HQ) C

P I H> i P C 0) 00 C H 00 C w H. *> I E O

0) O M P - 'H E * - * H H 1—1 H I H I H, 0

E M> i 0) 1 H - I H S 1 H M1 M 00 P M M

- TD a HOTO H Cv Ό Cv Cv Ό i — i P I 0) 0 (0 H Si i — i H 1—1 H H I H C I H Ή -— H E 3

HXliO CM I E> 1 O E Q) OE lie I H I

Cv H I Sv Cv H> i M H P M H 00 H H H O0

0) CvtD m CO i M COM H Ό M i —Ή wHI

P Ci - X O Si Φ Cv Cm M> 1> 1 O i Ό IM H

o o) m h o) m a p .e a oo a mcv-h m «pc

3 P -1 — i .CXJi — i H Hi — i 3 H i — i O I E 1 —'-- 'H

E-ι HTiO 0 Cm (0 MO ί H Ό (0 Svi-VH vjih M I H H H £! I Was PII ÄH M Ι0ΟΌ O'— i O Ό Ä h in Omin imm (0 h Cm · —ή

0 H CO H> i Ό - H - - M1 - - Mpva IIE

H H P M CO I H ϋ O H -vii H P S ^ OCvH

JC s® o vinvI I l · —I OT I · -> 0) P (0 MlM

1 SMH l - O - O H - O P 0) I Oi —'Cv ^ acv ^: (N M1 H -v H H Λ H H I 11) 10 CvHa

vv 0 a 0 vv I 0 Ή '—i H 0 H i — 1 HO H Cv (0 -H £ 3 H I — I

> —I M I— 'M I HIOO I Cv CO Ό I> i (0 Ό -i — i H TD H s ID

I a H TD M1 H PH ^ SiP H M1> i P H lO H> -> H TD> i I

00 OH Cv · —i H (0 M vv p (0 M vp 10 M - HOM ipm vvcoSuC wNM0 vv q) m 0 vvQJMO in Cm h 0 in a) - i Ä Sh iCvCvh icoCvh icoCvh -CvOh - co h 'jo co 'J p aii ^ o a. * <f oaci: ^ e en λ: ow 3 3 HXXP. *

(0 l M

rt CO 0) H

w36m h σι o m in M h oo ^ oo ^ ^ 1 oo 0) co a Q)

O

X H D ϋ O I X

D H M CO en O H (N 00 <co a) m1 M * m in m in H ω E h h h h h h I: 67 89 487 σ 'o in cm cs U cm in ^ m σ'

° CM CM (N Ή H

I I I I I

• 0- 00 00 O O

a CM rf -M1 \ o σ '(Λ CM CM CM i — I I — 1

I I

I I — I <-. I II

H (0 II (0 —I MO

73 I H H II -HI 0 I M

I in iC H in h 0 a i — '73 in v H H 73 - r — I · Η · Η '• ι — I h h ir — I ^ ίΟή a * —I jc,

'M1 1—'> i 73 in> -> C W 73 I CM H

10 CMH - Ο Η -P H H CN73

-—IH + Jg ΊΉ (Λ <0 M I C

• MO α) · Η 10 -P M 0 --0) - H CO * M ε M »- 'CO (0 Η · Η Ή · Μ

Cm -p τ3 ι> ι η -μ Maj * η ^ h

> 1 (0 · Η · Μ * a H <0 H 0) r-, Ο> ι -Η -H

P M M W I—. Cm M 73 a-HM Cm H H

0)> 1 0 ^ (0 Si Cm H MHO -P CM M

co an ii -pap a Cm Cm o) Si-p (Or - .. * h * m Q) ι — ι O I> ι £ ε · Ρ · Η

· · Ή 0 I - W Ή H H C H 0) C

• HHM Ο Ή (0 H JC Id) »Η ε 0 H CM 73 M> —ι -> 10 —-Η Η> ι · Η X3

S '^ 1 ^ 1 730 M> t Μ · Η - rH Cm M M

S C .C CM H H CO H H H COO

Cd) -H £ 0-H Si 0) CM> iH-H 0) 3 J *

H M O -HCO 0.3 i> iM £ S Cm M M H I

CO ~ 73-P-M C - -P S -P - MH 00

-PH- I (0 Μ -Η · Μ * Q) -P -M I -rH I

(0Η-Η inMO COH-M ε d) C ^ M H

M> irH -> i H -P Cm H -MHO '—'PC

0) Cm H nji a J * (0 CM Η ΗΜΛ ‘« M - · * M

a-P-M I ι — ι 0 M-P-H JmMM II -M

H 0) M ~ HM 0) 0) M SO IC ^ 00 73 a ε -p mho a ε -pc 3 j * ii-m I * H * HH ^ i -rl "M" MO rl I Ή O '· ε

Ή M C Si S .C aMC H H 00 H I M

d) 100 S -P H 100 w-H I Si '-' M

-PM 3d COO H 3d IM-H> 1 -H> i O HHM 0) CO I Η Μ Ί1 MC -PHa 3 CM H (0 H <0 - H 4H (0 <—ιι -ΗΗ) Oi - > EH> 1 -HX -H - -HH -HX ή I · Η ε> 1 (0

-P M I M-MH Cm M I 100 73 I -P I

3 -P oo OHH Cm P oo ή in d) m JQ- ^ I Ο CM H o ^ -l I I ε I CO -

O I H H S M C0I * H 0 0s M 0 (0H

H 00 C J * C P P00C MlM Mi - "- '

J * 1— * H H -M H C 1—1 H 73 r-M Cm Ό h O

Cm i -h 73C0C d) i-H Cm-Ha CmHH

C0O73 Ι-ΡΟ Λ 73 dHn £> 1 O H

ι ι h in ίο Λ ι ι h -H Cm (0 -h 3m co 73

Ο ε -MM M1 O E 73 Cm I O C MM

• —MH CM (U (0 —- M H I P in I H <0 M

> - * 73 M - aj * 1-173 M in 0) - in ill M O

l ^ i ^ i I HI l ^ i ^ i - CO Η -M> iH

ifd a t> a co Mid a ^ co> - m io acc 3

3 H X X P X (0 I M

• r-) CO d) CM 0- CO σ 'CM

- 3 ε m CD CO vO IN

M * H 00 dl (0 a d) o X

X -H O X J I X

Dm M m in vo r- co <co 0) in in in in

Eh ω ε H H H H H

68 8 9 437

Example 159 4 - {[4- (2-Furanylcarbonyl) -1-piperazinyl] acetyl} -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5 -a] pyrimidine-3-carbonitrile, 5 hydrochloride 2.2 g portion of 2-furanylcarbonylpiperazine, 4 g 4- (chloroacetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile and 1.6 g of sodium carbonate in 60 ml of toluene were reacted as described in Example 79 to give 3.3 g of base as a hygroscopic solid. This solid was dissolved in ethanol, 10 ml of 3 N ethanolic hydrogen chloride was added, and the mixture was stirred. The solid was collected, washed with ethanol and ether and then dried to give 1.2 g of the desired product, m.p. 240-243 ° C.

Example 160 4 - ({4- [2- (dimethylamino) ethyl] -1-piperazinyl} acetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5- a] pyrimidine-3-carbonitrile, dihydrochloride

A mixture of 1.7 g of 2-dimethylaminoethylpiperazine, 3.8 g of 4- (chloroacetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [11,5-a] pyramidin-3- carbon-carbonitrile, 1.2 g of sodium carbonate and 65 ml of toluene were reacted as described in Example 79 to give 3.2 g of a solid. The solid was reacted with ethanolic hydrogen chloride to give 170 mg of the desired product, m.p. 229-231 ° C. Example 161 4,5-Dihydro-4- (1-piperazinylacetyl) -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyramidine-3-carbonitrile

A mixture of 1.56 g of 4,5-dihydro-4- (iodoacetyl-35-yl) -7- [3- (trifluoromethyl) phenyl] pyrazolo] 1,5-α] Pyrimide: 69 6 9 4 8 7 Mididine-3-carbonitrile and 1 g of piperazine in 50 ml of dioxane were heated in the presence of argon and stirred at reflux for 18 hours. The reaction was cooled, the solid was collected, removed by filtration and the filtrate evaporated. The residue was crystallized by trituration with ether to give 1.3 g of crystals. These crystals were heated to a solution in 10 ml of ethyl acetate, diluted with 10 ml of hexane and filtered. The filtrate was cooled to give a solid which was collected, washed with hexane and dried to give 400 mg of the desired product, m.p. 151-154 ° C.

Example 162 4,5-Dihydro-4 - {[4- (phenylmethyl) -1-piperazinyl-15-yl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine- 3-carboxylic acid, ethyl ester, dihydrochloride

A mixture of 2.065 g of 4- (chloroacetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] -20 pyrimidine-3-carboxylic acid ethyl ester, 535 mg 1,8-Bis (dimethylamino) naphthalene, N, N, N ', N'-tetramethyl-1,8-naphthalenediamine, 2.88 g of N-benzylpiperazine and 100 ml of dry ether were stirred at room temperature overnight and then the mixture was filtered. . The filtrate was evaporated, the residue was dissolved in 300 ml of ether and 1 ml of concentrated hydrochloric acid in 50 ml of water were added. The solid was collected to give 845 mg of the desired product, m.p. 228-230 ° C.

Example 163 4,5-Dihydro-6-methyl-4 - {[4- (phenylmethyl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [ 5-a] pyrimidine-3-carbonitrile, dihydrochloride

Mixture of 3.4 g of 4- (chloroacetyl) -4,5-di-35-hydro-6-methyl-7- [3- (trifluoromethyl) phenyl] pyrazolo [70-a] pyrimidine -3-carbonitrile, 1.1 g of sodium carbonate, 1.7 g of N-benzylpiperazine and 115 ml of toluene were reacted as described in Example 79 to give the base form of the product which was converted to the dihydrochloride salt by the method of Example 160 to give 2, 4 g, m.p. 204-206 ° C.

Example 164 4,5-Dihydro-6-methyl-4 - {[4- (2-pyridinyl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5- a] pyrimidine-3-carbonitrile

A mixture of 2 g of 1- (2-pyridinyl) piperazine, 2 g of 4- (chloroacetyl) -4,5-dihydro-6-methyl-7- [3- (trifluoromethyl) phenyl] pyrazolo [1.5 -a] pyrimidine-3-carbonitrile and 60 ml of acetone, heated at reflux on a steam bath for eight hours and then evaporated. The residue was stirred in water and the solid was collected. The solid was dissolved in dilute hydrochloric acid, filtered and the filtrate basified with dilute ammonium hydroxide. Solid 20 was collected, washed with water and dried in vacuo to give 2.67 g of the desired product, m.p. 132-134 ° C.

Example 165 7- (3-Chloro-phenyl) -4,5-dihydro-6-methyl-4 - {[4-5 (phenylmethyl) -piperazinyl] -acetyl} -pyrazolo-1,5-a] pyrimidine-3-carbonitrile, dihydrochloride

A mixture of 3.1 g of 4- (chloroacetyl-7- (3-chlorophenyl) -4,5-dihydro-6-methylpyrazolo [1,5-a] pyrimidine-3-carbonitrile, 1.1 g of sodium carbonate, 1.7 g of N-30 benzylpiperazine and 115 ml of toluene were reacted as described in Example 16 to give the base form of the product which was converted to the dihydrochloride salt according to the method of Example 160 to give 1.3 g, mp 201-203 ° C.

7i 89487

Example 166 7- (4-Chloro-phenyl) -4,5-dihydro-6-methyl-4 - {[4- (phenylmethyl) -piperazinyl] -acetyl} -pyrazolo [1,5-a] pyrimidine-3-carbonitrile, dihydrochloride Mixture with 3.1 g of 4- (chloroacetyl) -7- (4-chlorophenyl) -4,5-dihydro-6-methylpyrazolo [1,5-a] pyrimidine-3-carbonitrile, 1.3 g of sodium carbonate, 2 g of N-benzylpiperazine and 130 ml of toluene were reacted as described in Example 79 to give the base form of the product which was converted to the dihydrochloride salt by the method of Example 160 to give 1.5 g, m.p. 238-240 ° C.

Example 167 7- (4-Chloro-phenyl) -4,5-dihydro-4- (1-piperazinyl-15-acetyl) -pyrazolo [1,5-a] pyramidine-3-carbonitrile, hydroiodide salt

A mixture of 5 g of 7- (4-chlorophenyl) -4- (iodoacetyl) -4,5-dihydropyrazolo [1,5-a] pyrimidine-3-carbonitrile and 3.15 g of piperazine in acetone was heated -20 at reflux for six hours, then at room temperature overnight and evaporated. The residue was taken up in water, evaporated and recrystallized from ethanol to give 3.27 g of the desired product, m.p. 231-232 ° C.

Example 168 4,5-Dihydro-6-methyl-7- [3- (trifluoromethyl) -4 - [(4 - {[3- (trifluoromethyl) phenyl] methyl} piperazinyl) acetyl] pyrazolo [1, 5-a] Pyrimidine-3-carbonitrile hydrochloride A mixture of 1.83 g of 4- (chloroacetyl) -7- [3- (trifluoromethyl) phenyl] -4,5-dihydro-6-methylpyrazolo - [ 1,5-α] Pyrimidine-3-carbonitrile, 1.5 g of 3- (trifluoromethyl) benzylpiperazine, 2 g of potassium carbonate and 60 ml of toluene were reacted as described in Example 79 to give the base form of the product, which 72 89 4 8 7 was converted to the hydrochloride salt by the method of Example 160 to give 1.78 g, m.p. 195-198 ° C.

Example 169 4 - ({4 - [(2,6-dichlorophenyl) methyl] -1-piperazin-5-ylacetyl) -4,5-dihydro-6-methyl-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile, hydrochloride

A mixture of 1 g of 4- (chloroacetyl) -7- [3- (trifluoromethyl) phenyl] -4,5-dihydro-6-methylpyrazolo-10 [1,5-a] pyrimidine-3-carbonitrile, 1 g of 2,6-dichlorobenzylpiperazine, 600 mg of potassium carbonate and 100 ml of toluene were reacted as described in Example 79 to give the base form of the product which was converted to the hydrochloride salt by the method of Example 160 to give 1.66 g of product, m.p. 252-254 ° C.

Example 170 4- (Chloroacetyl) -4,5-dihydro-7-phenylpyrazolo [1,5-a] pyrimidine-3-carbonitrile

The above compound is prepared from 7-phenyl-pyr-20-azolo [1,5-a] pyrimidine-3-carbonitrile by the method of Example 64.

Example 171 4,5-Dihydro-4 - {[4- (phenylmethyl) -1-piperazinyl] acetyl} -7-phenylpyrazolo [1,5-a] pyrimidine-3-carbonitrile

The above compound is obtained from N-benzylpiperazine and 4- (chloroacetyl) -4,5-dihydro-7-phenylpyrazolo [1,5-a] pyrimidine-3-carbonitrile by the method of Example 79.

Example 172 4- (Chloroacetyl) -4,5-dihydro-7- (3-methoxyphenyl) pyrazolo [1,5-a] pyrimidine-3-carbonitrile

The above compound is prepared from 7- (3-methoxy-phenyl) pyrazolo [1,5-a] pyrimidine-3-carbonitrile by the method of Example 64.

73 8 9 4 8 7

Example 173 4,5-Dihydro-4 - {[4- (phenylmethyl) -1-piperazinyl] acetyl} -7- [3-methoxyphenyl) pyrazolo [1,5-a] pyrimidine-3-carbonitrile said compound is obtained from N-benzylpiperazine and 4- (chloroacetyl) -4,5-dihydro-7- (3-methoxyphenyl) pyrazolo [1,5-a] pyrimidine-3-carbonitrile by the method of Example 79.

Example 174 3-Chloro-4- (chloroacetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine A dose of 13.3 g of 3-chloro-7 - [3- (trifluoromethyl) phenyl) pyrazolo [1,5-a] pyrimidine and 7 g of sodium cyanoborohydride in 150 ml of acetic acid were reacted as described in Example 64 to give 6.7 g of 3-chloro. -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine.

A 4.3 g portion of the above compound and 5.8 g of chloroacetic anhydride in 35 ml of toluene were reacted as described in Example 64 to give 1.5 g of the desired intermediate, m.p. 116-119 ° C.

Example 175 4- (Chloroacetyl) -4,5-dihydro-7- (3-methylphenyl) pyrazolo [1,5-a] pyrimidine-3-carbonitrile This compound is obtained from 7- (3-methylphenyl) pyrazolo [ 1,5-a] pyrimidine-3-carbonitrile by the method of Example 64.

Example 176 4,5-Dihydro-4 - {[4- (phenylmethyl) -1-piperazinyl] acetyl} -7- (3-methylphenyl) pyrazolo [1,5-a] pyrimidine

According to the procedure of Example 79, N-benzylpiperazine is reacted with 4- (chloroacetyl) -4,5-dihydro-7- (3-methylphenyl) pyrazolo! With 1,5-a] pyrimidine-3-carbonitrile. The title compound is obtained.

74 89487

Example 177 4- (Chloroacetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenylpyrazolo [1,5-a] pyriroidin-3-carboxamide 5 A mixture of 2 g of 4- (chloroacetyl) ) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile and 20 ml of concentrated sulfuric acid were stirred at room temperature for two hours, then poured into ice water, stirred and filtered. The product 10 was washed with water and dried, yielding 2 g of the desired intermediate, m.p. 174-176 ° C.

Example 178 3-Bromo-4- (chloroacetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine From the reaction of 10.0 g of 3- bromo-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine (U.S. Patent 4,178,449) with 4.59 g of sodium cyanoborohydride in 130 ml of acetic acid at 25 ° C: for 5 hours, 4.4 g of 3-bromo-4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine were obtained as yellow crystals, m.p. 101-103 ° C.

A 2.5 g portion of the above compound and 3.0 g of chloroacetic anhydride in 40 ml of toluene were reacted as described in Example 64 to give 0.8 g of the title compound, m.p. 128-130 ° C.

Example 179 7- (3-Chloro-phenyl) -4,5-dihydro-6-methyl-4 - [(4 - {[3- (trifluoromethyl) -phenyl] -methyl} -1-piperazin-30-yl) -acetyl] -pyrazolo [1,5-a] pyrimidine-3-carbonitrile

The above compound was prepared by reacting 4- (3-trifluoromethyl) phenylmethylpiperazine with the compound of Example 75 according to the method of Example 79, m.p. 133-135 ° C.

vs 39487

Example 180 4,5-Dihydro-4 - ({4 - [(3-trifluoromethylphenyl) methyl] -1-piperazinyl} acetyl) -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5- a] pyramidine-3-carb-5 bonitrile

The above compound was prepared by reacting 4- (3-trifluoromethyl) phenylmethylpiperazine with the compound of Example 64 according to the method of Example 79, m.p. 178-180 ° C.

Example 181 7- (2,5-Dichlorophenyl) -4,5-dihydro-4 - [(4-phenyl-1-piperidinyl) acetyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile

The above compound was prepared by reacting 4-phenylpiperidine with the compound of Example 72 according to the method of Example 79, m.p. 199-200 ° C. Example 182 7- (2,5-Dichlorophenyl) -4,5-dihydro-4 - {[4- (phenylmethyl) -1-piperidinyl] acetyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile

The above compound was prepared by reacting 4-benzylpiperidine with the compound of Example 72 according to the method of Example 79, m.p. 157-158 ° C.

Example 183 7- (3-Chloro-phenyl) -4 - ({4 - [(3-chloro-phenyl) -methyl] -1-piperazinyl-acetyl) -4,5-dihydro-6-methyl-pyrazolo [1,5- a] pyrimidine-3-carbonitrile, dihydrochloride The above compound was prepared by reacting 4- (3-chlorophenyl) methylpiperazine with the compound of Example 75 according to the methods of Example 79, then Example 140, m.p. 208-210 ° C.

35 76 59 48 7

Example 184 4,5-Dihydro-4 - {[4- (2-phenylethyl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile , dihydrochloride

The above compound was prepared by reacting 4- (2-phenylethyl) piperazine with the compound of Example 64 according to the methods of Example 79, then Example 140, m.p. 235-237 ° C.

Example 185 7- (4-chlorophenyl) -4 - ({4 - [(3-chlorophenyl) methyl] -1-piperazinyl} acetyl) -4,5-dihydro-6-methylpyrazolo [1,5-a] ] pyrimidine-3-carbonitrile, dihydrochloride The above compound was prepared by reacting 4- (3-chlorophenyl) methylpiperazine with the compound of Example 77 according to the methods of Example 79, then Example 140, m.p. 250 ° C (by sintering).

Example 186 20 4 - ({4- [bis (4-fluorophenyl) methyl] -1-piperazinyl} acetyl) -4,5-dihydro-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5 -a] pyrimidine-3-carbonitrile, dihydrochloride

The above compound was prepared by reacting 4-bis-25 (4-fluorophenyl) methylpiperazine with the compound of Example 1 according to the methods of Example 79, then Example 140, m.p. 255-258 ° C.

Example 187 4,5-Dihydro-6-methyl-4 - {[4- (phenylmethyl) -1-piperazinyl] acetyl} 7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine -3-carbonitrile dihydrochloride

The above compound was prepared by reacting N-benzylpiperazine with compound 35 of Example 73 according to the methods of Example 79, then Example 140, m.p. 204 - 206 eC.

77 89 4 8 7

Example 188 N- {3- [4- (Chloroacetyl) - (3-cyano-4,5-dihydropyrazolo [1,5-a] pyrimidin-7-yl] phenyl] acetamide

A mixture of 7.0 g of 3'-acetamido-3- (N, N-dimethylamino) acrylophenone and 3.3 g of 3-amino-4-cyanopyrazole in 100 ml of acetic acid was heated to reflux. eight hours. The crystals formed on cooling were filtered and dried to give 7.4 g of N- [3- (3-cyanopyrazolo [1,5-a] pyrimidin-7-yl) phenyl] acetamide, m.p. 254-256 ° C. This was reacted with sodium cyanoborohydride (14.8 g in 50 ml of acetic acid) to give 3.0 g of N- [3- (3-cyano-4,5-dihydropyrazolo [1,5-a] pyrimidine-7 -yl) phenyl] -acetamide, m.p. 251-254 ° C. This was reacted with chloroacetic anhydride and sodium carbonate in toluene as in Example 66 to give the title product.

Example 189 N- {3- [4- (Chloro-acetyl) - (3-cyano-4,5-dihydro-pyrazolo [1,5-a] pyrimidinyl) -phenyl-N-methyl-acetamide to 33 g of 3'- acetamido-3-dimethylaminoacrylophenone in 170 ml of dimethylformamide was added 6.8 g of 60% sodium hydride, followed by 40 g of methyl 25-iodide, to give 10.5 g of 3 '- (N- methylacetamido) -3- (N, N-dimethylamino) acrylophenone, m.p. 129-131 ° C.

This was reacted with 4.60 g of 3-amino-4-cyanopyxazole in 150 ml of acetic acid at reflux for 16 hours to give 7.4 g of N- [3- (3-cyanopyrazolo [1, 5-a] pyrimidinyl) phenyl] -N-methylacetamide as yellow crystals, m.p. 201-203 ° C. This was reacted with sodium cyanoborohydride to give N- [3- (3-cyano-4,5-dihydropyrazolo [1,5-a] pyrimidin-7-yl) phenyl] -N-methylacet-35-amide as yellow crystals, mp. 114-120 ° C. This is reacted with chloroacetic anhydride and sodium carbonate in toluene as in Example 66 to give the title compound.

Example 190 N- (3 - {[4- (phenylmethyl) -1-piperazinyl] acetyl- (3-cyano-4,5-dihydropyrazolo [1,5-a] pyrimidin-7-yl)} phenyl) acetamide

The above compound is obtained from N-benzylpiperazine and N- {3- [4- (chloroacetyl) - (3-cyano-4,5-dihydro-10-pyrazolo [1,5-a] pyrimidin-7-yl)] phenyl } from acetamide by the method of Example 79.

Example 191 N- (3 - {[4- (Phenylmethyl) -1-piperazinyl] acetyl- (3-cyano-4,5-dihydropyrazolo [1,5-a] pyrimidin-7-yl} phenyl ) -N-methylacetamide

The above compound is obtained from N-benzylpiperazine and N- {3- [4- (chloroacetyl) - (3-cyano-4,5-dihydropyrazolo [1,5-a] pyrimidin-7-yl] phenyl} -N-methylacetamide by the method of Example 79.

Example 192 4,5-Dihydro-6-ethyl-4 - {[4- (phenylmethyl) -1-piperazinyl] acetyl} -7- [3- (trifluoromethyl) phenylpyrazolo [1,5-a] pyrimidine- 3-Carbonitrile A mixture of 3.3 g of 4- (chloroacetyl) -4,5-di-hydro-6-ethyl-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5- a] pyrimidine-3-carbonitrile, 1.6 ml of 1-benzylpiperazine and 1 g of sodium carbonate in 110 ml of toluene were stirred at reflux for 18 hours. The mixture was treated with 10 ml of 5 N sodium hydroxy-30 dia and the organic phase was separated, dried over sodium sulphate and evaporated to give a dark oil. This was dissolved in ether and mixed with ethanolic hydrogen chloride to give a white solid which was recrystallized from acetonitrile to give 3.4 g of the title compound, m.p. 184-186 ° C.

79 3 9 4 8 7

The reagents were prepared as follows:

Using the procedure of Example 65, 4,5-dihydro-6-ethyl-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile was reacted with chloro-5-acetyl chloride to give 4- (chloroacetyl) -4,5-dihydro-6-ethyl-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile, m.p. 150-152 ° C.

According to the procedure of Example 64, 6-ethyl-7-10 [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile was reacted with sodium cyanoborohydride in acetic acid to give a 4,5-dihydro derivative. mp. 185 - 187 "C.

A mixture of 4.0 g of 3-dimethylamino-2-ethyl-3'-trifluoromethylacrylophenone and 1.5 g of 3-amino-4-cyanopyrazole in 75 ml of glacial acetic acid was heated at reflux for two hours to give 6-ethyl-7- [3- (trifluoromethyl) phenyl] pyrazolo [1,5-a] pyrimidine-3-carbonitrile, m.p. 135-137 ° C.

Reaction of 3'-trifluoromethylbutyrophenone with dimethylformamide dimethyl acetal gave the above acrylophenone as a liquid, b.p. 90-95 ° C (0.05 mmHg).

To 30.0 g of 2-morpholinyl-3'-trifluoromethylphenyl-25-acetonitrile in 250 ml of N, N-dimethylformamide at 10 ° C was added 5.2 g of 50% sodium hydride mineral oil, and to this 18.7 g of iodopropane were added. The reaction mixture was stirred for 18 hours and then poured into water and the resulting oil was collected to give 33.2 g of 2-morpholinyl-2-propyl-3'-trifluoromethyl phenylacetonitrile. This was hydrolyzed by heating in 70% acetic acid, then neutralized with sodium hydroxide to give 15.3 g of 3'-trifluoromethylbutyrophenone as a yellow liquid, b.p. 60-65 ° C 35 (0.05 mmHg).

Claims (5)

80 89487 Claim A process for the treatment of therapeutically active 4 - [(substituted) alkylcarbonyl] -4,5-dihydro- and 4,5,5,7-tetrahydro-5-7-[[(substituted) phenyl] pyrazolo [1, 5-a] for the preparation of pyramidine-3-carbonitriles of the formula □ XO) R <-f N R 5 - ^ - I CN? R 10 is C-CH 2 -N 2 -N-R 10 wherein R 7 is a mono- or di-substituent which is hydrogen, lower C 1-3 alkyl, lower C 1-3 alkoxy, halogen, nitro or trifluoro-methyl; R 4 and R 5 are both hydrogen or C 1-3 alkyl; and R 10 is C 1-6 alkyl or benzyl, which may be substituted on the phenyl ring by C 1-3 alkyl, C 1-4 alkoxy, chlorine, fluorine or trifluoromethyl; 25 and their pharmacologically acceptable acid addition salts, characterized in that the amine of formula R10 - ^ _ NH (1) wherein R10 is as defined above is reacted with a compound of formula 35 I: β1 89487 Φ R 4 (2) R 5 ___ J 1 = ± -CN N o = c-ch 2 x 10 wherein R 7, R 4 and R 5 are as defined above and X is chlorine or iodine. 82 39 487 For the preparation of therapeutic agents Active 4 - [(substituted) alkylcarbonyl] -4,5-dihydro- and 5,5,6,6,7-tetrahydro-7 - [(substituted) phenyl] pyrazolo - [1 , 5-a] pyrimidine-3-carbonitrile with formula ft 10 X? / - \ 0 0 = C-CH2-N N-R10 in which R7 is a mono- or disubstituted substituent, in which case C1-6-alkyl, lower C1-3-alkoxy, halogen, nitro or tri-fluoromethyl; R4 and R5 are selected from C1-3 alkyl; and R 10 is C 1-3 alkyl or benzyl, the phenyl ring having the substituent C 1-3 alkyl, C 1-3 alkoxy, chloro, fluoro or trifluoromethyl; 25 on the basis of the pharmacological action of the pharmacologically acceptable substance, which may be added to the formulation 30 R10-N NH (1) in which R10 is defined as having a reagent with a formulation of 35 l · 83 89487 o N 5 R4 γ N (2) R5 ^ \ n / i = -1xn f o = c-ch2x 10. When R7, R4 and R5 are defined and X is chlorine or iodine.